Amide prodrugs and uses thereof

Abstract

Described herein are amide prodrugs, methods for making such compounds, pharmaceutical compositions and formulations containing such compounds, and methods for 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 / 370,753, filed August 8, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] The blood-brain barrier is composed of tightly junctioned endothelial cells that restrict the passage of pathogens and certain types of small and large molecules from the blood to the brain. This important protective function also limits the diffusion of therapeutic drugs into the brain, representing a major challenge for the development of new medicines for CNS diseases. Summary of the Invention

[0003] In one embodiment, the present specification provides a compound of formula (I):

[0004] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, R 1 is hydrogen, -OR 7 , -NR 7 R 8 , 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; and is selected from 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 substituted with halogen, C1-C6 alkyl, C 1-6 Haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 , -N(R 10 )(R11 ), and -S(O)R 13 and optionally substituted with one or more groups selected from R 2 is -NR 7 R 8 , C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -C1-C6 alkyl-C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl, phenyl, and -C1-C6 alkyl-phenyl; and is selected from C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -C1-C6 alkyl-C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are substituted with halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)R 13 or R 1 and R 2 are combined to form halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -S(O)R 13 forming a C2-C9 heterocycloalkyl optionally substituted with one or more groups selected from R 3 is 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, and C 1-9 heteroaryl; C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 optionally substituted with one, two, or three groups selected from R 4 are each independently halogen, -CN, or 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 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 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 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, -S(=O)(=NH)N(R10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 optionally substituted with one, two, or three groups selected from R 5 and R 6 are independently selected from hydrogen and C1-C6 alkyl; R 7 and R 8 are each independently selected from hydrogen and C1-C6 alkyl; R 9a and R 9b are independently hydrogen, 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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 optionally substituted with one, two, or three groups selected from R 9c is 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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 optionally substituted with one, two, or three groups selected from R 10 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 3-6Cycloalkyl, C 2-9 Heterocycloalkyl, -C 1-6 Alkyl-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -C 1-6 Alkyl-C 6-10 Aryl, C 1-9 Heteroaryl, and -C 1-6 Alkyl-C 1-9 heteroaryl; C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 Aryl, -C 1-6 Alkyl-C 6-10 Aryl, C 1-9 Heteroaryl, and -C 1-6 Alkyl-C 1-9 Heteroaryl is substituted with halogen, -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 optionally substituted with one, two, or three groups selected from heteroaryl; R 11 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 12 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 13 are each independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -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 optionally substituted with one, two, or three groups selected from heteroaryl, and m is 0, 1, 2, or 3.

[0005] In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 is hydrogen. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R 9a and R 9b are independently hydrogen and C 1-6 In some embodiments, there are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b is hydrogen. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R 9c is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10C optionally substituted with one, two, or three groups selected from 1-6 In some embodiments, there are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9c is unsubstituted C 1-6 In some embodiments, there are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9c is —CH. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C 1-6 Alkyl, C 6-10 Aryl, and C 1-9 heteroaryl; C 1-6 Alkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 C optionally substituted with one, two, or three groups selected from 6-10 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R 3 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C 1-6 Alkyl and -OR 10 and R is phenyl optionally substituted with one, two, or three groups selected from 10 is hydrogen, C 1-6 Alkyl, and C 1-6 In some embodiments, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 C optionally substituted with one, two, or three groups selected from 1-9 In some embodiments, there are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and -OR 10 and R is pyridyl optionally substituted with one, two, or three groups selected from 10 is hydrogen, C 1-6 Alkyl, and C 1-6 In some embodiments, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 C optionally substituted with one, two, or three groups selected from 1-6 In some embodiments, there are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is halogen, -OR 10 , and -N(R 10 )(R 11 C optionally substituted with one, two, or three groups selected from 1-6 In some embodiments, there are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is unsubstituted C 1-6 In some embodiments, there are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 teeth,

[0006] [ka] In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 teeth,

[0007] [ka] In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

[0008] In some embodiments, Formula (Ia)

[0009] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0010] In some embodiments, there is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is hydrogen. In some embodiments, there are compounds of Formula (I) or (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R 1 is C1-C6 alkyl. In some embodiments, there is a compound of Formula (I) or (Ia), 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)R 13 In some embodiments, there is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2is a halogen, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 In some embodiments, there is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C2-C6 alkyl substituted with one or more -OH. In some embodiments, there is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C2-C6 alkyl substituted with one or more halogens. In some embodiments, there is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted C2-C6 alkyl. In some embodiments, there is a compound of Formula (I) or (Ia), 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 In some embodiments, there is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an unsubstituted C-C cycloalkyl. In some embodiments, there is a compound of Formula (I) or (Ia), 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)R 13 C optionally substituted with one or more groups selected from 1-9 In some embodiments, there is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 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 Heteroaryl, C 1-9 Heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments, there is a compound of Formula (I) or (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, there is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 are combined to form halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -S(O)R 13 In some embodiments, a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, is provided, wherein R 1 and R 2 are combined to form an unsubstituted C2-C9 heterocycloalkyl.

[0011] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.In some embodiments, the pharmaceutical composition comprising a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, further comprises a peripherally localized fatty acid amide hydrolase (FAAH) inhibitor.In some embodiments, the pharmaceutical composition comprising a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, further comprises a peripherally localized fatty acid amide hydrolase (FAAH) inhibitor, and the peripherally localized FAAH inhibitor is ASP-3652.

[0012] In another aspect, described herein is a method of treating a CNS disease or disorder in a patient in need thereof, said method comprising administering to the patient a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there 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) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from the group consisting of acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHL or AHLE), adult Refsum's disease, infantile Refsum's disease, Alexander's disease, Alzheimer's disease, Barro's concentric sclerosis, Canavan's disease, central pontine myelinolysis (CPM), cerebral palsy, cerebrotendinous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic's syndrome, diffuse myelinoclastic sclerosis, encephalomyelitis, Guillain-Barré syndrome, Huntington's disease (HD), idiopathic inflammatory demyelinating disease (HDD), Krabbe's disease, Leber's hereditary optic neuropathy, neuropathy, leukodystrophy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy (MLD), multifocal motor neuropathy (MMN), multiple sclerosis (MS), Niemann-Pick disease type C, paraproteinemic demyelinating polyneuropathy, Parkinson's disease (PD), Pelizaeus-Merzbach disease (PMD), progressive multifocal leukoencephalopathy (PML), tropical spastic paraplegia (TSP), X-linked adrenoleukodystrophy (X-ALD, ALO, or X-linked ALO), and Zellweger syndrome. In some embodiments, there 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) or (Ia), 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, groups and substituents thereof will be chosen by one skilled 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. It will be understood, however, that the detailed description and specific examples, while indicating particular embodiments, are given by way of example only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0015] Sphingosine-1-phosphate is a pleiotropic signaling factor that mediates diverse biological responses through interactions with members of the endothelial cell differentiation gene family (EDG receptors) 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 various cell types. 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 primarily expressed in the immune and hematopoietic systems and typically mediates immune cell proliferation and cytokine production in the presence of high concentrations of S1P.

[0016] Selective modulation of S1P1 and S1P5 receptors simultaneously in brain tissue from patients with neurological disorders should provide neuroprotective and remyelination benefits. S1P1 / 5 receptors are expressed on astrocytes, microglia, neurons, and oligodendroglia and have been shown to regulate processes associated with demyelinating neuropathology, including astrocyte activation, microglial activation, oligodendrocyte precursor cell migration and maturation, and oligodendroglial cell survival. Studies in the EAE mouse model of MS have shown that genetic deletion or pharmacological functional antagonism of S1P1 reduces demyelination, axonal loss, and astrogliosis. S1P5 is highly expressed on myelinating oligodendrocytes, and stimulation / modulation of S1P5 has been shown to promote the survival of mature oligodendrocytes. The use of a dual S1P1 / S1P5 agonist or a selective S1P5 agonist in a conditional demyelination Xenopus tadpole model increased myelinated internodes compared to controls—use of a selective S1P1 agonist did not result in the same phenotype. On the other hand, higher S1P1 expression compared to S1P5 in astrocytes, microglia, and endothelial cells is associated with reduced cytokine release and inflammatory signaling and improved BBB integrity. Collectively, these data suggest that modulation of both receptor subtypes simultaneously may result in improved treatment of multiple neurological disorders.

