Derivatives of ureas as allosteric modulators of CB1

Abstract

To provide a method for treating a disease mediated by cannabinoid 1 receptor (CB1R).SOLUTION: Heteroaryl and aliphatic analogs of diarylurea-based CB1R allosteric modulators of Formula (I) are provided. Exemplary analogs can provide improved potency and pharmacokinetic properties. Also provided are methods of using the analogs to treat diseases mediated by CB1R, such as substance abuse and adiposity.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 868,126, filed June 28, 2019, which is incorporated herein by reference in its entirety.

[0002] government benefits This invention was made with government support under Grant No. DA040693 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0003] The subject matter of the present disclosure relates to urea-based cannabinoid 1 receptor (CB1R) allosteric modulator compounds, and pharmaceutical compositions and uses thereof. Uses of the compounds include modulating CB1R activity and treating CB1R-mediated diseases and conditions, such as obesity, drug abuse, alcoholism, anxiety, depression, metabolic syndrome, stroke, hypotension, impaired fertility, cancer, inflammation, Parkinson's disease, paralytic ileus, and osteoporosis. [Background technology]

[0004] According to the 2017 National Survey on Drug Use and Health, 18.7 million adults in the United States suffered from substance abuse disorders. There are currently no FDA-approved medications for the treatment of craving for stimulants (e.g., cocaine, methamphetamine) and cannabis (marijuana). There are medications available for relapse prevention for other addictive substances (e.g., opioids, tobacco, and alcohol). However, while these medications can be effective in treating withdrawal symptoms, long-term abstinence rates remain low. For example, even with several medications for smoking cessation, 1-year abstinence rates are only about 20%, compared with about 10% for placebo. Thus, there is an unmet need for medications that reduce substance craving over the long term.

[0005] The cannabinoid 1 and cannabinoid 2 receptors (CB1R and CB2R, respectively) belong to the class A rhodopsin-like superfamily of G protein-coupled receptors (GPCRs). CB1R is one of the most abundantly expressed receptors in the brain. See Matsuda et al., Nature 1990, 346, 561-564. CB1R plays a role in many physiological processes, such as pain, learning and memory, appetite and feeding behavior, anxiety and depression. See Porter et al., Pharmacol. Ther. 2001, 90, 45-60; Harkany et al., Trends Pharmacol. Sci. 2007, 28, 83-92; and Kreitzer and Regehr, Curr. Opin. Neurobiol. 2002, 12, 324-330. (-)-trans-Δ 9Because tetrahydrocannabinol (THC), the primary phytocannabinoid found in marijuana, has been known for centuries to induce appetite and weight gain, as well as addiction, CB1R has been investigated to develop 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; and Huestis et al., Psychopharmacology (Berl) 2007, 194, See 505-515. Other potential uses of CB1R antagonists / inverse agonists include the treatment of cancer, fertility disorders in women, 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, the first CB1R inverse agonist / antagonist to receive FDA approval for the treatment of obesity in 2006, rimonabant (also known as SR141716A), was subsequently withdrawn due to side effects, including suicidal ideation.

[0006] Thus, there is a continuing need for additional compounds that can modulate CB1 activity to treat substance addiction and other conditions that can be regulated via CB1R, e.g., additional CB1R modulator compounds with reduced side effects, improved pharmacokinetic properties (e.g., metabolic stability), and improved efficacy. Summary of the Invention

[0007] In some embodiments, the subject matter of the present disclosure has formula (I):

[0008] [ka] wherein X is -C- or -N-; each of R, R, R, and R is independently selected from the group consisting of H, alkyl, substituted alkyl, halo, haloalkyl, alkoxy, nitro, and cyano, or R and R together form an alkylene group; R is present or absent and, if present, is selected from the group consisting of H, alkyl, substituted alkyl, halo, haloalkyl, alkoxy, nitro, and cyano; L is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene, heterocycloalkylene, substituted arylene, heteroarylene, and substituted heteroarylene; and R is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylamino, dialkylamino, acylamino, N-heterocycle, and substituted N-heterocycle. or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, X1 is -C-.

[0009] In some embodiments, R1, R2, R4, and R5 are each H, and the compound of Formula (I) has the formula (Ia):

[0010] [ka] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R3 is Cl. In some embodiments, L1 is selected from the group including thiophenylene, pyridinylene, thiazolylene, alkylene, and substituted alkylene. In some embodiments, R6 is selected from the group including phenyl, substituted phenyl, pyridinyl, furanyl, substituted furanyl, and -NHC(=O)CH3.

[0011] In some embodiments, L is thiophenylene and the compound has the formula (II):

[0012] [ka] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R6 is selected from phenyl, substituted phenyl, or pyridinyl.

[0013] In some embodiments, R3 is Cl, R6 is phenyl or substituted phenyl, and the compound of Formula (II) has the formula (IIa):

[0014] [ka] wherein n is 0, 1, 2, 3, 4, or 5, and each R is independently selected from the group consisting of halo, nitro, hydroxy, cyano, alkyl, aryl, acyl, ester, alkoxy, sulfonyl, and dialkylamino. or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, n is 1 or 2 and each R7 is halo, optionally chloro or fluoro. In some embodiments, n is 1 and R7 is methoxy or methyl.

[0015] In some embodiments, the compound is 1-(4-chlorophenyl)-3-(5-phenylthiophen-2-yl)urea (11), 1-(4-chlorophenyl)-3-[5-(4-fluorophenyl)thiophen-2-yl]urea (18), 1-(4-chlorophenyl)-3-[5-(3-fluorophenyl)thiophen-2-yl]urea (19), 1-(4-chlorophenyl)-3-[5-(2,4-difluorophenyl)thiophen-2-yl]urea (20), 1-(4-chlorophenyl)-3-[5-(2-chlorophenyl)thiophen-2-yl]urea (21), 1-(4-chlorophenyl)-3-[5-(3-chlorophenyl)thiophen-2-yl]urea (22), 1-(4-chlorophenyl)-3-[5-(4-chlorophenyl)thiophen-2-yl]urea (23), 1-(4-chlorophenyl)-3-[5-(3,4-dichlorophenyl)thiophen-2-yl]urea (24), 1-(4-chlorophenyl)-3-[5-(3,5-dichlorophenyl)thiophen-2-yl]urea (25), 3-[5-(3-acetylphenyl)thiophen-2-yl]-1-(4-chlorophenyl)urea (26), Methyl 3-(5-{[(4-chlorophenyl)carbamoyl]amino}thiophen-2-yl)benzoate (27), 1-(4-chlorophenyl)-3-[5-(3-methanesulfonylphenyl)thiophen-2-yl]urea (28), 1-(4-chlorophenyl)-3-[5-(2-methoxyphenyl)thiophen-2-yl]urea (29), 1-(4-chlorophenyl)-3-[5-(3-methoxyphenyl)thiophen-2-yl]urea (30), 1-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)thiophen-2-yl]urea (31), 1-(4-chlorophenyl)-3-[5-(3-methylphenyl)thiophen-2-yl]urea (32), 1-(4-chlorophenyl)-3-{5-[3-(dimethylamino)phenyl]thiophen-2-yl}urea (33), 1-(4-chlorophenyl)-3-[5-(pyridin-3-yl)thiophen-2-yl]urea (34), and 1-(4-chlorophenyl)-3-[5-(pyridin-4-yl)thiophen-2-yl]urea (35); or a pharmaceutically acceptable salt or solvate thereof.

[0016] In some embodiments, L is ethylene or substituted ethylene and the compound of Formula (Ia) has the formula (III):

[0017] [ka] [In the formula, R8, R9, R 10 , and R 11 are independently selected from the group including H, halo, and alkyl, or R, R, R 10 , and R 11 two of which together form an alkylene group] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R3 is chloro and R8, R9, R 10 , and R 11 is H and R6 is phenyl or substituted phenyl, the compound of formula (III) has the formula (IIIa):

[0018] [ka] wherein n is 0, 1, 2, 3, 4, or 5, and each R is independently selected from the group consisting of halo, nitro, hydroxyl, cyano, alkyl, perfluoroalkyl, aryl, acyl, ester, alkoxyl, sulfonyl, and dialkylamino. or a pharmaceutically acceptable salt or solvate thereof.

[0019] In some embodiments, each R7 is independently selected from the group consisting of fluoro, chloro, methyl, tert-butyl, phenyl, nitro, methoxy, dimethylamino, cyano, and trifluoromethyl. trans-1-(4-chlorophenyl)-3-(2-phenylcyclopropyl)urea (15), cis-1-(4-chlorophenyl)-3-(2-phenylcyclopropyl)urea (16), 3-(4-chlorophenyl)-1-(2-phenylethyl)urea (44), 1-[2-(4-tert-butylphenyl)ethyl]-3-(4-chlorophenyl)urea (45), 3-(4-chlorophenyl)-1-[2-(4-phenylphenyl)ethyl]urea (46), 3-(4-chlorophenyl)-1-[2-(4-chlorophenyl)ethyl]urea (47), 3-(4-chlorophenyl)-1-[2-(4-nitrophenyl)ethyl]urea (48), 3-(4-chlorophenyl)-1-[2-(4-hydroxy-3-methoxyphenyl)ethyl]urea (49), 3-(4-chlorophenyl)-1-{2-[3-(dimethylamino)phenyl]ethyl}urea (50), 3-(4-chlorophenyl)-1-{2-[4-(dimethylamino)phenyl]ethyl}urea (51), 3-(4-chlorophenyl)-1-[2-(4-methanesulfonylphenyl)ethyl]urea (52), 3-(4-chlorophenyl)-1-[2-(2-methoxyphenyl)ethyl]urea (53), 3-(4-chlorophenyl)-1-[2-(3-methoxyphenyl)ethyl]urea (54), 3-(4-chlorophenyl)-1-[2-(3-methoxyphenyl)ethyl]urea (55), 3-(4-chlorophenyl)-1-[2-(3,4-dimethoxyphenyl)ethyl]urea (56), 3-(4-chlorophenyl)-1-[2-(3,5-dimethoxyphenyl)ethyl]urea (57), 3-(4-chlorophenyl)-1-[2-(4-hydroxyphenyl)ethyl]urea (58), 3-(4-chlorophenyl)-1-[2-(4-methylphenyl)ethyl]urea (59), 3-(4-chlorophenyl)-1-[2-(3-methylphenyl)ethyl]urea (60), 3-(4-chlorophenyl)-1-[2-(2-fluorophenyl)ethyl]urea (61), 3-(4-chlorophenyl)-1-[2-(3-fluorophenyl)ethyl]urea (62), 3-(4-chlorophenyl)-1-[2-(4-fluorophenyl)ethyl]urea (63), 3-(4-chlorophenyl)-1-[2-(3,4-difluorophenyl)ethyl]urea (64), 3-(4-chlorophenyl)-1-[2-(2,4,6-trifluorophenyl)ethyl]urea (65), 3-(4-chlorophenyl)-1-[2-(2,3,4,5,6-pentafluorophenyl)ethyl]urea (66), 3-(4-chlorophenyl)-1-[2-(2-chlorophenyl)ethyl]urea (67), 3-(4-chlorophenyl)-1-[2-(3-chlorophenyl)ethyl]urea (68), 3-(4-chlorophenyl)-1-[2-(2,4-dichlorophenyl)ethyl]urea (69), 3-(4-chlorophenyl)-1-[2-(2-chloro-6-fluorophenyl)ethyl]urea (70), 3-(4-chlorophenyl)-1-[2-(4-bromophenyl)ethyl]urea (71), 3-(4-chlorophenyl)-1-[2-(4-cyanophenyl)ethyl]urea (72), 3-(4-chlorophenyl)-1-{2-[2-(trifluoromethyl)phenyl]ethyl}urea (73), 3-(4-chlorophenyl)-1-{2-[3-(trifluoromethyl)phenyl]ethyl}urea (74), 3-(4-chlorophenyl)-1-{2-[4-(trifluoromethyl)phenyl]ethyl}urea (75), 3-(4-chlorophenyl)-1-[2-(pyridin-4-yl)ethyl]urea (76), 3-(4-chlorophenyl)-1-[2-(pyridin-3-yl)ethyl]urea (77) 3-(4-chlorophenyl)-1-[2-(pyridin-2-yl)ethyl]urea (78), 1-(4-chlorophenyl)-3-[2-(5-methylfuran-2-yl)ethyl]urea (79), 3-(4-chlorophenyl)-1-[2-(4-methylpiperazin-1-yl)ethyl]urea (80), 3-(4-chlorophenyl)-1-[2-(piperidin-1-yl)ethyl]urea (81), 3-(4-chlorophenyl)-1-[2-(morpholin-4-yl)ethyl]urea (82), 1-(4-chlorophenyl)-3-[2-(pyrrolidin-1-yl)ethyl]urea (83), N-(2-{[(4-chlorophenyl)carbamoyl]amino}ethyl)acetamide (84), 3-(4-chlorophenyl)-1-(2-methyl-2-phenylpropyl)urea (38), 3-(4-chlorophenyl)-1-(2,2-difluoro-2-phenylethyl)urea (39), 3-(4-chlorophenyl)-1-(2-methyl-1-phenylpropan-2-yl)urea (40), 1-(4-chlorophenyl)-3-[(1-phenylcyclopropyl)methyl]urea (41), and 3-(1-benzylcyclopropyl)-1-(4-chlorophenyl)urea (42); or a pharmaceutically acceptable salt or solvate thereof.

[0020] In some embodiments, the compound is 3-(4-chlorophenyl)-1-{2-methoxy-5-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (6), 1-(4-chlorophenyl)-3-(4-phenylpyridin-2-yl)urea (7), 1-(4-chlorophenyl)-3-(6-phenylpyridin-2-yl)urea (8), 1-(4-chlorophenyl)-3-(5-phenylpyridin-3-yl)urea (9), 1-(4-chlorophenyl)-3-(2-phenylpyridin-4-yl)urea (10), 1-(4-chlorophenyl)-3-(4-phenylthiophen-2-yl)urea (12), 1-(4-chlorophenyl)-3-(5-phenylthiophen-3-yl)urea (13), 1-(4-chlorophenyl)-3-(5-phenyl-1,3-thiazol-2-yl)urea (14), 3-(4-chlorophenyl)-1-[(3R)-1-phenylpiperidin-3-yl]urea (17), 1-benzyl-3-(4-chlorophenyl)urea (36), 3-(4-chlorophenyl)-1-(3-phenylpropyl)urea (37), and trans-1-(4-chlorophenyl)-3-[(2-phenylcyclopropyl)methyl]urea (43); or a pharmaceutically acceptable salt or solvate thereof.

[0021] In some embodiments, the presently disclosed subject matter provides a pharmaceutical composition comprising one of the disclosed compounds and a pharmaceutically acceptable carrier.

[0022] In some embodiments, the presently disclosed subject matter provides a method of treating a cannabinoid 1 receptor (CB1R)-mediated disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the presently disclosed subject matter or a pharmaceutical composition thereof. In some embodiments, the subject is a mammal, optionally a human.

[0023] In some embodiments, the disease or condition is selected from the group consisting of drug addiction, obesity, cancer, pain, female infertility, memory loss, cognitive impairment, Parkinson's disease, dyskinesia, tardive dyskinesia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Tourette's syndrome, stroke, atherosclerosis, hypotension, intestinal hypomotility in paralytic ileus, inflammation, osteoporosis, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, depression and other mood disorders, gastrointestinal disorders, and metabolic disorders. In some embodiments, the disease is obesity or drug addiction, and optionally the drug addiction is selected from cocaine addiction, opioid addiction, amphetamine addiction, cannabinoid addiction, tobacco addiction, and alcohol addiction.

[0024] In some embodiments, the compound is a compound of Formula (II) or Formula (III). 1-(4-chlorophenyl)-3-(5-phenylthiophen-2-yl)urea (11), 1-(4-chlorophenyl)-3-[5-(2,4-difluorophenyl)thiophen-2-yl]urea (20), 1-(4-chlorophenyl)-3-[5-(2-chlorophenyl)thiophen-2-yl]urea (21), 1-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)thiophen-2-yl]urea (31), 3-(4-chlorophenyl)-1-[2-(3-chlorophenyl)ethyl]urea (68), and 3-(4-chlorophenyl)-1-{2-[3-(trifluoromethyl)phenyl]ethyl}urea (74); or a pharmaceutically acceptable salt or solvate thereof.

[0025] In some embodiments, the presently disclosed subject matter provides a method of treating obesity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the presently disclosed subject matter or a pharmaceutical composition thereof. 1-(4-chlorophenyl)-3-(5-phenylthiophen-2-yl)urea (11), 1-(4-chlorophenyl)-3-[5-(2,4-difluorophenyl)thiophen-2-yl]urea (20), 1-(4-chlorophenyl)-3-[5-(2-chlorophenyl)thiophen-2-yl]urea (21), 1-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)thiophen-2-yl]urea (31), 3-(4-chlorophenyl)-1-[2-(3-chlorophenyl)ethyl]urea (68), and 3-(4-chlorophenyl)-1-{2-[3-(trifluoromethyl)phenyl]ethyl}urea (74); or a pharmaceutically acceptable salt or solvate thereof.

[0026] In some embodiments, the presently disclosed subject matter 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, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the presently disclosed subject matter or a pharmaceutical composition thereof. In some embodiments, the substance abuse and / or addiction is selected from cocaine addiction, opioid addiction, amphetamine addiction, cannabinoid addiction, tobacco addiction, and alcohol addiction. In some embodiments, administration prevents or inhibits relapse. In some embodiments, the compound is 1-(4-chlorophenyl)-3-(5-phenylthiophen-2-yl)urea (11), 1-(4-chlorophenyl)-3-[5-(2,4-difluorophenyl)thiophen-2-yl]urea (20), 1-(4-chlorophenyl)-3-[5-(2-chlorophenyl)thiophen-2-yl]urea (21), 1-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)thiophen-2-yl]urea (31), 3-(4-chlorophenyl)-1-[2-(3-chlorophenyl)ethyl]urea (68), and 3-(4-chlorophenyl)-1-{2-[3-(trifluoromethyl)phenyl]ethyl}urea (74); or a pharmaceutically acceptable salt or solvate thereof.

[0027] In some embodiments, the presently disclosed subject matter provides a method for modulating the activity of cannabinoid 1 receptor (CB1R), comprising contacting a sample containing CB1R with a compound of the presently disclosed subject matter or a pharmaceutical composition thereof.

[0028] It is an object of the presently disclosed subject matter to provide compounds of formula (I) that have activity, for example, as CB1 allosteric modulators (e.g., CB1 negative allosteric modulators), and pharmaceutical compositions comprising the compounds, as well as methods of using the compounds or pharmaceutical compositions thereof to treat disorders, such as drug addiction, pain, obesity, inflammation, anxiety, and depression.

[0029] While certain objects of the presently disclosed subject matter have been set forth above and are addressed in whole or in part by the presently disclosed subject matter, other objects and aspects will become apparent as the description proceeds when taken in conjunction with the accompanying examples best described herein below.

[0030] The presently disclosed subject matter can be better understood with reference to the following figures. The components in the figures are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the presently disclosed subject matter. The drawings are not intended to limit the scope of the presently disclosed subject matter, which is detailed in the appended or later amended claims, but are intended merely to clarify and illustrate the presently disclosed subject matter.

[0031] For a more complete understanding of the subject matter of this disclosure, reference is now made to the following drawings: [Brief explanation of the drawings]

[0032] [Figure 1A] 1 is a graph showing the activity of compound 11, an exemplary allosteric modulator of the cannabinoid 1 receptor (CB1R), against 100 nanomolar (nM) of CP55,940, a CB1R agonist, in a calcium mobilization assay in stable human CB1R-CHO-RD-HGA16 cells expressing human CB1R. [Figure 1B] 1 is a graph showing the activity of compound 11, an exemplary allosteric modulator of the cannabinoid 1 receptor (CB1R), against 100 nanomolar (nM) of the CB1R agonist CP55,940 in a sulfur-35 guanosine 5′-O-[gamma-thio]triphosphate [35S]GTPγS binding assay in stable HEK293 cells stably expressing the human CB1R. [Figure 1C] 1 is a graph showing the activity of compound 11, an exemplary allosteric modulator of the cannabinoid 1 receptor (CB1R), against 100 nanomolar (nM) of CP55,940, a CB1R agonist, in a sulfur-35 guanosine 5'-O-[gamma-thio]triphosphate [35S]GTPγS binding assay in the cerebellum of male ICR mice. [Figure 2]Graph showing the intrinsic activity of cannabinoid 1 receptor (CB1R) allosteric modulators and a CB1-selective antagonist / inverse agonist (SR141716) in the absence of the CB1R agonist CP55,940. Activity is reported as the percentage (%) of basal sulfur-35 guanosine 5'-O-[gamma-thio]triphosphate ([35S]GTPγS) binding as a function of the logarithm of modulator or agonist concentration (in moles per liter (M)). Allosteric modulators include PSNCBAM-1 (downward-pointing triangles) and four urea-based compounds of the presently disclosed subject matter: Compound 14 (flower), Compound 9 (star), Compound 35 (diamond), and Compound 11 (upward-pointing triangles). Data for SR141716 are shown as circles. [Figure 3A]

[0023] Figure 1 shows paired graphs showing the behavioral effects of Compound 11 and Compound 68 in a drug-induced reinstatement of cocaine-seeking study in rats. The effect of pretreatment with 10 milligrams per kilogram (mg / kg) of Compound 68 (gray bars) or Compound 11 (black bars) prior to cocaine-induced reinstatement of cocaine-seeking behavior on active lever responding is shown in the left graph, while the effect on inactive lever responding is shown in the right graph. In both graphs, the effect of vehicle treatment (open bars) is shown as a control. *p<0.05. [Figure 3B] Graph showing the effect of Compound 68 and Compound 11 on locomotion in rats. Locomotion is expressed as total distance (millimeters (mm)) versus time (minutes) after administration. The effect of vehicle treatment is also shown as a control. [Figure 4] FIG. 1 is a graph of the brain and plasma pharmacokinetic profile of Compound 68 after a single ip dose at 10 mg / kg to male Sprague-Dawley rats. DETAILED DESCRIPTION OF THE INVENTION

[0033] The subject matter of the present disclosure will now be described more fully hereinafter with reference to the accompanying examples, in which representative embodiments are set forth. However, the subject matter of the present disclosure may be embodied in other forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the embodiments to those skilled in the art.

[0034] 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 by reference in their entirety.

[0035] Throughout this specification and claims, a given chemical formula or name, unless specifically indicated otherwise, is intended to encompass all optical and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist.

[0036] I. Definition In accordance with long-standing patent law convention, the terms "a," "an," and "the" when used in this application, including the claims, refer to "one or more." Thus, for example, reference to a "solvent" includes mixtures of one or more solvents, two or more solvents, etc.

[0037] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the presently disclosed subject matter.

[0038] As used herein, the term "about," when referring to a measurable value, such as weight, molar equivalent, time, temperature, etc., is meant to encompass variations of, in one example, ±20% or ±10%, in another example, ±5%, in another example, ±1%, and in yet another example, ±0.1% from the specified amount, as such variations are appropriate for practicing the disclosed methods.

[0039] The term "and / or," when used to describe two or more activities, conditions, or results, refers to a situation where both of the listed conditions are included, or where only one of the two listed conditions is included.

[0040] The term "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. "Comprising" is a term of art used in claim language to mean that the specified elements are required, but that other elements may be added to further form a composition within the scope of the claim.

[0041] As used herein, the phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. When the phrase "consisting of" appears in a clause in the body of a claim rather than immediately following the preamble, it limits only the elements recited in that clause and does not exclude other elements from the claim as a whole.

[0042] As used herein, the phrase "consisting essentially of" limits the scope of a claim to particular materials or steps, and those that do not materially affect the basic and novel characteristics of the claimed subject matter.

[0043] With respect to the terms "comprising," "consisting of," and "consisting essentially of," when one of these three terms is used herein, the subject matter of this disclosure and claims may include the use of either of the other two terms.

[0044] As used herein, the term "alkyl" refers to a C1-C20 hydrocarbon chain that is linear (i.e., "straight chain"), branched, or cyclic, saturated or at least partially and optionally fully unsaturated (i.e., alkenyl and alkynyl), and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl, ethenyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, butadienyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, and 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" can refer to a C1-6 or C1-C5 alkyl group. "Higher alkyl" refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain embodiments, "alkyl" refers, in particular, to C1-CC straight or branched chain alkyls.

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

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

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

[0048] "Cyclic" and "cycloalkyl" refer to a non-aromatic monocyclic or polycyclic ring system of about 3 to about 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. In some embodiments, a cycloalkyl ring system contains 3 to 6 carbon atoms. A cycloalkyl group may optionally be partially unsaturated. A cycloalkyl group may also be optionally substituted with alkyl group substituents as defined herein. One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms can be optionally inserted along the cyclic alkyl chain, and the nitrogen substituents are hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, thus providing a heterocyclic group. Representative monocyclic cycloalkyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Furthermore, a cycloalkyl group may optionally be substituted with a linking group, e.g., an alkylene group as defined herein below, e.g., methylene, ethylene, propylene, and the like. In such cases, the cycloalkyl group may be referred to as, for example, cyclopropylmethyl, cyclobutylmethyl, etc. Additionally, multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl.

[0049] Thus, as used herein, the term "substituted cycloalkyl" includes cycloalkyl groups, as defined herein, where one or more atoms or functional groups of the cycloalkyl group have been replaced with another atom or functional group, including, for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, cyano, amino, alkylamino, dialkylamino, ester, acyl, amido, sulfonyl, sulfate, and mercapto.

[0050] The term "aryl" is used herein to refer to an aromatic substituent, which may be a single aromatic ring or multiple aromatic rings fused together, covalently bonded, or linked to a common group, such as, but not limited to, a methylene or ethylene moiety. The common linking group may also be a carbonyl, as in benzophenone, or an oxygen, as in diphenyl ether, or a nitrogen, as in diphenylamine. The term "aryl" specifically encompasses heteroaromatic compounds (i.e., "heteroaryl"). The aromatic ring(s) may include, among others, phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine, and benzophenone. In certain embodiments, the term "aryl" refers to a cyclic aromatic containing about 5 to about 10 carbon atoms, e.g., 5, 6, 7, 8, 9, or 10 carbon atoms, including 5- and 6-membered hydrocarbon and heteroaromatic rings.

[0051] Aryl groups can be optionally substituted with one or more aryl group substituents, which can be the same or different ("substituted aryl"); "aryl group substituents" include alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkyloxyl, carboxyl, acyl, halo, nitro, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxyl, acylamino, aroylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylthio, alkylthio, alkylene, and -NR'R'', where R' and R'' can each independently be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and aralkyl.

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

[0053] Illustrative 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.

[0054] "Heterocyclic," "heterocycle," or "heterocyclo," as used herein alone or as part of another group, refers to an aliphatic (e.g., fully or partially saturated heterocyclo) or aromatic (e.g., heteroaryl) 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 a cyclic alkyl or aryl carbon chain. Monocyclic ring systems are exemplified by any 5- or 6-membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen, and sulfur. Five-membered rings have zero to two double bonds, and six-membered rings have zero to three double bonds. Representative examples of monocyclic ring systems include, but are not limited to, ethylene oxide, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazolidine, isothiazolidine, isoxazole, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperazine, cyclohexane, cyclohexane-1, cyclohexane-2, cyclohexane-3, cyclohexane-4, cyclohexane-5, cyclohexane-6, cyclohexane-7, cyclohexane-8, cyclohexane-9, cyclohexane-10, cyclohexane-11, cyclohexane-12, cyclohexane-13, cyclohexane-14, cyclohexane-15, cyclohexane-16, cyclohexane-17, cyclohexane-18, cyclohexane-19, cyclohexane-20, cyclohexane-21, cyclohexane-22, cyclohexane-23, cyclohexane-24, cyclohexane-25, cyclohexane-26, cyclohexane-27, cyclohexane-28, cyclohexane-29, cyclohexane-30, cyclohexane-31, cyclohexane-32, cyclohexane-33, cyclohexane-34, cyclohexane-35, cyclohexane-46, cyclohexane-47, cyclohexane-58, cyclohexane-59 ... These include lysine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene (also known as thiolane), tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, thiopyran, triazine, triazole, trithiane, etc. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group, as defined herein, a cycloalkyl group, as defined herein, or another monocyclic ring system, as defined herein.Representative examples of bicyclic ring systems include, but are not limited to, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxin, 1,3-benzodioxole, carbazole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, purine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, etc. These rings, including quaternized derivatives thereof, can be optionally substituted with one or more alkyl and / or aryl group substituents.

[0055] "Substituted heterocyclic," as used herein, refers to a heterocyclic group in which one or more hydrogen atoms are replaced by an alkyl or aryl group substituent.

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

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

[0058] The term "heteroaryl" refers to an aromatic monocyclic or bicyclic ring system (fused, bridged, or spirocyclic ring systems) containing one or more heteroatoms (e.g., 1, 2, or 3 heteroatoms selected from oxygen, sulfur, and substituted or unsubstituted nitrogen; N-oxide, sulfur oxide, and dioxide are permissible heteroatom substitutions) inserted along a cyclic aryl carbon chain. In some embodiments, the monocyclic heteroaryl group is a 5- to 7-membered aromatic ring. Representative heteroaryl groups include, but are not limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiaciazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzoxazole, benzothiophene, indole, indazole, benzimidazole, imidazopyridine, pyrazolopyrindine, and pyrazolopyrimidine.

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

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

[0061] "Alkylene" can refer to a straight-chain 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 can be straight-chain, branched, or cyclic. Alkylene groups can also be optionally unsaturated (i.e., containing alkene or alkyne groups) and / or substituted with one or more "alkyl group substituents." One or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms can be optionally inserted along the alkylene group (also referred to herein as "alkylaminoalkyl"), wherein the nitrogen substituent is alkyl as previously described. Exemplary alkylene groups include methylene (-CH-); ethylene (-CH-CH-); propylene (-(CH-); cyclohexylene (-CH-); cyclohexylene (-CH-). 10 -);-CH=CH-CH=CH-;-CH=CH-CH2-;-(CH2) q -N(R)-(CH2) r - (wherein q and r are each independently an integer from 0 to about 20, e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or lower alkyl); methylenedioxyl (-O-CH2-O-); and ethylenedioxyl (-O-(CH2)2-O-). The alkylene group can have from about 2 to about 3 carbon atoms, and can further have from 6 to 20 carbon atoms.

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

[0063] The term "aralkylene" refers to a divalent group including combinations of alkylene and arylene groups (eg, -arylene-alkylene-, alkylene-arylene-alkylene-, arylene-alkylene-arylene-, etc.).

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

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

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

[0067] "Aryloxyl" and "aryloxy" refer to an aryl-O- group in which the aryl group is as defined above, including substituted aryl. The term "aryloxyl," as used herein, can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alkyl, or alkoxyl-substituted phenyloxyl or hexyloxyl.

