Treatment of obesity

Abstract

Obesity and type 2 diabetes are among the greatest health challenges facing not only the U.S, but the entire world. Weight loss significantly improves morbidity and mortality associated with obesity and associated metabolic diseases, such as type 2 diabetes. Provided herein are compositions and methods for treating obesity and metabolic diseases or disorders.

Description

WSGR Docket No. 59475-709.601TREATMENT OF OBESITYCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 681,589 filed August 9, 2024, which is incorporated herein by reference for all purposes in its entirety.BACKGROUND

[0002] Despite public health education and other initiatives, obesity and type 2 diabetes are among the greatest health challenges facing not only the U.S, but the entire world. Weight loss significantly improves morbidity and mortality associated with obesity and associated metabolic disease, such as type 2 diabetes. However, rigid dietary intervention increases the risk for disinhibited eating and weight regain. In recent years it became clear that hypothalamic dysfunction plays a major role in many forms of severe obesity, such as common obesity, monogenic obesity, and hypothalamic obesity. While therapies based on endogenous gut peptides such as glucagon-like peptide- 1 (GUP-1) receptor agonists (GUP- IRAs) have been compelling therapeutic agents for obesity and type 2 diabetes, only a few have achieved partial long-term weight loss (>5-15% in adults at 1 year), and all have shown significant side-effects, including nausea / malaise and gastrointestinal ailments.

[0003] In recent years, cannabinoid receptor type 1 (CB1) modulators have been discovered and tested in forms of obesity. To reduce the burden and risk of obesity-associated diseases, there is dire unmet clinical need for new anti -obesity agents with increased efficacy, safety, and patient tolerance. The present disclosure addresses this unmet need.BRIEF SUMMARY

[0004] Provided herein are methods of treating obesity or type 2 diabetes in a subject in need thereof, the method comprising: administering to the subject a therapeutically-effective amount of (a) atherapeutically-effective amount of an anti -obesity agent that functions through a pathway other than CB 1 modulation. Further provided are methods of treatment where the anti -obesity agent is a GUP-1 modulator. Further provided are methods of treatment where the anti -obesity agent is a GUP-l / GIP modulator. Further provided are methods of treatment where the anti -obesity agent is a GUP-1 agonist. Further provided are methods of treatment where the anti -obesity agent is a GUP-l / GIP / Glucagon agonist. Further provided are methods of treatment where the anti -obesity agent is a GUP-l / amylin agonist. Further provided are methods of treatment where the anti -obesity agent is a GUP-l / glucagon agonist. Further provided are methods ofWSGR Docket No. 59475-709.601 treatment where the anti -obesity agent is a GLP-1 agonist / GIP antagonist. Further provided are methods of treatment where the anti -obesity agent is semaglutide (Wegovy) or tirzapatide (Zepbound). Further provided are methods of treatment where the anti -obesity agent is selected from orforglipron (Eh Lilly, GLP-1 agonist), retatrutide (Eh Lilly, GLP-1 / GIP / Glucagon agonist), semaglutide (Novo Nordisk, GLP-1 agonist ), cagrilintide / semaglutide (Novo Nordisk, GLP-l / amylin agonist), survodutide (Boehringer / Zealand) GLP-1 / glucagon agonist, danuglipron (Pfizer, GLP-1 agonist), maridebart cafraglutide (Amgen, GLP-1 agonist, GIP antagonist), GSBR-1290 (Structure Therapeutics, GLP-1 agonist ), VK2735 (Viking Therapeutics, dual agonist of the glucagon -like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors), RG 6641 (CT-868, Roche, GLP-l / GIP agonist), RG 6640 (CT-388, Roche, GLP-l / GIP agonist), and RG 6652 (CT-996, Roche, GLP-1 agonist). Further provided herein are methods wherein the anti -obesity agent comprises a modulator of one or more of GLP-1, GLP-1R, gastric inhibitory polypeptide (GIP), glucagon, or amylin. Further provided herein are methods wherein the anti -obesity agent comprises a modulator of two or more of GLP-1, GLP-1R, gastric inhibitory polypeptide (GIP), glucagon, or amylin. Further provided herein are methods wherein the anti-obesity agent comprises an agonist of one or more of GLP-1, GLP-1R, gastric inhibitory polypeptide (GIP), glucagon, or amylin. Further provided herein are methods wherein the anti -obesity agent comprises an agonist of two or more of GLP-1, gastric inhibitory polypeptide (GIP), and glucagon. Further provided herein are methods wherein the anti-obesity agent comprises an antagonist of gastric inhibitory polypeptide (GIP). Further provided herein are methods wherein the at least one anti -obesity agent comprises one or more of zepbound, orforglipron, retatrutide, oral semaglutide, cagrilintide / semaglutide, survodutide, danuglipron, maridebart cafraglutide, GSBR-1290, VK2735, RG 6641 (CT-868), RG 6640 (CT-388), and RG 6652 (CT-996). Further provided herein are methods wherein the at least one antiobesity agent comprises one or more of liraglutide, orlistat, sibutramine, methamphetamine, ionamin, phentermine, bupropion, diethylpropion, phendimetrazine, benzphetermine, bromocriptine, lorcaserin, and topiramate. Further provided herein are methods wherein the compound and the anti -obesity agent are delivered in a single dosage form. Further provided herein are methods wherein the compound and the anti-obesity agent are delivered in a single parenteral or oral dosage form. Further provided herein are methods wherein the anti -obesity agent is delivered via parenteral or oral dosage form. Further provided herein are methods wherein the compound agent is delivered via parenteral or oral administration.Further provided herein are methods wherein the administering occurs daily, weekly, or monthly. Further provided herein are methods wherein the compound is administered in a dose of 0.5-300 mg. Further provided herein are methods wherein the anti -obesity agent is administered in a dose of 0.01-10 mg. Further provided herein are methods wherein the combination of (a) and (b) allows for a lower dosage of (b) to achieve the same therapeutic effect in treating the disease. A composition comprising: a compoundWSGR Docket No. 59475-709.601 having the structureleast one therapeutically effective amount of an anti -obesity agent that functions through a pathway other than CB 1 modulation. Further provided herein are methods wherein the composition is formulated for oral administration. Further provided herein are methods wherein the composition is formulated for parenteral administration. Further provided herein are methods wherein the composition comprises at least one excipient.

[0005] Provided herein are methods of treating a metabolic disease in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of (a) a CB1 modulator, and (b) at least one therapeutically-effective amount of an agent that functions through a pathway other than CB1 modulation. Further provided herein are methods wherein the CB1 modulator comprises a CB1 antagonist. Further provided herein are methods wherein the CB1 modulator comprises a CB1 inverse agonist or reverse agonist. Further provided herein are methods wherein the CB1 modulator comprises ((R)-(+)-N-tert-butyl- 3-[(4-chloro)phenyl-(2- trifluoromethyl)phenyl]methoxyazetidine-l-carboxamide, ((S)-(-)-N-tert-butyl-3-[(4- chloro)phenyl-(2- trifluoromethyl)phenyl]methoxyazetidine-l-carboxamide, (N-tert-butyl-3-[(4-chloro)phenyl-(2- trifluoromethyl)phenyl]methoxyazetidine-l-carboxamide, cannabigerol, ibipinabant, otenabant, tetrahydrocannabivarin, virodhamine, rimonabant, taranabant, surinabant or drinabant. Further provided herein are methods wherein the CB1 modulator comprises ((R)-(+)-N-tert-butyl- 3-[(4-chloro)phenyl-(2- trifluoromethyl)phenyl]methoxyazetidine-l -carboxamide. Further provided herein are methods wherein the CB1 modulator comprises MAFP, NESS 0327, AM-251, LY-320135, AM 281, MJ 15, amauromine, AM 404, virodhamine hydrochloride, NIDA-41020, SLV 319, URB447, falcarinol, CB-25, 0-1821, or AVE- 1625 (drinabant). Further provided herein are methods wherein the CB1 modulator comprises rimonabant, taranabant, MK-0364, AM251, AM1387, AM4113, cannabigerol, ibipinabant, otenabant, surinabant, tetrahydrocannabivarin and virodamine, TM-38837, AM6545, or a CB1 targeting-antibody Further provided herein are methods wherein the CB 1 modulator comprises rimonabant or drinabant. Further provided herein are methods wherein the CB 1 modulator comprises rimonabant, taranabant, surinabant or drinabant. Further provided herein are methods wherein the at least one agent comprises one or more of zepbound, orforglipron, retatrutide, oral semaglutide, cagrilintide / semaglutide, survodutide, danuglipron, maridebart cafraglutide, GSBR-1290, VK2735, RG 6641 (CT-868), RG 6640 (CT-388), and RG 6652 (CT-996). Further provided herein are methods wherein the at least one antiobesity agent comprises one or more of liraglutide, orlistat, sibutramine, methamphetamine, ionamin, phentermine, bupropion, diethylpropion, phendimetrazine, benzphetermine, bromocriptine, lorcaserin, topiramate, fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram, duloxetine, and venlafaxine. Further provided herein are methods wherein the metabolic disease comprises obesity, typeWSGR Docket No. 59475-709.601II diabetes, diabetic retinopathy, fatty liver disease (FLD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, liver cancer, or liver cirrhosis.

[0006] Further provided herein are compositions wherein the compound is a salt, polymorph, solvate, hydrate, stereoisomer, or isotope thereof. Further provided herein are compositions wherein the compound is a solid. Further provided herein are compositions wherein the compound is a crystalline solid. Further provided herein are injectable compositions.INCORPORATION BY REFERENCE

[0007] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entireties to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DESCRIPTION

[0008] The novel features of the present disclosure are set forth with particularity in the appended claims. An understanding of the features and advantages of the present disclosure may be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the present disclosure are utilized.

[0009] Provided herein are compositions and methods of treating obesity or excessive weight. In some instances, compositions and methods comprise two or more components. In some instances, the first component comprises a CB 1 modulator, and the second component comprises an agent that functions through a pathway other than CB1 modulation. In some instances, the first component comprises Compound 1, and the second component comprises an anti -obesity agent.CB1 Modulators

[0010] Provided herein are CB 1 modulators in combination with at least one additional agent. In some embodiments, the CB 1 modulator is a CB 1 inhibitor. In some embodiments, the CB 1 inhibitor comprises antagonist, inverse agonist, or reverse agonist. In some embodiments, the CB 1 inhibitor comprises ANEB-001, rimonabant, taranabant, MK-0364, AM251, AM1387, AM4113, cannabigerol, ibipinabant, otenabant, surinabant, tetrahydrocannabivarin and virodamine, TM-38837, AM6545, or a CB1 targetingantibody. In some embodiments, the CB1 inhibitor comprises methylphosphonofluoridic acid 5,8,11,14- eicosatetraenyl ester (MAFP, CAS 188404-10-6), NESS 0327 (8-chloro-l-(2,4-dichlorophenyl)-l,4,5,6- tetrahydro-N-l-piperidinyl-benzo[6,7]cyclohepta[l,2-c]pyrazole-3-carboxamide, CAS 494844-07-4), AM-251 (CAS 183232-66-8), LY-320135 (CAS 176977-56-3), AM 281 (CAS 202463-68-1), MJ 15 (CAS 944154-76-1), amauromine (CAS 88360-87-6), AM 404 (183718-77-6), virodhamine hydrochloride (443129-35-9), NIDA-41020 (CAS 502486-89-7), SLV 319 (CAS 362519-49-1), URB447 (CAS 1132922-57-6), falcarinol (CAS 4117-12-8), CB-25 (CAS 869376-63-6), 0-1821 (35482-50-9), or AVE-1625 (drinabant, CAS 358970-97-5. In some instances, the CB1 modulator comprises rimonabant, taranabant, surinabant or drinabant.WSGR Docket No. 59475-709.601Compound 1

[0011] In some instances, a CB1 inhibitor comprises Compound 1 (i.e., ANEB-001). As described herein, Compound 1 (ANEB-001) refers to (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide, which has the chemical structure as shown below:Compound 1, a stereoisomer thereof or a pharmaceutically acceptable solvate or hydrate thereof.

[0012] Compound 1 is a CB1 modulator. CB1 modulators, such as a CB1 inhibitor, are useful in the treatment of various conditions and disorders, including but not limited to obesity and diabetes.

[0013] The preparation and uses of Compound 1 have been previously described (see, Example 81 of US 7,504,522, which is incorporated by reference).

[0014] In some embodiments compounds herein can include all stereoisomers, enantiomers, diastereomers, mixtures, racemates, atropisomers, and tautomers thereof.

[0015] In some embodiments as disclosed herein, Compound 1 is crystalline. As used herein, “crystalline form,” “polymorph,” “Form,” and “form” may be used interchangeably herein, and are meant to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, salts, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to. Compounds of the present disclosure include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. In some embodiments, the crystalline form is a single solid-state form. In some instances, method described herein comprises treatment with a crystalline form of Compound 1.

