Amide prodrugs and their use

Abstract

This specification describes fatty acid amide hydrolase (FAAH)-cleavable prodrugs of compounds that modulate sphingosine-1-phosphate receptor 5 (S1P5), methods for producing such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds in treating CNS diseases or disorders.

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 367,569, filed on July 1, 2022, which is hereby incorporated by reference in its entirety. Background of the Invention

[0002] The blood-brain barrier is composed of tightly connected 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 agents into the brain, which is a major challenge for the development of new drugs for CNS diseases.

Summary of the Invention

[0003] In one aspect, a compound having the structure of formula (I)

[0004]

Chemical Formula

[0005] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 And R 6is hydrogen. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b are independently selected from hydrogen and C 1-6 alkyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a is hydrogen and R 9b is C 1-6 alkyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a is hydrogen and R 9b is -CH3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), and -C(O)R 13 , wherein C 1-6 alkyl is optionally substituted with one, two, or three groups selected from halogen, C 1-6 haloalkyl, -OR 10 and -N(R 10 )(R 11 ). In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , -SR 10 , and -N(R 10 )(R 11 ), wherein C 1-6 alkyl is -OR 10 and -N(R 10 )(R 11In some embodiments, the compound is of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R 3 -OR 10 , -SR 10 , and -N(R 10 )(R 11 ), where R 10 and R 11 are independently hydrogen, C 1-6 Alkyl, and C 1-6 In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein R 3 is selected from -O(CH2)3CF3, -O(CH2)4CF3, -O(CH2)5CF3, -S(CH2)3CF3, -S(CH2)4CF3, -S(CH2)5CF3, -N(H)(CH2)3CF3, -N(H)(CH2)4CF3, and -N(H)(CH2)5CF3. In some embodiments, a compound of Formula (I), or a pharma- ceutically acceptable salt or solvate thereof, wherein m is 0.

[0006] In some embodiments, formula (Ia)

[0007] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0008] In some embodiments, the formula (Iaa)

[0009] [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0010] In some embodiments, a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is hydrogen. In some embodiments, a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is C1-C6 alkyl. In some embodiments, a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl optionally substituted with one or more groups selected from halogen, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl substituted with one or more groups selected from halogen, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ). In some embodiments, there is a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl substituted with one or more -OH. In some embodiments, there is a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl substituted with one or more halogen. In some embodiments, a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted C1-C6 alkyl. In some embodiments, a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3. In some embodiments, the compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen, C1-C6 alkyl, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ) and is optionally substituted with one or more groups selected from C 3-6 cycloalkyl. In some embodiments, the compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted C3-C6 cycloalkyl. In some embodiments, the compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 and is optionally substituted with one or more groups selected from C 1-9 heteroaryl. In some embodiments, the compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ) and -S(O)2R 13 and is optionally substituted with one or more groups selected from C 1-9 heteroaryl, wherein C 1-9 heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. In some embodiments, the compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2is selected from unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl. In some embodiments, the compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is hydrogen. In some embodiments, the compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein 1 and R 2 combine to form C2-C9 heterocycloalkyl optionally substituted with one or more groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, the compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein 1 and R 2 combine to form unsubstituted C2-C9 heterocycloalkyl.

[0011] In another aspect, pharmaceutical compositions are described herein that comprise a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, and further comprises a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments, the pharmaceutical composition comprises a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, and further comprises a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

[0012] In another aspect, the present specification describes a method for treating a CNS disease or disorder in a patient in need of treatment of a CNS disease or disorder, the method comprising administering to the patient a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, it is a method for treating a CNS disease or disorder in a patient in need of treatment of a CNS disease or disorder, the method comprising administering to the patient a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHL or AHLE), adult Refsum disease, infantile Refsum disease, Alexander disease, Alzheimer's disease, Balo concentric sclerosis, Canavan disease, central pontine myelinolysis (CPM), cerebral palsy, cerebrotendinous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic's syndrome, diffuse myelinoclastic sclerosis, encephalomyelitis, Guillain-Barre syndrome, Huntington's disease (HD), idiopathic inflammatory demyelinating disease (HDD), Krabbe disease, Leber hereditary opticneuropathy), leukodystrophy, Marburg multiple sclerosis, Marchiafava - Bignami disease, metachromatic leukodystrophy (MLD), multifocal motor neuropathy (MMN), multiple sclerosis (MS), Neiman Pick Type - C, paraproteinemic demyelinating polyneuropathy, Parkinson’s disease (PD), Pelizaeus - Merzbacher disease (PMD), progressive multifocal leukoencephalopathy (PML), tropical spastic paraparesis (TSP), X - linked adrenoleukodystrophy (X - ALD, ALO, or X - linked ALO), and Zellweger syndrome. In some embodiments, a method for treating a CNS disease or disorder in a patient in need thereof is provided, the method comprising administering to the patient a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from multiple sclerosis and X - linked adrenoleukodystrophy.

[0013] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, the groups and their substituents are selected by one of ordinary skill in the art to provide stable moieties and compounds.

[0014] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. However, it is to be understood that the specific embodiments and examples, while indicating particular embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to one of ordinary skill in the art from the form of the disclosure for carrying out the invention.

Embodiments for Carrying Out the Invention

[0015] Sphingosine-1-phosphate is a pleiotropic signaling factor that mediates diverse biological responses through interaction with members of the endothelial cell differentiation gene family (EDG receptors), a family of plasma membrane-localized G protein-coupled receptors. Five members of this family, S1P1 (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6), and S1P5 (EDG-8), have been identified across a variety of cell types. The receptor subtypes S1P1, S1P2, and S1P3 are widely expressed in both peripheral tissues and the central nervous system (CNS) and play important roles in cardiovascular regulation, lymphocyte trafficking, and neurogenesis. The S1P4 receptor is mainly expressed in the immune and hematopoietic systems and typically mediates immune cell proliferation and cytokine production in the presence of high concentrations of S1P. S1P5 receptor expression is notably more restricted and is mainly expressed in oligodendrocytes in the CNS, which is thought to play an important role in myelin biology as well as in natural killer cells and other lymphocytes in the spleen that are thought to mediate cell trafficking. S1P5 is also thought to be important in regulating the permeability and integrity of the blood-brain barrier. Oligodendrocyte precursor cells (OPCs), pre-oligodendrocytes, and fully differentiated mature oligodendrocyte cells all express the S1P5 receptor at high levels.Activation of the S1P5 receptor can promote the survival of OPCs and mature pre-oligodendrocytes into myelinating oligodendrocytes. Indeed, preclinical models in mice and Xenopus tadpoles have shown evidence of S1P5-mediated remyelination. Furthermore, administration of a selective S1P5 agonist has been reported to normalize proteinopathies and improve clinical scores in several animal models of neurodegenerative disease. These data support the use of S1P5 agonists in the treatment of various neuropathies, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Niemann-Pick disease type C, and others.

[0016] Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase that can degrade the fatty acid amide family of signaling lipids and hydrolyze selected amide prodrugs. FAAH is highly conserved among species and is expressed to varying degrees in many tissues, including the central nervous system (CNS). Selected carboxylic acids can be converted to more permeable amide prodrugs, which 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 the delivery of a greater amount of carboxylic acid to the CNS compared to the administration of the parent alone. However, FAAH expressed peripherally simultaneously hydrolyzes the prodrug, which results in a significant amount of non-productive prodrug conversion. Co-administration of a peripherally restricted FAAH inhibitor and a CNS permeable FAAH convertible prodrug increases the selectivity of prodrug delivery to the CNS. It also reduces the exposure of the parent molecule in plasma and peripheral tissues compared to that observed when the prodrug is administered alone.

[0017] Specific terms Unless otherwise defined, the following terms used in this application are defined below. In addition to the term "including", the use of other forms such as "include", "includes", and "included" is not limiting. The headings of paragraphs used in this specification are for organization purposes only and are not to be construed as limiting the subject matter described.

[0018] As used herein, C1-C x refers to C1-C2, C1-C3,... C1-C xIt includes. As just one example, a group designated as "C1-C4" means that there are 1 to 4 carbon atoms in that part, that is, a group containing one carbon atom, two carbon atoms, three carbon atoms, or four carbon atoms. Thus, as just one example, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl group, that is, the alkyl group is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0019] The term "alkyl" group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight-chain. In some embodiments, the "alkyl" group has 1 to 10 carbon atoms, that is, C1-C 10 has alkyl. Whenever it appears in this specification, a numerical range such as "1 to 10" refers to each integer within the given range. For example, "1 to 10 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, etc., up to 10 carbon atoms at most. However, this definition also encompasses the occurrence of the term "alkyl" when no numerical range is specified. In some embodiments, the alkyl is C1-C6 alkyl. In one aspect, the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are by no means limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0020] The term "alkylene" refers to a divalent alkyl radical. Any of the above monovalent alkyl groups can be alkylene by removal of a second hydrogen atom from the alkyl. In some embodiments, alkylene is C1-C6 alkylene. In other embodiments, alkylene is C1-C4 alkylene. In certain embodiments, alkylene contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, alkylene contains 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, alkylene contains 1 carbon atom (e.g., C1 alkylene). In other embodiments, alkyl contains 2 carbon atoms (e.g., C2 alkylene). In other embodiments, alkyl contains 2 to 4 carbon atoms (e.g., C2-C4 alkylene). Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc.

[0021] "Deuteroalkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl are replaced by deuterium.

[0022] The term "alkenyl" refers to a type of alkyl group in which there is at least one carbon-carbon double bond. In one embodiment, the alkenyl group has the formula -C(R)=CR2, where R refers to the remainder of the alkenyl group, which may be the same or different. In some embodiments, R is H or alkyl. In some embodiments, alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, etc. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0023] The term "alkynyl" refers to a type of alkyl group in which there is at least one carbon-carbon triple bond. In one embodiment, the alkynyl group has the formula -C≡C-R, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, the alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, -CH2C≡CH.

