Combining brain-targeted activity with fatty acid amide hydrolase (FAAH)-cleavable prodrugs and peripherally restricted FAAH inhibitors

Abstract

Provided herein are fatty acid amide (FAAH) cleavable prodrugs of compounds that modulate targets in the brain, including sphingosine-1-phosphate receptor 1 (S1P1), lysophosphatidic acid receptor 1 (LPA1), G protein-coupled receptor 120 (GPR120), prostacyclin (PGI2), and transthyretin (TTR). Also provided are pharmaceutical compositions comprising these prodrugs in combination with a peripherally restricted FAAH inhibitor and at least one pharma- ceutically acceptable excipient, and the use of these compounds and compositions in the treatment of CNS diseases or disorders.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 185,253, filed May 6, 2021, which is incorporated by reference in its entirety. [Background technology]

[0002] The blood-brain barrier is composed of tightly interconnected endothelial cells that restrict 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, presenting a major challenge for the development of novel medicines for CNS diseases. Summary of the Invention

[0003] In one embodiment provided herein, a compound of formula (I):

[0004] [ka] A fatty acid amide hydrolase (FAAH) cleavable prodrug of the formula: R 1 is an amide prodrug moiety and the prodrug of formula (I) is

[0005] [ka] It is enzymatically cleaved in the brain by fatty acid amide hydrolase (FAAH) to release

[0006] [ka] is a moiety that modulates a target in the brain, and a pharma- ceutical composition, or a pharma-ceutical acceptable salt or solvate thereof, further comprising a peripherally restricted FAAH inhibitor.

[0007] In some embodiments, the target is selected from sphingosine-1-phosphate receptor 1 (S1P1), lysophosphatidic acid receptor 1 (LPA1), G protein-coupled receptor 120 (GPR120), prostacyclin (PGI2), and transthyretin (TTR).

[0008] In some embodiments, the target is S1P1. In some embodiments, the target is S1P1 and R 2 teeth

[0009] [ka] is selected from.

[0010] In some embodiments, the target is LPA1. In some embodiments, the target is LPA1 and R 2 teeth

[0011] [ka] is selected from.

[0012] In some embodiments, the target is GPR120. In some embodiments, the target is GPR120 and R 2 teeth

[0013] [ka] It is.

[0014] In some embodiments, the target is TTR. In some embodiments, the target is TTR and R 2 teeth

[0015] [ka] is selected from.

[0016] In some embodiments, the target is PGI2. In some embodiments, the target is PGI2 and R 2 teeth

[0017] [ka] It is.

[0018] In some embodiments, R 1 is optionally replaced by C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 2-9 Heterocycloalkyl, optionally substituted C 6-10 Aryl, and optionally substituted C 1-9 In some embodiments, R 1 is optionally replaced by C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 2-9 Heterocycloalkyl, optionally substituted C 6-10 Aryl, and optionally substituted C 1-9 heteroaryl; C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl is halogen, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 In some embodiments, R is optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl. 1 is the unsubstituted C 1-6 Alkyl, unsubstituted C 3-6 Cycloalkyl, unsubstituted C 2-9 Heterocycloalkyl, unsubstituted C 6-10 Aryl and unsubstituted C 1-9 In some embodiments, R 1 teeth,

[0019] [ka] is selected from.

[0020] In some embodiments, the peripherally restricted FAAH inhibitor is ASP-3652.

[0021] In another aspect, a method for treating a CNS disease or disorder in a patient in need of such treatment comprises administering to the patient a therapeutically effective amount of a pharmaceutical composition as described herein.In some embodiments, the CNS disease or disorder is selected from multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and Alzheimer's disease.In some embodiments, the CNS disease or disorder is selected from epilepsy, ischemic stroke, traumatic brain injury, and autoimmune encephalomyelitis.In some embodiments, the CNS disease or disorder is selected from ischemic stroke, schizophrenia, depression, mood disorder, attention deficit hyperactivity disorder, post-traumatic stress disorder, and Alzheimer's dementia.In some embodiments, the CNS disease or disorder is selected from familial amyloid polyneuropathy, familial leptomeningeal amyloidosis, Alzheimer's disease, stroke, dementia, transient focal neurological deficits, cognitive impairment, and CNS amyloidosis. In some embodiments, the CNS disease or disorder is selected from Degos disease, reversible cerebral vasoconstriction syndrome, Sneddon syndrome, amyloid-β associated vasculopathy, Susac syndrome, and neurosarcoidosis.

[0022] In another aspect, a method for determining whether a patient has a brain tumor comprising administering to the patient a pharmaceutical composition as described herein.

[0023] [ka] This is a method for increasing the concentration of

[0024] In another aspect herein, a compound of formula (II):

[0025] [ka] or a pharma- ceutically acceptable salt or solvate thereof, During the ceremony, R 1 but,

[0026] [ka] is an amide prodrug moiety that is enzymatically cleaved by fatty acid amide hydrolase (FAAH) in the brain to release

[0027] [ka] is a moiety that modulates S1P1 in the brain, or a pharma- ceutically acceptable salt or solvate thereof.

[0028] In some embodiments, R 2 but,

[0029] [ka] is a compound of formula (II) selected from

[0030] In another aspect herein, a compound of formula (III):

[0031] [ka] or a pharma- ceutically acceptable salt or solvate thereof, During the ceremony, R 1 but,

[0032] [ka] is an amide prodrug moiety that is enzymatically cleaved by fatty acid amide hydrolase (FAAH) in the brain to release

[0033] [ka] is a moiety that regulates LPA1 in the brain, or a pharma- ceutically acceptable salt or solvate thereof.

[0034] In some embodiments, R 2 but,

[0035] [ka] is a compound of formula (III) selected from

[0036] In another aspect herein, a compound of formula (IV):

[0037] [ka] or a pharma- ceutically acceptable salt or solvate thereof, During the ceremony, R 1 but,

[0038] [ka] is an amide prodrug moiety that is enzymatically cleaved by fatty acid amide hydrolase (FAAH) in the brain to release

[0039] [ka] is a moiety that modulates GPR120 in the brain, or a pharma- ceutically acceptable salt or solvate thereof.

[0040] In some embodiments, R 2 but,

[0041] [ka] is a compound of formula (IV),

[0042] In some embodiments, R 1 , optionally replaced by C 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted C 2-9Heterocycloalkyl, optionally substituted C 6-10 Aryl, and optionally substituted C 1-9 In some embodiments, R is a compound of formula (II), (III), or (IV) that is heteroaryl. 1 But, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is halogen, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 In some embodiments, R is a compound of formula (II), (III), or (IV) optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl.1 But the unsubstituted C 1-6 Alkyl, unsubstituted C 3-6 Cycloalkyl, unsubstituted C 2-9 Heterocycloalkyl, unsubstituted C 6-10 Aryl and unsubstituted C 1-9 A compound of formula (II), (III), or (IV) which is heteroaryl.

[0043] In another aspect herein, a compound of formula (V):

[0044] [ka] or a pharma- ceutically acceptable salt or solvate thereof, During the ceremony, R 1 but,

[0045] [ka] is an amide prodrug moiety that is enzymatically cleaved by fatty acid amide hydrolase (FAAH) in the brain to release

[0046] [ka] is a moiety that modulates TTR in the brain, or a pharma- ceutically acceptable salt or solvate thereof.

[0047] In some embodiments, R 2 but,

[0048] [ka] is a compound of formula (V):

[0049] In some embodiments, R 1 But, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6Cycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; C 3-6 Cycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is halogen, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 In some embodiments, R is a compound of formula (V) optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl. 1 But the unsubstituted C 1-4 Alkyl, unsubstituted C 3-6 Cycloalkyl, unsubstituted C 6-10 Aryl and unsubstituted C 1-9 heteroaryl.

[0050] In some embodiments, R 2 but,

[0051] [ka] is a compound of formula (V):

[0052] In some embodiments, R 1 But -CH 3 , C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is halogen, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 In some embodiments, R is a compound of formula (V) optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl. 1 But -CH 3, unsubstituted C 3-6 Cycloalkyl, unsubstituted C 2-9 Heterocycloalkyl, unsubstituted C 6-10 Aryl and unsubstituted C 1-9 The compound of formula (V) is heteroaryl.

[0053] In another aspect herein, a compound of formula (VI):

[0054] [ka] or a pharma- ceutically acceptable salt or solvate thereof, During the ceremony, R 1 but,

[0055] [ka] is an amide prodrug moiety that is enzymatically cleaved by fatty acid amide hydrolase (FAAH) in the brain to release

[0056] [ka] is a moiety that regulates PGI2 in the brain, or a pharma- ceutically acceptable salt or solvate thereof.

[0057] In some embodiments, R 2 but,

[0058] [ka] is a compound of formula (VI),

[0059] In some embodiments, R 1 But -CH 3 , optionally replaced by C 3-6 Cycloalkyl, optionally substituted C 2-9 Heterocycloalkyl, optionally substituted C 6-10Aryl, and optionally substituted C 2-9 heteroaryl; C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl is halogen, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 In some embodiments, R is a compound of formula (VI) optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl. 1 But -CH 3 , unsubstituted C 3-6 Cycloalkyl, unsubstituted C 2-9 Heterocycloalkyl, unsubstituted C 6-10 Aryl and unsubstituted C 1-9 The compound of formula (VI) is heteroaryl.

[0060] In some embodiments, R 1 but,

[0061] [ka] is a compound of formula (II), (III), (IV), (V), or (VI) selected from:

[0062] In another aspect is a pharmaceutical composition comprising a compound of formula (II), (III), (IV), (V) or (VI), or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a peripherally restricted FAAH inhibitor. In some embodiments, the pharmaceutical composition comprises a peripherally restricted FAAH inhibitor that is ASP-3652.

