Methods for treating depression

Abstract

Provided herein are methods for treating depression using a fatty acid amide hydrolase (FAAH) cleavable prodrug of a thyroid hormone receptor (TR [beta]) agonist.

Description

[0001] Cross-reference

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 375,192, filed on September 9, 2022, which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION

[0003] The blood-brain barrier is composed of endothelial cells with tight junctions that restrict the entry of pathogens and specific types of small and large molecules from the blood into the brain. This crucial protective function also limits the diffusion of therapeutic agents into the brain, thus posing a significant challenge to the development of new drugs for treating depression. SUMMARY OF THE INVENTION

[0004] In one aspect, provided herein is a method of treating depression, an anxiety disorder, or pain in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

[0005]

[0006] Wherein:

[0007] R 1 and R 2 are independently selected from hydrogen, -OR 5 , -NR 5 R 6 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl are optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 ;

[0008] R 3 and R 4 are independently selected from -F, -Cl, -Br, and -I;

[0009] R 5 and R 6 are independently selected from hydrogen and C1-C6 alkyl; and

[0010] R 7 and R 8 are independently selected from hydrogen, -F, -Cl, -Br, and -I.

[0011] In another aspect, the present disclosure provides a method of treating a patient in need of treatment for depression, an anxiety disorder, or pain, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof:

[0012]

[0013] Wherein:

[0014] R 1 and R 2 are independently selected from hydrogen, -OR 5 , -NR 5 R 6 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl are optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 ;

[0015] R 3 and R 4 are independently selected from -F, -Cl, -Br, and -I;

[0016] R 5 and R 6 are independently selected from hydrogen and C1-C6 alkyl; and

[0017] R 7 and R 8 are independently selected from hydrogen, -F, -Cl, -Br, and -I, wherein at least one of R 7 and R 8 is not hydrogen.

[0018] In some embodiments, R 7 is hydrogen. In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is -F. In some embodiments, R 7 is -F.

[0019] In another aspect, the present disclosure provides a method for treating depression, anxiety disorder, or pain in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof:

[0020]

[0021] Wherein:

[0022] R 1 and R 2 are independently selected from hydrogen, -OR 5 , -NR 5 R 6 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl are optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 ;

[0023] R 3 and R 4 are independently selected from -F, -Cl, -Br, and -I; and

[0024] R 5 and R 6 are independently selected from hydrogen and C1-C6 alkyl.

[0025] In some embodiments, R 1 is hydrogen. In some embodiments, R 2 is C1-C6 alkyl optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is C1-C6 alkyl substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 In some embodiments, R 2is a C1-C6 alkyl group substituted by one or more -OH. In some embodiments, R 2 is a C1-C6 alkyl group substituted by one or more halogen groups. In some embodiments, R 2 is an unsubstituted C1-C6 alkyl group. In some embodiments, R 2 is a phenyl group optionally substituted by one or more of the following: halogen group, cyano group, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is a -C1-C6 alkyl-phenyl group optionally substituted by one or more of the following: halogen group, cyano group, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 3 and R 4 are independently selected from -F, -Cl and -Br. In some embodiments, R 3 and R 4 are both -Br. In some embodiments, R 3 and R 4 are both -Br. In some embodiments, R 3 and R 4 are both -Cl. In some embodiments, R 3 and R 4 are both -F.

[0026] In some embodiments of the methods described herein, it is a method for treating depression in a patient in need thereof. In some embodiments, the depression is major depressive disorder, treatment-resistant depression, seasonal affective disorder, psychotic depression, postpartum depression, melancholic depression, atypical depression or catatonic depression. In some embodiments, the depression is bipolar depression, bipolar treatment-resistant depression, disruptive mood dysregulation disorder, persistent depressive disorder, dysthymia, premenstrual dysphoric disorder, drug-induced depressive disorder, postpartum depression, perimenopausal depression, multi-infarct dementia with depression, senile dementia with depression, Alzheimer's disease with depression, vascular dementia with dysthymia, vascular dementia with depression or depressive disorder not otherwise specified.

[0027] In some embodiments of the methods described herein, it is a method for treating an anxiety disorder in a patient in need thereof. In some embodiments, the anxiety disorder is obsessive-compulsive disorder, post-traumatic stress disorder or severe phobia. In some embodiments, the severe phobia is agoraphobia or social phobia.

[0028] In some embodiments of the methods described herein, it is a method for treating pain in a patient in need thereof. In some embodiments, the pain is selected from migraine, chronic pain, chronic neuropathic pain, chronic muscle pain, chronic joint pain, diabetic neuropathy, fibromyalgia, back pain and osteoarthritis pain.

[0029] In some embodiments, it is a method for treating depression, anxiety disorder or pain in a patient in need thereof, the method further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, it is a method for treating depression, anxiety disorder or pain in a patient in need thereof, the method further comprising administering to the patient a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

[0030] In some embodiments, it is a method of treating depression, anxiety disorder, or pain in a patient in need thereof, the method further comprising administering to the patient a selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI). In some embodiments, it is a method of treating depression, anxiety disorder, or pain in a patient in need thereof, the method further comprising administering to the patient a selective serotonin reuptake inhibitor (SSRI). In some embodiments, it is a method of treating depression, anxiety disorder, or pain in a patient in need thereof, the method further comprising administering to the patient a selective serotonin reuptake inhibitor (SSRI), wherein the selective serotonin reuptake inhibitor (SSRI) is citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline. In some embodiments, it is a method of treating depression, anxiety disorder, or pain in a patient in need thereof, the method further comprising administering to the patient a serotonin and norepinephrine reuptake inhibitor (SNRI). In some embodiments, it is a method of treating depression, anxiety disorder, or pain in a patient in need thereof, the method further comprising administering to the patient a serotonin and norepinephrine reuptake inhibitor (SNRI), wherein the serotonin and norepinephrine reuptake inhibitor (SNRI) is desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, tramadol, or venlafaxine. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The novel features of the present disclosure are set forth with particularity in the appended claims. A more complete understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that illustrates embodiments in which the principles of the present disclosure are utilized, along with the accompanying drawings, in which:

[0032] Figure 1 Depiction of TRβ target engagement in the brain is demonstrated by increased expression of an in vivo T3-responsive target gene.

[0033] Figure 2 Depiction of brain and plasma concentrations after 21-day repeated administration of LL-341070 measured 4 hours after the final dose.

[0034] Figure 3Depict the expression and specific activity of FAAH in multiple species and tissue types.

[0035] Figure 4 Depict the concentration of ABX-002A in the brain, liver, kidney, lung, and heart measured 1 hour after administration of 30 different prodrugs of ABX-002A by SC.

[0036] Figure 5 Depict the plasma, liver, and brain concentrations after treatment with ABX-002 prodrug with or without a peripheral or global FAAH inhibitor.

[0037] Figure 6A Depict the comparison of T3 target gene induction in the brain and T3 target gene induction in the liver after a single administration of ABX-002A.

[0038] Figure 6B Depict the comparison of T3 target gene induction in the brain and T3 target gene induction in the liver after a single administration of ABX-002.

[0039] Figure 6C Depict the comparison of T3 target gene induction in the brain and T3 target gene induction in the liver after a single administration of ABX-002 plus a FAAH inhibitor.

[0040] Figure 7A Depict the gene expression in the brain and liver and the effect on T4 after administration of ABX-002A.

[0041] Figure 7B Depict the gene expression in the brain and liver and the effect on T4 after administration of ABX-002.

[0042] Figure 7C Gene expression in the brain and liver and the effect on T4 after administration of ABX-002 plus a peripheral FAAH inhibitor.

[0043] Figure 7D Depict the gene expression in the brain and liver and the effect on T4 after administration of ABX-002 plus a global FAAH inhibitor. Detailed Description

[0044] Typical antidepressants (i.e., selective serotonin reuptake inhibitors) are thought to improve major depressive disorder (MDD) by increasing synaptic 5-HT concentrations in brain regions associated with emotional stress, including the dorsal raphe, prefrontal cortex, hippocampus, amygdala, and hypothalamus. Preclinical experience with the combination of triiodothyronine (T3) and antidepressants has shown that the mechanism of action involves enhancing 5-HT function, including increasing 5-HT release and downregulating inhibitory mechanisms related to 5-HT release. Specifically, T3 has been shown to potentiate 5-HT release in the prefrontal cortex stimulated by antidepressants, in part due to enhanced downregulation of inhibitory 5-HT1A and 1B autoreceptors and their signaling within the dorsal raphe. Clinical practice patterns and guidelines, as well as published literature, support the clinical experience of T3 augmentation in MDD. To date, the largest randomized study of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) included T3 treatment as an alternative for insufficient antidepressant response. Specifically, T3 augmentation increased the remission rate in patients who had failed two previous antidepressant regimens. The dose level of T3 is limited by hormonal activity in peripheral tissues, i.e., the heart and bone. As shown by Jonklaas et al., (2015), a treatment-related dose of 50 μg increases heart rate and decreases TSH in the acute setting. Identification of analogs with improved therapeutic indices is highly desirable for clinical use in MDD and other conditions. To this end, some approaches have focused on increasing TRβ selectivity, as the heart and bone are highly enriched in TRα. As an example, the peripherally restricted molecule resmetirom is highly selective for TRβ. However, resmetirom and other thyromimetics do not have brain penetrance and thus cannot be used to treat MDD.

[0045] The compounds disclosed herein are prodrugs of potent thyroid hormone β receptor selective agonists and are expected to differ from thyroid hormones in that they have enhanced brain effects and reduced peripheral side effects in patients with MDD who are insufficiently responsive to antidepressants. These compounds are brain-directed thyromimetic prodrugs that are activated by the intracellular enzyme fatty acid amide hydrolase (FAAH). Specifically, ABX-002 is an orally administered amide prodrug that acts as a full agonist of the thyroid hormone receptor. Upon entry into tissues, FAAH hydrolyzes the amide to release the active carboxylic acid compound ABX-002A. ABX-002A is a full agonist of TRβ and TRα, with 15-fold selectivity for TRβ, which helps to avoid effects on the heart and bones. In humans, FAAH is ubiquitously expressed but enriched in the central nervous system (CNS), which enhances delivery to the brain and is further enriched in the hippocampus and cortex, two brain regions that are both associated with MDD. In mice, oral administration of ABX-002 increased the selective delivery of the active metabolite to the brain by >30-fold compared to administration of the active metabolite alone, resulting in a brain-plasma ratio >0.8 and a brain-heart ratio >3.5. In rodent studies, exogenous T3 administration resulted in higher T3 concentrations in the heart than in the brain, meaning gene expression changes at lower doses than in the brain, which is consistent with the dose-limiting toxicity described in patients. The selective delivery of ABX-002 to the CNS allows the dose to maximize the benefits of the thyroid hormone agonist on the CNS without the dose-limiting adverse effects on peripheral tissues observed with T3 treatment. The selective distribution to CNS tissues combined with receptor selectivity for TRβ makes ABX-002A potentially offer a safety advantage over triiodothyronine (T3).

[0046] Certain terms

[0047] Unless the context clearly dictates otherwise, the singular forms “a,” “an,” and “the” include plural referents. Thus, for example, reference to “a drug” includes reference to one or more such drugs, and reference to “an excipient” includes reference to one or more such excipients. When ranges are used herein, it is intended to include all combinations and subcombinations of the range and the specific embodiments therein. The term “about,” when referring to a numerical value or numerical range, means that the recited numerical value or numerical range is an approximation within experimental variability (or within statistical experimental error), and thus, the numerical value or numerical range varies between 1% and 15% of the stated numerical value or numerical range.

[0048] As used herein, the terms "preparation" and "composition" are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. In some aspects, the terms "preparation" and "composition" may be used to refer to a mixture of one or more active agents with a carrier or other excipients.