[0016] Provided herein are crystalline forms of Compound 1. In some instances, a crystalline form comprises a polymorph of Compound 1. In some instances, a polymorph of Compound 1 is described in US2023 / 0139815, which is incorporated by reference in its entirety. In some embodiments, the crystalline form of compound 1 is Crystalline Form I. In some embodiments, Crystalline Form I is characterized by: an X-ray powder diffraction pattern comprising peaks at 10.2 ± 0.2° 2-0, 18.1 ± 0.2° 2- 0, and 20.7 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, the crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 10.2 ± 0.2° 2-0, 18.1 ± 0.2° 2-0, and 20.7 ± 0.2° 2-0, and as measured by X-rayWSGR Docket No. 59475-709.601 powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, Crystalline Form I is characterized by an X-ray powder diffraction pattern comprising peaks at about 10.2° 2-0, about 18.1° 2- 0, and about 20.7° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from 9.8 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, and 22.9 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, the X-ray powder diffraction pattern further comprises at least one peak selected from about 9.8° 2-0, about 15.0° 2-0, and about 22.9° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, the X-ray powder diffraction patern further comprises at least one peak selected from 7.1 ± 0.2° 2-0, 11.6 ± 0.2° 2-0, 13.5 ± 0.2° 2-0, 14.4 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 14.8 ± 0.2° 2-0, 16.2 ± 0.2° 2-0, 19.0 ± 0.2° 2-0, 19.3 ± 0.2° 2-0, 19.6 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 22.6 ± 0.2° 2-0, 23.2 ± 0.2° 2-0, and 27.7 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, the X-ray powder diffraction patern further comprises at least one peak selected from about 7.1° 2-0, about 11.6° 2-0, about 13.5° 2-0, about 14.4° 2-0, about 14.6° 2-0, about 14.8 ° 2-0, about 16.2° 2-0, about 19.0° 2-0, about 19.3° 2-0, about 19.6° 2-0, about 20.4° 2-0, about 22.6° 2-0, about 23.2° 2-0, and about 27.7° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, the X-ray powder diffraction patern comprises peaks at 7.1 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 11.6 ± 0.2° 2-0, 13.5 ± 0.2° 2-0, 14.4 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 14.8 ± 0.2° 2- 0, 15.0 ± 0.2° 2-0, 16.2 ± 0.2° 2-0, 18.1 ± 0.2° 2-0, 19.0 ± 0.2° 2-0, 19.3 ± 0.2° 2-0, 19.6 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.7 ± 0.2° 2-0, 22.6 ± 0.2° 2-0, 22.9 ± 0.2° 2-0, 23.2 ± 0.2° 2-0, and 27.7 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, the X-ray powder diffraction patern comprises at least one peak selected from 7.1 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 11.6 ± 0.2° 2-0, 13.5 ± 0.2° 2-0, 14.4 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 14.8 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 16.2 ± 0.2° 2-0, 18.1 ± 0.2° 2-0, 19.0 ± 0.2° 2-0, 19.3 ± 0.2° 2-0, 19.6 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.7 ± 0.2° 2-0, 22.6 ± 0.2° 2-0, 22.9 ± 0.2° 2-0, 23.2 ± 0.2° 2-0, and 27.7 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, the X-ray powder diffraction patern comprises at least two peaks selected from 7.1 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 11.6 ± 0.2° 2-0, 13.5 ± 0.2° 2-0, 14.4 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 14.8 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 16.2 ± 0.2° 2-0, 18.1 ± 0.2° 2-0, 19.0 ± 0.2° 2-0, 19.3 ± 0.2° 2-0, 19.6 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.7 ± 0.2° 2-0, 22.6 ± 0.2° 2-0, 22.9 ± 0.2° 2-0, 23.2 ± 0.2° 2-0, and 27.7 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, the X-ray powder diffraction patern comprises at least three peaks selected from 7.1 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 11.6 ± 0.2° 2-0, 13.5 ± 0.2° 2-0, 14.4 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 14.8 ± 0.2° 2- 0, 15.0 ± 0.2° 2-0, 16.2 ± 0.2° 2-0, 18.1 ± 0.2° 2-0, 19.0 ± 0.2° 2-0, 19.3 ± 0.2° 2-0, 19.6 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.7 ± 0.2° 2-0, 22.6 ± 0.2° 2-0, 22.9 ± 0.2° 2-0, 23.2 ± 0.2° 2-0, and 27.7 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, the X-ray powder diffraction patern comprises at least four peaks selected from 7.1 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 11.6 ± 0.2° 2-0, 13.5 ± 0.2° 2-0, 14.4 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 14.8 ± 0.2° 2-0,WSGR Docket No. 59475-709.60115.0 ± 0.2° 2-0, 16.2 ± 0.2° 2-0, 18.1 ± 0.2° 2-0, 19.0 ± 0.2° 2-0, 19.3 ± 0.2° 2-0, 19.6 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.7 ± 0.2° 2-0, 22.6 ± 0.2° 2-0, 22.9 ± 0.2° 2-0, 23.2 ± 0.2° 2-0, and 27.7 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, the X-ray powder diffraction pattern comprises at least five peaks selected from 7.1 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 11.6 ± 0.2° 2-0, 13.5 ± 0.2° 2-0, 14.4 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 14.8 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 16.2 ± 0.2° 2-0, 18.1 ± 0.2° 2-0, 19.0 ± 0.2° 2-0, 19.3 ± 0.2° 2-0, 19.6 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.7 ± 0.2° 2-0, 22.6 ± 0.2° 2-0, 22.9 ± 0.2° 2-0, 23.2 ± 0.2° 2-0, and 27.7 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, the X-ray powder diffraction patern comprises at least six peaks selected from 7.1 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 11.6 ± 0.2° 2-0, 13.5 ± 0.2° 2-0, 14.4 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 14.8 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 16.2 ± 0.2° 2-0, 18.1 ± 0.2° 2-0, 19.0 ± 0.2° 2-0, 19.3 ± 0.2° 2-0, 19.6 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.7 ± 0.2° 2-0, 22.6 ± 0.2° 2-0, 22.9 ± 0.2° 2-0, 23.2 ± 0.2° 2-0, and 27.7 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, the X-ray powder diffraction patern comprises at least seven peaks selected from 7.1 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 11.6 ± 0.2° 2-0, 13.5 ± 0.2° 2-0, 14.4 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 14.8 ± 0.2° 2- 0, 15.0 ± 0.2° 2-0, 16.2 ± 0.2° 2-0, 18.1 ± 0.2° 2-0, 19.0 ± 0.2° 2-0, 19.3 ± 0.2° 2-0, 19.6 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.7 ± 0.2° 2-0, 22.6 ± 0.2° 2-0, 22.9 ± 0.2° 2-0, 23.2 ± 0.2° 2-0, and 27.7 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, the X-ray powder diffraction patern comprises at least eight peaks selected from 7.1 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 11.6 ± 0.2° 2-0, 13.5 ± 0.2° 2-0, 14.4 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 14.8 ± 0.2° 2- 0, 15.0 ± 0.2° 2-0, 16.2 ± 0.2° 2-0, 18.1 ± 0.2° 2-0, 19.0 ± 0.2° 2-0, 19.3 ± 0.2° 2-0, 19.6 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.7 ± 0.2° 2-0, 22.6 ± 0.2° 2-0, 22.9 ± 0.2° 2-0, 23.2 ± 0.2° 2-0, and 27.7 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, the X-ray powder diffraction patern comprises at least nine peaks selected from 7.1 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 11.6 ± 0.2° 2-0, 13.5 ± 0.2° 2-0, 14.4 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 14.8 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 16.2 ± 0.2° 2-0, 18.1 ± 0.2° 2-0, 19.0 ± 0.2° 2-0, 19.3 ± 0.2° 2-0, 19.6 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.7 ± 0.2° 2-0, 22.6 ± 0.2° 2-0, 22.9 ± 0.2° 2-0, 23.2 ± 0.2° 2-0, and 27.7 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, the X-ray powder diffraction patern comprises at least ten peaks selected from 7.1 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 11.6 ± 0.2° 2-0, 13.5 ± 0.2° 2-0, 14.4 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 14.8 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 16.2 ± 0.2° 2-0, 18.1 ± 0.2° 2-0, 19.0 ± 0.2° 2-0, 19.3 ± 0.2° 2-0, 19.6 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.7 ± 0.2° 2-0, 22.6 ± 0.2° 2-0, 22.9 ± 0.2° 2-0, 23.2 ± 0.2° 2-0, and 27.7 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, the X-ray powder diffraction patern comprises at least fifteen peaks selected from 7.1 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 11.6 ± 0.2° 2-0, 13.5 ± 0.2° 2-0, 14.4 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 14.8 ± 0.2° 2- 0, 15.0 ± 0.2° 2-0, 16.2 ± 0.2° 2-0, 18.1 ± 0.2° 2-0, 19.0 ± 0.2° 2-0, 19.3 ± 0.2° 2-0, 19.6 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.7 ± 0.2° 2-0, 22.6 ± 0.2° 2-0, 22.9 ± 0.2° 2-0, 23.2 ± 0.2° 2-0, and 27.7 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments,WSGR Docket No. 59475-709.601 the X-ray powder diffraction pattern comprises peak at about 7.1° 2-0, about 9.8° 2-0, about 10.2° 2-0, about 11.6° 2-0, about 13.5° 2-0, about 14.4° 2-0, about 14.6° 2-0, about 14.8° 2-0, about 15.0° 2-0, about 16.2° 2-0, about 18.1° 2-0, about 19.0° 2-0, about 19.3° 2-0, about 19.6° 2-0, about 20.4° 2-0, about 20.7° 2-0, about 22.6° 2-0, about 22.9° 2-0, about 23.2° 2-0, and about 27.7° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A.

[0017] In some embodiments, the crystalline form of compound 1 is Crystalline Form II. In some embodiments, the crystalline form of compound 1 is Crystalline Form II of (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide. In some embodiments, Crystalline Form II is characterized as having an X-ray powder diffraction pattern comprising peaks at 15.2 ± 0.2° 2-0, 18.2 ± 0.2° 2-0, and 20.8 ± 0.2° 2-0 as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A; In some embodiments, the crystalline form of compound 1 is Crystalline Form II of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l- carboxamide. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising peaks at 15.2 ± 0.2° 2-0, 18.2 ± 0.2° 2-0, and 20.8 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising peaks at about 15.2° 2-0, about 18.2° 2- 0, and about 20.8° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern further comprising at least one peak selected from 10.2 ± 0.2° 2-0, 19.2 ± 0.2° 2-0, 20.6 ± 0.2° 2-0, and 22.8 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising peaks at about 10.2° 2-0, about 19.2° 2-0, about 20.6° 2-0, and about 22.8° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern further comprising at least one peak selected from 7.0 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 13.6 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 16.1 ± 0.2° 2-0, 19.7 ± 0.2° 2-0, 20.3 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern fur comprising at least one peak selected from about 7.0° 2-0, about 9.8° 2-0, about 13.6° 2-0, about 14.6° 2-0, about 15.0° 2-0, about 16.1° 2-0, about 19.7° 2-0, about 20.3° 2-0, and about 20.4° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising a peak selected from 7.0 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 13.6 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 15.2 ± 0.2° 2-0, 16.1 ± 0.2° 2-0, 18.2 ± 0.2° 2-0, 19.2 ± 0.2° 2-0, 19.7 ± 0.2° 2-0, 20.3 ± 0.2° 2- 0, 20.4 ± 0.2° 2-0, 20.6 ± 0.2° 2-0, 20.8 ± 0.2° 2-0, and 22.8 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising at least one peak selected from 7.0 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 13.6 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 15.2 ± 0.2° 2-0, 16.1 ± 0.2° 2-0, 18.2 ± 0.2° 2-0, 19.2 ± 0.2° 2-0, 19.7 ± 0.2° 2-0, 20.3 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.6 ±WSGR Docket No. 59475-709.6010.2° 2-0, 20.8 ± 0.2° 2-0, and 22.8 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising at least two peaks selected from 7.0 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 13.6 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 15.2 ± 0.2° 2-0, 16.1 ± 0.2° 2-0, 18.2 ± 0.2° 2-0, 19.2 ± 0.2° 2-0, 19.7 ± 0.2° 2-0, 20.3 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.6 ± 0.2° 2-0, 20.8 ± 0.2° 2-0, and 22.8 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising at least three peaks selected from 7.0 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 13.6 ± 0.2° 2- 0, 14.6 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 15.2 ± 0.2° 2-0, 16.1 ± 0.2° 2-0, 18.2 ± 0.2° 2-0, 19.2 ± 0.2° 2-0, 19.7 ± 0.2° 2-0, 20.3 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.6 ± 0.2° 2-0, 20.8 ± 0.2° 2-0, and 22.8 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising at least four peaks selected from 7.0 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 13.6 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 15.2 ± 0.2° 2-0, 16.1 ± 0.2° 2-0, 18.2 ± 0.2° 2-0, 19.2 ± 0.2° 2-0, 19.7 ± 0.2° 2-0, 20.3 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.6 ± 0.2° 2-0, 20.8 ± 0.2° 2-0, and 22.8 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising at least five peaks selected from 7.0 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 13.6 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 15.2 ± 0.2° 2-0,16.1 ± 0.2° 2-0, 18.2 ± 0.2° 2-0, 19.2 ± 0.2° 2-0, 19.7 ± 0.2° 2-0, 20.3 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.6 ± 0.2° 2-0, 20.8 ± 0.2° 2-0, and 22.8 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising at least six peaks selected from 7.0 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 13.6 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 15.2 ± 0.2° 2-0, 16.1 ± 0.2° 2-0, 18.2 ± 0.2° 2-0,19.2 ± 0.2° 2-0, 19.7 ± 0.2° 2-0, 20.3 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.6 ± 0.2° 2-0, 20.8 ± 0.2° 2-0, and 22.8 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising at least seven peaks selected from 7.0 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 13.6 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 15.2 ± 0.2° 2-0, 16.1 ± 0.2° 2-0, 18.2 ± 0.2° 2-0, 19.2 ± 0.2° 2-0, 19.7 ± 0.2° 2-0, 20.3 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.6 ± 0.2° 2-0, 20.8 ± 0.2° 2-0, and 22.8 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising at least eight peaks selected from 7.0 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 13.6 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 15.2 ± 0.2° 2-0, 16.1 ± 0.2° 2-0, 18.2 ± 0.2° 2-0, 19.2 ± 0.2° 2-0, 19.7 ± 0.2° 2-0, 20.3 ± 0.2° 2- 0, 20.4 ± 0.2° 2-0, 20.6 ± 0.2° 2-0, 20.8 ± 0.2° 2-0, and 22.8 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising at least nine peaks selected from 7.0 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 13.6 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 15.2 ± 0.2° 2-0, 16.1 ± 0.2° 2-0, 18.2 ± 0.2° 2-0, 19.2 ± 0.2° 2-0, 19.7 ± 0.2° 2-0, 20.3 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.6 ±WSGR Docket No. 59475-709.6010.2° 2-0, 20.8 ± 0.2° 2-0, and 22.8 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising at least ten peaks selected from 7.0 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 13.6 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 15.2 ± 0.2° 2-0, 16.1 ± 0.2° 2-0, 18.2 ± 0.2° 2-0, 19.2 ± 0.2° 2-0, 19.7 ± 0.2° 2-0, 20.3 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.6 ± 0.2° 2-0, 20.8 ± 0.2° 2-0, and 22.8 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A. In some embodiments, Crystalline Form II is characterized by an X-ray powder diffraction pattern comprising at least fifteen peaks selected from 7.0 ± 0.2° 2-0, 9.8 ± 0.2° 2-0, 10.2 ± 0.2° 2-0, 13.6 ± 0.2° 2-0, 14.6 ± 0.2° 2-0, 15.0 ± 0.2° 2-0, 15.2 ± 0.2° 2-0, 16.1 ± 0.2° 2-0, 18.2 ± 0.2° 2-0, 19.2 ± 0.2° 2-0, 19.7 ± 0.2° 2-0, 20.3 ± 0.2° 2-0, 20.4 ± 0.2° 2-0, 20.6 ± 0.2° 2-0, 20.8 ± 0.2° 2-0, and 22.8 ± 0.2° 2-0, as measured by X-ray powder diffraction using an X-ray wavelength of 1.5406 A.Metabolites of Compound 1