[0063] In another aspect, a method of treating a CNS disease or disorder in a patient in need of such treatment comprises administering to the patient a compound of formula (II), (III), (IV), (V), or (VI), or a pharma- ceutically acceptable salt or solvate thereof. In another aspect, a method of treating a CNS disease or disorder in a patient in need of such treatment comprises administering to the patient a pharmaceutical composition comprising a compound of formula (II), (III), (IV), (V), or (VI), or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient. In some embodiments, the CNS disease or disorder is selected from multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and Alzheimer's disease. In some embodiments, the CNS disease or disorder is selected from epilepsy, ischemic stroke, traumatic brain injury, and autoimmune encephalomyelitis. In some embodiments, the CNS disease or disorder is selected from ischemic stroke, schizophrenia, depression, mood disorder, attention deficit hyperactivity disorder, post-traumatic stress disorder, and Alzheimer's dementia.In some embodiments, the CNS disease or disorder is selected from familial amyloid polyneuropathy, familial leptomeningeal amyloidosis, Alzheimer's disease, stroke, dementia, transient focal neurological deficits, cognitive impairment, and CNS amyloidosis.In some embodiments, the CNS disease or disorder is selected from Degos disease, reversible cerebral vasoconstriction syndrome, Sneddon syndrome, amyloid-β-related angiopathy, Susac syndrome, and neurosarcoidosis.

[0064] In another aspect, a method for determining whether a patient has a brain tumor comprising administering to the patient a compound described herein.

[0065] [ka] This is a method for increasing the concentration of DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0066] Fatty acid hydrolases (FAAHs) are integral membrane serine hydrolases that can degrade the fatty acid amide family of signaling lipids to hydrolyze selected amide prodrugs. FAAHs are highly conserved among species and expressed to various degrees in many tissues, including the central nervous system (CNS). Selected carboxylic acids can be converted to highly permeable amide prodrugs that can then cross the blood-brain barrier, where they can be converted to active molecules by the action of FAAH on the prodrug. This results in higher amounts of carboxylic acids being delivered to the CNS compared to parent dosing alone. However, peripherally expressed FAAHs can simultaneously hydrolyze the prodrug, resulting in a significant amount of non-productive prodrug conversion. Coadministration of peripherally restricted FAAH inhibitors with CNS-permeable FAAH-convertible prodrugs improves the selectivity of prodrug delivery to the CNS. In addition, exposure of the parent molecule in plasma and peripheral tissues is less than that observed when the prodrug is administered alone.

[0067] 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 a reference to one or more of such drugs, and a reference to "an excipient" includes a reference to one or more of such excipients. When ranges are used herein, it is intended that all combinations and subcombinations of ranges and specific embodiments therein are included. When referring to a number or range of numbers, the term "about" means that the number or range of numbers referred to is an approximation within experimental variation (or within statistical experimental error), such that the number or range of numbers varies between 1% and 15% of the stated number or range of numbers.

[0068] The terms "formulation" and "composition" are used interchangeably as used herein and refer to a mixture of two or more compounds, elements, or molecules. In some embodiments, the terms "formulation" and "composition" may also be used to refer to a mixture of one or more active agents with a carrier or other excipient.

[0069] 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 biological activity when administered to a subject in a significant or effective amount.

[0070] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to include all pharmaceutically appropriate salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0071] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free bases, and 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, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanediol acids, aromatic acids, and aliphatic and aromatic sulfonic acids, including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, 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. Additionally, salts of amino acids such as arginate, gluconate, galacturonate, and the like are contemplated (see, for example, 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 form with a sufficient amount of the desired acid to produce the salt.

[0072] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, pharma-ceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, 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.

[0073] It should be understood that reference to pharmaceutically acceptable salts includes solvent addition forms (solvates). Solvates contain stoichiometric or non-stoichiometric amounts and are formed during the process of product formation or isolation with 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, heptane, toluene, anisole, acetonitrile, etc. In one embodiment, solvates are formed with, but not limited to, Class 3 solvents. Solvent categories are defined, for example, by the International Conference on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.

[0074] The term "effective amount" or "therapeutically effective amount" as used herein refers to an amount of an administered drug or compound sufficient to alleviate 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 the disease, or other desired alteration of a biological system. For example, an "effective amount" in therapeutic applications is the amount of a composition containing a compound disclosed herein that is required to produce a clinically significant reduction in the disease. An appropriate "effective" amount in any individual case may optionally be determined using techniques such as dose escalation studies.

[0075] 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.

[0076] The term "peripherally restricted FAAH inhibitor" as used herein refers to a FAAH inhibitor that inhibits fatty acid amide hydrolase (FAAH) in the peripheral nervous system to a greater extent than in the central nervous system upon systemic administration. In some embodiments, the peripherally restricted FAAH inhibitor is 60% peripherally restricted. In some embodiments, the peripherally restricted FAAH inhibitor is 70% peripherally restricted. In some embodiments, the peripherally restricted FAAH inhibitor is 80% peripherally restricted. In some embodiments, the peripherally restricted FAAH inhibitor is 90% peripherally restricted. In some embodiments, the peripherally restricted FAAH inhibitor is 95% peripherally restricted.

[0077] The term "target in the brain", as used herein, refers to a biological target that is activated in the brain but is itself present in the CNS or both the CNS and the periphery. In some embodiments, the target is in the CNS. In some embodiments, the target is in the CNS and the periphery. As a result of target activation in the brain, the activated target may induce a biological effect in the CNS, the periphery, or both the CNS and the periphery. In some embodiments, the activated target induces a biological effect in the CNS. In some embodiments, the activated target induces a biological effect primarily in the CNS. In some embodiments, the activated target induces a biological effect in the periphery. In some aspects, the activated target induces a biological effect in both the CNS and the periphery. In some embodiments, the term "target in the brain" refers to a target in the mammalian brain. In some embodiments, the term "target in the brain" refers to a target in the mammalian brain that is human.

[0078] target S1P1 Sphingosine-1-phosphate receptor 1 (S1P receptor 1 or S1P1), also known as endothelial differentiation gene 1 (EDG1), is a class A G protein-coupled receptor expressed on lymphocytes, neurons, and endothelium. There are five GPCRs (S1P1-5) in this family that recognize the sphingolipid sphingosine-1 phosphate (S1P) and perform various functions. S1P1 regulates vascular development and lymphocyte trafficking, and its agonists have been approved for the treatment of relapsing forms of multiple sclerosis. Sustained activation (agonism) of S1P1 expressed on lymphocytes results in receptor internalization and proteasomal degradation, resulting in "functional antagonism" of S1P1. S1P1 agonists, which can efficiently penetrate the CNS, have been reported to reduce disease severity of experimental autoimmune encephalomyelitis (EAE) in mice because they can induce receptor signaling and the degradation of S1P1 expressed on neurons and astrocytes.

[0079] LPA1 Lysophosphatidic acid receptor 1 (LPA1) is a G protein-coupled receptor that binds extracellular lysophosphatidic acid (LPA), which activates second messenger pathways to elicit several cellular responses that regulate cell activity, cell migration, cytoskeletal reorganization, and cell proliferation. LPA1 activation induces microglial activation in the CNS, and the receptor is a key regulator of neuroinflammation. LPA1 activation also plays an important role in the induction of demyelination. Inhibition of LPA1 activity in the CNS may have beneficial effects on a number of CNS diseases, including neuroinflammation and demyelination.

[0080] GPR120 GPR120 / FFAR4 is a receptor for unsaturated long-chain fatty acids expressed in macrophages, eosinophils, and adipose tissue that has been reported to mediate anti-inflammatory mechanisms. In a C57BL / 6 model of middle cerebral artery occlusion (MCAO) and in vitro model of oxygen glucose deprivation (OGD), we observed increased expression of GPR120 in microglia and neurons after MCAO-induced ischemia. Treatment with RAR agonists inhibited OGD-induced inflammatory responses in primary microglial cells and mouse microglial BV2 cells, whereas silencing of GPR120 strongly exacerbated inflammation induced by OGD and abolished the anti-inflammatory effect. Furthermore, knockdown of GPR120 impaired the anti-apoptotic effect of RAR agonists on OGD-induced rat pheochromocytoma (PC12) cells. GPR120 activation has also been reported to protect against focal cerebral ischemic injury by preventing inflammation and apoptosis.

[0081] PGI2 analogues or prostaglandin I2 (IP) receptor agonists Prostacyclin (prostaglandin I2) is a metabolic product of arachidonic acid or prostaglandin endoperoxides and is released from vascular endothelial cells. Type I prostaglandin receptors (IP3 receptors) are G protein-coupled receptors that couple with the activation of adenylate cyclase, thereby catalyzing the formation of 3',5' cyclic adenosine monophosphate (cAMP), a second messenger involved in vascular tone. IP receptors are expressed on vascular smooth muscle and platelets, where they function as vasorelaxants and as inhibitors of platelet aggregation. Prostacyclin has also been reported to promote axonal remodeling of neuronal network injury following CNS inflammation. In addition, tests under pathological conditions have revealed that a stable analog of prostacyclin reduces cerebral edema after occlusion of the middle cerebral artery. Prostacyclin signaling is thought to act directly on endothelial cells, enhancing endothelial barrier function and reducing edema formation. Signaling in perivascular cells such as pericytes contributes to reducing capillary hydrodynamic permeability under pathological conditions in the adult CNS. Prostacyclin receptor signaling inhibitors have been reported to impair motor recovery, and IP receptor agonists promote axonal remodeling and motor recovery after induction of EAE. These findings reveal that angiogenesis plays a key role in neuronal rewiring, while suggesting that prostacyclin is a promising molecule for enhancing functional recovery in CNS diseases.

[0082] TTR Stabilizer Analogues Transthyretin (TTR) is a homo-tetramer composed of 127 amino acid subunits carrying thyroxine and holo-retinol binding protein (holo-RBP) in blood. Transthyretin is secreted into blood by the liver at a steady-state concentration of approximately 3-6 μM and into cerebrospinal fluid (CSF) by the choroid plexus (CP) at a steady-state concentration of approximately 300 nM. TTR misfolding, aggregation, and deposition (amyloidogenesis) are associated with amyloid diseases, including senile systemic amyloidosis, familial amyloid polyneuropathy, or cardiomyopathy. TTR tetramers are nonamyloidogenic, but under partially denaturing conditions undergo dissociation, monomeric misfolding, and misassembly into numerous aggregated structures, including amyloid. TTR has also been reported to counter the neurotoxic effects of Aβ peptides by reducing their aggregation and enhancing the clearance of oligomers and plaques in the brain.

