Amide prodrugs and uses thereof

Abstract

Described herein are amide prodrugs, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of CNS diseases or disorders.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 370,753, filed on August 8, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] The blood-brain barrier is composed of tightly connected endothelial cells that restrict the passage of pathogens and specific types of small and large molecules from the blood into the brain. This critical protective function also limits the diffusion of therapeutic drugs into the brain, representing an important challenge for the development of new drugs for CNS diseases. Summary of the invention

[0004] In one aspect, described herein are compounds having the structure of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0005]

[0006] in:

[0007] R 1 Selected from 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, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 One or more groups in are substituted;

[0008] R 2 Selected from -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 1-9heteroaryl, phenyl and -C1-C6 alkyl-phenyl, wherein 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 optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 or R 1 With R 2 Combination forms C2-C9 heterocycloalkyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 One or more groups in are substituted;

[0009] R 3 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, wherein 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 selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted;

[0010] Each R 4 are independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-6 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(R 10 )(R 11 )、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 and -CH2S(O)2N(R 10 )(R 11 ), where 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 optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR10 One, two or three groups are substituted;

[0011] R 5 and R 6 Independently selected from hydrogen and C1-C6 alkyl;

[0012] Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl;

[0013] R 9a and R 9b are independently selected from 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 ), where 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 optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted;

[0014] R 9c Selected from 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 ), where C 1-6 Alkyl, 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 optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted;

[0015] Each R 10 are independently selected from 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, wherein 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 optionally selected from 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 One, two or three groups of heteroaryl are substituted;

[0016] Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0017] Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0018] Each R 13 C is independently selected 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, wherein 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 optionally selected from 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 One, two or three groups of heteroaryl are substituted; and

[0019] m is 0, 1, 2 or 3.

[0020] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b are independently selected from hydrogen and C 1-6 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 9c C 1-6 Alkyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 9c For unsubstituted C 1-6 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 9c In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 Selected from C 1-6 Alkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 C 6-10 Aryl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10、-N(R 10 )(R 11 ) and -C(O)OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is phenyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is phenyl, which is optionally selected from C 1-6 Alkyl and -OR 10 One, two or three groups are substituted, wherein R 10 Selected from hydrogen, C 1-6 Alkyl and C 1-6 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 C 1-9 Heteroaryl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is pyridinyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is pyridinyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR 10 One, two or three groups are substituted, wherein R 10 Selected from hydrogen, C 1-6 Alkyl and C 1-6In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 C 1-6 Alkyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 C 1-6 Alkyl, which is optionally selected from halogen, -OR 10 and -N(R 10 )(R 11 ) is substituted with one, two or three groups. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 For unsubstituted C 1-6 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 for In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 for In some embodiments is a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

[0021] In some embodiments is a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof having the structure of Formula (Ia):

[0022]

[0023] In some embodiments is a compound of Formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 In some embodiments, the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 In some embodiments, the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C2-C6 alkyl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R11 ) and -S(O)2R 13 In some embodiments, the compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group selected from halogen, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with one or more groups. In some embodiments, it is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group substituted with one or more -OH groups. In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group substituted with one or more halogens. In some embodiments, it is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an unsubstituted C2-C6 alkyl. In some embodiments, it is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with one or more groups. In some embodiments, it is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an unsubstituted C3-C6 cycloalkyl. In some embodiments, it is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 C 1-9 Heteroaryl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, R 2 C 1-9 Heteroaryl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R11 ) and -S(O)2R 13 One or more groups are substituted, wherein C 1-9 The heteroaryl group is selected from pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. In some embodiments, the 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, it is a compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 Combination forms C2-C9 heterocycloalkyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 Combine to form an unsubstituted C2-C9 heterocycloalkyl group.