[0017] 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 across 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 and be converted to active molecules by the action of FAAH on the prodrug. This results in greater delivery of carboxylic acids to the CNS compared with administration of the parent molecule alone. However, peripherally expressed FAAH simultaneously hydrolyzes the prodrug, resulting in a significant amount of non-productive prodrug conversion. Coadministration of a peripherally restricted FAAH inhibitor with 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.

[0018] Specific Terms Unless otherwise specified, definitions of the following terms used in this application are provided below. The use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting. The paragraph headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0019] As used herein, C1-C x is C1-C2, C1-C3...C1-C xBy way of example only, a group designated as "C1-C4" indicates that there are 1 to 4 carbon atoms in the moiety, i.e., the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that the alkyl group has 1 to 4 carbon atoms, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.

[0020] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group is branched or straight-chain. In some embodiments, an "alkyl" group has 1 to 10 carbon atoms (i.e., C1-C 10 (Alkyl). Numerical ranges such as "1 to 10," whenever they appear herein, refer to each integer within the specified 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, and so on, up to 10 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" without a specified numerical range. In some embodiments, alkyl is C1-C6 alkyl. In one aspect, alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0021] An "alkylene" group refers to a divalent alkyl radical. Any of the above monovalent alkyl groups may be alkylene by removal of a second hydrogen atom from the alkyl. In some embodiments, alkylene is a C1-C6 alkylene. In other embodiments, alkylene is a C1-C4 alkylene. In certain embodiments, alkylene contains 1 to 4 carbon atoms (e.g., a C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (e.g., a C1-C3 alkylene). In other embodiments, alkylene contains 1 to 2 carbon atoms (e.g., a C1-C2 alkylene). In other embodiments, alkylene contains 1 carbon atom (e.g., a C1 alkylene). In other embodiments, alkylene contains 2 carbon atoms (e.g., a C2 alkylene). In other embodiments, alkylene contains 2 to 4 carbon atoms (e.g., a 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-, and the like.

[0022] A "deuterated alkyl" refers to an alkyl group where one or more hydrogen atoms of the alkyl are replaced with deuterium.

[0023] The term "alkenyl" refers to a species of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an 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, and the like. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0024] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. In some embodiments, alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -CH2C≡CH.

[0025] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0026] The term "alkylamine" refers to -N(alkyl) x H y It refers to a 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.

[0027] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π-electrons (n is an integer). The term "aromatic" includes both carbocyclic aryl ("aryl", e.g., phenyl) and heterocyclic aryl (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon or nitrogen atoms) groups.

[0028] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the ring backbone are all carbon atoms. Thus, the term distinguishes carbocycle from "heterocyclic" rings or "heterocycles," in which the ring backbone contains at least one atom other than carbon. In some embodiments, at least one of the two rings in a bicyclic carbocycle is aromatic. In some embodiments, both rings in a bicyclic carbocycle are aromatic. Carbocycles include cycloalkyl and aryl.

[0029] 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, the aryl is phenyl or naphthyl. In some embodiments, the aryl is phenyl. In some embodiments, the aryl is C6-C 10 Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0030] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is optionally fused with an aromatic ring, and the point of attachment is to a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl group is selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicyclo[1.1.1]pentyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl. In some embodiments, the cycloalkyl is a monocyclic cycloalkyl. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Multicyclic cycloalkyls include, for example, adamantyl, norbornyl (ie, bicyclo[2.2.2]octyl and bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0031] The term "halo" or alternatively "halogen" or "halide" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0032] The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by halogen atoms. In one embodiment, the fluoroalkyl is a C1-C6 fluoroalkyl.

[0033] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by fluorine atoms. In one aspect, 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, etc.

[0034] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl is selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one embodiment, the heteroalkyl is a C1-C6 heteroalkyl.

[0035] The term "heteroalkylene" refers to a divalent heteroalkyl radical.

[0036] The term "heterocycle" or "heterocyclic" refers to aromatic heterocycles (also known as heteroaryls) and heterocycloalkyl rings (also known as heteroalicyclic groups) containing 1 to 4 heteroatoms in the ring, where each heteroatom in the ring is selected from O, S, and N, and each heterocyclic group has 3 to 10 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. In some embodiments, heterocycles are monocyclic, bicyclic, polycyclic, spirocyclic, or bridged compounds. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) contain rings having 3 to 10 atoms in their ring system, and aromatic heterocyclic groups contain rings having 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems.Examples of non-aromatic heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, and o- azepinyl, 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, These include 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 are 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 C-linked or N-linked where possible. For example, groups derived from pyrrole include pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). Furthermore, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-linked), or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, e.g., 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.

[0037] The term "heteroaryl" or, alternatively, "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Bicyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, heteroaryls contain 0 to 4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl is a C1-C9 heteroaryl. In some embodiments, a monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, a monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6-C9 heteroaryl.

[0038] A "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 an 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 a C2-C 10 In another embodiment, heterocycloalkyl is C-C 10 Heterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0039] The term "oxo" refers to the =O radical.

[0040] The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties when the atoms connected by the bond are considered to be part of a larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent, thereby allowing for the formation of a bond between the remaining specified groups.

[0041] The term "moiety" refers to a specific segment or functional group of a molecule. Chemical moieties tend to be recognized as chemical entities embedded in or attached to a molecule.

[0042] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional groups individually and independently selected from D, halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), 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, —NH, —NH(CH), —N(CH), —OH, —COH, —CO(C-C alkyl), —C(═O)NH, —C(═O)NH(C-C alkyl), —C(═O)N(C-C alkyl), —S(═O)NH, —S(═O)NH(C-C alkyl), —S(═O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, —SC-C alkyl, —S(═O)C-C alkyl, and —S(═O)C-C alkyl. In some embodiments, optional substituents are independently selected from D, halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -CH, -CHCH, -CF, -OCH, and -OCF. In some embodiments, substituted groups are substituted with one or two of the foregoing groups. In some embodiments, optional substituents on aliphatic carbon atoms (acyclic or cyclic) include oxo (=O).

[0043] As used herein, the term "acceptable" with respect to a formulation, composition, or ingredient means having no lasting adverse effects on the health status of the subject being treated.

[0044] The term "modulate" as used herein means to interact with a target directly or indirectly so as to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or expanding the activity of the target.

[0045] The term "modulator" as used herein refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, those of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an agonist.

[0046] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Those skilled in the art are familiar with 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.

[0047] The term "co-administration," as used herein, is meant to encompass the administration of selected therapeutic agents to a single patient and is 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.

[0048] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient quantity of an agent or compound being administered to relieve to some extent one or more of the symptoms of the disease or disorder being treated. Results include reduction and / or alleviation of the signs, symptoms, or causes of a disease, or other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the quantity of a composition comprising a compound as disclosed herein that is required to produce a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0049] The terms "enhance" or "enhancing," as used herein, means to increase or prolong, either in potency or duration, a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An "enhancing-effective amount," as used herein, refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0050] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or co-administration of more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that both active ingredients, such as the compounds described herein or pharmaceutically acceptable salts thereof, and auxiliary agents are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, such as the compounds described herein or pharmaceutically acceptable salts thereof, and auxiliary agents are administered to a patient simultaneously, concurrently, or sequentially as separate entities without any specific intervening time limit, such that administration provides an effective level of the two compounds to the patient's body. The latter term also applies to cocktail therapy, for example, the administration of three or more active ingredients.

[0051] The terms "kit" and "article of manufacture" are used synonymously.

[0052] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the following classes of mammals: humans, non-human primates such as chimpanzees, and other ape and monkey species; livestock such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0053] The terms "treat," "treating," or "treatment," as used herein, include alleviating, relieving, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., arresting the progression of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or arresting a symptom of a disease or condition prophylactically and / or therapeutically.

[0054] compound The compounds described herein, including pharmaceutically acceptable salts, active metabolites, and pharmaceutically acceptable solvates thereof, are amide prodrugs of dual S1P1 and S1P5 receptor agonists.