[0068] "Aralkyloxyl" or "aralkoxy" refers to an aralkyl-O- group in which the aralkyl group is as previously described. An exemplary aralkyloxyl group is benzyloxyl.

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

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

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

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

[0073] The term "haloalkyl" refers to an alkyl group, as defined herein, that is substituted with one or more halo groups.

[0074] The term "perhaloalkyl" refers to an alkyl group, as defined herein, in which all C-H bonds have been replaced by carbon-halogen bonds. The term "perfluoroalkyl" refers to an alkyl group in which all C-H bonds have been replaced by C-F bonds. An exemplary perfluoroalkyl group is trifluoromethyl (-CF).

[0075] The term "sulfonyl" refers to the group -S(=O)R, where R is alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl. The term "alkylsulfonyl" refers to the group -S(=O)R, where R is alkyl or substituted alkyl. In some embodiments, the sulfonyl group is -S(=O)CH.

[0076] The term "ester" refers to the group R'-OC(=O)-, where the carbonyl carbon is bonded to another carbon atom and R' is alkyl, cycloalkyl, aralkyl, or aryl, wherein the alkyl, cycloalkyl, aralkyl, or aryl is optionally substituted. The term "esterification" can refer to forming an ester by contacting a compound containing a carboxylic acid or a derivative thereof (e.g., an acid chloride) with a compound containing a hydroxyl group (e.g., an alcohol or phenol).

[0077] The term "amide" refers to a compound comprising the structure R'-NR"-C(=O)-R, where R is alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl; and 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.

[0078] The term "urea," as used herein, refers to a compound comprising the structure R-NR'-C(=O)-NR'-R, where each R is independently alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl, and each R' is independently H, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl.

[0079] [ka] As used herein, a structure generally represented by a formula such as refers to a ring structure, for example, but not limited to, aliphatic and / or aromatic ring compounds of 3-carbon, 4-carbon, 5-carbon, 6-carbon, etc., containing substituent R groups, where the R groups may be present or absent, and if present, one or more R groups may each be substituted on one or more available carbon atoms of the ring structure. The presence or absence of R groups and the number of R groups are determined by the value of the integer n. When there are more than one R group, each R group is substituted on an available carbon of the ring structure, but not on another R group. For example, the structure:

[0080] [ka] [wherein n is an integer of 0 to 2] includes, but is not limited to,

[0081] [ka] and the like.

[0082] When a named atom of an aromatic ring or heteroaromatic ring is defined as "absent," the named atom is replaced by a direct bond. When a linking group or spacer group is defined as absent, the linking group or spacer group is replaced by a direct bond.

[0083] For example, the structure:

[0084] [ka] In the figure, the straight lines intersecting the wavy lines indicate the sites at which the chemical moiety may be attached to another group.

[0085] The term "amine" refers to a molecule having the formula N(R)3, or a protonated form thereof, where each R is independently H, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, or two R groups together form an alkylene or arylene group. The term "primary amine" refers to an amine in which at least two R groups are H. The term "secondary amine" refers to an amine in which only one R group is H. The term "alkylamine" can refer to an amine in which two R groups are H and the other R group is alkyl or substituted alkyl. A "dialkylamine" can refer to an amine in which two R groups are alkyl. An "arylamine" can refer to an amine in which one R group is aryl. Amines can also be protonated, i.e., have the formula [NH(R)3]. + It can also have:

[0086] 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" can refer to the group -N(R)2, where each R is H, alkyl, or substituted alkyl, and at least one R is alkyl or substituted alkyl. The term "dialkylamino" refers to an aminoalkyl group where both R groups are alkyl or substituted alkyl, which can be the same or different.

[0087] The terms "acylamino" 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 R' is selected from alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl.

[0088] The term "cyano" refers to the group --C.ident.N.

[0089] The terms "hydroxyl" and "hydroxy" refer to the group --OH.

[0090] The terms "mercapto" and "thiol" refer to the group --SH.

[0091] The term "oxo" refers to a compound as described herein above, wherein a carbon atom has been replaced by an oxygen atom.

[0092] The term "nitro" refers to the group --NO.sub.2.

[0093] The term "thioalkyl" can refer to the 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 the group -SR, where R is aralkyl and aryl, respectively.

[0094] When the term "independently selected" is used, the substituents being referred to (e.g., R groups, e.g., R and R groups, or X and Y groups) can be the same or different. For example, both R and R can be substituted alkyl, or R can be hydrogen and R can be substituted alkyl, etc.

[0095] A designated "R," "R'," "X," "Y," "Y'," "A," "A'," "B," "L," or "Z" group will generally have the art-recognized structure corresponding to the group with that name, unless otherwise specified herein. For illustrative purposes, certain representative "R," "X," and "Y" groups, as described above, are defined below. These definitions are intended to supplement and illustrate, not preclude, definitions that would be apparent to one of skill in the art upon review of this disclosure.

[0096] The terms "treatment" and "treating" and the like, as used herein, refer to any treatment of a disease and / or condition in an animal or mammal, particularly a human, and include: (i) preventing a disease, disorder, and / or condition from occurring in a human who is susceptible to or at risk of exposure to an agent that may cause the disease, disorder, and / or condition, but has not yet been diagnosed with the disease, disorder, and / or condition; (ii) inhibiting the disease, disorder, and / or condition, i.e., arresting its development; and (iii) alleviating the disease, disorder, and / or condition, i.e., causing reversal of the disease, disorder, and / or condition.

[0097] "Protecting group," as used herein, includes any suitable protecting group, and "protected form" refers to a substituent in which an atom, e.g., hydrogen, has been removed and replaced with a corresponding protecting group. Protecting groups are well known. See generally T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples include, but are not limited to, hydroxy-protecting groups (to generate protected forms of hydroxy); carboxy-protecting groups (to generate protected forms of carboxylic acids); amino-protecting groups (to generate protected forms of aminos); sulfhydryl-protecting groups (to generate protected forms of sulfhydryls), and the like. 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, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl, triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, acetyl (Ac), benzoyl (Bn), and trimethylsilyl (TMS); formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz); and hemithioacetals such as 1-ethoxyethyl and methoxymethyl, thioesters, or thiocarbonates.

[0098] The term "allosteric modulator," as used herein, refers to a compound (or "ligand") that binds to a site on a macromolecule (e.g., a receptor) that is distinct from the orthosteric site (i.e., the primary binding site of the macromolecule). Allosteric modulators can indirectly affect the effect of an orthosteric 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 distinct from the orthosteric site, resulting in a change in receptor conformation. As a result, the interaction properties of the receptor with the orthosteric ligand(s) and the cellular host environment can be modified in either a positive or negative direction, and are referred to as positive allosteric modulators ("PAMs") and negative allosteric modulators ("NAMs"), respectively. Allosteric modulators can exhibit the following pharmacological properties: (i) affinity modulation, where the resulting conformation can alter the association / dissociation rate on the orthosteric ligand; (ii) potency modulation, where the allosteric effect can modify the intracellular response, resulting in changes in the signaling capacity of the orthosteric ligand; and / or (iii) agonism / inverse agonism, where the allosteric modulator can disrupt receptor signaling in either a positive or negative direction, with or without the orthosteric modulator.

[0099] II. General considerations Preclinical and clinical studies suggest that CB1R blockade is a promising strategy for the treatment of many common drugs of abuse, as well as several other conditions, including, but not limited to, obesity, anxiety, cancer, inflammation, Parkinson's disease, osteoporosis, female infertility, metabolic disorders, pain, stroke, hypotension, and intestinal hypomotility. Unfortunately, to date, the use of CB1R antagonists / inverse agonists in clinical practice has been limited by psychiatric side effects, such as depression, anxiety, or even suicidal ideation.

[0100] 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 maintaining 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. See Bouaboula et al., J. Biol. Chem. 1997, 272, 22330-22339. Because constitutive activity is important for maintaining cellular homeostasis, the side effects of the CB1R antagonist / inverse agonist rimonabant are thought to result from its CB1R inverse agonism, which reduces basal CB1R tone. Therefore, it has been hypothesized that neutral antagonists, which attenuate CB1R signaling in overactive states but do not alter basal CB1R levels, 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 disadvantage of central nervous system (CNS) side effects. See Chorvat, Bioorg. Med. Chem. Lett. 2013, 23, 4751-4760.

[0101] Additionally, the discovery of the CB1R allosteric binding site has provided a promising alternative approach to modulating CB1R signaling for therapeutic benefit. Allosteric modulators target CB1R at the allosteric binding site and offer several advantages over orthosteric ligands, including better receptor subtype selectivity, a lower risk of overdose due to a "ceiling" effect, and a more transient pharmacological effect as a result of their dependence on the presence of endogenous cannabinoids. See Nguyen et al., Med. Res. Rev. 2017, 37, 441-474.

[0102] The structures of two previously studied CB1R negative allosteric modulators, Org27569 (1) and PSNCBAM-1 (2), are shown in Scheme 1 below. See German et al., J. Med. Chem. 2014, 57, 7758-7769; and Nguyen et al., Bioorg. Med. Chem. 2015, 23, 2195-2203. Compound 2, for example, exhibits positive binding cooperativity with CP55,940, a cannabinoid receptor agonist that mimics the effects of THC, reducing the efficacy of the agonist in several functional assays and reducing food intake and body weight in rats. See Horswill et al., Br. J. Pharmacol. 2007, 152, 805-814.

[0103] Structure-activity relationship (SAR) efforts on compound 2 indicated that the pyrrolidinyl ring is not required for CB1R modulating activity, e.g., [ 35 S]GTPγS binding assay, and showed greater potency than compound 2. 3It has been shown that the pyridinyl ring can be replaced with a substituted phenyl ring or a five-membered heterocycle, as in RTICBM-229 (5), also shown in Scheme 1, which exhibits higher maximum binding levels in the [H]CP55,940 binding assay. See German et al., J. Med. Chem. 2014, 57, 7758-7769; Nguyen et al., J. Med. Chem. 2017, 60, 7410-7424; and Nguyen et al., ACS Chem. Neurosci. 2019, 10, 518-527.

[0104] [ka]

[0105] Scheme 1. Structures of representative indole- and diaryl urea-based CB1 allosteric modulators. Efforts to optimize diaryl urea compound 2 also led to compound RTICBM-74 (4). See Scheme 1. Compound 4 attenuated prime-induced restatement of cocaine seeking, while RTICBM-28 (3), in which the chloro group on the outer phenyl ring of 2 was replaced with a cyano, reduced the potency of THC in drug discrimination, demonstrating the therapeutic potential of these CB1R allosteric modulators for treating cocaine relapse (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 phenyl ring indicated that the 4-position favors electron-withdrawing functionality. See German et al., J. Med. Chem. 2014, 57, 7758-7769.

[0106] The subject matter of the present disclosure is based in part on further efforts to broaden the SAR understanding of the diaryl urea scaffold of 2 through structural optimization at the central phenyl ring. See Scheme 2 below. The compounds described herein are believed to be the first series in which substitution / replacement of the central phenyl ring of compound 2 has been investigated. More specifically, the compounds of the present disclosure are those in which the central phenyl ring has been replaced with a variety of heteroaryl rings, including pyridine, thiophenone, and thiazole, as well as non-aromatic rings, such as cyclopropyl or piperidinyl rings, and acyclic aliphatic groups (e.g., ethylene).

[0107] [ka]

[0108] Strategy for investigating SAR in Scheme 2.2. As described below in Example 2, replacing the central phenyl ring of compound 2 with a heteroaryl or alkylene moiety improved or maintained CB1R modulating activity. Some of the compounds disclosed herein, such as 1-(4-chlorophenyl)-3-(5-phenylthiophen-2-yl)urea (11) and 1-(4-chlorophenyl)-3-[5-(2,4-difluorophenyl)thiophen-2-yl]urea (20), exhibited calcium mobilization and [ 35They had better in vitro potency at the CB1 receptor than Compound 2 while maintaining good selectivity over the CB2 receptor in a [S]GTP-γ-S binding assay. As described in Example 3 below, two exemplary compounds of the presently disclosed subject matter, i.e., Compounds 11 and 20, exhibited better metabolic stability in liver enzymes than Compound 2, while Compound 11 was more soluble than Compound 2. As described in Example 4, exemplary Compound 68 demonstrated good in vivo potency at 10 mg / kg when administered by intraperitoneal injection in a rat model of reinstatement of cocaine-seeking behavior. Furthermore, unlike CB1 receptor inverse agonists / antagonists, such as SR141716, the compounds of the present disclosure advantageously exhibit little to no inverse agonism. Therefore, they are expected to be less likely to cause psychiatric side effects, which is a significant advance over existing compounds.

[0109] III. Urea-based CB1R allosteric modulators In some embodiments, the subject matter of the present disclosure has formula (I):

[0110] [ka] [In the formula, X1 is -C- or -N-; each of R1, R2, R3, and R5 is independently selected from the group consisting of H, alkyl (e.g., C1-C6 alkyl), substituted alkyl (e.g., C1-C6 substituted alkyl), halo, haloalkyl (e.g., C1-C6 haloalkyl, e.g., C1-C6 perfluoroalkyl), alkoxy (e.g., C1-C6 alkoxy), nitro, and cyano; or R2 and R3 together form an alkylene group (e.g., an oxo-containing alkylene group, e.g., -OCHO-, or an alkene-containing alkylene group, e.g., -CH=CH-CH=CH-); R4 is present (i.e., when X1 is -C-) or absent (i.e., when X1 is -N-), and when present is selected from the group including H, alkyl (e.g., C1-C6 alkyl), substituted alkyl (e.g., C1-C6 substituted alkyl), halo, haloalkyl (e.g., C1-C6 haloalkyl, such as C1-C6 perfluoroalkyl), alkoxy (e.g., C1-C6 alkoxy), nitro, and cyano; L1 is selected from the group consisting of alkylene (e.g., C1-C6 saturated alkylene), substituted alkylene (e.g., C1-C6 substituted alkylene), cycloalkylene (e.g., cyclopropylene), substituted cycloalkylene (e.g., substituted cyclopropylene), heterocycloalkylene (e.g., piperidinylene), substituted arylene (e.g., substituted phenylene), heteroarylene (e.g., thiophenylene, pyridinylene, thiazolylene), and substituted heteroarylene; and R6 is selected from the group consisting of aryl (e.g., phenyl), substituted aryl (e.g., substituted phenyl), heteroaryl (e.g., pyridinyl or furanyl), substituted heteroaryl, alkylamino, dialkylamino (e.g., dimethylamino), acylamino (i.e., -NHC(=O)CH3), N-heterocycle (e.g., piperazinyl, piperidinyl, morpholinyl, or pyrrolidinyl), and substituted N-heterocycle. or a pharmaceutically acceptable salt or solvate thereof.

[0111] In some embodiments, X1 is -C-. In some embodiments, R1 and R5 are each H.

[0112] In some embodiments, each of R, R, R, and R is H, and the compound of Formula (I) has the formula (Ia):

[0113] [ka] wherein R3, L1 and R6 are as defined for compounds of formula (I). or a pharmaceutically acceptable salt or solvate thereof.

[0114] In some embodiments, R3 is an electron-withdrawing group. The term "electron-withdrawing" refers to an atom, substituent, or moiety that, compared to a hydrogen atom, attracts electron density toward itself from neighboring atoms (e.g., through inductive or resonance effects). In some embodiments, R3 is an electron-withdrawing group, such as, but not limited to, halo (e.g., fluoro, chloro, or bromo), trihalomethyl (e.g., trifluoromethyl), formyl, acyl (e.g., acetyl), -C(=O)OH, ester (e.g., methyl ester (-C(=O)-OCH3), cyano, and nitro. In some embodiments, R3 is halo, nitro, or cyano. In some embodiments, R3 is Cl.

[0115] In some embodiments, L is selected from the group including thiophenylene, pyridinylene, thiazolylene, alkylene (e.g., methylene, ethylene, propylene, or butylene), and substituted alkylene (e.g., alkyl-substituted alkylene or halo-substituted alkylene). For example, L is

[0116] [ka] TIFF2026032033000016.tif63132.

[0117] In some embodiments, R6 is selected from the group including aryl (e.g., phenyl or naphthyl), substituted aryl (e.g., substituted phenyl), heteroaryl (e.g., pyridinyl or furanyl), substituted heteroaryl (e.g., substituted furanyl), and acylamino. In some embodiments, R6 is selected from substituted aryl, heteroaryl, substituted heteroaryl, and acylamino. In some embodiments, R6 is selected from substituted phenyl, pyridinyl, furanyl, and -NHC(=O)CH3.

[0118] In some embodiments, L is thiophenylene and the compound has the formula (II):

[0119] [ka] wherein R3 and R6 are as defined above for compounds of formula (I). or a pharmaceutically acceptable salt or solvate thereof.

[0120] In some embodiments, R3 is an electron withdrawing group. In some embodiments, R3 is halo. In some embodiments, R3 is chloro.

[0121] In some embodiments, R6 is phenyl, substituted phenyl, or pyridinyl. In some embodiments, R6 is substituted phenyl or pyridinyl (e.g., 3-pyridinyl or 4-pyridinyl). For example, R6 can be phenyl substituted with one or more halo, alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), acyl, ester, sulfonyl, or dialkylamino groups. In some embodiments, R6 is phenyl substituted with one or more fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, acyl, —C(═O)OMe, —S(═O)2Me, or dimethylamino groups. In some embodiments, R6 is mono- or di-substituted phenyl.

[0122] In some embodiments, R3 is Cl, R6 is phenyl or substituted phenyl, and the compound of Formula (II) has the formula (IIa):

[0123] [ka] [In the formula, n is 0, 1, 2, 3, 4, or 5; each R7 is independently selected from the group including halo, nitro, hydroxyl, cyano, alkyl, aryl, acyl, ester, alkoxyl, sulfonyl, and dialkylamino; or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, n is 1, 2, 3, 4, or 5.

[0124] In some embodiments, n is 1 or 2. In some embodiments, R7 is halo. In some embodiments, R7 is chloro or fluoro.

[0125] In some embodiments, n is 1 and R7 is chloro, fluoro, methoxy, dimethylamino, or methyl. In some embodiments, R7 is chloro, fluoro, methoxy, or methyl.

[0126] In some embodiments, the compound of formula (II) is 1-(4-chlorophenyl)-3-(5-phenylthiophen-2-yl)urea (11), 1-(4-chlorophenyl)-3-[5-(4-fluorophenyl)thiophen-2-yl]urea (18), 1-(4-chlorophenyl)-3-[5-(3-fluorophenyl)thiophen-2-yl]urea (19), 1-(4-chlorophenyl)-3-[5-(2,4-difluorophenyl)thiophen-2-yl]urea (20), 1-(4-chlorophenyl)-3-[5-(2-chlorophenyl)thiophen-2-yl]urea (21), 1-(4-chlorophenyl)-3-[5-(3-chlorophenyl)thiophen-2-yl]urea (22), 1-(4-chlorophenyl)-3-[5-(4-chlorophenyl)thiophen-2-yl]urea (23), 1-(4-chlorophenyl)-3-[5-(3,4-dichlorophenyl)thiophen-2-yl]urea (24), 1-(4-chlorophenyl)-3-[5-(3,5-dichlorophenyl)thiophen-2-yl]urea (25), 3-[5-(3-acetylphenyl)thiophen-2-yl]-1-(4-chlorophenyl)urea (26), Methyl 3-(5-{[(4-chlorophenyl)carbamoyl]amino}thiophen-2-yl)benzoate (27), 1-(4-chlorophenyl)-3-[5-(3-methanesulfonylphenyl)thiophen-2-yl]urea (28), 1-(4-chlorophenyl)-3-[5-(2-methoxyphenyl)thiophen-2-yl]urea (29), 1-(4-chlorophenyl)-3-[5-(3-methoxyphenyl)thiophen-2-yl]urea (30), 1-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)thiophen-2-yl]urea (31), 1-(4-chlorophenyl)-3-[5-(3-methylphenyl)thiophen-2-yl]urea (32), 1-(4-chlorophenyl)-3-{5-[3-(dimethylamino)phenyl]thiophen-2-yl}urea (33), 1-(4-chlorophenyl)-3-[5-(pyridin-3-yl)thiophen-2-yl]urea (34), and 1-(4-chlorophenyl)-3-[5-(pyridin-4-yl)thiophen-2-yl]urea (35); or a pharmaceutically acceptable salt or solvate thereof.

[0127] In some embodiments, the compound of formula (II) is other than 1-(4-chlorophenyl)-3-(5-phenylthiophen-2-yl)urea (11). Thus, in some embodiments, the compound of formula (II) is 1-(4-chlorophenyl)-3-[5-(4-fluorophenyl)thiophen-2-yl]urea (18), 1-(4-chlorophenyl)-3-[5-(3-fluorophenyl)thiophen-2-yl]urea (19), 1-(4-chlorophenyl)-3-[5-(2,4-difluorophenyl)thiophen-2-yl]urea (20), 1-(4-chlorophenyl)-3-[5-(2-chlorophenyl)thiophen-2-yl]urea (21), 1-(4-chlorophenyl)-3-[5-(3-chlorophenyl)thiophen-2-yl]urea (22), 1-(4-chlorophenyl)-3-[5-(4-chlorophenyl)thiophen-2-yl]urea (23), 1-(4-chlorophenyl)-3-[5-(3,4-dichlorophenyl)thiophen-2-yl]urea (24), 1-(4-chlorophenyl)-3-[5-(3,5-dichlorophenyl)thiophen-2-yl]urea (25), 3-[5-(3-acetylphenyl)thiophen-2-yl]-1-(4-chlorophenyl)urea (26), Methyl 3-(5-{[(4-chlorophenyl)carbamoyl]amino}thiophen-2-yl)benzoate (27), 1-(4-chlorophenyl)-3-[5-(3-methanesulfonylphenyl)thiophen-2-yl]urea (28), 1-(4-chlorophenyl)-3-[5-(2-methoxyphenyl)thiophen-2-yl]urea (29), 1-(4-chlorophenyl)-3-[5-(3-methoxyphenyl)thiophen-2-yl]urea (30), 1-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)thiophen-2-yl]urea (31), 1-(4-chlorophenyl)-3-[5-(3-methylphenyl)thiophen-2-yl]urea (32), 1-(4-chlorophenyl)-3-{5-[3-(dimethylamino)phenyl]thiophen-2-yl}urea (33), 1-(4-chlorophenyl)-3-[5-(pyridin-3-yl)thiophen-2-yl]urea (34), and 1-(4-chlorophenyl)-3-[5-(pyridin-4-yl)thiophen-2-yl]urea (35); or a pharmaceutically acceptable salt or solvate thereof.

[0128] In some embodiments, the compound of Formula (II) is selected from the group consisting of 1-(4-chlorophenyl)-3-(5-phenylthiophen-2-yl)urea (11), 1-(4-chlorophenyl)-3-[5-(2,4-difluorophenyl)thiophen-2-yl]urea (20), 1-(4-chlorophenyl)-3-[5-(2-chlorophenyl)thiophen-2-yl]urea (21), and 1-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)thiophen-2-yl]urea (31). In some embodiments, the compound of Formula (II) is selected from 1-(4-chlorophenyl)-3-[5-(2,4-difluorophenyl)thiophen-2-yl]urea (20), 1-(4-chlorophenyl)-3-[5-(2-chlorophenyl)thiophen-2-yl]urea (21), and 1-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)thiophen-2-yl]urea (31).

[0129] In some embodiments, L in Formula (I) is ethylene or substituted ethylene, and the compound of Formula (Ia) has the formula (III):

[0130] [ka] wherein R3 and R6 are as defined above for compounds of formula (I), and R8, R9, R 10 , and R 11 are each independently selected from the group including H, halo, and alkyl (e.g., C1-C6 alkyl), or R8, R9, R 10 , and R 11 two of which together form an alkylene group] or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, R, R, R10 , and R 11 two of R taken together form a methylene or ethylene group. 10 and R 11 together form an ethylene group, whereby R 10 and R 11 together with the carbon atom to which R is attached to form a cyclopropyl ring. 10 together form a methylene group, whereby R and R 10 together with the carbon atom to which R, R, R 10 , and R 11 are independently selected from H, methyl, and fluoro. 10 , and R 11 Two of the following (e.g., R8 and R9 or R 10 and R 11 ) is methyl or fluoro. In some embodiments, R, R, R 10 , and R 11 Each of is H.

[0131] In some embodiments, R3 is an electron withdrawing group. In some embodiments, R3 is halo. In some embodiments, R3 is chloro.

[0132] In some embodiments, R6 is phenyl, substituted phenyl, heteroaryl (e.g., furanyl or pyridinyl), or substituted heteroaryl (e.g., methyl-substituted furanyl). In some embodiments, R6 is phenyl, substituted phenyl, or methyl-substituted furanyl. In some embodiments, R6 is phenyl or substituted phenyl. For example, R6 can be phenyl substituted with one or more halo, alkyl (e.g., C1-C6 alkyl), alkoxy (e.g., C1-C6 alkoxy), acyl (e.g., acetyl), ester, sulfonyl, or dialkylamino groups. In some embodiments, R6 can be phenyl substituted with one or more fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, acyl, —C(═O)OMe, —S(═O)2Me, or dimethylamino groups. In some embodiments, R6 is mono- or di-substituted phenyl. In some embodiments, R6 is tri- or penta-fluoro-substituted phenyl.

[0133] In some embodiments, R3 is chloro and R8, R9, R 10 , and R 11 is H and R6 is phenyl or substituted phenyl, the compound of formula (III) has the formula (IIIa):

[0134] [ka] [In the formula, n is 0, 1, 2, 3, 4, or 5; each R7 is independently selected from the group including halo, nitro, hydroxyl, cyano, alkyl (e.g., C1-C6 alkyl), perfluoroalkyl (e.g., C1-C6 perfluoroalkyl), aryl, acyl, ester, alkoxy (e.g., C1-C6 alkoxy), sulfonyl, and dialkylamino. or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, each R7 is independently selected from the group consisting of fluoro, chloro, methyl, tert-butyl, phenyl, nitro, methoxy, dimethylamino, cyano, and trifluoromethyl. In some embodiments, n is 1, 2, 3, 4, or 5.

[0135] In some embodiments, the compound of formula (III) is trans-1-(4-chlorophenyl)-3-(2-phenylcyclopropyl)urea (15), cis-1-(4-chlorophenyl)-3-(2-phenylcyclopropyl)urea (16), 3-(4-chlorophenyl)-1-(2-phenylethyl)urea (44), 1-[2-(4-tert-butylphenyl)ethyl]-3-(4-chlorophenyl)urea (45), 3-(4-chlorophenyl)-1-[2-(4-phenylphenyl)ethyl]urea (46), 3-(4-chlorophenyl)-1-[2-(4-chlorophenyl)ethyl]urea (47), 3-(4-chlorophenyl)-1-[2-(4-nitrophenyl)ethyl]urea (48), 3-(4-chlorophenyl)-1-[2-(4-hydroxy-3-methoxyphenyl)ethyl]urea (49), 3-(4-chlorophenyl)-1-{2-[3-(dimethylamino)phenyl]ethyl}urea (50), 3-(4-chlorophenyl)-1-{2-[4-(dimethylamino)phenyl]ethyl}urea (51), 3-(4-chlorophenyl)-1-[2-(4-methanesulfonylphenyl)ethyl]urea (52), 3-(4-chlorophenyl)-1-[2-(2-methoxyphenyl)ethyl]urea (53), 3-(4-chlorophenyl)-1-[2-(3-methoxyphenyl)ethyl]urea (54), 3-(4-chlorophenyl)-1-[2-(3-methoxyphenyl)ethyl]urea (55), 3-(4-chlorophenyl)-1-[2-(3,4-dimethoxyphenyl)ethyl]urea (56), 3-(4-chlorophenyl)-1-[2-(3,5-dimethoxyphenyl)ethyl]urea (57), 3-(4-chlorophenyl)-1-[2-(4-hydroxyphenyl)ethyl]urea (58), 3-(4-chlorophenyl)-1-[2-(4-methylphenyl)ethyl]urea (59), 3-(4-chlorophenyl)-1-[2-(3-methylphenyl)ethyl]urea (60), 3-(4-chlorophenyl)-1-[2-(2-fluorophenyl)ethyl]urea (61), 3-(4-chlorophenyl)-1-[2-(3-fluorophenyl)ethyl]urea (62), 3-(4-chlorophenyl)-1-[2-(4-fluorophenyl)ethyl]urea (63), 3-(4-chlorophenyl)-1-[2-(3,4-difluorophenyl)ethyl]urea (64), 3-(4-chlorophenyl)-1-[2-(2,4,6-trifluorophenyl)ethyl]urea (65), 3-(4-chlorophenyl)-1-[2-(2,3,4,5,6-pentafluorophenyl)ethyl]urea (66), 3-(4-chlorophenyl)-1-[2-(2-chlorophenyl)ethyl]urea (67), 3-(4-chlorophenyl)-1-[2-(3-chlorophenyl)ethyl]urea (68), 3-(4-chlorophenyl)-1-[2-(2,4-dichlorophenyl)ethyl]urea (69), 3-(4-chlorophenyl)-1-[2-(2-chloro-6-fluorophenyl)ethyl]urea (70), 3-(4-chlorophenyl)-1-[2-(4-bromophenyl)ethyl]urea (71), 3-(4-chlorophenyl)-1-[2-(4-cyanophenyl)ethyl]urea (72), 3-(4-chlorophenyl)-1-{2-[2-(trifluoromethyl)phenyl]ethyl}urea (73), 3-(4-chlorophenyl)-1-{2-[3-(trifluoromethyl)phenyl]ethyl}urea (74), 3-(4-chlorophenyl)-1-{2-[4-(trifluoromethyl)phenyl]ethyl}urea (75), 3-(4-chlorophenyl)-1-[2-(pyridin-4-yl)ethyl]urea (76), 3-(4-chlorophenyl)-1-[2-(pyridin-3-yl)ethyl]urea (77) 3-(4-chlorophenyl)-1-[2-(pyridin-2-yl)ethyl]urea (78), 1-(4-chlorophenyl)-3-[2-(5-methylfuran-2-yl)ethyl]urea (79), 3-(4-chlorophenyl)-1-[2-(4-methylpiperazin-1-yl)ethyl]urea (80), 3-(4-chlorophenyl)-1-[2-(piperidin-1-yl)ethyl]urea (81), 3-(4-chlorophenyl)-1-[2-(morpholin-4-yl)ethyl]urea (82), 1-(4-chlorophenyl)-3-[2-(pyrrolidin-1-yl)ethyl]urea (83), N-(2-{[(4-chlorophenyl)carbamoyl]amino}ethyl)acetamide (84), 3-(4-chlorophenyl)-1-(2-methyl-2-phenylpropyl)urea (38), 3-(4-chlorophenyl)-1-(2,2-difluoro-2-phenylethyl)urea (39), 3-(4-chlorophenyl)-1-(2-methyl-1-phenylpropan-2-yl)urea (40), 1-(4-chlorophenyl)-3-[(1-phenylcyclopropyl)methyl]urea (41), and 3-(1-benzylcyclopropyl)-1-(4-chlorophenyl)urea (42); or a pharmaceutically acceptable salt or solvate thereof.

