Methods for treating depression

Abstract

Provided herein are methods for treating depression with fatty acid amide hydrolase (FAAH)-cleavable prodrugs of thyroid hormone receptor (TRβ) agonists.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 375,192, filed September 9, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] The blood-brain barrier, composed of tightly interconnected endothelial cells, restricts the passage of pathogens and certain types of small and large molecules from the blood to the brain. This important protective function also limits the diffusion of therapeutic drugs into the brain, posing a major challenge to the development of new medications for depression. Summary of the Invention

[0003] In one embodiment, there is provided a method of treating depression, anxiety disorders, or pain in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I)

[0004] [ka] (In the formula, R 1 and R 2 are independently 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 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl are selected from halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 and optionally substituted with one or more of R3 and R 4 is independently selected from -F, -Cl, -Br, and -I; R 5 and R 6 is independently selected from hydrogen and C1-C6 alkyl, and R 7 and R 8 are independently selected from hydrogen, —F, —Cl, —Br, and —I), or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof.

[0005] In another embodiment, there is provided a method of treating depression, anxiety disorders, or pain in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of formula (II)

[0006] [ka] (In the formula, R 1 and R 2 are independently 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 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl are selected from halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 and optionally substituted with one or more of R 3 and R 4 is independently selected from -F, -Cl, -Br, and -I; R 5 and R6 is independently selected from hydrogen and C1-C6 alkyl, and R 7 and R 8 are independently selected from hydrogen, -F, -Cl, -Br, and -I; R 7 and R 8 wherein at least one of is not hydrogen), or a pharmaceutically acceptable salt or solvate thereof.

[0007] 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.

[0008] In another embodiment, there is provided a method of treating depression, anxiety disorders, or pain in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of formula (III)

[0009] [ka] (In the formula, R 1 and R 2 are independently 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 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl are selected from halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5and optionally substituted with one or more of R 3 and R 4 is independently selected from -F, -Cl, -Br, and -I, and R 5 and R 6 are independently selected from hydrogen and C1-C6 alkyl or a pharmaceutically acceptable salt or solvate thereof, in a therapeutically effective amount.

[0010] In some embodiments, R 1 is hydrogen. In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C1-C6 alkyl substituted with one or more of 2 is C1-C6 alkyl substituted with one or more -OH. In some embodiments, R 2 is C1-C6 alkyl substituted with one or more of halo. In some embodiments, R 2 is unsubstituted C1-C6 alkyl. In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is phenyl optionally substituted with one or more of 2Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is -C1-C6 alkyl-phenyl optionally substituted with one or more of 3 and R 4 is independently selected from -F, -Cl, and -Br. In some embodiments, R 3 and R 4 and R are both -Br. In some embodiments, R 3 and R 4 and R are both -Br. In some embodiments, R 3 and R 4 and R are both -Cl. In some embodiments, R 3 and R 4 are both -F.

[0011] In some embodiments of the method described herein, a method for treating depression in a patient who needs treatment for depression is described.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, depressed mood, premenstrual dysphoric disorder, drug-induced depressive disorder, postpartum depression, perimenopausal depression, multi-infarct dementia with depression, presenile dementia with depression, senile dementia with depression, vascular dementia with depressed mood, vascular dementia with depression, or unspecified depressive disorder.

[0012] In some embodiments of the method described herein, a method for treating anxiety disorder in a patient in need of such treatment is described.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.

[0013] In some embodiments of the methods described herein, methods are provided for treating pain in a patient in need thereof, in some embodiments, the pain is selected from migraine pain, chronic pain, chronic nerve pain, chronic muscle pain, chronic joint pain, diabetic neuropathy, fibromyalgia, low back pain, and osteoarthritis pain.

[0014] In some embodiments, there are methods for treating depression, anxiety disorders, or pain in a patient in need thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, there are methods for treating depression, anxiety disorders, or pain in a patient in need thereof, further comprising administering to the patient a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

[0015] In some embodiments, there are methods of treating depression, anxiety disorders, or pain in a patient in need thereof, further comprising administering to the patient a selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SRNI). In some embodiments, there are methods of treating depression, anxiety disorders, or pain in a patient in need thereof, further comprising administering to the patient a selective serotonin reuptake inhibitor (SSRI). In some embodiments, there are methods for treating depression, anxiety disorders, or pain in a patient in need thereof, further comprising administering to the patient a selective serotonin reuptake inhibitor (SSRI), where the selective serotonin reuptake inhibitor (SSRI) is citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline. In some embodiments, there are methods for treating depression, anxiety disorders, or pain in a patient in need thereof, further comprising administering to the patient a serotonin and norepinephrine reuptake inhibitor (SRNI). In some embodiments, there are methods of treating depression, anxiety disorders, or pain in a patient in need thereof, further comprising administering a serotonin and norepinephrine reuptake inhibitor (SRNI) to the patient, wherein the serotonin and norepinephrine reuptake inhibitor (SRNI) is desvenlafaxine, duloxetine, levomilnacipran, milnacipran, sibutramine, tramadol, or venlafaxine. [Brief explanation of the drawings]

[0016] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings.

[0017] [Figure 1] FIG. 1 shows that target engagement of TRβ in the brain is demonstrated by increased expression of T3-responsive target genes in vivo. [Figure 2] FIG. 2 shows brain and plasma concentrations of LL-341070 measured 4 hours after the final dose after 21 days of repeated dosing. [Figure 3] FIG. 3 shows the expression and specific activity of FAAH across species and tissue types. [Figure 4] FIG. 4 shows the concentrations of ABX-002A in the brain, liver, kidney, lung, and heart measured 1 hour after SC administration of 30 different prodrugs of ABX-002A. [Figure 5] FIG. 5 shows plasma, liver, and brain concentrations following ABX-002 prodrug treatment with or without peripheral or global FAAH inhibitors. [Figure 6A] FIG. 6A shows the induction of T3-target genes in the brain versus liver after a single dose of ABX-002A. [Figure 6B] FIG. 6B shows induction of T3 target genes in brain versus liver after a single dose of ABX-002. [Figure 6C] FIG. 6C shows induction of T3 target genes in brain versus liver after a single dose of ABX-002 plus a FAAH inhibitor. [Figure 7A] FIG. 7A shows gene expression in the brain and liver, and the effect on T4 after administration of ABX-002A. [Figure 7B] FIG. 7B shows the effects on gene expression in the brain and liver, and on T4, following administration of ABX-002. [Figure 7C]FIG. 7C shows gene expression in the brain and liver, and the effect on T4 after administration of ABX-002 plus a peripheral FAAH inhibitor. [Figure 7D] FIG. 7D shows gene expression in the brain and liver, and the effect on T4 after administration of ABX-002 plus a global FAAH inhibitor. DETAILED DESCRIPTION OF THE INVENTION

[0018] Typical antidepressants (i.e., selective serotonin reuptake inhibitors) are thought to improve major depressive disorder (MDD) through their ability to increase synaptic 5-HT concentrations in brain regions involved in affective tone, including the dorsal raphe, prefrontal cortex, hippocampus, amygdala, and hypothalamus. Nonclinical experience using triiodothyronine (T3) in combination with antidepressants suggests a mechanism of action involving enhancement of 5-HT function, including increased 5-HT release and downregulation of inhibitory mechanisms involved in 5-HT release. Specifically, T3 has been shown to increase antidepressant-stimulated 5-HT release in the prefrontal cortex, in part due to enhanced inhibitory 5-HT1A and 1B autoreceptors and downregulation of their signaling within the dorsal raphe. Clinical experience with T3 enhancement in MDD is supported by clinical practice patterns and guidance, as well as published literature. The largest randomized study to date on treatment options for alleviating depression (STAR*D) incorporated T3 treatment as an option to augment inadequate antidepressant responses. Specifically, T3 augmentation increased remission rates in patients who had failed two previous antidepressant regimens. T3 dose levels are limited by the hormone's activity in peripheral tissues, namely the heart and bone. As shown by Jonklaas et al. (2015), a therapeutically appropriate dose of 50 μg both increases heart rate and decreases TSH in the acute phase. Identifying analogs with improved therapeutic indices is highly desirable for clinical use in MDD and other disorders. Because TRa is highly enriched in the heart and bone, several approaches to this end have focused on enhancing TRb selectivity. For example, resmetirom, a peripherally restricted molecule, is highly selective for TRb. However, resmetirom and other thyromimetics are not brain penetrant and therefore are not useful in treating MDD.

[0019] The compounds disclosed herein are potent thyroid hormone beta receptor-selective agonist prodrugs that are expected to be differentiated from thyroid hormones based on their enhanced brain effects and reduced peripheral side effects in patients with MDD and an inadequate response to antidepressants. The compounds are brain-directed thyromimetic prodrugs activated by the intracellular enzyme fatty acid amide hydrolase (FAAH). In particular, ABX-002 is an orally administered amide prodrug that exerts its effects as a full agonist of the thyroid hormone receptor. Upon entering tissues, FAAH hydrolyzes the amide to release the active carboxylic acid compound, ABX-002A. ABX-002A is a full agonist of both TRb and TRa, with 15-fold selectivity over TRβ, helping to avoid effects in both the heart and bone. In humans, FAAH is ubiquitously expressed but enriched in the central nervous system (CNS), resulting in abundant delivery to the brain and further enrichment in the hippocampus and cortex (both brain regions implicated in MDD). In mice, oral administration of ABX-002 improved selective delivery of the active metabolite to the brain by >30-fold compared with administration of the active metabolite, resulting in a brain-to-plasma ratio of >0.8 and a brain-to-heart ratio of >3.5. In rodent studies, exogenous T3 administration resulted in higher T3 concentrations in the heart than in the brain, leading to changes in gene expression at lower doses than in the brain, consistent with the dose-limiting toxicities described in patients. Selective delivery of ABX-002 to the CNS allows for doses that maximize the CNS benefits of thyroid hormone agonism without the concomitant dose-limiting adverse effects on peripheral tissues observed with T3 treatment. Selective distribution to CNS tissues combined with receptor selectivity for TRβ gives ABX-002A the potential to offer a relative safety advantage over triiodothyronine (T3).