[0024] An "alkoxy" group refers to an (alkyl)O- group, where alkyl is as defined herein.

[0025] The term "alkylamine" refers to -N(alkyl) x H y group, where x is 0 and y is 2, or x is 1 and y is 1, or x is 2 and y is 0.

[0026] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n + 2π electrons, where n is an integer. The term "aromatic" includes both carbocyclic aryl ("aryl", e.g., phenyl) groups and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic groups or fused-ring polycyclic (i.e., rings that share adjacent pairs of adjacent carbon or nitrogen atoms) groups.

[0027] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which all of the atoms forming the ring skeleton are carbon atoms. Thus, the term distinguishes carbocyclic from "heterocyclic" rings or "heterocycles" in which the ring skeleton contains at least one atom different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include cycloalkyl and aryl.

[0028] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is C6-C 10 aryl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0029] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, where each of the atoms forming the ring (i.e., the backbone atoms) is a carbon atom. In some embodiments, cycloalkyl is a spirocyclic compound or a bridged compound. In some embodiments, cycloalkyl is optionally fused to an aromatic ring, and the point of attachment is to a carbon other than an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 cyclic atoms. In some embodiments, cycloalkyl groups are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. In some embodiments, cycloalkyl is C3-C6 cycloalkyl. In some embodiments, cycloalkyl is monocyclic cycloalkyl. Monocyclic cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic carbocyclyl includes, but is not limited to, adamantyl, norbornyl (i.e., bicyclo[2.2.2]octyl and bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0030] The term "halo", or alternatively "halogen" or "halide", means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0031] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by halogen atoms. In one aspect, fluoroalkyl is C1-C6 fluoroalkyl.

[0032] "Fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by fluorine atoms. In one embodiment, the fluoroalkyl is a C1-C6 fluoroalkyl. In some embodiments, the fluoroalkyl is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0033] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or a combination thereof. The heteroalkyl is attached to the remainder of the molecule by a carbon atom of the heteroalkyl. In one embodiment, the heteroalkyl is a C1-C6 heteroalkyl.

[0034] The term "heteroalkylene" refers to a divalent heteroalkyl group.

[0035] The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroaliphatic groups) that contain 1 to 4 heteroatoms in the ring, where each heteroatom of the ring is independently selected from O, S, and N, and each heterocyclic group of the ring has 3 to 10 atoms in its ring system, provided that no ring contains two adjacent O atoms or S atoms. In some embodiments, the heterocycle is monocyclic, bicyclic, polycyclic, spirocyclic, or a bridged compound. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in their ring systems, and aromatic heterocyclic groups include rings having 5 to 10 atoms in their ring systems. Heterocyclic groups include benzo-fused ring systems.Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 2-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl, 5-azabicyclo[2.1.1]hexanyl, 6-azabicyclo[3.1.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 8-azabicyclo[3.2.1]octanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolidinyl.Examples of aromatic heterocyclic groups include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are, where possible, C-bonded (or C-linked) or N-bonded. For embodiments, groups derived from pyrrole include pyrrol-1-yl (N-bonded) or pyrrol-3-yl (C-bonded). Further, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-bonded), or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-bonded). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0036] The term "heteroaryl" or alternatively "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Exemplary examples of heteroaryl groups include monocyclic heteroaryl and bicyclic heteroaryl. Monocyclic heteroaryl includes pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryl includes indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolidine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryl contains 0 to 4 N atoms in the ring. In some embodiments, heteroaryl contains 1 to 4 N atoms in the ring. In some embodiments, heteroaryl contains 0 to 4 N atoms, 0 to 1 O atom, and 0 to 1 S atom in the ring. In some embodiments, heteroaryl contains 1 to 4 N atoms, 0 to 1 O atom, and 0 to 1 S atom in the ring. In some embodiments, heteroaryl is C1-C9 heteroaryl. In some embodiments, monocyclic heteroaryl is C1-C5 heteroaryl. In some embodiments, monocyclic heteroaryl is 5- or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is C6-C9 heteroaryl.

[0037] The term "heterocycloalkyl" or "heteroalicyclic" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl is fused with aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The term heteroalicyclic also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In one aspect, the heterocycloalkyl is C2-C 10 is a heterocycloalkyl. In another aspect, the heterocycloalkyl is C4-C 10 is a heterocycloalkyl. In some embodiments, the heterocycloalkyl contains 0 to 2 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 0 to 2 N atoms, 0 to 2 O atoms, and 0 to 1 S atom in the ring.

[0038] The term "oxo" refers to the =O radical.

[0039] The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties when the atoms linked by the bond are considered to be part of a larger substructure. In one aspect, when the group described herein is a single bond, the referenced group does not exist, thereby allowing the formation of a bond between the remaining specified groups.

[0040] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical substance embedded in or added to a molecule.

[0041] The terms "optionally substituted" or "substituted" mean that the referenced group is optionally substituted with one or more additional groups independently selected from D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, alkenyl, alkynyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from D, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), -C(=O)N(C1-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and -S(=O)2C1-C4alkyl. In some embodiments, the optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3, and -OCF3. In some embodiments, the substituted group is substituted with one or two of the aforementioned groups. In some embodiments, the optional substituent on an aliphatic carbon atom (acyclic or cyclic) contains oxo (=O).

[0042] As used herein, with respect to a formulation, composition, or ingredient, the term "acceptable" means having no persistent adverse effect on the health of the subject being treated.

[0043] As used herein, the term "modulate" means to interact directly or indirectly with a target to change the activity of the target, and includes, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, restricting the activity of the target, or prolonging the activity of the target.

[0044] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions of agonists, partial agonists, inverse agonists, antagonists, degraders, or combinations thereof. In some embodiments, the modulator is an agonist.

[0045] As used herein, terms such as "administer", "administering", "administration" refer to methods that can be used to effect delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral route, duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intracascular, or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with the administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0046] As used herein, terms such as "co-administration" mean the administration of the selected therapeutic agent(s) to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration, or at the same or different times.

[0047] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to a sufficient amount of an administered agent or compound to reduce to some extent one or more of the symptoms of the disease or disorder being treated. The results include a decrease and / or alleviation of the signs, symptoms, or causes of the disease, or other desired changes in the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound as disclosed herein required to clinically significantly reduce the symptoms of the disease. The appropriate "effective" amount in an individual case can optionally be determined using techniques such as dose escalation studies.

[0048] As used herein, the terms "enhance" or "enhancing" mean to increase or prolong a desired effect, either in potency or duration. Thus, with respect to enhancing the effect of a therapeutic agent, the term "enhancing" refers to the ability to increase or prolong the effect of another therapeutic agent on a system, either in potency or duration. An "enhancing-effective amount" as used herein refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0049] The term "pharmaceutical combination", as used herein, means a product resulting from the mixing or combining of multiple active ingredients, including both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that both the active ingredient, e.g., a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredient, e.g., a compound described herein, or a pharmaceutically acceptable salt thereof, and a co-agent are administered to a patient as separate entities, simultaneously, concurrently, or sequentially, without specific intervening time limits, such administration providing effective levels of two compounds in the patient's body. The latter also applies to cocktail therapies, e.g., the administration of three or more active ingredients.

[0050] The terms "kit" and "article of manufacture" are used synonymously.

[0051] The term "subject" or "patient" includes mammals. Examples of mammals include members of the following mammalian classes: humans; non-human primates such as chimpanzees; other apes and monkey species; domestic animals such as cows, horses, sheep, goats, pigs; laboratory animals such as rabbits, dogs, and cats; and rodents such as rats, mice, and guinea pigs, but are not limited thereto. In one aspect, the mammal is a human.

[0052] The terms "treat", "treating", or "treatment" as used herein include alleviating, reducing, or improving at least one symptom of a disorder or disease, preventing additional symptoms, inhibiting a disorder or disease, e.g., arresting the progression of a disorder or disease, reducing a disorder or disease, causing regression of a disorder or disease, alleviating a condition caused by a disorder or disease, or prophylactically and / or therapeutically halting the symptoms of a disorder or disease.

[0053] Compound The amide compounds of formula (I), (Ia), or (Iaa) described herein, or a pharmaceutically acceptable salt or solvate thereof, are prodrugs of S1P5 receptor agonists.

[0054] In some embodiments, formula (I)

[0055]

Chemical formula

[0056] For any or all of the embodiments, the substituents are selected from a subset of the recited alternatives. For example, in some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R6 is hydrogen. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is C 1-6 alkyl and R6 is hydrogen. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 are C 1-6 alkyl.

[0057] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, R 9a and R 9b are independently selected from hydrogen and C 1-6 alkyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a is hydrogen and R 9b is C 1-6 alkyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a is hydrogen and R 9b is -CH3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b are C 1-6 alkyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b are -CH3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b are hydrogen.

[0058] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, R 3 is C 1-6 alkyl, C1-6 Haloalkyl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), and -C(O)R 13 selected from, where C 1-6 alkyl is optionally substituted with one, two, or three groups selected from halogen, C 1-6 haloalkyl, -OR 10 and -N(R 10 )(R 11 ). In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , -SR 10 , and -N(R 10 )(R 11 ), where C 1-6 alkyl is optionally substituted with one group selected from -OR 10 and -N(R 10 )(R 11 ). In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, R 3 is -OR 10 and -N(R 10 )(R 11 ), C 1-6 alkyl is optionally substituted with one group selected from -OR 10 and -N(R 10 )(R 11 ). In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1-6 is selected from -OR 3 , -SR 10 , and -N(R 10 )(R 10 )(R 11 ), where R 10 and R 11 are independently hydrogen, C 1-6 alkyl, and C1-6 is selected from haloalkyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -OR 10 wherein R 10 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -SR 10 wherein R 10 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from -N(R 10 )(R 11 ) wherein R 10 and R 11 are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from -O(CH2)3CF3, -O(CH2)4CF3, -O(CH2)5CF3, -S(CH2)3CF3, -S(CH2)4CF3, -S(CH2)5CF3, -N(H)(CH2)3CF3, -N(H)(CH2)4CF3, and -N(H)(CH2)5CF3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -O(CH2)3CF3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -O(CH2)4CF3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3is -O(CH2)5CF3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -S(CH2)3CF3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -S(CH2)4CF3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -S(CH2)5CF3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -N(H)(CH2)3CF3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -N(H)(CH2)4CF3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is -N(H)(CH2)5CF3.