[0049] The terms "active agent", "active pharmaceutical agent", "drug", "active ingredient", and variations thereof are used interchangeably to refer to an agent or substance that has a measurable specified or selected physiological activity when administered to a subject in a significant or effective amount.

[0050] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. Pharmaceutically acceptable salts of any of the compounds described herein are intended to cover any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0051] "Pharmaceutically acceptable acid addition salts" refer to those salts that retain the biological effectiveness and properties of the free base and are not undesirable, biologically or otherwise, and are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Thus, exemplary salts include sulfates, bisulfates, hydrogen sulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Also contemplated are salts of amino acids such as arginine salts, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt.

[0052] "Pharmaceutically acceptable base addition salts" refers to salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, diaminobenzyl, N-methylglucamine, glucamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al. (supra).

[0053] It is understood that reference to pharmaceutically acceptable salts includes solvate addition forms (solvates). Solvates contain a stoichiometric or non-stoichiometric amount of solvent and are formed with a pharmaceutically acceptable solvent during the formation or isolation of the product, such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropanol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, acetonitrile, etc. In one aspect, solvates are formed using, but not limited to, one or more Class 3 solvents. The types of solvents are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvents", Q3C(R3), (November 2005). When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholate is formed.

[0054] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of an agent or compound administered that will, to some extent, alleviate one or more symptoms of a disease or condition being treated. The result can be a reduction and / or amelioration of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. By way of example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as disclosed herein required to provide a clinically significant reduction of a disease. The appropriate "effective" amount in any individual case can be determined using techniques such as dose escalation studies.

[0055] The terms "subject", "individual", and "patient" are used interchangeably herein to refer to a mammal. Mammals include, but are not limited to, mice, monkeys, humans, farm animals, sport animals, and pets.

[0056] As used herein, the term "peripherally restricted FAAH inhibitor" refers to a fatty acid amide hydrolase (FAAH) inhibitor that inhibits FAAH to a greater extent in the periphery than in the central nervous system at a systemic dose. In some embodiments, the peripherally restricted FAAH inhibitor is 60% peripherally restricted. In some embodiments, the peripherally restricted FAAH inhibitor is 70% peripherally restricted. In some embodiments, the peripherally restricted FAAH inhibitor is 80% peripherally restricted. In some embodiments, the peripherally restricted FAAH inhibitor is 90% peripherally restricted. In some embodiments, the peripherally restricted FAAH inhibitor is 95% peripherally restricted.

[0057] Target

[0058] Thyroid hormone (TH) is a key signal for oligodendrocyte differentiation and myelination during development and also stimulates remyelination in adult models of multiple sclerosis (MS) (Calzà L et al., Brain Res Revs 48:339-346, 2005). However, TH is not an acceptable long-term therapy because there is little therapeutic window to achieve remyelination while avoiding the cardiac toxicity and bone demineralization associated with chronic hyperthyroidism. Some thyroid hormone analogs can activate thyroid hormone-responsive genes by exploiting the molecular and physiological characteristics of thyroid hormone receptors while avoiding the associated drawbacks of TH (Malm J et al., Mini Rev Med Chem 7:79-86, 2007). These receptors are expressed in two major forms with heterogeneous tissue distribution and overlapping but distinct sets of target genes (Yen PM, Physiol Rev 81:1097-1142, 2001). TRα is enriched in the heart, brain, and bone, while TRβ is enriched in the liver (O’Shea PJ et al., NuclRecept Signal 4:e011, 2006).

[0059] Developing selective thyromimetics has been challenging because of the high sequence homology of thyroid hormone receptor subtypes; that is, there is only one amino acid residue difference on the inner surface of the ligand-binding domain cavity between the α1 form and the β1 form.

[0060] Methods

[0061] In some embodiments, described herein is a method of treating a patient in need thereof for depression, an anxiety disorder, or pain, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating a patient in need thereof for depression, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating a patient in need thereof for depression, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method of treating a patient in need thereof for depression, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652. In some embodiments, described herein is a method of treating a patient in need thereof for an anxiety disorder, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating a patient in need thereof for an anxiety disorder, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method of treating a patient in need thereof for an anxiety disorder, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652. In some embodiments, described herein is a method of treating a patient in need thereof for pain, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating a patient in need thereof for pain, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method of treating a patient in need thereof for pain, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

[0062] In some embodiments, described herein is a method of treating depression, an anxiety disorder, or pain in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating depression in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating depression in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method of treating depression in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652. In some embodiments, described herein is a method of treating an anxiety disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating an anxiety disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method of treating an anxiety disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652. In some embodiments, described herein is a method of treating pain in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating pain in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method of treating pain in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

[0063] In some embodiments, described herein is a method of treating depression, an anxiety disorder, or pain in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating depression in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating depression in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method of treating depression in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652. In some embodiments, described herein is a method of treating an anxiety disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating an anxiety disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method of treating an anxiety disorder in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652. In some embodiments, described herein is a method of treating pain in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating pain in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method of treating pain in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

[0064] In some embodiments, described herein is a method of treating a patient in need of treatment for depression, an anxiety disorder, or pain, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating a patient in need of treatment for depression, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating a patient in need of treatment for depression, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method of treating a patient in need of treatment for depression, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652. In some embodiments, described herein is a method of treating a patient in need of treatment for an anxiety disorder, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating a patient in need of treatment for an anxiety disorder, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method of treating a patient in need of treatment for an anxiety disorder, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652. In some embodiments, described herein is a method of treating a patient in need of treatment for pain, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein is a method of treating a patient in need of treatment for pain, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method of treating a patient in need of treatment for pain, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt or solvate thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

[0065] In some embodiments of the methods for treating depression described herein, the depression is major depressive disorder, treatment-resistant depression, seasonal affective disorder, psychotic depression, postpartum depression, melancholic depression, atypical depression, or catatonic depression. In some embodiments of the methods for treating depression described herein, the depression is major depressive disorder. In some embodiments of the methods for treating depression described herein, the depression is treatment-resistant depression. In some embodiments of the methods for treating depression described herein, the depression is seasonal affective disorder. In some embodiments of the methods for treating depression described herein, the depression is psychotic depression. In some embodiments of the methods for treating depression described herein, the depression is postpartum depression. In some embodiments of the methods for treating depression described herein, the depression is melancholic depression. In some embodiments of the methods for treating depression described herein, the depression is atypical depression. In some embodiments of the methods for treating depression described herein, the depression is catatonic depression.

[0066] In some embodiments of the methods for treating depression described herein, the depression is bipolar depression, bipolar treatment-resistant depression, disruptive mood dysregulation disorder, persistent depressive disorder, major depressive disorder, premenstrual dysphoric disorder, medication-induced depressive disorder, postpartum depression, perimenopausal depression, multi-infarct dementia with depression, dementia with depression, senile dementia with depression, vascular dementia with major depressive disorder, vascular dementia with depression, or depressive disorder, not otherwise specified. In some embodiments of the methods for treating depression described herein, the depression is bipolar depression. In some embodiments of the methods for treating depression described herein, the depression is bipolar treatment-resistant depression. In some embodiments of the methods for treating depression described herein, the depression is disruptive mood dysregulation disorder. In some embodiments of the methods for treating depression described herein, the depression is persistent depressive disorder. In some embodiments of the methods for treating depression described herein, the depression is major depressive disorder. In some embodiments of the methods for treating depression described herein, the depression is premenstrual dysphoric disorder. In some embodiments of the methods for treating depression described herein, the depression is medication-induced depressive disorder. In some embodiments of the methods for treating depression described herein, the depression is postpartum depression. In some embodiments of the methods for treating depression described herein, the depression is perimenopausal depression. In some embodiments of the methods for treating depression described herein, the depression is multi-infarct dementia with depression. In some embodiments of the methods for treating depression described herein, the depression is dementia with depression. In some embodiments of the methods for treating depression described herein, the depression is senile dementia with depression. In some embodiments of the methods for treating depression described herein, the depression is vascular dementia with major depressive disorder. In some embodiments of the methods for treating depression described herein, the depression is vascular dementia with depression. In some embodiments of the methods for treating depression described herein, the depression is depressive disorder, not otherwise specified.

[0067] In some embodiments of the methods of treating an anxiety disorder described herein, the anxiety disorder is obsessive-compulsive disorder, post-traumatic stress disorder, or severe phobia. In some embodiments of the methods of treating an anxiety disorder described herein, the anxiety disorder is obsessive-compulsive disorder. In some embodiments of the methods of treating an anxiety disorder described herein, the anxiety disorder is post-traumatic stress disorder. In some embodiments of the methods of treating an anxiety disorder described herein, the anxiety disorder is severe phobia. In some embodiments of the methods of treating an anxiety disorder described herein, the anxiety disorder is severe phobia, wherein the severe phobia is agoraphobia or social phobia. In some embodiments of the methods of treating an anxiety disorder described herein, the anxiety disorder is severe phobia, wherein the severe phobia is agoraphobia. In some embodiments of the methods of treating an anxiety disorder described herein, the anxiety disorder is severe phobia, wherein the severe phobia is social phobia.

[0068] In some embodiments of the methods of treating pain described herein, the pain is selected from migraine, chronic pain, chronic neuropathic pain, chronic muscular pain, chronic joint pain, diabetic neuropathy, fibromyalgia, back pain, and osteoarthritis pain. In some embodiments of the methods of treating pain described herein, the pain is migraine. In some embodiments of the methods of treating pain described herein, the pain is chronic pain. In some embodiments of the methods of treating pain described herein, the pain is chronic neuropathic pain. In some embodiments of the methods of treating pain described herein, the pain is chronic muscular pain. In some embodiments of the methods of treating pain described herein, the pain is chronic joint pain. In some embodiments of the methods of treating pain described herein, the pain is diabetic neuropathy. In some embodiments of the methods of treating pain described herein, the pain is fibromyalgia. In some embodiments of the methods of treating pain described herein, the pain is back pain. In some embodiments of the methods of treating pain described herein, the pain is osteoarthritis pain.

[0069] In some embodiments, the methods of treatment described herein further comprise administering to the patient a selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI).

[0070] In some embodiments, the methods of treatment described herein further comprise administering to a patient a selective serotonin reuptake inhibitor (SSRI). In some embodiments, the methods of treatment described herein further comprise administering to a patient a selective serotonin reuptake inhibitor (SSRI), wherein the SSRI is citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline. In some embodiments, the methods of treatment described herein further comprise administering to a patient a selective serotonin reuptake inhibitor (SSRI), wherein the SSRI is citalopram. In some embodiments, the methods of treatment described herein further comprise administering to a patient a selective serotonin reuptake inhibitor (SSRI), wherein the SSRI is escitalopram. In some embodiments, the methods of treatment described herein further comprise administering to a patient a selective serotonin reuptake inhibitor (SSRI), wherein the SSRI is fluoxetine. In some embodiments, the methods of treatment described herein further comprise administering to a patient a selective serotonin reuptake inhibitor (SSRI), wherein the SSRI is fluvoxamine. In some embodiments, the methods of treatment described herein further comprise administering to a patient a selective serotonin reuptake inhibitor (SSRI), wherein the SSRI is paroxetine. In some embodiments, the methods of treatment described herein further comprise administering to a patient a selective serotonin reuptake inhibitor (SSRI), wherein the SSRI is sertraline.