[0020] Specific Terms The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "a drug" includes one or more such drugs, and a reference to "an excipient" includes one or more such excipients. When ranges are used herein, all combinations and subcombinations of ranges, and specific embodiments therein, are intended to be included. The term "about," when referring to a numerical value or numerical range, indicates that the referenced numerical value or numerical range is approximate within experimental variability (or within statistical experimental error), and thus the numerical value or numerical range may vary from 1% to 15% of the stated numerical value or numerical range.

[0021] The terms "formulation" and "composition" are used interchangeably herein and refer to a mixture of two or more compounds, elements, or molecules. In some embodiments, the terms "formulation" and "composition" can be used to refer to a mixture of one or more active agents with a carrier or other excipient.

[0022] 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, specific, or selected physiological activity when administered to a subject in a significant or effective amount.

[0023] "Pharmaceutically acceptable salt" includes both acid addition salt and base addition salt.The pharmaceutically acceptable salt of any one of the compounds described herein is intended to include 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.

[0024] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, 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, including aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanediol acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, as well as 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, and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, e.g., Berge SM 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 with a sufficient amount of the desired acid to produce the salt.

[0025] "Pharmaceutically acceptable base addition salts" refer 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 metals 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, and the like. 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, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0026] It should be understood that a reference to a pharmaceutically acceptable salt includes its solvent addition form (solvate).Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and are formed during the product formation or isolation process using pharmaceutically acceptable solvents such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptanes, toluene, anisole, acetonitrile, etc. In one embodiment, solvates are formed using, but not limited to, Class 3 solvents. Solvent categories 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). Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol.

[0027] As used herein, an "effective amount" or "therapeutically effective amount" refers to a sufficient quantity of an agent or compound being administered that will relieve to some extent one or more of the symptoms of the disease or disorder being treated. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound as disclosed herein that is required to bring about a clinically significant reduction in the disease. An appropriate "effective" amount in any individual case may be determined using techniques such as dose escalation studies.

[0028] The terms "subject," "individual," and "patient" are used interchangeably herein to refer to mammals, including, but not limited to, murines, simians, humans, farm animals, sport animals, and pets.

[0029] As used herein, the term "peripherally restricted FAAH inhibitor" refers to a fatty acid amide hydrolase (FAAH) inhibitor that, upon systemic administration, inhibits FAAH to a greater extent in the periphery than in the central nervous system. In some embodiments, a peripherally restricted FAAH inhibitor is 60% peripherally restricted. In some embodiments, a peripherally restricted FAAH inhibitor is 70% peripherally restricted. In some embodiments, a peripherally restricted FAAH inhibitor is 80% peripherally restricted. In some embodiments, a peripherally restricted FAAH inhibitor is 90% peripherally restricted. In some embodiments, a peripherally restricted FAAH inhibitor is 95% peripherally restricted.

[0030] target 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) (Calza L et al., Brain Res Revs 48:339-346, 2005). However, TH is not an acceptable long-term treatment because there is virtually no therapeutic window in which remyelination can be achieved while avoiding the cardiotoxicity and bone demineralization associated with chronic hyperthyroidism. By exploiting the molecular and physiological characteristics of the thyroid hormone receptor, some thyroid hormone analogs can activate thyroid hormone-responsive genes 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, which have heterogeneous tissue distributions 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, Nucl Recept Signal 4:e011, 2006).

[0031] The development of selective thyromimetics has been difficult due to the high sequence homology of thyroid hormone receptor subtypes, i.e., only one amino acid residue on the interior surface of the ligand-binding domain cavity varies between the α1 and β1 forms.

[0032] method In some embodiments, described herein is a method for treating depression, anxiety disorder, or pain in a patient in need of such treatment, 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 for treating depression in a patient in need of such treatment, 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 for treating depression in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method for treating depression in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and 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 for treating an anxiety disorder in a patient in need of such treatment, 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 for treating an anxiety disorder in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein are methods of treating an anxiety disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and 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 for treating pain in a patient in need of pain treatment, 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 for treating pain in a patient in need of pain treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method for treating pain in a patient in need of pain treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering to the patient a peripherally restricted FAAH inhibitor, and the peripherally restricted FAAH inhibitor is ASP-3652.

[0033] In some embodiments, described herein is a method for treating depression, anxiety disorder, or pain in a patient in need of such treatment, 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 for treating depression in a patient in need of such treatment, 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 for treating depression in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method for treating depression in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, and 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 for treating an anxiety disorder in a patient in need of such treatment, 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 for treating an anxiety disorder in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein are methods of treating an anxiety disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, and 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 for treating pain in a patient in need of pain treatment, 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 for treating pain in a patient in need of pain treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method for treating pain in a patient in need of pain treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering to the patient a peripherally restricted FAAH inhibitor, and the peripherally restricted FAAH inhibitor is ASP-3652.

[0034] In some embodiments, described herein is a method for treating depression, anxiety disorder, or pain in a patient in need of such treatment, 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 for treating depression in a patient in need of such treatment, 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 for treating depression in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method for treating depression in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, and 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 for treating an anxiety disorder in a patient in need of such treatment, 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 for treating an anxiety disorder in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein are methods of treating an anxiety disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, and 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 for treating pain in a patient in need of pain treatment, 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 for treating pain in a patient in need of pain treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method for treating pain in a patient in need of pain treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering to the patient a peripherally restricted FAAH inhibitor, and the peripherally restricted FAAH inhibitor is ASP-3652.

[0035] In some embodiments, described herein is a method for treating depression, anxiety disorder, or pain in a patient in need of such treatment, 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 for treating depression in a patient in need of such treatment, 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 for treating depression in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein is a method for treating depression in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, and 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 for treating an anxiety disorder in a patient in need of such treatment, 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 for treating an anxiety disorder in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering to the patient a peripherally restricted FAAH inhibitor. In some embodiments, described herein are methods of treating an anxiety disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, and 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 for treating pain in a patient in need of pain treatment, 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 for treating pain in a patient in need of pain treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering to the patient a peripherally restricted FAAH inhibitor.In some embodiments, described herein is a method for treating pain in a patient in need of pain treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (IV), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering to the patient a peripherally restricted FAAH inhibitor, and the peripherally restricted FAAH inhibitor is ASP-3652.

[0036] In some embodiments of the methods of 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 of treating depression described herein, the depression is major depressive disorder. In some embodiments of the methods of treating depression described herein, the depression is treatment-resistant depression. In some embodiments of the methods of treating depression described herein, the depression is seasonal affective disorder. In some embodiments of the methods of treating depression described herein, the depression is psychotic depression. In some embodiments of the methods of treating depression described herein, the depression is postpartum depression. In some embodiments of the methods of treating depression described herein, the depression is melancholic depression. In some embodiments of the methods of treating depression described herein, the depression is atypical depression. In some embodiments of the methods of treating depression described herein, the depression is catatonic depression.

[0037] 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, depressed mood, premenstrual dysphoric disorder, medication-induced depressive disorder, postpartum depression, perimenopausal depression, multi-infarct dementia with depression, presenile dementia with depression, senile dementia with depression, vascular dementia with depressed mood, vascular dementia with depression, or unspecified depressive disorder. 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 depressed mood. In some embodiments of the methods for treating depression described herein, the depression is persistent depressive disorder. In some embodiments of the methods of treating depression described herein, the depression is medication-induced depressive disorder. In some embodiments of the methods of treating depression described herein, the depression is postpartum depression. In some embodiments of the methods of treating depression described herein, the depression is perimenopausal depression. In some embodiments of the methods of treating depression described herein, the depression is multi-infarct dementia with depression. In some embodiments of the methods of treating depression described herein, the depression is presenile dementia with depression. In some embodiments of the methods of treating depression described herein, the depression is senile dementia with depression. In some embodiments of the methods of treating depression described herein, the depression is vascular dementia with depressed mood. In some embodiments of the methods of treating depression described herein, the depression is vascular dementia with depression.In some embodiments of the methods of treating depression described herein, the depression is unspecified depressive disorder.

[0038] In some embodiments of the methods for treating an anxiety disorder described herein, the anxiety disorder is obsessive-compulsive disorder, post-traumatic stress disorder, or a severe phobia. In some embodiments of the methods for treating an anxiety disorder described herein, the anxiety disorder is obsessive-compulsive disorder. In some embodiments of the methods for treating an anxiety disorder described herein, the anxiety disorder is post-traumatic stress disorder. In some embodiments of the methods for treating an anxiety disorder described herein, the anxiety disorder is a severe phobia. In some embodiments of the methods for treating an anxiety disorder described herein, the anxiety disorder is a severe phobia, and the severe phobia is agoraphobia or social phobia. In some embodiments of the methods for treating an anxiety disorder described herein, the anxiety disorder is a severe phobia, and the severe phobia is agoraphobia. In some embodiments of the methods for treating an anxiety disorder described herein, the anxiety disorder is a severe phobia, and the severe phobia is social phobia.

[0039] In some embodiments of the methods of treating pain described herein, the pain is selected from migraine pain, chronic pain, chronic nerve pain, chronic muscle pain, chronic joint pain, diabetic neuropathy, fibromyalgia, low back pain, and osteoarthritis pain. In some embodiments of the methods of treating pain described herein, the pain is migraine pain. 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 nerve pain. In some embodiments of the methods of treating pain described herein, the pain is chronic muscle 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 low back pain. In some embodiments of the methods of treating pain described herein, the pain is osteoarthritis pain.

[0040] 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 (SRNI).