[0059] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

[0060] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 is independently halogen, -CN, C 1-6 alkyl, -OR 10 , -SR 10 , -N(R 10 )(R 11)、 -C(O)OR 10 、 -C(O)R 13 、 -C(O)N(R 10 )(R 11 )、 -S(O)2R 13 、 and -S(O)2N(R 10 )(R 11 ) - selected from, where C 1-6 alkyl is optionally substituted with one, two or three groups selected from halogen, C 1-6 haloalkyl, -OR 10 、 -N(R 10 )(R 11 ) and -C(O)OR 10 ). In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 is independently selected from halogen, -CN, C 1-6 alkyl, -OR 10 、 and -N(R 10 )(R 11 ), where C 1-6 alkyl is optionally substituted with one, two, or three groups selected from halogen, C 1-6 haloalkyl, -OR 10 、 -N(R 10 )(R 11 )、 and -C(O)OR 10 ). In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where each R 4 is independently selected from halogen, C 1-6 alkyl, -OR 10 ), where C 1-6 alkyl is optionally substituted with one, two or three groups selected from halogen, C 1-6 haloalkyl and -OR 10 ).

[0061] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where R 1is selected from hydrogen and C1-C6 alkyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is hydrogen. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is C1-C6 alkyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -CH3.

[0062] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl, phenyl and -C1-C6 alkyl-phenyl are optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9Heteroaryl, phenyl and -C1-C6 alkyl-phenyl are optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl, and phenyl, wherein C1-C6 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl, and phenyl are optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is selected from hydrogen, C1-C6 alkyl, C6 alkenyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, and C 1-9 heteroaryl, wherein C1-C6 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl are optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 .

[0063] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl optionally substituted with one, two, or three groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl substituted with one or more groups selected from halogen, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ). In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl substituted with one, two, or three groups selected from halogen, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ). In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl substituted with one, two, or three halogens. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl substituted with one, two, or three C1-6 It is C1-C6 alkyl substituted with haloalkyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl substituted with one, two, or three -OR 10 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl substituted with one, two, or three -OH. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl substituted with one, two, or three -N(R 10 )(R 11 ).

[0064] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is unsubstituted C1-C6 alkyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -CH3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -CH2CH3.

[0065] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is hydrogen.

[0066] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13is C3-C6 cycloalkyl optionally substituted with one or more groups selected from. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 is C3-C6 cycloalkyl optionally substituted with one or more groups selected from. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 is C3-C6 cycloalkyl optionally substituted with one, two, or three groups selected from. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ) is C3-C6 cycloalkyl substituted with one or more groups selected from. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ) is C3-C6 cycloalkyl substituted with one, two, three groups selected from. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2is C1-C6 alkyl substituted with one, two, or three halogens. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3-C6 cycloalkyl substituted with one, two, or three C 1-6 haloalkyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3-C6 cycloalkyl substituted with one, two, or three -OR 10 . In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3-C6 cycloalkyl substituted with one, two, or three -OH. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3-C6 cycloalkyl substituted with one, two, or three -N(R 10 )(R 11 ).

[0067] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted C3-C6 cycloalkyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted cyclopropyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted cyclobutyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted cyclopentyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted cyclohexyl.

[0068] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 optionally substituted C 1-9 heteroaryl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ) and -S(O)2R 13 optionally substituted C 1-9 heteroaryl, wherein C 1-9 heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is pyridyl optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13is a pyridazinyl optionally substituted with one or more groups selected from. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 is a pyrimidinyl optionally substituted with one or more groups selected from. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 is a pyrazinyl optionally substituted with one or more groups selected from.

[0069] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is selected from unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted pyridyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted pyridazinyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted pyrimidinyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted pyrazinyl.

[0070] In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 combine to form a C2-C9 heterocycloalkyl optionally substituted with one or more groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 combine to form a C2-C9 heterocycloalkyl optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 combine to form an unsubstituted C2-C9 heterocycloalkyl.

[0071] In some embodiments, a compound of formula (Ia)

[0072]

Chemical Formula

[0073] In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from hydrogen and C1-C6 alkyl. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is hydrogen. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is C1-C6 alkyl. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -CH3.

[0074] In some embodiments, a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein, wherein R 2 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl, phenyl and -C1-C6 alkyl-phenyl are optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9Selected from heteroaryl and phenyl, wherein C1-C6 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C1-9 heteroaryl, phenyl are halogen, C1-C6 alkyl, C 1-6 haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 are optionally substituted with one or more groups selected from. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, and C 1-9 heteroaryl, wherein C1-C6 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, and C 1-9 heteroaryl are halogen, C1-C6 alkyl, C 1-6 haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 are optionally substituted with one or more groups selected from.

[0075] In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R10 )(R 11 )、and -S(O)2R 13 is C1-C6 alkyl optionally substituted with one, two, or three groups selected from. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 )-substituted C1-C6 alkyl. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is halogen, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 )-substituted C1-C6 alkyl by one, two, or three groups selected from. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl substituted with one, two, or three halogens. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl substituted with one, two, or three C 1-6 haloalkyl. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl substituted with one, two, or three -OR 10 . In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl substituted with one, two, or three -OH. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl substituted with one, two, or three -N(R10 )(R 11 ) is C1-C6 alkyl substituted with 10 .

[0076] In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted C1-C6 alkyl. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -CH3. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -CH2CH3.

[0077] In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is hydrogen.

[0078] In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3-C6 cycloalkyl optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3-C6 cycloalkyl optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2is C3-C6 cycloalkyl optionally substituted with one, two, or three groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3-C6 cycloalkyl substituted with one or more groups selected from halogen, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ). In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3-C6 cycloalkyl substituted with one, two, or three groups selected from halogen, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ). In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl substituted with one, two, or three halogens. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3-C6 cycloalkyl substituted with one, two, or three C 1-6 haloalkyls. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3-C6 cycloalkyl substituted with one, two, or three -OR 10 . In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2is a C3-C6 cycloalkyl substituted with 1, 2, or 3 -OH. In some embodiments, the compound is of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, wherein R 2 can have one, two, or three -N(R 10 )(R 11 ) is a C3-C6 cycloalkyl substituted with

[0079] In some embodiments, the compound is a compound of Formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, wherein R 2 is an unsubstituted C3-C6 cycloalkyl. In some embodiments, the compound is of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted cyclopropyl. In some embodiments, the compound is of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted cyclobutyl. In some embodiments, the compound is of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted cyclopentyl. In some embodiments, the compound is of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted cyclohexyl.

[0080] In some embodiments, the compound is a compound of Formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, wherein R 2 is halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)R 13 C optionally substituted with one or more groups selected from 1-9 In some embodiments, the compound is of formula (Ia), or a pharma- ceutically acceptable salt or solvate thereof, wherein R 2 is halogen, C1-C6 alkyl, C 1-6Haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ) and -S(O)2R 13 Optionally substituted with one or more groups selected from C 1-9 heteroaryl, where C 1-9 heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where R 2 is halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 Optionally substituted with one or more groups selected from pyridyl. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where R 2 is halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 Optionally substituted with one or more groups selected from pyridazinyl. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where R 2 is halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 Optionally substituted with one or more groups selected from pyrimidinyl. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where R 2 is halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R11 ) and -S(O)2R 13 is pyrazinyl optionally substituted with one or more groups selected from

[0081] In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is selected from unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted pyridyl. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted pyridazinyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is pyrimidinyl. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is pyrazinyl.

[0082] In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 combine to form a C2-C9 heterocycloalkyl optionally substituted with one or more groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 combine to form a C2-C9 heterocycloalkyl optionally substituted with one or more groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , -N(R10 )(R 11 )、and -S(O)2R 13 optionally substituted with one, two, or three groups selected from C2-C9 heterocycloalkyl. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 combine to form unsubstituted C2-C9 heterocycloalkyl.

[0083] In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, is described herein,

[0084]

Chemical formula

[0085] In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from hydrogen and C1-C6 alkyl. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is hydrogen. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is C1-C6 alkyl. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -CH3.

[0086] In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl, phenyl and -C1-C6 alkyl-phenyl are halogen, C1-C6 alkyl, C 1-6 haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 -, -N(R 10 )(R11 ) and -S(O)2R 13 is optionally substituted with one or more groups selected from. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl, phenyl, and -C1-C6 alkyl-phenyl, wherein C1-C6 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl, phenyl and -C1-C6 alkyl-phenyl are halogen, C1-C6 alkyl, C 1-6 haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 is optionally substituted with one or more groups selected from. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl, and C6 alkyl-phenyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl, and -C1-C6 alkyl-phenyl are halogen, C1-C6 alkyl, C 1-6 haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 is optionally substituted with one or more groups selected from. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, and C1-9 heteroaryl, wherein C1-C6 alkyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, and C 1-9 Heteroaryl is any of halogen, C1-C6 alkyl, C 1-6 Haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)R 13 is optionally substituted with one or more groups selected from

[0087] In some embodiments, the compound is a compound of formula (Iaa), or a pharma- ceutically acceptable salt or solvate thereof, wherein R 2 is halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)R 13 In some embodiments, the compound is of formula (Iaa), or a pharma- ceutically acceptable salt or solvate thereof, wherein R 2 is halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)R 13 In some embodiments, the compound is of formula (Iaa), or a pharma- ceutically acceptable salt or solvate thereof, wherein R 2 is a halogen, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 In some embodiments, the compound is of formula (Iaa), or a pharma- ceutically acceptable salt or solvate thereof, wherein R 2 is a halogen, C1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 ), and is a C1-C6 alkyl substituted with one, two, or three of these three groups. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C1-C6 alkyl substituted with one, two, or three halogens. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C1-C6 alkyl substituted with one, two, or three C 1-6 haloalkyls. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C1-C6 alkyl substituted with one, two, or three -OR 10 . In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C1-C6 alkyl substituted with one, two, or three -OH groups. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C1-C6 alkyl substituted with one, two, or three -N(R 10 )(R 11 ).