[0018] Provided herein are metabolites of Compound 1. In some instances, a metabolite of Compound 1 comprises an oxidized form of Compound 1. In some instance, one or more functional groups of compound 1 are oxidized to an alcohol, aldehyde, ketone, epoxide, hydroxylamine, N-oxide, imine, diol, or carboxylic acid. In some instances, at least one C-H bond of Compound 1 is oxidized to an alcohol. In some instances, at least two C-H bonds of Compound 1 (e.g., CH2 group) are oxidized to a ketone. In some instances, at least three C-H bonds (e.g., CH3 group) of Compound 1 are oxidized to a carboxylic acid. In some instances, at least 1, 2, 3, 4, or more functional groups are oxidized. In some instances, metabolites of Compound 1 are used in the compositions, formulations, and methods described herein.

[0019] Provided herein is a metabolite of Compound 1 is described as Compound 2 and refers to 3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)-N-( 1 -hydroxy-2-methylpropan-2-yl)azetidine- 1 - carboxamide, which has the chemical structure as shown below:Compound 2.

[0020] Provided herein is a metabolite of Compound 1 is described as Compound 3 and refers to 2-(3- ((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamido)-2 -methylpropanoic acid, which has the chemical structure as shown below:WSGR Docket No. 59475-709.601, Compound 3.

[0021] In some instances, provided herein are compositions comprising a salt, polymorph, solvate, hydrate, stereoisomer, or isotope of Compounds 2 or 3. In some instances, Compounds 2 or 3 are solids. In some instances, Compounds 2 or 3 are crystalline solids. In some instances, after treatment of a patient with Compound 1, at least 1%, 2%, 5%, 10%, 15%, 20%, 25%, 30%, 50%, 60%, 70%, 80%, 90%, or at least 95% of compound is converted into compounds 2 or 3 in-vivo. In some instances, the present disclosure comprises methods of synthetic preparation of Compounds 2 or 3.

[0022] Metabolites may be combined one or more agents disclosed herein (e.g., and anti-obesity agent).Metabolic Diseases and Combination Therapy

[0023] Provided herein are combination therapies to treat metabolic diseases. In some instances, combination therapies comprise a CB1 modulator and an additional agent that that functions through a pathway other than CB1 modulation. Metabolic diseases may comprise one or more conditions. In some instances, metabolic diseases include but are not limited to obesity, type II diabetes, diabetic retinopathy, fatty liver disease (FLD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, liver cancer, or liver cirrhosis. A patient in some instance may have multiple metabolic diseases. Additional agents may be administered orally or by parenteral injection. In some instances, a method of treating a metabolic disease in a subject in need thereof comprises administering to the subject a therapeutically effective amount of a CB1 modulator, and at least one therapeutically- effective amount of an agent that functions through a pathway other than CB 1 modulation.

[0024] Comorbidities may also exist between metabolic diseases. In addition to being overweight or obese, a subject or patient can further have overweight- or obesity-related comorbidities, i.e., diseases and other adverse health conditions associated with, exacerbated by, or precipitated by being overweight or obese. Contemplated herein is the compound of the current disclosure administered in combination with at least one other agent that has previously been shown to treat these overweight- or obesity-related conditions. Provided herein are combination therapies comprising a CB1 modulator (e.g., ANEB-001) and one or more additional agents. In some embodiments, an agent treats a metabolic disease described herein. In some embodiments, an agent comprises an anti-obesity agent. Such agents may be formulated for administration sequentially with a CB1 modulator or combined into a single administration.

[0025] Type II diabetes has been associated with obesity. Certain complications of Type II diabetes, e.g., disability and premature death, can be prevented, ameliorated, or eliminated by sustained weight loss (Astrup, A. Pub Health Nutr (2001) 4:499-515). Agents administered to treat Type II diabetes include sulfonylureas (e.g., Chlorpropamide, Glipizide, Glyburide, Glimepiride); meglitinides (e.g., Repaglinide and Nateglinide); biguanides (e.g., Metformin); thiazolidinediones (Rosiglitazone,WSGR Docket No. 59475-709.601Troglitazone, and Pioglitazone); dipeptidylpeptidase-4 inhibitors (e.g., Sitagliptin, Vildagliptin, and Saxagliptin); glucagon-like peptide-1 mimetics (e.g., exenatide and liraglutide); and alpha-glucosidase inhibitors (e.g., Acarbose and Miglitol.

[0026] Another aspect of this disclosure provides methods for facilitating and maintaining weight loss in a subject involving administering to the subject an amount of a disclosed compound effective to result in weight loss in the subject; and administering a therapeutically effective amount of a different weight loss agent to maintain a reduced weight in the subject. Weight loss agents include serotonin and noradrenergic re-uptake inhibitors; noradrenergic re-uptake inhibitors; selective serotonin re-uptake inhibitors; and intestinal lipase inhibitors. Particular weight loss agents include liraglutide, orlistat, sibutramine, methamphetamine, ionamin, phentermine, bupropion, diethylpropion, phendimetrazine, benzphetamine, bromocriptine, lorcaserin, topiramate, or agents acting to modulate food intake by blocking ghrelin action, inhibiting diacylglycerol acyltransferase 1 (DGAT1) activity, inhibiting stearoyl Co A desaturase 1 (SCD1) activity, inhibiting neuropeptide Y receptor 1 function, activating neuropeptide Y receptor 2 or 4 function, or inhibiting activity of sodium -glucose cotransporters 1 or 2. These compounds are administered in regimens and at dosages known in the art.

[0027] An anti -obesity agent may modulate one or more targets related to obesity. Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted from enteroendocrine cells in the gut after eating. Without being bound by theory, GLP-1 plays a potential role in regulation of post-prandial glycemia by directly augmenting meal-induced insulin secretion from the pancreatic beta-cells, as well as in promoting satiety by delaying the transit of food through the gut. GLP-1 also mediates intracellular signaling via the GLP-1 receptor (GLP-1 R) in the family of G-protein coupled receptors that are present on the cell membrane and can result in accumulation of the secondary messenger cyclic adenosine monophosphate (cAMP) upon activation. GLP-1R agonists are currently being investigated in connection with diabetes, obesity, and NASH. GLP-1R agonists include peptides, such as exenatide, liraglutide, and dulaglutide, that have been approved for the management of type 2 diabetes. In some cases, such peptides are predominantly administered by subcutaneous injection. In some instances, peptides are too quickly broken down in the stomach. However, oral GLP-1R agonists are also under investigation for treatment of type 2 diabetes. Some GLP-1R agonists, such as liraglutide, dulaglutide, and exenatide are resistant to rapid degradation by dipeptidyl peptidase 4, resulting in longer half-lives than endogenous GLP-1.

[0028] In addition to Glucagon-like Peptide-1 (GLP-1), Glucose-dependent insulinotropic peptide (GIP) is an incretin which regulates the amount of insulin that is secreted after eating (Kim and Egan, Pharm Rev 60:470-512 (2008)). Specifically, GIP exerts glucose -dependent stimulatory effects on insulin secretion and ensures prompt insulin-mediated uptake of glucose into tissues. GLP-1 stimulates insulin synthesis and secretion, inhibition of glucagon secretion, and inhibition of food intake. Although GLP-1 has been targeted extensively for metabolic diseases such as diabetes, GIP antagonists have also been suggested for the treatment of diabetes McLean et al., Am J Physiol Endocrinol Metab 296(6): E1746- 1755 (2007).WSGR Docket No. 59475-709.601

[0029] In some embodiments, an anti -obesity agent is a GLP-1 modulator. In some embodiments, an anti -obesity agent is a is a GLP-l / GIP modulator. In some embodiments, an anti -obesity agent is a GLP-1 agonist. In some embodiments, an anti -obesity agent is a GLP-l / GIP / Glucagon agonist. In some embodiments, an anti -obesity agent is a GLP-l / amylin agonist. In some embodiments, an anti -obesity agent is a GLP-1 / glucagon agonist. In some embodiments, an anti-obesity agent is a GLP-l / amylin agonist. In some embodiments, an anti -obesity agent is a GLP-1 agonist / GIP antagonist. In some embodiments, an anti -obesity agent comprises semaglutide (Wegovy) or tirzapatide (Zepbound). In some embodiments, the anti-obesity agent is selected from orforglipron (Eli Lilly, GLP-1 agonist), retatrutide (Eli Lilly, GLP-l / GIP / Glucagon agonist), semaglutide (Novo Nordisk, GLP-1 agonist ), cagrilintide / semaglutide (Novo Nordisk, GLP-l / amylin agonist), survodutide (Boehringer / Zealand) GLP-1 / glucagon agonist, danuglipron (Pfizer, GLP-1 agonist), maridebart cafraglutide (Amgen, GLP-1 agonist, GIP antagonist), GSBR-1290 (Structure Therapeutics, GLP-1 agonist ), VK2735 (Viking Therapeutics, dual agonist of the glucagon -like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors), RG 6641 (CT-868, Roche, GLP-l / GIP agonist), RG 6640 (CT-388, Roche, GLP-l / GIP agonist), and RG 6652 (CT-996, Roche, GLP-1 agonist). GLP-1 agonists have been described in WO 99 / 07404, US patent no. 6,268,343, W02006 / 097537, W02005 / 000892, W001 / 04156, and W02000 / 34331. Peptides have been stated to bind to and activate both the glucagon receptor and the GLP-1 receptor and to suppress body weight gain (see, e.g., WO2011 / 075393, W02014 / 041195, WO2015 / 183054, W02016 / 065090, W02016 / 108617, WO2017 / 074798).

[0030] In some embodiments, an anti-obesity agent is a serotonin-norepinephrine reuptake inhibitor. In some embodiments, an anti-obesity agent comprises sibutramine, desmethylsibutramine, didesmethylsibutramine, fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram, duloxetine, and venlafaxine.