[0071] In some embodiments, the methods of treatment described herein further comprise administering to a patient a serotonin and norepinephrine reuptake inhibitor (SRNI), wherein the SRNI is desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, tramadol, or venlafaxine. In some embodiments, the methods of treatment described herein further comprise administering to a patient a serotonin and norepinephrine reuptake inhibitor (SRNI), wherein the SRNI is desvenlafaxine. In some embodiments, the methods of treatment described herein further comprise administering to a patient a serotonin and norepinephrine reuptake inhibitor (SRNI), wherein the SRNI is duloxetine. In some embodiments, the methods of treatment described herein further comprise administering to a patient a serotonin and norepinephrine reuptake inhibitor (SRNI), wherein the SRNI is levomilnacipran. In some embodiments, the methods of treatment described herein further comprise administering to a patient a serotonin and norepinephrine reuptake inhibitor (SRNI), wherein the SRNI is milnacipran. In some embodiments, the methods of treatment described herein further comprise administering to a patient a serotonin and norepinephrine reuptake inhibitor (SRNI), wherein the SRNI is sibutramine. In some embodiments, the methods of treatment described herein further comprise administering to a patient a serotonin and norepinephrine reuptake inhibitor (SRNI), wherein the SRNI is tramadol. In some embodiments, the methods of treatment described herein further comprise administering to a patient a serotonin and norepinephrine reuptake inhibitor (SRNI), wherein the SRNI is venlafaxine.

[0072] Compound

[0073] The compounds described herein are fatty acid amide hydrolase (FAAH)-cleavable prodrugs. In some embodiments, the compounds described herein comprise a fatty acid amide hydrolase (FAAH)-cleavable prodrug of formula (I), wherein the prodrug of formula (I) is a prodrug of a TRβ agonist. In some embodiments, the compounds described herein comprise a fatty acid amide hydrolase (FAAH)-cleavable prodrug of formula (II), wherein the prodrug of formula (II) is a prodrug of a TRβ agonist. In some embodiments, the compounds described herein comprise a fatty acid amide hydrolase (FAAH)-cleavable prodrug of formula (III), wherein the prodrug of formula (III) is a prodrug of a TRβ agonist. In some embodiments, the compounds described herein comprise a fatty acid amide hydrolase (FAAH)-cleavable prodrug of formula (IV), wherein the prodrug of formula (IV) is a prodrug of a TRβ agonist.

[0074] In some embodiments, a method of treating a patient in need of treatment for depression, an anxiety disorder, or pain is described herein, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

[0075]

[0076] Wherein:

[0077] R 1 and R 2 are independently selected from hydrogen, -OR 5 , -NR 5 R 6 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl are optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 ;

[0078] R 3 and R 4 are independently selected from -F, -Cl, -Br, and -I;

[0079] R 5 and R 6 are independently selected from hydrogen and C1-C6 alkyl; and

[0080] R 7 and R 8 are independently selected from hydrogen, -F, -Cl, -Br, and -I.

[0081] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is -F. In some embodiments, R 7 is -Cl. In some embodiments, R 7 is -Br.

[0082] In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is -F. In some embodiments, R 8 is -Cl. In some embodiments, R 8 is -Br.

[0083] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is C 1-6 alkyl.

[0084] In some embodiments, R 2 is C1-C6 alkyl optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is C1-C6 alkyl substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is C1-C6 alkyl substituted with one or more halo groups. In some embodiments, R 2 is C1-C6 alkyl substituted with one cyano group. In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -OR 5 . In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -OH groups. In some embodiments, R 2 is C1-C6 alkyl substituted with one -OH group. In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -NR 5 R 6 . In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -NH2 groups. In some embodiments, R 2 is C1-C6 alkyl substituted with one -NH2 group. In some embodiments, R 2 is C1-C6 alkyl substituted with one -S(O)2R 5 . In some embodiments, R 2 is C1-C6 alkyl substituted with one -S(O)2H group. In some embodiments, R 2 is C1-C6 alkyl substituted with one -S(O)2OR 5 . In some embodiments, R 2 is C1-C6 alkyl substituted with one -S(O)2OH group. In some embodiments, R2 is an unsubstituted C1-C6 alkyl group. In some embodiments, R 2 is -CH3. In some embodiments, R 2 is -CH2CH3. In some embodiments, R 2 is -CH2CH2CH3.

[0085] In some embodiments, R 2 is a C2-C6 alkenyl group optionally substituted with one or more of the following: halogen, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is an unsubstituted C2-C6 alkenyl group.

[0086] In some embodiments, R 2 is a C2-C6 alkynyl group optionally substituted with one or more of the following: halogen, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is an unsubstituted C2-C6 alkynyl group.

[0087] In some embodiments, R 2 is a C3-C6 cycloalkyl group optionally substituted with one or more of the following: halogen, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is an unsubstituted C3-C6 cycloalkyl group.

[0088] In some embodiments, R 2 is a C3-C6 heterocycloalkyl group optionally substituted with one or more of the following: halogen, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is an unsubstituted C3-C6 heterocycloalkyl group.

[0089] In some embodiments, R2 is a phenyl group optionally substituted with one or more of the following: a halogen group, a cyano group, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is a phenyl group substituted with one or more of the following: a halogen group, a cyano group, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is a phenyl group substituted with one or more halogen groups. In some embodiments, R 2 is a phenyl group substituted with one or more -OR 5 . In some embodiments, R 2 is a phenyl group substituted with one or more -OH. In some embodiments, R 2 is an unsubstituted phenyl group.

[0090] In some embodiments, R 2 is a -C1-C6 alkyl-phenyl group optionally substituted with one or more of the following: a halogen group, a cyano group, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is an unsubstituted -C1-C6 alkyl-phenyl group.

[0091] In some embodiments, R 2 is -OR 5 . In some embodiments, R 2 is -OH. In some embodiments, R 2 is -NR 5 R 6 . In some embodiments, R 2 is -NH2.

[0092] In some embodiments, R 2 is hydrogen.

[0093] In some embodiments, R 3 and R 4 are independently selected from -F, -Cl, and -Br. In some embodiments, R 3 and R 4are both -Br. In some embodiments, R 3 and R 4 are both -Br. In some embodiments, R 3 and R 4 are both -Cl. In some embodiments, R 3 and R 4 are both -F. In some embodiments, R 3 is -Cl, and R 4 is -Br. In some embodiments, R 3 is -F, and R 4 is -Br. In some embodiments, R 3 is -F, and R 4 is -Cl.

[0094] In some embodiments, described herein is a method of treating a patient in need of treatment for depression, an anxiety disorder, or pain, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof:

[0095]

[0096] wherein:

[0097] R 1 and R 2 are independently selected from hydrogen, -OR 5 , -NR 5 R 6 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl are optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 ;

[0098] R 3 and R 4 are independently selected from -F, -Cl, -Br, and -I;

[0099] R 5 and R 6 are independently selected from hydrogen and C1-C6 alkyl; and

[0100] R 7 and R 8Independently selected from hydrogen, -F, -Cl, -Br, and -I, where R 7 and R 8 at least one of which is not hydrogen.

[0101] In some embodiments, R 7 is hydrogen. In some embodiments, R 7 is -F. In some embodiments, R 7 is -Cl. In some embodiments, R 7 is -Br.

[0102] In some embodiments, R 8 is hydrogen. In some embodiments, R 8 is -F. In some embodiments, R 8 is -Cl. In some embodiments, R 8 is -Br.

[0103] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is C 1-6 alkyl.

[0104] In some embodiments, R 2 is C1-C6 alkyl optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is C1-C6 alkyl substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is C1-C6 alkyl substituted with one or more halo groups. In some embodiments, R 2 is C1-C6 alkyl substituted with one cyano group. In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -OR 5 . In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -OH groups. In some embodiments, R 2 is C1-C6 alkyl substituted with one -OH group. In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -NR5 R 6 Substituted C1-C6 alkyl. In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -NH2. In some embodiments, R 2 is C1-C6 alkyl substituted with one -NH2. In some embodiments, R 2 is C1-C6 alkyl substituted with one -S(O)2R 5 Substituted C1-C6 alkyl. In some embodiments, R 2 is C1-C6 alkyl substituted with one -S(O)2H. In some embodiments, R 2 is C1-C6 alkyl substituted with one -S(O)2OR 5 Substituted C1-C6 alkyl. In some embodiments, R 2 is C1-C6 alkyl substituted with one -S(O)2OH. In some embodiments, R 2 is unsubstituted C1-C6 alkyl. In some embodiments, R 2 is -CH3. In some embodiments, R 2 is -CH2CH3. In some embodiments, R 2 is -CH2CH2CH3.

[0105] In some embodiments, R 2 is C2-C6 alkenyl optionally substituted with one or more of the following: halogen, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is unsubstituted C2-C6 alkenyl.

[0106] In some embodiments, R 2 is C2-C6 alkynyl optionally substituted with one or more of the following: halogen, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is unsubstituted C2-C6 alkynyl.

[0107] In some embodiments, R 2 is C3-C6 cycloalkyl optionally substituted with one or more of the following: halogen, cyano, -OR 5 , -NR 5 R6 、 -S(O)2R 5 or -S(O)2OR 5 。 In some embodiments, R 2 is unsubstituted C3-C6 cycloalkyl.

[0108] In some embodiments, R 2 is C3-C6 heterocycloalkyl optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 。 In some embodiments, R 2 is unsubstituted C3-C6 heterocycloalkyl.

[0109] In some embodiments, R 2 is phenyl optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 。 In some embodiments, R 2 is phenyl substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 。 In some embodiments, R 2 is phenyl substituted with one or more halo groups. In some embodiments, R 2 is phenyl substituted with one or more -OR 5 groups. In some embodiments, R 2 is phenyl substituted with one or more -OH groups. In some embodiments, R 2 is unsubstituted phenyl.

[0110] In some embodiments, R 2 is -C1-C6 alkyl-phenyl optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 。 In some embodiments, R 2 is unsubstituted -C1-C6 alkyl-phenyl.

[0111] In some embodiments, R 2 is -OR 5 。In some embodiments, R 2 is -OH。In some embodiments, R 2 is -NR 5 R 6 。In some embodiments, R 2 is -NH2。

[0112] In some embodiments, R 2 is hydrogen。

[0113] In some embodiments, R 3 and R 4 are independently selected from -F, -Cl, and -Br。In some embodiments, R 3 and R 4 are both -Br。In some embodiments, R 3 and R 4 are both -Br。In some embodiments, R 3 and R 4 are both -Cl。In some embodiments, R 3 and R 4 are both -F。In some embodiments, R 3 is -Cl, and R 4 is -Br。In some embodiments, R 3 is -F, and R 4 is -Br。In some embodiments, R 3 is -F, and R 4 is -Cl。

[0114] In some embodiments, a method of treating a patient in need of treatment for depression, an anxiety disorder, or pain is described herein, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof:

[0115]

[0116] wherein:

[0117] R 1 and R 2 are independently selected from hydrogen, -OR 5 、-NR 5 R 6, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl, where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl are optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 ;

[0118] R 3 and R 4 are independently selected from -F, -Cl, -Br, and -I; and

[0119] R 5 and R 6 are independently selected from hydrogen and C1-C6 alkyl.

[0120] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is C 1-6 alkyl.

[0121] In some embodiments, R 2 is C1-C6 alkyl optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is C1-C6 alkyl substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is C1-C6 alkyl substituted with one or more halo groups. In some embodiments, R 2 is C1-C6 alkyl substituted with one cyano group. In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -OR 5 . In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -OH groups. In some embodiments, R 2is a C1-C6 alkyl group substituted by a -OH. In some embodiments, R 2 is a C1-C6 alkyl group substituted by one or more -NR 5 R 6 substituents. In some embodiments, R 2 is a C1-C6 alkyl group substituted by one or more -NH2 substituents. In some embodiments, R 2 is a C1-C6 alkyl group substituted by a -NH2 substituent. In some embodiments, R 2 is a C1-C6 alkyl group substituted by a -S(O)2R 5 substituent. In some embodiments, R 2 is a C1-C6 alkyl group substituted by a -S(O)2H substituent. In some embodiments, R 2 is a C1-C6 alkyl group substituted by a -S(O)2OR 5 substituent. In some embodiments, R 2 is a C1-C6 alkyl group substituted by a -S(O)2OH substituent. In some embodiments, R 2 is an unsubstituted C1-C6 alkyl group. In some embodiments, R 2 is -CH3. In some embodiments, R 2 is -CH2CH3. In some embodiments, R 2 is -CH2CH2CH3.