[0088] In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted C1-C6 alkyl. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -CH3. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -CH2CH3.

[0089] In some embodiments, it is a compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is hydrogen.

[0090] In some embodiments, it is a compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3-C6 cycloalkyl optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, it is a compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3-C6 cycloalkyl optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, it is a compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3-C6 cycloalkyl optionally substituted with one, two, or three groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, it is a compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3-C6 cycloalkyl optionally substituted with one or more groups selected from halogen, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11is C3-C6 cycloalkyl substituted with one or more groups selected from 2 is halogen, C 1-6 haloalkyl, -OR 10 , and -N(R 10 )(R 11 ) and is C3-C6 cycloalkyl substituted with one, two, or three of the three groups selected from. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C1-C6 alkyl substituted with one, two, or three halogens. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3-C6 cycloalkyl substituted with one, two, or three C 1-6 haloalkyl. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3-C6 cycloalkyl substituted with one, two, or three -OR 10 . In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3-C6 cycloalkyl substituted with one, two, or three -OH. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C3-C6 cycloalkyl substituted with one, two, or three -N(R 10 )(R 11 ).

[0091] In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2is unsubstituted C3-C6 cycloalkyl. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted cyclopropyl. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted cyclobutyl. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted cyclopentyl. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted cyclohexyl.

[0092] In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 heteroaryl. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1-9 is C optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 2 haloalkyl, -CN, -OR 1-6 , -N(R 10 )(R 10 ) and -S(O)2R 11 ) heteroaryl, wherein C 13 heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1-9 is C optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-9 haloalkyl, -CN, -OR 2is pyridyl optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is pyridazinyl optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is pyrimidinyl optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is pyrazinyl optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C 1-6 haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 .

[0093] In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2is selected from unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl, and unsubstituted pyrazinyl. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted pyridyl. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted pyridazinyl. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted pyrimidinyl. In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted pyrazinyl.

[0094] In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 combine to form C2-C9 heterocycloalkyl optionally substituted with one or more groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 combine to form C2-C9 heterocycloalkyl optionally substituted with one, two, or three groups selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -S(O)2R 13 . In some embodiments, the compound of formula (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R 2 combine to form an unsubstituted C2-C9 heterocycloalkyl.

[0095] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, the groups and their substituents are selected by one of ordinary skill in the art to provide stable moieties and compounds.

[0096] In some embodiments,

[0097]

Chemical formula

[0098]

Chemical formula

[0099] In some embodiments,

[0100]

Chemical formula

[0101] In one embodiment, the compounds described herein are in the form of a pharmaceutically acceptable salt. Similarly, active metabolites of these compounds having the same type of activity are included within the scope of the present disclosure. Additionally, the compounds described herein can exist not only in the unsolvated form, but also in solvated forms including pharmaceutically acceptable solvents such as water, ethanol, etc. Solvated forms of the compounds presented herein are likewise considered to be disclosed herein.

[0102] "Pharmaceutically acceptable" as used herein refers to substances such as carriers or diluents that do not inhibit the biological activity or properties of a compound and are relatively non-toxic, i.e., the substance can be administered to an individual without causing undesirable biological effects or interacting in a harmful way with any component of the composition in which it is included.

[0103] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent that consists of the cationic form of the therapeutically active agent combined with a suitable anion, or alternatively, in an alternative embodiment, the anionic form of the therapeutically active agent combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are typically more soluble than the non-ionized species and are rapidly soluble in gastric and intestinal fluids, and are thus useful in solid dosage forms. Furthermore, since their solubility is often pH-dependent, selective dissolution in one or another part of the gastrointestinal tract is possible, and this ability can be manipulated as one aspect of delayed and sustained release behavior. Additionally, since the salt-forming molecule can be in equilibrium with the neutral form, passage through biological membranes can be regulated.

[0104] In some embodiments, the pharmaceutically acceptable salts are obtained by reacting the compounds described herein with an acid to provide a "pharmaceutically acceptable acid addition salt". In some embodiments, the compounds described herein (i.e., in free base form) are basic and are reacted with an organic or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, monomethyl fumarate, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid.

[0105] In some embodiments, the compounds described herein are prepared as chloride salts, sulfate salts, bromide salts, mesylate salts, maleate salts, citrate salts, or phosphate salts.

[0106] In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound described herein with a base to provide a "pharmaceutically acceptable base addition salt".

[0107] In some embodiments, the compounds described herein are acidic and are reacted with a base. In such situations, the acidic proton of the compounds described herein is replaced by a metal ion, such as a lithium, sodium, potassium, magnesium, calcium, or aluminum ion. In some cases, the compounds described herein coordinate with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine, but are not limited thereto. In other cases, the compounds described herein form salts with amino acids such as arginine, lysine, but are not limited thereto. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, etc. In some embodiments, the compounds provided herein are prepared as sodium salts, calcium salts, potassium salts, magnesium salts, meglumine salts, N-methylglucamine salts, or ammonium salts.

[0108] It should be understood that references to pharmaceutically acceptable salts include solvated forms. In some embodiments, solvates include either a stoichiometric or non-stoichiometric amount of the solvent and are formed during the process of isolating or purifying the compound using a pharmaceutically acceptable solvent such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated forms as well as solvated forms.

[0109] The methods and formulations described herein include the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of the compounds described herein, as well as active metabolites of these compounds having the same type of activity.

[0110] In some embodiments, sites on the organic radicals (e.g., alkyl groups, aromatic rings) of the compounds described herein are susceptible to various metabolic reactions. By incorporation of appropriate substituents on the organic radical, this metabolic pathway is reduced, minimized, or eliminated. In certain embodiments, suitable substituents for reducing or removing the sensitivity of the aromatic ring to metabolic reactions are, by way of example only, halogen, deuterium, alkyl groups, haloalkyl groups, or deuterated alkyl groups.

[0111] In another embodiment, the compounds described herein are labeled isotopically (e.g., using a radioisotope), or by other means including but not limited to the use of a chromophore moiety or a fluorescent moiety, bioluminescent labels, or chemiluminescent labels.

[0112] The compounds described herein include isotopically labeled compounds, which are identical to those described in the various formulas and structures presented herein, except that one or more atoms are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl, and the like. In one aspect, isotopically labeled compounds described herein, such as compounds incorporating radioactive isotopes such as 3 H and 14 C, are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium provides certain therapeutic advantages resulting from greater metabolic stability, such as an extended half-life or a reduced required dose in vivo. In some embodiments, one or more hydrogen atoms of the compounds described herein are replaced with deuterium.

[0113] In some embodiments, the compounds described herein have one or more stereocenters, and each stereocenter independently exists in either the R or S configuration. The compounds presented herein include all diastereomers, enantiomers, atropisomers, and epimeric forms, as well as suitable mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as suitable mixtures thereof.

[0114] Individual stereoisomers can be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers, and recovering the optically pure enantiomer. In some embodiments, the resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, the diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, the separation of stereoisomers is effected by chromatography or by formation of diastereomeric salts followed by separation by recrystallization, or by chromatography, or by any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981. In some embodiments, the stereoisomers are obtained by stereoselective synthesis.

[0115] Synthesis of Compounds The compounds described herein are synthesized using standard synthetic techniques or methods known in the art in combination with the methods described herein.

[0116] Unless otherwise specified, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are utilized.

[0117] The compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced-ORganic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein, such as variations in solvents, reaction temperatures, reaction times, and various chemical reagents and other reaction conditions, may also be utilized. Starting materials are available from commercial sources or are readily prepared.

[0118] Appropriate references and papers that detail the synthesis of reactants useful in the preparation of the compounds described herein or provide a reference to a description of the preparation include, for example, "Synthetic-ORganic Chemistry", John Wiley & Sons, Inc., New York; S.R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H.O. House, "Modern Synthetic Reactions", 2nd Ed., W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced-ORganic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Further appropriate references and papers that detail the synthesis of reactants useful in the preparation of the compounds described herein or provide a reference to a paper that describes the preparation include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R.C.“Comprehensive-ORganic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced-ORganic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai’s 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T.W.G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., “Intermediate-ORganic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial-ORganic Chemicals: Starting Materials and Intermediates: An Ullmann’s Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes are included.

[0119] In some embodiments, the compounds are prepared as described in the examples.

[0120] Treatment method In some embodiments, provided herein is a method of treating a CNS disease or disorder in a patient in need thereof, the method comprising administering to the patient a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided is a method of treating a CNS disease or disorder in a patient in need thereof, the method comprising administering to the patient a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHL or AHLE), adult Refsum disease, infantile Refsum disease, Alexander disease, Alzheimer's disease, Baló concentric sclerosis, Canavan disease, central pontine myelinolysis (CPM), cerebral palsy, cerebrotendinous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic's syndrome, diffuse demyelinating sclerosis, encephalomyelitis, Guillain–Barré syndrome, Huntington's disease (HD), idiopathic inflammatory demyelinating disease (HDD), Krabbe disease, Leber hereditary optic neuropathy, leukodystrophy, Marburg multiple sclerosis, multi-focal motor neuropathy (MMN), multiple sclerosis (MS), Niemann–Pick disease type C, paraproteinemic demyelinating polyneuropathy, Parkinson's disease (PD), Pelizaeus–Merzbacher disease (PMD), progressive multifocal leukoencephalopathy (PML), tropical spastic paraparesis (TSP), X-linked adrenoleukodystrophy (X-ALD, ALO, or X-linked ALO), and Zellweger syndrome. In some embodiments, provided is a method of treating a CNS disease or disorder in a patient in need thereof, the method comprising administering to the patient a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from multiple sclerosis.In some embodiments, a method for treating a CNS disease or disorder in a patient in need of treatment of a CNS disease or disorder is provided, the method comprising administering to the patient a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from X-linked adrenoleukodystrophy.