[0136] In addition to the compounds of formula (II) and (III) above (which are also compounds of formula (I)), in some embodiments, the compound of formula (I) is 3-(4-chlorophenyl)-1-{2-methoxy-5-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (6), 1-(4-chlorophenyl)-3-(4-phenylpyridin-2-yl)urea (7), 1-(4-chlorophenyl)-3-(6-phenylpyridin-2-yl)urea (8), 1-(4-chlorophenyl)-3-(5-phenylpyridin-3-yl)urea (9), 1-(4-chlorophenyl)-3-(2-phenylpyridin-4-yl)urea (10), 1-(4-chlorophenyl)-3-(4-phenylthiophen-2-yl)urea (12), 1-(4-chlorophenyl)-3-(5-phenylthiophen-3-yl)urea (13), 1-(4-chlorophenyl)-3-(5-phenyl-1,3-thiazol-2-yl)urea (14), 3-(4-chlorophenyl)-1-[(3R)-1-phenylpiperidin-3-yl]urea (17), 1-benzyl-3-(4-chlorophenyl)urea (36), 3-(4-chlorophenyl)-1-(3-phenylpropyl)urea (37), and trans-1-(4-chlorophenyl)-3-[(2-phenylcyclopropyl)methyl]urea (43); or a pharmaceutically acceptable salt or solvate thereof.

[0137] In some embodiments, the compound of Formula (I) is other than compound 9, 11, or 14. In some embodiments, the compound of Formula (I) is selected from the group including compounds 6-8, 10, 12, 13, 17, 36, 37, and 43.

[0138] In some embodiments, a compound of Formula (I), (Ia), (II), (IIa), (III), or (IIIa) has an IC for human CB1R (hCB1R) of 1,000 nM or less (e.g., 1,000 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 250 nM or less, 200 nM or less, or 150 nM or less) as measured using a calcium mobilization assay. 50 In some embodiments, compounds of Formula (I), (Ia), (II), (IIa), (III), or (IIIa) have an IC for hCB1R of 100 nM or less as measured using a calcium mobilization assay. 50 In some embodiments, the compound has 1-(4-chlorophenyl)-3-(5-phenylthiophen-2-yl)urea (11), 1-(4-chlorophenyl)-3-(4-phenylthiophen-2-yl)urea (12), 1-(4-chlorophenyl)-3-(5-phenylthiophen-3-yl)urea (13), 1-(4-chlorophenyl)-3-(5-phenyl-1,3-thiazol-2-yl)urea (14), 1-(4-chlorophenyl)-3-[5-(4-fluorophenyl)thiophen-2-yl]urea (18), 1-(4-chlorophenyl)-3-[5-(3-fluorophenyl)thiophen-2-yl]urea (19), 1-(4-chlorophenyl)-3-[5-(2,4-difluorophenyl)thiophen-2-yl]urea (20), 1-(4-chlorophenyl)-3-[5-(2-chlorophenyl)thiophen-2-yl]urea (21), 1-(4-chlorophenyl)-3-[5-(3-chlorophenyl)thiophen-2-yl]urea (22), 1-(4-chlorophenyl)-3-[5-(4-chlorophenyl)thiophen-2-yl]urea (23), 1-(4-chlorophenyl)-3-[5-(3,5-dichlorophenyl)thiophen-2-yl]urea (25), 1-(4-chlorophenyl)-3-[5-(2-methoxyphenyl)thiophen-2-yl]urea (29), 1-(4-chlorophenyl)-3-[5-(3-methoxyphenyl)thiophen-2-yl]urea (30), 1-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)thiophen-2-yl]urea (31), 1-(4-chlorophenyl)-3-[5-(3-methylphenyl)thiophen-2-yl]urea (32), 1-(4-chlorophenyl)-3-{5-[3-(dimethylamino)phenyl]thiophen-2-yl}urea (33), 1-(4-chlorophenyl)-3-[5-(pyridin-3-yl)thiophen-2-yl]urea (34), 1-(4-chlorophenyl)-3-[5-(pyridin-4-yl)thiophen-2-yl]urea (35), 3-(4-chlorophenyl)-1-(2-phenylethyl)urea (44), 1-[2-(4-tert-butylphenyl)ethyl]-3-(4-chlorophenyl)urea (45), 3-(4-chlorophenyl)-1-[2-(4-nitrophenyl)ethyl]urea (48), 3-(4-chlorophenyl)-1-[2-(3-methylphenyl)ethyl]urea (60), 3-(4-chlorophenyl)-1-[2-(3-fluorophenyl)ethyl]urea (62), 3-(4-chlorophenyl)-1-[2-(3,4-difluorophenyl)ethyl]urea (64), 3-(4-chlorophenyl)-1-[2-(2,4,6-trifluorophenyl)ethyl]urea (65), 3-(4-chlorophenyl)-1-[2-(2,3,4,5,6-pentafluorophenyl)ethyl]urea (66), 3-(4-chlorophenyl)-1-[2-(3-chlorophenyl)ethyl]urea (68), and 3-(4-chlorophenyl)-1-{2-[3-(trifluoromethyl)phenyl]ethyl}urea (74); or a pharmaceutically acceptable salt or solvate thereof.

[0139] In some embodiments, the compound is 1-(4-chlorophenyl)-3-(5-phenylthiophen-2-yl)urea (11), 1-(4-chlorophenyl)-3-[5-(2,4-difluorophenyl)thiophen-2-yl]urea (20), 1-(4-chlorophenyl)-3-[5-(2-chlorophenyl)thiophen-2-yl]urea (21), 1-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)thiophen-2-yl]urea (31), 3-(4-chlorophenyl)-1-[2-(3-chlorophenyl)ethyl]urea (68), and 3-(4-chlorophenyl)-1-{2-[3-(trifluoromethyl)phenyl]ethyl}urea (74); or a pharmaceutically acceptable salt or solvate thereof.

[0140] In some embodiments, the compound is other than Compound 9, Compound 11, or Compound 14.

[0141] As indicated above, it should be understood that the compounds of the present disclosure may include pharmaceutically acceptable salts, including, but not limited to, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts, and combinations thereof.

[0142] Acid addition salts include salts of inorganic and organic acids. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylenesalicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulfate, nitrate, phosphate, perchlorate, borate, acetate, benzoate, hydroxynaphthoate, glycerophosphate, ketoglutarate, and the like.

[0143] 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.

[0144] Examples of metal salts include lithium salts, sodium salts, potassium salts, magnesium salts, etc. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts, etc. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline, etc.

[0145] Furthermore, the compounds of the present disclosure may have one or more polymorphic or amorphous crystalline forms, which are intended to be included within the scope of the presently disclosed subject matter as such. In addition, some of the compounds of the presently disclosed subject matter may form solvates with water (i.e., hydrates) or common organic solvents (e.g., tetrahydrofuran (THF), ethanol (EtOH), methanol (MeOH), etc.). Thus, solvates of the compounds of Formulas (I), (Ia), (II), (IIa), (III), and (IIIa) are also intended to be included within the scope of the presently disclosed subject matter.

[0146] IV. Pharmaceutical Compositions The compounds disclosed herein can be formulated according to routine procedures compatible with the desired route of administration. Thus, in some embodiments, the presently disclosed subject matter provides a pharmaceutical composition comprising a therapeutically effective amount of the above-disclosed compound (e.g., a compound of Formula (I), (Ia), (II), (IIa), (III) and / or Formula (IIIa)), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. The therapeutically effective amount can be determined by testing the compound in an in vitro or in vivo model and then extrapolating therefrom to the dosage in the intended subject, e.g., human. The therapeutically effective amount should be sufficient to exert a therapeutically useful effect in the subject treated with the composition without undesirable side effects.

[0147] 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, 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 use in the presently disclosed subject matter 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 use in the presently disclosed subject matter include, but are not limited to, water, ethanol, alcoholic / aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets, and the like.

[0148] The liquid carrier suitable for use in the subject matter of the present disclosure 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 both, 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 adjusters, stabilizers, or osmotic pressure adjusters.

[0149] Liquid carriers suitable for use in the presently disclosed subject matter include, but are not limited to, water (partially containing the above-mentioned additives, such as cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (monohydric and polyhydric alcohols, including 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 are useful in sterile liquid forms containing compounds for parenteral administration. Liquid carriers for pressurized compounds disclosed herein may be halogenated hydrocarbons or other pharmaceutically acceptable propellants.

[0150] Solid carriers suitable for use in the presently disclosed subject matter include, but are not limited to, inert materials such as lactose, starch, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, mannitol, etc. The solid carrier may further comprise one or more substances that act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, or tablet disintegrants, and may also be encapsulating materials. In powders, the carrier may be a finely divided solid mixed with the finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compressed into the desired shape and size. Powders and tablets preferably contain up to 99% of the active compound. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low-melting waxes, and ion exchange resins.

[0151] Parenteral carriers suitable for use in 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 carriers include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Preservatives and other additives can also be present, such as antimicrobials, antioxidants, chelating agents, inert gases, and the like.

[0152] Carriers suitable for use in the presently disclosed subject matter can be mixed with disintegrants, diluents, granulating agents, lubricants, binders, etc., as needed, using conventional techniques known in the art. Carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art. The compounds disclosed herein can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents, such as suspending, stabilizing, and / or dispersing agents. The compounds disclosed herein can also be formulated as preparations for implantation or injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., emulsifying agents in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt). Alternatively, the active ingredient can be in powder form, for example, for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Suitable formulations for each of these methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa.

[0153] For example, formulations for parenteral administration may contain sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, hydrogenated naphthalene, and the like 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, as excipients, for example, lactose, 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 in the form of a gel for application to the nasal cavity. Formulations for parenteral administration may also contain glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.

[0154] Furthermore, formulations for intravenous administration can include a solution in sterile isotonic aqueous buffer.If necessary, the formulation can also include a solubilizing agent and a local anesthetic to ease pain at the injection site.Generally, the ingredients are supplied separately or mixed together in unit dosage form, for example, as a lyophilized powder or water-free concentrate, in a sealed container, for example, an ampoule or sachet indicating the quantity of active ingredient.When the compound is administered by injection, it can be dispensed into a formulation using an infusion bottle containing sterile pharmaceutical-grade water, saline, or dextrose / water.When the compound is administered by injection, an ampoule of sterile water for injection or saline can be provided, allowing the ingredients to be mixed prior to administration.

[0155] 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.

[0156] The compound can also be formulated for topical administration.Suitable topical formulations include one or more compounds in the form of a liquid, lotion, cream, or gel.Topical administration can be achieved by applying directly to the treatment area.For example, such application can be achieved by rubbing a formulation (e.g., a lotion or gel) onto the skin of the treatment area, or by spraying a liquid formulation onto the treatment area.

[0157] In some formulations, the bioimplant material can be coated with compounds to improve the interaction between the cells and the implant.

[0158] The compound formulation may contain minor amounts of wetting or emulsifying agents, or pH buffering agents.The compound formulation may be a solution, suspension, emulsion, tablet, pill, capsule, sustained-release formulation, or powder.

[0159] The compounds can be formulated as a suppository, with traditional binders and carriers such as triglycerides.

[0160] Oral formulation can include standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, polyvinylpyrrolidone, sodium saccharin, cellulose, magnesium carbonate, and the like.

[0161] In some embodiments, pharmaceutical compositions comprising a compound of the presently disclosed subject matter may include an agent that controls the release of the compound, thereby providing a timed or sustained release compound.

[0162] V. Treatment Methods As mentioned above, the CB1 and CB2 cannabinoid receptors belong to the G protein-coupled receptor (GCPR) family, a receptor superfamily with a characteristic pattern of seven transmembrane domains, which inhibit N-type calcium channels and / or inhibit adenylate cyclase to inhibit Q-type calcium channels.

[0163] 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 (motor function, coordination of body posture and balance), basal ganglia (motor control), hypothalamus (thermoregulation, neuroendocrine release, appetite), spinal cord (nociception), and cerebral cortex (emesis), as well as peripheral regions, such as lymphoid organs (cell-mediated and innate immunity), vascular smooth muscle cells (blood pressure), the gastrointestinal tract (controlling esophageal and gastrointestinal motility, and the innate anti-inflammatory response in the gastrointestinal tract (e.g., in the esophagus, duodenum, jejunum, ileum, and colon)), pulmonary smooth muscle cells (bronchodilation), and the ciliary body of the eye (intraocular pressure). CB2 receptors appear to be primarily expressed peripherally in lymphoid tissues (cell-mediated and innate immunity), peripheral nerve endings (peripheral nervous system), splenic immune cells (immune system regulation), and the retina (intraocular pressure). CB2 mRNA is also found in the CNS in the granule cells of the cerebellum (coordination of motor functions).

[0164] Accordingly, cannabinoid receptor allosteric modulators, including compounds of Formula (I), (Ia), (II), (IIa), (III), and (IIIa), are useful for treating, ameliorating, or preventing cannabinoid receptor-mediated syndromes, disorders, or diseases, including, but not limited to, appetite control, regulation of metabolism, diabetes, intraocular pressure associated with glaucoma, pain, social and mood disorders, seizure-related disorders, substance abuse disorders, learning, cognition, and / or memory disorders, intestinal disorders, respiratory disorders, locomotor activity disorders, movement disorders, immune disorders, or inflammatory disorders, control of organ contractions and muscle spasms, enhancing learning, cognition, and / or memory, modulating cell proliferation (e.g., treating cancer), providing neuroprotection, and the like.

[0165] Appetite-related syndromes, disorders, or diseases include obesity, overweight, anorexia, hyperphagia, cachexia, appetite dysregulation, etc. Obesity-related syndromes, disorders, or diseases include obesity as a result of genetics, diet, food intake, metabolic syndrome, disorders, or diseases, hypothalamic disorders or diseases, aging, decreased activity, abnormal fat mass distribution, abnormal fat compartment distribution, etc. Metabolic syndromes, disorders, or diseases include metabolic syndrome, dyslipidemia, elevated blood pressure, diabetes, insulin sensitivity or resistance, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, atherosclerosis, hepatomegaly, steatosis, abnormal alanine aminotransferase levels, inflammation, atherosclerosis, etc. Diabetes-related syndromes, disorders, or diseases include glucose dysregulation, insulin resistance, glucose intolerance, hyperinsulinemia, dyslipidemia, hypertension, obesity, etc.

[0166] Type II diabetes (non-insulin-dependent diabetes mellitus (NIDDM)) is a metabolic disorder (i.e., a metabolic syndrome, disorder, or disease) in which glucose dysregulation and insulin resistance result in chronic, long-term medical complications in both adolescents and adults, affecting the eyes, kidneys, nerves, and blood vessels, potentially leading to blindness, end-stage renal disease, myocardial infarction, or limb amputation. Glucose dysregulation includes the inability to make enough insulin (abnormal insulin secretion) and the inability to use insulin effectively (resistance to insulin action in target organs and tissues). Individuals with type II diabetes have a relative insulin deficiency; that is, in such individuals, plasma insulin levels are lower than would be expected for the level of plasma glucose present, but are normal to elevated in absolute terms. Type II diabetes is characterized by the following clinical signs or symptoms: persistently high 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 micro- and macrovascular complications can lead to blindness, end-stage renal disease, limb amputation, and myocardial infarction. Insulin resistance syndrome (IRS) (also known as syndrome X, metabolic syndrome, or metabolic syndrome X) is a disorder that confers risk factors for developing type 2 diabetes and cardiovascular disease, and includes glucose intolerance, hyperinsulinemia, insulin resistance, dyslipidemia (e.g., high triglycerides, low HDL-cholesterol), hypertension, and obesity.

[0167] Social or mood-related syndromes, disorders, or diseases include depression, anxiety, psychosis, social-affective 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 as a result of aging, disease, drug side effects (adverse events), etc.

[0168] Muscle spasm syndromes, disorders, or diseases include multiple sclerosis, cerebral palsy, etc. Locomotor activity and movement syndromes, disorders, or diseases include stroke, Parkinson's disease, multiple sclerosis, epilepsy, etc. Gut-related syndromes, disorders, or diseases include disorders associated with intestinal dysmotility (with or without pain, diarrhea, or constipation), irritable bowel syndrome (and other forms of intestinal dysmotility), inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease, etc.), and celiac disease. Respiratory-related syndromes, disorders, or diseases include chronic pulmonary obstructive disorder, emphysema, asthma, bronchitis, etc. Immune or inflammation-related syndromes, disorders, or diseases include allergies, rheumatoid arthritis, dermatitis, autoimmune diseases, immunodeficiencies, chronic neuropathic pain, etc.

[0169] Cell proliferation-related syndromes, disorders, or diseases include cancer, 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. Pain-related syndromes, disorders, or diseases include central and peripheral pathway-mediated pain, bone and joint pain, migraine-related pain, cancer pain, menstrual pain, labor pain, etc. Neurodegeneration-related syndromes, disorders, or diseases include Parkinson's disease, multiple sclerosis, epilepsy, ischemia, or secondary biochemical damage associated with traumatic head or brain injury, brain inflammation, eye injury, or stroke.

[0170] Based on their antagonist activity, the compounds of the present disclosure are useful in treating CB1 receptor-mediated diseases, such as psychoses including schizophrenia, anxiety disorders, stress, depression, epilepsy, neurodegenerative disorders, spinocerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheral neuropathy, glaucoma, migraine, Parkinson's disease, Alzheimer's disease, Huntington's disease, Raynaud's syndrome, tremors, obsessive-compulsive disorder (OCD), amnesia, senile dementia, thymic disorders, Tourette's syndrome, tardive dyskinesia, bipolar disorder, cancer, and other conditions. The compounds of the present disclosure may be useful as pharmaceutical agents for the prevention and / or treatment of substance-induced dyskinesia, ataxia, septic shock, hemorrhagic shock, hypotension, insomnia, immunological disorders including inflammation, multiple sclerosis, vomiting, diarrhea, asthma, appetite disorders such as anorexia nervosa and anorexia, obesity, non-insulin-dependent diabetes mellitus (NIDDM), memory disorders, urinary disorders, cardiovascular disorders, infertility disorders, infectious diseases, demyelination-related diseases, neuritis, viral encephalitis, cerebrovascular accidents, liver cirrhosis, or gastrointestinal disorders including intestinal transit disorders. In addition, the compounds of the present disclosure may be used as pharmaceutical agents for the treatment of substance addiction. For example, in some embodiments, the compounds of the present disclosure may be used to treat withdrawal symptoms from chronic treatment, alcoholism, or drug abuse (e.g., opioids, barbiturates, marijuana, cocaine, heroin, amphetamines, phencyclidine, hallucinogens, benzodiazepine compounds, etc.). Additionally, compounds of the present disclosure may be useful as agents for enhancing the analgesic activity of analgesics or anesthetics, or as agents for smoking cessation (withdrawal from smoking or nicotine dependence).

[0171] 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, comprising administering to the subject a therapeutically effective amount of one or more compounds of formula (I), (Ia), (II), (IIa), (III), or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0172] With respect to the methods of the presently disclosed subject matter, preferred subjects are vertebrate subjects. Preferred vertebrates are warm-blooded, and preferred warm-blooded vertebrates are mammals. The subject treated by the methods of the presently disclosed subject matter is preferably human, although it should be understood that the principles of the presently disclosed subject matter are effective with respect to all vertebrate species encompassed by the term "subject." In this context, a vertebrate is understood to be any vertebrate species for which treatment of a CB1R-mediated condition is desired. As used herein, the term "subject" includes both human and animal subjects. Thus, veterinary therapeutic uses are provided in accordance with the presently disclosed subject matter.

[0173] Thus, the presently disclosed subject matter provides treatments for mammals, such as humans, and mammals important because they are endangered, such as Siberian tigers; economically important animals, 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; swine, including pigs, hogs, and wild boars; ruminants and / or ungulates, such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels; and horses. Also provided are treatments for birds, including endangered and / or zoo-raised bird species, and poultry, more particularly domesticated poultry, i.e., captive birds, such as turkeys, chickens, ducks, geese, and guinea fowl, which are also economically important to humans. Thus, also provided is the treatment of livestock, including, but not limited to, domesticated pigs, ruminants, ungulates, horses (including racehorses), poultry, etc. In some embodiments, the subject is a human.

[0174] In some embodiments, the CB1R-mediated disease or condition includes, but is 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 desmotrophic small round cell tumors), pain (e.g., chronic pain, acute pain, somatic pain, visceral pain, neuropathic pain, etc.), and / or other conditions. pain), inflammatory pain), female infertility, memory loss, cognitive impairment, Parkinson's disease, dyskinesia, tardive dyskinesia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Tourette's syndrome, stroke, atherosclerosis, hypotension, intestinal hypomotility in paralytic ileus, inflammation, osteoporosis, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, depression and other mood disorders, gastrointestinal disorders, and metabolic disorders.

[0175] Treatment of anxiety may 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. Eating disorders include, but are not limited to, anorexia, binge eating, and bulimia. Mood disorders include, but are not limited to, manic-depressive illness (bipolar disorder), major depression, and postpartum depression. Cognitive dysfunction includes disorders such as dementia, attention deficit hyperactivity disorder (ADHD), autism and autism spectrum disorder (ASD), Down syndrome, traumatic brain injury (TBI), dyslexia, etc. Alcoholism and substance abuse-related disorders can include abuse of and / or dependence on alcohol, nicotine, or other drugs (e.g., opiates (e.g., heroin), cannabinoids, inhalants, and psychostimulants such as cocaine, amphetamines, and methamphetamines).

[0176] More specifically, diseases or conditions in which inhibition of biological activity at CB1R or signal transduction via CB1R is desirable include, but are not limited to, obesity, alcoholism, and other substance abuse and / or addiction-related disorders. Accordingly, in some embodiments, the presently disclosed subject matter provides a method of treating obesity in a subject in need thereof, comprising administering to the subject a compound of one of Formulas (I), (Ia), (II), (IIa), (III), or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the subject is a human.

[0177] By way of further example, the CB1R allosteric modulators of the present disclosure may find use in treating substance use, abuse, and / or addiction (including drug, alcohol, and nicotine addiction), addictive behaviors, and symptoms and conditions associated with the substance abuse and addiction exemplified herein. In some embodiments, the addiction is to at least one of nicotine, ethanol, cocaine, opioids, amphetamines, marijuana, or synthetic cannabinoid agonists.

[0178] Dependence on substances, such as alcohol, opiates, cannabinoids, nicotine, marijuana, and psychostimulants, is typically associated with several harmful or negative behaviors exhibited by addicts, which may exacerbate, prolong, or lead to relapse, substance use, or abuse, reinforce or worsen addiction, or lead to relapse into addiction and addictive behavioral patterns. Other examples of negative behaviors associated with substance use or addiction include anxiety, dysphoria, stress reactivity, and cue reactivity. One particular problem with alcoholism, as with substance addiction in general, is the chronic, relapsing nature of the disorder. This behavioral pattern can be effectively modeled in rodents, and numerous studies have demonstrated the ability of drug priming, psychological stress, or the re-presentation of cues previously associated with drug availability after extinction to reinstate drug-seeking behavior even in the absence of subsequent drug reward.

[0179] In some embodiments, the presently disclosed subject matter provides methods for preventing or inhibiting substance abuse and / or dependence, addictive behavior, or symptoms, behaviors, or conditions associated with substance abuse and / or dependence, comprising administering to a subject in need thereof an effective amount of a CB1R allosteric modulator compound of the present disclosure (i.e., a compound of Formula (I), (Ia), (II), (IIa), (III), or (IIIa) or a pharmaceutically acceptable salt or solvate thereof), or a pharmaceutically acceptable composition comprising such a compound. In some embodiments, the subject is human.

[0180] In some embodiments, the behavior associated with substance abuse and / or dependence includes substance use (i.e., self-administration) and / or substance-seeking behavior. In some embodiments, the substance abuse and / or dependence includes alcohol abuse and / or dependence (i.e., alcoholism). In some embodiments, the substance abuse and / or dependence includes nicotine abuse and / or dependence. In some embodiments, the substance abuse and / or dependence includes opiate abuse and / or dependence. In some embodiments, the behavior associated with substance abuse or dependence is relapse.

[0181] In some embodiments, the compound administered in one of the methods of the presently disclosed subject matter is a compound of Formula (II), Formula (IIa), Formula (III), or Formula (IIIa). In some embodiments, the compound is selected from 7, 9, 10-15, 17-35, 44-48, 51, 54, 55, 59-75, and 79. In some embodiments, the compound is selected from 11-14, 18-23, 25, 29, 30-35, 44, 45, 48, 60, 62, 64, 65, 66, 68, and 74. In some embodiments, the compound is selected from 11, 20, 21, 31, 68, and 74. In some embodiments, the compound is other than 9, 11, or 14.

[0182] An effective amount of a compound disclosed herein includes an amount sufficient to produce a noticeable effect, such as, but not limited to, a reduction or cessation of self-administration of alcohol or another substance of abuse, weight loss, lack of weight gain, etc. The actual dosage level of the active compound in the therapeutic compounds of the presently disclosed subject matter can be varied to administer an amount of the active compound effective to achieve the desired therapeutic response for a particular subject and / or application. Preferably, a minimum dose is administered, and the dose is gradually increased to the minimum effective amount in the absence of dose-limiting toxicity. Determination and adjustment of a therapeutically effective dose, as well as evaluation of when and how to make such adjustments, are known to those skilled in the art.

[0183] The therapeutically effective amount of a compound may depend on several factors. For example, the species, age, and weight of the subject, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration are all factors that may be considered. In some embodiments, the therapeutically effective amount ranges from about 0.1 to about 100 mg / kg of subject body weight / day. In some embodiments, the therapeutically effective amount ranges from about 0.1 to about 20 mg / kg of body weight / day. Thus, for a 70 kg adult mammal, an example of a practical amount per day would be between about 10 and about 2000 mg. This amount can be administered in a single dose per day, or in divided doses administered several times (e.g., 2, 3, 4, or 5 times) per day so that the total daily dose remains the same. An effective amount of the salt or solvate thereof can be determined as a percentage of the effective amount of the compound itself.

[0184] The compounds of the presently disclosed subject matter may also be useful as adjunctive, additional, or complementary therapy for the treatment of the above-mentioned diseases / disorders, where adjunctive, additional, or complementary therapy refers to the simultaneous or sequential administration of the compounds of the presently disclosed subject matter to a subject who has already received, is receiving, or will receive one or more additional therapeutic agents for the treatment of the indicated condition, such as one or more known antidepressants, antipsychotics, or anxiolytics.

[0185] In some embodiments, the presently disclosed subject matter provides a compound of Formula (I), (Ia), (II), (IIa), (III), or (IIIa) for use as an active therapeutic substance. In some embodiments, the compound is for use in treating a disease mediated by CB1R. In some embodiments, the presently disclosed subject matter provides use of a compound of Formula (I), (Ia), (II), (IIa), (III), or (IIIa) for the preparation of a medicament for the treatment of a disease mediated by CB1R.

[0186] In some embodiments, the presently disclosed subject matter provides a method for modulating CB1R activity, the method comprising contacting a sample containing CB1R with a compound of one of Formulas (I), (Ia), (II), (IIa), (III), or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In some embodiments, the sample is an ex vivo sample. In some embodiments, the sample comprises a biological fluid, such as plasma, cerebrospinal fluid, or saliva. In some embodiments, the sample comprises an organ, tissue, cell, or cell extract. In some embodiments, the sample is derived from a subject. In some embodiments, the method may further comprise contacting the sample with a second compound, e.g., a compound having or suspected of having CB1R agonist or antagonist activity.

[0187] VI. Methods for Preparing Urea Derivatives The antagonists of the present disclosure can be prepared using standard synthetic methods known in the art. For example, the compounds can be prepared by the methods described herein below, or by modifications thereof that will be apparent to those skilled in the art based on this disclosure. If necessary, protecting groups known in the art can be used during the synthesis of the compounds.

[0188] Generally, the urea-based compounds of the present disclosure can be prepared by coupling an amine (e.g., representing the right side of the compound of Formula (I), i.e., representing the L1 and R6 groups) with an isocyanate (e.g., representing the left side of the molecule). For example, some of the compounds of the present disclosure can be prepared by coupling an amine derivative of the L1-R6 groups of Formula (I) with 4-chlorophenylisocyanate. Alternatively, the urea can be prepared by the Curtius reaction of an amine with an acyl azide, which itself can be prepared by reacting an acid chloride or anhydride with sodium azide or trimethylsilyl azide. In some embodiments, the amine representing the right side of the urea can be purchased from a commercial source. In some embodiments, the amine can be prepared, for example, by a Suzuki coupling reaction (e.g., reacting an aryl halide with an aryl boronic acid in the presence of a Pd(0) catalyst, e.g., Pd(PPh3)4), or another suitable coupling reaction of precursors of the L1 and R6 groups of the compound of Formula (I). In some embodiments, one of the coupling partners contains a nitro group, which can be reduced to an amino group after the coupling reaction with a suitable reducing agent (e.g., Raney nickel). Schemes 3-7 below illustrate the synthesis of compounds of Formula (I) with different L groups. As will be appreciated by those skilled in the art, these schemes can be adapted to prepare additional compounds by using other starting materials.

[0189] More specifically, compound 6 is an exemplary compound of Formula (I) in which L is a substituted arylene and was prepared from 2-bromo-6-(pyrrolidin-1-yl)pyridine as shown in Scheme 3 below. See German et al., J. Med. Chem. 2014, 57, 7758-7769. 2-Bromo-6-(pyrrolidin-1-yl)pyridine was subjected to Suzuki coupling with 4-methoxy-3-nitrophenylboronic acid to give nitro compound 85, which was then reduced with Raney nickel and hydrazine to give amine 86. Urea 6 was then obtained by coupling 86 with 4-chlorophenyl isocyanate. Additional compounds with a central substituted phenyl ring can be prepared by replacing 4-methoxy-3-nitrophenylboronic acid with another nitrophenylboronic acid and / or replacing 2-bromo-6-(pyrrolidin-1-yl)pyridine with another aryl halide.

[0190] [ka]

[0191] Scheme 3. Synthesis of compound 6. Reagents and conditions: a) 4-methoxy-3-nitro-phenylboronic acid, Pd(PPh3)4, aqueous NaHCO3, DME, reflux, 16 h b) N2H4.H2O, Raney-Ni, EtOH, 60 °C, 1 h c) 4-ClPhNCO, CHCl3, 60 °C, 16 h.

[0192] Compounds 7-10 containing a central pyridinyl ring were prepared as shown below in Scheme 4. As shown in Scheme 4, the corresponding bromopyridine amines were subjected to Suzuki coupling with phenylboronic acid to give intermediates 87-90, which were then coupled with 4-chlorophenyl isocyanate to give compounds 7-10. Additional compounds with a central pyridinyl ring can be made in an analogous manner using other substituted phenylboronic acids and / or further substituted bromo-aminopyridines.