[0041] In some embodiments, the methods of treatment described herein further comprise administering a selective serotonin reuptake inhibitor (SSRI) to the patient. In some embodiments, the methods of treatment described herein further comprise administering a selective serotonin reuptake inhibitor (SSRI) to the patient, wherein the SSRI is citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, or sertraline. In some embodiments, the methods of treatment described herein further comprise administering a selective serotonin reuptake inhibitor (SSRI) to the patient, wherein the SSRI is citalopram. In some embodiments, the methods of treatment described herein further comprise administering a selective serotonin reuptake inhibitor (SSRI) to the patient, wherein the SSRI is escitalopram. In some embodiments, the methods of treatment described herein further comprise administering a selective serotonin reuptake inhibitor (SSRI) to the patient, wherein the SSRI is fluoxetine. In some embodiments, the methods of treatment described herein further comprise administering a selective serotonin reuptake inhibitor (SSRI) to the patient, wherein the SSRI is fluvoxamine. In some embodiments, the methods of treatment described herein further comprise administering a selective serotonin reuptake inhibitor (SSRI) to the patient, wherein the SSRI is paroxetine. In some embodiments, the methods of treatment described herein further comprise administering a selective serotonin reuptake inhibitor (SSRI) to the patient, wherein the SSRI is sertraline.

[0042] In some embodiments, the methods of treatment described herein further comprise administering to the 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 the 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 the 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 the 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 a serotonin and norepinephrine reuptake inhibitor (SRNI) to the patient, wherein the SRNI is milnacipran. In some embodiments, the methods of treatment described herein further comprise administering a serotonin and norepinephrine reuptake inhibitor (SRNI) to the patient, wherein the SRNI is sibutramine. In some embodiments, the methods of treatment described herein further comprise administering a serotonin and norepinephrine reuptake inhibitor (SRNI) to the patient, wherein the SRNI is tramadol. In some embodiments, the methods of treatment described herein further comprise administering a serotonin and norepinephrine reuptake inhibitor (SRNI) to the patient, wherein the SRNI is venlafaxine.

[0043] compound 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), where 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), where 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), where 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), where the prodrug of formula (IV) is a prodrug of a TRβ agonist.

[0044] In some embodiments, there is provided a method for treating depression, anxiety disorders, or pain in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I):

[0045] [ka] (In the formula, R 1 and R 2 are independently 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 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl are selected from halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R5 , or -S(O)2OR 5 and optionally substituted with one or more of R 3 and R 4 is independently selected from -F, -Cl, -Br, and -I; R 5 and R 6 is independently selected from hydrogen and C1-C6 alkyl, and R 7 and R 8 are independently selected from hydrogen, —F, —Cl, —Br, and —I), or a pharmaceutically acceptable salt or solvate thereof, to a patient.

[0046] 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.

[0047] 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.

[0048] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is C1-C6 alkyl.

[0049] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C1-C6 alkyl substituted with one or more of 2 is C1-C6 alkyl substituted with one or more of halo. In some embodiments, R 2 is C1-C6 alkyl substituted with one cyano. In some embodiments, R 2 is one or more -OH 5 In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -OH. In some embodiments, R 2 is C1-C6 alkyl substituted with one -OH. In some embodiments, R 2 is one or more -NR 5 R 6 In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -NH2. In some embodiments, R 2 is C-C alkyl substituted with one -NH. In some embodiments, R 2 is one -S(O)2R 5 In some embodiments, R 2 is C-C alkyl substituted with one -S(O)H. In some embodiments, R 2 is one -S(O)2OR 5 In some embodiments, R 2 is C-C alkyl substituted with one -S(O)OH. In some embodiments, R 2 is unsubstituted C1-C6 alkyl. In some embodiments, R2 is —CH3. In some embodiments, R 2 is -CH2CH3. In some embodiments, R 2 is -CH2CH2CH3.

[0050] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C-C alkenyl optionally substituted with one or more of 2 is unsubstituted C2-C6 alkenyl.

[0051] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C2-C6 alkynyl optionally substituted with one or more of 2 is unsubstituted C2-C6 alkynyl.

[0052] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C-C cycloalkyl optionally substituted with one or more of 2 is unsubstituted C3-C6 cycloalkyl.

[0053] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5, or -S(O)2OR 5 In some embodiments, R is a C-C heterocycloalkyl optionally substituted with one or more of 2 is an unsubstituted C3-C6 heterocycloalkyl.

[0054] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is phenyl optionally substituted with one or more of 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is phenyl substituted with one or more of 2 is phenyl substituted with one or more of halo. In some embodiments, R 2 is one or more -OH 5 In some embodiments, R 2 is phenyl substituted with one or more -OH. In some embodiments, R 2 is unsubstituted phenyl.

[0055] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is -C1-C6 alkyl-phenyl optionally substituted with one or more of 2 is unsubstituted -C1-C6 alkyl-phenyl.

[0056] In some embodiments, R 2HA-OR 5 In some embodiments, R 2 is —OH. In some embodiments, R 2 Ha-NR 5 R 6 In some embodiments, R 2 is -NH2.

[0057] In some embodiments, R 2 is hydrogen.

[0058] In some embodiments, R 3 and R 4 is independently selected from -F, -Cl, and -Br. In some embodiments, R 3 and R 4 and R are both -Br. In some embodiments, R 3 and R 4 and R are both -Br. In some embodiments, R 3 and R 4 and R are both -Cl. In some embodiments, R 3 and R 4 and R 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.

[0059] In some embodiments, there is provided a method for treating depression, anxiety disorders, or pain in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of formula (II)

[0060] [ka] (In the formula, R 1 and R 2 are independently hydrogen, -OR5 , -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 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl are selected from halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 and optionally substituted with one or more of R 3 and R 4 is independently selected from -F, -Cl, -Br, and -I; R 5 and R 6 is independently selected from hydrogen and C1-C6 alkyl, and R 7 and R 8 are independently selected from hydrogen, -F, -Cl, -Br, and -I; R 7 and R 8 wherein at least one of is not hydrogen), or a pharmaceutically acceptable salt or solvate thereof, to a patient.

[0061] 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.

[0062] 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 8is -Br.

[0063] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is C1-C6 alkyl.

[0064] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C1-C6 alkyl substituted with one or more of 2 is C1-C6 alkyl substituted with one or more of halo. In some embodiments, R 2 is C1-C6 alkyl substituted with one cyano. In some embodiments, R 2 is one or more -OH 5 In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -OH. In some embodiments, R 2 is C1-C6 alkyl substituted with one -OH. In some embodiments, R 2 is one or more -NR 5 R 6 In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -NH2. In some embodiments, R 2 is C-C alkyl substituted with one -NH. In some embodiments, R 2is one -S(O)2R 5 In some embodiments, R 2 is C-C alkyl substituted with one -S(O)H. In some embodiments, R 2 is one -S(O)2OR 5 In some embodiments, R 2 is C-C alkyl substituted with one -S(O)OH. 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.

[0065] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C-C alkenyl optionally substituted with one or more of 2 is unsubstituted C2-C6 alkenyl.

[0066] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C2-C6 alkynyl optionally substituted with one or more of 2 is unsubstituted C2-C6 alkynyl.

[0067] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C-C cycloalkyl optionally substituted with one or more of 2 is unsubstituted C3-C6 cycloalkyl.

[0068] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C-C heterocycloalkyl optionally substituted with one or more of 2 is an unsubstituted C3-C6 heterocycloalkyl.

[0069] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is phenyl optionally substituted with one or more of 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is phenyl substituted with one or more of 2 is phenyl substituted with one or more of halo. In some embodiments, R 2 is one or more -OH 5 In some embodiments, R 2 is phenyl substituted with one or more -OH. In some embodiments, R 2 is unsubstituted phenyl.

[0070] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is -C1-C6 alkyl-phenyl optionally substituted with one or more of 2 is unsubstituted -C1-C6 alkyl-phenyl.

[0071] In some embodiments, R 2 HA-OR 5 In some embodiments, R 2 is —OH. In some embodiments, R 2 Ha-NR 5 R 6 In some embodiments, R 2 is -NH2.

[0072] In some embodiments, R 2 is hydrogen.

[0073] In some embodiments, R 3 and R 4 is independently selected from -F, -Cl, and -Br. In some embodiments, R 3 and R 4 and R are both -Br. In some embodiments, R 3 and R 4 and R are both -Br. In some embodiments, R 3 and R 4 and R are both -Cl. In some embodiments, R 3 and R 4 and R 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 R4 is -Cl.

[0074] In some embodiments, there is provided a method for treating depression, anxiety disorders, or pain in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of formula (III)

[0075] [ka] (In the formula, R 1 and R 2 are independently 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 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl are selected from halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 and optionally substituted with one or more of R 3 and R 4 is independently selected from -F, -Cl, -Br, and -I; and R 5 and R 6 are independently selected from hydrogen and C1-C6 alkyl), or a pharmaceutically acceptable salt or solvate thereof, to a patient.

[0076] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is C1-C6 alkyl.

[0077] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C1-C6 alkyl substituted with one or more of 2 is C1-C6 alkyl substituted with one or more of halo. In some embodiments, R 2 is C1-C6 alkyl substituted with one cyano. In some embodiments, R 2 is one or more -OH 5 In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -OH. In some embodiments, R 2 is C1-C6 alkyl substituted with one -OH. In some embodiments, R 2 is one or more -NR 5 R 6 In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -NH2. In some embodiments, R 2 is C-C alkyl substituted with one -NH. In some embodiments, R 2 is one -S(O)2R 5 In some embodiments, R 2 is C-C alkyl substituted with one -S(O)H. In some embodiments, R 2 is one -S(O)2OR 5In some embodiments, R 2 is C-C alkyl substituted with one -S(O)OH. 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.

[0078] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C-C alkenyl optionally substituted with one or more of 2 is unsubstituted C2-C6 alkenyl.

[0079] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C2-C6 alkynyl optionally substituted with one or more of 2 is unsubstituted C2-C6 alkynyl.

[0080] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C-C cycloalkyl optionally substituted with one or more of 2 is unsubstituted C3-C6 cycloalkyl.

[0081] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C-C heterocycloalkyl optionally substituted with one or more of 2 is an unsubstituted C3-C6 heterocycloalkyl.