[0121] In some embodiments, described herein is a method of treating a CNS disease or disorder in a patient in need thereof, the method comprising administering to the patient a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering to the patient a peripheral-restricted fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments, it is a method of treating a CNS disease or disorder in a patient in need thereof, the method comprising administering to the patient a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHL or AHLE), adult Refsum disease, infantile Refsum disease, Alexander disease, Alzheimer's disease, Baló concentric sclerosis, Canavan disease, central pontine myelinolysis syndrome (CPM), cerebral palsy, cerebrotendinous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic's syndrome, diffuse demyelinating sclerosis, encephalomyelitis, Guillain-Barré syndrome, Huntington's disease (HD), idiopathic inflammatory demyelinating disease (HDD), Krabbe disease, Leber hereditary optic neuropathy, leukodystrophy, Marburg multiple sclerosis, multi-focal motor neuropathy (MMN), multiple sclerosis (MS), Niemann-Pick disease type C, paraproteinemic demyelinating polyneuropathy, Parkinson's disease (PD), Pelizaeus-Merzbacher disease (PMD), progressive multifocal leukoencephalopathy (PML), tropical spastic paraparesis (TSP), X-linked adrenoleukodystrophy (X-ALD, ALO, or X-linked ALO), and Zellweger syndrome, and the method further comprises administering to the patient a peripheral-restricted fatty acid amide hydrolase (FAAH) inhibitor.In some embodiments, a method of treating a CNS disease or disorder in a patient in need thereof, the method comprising administering to the patient a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from multiple sclerosis, and the method further comprising administering to the patient a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments, a method of treating a CNS disease or disorder in a patient in need thereof, the method comprising administering to the patient a compound of formula (I), (Ia), or (Iaa), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is X-linked adrenoleukodystrophy, and the method further comprising administering to the patient a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor.

[0122] In some embodiments of the methods described herein, the peripherally restricted FAAH inhibitor is ASP-3652.

[0123] Pharmaceutical composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated by conventional methods using one or more pharmaceutically acceptable inert ingredients that facilitate the processing of the active compound into a pharmaceutically used preparation. The appropriate formulation depends on the route of administration selected. An overview of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), which are hereby incorporated by reference for the purposes of disclosure.

[0124] In some embodiments, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent, either in a pharmaceutical composition. In some embodiments disclosed herein, the pharmaceutical composition further comprises a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments, the pharmaceutical composition further comprises a peripherally restricted FAAH inhibitor, and the peripherally restricted FAAH inhibitor is ASP-3652.

[0125] Administration of the compounds and compositions described herein can be achieved by methods that enable delivery of the compounds to the site of action. These methods include, but are not limited to, enteral routes (including oral, gastric, or duodenal feeding tubes, rectal suppositories, and rectal enemas), parenteral routes (including injection or infusion into the artery, heart, dermis, duodenum, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including epithelial, dermal, enema, ophthalmic, otic, intranasal, vaginal) administration, although the most appropriate route can depend, for example, on the disease or disorder of the recipient.

[0126] In some embodiments, a pharmaceutical composition suitable for oral administration is presented as individual units, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, as a solution or suspension in an aqueous liquid or a non-aqueous liquid, or as an oil-in-water emulsion or a water-in-oil emulsion in an oily liquid. In some embodiments, the active ingredient is presented as a bolus, a lozenge, or a paste.

[0127] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets can be made by compression or molding, optionally together with one or more accessory ingredients. Compressed tablets can be prepared by mixing, optionally, a binder, an inert diluent, or a lubricant, surfactant, or dispersing agents, and compressing the active ingredient in a free-flowing form such as powder or granules with a suitable machine. Molded tablets can be made by molding a mixture of a powdered compound moistened with an inert liquid diluent with a suitable machine. In some embodiments, the tablets are coated or scored and formulated to provide delayed or controlled release of the active ingredient therein. All formulations for oral administration need to be in a dosage suitable for such administration. Push-fit capsules can contain the active ingredient in combination with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. The sugar-coated tablet core is provided with a suitable coating. For this purpose, a concentrated sugar solution can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments can be added to the tablets or the sugar-coated tablet coating for identification or to characterize different combinations of doses of the active compound.

[0128] In some embodiments, the pharmaceutical composition is formulated for parenteral administration by infusion, such as by bolus injection or continuous infusion. Formulations for infusion can be presented in unit dosage form, for example, in ampoules or multi-dose containers, together with additional preservatives. The composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain formulatory agents such as suspending agents, stabilizing agents, and / or dispersing agents. The composition can be presented in single-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored in a powder form, or in a freeze-dried (lyophilized) state that requires only the addition of a sterile liquid carrier, such as physiological saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the type described above.

[0129] Pharmaceutical compositions for parenteral administration can include aqueous and non-aqueous (oily) sterile injection solutions of an active compound containing antioxidants, buffers, bacteriostatic agents, and solutes that render the formulation isotonic with the blood of the desired recipient, and aqueous and non-aqueous sterile suspensions that can contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound to allow for the preparation of highly concentrated solutions.

[0130] The pharmaceutical composition can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compound can be formulated with a suitable polymeric material or hydrophobic material (e.g., as an emulsion in an acceptable oil) or ion exchange resins or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

[0131] For buccal or sublingual administration, the composition can take the form of tablets, lozenges, troches, or gels formulated in a conventional manner. Such compositions can contain the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0132] The pharmaceutical composition can also be formulated into rectal compositions such as suppositories or retention enemas containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0133] The pharmaceutical composition can be administered locally, i.e., by non - systemic administration. This includes topically applying the compounds of the invention to the skin or mouth and dropping such compounds into the ear, eye, and nose such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0134] Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid formulations suitable for percutaneous penetration to the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may be included at 0.001 w / w% to 10 w / w% of the formulation, for example, 1% to 2% by weight of the formulation, for topical administration.

[0135] Pharmaceutical compositions for administration by inhalation are preferably delivered from an insufflator, a nebulizer pressurized pack, or other convenient means for delivering an aerosol spray. The pressurized pack may contain a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve for delivering a metered amount. Alternatively, for administration by inhalation or insufflation, the pharmaceutical preparation may be in the form of a dry powder composition, for example, a powder mix of the compound with a suitable powder base such as lactose or starch. The powder composition may be provided in unit dosage form, for example, in capsules, cartridges, gelatin, or blister packs from which the powder may be administered using an inhalator or insufflator.

[0136] In some embodiments, the compounds disclosed herein are formulated in a manner such that delivery of the compound to a particular region of the gastrointestinal tract is achieved. For example, the compounds disclosed herein are formulated for oral delivery using bioadhesive polymers, pH-sensitive coatings, time dependent, biodegradable polymers, microflora activated systems, etc. to effect delivery of the compound to a particular region of the gastrointestinal tract.

[0137] In some embodiments, the compounds disclosed herein are formulated to provide controlled release of the compound. Controlled release refers to releasing the compounds described herein from the dosage form in which they are incorporated, over a prolonged period of time, according to a desired profile. Controlled release profiles include, for example, sustained release, prolonged release, pulsed release, and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow for delivery of the agent to a subject over a prolonged period of time, according to a desired profile. Such release rates provide therapeutically effective levels of the agent over a prolonged period of time, thereby providing a longer period of pharmacological response while minimizing side effects as compared to conventional rapid release dosage forms. Such longer response periods provide a number of unique advantages not achievable with the corresponding short acting, immediate release preparations.

[0138] Approaches for delivering intact therapeutic compounds to a particular region of the gastrointestinal tract (e.g., the colon, etc.) include:

[0139] (i) Coating with polymers: Intact molecules can be delivered to the colon without being absorbed in the upper part of the intestine by coating the drug molecules with an appropriate polymer that decomposes only in the colon.

[0140] (ii) Coating with pH-sensitive polymers: Most of the enteric and colon targeted delivery systems are based on the coating of tablets or pellets filled in conventional hard gelatin capsules. The most commonly used pH-dependent coating polymer is methacrylic acid copolymers, generally known as Eudragit® S, more specifically Eudragit® L and Eudragit® S. Eudragit® L100 and S100 are copolymers of methacrylic acid and methyl methacrylate.

[0141] (iii) Coating with biodegradable polymers;

[0142] (iv) Embedding in a matrix:

[0143] (v) Embedding in biodegradable matrices and hydrogels;

[0144] (vi) Embedding in a pH-sensitive matrix;

[0145] (vii) Sustained release systems;

[0146] (viii) Redox-sensitive polymers;

[0147] (ix) Bioadhesive systems;

[0148] (x) Coating with microparticles;

[0149] (xi) Osmotic pressure-controlled drug delivery;

[0150] Another approach to colon-targeted drug delivery or controlled release systems involves embedding the drug in a polymeric matrix, entrapping it, and releasing it in the colon. These matrices can be pH-sensitive or biodegradable. Matrix-Based Systems, such as multi-matrix (MMX)-based delayed-release tablets, ensure drug release in the colon.