[0122] In some embodiments, R 2 is a C2-C6 alkenyl group optionally substituted by one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is an unsubstituted C2-C6 alkenyl group.

[0123] In some embodiments, R 2 is a C2-C6 alkynyl group optionally substituted by one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is an unsubstituted C2-C6 alkynyl group.

[0124] In some embodiments, R 2is a C3-C6 cycloalkyl optionally substituted with one or more of the following: halo, cyano, -OR 5 、-NR 5 R 6 、-S(O)2R 5 or -S(O)2OR 5 。In some embodiments, R 2 is an unsubstituted C3-C6 cycloalkyl.

[0125] In some embodiments, R 2 is a C3-C6 heterocycloalkyl optionally substituted with one or more of the following: halo, cyano, -OR 5 、-NR 5 R 6 、-S(O)2R 5 or -S(O)2OR 5 。In some embodiments, R 2 is an unsubstituted C3-C6 heterocycloalkyl.

[0126] In some embodiments, R 2 is a phenyl optionally substituted with one or more of the following: halo, cyano, -OR 5 、-NR 5 R 6 、-S(O)2R 5 or -S(O)2OR 5 。In some embodiments, R 2 is a phenyl substituted with one or more of the following: halo, cyano, -OR 5 、-NR 5 R 6 、-S(O)2R 5 or -S(O)2OR 5 。In some embodiments, R 2 is a phenyl substituted with one or more halo groups. In some embodiments, R 2 is a phenyl substituted with one or more -OR 5 。In some embodiments, R 2 is a phenyl substituted with one or more -OH groups. In some embodiments, R 2 is an unsubstituted phenyl.

[0127] In some embodiments, R 2 is a -C1-C6 alkyl-phenyl optionally substituted with one or more of the following: halo, cyano, -OR 5 、-NR 5 R 6 、-S(O)2R 5 or -S(O)2OR5 。In some embodiments, R 2 is unsubstituted -C1-C6 alkyl-phenyl.

[0128] In some embodiments, R 2 is -OR 5 。In some embodiments, R 2 is -OH. In some embodiments, R 2 is -NR 5 R 6 。In some embodiments, R 2 is -NH2.

[0129] In some embodiments, R 2 is hydrogen.

[0130] In some embodiments, R 3 and R 4 are independently selected from -F, -Cl, and -Br. In some embodiments, R 3 and R 4 are both -Br. In some embodiments, R 3 and R 4 are both -Br. In some embodiments, R 3 and R 4 are both -Cl. In some embodiments, R 3 and R 4 are both -F. In some embodiments, R 3 is -Cl and R 4 is -Br. In some embodiments, R 3 is -F and R 4 is -Br. In some embodiments, R 3 is -F and R 4 is -Cl.

[0131] In some embodiments, a method for treating depression, anxiety disorder, or pain in a patient in need thereof is described herein, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt or solvate thereof:

[0132]

[0133] wherein:

[0134] R 1 and R 2 are independently selected from hydrogen, -OR 5 , -NR 5 R 6, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl, where the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl are optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 ; and

[0135] R 5 and R 6 are independently selected from hydrogen and C1-C6 alkyl.

[0136] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is C 1-6 alkyl.

[0137] In some embodiments, R 2 is C1-C6 alkyl optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is C1-C6 alkyl substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is C1-C6 alkyl substituted with one or more halo groups. In some embodiments, R 2 is C1-C6 alkyl substituted with one cyano group. In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -OR 5 . In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -OH groups. In some embodiments, R 2 is C1-C6 alkyl substituted with one -OH group. In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -NR 5 R 6Substituted C1-C6 alkyl. In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -NH2. In some embodiments, R 2 is C1-C6 alkyl substituted with one -NH2. In some embodiments, R 2 is C1-C6 alkyl substituted with one -S(O)2R 5 . In some embodiments, R 2 is C1-C6 alkyl substituted with one -S(O)2H. In some embodiments, R 2 is C1-C6 alkyl substituted with one -S(O)2OR 5 . In some embodiments, R 2 is C1-C6 alkyl substituted with one -S(O)2OH. In some embodiments, R 2 is unsubstituted C1-C6 alkyl. In some embodiments, R 2 is -CH3. In some embodiments, R 2 is -CH2CH3. In some embodiments, R 2 is -CH2CH2CH3.

[0138] In some embodiments, R 2 is C2-C6 alkenyl optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is unsubstituted C2-C6 alkenyl.

[0139] In some embodiments, R 2 is C2-C6 alkynyl optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is unsubstituted C2-C6 alkynyl.

[0140] In some embodiments, R 2 is C3-C6 cycloalkyl optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R5 or -S(O)2OR 5 . In some embodiments, R 2 is unsubstituted C3-C6 cycloalkyl.

[0141] In some embodiments, R 2 is C3-C6 heterocycloalkyl optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is unsubstituted C3-C6 heterocycloalkyl.

[0142] In some embodiments, R 2 is phenyl optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is phenyl substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is phenyl substituted with one or more halo groups. In some embodiments, R 2 is phenyl substituted with one or more -OR 5 . In some embodiments, R 2 is phenyl substituted with one or more -OH. In some embodiments, R 2 is unsubstituted phenyl.

[0143] In some embodiments, R 2 is -C1-C6 alkyl-phenyl optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 . In some embodiments, R 2 is unsubstituted -C1-C6 alkyl-phenyl.

[0144] In some embodiments, R2 is - OR 5 . In some embodiments, R 2 is - OH. In some embodiments, R 2 is - NR 5 R 6 . In some embodiments, R 2 is - NH2.

[0145] In some embodiments, R 2 is hydrogen.

[0146] In some embodiments of the fatty acid amide hydrolase (FAAH) - cleavable prodrugs described herein, the prodrug has a structure selected from the following:

[0147] or a pharmaceutically acceptable salt or solvate thereof.

[0148] In some embodiments of the fatty acid amide hydrolase (FAAH) - cleavable prodrugs described herein, the prodrug has a structure selected from the following:

[0149]

[0150]

[0151]

[0152] or a pharmaceutically acceptable salt or solvate thereof.

[0153] In some embodiments of the fatty acid amide hydrolase (FAAH) - cleavable prodrugs described herein, the prodrug has a structure selected from the following:

[0154]

[0155]

[0156] or a pharmaceutically acceptable salt or solvate thereof.

[0157] In some embodiments of the fatty acid amide hydrolase (FAAH) - cleavable prodrugs described herein, the prodrug has a structure selected from the following:

[0158]

[0159]

[0160] Drug composition

[0161] In some embodiments, described herein are drug compositions comprising a fatty acid amide hydrolase (FAAH)-cleavable prodrug of formula (I), (II), (III), or (IV) described herein. In some embodiments, described herein are drug compositions comprising a fatty acid amide hydrolase (FAAH)-cleavable prodrug of formula (I), (II), (III), or (IV) described herein and a pharmaceutically acceptable excipient. In some embodiments, described herein are drug compositions comprising a fatty acid amide hydrolase (FAAH)-cleavable prodrug of formula (I) described herein and a pharmaceutically acceptable excipient. In some embodiments, described herein are drug compositions comprising a fatty acid amide hydrolase (FAAH)-cleavable prodrug of formula (II) described herein and a pharmaceutically acceptable excipient. In some embodiments, described herein are drug compositions comprising a fatty acid amide hydrolase (FAAH)-cleavable prodrug of formula (III) described herein and a pharmaceutically acceptable excipient. In some embodiments, described herein are drug compositions comprising a fatty acid amide hydrolase (FAAH)-cleavable prodrug of formula (IV) described herein and a pharmaceutically acceptable excipient.

[0162] Peripherally-restricted FAAH inhibitor

[0163] In some embodiments, described herein are drug compositions that comprise a fatty acid amide hydrolase (FAAH)-cleavable prodrug of formula (I), (II), (III), or (IV) described herein and further comprise a peripherally-restricted FAAH inhibitor. In some embodiments, the peripherally-restricted FAAH inhibitor is disclosed in US2008 / 0306046, which is incorporated herein by reference in its entirety.

[0164] In some embodiments, the peripherally-restricted FAAH inhibitor is a compound of formula (X) or a pharmaceutically acceptable salt thereof:

[0165]

[0166] Wherein:

[0167] Ring A is a benzene ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, or a 5- to 7-membered nitrogen-containing heterocycle;

[0168] L is a single bond, a lower alkylene, a lower alkenylene, -N(R 15 )-C(=O)-, -C(=O)-N(R 15 )-, -(lower alkenylene)-C(=O), -O-, or C(=O);

[0169] R 15is H or lower alkyl;

[0170] X is CH or N;

[0171] R 8 、R 9 and R 10 are each independently selected from:

[0172] (i) a group selected from: H, halo, -CN, CF3, lower alkyl, and -O-lower alkyl;

[0173] (ii) an aryl group optionally substituted with 1 to 5 groups independently selected from: H, halo, -CN, CF3, lower alkyl, and -O-lower alkyl;

[0174] (iii) a nitrogen-containing heteroaryl group optionally substituted with 1 to 5 groups independently selected from: H, halo, -CN, -CF3, lower alkyl, and -O-lower alkyl;

[0175] (iv) R 16 -(lower alkenylene)-O-;

[0176] (v) R 16 -(lower alkenylene)-N(R 15 )-; or

[0177] (vi) R 17 R 18 N-C(=O)-;

[0178] R 16 is

[0179] (i) an aryl group optionally substituted with 1 to 5 groups independently selected from: H, halo, -CN, -CF3, lower alkyl, and -O-lower alkyl;

[0180] (ii) a nitrogen-containing heteroaryl group optionally substituted with 1 to 5 groups independently selected from: H, halo, -CN, -CF3, lower alkyl, and -O-lower alkyl; or

[0181] (iii) a 3- to 8-membered cycloalkyl group;

[0182] R 17 and R 18 are each independently selected from H, lower alkyl, and 3- to 8-membered cycloalkyl; or R 17 and R 18 may together with the nitrogen atom to which they are bonded form a 3- to 8-membered nitrogen-containing heterocycle;

[0183] R 11 is selected from H, lower alkyl, and oxo (=O); and

[0184] R 12 , R 13 and R 14 One of them is -C(=O)-O-(lower alkyl) or -CO2H, and the rest are H.

[0185] In some embodiments, the peripherally restricted FAAH inhibitor is 5-(((4-(4-((3-fluorobenzyl)oxy)phenoxy)piperidin-1-yl)carbonyl)oxy)nicotinic acid. In some embodiments, the peripherally restricted FAAH inhibitor is 5-(((4-(2-phenylethyl)piperidin-1-yl)carbonyl)oxy)nicotinic acid. In some embodiments, the peripherally restricted FAAH inhibitor is 5-(((4-(4-(2-cyclohexylethoxy)phenoxy)piperidin-1-yl)carbonyl)oxy)nicotinic acid. In some embodiments, the peripherally restricted FAAH inhibitor is 5-(((4-((E)-2-phenylvinyl)piperidin-1-yl)carbonyl)oxy)nicotinic acid. In some embodiments, the peripherally restricted FAAH inhibitor is 5-(((4-(3-(1-(6-methylpyridin-2-yl)piperidin-4-yl)propyl)piperidin-1-yl)carbonyl)oxy)nicotinic acid. In some embodiments, the peripherally restricted FAAH inhibitor is 5-(methoxycarbonyl)pyridin-3-yl 4-(2-phenylethyl)piperazine-1-carboxylate. In some embodiments, the peripherally restricted FAAH inhibitor is ASP-3652. In some embodiments, the peripherally restricted FAAH inhibitor is ASP-3652, which is 5-(((4-(2-phenylethyl)piperidin-1-yl)carbonyl)oxy)nicotinic acid.