[0083] Pharmaceutical Compositions and Compounds In some embodiments herein, the compound of formula (I):

[0084] [ka] A fatty acid amide hydrolase (FAAH) cleavable prodrug of the formula: R 1 is an amide prodrug moiety and the prodrug of formula (I) is

[0085] [ka] It is enzymatically cleaved in the brain by fatty acid amide hydrolase (FAAH) to release

[0086] [ka] is a moiety that modulates a target in the brain, and a pharma- ceutical composition, or a pharma- ceutical acceptable salt or solvate thereof, further comprising a peripherally restricted FAAH inhibitor.

[0087] In some embodiments, the target is selected from sphingosine-1-phosphate receptor 1 (S1P1), lysophosphatidic acid receptor 1 (LPA1), G protein-coupled receptor 120 (GPR120), prostacyclin (PGI2), and transthyretin (TTR).

[0088] In some embodiments, the target is S1P1. In some embodiments, the target is S1P1 and R 2 teeth

[0089] [ka] is selected from.

[0090] In some embodiments, the target is LPA1. In some embodiments, the target is LPA1 and R 2 teeth

[0091] [ka] is selected from.

[0092] In some embodiments, the target is GPR120. In some embodiments, the target is GPR120 and R 2 teeth

[0093] [ka] It is.

[0094] In some embodiments, the target is TTR. In some embodiments, the target is TTR and R 2teeth

[0095] [ka] is selected from.

[0096] In some embodiments, the target is PGI2. In some embodiments, the target is PGI2 and R 2 teeth

[0097] [ka] It is.

[0098] In some embodiments, R 1 is optionally replaced by C 1-6 In some embodiments, R 1 are halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-6 In some embodiments, R 1 are halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-6 In some embodiments, R 1 are halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 1-6 In some embodiments, R 1 is the unsubstituted C 1-6 It is an alkyl.

[0099] In some embodiments, R 1 is optionally replaced by C 3-6 In some embodiments, R 1 are halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 3-6 In some embodiments, R 1 are halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 3-6 In some embodiments, R 1 are halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 3-6 In some embodiments, R 1 is the unsubstituted C3-6 It is cycloalkyl.

[0100] In some embodiments, R 1 is optionally replaced by C 2-9 In some embodiments, R 1 are halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 2-9 In some embodiments, R 1 are halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 2-9 In some embodiments, R 1 are halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 2-9 In some embodiments, R 1 is the unsubstituted C 2-9 It is a heterocycloalkyl.

[0101] In some embodiments, R 1 is optionally replaced by C 6-10 In some embodiments, R 1 are halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 6-10 In some embodiments, R 1 are halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 6-10 In some embodiments, R 1 are halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 6-10 In some embodiments, R 1 is the unsubstituted C 6-10 It is aryl.

[0102] In some embodiments, R 1 is optionally replaced by C 1-9 In some embodiments, R 1 are halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2, -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-9 In some embodiments, R 1 are halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-9 In some embodiments, R 1 are halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 1-9 In some embodiments, R 1 is the unsubstituted C 1-9 It is heteroaryl.

[0103] In some embodiments, R 1 is -CH 3 In some embodiments, R 1 is -CH 2 CH 3 In some embodiments, R 1 is -CH 2 CH 2 CH 3 In some embodiments, R 1 is -CHCH 3 ) 2 In some embodiments, R 1 teeth,

[0104] [ka] In some embodiments, R 1 teeth,

[0105] [ka] In some embodiments, R 1 teeth,

[0106] [ka] In some embodiments, R 1 teeth,

[0107] [ka] In some embodiments, R 1 teeth,

[0108] [ka] In some embodiments, R 1 teeth,

[0109] [ka] In some embodiments, R 1 teeth,

[0110] [ka] In some embodiments, R 1 teeth,

[0111] [ka] In some embodiments, R 1 teeth,

[0112] [ka] In some embodiments, R 1 teeth,

[0113] [ka] In some embodiments, R 1 teeth,

[0114] [ka] It is.

[0115] In some embodiments, the fatty acid amide hydrolase (FAAH) cleavable prodrug of formula (I) is

[0116] [ka]

[0117] [ka]

[0118] [ka]

[0119] [ka] is selected from.

[0120] In some embodiments of the pharmaceutical compositions described herein, the peripherally restricted FAAH inhibitor is ASP-3652.

[0121] In some embodiments herein, the compound of formula (II):

[0122] [ka] or a pharma- ceutically acceptable salt or solvate thereof, During the ceremony, R 1 but,

[0123] [ka] is an amide prodrug moiety that is enzymatically cleaved by fatty acid amide hydrolase (FAAH) in the brain to release

[0124] [ka] is a moiety that modulates S1P1 in the brain, or a pharma- ceutically acceptable salt or solvate thereof.

[0125] In some embodiments, R 2but,

[0126] [ka] is a compound of formula (II) selected from

[0127] In some embodiments, R 2 but,

[0128] [ka] is a compound of formula (II)

[0129] In some embodiments, R 2 but,

[0130] [ka] is a compound of formula (II)

[0131] In some embodiments, R 1 , optionally replaced by C 1-6 In some embodiments, R is a compound of formula (II). 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-6 In some embodiments, R is a compound of formula (II). 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-6 In some embodiments, R is a compound of formula (II). 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 1-6 In some embodiments, R is a compound of formula (II). 1 is unsubstituted C 1-6 The compound of formula (II) is

[0132] In some embodiments, R 1 , optionally replaced by C 3-6 In some embodiments, R is a compound of formula (II) in which R is cycloalkyl. 1But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 3-6 In some embodiments, R is a compound of formula (II) in which R is cycloalkyl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 3-6 In some embodiments, R is a compound of formula (II) in which R is cycloalkyl. 1But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 3-6 In some embodiments, R is a compound of formula (II) in which R is cycloalkyl. 1 is unsubstituted C 3-6 The compound of formula (II) is cycloalkyl.

[0133] In some embodiments, R 1 , optionally replaced by C 2-9 In some embodiments, R is a compound of formula (II) which is heterocycloalkyl. 2 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 2-9 In some embodiments, R is a compound of formula (II) that is heterocycloalkyl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 2-9 In some embodiments, R is a compound of formula (II) that is heterocycloalkyl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 2-9 In some embodiments, R is a compound of formula (II) that is heterocycloalkyl. 1 is unsubstituted C 2-9 A compound of formula (II) which is a heterocycloalkyl.

[0134] In some embodiments, R 1 , optionally replaced by C 6-10 In some embodiments, R is a compound of formula (II) in which R is aryl. 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2, -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 6-10 In some embodiments, R is a compound of formula (II) in which R is aryl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 6-10 In some embodiments, R is a compound of formula (II) in which R is aryl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 6-10 In some embodiments, R is a compound of formula (II) in which R is aryl. 1 is unsubstituted C 6-10 The compound of formula (II) is aryl.

[0135] In some embodiments, R 1 , optionally replaced by C 1-9 In some embodiments, R is a compound of formula (II) that is heteroaryl. 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-9 In some embodiments, R is a compound of formula (II) that is heteroaryl. 1But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-9 In some embodiments, R is a compound of formula (II) that is heteroaryl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 1-9 In some embodiments, R is a compound of formula (II) that is heteroaryl. 1 is unsubstituted C 1-9 The compound of formula (II) is heteroaryl.

[0136] In some embodiments, R 1 Ga-CH 3 In some embodiments, R 1 Ga-CH 2 CH 3 In some embodiments, R 1 Ga-CH 2 CH 2 CH 3 In some embodiments, R 2 Ga-CHCH 3 ) 2 In some embodiments, R 1but,

[0137] [ka] In some embodiments, R 1 but,

[0138] [ka] In some embodiments, R 1 but,

[0139] [ka] In some embodiments, R 1 but,

[0140] [ka] In some embodiments, R 1 but,

[0141] [ka] In some embodiments, R 1 but,

[0142] [ka] In some embodiments, R 1 but,

[0143] [ka] In some embodiments, R 1 but,

[0144] [ka] In some embodiments, R 1 but,

[0145] [ka] In some embodiments, R 1 but,

[0146] [ka] In some embodiments, R 1 but,

[0147] [ka] is a compound of formula (II)

[0148] In some embodiments, the compound of formula (II) is

[0149] [ka]

[0150] [ka] is selected from.

[0151] In some embodiments herein, the compound of formula (III):

[0152] [ka] or a pharma- ceutically acceptable salt or solvate thereof, During the ceremony, R 1 but,

[0153] [ka] is an amide prodrug moiety that is enzymatically cleaved by fatty acid amide hydrolase (FAAH) in the brain to release

[0154] [ka] is a moiety that regulates LPA1 in the brain, or a pharma- ceutically acceptable salt or solvate thereof.

[0155] In some embodiments, R 2 but,

[0156] [ka] is a compound of formula (III) selected from

[0157] In some embodiments, R 2 but,

[0158] [ka] is a compound of formula (III):

[0159] In some embodiments, R 2 but,

[0160] [ka] is a compound of formula (III):

[0161] In some embodiments, R 2 but,

[0162] [ka] is a compound of formula (III):

[0163] In some embodiments, R 2 but,

[0164] [ka] is a compound of formula (III):

[0165] In some embodiments, R 1 , optionally replaced by C 1-6 In some embodiments, R is a compound of formula (III). 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-6 In some embodiments, R is a compound of formula (III). 1But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-6 In some embodiments, R is a compound of formula (III). 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 1-6 In some embodiments, R is a compound of formula (III). 1 is unsubstituted C 1-6 The compound of formula (III) is

[0166] In some embodiments, R 1 , optionally replaced by C 3-6 In some embodiments, R is a compound of formula (III) in which R is cycloalkyl. 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 3-6 In some embodiments, R is a compound of formula (III) in which R is cycloalkyl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 3-6 In some embodiments, R is a compound of formula (III) in which R is cycloalkyl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 3-6 In some embodiments, R is a compound of formula (III) in which R is cycloalkyl. 1 is unsubstituted C3-6 The compound of formula (III) is cycloalkyl.

[0167] In some embodiments, R 1 , optionally replaced by C 2-9 In some embodiments, R is a compound of formula (III) which is heterocycloalkyl. 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 2-9 In some embodiments, R is a compound of formula (III) which is heterocycloalkyl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 2-9 In some embodiments, R is a compound of formula (III) which is heterocycloalkyl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 2-9 In some embodiments, R is a compound of formula (III) which is heterocycloalkyl. 1 is unsubstituted C 2-9 Heterocycloalkyl is a compound of formula (III).