[0151] Additional pharmaceutical approaches for the targeted delivery of therapeutic agents to specific regions of the gastrointestinal tract are known. Chourasia MK, Jain SK, Pharmaceutical approaches to colon targeted drug delivery systems., J Pharm Sci. 2003 Jan-Apr;6(1):33-66. Patel M, Shah T, Amin A. Therapeutic opportunities in colon-specific Drug-delivery systems Crit Rev Ther Drug Carrier Syst. 2007;24(2):147-202. Colon targeted drug delivery systems--an overview. Curr Drug Deliv. 2008 Jul;5(3):186-98. Van den Mooter G. Expert Opin Drug Deliv. 2006 Jan;3(1):111-25. Seth Amidon, Jack E. Brown, and Vivek S. Dave, Colon-Targeted-ORal Drug Delivery Systems: Design Trends and Approaches, AAPS PharmSciTech. 2015 Aug;16(4):731-741.

[0152] In particular, in addition to the components specifically mentioned above, the compounds and compositions described herein may include other conventional agents in the art, depending on the type of formulation in question. For example, it should be understood that agents suitable for oral administration may include flavoring agents.

[0153] Methods of Administration and Treatment Regimens In some embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, are used in the preparation of a medicament for the treatment of a disease or disorder in a mammal that would benefit from administration of an S1P5 receptor agonist. In a mammal in need of treatment of a disease or disorder described herein, a method for treating any of the diseases or disorders described herein comprises administering to the mammal a therapeutically effective amount of at least one compound described herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof.

[0154] In some embodiments disclosed herein, the method is administering an S1P5 receptor agonist in combination with an additional therapeutic agent. In some embodiments, provided is a method of administering an S1P5 receptor agonist in combination with a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments, the method is administering an S1P5 receptor agonist in combination with a peripherally restricted FAAH inhibitor, where the peripherally restricted FAAH inhibitor is ASP-3652.

[0155] In certain embodiments, a composition containing a compound described herein is administered for prophylactic and / or therapeutic treatment. In certain therapeutic uses, the composition is administered to a patient already suffering from a disease or disorder in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or disorder. The amount effective for this use depends on the severity and course of the disease or disorder, previous treatment, the health condition, weight, and response of the patient to the drug, as well as the judgment of the physician administering the treatment. The therapeutically effective amount may optionally be determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0156] In prophylactic applications, a composition containing a compound described herein is administered to a patient who is susceptible to or otherwise at risk of developing a particular disease, disorder or illness. Such an amount is defined as a "prophylactically effective amount or dose". In this use, the exact amount also depends on the health condition, weight, etc. of the patient. When used in a patient, the effective amount for this use depends on the severity and course of the disease, disorder or illness, previous treatment, the health condition of the patient and response to the drug, as well as the judgment of the physician administering the treatment. In one aspect, prophylactic treatment includes administering to a mammal that has previously experienced and is currently in remission from at least one symptom of the disease being treated a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof to prevent recurrence of the symptoms of the disease or disorder.

[0157] In certain embodiments where the patient's disease does not improve, at the discretion of the physician, the compound is administered chronically, i.e., over a long period, including over the patient's lifetime, to improve or otherwise control or limit the symptoms of the patient's disease or disorder.

[0158] In certain embodiments, if the patient's condition improves, the dosage of the administered drug is temporarily reduced or temporarily discontinued for a certain period (i.e., a "drug holiday"). In certain embodiments, the length of the drug holiday is, by way of example only, between 2 days and 1 year, including 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The reduction in dosage during the drug holiday is, by way of example only, between 10% and 100%, including 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0159] When improvement in the patient's condition occurs, a maintenance dose is administered as needed. Subsequently, in certain embodiments, the dosage or the frequency of administration, or both, are reduced to a level at which improvement of the disease, disorder, or illness is maintained, depending on the symptoms. However, in certain embodiments, the patient requires long-term intermittent treatment upon recurrence of the symptoms.

[0160] The amount of a given drug corresponding to such an amount varies depending on factors such as the specific compound, the disease state and its severity, and the individuality (e.g., weight, gender) of the subject or host in need of treatment. Nevertheless, it is determined according to the specific circumstances surrounding the case, including, for example, the specific drug being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0161] However, generally, the dosages used for the treatment of adult humans typically range from 0.01 mg to 5000 mg per day. In one aspect, the dosages used for the treatment of adult humans are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dosage is conveniently presented as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example, 2, 3, 4 or more sub-doses per day.

[0162] In one embodiment, a daily dosage suitable for the compounds described herein, or a pharmaceutically acceptable salt thereof, is from about 0.01 to about 50 mg / kg per body weight. In some embodiments, the daily dosage or the amount of the active ingredient in the dosage form may be less than or greater than the ranges indicated herein, based on many variables regarding the individual treatment regimens. In various embodiments, the daily dosage and unit dosage are variable depending on many variables including, but not limited to, the activity of the compound used, the disease or disorder being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or disorder being treated, and the judgment of the medical personnel.

[0163] The toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of LD 50 and ED 50 . The dosage ratio between toxicity and therapeutic effect is the therapeutic index, which is expressed as the ratio between LD 50 and ED 50 . In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating a therapeutically effective daily dosage range and / or therapeutically effective unit dosage for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is within the range of blood concentrations that include the ED 50 with minimal toxicity. In certain embodiments, the daily dosage range and / or unit dosage vary within this range depending on the dosage form employed and the route of administration utilized.

[0164] In any of the foregoing embodiments, an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by infusion to a mammal, and / or (e) administered topically to a mammal, and / or (f) administered non-systemically or topically to a mammal, which is a further embodiment.

[0165] In any of the foregoing embodiments, there is a further embodiment that includes a single administration of an effective amount of the compound, (i) where the compound is administered once a day, or (ii) where the compound is administered to the mammal multiple times over a day, including further embodiments.

[0166] In any of the foregoing embodiments, there are further embodiments that include multiple administrations of an effective amount of the compound, (i) where the compound is administered continuously or intermittently, similar to the case of a single administration, (ii) where the interval between multiple administrations is every 6 hours, (iii) where the compound is administered to the mammal every 8 hours, (iv) where the compound is administered to the mammal every 12 hours, (v) where the compound is administered to the mammal every 24 hours, including further embodiments. In a further or alternative embodiment, the method includes a drug withdrawal period, where the administration of the compound is temporarily interrupted or the dose of the administered compound is temporarily reduced, and at the end of the drug withdrawal period, the administration of the compound is resumed. In one embodiment, the length of the drug withdrawal period varies from 2 days to 1 year.

[0167] In certain examples, it is appropriate to administer at least one compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0168] In one embodiment, the therapeutic effectiveness of one of the compounds described herein is enhanced by the administration of an adjuvant (i.e., the adjuvant alone has minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic effect on the patient is enhanced). Alternatively, in some embodiments, the effect experienced by the patient is increased by administering one of the compounds described herein together with another agent having a similar therapeutic effect (which also includes a treatment regimen).

[0169] In certain embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, are co-administered with a second therapeutic agent, where the compounds described herein, or pharmaceutically acceptable salts thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall effect than the administration of either therapeutic agent alone.

[0170] In any case, regardless of the disease, disorder or condition being treated, the overall effect experienced by the patient may be additive of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0171] In certain embodiments, the various therapeutically effective amounts of the compounds disclosed herein are utilized in formulating pharmaceutical compositions and / or in treatment regimens in which the compounds disclosed herein are administered in combination with one or more additional agents such as additional therapeutically active drugs, adjuvants, etc. The therapeutically effective amounts of the drugs and other agents used in combination treatment regimens are optionally determined by means similar to those specified above for the active ingredient itself. Further, the methods of prevention / treatment described herein include the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen includes a treatment regimen in which administration of a compound described herein, or a pharmaceutically acceptable salt thereof, is initiated before, during, or after treatment with a second agent described herein and continues until any point during or after treatment with the second agent. A combination treatment regimen includes a treatment in which a compound described herein, or a pharmaceutically acceptable salt thereof, and a second agent used in combination are administered simultaneously or at different times and / or at intervals that vary during the course of treatment. The combination therapy further includes periodic treatments that are initiated and stopped at various times to assist in the clinical management of the patient.

[0172] It should be understood that dosing regimens for treating, preventing, or ameliorating a disease for which relief is sought are modified in accordance with various factors (e.g., the disease, disorder or illness the subject is suffering from; the subject's age, weight, sex, diet, and medical condition). Thus, in some instances, the dosing regimen actually utilized will vary and, in some embodiments, will deviate from the dosing regimens set forth herein.

[0173] In the combination therapies described herein, the dosage of the co-administered compounds will vary depending on factors such as the type of codrug used, the particular drugs employed, the disease or disorder being treated, and the like. In further embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously with, or sequentially to, the one or more other therapeutic agents.

[0174] In combination therapies, multiple therapeutic agents, one of which is one of the compounds described herein, are administered in any order or even simultaneously. When the administration is simultaneous, the multiple therapeutic agents are provided, by way of example only, in a single integrated form or in multiple forms (e.g., as a single pill or as two separate pills).

[0175] The compounds described herein, or pharmaceutically acceptable salts thereof, and combination therapies are administered before, during, or after the occurrence of a disease or disorder, and the timing of administration of the composition containing the compound varies. Thus, in one embodiment, the compounds described herein are used as prophylactic agents and are continuously administered to a subject having a tendency to develop a disease or disorder in order to prevent the occurrence of the disease or disorder. In another embodiment, the compounds and compositions are administered to the subject as soon as possible during or after the onset of symptoms. In a specific embodiment, the compounds described herein are administered as soon as practicable after the onset of a disease or disorder has been detected or suspected, and for the duration of time necessary for treatment of the disease. In some embodiments, the length of treatment required varies and the length of treatment is adjusted to fit the specific needs of each subject. For example, in a specific embodiment, the compounds described herein or formulations containing the compounds are administered for at least two weeks, from about one month to about five years.

Examples

[0176] The following examples are provided for illustrative purposes only and are not intended to limit the claims provided herein.