[0055] In some embodiments, the compounds of formula (I)

[0056] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, R 1 is hydrogen, -OR 7 , -NR7 R 8 , 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; and is selected from 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 substituted with halogen, C1-C6 alkyl, C 1-6 Haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)R 13 and optionally substituted with one or more groups selected from R 2 is -NR 7 R 8 , C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -C1-C6 alkyl-C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl, phenyl, and -C1-C6 alkyl-phenyl; and is selected from C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -C1-C6 alkyl-C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are substituted with halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)R 13 or R 1 and R 2 are combined to form halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R11 ), and -S(O)R 13 forming a C2-C9 heterocycloalkyl optionally substituted with one or more groups selected from R 3 is 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, and C 1-9 heteroaryl; 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, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 optionally substituted with one, two, or three groups selected from R 4 are each independently halogen, -CN, or 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 )C(O)N(R 10 )(R11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 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 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, -S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 optionally substituted with one, two, or three groups selected from R 5 and R 6 are independently selected from hydrogen and C1-C6 alkyl; R 7 and R 8 are each independently selected from hydrogen and C1-C6 alkyl; R9a and R 9b are independently hydrogen, 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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 optionally substituted with one, two, or three groups selected from R 9c is 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 ) and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 optionally substituted with one, two, or three groups selected from R 10 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 Aryl, -C 1-6 Alkyl-C 6-10 Aryl, C 1-9 Heteroaryl, and -C 1-6 Alkyl-C 1-9 heteroaryl; C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 Aryl, -C 1-6 Alkyl-C 6-10 Aryl, C 1-9 Heteroaryl, and -C 1-6 Alkyl-C 1-9 Heteroaryl is substituted with halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 11 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 12 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 13 are each independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -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 optionally substituted with one, two, or three groups selected from heteroaryl, and m is 0, 1, 2, or 3.

[0057] For any or all of the embodiments, the substituents are selected from among a subset of the listed alternatives. For example, in some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, is described herein, and R 5 and R 6is hydrogen. In some embodiments, the compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, are described herein, wherein R 5 is C 1-6 alkyl, and R 6 is hydrogen. In some embodiments, the compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, are described herein, wherein R 5 and R 6 is C 1-6 It is alkyl.

[0058] In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b are independently hydrogen and C 1-6 In some embodiments, there are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a is hydrogen and R 9b is C 1-6 In some embodiments, there are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a is hydrogen and R 9b is —CH. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b is C 1-6 In some embodiments, there are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b is —CH. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b is hydrogen.

[0059] In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9c is a halogen, C 1-6Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 C optionally substituted with one, two, or three groups selected from 1-6 In some embodiments, there are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9c is unsubstituted C 1-6 In some embodiments, there are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9c is —CH. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9c is -CH2CH3.

[0060] In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C 1-6 Alkyl, C 6-10 Aryl, and C 1-9heteroaryl; C 1-6 Alkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 C optionally substituted with one, two, or three groups selected from 6-10 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R 3 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C 1-6 Alkyl and -OR 10 and R is phenyl optionally substituted with one, two, or three groups selected from 10 is hydrogen, C 1-6 Alkyl, and C 1-6 In some embodiments, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C 1-6 Alkyl and -OR10 and R is phenyl optionally substituted with one, two, or three groups selected from 10 is C 1-6 In some embodiments, there are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is C 1-6 Alkyl and -OR 10 and R is phenyl substituted with one or two groups selected from 10 is C 1-6 It is alkyl.

[0061] In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 C optionally substituted with one, two, or three groups selected from 1-9 In some embodiments, there are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, and -OR 10 and R is pyridyl optionally substituted with one, two, or three groups selected from 10 is hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl.

[0062] In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is a halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 C optionally substituted with one, two, or three groups selected from 1-6 In some embodiments, there are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is halogen, -OR 10 , and -N(R 10 )(R 11 C optionally substituted with one, two, or three groups selected from 1-6 In some embodiments, there are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is unsubstituted C 1-6 It is alkyl.

[0063] In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 teeth

[0064] [ka] is.

[0065] In some embodiments, compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, are those in which m is 0.

[0066] In some embodiments, there is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. In some embodiments, there is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2. In some embodiments, there is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein m is 3. In some embodiments, there is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 are each independently halogen, -CN, or 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)R 13 , and -S(O)N(R 10 )(R 11 )- is selected from C 1-6 Alkyl is halogen, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10 In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 are each independently halogen, -CN, or C 1-6 Alkyl, -OR 10 , and -N(R 10 )(R 11 ) and C 1-6 Alkyl is halogen, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -C(O)OR 10In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 4 are each independently a halogen, C 1-6 Alkyl, -OR 10 Selected from C 1-6 Alkyl is halogen, C 1-6 Haloalkyl and -OR 10 and optionally substituted with one, two, or three groups selected from:

[0067] In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from hydrogen and C1-C6 alkyl. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R 1 is hydrogen. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R 1 is C1-C6 alkyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -CH3.

[0068] In some embodiments, there is a 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)R 13 In some embodiments, there is a 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 )(R11 ), and -S(O)R 13 In some embodiments, there is a 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)R 13 In some embodiments, there is a compound of formula (I), or a pharmaceutically 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, there is a compound of formula (I), or a pharmaceutically 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, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl substituted with 1, 2, or 3 halogens. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 One, two, or three C's 1-6 In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -OR 10In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl substituted with 1, 2, or 3 -OH. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 can be one, two, or three -N(R 10 )(R 11 ) is a C2-C6 alkyl substituted with

[0069] In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted C2-C6 alkyl.

[0070] In some embodiments, there is a 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)R 13 In some embodiments, there is a 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)R 13 In some embodiments, there is a 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 )(R11 ), and -S(O)R 13 In some embodiments, there is a compound of formula (I), or a pharmaceutically 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, there is a compound of formula (I), or a pharmaceutically 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, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C-C cycloalkyl optionally substituted with 1, 2, or 3 halogens. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 One, two, or three Cs 1-6 In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -OR 10 In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl substituted with 1, 2, or 3 -OH. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 can be one, two, or three -N(R 10 )(R11 ) is a C3-C6 cycloalkyl substituted with

[0071] In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an unsubstituted C-C cycloalkyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted cyclopropyl. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R 2 is unsubstituted cyclobutyl. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R 2 is unsubstituted cyclopentyl. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R 2 is unsubstituted cyclohexyl.

[0072] In some embodiments, there is a 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)R 13 In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted -C1-C6 alkyl-C3-C6 cycloalkyl. In some embodiments, there is a 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)R 13 In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted —CH2—C3-C6 cycloalkyl.

[0073] In some embodiments, there is a 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)R 13 C optionally substituted with one or more groups selected from 1-9 In some embodiments, there are compounds 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)R 13 C optionally substituted with one or more groups selected from 1-9 Heteroaryl, C 1-9 Heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments, there is a 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)R 13 In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2is halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)R 13 In some embodiments, there is a 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)R 13 In some embodiments, there is a 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)R 13 and pyrazinyl optionally substituted with one or more groups selected from:

[0074] In some embodiments, there is a 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, there is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted pyridyl. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R 2 is unsubstituted pyridazinyl. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2is unsubstituted pyrimidinyl. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R 2 is unsubstituted pyrazinyl.

[0075] In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 are combined to form halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -S(O)R 13 In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 are combined to form halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -S(O)R 13 In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 are combined to form an unsubstituted C2-C9 heterocycloalkyl.

[0076] In some embodiments, Formula (Ia)

[0077] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, R 1is hydrogen, -OR 7 , -NR 7 R 8 , 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; and is selected from 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 substituted with halogen, C1-C6 alkyl, C 1-6 Haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)R 13 and optionally substituted with one or more groups selected from R 2 is -NR 7 R 8 , C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -C1-C6 alkyl-C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 heteroaryl, phenyl, and -C1-C6 alkyl-phenyl; and is selected from C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -C1-C6 alkyl-C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl, and -C1-C6 alkyl-phenyl are substituted with halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 , -N(R 10 )(R 11 ), and -S(O)R 13 or R 1 and R 2 are combined to form halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10, -N(R 10 )(R 11 ), and -S(O)R 13 forming a C2-C9 heterocycloalkyl optionally substituted with one or more groups selected from R 7 and R 8 are each independently selected from hydrogen and C1-C6 alkyl; R 10 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 Aryl, -C 1-6 Alkyl-C 6-10 Aryl, C 1-9 Heteroaryl, and -C 1-6 Alkyl-C 1-9 heteroaryl; C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 Aryl, -C 1-6 Alkyl-C 6-10 Aryl, C 1-9 Heteroaryl, and -C 1-6 Alkyl-C 1-9 Heteroaryl is substituted with halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 11 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl, and R 13 are each independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl; C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -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 heteroaryl.