[0031] In some embodiments, an anti-obesity agent comprises tetrahydrolipstatin (orlistat), alizyme (cetilistat), a MC4 receptor agonist, a NPY receptor agonist such as e.g., a NPY2 antagonist (e.g., velneperit), a 5HT2c receptor agonist (e.g., lorcaserin), a Ghrelin antagonist, Pyy 3-36, leptin, a DGAT-1 inhibitor, a noradrenalinedopamine-5HT reuptake inhibitor (e.g., tesofensine), bupropion / naltrexone, bupropion / zonisamide, topiramate / phentermine and pramlintide / metreleptin; or a MCH antagonist, a CCK inhibitor, a FAS inhibitor, an ACC inhibitor, a SCD inhibitor, a beta3 adrenoreceptor agonist, a MTP inhibitor (e.g., lomitapide) or amylin or an amylin analogue (e.g., davalintide or pramlintide).

[0032] In some embodiments, an anti-obesity agent comprises serotonergic appetite suppressants. In some embodiments, an anti-obesity agent comprises fenfluramine.

[0033] The term “metabolic disease” or “metabolic disorder” refers to a group of identified disorders in which errors of metabolism, imbalances in metabolism, or sub-optimal metabolism occur, which may involve glucose (carbohydrate), fatty acid and / or protein oxidation pathways. Accordingly, when unbalanced, these disorders are typically manifested by an unfavorable metabolic status characterized by abnormal blood levels of glucose, ROS and / or FFA compared to their respective levels in healthy controlWSGR Docket No. 59475-709.601 subjects, as described herein. Such disorders include without limitation diabetes and disorders associated with nutritional or endocrine imbalance.

[0034] An unfavorable metabolic status may also occur as a result of chronic inflammatory disorders, in which a non-resolving, unbalanced inflammatory process is accompanied by secondary metabolic complications manifested by abnormal blood levels of glucose, ROS and / or FFA compared to their respective levels in healthy control subjects. Non-limitative examples of such disorders are sepsis and autoimmune diseases.

[0035] Syndrome X (or metabolic syndrome) denotes a set of signs and symptoms associated with the accumulation of fat in the abdomen. This form of fat distribution is common in middle-aged men and is often visible as a pot belly or paunch. Syndrome X is characterized by a number of disorders including gout, impaired glucose metabolism (increasing susceptibility to diabetes), raised blood pressure, and elevated blood cholesterol levels. People with Syndrome X have a high risk of heart disease. Syndrome X is defined as a constellation of metabolic abnormalities in serum or plasma insulin / glucose level ratios, lipids, uric acid levels, vascular physiology, and coagulation factor imbalances by the American Association of Clinical Endocrinologists. The term “syndrome X” as used herein thus refers to a condition characterized by positive diagnosis of at least two of the following: Non-insulin-dependent diabetes, blood pressure above a level considered normal, insulin level above a level considered normal, dyslipidemia, and obesity.

[0036] The combinations of the present disclosure can be provided in accordance with one embodiment as part of a kit. Accordingly, in some embodiments, a kit for administering a combination to a patient in need thereof is provided wherein the kit comprises a combination as described herein.

[0037] In one embodiment the kit is provided with a device for administering the composition to a patient, e.g., syringe needle, pen device, jet injector or another needle-free injector. The kit may alternatively or in addition include one or more containers, e.g., vials, tubes, bottles, single or multichambered pre-filled syringes, cartridges, infusion pumps (external or implantable), jet injectors, prefilled pen devices and the like, optionally containing the combination in a lyophilized form or in an aqueous solution. The kits in some embodiments comprise instructions for use. In accordance with one embodiment the device of the kit is an aerosol dispensing device, wherein the composition is prepackaged within the aerosol device. In another embodiment the kit comprises a syringe and a needle, and in one embodiment the sterile composition is prepackaged within the syringe.

[0038] A combination described herein may be useful in the following metabolic diseases:(a) prevention and / or treatment of all forms of diabetes, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin dependent diabetes, MODY (maturity onset diabetes of the young), gestational diabetes, and / or for reduction ofHbAlC;(b) delaying or preventing diabetic disease progression, such as progression in type 2 diabetes, delaying the progression of impaired glucose tolerance (IGT) to insulin requiring type 2 diabetes, delaying, or preventing insulin resistance, and / or delaying the progression of noninsulin requiring type 2 diabetes to insulin requiring type 2 diabetes;WSGR Docket No. 59475-709.601(c) improving B-cell function, such as decreasing B-cell apoptosis, increasing B-cell function and / or B-cell mass, and / or for restoring glucose sensitivity to B-cells; (d) prevention and / or treatment of cognitive disorders and / or neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and / or multiple sclerosis; (e) prevention and / or treatment of eating disorders, such as obesity, e.g., by decreasing food intake, reducing body weight, suppressing appetite, inducing satiety; treating or preventing binge eating disorder, bulimia nervosa, and / or obesity induced by administration of an antipsychotic or a steroid; reduction of gastric motility; delaying gastric emptying; increasing physical mobility; and / or prevention and / or treatment of comorbidities to obesity, such as osteoarthritis and / or urine incontinence;(f) prevention and / or treatment of diabetic complications, such as angiopathy; neuropathy, including peripheral neuropathy; nephropathy; and / or retinopathy;(g) improving lipid parameters, such as prevention and / or treatment of dyslipidemia, lowering total serum lipids; increasing HDL; lowering small, dense LDL; lowering VLDL; lowering triglycerides; lowering cholesterol; lowering plasma levels of lipoprotein a (Lp(a)) in a human; inhibiting generation of apolipoprotein a (apo(a)) in vitro and / or in vivo;(h) prevention and / or treatment of cardiovascular diseases, such as syndrome X, atherosclerosis, myocardial infarction, coronary heart disease, reperfusion injury, stroke, hypoxia, cerebral ischemia, an early cardiac or early cardiovascular disease, left ventricular hypertrophy, coronary artery disease, hypertension, essential hypertension, acute hypertensive emergency, cardiomyopathy, heart insufficiency, exercise intolerance, acute and / or chronic heart failure, arrhythmia, cardiac dysrhythmia, syncopy, angina pectoris, cardiac bypass and / or stent reocclusion, intermittent claudication (atherosclerosis obliterans), diastolic dysfunction, and / or systolic dysfunction; and / or reduction of blood pressure, such as reduction of systolic blood pressure;(i) prevention and / or treatment of gastrointestinal diseases, such as inflammatory bowel disease, short bowel syndrome, or Crohn's disease or colitis; dyspepsia, and / or gastric ulcers; and / or inflammation, such as psoriasis, psoriatic arthritis, rheumatoid arthritis, and / or systemic lupus erythematosus;(j) prevention and / or treatment of critical illness, such as treatment of a critically ill patient, a critical illness poly-nephropathy (CIPNP) patient, and / or a potential CIPNP patient; prevention of development of critical illness or CIPNP; prevention, treatment, and / or cure of systemic inflammatory response syndrome (SIRS) in a patient;(k) prevention and / or treatment of polycystic ovary syndrome (PCOS);(l) prevention and / or treatment of cerebral disease, such as cerebral ischemia, cerebral hemorrhage, and / or traumatic brain injury;(m) prevention and / or treatment of sleep apnea;(n) prevention and / or treatment of abuse, such as alcohol abuse and / or drug abuse; and / orWSGR Docket No. 59475-709.601(o) prevention or treatment of fatty liver conditions, including but not limited to Fatty Liver Disease (FLD), nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH).Compositions and Formulations

[0039] In another aspect, the present disclosure provides compositions, including pharmaceutical compositions and injectable compositions. In some instances, provided herein are compositions or formulations of CB1 modulators. In some instances, provided herein are compositions or formulations of additional agents, such as anti -obesity agents. In some instances, compositions or formulations comprise both a CB1 modulators and an additional agent disclosed herein (e.g., anti -obesity agents). Pharmaceutical Composition

[0040] In one aspect, the present disclosure provides a pharmaceutical composition comprising the (R)- A'-(tcrt-biityl)-3-((4-chlorophcnyl)(2-(trifluoromcthyl)phcnyl)mcthoxy)azctidinc- 1 -carboxamide, and at least one pharmaceutically acceptable excipient. In some instances, a pharmaceutical composition comprises Compound 2, 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)-N-(l-hydroxy-2- methylpropan-2-yl)azetidine- 1 -carboxamide and at least one pharmaceutically acceptable excipient. In some instances, a pharmaceutical composition comprises 2-(3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamido)-2-methylpropanoic acid and at least one pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition comprises at least one additional agent (e.g., anti -obesity agent).

[0041] In some embodiments, the one or more compositions, polymorphs of Compound 1 or metabolite thereof are formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds / polymorphs into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington ’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999).

[0042] In some embodiments, the present disclosure provides pharmaceutical compositions comprising Compound 1, polymorphs of Compound 1 or metabolite thereof and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In certain embodiments, the pharmaceutical compositions include Compound 1, or one or more polymorphs of Compound 1 or metabolite thereof.

[0043] A pharmaceutical composition, as used herein, refers to a mixture of one or more of Compound 1, polymorphs of Compound 1 or metabolite thereof, optionally with a second agent, with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickeningWSGR Docket No. 59475-709.601 agents, and / or excipients. In certain embodiments, the pharmaceutical composition facilitates administration of the polymorphs to an organism. In some embodiments, in practicing the methods of treatment or use as described herein, therapeutically effective amounts of one or more of Compound 1, polymorphs of Compound 1 or metabolite thereof are administered in a pharmaceutical composition to a subject having a condition or disorder to be treated. In specific embodiments, the subject is a human. In certain embodiments, therapeutically effective amounts vary depending on the severity of the condition or disorder, the age and relative health of the subject and other factors. The one or more of Compound 1, polymorphs of Compound 1 or metabolite thereof described herein are used singly or in combination with one or more therapeutic agents as components of mixtures.

[0044] In some embodiments, Compound 1, polymorphs of Compound 1 or metabolite thereof are subjected to spray drying prior to being formulated.

[0045] In some embodiments, the pharmaceutical composition is formulated for oral, parenteral, intravenous (IV), intramuscular (IM), subcutaneous (SC), endotracheal, sublingual, buccal, intralingual, submental, transdermal, suppository, or intranasal administration.

[0046] In various embodiments of the methods described herein, the amount of (R)-N-(tert-butyl)-3- ((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide in the bloodstream of the subject reaches at least 30 ng / mL after 24 hours after oral administration. In various embodiments of the methods described herein, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide in the bloodstream of the subject reaches at least 10 ng / mL after 24 hours after oral administration.

[0047] In one embodiment, the compounds and polymorphs of Compound 1 or a metabolite thereof described herein are formulated for oral administration. The compounds, polymorphs of Compound 1 or metabolite thereof are formulated by combining the compounds or polymorphs with, e.g., pharmaceutically acceptable carriers or excipients. In various embodiments, the compositions, polymorphs described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions, and the like.

[0048] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the compounds or polymorphs described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.WSGR Docket No. 59475-709.601

[0049] In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and / or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and / or pigments are optionally utilized to characterize different combinations of active compound doses.

[0050] In certain embodiments, therapeutically effective amounts of at least one of Compound 1 or polymorphs described herein is formulated into other oral dosage forms. Oral dosage forms include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In specific embodiments, push-fit capsules contain the active ingredients in admixture with one or more filler. Fillers include, by way of example only, lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In other embodiments, soft capsules, contain one or more active compound that is dissolved or suspended in a suitable liquid. Suitable liquids include, by way of example only, one or more fatty oil, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers are optionally added. In other embodiments, Compound 1 or metabolite thereof is formulated as a softgel.

[0051] In one embodiment, Compound 1, or one or more polymorphs of Compound 1 or metabolite thereof are formulated in an aqueous solution. In other embodiments, Compound 1, or one or more polymorphs of Compound 1 or metabolite thereof are formulated for transmucosal administration. In still other embodiments wherein the one or more polymorphs described herein are formulated for other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions. In specific embodiments, such solutions include physiologically compatible buffers and / or excipients. In some instances, parenteral formulations comprise a second agent disclosed herein (e.g., an anti-obesity agent).

[0052] In other embodiments, therapeutically effective amounts of at least one of the polymorphs of Compound 1 or metabolite thereof as described herein are formulated for buccal or sublingual administration. Formulations suitable for buccal or sublingual administration include, by way of example only, tablets, lozenges, or gels.

[0053] In still other embodiments, Compound 1 or the polymorphs described herein are formulated for parental injection, including formulations suitable for bolus injection or continuous infusion. In specific embodiments, formulations for injection are presented in unit dosage form (e.g., in ampoules) or in multi-dose containers. Preservatives are, optionally, added to the injection formulations. In still other embodiments, the pharmaceutical composition of a polymorph of Compound 1 or metabolite thereof is formulated in a form suitable for parenteral injection as sterile suspension, solution, or emulsion in oily or aqueous vehicles. Parenteral injection formulations optionally contain formulatory agents such as suspending, stabilizing and / or dispersing agents. In specific embodiments, pharmaceutical formulations for parenteral administration include aqueous solutions of the active polymorphs in water-soluble form. In additional embodiments, suspensions of the active polymorphs are prepared as appropriate oilyWSGR Docket No. 59475-709.601 injection suspensions. Suitable lipophilic solvents or vehicles for use in the pharmaceutical compositions described herein include, by way of example only, fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In certain specific embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension contains suitable stabilizers or agents which increase the solubility of the polymorphs to allow for the preparation of highly concentrated solutions. Alternatively, in other embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. In some instances, parenteral formulations comprise a second agent disclosed herein (e.g., an anti -obesity agent).