[0193] [ka]

[0194] Scheme 4. Synthesis of Compounds 7-10. Reagents and Conditions: a) Phenylboronic acid, Pd(PPh3)4, aqueous NaHCO3, DME, reflux, 16 hours b) 4-ClPhNCO, CHCl3, 60 °C, 16 hours.

[0195] Thiophenyl- and cyclopropyl-containing compounds can be prepared following routes similar to those shown for exemplary compounds 12, 13, 15, and 16 in Scheme 5 below. As shown in Scheme 5, bromothiophene carboxylic acid was subjected to Suzuki coupling with phenylboronic acid to give intermediates 91 and 92. Final products 12 and 13 were obtained by microwave-assisted coupling of carboxylic acids 91 and 92, respectively, with 4-chlorophenylamine via Curtius rearrangement (see Kulkarni et al., J. Org. Chem. 2017, 82, 992-999) in the presence of diphenylphosphoryl azide. Similarly, cyclopropenyl compounds 15 and 16 were obtained from the Curtius rearrangement reaction of the corresponding cis- or trans-2-phenylcyclopropane-1-carboxylic acid and 4-chlorophenylamine, respectively. Again, additional compounds bearing a central thiophenyl or cyclopropenyl group can be prepared by using substituted phenylboronic acids and / or other halophenylamines.

[0196] [ka]

[0197] Scheme 5. Synthesis of compounds 12, 13, 15, and 16. Reagents and conditions: a) phenylboronic acid, Pd(PPh3)4, aqueous NaHCO3, DME, reflux, 16 h b) 4-ClPhNH2, DPPA, Et3N, toluene, mw, 100 °C, 5 min.

[0198] Suzuki coupling between 2-bromo-5-nitrothiazole and phenylboronic acid did not afford the thiazole intermediate 93. Therefore, a different route for forming the thiazole ring of compounds bearing a central thiazole group was explored. Compounds bearing a central thiazole group can be prepared in a similar manner to that shown for exemplary thiazole compound 14. See Scheme 6 below. Treatment of phenylacetaldehyde with bromine gave 2-bromo-2-phenylacetaldehyde, which underwent cyclization with thiourea to afford intermediate 93. See Guo and Yan, Eur. J. Inorg. Chem. 2010, 1267-1274. Coupling of 93 with 4-chlorophenyl isocyanate afforded 14. Additional thiazole-containing compounds can be prepared by replacing phenylacetaldehyde with aryl-substituted phenylacetaldehydes.

[0199] [ka]

[0200] Scheme 6. Synthesis of compound 14. Reagents and conditions: a) bromine, DCM, -10°C, 30 min, then reflux, 16 h b) thiourea, EtOH, reflux, 8 h c) 4-ClPhNCO, CHCl3, 60°C, 16 h.

[0201] Piperidine compounds can be prepared as shown below in Scheme 7 for exemplary piperidine compound 17. Copper-catalyzed coupling between (R)-3-(Boc-amino)piperidine and phenylboronic acid gave intermediate 94. Removal of the Boc protecting group resulted in amine 95, which was then subjected to coupling with 4-chlorophenyl isocyanate to give compound 17.

[0202] [ka]

[0203] Scheme 7. Synthesis of compound 17. Reagents and conditions: a) PhB(OH)2, Cu(OAc)2, Et3N, DCM, 60°C, 72 hours b) 4N HCl / 1,4-dioxane, room temperature, 1 hour c) 4-ClPhNCO, CHCl3, 60°C, 16 hours.

[0204] The standard procedure utilized to prepare 5-phenyl-thiophen-2-yl analogs is shown below in Scheme 8. Starting with Suzuki coupling between 2-bromo-5-nitrothiophene and substituted phenylboronic acids, nitro intermediates 96-113 and 140 were obtained, which were reduced with Raney-Ni and hydrazine to give amines 114-131 and 141. Coupling of these amines with 4-chlorophenyl isocyanate gave compounds 11 and 18-35.

[0205] [ka]

[0206] Scheme 8. Synthesis of Compounds 11 and 18-35. Reagents and Conditions: a) Corresponding phenylboronic acid, Pd(PPh3)4, aqueous NaHCO3, DME, reflux, 16 h; b) N2H4.H2O, Raney-Ni, EtOH, 60 °C, 1 h; c) 4-ClPhNCO, CHCl3, 60 °C, 16 h.

[0207] Compounds in which the central ring is replaced by an aliphatic group, such as exemplary compounds 36-39 and 41-84, were obtained by coupling the corresponding aliphatic primary amines with 4-chlorophenyl isocyanate, as shown in Scheme 9 below. Primary amines were either purchased from commercial suppliers or prepared as shown in Scheme 9. Carboxamide 132 was prepared from the amide coupling of trans-2-phenylcyclopropane-1-carboxylic acid with ammonia. Amines 133-135 were prepared from the reduction of the corresponding benzonitriles or carboxamides with borane dimethyl sulfide. Alternatively, amines 136 and 137 were obtained from the reduction of the corresponding substituted benzonitriles with LiAlH in THF.

[0208] To prepare 40, alkylation of the enolate anion of methyl isobutyrate with benzyl bromide gave intermediate 138, which was hydrolyzed to give acid 139, which was subjected to microwave-assisted coupling via Curtius rearrangement (see Kulkarni et al., J. Org. Chem. 2017, 82, 992-999) with 4-chlorophenylamine in the presence of diphenylphosphoryl azide to give compound 40.

[0209] [ka]

[0210] Scheme 9. Synthesis of Compounds 36-84. Reagents and Conditions: a) (i) BH3.Me2S, THF, 0°C to RT, 16 h; (ii) 2N HCl / Et2O, RT; b) (i) COCl2, DCM, DMF, RT, 3 h; (ii) 28% aqueous NH4OH, MeCN, RT, 16 h; c) LiAlH4, AlCl3, THF, RT, 16 h; d) Corresponding amine, CHCl3, 60°C, 16 h; e) (i) LDA, THF, -78°C, 1 h; (ii) BnBr, -78°C, 2 h; f) LiOH, MeOH, HO, RT, 3 h; g) 4-ClPhNH2, DPPA, Et3N, toluene, mw, 100°C, 5 min. [Example]

[0211] The following examples are included to provide guidance to those skilled in the art for practicing representative embodiments of the presently disclosed subject matter. In light of this disclosure and the general level of skill of those skilled in the art, they will appreciate that the following examples are intended to be illustrative only, and that numerous changes, variations, and modifications can be employed without departing from the scope of the presently disclosed subject matter.

[0212] [Example 1] Synthesis of CB1 allosteric modulators All solvents and chemicals were reagent grade. Unless otherwise noted, all reagents and solvents were purchased from commercial suppliers and used as received. Flash column chromatography was performed on a Teledyne ISCO COMBIFLASH™ Rf system (Teledyne ISCO Co., Lincoln, Nebraska, United States of America) using packed columns. Solvents used included hexane, ethyl acetate (EtOAc), dichloromethane, and methanol. Compound purity and characterization were established by a combination of high-pressure liquid chromatography (HPLC), thin-layer chromatography (TLC), mass spectrometry (MS), and nuclear magnetic resonance (NMR) analysis. 1 H and 13C NMR spectra were recorded on a Bruker Avance DPX-300 (300 MHz) spectrometer (Bruker Corporation, Billerica, Massachusetts, United States of America) and determined in CDCl3, DMSO-d6, or CD3OD with tetramethylsilane (TMS) (0.00 ppm) or the solvent peak as the internal standard. Chemical shifts are reported in ppm relative to the reference signal, and coupling constant (J) values ​​are reported in hertz (Hz). TLC was performed on EMD-precoated silica gel 60 F254 plates (MilliporeSigma, Merck KGH, Darmstadt, Germany), and spots were visualized using UV light or iodine staining. Nominal mass spectra were obtained using an Agilent 1260 Infinity II system with electrospray ionization (ESI) (Agilent Technologies, Santa Clara, California, United States of America). High-resolution mass spectra were obtained using an Agilent 1290 Infinity UHPLC-6230 TOF system (ESI) (Agilent Technologies, Santa Clara, California, United States of America). All final compounds were greater than 95% pure as determined by HPLC using a 15-minute gradient elution of 5 to 95% solvent B at 1 mL / min on an Agilent 1100 system using an Agilent ZORBAX™ SB-Phenyl, 2.1 mm × 150 mm, 5 μm column (Agilent Technologies, Santa Clara, California, United States of America), followed by 10 minutes of 95% solvent B (solvent A: water with 0.1% TFA; solvent B: acetonitrile with 0.1% TFA and 5% water; absorbance was monitored at 220 and 280 nm).

[0213] General Procedure A. To a mixture of aryl bromide (1 equivalent), boronic acid (1.1 equivalents) in dimethoxyethane (0.1 M) was added 1 M aqueous NaHCO3 (3 equivalents), followed by Pd(Ph3)4 (0.075 equivalents). The reaction mixture was refluxed overnight under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 solution and brine. The combined organic layers were dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (SiO2, ethyl acetate / hexanes) to give the desired product.

[0214] 2-(4-Methoxy-3-nitrophenyl)-6-(pyrrolidin-1-yl)pyridine (85) was reacted with 2-bromo-6-(pyrrolidin-1-yl)pyridine (0.30 g, 1.32 mmol, German et al. , J. Med. Chem. 2014, 57, 7758-7769) and 4-methoxy-3-nitrophenylboronic acid (0.29 g, 1.45 mmol) according to general procedure A as a yellow solid (0.12 g, 30%). 1 H NMR (300 MHz, CDCl3) δ 8.23 ​​(dd, J = 1.22, 8.76 Hz, 1H), 7.46 - 7.56 (m, 1H), 7.13 (d, J = 8.85 Hz, 1H), 6.91 - 7.00 (m, 2H), 6.34 (d, J = 8.48 Hz, 1H), 3.54 (t, J = 6.50 Hz, 4H), 1.99 - 2.07 (m, 4H). MS (ESI) m / z [M+H] + Calculated value: 300.1; Measured value: 300.4.

[0215] 4-Phenylpyridin-2-amine (87) was prepared from phenylboronic acid (0.10 g, 0.58 mmol) and 4-bromopyridin-2-amine (0.08 g, 0.64 mmol) according to general procedure A as a white solid (0.09 g, 89%). 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J = 5.27 Hz, 1H), 7.62 - 7.73 (m, 2H), 7.51 - 7.61 (m, 3H), 7.38 - 7.49 (m, 5H), 6.88 (d, J = 5.27 Hz, 1H), 6.70 (s, 1H), 4.57 (br. s., 2H). MS (ESI) m / z [M+H] + Calculated: 171.1; Measured: 171.1.

[0216] 6-Phenylpyridin-2-amine (88) was prepared from 6-bromopyridin-2-amine (0.10 g, 0.58 mmol) and phenylboronic acid (0.08 g, 0.64 mmol) according to general procedure A as a yellow liquid (0.10 g, 79%). 1 H NMR (300 MHz, CDCl3) δ 7.92 (dd, J = 1.22, 8.19 Hz, 2H), 7.32 - 7.52 (m, 4H), 7.07 (d, J = 7.35 Hz, 1H), 6.43 (d, J = 8.10 Hz, 1H), 4.55 (br. s., 2H). MS (ESI) m / z [M+H] + Calculated: 171.1; Measured: 171.2.

[0217] 5-Phenylpyridin-3-amine (89) was prepared from 5-bromopyridin-3-amine (0.10 g, 0.58 mmol) and phenylboronic acid (0.08 g, 0.64 mmol) according to general procedure A as a white solid (0.10 g, 60%). 1 H NMR (300 MHz, CDCl3) δ 8.24 (d, J = 1.70 Hz, 1H), 8.06 (d, J = 2.45 Hz, 1H), 7.62 - 7.71 (m, 3H), 7.42 - 7.47 (m, 3H), 7.15 (dd, J = 1.88, 2.64 Hz, 1H), 3.89 (br. s., 2H). MS (ESI) m / z [M+H] + Calculated: 171.1; Measured: 171.0.

[0218] 2-Phenylpyridin-4-amine (90) was prepared from 2-bromopyridin-4-amine (0.10 g, 0.58 mmol) and phenylboronic acid (0.08 g, 0.64 mmol) according to general procedure A as a yellow liquid (0.04 g, 44%). 1 H NMR (300 MHz, CDCl3) δ 8.30 (d, J = 5.46 Hz, 1H), 7.91 (s, 2H), 7.32 - 7.49 (m, 3H), 6.93 (s, 1H), 6.47 (dd, J = 2.17, 5.56 Hz, 1H), 4.25 (br. s., 2H). MS (ESI) m / z [M+H] + Calculated: 171.1; Measured: 171.2.

[0219] 2-Nitro-5-phenylthiophene (140) was prepared from 2-bromo-5-nitrothiophene (0.20 g, 0.96 mmol) and phenylboronic acid (0.13 g, 1.06 mmol) according to general procedure A as a yellow liquid (0.06 g, 28%). 1 H NMR (300 MHz, CDCl3): δ 7.91 (d, J = 4.10 Hz, 1H), 7.61-7.64 (m, 2H), 7.42-7.48 (m, 3H), 7.24 (d, J = 5.20 Hz, 1H) ppm. MS (ESI) m / z [MH] - Calculated: 203.1; Measured: 203.3.

[0220] 2-(4-Fluorophenyl)-5-nitrothiophene (96) was prepared from 2-bromo-5-nitrothiophene (0.20 g, 0.96 mmol) and 4-fluorophenylboronic acid (0.15 g, 1.06 mmol) according to general procedure A as a white solid (0.03 g, 12%). 1 H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 4.33 Hz, 1H), 7.62 (dd, J = 5.18, 8.76 Hz, 2H), 7.11 - 7.21 (m, 3H).

[0221] 2-(3-Fluorophenyl)-5-nitrothiophene (97) was prepared from 2-bromo-5-nitrothiophene (0.21 g, 1 mmol) and 3-fluorophenylboronic acid (0.15 g, 1.1 mmol) according to general procedure A as a yellow solid (0.10 g, 45%). 1 H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 4.33 Hz, 1H), 7.39 - 7.49 (m, 2H), 7.29 - 7.36 (m, 1H), 7.25 (d, J = 4.33 Hz, 1H), 7.09 - 7.18 (m, 1H).

[0222] 2-(2,4-Difluorophenyl)-5-nitrothiophene (98) was prepared from 2-bromo-5-nitrothiophene (0.21 g, 1 mmol) and 2,4-fluorophenylboronic acid (0.20 g, 1.0 mmol) according to general procedure A as a yellow solid (0.07 g, 29%). 1 H NMR (300 MHz, CDCl3) δ 7.93 (d, J = 0.75 Hz, 1H), 7.64 (dt, J = 6.03, 8.85 Hz, 1H), 7.34 (d, J = 4.33 Hz, 1H), 6.93 - 7.05 (m, 2H).

[0223] 2-(2-Chlorophenyl)-5-nitrothiophene (99) was prepared from 2-bromo-5-nitrothiophene (0.21 g, 1 mmol) and 2-chlorophenylboronic acid (0.21 g, 1.0 mmol) according to general procedure A as a yellow solid (0.08 g, 33%). 1 H NMR (300 MHz, CDCl3) δ 7.92 (d, J = 4.33 Hz, 1H), 7.50 - 7.57 (m, 2H), 7.34 - 7.40 (m, 2H), 7.29 (d, J = 4.33 Hz, 1H).

[0224] 2-(3-Chlorophenyl)-5-nitrothiophene (100) was prepared from 2-bromo-5-nitrothiophene (0.21 g, 1 mmol) and 3-chlorophenylboronic acid (0.17 g, 1.0 mmol) according to general procedure A as a yellow solid (0.09 g, 38%). 1 H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 4.33 Hz, 1H), 7.59 - 7.63 (m, 1H), 7.48 - 7.53 (m, 1H), 7.38 - 7.44 (m, 2H), 7.23 - 7.27 (m, 1H).

[0225] 2-(4-Chlorophenyl)-5-nitrothiophene (101) was prepared from 2-bromo-5-nitrothiophene (0.21 g, 1 mmol) and 4-chlorophenylboronic acid (0.17 g, 1.0 mmol) according to general procedure A as a yellow solid (0.09 g, 38%). 1 H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 4.33 Hz, 1H), 7.54 - 7.59 (m, 2H), 7.41 - 7.46 (m, 2H), 7.22 (d, J = 4.33 Hz, 1H).

[0226] 2-(3,4-Dichlorophenyl)-5-nitrothiophene (102) was prepared from 2-bromo-5-nitrothiophene (0.20 g, 1 mmol) and 2,4-dichlorophenylboronic acid (0.20 g, 1.1 mmol) according to general procedure A as a yellow solid (0.02 g, 8%). 1 H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 4.33 Hz, 1H), 7.72 (d, J = 2.07 Hz, 1H), 7.55 (s, 1H), 7.43 - 7.47 (m, 1H), 7.24 (d, J = 4.33 Hz, 1H).

[0227] 2-(3,5-Dichlorophenyl)-5-nitrothiophene (103) was prepared from 2-bromo-5-nitrothiophene (0.21 g, 1 mmol) and 3,5-dichlorophenylboronic acid (0.21 g, 1.1 mmol) according to general procedure A as a yellow solid (0.05 g, 16%). 1 H NMR (300 MHz, CDCl3) δ 7.89 - 7.94 (m, 1H), 7.50 (br. s., 2H), 7.40 - 7.45 (m, 1H), 7.24 - 7.29 (m, 1H).

[0228] 1-[3-(5-nitrothiophen-2-yl)phenyl]ethan-1-one (104) was prepared from 2-bromo-5-nitrothiophene (0.21 g, 1 mmol) and 3-(methoxycarbonyl)phenylboronic acid (0.20 g, 1.1 mmol) according to general procedure A as a yellow solid (0.09 g, 40%). 1 H NMR (300 MHz, CDCl3) δ 8.22 (s, 1H), 8.00 (d, J = 6.59 Hz, 1H), 7.91 - 7.96 (m, 1H), 7.77 - 7.86 (m, 1H), 7.53 - 7.63 (m, 1H), 7.23 - 7.37 (m, 2H), 2.67 (s, 3H).

[0229] Methyl 3-(5-nitrothiophen-2-yl)benzoate (105) was prepared from 2-bromo-5-nitrothiophene (0.21 g, 1 mmol) and 3-acetoxyphenylboronic acid (0.18 g, 1.1 mmol) according to general procedure A as a red solid (0.09 g, 33%). 1 H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 8.10 (d, J = 7.91 Hz, 1H), 7.91 - 7.96 (m, 1H), 7.81 (d, J = 7.91 Hz, 1H), 7.51 - 7.59 (m, 1H), 7.33 (d, J = 4.33 Hz, 1H), 3.97 (s, 3H).

[0230] 2-(3-Methanesulfonylphenyl)-5-nitrothiophene (106) was prepared from 2-bromo-5-nitrothiophene (0.21 g, 1 mmol) and 3-(methylsulfonyl)phenylboronic acid (0.22 g, 1.1 mmol) according to general procedure A as a red solid (0.08 g, 28%). 1 H NMR (300 MHz, CDCl3) δ 8.20 (t, J = 1.60 Hz, 1H), 8.01 (d, J = 7.91 Hz, 1H), 7.95 (d, J = 4.33 Hz, 1H), 7.90 (d, J = 7.91 Hz, 1H), 7.66 - 7.73 (m, 1H), 7.37 (d, J = 4.33 Hz, 1H), 3.12 (s, 3H).

[0231] 2-(2-Methoxyphenyl)-5-nitrothiophene (107) was prepared from 2-bromo-5-nitrothiophene (0.21 g, 1 mmol) and 2-methoxyphenylboronic acid (0.17 g, 1.1 mmol) according to general procedure A as a yellow solid (0.20 g, 85%). 1 H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 4.52 Hz, 1H), 7.73 (dd, J = 1.22, 7.82 Hz, 1H), 7.38 - 7.44 (m, 2H), 7.01 - 7.11 (m, 2H), 4.01 (s, 3H).

[0232] 2-(3-Methoxyphenyl)-5-nitrothiophene (108) was prepared from 2-bromo-5-nitrothiophene (0.21 g, 1 mmol) and 3-methoxyphenylboronic acid (0.17 g, 1.1 mmol) according to general procedure A as a yellow solid (0.15 g, 66%). 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 4.33 Hz, 1H), 7.31 - 7.35 (m, 1H), 7.18 - 7.25 (m, 2H), 7.13 (t, J = 1.98 Hz, 1H), 6.98 (dd, J = 1.98, 8.19 Hz, 1H), 3.87 (s, 3H).

[0233] 2-(4-Methoxyphenyl)-5-nitrothiophene (109) was prepared from 2-bromo-5-nitrothiophene (0.21 g, 1 mmol) and 4-methoxyphenylboronic acid (0.17 g, 1.1 mmol) according to general procedure A as a yellow solid (0.15 g, 80%). 1 H NMR (300 MHz, CDCl3) δ 7.85 - 7.91 (m, 1H), 7.57 (d, J = 8.10 Hz, 2H), 7.10 - 7.17 (m, 1H), 6.97 (d, J = 6.41 Hz, 2H), 3.86 (s, 3H).

[0234] 2-(3-Methylphenyl)-5-nitrothiophene (110) was prepared from 2-bromo-5-nitrothiophene (0.21 g, 1 mmol) and 3-methylphenylboronic acid (0.17 g, 1.1 mmol) according to general procedure A as a yellow solid (0.08 g, 35%). 1 H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 4.33 Hz, 1H), 7.41 - 7.46 (m, 2H), 7.34 (t, J = 7.82 Hz, 1H), 7.21 - 7.27 (m, 2H), 2.42 (s, 3H).

[0235] N,N-Dimethyl-3-(5-nitrothiophen-2-yl)aniline (111) was prepared from 2-bromo-5-nitrothiophene (0.21 g, 1 mmol) and 3-(N,N-dimethylamino)phenylboronic acid (0.18 g, 1.1 mmol) according to general procedure A as an orange solid (0.06 g, 26%). 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J = 4.33 Hz, 1H), 7.25 - 7.32 (m, 1H), 7.21 (d, J = 4.33 Hz, 1H), 6.95 (d, J = 7.72 Hz, 1H), 6.86 (s, 1H), 6.78 (dd, J = 1.88, 8.29 Hz, 1H), 3.01 (s, 6H).

[0236] 3-(5-Nitrothiophen-2-yl)pyridine (112) was prepared from 2-bromo-5-nitrothiophene (0.21 g, 1 mmol) and 3-pyridylboronic acid (0.14 g, 1.1 mmol) according to general procedure A as an orange solid (0.07 g, 34%). 1 H NMR (300 MHz, CDCl3) δ 8.92 (d, J = 1.88 Hz, 1H), 8.68 (d, J = 3.96 Hz, 1H), 7.89 - 7.97 (m, 2H), 7.42 (dd, J = 4.90, 7.91 Hz, 1H), 7.32 (d, J = 4.14 Hz, 1H). MS (ESI) m / z [M+H] + Calculated: 207.1; Measured: 207.1.

[0237] 4-(5-Nitrothiophen-2-yl)pyridine (113) was prepared from 2-bromo-5-nitrothiophene (0.21 g, 1 mmol) and 4-pyridylboronic acid (0.14 g, 1.1 mmol) according to general procedure A as a yellow solid (0.07 g, 17%). 1 H NMR (300 MHz, CDCl3) δ 8.69 - 8.76 (m, 2H), 7.95 (d, J = 4.14 Hz, 1H), 7.48 - 7.54 (m, 2H), 7.43 (d, J = 4.33 Hz, 1H). MS (ESI) m / z [M+H] + Calculated: 207.1; Measured: 207.2.

[0238] General Procedure B. To a solution of the nitrobenzene derivative (1 equiv.) in ethanol (0.1 M) was added hydrazine hydrate (15 equiv.). The reaction was stirred at 50° C. for 15 min, and an excess of Raney nickel slurry in water (1.2 equiv.) was slowly added. After 1 h, effervescence ceased, and the mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was either used in the next step without purification or purified by column chromatography (SiO, ethyl acetate / hexanes) to give the desired product.

[0239] 2-Methoxy-5-[6-(pyrrolidin-1-yl)pyridin-2-yl]aniline (86) was prepared from 85 (0.12 g, 0.4 mmol) according to general procedure B as a white solid (0.10 g, 93%). 1 H NMR (300 MHz, CDCl3) δ 7.49 (d, J = 2.07 Hz, 1H), 7.44 - 7.48 (m, 1H), 7.39 - 7.43 (m, 1H), 6.92 (d, J = 7.54 Hz, 1H), 6.83 (d, J = 8.48 MS (ESI) m / z [M+H] + Calculated: 270.1; Measured: 270.3.

[0240] 5-Phenylthiophen-2-amine (141) was prepared from 140 (0.06 g, 0.3 mmol) according to general procedure B as a white solid (0.05 g, 96%). 1 H NMR (300 MHz, CDCl3) δ 7.46 (s, 2H), 7.31 (d, J = 15.26 Hz, 2H), 7.18 (d, J = 7.54 Hz, 1H), 6.93 (s, 1H), 6.15 (d, J = 3.77 Hz, 1H), 3.82 (br. s., 2H). MS (ESI) m / z [M+H] +Calculated: 176.1; Measured: 176.1.

[0241] 5-(4-Fluorophenyl)thiophen-2-amine (114) was prepared from 96 (0.03 g, 0.12 mmol) according to general procedure B as a white solid (0.01 g, 36%). 1 H NMR (300 MHz, CDCl3) δ 7.34 - 7.46 (m, 2H), 6.95 - 7.07 (m, 2H), 6.83 (d, J = 2.45 Hz, 1H), 6.11 - 6.19 (m, 1H), 3.82 (br. s., 2H). MS (ESI) m / z [M+H] + Calculated: 194.1; Measured: 194.2.

[0242] 5-(3-Fluorophenyl)thiophen-2-amine (115) was prepared from 97 (0.10 g, 0.45 mmol) according to general procedure B as a white solid (0.07 g, 82%). 1 H NMR (300 MHz, CDCl3) δ 7.24 (d, J = 9.42 Hz, 2H), 7.14 (d, J = 9.80 Hz, 1H), 6.91 - 7.00 (m, 1H), 6.80 - 6.90 (m, 1H), 6.10 - 6.20 (m, 1H), 3.88 (br. s., 2H). MS (ESI) m / z [M+H] + Calculated: 194.1; Measured: 194.3.

[0243] 5-(2,4-Difluorophenyl)thiophen-2-amine (116) was prepared from 98 (0.07 g, 0.68 mmol) according to general procedure B as a white solid (0.03 g, 49%). 1H NMR (300 MHz, CDCl3) δ 7.41 (dt, J = 6.41, 8.57 Hz, 15H), 7.01 (dd, J = 1.13, 3.77 Hz, 14H), 6.79 - 6.90 (m, 29H), 6.17 (d, J = 3.77 Hz, 14H), 3.88 (br. s., 28H). MS (ESI) m / z [M+H] + Calculated: 212.1; Measured: 212.1.

[0244] 5-(2-Chlorophenyl)thiophen-2-amine (117) was prepared from 99 (0.08 g, 0.33 mmol) according to general procedure B as a white solid (0.04 g, 56%). 1 H NMR (300 MHz, CDCl3) δ 7.45 (dd, J = 1.51, 7.72 Hz, 1H), 7.41 (dd, J = 1.32, 7.72 Hz, 1H), 7.19 - 7.24 (m, 1H), 7.16 (dd, J = 1.51, 7.54 Hz, 1H), 7.03 (s, 1H), 6.19 (d, J = 3.77 Hz, 1H), 3.87 (br. s., 2H). MS (ESI) m / z [M+H] + Calculated: 210.1; Measured: 210.1.

[0245] 5-(3-chlorophenyl)thiophen-2-amine (118) was prepared from 100 (0.09 g, 0.38 mmol) according to general procedure B as a white solid (0.04 g, 20%). 1 H NMR (300 MHz, CDCl3) δ 7.42 (t, J = 1.70 Hz, 1H), 7.28 - 7.34 (m, 1H), 7.19 - 7.24 (m, 1H), 7.09 - 7.16 (m, 1H), 6.94 (d, J = 3.77 Hz, 1H), 6.15 (d, J = 3.77 Hz, 1H), 3.89 (br. s., 2H). MS (ESI) m / z [M+H] + Calculated value: 210.0; Measured value: 210.1.

[0246] 5-(4-Chlorophenyl)thiophen-2-amine (119) was prepared from 101 (0.10 g, 0.40 mmol) according to general procedure B as a white solid (0.03 g, 29%). 1 H NMR (300 MHz, CDCl3) δ 7.33 - 7.40 (m, 2H), 7.23 - 7.30 (m, 2H), 6.90 (d, J = 3.77 Hz, 1H), 6.15 (d, J = 3.58 Hz, 1H), 3.86 (br. s., 2H). MS (ESI) m / z [M+H] + Calculated value: 210.0; Measured value: 210.2.

[0247] 5-(2,4-Dichlorophenyl)thiophen-2-amine (120) was prepared from 102 (0.02 g, 0.07 mmol) according to general procedure B as a white solid (0.01 g, 36%). 1 H NMR (300 MHz, CDCl3) δ 7.50 (d, J = 2.07 Hz, 1H), 7.33 - 7.39 (m, 1H), 7.23 (d, J = 2.26 Hz, 1H), 6.92 (d, J = 3.77 Hz, 1H), 6.15 (d, J = 3.77 Hz, 1H), 3.91 (br. s., 2H). MS (ESI) m / z [M+H] + Calculated: 244.0; Measured: 244.0.

[0248] 5-(3,5-Dichlorophenyl)thiophen-2-amine (121) was prepared from 103 (0.05 g, 0.16 mmol) according to general procedure B as a pale yellow solid (0.01 g, 38%). 1 H NMR (300 MHz, CDCl3) δ 7.29 (d, J = 1.70 Hz, 2H), 7.13 (s, 1H), 6.95 (d, J = 3.77 Hz, 1H), 6.14 (d, J = 3.77 Hz, 1H), 3.95 (br. s., 2H). MS (ESI) m / z [M+H] +Calculated: 244.0; Measured: 244.1.

[0249] 1-[3-(5-aminothiophen-2-yl)phenyl]ethan-1-one (122) was prepared from 104 (0.10 g, 0.40 mmol) according to general procedure B as a yellow solid (0.06 g, 68%). 1 H NMR (300 MHz, CDCl3) δ 7.99 - 8.05 (m, 1H), 7.74 (d, J = 6.40 Hz, 1H), 7.63 (d, J = 5.84 Hz, 1H), 7.41 (d, J = 7.16 Hz, 1H), 6.96 - 7.05 (m, 1H), 6.13 - 6.24 (m, 1H), 3.91 (br. s., 2H), 2.62 (s, 3H). MS (ESI) m / z [M+H] + Calculated: 218.1; Measured: 218.2.