[0078] In some embodiments, there is a 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, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is hydrogen. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1is C1-C6 alkyl. In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -CH3.

[0079] In some embodiments, there is a compound of formula (Ia), 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)R 13 In some embodiments, there is a compound of Formula (Ia), 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)R 13 In some embodiments, there is a compound of Formula (Ia), 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)R 13 In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a halogen, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11In some embodiments, there is a compound of formula (Ia), or a pharmaceutically 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, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl substituted with 1, 2, or 3 halogens. In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 One, two, or three C's 1-6 In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -OR 10 In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl substituted with 1, 2, or 3 -OH. In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 can be one, two, or three -N(R 10 )(R 11 ) is a C2-C6 alkyl substituted with

[0080] In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted C2-C6 alkyl.

[0081] In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 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, there is a compound of Formula (Ia), 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)R 13 In some embodiments, there is a compound of Formula (Ia), 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)R 13 In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically 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, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a halogen, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C-C cycloalkyl substituted with 1, 2, or 3 halogens. In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 One, two, or three Cs 1-6 In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 -OR 10 In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl substituted with 1, 2, or 3 -OH. In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 can be one, two, or three -N(R 10 )(R 11 ) is a C3-C6 cycloalkyl substituted with

[0082] In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an unsubstituted C-C cycloalkyl. In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted cyclopropyl. In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted cyclobutyl. In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2is unsubstituted cyclopentyl. In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted cyclohexyl.

[0083] In some embodiments, there is a compound of formula (Ia), 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)R 13 In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted -C1-C6 alkyl-C3-C6 cycloalkyl. In some embodiments, there is a compound of Formula (Ia), 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)R 13 In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted —CH2—C3-C6 cycloalkyl.

[0084] In some embodiments, there is a compound of formula (Ia), 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)R13 C optionally substituted with one or more groups selected from 1-9 In some embodiments, there is a compound of Formula (Ia), 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)R 13 C optionally substituted with one or more groups selected from 1-9 Heteroaryl, C 1-9 Heteroaryl is selected from pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments, there is a compound of Formula (Ia), 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)R 13 In some embodiments, there is a compound of Formula (Ia), 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)R 13 In some embodiments, there is a compound of Formula (Ia), 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)R 13In some embodiments, there is a compound of Formula (Ia), 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)R 13 and pyrazinyl optionally substituted with one or more groups selected from:

[0085] In some embodiments, there is a 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, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted pyridyl. In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted pyridazinyl. In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted pyrimidinyl. In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted pyrazinyl.

[0086] In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 are combined to form halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -S(O)R 13In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 are combined to form halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), and -S(O)R 13 In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 are combined to form an unsubstituted C2-C9 heterocycloalkyl.

[0087] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the art to provide stable moieties and compounds.

[0088] In some embodiments,

[0089] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0090] In some embodiments,

[0091] [ka] or a pharmaceutically acceptable salt or solvate thereof.

[0092] In some embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts.Similarly, the active metabolites of these compounds with the same type of activity are included within the scope of this disclosure.In addition, the compounds described herein can exist not only in unsolvated form, but also in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc.The solvated form of the compounds presented herein is also considered to be disclosed herein.

[0093] "Pharmaceutically acceptable," as used herein, refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., it may be administered to an individual without causing undesired biological effects or interacting in a deleterious way with any of the components of the composition in which it is contained.

[0094] 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 in combination with a suitable anion, or in an alternative embodiment, the anionic form of the therapeutically active agent in combination 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 non-ionic species, dissolve rapidly in gastric and intestinal fluids, and are therefore useful in solid dosage forms. Furthermore, their solubility is often pH-dependent, allowing for selective dissolution in one part of the gastrointestinal tract or another, an ability that can be manipulated as an aspect of delayed- and sustained-release behavior. Furthermore, salt-forming molecules can be in equilibrium with neutral forms, thereby modulating their passage through biological membranes.

[0095] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid to provide a "pharmaceutically acceptable acid addition salt." In some embodiments, a compound described herein (i.e., in free base form) is basic and is 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, dodecyl sulfuric 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.

[0096] In some embodiments, the compounds described herein are prepared as chloride, sulfate, bromide, mesylate, maleate, citrate, or phosphate salts.

[0097] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base to provide a "pharmaceutically acceptable base addition salt."

[0098] In some embodiments, the compounds described herein are acidic and react with a base. Under these circumstances, the acidic protons of the compounds described herein are exchanged with metal ions, such as lithium, sodium, potassium, magnesium, calcium, or aluminum ions. In some cases, the compounds described herein cooperate with organic bases, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids, such as arginine and lysine. 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, and the like. In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts.

[0099] It should be understood that reference to a pharmaceutically acceptable salt includes solvent addition forms. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of solvent and are formed during the process of separating or purifying a compound with a pharmaceutically acceptable solvent, such as water or ethanol. 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 solvated and unsolvated forms.

[0100] 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 that have the same type of activity.

[0101] In some embodiments, the organic radical (e.g., alkyl group, aromatic ring) moiety of the compounds described herein is susceptible to various metabolic reactions. By incorporating appropriate substituents on the organic radical, this metabolic pathway can be reduced, minimized, or eliminated. In certain embodiments, suitable substituents for reducing or eliminating the susceptibility of the aromatic ring to metabolic reactions are, by way of example only, halogen, deuterium, alkyl group, haloalkyl group, or deuterated alkyl group.

[0102] In another embodiment, the compounds described herein are labeled with isotopes (e.g., with radioisotopes) or by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0103] The compounds described herein include isotopically labeled compounds, which are identical to those detailed in the various formulas and structures presented herein except for the fact that one or more atoms have been replaced with an atom 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 compounds of the invention include, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 In one embodiment, the isotopes of the isotopes described herein, e.g., 3 H and 14Compounds incorporating radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium provides certain therapeutic advantages due to greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen atoms of the compounds described herein are replaced with deuterium.

[0104] In some embodiments, the compounds described herein contain one or more stereocenters, and each stereocenter independently exists in either the R or S configuration. The compounds provided herein include all diastereomeric, enantiomeric, atropisomeric, and epimeric forms, and the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and the appropriate mixtures thereof.

[0105] Individual stereoisomers can be obtained, as needed, 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 enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is carried out by chromatography, or by formation of diastereomeric salts followed by recrystallization or chromatographic separation, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0106] Compound synthesis The compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

[0107] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0108] The compounds are prepared using standard organic chemistry techniques, such as those described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may also be utilized, such as variations in solvents, reaction temperatures, reaction times, and different chemical reagents and other reaction conditions. Starting materials are available from commercial sources or are readily prepared.

[0109] Suitable references and articles detailing the synthesis of reactants useful in preparing the compounds described herein or providing references to articles describing their 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.G. Gilchrist, "Heterocyclic Chemistry," 2nd Ed., John Wiley & Sons, New York, 1992; and J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th Ed., Wiley Interscience, New York, 1992. Additional suitable references and papers detailing the synthesis of or referencing articles describing the preparation of reactants useful in the preparation of the compounds described herein 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, RV "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC "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,TWG“Organic Chemistry”7th Edition(2000)John Wiley & Sons,ISBN:0-471-19095-0;Stowell,JC,“Intermediate Organic Chemistry”2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; the 8-volume "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X; the 55-volume "Organic Reactions" (1942-2000) John Wiley & Sons; and the 73-volume "Chemistry of Functional Groups" John Wiley & Sons.

[0110] In some embodiments, the compounds are prepared as described in the Examples.