[0054] In still other embodiments, Compound 1 or polymorphs of Compound 1 or metabolite thereof are administered topically. The one or more polymorphs described herein are formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, or ointments. Such pharmaceutical compositions optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.

[0055] In yet other embodiments, Compound 1 or one or more polymorphs of Compound 1 or metabolite thereof are formulated for transdermal administration. In specific embodiments, transdermal formulations employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and / or dispersed in a polymer or an adhesive. In various embodiments, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. In additional embodiments, the transdermal delivery of Compound 1, or one or more polymorphs of Compound 1 or metabolite thereof is accomplished by means of iontophoretic patches and the like. In certain embodiments, transdermal patches provide controlled delivery of Compound 1, or one or more polymorphs of Compound 1, or a metabolite thereof. In specific embodiments, the rate of absorption is slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. In alternative embodiments, absorption enhancers are used to increase absorption. Absorption enhancers or carriers include absorbable pharmaceutically acceptable solvents that assist passage through the skin. For example, in one embodiment, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

[0056] In other embodiments, the Compound 1, or one or more polymorphs of Compound 1 or metabolite thereof are formulated for administration by inhalation. Various forms suitable for administration by inhalation include, but are not limited to, aerosols, mists, or powders. Pharmaceutical compositions of the polymorphs of Compound 1 or metabolite thereof are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In specific embodiments, the dosage unit of a pressurized aerosol isWSGR Docket No. 59475-709.601 determined by providing a valve to deliver a metered amount. In certain embodiments, capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0057] In still other embodiments, the Compound 1, or one or more polymorphs of Compound 1 or metabolite thereof are formulated in rectal compositions for suppository administration such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.

[0058] In certain embodiments, pharmaceutical compositions are formulated in any conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active polymorphs into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are optionally used as suitable. Pharmaceutical compositions comprising the Compound 1 , or one or more polymorphs of Compound 1 or metabolite thereof are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0059] Pharmaceutical compositions include at least one pharmaceutically acceptable carrier, diluent or excipient and Compound 1 or at least one polymorph of Compound 1 or metabolite thereof described herein as an active ingredient. The active ingredient is in acid-free or base-free form, or in a pharmaceutically acceptable salt form. All tautomers of the compounds described herein are included within the scope of the compounds presented herein. Additionally, the compounds described herein encompass unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein. In addition, the pharmaceutical compositions optionally include other medicinal or pharmaceutical agents, carriers, adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure, buffers, and / or other therapeutically valuable substances.

[0060] Methods for the preparation of compositions, comprising the Compound 1, or one or more polymorphs of Compound 1 or metabolite thereof described herein include formulating the polymorphs with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories. Liquid compositions include solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein. Semi-solid compositions include, but are not limited to, gels, suspensions, and creams. The form of the pharmaceutical compositions described herein include liquidWSGR Docket No. 59475-709.601 solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions also optionally contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and so forth.

[0061] In some embodiments, pharmaceutically acceptable carriers or excipients for formulations described herein may comprise one or more polymers. In some embodiments, the pharmaceutically acceptable carrier is a polymer. Examples of polymers suitable for oral, buccal, intranasal, transdermal, thin-fdm, suppository or other administration include biocompatible and biodegradable polymers. Further examples of biocompatible polymers include natural or synthetic polymers such as polystyrene, polylactic acid, polyketal, butadiene styrene, styreneacrylic-vinyl terpolymer, polymethylmethacrylate, polyethylmethacrylate, polyalkylcyanoacrylate, styrene-maleic anhydride copolymer, polyvinyl acetate, polyvinylpyridine, polydivinylbenzene, polybutyleneterephthalate, acrylonitrile, vinylchloride-acrylates, poly caprolactone, poly(alkyl cyanoacrylates), poly(lactic-co-glycolic acid), and the like. In some instances, the carrier is Labrasol. In some instances, the carrier is methyl cellulose. In further embodiments, the pharmaceutically acceptable carrier comprises one or more biodegradable polymers. Use of biodegradable polymers provides the advantages of using a formulation that will eventually disintegrate, which facilitates release of the benzofuran compound and elimination of the carrier in vivo. However, benzofuran compounds can also be released from the matrix of non-biodegradable polymers as a result of gradual efflux from channels within the polymer matrix, including those formed by soluble materials included in the polymer matrix.

[0062] Examples of biodegradable polymers include polylactide polymers include poly(D,L-lactide)s; poly(lactide-co-glycolide) (PLGA) copolymers; polyglycolide (PGA) and polydioxanone; caprolactone polymers; chitosan; hydroxybutyric acids; polyanhydrides and polyesters; polyphosphazenes; and polyphosphoesters. In some instances, the biodegradable polymer for use in the nanoparticles is polyD, L-lactide-co-glycolide).

[0063] Functionalized poly (D,L-lactide)s can also be used as biodegradable polymers in the nanoparticles described herein. Examples of functionalized poly(D,L-lactide)s include poly(L-lactide), acrylate terminated; poly(L-lactide), amine terminated; poly(L-lactide), azide terminated; poly(L-lactide), 2-bromoisobutyryl terminated; poly(L-lactide), 2-bromoisobutyryl terminated; poly(L-lactide) 4-cyano- 4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentonate; poly(L-lactide) N-2-hydroxyethylmaleimide terminated; poly(L-lactide) 2-hydroxyethyl, methacrylate terminated; poly(L-lactide), propargyl terminated; or poly(L-lactide), thiol terminated.

[0064] Other biodegradable polymers that can be used in the nanoparticles include AB eblock copolymers such as polyfcthylcnc glycol) methyl ether-block-poly(D,L-lactide); polyfcthylcnc glycol) methyl ether-block-poly(lactide-co-glycolide) PEG; polyfcthylcnc glycol)-block-poly(.epsilon.- caprolactone) methyl ether PEG; and polypyrrole-block-poly(caprolactone). Further biodegradable polymers include ABA triblock copolymers such as polylactide-block-polyfethylene glycol)-block- polylactide PLA; poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co- glycolide); poly(lactide-co-caprolactone)-block-poly(ethylene glycol)-block-poly(lactide-co-WSGR Docket No. 59475-709.601 caprolactone); polycaprolactone-block-polytetrahydrofuran-block-polycaprolactone; and polyglycolide- block-poly(ethylene glycol)-block-polyglycolide PEG.

[0065] Biodegradable polymers also include various natural polymers. Examples of natural polymers include polypeptides including those modified non-peptide components, such as saccharide chains and lipids; nucleotides; sugar-based biopolymers such as polysaccharides; cellulose; carbohydrates and starches; dextrans; lignins; polyamino acids; adhesion proteins; lipids and phospholipids (e.g., phosphorylcholine). In some embodiments, the polymer is a cellulose derivative such as hydroxypropyl methylcellulose polymers. Hydroxypropyl methyl cellulose (HPMC) is a non-ionic cellulose ether made through a series of chemical processes, with the natural polymer cellulose as the raw material. The product is a non-ionic cellulose ether in the shape of white powder, odorless and tasteless. HPMC is also known as hypromellose, is a methylcellulose modified with a small amount of propylene glycol ether groups attached to the anhydroglucose of the cellulose.

[0066] Useful pharmaceutical compositions also, optionally, include solubilizing agents to aid in the solubility of a polymorph of Compound 1 or metabolite thereof. The term “solubilizing agent” generally includes agents that result in formation of a micellar solution or a true solution of the agent. Certain acceptable nonionic surfactants, for example polysorbate 80, are useful as solubilizing agents, as can ophthalmically acceptable glycols, polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

[0067] Furthermore, useful pharmaceutical compositions optionally include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

[0068] Additionally, useful compositions also, optionally, include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.

[0069] Still other useful compositions include one or more surfactants to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40.Injectable Compositions

[0070] In some embodiments, Compound 1 or metabolite thereof is formulated into an injectable composition. In some embodiments, the injectable composition comprises (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide, or the pharmaceutical composition described herein, an opioid antagonist, and a benzodiazepine antagonist. In some embodiments, the benzodiazepine antagonist is flumazenil. In some embodiments, the opioid antagonistWSGR Docket No. 59475-709.601 is naloxone or naltrexone. In some embodiments, the opioid antagonist is samidorphan. In some embodiments, the opioid antagonist is naltrexone. In some embodiments, the injectable composition is formulated in a single dose injectable device.Methods of Making Compound 1 and Polymorphic Forms Thereof

[0071] In another aspect, the present disclosure provides methods of making one or more polymorphs or metabolites of Compound 1:Compound 1, or a pharmaceutically acceptable solvate or hydrate thereof.

[0072] The preparation and uses of Compound 1 have been previously described (see, Example 81 of US 7,504,522, which is incorporated by reference).Methods of Treatment

[0073] Methods provided herein may comprise measurement of one or more metrics followed by treatment with compounds described herein (e.g., Compound 1 or a metabolite thereof). In one aspect, the present disclosure provides a method of treating obesity or a metabolic disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide and an anti -obesity agent that functions through a pathway other than CB 1 modulation, or the pharmaceutical composition as described herein.

[0074] In some embodiments, a method of treatment comprises a method of treating an excessive weight in a subject. In some embodiments, excessive weight comprises a body mass index (BMI) that is greater than a BMI designated as normal. In some cases, an excessive weight comprises a BMI about 5%-100% greater than a BMI designated as normal, or in some cases a BMI greater than 100% of a BMI designated as normal.

[0075] In various embodiments of the methods as described herein, (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is Form I. In another embodiment, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l- carboxamide is Form II.

[0076] In various embodiments of the methods as described here, the amount of ( R)- / V-(tcrt-bnty 1 )-3 - ((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide is between about 0.1 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is between about 1 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2-WSGR Docket No. 59475-709.601(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is between about 0.5 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is between about 2 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is between about 5 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is between about 10 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is between about 15 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is between about 20 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is between about 25 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is between about 30 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is between about 35 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is between about 40 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is between about 45 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is between about 50 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is between about 75 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is between about 100 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is between about 125 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is between about 150 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is between about 175 mg to about 200 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is 25-500, 25-400, 25-300, 25-250, 25-200, 25-150, 25-100, or 25-75 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide is 50-500, 50-400, 50-300, 50-250, 50-200, 50-150, 50-100, or 50-75 mg. In another embodiment, the amount of (R)-JV-(tert-butyl)-WSGR Docket No. 59475-709.6013-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide is 75-500, 75-400, 75- 300, 75-250, 75-200, 75-150, 75-100, or 75-125 mg. In another embodiment, the amount of (R)- / V-(tert- butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide is 100-500, 100- 400, 100-300, 100-250, 100-200, 100-150, 100-125 mg. In another embodiment, the amount of (R)-JV- (tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide is 1-200 mg, 10-50 mg, 10-30 mg, or 20-30 mg. In another embodiment, the amount of (R)- / V-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide is 5-300 mg, 5-100 mg, or 10-30 mg. In another embodiment, the amount of ( R)- / V-(tcrt-bnty 1 )-3 -((4-chlorophcnyl )(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is 1-50, 1-30, 1-25, 1-20, 1-15, 1-10, 1-5, or 1-3 mg. In another embodiment, the amount of (R)- / V-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is 50, 30, 25, 20, 15, 10, 5, 3 or 1 mg.

[0077] In some embodiments, the CB1 inhibitor is administered in a dose of 0. 1-500 mg, 0.5-300 mg, 1-300 mg, 2-300 mg, 5-300 mg, 10-300 mg, 15-300 mg, 20-300 mg, 25-300 mg, 30-300 mg, 50-300 mg, 75-300 mg, 100-300 mg, 150-300 mg, 200-300 mg, 250-300 mg, 0.1-100 mg, 0.5-100 mg, 1-100 mg, 2- 100 mg, 5-100 mg, 10-100 mg, 15-100 mg, 20-100 mg, 25-100 mg, 30-100 mg, 50-100 mg, 0.5-25, 1-25 mg, 2-25 mg, 5-25 mg, 10-25 mg, 15-25 mg, or 20-25 mg. In another embodiment, the CB1 inhibitor is (R)-A'-(tcrt-butyl)-3-((4-chlorophcnyl)(2-(trifhioromcthyl)phcnyl)mcthoxy)azctidinc- 1 -carboxamide in an amount of 25-500, 25-400, 25-300, 25-250, 25-200, 25-150, 25-100, or 25-75 mg.