[0186] excipient

[0187] Suitable optional excipients for use in the pharmaceutical compositions described herein include any excipients commonly used in pharmacy and are selected based on compatibility with the active agent and the release profile properties of the desired dosage form. Excipients include, but are not limited to, binders, fillers, flow aids, disintegrants, lubricants, glidants, polymeric carriers, plasticizers, stabilizers, surfactants, and the like. An overview of the excipients described herein can be found, for example, in the following: Remington: The Science and Practice of Pharmacy, 19th Edition (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, 7th Edition (Lippincott Williams & Wilkins, 1999), which are hereby incorporated by reference in their entirety.

[0188] Binders impart adhesiveness to solid oral dosage form formulations: for powder-filled capsule formulations, they assist in forming a plug that can be filled into soft or hard shell capsules, and for tablet formulations, they ensure that the tablets remain intact after compression and help ensure uniform blending prior to the compression or filling step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethyl cellulose, methyl cellulose (e.g., ), hydroxypropyl methyl cellulose (e.g., hypromellose USP Pharmacoat-603), hydroxypropyl methyl cellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., ), ethyl cellulose (e.g., ) and microcrystalline cellulose (e.g., ), microcrystalline dextrin, amylose, magnesium aluminum silicate, polygalacturonic acid, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sugars such as sucrose (e.g., ), glucose, dextran, molasses, mannitol, sorbitol, xylitol (e.g., ) Lactose, natural or synthetic gums such as gum arabic, tragacanth, ghatti gum, isapol husk mucilage, starch, polyvinylpyrrolidone (e.g., CL, CL, XL-10 and K-12), larch arabinogalactan, magnesium aluminum silicate polyethylene glycol, wax, sodium alginate, etc.

[0189] Fillers or diluents increase the volume of pharmaceutical formulations. Such compounds include, for example, lactose; starch; mannitol; sorbitol; dextrose; microcrystalline cellulose such as calcium hydrogen phosphate; dicalcium phosphate dihydrate; tricalcium phosphate; calcium phosphate; anhydrous lactose; spray-dried lactose; pregelatinized starch; compressible sugars such as (Amstar); hydroxypropylmethyl cellulose; sucrose-based diluents; powdered sugar; calcium bisulfate monohydrate; calcium sulfate dihydrate; calcium lactate trihydrate; dextran binder; hydrolyzed cereal solids; amylose; powdered cellulose; calcium carbonate; glycine; kaolin; sodium chloride; inositol; bentonite; etc.

[0190] Glidants improve the flow characteristics of powder mixtures. Such compounds include, for example, colloidal silica such as tricalcium phosphate, talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, kaolin, and micronized amorphous silica etc.

[0191] Lubricants are compounds that prevent, reduce, or inhibit adhesion or friction of materials. Exemplary lubricants include, for example, stearic acid; calcium hydroxide, talc; hydrocarbons such as mineral oil, or hydrogenated vegetable oils such as hydrogenated soybean oil higher fatty acids and their alkali metal and alkaline earth metal salts, such as aluminum salts, calcium salts, magnesium salts, zinc salts, stearic acid, sodium stearate, magnesium stearate, glycerol, talc, wax, boric acid, sodium acetate, leucine, polyethylene glycol or methoxypolyethylene glycol such as Carbowax TM , sodium oleate, glyceryl behenate glyceryl palmitostearate colloidal silica such as Syloid TM , starch such as corn starch, silicone oil, surfactants, etc. Hydrophilic lubricants include, for example, sodium stearyl fumarate (currently sold under the trade name ), polyethylene glycol (PEG), magnesium lauryl sulfate, sodium lauryl sulfate (SLS), sodium benzoate, sodium chloride, etc.

[0192] Disintegrants promote the decomposition or disintegration of pharmaceutical formulations after administration. Examples of disintegrants include starches, such as natural starches like corn starch or potato starch, pregelatinized starches such as National 1551 or or sodium starch glycolate such as or celluloses, such as wood products, microcrystalline cellulose, for example and methylcellulose, cross-linked carboxymethyl cellulose or cross-linked cellulose, such as sodium cross-linked carboxymethyl cellulose cross-linked carboxymethyl cellulose or cross-linked carboxymethyl starch; cross-linked starches, such as sodium starch glycolate; cross-linked polymers, such as cross-linked polyvinylpyrrolidone; cross-linked polyvinylpyrrolidone; alginate-based substances, such as alginic acid or salts of alginic acid such as sodium alginate; clays, such as HV (magnesium aluminum silicate); gums, such as agar, guar gum, locust bean gum, karaya gum, pectin or tragacanth gum; sodium starch glycolate; bentonite; natural sponges; resins, such as cation exchange resins; citrus pulp; sodium lauryl sulfate; combinations of sodium lauryl sulfate and starch; and so on.

[0193] Polymeric carriers include compounds such as: polyvinylpyrrolidone, for example polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or polyvinylpyrrolidone K30, polyvinylpyrrolidone vinyl acetate (PVPVA 64), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS) and methyl methacrylate polymers (Eudragit polymers), etc.

[0194] Stabilizers include compounds such as: any antioxidant, for example butylated hydroxytoluene (BHT), sodium ascorbate and tocopherol; buffers, acids, etc.

[0195] Surfactants include compounds such as: sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbate, polaxomer, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide such as (BASF), d-α-tocopheryl polyethylene glycol succinate (vitamin E TPGS); and so on.

[0196] The excipients mentioned above are given only as examples and are not intended to include all possible choices. Other suitable classes of excipients include colorants, granulating agents, preservatives, defoaming agents, plasticizers, etc. Additionally, many excipients may have more than one role or function, or may be classified in more than one group; the classification is merely descriptive and is not intended to limit any use of a particular excipient.

[0197] The disclosed pharmaceutical formulations are administered to patients (animals and humans) in need of such treatment in a dosage that will provide optimal pharmaceutical efficacy. It is to be understood that the dosage required for use in any particular application will vary from patient to patient, depending not only on the particular pharmaceutical formulation selected, but also on the nature of the condition being treated, the age and condition of the patient, concurrent medications or special diets followed by the patient, and other factors, where the appropriate dosage is ultimately at the discretion of the attending physician.

[0198] Although the preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous changes, variations, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be used to practice the invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents be covered by those claims.

[0199] Examples

[0200] The following examples are provided for illustrative purposes and are not intended to limit the scope of the claims provided herein. All literature citations in these examples as well as throughout this specification are hereby incorporated by reference for all legal purposes for which they serve. The starting materials and reagents for the synthesis of the compounds described herein may be synthesized or obtained from commercial sources such as, but not limited to, Sigma - Aldrich, Acros Organics, Fluka, and Fischer Scientific. In some embodiments, the compounds provided herein are synthesized as described in US2019 / 0210950, which patent is incorporated by reference herein. In some embodiments, the compounds provided herein are synthesized as described in US 2021 / 0002208, which patent is incorporated by reference herein. In some embodiments, the compounds provided herein are synthesized as described in WO 2021 / 108549, which patent is incorporated by reference herein. In some embodiments, the compounds provided herein are synthesized as described in PCT / US2022 / 028187, which patent is incorporated by reference herein.

[0201] Example 1: FAAH Substrate Evaluation

[0202] Purified recombinant human FAAH (rhFAAH) was purchased from Cayman Chemical (Ann Arbor, MI, USA). The total volume of each incubation was 400 μL and consisted of Tris-EDTA buffer at pH 8.0 containing a final concentration of 0.5 ng / μL rhFAAH, 1 μM test compound, 1.25% ethanol or 1 μM PF-3845 (FAAH inhibitor), and 0.1% bovine serum albumin. The positive control was LL-341001. Incubations were carried out at room temperature. At 0, 5, 15, 30, and 60 minutes, 30 μL aliquots of the reaction mixture were removed and mixed with 300 μL of acetonitrile containing 5 ng / mL terfenadine and 10 ng / mL tolbutamide as internal standards to quench the reaction. The resulting mixture was centrifuged at 4000 rpm for 15 minutes at 4 °C, and 100 μL of the supernatant was prepared for LC-MS / MS analysis to measure the formation of the acid metabolite.

[0203] LC-MS / MS analysis

[0204] An Acquity ultra performance LC system from Waters was used for sample analysis. Chromatography was performed on a reversed-phase Kinetex 2.6 μm C18 column (2.1 × 30 mm, ). Mobile phase A consisted of 0.1% formic acid in water, and mobile phase B consisted of 0.1% formic acid in acetonitrile. For the acid metabolite from the positive control, the run time was 2 min and the flow rate was 0.8 mL / min, or for the acid metabolite of the test compound, the run time was 1.5 min and the flow rate was 0.9 mL / min. The mass spectrometers (API-5500 and API Q Trap 4000 Applied Biosystems / MDS SCIEX Instruments, Framingham, MA, USA) were operated in ESI positive or negative ion MRM mode.

[0205] Data analysis

[0206] The formation of the acid metabolite was monitored and quantified using a 1 μM calibration point. The observed rate constant (ke) of acid metabolite formation was calculated by plotting the metabolite concentration versus incubation time (where the slope is ke), and is shown in Table 1.

[0207] Table 1

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216] A = ke ≥ 0.1; B = ke < 0.1 and > 0; C = ke is 0; NT = Not Tested.

[0217] Example 2: In Vitro Prodrug and Agonist TRβ Receptor Selectivity

[0218] Evaluate the potency and selectivity of LL-341070 and LL-341070A (LL-341070 is Compound 31 described herein, which is activated to LL-341070A; LL-341070A is 2-(3,5-dichloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)phenoxy)acetic acid) against the thyroid hormone β receptor (TRβ). LL-341070 is a thyromimetic prodrug of formula (I) described herein. After fatty acid amide hydrolase (FAAH)-mediated conversion, LL-341070 delivers LL-341070A, a potent and selective small molecule agonist of the thyroid hormone receptor (TR)β. In vitro potency was determined by administering the test compounds to a luciferase-based TR reporter cell line, using thyroid hormone (T3) as a positive control. Table 2 depicts the potency profiles of the LL-341070 prodrug and the LL-341070A active metabolite against TRβ and TRα, as measured by the half maximal effective concentration (EC50), where the TRα bias against T3 was selectively measured and adjusted in the assay. Both LL-341070 and LL-341070A showed enhanced selectivity for TRβ, and LL-341070A showed enhanced potency.

[0219] Table 2

[0220]

[0221] Example 3: Engagement of TRβ in the Brain Increases Expression of T3 Target Genes In Vivo

[0222] Figure 1Depiction of TRβ target engagement in the brain is demonstrated by increased expression of in vivo T3-responsive target genes. Single PO administration of LL-341070 (in the range of about 0.1 μg / kg to about 300 μg / kg) or T3 (about 300 μg / kg) in male C57BL / 6 mice increased the expression of Hr, Dio3, Klf9 in the brain (quantified by QuaniPlex) and the composite mean log2 fold change. At various treatment concentrations, Klf9, a T3-responsive gene associated with in vitro myelin regeneration, was upregulated. This increased expression was confirmed (by Nanostring quantification) in the brains of rats in the cuprizone model with 21-day repeated administration of 30 μg / kg or 100 μg / kg of LL-341070 or T3 administered at 300 μg / kg (as previously discussed). Of concern, Dio3 had an enhanced increase in expression with repeated dosing.