[0177] When used throughout the above and the entire description of the present invention, the following abbreviations shall be understood to have the following meanings unless otherwise indicated. 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 Dibenzylideneacetone DCE Dichloroethane (ClCH2CH2Cl) DCM Dichloromethane (CH2Cl2) 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 EEDQ 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline eq Equivalent Et Ethyl Et2O 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 HPLC High performance liquid chromatography KHMDS Potassium bis(trimethylsilyl)amide NaHMDS Sodium bis(trimethylsilyl)amide LiHMDS Lithium bis(trimethylsilyl)amide LAH Lithium aluminum hydride LCMS Liquid chromatography mass spectrometry Me Methyl MeOH Methanol MS Mass spectrometry Ms Mesyl NBS N-Bromosuccinimide NMM N-Methyl-morpholine NMP N-Methyl-pyrrolidin-2-one NMR Nuclear magnetic resonance PCC Pyridinium chlorochromate Ph Phenyl PPTS Pyridinium p-toluenesulfonate iPr / i-Pr Iso-propyl TBS tert-Butyldimethylsilyl RP-HPLC Reverse phase high performance liquid chromatography TFA Trifluoroacetic acid TEA Triethylamine THF Tetrahydrofuran TLC Thin layer chromatography

[0178] Example 1: Synthesis of (S)-1-((3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxylic acid (Compound 1)

[0179]

Chem.

[0180] To a solution of A-3 (28.4 g, 113 mmol) in ethanol (280 mL) and water (70 mL), KOH (15.9 g, 284 mmol) was added and the mixture was stirred at 80 °C for 3 h. The reaction was adjusted to pH = 2 - 3 with 6N HCl. The mixture was diluted with water (100 mL) and extracted with DCM (200 mL * 3). The combined organic phases were washed with brine (350 mL), dried over Na2SO4, and concentrated under reduced pressure to give A-4 (22.2 g, 88% yield) as a red oil.

[0181] To a solution of A-4 (22.2 g, 99.9 mmol) in acetic acid (220 mL), 10% Pd / C (2.22 g) was added. The mixture was stirred at room temperature for 16 h under a H2 balloon. The reaction was filtered and the filtrate was concentrated. Water was added to the residue and the mixture was extracted with DCM. The organic layer was washed with water and brine, dried over Na2SO4, and then concentrated under reduced pressure to give A-5 (16.0 g, 77% yield) as a gray oil.

[0182] To a solution of A-5 (16.0 g, 76.8 mmol) in DCM (160 mL), oxalyl chloride (48.8 g, 384.0 mmol) was added at room temperature. The mixture was stirred at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure to give A-6 (15.0 g, 86% yield) as a red oil.

[0183] To a solution of AlCl3 (17.6 g, 132.4 mmol) in DCM (150 mL) was added A-6 (15.0 g, 66.2 mmol) in DCM dropwise at 0 °C. The mixture was stirred at room temperature for 16 h. 6N HCl (100 mL) and water (50 mL) were added to the reaction mixture. The mixture was extracted with DCM (80 mL * 3). The combined organic layers were washed with water, brine, dried over Na2SO4, and then concentrated. The residue was purified by flash column chromatography to give A-7 (8.6 g, 74% yield) as a yellow solid.

[0184] To a solution of A-7 (8.6 g, 48.9 mmol) in dry DMF (50 mL) were added CH3I (10.4 g, 73.4 mmol) and K2CO3 (13.5 g, 97.8 mmol). The mixture was stirred at room temperature for 4 h. Water was added and the mixture was extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by flash column chromatography to give A-8 (7.1 g, 76% yield) as a yellow solid.

[0185] To a solution of A-8 (7.1 g, 37.3 mmol) in MeOH (70 mL) was added NaBH4 (2.82 g, 74.6 mmol) at 0 °C. The mixture was stirred at room temperature for 4 h. Water was added and the mixture was extracted with DCM. The organic layer was washed with water, brine, dried over Na2SO4, and then concentrated under reduced pressure to give A-9 (6.9 g, 96% yield) as a yellow oil.

[0186] To a solution of A-9 (6.9 g, 35.9 mmol) in DMF (70 mL) was added POCl3 (16.5 g, 108.0 mmol) dropwise at room temperature. The mixture was stirred at 60 °C for 16 h. The reaction was poured into cold water (400 mL) and the mixture was stirred at room temperature for 10 min. The mixture was extracted with EtOAc (100 mL * 2). The combined organic layers were washed with water, brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by flash column chromatography to give A-10 (6.5 g, 90% yield) as a yellow oil.

[0187] To a solution of A-10 (6.5 g, 32.1 mmol) in DCM (70 mL) was added BBr3 (17.7 g, 70.7 mmol) at 0 °C. The mixture was stirred at 0 °C for 4 h. Water (100 mL) was added to the reaction, and the mixture was extracted with DCM (80 mL × 3). The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography to give racemic A-11 (4.5 g, 74.4% yield) as a brown solid. Racemic A-11 was purified by chiral separation (using HPLC (column used: Daicel Corporation CHIRALCEL OJ-H (4.6 mm I.D. × 250 mm L), mobile phase: normal hexane:2-propanol = 80:20, flow rate: 1 mL / min, temperature: 40 °C, wavelength: 245 nm)), and at the second peak (retention time: about 8.11 min), A-11 (1.9 g) was obtained as a brown solid.

[0188] To a solution of A-12 (1.5 g, 10.1 mmol) in DCE (20 mL) was added DIEA (1.3 g, 10.1 mmol) at room temperature. After stirring for 10 min, A-11 (1.9 g, 10.1 mmol) and AcOH (60.6 mg, 1.01 mmol) were added. The mixture was stirred at room temperature for 2 h. NaBH(OAc)3 (4.28 g, 20.2 mmol) was added, and the resulting mixture was stirred at room temperature for 16 h. Water was added, and the mixture was extracted with DCM. The organic layer was washed with brine and concentrated. The residue was purified by flash column chromatography to give A-13 (2.4 g, 83% yield) as a red oil.

[0189] To a solution of A-13 (2.4 g, 8.4 mmol) in MeCN (25 mL) were added 4-bromo-1,1,1-trifluorobutane (3.2 g, 16.7 mmol) and K2CO3 (2.3 g, 16.7 mmol) at room temperature. The mixture was stirred at 70 °C for 16 h. The reaction mixture was cooled to room temperature. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (30 mL × 3). The combined organic phases were dried and concentrated. The residue was purified by flash column chromatography to give A-15 (1.7 g, 51% yield) as a white solid.

[0190] To a solution of A-15 (1.7 g, 4.3 mmol) in THF (16 mL) were added LiOH.H2O (361.0 mg, 8.6 mmol) and water (4 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was adjusted to pH = 5 - 6 with 1N HCl, and water (20 mL) was added. The mixture was extracted with EtOAc (20 mL * 3). The combined organic phases were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, and concentrated. The residue was purified by reverse-phase column chromatography to give Compound 1 (1.5 g, 91% yield) as a white solid. LCMS: 384.3 [M+1]+. Compound 1 is an S1P5 agonist.

[0191] Example 2: Synthesis of N-((S)-1-hydroxypropan-2-yl)-1-(((S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 2)

[0192]

Chemical Structure

[0193] Example 3: Synthesis of (S)-1-((3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)-N-(pyrimidin-5-yl)azetidine-3-carboxamide (compound 3)

[0194]

Chemical formula

[0195] Example 4: Synthesis of (S)-1-((3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)-N-(pyridazin-4-yl)azetidine-3-carboxamide (compound 4)

[0196]

Chemical formula

[0197] Example 5: Synthesis of (S)-N-(2-Methoxyethyl)-1-((3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 5)

[0198]

Chem.

[0199] Example 6: Synthesis of (S)-1-((3-Methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)-N-neopentylazetidine-3-carboxamide (Compound 6)

[0200]

Chem.

[0201] Example 7: Synthesis of (S)-N-isobutyl-1-((3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 7)

[0202] [Chemical formula] (S)-N-isobutyl-1-((3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 7) was prepared starting from Compounds 1 and 2-methylpropan-1-amine as described in Example 2. MS (ESI): 439.3 (M+H).

[0203] Example 8: Synthesis of N-((R)-sec-butyl)-1-(((S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 8)

[0204] [Chemical formula] N-((R)-sec-butyl)-1-(((S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 8) was prepared starting from Compounds 1 and (2R)-butan-2-amine as described in Example 2. MS (ESI): 439.3 (M+H).

[0205] Example 9: Synthesis of (S)-N-methyl-1-((3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)-N-neopentylazetidine-3-carboxamide (Compound 9)

[0206] [Chemical formula] (S)-N-Methyl-1-((3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)-N-neopentylazetidine-3-carboxamide (Compound 9) was prepared starting from Compound 1 and (2,2-dimethylpropyl)(methyl)amine as described in Example 2. MS (ESI): 467.3 (M+H).

[0207] Example 10: Synthesis of (S)-1-((3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)-N-propylazetidine-3-carboxamide (Compound 10)

[0208]

Chemical formula

[0209] Example 11: Synthesis of (S)-N,N-dimethyl-1-((3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 11)

[0210]

Chemical formula

[0211] Example 12: Synthesis of (S)-N-methyl-1-((3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 12)

[0212]

Chem.

[0213] Example 13: Synthesis of (S)-1-((3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)-N-(pyridin-3-yl)azetidine-3-carboxamide (Compound 13)

[0214]

Chem.

[0215] Example 14: Synthesis of N-((R)-1-hydroxypropan-2-yl)-1-(((S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 14)

[0216]

Chem.

[0217] Example 15: Synthesis of N-((S)-2-hydroxypropyl)-1-(((S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 15)

[0218]

Chem.

[0219] Example 16: Synthesis of (S)-N-methyl-1-((3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)-N-propylazetidine-3-carboxamide (Compound 16)

[0220]

Chem.