[0078] In some embodiments, the anti -obesity agent is administered in a dose of 0.01-10 mg, 0.02-10 mg, 0.05-10 mg, 0.1-10 mg, 0.2-10 mg, 0.5-10 mg, 1.0-10 mg, 2.0-10 mg, 5.0-10 mg, 0.01-5 mg, 0.02-5 mg, 0.05-5 mg, 0.1-5 mg, 0.2-5 mg, 0.5-5 mg, 1.0-5 mg, 2.0-5 mg, 0.01-2 mg, 0.02-2 mg, 0.05-2 mg, 0.1-2 mg, 0.2-2 mg, 0.5-2 mg, 1.0-2 mg, 0.01-1 mg, 0.02-1 mg, 0.05-1 mg, 0.1-1 mg, 0.2-1 mg, or 0.5-1 mg. The GLP-1 agonist may be administered at a dose of up to about 50 mg, such as up to about 40 mg, up to about 30 mg, up to about 20 mg or up to about 10 mg. The GLP-1 agonist may be administered at a dose of from about 0.25 mg to about 100 mg, such as from about 0.25 mg to about 90 mg, such as from about 0.25 mg to about 80 mg, such as from about 0.25 mg to about 70 mg, such as from about 0.25 mg to about 60 mg, about 0.25 mg to about 50 mg, such as from about 0.25 mg to about 40 mg, such as from about 0.25 mg to about 30 mg, from about 0.25 mg to about 20 mg, from about 0.25 mg to about 14 mg or from about 0.25 mg to about 10 mg. The GLP-1 agonist may be administered at a dose of from about 1 mg to about 50 mg, such as from about 1 mg to about 30 mg, from about 1 mg to about 20 mg, from about 1 mg to about 14 mg or from about 1 mg to about 10 mg. The GLP-1 agonist may be administered at a dose of about 0.25 mg, about 0.5 mg, about 0.6 mg, about 1 mg, about 1.2 mg, about 1.5 mg, about 1.8 mg, about 2 mg, about 3 mg, about 4.5 mg, about 5 mg, about 7 mg, about 10 mg, about 14 mg, about 20 mg, about 30 mg or about 50 mg. The GLP-1 agonist may be administered at a dose of up to about 10 mg / kg body weight of the subject, such as up to about 5 mg / kg body weight or up to about 1 mg / kg body weight. The GLP-1 agonist may be administered at a dose of from about 0.01 to about 10 mg / kg body weight of the subject, such as from about 0.01 to about 5 mg / kg body weight, from about 0.01 to about 1 mg / kg body weight, from about 0.05 to about 10 mg / kg body weight, from about 0.05 to about 5 mg / kgWSGR Docket No. 59475-709.601 body weight, from about 0.05 to about 1 mg / kg body weight or from about 0.05 to about 0.5 mg / kg body weight. Exenatide is preferably administered by subcutaneous injection twice daily, at least 6 hours apart and each time before a main meal. Initially, 5 mg are administered twice daily for at least 1 month, then the dose may be increased to 10 mg twice daily if necessary. Alternatively, exenatide may be administered by subcutaneous injection once weekly at a dose of 2 mg. Liraglutide is preferably administered by subcutaneous injection once daily. Initially, 0.6 mg are administered once daily for at least 1 week, then the dose is increased to 1.2 mg once daily for at least 1 week, and then the dose may be increased to 1.8 mg once daily if necessary. Semaglutide is preferably administered by subcutaneous injection once weekly. Semaglutide may be administered subcutaneously at a dose of up to about 7.2 mg. In a preferred embodiment, 0.25 mg are initially administered once weekly for at least 4 weeks, then the dose is increased to 0.5 mg once weekly for at least 4 weeks, then the dose is increased to 1 mg once weekly for at least 4 weeks, then the dose is increased to 1.7 mg once weekly for at least 4 weeks, and then the dose is increased to 2.4 mg once weekly; the dose is maintained at 2.4 mg for the course of the treatment. Alternatively, semaglutide may be administered orally once daily on an empty stomach. Semaglutide may be administered orally once daily at a dose of up to about 50 mg, such as about 50 mg, about 40 mg, about 30 mg, about 20 mg or about 10 mg. In a preferred embodiment, 3 mg are initially administered once daily for at least 1 month, then the dose is increased to 7 mg once daily for at least 1 month, and then the dose may be increased to 14 mg once daily if necessary. Dulaglutide is preferably administered by subcutaneous injection once weekly at a dose of 0.75 mg. Alternatively, if dulaglutide is administered in combination with another drug (such as a GIP agonist), dulaglutide is preferably administered initially at 1.5 mg once weekly for at least 4 weeks, then the dose is increased to 3 mg once weekly for at least 4 weeks, and then the dose may be increased to 4.5 mg once weekly if necessary. Lixisenatide is preferably administered by subcutaneous injection once daily, taken within 1 hour before a meal. Initially, 10 mg are administered once daily for 2 weeks, then the dose is increased to 20 mg once daily. Albiglutide is preferably administered by subcutaneous injection once weekly at a dose of 30 mg. The dose may be increased to 50 mg if the glycaemic response is inadequate. Taspoglutide is preferably administered by subcutaneous injection once weekly.

[0079] In another embodiment, the CB1 inhibitor is (R)-A-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide in an amount of 25-500, 25-400, 25-300, 25- 250, 25-200, 25-150, 25-100, or 25-75 mg and the anti-obesity agent is administered in a dose of 0.01-10 mg, 0.02-10 mg, 0.05-10 mg, 0.1-10 mg, 0.2-10 mg, 0.5-10 mg, 1.0-10 mg, 2.0-10 mg, 5.0-10 mg, 0.01-5 mg, 0.02-5 mg, 0.05-5 mg, 0.1-5 mg, 0.2-5 mg, 0.5-5 mg, 1.0-5 mg, 2.0-5 mg, 0.01-2 mg, 0.02-2 mg, 0.05-2 mg, 0.1-2 mg, 0.2-2 mg, 0.5-2 mg, 1.0-2 mg, 0.01-1 mg, 0.02-1 mg, 0.05-1 mg, 0.1-1 mg, 0.2-1 mg, or 0.5-1 mg.

[0080] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the CB 1 inhibitor and / or additional agent, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day, e.g., two, three, four or more times daily. In some embodiments,WSGR Docket No. 59475-709.601 the compounds described herein are administered daily, every other day, every other day 3 times a week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 3 days, every 4 days, every 5 days, every 6 days, weekly, bi-weekly, 3 times a week, 4 times a week, 5 times a week, 6 times a week, once a month, twice a month, 3 times a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months. In some embodiments, the compounds described herein are administered daily. In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered every 8 hours; (iv) the compound is administered every 12 hours; (v) the compound is administered to the mammal every 24 hours.

[0081] In certain embodiments wherein a patient's status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (e.g., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during a drug holiday is, by way of example only, by 10%- 100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended, or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 7 days. In one embodiment, the length of the drug holiday is 7 days. In one embodiment, the length of the drug holiday is 14 days. In one embodiment, the length of the drug holiday is 28 days.

[0082] Compounds described herein (e.g., Compound 1 or metabolite thereof) in some instances have desirable PK profdes. In some instances, concentrations (e.g., Cmax, AUC, etc.) of Compound 1 or metabolite thereof are measured in plasma.

[0083] In various embodiments of the methods described herein, the amount of (R)-N-(tert-butyl)-3- ((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide in the bloodstream of the subject reaches at least about 50 ng / mL, at least about 100 ng / mL or at least about 200 ng / mL within one hour after oral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within 50 minutes after oral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l- carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within 40 minutes after oral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within 30 minutes after oral administration. In another embodiment, the amount of (R)-WSGR Docket No. 59475-709.601N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within 20 minutes after oral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within 10 minutes after oral administration. In another embodiment, the amount of (R)- N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within 5 minutes after oral administration.

[0084] In various embodiments of the methods described herein, the amount of (R)-N-(tert-butyl)-3- ((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide in the bloodstream of the subject reaches at least 200 ng / mL within one hour after oral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l- carboxamide in the bloodstream of the subject reaches at least 150 ng / mL within 50 minutes after oral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide in the bloodstream of the subject reaches at least 150 ng / mL within 40 minutes after oral administration. In another embodiment, the amount of (R)- N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide in the bloodstream of the subject reaches at least 150 ng / mL within 30 minutes after oral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide in the bloodstream of the subject reaches at least 150 ng / mL within 20 minutes after oral administration. In another embodiment, the amount of (R)- N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide in the bloodstream of the subject reaches at least 150 ng / mL within 10 minutes after oral administration. In another embodiment, the amount of (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide in the bloodstream of the subject reaches at least 150 ng / mL within 5 minutes after oral administration.

[0085] In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is dosed to provide a Tmax of no more than 5,4, 3, 2.5, 2.25, 2, 1.75, 1.5, 1.25, 1, 0.75, 0.5, or 0.25 hours. In some instances, (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide is dosed to provide a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at 100-200 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5- 1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at 25-250 mg provides a Tmax of 0.1- 5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5- 1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 200 mg provides aWSGR Docket No. 59475-709.601Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 150 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)-3- ((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 100 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5- 3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide dosed at no more than 75 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5- 3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide dosed at no more than 50 mg provides a Tmax of 0.1 -5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5- 3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide dosed at no more than 30 mg provides a Tmax of 0.1 -5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5- 3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide dosed at no more than 20 mg provides a Tmax of 0.1 -5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5- 3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide dosed at 10-50 mg provides a Tmax of 0.1 -5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5- 2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at 20-75 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide dosed at 15-50 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide dosed at 10-100 mg provides a Tmax of 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1, 0.25-3, 0.25-2, 0.25-1.5, 0.25-1, 0.5-3, 0.5-2.5, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.75, or 0.1-0.75 hr. In some instances, the dosage is oral.

[0086] In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 200 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100-500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 100 mg provides aWSGR Docket No. 59475-709.601Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100-500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 75 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100-500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 50 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100-500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 30 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100-500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 20 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100-500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 15 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100-500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 10 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100-500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 5 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100-500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 1 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100-500 ng / mL, about 100-400 ng / mL, or about 100-300 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at 15-50 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100-500 ng / mL, about 100-400 ng / mL, or about 100-WSGR Docket No. 59475-709.601300 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at 20-50 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100-500 ng / mL, about 100-400 ng / mL, or about 100- 300 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at 10-75 mg provides a Cmax of about 100-500 ng / mL, about 50-1000 ng / mL, about 50-400 ng / mL, about 50-300 ng / mL, about 50-200 ng / mL, about 50-500 ng / mL, about 75-750 ng / mL, about 100-500 ng / mL, about 100-400 ng / mL, or about 100- 300 ng / mL. In some instances, the dosage is oral.

[0087] In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide provides a dosage normalized plasma AUCiast of about 25-600 h*ng / mL / mg, about 25-500 h*ng / mL / mg, about 25-450 h*ng / mL / mg, about 50-500 h*ng / mL / mg, about 50-450 h*ng / mL / mg, about 50-400 h*ng / mL / mg, about 50-300 h*ng / mL / mg, about 50-250 h*ng / mL / mg, about 40-300 h*ng / mL / mg, or about 50-200 h*ng / mL / mg. In some instances, (R)- N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide dosed at no more than 200 mg provides a AUCiast of about 1000-3500 h*ng / mL, about 1000-3000 ng / mL, about 1250-3000 ng / mL, about 1500-2800 ng / mL, about 1000-2500 ng / mL, or about 1200-3000 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l- carboxamide dosed at no more than 150 mg provides a AUCiast of about 1000-3500 h*ng / mL, about 1000-3000 ng / mL, about 1250-3000 ng / mL, about 1500-2800 ng / mL, about 1000-2500 ng / mL, or about 1200-3000 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 100 mg provides a AUCiast of about 1000-3500 h*ng / mL, about 1000-3000 ng / mL, about 1250-3000 ng / mL, about 1500- 2800 ng / mL, about 1000-2500 ng / mL, or about 1200-3000 ng / mL. In some instances, (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide dosed at no more than 75 mg provides a AUCiast of about 1000-3500 h*ng / mL, about 1000-3000 ng / mL, about 1250-3000 ng / mL, about 1500-2800 ng / mL, about 1000-2500 ng / mL, or about 1200-3000 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide dosed at no more than 50 mg provides a AUCiast of about 1000-3500 h*ng / mL, about 1000-3000 ng / mL, about 1250-3000 ng / mL, about 1500-2800 ng / mL, about 1000-2500 ng / mL, or about 1200-3000 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine- 1-carboxamide dosed at no more than 40 mg provides a AUCiast of about 1000-3500 h*ng / mL, about 1000-3000 ng / mL, about 1250-3000 ng / mL, about 1500-2800 ng / mL, about 1000-2500 ng / mL, or about 1200-3000 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine- 1-carboxamide dosed at no more than 30 mg provides a AUCiast of about 1000-3500 h*ng / mL, about 1000-3000 ng / mL, about 1250-3000 ng / mL, about 1500- 2800 ng / mL, about 1000-2500 ng / mL, or about 1200-3000 ng / mL. In some instances, (R)-N-(tert-butyl)- 3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide dosed at no more thanWSGR Docket No. 59475-709.60120 mg provides a AUCiast of about 1000-3500 h*ng / mL, about 1000-3000 ng / mL, about 1250-3000 ng / mL, about 1500-2800 ng / mL, about 1000-2500 ng / mL, or about 1200-3000 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide dosed at no more than 15 mg provides a AUCiast of about 1000-3500 h*ng / mL, about 1000-3000 ng / mL, about 1250-3000 ng / mL, about 1500-2800 ng / mL, about 1000-2500 ng / mL, or about 1200-3000 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine- 1-carboxamide dosed at no more than 10 mg provides a AUCiast of about 500-3500 h*ng / mL, about 500- 3000 ng / mL, about 1250-3000 ng / mL, about 1500-2800 ng / mL, about 1000-2500 ng / mL, or about 1200- 3000 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine- 1-carboxamide dosed at no more than 5 mg provides a AUCiast of about 100-3500 h*ng / mL, about 200-3000 ng / mL, about 1250-3000 ng / mL, about 500-2800 ng / mL, about 300-2500 ng / mL, or about 400-3000 ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine- 1-carboxamide dosed at no more than 1 mg provides a AUCiast of about 100-3500 h*ng / mL, about 100-3000 ng / mL, about 125-3000 ng / mL, about 150-2800 ng / mL, about 200-2500 ng / mL, or about 500-3000 ng / mL. In some instances, the dosage is oral.