[0223] Example 4: In Vivo Tissue Distribution Demonstrates Enhanced Brain Exposure of the Active Compound Compared to the Prodrug

[0224] In mouse and rat cuprizone models, in vivo brain exposure of the active compound compared to the prodrug was evaluated by tissue distribution (TD) assays, measured as the brain-to-plasma brain exposure ratio after thyroxine treatment. As shown in Table 3, in male C57BL / 6 mice, when measured in the brain and plasma, single PO administration of LL-341070 (100 μg / kg) or LL-341070A (100 μg / kg) showed enhanced brain exposure of the active compound LL-341070A compared to the prodrug LL-341070, resulting in a brain-to-plasma AUC ratio of LL-341070A > 1, where AUC is 0 - 24 h. The data showed that the AUC of LL-341070A in the brain was approximately 7-fold higher than that of the prodrug LL-341070. Table 3 also depicts the brain-to-plasma AUC ratio. As Figure 2 shown, in the rat cuprizone model, when measured in the brain and plasma 4 hours after the final dose, 21-day repeated administration of LL-341070 (30 μg / kg or 100 μg / kg) or LL-341070A (30 μg / kg or 100 μg / kg) showed enhanced brain exposure of the active compound LL-341070A compared to the prodrug LL-341070.

[0225] Table 3

[0226]

[0227] Example 5: FAAH Expression is Enriched in the Brain

[0228] As Figure 3As shown, the mechanism by which thyromimetic drugs disrupt the thyroid hormone axis (THA) was elucidated using brain-directed thyromimetic prodrugs (such as ABX-002, which is Compound 1 described herein and is activated to ABX-002A) activated by fatty acid amide hydrolase (FAAH). Delivery of potent thyromimetic drugs was altered to help determine whether feedback control of the THA originated from central (hypothalamic) or peripheral (pituitary) mechanisms and potentially enhance the therapeutic index of thyromimetic drugs. These studies were conducted using recombinant FAAH, tissue-derived S9 fractions, in vivo tissue distribution (TD), gene expression in the brain and liver, and the effect on T4 as a marker of THA disruption in mice. Northern blot assays confirmed FAAH expression in multiple species (rodents and humans), and in the brain, relative mRNA FAAH expression was enhanced. The FAAH specific activity (AMC cleavage assay) of tissue-derived S9 fractions from different organs (liver, brain, small intestine) from multiple species (mouse, rat, non-human primate, human), calculated as a percentage of liver activity, was shown to increase in the brains of humans and non-human primates.

[0229] Example 6: Enhanced Delivery of ABX-002A to the Brain by FAAH Expression

[0230] To evaluate delivery, the concentration of ABX-002A in the brain, liver, kidney, lung, and heart was measured 1 hour after SC administration of 30 different prodrugs of ABX-002A. As Figure 4 shown, the brain-to-plasma ratio of the prodrug increased relative to ABX-002A, while the tissue-to-plasma ratio in peripheral organs (liver, kidney, lung, and heart) showed a linear (constant) tissue-to-plasma relationship. The data show that FAAH is highly expressed in the CNS and that the ABX prodrug enhances delivery of the active metabolite to the brain by >30-fold, with a brain-to-plasma ratio >1. In organs other than the brain, the data show that tissue concentration is driven by the plasma concentration of the active metabolite ABX-002A.

[0231] Example 7: Global and Peripheral FAAH Inhibitors Alter Metabolite Distribution in Mice

[0232] The ability of global penetrant and peripheral-restricted FAAH inhibitors (GFI and PFI, respectively) to alter the distribution of ABX-002 and ABX-002A was evaluated. Table 4 depicts the potency profiles (measured as apparent IC 50 (nM)) of peripheral and global FAAH inhibitors: LL-650177 (PFI), URB9373 (PFI), and PF-044578454 (GFI), which were obtained after pre-incubation with recombinant human FAAH and 7-amino-4-methylcoumarin (AMC) for 30 min.

[0233] Table 4

[0234] FAAH inhibitor <![CDATA[Apparent IC 50 (nM)]]> Distribution LL-650177 9.1 Periphery URB937 69 Periphery PF-04457845 3.0 Global

[0235] Figure 5 Plasma, liver, and brain concentrations are shown after administration of the prodrug (ABX-002) with or without co-administration of PFI or GFI. Prodrug levels do not change with FAAH inhibition or increase slightly with FAAH inhibition. Active metabolite (ABX-002A) levels are decreased in plasma and liver under PFI and decreased in all organs under GFI. Table 5 depicts the inhibition of the active metabolite in plasma, liver, and brain in the form of AUC after co-administration of the prodrug (ABX-002) (LL-650177 or PF-044578454). Tissue distribution studies in mice confirm global and peripheral inhibition of FAAH.

[0236] Table 5

[0237] FAAH inhibitor Plasma Liver Brain LL-650177 89％ 91％ -12％ PF-04457845 94％ 94％ 83％

[0238] Example 8: Induction of T3-Regulated Genes Considering a Prodrug and an FAAH Inhibitor

[0239] Before dosing in the study, female C57BL / 6 mice (n = 5 / group) at 6 - 8 weeks of age were acclimated to the study room for at least 3 days. On day 0 at time = -1 hour, non-fasted mice were orally (PO) administered a single dose of PFI or vehicle. A single dose was administered at 5 mL / kg based on recent body weight and collected once during the entire study. After the PFI or vehicle dose, the animals were administered a single dose of the test article at time = 0 hour. One group (n = 5) was only PO administered 300 ug / kg of T3 at time = 0 hour. Approximately 4 hours after the test article dose (t = 4 hours), the animals were euthanized humanely and brain, liver, heart, pituitary, spinal cord, and plasma samples were collected.

[0240] Sample preparation

[0241] a. Expression analysis samples - At the end point, multiple organs were collected and the tissues were processed immediately as described below.

[0242] i. Brain: For each mouse, the skull was opened and the brain was removed. The cerebellum was excised, and the cerebral cortex was cut sagittally in half and the left half was collected. After rinsing the tissue with ice-cold 0.9% NaCl to remove extraneous blood, the cerebral cortex specimens were placed into tubes containing 1.2 m L of pre-cooled RNALater and stored at 4 °C.

[0243] ii. Liver: For each mouse, a liver biopsy (100 - 150 mg) was collected from the left lateral liver lobe. After rinsing the biopsy with ice-cold 0.9% NaCl to remove extraneous blood, the sample was placed into 1.2 mL of pre-cooled RNALater and stored at 4 °C.

[0244] iii. Left ventricle: For each mouse, the left ventricle (LV) blood was cleared using the PBI standard method, and half of the LV free wall was collected. After rinsing the tissue with ice-cold 0.9% NaCl to remove extraneous blood, the LV free wall was placed into 1.2 m mL of pre-cooled RNALate r and stored at 4 °C. The LV tissue was retained at PBI for potential future analysis or until an appropriate gene could be identified, for up to 6 months after the end of the survival phase of the study. Sample disposal was confirmed prior to discarding.

[0245] iv. Pituitary gland: For each mouse, the pituitary gland was collected after removal of the brain. After rinsing the pituitary with ice-cold 0.9% NaCl to remove extraneous blood, the specimen was placed into 0.15 mL of pre-cooled RNALater and stored at 4 °C. The pituitary tissue was retained at PBI for potential future analysis or until an appropriate gene could be identified, for up to 6 months after the end of the survival phase of the study. Sample disposal was confirmed prior to discarding.

[0246] b. Pharmacokinetic samples - At the end point, blood and tissue specimens were processed immediately as described below. Samples for PK analysis were retained at PBI at -80 °C for up to 90 days after the end of the survival phase of the study.

[0247] i. Plasma: Whole blood (approx. 300 μL) was collected into K3EDTA by cardiac puncture under isoflurane anesthesia. The blood was placed immediately on wet ice. After the end of the dissection procedure, the blood was centrifuged at 4 °C at 10,000 × g for 10 minutes. Plasma (approx. 125 μL) was aliquoted into appropriately labeled tubes and snap-frozen.

[0248] ii. Liver: For each mouse, a liver biopsy (30 - 50 mg) was collected from the left lateral liver lobe. After rinsing the biopsy with ice-cold 0.9% NaCl to remove extraneous blood, the sample was placed into appropriately labeled tubes and snap-frozen in liquid nitrogen.

[0249] iii. Brain: For each mouse, a midbrain biopsy (30 - 50 mg) was collected from the right cerebral cortex. After rinsing the tissue with ice-cold 0.9% NaCl to remove extraneous blood, the biopsy was placed into appropriately labeled tubes and snap-frozen.

[0250] iv. Left Ventricle: For each mouse, the blood in the left ventricle (LV) will be cleared using the PBI standard method, and half of the LV free wall will be collected. After rinsing the tissue with ice-cold 0.9% NaCl to remove unrelated blood, the LV free wall will be placed into appropriately labeled tubes and snap-frozen.

[0251] Target engagement

[0252] Using a hybridization-based in situ RNA quantification method (NanoString, Seattle, WA), the expression changes of selected genes identified by transcriptomic analysis will be measured from the purified RNA. Briefly, fresh tissue will be collected in RNALater TM stabilization solution (ThermoFisher Scientific; Carlsbad, CA) and frozen at -20 °C until ready for RNA extraction. Whole blood will be collected by terminal cardiac puncture into MiniCollect K2EDTA tubes (catalog number 450480) from Greinder Bio-one GmbH (Kremsmunster, Austria), and processed into plasma by centrifuging at 2000 × g for 10 minutes at 4 °C. For RNA extraction, the tissue will be homogenized in TRIzol reagent (ThermoFisher Scientific, catalog number 15596026) using a bead homogenizer, and RNA will be extracted according to the manufacturer's protocol and purified using an Econospin RNA microspin column for RNA (EphochLife Sciences, Missouri City, TX, catalog number 1940 - 250) according to the manufacturer's protocol. Specific gene probes will be designed by the NanoString bioinformatics team using the identified target sequences based on the NCBI Reference Sequence (RefSeq) database. Custom probes will be synthesized by Integrated DNA Technologies (IDT; Coralville, IA). According to the manufacturer's protocol (NanoString, Inc, Seattle, WA), using the nCounterPlexSet-12 reagent pack (catalog number PS-GX-PTK-12 (CSO)), the mRNA expression will be analyzed using a multiplexing method on the SPRINT Profiler NanoString system.

[0253] Data analysis

[0254] After single administration of the drug, the T3 target gene increases, where the relative activity in the brain versus the liver is determined by prodrug and / or FAAH inhibition. In different dosing paradigms, the relative activity in the brain versus the liver (as a marker of peripheral activity) varies >1500-fold. Figure 6A , 6B and 6C show the induction of T3-regulated genes in the brain (blue) and liver (orange) 4 h after single administration of (A) the active metabolite or (B) the prodrug alone or (C) the prodrug + PFI (URB937). RNA was analyzed by Nanostring; the average fold change of multiple genes was calculated on a log2 scale and normalized to data obtained for T3 at 300 mg / kg. PFI administration reduces the potency of the prodrug to activate T3-regulated genes in the liver to <1 / 10, without affecting activity or exposure in the brain. PFI also reduces the potency for THA, which is consistent with negative feedback based on circulating peripheral metabolites rather than brain exposure. Thus, the use of PFI allows the on-target brain effect to be separated from the effect on THA.