[0168] In some embodiments, R 1 , optionally replaced by C 6-10 In some embodiments, R is a compound of formula (III) in which R is aryl. 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O)2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 6-10 In some embodiments, R is a compound of formula (III) in which R is aryl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 6-10 In some embodiments, R is a compound of formula (III) in which R is aryl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 6-10 In some embodiments, R is a compound of formula (III) in which R is aryl. 1 is unsubstituted C 6-10 The compound of formula (III) is aryl.

[0169] In some embodiments, R 1, optionally replaced by C 1-9 In some embodiments, R is a compound of formula (III) which is heteroaryl. 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-9 In some embodiments, R is a compound of formula (III) which is heteroaryl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-9 In some embodiments, R is a compound of formula (III) which is heteroaryl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 1-9 In some embodiments, R is a compound of formula (III) which is heteroaryl. 1 is unsubstituted C 1-9 The compound of formula (III) is heteroaryl.

[0170] In some embodiments, R 1 Ga-CH 3 In some embodiments, R 1 Ga-CH 2 CH 3 In some embodiments, R 1 Ga-CH 2 CH 2 CH 3 In some embodiments, R 1 Ga-CHCH 3 ) 2 In some embodiments, R 2 but,

[0171] [ka] In some embodiments, R 1 but,

[0172] [ka] In some embodiments, R 1 but,

[0173] [ka] In some embodiments, R 1 but,

[0174] [ka] In some embodiments, R 1 but,

[0175] [ka] In some embodiments, R 1 but,

[0176] [ka] In some embodiments, R 1 but,

[0177] [ka] In some embodiments, R 2 but,

[0178] [ka] In some embodiments, R 1 but,

[0179] [ka] In some embodiments, R 1 but,

[0180] [ka] In some embodiments, R 1 but,

[0181] [ka] is a compound of formula (III):

[0182] In some embodiments, the compound of formula (III) is

[0183] [ka] is selected from.

[0184] In some embodiments herein, the compound of formula (IV):

[0185] [ka] or a pharma- ceutically acceptable salt or solvate thereof, During the ceremony, R 1 but,

[0186] [ka] is an amide prodrug moiety that is enzymatically cleaved by fatty acid amide hydrolase (FAAH) in the brain to release

[0187] [ka] is a moiety that modulates GPR120 in the brain, or a pharma- ceutically acceptable salt or solvate thereof.

[0188] In some embodiments, R 2 but,

[0189] [ka] is a compound of formula (IV),

[0190] In some embodiments, R 1 , optionally replaced by C 1-6 In some embodiments, R is a compound of formula (IV). 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-6 In some embodiments, R is a compound of formula (IV). 1 But halogens, -OH, -NH 2, -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-6 In some embodiments, R is a compound of formula (IV). 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 1-6 In some embodiments, R is a compound of formula (IV). 1 is unsubstituted C 1-6 The compound of formula (IV) is

[0191] In some embodiments, R 1 , optionally replaced by C 3-6 In some embodiments, R is a compound of formula (IV) in which R is cycloalkyl. 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 3-6 In some embodiments, R is a compound of formula (IV) in which R is cycloalkyl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 3-6 In some embodiments, R is a compound of formula (IV) in which R is cycloalkyl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 3-6 In some embodiments, R is a compound of formula (IV) in which R is cycloalkyl. 1 is unsubstituted C 3-6 The compound of formula (IV) is cycloalkyl.

[0192] In some embodiments, R 1 , optionally replaced by C 2-9 In some embodiments, R is a compound of formula (IV) which is heterocycloalkyl. 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 2-9 In some embodiments, R is a compound of formula (IV) which is heterocycloalkyl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 2-9 In some embodiments, R is a compound of formula (IV) which is heterocycloalkyl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 2-9 In some embodiments, R is a compound of formula (IV) which is heterocycloalkyl. 1 is unsubstituted C 2-9 Heterocycloalkyl is a compound of formula (IV).

[0193] In some embodiments, R 1 , optionally replaced by C 6-10 In some embodiments, R is a compound of formula (IV) in which R is aryl. 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl)2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 6-10 In some embodiments, R is a compound of formula (IV) in which R is aryl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 6-10 In some embodiments, R is a compound of formula (IV) in which R is aryl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 6-10 In some embodiments, R is a compound of formula (IV) in which R is aryl. 1 is unsubstituted C 6-10 The compound of formula (IV) is aryl.

[0194] In some embodiments, R 1 , optionally replaced by C 1-9In some embodiments, R is a compound of formula (IV) which is heteroaryl. 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-9 In some embodiments, R is a compound of formula (IV) which is heteroaryl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-9In some embodiments, R is a compound of formula (IV) which is heteroaryl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 1-9 In some embodiments, R is a compound of formula (IV) which is heteroaryl. 1 is unsubstituted C 1-9 The compound of formula (IV) is heteroaryl.

[0195] In some embodiments, R 1 Ga-CH 3 In some embodiments, R 1 Ga-CH 2 CH 3 In some embodiments, R 1 Ga-CH 2 CH 2 CH 3 In some embodiments, R 1 Ga-CHCH 3 ) 2 In some embodiments, R 2 but,

[0196] [ka] In some embodiments, R 1 but,

[0197] [ka] In some embodiments, R 1 but,

[0198] [ka] In some embodiments, R 1 but,

[0199] [ka] In some embodiments, R 1 but,

[0200] [ka] In some embodiments, R 1 but,

[0201] [ka] In some embodiments, R 1 but,

[0202] [ka] In some embodiments, R 1 but,

[0203] [ka] In some embodiments, R 1 but,

[0204] [ka] In some embodiments, R 1 but,

[0205] [ka] In some embodiments, R 1 but,

[0206] [ka] is a compound of formula (IV),

[0207] In some embodiments, the compound of formula (IV) is

[0208] [ka] is selected from.

[0209] In some embodiments herein, the compound of formula (V):

[0210] [ka] or a pharma- ceutically acceptable salt or solvate thereof, During the ceremony, R 1 but,

[0211] [ka] is an amide prodrug moiety that is enzymatically cleaved by fatty acid amide hydrolase (FAAH) in the brain to release

[0212] [ka] is a moiety that modulates TTR in the brain, or a pharma- ceutically acceptable salt or solvate thereof.

[0213] In some embodiments, R 2 but,

[0214] [ka] is a compound of formula (V):

[0215] In some embodiments, R 2 but,

[0216] [ka] and R 1 C 1-4 In some embodiments, R is a compound of formula (V). 2 but,

[0217] [ka] and R 1 C 1-4 A compound of formula (V) which is haloalkyl.

[0218] In some embodiments, R 2 but,

[0219] [ka] and R 1 , optionally replaced by C 3-6 In some embodiments, R is a compound of formula (V) in which R is cycloalkyl. 2 but,

[0220] [ka] and R 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2, -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 3-6 A compound of formula (V) which is cycloalkyl. In some embodiments, R 2 but,

[0221] [ka] and R 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 3-6 In some embodiments, R is a compound of formula (V) in which R is cycloalkyl. 2 but,

[0222] [ka] and R 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 3-6 In some embodiments, R is a compound of formula (V) in which R is cycloalkyl. 2 but,

[0223] [ka] and R 1 is unsubstituted C 3-6 A compound of formula (V) which is cycloalkyl.

[0224] In some embodiments, R 2 but,

[0225] [ka] and R 1 , optionally replaced by C 6-10 In some embodiments, R is a compound of formula (V), 2 but,

[0226] [ka] and R 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 6-10 In some embodiments, R is a compound of formula (V), 2 but,

[0227] [ka] and R 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 6-10 In some embodiments, R is a compound of formula (V), 2 but,

[0228] [ka] and R 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 6-10 In some embodiments, R is a compound of formula (V), 2 but,

[0229] [ka] and R 1 is unsubstituted C 6-10 The compound of formula (V) is aryl.

[0230] In some embodiments, R 2 but,

[0231] [ka] and R 1 , optionally replaced by C 1-9 In some embodiments, R is a compound of formula (V) in which R is heteroaryl. 2 but,

[0232] [ka] and R 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-9 In some embodiments, R is a compound of formula (V) in which R is heteroaryl. 2 but,

[0233] [ka] and R 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-9 In some embodiments, R is a compound of formula (V) in which R is heteroaryl. 2 but,

[0234] [ka] and R 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 1-9 In some embodiments, R is a compound of formula (V) in which R is heteroaryl. 2 but,

[0235] [ka] and R 1 is unsubstituted C 1-9 The compound of formula (V) is heteroaryl.

[0236] In some embodiments, R 2 but,

[0237] [ka] is a compound of formula (V):

[0238] In some embodiments, R 2 but,

[0239] [ka] and R 1 C 1-4 In some embodiments, R is a compound of formula (V). 2 but,

[0240] [ka] and R 1 C 1-4 A compound of formula (V) which is haloalkyl.

[0241] In some embodiments, R 2 but,

[0242] [ka] and R 1 , optionally replaced by C 3-6 In some embodiments, R is a compound of formula (V) in which R is cycloalkyl. 2 but,

[0243] [ka] and R 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 3-6 In some embodiments, R is a compound of formula (V) in which R is cycloalkyl. 2 but,

[0244] [ka] and R 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 3-6 In some embodiments, R is a compound of formula (V) in which R is cycloalkyl. 2 but,

[0245] [ka] and R 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 3-6 In some embodiments, R is a compound of formula (V) in which R is cycloalkyl. 2 but,

[0246] [ka] and R 1 is unsubstituted C 3-6 A compound of formula (V) which is cycloalkyl.

[0247] In some embodiments, R 2 but,

[0248] [ka] and R 1 , optionally replaced by C 2-9 In some embodiments, R is a compound of formula (V) that is heterocycloalkyl. 2 but,

[0249] [ka] and R 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 2-9 In some embodiments, R is a compound of formula (V) that is heterocycloalkyl. 2 but,

[0250] [ka] and R 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 2-9 In some embodiments, R is a compound of formula (V) that is heterocycloalkyl. 2 but,

[0251] [ka] and R 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 2-9 In some embodiments, R is a compound of formula (V) that is heterocycloalkyl. 2 but,

[0252] [ka] and R 1 is unsubstituted C 2-9 A compound of formula (V) which is a heterocycloalkyl.