[0250] Methyl 3-(5-aminothiophen-2-yl)benzoate (123) was prepared from 105 (0.09 g, 0.33 mmol) according to general procedure B as a yellow solid (0.04 g, 49%). 1 H NMR (300 MHz, CDCl3) δ 8.09 - 8.16 (m, 1H), 7.83 (d, J = 6.22 Hz, 1H), 7.57 - 7.67 (m, 1H), 7.32 - 7.44 (m, 1H), 6.98 - 7.05 (m, 1H), 6.13 - 6.21 (m, 1H), 3.93 (s., 3H), 3.82 (br. s., 2H). MS (ESI) m / z [M+H] + Calculated: 234.1; Measured: 234.3.

[0251] 5-(3-Methanesulfonylphenyl)thiophen-2-amine (124) was prepared from 106 (0.08 g, 0.28 mmol) according to general procedure B as a yellow solid (0.04 g, 54%). 1H NMR (300 MHz, CDCl3) δ 7.98 (t, J = 1.79 Hz, 1H), 7.64 - 7.73 (m, 2H), 7.45 - 7.54 (m, 1H), 7.05 (d, J = 3.77 Hz, 1H), 6.17 (d, J = 3.77 Hz, 1H), 3.99 (br. s., 2H), 3.07 (s, 3H). MS (ESI) m / z [M+H] + Calculated value: 254.1; Measured value: 254.3.

[0252] 5-(2-Methoxyphenyl)thiophen-2-amine (125) was prepared from 107 (0.20 g, 0.85 mmol) according to general procedure B as a white solid (0.04 g, 18%). 1 H NMR (300 MHz, CDCl3) δ 7.51 (dd, J = 1.51, 7.72 Hz, 1H), 7.09 - 7.21 (m, 2H), 6.89 - 6.99 (m, 2H), 6.17 (d, J = 3.77 Hz, 1H), 3.90 (s, 3H), 3.80 (br. s., 2H). MS (ESI) m / z [M+H] + Calculated: 206.1; Measured: 206.2.

[0253] 5-(3-Methoxyphenyl)thiophen-2-amine (126) was prepared from 108 (0.15 g, 0.65 mmol) according to general procedure B as a yellow solid (0.06 g, 43%). 1 H NMR (300 MHz, CDCl3) δ 7.21 (d, J = 7.91 Hz, 1H), 7.05 (d, J = 7.72 Hz, 1H), 6.99 (t, J = 1.98 Hz, 1H), 6.92 (d, J = 3.77 Hz, 1H), 6.71 - 6.76 (m, 1H), 6.15 (d, J = 3.77 Hz, 1H), 3.80 (s, 3H). MS (ESI) m / z [M+H] + Calculated: 206.1; Measured: 206.2.

[0254] 5-(4-Methoxyphenyl)thiophen-2-amine (127) was prepared from 109 (0.19 g, 0.80 mmol) according to general procedure B as a white solid (0.02 g, 12%). 1 H NMR (300 MHz, CDCl3) δ 7.38 (d, J = 8.67 Hz, 2H), 6.87 (d, J = 8.67 Hz, 2H), 6.79 (d, J = 3.77 Hz, 1H), 6.15 (d, J = 3.58 Hz, 1H), 3.81 (s, 3H). MS (ESI) m / z [M+H] + Calculated: 206.1; Measured: 206.2.

[0255] 5-(3-Methylphenyl)thiophen-2-amine (128) was prepared from 110 (0.08 g, 0.35 mmol) according to general procedure B as an orange liquid (0.02 g, 35%). 1 H NMR (300 MHz, CHCl3) δ 7.24 - 7.29 (m, J = 5.70 Hz, 2H), 7.21 (d, J = 7.35 Hz, 1H), 7.00 (d, J = 7.35 Hz, 1H), 6.91 (d, J = 3.58 Hz, 1H), 6.15 (d, J = 3.77 Hz, 1H), 3.80 (br. s., 2H), 2.35 (s, 3H). MS (ESI) m / z [M+H] + Calculated: 190.1; Measured: 190.3.

[0256] 5-[3-(dimethylamino)phenyl]thiophen-2-amine (129) was prepared from 111 (0.06 g, 0.26 mmol) according to general procedure B as an orange liquid (0.06 g, quantitative). 1H NMR (300 MHz, CDCl3) δ 7.18 (t, J = 8.01 Hz, 1H), 6.90 (d, J = 3.77 Hz, 1H), 6.84 (d, J = 7.72 Hz, 1H), 6.80 (t, J = 1.98 Hz, 1H), 6.59 (dd, J MS (ESI) m / z [M+H] + Calculated: 219.1; Measured: 219.3.

[0257] 5-(pyridin-3-yl)thiophen-2-amine (130) was prepared from 112 (0.07 g, 0.34 mmol) according to general procedure B as a white liquid (0.06 g, 14%). 1 H NMR (300 MHz, CDCl3) δ 8.73 (d, J = 2.07 Hz, 1H), 8.40 (dd, J = 1.32, 4.71 Hz, 1H), 7.70 (td, J = 1.88, 8.10 Hz, 1H), 7.20 - 7.25 (m, 1H), 6.99 (d, J = 3.77 Hz, 1H), 6.19 (d, J = 3.77 Hz, 1H), 3.94 (br. s., 2H). MS (ESI) m / z [M+H] + Calculated: 177.1; Measured: 177.4.

[0258] 5-(pyridin-4-yl)thiophen-2-amine (131) was prepared from 113 (0.04 g, 0.17 mmol) according to general procedure B as a white liquid (0.005 g, 16%). 1 H NMR (300 MHz, CDCl3) δ 8.44 - 8.50 (m, 2H), 7.27 - 7.31 (m, 2H), 7.17 (d, J = 3.77 Hz, 1H), 6.18 (d, J = 3.77 Hz, 1H), 4.06 (br. s., 2H). MS (ESI) m / z [M+H] +Calculated: 177.1; Measured: 177.3.

[0259] 5-Phenyl-1,3-thiazol-2-amine hydrobromide (93). To a solution of phenylacetaldehyde (0.49 mL, 4.16 mmol) in dichloromethane (1.5 mL) was added dropwise 15 mL of bromine (0.21 mL) at -10 °C. The reaction mixture was warmed to room temperature and then refluxed for 16 h. After cooling to room temperature, the reaction mixture was quenched with a saturated solution of sodium bicarbonate and extracted with dichloromethane (3x). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated to give crude 2-bromo-2-phenylacetaldehyde, which was added to a suspension of thiourea (0.38 g, 5 mmol) in ethanol (10 mL). The reaction mixture was refluxed for 8 h. After cooling to room temperature, the solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel, MeOH / dichloromethane) to give the product as a white solid (0.56 g, 77%). 1 H NMR (300 MHz, CDCl3) δ 8.75 (br. s., 2H), 7.36 - 7.46 (m, 5H), 7.21 (s, 1H). MS (ESI) m / z [M+H] + Calculated: 177.1; Measured: 177.4.

[0260] tert-Butyl N-[(3R)-1-phenylpiperidin-3-yl]carbamate (94). To a solution of (R)-3-(Boc-amino)piperidine (0.16 g, 1 mmol) in dichloromethane (4 mL) in a sealed tube, triethylamine (0.28 mL, 2 mmol), copper acetate (0.20 g, 1.1 mmol), and phenylboronic acid (0.27 g, 2.2 mmol) were added. The reaction was purged with nitrogen, sealed, and heated at 60 °C for 3 days. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with 10% v / v MeOH / DCM. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (silica gel, MeOH / DCM) to give the product as a colorless liquid (0.09 g, 32%). 1H NMR (300 MHz, CDCl3) δ 7.27 - 7.29 (m, 1H), 7.22 - 7.25 (m, 1H), 6.94 (d, J = 7.72 Hz, 2H), 6.82 - 6.89 (m, 1H), 4.93 (br. s., 1H), 3.87 (br. s., 1H), 3.32 (d, J = 11.11 Hz, 1H), 2.94 - 3.21 (m, 3H), 1.54 - 1.88 (m, 4H), 1.46 (s, 9H).

[0261] (3R)-1-Phenylpiperidin-3-amine hydrochloride (95) A solution of 4N HCl in 1,4-dioxane (0.09 g, 0.32 mmol) was added to 94 and stirred at room temperature for 1 hour. The reaction mixture was then concentrated under reduced pressure to give the desired product as a white solid (0.07 g, quantitative). MS (ESI) m / z [M+H] + Calculated: 176.1; Measured: 176.3.

[0262] General Procedure C. To a solution of arylamine (1 equiv.) in anhydrous chloroform (0.04 M) was added 4-chlorophenyl isocyanate (1 equiv.) at room temperature. The reaction mixture was then heated at 60° C. for 16 hours. The precipitated product was filtered and washed thoroughly with dichloromethane.

[0263] General Procedure D. To a solution of 4-chloroaniline (1 equiv.) in toluene (0.2 M) was added acid (1.5 equiv.), triethylamine (3 equiv.), and diphenylphosphoryl azide (1.2 equiv.). The reaction mixture was heated to 100 °C for 5 min by microwave irradiation. Upon cooling to room temperature, the reaction mixture was diluted with ethyl acetate and acidified to pH 4-5 with 1 N HCl solution. The phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic fractions were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO, ethyl acetate:hexanes) to give the desired product.

[0264] 3-(4-Chlorophenyl)-1-{2-methoxy-5-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (6) was prepared from 86 (0.02 g, 0.11 mmol) according to general procedure C as a white solid (0.03 g, 64%). 1 H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.85 (d, J = 2.07 Hz, 1H), 8.38 (s, 1H), 7.75 (dd, J = 2.07, 8.48 Hz, 1H), 7.52 - 7.66 (m, 3H), 7.40 (d, J = 8.85 Hz, 2H), 7.15 (d, J = 8.67 Hz, 1H), 7.03 (d, J = 7.54 Hz, 1H), 6.42 (d, J = 8.29 Hz, 1H), 3.99 (s, 3H), 3.48 - 3.59 (m, 4H), 1.99 - 2.10 (m, 4H). 13 C NMR (75 MHz, DMSO-d6) d 156.6, 154.3, 152.3, 148.3, 138.8, 137.7, 132.2, 128.6, 128.3, 125.2, 120.4, 119.5, 116.9, 110.6, 106.6, 104.4, 55.9, 46.2, 25.0. MS (ESI) m / z [M+H] + Calculated value: 423.1; Measured value: 423.3.

[0265] 1-(4-chlorophenyl)-3-(4-phenylpyridin-2-yl)urea (7) was prepared from 87 (0.09 g, 0.51 mmol) according to general procedure C as a white solid (0.10 g, 60%). 1H NMR (300 MHz, DMSO-d6) δ 10.61 (br. s., 1H), 9.57 (s, 1H), 8.36 (d, J = 5.27 Hz, 1H), 7.82 (s, 1H), 7.73 (d, J = 6.78 Hz, 2H), 7.57 - 7.61 (m, 2H), 7.54 (d, J = 7.72 Hz, 2H), 7.49 - 7.52 (m, 1H), 7.37 (d, J = 8.48 Hz, 2H), 7.33 - 7.35 (m, 1H). 13 MS (ESI) m / z [M+H] + Calculated: 324.1; Measured: 324.2.

[0266] 1-(4-Chlorophenyl)-3-(6-phenylpyridin-2-yl)urea (8) was prepared from 88 (0.08 g, 0.45 mmol) according to general procedure C as a white solid (0.08 g, 56%). 1 H NMR (300 MHz, DMSO-d6) δ 10.73 (br. s., 1H), 9.64 (s, 1H), 8.01 (d, J = 7.35 Hz, 2H), 7.83 - 7.90 (m, 1H), 7.50 - 7.60 (m, 5H), 7.47 (d, J = 7.91 Hz, 2H), 7.39 (d, J = 8.67 Hz, 2H). 13 MS (ESI) m / z [M+H] + Calculated: 324.1; Measured: 324.2.

[0267] 1-(4-Chlorophenyl)-3-(5-phenylpyridin-3-yl)urea (9) was prepared from 89 (0.07 g, 0.37 mmol) according to general procedure C as a white solid (0.04 g, 35%). 1 H NMR (300 MHz, DMSO-d6) δ 9.05 (s, 1H), 9.00 (s, 1H), 8.59 (d, J = 2.07 Hz, 1H), 8.51 (d, J = 1.51 Hz, 1H), 8.23 ​​(s, 1H), 7.69 (d, J = 7.16 Hz, 2H), 7.48 - 7.57 (m, 4H), 7.45 (d, J = 6.97 Hz, 1H), 7.35 (d, J = 8.85 Hz, 2H). 13 MS (ESI) m / z [M+H] + Calculated: 324.1; Measured: 324.1.

[0268] 1-(4-Chlorophenyl)-3-(2-phenylpyridin-4-yl)urea (10) was prepared from 90 (0.05 g, 0.27 mmol) according to general procedure C as a white solid (0.04 g, 45%). 1 H NMR (300 MHz, DMSO-d6) δ 9.26 (s, 1H), 9.13 (s, 1H), 8.47 (d, J = 5.65 Hz, 1H), 7.96 - 8.02 (m, 3H), 7.43 - 7.55 (m, 5H), 7.33 - 7.41 (m, 3H). 13 MS (ESI) m / z [M+H] + Calculated: 324.1; Measured: 324.2.

[0269] 1-(4-Chlorophenyl)-3-(5-phenylthiophen-2-yl)urea (11) was prepared from 141 (0.05 g, 0.30 mmol) according to general procedure C as a white solid (0.06 g, 57%). 1 H NMR (300 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.96 (s, 1H), 7.53 (dd, J = 8.19, 14.22 Hz, 4H), 7.31 - 7.41 (m, 4H), 7.20 - 7.26 (m, 2H), 6.58 (d, J = 3.96 Hz, 1H). 13 C NMR (75 MHz, DMSO-d6) δ 151.4, 140.6, 138.3, 134.5, 132.5, 129.0, 128.6, 126.4, 125.7, 124.3, 120.8, 120.0, 110.6. MS (ESI) m / z [MH] - Calculated value: 327.1; Measured value: 327.3.

[0270] 1-(4-Chlorophenyl)-3-(4-phenylthiophen-2-yl)urea (12) was prepared from 91 (0.03 g, 0.16 mmol) according to general procedure D as a white solid (0.04 g, 65%). 1 H NMR (300 MHz, DMSO-d6) δ 9.77 (s, 1H), 9.02 (s, 1H), 7.65 (d, J = 7.54 Hz, 2H), 7.52 (d, J = 8.48 Hz, 2H), 7.31 - 7.45 (m, 4H), 7.28 (d, J = 7.35 Hz, 2H), 6.97 (s, 1H). 13 C NMR (75 MHz, DMSO-d6) δ 151.6, 141.5, 138.3, 137.8, 135.4, 128.7, 128.6, 126.9, 125.6, 119.9, 111.4, 108.2. MS (ESI) m / z [MH] - Calculated value: 327.1; Measured value: 327.4.

[0271] 1-(4-Chlorophenyl)-3-(5-phenylthiophen-3-yl)urea (13) was prepared from 92 (0.03 g, 0.5 mmol) according to general procedure D as a white solid (0.04 g, 65%). 1 H NMR (300 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.87 (s, 1H), 7.64 (d, J = 1.32 Hz, 1H), 7.61 (s, 1H), 7.48 - 7.52 (m, 2H), 7.39 - 7.46 (m, 3H), 7.27 - 7.37 (m, 4H). 13 C NMR (75 MHz, DMSO-d6) δ 152.2, 141.3, 138.7, 137.7, 133.6, 129.1, 128.6, 127.7, 125.3, 125.0, 119.7, 117.6, 106.0. MS (ESI) m / z [M+H] + Calculated value: 329.1; Measured value: 329.2.

[0272] 1-(4-Chlorophenyl)-3-(5-phenyl-1,3-thiazol-2-yl)urea (14) was prepared from 93 (0.03 g, 0.2 mmol) according to general procedure C as a white solid (0.02 g, 34%). 1 H NMR (300 MHz, DMSO-d6) δ 10.77 (br. s., 1H), 9.14 (s, 1H), 7.80 (s, 1H), 7.52 - 7.62 (m, 4H), 7.48 (d, J = 8.85 Hz, 1H), 7.33 - 7.45 (m, 5H), 7.26 - 7.32 (m, 1H). 13 C NMR (75 MHz, DMSO-d6) δ 138.5, 137.7, 131.6, 129.1, 128.7, 128.6, 127.3, 126.3, 125.5, 125.4, 120.2, 119.8. MS (ESI) m / z [M+H] + Calculated value: 330.1; Measured value: 330.0.

[0273] trans-1-(4-chlorophenyl)-3-(2-phenylcyclopropyl)urea (15) was prepared from trans-2-phenylcyclopropane-1-carboxylic acid (0.06 g, 0.38 mmol) according to general procedure D as a white solid (0.05 g, 80%). 1 H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.44 (s, 1H), 7.41 (s, 1H), 7.23 - 7.31 (m, 4H), 7.17 (d, J = 7.16 Hz, 1H), 7.10 - 7.15 (m, 2H), 6.64 (d, J = 2.64 Hz, 1H), 2.72 (dd, J = 4.33, 7.16 Hz, 1H), 1.97 (ddd, J = 3.30, 6.36, 9.18 Hz, 1H), 1.10 - 1.21 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 155.6, 141.4, 139.3, 128.4, 128.1, 125.9, 125.5, 124.6, 119.3, 32.7, 24.5, 15.7. MS (ESI) m / z [MH] - Calculated: 285.1; Measured: 285.6.

[0274] cis-1-(4-chlorophenyl)-3-(2-phenylcyclopropyl)urea (16) was prepared from cis-2-phenylcyclopropane-1-carboxylic acid (0.06 g, 0.38 mmol) according to general procedure D as a white solid (0.06 g, 83%). 1 H NMR (300 MHz, CDCl3) δ 7.26 (s, 2H), 7.17 - 7.25 (m, 3H), 7.11 - 7.16 (m, 2H), 7.00 - 7.06 (m, 2H), 6.78 (s, 1H), 4.67 (br. s., 1H), 2.84 - 2.95 (m, 1H), 2.25 - 2.37 (m, 1H), 1.38 (td, J = 6.50, 9.23 Hz, 1H), 1.08 (dt, J = 4.33, 6.40 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 155.1, 135.9, 134.6, 134.6, 127.8, 127.4, 127.3, 125.7, 120.3, 27.8, 21.5, 11.8. MS (ESI) m / z [M+H] + Calculated: 287.1; Measured: 287.2.

[0275] 3-(4-Chlorophenyl)-1-[(3R)-1-phenylpiperidin-3-yl]urea (17) was prepared from 95 (0.05 g, 0.32 mmol) according to general procedure C as a white solid (0.03 g, 32%). 1 H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.37 - 7.44 (m, 2H), 7.23 - 7.29 (m, 2H), 7.17 - 7.22 (m, 2H), 6.95 (d, J = 7.91 Hz, 2H), 6.76 (t, J = 7.16 Hz, 1H), 6.35 (d, J = 7.72 Hz, 1H), 3.77 (dd, J = 3.67, 7.82 Hz, 1H), 3.41 - 3.49 (m, 1H), 3.25 (br. s., 1H), 2.94 - 3.06 (m, 1H), 2.84 (dd, J = 7.82, 11.96 Hz, 1H), 1.70 - 1.86 (m, 2H), 1.57 - 1.67 (m, 1H), 1.41 - 1.53 (m, 1H). 13 C NMR (75 MHz, DMSO-d6) δ 154.4, 151.2, 139.4, 128.9, 128.4, 124.4, 119.0, 118.7, 116.0, 54.4, 48.9, 45.1, 29.7, 22.6. MS (ESI) m / z [M+H] + Calculated value: 329.1; Measured value: 329.2.

[0276] 1-(4-chlorophenyl)-3-[5-(4-fluorophenyl)thiophen-2-yl]urea (18) was prepared from 114 (0.01 g, 0.04 mmol) according to general procedure C as a white solid (0.01 g, 71%). 1 H NMR (300 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.98 (s, 1H), 7.58 (dd, J = 5.46, 8.85 Hz, 2H), 7.50 (d, J = 8.85 Hz, 2H), 7.34 (d, J = 8.85 Hz, 2H), 7.15 - 7.25 (m, 3H), 6.57 (d, J = 3.96 Hz, 1H). 13 C NMR (75 MHz, DMSO-d6) δ 151.4, 140.6, 138.3, 131.4, 128.6, 126.3, 126.1, 125.7, 120.9, 120.0, 116.0, 115.7, 110.6. MS (ESI) m / z [MH] - Calculated: 345.1; Measured: 345.1.

[0277] 1-(4-Chlorophenyl)-3-[5-(3-fluorophenyl)thiophen-2-yl]urea (19) was prepared from 115 (0.07 g, 0.37 mmol) according to general procedure C as a white solid (0.g, %). 1 H NMR (300 MHz, DMSO-d6) δ 9.91 (br. s., 1H), 8.99 (br. s., 1H), 7.51 (d, J = 7.91 Hz, 2H), 7.35 (d, J = 8.85 Hz, 6H), 6.95 - 7.12 (m, 1H), 6.49 - 6.69 (m, 1H). 13 C NMR (75 MHz, DMSO-d6) δ 164.3, 161.1, 151.4, 141.4, 138.2, 136.9, 130.9, 128.6, 125.8, 122.2, 120.3, 120.3, 120.0, 112.8, 110.7. MS (ESI) m / z [MH] - Calculated: 345.1; Measured: 345.2.

[0278] 1-(4-Chlorophenyl)-3-[5-(2,4-difluorophenyl)thiophen-2-yl]urea (20) was prepared from 116 (0.03 g, 0.14 mmol) according to general procedure C as a white solid (0.04 g, 72%). 1 H NMR (300 MHz, DMSO-d6) δ 9.92 (s, 9H), 9.01 (s, 9H), 7.66 - 7.78 (m, 9H), 7.51 (d, J = 8.85 Hz, 18H), 7.21 - 7.41 (m, 37H), 7.07 - 7.18 (m, 9H), 6.62 (d, J = 3.96 Hz, 9H). 13 C NMR (75 MHz, DMSO-d6) δ 151.4, 141.9, 138.2, 128.7, 128.6, 125.8, 124.6, 123.7, 120.0, 118.8, 112.3, 112.0, 109.9, 104.6, 96.3. MS (ESI) m / z [MH] - Calculated value: 363.1; Measured value: 363.3.

[0279] 1-(4-chlorophenyl)-3-[5-(2-chlorophenyl)thiophen-2-yl]urea (21) was prepared from 117 (0.03 g, 0.18 mmol) according to general procedure C as a white solid (0.01 g, 13%). 1 H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.99 (s, 1H), 7.59 (dd, J = 1.51, 7.72 Hz, 1H), 7.48 - 7.55 (m, 3H), 7.25 - 7.41 (m, 4H), 7.21 (d, J = 3.96 Hz, 1H), 6.62 (d, J = 3.96 Hz, 1H). 13C NMR (75 MHz, DMSO-d6) δ 151.4, 142.3, 138.2, 132.9, 130.5, 130.5, 130.3, 128.6, 128.5, 128.2, 127.6, 125.8, 125.3, 120.0, 109.7. MS (ESI) m / z [MH] - Calculated: 361.1; Measured: 361.0.

[0280] 1-(4-chlorophenyl)-3-[5-(3-chlorophenyl)thiophen-2-yl]urea (22) was prepared from 118 (0.02 g, 0.08 mmol) according to general procedure C as a white solid (0.01 g, 64%). 1 H NMR (300 MHz, DMSO-d6) δ 9.94 (br. s., 1H), 9.02 (br. s., 1H), 7.61 (d, J = 1.70 Hz, 1H), 7.47 - 7.57 (m, 3H), 7.30 - 7.43 (m, 4H), 7.21 - 7.29 (m, 1H), 6.59 (d, J = 3.96 Hz, 1H). 13 C NMR (75 MHz, DMSO-d6) δ 150.4, 140.5, 137.2, 135.6, 132.8, 129.8, 129.5, 127.6, 124.9, 124.8, 122.6, 121.8, 121.3, 119.0, 109.6. MS (ESI) m / z [MH] - Calculated: 361.1; Measured: 361.3.

[0281] 1-(4-chlorophenyl)-3-[5-(4-chlorophenyl)thiophen-2-yl]urea (23) was prepared from 119 (0.02 g, 0.12 mmol) according to general procedure C as a white solid (0.03 g, 60%). 1H NMR (300 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.98 (s, 1H), 7.54 (dd, J = 8.57, 18.37 Hz, 4H), 7.37 (dd, J = 8.57, 17.80 Hz, 4H), 7.26 (d, J = 3.77 Hz, 1H), 6.58 (d, J = 3.77 Hz, 1H). 13 C NMR (75 MHz, DMSO-d6) δ 150.4, 140.1, 137.2, 132.4, 130.0, 129.6, 127.9, 127.6, 124.8, 120.6, 119.0, 109.6. MS (ESI) m / z [MH] - Calculated: 361.1; Measured: 361.2.

[0282] 1-(4-Chlorophenyl)-3-[5-(3,4-dichlorophenyl)thiophen-2-yl]urea (24) was prepared from 120 (0.01 g, 0.03 mmol) according to general procedure C as a white solid (0.01 g, 67%). 1 H NMR (300 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.02 (s, 1H), 7.82 (d, J = 2.07 Hz, 1H), 7.57 - 7.62 (m, 1H), 7.48 - 7.54 (m, 3H), 7.39 (d, J = 3.96 Hz, 1H), 7.35 (d, J = 8.85 Hz, 2H), 6.60 (d, J = 3.96 Hz, 1H). 13 C NMR (75 MHz, DMSO-d6) δ 151.4, 142.0, 138.2, 135.3, 131.7, 131.0, 129.4, 128.6, 128.2, 125.8, 125.5, 124.2, 122.9, 120.0, 110.6. MS (ESI) m / z [MH] - Calculated: 397.1; Measured: 397.1.

[0283] 1-(4-Chlorophenyl)-3-[5-(3,5-dichlorophenyl)thiophen-2-yl]urea (25) was prepared from 121 (0.02 g, 0.06 mmol) according to general procedure C as a white solid (0.01 g, 54%). 1 H NMR (300 MHz, DMSO-d6) δ 10.01 (br. s., 1H), 9.04 (br. s., 1H), 7.55 - 7.62 (m, 2H), 7.44 - 7.54 (m, 3H), 7.30 - 7.42 (m, 3H), 6.61 (s., 1H). 13 C NMR (75 MHz, DMSO-d6) δ 150.3, 141.4, 137.0, 137.0, 133.6, 127.7, 127.6, 124.8, 124.1, 122.6, 121.3, 119.0, 109.6. MS (ESI) m / z [MH] - Calculated: 397.1; Measured: 397.2.

[0284] 3-[5-(3-acetylphenyl)thiophen-2-yl]-1-(4-chlorophenyl)urea (26) was prepared from 122 (0.06 g, 0.28 mmol) according to general procedure C as a yellow solid (0.01 g, 7%). 1 H NMR (300 MHz, DMSO-d6) δ 9.91 (br. s., 1H), 9.01 (br. s., 1H), 8.05 (s, 1H), 7.77 - 7.88 (m, 2H), 7.51 (d, J = 5.27 Hz, 3H), 7.30 - 7.42 (m, 3H), 6.56 - 6.65 (m, 1H), 2.63 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 197.8, 151.4, 141.3, 138.2, 137.5, 134.9, 131.3, 129.4, 128.7, 128.6, 126.0, 125.8, 123.4, 121.9, 120.0, 110.6, 26.8. MS (ESI) m / z [MH] - Calculated: 369.1; Measured: 369.1.

[0285] Methyl 3-(5-{[(4-chlorophenyl)carbamoyl]amino}thiophen-2-yl)benzoate (27) was prepared from 123 (0.04 g, 0.16 mmol) according to general procedure C as a white solid (0.05 g, 85%). 1 H NMR (300 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.01 (s, 1H), 8.07 (s, 1H), 7.86 (d, J = 7.91 Hz, 1H), 7.78 (d, J = 7.72 Hz, 1H), 7.46 - 7.57 (m, 3H), 7.34 (d, J = 8.85 Hz, 3H), 6.60 (d, J = 3.77 Hz, 1H), 3.88 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 166.0, 151.4, 141.3, 138.2, 135.0, 131.0, 130.4, 129.5, 128.7, 128.6, 126.7, 125.8, 124.4, 121.8, 120.0, 110.6, 52.2. MS (ESI) m / z [MH] - Calculated value: 385.1; Measured value: 385.4.

[0286] 1-(4-Chlorophenyl)-3-[5-(3-methanesulfonylphenyl)thiophen-2-yl]urea (28) was prepared from 124 (0.04 g, 0.15 mmol) according to general procedure C as a white solid (0.05 g, 75%). 1 H NMR (300 MHz, DMSO-d6) δ 9.98 (br. s., 1H), 9.03 (br. s., 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.70 - 7.79 (m, 1H), 7.59 - 7.68 (m, 1H), 7.48 - 7.57 (m, 2H), 7.40 - 7.46 (m, 1H), 7.28 - 7.39 (m, 2H), 6.63 (s, 1H), 3.29 (s, 3H). 13C NMR (75 MHz, DMSO-d6) δ 151.4, 142.0, 141.7, 138.2, 135.7, 130.2, 130.1, 128.8, 128.6, 125.9, 124.2, 122.8, 122.0, 120.0, 110.6, 43.4. MS (ESI) m / z [MH] - Calculated value: 405.1; Measured value: 405.4.

[0287] 1-(4-chlorophenyl)-3-[5-(2-methoxyphenyl)thiophen-2-yl]urea (29) was prepared from 125 (0.02 g, 0.15 mmol) according to general procedure C as a white solid (0.04 g, 78%). 1 H NMR (300 MHz, DMSO-d6) δ 9.72 (br. s., 1H), 8.93 (br. s., 1H), 7.58 - 7.68 (m, 1H), 7.46 - 7.57 (m, 2H), 7.26 - 7.39 (m, 3H), 7.15 - 7.24 (m, 1H), 7.04 - 7.13 (m, 1H), 6.92 - 7.02 (m, 1H), 6.53 - 6.63 (m, 1H), 3.89 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 154.7, 151.4, 141.4, 138.4, 128.6, 128.5, 127.3, 126.8, 125.6, 123.1, 122.7, 120.9, 119.9, 112.1, 109.7, 55.6. MS (ESI) m / z [MH] - Calculated: 357.1; Measured: 357.3.