[0221] Example 17: Synthesis of N-((S)-sec-butyl)-1-(((S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 17)

[0222]

Chemical Structure

[0223] Example 18: Synthesis of N-((S)-1-methoxypropan-2-yl)-1-(((S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 18)

[0224]

Chemical Structure

[0225] Example 19: Synthesis of (S)-N-(cyclopropylmethyl)-1-((3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 19)

[0226] [Chemical formula] (S)-N-(Cyclopropylmethyl)-1-((3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 19) was prepared starting from Compound 1 and cyclopropylmethanamine as described in Example 2. MS(ESI): 437.3 (M+H).

[0227] Example 20: Synthesis of (S)-N-cyclopropyl-1-((3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 20)

[0228] [Chemical formula] (S)-N-cyclopropyl-1-((3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 20) was prepared starting from Compound 1 and cyclopropanamine as described in Example 2. MS(ESI): 423.3 (M+H).

[0229] Example 21: Synthesis of N-((R)-2-hydroxypropyl)-1-(((S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 21)

[0230] [Chemical formula] N-((R)-2-Hydroxypropyl)-1-(((S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 21) was prepared starting from Compound 1 and (R)-1-aminopropan-2-ol as described in Example 2. MS (ESI): 441.3 (M+H).

[0231] Compounds 22 - 25 were prepared using the same procedure as described in the foregoing Examples.

[0232]

Table 1

[0233] Example 22: FAAH Substrate Evaluation Purified recombinant human FAAH (rhFAAH) was purchased from Cayman Chemical (Ann Arbor, MI, USA). The total volume of each incubation was 400 μL and contained, in Tris-EDTA buffer at pH 8.0, 0.5 ng / μL of rhFAAH, 1 μM of test compound, 1.25% ethanol or 1 μM of PF-3845 (FAAH inhibitor), and 0.1% bovine serum albumin. The positive control was LL-341001. Incubations were carried out at room temperature. At 0, 5, 15, 30 and 60 minutes, 30 μL aliquots of the reaction mixture were removed and quenched by mixing with 300 μL of acetonitrile containing 5 ng / mL of promethazine and 10 ng / mL of tolbutamide as internal standards. The resulting mixtures were centrifuged at 4000 rpm at 40 °C for 15 minutes and 100 μL of the supernatant was subjected to LC-MS / MS analysis to measure the formation of acid metabolite.

[0234] LC-MS / MS Analysis The Waters Acquity Ultra Performance LC system was used for sample analysis. Chromatography was performed on a reversed-phase Kinetex 2.6μm C18 column, 2.1×30mm, 100Å. Mobile phase A was composed of water with 0.1% formic acid, and mobile phase B was composed of acetonitrile with 0.1% formic acid. For acid metabolites from the positive control, it was run at a flow rate of 0.8 mL / min for 2 minutes, and for acid metabolites of the test compound, it was run at a flow rate of 0.9 mL / min for 1.5 minutes. The mass spectrometers (API-5500 and API Q Trap 4000 Applied Biosystems / MDS SCIEX Instruments, Framingham, MA, USA) were operated in ESI positive or negative ion MRM mode.

[0235] Data analysis The formation of acid metabolites was monitored and quantified using one calibration point of 1 μM. The rate constant (ke) observed for acid metabolite formation was calculated by plotting metabolite concentration against incubation time, with the gradient being ke, as shown in Table 1.

[0236]

Table 2

[0237] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are intended to be included within the spirit and scope of this application and the appended claims.

Claims

1. Equation (I) 【Chemistry 1】 A compound thereof, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, R １ is selected from hydrogen or C1-C6 alkyl, R ２ is hydrogen, -OR ７ , -NR ７ R ８ , C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, C ２ -C ９ heterocycloalkyl, C １－９ heteroaryl, phenyl, and -C １ -C ６ alkyl-phenyl, where C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, C ２ -C ９ heterocycloalkyl, C １－９ heteroaryl, phenyl, and -C １ -C ６ alkyl-phenyl is optionally substituted with one or more groups selected from halogen, C １ -C ６ alkyl, C １－６ haloalkyl, C ３ -C ６ cycloalkyl, -CN, -OR １０ , -N(R １０ )(R １１ ), and -S(O) ２ R １３ or R １ and R ２ combine to be optionally substituted with one or more groups selected from halogen, C １－６ alkyl, C １－６ haloalkyl, -OR １０ , -N(R １０ )(R １１ ), and -S(O) ２ R １３ alkyl optionally substituted with ２ -C ９ Forms heterocycloalkyl groups, R ３ R10 is selected from -OR10, -SR10, and -N(R10)(R11), where R10 and R11 are independently selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. Each R ４ is independently halogen, -CN, C １－６ alkyl, C １－６ haloalkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, C ２－９ heterocycloalkyl, C ６－１０ aryl, C １－９ heteroaryl, -OR １０ , -SR １０ , -N(R １０ )(R １１ ), -C(O)OR １０ , -OC(O)N(R １０ )(R １１ ), -N(R １２ )(O)N(R １０ )(R １１ ), -N(R １２ )(O)OR １３ , -N(R １２ )(O)R ２ R １３ , -C(O)R １３ , -S(O)R １３ , -OC(O)R １３ , -C(O)N(R １０ )(R １１ ), -C(O)C(O)N(R １０ )(R １１ ), -N(R １２ )(O)R １３ , -S(O) ２ R<于 １３ , -S(O) ２ N(R １０ )(R １１ ), -S(=O)(=NH)N(R １０ )(R １１ ), -CH ２ C(O)N(R １０ )(R １１ ), -CH ２ N(R １２ )(O)R １３ , -CH ２ S(O) ２ R １３ , and -CH ２ S(O) ２ N(R １０ )(R １１ ) is selected, where C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryls are halogens, C １－６ Alkyl, C １－６ Haloalkyl, -OR １０ , -N(R １０ ) (Caution １１ ), and -C(O)OR １０ It is optionally replaced by one, two, or three elements selected from the following: R ５ and R ６ These are independently hydrogen and C １ -C ６ Selected from alkyl groups, Each R ７ and each R ８ These are independently hydrogen and C １ -C ６ Selected from alkyl groups, R ９ａ and R ９ｂ These are independently selected from hydrogen and C1-6 alkyl groups. Each R １０ These are independently hydrogen and C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, -C １－６ Alkyl-C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, -C １－６ Alkyl-C ２－９ Heterocycloalkyl, C ６－１０ Ariel, -C １－６ Alkyl-C ６－１０ Ariel, C １－９ Heteroaryls, and -C １－６ Alkyl-C １－９ Selected from heteroaryls, where C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, -C １－６ Alkyl-C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, -C １－６ Alkyl-C ２－９ Heterocycloalkyl, C ６－１０ Ariel, -C １－６ Alkyl-C ６－１０ Ariel, C １－９ Heteroaryls, and -C １－６ Alkyl-C １－９ Heteroaryls are halogens, -CN, hydroxy, 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 It is optionally substituted with one, two, or three groups selected from heteroaryls. Each R １１ These are independently hydrogen and C １－６ Alkyl and C １－６ Selected from haloalkyls, Each R １２ These are independently hydrogen and C １－６ Alkyl and C １－６ Selected from haloalkyls, Each R １３ C is independent １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Selected from heteroaryls, where C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Aryl, and C １－９ Heteroaryls are halogens, -CN, hydroxy, 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 It is optionally substituted with one, two, or three groups selected from heteroaryls. m is 0, 1, 2, or 3. A compound, or a pharmaceutically acceptable salt or solvate thereof.

2. R ５ and R ６ The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a is hydrogen, R 9b is -CH3, and m is 0.

3. The compound according to Claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from -O(CH2)3CF3, -O(CH2)4CF3, -O(CH2)5CF3, -S(CH2)3CF3, -S(CH2)4CF3, -S(CH2)5CF3, -N(H)(CH2)3CF3, -N(H)(CH2)4CF3, and -N(H)(CH2)5CF3.

4. Formula (Iaa) 【Chemistry 2】 A compound according to claim 1 having the structure, or a pharmaceutically acceptable salt or solvate thereof.

5. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen.

6. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is a C1-C6 alkyl optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C1-6 haloalkyl, -CN, -OR10, -N(R10)(R11), and -S(O)2R13.

7. The compound according to claim 6, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is a C1-C6 alkyl substituted with one or more groups selected from halogen, C1-6 haloalkyl, -OR10, and -N(R10)(R11).

8. The compound according to claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is a C1-C6 alkyl group substituted with one or more -OH groups, or R2 is a C1-C6 alkyl group substituted with one or more halogen groups.

9. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is an unsubstituted C1-C6 alkyl group. 【Request Item 10】 【Chemistry 3-1】 【Chemistry 3-2】 A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, selected from the above.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

12. The pharmaceutical composition according to claim 11, further comprising a peripheral restriction fatty acid amide hydrolase (FAAH) inhibitor.

13. The pharmaceutical composition according to claim 12, wherein the peripherally restrictive FAAH inhibitor is ASP-3652.

14. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a drug for treating a CNS disease or CNS disorder in a patient requiring treatment for a CNS disease or CNS disorder.

15. The CNS disease or CNS disorder is acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHL or AHLE), adult-onset Refsum disease, infantile Refsum disease, Alexander disease, Alzheimer's disease, Barlow concentric sclerosis, Canavan disease, central pontine demyelinating syndrome (CPM), cerebral palsy, cerebral tendon xanthomatous disease, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic syndrome, diffuse demyelinating sclerosis, encephalomyelitis, Guillain-Barré syndrome, idiopathic inflammatory demyelinating disease (HDD), Krabbe disease, Leber's hereditary optic neuropathy, white matter The use according to claim 14, selected from dystrophy, Marburg multiple sclerosis, multi-afaba bignami disease, metachromatic leukodystrophy (MLD), multifocal motor neuropathy (MMN), multiple sclerosis (MS), paraproteinase demyelinating polyneuropathy, Pelizaeus-Merzbacher disease (PMD), progressive multifocal leukoencephalopathy (PML), tropical spastic paraplegia (TSP), X-linked adrenoleukodystrophy (X-ALD, ALO, or X-linked ALO), and Zellberger syndrome.

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