[0255] Example 9: T4 corresponds to peripheral activity

[0256] Before the dose administration in the study, female C57BL / 6 mice (n = 5 / group) at 6 - 8 weeks of age were acclimated to the study room for at least 3 days. Mice were dosed at 5 mL / kg based on their most recent body weight, collected once during the entire study period. Based on their most recent body weight, collected once during the entire study period, mice were placed into weight - matched treatment - dosing cohorts. Mice were orally (PO) administered a single dose of PFI or vehicle (n = 5 / group) daily at time = -1 hour for 7 days. After the PFI (100 μg / kg) or vehicle dose (10 mL / kg, p.o.), the test article was administered to the animals daily at time = 0 hour. The test article was administered at one of eight dose levels (0.1, 0.3, 1, 3, 10, 30, 100, or 300 μg / kg) on days 1–7, for a total of seven doses. Mice were PO dosed with (A) the active metabolite or (B) the prodrug alone; (C) the prodrug + PFI (LL - 650177) or (D) the prodrug + GFI, QD, for 7 days. Approximately 4 or 8 hours (t = 4 hours or t = 8 hours) after the test article dose, the animals were euthanized humanely using standard procedures, and brain, liver, and plasma samples were collected. As described below, RNA from samples collected 4 hours after the final dose was quantified using a hybridization - based in situ RNA quantification method (NanoString, Seattle, WA). As described below, RNA from samples collected 8 hours after the final dose was quantified using a hybridization - based in situ RNA quantification method (QuantiGene Plex). On the last day of dosing, mice were dosed according to the schedule to mitigate the effect of the diurnal rhythm on thyroid hormone - sensitive gene expression. Thus, at the end - point sacrifice, the treatment groups were balanced for "time of day". Mice were anesthetized 4 or 8 hours after the final dose, blood was collected by retro - orbital puncture, and they were euthanized using standard procedures. Immediately after euthanasia, tissues were collected and processed according to the following protocol.

[0257] Sample preparation

[0258] a. Expression analysis samples - At the end - point, multiple organs were collected and tissues were processed immediately as described below.

[0259] i. Brain: For each mouse, the skull was opened and the brain was removed. The cerebellum was excised, and the cerebral cortex was cut sagittally in half and the left half was collected. After rinsing the tissue with ice - cold 0.9% NaCl to remove extraneous blood, the cerebral cortex specimens were placed into tubes containing 1.2 mL of pre - cooled RNALater and stored at 4°C.

[0260] ii. Liver: For each mouse, a liver biopsy (100 - 150 mg) was collected from the left lateral liver lobe. After rinsing the biopsy with ice-cold 0.9% NaCl to remove extraneous blood, the sample was placed into 1.2 mL of pre-chilled RNALater and stored at 4°C.

[0261] iii. Left ventricle: For each mouse, the left ventricle (LV) blood was cleared using the PBI standard method, and half of the LV free wall was collected. After rinsing the tissue with ice-cold 0.9% NaCl to remove extraneous blood, the LV free wall was placed into 1.2 mL of pre-chilled RNALater and stored at 4°C. The LV tissue was retained at PBI for potential future analysis or until an appropriate gene could be identified, for up to 6 months after the end of the survival phase of the study. Sample disposition was confirmed prior to discard.

[0262] iv. Pituitary gland: For each mouse, the pituitary gland was collected after removal of the brain. After rinsing the pituitary with ice-cold 0.9% NaCl to remove extraneous blood, the specimen was placed into 0.15 mL of pre-chilled RNALater and stored at 4°C. The pituitary tissue was retained at PBI for potential future analysis or until an appropriate gene could be identified, for up to 6 months after the end of the survival phase of the study. Sample disposition was confirmed prior to discard.

[0263] b. Pharmacokinetic samples - At the end point, blood and tissue specimens were processed immediately as described below. Samples for PK analysis were retained at PBI at -80°C for up to 90 days after the end of the survival phase of the study.

[0264] i. Plasma: Whole blood (approx. 300 μL) was collected into K3EDTA by cardiac puncture under isoflurane anesthesia. The blood was placed immediately on wet ice. After the end of the dissection procedure, the blood was centrifuged at 10,000 × g for 10 minutes at 4°C. Plasma (approx. 125 μL) was aliquoted into appropriately labeled tubes and snap frozen.

[0265] ii. Liver: For each mouse, a liver biopsy (30 - 50 mg) was collected from the left lateral liver lobe. After rinsing the biopsy with ice-cold 0.9% NaCl to remove extraneous blood, the sample was placed into appropriately labeled tubes and snap frozen in liquid nitrogen.

[0266] iii. Brain: For each mouse, a midbrain biopsy (30 - 50 mg) was collected from the right cerebral cortex. After rinsing the tissue with ice-cold 0.9% NaCl to remove extraneous blood, the biopsy was placed into appropriately labeled tubes and snap frozen.

[0267] iv. Left Ventricle: For each mouse, the blood in the left ventricle (LV) will be cleared using the PBI standard method, and half of the LV free wall will be collected. After rinsing the tissue with ice-cold 0.9% NaCl to remove unrelated blood, the LV free wall will be placed in appropriately labeled tubes and snap-frozen.

[0268] Target engagement

[0269] Tissue samples for biochemical analysis will be prepared by cryogenic pulverization under liquid nitrogen and dissolved using the standard method of PBI. Using a hybridization-based in situ RNA quantification method (NanoString or QuantiGene Plex), changes in the expression (mRNA expression) of selected genes identified by transcriptomic analysis will be measured from purified RNA. Target gene expression data are presented as the ratio to the geometric mean of appropriately expressed normalization genes. Briefly, fresh tissue will be collected in RNALater TM stabilization solution (ThermoFisher Scientific; Carlsbad, CA) and frozen at -20 °C until ready for RNA extraction. Whole blood will be collected by terminal cardiac puncture in MiniCollect K2EDTA tubes (catalog number 450480) from Greinder Bio-one GmbH (Kremsmunster, Austria) and processed into plasma by centrifugation at 2000 × g for 10 minutes at 4 °C. For RNA extraction, the tissue will be homogenized in TRIzol reagent (ThermoFisher Scientific, catalog number 15596026) using a bead homogenizer, and RNA will be extracted according to the manufacturer's protocol and purified using the Econospin RNA Micro Spin / Column for RNA (Ephoch Life Sciences, Missouri City, TX, catalog number 1940-250) according to the manufacturer's protocol. Specific gene probes will be designed by the NanoString bioinformatics team using the identified target sequences based on the NCBI Reference Sequence (RefSeq) database. Custom probes will be synthesized by Integrated DNA Technologies (IDT; Coralville, IA). According to the manufacturer's protocol (NanoString, Inc, Seattle, WA), using the nCounterPlexSet-12 reagent kit (catalog number PS-GX-PTK-12 (CSO)), the mRNA expression will be analyzed using the multiplexing method on the SPRINT Profiler NanoString system.

[0270] T4 analysis

[0271] T4 in the terminal plasma samples was measured using an ELISA kit (Biovision, Inc., Thyroxine [T4] [Mouse / Rat] ELISA Kit, Catalog No.: K7421-100). The assay was performed with minor modifications based on previous assay validation work according to the manufacturer's instructions. Briefly, for each assay, a seven-point standard curve (25, 15, 10, 5, 2, 1 μg / dL) of the provided T4 diluted in the assay buffer was prepared in duplicate. Plasma samples (undiluted), blanks (assay buffer), and standards were added to separate wells pre-coated with the T4 capture antibody in a 96-well plate, and then the T4 enzyme conjugate was added to each well. The plate was then gently shaken (600 rpm) for 20 - 30 s for mixing, covered with an acetate plate seal membrane, and incubated at room temperature (RT) with gentle shaking (600 rpm) for 1 h. The plate contents were aspirated and washed three times with 1× wash buffer, then blotted dry on a paper towel to remove excess liquid. Then, the TMB substrate was added to each well and the plate was sealed with an acetate seal membrane and incubated at room temperature in the dark for 15 min. Then, the stop solution was added to each well and the plate was gently shaken to mix the solution. Absorbance was read at 450 nm using a Varioskan Lux plate reader (ThermoFisher Scientific, Carlsbad, CA) 15 min after the addition of the stop solution. The relative optical density (OD) was background-corrected against the blank sample and the standard curve. The T4 concentration was interpolated using a four-parameter curve fitting method. The concentration of the unknown sample was determined using GraphPad Prism software (GraphPad Prism 9.0.2, GraphPad Software, San Diego, CA).

[0272] Data analysis

[0273] Figure 7A 、 7B Figures 7C and 7D show gene expression in the brain (blue) and liver (orange) and the effect on T4 (gray) in mice that had been dosed (QD, for 7 days) with (A) the active metabolite or (B) the prodrug alone; (C) the prodrug + PFI (LL-650177) or (D) the prodrug + GFIPO, 4 or 8 h after the last dose. After 7 days of treatment, both the prodrug and the active metabolite decreased T4 levels. Table 6 reports the ED 50 values in μg / kg for each treatment type.

[0274] Table 6

[0275]

[0276] Use T4 as a marker for the impact on THA; T4 corresponds more to peripheral activity as compared to corresponding to CNS activation of the target gene. The negative regulation of thyromimetics on T4 does not seem to be mainly centrally mediated, because the effects on THA and hepatic gene expression correspond more closely to plasma distribution as compared to corresponding to exposure or activity in the CNS, thus indicating a mainly pituitary-driven effect. The combination of a thyromimetic prodrug and PFI can further enhance the delivery of the thyromimetic to the brain and maximize central targeting distribution.

[0277] Example 10: Phase II Study - Evaluate the Efficacy and Safety of ABX-002 in the Adjunctive Treatment of Adult Major Depressive Disorder (MDD)

[0278] This is a Phase 2 randomized, double-blind, placebo-controlled study to investigate the efficacy, safety, PK, and pharmacodynamics of daily oral doses of ABX-002 or placebo in adult subjects with MDD.

[0279] The study consists of 3 phases: a screening period of up to 28 days, a treatment period of 28 days, and an observation period of 8 weeks.

[0280] 28-day screening period - At the screening visit, subjects will be evaluated for inclusion / exclusion criteria. Subjects meeting all inclusion and exclusion criteria will be randomly assigned in a 1:1 ratio to receive a single daily oral dose of ABX-002 or placebo for 28 days, in addition to continuing their standard care serotonin antidepressant.

[0281] 28-day treatment period - During the treatment period, the efficacy, safety, and PK of the subjects will be regularly evaluated. EEG and slit lamp examinations will be performed at the end of the treatment period. EEG and slit lamp examinations will be performed at the end of the treatment period. After the main time point on Day 28, all subjects will continue treatment with their background SSRI / SNRI.

[0282] Observation period - Subjects who respond to treatment will enter an 8-week observation period. A follow-up examination will be performed 14 days after the end of the treatment period. A slit lamp examination will be performed 12 weeks after the end of the treatment period. If the subject and the investigator choose to change the MDD treatment during the observation period, the subject will be followed up for safety, but no further efficacy data will be collected. During the observation period, all AEs (regardless of causality) will be reported within 14 days after the last dose of the study drug. After 14 days, an AE should only be reported if it is related to the Eye Disorders System Organ Class in MedDRA24.

[0283] The study treatment (ASK1 inhibitor or placebo) will consist of ABX-002 capsules or a matching placebo, administered orally once daily.

[0284] The primary endpoint for efficacy assessment will be the change in the MADRS score from baseline to Day 28. The determination of efficacy will be based on a two-sided p-value < 0.05. Secondary endpoints will include the change in the Sheehan Disability Scale (SDS) score from baseline to Day 28, the change in CGI-S, the change in SDQ (and energy subscale), the change in C-SSRS, the change in HAM-D, and the proportion of MADRS responders (≥ 50% reduction from baseline) and MADRS remission (≤ 9 on Day 28). The change in MADRS from baseline on Day 28 will be evaluated using a repeated measures mixed model (MMRM). This model will include fixed effects for treatment group, visit, treatment-by-visit interaction, and baseline MADRS score.

[0285] Inclusion criteria :

[0286] · Be able to give informed consent and HIPAA authorization

[0287] · Be 18 - 65 years of age at the screening visit.

[0288] · Be able to understand the nature of the trial and, in the opinion of the investigator, will comply with the protocol requirements.

[0289] · Have a preliminary diagnosis of MDE as part of MDD according to SCID-5-CV, DSM-5 and meet the SAFER criteria (SAFER questions 1 - 4 must score "definitely" or "possibly", and SAFER questions 5 - 8 must score "definitely").