[0082] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is phenyl optionally substituted with one or more of 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is phenyl substituted with one or more of 2 is phenyl substituted with one or more of halo. In some embodiments, R 2 is one or more -OH 5 In some embodiments, R 2 is phenyl substituted with one or more -OH. In some embodiments, R 2 is unsubstituted phenyl.

[0083] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5In some embodiments, R is -C1-C6 alkyl-phenyl optionally substituted with one or more of 2 is unsubstituted -C1-C6 alkyl-phenyl.

[0084] In some embodiments, R 2 HA-OR 5 In some embodiments, R 2 is —OH. In some embodiments, R 2 Ha-NR 5 R 6 In some embodiments, R 2 is -NH2.

[0085] In some embodiments, R 2 is hydrogen.

[0086] In some embodiments, R 3 and R 4 is independently selected from -F, -Cl, and -Br. In some embodiments, R 3 and R 4 and R are both -Br. In some embodiments, R 3 and R 4 and R are both -Br. In some embodiments, R 3 and R 4 and R are both -Cl. In some embodiments, R 3 and R 4 and R 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.

[0087] In some embodiments, there is provided a method for treating depression, anxiety disorders, or pain in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of formula (IV):

[0088] [ka] (In the formula, R 1 and R 2 are independently 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 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, phenyl, and -C1-C6 alkyl-phenyl are selected from halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 and R 5 and R 6 are independently selected from hydrogen and C1-C6 alkyl), or a pharmaceutically acceptable salt or solvate thereof, to a patient.

[0089] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is C1-C6 alkyl.

[0090] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R 2 Halo, cyano, -OR 5 , -NR5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C1-C6 alkyl substituted with one or more of 2 is C1-C6 alkyl substituted with one or more of halo. In some embodiments, R 2 is C1-C6 alkyl substituted with one cyano. In some embodiments, R 2 is one or more -OH 5 In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -OH. In some embodiments, R 2 is C1-C6 alkyl substituted with one -OH. In some embodiments, R 2 is one or more -NR 5 R 6 In some embodiments, R 2 is C1-C6 alkyl substituted with one or more -NH2. In some embodiments, R 2 is C-C alkyl substituted with one -NH. In some embodiments, R 2 is one -S(O)2R 5 In some embodiments, R 2 is C-C alkyl substituted with one -S(O)H. In some embodiments, R 2 is one -S(O)2OR 5 In some embodiments, R 2 is C-C alkyl substituted with one -S(O)OH. 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 2is -CH2CH2CH3.

[0091] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C-C alkenyl optionally substituted with one or more of 2 is unsubstituted C2-C6 alkenyl.

[0092] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C2-C6 alkynyl optionally substituted with one or more of 2 is unsubstituted C2-C6 alkynyl.

[0093] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C-C cycloalkyl optionally substituted with one or more of 2 is unsubstituted C3-C6 cycloalkyl.

[0094] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is a C-C heterocycloalkyl optionally substituted with one or more of 2is an unsubstituted C3-C6 heterocycloalkyl.

[0095] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is phenyl optionally substituted with one or more of 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is phenyl substituted with one or more of 2 is phenyl substituted with one or more of halo. In some embodiments, R 2 is one or more -OH 5 In some embodiments, R 2 is phenyl substituted with one or more -OH. In some embodiments, R 2 is unsubstituted phenyl.

[0096] In some embodiments, R 2 Halo, cyano, -OR 5 , -NR 5 R 6 , -S(O)2R 5 , or -S(O)2OR 5 In some embodiments, R is -C1-C6 alkyl-phenyl optionally substituted with one or more of 2 is unsubstituted -C1-C6 alkyl-phenyl.

[0097] In some embodiments, R 2 HA-OR 5 In some embodiments, R 2 is —OH. In some embodiments, R 2 Ha-NR5 R 6 In some embodiments, R 2 is -NH2.

[0098] In some embodiments, R 2 is hydrogen.

[0099] In some embodiments of the fatty acid amide hydrolase (FAAH) cleavable prodrugs described herein, the prodrug is

[0100] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0101] In some embodiments of the fatty acid amide hydrolase (FAAH) cleavable prodrugs described herein, the prodrug is

[0102] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0103] In some embodiments of the fatty acid amide hydrolase (FAAH) cleavable prodrugs described herein, the prodrug is

[0104] [ka] [ka] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0105] In some embodiments of the fatty acid amide hydrolase (FAAH) cleavable prodrugs described herein, the prodrug is

[0106] [ka] [ka] The compound has a structure selected from:

[0107] Pharmaceutical Composition In some embodiments, described herein are pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 pharmaceutical compositions comprising a fatty acid amide hydrolase (FAAH)-cleavable prodrug of formula (IV) described herein and a pharmaceutically acceptable excipient.

[0108] Peripherally restricted FAAH inhibitors In some embodiments, the present invention provides a pharmaceutical composition comprising a fatty acid amide hydrolase (FAAH) cleavable prodrug of Formula (I), (II), (III), or (IV) described herein and a pharmaceutically acceptable FAAH inhibitor, and further comprising a peripherally restricted FAAH inhibitor. In some embodiments, the peripherally restricted FAAH inhibitor is disclosed in U.S. Patent Application Publication No. 2008 / 0306046, the entire contents of which are incorporated herein by reference.

[0109] In some embodiments, the peripherally restricted FAAH inhibitor has formula (X):

[0110] [ka] (In the formula, Ring A is a benzene ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, or a 5- to 7-membered nitrogen-containing heterocycle; 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), R 15 is H or lower alkyl, X is CH or N; R 8 , R 9 and R 10 are each independently (i) a group selected from the group consisting of H, halo, —CN, CF3, lower alkyl, and —O-lower alkyl; (ii) aryl optionally substituted with 1 to 5 groups independently selected from the group consisting of H, halo, —CN, CF 3 , lower alkyl, and —O-lower alkyl; (iii) nitrogen-containing heteroaryl optionally substituted with 1 to 5 groups independently selected from the group consisting of H, halo, —CN, —CF3, lower alkyl, and —O-lower alkyl; (iv)R 16 -(lower alkenylene)-O-, (v)R 16 -(lower alkenylene)-N(R 15 )-,or (vi)R 17 R 18 NC(=O) is selected from R 16 teeth, (i) aryl optionally substituted with 1 to 5 groups independently selected from the group consisting of H, halo, —CN, —CF 3 , lower alkyl, and —O-lower alkyl; (ii) a nitrogen-containing heteroaryl optionally substituted with 1 to 5 groups independently selected from the group consisting of H, halo, —CN, —CF 3 , lower alkyl, and —O-lower alkyl; or (iii) 3- to 8-membered cycloalkyl; 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 form a 3- to 8-membered nitrogen-containing heterocycle together with the nitrogen atom to which they are attached, R 11 is selected from H, lower alkyl, and oxo (=O); R 12 , R 13 , and R 14 wherein one of is —C(═O)—O—(lower alkyl) or —CO 2 H, and the other is H, or a pharmaceutically acceptable salt thereof.

[0111] 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.

[0112] excipients Optional excipients suitable for use in the pharmaceutical compositions described herein include any excipients commonly used in pharmaceuticals and are selected based on their compatibility with the active pharmaceutical agent and the desired release profile characteristics of the dosage form. Excipients include, but are not limited to, binders, fillers, flow aids, disintegrants, lubricants, glidants, polymer carriers, plasticizers, stabilizers, surfactants, etc. Compendia of excipients described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference in their entireties.

[0113] Binders impart cohesion to solid oral dosage form formulations: in powder-filled capsule formulations, binders aid in the formation of plugs that can be filled into soft- or hard-shell capsules, and in tablet formulations, binders ensure that the tablet remains intact after compression and ensure blend uniformity before the compression or filling step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel (登録商標)), hydroxypropyl methylcellulose (e.g., Hypromellose USP Pharmacoat-603), hydroxypropyl methylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel (登録商標) ), ethyl cellulose (e.g., Ethocel (登録商標) ), and microcrystalline cellulose (e.g., Avicel (登録商標) ), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acid, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sucrose (e.g., Dipac (登録商標) ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab (登録商標) ), sugars such as lactose, natural or synthetic gums such as acacia, tragacanth, and ghatti, mucilage of isapol husk, starch, polyvinylpyrrolidone (e.g., Polyvidone (登録商標) CL, Kollidon (登録商標) CL, Polyplasdone (登録商標) XL-10, and Povidone (登録商標) K-12), Larch Arabinogalactan, Veegum (登録商標) , polyethylene glycol, wax, sodium alginate, etc.

[0114] Fillers or diluents increase the bulk of a pharmaceutical formulation. Examples of such compounds include lactose, starch, mannitol, sorbitol, dextrose, Avicel, etc. (登録商標)Microcrystalline cellulose, dibasic calcium phosphate, calcium phosphate dihydrate, tribasic calcium phosphate, calcium phosphate, anhydrous lactose, spray-dried lactose, pregelatinized starch, pregelatinized, Di-Pac (登録商標) Compressible sugars such as Amstar, hydroxypropyl methylcellulose, sucrose-based diluents, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, sodium chloride, inositol, bentonite, and the like.

[0115] Glidants improve the flow properties of powder mixtures. Such compounds include, for example, Cab-o-sil. (登録商標) Colloidal silicon dioxide, such as tribasic calcium phosphate, talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, kaolin, and finely divided amorphous silicon dioxide (Syloid (登録商標) ) etc.

[0116] A lubricant is a compound that prevents, reduces, or inhibits adhesion or friction of materials. Exemplary lubricants include, for example, stearic acid, calcium hydroxide, talc, hydrocarbons such as mineral oil, or hydrogenated soybean oil (Sterotex). (登録商標) ), Lubritab (登録商標) , Cutina (登録商標) Hydrogenated vegetable oils, higher fatty acids and salts of higher fatty acids with alkali metals and alkaline earth metals such as aluminum, calcium, magnesium, and zinc, stearic acid, sodium stearate, magnesium stearate, glycerol, talc, wax, Stearowet (登録商標), boric acid, sodium acetate, leucine, polyethylene glycol or methoxypolyethylene glycol such as Carbowax™, sodium oleate, glyceryl behenate (Compitrol 888 (登録商標) ), Glyceryl Palmitostearate (Precirol (登録商標) ), Syloid(trademark), Carb-O-Sil (登録商標) Examples of the hydrophilic lubricant include colloidal silica such as corn starch, starch such as corn starch, silicone oil, and surfactants. (登録商標) commercially available from Pharmacy, Inc.), polyethylene glycol (PEG), magnesium lauryl sulfate, sodium lauryl sulfate (SLS), sodium benzoate, sodium chloride, and the like.