[0253] In some embodiments, R 2 but,

[0254] [ka] and R 1 , optionally replaced by C 6-10 The compound of formula (V) is aryl. In some embodiments, R 2 but,

[0255] [ka] and R 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 6-10 In some embodiments, R is a compound of formula (V), 2 but,

[0256] [ka] and R 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 6-10 In some embodiments, R is a compound of formula (V), 2 but,

[0257] [ka] and R 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 6-10 In some embodiments, R is a compound of formula (V), 2 but,

[0258] [ka] and R 1 is unsubstituted C 6-10 The compound of formula (V) is aryl.

[0259] In some embodiments, R 2 but,

[0260] [ka] and R 1 , optionally replaced by C 1-9 In some embodiments, R is a compound of formula (V) in which R is heteroaryl. 2 but,

[0261] [ka] and R 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-9 In some embodiments, R is a compound of formula (V) in which R is heteroaryl. 2 but,

[0262] [ka] and R 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 1-9 In some embodiments, R is a compound of formula (V) in which R is heteroaryl. 2 but,

[0263] [ka] and R 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 1-9 In some embodiments, R is a compound of formula (V) in which R is heteroaryl. 2 but,

[0264] [ka] and R 1 is unsubstituted C 1-9 The compound of formula (V) is heteroaryl.

[0265] In some embodiments, R 1 Ga-CH 3 In some embodiments, R 1 Ga-CH 2 CH 3 In some embodiments, R 1 Ga-CH 2 CH 2 CH 3 In some embodiments, R 1 Ga-CHCH 3 ) 2 In some embodiments, R 1 but,

[0266] [ka] In some embodiments, R 1 but,

[0267] [ka] In some embodiments, R 1 but,

[0268] [ka] In some embodiments, R 1 but,

[0269] [ka] In some embodiments, R 1 but,

[0270] [ka] In some embodiments, R 1 but,

[0271] [ka] In some embodiments, R 1 but,

[0272] [ka] In some embodiments, R 1 but,

[0273] [ka] In some embodiments, R 1 but,

[0274] [ka] In some embodiments, R 1 but,

[0275] [ka] In some embodiments, R 1 but,

[0276] [ka] is a compound of formula (V):

[0277] In some embodiments, the compound of formula (V) is

[0278] [ka] is selected from.

[0279] In some embodiments herein, the compound of formula (VI):

[0280] [ka] or a pharma- ceutically acceptable salt or solvate thereof, During the ceremony, R 1 but,

[0281] [ka] is an amide prodrug moiety that is enzymatically cleaved by fatty acid amide hydrolase (FAAH) in the brain to release

[0282] [ka] is a moiety that regulates PGI2 in the brain, or a pharma- ceutically acceptable salt or solvate thereof.

[0283] In some embodiments, R 2 but,

[0284] [ka] is a compound of formula (VI),

[0285] In some embodiments, R 1 Ga-CH 3 is a compound of formula (VI),

[0286] In some embodiments, R 1 , optionally replaced by C 3-6 In some embodiments, R is a compound of formula (VI) in which R is cycloalkyl. 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 3-6 In some embodiments, R is a compound of formula (VI) in which R is cycloalkyl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 3-6 In some embodiments, R is a compound of formula (VI) in which R is cycloalkyl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 3-6 In some embodiments, R is a compound of formula (VI) in which R is cycloalkyl. 1 is unsubstituted C 3-6 The compound of formula (VI) is cycloalkyl.

[0287] In some embodiments, R 1 , optionally replaced by C 2-9 In some embodiments, R is a compound of formula (VI) in which R is heterocycloalkyl. 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 2-9 In some embodiments, R is a compound of formula (VI) in which R is heterocycloalkyl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 2-9 In some embodiments, R is a compound of formula (VI) in which R is heterocycloalkyl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 2-9 In some embodiments, R is a compound of formula (VI) in which R is heterocycloalkyl. 1 is unsubstituted C 2-9 Heterocycloalkyl is a compound of formula (VI).

[0288] In some embodiments, R 1 , optionally replaced by C 6-10 In some embodiments, R is a compound of formula (VI), 1But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 6-10 In some embodiments, R is a compound of formula (VI), 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 6-10 In some embodiments, R is a compound of formula (VI), 1But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 6-10 In some embodiments, R is a compound of formula (VI), 1 is unsubstituted C 6-10 The compound of formula (VI) is aryl.

[0289] In some embodiments, R 1 , optionally replaced by C 2-9 In some embodiments, R is a compound of formula (VI) in which R is heteroaryl. 1 But halogens, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , -C(O)OH, -C(O)OC 1-6 Alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 Alkyl) 2 , -C(O)C 1-6 Alkyl, -S(O) 2 C 1-6 Alkyl, -S(O) 2 NH 2 , -S(O) 2 N(H)(C 1-6 alkyl), -S(O) 2 N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 2-9 In some embodiments, R is a compound of formula (VI) in which R is heteroaryl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from heteroaryl 2-9 In some embodiments, R is a compound of formula (VI) in which R is heteroaryl. 1 But halogens, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 Alkyl) 2 , C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 C optionally substituted with 1, 2, 3, 4, or 5 groups independently selected from alkoxy 2-9 In some embodiments, R is a compound of formula (VI) in which R is heteroaryl. 1 is unsubstituted C 2-9 The compound of formula (VI) is heteroaryl.

[0290] In some embodiments, R 1 Ga-CH 3 In some embodiments, R 1 but,

[0291] [ka] In some embodiments, R1 but,

[0292] [ka] In some embodiments, R 1 but,

[0293] [ka] In some embodiments, R 1 but,

[0294] [ka] In some embodiments, R 1 but,

[0295] [ka] In some embodiments, R 1 but,

[0296] [ka] In some embodiments, R 1 but,

[0297] [ka] In some embodiments, R 1 but,

[0298] [ka] In some embodiments, R 1 but,

[0299] [ka] In some embodiments, R 1 but,

[0300] [ka] is a compound of formula (VI),

[0301] In some embodiments, the compound of formula (VI) is

[0302] [ka] is selected from.

[0303] In some embodiments, the pharmaceutical composition comprises a compound of formula (II), (III), (IV), (V), or (VI), or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of formula (II), (III), (IV), (V), or (VI), or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient, further comprising a peripherally restricted FAAH inhibitor. In some embodiments, the pharmaceutical composition comprises a compound of formula (II), (III), (IV), (V), or (VI), or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable excipient, further comprising a peripherally restricted FAAH inhibitor that is ASP-3652.

[0304] Peripherally restricted FAAH inhibitors In some embodiments, the pharmaceutical compositions described herein comprise 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 entirety of which is incorporated herein by reference.

[0305] In some embodiments, the peripherally restricted FAAH inhibitor has formula (X):

[0306] [ka] or a pharma- ceutically acceptable salt thereof, During the ceremony, 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) H, halo, -CN, CF 3 a group selected from the group consisting of -O-lower alkyl, -O-lower alkyl, (ii) H, halo, -CN, CF 3 aryl optionally substituted with 1 to 5 groups independently selected from the group consisting of -O-lower alkyl, -O-lower alkyl, and -O-(lower alkyl); (iii) H, halo, -CN, -CF 3 a nitrogen-containing heteroaryl optionally substituted with 1 to 5 groups independently selected from the group consisting of -O-(lower alkyl), -O-(lower alkyl), and -O-(lower alkyl); (iv) R 16 -(lower alkenylene)-O-, (v)R 16 -N-(lower alkenylene)-(R 15 )-,or (vi)R 17 R 18 NC(=O)-, R 16 teeth, (i) H, halo, -CN, -CF 3 aryl optionally substituted with 1 to 5 groups independently selected from the group consisting of -O-lower alkyl, -O-lower alkyl, and -O-(lower alkyl); (ii) H, halo, -CN, -CF 3 a nitrogen-containing heteroaryl optionally substituted with 1 to 5 groups independently selected from the group consisting of -O-, -(lower alkyl), and -O-(lower alkyl); (iii) 3- to 8-membered cycloalkyl and 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 it is bonded, R 11 is selected from H, lower alkyl, and oxo (=O); R 12 , R 13 , and R 14 One of the groups is -C(=O)-(O)-(lower alkyl) or -CO 2 H and the rest is H.

[0307] 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.

[0308] method In some embodiments, a method for treating a CNS disease or disorder in a patient in need of such treatment comprises administering to the patient a pharmaceutical composition as described herein, comprising a prodrug capable of being cleaved by fatty acid amide hydrolase (FAAH) of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, a pharma- ceutically acceptable excipient, and a peripherally restricted FAAH inhibitor. In some embodiments, a method for treating a CNS disease or disorder in a patient in need of such treatment comprises administering to the patient a pharmaceutical composition as described herein, comprising a prodrug capable of being cleaved by fatty acid amide hydrolase (FAAH) of formula (II), or a pharma- ceutically acceptable salt or solvate thereof, a pharma- ceutically acceptable excipient, and a peripherally restricted FAAH inhibitor ASP-3652. In some embodiments, a method of treating a CNS disease or disorder in a patient in need of such treatment comprises administering to the patient a pharmaceutical composition as described herein comprising a fatty acid amide hydrolase (FAAH) cleavable prodrug of formula (I), or a pharma- ceutical acceptable salt or solvate thereof, a pharma- ceutical acceptable excipient, and a peripherally restricted FAAH inhibitor, wherein the CNS disease or disorder is selected from the group consisting of multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and rheumatoid arthritis. Son's disease, Alzheimer's disease, epilepsy, ischemic stroke, traumatic brain injury, autoimmune encephalomyelitis, schizophrenia, depression, mood disorder, attention deficit hyperactivity disorder, post-traumatic stress disorder, familial amyloid polyneuropathy, familial leptomeningeal amyloidosis, dementia, transient focal neurological deficits, cognitive impairment, CNS amyloidosis, Degos disease, reversible cerebral vasoconstriction syndrome, Sneddon syndrome, amyloid-β related angiopathy, Susac syndrome, and neurosarcoidosis.In some embodiments, a method of treating a CNS disease or disorder in a patient in need of such treatment comprises administering to the patient a pharmaceutical composition described herein comprising a fatty acid amide hydrolase (FAAH) cleavable prodrug of formula (II), or a pharma- ceutical acceptable salt or solvate thereof, a pharma- ceutical acceptable excipient, and a peripherally restricted FAAH inhibitor, ASP-3652; wherein the CNS disease or disorder is selected from the group consisting of multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, glaucoma, and the like. The method is selected from Parkinson's disease, Alzheimer's disease, epilepsy, ischemic stroke, traumatic brain injury, autoimmune encephalomyelitis, schizophrenia, depression, mood disorders, attention deficit hyperactivity disorder, post-traumatic stress disorder, familial amyloid polyneuropathy, familial leptomeningeal amyloidosis, dementia, transient focal neurological deficits, cognitive impairment, CNS amyloidosis, Degos disease, reversible cerebral vasoconstriction syndrome, Sneddon syndrome, amyloid-β related angiopathy, Susac syndrome, and neurosarcoidosis.