[0111] Treatment method In some embodiments, described herein are methods of treating a CNS disease or disorder in a patient in need thereof, the methods comprising administering to the patient a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, there 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) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from the group consisting of acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHL or AHLE), adult Refsum's disease, infantile Refsum's disease, Alexander's disease, Alzheimer's disease, Barro's concentric sclerosis, Canavan's disease, central pontine myelinolysis (CPM), cerebral palsy, cerebrotendinous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic's syndrome, diffuse myelinoclastic sclerosis, encephalomyelitis, Guillain-Barré syndrome, Huntington's disease (HD), idiopathic inflammatory demyelinating disease (HDD), Krabbe's disease, Leber's hereditary optic neuropathy, neuropathy, leukodystrophy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy (MLD), multifocal motor neuropathy (MMN), multiple sclerosis (MS), Niemann-Pick disease type C, paraproteinemic demyelinating polyneuropathy, Parkinson's disease (PD), Pelizaeus-Merzbach disease (PMD), progressive multifocal leukoencephalopathy (PML), tropical spastic paraplegia (TSP), X-linked adrenoleukodystrophy (X-ALD, ALO, or X-linked ALO), and Zellweger syndrome. In some embodiments, there 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) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from multiple sclerosis.In some embodiments, there 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) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is X-linked adrenoleukodystrophy.

[0112] In some embodiments, there 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) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, and further comprising administering to the patient a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments, there 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) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from the group consisting of acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHL or AHLE), adult Refsum's disease, infantile Refsum's disease, Alexander's disease, Alzheimer's disease, Barro's concentric sclerosis, Canavan's disease, central pontine myelinolysis (CPM), cerebral palsy, cerebrotendinous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic's syndrome, diffuse myelinoclastic sclerosis, encephalomyelitis, Guillain-Barré syndrome, Huntington's disease (HD), idiopathic inflammatory demyelinating disease (HDD), Krabbe's disease, Leber's hereditary optic neuropathy, The disease is selected from the group consisting of leukodystrophy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy (MLD), multifocal motor neuropathy (MMN), multiple sclerosis (MS), Niemann-Pick disease type C, paraproteinemic demyelinating polyneuropathy, Parkinson's disease (PD), Pelizaeus-Merzbach disease (PMD), progressive multifocal leukoencephalopathy (PML), tropical spastic paraplegia (TSP), X-linked adrenoleukodystrophy (X-ALD, ALO, or X-linked ALO), and Zellweger syndrome, and the method further comprises administering to the patient a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor.In some embodiments, there are methods 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) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is selected from multiple sclerosis, and the method further comprises administering to the patient a peripherally confined fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments, there are methods 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) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the CNS disease or disorder is X-linked adrenoleukodystrophy, and the method further comprises administering to the patient a peripherally confined fatty acid amide hydrolase (FAAH) inhibitor.

[0113] In some embodiments of the methods described herein, the peripherally restricted FAAH inhibitor is ASP-3652.

[0114] Pharmaceutical Composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of active compounds into pharmaceutical preparations. Suitable formulations depend on the route of administration selected. Summaries of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for disclosure.

[0115] In some embodiments, the compound described herein is administered alone or in pharmaceutical compositions with pharmaceutically acceptable carriers, excipients or diluents.In some embodiments disclosed herein, the pharmaceutical composition further comprises a peripherally localized fatty acid amide hydrolase (FAAH) inhibitor.In some embodiments, the pharmaceutical composition further comprises a peripherally localized FAAH inhibitor, and the peripherally localized FAAH inhibitor is ASP-3652.

[0116] The administration of compound and composition described herein can be achieved by the method that allows compound to be delivered to the site of action.These methods include but are not limited to enteral route (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral route (including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous injection or infusion), inhalation, transdermal, transmucosal, sublingual, buccal and topical (including epidermal, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, but the most suitable route can depend on the condition or disorder of recipient, for example.

[0117] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete 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 or water-in-oil liquid emulsion, hi some embodiments, the active ingredient is presented as a bolus, electuary, or paste.

[0118] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, as well as sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surfactant, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, tablets are coated or scored and formulated to provide a delayed or controlled release of the active ingredient therein. All formulations intended for oral administration should be in dosages suitable for such administration. Push-fit capsules can contain the active ingredient in combination with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active compounds can be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycol.In some embodiments, stabilizers are added.Sugared tablet cores are provided with suitable coatings.For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.Dyes or pigments can be added to tablets or sugared tablet coatings for identification or to characterize different combinations of active compound dosages.

[0119] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or multi-dose containers, with added preservatives. The compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing, and / or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, e.g., sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, e.g., saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind described above.

[0120] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that make the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may further contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions.

[0121] Pharmaceutical compositions can also be formulated as depot preparations.Such long-acting preparations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.Therefore, for example, compound can be formulated with suitable polymeric or hydrophobic materials (for example, as emulsion in acceptable oil) or ion exchange resin, or as poorly soluble derivatives, for example, as poorly soluble salts.

[0122] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in a conventional manner. Such compositions may comprise the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

[0123] The pharmaceutical compositions may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0124] Pharmaceutical compositions can be administered topically, i.e., non-systemically. This includes applying the compound to the external epidermis or buccal cavity, and instilling the compound into the ear, eye, and nose, so that the compound does not enter the bloodstream in large amounts. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0125] Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin 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 comprise 0.001% to 10% w / w, for example 1% to 2% by weight, of the formulation for topical administration.

[0126] Pharmaceutical compositions administered by inhalation are conveniently delivered from an insufflator, a nebulizer, a pressurized pack, or other conventional means for delivering an aerosol spray.Pressurized packs can contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases.In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount.Alternatively, for administration by inhalation or insufflation, pharmaceutical preparations can be in the form of a dry powder composition, for example, a powder mix of the compound and a suitable powder base, such as lactose or starch.The powder composition can be presented in a unit dosage form, for example, in capsules, cartridges, gelatin, or blister packs, from which the powder can be administered using an inhaler or insufflator.

[0127] In some embodiments, the compounds disclosed herein are formulated to achieve the delivery of the compound to specific regions of the gastrointestinal tract.For example, the compounds disclosed herein are formulated for oral delivery by bioadhesive polymers, pH-sensitive coatings, time-dependent biodegradable polymers, microflora activation systems, etc., to achieve the delivery of the compound to specific regions of the gastrointestinal tract.

[0128] In some embodiments, the compounds disclosed herein are formulated to provide controlled release of the compounds. Controlled release refers to the release of the compounds described herein from a dosage form in which the compounds described herein are incorporated according to a desired profile over a long period of time. Controlled release profiles include, for example, sustained release, extended release, pulsed release, and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow the delivery of drugs to a subject over a long period of time according to a predetermined profile. Such release rates provide therapeutically effective levels of drugs over a long period of time, thereby providing a longer-lasting pharmacological response while minimizing side effects compared to conventional rapid-release dosage forms. Such long-term response provides many unique advantages that cannot be achieved with corresponding short-acting immediate-release preparations.

[0129] Approaches for delivering intact therapeutic compounds to specific regions of the gastrointestinal tract (e.g., the colon, etc.) include:

[0130] (i) Polymer coating: Intact molecules can be delivered to the colon without being absorbed in the upper part of the intestine by coating the drug molecules with suitable polymers that degrade only in the colon.

[0131] (ii) Coatings with pH-sensitive polymers: The majority of enteric and colon-targeted delivery systems are based on coating tablets or pellets that are filled into conventional hard gelatin capsules. The most commonly used pH-dependent coating polymers are methacrylic acid copolymers, commonly known as Eudragit® S, and more specifically as Eudragit® L and Eudragit® S. Eudragit® L100 and S100 are copolymers of methacrylic acid and methyl methacrylate.

[0132] (iii) coating with biodegradable polymers;

[0133] (iv) embedding into a matrix;

[0134] (v) embedding in biodegradable matrices and hydrogels;

[0135] (vi) embedding in a pH-sensitive matrix;

[0136] (vii) sustained release system;

[0137] (viii) Redox sensitive polymer;

[0138] (ix) bioadhesive systems;

[0139] (x) coating with fine particles;

[0140] (xi) osmotically controlled drug delivery;

[0141] Another approach to colon-targeted drug delivery or controlled release systems involves embedding drugs in polymer matrices to entrap and release the drug 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.

[0142] Additional pharmaceutical approaches to 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.Kumar P,Mishra B.Colon targeted drug delivery systems--an overview.Curr Drug Deliv.2008 Jul;5(3):186-98.Van den Mooter G.Colon drug delivery.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.

[0143] It will be understood that, among other things, in addition to the ingredients mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question; for example, formulations suitable for oral administration may include flavoring agents.

[0144] Dosage and treatment regimens In one embodiment, 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 the administration of a dual S1P1 and S1P5 receptor agonist. A method for treating any of the diseases or disorders described herein in a mammal in need of such treatment 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.