[0117] Disintegrants facilitate the breakup or disintegration of the pharmaceutical formulation after administration. Examples of disintegrants include starches, such as natural starches such as corn starch or potato starch, National 1551 or Amijel (登録商標) Pregelatinized starch such as Promogel (登録商標) or Explotab (登録商標) Cellulose such as sodium starch glycolate, wood products, microcrystalline cellulose, e.g., Avicel (登録商標) , Avicel (登録商標) PH101, Avicel (登録商標) PH102, Avicel (登録商標) PH105, Elcema (登録商標) P100, Emcocel (登録商標) , Vivacel (登録商標) , Ming Tia (登録商標) , and Solka-Floc (登録商標) , methylcellulose, croscarmellose, or cross-linked sodium carboxymethylcellulose (Ac-Di-Sol (登録商標)Cross-linked celluloses such as cross-linked carboxymethylcellulose, or cross-linked croscarmellose, cross-linked starches such as sodium starch glycolate, cross-linked polymers such as crospovidone, cross-linked polyvinylpyrrolidone, alginic acid or salts of alginic acid such as sodium alginate, alginates, Veegum (登録商標) Examples include clays such as HV (magnesium aluminum silicate), gums such as agar, guar, locust bean, karaya, pectin, or tragacanth, resins such as sodium starch glycolate, bentonite, natural sponge, cation exchange resins, citrus pulp, sodium lauryl sulfate, and sodium lauryl sulfate in combination with starch.

[0118] Polymeric carriers include compounds such as polyvinylpyrrolidones, such as polyvinyl polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone vinyl acetate (PVPVA 64), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetylsuccinate (HPMC AS), and methyl methacrylate polymers (Eudragit polymers).

[0119] Stabilizers include compounds such as any antioxidants, buffers, acidic substances, for example, butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0120] Surfactants include sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide (e.g., Pluronic (登録商標)(BASF), and d-α-tocopheryl polyethylene glycol succinate (vitamin E TPGS).

[0121] The foregoing excipients are provided by way of example only and are not intended to encompass all possible choices. Other suitable excipient categories include colorants, granulating agents, preservatives, antifoaming agents, plasticizers, etc. Furthermore, many excipients may have multiple roles or functions or may be classified into multiple groups, and the classifications are merely descriptive and are not intended to limit the use of any particular excipient.

[0122] The disclosed pharmaceutical formulations are administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmacological efficacy. It is understood that the dosage required for any particular use will vary from patient to patient, depending not only on the particular pharmaceutical formulation selected, but also on the nature of the disease being treated, the age and condition of the patient, concomitant medications or special diets followed by the patient, and other factors, and that proper dosing will ultimately be at the discretion of the attending physician.

[0123] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It will be understood that various alternatives to the embodiments of the invention described herein are available for practicing 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 thereby. [Example]

[0124] The following examples are provided for illustrative purposes and do not limit the scope of the claims provided herein. These examples and all literature citations herein are incorporated by reference for all legal purposes. In other embodiments, the starting materials and reagents used in 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 U.S. Patent Application Publication No. 2019 / 0210950, which is incorporated herein by reference. In some embodiments, the compounds provided herein are synthesized as described in U.S. Patent Application Publication No. 2021 / 0002208, which is incorporated herein by reference. In some embodiments, the compounds provided herein are synthesized as described in International Patent Application Publication No. WO2021 / 108549, which is incorporated herein by reference. In some embodiments, the compounds provided herein are synthesized as described in International Patent Application Publication No. PCT / US2022 / 028187, which is incorporated herein by reference.

[0125] Example 1: FAAH substrate evaluation Purified recombinant human FAAH (rhFAAH) was purchased from Cayman Chemical (Ann Arbor, MI, USA). The total volume of each incubation was 400 μL, containing a final 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 in Tris-EDTA buffer at pH 8.0. The positive control was LL-341001. Incubations were performed 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 at 4°C for 15 min, and 100 μL of the supernatant was prepared for measuring the formation of acid metabolites by LC-MS / MS analysis.

[0126] LC-MS / MS analysis A Waters Acquity Ultra Performance LC system was used for sample analysis. Chromatography was performed on a reversed-phase Kinetex 2.6 μm C18 column, 2.1 × 30 mm, 100 Å. Mobile phase A consisted of 0.1% formic acid in water, and mobile phase B consisted of 0.1% formic acid in acetonitrile. A 2-minute run time and a 0.8 mL / min flow rate were used for acid metabolites from the positive control, and a 1.5-minute run time and a 0.9 mL / min flow rate were used for acid metabolites of the test compounds. Mass spectrometers (API-5500 and API Q Trap 4000, Applied Biosystems / MDS SCIEX Instruments, Framingham, MA, USA) were operated in ESI positive-ion or negative-ion MRM mode.

[0127] Data analysis The formation of acid metabolites was monitored and quantified using a single calibration point of 1 μM. The observed rate constants (ke) for acid metabolite formation were calculated by plotting metabolite concentration against incubation time, with the slope being k and are shown in Table 1.

[0128] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0129] Example 2: TRβ receptor selectivity of prodrugs and agonists in vitro 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) were evaluated for potency and selectivity for thyroid hormone beta receptor (TRβ). LL-341070 is a thyromimetic prodrug of formula (I) described herein. After fatty acid amide hydrolase (FAAH)-mediated conversion, LL-341070 yields LL-341070A, a potent and selective small molecule agonist of thyroid hormone receptor (TR)β. In vitro potency was determined via test compound administration to a luciferase-based TR reporter cell line, using thyroid hormone (T3) as a positive control. Table 2 shows the potency profiles of the LL-341070 prodrug and the LL-341070A active metabolite against TRβ and TRα, as measured at half-maximal effective concentrations (EC50), with selectivity measures adjusted for the TRα bias of T3 in the assay. Both LL-341070 and LL-341070A show enhanced selectivity for TRβ, with LL-341070A showing enhanced potency.

[0130] [Table 2]

[0131] Example 3: Engagement of TRβ in the brain increases expression of T3 target genes in vivo Figure 1 shows that target engagement of TRβ in the brain is demonstrated by increased expression of T3-responsive target genes in vivo. Single PO administration of LL-341070 (ranging from approximately 0.1 μg / kg to approximately 300 μg / kg) or T3 (approximately 300 μg / kg) in male C57BL / 6 mice increases Hr, Dio3, and Klf9 expression (quantified by QuaniPlex) and the composite average log2 fold change in the brain. Klf9, a T3-responsive gene associated with in vitro myelin regeneration, is upregulated at various treatment concentrations. This increased expression was confirmed in the brains of rat cuprizone models (quantified by Nanostring) that received repeated 21-day administration of LL-341070 at 30 μg / kg or 100 μg / kg (as discussed previously) or T3 at 300 μg / kg. Interestingly, Dio3 has enhanced expression that increases with repeated administration.

[0132] Example 4: In vivo tissue distribution demonstrates enhanced brain exposure of active compounds compared to prodrugs The in vivo brain exposure of the active compound compared to the prodrug was evaluated in mouse and rat cuprizone models via tissue distribution (TD) assays, measured as the brain-to-plasma brain exposure ratio after thyromimetic administration. As shown in Table 3, a single PO administration of LL-341070 (100 μg / kg) or LL-341070A (100 μg / kg) in male C57BL / 6 mice resulted in a brain-to-plasma AUC ratio of >1 for LL-341070A (AUC from 0 to 24 h), demonstrating enhanced brain exposure of the active compound LL-341070A compared to the prodrug LL-341070. The data indicate that the AUC of LL-341070A in the brain is approximately 7-fold higher than that of the prodrug LL-341070. Table 3 also shows the brain-to-plasma AUC ratios. As shown in Figure 2 , 21-day repeated administration of LL-341070 (30 μg / kg or 100 μg / kg) or LL-341070A (30 μg / kg or 100 μg / kg) in the rat cuprizone model demonstrated enhanced brain exposure of the active compound LL-341070A compared to the prodrug LL-341070, as measured in brain and plasma 4 hours after the final dose.

[0133] [Table 3]

[0134] Example 5: FAAH expression is enriched in the brain To elucidate the mechanism by which thyromimetics disrupt the thyroid hormone axis (THA), thyromimetics were utilized (e.g., ABX-002, activated to ABX-002A, compound 1 described herein) that is targeted to the brain and activated by fatty acid amide hydrolase (FAAH), as shown in Figure 3. The delivery of potent thyromimetics was altered to identify whether feedback control over THA originates from a central (hypothalamus) or peripheral (pituitary) mechanism, potentially enhancing the therapeutic index of thyromimetics. These studies were performed using recombinant FAAH, tissue-derived S9 fractions, in vivo tissue distribution (TD), gene expression in brain and liver, and effects on T4 in mice as a marker of THA disruption. Northern blot assays confirmed cross-species (rodent and human) expression of FAAH and enhanced relative mRNA FAAH expression in the brain. FAAH-specific activity (cleavage of AMC assay) from tissue-derived S9 fractions of different organs (liver, brain, small intestine) across species (mouse, rat, non-human primate, human), calculated as a percentage of liver activity, was shown to be increased in human and non-human primate brain.