[0309] In some embodiments, the method of treating a CNS disease or disorder in a patient in need of treatment comprises administering to the patient a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the method of treating a CNS disease or disorder in a patient in need of treatment comprises administering to the patient a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. In some embodiments, the method of treating a CNS disease or disorder in a patient in need of treatment comprises administering to the patient a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient and a peripherally restricted FAAH inhibitor. In some embodiments, the method of treating a CNS disease or disorder in a patient in need of such treatment comprises administering to the patient a pharmaceutical composition comprising a compound of formula (II) or its pharmaceutically acceptable salt or solvate, a pharmaceutically acceptable excipient, and the peripherally restricted FAAH inhibitor ASP-3652. In some embodiments, the CNS disease or disorder is selected from multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and Alzheimer's disease.

[0310] In some embodiments, the method of treating a CNS disease or disorder in a patient in need of treatment comprises administering to the patient a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the method of treating a CNS disease or disorder in a patient in need of treatment comprises administering to the patient a pharmaceutical composition comprising a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. In some embodiments, the method of treating a CNS disease or disorder in a patient in need of treatment comprises administering to the patient a pharmaceutical composition comprising a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient and a peripherally restricted FAAH inhibitor. In some embodiments, the method of treating a CNS disease or disorder in a patient in need of such treatment comprises administering to the patient a pharmaceutical composition comprising a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof, a pharmaceutically acceptable excipient, and the peripherally restricted FAAH inhibitor ASP-3652. In some embodiments, the CNS disease or disorder is selected from epilepsy, ischemic stroke, traumatic brain injury, and autoimmune encephalomyelitis.

[0311] In some embodiments, the method of treating a CNS disease or disorder in a patient in need of treatment comprises administering to the patient a compound of formula (IV) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the method of treating a CNS disease or disorder in a patient in need of treatment comprises administering to the patient a pharmaceutical composition comprising a compound of formula (IV) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. In some embodiments, the method of treating a CNS disease or disorder in a patient in need of treatment comprises administering to the patient a pharmaceutical composition comprising a compound of formula (IV) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient and a peripherally restricted FAAH inhibitor. In some embodiments, the method of treating a CNS disease or disorder in a patient in need of such treatment comprises administering to the patient a pharmaceutical composition comprising a compound of formula (IV) or its pharmaceutically acceptable salt or solvate, a pharmaceutically acceptable excipient, and the peripherally restricted FAAH inhibitor ASP-3652.In some embodiments, the CNS disease or disorder is selected from ischemic stroke, schizophrenia, depression, mood disorder, attention deficit hyperactivity disorder, post-traumatic stress disorder, and Alzheimer's dementia.

[0312] In some embodiments, the method of treating a CNS disease or disorder in a patient in need of treatment comprises administering to the patient a compound of formula (V), or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the method of treating a CNS disease or disorder in a patient in need of treatment comprises administering to the patient a pharmaceutical composition comprising a compound of formula (V), or a pharma-ceutically acceptable salt or solvate thereof, and a pharma-ceutically acceptable excipient. In some embodiments, the method of treating a CNS disease or disorder in a patient in need of treatment comprises administering to the patient a pharmaceutical composition comprising a compound of formula (V), or a pharma-ceutically acceptable salt or solvate thereof, and a pharma-ceutically acceptable excipient, and a peripherally restricted FAAH inhibitor. In some embodiments, a method of treating a CNS disease or disorder in a patient in need of such treatment comprises administering to the patient a pharmaceutical composition comprising a compound of formula (V), or a pharma- ceutical acceptable salt or solvate thereof, a pharma- ceutical acceptable excipient, and the peripherally restricted FAAH inhibitor ASP-3652. In some embodiments, the CNS disease or disorder is selected from familial amyloid polyneuropathy, familial leptomeningeal amyloidosis, Alzheimer's disease, stroke, dementia, transient focal neurological deficits, cognitive impairment, and CNS amyloidosis.

[0313] In some embodiments, the method of treating a CNS disease or disorder in a patient in need of treatment comprises administering to the patient a compound of formula (VI) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the method of treating a CNS disease or disorder in a patient in need of treatment comprises administering to the patient a pharmaceutical composition comprising a compound of formula (VI) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient. In some embodiments, the method of treating a CNS disease or disorder in a patient in need of treatment comprises administering to the patient a pharmaceutical composition comprising a compound of formula (VI) or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient and a peripherally restricted FAAH inhibitor. In some embodiments, a method of treating a CNS disease or disorder in a patient in need of such treatment comprises administering to the patient a pharmaceutical composition comprising a compound of formula (VI), or a pharma- ceutical acceptable salt or solvate thereof, a pharma- ceutical acceptable excipient, and the peripherally restricted FAAH inhibitor ASP-3652. In some embodiments, the CNS disease or disorder is selected from Degos disease, reversible cerebral vasoconstriction syndrome, Sneddon syndrome, amyloid-β-associated angiopathy, Susac syndrome, and neurosarcoidosis.

[0314] Excipients Optional excipients suitable for use in the pharmaceutical compositions described herein include any excipient commonly used in pharmaceuticals and are selected based on compatibility with the active pharmaceutical agent and the release profile characteristics of the desired dosage form. Excipients include, but are not limited to, binders, fillers, flow aids, disintegrants, lubricants, glidants, polymer carriers, plasticizers, stabilizers, surfactants, etc. Summary summaries 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, Pa., 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.

[0315] Binders impart cohesiveness to the solid oral dosage formulation. In powder-filled capsule formulations, binders aid in the formation of a fillable plug in a soft or hard shell capsule, and in tablet formulations, they help ensure that the tablet remains intact after compression and ensure uniformity of the blend prior to the compression or filling step. Materials suitable for use as binders in the solid dosage forms described herein include carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropyl methylcellulose (e.g., Hypromellose USP Pharmacoat-603, hydroxypropyl methylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonite, gelatin, polyvinylpyrrolidone / vinyl acetate copolymers, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, sugars such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, natural or synthetic gums such as acacia, tragacanth, gum ghatti, isapol shell mucilage, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like.

[0316] Fillers or diluents increase the bulk in pharmaceutical formulations. Such compounds include, for example, lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel®, dibasic calcium phosphate dicalcium phosphate dihydrate, tricalcium phosphate, calcium phosphate, anhydrous lactose, spray-dried lactose, pregelatinized starch, compressible sugars such as Di-Pac® (Amstar), hydroxypropyl methylcellulose, sucrose-based diluents, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, hydrolyzed grain solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, sodium chloride, inositol, bentonite, and the like.

[0317] Glidants improve the flow properties of powder mixtures and include, for example, colloidal silicon dioxide such as Cab-o-sil®, tribasic calcium phosphate, talc, corn starch, DL-leucine, sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearate, kaolin, and micronized amorphous silicon dioxide (Syloid®).

[0318] Lubricants are compounds that prevent, reduce, or inhibit adhesion or friction of materials.Exemplary lubricants include, for example, stearic acid, calcium hydroxide, talc, hydrocarbons such as mineral oil or hydrous vegetable oil such as hydrous soybean oil (Sterotex®), Lubritab®, Cutina®, higher fatty acids and their alkali metal salts and alkaline earth metal salts such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearate, magnesium stearate, glycerol, talc, wax, Stearowet®, boric acid, sodium acetate, leucine, polyethylene glycol or methoxypolyethylene glycol, for example Carbowax™, sodium oleate, glyceryl behenate (Compitrol 888R), glyceryl palmitostearate (Precirol®), colloidal silica such as Syloid™, starch such as Carb-O-Sil®, corn starch, silicone oil, surfactants, etc. Hydrophilic lubricants include, for example, sodium stearyl fumarate (currently available under the trade name PRUV®), polyethylene glycol (PEG), magnesium lauryl sulfate, sodium lauryl sulfate (SLS), sodium benzoate, sodium chloride, and the like.

[0319] Disintegrants facilitate the breakup or disintegration of pharmaceutical formulations after administration. Examples of disintegrants include starches, such as natural starches, such as corn starch and potato starch, pregelatinized starches, such as National 1551 and Amijel®, or sodium starch glycolate, such as Promogel® and Explotab®, cellulose, such as wood products, microcrystalline cellulose, such as Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Examples include Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked cellulose, e.g., crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose, crosslinked starches such as sodium starch glycolate, crosslinked polymers such as crospovidone, crosslinked polyvinylpyrrolidone, alginates such as alginic acid or salts of alginic acid such as sodium alginate, clays such as Veegum® HV (magnesium aluminum silicate), gums such as agar, guar, locust bean, karaya, pectin, or tragacanth, sodium starch glycolate, resins such as bentonite, natural sponge, cation exchange resins, citrus pulp, sodium lauryl sulfate in starch formulations, and the like.

[0320] Polymeric carriers include compounds such as polyvinylpyrrolidone, e.g., polyvinylpolyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone vinyl acetate (PVPVA64), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetylsuccinate (HPMC AS), and methyl methacrylate polymers (Eudragit polymers).

[0321] Stabilizers include any antioxidant, for example, compounds such as butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol, buffers, acids, and the like.

[0322] Surfactants include compounds such as sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, poloxamers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic® (BASF), d-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS), and the like.

[0323] The above excipients are provided as examples only and are not intended to include all possible options. Other suitable excipient types include colorants, granulating agents, preservatives, antifoaming agents, plasticizers, etc. In addition, many excipients may have multiple roles or functions or may be classified into multiple groups. This classification is merely illustrative and is not intended to limit the use of a particular excipient.