[0288] 1-(4-chlorophenyl)-3-[5-(3-methoxyphenyl)thiophen-2-yl]urea (30) was prepared from 126 (0.04 g, 0.28 mmol) according to general procedure C as a white solid (0.06 g, 55%). 1H NMR (300 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.98 (s, 1H), 7.52 (d, J = 8.67 Hz, 2H), 7.35 (d, J = 8.85 Hz, 2H), 7.21 - 7.28 (m, 2H), 7.06 - 7.17 (m, 2H), 6.75 - 6.85 (m, 1H), 6.58 (d, J = 3.77 Hz, 1H), 3.80 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 159.7, 151.4, 140.7, 138.3, 135.8, 132.4, 130.0, 128.6, 125.8, 121.2, 120.0, 116.8, 112.1, 110.5, 109.7, 55.0. MS (ESI) m / z [MH] - Calculated: 357.1; Measured: 357.2.

[0289] 1-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)thiophen-2-yl]urea (31) was prepared from 127 (0.02 g, 0.10 mmol) according to general procedure C as a white solid (0.03 g, 86%). 1 H NMR (300 MHz, DMSO-d6) δ 9.73 (br. s., 1H), 8.93 (br. s., 1H), 7.49 (t, J = 8.95 Hz, 4H), 7.34 (d, J = 8.48 Hz, 2H), 7.07 (d, J = 3.01 Hz, 1H), 6.94 (d, J = 8.29 Hz, 2H), 6.54 (d, J = 3.01 Hz, 1H), 3.76 (s, 3H). 13 MS (ESI) m / z [MH] - Calculated: 357.1; Measured: 357.3.

[0290] 1-(4-Chlorophenyl)-3-[5-(3-methylphenyl)thiophen-2-yl]urea (32) was prepared from 128 (0.02 g, 0.12 mmol) according to general procedure C as a white solid (0.03 g, 62%). 1 H NMR (300 MHz, DMSO-d6) δ 9.81 (br. s., 1H), 8.96 (br. s., 1H), 7.46 - 7.57 (m, 2H), 7.30 - 7.43 (m, 4H), 7.17 - 7.29 (m, 2H), 6.98 - 7.07 (m, 1H), 6.51 - 6.63 (m, 1H), 2.33 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 151.4, 140.4, 138.3, 138.1, 134.4, 132.7, 128.8, 128.6, 127.1, 125.7, 124.9, 121.5, 120.7, 119.9, 110.6, 21.0. MS (ESI) m / z [MH] - Calculated: 341.1; Measured: 341.4.

[0291] 1-(4-Chlorophenyl)-3-{5-[3-(dimethylamino)phenyl]thiophen-2-yl}urea (33) was prepared from 129 (0.06 g, 0.26 mmol) according to general procedure C as a white solid (0.06 g, 58%). 1 H NMR (300 MHz, DMSO-d6) δ 9.79 (br. s., 1H), 8.97 (br. s., 1H), 7.47 - 7.58 (m, 2H), 7.35 (d, J = 6.59 Hz, 2H), 7.10 - 7.22 (m, 2H), 6.79 - 6.92 (m, 2H), 6.51 - 6.65 (m, 2H), 2.93 (s, 6H). 13C NMR (75 MHz, DMSO-d6) δ 151.4, 150.7, 140.1, 138.3, 135.0, 133.7, 129.4, 128.6, 125.7, 120.4, 119.9, 112.8, 110.9, 110.4, 108.1. MS (ESI) m / z [MH] - Calculated value: 370.1; Measured value: 370.2.

[0292] 1-(4-Chlorophenyl)-3-[5-(pyridin-3-yl)thiophen-2-yl]urea (34) was prepared from 130 (0.08 g, 0.05 mmol) according to general procedure C as a white solid (0.02 g, 88%). 1 H NMR (300 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.01 (s, 1H), 8.81 (d, J = 2.07 Hz, 1H), 8.40 (dd, J = 1.32, 4.71 Hz, 1H), 7.93 (td, J = 1.81, 8.05 Hz, 1H), 7.51 (d, J = 9.04 Hz, 2H), 7.33 - 7.41 (m, 4H), 6.62 (d, J = 3.96 Hz, 1H). 13 MS (ESI) m / z [MH] - Calculated value: 328.1; Measured value: 328.4.

[0293] 1-(4-Chlorophenyl)-3-[5-(pyridin-4-yl)thiophen-2-yl]urea (35) was prepared from 131 (0.004 g, 0.03 mmol) according to general procedure C as a yellow solid (0.007 g, 75%). 1H NMR (300 MHz, DMSO-d6) δ 10.07 (br. s., 1H), 9.05 (br. s., 1H), 8.42 - 8.53 (m, 2H), 7.43 - 7.61 (m, 5H), 7.36 (d, J = 7.91 Hz, 2H), 6.62 - 6.68 (m, 1H). 13 C NMR (75 MHz, DMSO-d6) δ 150.0, 143.2, 141.4, 138.1, 128.9, 128.6, 125.9, 124.3, 120.1, 119.8, 118.3, 110.7. MS (ESI) m / z [MH] - Calculated value: 328.1; Measured value: 328.4.

[0294] 2-Methyl-2-phenylpropan-1-amine hydrochloride (133) To a solution of 2-methyl-2-phenylpropanenitrile (0.15 ml, 1 mmol) in anhydrous THF (4 ml) was added BH3.Me2S (0.5 ml, 1 mmol) dropwise at 0 °C. The reaction mixture was allowed to warm to room temperature and then refluxed for 16 h. Upon cooling to room temperature, the reaction was quenched by slow addition of methanol, and the mixture was concentrated in vacuo. This quenching was repeated two more times. The crude product was dissolved in a minimum amount of diethyl ether and treated with 2 N ethereal HCl. The white solid precipitate was filtered and washed with ice-cold diethyl ether to give the pure product (0.17 g, 92%). 1 H NMR (300 MHz, CD3OD) δ 7.37 - 7.48 (m, 4H), 7.26 - 7.32 (m, 1H), 3.18 (s, 2H), 1.44 (s, 6H). MS (ESI) m / z [M+H] + Calculated value: 150.1; Measured value: 150.2.

[0295] 2,2-Difluoro-2-phenylethan-1-amine hydrochloride (134) was prepared from 2,2-difluoro-2-phenylacetamide (0.17 g, 1 mmol) according to the same procedure as 14014-151 to give the desired product as a yellow solid (0.11 g, 58%). 1H NMR (300 MHz, CD3OD) δ 7.39 - 7.76 (m, 5H), 3.70 (d, J = 15.64 Hz, 2H). MS (ESI) m / z [M+H] + Calculated: 158.1; Measured: 158.2.

[0296] Methyl 2,2-dimethyl-3-phenylpropanoate (138). To a solution of 2 M LDA in THF (1.2 mL, 1.2 mmol) at −78° C., methyl isobutyrate (0.11 mmol, 1 mmol) was added dropwise. After 1 h, a solution of benzyl bromide (0.12 mL, 1.2 mL) in THF (0.5 mL) was added dropwise. The reaction was stirred at −78° C. for 1.5 h and slowly warmed to room temperature. The reaction was then quenched with saturated NH4Cl and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give the crude product as an orange liquid (2.0 g, quantitative). 1 H NMR (300 MHz, CDCl3) δ 7.31 - 7.35 (m, 1H), 7.20 - 7.25 (m, 2H), 7.07 - 7.13 (m, 2H), 3.66 (s, 3H), 2.85 (s, 2H), 1.18 (s, 6H).

[0297] 2,2-Dimethyl-3-phenylpropanoic acid (139). To a solution of methyl 2,2-dimethyl-3-phenylpropanoate (2.0 g, 10 mmol) in methanol (20 ml) was added a solution of lithium hydroxide (1.20 g) in water (20 ml) at room temperature. The reaction mixture was stirred for 3 hours, after which the reaction volume was reduced by evaporation in vacuo. The reaction mixture was then diluted with ethyl acetate and adjusted to pH 3 with 4 N HCl. The phases were separated, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give the crude product as a white solid (1.8 g, quantitative). 1H NMR (300 MHz, CDCl3) δ 7.23 - 7.29 (m, 3H), 7.14 - 7.19 (m, 2H), 2.89 (s, 2H), 1.21 (s, 6H). MS (ESI) m / z [MH] - Calculated: 177.1; Measured: 177.2.

[0298] trans-2-Phenylcyclopropane-1-carboxamide (132). To a solution of trans-2-phenylcyclopropane-1-carboxylic acid (0.16 g, 1 mmol) in anhydrous dichloromethane (5 mL) was added oxalyl chloride (0.1 mL, 1.21 mmol) and 2–3 drops of DMF. The reaction was stirred at room temperature for 3 h, after which the solvent was evaporated in vacuo. The residue was then diluted in anhydrous acetonitrile (5 mL) and treated with concentrated aqueous ammonium hydroxide 25% (0.5 mL). The reaction was stirred at room temperature for 16 h, after which it was diluted with ethyl acetate. The phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give the product as a white solid (0.17 g, quantitative). 1 H NMR (300 MHz, CDCl3) δ 7.27 - 7.33 (m, 2H), 7.19 - 7.24 (m, 1H), 7.08 - 7.13 (m, 2H), 5.29 - 5.69 (m, 2H), 2.48 - 2.56 (m, 1H), 1.60 - 1.71 (m, 2H), 1.27 - 1.36 (m, 1H). MS (ESI) m / z [M+H] + Calculated: 162.1; Measured: 162.2.

[0299] trans-(2-Phenylcyclopropyl)methanamine hydrochloride (135) was prepared from 132 (0.17 g, 1 mmol) following the same procedure as for 14014-151 to give the desired product as a yellow solid (0.14 g, 78%). 1H NMR (300 MHz, CD3OD) δ 7.06 - 7.44 (m, 5H), 3.54 - 3.62 (m, 2H), 2.95 - 3.05 (m, 1H), 1.55 - 1.64 (m, 2H), 1.03 - 1.14 (m, 1H). MS (ESI) m / z [M+H] + Calculated: 148.1; Measured: 148.2.

[0300] 2-(2,4,6-Trifluorophenyl)ethan-1-amine (136). To a solution of LiAlH in THF at 0 °C, anhydrous AlCl was added. After 5 min, 2,4,6-trifluorobenzonitrile (0.13 ml, 1 mmol) was added dropwise slowly. After stirring at room temperature for 1 h, the remaining LiAlH was carefully quenched with water and then with 1.6 ml of 6 N HSO. The pH of the solution was adjusted to 11 with KOH pellets and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous MgSO, filtered, and concentrated in vacuo. The crude product (0.16 g, 90%) as a yellow liquid was used in the next step without further purification. 1 H NMR (300 MHz, CDCl3) δ 6.59 - 6.69 (m, 3H), 2.87 - 2.95 (m, 2H), 2.71 - 2.80 (m, 2H). MS (ESI) m / z [M+H] + Calculated: 176.1; Measured: 176.5.

[0301] 2-(2,3,4,5,6-Pentafluorophenyl)ethan-1-amine (137) was prepared from 2,3,4,5,6-pentafluorobenzonitrile (0.12 ml, 1 mmol) according to the same procedure as 14014-165 to give the desired product as a yellow liquid (0.17 g, 81%). 1 H NMR (300 MHz, CDCl3) δ 3.53 - 3.86 (m, 1H), 2.77 - 3.08 (m, 1H), 1.57 - 2.17 (m, 2H). MS (ESI) m / z [M+H] + Calculated: 212.1; Measured: 212.1.

[0302] 1-Benzyl-3-(4-chlorophenyl)urea (36) was prepared from benzylamine (0.05 g, 0.32 mmol) according to general procedure C as a white solid (0.06 g, 71%). 1 H NMR (300 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.44 (d, J = 8.85 Hz, 2H), 7.20 - 7.37 (m, 7H), 6.66 (t, J = 5.75 Hz, 1H), 4.30 (d, J = 6.03 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 155.0, 140.2, 139.4, 128.4, 128.3, 127.1, 126.7, 124.5, 119.2, 42.7. MS (ESI) m / z [M+H] + Calculated: 261.1; Measured: 261.3.

[0303] 3-(4-Chlorophenyl)-1-(3-phenylpropyl)urea (37) was prepared from 3-phenylpropylamine (0.05 ml, 0.32 mmol) according to general procedure C as a white solid (0.08 g, 82%). 1 H NMR (300 MHz, CDCl3) δ 7.17 - 7.31 (m, 7H), 7.09 (d, J = 6.78 Hz, 2H), 5.42 (t, J = 5.37 Hz, 1H), 3.18 (q, J = 6.78 Hz, 2H), 2.57 (t, J = 7.63 Hz, 2H), 1.70 - 1.78 (m, 2H). 13 C NMR (75 MHz, CHCl3) δ 156.1, 141.3, 137.4, 129.1, 128.5, 128.4, 128.3, 126.0, 121.5, 39.9, 33.1, 31.6. MS (ESI) m / z [M+H] + Calculated: 289.1; Measured: 289.3.

[0304] 3-(4-Chlorophenyl)-1-(2-phenylethyl)urea (44) was prepared from phenethylamine (0.04 ml, 0.32 mmol) according to general procedure C as a white solid (0.06 g, 63%). 1 H NMR (300 MHz, CDCl3) δ 7.29 - 7.35 (m, 2H), 7.15 - 7.25 (m, 7H), 6.12 (br. s., 1H), 4.58 (br. s., 1H), 3.53 (q, J = 6.59 Hz, 2H), 2.85 (t, J = 6.69 Hz, 2H). 13 C NMR (75 MHz, CHCl3) δ 155.1, 138.9, 137.0, 129.2, 128.9, 128.8, 128.7, 126.6, 122.0, 41.5, 36.0. MS (ESI) m / z [M+H] + Calculated: 275.1; Measured: 275.2.

[0305] 1-[2-(4-tert-butylphenyl)ethyl]-3-(4-chlorophenyl)urea (45) was prepared from 4-tert-butylphenethylamine (0.05 g, 0.32 mmol) according to general procedure C as a white solid (0.03 g, 29%). 1 H NMR (300 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.41 (d, J = 8.85 Hz, 2H), 7.33 (d, J = 8.29 Hz, 2H), 7.25 (d, J = 8.85 Hz, 2H), 7.16 (d, J = 8.10 Hz, 2H), 6.15 (t, J = 5.46 Hz, 1H), 3.27 - 3.32 (m, 2H), 2.70 (t, J = 7.16 Hz, 2H), 1.27 (s, 9H). 13 MS (ESI) m / z [M+H] +Calculated value: 331.1; Measured value: 331.2.

[0306] 3-(4-Chlorophenyl)-1-[2-(4-phenylphenyl)ethyl]urea (46) was prepared from 4-phenylphenethylamine (0.05 g, 0.32 mmol) according to general procedure C as a white solid (0.09 g, 76%). 1 H NMR (300 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.63 (dd, J = 8.10, 10.55 Hz, 4H), 7.31 - 7.50 (m, 7H), 7.25 (d, J = 8.85 Hz, 2H), 6.19 (t, J = 5.56 Hz, 1H), 3.36 - 3.42 (m, 2H), 2.80 (t, J = 6.97 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 155.0, 140.0, 139.5, 138.8, 138.0, 129.2, 128.9, 128.4, 127.2, 126.6, 126.5, 124.4, 119.0, 35.3, 30.6. MS (ESI) m / z [M+H] + Calculated value: 351.1; Measured value: 351.2.

[0307] 3-(4-Chlorophenyl)-1-[2-(4-chlorophenyl)ethyl]urea (47) was prepared from 4-chlorophenethylamine (0.05 g, 0.32 mmol) according to general procedure C as a white solid (0.07 g, 66%). 1 H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.38 (dd, J = 8.57, 11.59 Hz, 4H), 7.22 - 7.29 (m, 4H), 6.14 (t, J = 5.56 Hz, 1H), 3.28 - 3.33 (m, 2H), 2.74 (t, J = 6.97 Hz, 2H). 13C NMR (75 MHz, DMSO-d6) δ 154.9, 139.5, 138.5, 130.7, 130.5, 128.4, 128.2, 124.4, 119.0, 35.0. MS (ESI) m / z [M+H] + Calculated: 309.1; Measured: 309.1.

[0308] 3-(4-Chlorophenyl)-1-[2-(4-nitrophenyl)ethyl]urea (48) was prepared from 4-nitrophenethylamine hydrochloride (0.07 g, 0.32 mmol) according to general procedure C as a white solid (0.06 g, 54%). 1 H NMR (300 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.18 (d, J = 8.67 Hz, 2H), 7.53 (d, J = 8.67 Hz, 2H), 7.40 (d, J = 9.04 Hz, 2H), 7.25 (d, J = 9.04 Hz, 2H), 6.22 (t, J = 5.75 Hz, 1H), 3.37 - 3.43 (m, 2H), 2.90 (t, J = 6.88 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 154.9, 148.0, 146.1, 139.4, 130.0, 128.4, 124.4, 123.4, 119.1, 35.5, 30.6. MS (ESI) m / z [M+H] + Calculated value: 320.1; Measured value: 320.2.

[0309] 3-(4-Chlorophenyl)-1-[2-(4-hydroxy-3-methoxyphenyl)ethyl]urea (49) was prepared from 4-hydroxy-3-methoxyphenethylamine (0.07 g, 0.32 mmol) according to general procedure C as a white solid (0.03 g, 27%). 1H NMR (300 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.63 (s, 1H), 7.41 (d, J = 8.85 Hz, 2H), 7.25 (d, J = 8.67 Hz, 2H), 6.77 (s, 1H), 6.67 - 6.72 (m, 1H), 6.58 - 6.64 (m, 1H), 6.08 (t, J = 5.46 Hz, 1H), 3.75 (s, 3H), 3.24 - 3.30 (m, 2H), 2.63 (t, J = 6.97 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 154.9, 147.4, 144.8, 139.5, 130.1, 128.4, 124.3, 120.7, 119.0, 115.4, 112.8, 55.5, 35.3. MS (ESI) m / z [MH] - Calculated value: 319.1; Measured value: 319.4.

[0310] 3-(4-Chlorophenyl)-1-{2-[3-(dimethylamino)phenyl]ethyl}urea (50) was prepared from 3-dimethylaminophenethylamine (0.07 g, 0.33 mmol) according to general procedure C as a white solid (0.05 g, 50%). 1 H NMR (300 MHz, CDCl3) δ 7.13 - 7.24 (m, 5H), 6.59 - 6.64 (m, 1H), 6.53 - 6.58 (m, 2H), 6.14 (s, 1H), 4.60 - 4.67 (m, 1H), 3.53 (q, J = 6.53 Hz, 2H), 2.93 (s, 6H), 2.80 (t, J = 6.69 Hz, 2H). 13 C NMR (75 MHz, CHCl3) δ 155.2, 151.0, 139.7, 137.2, 129.5, 129.2, 128.8, 122.0, 116.9, 113.0, 110.9, 41.6, 40.6, 36.4. MS (ESI) m / z [M+H] + Calculated value: 318.1; Measured value: 318.2.

[0311] 3-(4-Chlorophenyl)-1-{2-[4-(dimethylamino)phenyl]ethyl}urea (51) was prepared from 4-dimethylaminophenethylamine (0.03 g, 0.18 mmol) according to general procedure C as a white solid (0.01 g, 17%). 1 H NMR (300 MHz, DMSO-d6) δ 8.63 - 8.71 (m, 1H), 7.41 (d, J = 9.04 Hz, 2H), 7.24 (d, J = 8.85 Hz, 2H), 7.04 (d, J = 8.67 Hz, 2H), 6.68 (d, J = 8.67 Hz, 2H), 6.08 - 6.16 (m, 1H), 3.26 (d, J = 6.22 Hz, 2H), 2.85 (s, 6H), 2.61 (t, J = 7.16 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 154.9, 149.1, 139.5, 129.0, 128.4, 126.9, 124.3, 119.0, 112.7, 40.9, 40.3, 34.8. MS (ESI) m / z [M+H] + Calculated value: 318.1; Measured value: 318.2.

[0312] 3-(4-Chlorophenyl)-1-[2-(4-methanesulfonylphenyl)ethyl]urea (52) was prepared from 2-(4-methylsulfonyl-phenyl)ethylamine hydrochloride (0.08 g, 0.32 mmol) according to general procedure C as a white solid (0.04 g, 35%). 1 H NMR (300 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.87 (d, J = 8.29 Hz, 2H), 7.52 (d, J = 8.29 Hz, 2H), 7.41 (d, J = 8.85 Hz, 2H), 7.25 (d, J = 8.85 Hz, 2H), 6.21 (t, J = 5.56 Hz, 1H), 3.36 - 3.43 (m, 2H), 3.20 (s, 3H), 2.87 (t, J = 6.88 Hz, 2H). 13C NMR (75 MHz, DMSO-d6) δ 155.0, 145.8, 139.4, 138.7, 129.6, 128.4, 127.0, 124.4, 119.1, 43.6, 35.5, 30.6. MS (ESI) m / z [M+H] + Calculated value: 353.1; Measured value: 353.2.

[0313] 3-(4-Chlorophenyl)-1-[2-(2-methoxyphenyl)ethyl]urea (53) was prepared from 2-methoxyphenethylamine (0.05 ml, 0.32 mmol) according to general procedure C as a white solid (0.05 g, 46%). 1 H NMR (300 MHz, DMSO-d6) δ 8.58 (br. s., 1H), 7.41 (d, J = 8.67 Hz, 2H), 7.25 (d, J = 8.48 Hz, 2H), 7.11 - 7.22 (m, 2H), 6.97 (d, J = 7.54 Hz, 1H), 6.89 (t, J = 7.16 Hz, 1H), 6.12 (br. s., 1H), 3.78 (s, 3H), 3.29 (d, J = 5.65 Hz, 2H), 2.68 - 2.77 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 157.3, 154.9, 139.5, 130.0, 128.4, 127.5, 127.2, 124.3, 120.2, 119.0, 110.7, 55.3, 30.3. MS (ESI) m / z [M+H] + Calculated value: 305.1; Measured value: 305.4.

[0314] 3-(4-Chlorophenyl)-1-[2-(3-methoxyphenyl)ethyl]urea (54) was prepared from 3-methoxyphenethylamine (0.05 ml, 0.32 mmol) according to general procedure C as a white solid (0.05 g, 47%). 1H NMR (300 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.41 (d, J = 8.85 Hz, 2H), 7.23 - 7.29 (m, 2H), 7.19 - 7.23 (m, 1H), 6.75 - 6.84 (m, 3H), 6.13 (t, J = 5.65 Hz, 1H), 3.74 (s, 3H), 3.29 - 3.34 (m, 2H), 2.72 (t, J = 7.06 Hz, 2H). 13 C NMR (75MHz, DMSO-d6) δ 159.3, 154.9, 141.0, 139.5, 129.3, 128.4, 124.4, 120.9, 119.0, 114.2, 111.5, 54.9, 40.4, 35.7. (ESI) m / z [M+H] + Calculated value: 305.1; Measured value: 305.4.

[0315] 3-(4-Chlorophenyl)-1-[2-(3-methoxyphenyl)ethyl]urea (55) was prepared from 4-methoxyphenethylamine (0.05 ml, 0.32 mmol) according to general procedure C as a white solid (0.07 g, 66%). 1 H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.41 (d, J = 9.04 Hz, 2H), 7.25 (d, J = 8.85 Hz, 2H), 7.15 (d, J = 8.48 Hz, 2H), 6.87 (d, J = 8.48 Hz, 2H), 6.11 (t, J = 5.56 Hz, 1H), 3.72 (s, 3H), 3.24 - 3.31 (m, 2H), 2.67 (t, J = 7.06 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 157.7, 154.9, 139.5, 131.3, 129.6, 128.4, 124.3, 119.0, 113.8, 55.0, 34.8. MS (ESI) m / z [M+H] + Calculated value: 305.1; Measured value: 305.4.

[0316] 3-(4-Chlorophenyl)-1-[2-(3,4-dimethoxyphenyl)ethyl]urea (56) was prepared from 3,4-dimethoxyphenethylamine (0.05 ml, 0.32 mmol) according to general procedure C as a white solid (0.04 g, 38%). 1 H NMR (300 MHz, CDCl3) δ 7.16 - 7.24 (m, 4H), 6.75 - 6.81 (m, 1H), 6.67 - 6.74 (m, 2H), 6.52 (s, 1H), 4.83 (t, J = 5.18 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.49 (q, J = 6.66 Hz, 2H), 2.77 (t, J = 6.69 Hz, 2H). 13 MS (ESI) m / z [M+H] + Calculated value: 335.1; Measured value: 335.3.

[0317] 3-(4-Chlorophenyl)-1-[2-(3,5-dimethoxyphenyl)ethyl]urea (57) was prepared from 3,5-dimethoxyphenethylamine (0.06 ml, 0.32 mmol) according to general procedure C as a white solid (0.08 g, 70%). 1 H NMR (300 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.41 (d, J = 8.67 Hz, 2H), 7.25 (d, J = 8.67 Hz, 2H), 6.40 (s, 2H), 6.35 (br. s., 1H), 6.11 (t, J = 5.09 Hz, 1H), 3.72 (s, 6H), 3.31 - 3.36 (m, 2H), 2.68 (t, J = 6.78 Hz, 2H). 13C NMR (75 MHz, DMSO-d6) δ 160.4, 154.9, 141.8, 139.5, 128.4, 124.4, 119.0, 106.6, 98.0, 55.0, 36.0. MS (ESI) m / z [M+H] + Calculated value: 335.1; Measured value: 335.3.

[0318] 3-(4-Chlorophenyl)-1-[2-(4-hydroxyphenyl)ethyl]urea (58) was prepared from 4-hydroxyphenethylamine (0.04 g, 0.32 mmol) according to general procedure C as a white solid (0.07 g, 78%). 1 H NMR (300 MHz, DMSO-d6) δ 9.19 (br. s., 1H), 8.62 (s, 1H), 7.41 (d, J = 8.67 Hz, 2H), 7.25 (d, J = 8.85 Hz, 2H), 7.02 (d, J = 8.29 Hz, 2H), 6.69 (d, J = 8.29 Hz, 2H), 6.10 (t, J = 5.46 Hz, 1H), 3.26 (q, J = 6.66 Hz, 2H), 2.62 (t, J = 7.16 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 155.6, 154.9, 139.5, 129.5, 128.4, 124.3, 119.0, 115.1, 34.9. MS (ESI) m / z [MH] - Calculated: 289.1; Measured: 289.2.

[0319] 3-(4-Chlorophenyl)-1-[2-(4-methylphenyl)ethyl]urea (59) was prepared from 4-methylphenethylamine (0.05 ml, 0.32 mmol) according to general procedure C as a white solid (0.03 g, 32%). 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.41 (d, J = 8.85 Hz, 2H), 7.25 (d, J = 8.85 Hz, 2H), 7.08 - 7.15 (m, 4H), 6.11 (t, J = 5.46 Hz, 1H), 3.26 - 3.32 (m, 2H), 2.69 (t, J = 7.16 Hz, 2H), 2.27 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 154.9, 139.5, 136.3, 135.0, 128.9, 128.5, 128.4, 124.3, 119.0, 35.3, 20.6. MS (ESI) m / z [M+H] + Calculated: 289.1; Measured: 289.2.

[0320] 3-(4-Chlorophenyl)-1-[2-(3-methylphenyl)ethyl]urea (60) was prepared from 3-methylphenethylamine (0.05 g, 0.32 mmol) according to general procedure C as a white solid (0.03 g, 62%). 1 H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.41 (d, J = 8.85 Hz, 2H), 7.25 (d, J = 8.85 Hz, 2H), 7.16 - 7.22 (m, 1H), 7.04 (d, J = 3.96 Hz, 2H), 7.01 (s, 1H), 6.14 (t, J = 5.65 Hz, 1H), 3.27 - 3.33 (m, 2H), 2.70 (t, J = 7.16 Hz, 2H), 2.29 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 154.9, 139.5, 139.3, 137.3, 129.3, 128.4, 128.2, 126.7, 125.6, 124.4, 119.0, 35.7, 21.0. MS (ESI) m / z [M+H] + Calculated: 289.1; Measured: 289.1.

[0321] 3-(4-Chlorophenyl)-1-[2-(2-fluorophenyl)ethyl]urea (61) was prepared from 2-fluorophenethylamine (0.04 ml, 0.32 mmol) according to general procedure C as a white solid (0.02 g, 21%). 1 H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.41 (d, J = 8.67 Hz, 2H), 7.21 - 7.35 (m, 4H), 7.11 - 7.20 (m, 2H), 6.22 (t, J = 5.27 Hz, 1H), 3.26 - 3.33 (m, 2H), 2.79 (t, J = 7.06 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 154.9, 139.4, 137.8, 132.5, 131.6, 128.4, 126.7, 125.8, 125.7, 124.5, 119.1, 32.6. MS (ESI) m / z [M+H] + Calculated: 293.1; Measured: 293.3.

[0322] 3-(4-Chlorophenyl)-1-[2-(3-fluorophenyl)ethyl]urea (62) was prepared from 3-fluorophenethylamine (0.04 ml, 0.32 mmol) according to general procedure C as a white solid (0.02 g, 17%). 1 H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.38 - 7.44 (m, 2H), 7.30 - 7.37 (m, 1H), 7.25 (d, J = 9.04 Hz, 2H), 7.08 (d, J = 8.67 Hz, 2H), 6.99 - 7.05 (m, 1H), 6.17 (t, J = 5.65 Hz, 1H), 3.32 - 3.40 (m, 2H), 2.77 (t, J = 7.06 Hz, 2H). 13C NMR (75 MHz, DMSO-d6) δ 154.9, 142.5, 142.4, 139.5, 130.2, 130.1, 128.4, 124.8, 124.8, 124.4, 119.1, 115.5, 115.2, 112.9, 112.7, 35.3. MS (ESI) m / z [MH] - Calculated: 291.1; Measured: 291.1.

[0323] 3-(4-Chlorophenyl)-1-[2-(4-fluorophenyl)ethyl]urea (63) was prepared from 4-fluorophenethylamine (0.04 ml, 0.32 mmol) according to general procedure C as a white solid (0.05 g, 48%). 1 H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.41 (d, J = 8.85 Hz, 2H), 7.21 - 7.31 (m, 4H), 7.09 - 7.17 (m, 2H), 6.15 (t, J = 5.56 Hz, 1H), 3.27 - 3.33 (m, 2H), 2.74 (t, J = 7.06 Hz, 2H). 13 MS (ESI) m / z [MH] - Calculated: 291.1; Measured: 291.0.

[0324] 3-(4-Chlorophenyl)-1-[2-(3,4-difluorophenyl)ethyl]urea (64) was prepared from 3,4-difluorophenethylamine (0.18 g, 1 mmol) according to general procedure C as a white solid (0.05 g, 50%). 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.38 - 7.43 (m, 2H), 7.28 - 7.38 (m, 2H), 7.22 - 7.27 (m, 2H), 7.08 (ddd, J = 2.26, 4.10, 6.26 Hz, 1H), 6.16 (t, J = 5.65 Hz, 1H), 3.28 - 3.34 (m, 2H), 2.74 (t, J = 6.97 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 154.9, 139.4, 137.4, 128.4, 125.5, 125.4, 124.4, 119.1, 117.6, 117.4, 117.2, 117.0, 34.7. MS (ESI) m / z [MH] - Calculated: 291.1; Measured: 291.1.