[0145] In some embodiments disclosed herein, provided is a method for administering dual S1P1 and S1P5 receptor agonists in combination with additional therapeutic agents.In some embodiments, provided is a method for administering dual S1P1 and S1P5 receptor agonists in combination with peripherally restricted fatty acid amide hydrolase (FAAH) inhibitors.In some embodiments, provided is a method for administering dual S1P1 and S1P5 receptor agonists in combination with peripherally restricted FAAH inhibitors, and the peripherally restricted FAAH inhibitor is ASP-3652.

[0146] In certain embodiments, compositions containing the compounds described herein are administered for preventive and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent at least one symptom of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose-finding clinical trials.

[0147] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or at risk of a particular disease, disorder, or condition. Such an amount is defined to be a "prophylactically effective amount or dose." For this application, the precise amount will vary depending on the patient's health, weight, and the like. When used in patients, the effective amount for this application will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status and response to the drugs, and the judgment of the treating physician. In one embodiment, prophylactic treatment involves administering a pharmaceutical composition containing a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal that has previously experienced at least one symptom of the disease being treated and is now in remission, to prevent the recurrence of the disease or condition symptoms.

[0148] In certain embodiments where the patient's condition does not improve, the compound is administered chronically, i.e., for an extended period of time, including for the patient's lifetime, at the physician's discretion, to ameliorate or otherwise manage or limit the symptoms of the patient's disease or disorder.

[0149] In certain embodiments where a patient's condition is improving, the dose of the administered drug is temporarily reduced or temporarily stopped for a period of time (i.e., a "drug holiday"). In certain embodiments, the length of the drug holiday is between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dose reduction during the drug holiday is, by way of example only, 10% to 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0150] Once improvement of the patient's condition occurs, a maintenance dose is administered as needed. Thereafter, in certain embodiments, the dosage or frequency of administration, or both, are reduced, depending on the symptoms, to a level at which the improved disease, disorder, or condition is maintained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon recurrence of symptoms.

[0151] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined by the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0152] In general, however, dosages used for adult human treatment typically range from 0.01 mg to 5000 mg per day. In one aspect, dosages utilized for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dosage is suitably presented as a single dose or as divided doses administered simultaneously or at appropriate intervals, e.g., as two, three, four or more subdoses per day.

[0153] In one embodiment, a suitable daily dosage for a compound described herein or a pharmaceutically acceptable salt thereof is about 0.01 to about 50 mg per kg of body weight. In some embodiments, the daily dosage or amount of active ingredient in a dosage form will be less than or greater than the ranges set forth herein, depending on many variables related to the individual treatment regimen. In various embodiments, the daily dosage and unit dosage will vary depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0154] The toxicity and therapeutic efficacy of such treatment regimens include, but are not limited to, LD 50 and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which is defined as the LD 50 and ED 50 In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating therapeutically effective daily dosage ranges and / or therapeutically effective unit dosages for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is at least 50 mg / kg / day with minimal toxicity and is expressed as a ratio between ED1 and ED2. In certain embodiments, data obtained from cell culture assays and animal studies are used in formulating therapeutically effective daily dosage ranges and / or therapeutically effective unit dosages for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is at least 50 mg / kg / day with minimal toxicity and ED1. 50 In certain embodiments, the daily dosage range and / or unit dosage amount varies within this range depending on the dosage form employed and the route of administration utilized.

[0155] In any of the foregoing aspects, in further embodiments, an effective amount of a 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 injection to a mammal, and / or (e) administered topically to a mammal, and / or (f) administered non-systemically or topically to a mammal.

[0156] In any of the foregoing aspects, further embodiments include a single administration of an effective amount of the compound, including further embodiments where (i) the compound is administered once daily, or (ii) the compound is administered multiple times throughout the day to the mammal.

[0157] In any of the foregoing aspects, further embodiments include multiple administrations of an effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently in a single dose, (ii) the interval between multiple administrations is every 6 hours, (iii) the compound is administered to the mammal every 8 hours, (iv) the compound is administered to the mammal every 12 hours, or (v) the compound is administered to the mammal every 24 hours. In further or alternative embodiments, the method includes a drug holiday, during which administration of the compound is temporarily suspended or the dose of the administered compound is temporarily reduced, and at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0158] In certain instances, it will be appropriate to administer at least one compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents.

[0159] 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 has minimal therapeutic benefit on its own, but when combined with another therapeutic agent, enhances the overall therapeutic benefit to the patient). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein with another agent (which also comprises a therapeutic regimen) that also has a therapeutic effect.

[0160] In one particular embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the compound described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder, or condition being treated, thereby providing a greater overall benefit than either therapeutic agent administered alone.

[0161] In either case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient will be additive of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0162] In certain embodiments, 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 effective drugs, adjuvants, etc. The therapeutically effective amounts of drugs and other agents used in combination therapy regimens are optionally determined by means similar to those specified above for the active ingredients themselves. Additionally, the prevention / treatment methods described herein encompass the use of metronomic dosing, i.e., providing more frequent, lower doses to minimize toxic side effects. In some embodiments, combination therapy regimens encompass treatment regimens 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 continued at any time during or after the end of treatment with the second agent. A combination therapy regimen includes treatments in which a compound described herein, or a pharmaceutically acceptable salt thereof, and a second agent used in combination are administered at the same time or at different times and / or at increasing or decreasing intervals during the treatment period. Combination therapy also includes periodic treatments that are started and stopped at various times to aid in the clinical management of the patient.

[0163] It will be understood that dosage regimens to treat, prevent, or ameliorate the condition for which relief is sought will be modified to accommodate a variety of factors (e.g., the disease, disorder, or condition from which the subject suffers, the subject's age, weight, sex, diet, and medical condition). Thus, in some instances, the dosage regimen actually utilized will vary and, in some embodiments, will deviate from the dosage regimens set forth herein.

[0164] With respect to the combination therapies described herein, the dosage of the co-administered compounds will vary depending on the type of co-drug used, the particular drug used, the disease or condition being treated, etc. In additional embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously or sequentially with the one or more other therapeutic agents.

[0165] In combination therapy, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order, or even simultaneously. When administration is simultaneous, the multiple therapeutic agents may, by way of example only, be provided in a single, unified form or in multiple forms (e.g., as a single pill or two separate pills).

[0166] The compounds described herein, or pharmaceutically acceptable salts thereof, as well as combination therapies, may be administered before, during, or after the onset of a disease or condition, and the timing of administering a composition containing the compound may vary. Thus, in one embodiment, the compounds described herein are used as prophylactics to prevent the onset of a disease or condition and are administered continuously to a subject prone to the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of symptoms. In certain embodiments, the compounds described herein are administered as soon as practicable after the onset of a disease or condition is detected or suspected, and for the duration necessary to treat the condition. In some embodiments, the duration of treatment required varies, and the treatment duration is tailored to the specific needs of each subject. For example, in certain embodiments, the compounds described herein, or formulations containing the compounds, are administered for at least two weeks, about one month, to about five years. [Example]

[0167] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0168] As used above, and throughout the description of the present invention, unless otherwise specified, the following abbreviations shall be understood to have the following meanings: ACN or MeCN acetonitrile AcOH acetic acid Ac Acetyl BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene Bn Benzyl BOC or Boc tert-butylcarbamate t-Bu tert-butyl Cy Cyclohexyl DBA or dba dibenzylidene acetone 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 NaHMDS Potassium bis(trimethylsilyl)amide NaHMDS sodium bis(trimethylsilyl)amide, LiHMDS Lithium bis(trimethylsilyl)amide LAH Lithium Anhydrous LCMS Liquid Chromatography Mass Spectrometry Me methyl MeOH Methanol MS mass spectrometry Ms. Mesir 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 i-Pr / iPr iso-propyl rt room temperature TBS tert-butyldimethylsilyl RP-HPLC Reversed-phase high-pressure liquid chromatography TFA trifluoroacetic acid TEA Triethylamine THF tetrahydrofuran TLC thin layer chromatography

[0169] 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)

[0170] [ka]

[0171] A mixture of A-1 (15.0 g, 92.5 mmol), K2CO3 (25.6 g, 185 mmol), and BnBr (15.8 g, 92.5 mmol) in MeCN (100 mL) was stirred at room temperature overnight. The mixture was filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (petroleum ether / EtOAc = 100 / 1, v / v) to give A-2 (20.7 g, 89% yield) as a yellow oil.