[0324] The pharmaceutical formulations of the present disclosure are administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. The dosage required for use in any particular application will vary from patient to patient, depending on the nature of the disease being treated, the age and condition of the patient, any concurrent medications or special diets the patient is following, and other factors in addition to the particular pharmaceutical formulation selected, and the appropriate dosage is ultimately at the discretion of the attending physician.

[0325] While preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be utilized in practicing the disclosure. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of the claims and their equivalents are covered thereby. EXAMPLES

[0326] The following examples are provided for illustrative purposes and are not intended to limit the scope of the claims provided herein.All references cited in these examples and throughout this specification are incorporated herein by reference for all legal purposes provided thereby.The starting materials and reagents used in the synthesis of the compounds described herein can be synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[0327] As used above, and throughout the description of the present invention, the following abbreviations, unless otherwise specified, shall be understood to have the following meanings: ACN or MeCN Acetonitrile AcOH Acetic acid Ac Acetyl BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene Bn Benzyl BOC or Boc tert-butyl carbamate t-Bu tert-Butyl Cy Cyclohexyl DBA or dba dibenzylidene acetone CDI 1,1-Carbonyldiimidazole DCE Dichloroethane (ClCH2 CH 2 Cl) DCM Dichloromethane (CH 2 Cl 2 ) DIPEA or DIEA Diisopropylethylamine DMAP 4-(N,N-dimethylamino)pyridine DME 1,2-Dimethoxyethane DMF N,N-Dimethylformamide DMA N,N-Dimethylacetamide DMSO Dimethyl sulfoxide Dppf or dppf 1,1'-bis(diphenylphosphino)ferrocene EDC or EDCI N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride eq equivalent Et Ethyl Et 2 O Diethyl ether EtOH Ethanol EtOAc Ethyl acetate HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HMPA Hexamethylphosphoramide HOBt 1-Hydroxybenzotriazole HPLC High Pressure Liquid Chromatography KHMDS Potassium bis(trimethylsilyl)amide NaHMDS Sodium bis(trimethylsilyl)amide LiHMDS Lithium bis(trimethylsilyl)amide LAH Lithium Aluminum Anhydrous LCMS Liquid Chromatography Mass Spectrometry Me Methyl MeOH Methanol MS mass spectroscopy Ms. Meshir MTBE Methyl tert-butyl ether NBS N-Bromosuccinimide NMM N-Methyl-morpholine NMP N-Methyl-pyrrolidin-2-one NMR nuclear magnetic resonance Ph Phenyl PPTS Pyridinium p-toluenesulfonate iPr / i-Pr iso-propyl rt room temperature TFA Trifluoroacetic acid TEA Triethylamine THF Tetrahydrofuran TLC Thin Layer Chromatography

[0328] Example 1: Synthesis of 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)-N-(pyridazin-3-yl)propenamide (2)

[0329] [ka]

[0330] To a solution of compound 1 (50.0 mg, 128.5 μmol) in DMF (2 mL) was added DIPEA (33.2 mg, 257.1 μmol), HATU (73.3 mg, 192.8 μmol), and pyridazin-3-amine (36.6 mg, 385.7 μmol) at room temperature. The mixture was stirred at room temperature overnight. Water (20 mL) was added and the mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (2×10 mL), brine (20 mL), and Na 2 SO 4 The mixture was dried at 40° C., concentrated to dryness and purified by preparative HPLC to give compound 2 (15 mg, 25.0% yield) as a yellow solid. LCMS: M+H=466.2.

[0331] Example 2: Synthesis of 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)-N-cyclopropylpropanamide (3)

[0332] [ka]

[0333] To a solution of compound 1 (50.0 mg, 0.13 mmol) in DMF (2 mL) was added DIPEA (34.0 mg, 0.26 mmol), HATU (74.0 mg, 0.2 mmol), and cyclopropylamine (7.0 mg, 0.13 mol) at room temperature. The mixture was stirred at room temperature overnight. 2 O (20 mL) was added and the mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), brine (20 mL) and Na 2 SO 4 The mixture was dried at 40° C. and concentrated to dryness. The residue was purified by preparative HPLC to give compound 3 (20 mg, 36.0% yield) as a white solid. LCMS: M+H=428.2.

[0334] Example 3: Synthesis of 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)-N-((1R,2R)-2-fluorocyclopropyl)propenamide (4) and 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)-N-((1R,2S)-2-fluorocyclopropyl)propenamide (5)

[0335] [ka]

[0336] To a solution of compound 1 (150 mg, 0.39 mmol) in DMF (3 mL) was added DIPEA (151 mg, 1.17 mmol), HATU (222 mg, 0.59 mmol), and 2-fluorocyclopropan-1-amine hydrochloride (47 mg, 0.42 mol) at room temperature. The reaction mixture was stirred at room temperature overnight. 2 O (20 mL) was added. The mixture was extracted with EtOAc (2×20 mL) and the combined organic layers were washed with water (2×20 mL), brine (20 mL) and Na 2 SO 4 The mixture was dried at 40° C. and concentrated to dryness. The residue was purified by preparative HPLC to give compound 4 (30 mg, 17.3% yield) and compound 5 (30 mg, 17.3% yield) as white solids. LCMS (compound 4): M+H=446.2. LCMS (compound 5): M+1=446.2.

[0337] Example 4: Synthesis of 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)-N-(3-fluoropropyl)propenamide (6)

[0338] [ka]

[0339] To a solution of compound 1 (200 mg, 514.29 μmol) and HATU (293.3 mg, 771.44 μmol) in DMF (3 mL) was added DIEA (199.4 mg, 1.54 mmol) and 3-fluoropropan-1-amine (47.5 mg, 617.15 μmol). The mixture was stirred at room temperature for 2 h. The mixture was filtered and purified by preparative HPLC to give compound 6 (10 mg, 4.1% yield) as a white solid. LCMS: M+H=448.35.

[0340] Example 5: Synthesis of 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)-N-(pyridin-4-yl)propenamide (7)

[0341] [ka]

[0342] To a solution of compound 1 (50 mg, 128.57 μmol), pyridin-4-amine (12.1 mg, 128.57 μmol), and HATU (73.3 mg, 192.86 μmol) in DMF (3 mL) was added DIEA (33.2 mg, 257.15 μmol). The mixture was stirred at room temperature for 2 h. The mixture was filtered and purified by preparative HPLC and RP-column to give compound 7 (8 mg, 13.4% yield) as a white solid. LCMS: M+H=465.2.

[0343] Example 6: Synthesis of 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)-N-(3,4-dimethylisoxazol-5-yl)propenamide (8)

[0344] [ka]

[0345] To a solution of compound 1 (50 mg, 128.57 umol) in DCM (5.0 mL) was added catalytic DMF and oxalyl chloride (129 mg, 1.0 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness to give the acid chloride as a colorless oil.

[0346] To a solution of the acid chloride (50 mg, 128.57 umol) in DCM (2.0 mL) was added 3,4-dimethylisoxazol-5-amine (28 mg, 257.14 umol) and DIPEA (66 mg, 514.28 umol). The mixture was stirred at room temperature for 1 h. Water (10 mL) was added and the mixture was extracted with DCM (3 x 10 mL). The combined organic phase was washed with brine (30 mL) and diluted with Na 2 SO 4The mixture was dried at rt, concentrated in vacuo and purified by preparative HPLC to give compound 8 (2 mg, 3.1% yield) as a white solid. LCMS: M-1=481.10.

[0347] Example 7: Synthesis of 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)propanamide (9)

[0348] [ka]

[0349] A solution of compound 1 (100 mg, 257.14 μmol) in DCM (2 mL) was added with DIPEA (66.4 mg, 514.30 μmol), HATU (147.4 mg, 385.71 μmol), and NH 3 (36.0 mg, 1.028 mmol) was added. The mixture was stirred at room temperature overnight. 2 O (20 mL) was added and extracted with DCM (2 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), brine (20 mL) and Na 2 SO 4 The mixture was dried at rt, concentrated to dryness and purified by preparative HPLC to give compound 9 (80 mg, 80.0% yield) as a white solid. LCMS: M+H=388.0.

[0350] Example 8: Synthesis of 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)-N-methylpropanamide (10)

[0351] [ka]

[0352] A solution of compound 1 (100 mg, 257.1 μmol) in DCM (2 mL) was added with DIPEA (66.4 mg, 514.3 μmol), HATU (147.4 mg, 385.7 μmol), and CH3 NH 2 (31.9 mg, 1.0 mmol) was added. The mixture was stirred at room temperature overnight. 2 O (20 mL) was added and the mixture was extracted with DCM (2 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), brine (20 mL) and Na 2 SO 4 The mixture was dried at rt, concentrated to dryness and purified by preparative HPLC to give the product compound 10 (80 mg, 80.0% yield) as a white solid. LCMS: M+H=402.0.

[0353] Example 9: Synthesis of 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-2,3-dimethylphenyl)-N-(2-hydroxyethyl)propenamide (11)

[0354] [ka]

[0355] To a solution of compound 1 (100 mg, 257.1 μmol) in DCM (2 mL) was added DIPEA (66.4 mg, 514.3 μmol), HATU (147.4 mg, 385.7 μmol), and 2-aminoethan-1-ol (62.8 mg, 1.03 mmol) at room temperature. The mixture was stirred at room temperature overnight. 2 O (20 mL) was added and the mixture was extracted with DCM (2 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), brine (20 mL) and Na 2 SO 4 The mixture was dried at 40° C., concentrated to dryness and purified by preparative HPLC to give compound 11 (70 mg, 63.0% yield) as a white solid. LCMS: M+H=431.2.

[0356] Compounds 12-57 in Table 1 were prepared as outlined in the previous examples starting with the appropriate carboxylic acid.

[0357] [Table 1-1]

[0358] [Table 1-2]

[0359] [Table 1-3]

[0360] [Table 1-4]

[0361] [Table 1-5]

[0362] [Table 1-6]

[0363] Example 10: FAAH Substrate Evaluation Purified recombinant human FAAH (rhFAAH) was purchased from Cayman Chemical (Ann Arbor, MI, USA). The total volume per incubation was 400 μL containing 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 min, aliquots of 30 μL of 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 subjected to LC-MS / MS analysis to measure the formation of acid metabolites.