[0325] 3-(4-Chlorophenyl)-1-[2-(2,4,6-trifluorophenyl)ethyl]urea (65) was prepared from 136 (0.11 g, 0.6 mmol) according to general procedure C as a white solid (0.11 g, 54%). 1 H NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.45 (d, J = 8.85 Hz, 2H), 7.30 (d, J = 8.85 Hz, 2H), 7.17 - 7.25 (m, 2H), 6.32 (t, J = 5.93 Hz, 1H), 3.33 (q, J = 6.59 Hz, 2H), 2.82 (t, J = 6.69 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 162.6, 159.3, 154.9, 139.4, 128.6, 128.4, 124.4, 119.8, 119.1, 111.2, 100.3, 30.6, 22.7. MS (ESI) m / z [M+H] + Calculated value: 329.1; Measured value: 329.2.

[0326] 3-(4-Chlorophenyl)-1-[2-(2,3,4,5,6-pentafluorophenyl)ethyl]urea (66) was prepared from 137 (0.17 g, 0.78 mmol) according to general procedure C as a white solid (0.07 g, 23%). 1 H NMR (300 MHz, CDCl3) d 7.50 (s, 1H), 7.24 - 7.27 (m, 2H), 7.18 - 7.23 (m, 2H), 5.53 (t, J = 5.65 Hz, 1H), 3.46 (q, J = 6.59 Hz, 2H), 2.93 (t, J = 6.69 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 155.0, 146.6, 143.5, 143.3, 143.2, 140.5, 139.3, 138.4, 137.2, 137.0, 135.3, 135.1, 128.6, 128.4, 124.6, 119.6, 119.2, 113.4, 113.2, 113.1, 112.9, 38.2, 23.2. MS (ESI) m / z [M+H] + Calculated value: 365.1; Measured value: 365.5.

[0327] 3-(4-Chlorophenyl)-1-[2-(2-chlorophenyl)ethyl]urea (67) was prepared from 2-chlorophenethylamine (0.05 ml, 0.32 mmol) according to general procedure C as a white solid (0.07 g, 17%). 1 H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.39 - 7.46 (m, 3H), 7.30 - 7.38 (m, 2H), 7.28 (d, J = 1.70 Hz, 4H), 6.24 (t, J = 5.56 Hz, 1H), 3.34 - 3.40 (m, 2H), 2.88 (t, J = 7.06 Hz, 2H). 13C NMR (75 MHz, DMSO-d6) δ 154.9, 139.5, 136.8, 133.1, 131.0, 129.2, 128.4, 128.1, 127.2, 124.4, 119.1, 33.5. MS (ESI) m / z [M+H] + Calculated value: 309.1; Measured value: 309.3.

[0328] 3-(4-Chlorophenyl)-1-[2-(3-chlorophenyl)ethyl]urea (68) was prepared from 3-chlorophenethylamine (0.05 ml, 0.32 mmol) according to general procedure C as a white solid (0.09 g, 92%). 1 H NMR (300 MHz, CDCl3) δ 7.27 - 7.31 (m, 1H), 7.22 - 7.25 (m, 3H), 7.17 - 7.21 (m, 3H), 7.06 - 7.11 (m, 1H), 6.11 (br. s., 1H), 4.55 (t, J = 5.46 Hz, 1H), 3.51 (q, J = 6.66 Hz, 2H), 2.83 (t, J = 6.78 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 154.9, 142.1, 139.4, 132.9, 130.1, 128.5, 128.4, 127.4, 126.1, 124.4, 119.1, 35.2. MS (ESI) m / z [M+H] + Calculated value: 309.1; Measured value: 309.0.

[0329] 3-(4-Chlorophenyl)-1-[2-(2,4-dichlorophenyl)ethyl]urea (69) was prepared from 2,4-dichlorophenethylamine (0.05 ml, 0.32 mmol) according to general procedure C as a white solid (0.02 g, 19%). 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.59 (d, J = 1.32 Hz, 1H), 7.37 - 7.43 (m, 4H), 7.25 (d, J = 9.04 Hz, 2H), 6.22 (t, J = 5.75 Hz, 1H), 3.28 - 3.34 (m, 2H), 2.86 (t, J = 6.97 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 154.9, 139.4, 136.1, 134.1, 132.3, 131.6, 128.6, 128.4, 127.3, 124.4, 119.1, 32.9. MS (ESI) m / z [MH] - Calculated: 341.1; Measured: 341.4.

[0330] 3-(4-Chlorophenyl)-1-[2-(2-chloro-6-fluorophenyl)ethyl]urea (70) was prepared from 2-chloro-6-fluorophenethylamine (0.06 g, 0.32 mmol) according to general procedure C as a white solid (0.02 g, 23%). 1 H NMR (300 MHz, DMSO-d6) δ 8.60 (br. s., 1H), 7.39 (s, 2H), 7.29 (d, J = 17.52 Hz, 5H), 6.29 (br. s., 1H), 3.29 - 3.37 (m, 2H), 2.87 - 2.99 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 154.9, 139.4, 134.5, 134.4, 129.0, 128.8, 128.4, 125.3, 125.3, 124.4, 119.1, 114.4, 114.1, 96.3, 27.0. MS (ESI) m / z [M+H] + Calculated value: 327.1; Measured value: 327.3.

[0331] 3-(4-Chlorophenyl)-1-[2-(4-bromophenyl)ethyl]urea (71) was prepared from 4-bromophenethylamine (0.08 g, 0.32 mmol) according to general procedure C as a white solid (0.06 g, 50%). 1 H NMR (300 MHz, CDCl3) δ 7.43 (d, J = 8.29 Hz, 2H), 7.18 - 7.25 (m, 4H), 7.08 (d, J = 8.29 Hz, 2H), 6.23 (s, 1H), 4.61 (br. s., 1H), 3.45 - 3.55 (m, 2H), 2.74 - 2.85 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 154.9, 139.5, 138.9, 131.1, 131.0, 128.4, 124.4, 119.1, 119.0, 35.0. MS (ESI) m / z [MH] - Calculated: 353.1; Measured: 353.1.

[0332] 3-(4-Chlorophenyl)-1-[2-(4-cyanophenyl)ethyl]urea (72) was prepared from 4-cyanophenethylamine (0.10 g, 0.64 mmol) according to general procedure C as a white solid (0.04 g, 22%). 1 H NMR (300 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.78 (d, J = 8.29 Hz, 2H), 7.45 (d, J = 8.10 Hz, 2H), 7.40 (d, J = 9.04 Hz, 2H), 7.24 (d, J = 8.85 Hz, 2H), 6.26 (t, J = 5.65 Hz, 1H), 3.35 - 3.42 (m, 2H), 2.84 (t, J = 6.97 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 154.9, 145.7, 139.4, 132.2, 129.8, 128.4, 124.4, 119.1, 118.9, 109.0, 35.8. MS (ESI) m / z [M+H] + Calculated value: 300.1; Measured value: 300.3.

[0333] 3-(4-Chlorophenyl)-1-{2-[2-(trifluoromethyl)phenyl]ethyl}urea (73) was prepared from 2-trifluoromethylphenethylamine (0.06 ml, 0.32 mmol) according to general procedure C as a white solid (0.07 g, 15%). 1 H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.70 (d, J = 7.91 Hz, 1H), 7.61 - 7.67 (m, 1H), 7.51 (d, J = 7.72 Hz, 1H), 7.44 - 7.48 (m, 1H), 7.39 - 7.43 (m, 2H), 7.25 (d, J = 9.04 Hz, 2H), 6.32 (t, J = 5.75 Hz, 1H), 3.36 - 3.43 (m, 1H), 2.93 (t, J = 7.16 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 154.9, 139.4, 137.8, 132.5, 131.6, 128.4, 126.7, 125.8, 125.7, 124.5, 119.1, 32.6. MS (ESI) m / z [M+H] + Calculated: 343.1; Measured: 343.3.

[0334] 3-(4-Chlorophenyl)-1-{2-[3-(trifluoromethyl)phenyl]ethyl}urea (74) was prepared from 3-trifluoromethylphenethylamine (0.06 ml, 0.32 mmol) according to general procedure C as a white solid (0.08 g, 76%). 1 H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.52 - 7.62 (m, 4H), 7.42 (d, J = 8.85 Hz, 2H), 7.24 (d, J = 8.85 Hz, 2H), 6.21 (t, J = 5.56 Hz, 1H), 3.34 - 3.44 (m, 2H), 2.86 (t, J = 6.97 Hz, 2H). 13MS (ESI) m / z [M+H] + Calculated: 343.1; Measured: 343.3.

[0335] 3-(4-Chlorophenyl)-1-{2-[4-(trifluoromethyl)phenyl]ethyl}urea (75) was prepared from 4-trifluoromethylphenethylamine (0.05 ml, 0.32 mmol) according to general procedure C as a white solid (0.07 g, 64%). 1 H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.67 (d, J = 7.91 Hz, 2H), 7.47 (d, J = 7.91 Hz, 2H), 7.40 (d, J = 8.85 Hz, 2H), 7.25 (d, J = 8.85 Hz, 2H), 6.18 (t, J = 5.65 Hz, 1H), 3.37 - 3.42 (m, 2H), 2.85 (t, J = 6.97 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 154.9, 144.5, 139.4, 129.5, 128.4, 125.1, 125.1, 125.0, 124.4, 119.1, 35.5. MS (ESI) m / z [M+H] + Calculated: 343.1; Measured: 343.3.

[0336] 3-(4-Chlorophenyl)-1-[2-(pyridin-4-yl)ethyl]urea (76) was prepared from 4-(2-aminoethyl)pyridine (0.04 ml, 0.32 mmol) according to general procedure C as a white solid (0.03 g, 34%). 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.48 (d, J = 5.84 Hz, 2H), 7.40 (d, J = 8.85 Hz, 2H), 7.22 - 7.30 (m, 4H), 6.19 (t, J = 5.65 Hz, 1H), 3.35 - 3.43 (m, 2H), 2.77 (t, J = 6.88 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 154.9, 149.5, 148.4, 139.4, 128.4, 124.4, 124.2, 119.1, 34.9. MS (ESI) m / z [M+H] + Calculated: 276.1; Measured: 276.1.

[0337] 3-(4-Chlorophenyl)-1-[2-(pyridin-3-yl)ethyl]urea (77) was prepared from 3-(2-aminoethyl)pyridine (0.04 g, 0.32 mmol) according to general procedure C as a white solid (0.08 g, 91%). 1 H NMR (300 MHz, CDCl3) δ 8.30 - 8.38 (m, 2H), 7.53 - 7.63 (m, 2H), 7.18 - 7.26 (m, 5H), 5.49 (t, J = 5.50 Hz, 1H), 3.52 (q, J = 5.71 Hz, 2H), 2.78 - 2.87 (m, 2H). 13 C NMR (75 MHz, CHCl3) δ 155.6, 149.8, 147.6, 137.5, 136.8, 135.0, 129.1, 128.2, 123.9, 121.0, 40.7, 33.3. MS (ESI) m / z [M+H] + Calculated: 276.1; Measured: 276.1.

[0338] 3-(4-Chlorophenyl)-1-[2-(pyridin-2-yl)ethyl]urea (78) was prepared from 2-(2-aminoethyl)pyridine (0.04 g, 0.32 mmol) according to general procedure C as a white solid (0.08 g, 84%). 1H NMR (300 MHz, CDCl3) δ 8.38 (d, J = 4.14 Hz, 1H), 7.87 (br. s., 1H), 7.55 - 7.62 (m, 1H), 7.10 - 7.24 (m, 6H), 6.15 - 6.24 (m, 1H), 3.62 (q, J = 5.84 Hz, 2H), 2.94 - 3.01 (m, 2H). 13 C NMR (75 MHz, CDCl3) δ 159.6, 156.0, 148.8, 137.8, 136.9, 129.0, 128.0, 123.6, 121.7, 121.3, 39.6, 37.6. MS (ESI) m / z [M+H] + Calculated: 276.1; Measured: 276.2.

[0339] 1-(4-Chlorophenyl)-3-[2-(5-methylfuran-2-yl)ethyl]urea (79) was prepared from 2-(5-methyl-2-furyl)ethanamine (0.04 ml, 0.32 mmol) according to general procedure C as a white solid (0.04 g, 44%). 1 H NMR (300 MHz, CDCl3) δ 7.18 - 7.25 (m, 4H), 6.34 (br. s., 1H), 5.84 - 5.96 (m, 2H), 4.90 (t, J = 5.75 Hz, 1H), 3.51 (q, J = 6.22 Hz, 2H), 2.80 (t, J = 6.40 Hz, 2H), 2.23 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 155.2, 151.2, 137.1, 129.2, 128.9, 122.1, 107.2, 106.1, 39.1, 28.6, 13.5. MS (ESI) m / z [M+H] + Calculated: 279.1; Measured: 279.1.

[0340] 3-(4-Chlorophenyl)-1-[2-(4-methylpiperazin-1-yl)ethyl]urea (80) was prepared from (4-methylpiperazin-1-yl)ethanamine (0.05 ml, 0.32 mmol) according to general procedure C as a white solid (0.04 g, 43%). 1 H NMR (300 MHz, CD3OD) δ 7.31 - 7.38 (m, 2H), 7.18 - 7.24 (m, 2H), 4.83 - 4.88 (m, 2H), 2.34 - 2.77 (m, 10H), 2.28 (s, 3H). 13 C NMR (75 MHz, CD3OD) δ 158.0, 140.0, 129.7, 128.1, 121.3, 58.6, 55.8, 53.7, 46.0, 37.8. MS (ESI) m / z [MH] - Calculated: 297.1; Measured: 297.2.

[0341] 3-(4-Chlorophenyl)-1-[2-(piperidin-1-yl)ethyl]urea (81) was prepared from 1-(2-aminoethyl)piperidine (0.05 ml, 0.32 mmol) according to general procedure C as a white solid (0.06 g, 66%). 1 H NMR (300 MHz, CDCl3) δ 8.53 (br. s., 1H), 7.24 - 7.33 (m, 2H), 7.12 - 7.22 (m, 2H), 6.13 (br. s., 1H), 3.97 - 4.12 (m, 1H), 3.26 - 3.39 (m, 2H), 2.35 - 2.60 (m, 6H), 1.53 - 1.66 (m, 4H), 1.46 (d, J = 4.71 Hz, 2H). 13 C NMR (75 MHz, CDCl3) δ 156.8, 138.1, 128.8, 127.5, 121.0, 77.5, 77.1, 76.6, 58.8, 54.5, 37.3, 25.3, 23.8. MS (ESI) m / z [M+H] + Calculated: 282.1; Measured: 282.3.

[0342] 3-(4-Chlorophenyl)-1-[2-(morpholin-4-yl)ethyl]urea (82) was prepared from 4-(2-aminoethyl)morpholine (0.04 ml, 0.32 mmol) according to general procedure C as a white solid (0.08 g, 82%). 1 H NMR (300 MHz, CDCl3) δ 7.56 (br. s., 1H), 7.19 - 7.32 (m, 4H), 5.52 - 5.64 (m, 1H), 3.62 - 3.77 (m, 4H), 3.34 (q, J = 5.46 Hz, 2H), 2.36 - 2.56 (m, 6H). 13 C NMR (75 MHz, CDCl3) δ 156.0, 137.6, 129.0, 128.3, 121.4, 66.8, 58.0, 53.5, 36.9. MS (ESI) m / z [M+H] + Calculated: 284.1; Measured: 284.5.

[0343] 1-(4-Chlorophenyl)-3-[2-(pyrrolidin-1-yl)ethyl]urea (83) was prepared from 1-(2-aminoethyl)pyrrolidine (0.04 ml, 0.32 mmol) according to general procedure C as a white solid (0.01 g, 12%). 1 H NMR (300 MHz, CDCl3) δ 8.67 (br. s., 0H), 6.99 - 7.33 (m, 4H), 5.96 (br. s., 1H), 3.32 (q, J = 5.15 Hz, 2H), 2.63 - 2.72 (m, 2H), 2.49 - 2.63 (m, 4H), 1.72 - 1.89 (m, 4H). 13 C NMR (75 MHz, CDCl3) δ 157.0, 138.3, 128.8, 127.5, 120.8, 56.7, 54.1, 39.7, 23.6. MS (ESI) m / z [M+H] + Calculated: 268.1; Measured: 268.1.

[0344] N-(2-{[(4-chlorophenyl)carbamoyl]amino}ethyl)acetamide (84) was prepared from N-acetylethylenediamine (0.03 ml, 0.32 mmol) according to general procedure C as a white solid (0.02 g, 24%). 1 H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 7.93 (br. s., 1H), 7.42 (d, J = 8.85 Hz, 2H), 7.25 (d, J = 8.85 Hz, 2H), 6.20 (br. s., 1H), 3.03 - 3.22 (m, 4H), 1.81 (s, 3H). 13 C NMR (75 MHz, DMSO-d6) δ 169.4, 155.1, 139.5, 128.4, 124.4, 119.1, 50.2, 30.6, 22.6. MS (ESI) m / z [M+H] + Calculated value: 256.1; Measured value: 256.4.

[0345] 3-(4-Chlorophenyl)-1-(2-methyl-2-phenylpropyl)urea (38) was prepared from 133 (0.10 g, 0.56 mmol) according to general procedure C as a white solid (0.14 g, 81%). 1 H NMR (300 MHz, CDCl3) δ 7.34 (d, J = 4.14 Hz, 4H), 7.20 - 7.25 (m, 1H), 7.16 - 7.20 (m, 2H), 7.05 - 7.11 (m, 2H), 6.14 (br. s., 1H), 4.37 (br. s., 1H), 3.45 (d, J = 6.03 Hz, 2H), 1.35 (s, 6H). 13 C NMR (75 MHz, CDCl3) δ 155.4, 146.6, 137.2, 129.0, 128.6, 128.5, 126.3, 126.0, 121.6, 51.7, 38.9, 26.6. MS (ESI) m / z [M+H] + Calculated value: 303.1; Measured value: 303.2.

[0346] 3-(4-Chlorophenyl)-1-(2,2-difluoro-2-phenylethyl)urea (39) was prepared from 134 (0.06 g, 0.29 mmol) according to general procedure C as a white solid (0.05 g, 52%). 1 H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.49 - 7.62 (m, 5H), 7.36 - 7.43 (m, 2H), 7.24 - 7.30 (m, 2H), 6.57 (t, J = 6.22 Hz, 1H), 3.88 (dt, J = 6.22, 14.98 Hz, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 154.6, 139.0, 135.0, 134.7, 134.3, 130.3, 128.6, 128.5, 125.2, 125.1, 125.1, 124.9, 124.2, 121.0, 119.2, 117.8, 45.1, 44.6, 44.2. MS (ESI) m / z [M+H] + Calculated value: 311.1; Measured value: 311.2.

[0347] 3-(4-Chlorophenyl)-1-(2-methyl-1-phenylpropan-2-yl)urea (40) was prepared from 139 (0.06 g, 0.38 mmol) according to general procedure D as a white solid (0.07 g, 57%). 1 H NMR (300 MHz, CDCl3) δ 7.20 - 7.27 (m, 5H), 7.12 - 7.19 (m, 4H), 6.21 (s, 1H), 4.41 (s, 1H), 3.03 (s, 2H), 1.33 (s, 6H). 13 C NMR (75 MHz, CDCl3) δ 154.4, 138.1, 137.4, 130.6, 129.2, 128.7, 128.1, 126.4, 122.0, 53.7, 45.5, 27.9. MS (ESI) m / z [M+H] + Calculated value: 303.1; Measured value: 303.2.

[0348] 1-(4-Chlorophenyl)-3-[(1-phenylcyclopropyl)methyl]urea (41) was prepared from (1-phenylcyclopropyl)methylamine (0.03 g, 0.2 mmol) according to general procedure C as a white solid (0.04 g, 68%). 1H NMR (300 MHz, CDCl3) δ 7.28 - 7.39 (m, 4H), 7.10 - 7.24 (m, 5H), 6.22 (br. s., 1H), 4.70 (br. s., 1H), 3.43 (d, J = 5.46 Hz, 2H), 0.89 (s, 4H). MS (ESI) m / z [M+H] + Calculated: 301.1; Measured: 301.4.

[0349] 3-(1-benzylcyclopropyl)-1-(4-chlorophenyl)urea (42) was prepared from (1-benzylcyclopropyl)amine hydrochloride hydrate (0.04 g, 0.2 mmol) according to general procedure C as a white solid (0.03 g, 48%). 1 H NMR (300 MHz, CDCl3) δ 7.29 - 7.34 (m, 2H), 7.27 - 7.28 (m, 1H), 7.20 - 7.24 (m, 2H), 7.17 - 7.20 (m, 2H), 7.10 - 7.15 (m, 2H), 6.34 (s, 1H), 4.86 (s, 1H), 2.86 (s, 2H), 0.91 - 0.98 (m, 4H). 13 C NMR (75 MHz, CDCl3) δ 153.5, 136.9, 135.5, 127.9, 127.3, 127.2, 126.8, 125.5, 119.6, 41.5, 33.3, 13.0. MS (ESI) m / z [M+H] + Calculated: 301.1; Measured: 301.4.

[0350] trans-1-(4-chlorophenyl)-3-[(2-phenylcyclopropyl)methyl]urea (43) was prepared from 135 (0.08 g, 0.45 mmol) according to general procedure C as a white solid (0.07 g, 51%). 1H NMR (300 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.38 - 7.46 (m, 2H), 7.20 - 7.29 (m, 4H), 7.11 - 7.15 (m, 1H), 7.04 - 7.10 (m, 2H), 6.32 (t, J = 5.56 Hz, 1H), 3.16 - 3.28 (m, 1H), 2.99 - 3.11 (m, 1H), 1.79 - 1.88 (m, 1H), 1.21 - 1.35 (m, 1H), 0.83 - 0.96 (m, 2H). 13 C NMR (75 MHz, DMSO-d6) δ 155.0, 142.8, 139.5, 128.4, 128.1, 125.5, 125.2, 124.4, 119.1, 42.9, 23.4, 21.3, 14.3. MS (ESI) m / z [M+H] + Calculated value: 301.1; Actual value: 301.2.

[0351] [Example 2] in vitroアッセイ Calcium mobilization assay: CHO-RD-HGA16 cells stably expressing human CB1 receptors (Molecular Devices, San Jose, California, United States of America) 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 normocin) into 96-well black-walled assay plates and incubated overnight at 37°C and 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 pre-warmed (37°C) assay buffer (1x HBSS, 20 mM HEPES, 2.5 mM probenecid, pH 7.4, 37°C). Growth medium was removed and cells were gently washed with 100 μL of pre-warmed (37°C) assay buffer. Cells were incubated in 200 μL of diluted Calcium 5 dye solution for 45 minutes at 37°C, 5% CO2. IC 50 For antagonist assays to determine values, the EC value of CP55,940 was 80 Concentrations were prepared at 10x the desired final concentration in 0.25% BSA / 0.5% DMSO / 0.5% EtOH / assay buffer, aliquoted into a 96-well polypropylene plate, and warmed to 37°C. Serial dilutions of test compounds were prepared at 10x the desired final concentration in 2.25% BSA / 4.5% DMSO / 4.5% EtOH / assay buffer. After the dye-loading incubation period, cells were pretreated with 25 μL of serial test compound dilutions and incubated for 15 minutes at 37°C. After the pretreatment incubation period, plates were read on a FLIPR Tetra (Molecular Devices, San Jose, California, United States of America). Calcium-mediated changes in fluorescence were monitored every 1 second over a 90-second period using the Tetra with 25 μL of CP55,940 EC 80Concentrations were added at 10 seconds and monitored (excitation / emission: 485 / 525 nm). Relative fluorescence units (RFU) were plotted against the logarithm of compound concentration. For agonist screening, the procedure described above was followed except that cells were pretreated with 2.25% BSA / 4.5% DMSO / 4.5% EtOH / assay buffer and single concentration dilutions of test compound were added to Tetra prepared in 0.25% BSA / 0.5% DMSO / 0.5% EtOH / assay buffer at 10x the desired final concentration. Test compound RFU was measured using CP55,940 E max Compared to RFU, %E max For the CB2 agonist and antagonist assays, the same procedure was followed except that stable human CB2-CHO-RD-HGA16 cells were used.

[0352] [ 35 S]GTPγS binding assay: For receptor signaling, membranes (10 μg protein) from either 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, then incubated for 60 min at 30°C with 30 μM GDP and 0.1 nM [ 35 S]GTPγS (Perkin Elmer Life Sciences, Boston, Massachusetts, United States of America). Nonspecific binding was determined by adding 30 μM unlabeled GTPγS. Concentration-response curves for allosteric modulators were performed in the presence of CP55,940 (100 nM or 1 μM) to determine the IC 50 The value was calculated.

[0353] cAMP assay: cAMP assays were performed as previously described (see Cawston et al., J. Med. Chem. 2015, 58, 5979–5988). Briefly, 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) adjacent to a yellow fluorescent protein (YFP) and Renilla luciferase (RLuc) assay, which can oxidize coelenterazine H and generate photons as a by-product. When cAMP binds to the Epac1 domain, it separates RLuc and YFP, so that only RLuc emits photons at a wavelength of 460 nm. In the absence of cAMP, RLuc excites YFP, emitting light at a wavelength of 535 nm. The plate reader measures both wavelengths, and the ratio 460 / 535 is calculated to quantify cAMP levels; an increase in this ratio indicates increased cAMP. Human embryonic kidney 293 (HEK293) cells stably transfected with human cannabinoid type 1 (CB1) were maintained at 37°C and 5% CO2 and seeded in 100 mM dishes for transfection. The following day, cells were fed with fresh culture medium and transfected with 5 μg of pcDNA3L-His-CAMYEL using linear polyethyleneimine (25 kDa, Polysciences, Warrington, Pennsylvania, United States of America) at a 1:6 DNA:PEI (ATCC, Manassas, Virginia, United States of America) ratio. The following day, cells were lifted using 1 mM EDTA in PBS and spun down at 200 × g for 5 min.The supernatant was removed, and the cells were resuspended in growth medium and seeded at 60,000 cells per well onto white 96-well plates coated with poly-D-lysine (Sigma Aldrich, St. Louis, Missouri, United States of America), with two rows of eight wells per plate, i.e., eight samples per plate (Perkin Elmer, Waltham, Massachusetts, United States of America), in duplicate. The next day, the medium was removed, the cells were rinsed with PBS, and buffers / reagents / drugs were added as follows: 175 μL of stimulation buffer (Ca) at 0 min; ... 2+ and Mg 2+ After addition of 25 μL of the allosteric modulator (5 μM bovine serum albumin in HBSS containing 5 mg / ml of CP55,940), 25 μL of coelenterazine (5 μM final) was added at 10 min, 25 μL of forskolin (10 μM final) was added at 15 min, and 25 μL of forskolin (10 μM final) with or without CP55,940 (100 nM final) was added at 25 min. Immediately after addition of forskolin and the probe agonist CP55,940, fluorescence was measured simultaneously at 460 nm and 535 nm at 1 second per well for 22 min at 37°C using a Clariostar (BMG Labtech, Ortenberg, Germany). The 460 / 535 ratio was calculated for each time point and plotted over time. Area under the curve analysis was performed for each replicate, averaged by condition / day, with each day serving as an independent experiment. Data were calculated as %FSK using the formula [(sample-basal) / (forskolin-basal) × 100]. I C 50 Values ​​were calculated from these normalized concentration-response data using Prism 6 (Graphpad Software, San Diego, California, United States of America) using a three-parameter nonlinear regression. Data are plotted as the average of at least N=3 independent experiments, either normalized to forskolin (concentration-response data) or the calculated 460 / 535 BRET ratio (time course data).

[0354] Data analysis: For calcium mobilization experiments, data were fitted with a three-parameter logistic curve and IC 50 Values ​​were generated (GraphPad Prism 6.0, Graphpad Software, San Diego, California, United States of America). 35 For [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 accomplished using GraphPad Prism 6.0 (Graphpad Software, San Diego, California, United States of America), and data were expressed as IC 50 For calculations, a three-parameter nonlinear regression was fitted with base and peak constrained to be >0 and =100, respectively.

[0355] Results: Compounds of the present disclosure exhibited a calcium mobilization assay using CHO cells overexpressing the human CB1R and a calcium mobilization assay in HEK cells overexpressing the human CB1R, as previously described. 35 The results for compound 11 are shown in Figures 1A and 1B. Some compounds were also shown to inhibit the [S]GTPγS binding in mouse cerebellum, which has high expression of CB1R. 35 S]GTPγS binding assay. The results for compound 11 are shown in Figure 1C. In addition, Table 1 shows the EC 80 IC of compounds 2 and 6-17 versus concentration 50 Indicates the value.

[0356] [Table 1] TIFF2026032033000029.tif235154

[0357] Because diaryl urea 2 has a planar structure, resulting in tight packing and limited water solubility, a methoxy group was introduced at the 2-position of the middle phenyl ring (6) to induce steric hindrance, thereby preventing the planar structure and tight packing. Unfortunately, the allosteric modulatory activity was attenuated (6, IC 50 =1268nM).

[0358] As shown before ( Nguyen et al. , J. Med. Chem. 2017, 60, 7410-7424), the pyrrolidinyl ring of compound 2 is not required for activity. Therefore, to simplify the synthetic effort, the pyrrolidinyl ring was removed when the middle phenyl ring was replaced with other aromatic heterocycles, such as pyridine, thiophene, and thiazole. Three pyridinyl analogs (7, 9, 10) showed a slight decrease in activity, while the activity of the 2,6-pyridinyl analog (8) was more attenuated. Interestingly, the five-membered ring analogs, i.e., thiophene and thiazole, showed better activity than their six-membered pyridine counterparts. In particular, the 2,5-thiophenyl analog (11, IC 50 = 7 nM) had significantly improved activity compared to 2. When the middle phenyl ring was replaced with a non-aromatic cyclic ring, such as cyclopropyl (15 and 16) or piperidinyl (17), the allosteric modulatory activity was reduced.

[0359] Compounds 6-17 bind to human CB1R 35 Results from the [S]GTPγS binding assay were in relatively good agreement with the calcium mobilization assay, but the potency was generally lower. Overall, compounds with weak activity in the calcium assay (6, 8, 15, 16, 17) showed a significantly higher [S]GTPγS activity than the [S]GTPγS binding assay. 35 The pyridinyl analogs (7, 9, and 10) that were moderately active in the calcium assay were also inactive in the [S]GTPγS binding assay. 35 The five-membered ring analogs showed no or weak activity in the [S]GTPγS binding assay. 35 S]GTPγS binding assay, still maintained good activity comparable to 2.