[0172] To a mixture of A-2 (20.7 g, 82 mmol) in THF (200 mL), MeMgBr (9.78 g, 82 mmol) was added slowly at 0 °C, and the mixture was stirred at room temperature overnight. The mixture was quenched with NH4Cl, and the mixture was poured into water and diluted with EtOAc (200 mL). * The mixture was extracted with 1N HCl (130 mL) and THF (100 mL) at room temperature for 3 hours. The mixture was extracted with EtOAc (100 mL × 3), and the organic phase was washed with water and brine, dried over NaSO, and concentrated. The residue was purified by silica gel flash chromatography to give A-3 (13 g, 73% yield) as a yellow solid.

[0173] POCl (13.5 g, 88.3 mmol) was slowly added to DMF (30 mL) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. A solution of A-3 (13 g, 51.9 mmol) in DCM (30 mL) was added and stirred at room temperature for 3 h. The reaction mixture was poured onto ice and extracted with EtOAc (20 mL × 3). The combined organic phase was washed with water, brine, dried over Na SO and concentrated. The residue was purified by silica gel flash chromatography to give A-4 (8.2 g, 57% yield) as a yellow solid.

[0174] To a mixture of A-4 (5 g, 18 mmol) in DCM (50 mL) was added BCl (4.21 g, 35.9 mmol) at 0 °C. The mixture was stirred for 4 h at 0 °C. The mixture was quenched with water and extracted with EtOAc (50 mL × 3). The combined organic phase was washed with water and brine, dried over NaSO, and concentrated. The residue was purified by silica gel flash chromatography (petroleum ether / EtOAc = 20 / 1 to 3 / 1, v / v) to give A-5 (2.0 g, 59% yield) as a yellow solid.

[0175] To a mixture of A-6 (3 g, 22 mmol) and MgCl (3.15 g, 33 mmol) in MeCN (30 mL) was added TEA (6.69 g, 66.1 mmol) at room temperature. The reaction mixture was stirred for 0.5 h at room temperature. Paraformaldehyde (3.31 g, 110 mmol) was added, and the reaction mixture was stirred at 85 °C overnight. The mixture was poured into water and extracted with EtOAc (50 mL × 3). The combined organic phase was washed with water, brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography to give A-7 (3.1 g, 86% yield) as a colorless oil.

[0176] A mixture of A-7 (3.1 g, 18.9 mmol), MeI (4.02 g, 28.3 mmol), and KCO (7.83 g, 56.6 mmol) in DMF (20 mL) was stirred at 40 °C for 2 h. The mixture was poured into water and EtOAc (30 mL) was added. * The combined organic phase was washed with water and brine, dried over Na2SO4, and concentrated to give A-8 (3.1 g, 92% yield) as a colorless oil.

[0177] To a mixture of A-8 (3.1 g, 17.4 mmol) in MeOH (30 mL) was added NaBH (1.32 g, 34.8 mmol) at 0 °C. The mixture was stirred overnight at room temperature. The mixture was poured into water and EtOAc (30 mL *The resulting mixture was extracted with 3). The combined organic phase was washed with water and brine, dried over NaSO, and concentrated. The residue was purified by silica gel flash chromatography to give A-9 (3.0 g, 96% yield) as a colorless oil.

[0178] To a solution of A-5 (2.2 g, 11.7 mmol) and PPh3 (3.99 g, 15.2 mmol) in THF (30 mL) at 0 °C, A-9 (2.11 g, 11.7 mmol) and DIAD (2.99 mL, 15.2 mmol) were added. The mixture was stirred overnight at room temperature. The mixture was poured into water and EtOAc (20 mL) was added. * The resulting mixture was extracted with 3). The combined organic phase was washed with water, brine, dried over NaSO, and concentrated. The residue was purified by silica gel flash chromatography to give A-10 (1.6 g, 39% yield) as a yellow solid.

[0179] A mixture of A-10 (1.6 g, 4.57 mmol), DIEA (708 mg, 5.48 mmol), AcOH (27.4 mg, 457 μmol), and A-11 (831 mg, 5.48 mmol) in DCE (20 mL) was stirred at room temperature overnight. NaBH(OAc) (2.9 g, 13.7 mmol) was added, and the mixture was stirred at room temperature for 4 h. The mixture was quenched with aqueous NH4Cl, poured into water, and diluted with EtOAc (50 mL). * The resulting mixture was extracted with 3). The combined organic phase was washed with water, brine, dried over NaSO, and concentrated. The residue was purified by silica gel flash chromatography to give A-12 (1.08 g, 53% yield) as a yellow solid.

[0180] To a mixture of A-12 (1.08 g, 2.4 mmol) in THF (6 mL) and water (3 mL), LiOH·HO (115 mg, 4.8 mmol) was added. The mixture was stirred overnight at room temperature. Water (10 mL) was added, and the mixture was adjusted to pH 4-5 with 1N HCl. The mixture was extracted with EtOAc (20 mL × 3), and the combined organic phase was washed with water and brine, dried over NaSO, and concentrated. The residue was purified by preparative HPLC to give compound 1 (670 mg, 64% yield) as a white solid. LCMS: 434.2 [M-1] + .

[0181] Compound 1 (selalifimod) has an S1P1 EC50=11.8 nM and an S1P5 EC50=1 nM.

[0182] Example 2: Synthesis of 1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)-N-methylazetidine-3-carboxamide (Compound 2)

[0183] [ka]

[0184] To a mixture of compound 1 (50 mg, 115 μmol) and DIEA (44.5 mg, 344 μmol) in DMF (5 mL) was added HATU (65.5 mg, 172 μmol) at 0° C. The mixture was stirred at 0° C. for 1 hour, and methanamine (17.8 mg, 574 μmol) was added. The mixture was stirred at room temperature overnight. Water (50 mL) was added, and the mixture was extracted with EtOAc (20 mL×3). The combined organic phase was washed with water (20 mL), brine (20 mL), and concentrated. The residue was purified by preparative HPLC to give 1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)-N-methylazetidine-3-carboxamide (compound 2) (10 mg, 22.3 μmol) as a white solid. MS(ESI):449.3(M+H).

[0185] Example 3: Synthesis of 1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)-N-(pyridin-3-yl)azetidine-3-carboxamide (Compound 3)

[0186] [ka]

[0187] Starting from compound 1 and pyridin-3-amine, 1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)-N-(pyridin-3-yl)azetidine-3-carboxamide (compound 3) was prepared as described in Example 2. MS (ESI): 510.2 (M+H).

[0188] Example 4: Synthesis of 1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)-N-(pyridazin-3-yl)azetidine-3-carboxamide (Compound 4)

[0189] [ka]

[0190] Starting from compound 1 and pyridazin-3-amine, 1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)-N-(pyridazin-3-yl)azetidine-3-carboxamide (compound 4) was prepared as described in Example 2. MS (ESI): 511.2 (M+H).

[0191] Example 5: Synthesis of N-(3-fluoropropyl)-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 5)

[0192] [ka]

[0193] Starting from compound 1 and 3-fluoropropan-1-amine, N-(3-fluoropropyl)-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (compound 5) was prepared as described in Example 2. MS (ESI): 495.3 (M+H).

[0194] Example 6: Synthesis of 1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)-N-(2,2,2-trifluoroethyl)azetidine-3-carboxamide (Compound 6)

[0195] [ka]

[0196] Starting from compound 1 and 2,2,2-trifluoroethan-1-amine, 1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)-N-(2,2,2-trifluoroethyl)azetidine-3-carboxamide (compound 6) was prepared as described in Example 2. MS (ESI): 517.3 (M+H).

[0197] Example 7: Synthesis of N-(cyclopropylmethyl)-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 7)

[0198] [ka]

[0199] Starting from compound 1 and 1-cyclopropylmethanamine, N-(cyclopropylmethyl)-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (compound 7) was prepared as described in Example 2. MS (ESI): 489.4 (M+H).

[0200] Example 8: Synthesis of N-cyclopropyl-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 8)

[0201] [ka]

[0202] Starting from compound 1 cyclopropanamine, N-cyclopropyl-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (compound 8) was prepared as described in Example 2. MS (ESI): 475.4 (M+H).