[0290] · Hamilton Depression Rating Scale (HAM-D) ≥ 19 at screening and baseline. The HAM-D score at the baseline visit should not be more than 25% lower than that at the screening visit. Montgomery- Depression Rating Scale (MADRS) score ≥ 24 at baseline.

[0291] · Clinical Global Impression of Severity (CGI-S) is moderate or more severe at baseline before screening and randomization.

[0292] · In the MDE, the subject has used a single SSRI or SNRI antidepressant adherently for at least 6 weeks at an adequate dose and is defined as having an insufficient response according to the Antidepressant Treatment Response Questionnaire (ATRQ). In the MDE, at least 1 and no more than 2 antidepressants have been adequately evaluated and are defined as having an insufficient response according to the ATRQ. The current SSRI / SNRI dose must have been stable in the past 4 weeks and is expected to remain stable during the screening and treatment periods of this study.

[0293] · The investigator and the subject are willing to continue the existing SSRI / SNRI during the treatment period of this study. If the subject responds to the treatment, the investigator and the subject are willing to continue the existing SSRI / SNRI during the observation period.

[0294] · In the samples obtained during the screening period, the subject should have a detectable plasma level of SSRI / SNRI.

[0295] · Women must have a negative serum pregnancy test at the time of screening and before randomization on Day 1.

[0296] · Women of childbearing potential and all male subjects must use effective contraception during the study and for 90 days after the last dose of the study drug.

[0297] · BMI is 18 - 35 kg / m2 (inclusive), and the minimum body weight is 50 kg.

[0298] Exclusion criteria:

[0299] · Have a history of schizophrenia or other psychotic disorders, or type I or type II bipolar disorder, delirium, dementia, amnesia, or cognitive impairment. Currently being treated for obsessive - compulsive disorder (OCD), attention - deficit / hyperactivity disorder (ADHD), post - traumatic stress disorder (PTSD), panic disorder, eating disorders according to DSM - 5 criteria.

[0300] · Have a preliminary diagnosis of borderline, antisocial, paranoid, schizoid, schizophreniform, or histrionic personality disorder according to DSM - 5 criteria.

[0301] · Have a history of non - response to augmentation with triiodothyronine ( or T3) for depression.

[0302] · Concurrently use other depression augmenters, including second - generation antipsychotics (SGA), lithium, bupropion, or a second SSRI / SNRI.

[0303] · Patients who discontinued second-generation antipsychotics (SGAs) used as augmentation for major depressive disorder (MDD) due to lack of treatment response are eligible for screening if they discontinued the SGA at least 30 days before screening.

[0304] · Received repetitive transcranial magnetic stimulation (rTMS) within 12 months before screening or are scheduled to receive rTMS during the study.

[0305] · Received >1 course of electroconvulsive therapy (ECT) in their lifetime or are scheduled to receive ECT during the study. History of vagus nerve stimulation (VNS) or deep brain stimulation (DBS).

[0306] · History of alcohol or illicit substance abuse / dependence (except use of caffeine or nicotine) within 12 months before screening or positive urine drug results for illicit substances at screening or baseline. A single positive urine drug screening result for illicit substances can be repeated once.

[0307] · Suicidal ideation (including answering "yes" to questions 4 or 5 in the screening version of the Columbia Suicide Severity Rating Scale [C-SSRS] [current or past 6 months]) or attempted suicide within 2 years before screening.

[0308] · Received a new psychotherapy or changed the intensity of psychotherapy within 8 weeks before screening. If there is psychotherapy, it must be expected to maintain the same intensity during the screening and 28-day treatment period of this study.

[0309] · Unstable residence, receiving Social Security disability, or legally incapacitated.

[0310] · History or current evidence (in the opinion of the investigator) of severe or unstable neurological, cardiovascular, gastrointestinal, respiratory, renal, hepatic, hematological, endocrine, or other medical conditions (including cancer) that would endanger the subject's safe participation in the study within 3 months before screening.

[0311] · History of previous myocardial infarction (MI), coronary balloon angioplasty or stent placement, heart failure, angina pectoris, or atrial fibrillation, atrial flutter, or ventricular tachycardia.

[0312] · Clinically significant abnormalities on electrocardiogram (ECG) at screening - QTc > 450 milliseconds in men and QTc > 470 milliseconds in women. A repeat ECG can be performed once, and if the values are below these values, the subject can be included.

[0313] · History of positive tests for hepatitis B, hepatitis C virus (HCV), or human immunodeficiency virus (HIV).

[0314] · Glycated hemoglobin (HbA1c) > 8% at screening.

[0315] · Creatinine clearance rate estimated based on the CKD-EPI equation ≤ 90 mL / min.

[0316] · Abnormal thyroid function tests at screening (e.g., TSH, T3, TT4, and FT4). Or a history of thyroid hormone replacement (e.g., a history of treating hypothyroidism or thyroid cancer).

[0317] · AST or ALT > 2 × ULN.

[0318] · Lenticular opacities based on ophthalmic examinations during screening.

[0319] · A history of clinically significant cataract, glaucoma, inflammatory eye disease, or any previous ophthalmic surgery or laser surgery in either eye. This may include subjects who have previously undergone LASIK surgery.

[0320] · Evidence of epileptiform activity on EEG during screening.

[0321] · A diagnosis of epilepsy or a history of seizures, including febrile seizures in childhood. Exclude the use of co-administered medications that can lower the seizure threshold (e.g., bupropion).

[0322] · Participated in any clinical study within 30 days before screening.

[0323] · Use of benzodiaz epine hypnotics. Subjects using non-benzodiaz epine hypnotics daily (e.g., zolpidem, zaleplon, eszopiclone) may continue to use them during the 28-day treatment period as long as the dose remains unchanged.

[0324] · Known allergy to ABX-002 or its excipients.

[0325] · Pregnant women, women planning to become pregnant within 90 days after the last dose, or women who are breastfeeding.

[0326] · Subjects who have previously participated in an ABX-002 clinical trial.

[0327] · Study site personnel or their immediate family members (spouse, parent, biological or adopted child, or sibling).

Claims

1. A method for treating depression, anxiety disorder or pain in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: Wherein: R 1 and R 2 are independently selected from hydrogen, -OR 5 , -NR 5 R 6 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl and -C1-C6 alkyl-phenyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl and -C1-C6 alkyl-phenyl are optionally substituted by one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 ; R 3 and R 4 are independently selected from -F, -Cl, -Br, and -I; R 5 and R 6 are independently selected from hydrogen and C1-C6 alkyl; and R 7 and R 8 are independently selected from hydrogen, -F, -Cl, -Br, and -I.

2. A method for treating depression, anxiety disorder or pain in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof: Wherein: R 1 and R 2 are independently selected from hydrogen, -OR 5 , -NR 5 R 6 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl, where the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl are optionally substituted with one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 ; R 3 and R 4 are independently selected from -F, -Cl, -Br, and -I; R 5 and R 6 are independently selected from hydrogen and C1-C6 alkyl; and R 7 and R 8 are independently selected from hydrogen, -F, -Cl, -Br, and -I, wherein at least one of 7 R 8 and R is not hydrogen.

3. The method according to claim 1 or 2, wherein R 7 is hydrogen.

4. The method according to claim 1 or 2, wherein R 8 is hydrogen.

5. The method according to any one of claims 1 - 3, wherein R 8 is -F.

6. The method according to any one of claims 1, 2 and 4, wherein R 7 is -F.

7. A method for treating depression, anxiety disorder or pain in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof: Wherein: R 1 and R 2 are independently selected from hydrogen, -OR 5 , -NR 5 R 6 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl and -C1-C6 alkyl-phenyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl and -C1-C6 alkyl-phenyl are optionally substituted by one or more of the following: halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 or -S(O)2OR 5 ; R 3 and R 4 are independently selected from -F, -Cl, -Br, and -I; and R 5 and R 6 are independently selected from hydrogen and C1-C6 alkyl.

8. The method according to any one of claims 1 - 7, wherein R 1 is hydrogen.

9. The method according to any one of claims 1 - 8, wherein R 2 is a C1 - C6 alkyl optionally substituted with one or more of the following: halo, cyano, -OR5 、 -NR 5 R 6 、 -S(O)2R 5 or -S(O)2OR 5 。 10. The method according to any one of claims 1 - 9, wherein R 2 is a C1 - C6 alkyl group substituted by one or more of the following: halogen, cyano, -OR 5 、 -NR 5 R 6 、 -S(O)2R 5 or -S(O)2OR 5 。 11. The method according to any one of claims 1 - 10, wherein R 2 is a C1 - C6 alkyl group substituted by one or more -OH groups.

12. The method according to any one of claims 1 - 10, wherein R 2 is a C1 - C6 alkyl group substituted by one or more halogen groups.

13. The method according to any one of claims 1 - 9, wherein R 2 is an unsubstituted C1 - C6 alkyl group.

14. The method according to any one of claims 1 - 8, wherein R 2 is a phenyl group optionally substituted by one or more of the following: halogen, cyano, -OR 5 、 -NR 5 R 6 、 -S(O)2R 5 or -S(O)2OR 5 。 15. The method according to any one of claims 1 - 8, wherein R 2 is a -C1 - C6 alkyl - phenyl group optionally substituted by one or more of the following: halogen, cyano, -OR 5 、 -NR 5 R 6 、 -S(O)2R 5 or -S(O)2OR 5 。 16. The method according to any one of claims 1 - 15, wherein R 3 and R 4 are independently selected from -F, -Cl, -Br.

17. The method according to any one of claims 1 - 16, wherein R 3 and R 4 are both -Br.

18. The method according to any one of claims 1 - 16, wherein R3 and R 4 are both -Cl.

19. The method according to any one of claims 1 - 16, wherein R 3 and R 4 are both -F.

20. A method of treating depression, anxiety disorder or pain in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound selected from the following or a pharmaceutically acceptable salt or solvate thereof: or a pharmaceutically acceptable salt or solvate thereof.

21. The method according to any one of claims 1 - 20, which is used for treating depression in a patient in need thereof.

22. The method according to any one of claims 1 - 21, wherein the depression is major depressive disorder, treatment - resistant depression, seasonal affective disorder, psychotic depression, postpartum depression, melancholic depression, atypical depression or catatonic depression.

23. The method according to any one of claims 1 - 21, wherein the depression is bipolar depression, bipolar treatment - resistant depression, disruptive mood dysregulation disorder, persistent depressive disorder, dysthymia, premenstrual dysphoric disorder, drug - induced depressive disorder, postpartum depression, perimenopausal depression, multi - infarct dementia with depression, senile dementia with depression, Alzheimer's disease with depression, vascular dementia with dysthymia, vascular dementia with depression or depressive disorder, not otherwise specified.

24. The method according to any one of claims 1 - 20, which is used for treating anxiety disorder in a patient in need thereof.

25. The method according to claim 24, wherein the anxiety disorder is obsessive - compulsive disorder, post - traumatic stress disorder or severe phobia.

26. The method according to claim 25, wherein the severe phobia is agoraphobia or social phobia.

27. The method according to any one of claims 1 - 20, which is used for treating pain in a patient in need thereof.

28. The method according to claim 27, wherein the pain is selected from migraine, chronic pain, chronic neuropathic pain, chronic muscle pain, chronic joint pain, diabetic neuropathy, fibromyalgia, back pain, and osteoarthritis pain.

29. The method according to any one of claims 1 to 28, further comprising: Administer a peripherally restricted FAAH inhibitor to the patient.

30. The method according to claim 29, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

31. The method according to any one of claims 1 to 30, further comprising: Administer a selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI) to the patient.

32. The method according to claim 31, wherein the selective serotonin reuptake inhibitor (SSRI) is citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline.

33. The method according to claim 31, wherein the serotonin and norepinephrine reuptake inhibitor (SNRI) is desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, tramadol, or venlafaxine.

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