[0135] Example 6: Expression of FAAH enhances delivery of ABX-002A to the brain To assess delivery, ABX-002A concentrations in the brain, liver, kidneys, lungs, and heart were measured 1 hour after SC administration of 30 different prodrugs of ABX-002A. As shown in Figure 4, the brain-to-plasma ratio increased for the prodrugs relative to ABX-002A, whereas the tissue-to-plasma ratios for peripheral organs (liver, kidney, lung, and heart) showed a linear (constant) tissue-to-plasma relationship. The data indicate that FAAH is highly expressed in the CNS and that ABX prodrugs enhance 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 indicate that tissue concentrations are driven by the plasma concentration of the active metabolite, ABX-002A.

[0136] Example 7: Systemic and peripheral FAAH inhibitors alter metabolite distribution in mice The ability of systemically permeable and peripherally restricted FAAH inhibitors (referred to as GFI and PFI, respectively) to alter the distribution of ABX-002 and ABX-002A was assessed. Table 4 shows the apparent IC 50 Potency profiles of peripheral and systemic FAAH inhibitors, measured in nM, LL-650177 (PFI), URB9373 (PFI), and PF-044578454 (GFI), were obtained after a 30-minute preincubation with FAAH and 7-amino-4-methylcoumarin (AMC).

[0137] [Table 4]

[0138] Figure 5 shows plasma, liver, and brain concentrations of the prodrug (ABX-002) after coadministration with PFI or GFI, or without PFI or GFI. Prodrug levels were unchanged or slightly increased with FAAH inhibition. Active metabolite (ABX-002A) levels were reduced in plasma and liver with PFI and in all organs with GFI. Table 5 shows the AUC of the inhibition of the active metabolite (LL-650177 or PF-044578454) in plasma, liver, and brain after coadministration of the prodrug (ABX-002). Tissue distribution studies in mice confirm systemic and peripheral inhibition of FAAH.

[0139] [Table 5]

[0140] Example 8: Induction of T3-regulated genes in the context of prodrugs and FAAH inhibitors Six- to eight-week-old female C57BL / 6 mice (n=5 / group) were allowed to acclimate to the laboratory for at least three days prior to dose administration in the study. On day 0, non-fasted mice received a single dose of PFI or vehicle orally (PO) at time = 1 hour. A single dose of 5 mL / kg was administered based on most recent body weight and collected once during the study period. Following PFI or vehicle administration, animals received a single dose of test article at time = 0 hours. One group (n=5) received 300 μg / kg T3 PO at time = 0 hours only. Approximately four hours after test article administration (t=4 hours), animals were humanely euthanized, and brain, liver, heart, pituitary gland, spinal cord, and plasma samples were collected.

[0141] Sample processing a. Expression Analysis Samples - At endpoint, multiple organs were harvested and tissues were immediately processed as described below.

[0142] i. Brain: For each mouse, the skull was opened and the brain was removed. The cerebellum was dissected, and the cerebral cortex was hemisected sagitally, and the left half was collected. After rinsing the tissue with ice-cold 0.9% NaCl to remove blood, the cerebral cortex specimen was placed in a tube containing 1.2 mL of pre-chilled RNALater and stored at 4°C.

[0143] ii. Liver: For each mouse, one liver biopsy (100-150 mg) was taken from the left hepatic lobe. After rinsing the biopsy with ice-cold 0.9% NaCl, the sample was placed in 1.2 mL of pre-chilled RNALater and stored at 4°C.

[0144] iii. Left ventricle: For each mouse, left ventricular (LV) blood was removed using standard PBI methods, and half of the LV free wall was collected. After rinsing the tissue with ice-cold 0.9% NaCl, the LV free wall was placed in 1.2 mL of pre-chilled RNALater and stored at 4°C. LV tissue was maintained in PBI for potential future analysis or until appropriate genes could be identified up to 6 months after the end of the in-life phase of the study. Disposal of the samples was approved prior to disposal.

[0145] iv. Pituitary gland: For each mouse, the pituitary gland was harvested after removal of the brain. After rinsing the pituitary gland with ice-cold 0.9% NaCl, the specimen was placed in 0.15 mL of pre-chilled RNALater and stored at 4°C. Pituitary tissue was kept at PBI for potential future analysis or until appropriate genes could be identified up to 6 months after the end of the in-life phase of the study. Disposal of the sample was approved prior to disposal.

[0146] b. Pharmacokinetic Samples—At endpoint, blood and tissue specimens were processed immediately as described below. Samples for PK analysis were maintained in PBI at −80° C. for up to 90 days after completion of the in-life phase of the study.

[0147] i. Plasma: Whole blood (~300 μL) was collected onto K3EDTA via cardiac puncture under isoflurane anesthesia. Blood was immediately placed on wet ice. After the collection procedure was completed, blood was centrifuged at 10,000 x g for 10 minutes at 4°C. Plasma (~125 μL) was aliquoted into appropriately labeled tubes and flash-frozen.

[0148] ii. Liver: For each mouse, one liver biopsy (30-50 mg) was taken from the left liver lobe. After rinsing the biopsy with ice-cold 0.9% NaCl, the sample was placed in an appropriately labeled tube and flash-frozen in liquid nitrogen.

[0149] 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, the biopsy was placed in an appropriately labeled tube and flash-frozen.

[0150] iv. Left ventricle: For each mouse, the left ventricle (LV) was cleared of blood using standard methods for PBI, and half of the LV free wall was collected. After rinsing the tissue with ice-cold 0.9% NaCl, the LV free wall was placed in an appropriately labeled tube and flash-frozen.

[0151] Target Engagement Changes in expression of select genes identified by transcriptome analysis were measured from purified RNA using a hybridization-based in situ RNA quantification method (NanoString, Seattle, WA). Briefly, fresh tissue was collected in RNALater™ stabilization solution, catalog number AM7021 (ThermoFisher Scientific; Carlsbad, CA) and frozen at -20°C until ready for RNA extraction. Whole blood was collected via terminal cardiac puncture into MiniCollect K2EDTA tubes, catalog number 450480, Greinder Bio-one GmbH (Kremsmunster, Austria) and processed to plasma by centrifugation at 2000 x g for 10 minutes at 4°C. For RNA extraction, tissues were homogenized using a bead homogenizer in TRIzol Reagent, catalog number 15596026 (ThermoFisher Scientific), and RNA was extracted and purified using Econospin RNA Mini Spin Columns for RNA (Ephoch Life Sciences, Missouri City, TX, catalog number 1940-250) according to the manufacturer's protocol. Specific gene probes were designed by the NanoString Bioinformatics Team using target sequences identified based on the NCBI Reference Sequence (RefSeq) database. Custom probes were synthesized by Integrated DNA Technologies (IDT; Coralville, IA). mRNA expression was analyzed using a multiplexed approach with the nCounter PlexSet-12 Reagent Pack, catalog number PS-GX-PTK-12 (CSO), on an nCounter® SPRINT Profiler NanoString system according to the manufacturer's protocol (NanoString, Inc., Seattle, WA).

[0152] Data analysis T3 target genes increased after a single dose of drug, accompanied by relative brain vs. liver activity as determined by prodrug and / or FAAH inhibition. Relative brain vs. liver activity (as a marker of peripheral activity) shifted by >1500-fold across different dosing paradigms. Figures 6A, 6B, and 6C show the induction of T3-regulated genes (T3-regulated genes) in the brain (blue) and liver (orange) 4 hours after a single dose of (A) active metabolite or (B) prodrug alone or (C) prodrug plus PFI (URB937). RNA was analyzed by Nanostring, and mean fold changes across genes were calculated on a log2 scale and normalized to data obtained for 300 mg / kg T3. PFI administration reduced the potency of the prodrug on T3-regulated gene activation in the liver by >10x without affecting brain activity or exposure. PFI also reduced THA potency, consistent with negative feedback based on circulating peripheral metabolites rather than brain exposure. Thus, the use of PFI allowed us to separate the intended brain effects from the effects on the THA.

[0153] Example 9: T4 parallels peripheral activity Six- to eight-week-old female C57BL / 6 mice (n=5 / group) were allowed to acclimate to the laboratory for at least three days prior to study dose administration. Mice were dosed at 5 mL / kg based on their most recent body weight collected once during the study period. Mice were placed into weight-matched treatment cohorts based on their most recent body weight collected once during the study period. Mice (n=5 / group) received a single oral (PO) dose of PFI or vehicle at time = -1 h daily for seven days. Following administration of PFI (100 μg / kg) or vehicle (10 mL / kg, PO), animals received the test substance at time = 0 h daily. Test substances were 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 administered (A) the active metabolite or (B) the prodrug alone, (C) the prodrug plus PFI (LL-650177), or (D) the prodrug plus GFI PO or QD for 7 days. Approximately 4 or 8 hours after test substance administration (t = 4 hours or t = 8 hours), animals were humanely euthanized using standard procedures, and brain, liver, and plasma samples were collected. 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) as described below. On the final day of administration, mice were dosed at scheduled times to mitigate the impact of diurnal effects on the expression of thyroid hormone-sensitive genes. Thus, treatment groups were balanced for "time of day" at the time of endpoint sacrifice. Mice were anesthetized 4 or 8 hours after the final dose, blood was collected via retroorbital puncture, and euthanized using standard procedures. Immediately after euthanasia, tissues were harvested and processed according to the following procedures.

[0154] Sample processing a. Expression Analysis Samples - At endpoint, multiple organs were harvested and tissues were immediately processed as described below.

[0155] i. Brain: For each mouse, the skull was opened and the brain was removed. The cerebellum was dissected, and the cerebral cortex was hemisected sagitally, and the left half was collected. After rinsing the tissue with ice-cold 0.9% NaCl to remove blood, the cerebral cortex specimen was placed in a tube containing 1.2 mL of pre-chilled RNALater and stored at 4°C.

[0156] ii. Liver: For each mouse, one liver biopsy (100-150 mg) was taken from the left hepatic lobe. After rinsing the biopsy with ice-cold 0.9% NaCl, the sample was placed in 1.2 mL of pre-chilled RNALater and stored at 4°C.