[0203] Example 9: Synthesis of (R)-N-(sec-butyl)-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 9)

[0204] [ka]

[0205] Starting from compound 1 and (2R)-butan-2-amine, (R)-N-(sec-butyl)-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (compound 9) was prepared as described in Example 2. MS (ESI): 491.4 (M+H).

[0206] Example 10: Synthesis of (S)—N-(sec-butyl)-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 10)

[0207] [ka]

[0208] Starting from compound 1 and (2S)-butan-2-amine, (S)-N-(sec-butyl)-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (compound 10) was prepared as described in Example 2. MS (ESI): 491.4 (M+H).

[0209] Example 11: Synthesis of 1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)-N-(3,3,3-trifluoropropyl)azetidine-3-carboxamide (Compound 11)

[0210] [ka]

[0211] Starting from compound 1 and 3,3,3-trifluoropropan-1-amine, 1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)-N-(3,3,3-trifluoropropyl)azetidine-3-carboxamide (compound 11) was prepared as described in Example 2.

[0212] Example 12: Synthesis of azetidin-1-yl(1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidin-3-yl)methanone (Compound 12)

[0213] [ka]

[0214] Starting from compound 1 and azetidine, azetidin-1-yl(1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidin-3-yl)methanone (compound 12) was prepared as described in Example 2. MS (ESI): 475.2 (M+H).

[0215] Compounds 13-23 were prepared in a similar manner as described in the previous examples.

[0216] [Table 1-1]

[0217] [Table 1-2]

[0218] Example 13: FAAH substrate evaluation Purified recombinant human FAAH (rhFAAH) was purchased from Cayman Chemical (Ann Arbor, MI, USA). The total volume of each incubation was 400 μL, containing a final concentration of 0.5 ng / μL rhFAAH, 1 μM test compound, 1.25% ethanol or 1 μM PF-3845 (FAAH inhibitor), and 0.1% bovine serum albumin in Tris-EDTA buffer (pH 8.0). Incubations were performed at room temperature. At 0, 5, 15, 30, and 60 min, 30 μL aliquots of the reaction mixture were removed and mixed with 300 μL of acetonitrile containing 5 ng / mL terfenadine and 10 ng / mL tolbutamide as internal standards to quench the reaction. The resulting mixture was centrifuged at 4000 rpm at 4°C for 15 min, and 100 μL of the supernatant was subjected to LC-MS / MS analysis to measure the formation of acid metabolites.

[0219] LC-MS / MS analysis A Waters Acquity Ultra Performance LC system was used for sample analysis. Chromatography was performed on a reversed-phase Kinetex 2.6 μm C18 column, 2.1 × 30 mm, 100 Å. Mobile phase A consisted of 0.1% formic acid in water, and mobile phase B consisted of 0.1% formic acid in acetonitrile. The flow rate for acid metabolites of the test compounds was 0.9 mL / min for 1.5 min. The mass spectrometers (API-5500 and API Q Trap 4000, Applied Biosystems / MDS SCIEX Instruments, Framingham, MA, USA) were operated in ESI positive or negative ion MRM mode.

[0220] Data analysis The formation of acid metabolites was monitored and quantified using a single calibration point of 1 μM. The observed rate constants (ke) for acid metabolite formation were calculated by plotting metabolite concentration against time of incubation, with the slope as ke, and are shown in Table 1.

[0221] [Table 2]

[0222] The examples and embodiments described herein are for illustrative purposes only, and various modifications and changes suggested to those skilled in the art are intended to be included within the spirit and scope of this application and the scope of 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 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, selected from 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 may be 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 and is optionally substituted thereby, R ２ is - NR ７ R ８ 、 C ２ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, -C １ -C ６ alkyl - C ３ -C ６ cycloalkyl, C ２ -C ９ heterocycloalkyl, C １－９ heteroaryl, phenyl, and -C １ -C ６ alkyl - phenyl selected from, C ２ -C ６ [[ID=CO2]]alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C ３ -C ６ cycloalkyl, -C １ -C ６ alkyl - C<(CO2) ３ -C ６ cycloalkyl, C ２ -C ９ heterocycloalkyl, C １－９ heteroaryl, phenyl, and -C １ -C ６ alkyl - phenyl are optionally substituted with one or more groups selected from halogen, C １ -C ６ alkyl, C １－６ haloalkyl, -CN, -OR １０ 、 -N(R １０ )(R １１ ), and -S(O) ２ R １３ or, R １ and R s ２ are combined to form halogen, C １－６ alkyl, C １－６ haloalkyl, -OR １０ 、 -N(R １０ It should be noted that there may be some inaccuracies in the translation due to the complexity and potential errors in the original text. It is recommended to double - check with the original patent content for a more accurate understanding.) (Caution １１ ), and -S(O) ２ R １３ C is optionally replaced with one or more elements selected from ２ -C ９ Forms heterocycloalkyl groups, R ３ is selected from 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, and C １－９ heteroaryl, and 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, and C １－９ heteroaryl is 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 -C(O)OR １０ and optionally substituted with one, two, or three groups selected therefrom, R ４ These are, independently, halogen, -CN, and C. １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Ariel, C １－９ heteroaryl, -OR １０ , -SR １０ , -N(R １０ ) (Caution １１ ), -C(O)OR １０ , -OC(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)OR １３ , -N(R １２ ) S(O) ２ R １３ , -C(O)R １３ , -S(O)R １３ , -OC(O)R １３ , -C(O)N(R １０ ) (Caution １１ ), -C(O)C(O)N(R １０ ) (Caution １１ ), -N(R １２ ) C(O)R １３ , -S(O) ２ R １３ , -S(O) ２ N(R) １０ ) (Caution １１ )-, -S(=O)(=NH)N(R １０ ) (Caution １１ ), -CH ２ C(O)N(R) １０ ) (Caution １１ ), -CH ２ N(R) １２ ) C(O)R １３ ien-CH ２ S(O) ２ R １３ , and -CH ２ S(O) ２ N(R) １０ ) (Caution １１ ) is selected from 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, R ７ and R ８ Each of them independently consists of 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. R ９ｃ is halogen, -CN, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, C ２－９ Heterocycloalkyl, C ６－１０ Ariel, C １－９ heteroaryl, -OR １０ , -SR １０ , -N(R １０ ) (Caution １１ ) is selected from 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 １０ Each of them is independently of 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, 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 Optionally substituted with one, two, or three groups selected from heteroaryls, R １１ Each of them is independently of hydrogen and C １－６ Alkyl and C １－６ Selected from haloalkyls, R １２ Each of them is independently of hydrogen and C １－６ Alkyl and C １－６ Selected from haloalkyls, R １３ Each is independent of 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 Selected from heteroaryls, 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 Optionally substituted with one, two, or three groups selected from heteroaryls, A compound, or a pharmaceutically acceptable salt or solvate thereof, where m is 0, 1, 2, or 3.

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

3. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R9c is a C1-6 alkyl optionally substituted with one, two, or three groups selected from halogen, C1-6 alkyl, C1-6 haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10.

4. The compound according to claim 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R9c is an unsubstituted C1-6 alkyl group.

5. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is a phenyl optionally substituted with one, two, or three groups selected from halogen, C1-6 alkyl, C1-6 haloalkyl, -OR10, -N(R10)(R11), and -C(O)OR10.

6. R3 is, 【Chemistry 2】 The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.

7. Formula (Ia) 【Transformation 3】 A compound according to claim 1 having the structure, or a pharmaceutically acceptable salt or solvate thereof.

8. The compound according to claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen.

9. The compound according to claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is a C2-C6 alkyl substituted with one or more groups selected from halogen, C1-6 haloalkyl, -OR10, and -N(R10)(R11).

10. The compound according to claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is a C3-C6 cycloalkyl group optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C1-6 haloalkyl, -OR10, and -N(R10)(R11).

11. The compound according to claim 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is a C1-9 heteroaryl 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, wherein the C1-9 heteroaryl is selected from pyridyl, pyridadinyl, pyrimidinyl, and pyrazinyl. 【Request Item 12】 【Chemistry 4】 【Transformation 5】 A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, selected from the above.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

14. The pharmaceutical composition according to claim 13, further comprising a peripherally localized fatty acid amide hydrolase (FAAH) inhibitor.

15. Use of the compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a drug for treating a CNS disease or disorder in a patient requiring treatment.

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