[0360] Some differences were observed between assays and between species. For example, 7 showed both 35 11 had no activity in the [S]GTPγS binding assay but showed moderate activity in calcium binding to the mouse CB1R. 35 S]GTPγS binding assay, but showed better potency than 2 against human CB1R 35 On the other hand, 12 showed comparable potency in the calcium and [S]GTPγS binding assay to human CB1R. 35 S]GTPγS binding assay but had comparable potency to mouse CB1R 35 Finally, 15 inhibited calcium and [S]GTPγS binding to mouse CB1R. 35 S]GTPγS binding assay, and its activity against human CB1R was weak. 35 S]GTPγS binding assay.

[0361] [Table 2] TIFF2026032033000031.tif241152TIFF2026032033000032.tif155152

[0362] With the encouraging results that thiophene 11 showed better or equipotent activity in all three assays mentioned above, a series of compounds of interest were prepared to investigate the effect of substituents on the phenyl ring of thiophene analogs and to compare these compounds with calcium and [ 35 S]GTPγS binding assay.

[0363] As shown in Table 2 above, the presence of one or two fluoro substituents and one chloro group (18, 19, 20–23) resulted in potency equivalent to that of 2 in the calcium assay. However, the inclusion of two chloro groups, as in the 3,4-dichloro and 3,5-dichloro analogs (24 and 25), slightly weakened activity. The addition of electron-withdrawing groups at the 3-position, such as acetyl, methoxycarbonyl, or methylsulfonyl, also weakened activity (26, 27, and 28). Of the three regioisomeric methoxy analogs, the 4-methoxy analog (31) was the most potent modulator, while the other two analogs showed slightly lower potency. The smaller 3-methyl group (32) was more potent than the larger 3-N,N-dimethylamino group (33). The two pyridinyl analogs (34 and 35) were also active, although their potency was slightly lower than that of their phenyl counterparts. Overall, these results indicate that small substituents are better tolerated on the phenyl ring than larger groups. The presence of heteroatoms is also tolerated, but results in a slight decrease in activity.

[0364] [ 35 The results from the [S]GTPγS binding assay were relatively consistent with those from the calcium assay. Compounds with equipotent activity to 2 in the calcium assay were [ 35 Compounds with weaker activity in the calcium assay also showed comparable activity in the [S]GTPγS binding assay (18, 19, 21, 22, 23, and 31). 35 Some compounds also showed weak activity in the [S]GTPγS binding assay (24–29 and 31–33). 35 S]GTPγS binding assay showed better activity than the calcium assay. For example, two pyridinyl analogs (34 and 35) showed better activity than the calcium assay. 35 S]GTPγS binding assay, whereas they showed weaker activity in calcium assays. 35 20 showed significantly better potency compared to 2 in the [S]GTPγS binding assay (IC 50= 84 nM vs. 2, IC 50 =455nM).

[0365] [Table 3] TIFF2026032033000034.tif241155TIFF2026032033000035.tif94155

[0366] Selected compounds were tested on mouse cerebellar membranes to assess the effect of CP55,940 induction [ 35 S]GTPγS binding assays. Some variation in potency ranking was observed across the three assays (see Table 3 above). 11 showed better potency than 2 in the calcium and mCB1R GTPγS assays, but comparable potency in the hCB1R GTPγS assay. 18 and 31 had comparable potency compared to 2 across the three assays. 20 had better potency in the calcium and hCB1R GTPγS assays, but comparable potency to 2 in the mGTPγS assay. 21 showed better potency in the calcium assay and comparable potency in the two GTPγS assays. Compounds 25, 30, and 33 were slightly less potent than 1 in the calcium assay, but showed weak activity in the two GTPγS assays. On the other hand, 35 showed slightly less potency in the calcium assay, but similar potency in the two GTPγS assays.

[0367] Interestingly, the allosteric regulatory activity was observed using mouse cerebellar membranes [ 35 In the [S]GTPγS binding assay, higher CP55,940 concentrations (i.e., 1 μM) appeared to be more potent. The most significant shift was observed at 20. At 100 nM CP55,940, its IC 50 The IC value was 190 nM, which decreased to 57 nM with 100 nM CP55,940. 35 also showed an IC value of 287 nM to 129 nM. 50This shift in inhibitory potency reflects the positive cooperativity characteristic of these PAM-antagonists.

[0368] Representative compounds were evaluated in a real-time kinetic BRET CAMYEL cAMP assay. In HEK-hCB1 cells, forskolin (5 μM) induced significant cAMP production, with a plateau reached after 5 min. The level of cAMP production was inhibited by the agonist CP55,940 (10 nM). All tested CB1 allosteric modulators immediately attenuated the CP55,940-inhibited cAMP production, without any "lag" period observed with some indole-based analogs. See Cawston et al., J. Med. Chem. 2015, 58, 5979-5988. Interestingly, with the exception of 21, and unlike 1, none of the diaryl urea-based compounds tested exhibited inverse agonism at concentrations up to 10 μM.

[0369] All compounds were screened for agonist activity at CB1R in a calcium mobilization assay and showed no significant agonist effect (CP55,940 E max No significant CB2R agonist activity (<30% of the CB2R activity, Supplementary Information) was observed for any of the compounds. All of these compounds were also screened for agonist and antagonist activity at CB2R to determine receptor subtype selectivity. Of the compounds, only 1 showed significant CB2R agonist activity (CP55,940 E max None of the compounds had significant CB2R antagonist activity (CP55,940 EC at 10 μM). 80 Concentration <50% inhibition or IC 50 values ​​>10 μM).

[0370] [Table 4] TIFF2026032033000037.tif156150

[0371] [Table 5] TIFF2026032033000039.tif234151TIFF2026032033000040.tif123151

[0372] [Table 6] TIFF2026032033000042.tif154151

[0373] CB1R has been shown to have constitutive activity required to maintain normal physiological function. SR141716 acts as a CB1R inverse agonist, reducing CB1R signaling by itself. It has been suggested that inhibition of this basal activity results in the adverse effects of SR141716. Therefore, the intrinsic activity of the compounds of the present disclosure was tested in the absence of the CB1R agonist CP55,940. As shown in Figure 2, SR141716 exhibited an IC of 2.8 nM. 50 At the highest concentration of 10 μM, compound 2 achieved the same level of inverse agonism as that produced by SR141716 alone (IC 50 = 1.47 μM). At 10 μM, compounds 9, 11, 14, and 35 showed only some inverse agonism. Notably, thiophene analog 11 produced almost no inverse agonism up to 10 μM. These results indicate that CB1R allosteric modulators are less likely to produce the adverse effects of SR141716.

[0374] [Example 3] Stability, solubility, permeability and pharmacokinetic studies

[0375] Metabolic stability assessment: Compounds were incubated with rat liver microsomes at 37°C for a total of 45 minutes. Reactions were performed in 100 mM potassium phosphate buffer, pH 7.4, containing 0.5 mg / mL rat liver microsomal protein. Phase 1 metabolism was assessed by adding NADPH to a final concentration of 1 mM and collecting samples at 0, 5, 15, 30, and 45 minutes. All collected samples were quenched 1:1 with ice-cold stop solution (1 μM labetalol and 1 μM glyburide in acetonitrile) and centrifuged to remove precipitated protein. The resulting supernatant was further diluted 1:4 with acetonitrile:water (1:1). Samples were analyzed by LC / MS / MS, and calculations of half-life and in vitro clearance were accomplished using Microsoft Excel (2007).

[0376] Kinetic solubility assessment: 10 μL of test compound stock solution (20 mM DMSO) was combined with 490 μL of phosphate buffer to achieve a target concentration of 400 μM. The solution was agitated for 2 hours at room temperature in a VX-2500 multi-tube vortexer (VWR International, Radnor, Pennsylvania, United States of America). Following agitation, the sample was filtered onto a glass fiber filter (1 μm), and the eluate was diluted 400-fold with a mixture of acetonitrile:water (1:1). In each experiment, nicardipine and imipramine were evaluated as reference compounds for low and high solubility, respectively. All samples were evaluated in triplicate and analyzed by LC-MS / MS using electrospray ionization against standards prepared in the same matrix.

[0377] Results: To advance CB1R allosteric modulators into therapeutic development, preliminary ADME evaluation of several of the compounds disclosed herein was performed. Compound 11 (T 1 / 2 = 65 min) is 2(T 1 / 2 = 13 min), which showed better metabolic stability than HCl (see Table 7 below). Solubility is another parameter for predicting compound absorption and generally reflects bioavailability ( Kerns et al., Curr. Drug Metab. 2008, 9, 879-885), which may be mitigated by formulation. As shown in Table 7 below, compound 11 (solubility = 1.5 μM) had improved solubility compared to compound 2 (solubility < 0.5 μM). Without wishing to be bound by any one theory, the improved solubility may be due to looser packing of the five-membered thiophene ring compared to the phenyl ring. 68 had limited metabolic stability to rat liver microsomes in vitro (T 1 / 2 = 9.6 min), demonstrated excellent blood-brain permeability in the MDCK-MDR1 Transwell assay, with Papp values ​​in both directions exceeding 15 × 10, the cutoff value generally considered for CNS passive permeability. -6 exceeded cm / s. 23 It is not a p-glycoprotein substrate (efflux ratio BA / AB<2.5). In vitro PK data were supported by in vitro pharmacokinetic studies, which showed that 68 is highly brain penetrant, with brain concentrations approximately twice those of plasma (K p = 2.01, Figure 4). It reached peak levels in both plasma and brain 30 min after ip administration, and C max The values ​​were 220.6 and 546 ng / mL in plasma and brain, respectively.

[0378] Permeability assessment. Bidirectional MDCK-MDR1 permeability assays were performed by Paraza Pharma Inc. (Montreal, Canada). Passage 5 MDCK-mdr1 cells were seeded onto permeable polycarbonate supports in 12-well Costar Transwell plates and allowed to grow and differentiate for 3 days. On day 3, the culture medium (DMEM supplemented with 10% FBS) was removed from both sides of the Transwell insert, and the cells were rinsed with warm HBSS. After the rinsing step, the chamber was filled with warm transport buffer (HBSS containing 10 mM HEPES and 0.25% BSA, pH 7.4), and the plate was incubated at 37°C for 30 minutes before measuring TEER (transepithelial electrical resistance).

[0379] The buffer in the donor chamber (apical for A-to-B assays and basolateral for B-to-A assays) was removed and replaced with a standard curve solution (10 μM test article in transport buffer). The plate was then placed under gentle agitation at 37°C. At designated time points (30, 60, and 90 min), an aliquot of transport buffer from the receiver chamber was removed and replenished with fresh transport buffer. The samples were quenched with ice-cold ACN containing an internal standard and then centrifuged to pellet the proteins. The resulting supernatant was further diluted with 50 / 50 ACN / HO (HO only for atenolol) and subjected to LC-MS / MS analysis. The reported apparent permeability (Papp) values ​​were calculated from a single measurement. Atenolol and propranolol were tested as low- and moderate-permeability standards. Bidirectional transport of digoxin was assessed to represent Pgp activity / expression.

[0380] The apparent permeability (Papp, measured in cm / s) of the compound is determined from two independent experiments in duplicate according to the following formula:

[0381]

number

[0382] Pharmacokinetic Evaluation. In vivo pharmacokinetic assays were performed by Paraza Pharma Inc. (Montreal, Canada). On the morning of the PK study, male Sprague-Dawley rats weighing 258–277 g were administered vehicle (5% Cremophor, 5% ethanol in saline) or 14014-149 (10 mg / kg, i.p.). At selected time points (0.25, 0.5, 1, 3, 5, 8, and 24 h postdose), two rats were anesthetized with isoflurane gas, and blood was collected by cardiac puncture (for plasma analysis), followed by systemic perfusion with phosphate-buffered saline (PBS, pH 7.4) to flush any residual blood from the organs. Brains were harvested and homogenized by mechanical disruption using a Polytron with 1:4 (w / v) 25% isopropanol in water. Brain homogenates were extracted for drug quantification by LC-MS / MS.

[0383] [Table 7]

[0384] [Example 4] Reinstatement of extinguished cocaine-seeking behavior Adult male Sprague-Dawley rats (Harlan, Indianapolis, Indiana, United States of America) weighing 280-300 g were used in the study. Animals were housed individually 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 experimental sessions.

[0385] The recovery procedure is described above. Jing et al. , Drug Alcohol Depend. 2014, Vol. 143, pp. 251-256, and Thorn et al.See Neuropsychopharmacology 2014, 39, 2309-2316. Briefly, rats were surgically implanted with a chronic indwelling jugular catheter. After a 1-week recovery period, rats were trained to press the active lever (left lever) for infusions of cocaine (0.75 mg / kg / inf) under a fixed-ratio [FR] schedule (starting with FR = 1, which was increased to FR = 5 within five training sessions) for 14 days. Reinforcer delivery involved the presentation of a stimulus light on the active lever, followed by a 30-second time-out period during which lever pressing had no planned consequences. After acquisition of cocaine self-administration, extinction of drug-seeking behavior occurred during daily 2-hour sessions during which lever pressing had no consequences. All other conditions remained unchanged. After 7 days of extinction, all rats reached extinction criterion (total responding <20% of training sessions).

[0386] Drug-induced reinstatement tests were performed the day after the final extinction session. Rats were pretreated 10 min with vehicle, Compound 2 (15, 30 mg / kg), or Compound 34 (10 mg / kg), followed by a priming injection of cocaine (10 mg / kg, i.p.), immediately followed by the start of the reinstatement session.

[0387] Data analysis: Data were expressed as mean ± SEM. Differences in active lever responses between the final extinction and reinstatement sessions were determined using a paired t-test (within-subject comparison). The effect of Compound 2 on reinstatement was analyzed by one-way analysis of variance (ANOVA) followed by a post-hoc Bonferroni test (between-subject comparison). The effect of Compound 34 on reinstatement was analyzed by Student's t-test. P<0.05 was considered statistically significant.

[0388] Results: Blockade of CB1 receptors in vivo using the antagonist / inverse agonist SR141716A has been shown to reduce palatable food intake, self-administration of several addictive drugs, and reinstatement of food- and drug-seeking behaviors. Rats pretreated with 1 and 2 have previously been shown to be less likely to seek addictive drugs, such as cocaine or methamphetamine, after a period of extinction. Therefore, two of the disclosed compounds, namely compounds 11 and 68, were tested to determine whether they would achieve the same effects in vivo.

[0389] As shown in Figure 3A, cocaine stimulation significantly reinstated extinguished active lever responses (t-test: t[7] = 16.29, p < 0.0001). Pretreatment with 68 (10 mg / kg, i.p.), but not with 11 (10 mg / kg, i.p.), attenuated cocaine-induced reinstatement of cocaine-seeking behavior. Interestingly, in contrast to compound 11, which showed a significant decrease in locomotion 5 min after administration, a dose of 10 mg / kg i.p. of compound 68 had no effect on locomotion. See Figure 3B.

[0390] It will be understood that various details of the presently disclosed subject matter can be changed without departing from the scope of the presently disclosed subject matter. Further, the above description is for purposes of illustration only, and not limitation.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, X 1 is -C- or -N-, R 1 , R 2 , R 3 , and R 5 each of R is independently selected from the group consisting of H, alkyl, substituted alkyl, halo, haloalkyl, alkoxy, nitro, and cyano; or R 2 and R 3 together form an alkylene group, R 4 is present or absent and, if present, is selected from the group consisting of H, alkyl, substituted alkyl, halo, haloalkyl, alkoxy, nitro, and cyano; L 1 is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene, heterocycloalkylene, substituted arylene, heteroarylene, and substituted heteroarylene; R 6 is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylamino, dialkylamino, acylamino, N-heterocycle, and substituted N-heterocycle. or a pharmaceutically acceptable salt or solvate thereof.

2. X 1 2. The compound of claim 1, wherein is -C-.

3. R 1 , R 2 , R 4 , and R 5 are each H, and the compound of formula (I) has formula (Ia): 【Chemistry 2】 3. The compound of claim 2, having the structure:

4. R 3 4. The compound of claim 3, wherein is Cl.

5. L 1 5. The compound of claim 3 or 4, wherein is selected from the group consisting of thiophenylene, pyridinylene, thiazolylene, alkylene, and substituted alkylene.

6. R 6 is phenyl, substituted phenyl, pyridinyl, furanyl, substituted furanyl, and -NHC(=O)CH 3 6. The compound according to any one of claims 3 to 5, selected from the group consisting of:

7. L 1 is thiophenylene and the compound has formula (II): 【Transformation 3】 7. The compound of any one of claims 3 to 6, having the structure: or a pharmaceutically acceptable salt or solvate thereof.

8. R 6 8. The compound of claim 7, wherein is selected from phenyl, substituted phenyl, or pyridinyl.

9. R 3 is Cl and R 6 is phenyl or substituted phenyl, and the compound of formula (II) is of formula (IIa): 【Chemistry 4】 [In the formula, n is 0, 1, 2, 3, 4, or 5; Each R 7 are independently selected from the group consisting of halo, nitro, hydroxy, cyano, alkyl, aryl, acyl, ester, alkoxy, sulfonyl, and dialkylamino, or a pharmaceutically acceptable salt or solvate thereof.

10. n is 1 or 2, and each R 7 10. The compound of claim 9, wherein is halo, optionally chloro or fluoro.

11. n is 1 and R 7 10. The compound of claim 9, wherein is methoxy or methyl.

12. 1-(4-chlorophenyl)-3-(5-phenylthiophen-2-yl)urea (11), 1-(4-chlorophenyl)-3-[5-(4-fluorophenyl)thiophen-2-yl]urea (18), 1-(4-chlorophenyl)-3-[5-(3-fluorophenyl)thiophen-2-yl]urea (19), 1-(4-chlorophenyl)-3-[5-(2,4-difluorophenyl)thiophen-2-yl]urea (20), 1-(4-chlorophenyl)-3-[5-(2-chlorophenyl)thiophen-2-yl]urea (21), 1-(4-chlorophenyl)-3-[5-(3-chlorophenyl)thiophen-2-yl]urea (22), 1-(4-chlorophenyl)-3-[5-(4-chlorophenyl)thiophen-2-yl]urea (23), 1-(4-chlorophenyl)-3-[5-(3,4-dichlorophenyl)thiophen-2-yl]urea (24), 1-(4-chlorophenyl)-3-[5-(3,5-dichlorophenyl)thiophen-2-yl]urea (25), 3-[5-(3-acetylphenyl)thiophen-2-yl]-1-(4-chlorophenyl)urea (26), Methyl 3-(5-{[(4-chlorophenyl)carbamoyl]amino}thiophen-2-yl)benzoate (27), 1-(4-chlorophenyl)-3-[5-(3-methanesulfonylphenyl)thiophen-2-yl]urea (28), 1-(4-chlorophenyl)-3-[5-(2-methoxyphenyl)thiophen-2-yl]urea (29), 1-(4-chlorophenyl)-3-[5-(3-methoxyphenyl)thiophen-2-yl]urea (30), 1-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)thiophen-2-yl]urea (31), 1-(4-chlorophenyl)-3-[5-(3-methylphenyl)thiophen-2-yl]urea (32), 1-(4-chlorophenyl)-3-{5-[3-(dimethylamino)phenyl]thiophen-2-yl}urea (33), 1-(4-chlorophenyl)-3-[5-(pyridin-3-yl)thiophen-2-yl]urea (34), and 1-(4-chlorophenyl)-3-[5-(pyridin-4-yl)thiophen-2-yl]urea (35); 10. The compound of claim 9, selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof.

13. L 1 is ethylene or a substituted ethylene, and the compound of formula (Ia) is a compound of formula (III): 【Transformation 5】 [In the formula, R 8 , R 9 , R 10 , and R 11 are each independently selected from the group consisting of H, halo, and alkyl, or R 8 , R 9 , R 10 , and R 11 two of which together form an alkylene group] 7. The compound of any one of claims 3 to 6, having the structure: or a pharmaceutically acceptable salt or solvate thereof.

14. R 3 is chloro and R 8 , R 9 , R 10 , and R 11 Each of the is H and R 6 is phenyl or substituted phenyl, and the compound of formula (III) is of formula (IIIa): 【Transformation 6】 [In the formula, n is 0, 1, 2, 3, 4, or 5; Each R 7 are independently selected from the group consisting of halo, nitro, hydroxyl, cyano, alkyl, perfluoroalkyl, aryl, acyl, ester, alkoxyl, sulfonyl, and dialkylamino.

14. The compound of claim 13, having the structure: or a pharmaceutically acceptable salt or solvate thereof.

15. Each R 7 is independently selected from the group consisting of fluoro, chloro, methyl, tert-butyl, phenyl, nitro, methoxy, dimethylamino, cyano, and trifluoromethyl.

16. trans-1-(4-chlorophenyl)-3-(2-phenylcyclopropyl)urea (15), cis-1-(4-chlorophenyl)-3-(2-phenylcyclopropyl)urea (16), 3-(4-chlorophenyl)-1-(2-phenylethyl)urea (44), 1-[2-(4-tert-butylphenyl)ethyl]-3-(4-chlorophenyl)urea (45), 3-(4-chlorophenyl)-1-[2-(4-phenylphenyl)ethyl]urea (46), 3-(4-chlorophenyl)-1-[2-(4-chlorophenyl)ethyl]urea (47), 3-(4-chlorophenyl)-1-[2-(4-nitrophenyl)ethyl]urea (48), 3-(4-chlorophenyl)-1-[2-(4-hydroxy-3-methoxyphenyl)ethyl]urea (49), 3-(4-chlorophenyl)-1-{2-[3-(dimethylamino)phenyl]ethyl}urea (50), 3-(4-chlorophenyl)-1-{2-[4-(dimethylamino)phenyl]ethyl}urea (51), 3-(4-chlorophenyl)-1-[2-(4-methanesulfonylphenyl)ethyl]urea (52), 3-(4-chlorophenyl)-1-[2-(2-methoxyphenyl)ethyl]urea (53), 3-(4-chlorophenyl)-1-[2-(3-methoxyphenyl)ethyl]urea (54), 3-(4-chlorophenyl)-1-[2-(3-methoxyphenyl)ethyl]urea (55), 3-(4-chlorophenyl)-1-[2-(3,4-dimethoxyphenyl)ethyl]urea (56), 3-(4-chlorophenyl)-1-[2-(3,5-dimethoxyphenyl)ethyl]urea (57), 3-(4-chlorophenyl)-1-[2-(4-hydroxyphenyl)ethyl]urea (58), 3-(4-chlorophenyl)-1-[2-(4-methylphenyl)ethyl]urea (59), 3-(4-chlorophenyl)-1-[2-(3-methylphenyl)ethyl]urea (60), 3-(4-chlorophenyl)-1-[2-(2-fluorophenyl)ethyl]urea (61), 3-(4-chlorophenyl)-1-[2-(3-fluorophenyl)ethyl]urea (62), 3-(4-chlorophenyl)-1-[2-(4-fluorophenyl)ethyl]urea (63), 3-(4-chlorophenyl)-1-[2-(3,4-difluorophenyl)ethyl]urea (64), 3-(4-chlorophenyl)-1-[2-(2,4,6-trifluorophenyl)ethyl]urea (65), 3-(4-chlorophenyl)-1-[2-(2,3,4,5,6-pentafluorophenyl)ethyl]urea (66), 3-(4-chlorophenyl)-1-[2-(2-chlorophenyl)ethyl]urea (67), 3-(4-chlorophenyl)-1-[2-(3-chlorophenyl)ethyl]urea (68), 3-(4-chlorophenyl)-1-[2-(2,4-dichlorophenyl)ethyl]urea (69), 3-(4-chlorophenyl)-1-[2-(2-chloro-6-fluorophenyl)ethyl]urea (70), 3-(4-chlorophenyl)-1-[2-(4-bromophenyl)ethyl]urea (71), 3-(4-chlorophenyl)-1-[2-(4-cyanophenyl)ethyl]urea (72), 3-(4-chlorophenyl)-1-{2-[2-(trifluoromethyl)phenyl]ethyl}urea (73), 3-(4-chlorophenyl)-1-{2-[3-(trifluoromethyl)phenyl]ethyl}urea (74), 3-(4-chlorophenyl)-1-{2-[4-(trifluoromethyl)phenyl]ethyl}urea (75), 3-(4-chlorophenyl)-1-[2-(pyridin-4-yl)ethyl]urea (76), 3-(4-chlorophenyl)-1-[2-(pyridin-3-yl)ethyl]urea (77) 3-(4-chlorophenyl)-1-[2-(pyridin-2-yl)ethyl]urea (78), 1-(4-chlorophenyl)-3-[2-(5-methylfuran-2-yl)ethyl]urea (79), 3-(4-chlorophenyl)-1-[2-(4-methylpiperazin-1-yl)ethyl]urea (80), 3-(4-chlorophenyl)-1-[2-(piperidin-1-yl)ethyl]urea (81), 3-(4-chlorophenyl)-1-[2-(morpholin-4-yl)ethyl]urea (82), 1-(4-chlorophenyl)-3-[2-(pyrrolidin-1-yl)ethyl]urea (83), N-(2-{[(4-chlorophenyl)carbamoyl]amino}ethyl)acetamide (84), 3-(4-chlorophenyl)-1-(2-methyl-2-phenylpropyl)urea (38), 3-(4-chlorophenyl)-1-(2,2-difluoro-2-phenylethyl)urea (39), 3-(4-chlorophenyl)-1-(2-methyl-1-phenylpropan-2-yl)urea (40), 1-(4-chlorophenyl)-3-[(1-phenylcyclopropyl)methyl]urea (41), and 3-(1-benzylcyclopropyl)-1-(4-chlorophenyl)urea (42); 14. The compound of claim 13, selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof.

17. 3-(4-chlorophenyl)-1-{2-methoxy-5-[6-(pyrrolidin-1-yl)pyridin-2-yl]phenyl}urea (6), 1-(4-chlorophenyl)-3-(4-phenylpyridin-2-yl)urea (7), 1-(4-chlorophenyl)-3-(6-phenylpyridin-2-yl)urea (8), 1-(4-chlorophenyl)-3-(5-phenylpyridin-3-yl)urea (9), 1-(4-chlorophenyl)-3-(2-phenylpyridin-4-yl)urea (10), 1-(4-chlorophenyl)-3-(4-phenylthiophen-2-yl)urea (12), 1-(4-chlorophenyl)-3-(5-phenylthiophen-3-yl)urea (13), 1-(4-chlorophenyl)-3-(5-phenyl-1,3-thiazol-2-yl)urea (14), 3-(4-chlorophenyl)-1-[(3R)-1-phenylpiperidin-3-yl]urea (17), 1-benzyl-3-(4-chlorophenyl)urea (36), 3-(4-chlorophenyl)-1-(3-phenylpropyl)urea (37), and trans-1-(4-chlorophenyl)-3-[(2-phenylcyclopropyl)methyl]urea (43); 10. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt or solvate thereof.

18. 18. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 and a pharmaceutically acceptable carrier.

19. A method for treating a cannabinoid 1 receptor (CB1R)-mediated disease or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of claims 1 to 17 or a pharmaceutical composition described in claim 18.

20. 20. The method of claim 19, wherein the subject is a mammal, optionally a human.

21. 21. The method of claim 19 or 20, wherein the disease or condition is selected from the group consisting of drug addiction, obesity, cancer, pain, female infertility, memory loss, cognitive impairment, Parkinson's disease, dyskinesia, tardive dyskinesia, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Tourette's syndrome, stroke, atherosclerosis, hypotension, intestinal hypomotility in paralytic ileus, inflammation, osteoporosis, hypercholesterolemia, dyslipidemia, diabetes, retinopathy, glaucoma, anxiety, depression and other mood disorders, gastrointestinal disorders, and metabolic disorders.

22. 22. The method of claim 21, wherein the disease is obesity or drug addiction, and optionally the drug addiction is selected from cocaine addiction, opioid addiction, amphetamine addiction, cannabinoid addiction, tobacco addiction, and alcohol addiction.

23. The compound has the formula (II): 【Transformation 7】 [Optionally, in the formula, R 3 is chloro, and optionally R 6 is a substituted phenyl] 23. The method of any one of claims 19 to 22, wherein the compound is

24. The compound has the formula (III): 【Transformation 8】 [Optionally, in the formula, R 3 is chloro, and optionally R 8 , R 9 , R 10 , and R 11 each of which is H] 23. The method of any one of claims 19 to 22, wherein the compound is

25. The compound is 1-(4-chlorophenyl)-3-(5-phenylthiophen-2-yl)urea (11), 1-(4-chlorophenyl)-3-[5-(2,4-difluorophenyl)thiophen-2-yl]urea (20), 1-(4-chlorophenyl)-3-[5-(2-chlorophenyl)thiophen-2-yl]urea (21), 1-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)thiophen-2-yl]urea (31), 3-(4-chlorophenyl)-1-[2-(3-chlorophenyl)ethyl]urea (68), and 3-(4-chlorophenyl)-1-{2-[3-(trifluoromethyl)phenyl]ethyl}urea (74); 23. The method of any one of claims 19 to 22, wherein the compound is selected from the group consisting of:

26. 19. A method of treating obesity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 17 or a pharmaceutical composition of claim 18.

27. The compound is 1-(4-chlorophenyl)-3-(5-phenylthiophen-2-yl)urea (11), 1-(4-chlorophenyl)-3-[5-(2,4-difluorophenyl)thiophen-2-yl]urea (20), 1-(4-chlorophenyl)-3-[5-(2-chlorophenyl)thiophen-2-yl]urea (21), 1-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)thiophen-2-yl]urea (31), 3-(4-chlorophenyl)-1-[2-(3-chlorophenyl)ethyl]urea (68), and 3-(4-chlorophenyl)-1-{2-[3-(trifluoromethyl)phenyl]ethyl}urea (74); or a pharmaceutically acceptable salt or solvate thereof.

28. 19. A method for preventing or inhibiting substance abuse and / or substance dependence, addictive behavior, or symptoms, behaviors, or conditions associated with substance abuse and / or substance dependence, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 17 or a pharmaceutical composition of 18.

29. 29. The method of claim 28, wherein the substance abuse and / or substance dependence is selected from cocaine dependence, opioid dependence, amphetamine dependence, cannabinoid dependence, tobacco dependence, and alcohol dependence.

30. 30. The method of claim 28 or 29, wherein administering prevents or inhibits recurrence.

31. The compound is 1-(4-chlorophenyl)-3-(5-phenylthiophen-2-yl)urea (11), 1-(4-chlorophenyl)-3-[5-(2,4-difluorophenyl)thiophen-2-yl]urea (20), 1-(4-chlorophenyl)-3-[5-(2-chlorophenyl)thiophen-2-yl]urea (21), 1-(4-chlorophenyl)-3-[5-(4-methoxyphenyl)thiophen-2-yl]urea (31), 3-(4-chlorophenyl)-1-[2-(3-chlorophenyl)ethyl]urea (68), and 3-(4-chlorophenyl)-1-{2-[3-(trifluoromethyl)phenyl]ethyl}urea (74); or a pharmaceutically acceptable salt or solvate thereof.

32. A method for regulating the activity of cannabinoid 1 receptor (CB1R), comprising contacting a sample containing CB1R with a compound described in any one of claims 1 to 17 or a pharmaceutical composition described in claim 18.

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