[0157] iii. Left Ventricle: For each mouse, left ventricular (LV) blood was removed using standard methods at PBI, and half of the LV free wall was collected. After rinsing the tissue with ice-cold 0.9% NaCl, the LV free wall was placed in 1.2 mL of pre-chilled RNALater and stored at 4°C. LV tissue was maintained at PBI for up to 6 months after the end of the in-life phase of the study for potential future analysis or until suitable genes could be identified. Disposal of the samples was approved prior to disposal.

[0158] iv. Pituitary gland: For each mouse, the pituitary gland was harvested after removal of the brain. Adherent blood was rinsed from the pituitary gland with ice-cold 0.9% NaCl, after which the specimen was placed in 0.15 mL of pre-chilled RNALater and stored at 4°C. Pituitary tissue was maintained in PBI for up to 6 months after the end of the in-life phase of the study for potential future analysis or until suitable genes could be identified. Disposition of the samples was approved prior to disposal.

[0159] b. Pharmacokinetic Samples—At endpoint, blood and tissue specimens were processed immediately as described below. Samples for PK analysis were maintained in PBI at −80°C for up to 90 days after the conclusion of the in-life phase of the study.

[0160] i. Plasma: Whole blood (~300 μL) was collected onto K3EDTA via cardiac puncture under isoflurane anesthesia. Blood was immediately placed on wet ice. After the collection procedure was completed, blood was centrifuged at 10,000 x g for 10 minutes at 4°C. Plasma (~125 μL) was aliquoted into appropriately labeled tubes and flash-frozen.

[0161] ii. Liver: For each mouse, one liver biopsy (30-50 mg) was taken from the left liver lobe. After rinsing the biopsy with ice-cold 0.9% NaCl, the sample was placed in an appropriately labeled tube and flash-frozen in liquid nitrogen.

[0162] 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, the biopsy was placed in an appropriately labeled tube and flash-frozen.

[0163] iv. Left ventricle: For each mouse, the left ventricle (LV) was cleared of blood using standard methods for PBI, and half of the LV free wall was collected. After rinsing the tissue with ice-cold 0.9% NaCl, the LV free wall was placed in an appropriately labeled tube and flash-frozen.

[0164] Target Engagement Tissue samples were prepared for biochemical analysis by cryopowdering on liquid nitrogen and lysing using standard methods from PBI. Changes in expression (mRNA expression) of select genes identified by transcriptome analysis were measured from purified RNA using hybridization-based in situ RNA quantification methods (NanoString or QuantiGene Plex). Target gene expression data were presented as ratios to the geometric mean of appropriately expressed normalized genes. Briefly, fresh tissue was cryopreserved using RNALater. (商標)The tissue was collected in stabilization solution, catalog number AM7021 (ThermoFisher Scientific; Carlsbad, CA) and frozen at -20°C until ready for RNA extraction. Whole blood was collected via terminal cardiac puncture into MiniCollect K2EDTA tubes, catalog number 450480 (Greinder Bio-one GmbH, Kremsmunster, Austria), and processed to plasma by centrifugation at 2000 x g for 10 minutes at 4°C. For RNA extraction, tissue was homogenized using a bead homogenizer in TRIzol Reagent, catalog number 15596026 (ThermoFisher Scientific). RNA was extracted and purified using Econospin RNA Mini Spin / Columns for RNA (Ephoch Life Sciences, Missouri City, TX, catalog number 1940-250) according to the manufacturer's protocol. Specific gene probes were designed by the NanoString Bioinformatics Team using target sequences identified based on the NCBI Reference Sequence (RefSeq) database. Custom probes were synthesized by Integrated DNA Technologies (IDT; Coralville, IA). mRNA expression was analyzed using a multiplexed approach with the nCounter PlexSet-12 Reagent Pack, catalog number PS-GX-PTK-12 (CSO), on an nCounter® SPRINT Profiler NanoString system according to the manufacturer's protocol (NanoString, Inc., Seattle, WA).

[0165] T4 analysis T4 was measured in terminal plasma samples using an ELISA kit (Biovision, Inc., Thyroxine [T4] [Mouse / Rat] ELISA Kit, Catalog Number: K7421-100). The assay was performed according to the manufacturer's instructions with minor modifications based on previous assay validation efforts. Briefly, a 7-point standard curve of the provided T4 diluted in assay buffer (25, 15, 10, 5, 2, and 1 μg / dL) was prepared in duplicate for each assay. Plasma samples (undiluted), blanks (assay buffer), and standards were added to separate wells of a 96-well plate precoated with T4 capture antibody, followed by the addition of T4 enzyme conjugate to each well. The plate was then mixed by gentle shaking (600 rpm) for 20–30 s, then covered with an acetate plate seal and incubated at room temperature (RT) with gentle shaking (600 rpm) for 1 h. The plate contents were aspirated, washed three times with 1X Wash Buffer, and then blotted with paper towels to remove excess liquid. TMB substrate was then added to each well, and the plate was secured with acetate seals and incubated at room temperature for 15 minutes, protected from light. Stop solution was then added to each well, and the plate was gently shaken to mix the solution. Absorbance was read at 450 nm within 15 minutes of adding the stop solution using a Varioskan Lux plate reader (Thermo Fisher Scientific, Carlsbad, CA). Relative optical density (OD) was background corrected against a blank sample and the standard curve. T4 concentrations were interpolated using a four-parameter curve fit. Unknown sample concentrations were determined using GraphPad Prism software (GraphPad Prism 9.0.2, GraphPad Software, San Diego, CA).

[0166] Data analysis Figures 7A, 7B, 7C, and 7D show the effects on gene expression in the brain (blue) and liver (orange), and T4 (gray) in mice treated with (A) active metabolite or (B) prodrug alone, (C) prodrug + PFI (LL-650177), or (D) prodrug + GFI, PO, QD, for 7 days, 4 or 8 hours after the last dose. Both the prodrug and active metabolite reduce T4 levels after 7 days of treatment. Table 6 shows the ED for each treatment type. 50 Values ​​are reported in μg / kg.

[0167] [Table 6]

[0168] Use of T4 as a marker of effect on THA; T4 parallels peripheral activity rather than CNS activation of target genes. Because effects on THA and hepatic gene expression more closely parallel plasma distribution rather than CNS exposure or activity, downregulation of T4 by thyromimetics does not appear to be largely centrally mediated, suggesting a primarily pituitary-driven effect. Combining a thyromimetic prodrug with a PFI may further enhance delivery of thyromimetics to the brain, maximizing centrally targeted distribution.

[0169] Example 10: Phase II Study - Evaluation of the Efficacy and Safety of ABX-002 in the Adjunctive Treatment of Major Depressive Disorder (MDD) in Adults A phase 2, randomized, double-blind, placebo-controlled study of the efficacy, safety, PK, and pharmacodynamics of daily oral doses of ABX-002 or placebo in adult subjects with MDD.

[0170] The study will include three periods: a 28-day screening period, a 28-day treatment period, and an 8-week observation period.

[0171] 28-Day Screening Period - At the screening visit, subjects will be assessed for inclusion / exclusion criteria. Subjects who meet all inclusion and exclusion criteria will be randomized 1:1 according to a computer-generated randomization code to receive a single oral daily dose of ABX-002 or placebo for 28 days, in addition to their ongoing standard of care serotonergic antidepressant.

[0172] 28-Day Treatment Period - Subjects will be evaluated periodically for efficacy, safety, and PK during treatment. EEG and slit lamp examinations will be obtained at the end of the treatment period. EEG and slit lamp examinations will be obtained at the end of the treatment period. After the primary time point on day 28, all subjects will continue treatment with their background SSRI / SNRI.

[0173] Observation Period - Subjects who respond to treatment will enter an 8-week observation period. A follow-up examination will occur 14 days after the end of the treatment period. A slit-lamp examination will occur 12 weeks after the end of the treatment period. If the subject and investigator choose to change their MDD treatment during the observation period, the subject will be followed for safety, but no further efficacy data will be collected. During the observation period, all AEs, regardless of causality, will be reported for 14 days after the last dose of study drug. AEs should be reported beyond 14 days only if they relate to the Eye Disorders System Organ Class in MedDRA24.

[0174] Study treatment (ASK1 inhibitor or placebo) consisted of ABX-002 capsules or matching placebo administered orally once daily.

[0175] The primary endpoint for efficacy assessment is the change from baseline to day 28 in the MADRS score. Efficacy determinations will be based on a two-sided p-value of <0.05. Secondary endpoints include change from baseline to day 28 in Sheehan Disability Scale (SDS) score, change in CGI-S, change in SDQ (and energy subscale), change in C-SSRS, change in HAM-D, and the proportion of MADRS responders (≥50% reduction from baseline) and MADRS remission (≤9 at day 28). Change from baseline in MADRS at day 28 will be assessed using a mixed model for repeated measures (MMRM). The model will include fixed effects for treatment group, visit, treatment by visit interaction, and baseline MADRS score.

[0176] Inclusion criteria: ·Ability to give informed consent and HIPAA authorization. ·Be between 18 and 65 years old at the time of the screening visit. Able to understand the nature of the clinical trial and, in the opinion of the investigator, will comply with the protocol requirements. A DSM-5 primary diagnosis of MDE as part of MDD by SCID-5-CV AND meets SAFER criteria (SAFER questions 1-4 must be scored as "Definitely" or "Possibly" and SAFER questions 5-8 must be scored as "Definitely"). Hamilton Depression Rating Scale (HAM-D) score ≥ 19 at screening and baseline. HAM-D score at baseline visit must not be more than 25% lower than at screening visit. Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 24 at baseline. A Clinical Global Impression of Severity (CGI-S) of moderately sick or worse at screening and baseline before randomization. In the MDE, the subject is on adherent use of a single SSRI or SNRI antidepressant at an appropriate dose for at least 6 weeks with an inadequate response as defined by the Antidepressant Treatment Response Questionnaire (ATRQ). In the MDE, at least one and no more than two antidepressants are adequately assessed with an inadequate response as defined by the ATRQ. Current SSRI / SNRI dosage must have been stable for the past 4 weeks and is expected to remain stable throughout screening and the treatment period of the study. The investigator and subject are willing to continue their existing SSRI / SNRI during the treatment period of this study. The investigator and subject are willing to continue their existing SSRI / SNRI during the observation period if the subject responds to treatment. Subjects should have detectable plasma levels of an SSRI / SNRI in a sample obtained during screening. Women must have a negative serum pregnancy test at screening and prior to randomization on Day 1. · Females of childbearing potential and all male subjects must practice effective contraception during the study and for 90 days after the last dose of study drug. ·BMI 18-35kg / m2 (inclusive) and minimum weight of 50kg.