[0088] In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine- 1-carboxamide provides a dosage normalized plasma AUCsh of about 5-60 h*ng / mL / mg, about 5-50 h*ng / mL / mg, about 5-45 h*ng / mL / mg, about 5-45 h*ng / mL / mg, about 7-60 h*ng / mL / mg, about 7-50 h*ng / mL / mg, about 7-45 h*ng / mL / mg, about 7-40 h*ng / mL / mg, about 10-60 h*ng / mL / mg, about 10-50 h*ng / mL / mg, about 10-50 h*ng / mL / mg, or about 10-40 h*ng / mL / mg. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine- 1-carboxamide dosed at no more than 200 mg provides a plasma AUCsh of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine- 1-carboxamide dosed at no more than 150 mg provides a plasma AUCsh of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine- 1-carboxamide dosed at no more than 100 mg provides a plasma AUCsh of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine- 1-carboxamide dosed at no more than 75 mg provides aWSGR Docket No. 59475-709.601 plasma AUCsh of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 50 mg provides a plasma AUCsh of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 40 mg provides a plasma AUCsh of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 30 mg provides a plasma AUCsh of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 25 mg provides a plasma AUCsh of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 20 mg provides a plasma AUCsh of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 15 mg provides a plasma AUCsh of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 10 mg provides a plasma AUCsh of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200WSGR Docket No. 59475-709.601 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 5 mg provides a plasma AUCA of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, (R)-N-(tert-butyl)-3-((4-chlorophenyl)(2- (trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide dosed at no more than 1 mg provides a plasma AUCsh of about 200-2000 h*ng / mL, about 200-1500 h*ng / mL, about 200-1200 h*ng / mL, about 300-2500 h*ng / mL, about 300-2000 h*ng / mL, about 300-1750 h*ng / mL, about 300-1500 h*ng / mL, about 400-3000 h*ng / mL, about 400-2000 h*ng / mL, about 400-1500 h*ng / mL, about 400-1200 h*ng / mL, or about 400-1000 h*ng / mL. In some instances, the dosage is oral.

[0089] Compositions and formulations described herein may be administered as daily or multiple doses. In some embodiments, described herein are methods of using the (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l -carboxamide as a weekly treatment. In some embodiments, described herein are methods of administering the (R)-N-(tert-butyl)-3-((4- chlorophenyl)(2-(trifluoromethyl)phenyl)methoxy)azetidine-l-carboxamide every four weeks.Additional Definitions

[0090] As used herein, “active agent” is used to indicate a chemical entity which has biological activity. In certain embodiments, an “active agent” is a compound having pharmaceutical utility. For example, an active agent may be an anti -cancer therapeutic.

[0091] As used herein, “modulation” refers to a change in activity as a direct or indirect response to the presence of a chemical entity as described herein, relative to the activity of in the absence of the chemical entity. The change may be an increase in activity or a decrease in activity and may be due to the direct interaction of the compound with the target or due to the interaction of the compound with one or more other factors that in turn affect the target's activity. For example, the presence of the chemical entity may, for example, increase or decrease the target activity by directly binding to the target, by causing (directly or indirectly) another factor to increase or decrease the target activity, or by (directly or indirectly) increasing or decreasing the amount of target present in the cell or organism.

[0092] As used herein, “therapeutically effective amount” of a chemical entity described herein refers to an amount effective, when administered to a human or non-human subject, to provide a therapeutic benefit such as amelioration of symptoms, slowing of disease progression, or prevention of disease.

[0093] “Treating” or “treatment” encompasses administration of Compound 1 or metabolite thereof, or a pharmaceutically acceptable salt thereof, to a mammalian subject, particularly a human subject, in need of such an administration and includes (i) arresting the development of clinical symptoms of the disease, such as cancer, (ii) bringing about a regression in the clinical symptoms of the disease, such as cancer, and / or (iii) prophylactic treatment for preventing the onset of the disease, such as cancer.WSGR Docket No. 59475-709.601

[0094] As used herein, a “pharmaceutically acceptable” component is one that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio.

[0095] “Pharmaceutically acceptable salts” include, but are not limited to salts with inorganic acids, such as hydrochlorate, carbonate, phosphate, hydrogenphosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as malate, malonate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, gluconate, methanesulfonate, Tris (hydroxymethylaminomethane), p-toluenesulfonate, propionate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, oxalate, pamoate, and alkanoate such as acetate, HOOC-(CH2)n-COOH where n is 0-4, and like salts. Other salts include sulfate, methanesulfonate, bromide, trifluoroacetate, picrate, sorbate, benzilate, salicylate, nitrate, phthalate or morpholine. Pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0096] In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.

[0097] As used herein, “subject” refers to a mammal that has been or will be the object of treatment, observation or experiment. The methods described herein can be useful in both human therapy and veterinary applications. In some embodiments, the subject is a human.

[0098] “Prodrugs” described herein include any compound that becomes Compound 1 or metabolite thereof when administered to a subject, e.g., upon metabolic processing of the prodrug. Similarly, “pharmaceutically acceptable salts” includes “prodrugs” of pharmaceutically acceptable salts. Examples of prodrugs include derivatives of functional groups, such as a carboxylic acid group, in Compound 1 or metabolite thereof. Exemplary prodrugs of a carboxylic acid group include, but are not limited to, carboxylic acid esters such as alkyl esters, hydroxyalkyl esters, arylalkyl esters, and aryloxyalkyl esters. Other exemplary prodrugs include lower alkyl esters such as ethyl ester, acyloxyalkyl esters such as pivaloyloxymethyl (POM), glycosides, and ascorbic acid derivatives. Other exemplary prodrugs include amides of carboxylic acids. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

[0099] A “solvate” is formed by the interaction of a solvent and a compound. The term “compound” is intended to include solvates of compounds. Similarly, “pharmaceutically acceptable salts” includes solvates of pharmaceutically acceptable salts. Suitable solvates are pharmaceutically acceptable solvates,WSGR Docket No. 59475-709.601 such as hydrates, including monohydrates and hemi-hydrates. Also included are solvates formed with the one or more crystallization solvents.

[0100] Pharmaceutically acceptable forms of the compounds recited herein include pharmaceutically acceptable salts, chelates, non-covalent complexes, prodrugs, and mixtures thereof.

[0101] A “chelate” is formed by the coordination of a compound to a metal ion at two (or more) points. The term “compound” is intended to include chelates of compounds. Similarly, “pharmaceutically acceptable salts” includes chelates of pharmaceutically acceptable salts.

[0102] A “non-covalent complex” is formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding). Such non-covalent complexes are included in the term “compound.” Similarly, pharmaceutically acceptable salts include “non-covalent complexes” of pharmaceutically acceptable salts.

[0103] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub combinations of ranges and specific embodiments therein are intended to be included.

[0104] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. In some instances of numerical ranges, “about” means ± 10%.

[0105] As used herein, “significant” refers to any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p < 0.05.

[0106] As used herein, ’’level” means the levels of Glasgow coma metric or coma scale.Select Enumerated Embodiments

[0107] 1. A method of treating obesity, excessive weight or type 2 diabetes in a subject in need thereof, the method comprising: administering to the subject a therapeutically-effective amount of a compound having the structureleast one therapeutically-effective amount of an anti-obesity agent that functions through a pathway other than CB 1 modulation.2. The method of embodiment 1, wherein the anti-obesity agent comprises a modulator of one or more of GLP-1, GLP-1R, gastric inhibitory polypeptide (GIP), glucagon, or amylin. 3. The method of embodiment 1, wherein the anti-obesity agent comprises a modulator of two or more of GLP-1, GLP-1R,WSGR Docket No. 59475-709.601 gastric inhibitory polypeptide (GIP), glucagon, or amylin. 4. The method of embodiment 1, wherein the anti -obesity agent comprises an agonist of one or more of GLP-1, GLP-1 R, gastric inhibitory polypeptide (GIP), glucagon, or amylin. 5. The method of embodiment 1, wherein the anti -obesity agent comprises an agonist of two or more of GLP-1, gastric inhibitory polypeptide (GIP), and glucagon. 6. The method of embodiment 1, wherein the anti -obesity agent comprises an antagonist of gastric inhibitory polypeptide (GIP). 7. The method of embodiment 1, wherein the at least one anti-obesity agent comprises one or more of zepbound, orforglipron, retatrutide, oral semaglutide, cagrilintide / semaglutide, survodutide, danuglipron, maridebart cafraglutide, GSBR-1290, VK2735, RG 6641 (CT-868), RG 6640 (CT-388), and RG 6652 (CT-996). 8. The method of embodiment 1, wherein the at least one anti -obesity agent comprises one or more of liraglutide, orlistat, sibutramine, methamphetamine, ionamin, phentermine, bupropion, diethylpropion, phendimetrazine, benzphetermine, bromocriptine, lorcaserin, and topiramate. 9. The method of any one of the preceding embodiments, wherein the compound and the anti -obesity agent are delivered in a single dosage form. 10. The method of embodiment 9, wherein the compound and the anti -obesity agent are delivered in a single parenteral or oral dosage form. 11. The method of any one of the preceding embodiments, wherein the anti-obesity agent is delivered via parenteral or oral dosage form. 12. The method of any one of the preceding embodiments, wherein the compound agent is delivered via parenteral or oral administration. 13. The method of any one of the preceding embodiments, wherein the administering occurs daily, weekly, or monthly. 14. The method of any one of the preceding embodiments, wherein the compound is administered in a dose of 0.5-300 mg. 15. The method of any one of the preceding embodiments, wherein the anti-obesity agent is administered in a dose of 0.01-10 mg. 16. The method of any one of the preceding embodiments, wherein the combination of (a) and (b) allows for a lower dosage of (b) to achieve the same therapeutic effect in treating the disease. 17. A composition comprising: a compound having the structureleast one therapeutically effective amount of an anti -obesity agent that functions through a pathway other than CB1 modulation. 18. The composition of embodiment 17, wherein the composition is formulated for oral administration. 19. The composition of embodiment 17, wherein the composition is formulated for parenteral administration. 20. The composition of any one of embodiments 17-19, wherein the composition comprises at least one excipient. 21 . A method of treating a metabolic disease in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a CB 1 modulator, and at least one therapeutically effective amount of an agent that functions through a pathway other than CB1 modulation. 22. The method of embodiment 21, wherein the CB1 modulator comprises a CB1 antagonist. 23. The method of embodiment 21, wherein the CB1 modulator comprises a CB1 inverse agonist or reverse agonist. 24. The method of embodiment 21, wherein the CB1 modulatorWSGR Docket No. 59475-709.601 comprises ((R)-(+)-N-tert-butyl- 3-[(4-chloro)phenyl-(2-trifluoromethyl)phenyl]methoxyazetidine-l- carboxamide, ((S)-(-)-N-tert-butyl-3-[(4- chloro)phenyl-(2-trifluoromethyl)phenyl]methoxyazetidine-l- carboxamide, (N-tert-butyl-3-[(4-chloro)phenyl-(2- trifluoromethyl)phenyl]methoxyazetidine-l- carboxamide, cannabigerol, ibipinabant, otenabant, tetrahydrocannabivarin, virodhamine, rimonabant, taranabant, surinabant or drinabant. 25. The method of embodiment 21, wherein the CB1 modulator comprises ((R)-(+)-N-tert-butyl- 3-[(4-chloro)phenyl-(2-trifluoromethyl)phenyl]methoxyazetidine-l- carboxamide. 26. The method of embodiment 21, wherein the CB1 modulator comprises MAFP, NESS 0327, AM-251, LY-320135, AM 281, MJ 15, amauromine, AM 404, virodhamine hydrochloride, NIDA- 41020, SLV 319, URB447, falcarinol, CB-25, 0-1821, or AVE-1625 (drinabant). 27. The method of embodiment 21, wherein the CB1 modulator comprises rimonabant, taranabant, MK-0364, AM251, AM1387, AM4113, cannabigerol, ibipinabant, otenabant, surinabant, tetrahydrocannabivarin and virodamine, TM-38837, AM6545, or a CB1 targeting-antibody 28. The method of embodiment 21, wherein the CB1 modulator comprises rimonabant or drinabant. 29. The method of embodiment 21, wherein the CB1 modulator comprises rimonabant, taranabant, surinabant or drinabant. 30. The method of any one of embodiments 21-29, wherein the at least one agent comprises one or more of zepbound, orforglipron, retatrutide, oral semaglutide, cagrilintide / semaglutide, survodutide, danuglipron, maridebart cafraglutide, GSBR-1290, VK2735, RG 6641 (CT-868), RG 6640 (CT-388), and RG 6652 (CT-996). 31. The method of any one of embodiments 21-29, wherein the at least one anti -obesity agent comprises one or more of liraglutide, orlistat, sibutramine, methamphetamine, ionamin, phentermine, bupropion, diethylpropion, phendimetrazine, benzphetermine, bromocriptine, lorcaserin, topiramate, fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram, duloxetine, and venlafaxine. 32. The method of any one of embodiments 21-31, wherein the metabolic disease comprises obesity, type II diabetes, diabetic retinopathy, fatty liver disease (FLD), non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver fibrosis, liver cancer, or liver cirrhosis.EXAMPLES

[0108] The following examples serve to further describe the manner of using the present disclosure. These examples are presented for illustrative purpose and should not serve to limit the true scope of the present disclosure.