[0364] 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, run at a flow rate of 0.8 mL / min for 2 min for acid metabolites from positive controls and 0.9 mL / min for 1.5 min for acid metabolites of test compounds. Mass spectrometers (API-5500 and API Q Trap 4000 Applied Biosystems / MDS SCIEX Instruments, Framingham, MA, USA) were operated under ESI positive or negative ion MRM mode.

[0365] 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 as ke and are shown in Table 2.

[0366] [Table 2]

[0367] Example 11: In Vitro Stability Evaluation in Mouse Plasma Male CD-1 mouse plasma is purchased from BioIVT (catalog number MSE00PLK2YNN) and thawed in a 37 °C water bath with the pH adjusted to 7.4 on the day of testing. After a 15 min pre-warming period in the 37 °C water bath, 398 µL of plasma is added with an aliquot of 2 µL stock solution of test compound or positive control (propantheline) in dimethyl sulfoxide (DMSO) to achieve a final concentration of 1 µM with 0.5% DMSO. After thorough mixing, the mixture is returned to the 37 °C water bath for incubation. At 0, 15, 30, 60, and 120 min, aliquots of 30 µL of reaction mixture are 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 is centrifuged at 4000 rpm at 4° C. for 15 min, and 100 μL of the supernatant is removed and mixed with 100 μL of water for liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0368] LC-MS / MS analysis A Shimadzu LC 30-AD HPLC system is used for sample analysis. Chromatography is performed on a reversed-phase Kinetex 2.6 μm C18 column, 3.0 × 30 mm, 100 Å. Mobile phase A contains 0.1% formic acid in water, mobile phase B contains 0.1% formic acid in acetonitrile, with a run time of 2 min. Mass spectrometers (API-4000 and API Q Trap 4500 Applied Biosystems / MDS SCIEX Instruments, Framingham, MA, USA) are operated under electrospray ionization (ESI) positive or negative ion multiple reaction monitoring (MRM) mode.

[0369] Data analysis The percentage of compound remaining at a particular time point is calculated based on the peak area ratio at time 0 (taken as 100%). The observed rate constant (k obs ) and the gradient is k obs The half-life (t 1 / 2) is expressed by the formula: t1 / 2 = 0.693 / k obs Obey and demand.

[0370] Example 12: In Vivo Tissue Distribution Study in Male CD-1 Mice Male CD-1 mice (n=6 / group), 7-10 weeks of age, are acclimated to the laboratory for a minimum of 3 days prior to dosing in the study. Test compounds are formulated in 1% N-methyl-2-pyrrolidone (NMP) and 1% solutol in phosphate buffered saline (PBS) at 0.1 mg / mL in a clear solution with a dose volume of 10 mL / kg. The peripherally restricted FAAH inhibitor LL-650021 is formulated in 0.5% carboxymethylcellulose in water at 0.1 mg / mL with a dose volume of 10 mL / kg. The concentration of the formulation is determined to meet the acceptance criteria within 20% of the target value.

[0371] Test compounds are administered to non-fasted mice at 1 mg / kg by subcutaneous (SC) injection or oral gavage (PO) with or without pretreatment with 1 mg / kg LL-650021 1 hour prior to test compound administration. Animals (n=2 per time point) are monitored by CO 2 Animals are sacrificed by inhalation. Blood samples (0.3 mL) are collected from the saphenous vein or other suitable site into pre-chilled K2EDTA tubes and placed on moist ice, and the brain and liver are harvested. Blood samples are centrifuged at 3200 g for 10 min at 4°C, plasma samples are transferred to polypropylene tubes, flash frozen on dry ice, and kept at -60°C or below until analysis. Tissues are washed with cold saline, blotted dry, weighed, and then homogenized in 15 mM PBS (pH 7.4):methanol = 2:1 buffer in a 1:10 ratio (obtaining an 11-fold dilution from 1 g tissue with 10 mL buffer). Tissue homogenates are kept at -60°C or below until analysis.

[0372] Sample extraction Extract plasma and tissue homogenates by protein precipitation. Aliquots of 10-50 µL plasma or 40-50 µL tissue homogenates are subjected to protein precipitation by adding 200-800 µL of acetonitrile containing internal standards (10 ng / mL LL-120001, and 100 ng / mL celecoxib, dexamethasone, glyburide, labetalol, tolbutamide, and verapamil), vortex-mixing at 800 rpm for 10 min, and centrifuging at 4000 rpm and 4 °C for 15 min. The supernatant was transferred to a 96-well plate and centrifuged at 4000 rpm at 4°C for 5 min before injection for LC-MS / MS analysis, or 200 μL of the supernatant was transferred to a 96-well plate, evaporated to dryness under a nitrogen stream at 25°C, reconstituted in 50 μL of 70% acetonitrile, vortex mixed at 800 rpm for 10 min, and centrifuged at 4000 rpm at 4°C for 5 min before injection for LC-MS / MS analysis.

[0373] LC-MS / MS analysis An Acquity Ultra Performance LC system from Waters is used for sample analysis. Separation is performed on an ACQUITY UPLC BEH C18 column (50 × 2.10 mm, 1.7 μm) at 50 °C with a flow rate of 0.6 mL / min. Mobile phase A consists of 2 mM ammonium acetate in 5:95 methanol:water, and mobile phase B consists of 2 mM ammonium acetate in 95:5 acetonitrile:water. The chromatography uses a linear gradient starting at 2% mobile phase B, going from 2% to 90% mobile phase B over 2.6 min, with a 0.2 min hold during the 90% B wash, and a 0.2 min re-equilibration at 2% B. Aliquots of 2-9 μL of sample are injected. The mass spectrometer (API-6500, Applied Biosystems / MDS SCIEX Instruments, Framingham, MA, USA) is operated under ESI in positive or negative ion MRM mode.

Claims

1. Formula (I): 【Chemistry 1】 A fatty acid amide hydrolase (FAAH) cleavable prodrug of the formula: R １ is an amide prodrug moiety, and said prodrug of formula (I) is 【Chemistry 2】 is enzymatically cleaved in the brain by the fatty acid amide hydrolase (FAAH) to release 【Chemistry 3】 is a moiety that modulates a target in the brain, and a pharma- ceutical composition, or a pharma-ceutical acceptable salt or solvate thereof, comprising a prodrug, wherein the prodrug is a moiety that modulates a target in the brain, and a pharma- ceutical composition, or a pharma-ceutical acceptable salt or solvate thereof, further comprising a peripherally restricted FAAH inhibitor.

2. 2. The pharmaceutical composition of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein the target is selected from sphingosine-1-phosphate receptor 1 (S1P1), lysophosphatidic acid receptor 1 (LPA1), G protein-coupled receptor 120 (GPR120), prostacyclin (PGI2), and transthyretin (TTR).

3. 3. The pharmaceutical composition of claim 2, or a pharma- ceutically acceptable salt or solvate thereof, wherein the target is S1P1.

4. The pharmaceutical composition of claim 2, or a pharma- ceutically acceptable salt or solvate thereof, wherein the target is LPA1.

5. The pharmaceutical composition of claim 2, or a pharma- ceutically acceptable salt or solvate thereof, wherein the target is GPR120.

6. The pharmaceutical composition of claim 2, or a pharma- ceutically acceptable salt or solvate thereof, wherein the target is TTR.

7. The pharmaceutical composition described in claim 2, or a pharma- ceutically acceptable salt or solvate thereof, wherein the target is PGI2.

8. R 2 is 【Chemistry 4】 3. The pharmaceutical composition of claim 2, wherein:

9. The pharmaceutical composition of claim 2, or a pharma- ceutically acceptable salt or solvate thereof, wherein R 1 is selected from optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted C 6-10 aryl, and optionally substituted C 1-9 heteroaryl.

10. The compound according to claim 1, wherein R 1 is selected from optionally substituted C 1-6 alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-9 heterocycloalkyl, optionally substituted C 6-10 aryl, and optionally substituted C 1-9 heteroaryl, and the C 1-6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6-10 aryl, and C 1-9 heteroaryl are not selected from halogen, -CN, -OH, -NH 2 , -N(H)(C 1-6 alkyl), N(C 1-6 alkyl) 2 , -C(O)OH, -C(O)O-C ​​1-6 alkyl, -C(O)NH 2 , -C(O)N(H)(C 1-6 alkyl), -C(O)N(C 1-6 10. The pharmaceutical composition of claim 9, or a pharma- ceutically acceptable salt or solvate thereof, optionally substituted by 1, 2, 3, 4, or 5 groups independently selected from: -C(O)Ci-6 alkyl, -S(O)2Ci-6 alkyl, -S(O)2NH2, -S(O)2N(H)(Ci-6 alkyl), -S(O)2N(Ci-6 alkyl)2, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and Ci-9 heteroaryl.

11. The pharmaceutical composition according to claim 9, wherein R 1 is selected from unsubstituted C 1-6 alkyl, unsubstituted C 3-6 cycloalkyl, unsubstituted C 2-9 heterocycloalkyl, unsubstituted C 6-10 aryl, and unsubstituted C 1-9 heteroaryl, or a pharma- ceutically acceptable salt or solvate thereof.

12. The R 1 is 【Chemistry 5】 3. The pharmaceutical composition of claim 2, or a pharma- ceutically acceptable salt or solvate thereof, selected from:

13. The fatty acid amide hydrolase (FAAH) cleavable prodrug of formula (I), 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 3. The pharmaceutical composition of claim 2, or a pharma- ceutically acceptable salt or solvate thereof, selected from:

14. Use of a pharmaceutical composition according to any one of claims 1 to 13, or a pharma- ceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating a CNS disease or disorder in a patient in need of such treatment.

15. The use of claim 14, wherein the CNS disease or disorder is selected from multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, Alzheimer's disease, epilepsy, ischemic stroke, traumatic brain injury, autoimmune encephalomyelitis, schizophrenia, depression, mood disorder, attention deficit hyperactivity disorder, post-traumatic stress disorder, Alzheimer's dementia, familial amyloid polyneuropathy, familial leptomeningeal amyloidosis, Alzheimer's disease, stroke, dementia, transient focal neurological deficits, cognitive impairment, CNS amyloidosis, Degos disease, reversible cerebral vasoconstriction syndrome, Sneddon syndrome, amyloid-β associated vasculopathy, Susac syndrome, and neurosarcoidosis.

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