[0177] Exclusion criteria: · History of schizophrenia or other psychotic disorder, or bipolar I or II disorder, delirium, dementia, amnestic disorder, or cognitive impairment. Current treatment for obsessive-compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), panic disorder, and eating disorders according to DSM-5 criteria. · A primary diagnosis of borderline, antisocial, paranoid, schizotypal, schizotypal, or histrionic personality disorder according to DSM-5 criteria. Triiodothyronine (Cytomel) for depression (登録商標) or T3) history of non-response to augmentation. · Current use of other augmenting medications for depression, including second-generation antipsychotics (SGAs), lithium, bupropion, or a second SSRI / SNRI. Discontinuation of second-generation antipsychotics (SGAs) for augmentation of MDD due to lack of treatment response may be screened for eligibility if the SGA was discontinued at least 30 days prior to screening. · Have undergone repetitive transcranial magnetic stimulation (rTMS) within 12 months of screening or plan to undergo rTMS during this study. · Have 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). A history of alcohol or illicit substance abuse / dependence (excluding caffeine or nicotine use) within 12 months of screening or a positive urine drug screen result for an illicit substance at screening or baseline. A single positive urine drug screen result for an illicit substance may be repeated once. Actively suicidal (including a YES answer to questions 4 or 5 [currently or over the last 6 months] on the Columbia Suicide Severity Rating Scale [C-SSRS] Screening Version) or attempted suicide within the 2 years prior to screening. New psychotherapy or change in the intensity of psychotherapy within the 8 weeks prior to screening. Psychotherapy, if present, should be expected to remain the same intensity throughout the screening and 28-day treatment periods of the study. Being housing unstable, receiving SS Disability, or legally incapacitated. History or current evidence of any serious or unstable neurological, cardiovascular, gastrointestinal, respiratory, renal, hepatic, hematological, or endocrinological disorder within the past 3 months prior to screening, or any other medical disorder, including cancer, that would jeopardize the subject's safe participation in the study (in the opinion of the investigator). · History of previous MI, coronary balloon angioplasty, or stent placement, heart failure, angina pectoris, or atrial fibrillation, atrial flutter, or ventricular tachycardia. Clinically significant abnormalities in the screening ECG - QTc > 450 msec in men and QTc > 470 msec in women. If one repeat ECG can be performed and the values ​​are below these values, the subject may be included. · History of a positive Hepatitis B, Hep C virus (HCV), or human immunodeficiency virus (HIV) test. · Glycosylated hemoglobin (HbA1c) >8% at screening. · Estimated creatinine clearance of ≤90 mL / min based on the CKD-EPI equation. Abnormal thyroid function tests at screening (e.g., TSH, T3, TT4, and FT4) or thyroid hormone replacement (e.g., history of treatment for hypothyroidism or thyroid cancer). ·AST or ALT>2×ULN. Lens opacity based on ophthalmic examination during screening. History of clinically significant cataract, glaucoma, presence of inflammatory eye disease in either eye, or previous ophthalmic or laser surgery. Subjects with previous LASIK surgery may be included. Evidence of epileptiform activity on EEG during screening. A diagnosis of epilepsy or a history of convulsions, including febrile seizures in childhood. Use of concomitant medications that may lower the seizure threshold is excluded (e.g., bupropion). Participated in any clinical research study within 30 days prior to screening. Benzodiazepine hypnotic use. Subjects with daily use of non-benzodiazepine hypnotics (e.g., zolpidem, zaleplon, eszopiclone) may continue to use them during the 28-day treatment period as long as the dose remains the same. ·Known hypersensitivity to ABX-002 or any of its excipients. Women who are pregnant, intend to become pregnant within 90 days of the last dose, or are breastfeeding. Subjects who have previously participated in a clinical trial with ABX-002. · Study site personnel or their close family members (spouse, parent, biological or adopted children or siblings).

Claims

1. 1. A method for treating depression, anxiety disorders, or pain in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) 【Chemical 1】 (In the formula, R １ and R ２ are independently hydrogen, -OR ５ , -NR ５ R ６ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C ３ -C ６ Heterocycloalkyl, phenyl, and —C １ -C ６ alkyl-phenyl; １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C ３ -C ６ Heterocycloalkyl, phenyl, and —C １ -C ６ Alkyl-phenyl is halo, cyano, -OR ５ , -NR ５ R ６ , -S(O) ２ R ５ , or -S(O) ２ OR ５ and optionally substituted with one or more of R ３ and R ４ is independently selected from —F, —Cl, —Br, and —I; R ５ and R ６ are independently hydrogen and C １ -C ６ alkyl, and R ７ and R ８ are independently selected from hydrogen, —F, —Cl, —Br, and —I), or a pharmaceutically acceptable salt or solvate thereof to said patient.

2. 1. A method for treating depression, anxiety disorders, or pain in a patient in need thereof, comprising administering a compound of formula (II) 【Chemistry 2】 (In the formula, R １ and R ２ are independently hydrogen, -OR ５ , -NR ５ R ６ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C ３ -C ６ Heterocycloalkyl, phenyl, and —C １ -C ６ alkyl-phenyl; １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C ３ -C ６ Heterocycloalkyl, phenyl, and —C １ -C ６ Alkyl-phenyl is halo, cyano, -OR ５ , -NR ５ R ６ , -S(O) ２ R ５ , or -S(O) ２ OR ５ and optionally substituted with one or more of R ３ and R ４ is independently selected from —F, —Cl, —Br, and —I; R ５ and R ６ are independently hydrogen and C １ -C ６ alkyl, and R ７ and R ８ are independently selected from hydrogen, —F, —Cl, —Br, and —I; R ７ and R ８ wherein at least one of is not hydrogen, or a pharmaceutically acceptable salt or solvate thereof.

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

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

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

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

7. 1. A method for treating depression, anxiety disorders, or pain in a patient in need thereof, comprising administering a compound of formula (III): 【Chemistry 3】 (In the formula, R １ and R ２ are independently hydrogen, -OR ５ , -NR ５ R ６ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C ３ -C ６ Heterocycloalkyl, phenyl, and —C １ -C ６ alkyl-phenyl; １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C ３ -C ６ Heterocycloalkyl, phenyl, and —C １ -C ６ Alkyl-phenyl is halo, cyano, -OR ５ , -NR ５ R ６ , -S(O) ２ R ５ , or -S(O) ２ OR ５ and optionally substituted with one or more of R ３ and R ４ is independently selected from —F, —Cl, —Br, and —I; and R ５ and R ６ are independently hydrogen and C １ -C ６ or a pharmaceutically acceptable salt or solvate thereof.

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

9. R ２ Halo, cyano, -OR ５ , -NR ５ R ６ , -S(O) ２ R ５ , or -S(O) ２ OR ５ C optionally substituted with one or more of １ -C ６ The method according to any one of claims 1 to 8, wherein the alkyl is alkyl.

10. R ２ Halo, cyano, -OR ５ , -NR ５ R ６ , -S(O) ２ R ５ , or -S(O) ２ OR ５ C substituted with one or more of １ -C ６ The method according to any one of claims 1 to 9, wherein the alkyl is alkyl.

11. R ２ is substituted with one or more —OH １ -C ６ The method according to any one of claims 1 to 10, wherein the alkyl is alkyl.

12. R ２ C substituted with one or more of halo １ -C ６ The method according to any one of claims 1 to 10, wherein the alkyl is alkyl.

13. R ２ is unsubstituted C １ -C ６ The method according to any one of claims 1 to 9, wherein the alkyl is alkyl.

14. R ２ Halo, cyano, -OR ５ , -NR ５ R ６ , -S(O) ２ R ５ , or -S(O) ２ OR ５ The method of any one of claims 1 to 8, wherein the aryl group is phenyl optionally substituted with one or more of:

15. R ２ Halo, cyano, -OR ５ , -NR ５ R ６ , -S(O) ２ R ５ , or -S(O) ２ OR ５ -C optionally substituted with one or more of １ -C ６ The method of any one of claims 1 to 8, wherein the alkyl is alkyl-phenyl.

16. R ３ and R ４ The method of any one of claims 1 to 15, wherein is independently selected from -F, -Cl, -Br.

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

18. R ３ and R ４ The method of any one of claims 1 to 16, wherein both are -Cl.

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

20. 1. A method of treating depression, anxiety, or pain in a patient in need thereof, comprising: 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 or a pharmaceutically acceptable salt or solvate thereof.

21. 21. A method according to any one of claims 1 to 20 for treating depression in a patient in need thereof.

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

23. 22. The method of any one of claims 1 to 21, wherein the depression is bipolar depression, bipolar treatment-resistant depression, severe mood dysregulation disorder, persistent depressive disorder, depressed mood, premenstrual dysphoric disorder, drug-induced depressive disorder, postpartum depression, perimenopausal depression, multi-infarct dementia with depression, presenile dementia with depression, senile dementia with depression, vascular dementia with depressed mood, vascular dementia with depression, or unspecified depressive disorder.

24. 21. A method according to any one of claims 1 to 20 for treating an anxiety disorder in a patient in need thereof.

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

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

27. A method according to any one of claims 1 to 20 for treating pain in a patient in need thereof.

28. 28. The method of claim 27, wherein the pain is selected from migraine pain, chronic pain, chronic nerve pain, chronic muscle pain, chronic joint pain, diabetic neuropathy, fibromyalgia, low back pain, and osteoarthritis pain.

29. 29. The method of any one of claims 1 to 28, further comprising administering to said patient a peripherally restricted FAAH inhibitor.

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

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

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

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

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