[0109] In carrying out the procedures of the methods described herein, it is of course to be understood that references to particular buffers, media, reagents, cells, culture conditions, and the like are not intended to be limiting, but are to be read so as to include all related materials that one of ordinary skill in the art would recognize as being of interest or value in the particular context in which that discussion is presented. For example, it is often possible to substitute on buffer system or culture medium for another and still achieve similar, if not identical, results. Those of skill in the art will have sufficient knowledge of such systems and methodologies so as to able, without undue experimentation, to make such substitutions as will optimally serve their purposes in using the methods and procedures disclosed herein.WSGR Docket No. 59475-709.601Example 1: ANEB-OOl / sibutramine combination therapy in a rat obesity model

[0110] Combination treatment of CB1 modulators (e.g., ANEB-001) and an anti -obesity agent (e.g., sibutramine) that functions through a pathway other than CB 1 modulation are evaluated in a rodent model of obesity.[OHl] Animals. 100 male SD rats (SV / 159 / 03) are divided into two groups of 20 and 80 respectively with approximately equal mean weights (mean ± SD: controls 349.9 ± 20.6, High fat diet 349.4 ± 17.96g). Rats are then housed in groups of 5 under a 12 h light cycle (lights on at 8:00 am) at a temperature of 20 + 2°C and humidity of 55 ± 15%. Animals have free access to either standard rodent chow (batch 14102003 / B, Beekay rat and mouse diet no 1 (BK001E), B & K universal, Hull, UK)) or a high fat diet (D12079B RD Western Diet, Research Diet Inc) and tap water. After 3 months, the HFD groups are expected to weigh -20% heavier than normal chow fed controls. Thirty-six of the high fat diet fed animals are then singly housed. Body weight and food and water consumption are recorded, and these measures are subsequently taken each day throughout the study between 9:00 and 11:30 am.

[0112] Drug Preparation. Methyl cellulose (Sigma Aldrich, Dorset, UK) is prepared using distilled water to produce a 1% weight / volume solution. The compounds to be evaluated can be dispersed into methyl cellulose by grinding in a pestle and mortar followed by sonication to give a 2mL / kg injection volume. Serial dilutions are made from the anti-obesity agent 30 mg / kg stock to give 10 and 3 mg / kg dose formulations. Serial dilutions are made from an ANEB-001 stock solution to give 3, 10, and 30 mg / kg dose formulations. All drug doses are calculated as free bases having been corrected for salt form.

[0113] Procedure. On Days 0 to 18 after weighing, animals are administered (po) 2 mL / kg solutions of vehicle (1 % methyl cellulose), e.g., at 3, 10, or 30 mg / kg ANEB-001; 3, or 10 mg / kg sibutramine; or a combination of both drugs at any of these dosages. Treatment groups consist of 6 rats, and these are randomly assigned. On Day 18, animals are divided into two groups. The first, are used to provide terminal plasma samples from animals last dosed 24 h previously (Day 17). The second group are administered a final treatment and terminal plasma samples taken 2 h later.

[0114] Drug levels. Drug levels are determined in the plasma and brain samples collected.

[0115] Data Analysis. All data are expressed as means ± SEM. Body weight data is expressed as daily body weight change from Day 0 (g). Body weight gain is analyzed by 2-way ANOVA with repeated measures (Treatments versus Treatment Day). Subsequently, data for each day is analyzed by 1-way ANOVA and if significant by post-hoc Dunnett's t tests where all groups are compared to vehicle control. Daily water and food consumptions are analyzed in the same way. For statistical tests p<0.05 is used to assign statistical significance.Example 2: ANEB-001 / semaglutide combination therapy in a mouse study of obesity

[0116] Combination treatment of CB1 modulators (e.g., ANEB-001) and an anti -obesity agent (e.g., semaglutide) that functions through a pathway other than CB 1 modulation are evaluated in a rodent model of obesity.

[0117] Male mice are housed at 22 + / - 2°C (12 h dark / light cycle). Eight-week-old male C57BL / 6J mice (Janvier Laboratories, Le Genest-Saint-Isles, France) are fed a chow diet (SAFE A03) or a high-fatWSGR Docket No. 59475-709.601 diet (HFD, D12492 or D12331; Research Diets) for 6 months before the study. GLP-1R knockout (GLP- 1R-K0) mice (14) were fed a HFD (D 12331; Research Diets) for 16 weeks before the study. The compounds are given, either i.p. or subcutaneously. The compounds are prepared in acceptable formulations, such as with 0.9% NaCl with Tween 80 (1%) and DMSO (4%) or in 50 mmol / L phosphate buffer (pH 7.4) with 0.05% Tween 80. Mice are randomly assigned to pharmacological treatment groups, and the experimenters are not blinded to the intervention groups. Animals are single housed or group housed. ANEB-001 is administered at 3, 10, and 30 mg / kg dose formulations. Semaglutide is administered at 0.2, 0.7, and 1.0 mg / kg dose formulations.

[0118] Energy Expenditure. Energy expenditure is calculated using an energy balance technique (total energy expenditure balance [TEEbal]).

[0119] Plasma and Tissues Analysis. Plasma insulin and leptin is determined by ELISA kit (Mercodia 10-1132-01 and 10-1113-01, and Millipore EZML-82K, respectively) and plasma and hepatic triglycerides by Thermo Scientific TR22421. For hepatic triglycerides extraction, livers (200 mg) are incubated overnight at 55°C in 30% ethanolic KOH. After 50% ethanol is added, they are centrifuged (13,000 rpm, 5 min), and 100 mb of MgCT (1 mol / L) was added to 100 mb of supernatant. Samples are centrifuged again (13,000 rpm, 5 min) before quantification. Unknown triolein equivalents are interpolated using logistic regression. Triglycerides content is calculated in mg / g tissue by triolein equivalents *2 * 0.012 / (tissue weight in grams).

[0120] Body Composition Analysis. Body composition analysis is performed with an EchoMRI-900 (Echo Medical Systems).

[0121] Glucose Metabolism. Glucose tolerance, insulin tolerance, and glucose-induced insulin release are performed as previously described using appropriate fasting durations and glucose / insulin concentrations. The glucose disappearance rate (KITT) is calculated as the slope of the decreasing line of blood glucose levels over 30 min from insulin administration.

[0122] Quantitative Real-time PCR. RNA tissue extraction and quantitative (q)PCR are performed as previously reported.

[0123] Statistical Analyses. Data are mean + / - SD and are analyzed using Prism 8 (GraphPad). ANOVA, followed by the appropriate post hoc test, is used.

[0124] While some embodiments have been shown and described, various modifications and substitutions may be made thereto without departing from the spirit and scope of the present disclosure. For example, for claim construction purposes, it is not intended that the claims set forth hereinafter be construed in any way narrower than the literal language thereof, and it is thus not intended that exemplary embodiments from the specification be read into the claims. Accordingly, it is to be understood that the present disclosure has been described by way of illustration and not limitations on the scope of the claims.

Claims

WSGR Docket No. 59475-709.601CLAIMSWHAT IS CLAIMED IS:

1. A method of treating obesity, or type 2 diabetes in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of(a) a compound having the structure(b) at least one therapeutically effective amount of an anti-obesity agent that functions through a pathway other than CB1 modulation.

2. The method of claim 1, wherein the anti-obesity agent comprises a modulator of one or more of GLP-1, GLP-1R, gastric inhibitory polypeptide (GIP), glucagon, or amylin.

3. The method of claim 1, wherein the at least one anti -obesity agent comprises one or more of zepbound, orforglipron, retatrutide, oral semaglutide, cagrilintide / semaglutide, survodutide, danuglipron, maridebart cafraglutide, GSBR-1290, VK2735, RG 6641 (CT-868), RG 6640 (CT- 388), and RG 6652 (CT-996).

4. The method of claim 1, wherein the at least one anti-obesity agent comprises one or more of liraglutide, orlistat, sibutramine, methamphetamine, ionamin, phentermine, bupropion, diethylpropion, phendimetrazine, benzphetermine, bromocriptine, lorcaserin, and topiramate.

5. The method of any one of the preceding claims, wherein the compound and the anti -obesity agent are delivered in a single dosage form.

6. The method of any one of the preceding claims, wherein the anti -obesity agent is delivered via parenteral or oral dosage form.

7. The method of any one of the preceding claims, wherein the compound agent is delivered via parenteral or oral administration.

8. The method of any one of the preceding claims, wherein the administering occurs daily, weekly, or monthly.

9. The method of any one of the preceding claims, wherein the compound is administered in a dose of 0.5-300 mg.

10. A composition comprising:(a) a compound having the structureWSGR Docket No. 59475-709.601(b) at least one therapeutically effective amount of an anti-obesity agent that functions through a pathway other than CB1 modulation.

11. The composition of claim 10, wherein the composition is formulated for parenteral or oral administration.

12. A method of treating a metabolic disease in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of(a) a CB 1 modulator, and(b) at least one therapeutically effective amount of an agent that functions through a pathway other than CB1 modulation.

13. The method of claim 12, wherein the CB1 modulator comprises a CB1 antagonist.

14. The method of claim 12, wherein the CB1 modulator comprises a CB1 inverse agonist or reverse agonist.

15. The method of claim 12, wherein the CB1 modulator comprises ((R)-(+)-N-tert-butyl- 3-[(4- chloro)phenyl-(2-trifluoromethyl)phenyl]methoxyazetidine-l-carboxamide, ((S)-(-)-N-tert-butyl- 3-[(4- chloro)phenyl-(2-trifluoromethyl)phenyl]methoxyazetidine-l-carboxamide, (N-tert-butyl- 3-[(4-chloro)phenyl-(2- trifluoromethyl)phenyl]methoxyazetidine-l-carboxamide, cannabigerol, ibipinabant, otenabant, tetrahydrocannabivarin, virodhamine, rimonabant, taranabant, surinabant or drinabant.

16. The method of claim 12, wherein the CB1 modulator comprises ((R)-(+)-N-tert-butyl- 3-[(4- chloro)phenyl-(2-trifluoromethyl)phenyl]methoxyazetidine-l-carboxamide, MAFP, NESS 0327, AM-251, LY-320135, AM 281, MJ 15, amauromine, AM 404, virodhamine hydrochloride, NIDA-41020, SLV 319, URB447, falcarinol, CB-25, 0-1821, or AVE-1625 (drinabant).

17. The method of claim 12, wherein the CB1 modulator comprises rimonabant, taranabant, MK- 0364, AM251, AM1387, AM4113, cannabigerol, ibipinabant, otenabant, surinabant, tetrahydrocannabivarin and virodamine, TM-38837, AM6545, or a CB1 targeting-antibody18. The method of any one of claims 1-17, wherein the at least one agent comprises one or more of zepbound, orforglipron, retatrutide, oral semaglutide, cagrilintide / semaglutide, survodutide, danuglipron, maridebart cafraglutide, GSBR-1290, VK2735, RG 6641 (CT-868), RG 6640 (CT- 388), and RG 6652 (CT-996).

19. The method of any one of claims 1-17, wherein the at least one anti-obesity agent comprises one or more of liraglutide, orlistat, sibutramine, methamphetamine, ionamin, phentermine, bupropion, diethylpropion, phendimetrazine, benzphetermine, bromocriptine, lorcaserin,WSGR Docket No. 59475-709.601 topiramate, fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram, duloxetine, and venlafaxine.

20. The method of any one of claims 12-19, wherein the metabolic disease comprises obesity, type II diabetes, diabetic retinopathy, fatty liver disease (FLD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, liver cancer, or liver cirrhosis.

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