[0024] In another aspect, described herein is 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, 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, further comprising a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments, 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, further comprising a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

[0025] In another aspect, described herein is a method of treating a CNS disease or condition in a patient in need thereof, comprising administering to the patient a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a method of treating a CNS disease or condition in a patient in need thereof, 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 condition is selected from acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHL or AHLE), adult Refsum disease, infantile Refsum disease, Alexander disease, Alzheimer's disease, Balo concentric sclerosis, Canavan disease, central pontine myelinolysis (CPM), cerebral palsy, cerebrotendineous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic syndrome, diffuse demyelinating sclerosis (diffuse myelinoclasticsclerosis), encephalomyelitis, Guillain-Barré syndrome, Huntington disease (HD), idiopathic inflammatory demyelinating diseases (HDD), Krabbe disease, Leber hereditary optic neuropathy, leukodystrophy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy (MLD), multifocal motor neuropathy (MMN), multiple sclerosis (MS), Neiman Pick Type-C, paraproteinemic demyelinating polyneuropathy, Parkinson disease (PD), Pelizaeus-Merzbacher 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 is a method of treating a CNS disease or disorder in a patient in need thereof, 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.

[0026] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are selected by one skilled in the art to provide stable moieties and compounds.

[0027] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only, as various changes and modifications within the spirit and scope of the present disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION

[0028] Sphingosine-1-phosphate is a pleiotropic signaling factor that mediates a variety of biological responses by interacting with members of the endothelial differentiation gene family of plasma membrane-localized G protein-coupled receptors (EDG receptors). Five members of this family have been identified across multiple cell types: S1P1 (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6), and S1P5 (EDG-8). Receptor subtypes S1P1, S1P2, and S1P3 are widely expressed in peripheral tissues and the central nervous system (CNS) and play key roles in cardiovascular regulation, lymphocyte trafficking, and neurogenesis. The S1P4 receptor is primarily expressed in the immune and hematopoietic systems and mediates immune cell proliferation and cytokine production, usually in the presence of high concentrations of S1P.

[0029] Selective modulation of both S1P1 and S1P5 receptors within brain tissue of patients with neurological diseases should provide neuroprotective and remyelinating benefits. S1P1 / 5 receptors are expressed on astrocytes, microglia, neurons, and oligodendrocytes, and have been shown to modulate processes associated with demyelinating neuropathologies, including astrocyte activation, microglia activation, oligodendrocyte precursor cell migration and maturation, and oligodendrocyte 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 S1P5 stimulation / modulation 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 resulted in an increase in myelinated internodes compared to controls, where the use of a selective S1P1 agonist did not result in the same phenotype. On the other hand, S1P1 was more highly expressed on astrocytes, microglia, and endothelial cells compared to S1P5 and was associated with reduced cytokine release and inflammatory signaling, as well as improved BBB integrity. Together, these data suggest that simultaneous modulation of both receptor subtypes may improve the treatment of a variety of neurological conditions.

[0030] Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase that degrades the fatty acid amide family of signaling lipids and can hydrolyze selected amide prodrugs. FAAH is highly conserved between species and expressed to varying degrees in many tissues, including the central nervous system (CNS). Selected carboxylic acids can be converted into more permeable amide prodrugs, which are then able to cross the blood-brain barrier, where they can be converted into active molecules by the action of FAAH on prodrugs. Compared with parent administration alone, this results in more carboxylic acids being delivered to the CNS. However, peripherally expressed FAAH hydrolyzes prodrugs at the same time, resulting in a large amount of non-productive prodrug conversion. The co-administration of peripherally restricted FAAH inhibitors and CNS permeable FAAH convertible prodrugs improves the selectivity of prodrug delivery to the CNS. Compared with what is observed when prodrugs are administered alone, it also results in a reduction in the exposure of the parent molecule in plasma and peripheral tissues.

[0031] Specific terms

[0032] Unless otherwise indicated, the following terms used in this application have the definitions given below. The use of the term "including" as well as other forms such as "include," "includes," and "included" is not limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0033] As used herein, C1-C x Including C1-C2, C1-C3...C1-C x By way of example only, a group designated as "C1-C4" means that there are from one to four carbon atoms in the moiety, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" means that there are from one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0034] "Alkyl" refers to an aliphatic hydrocarbon group. An alkyl group is a branched or straight chain. In some embodiments, an "alkyl" group has 1 to 10 carbon atoms, i.e., C1-C 10Alkyl. Whenever it appears herein, a numerical range (such as "1 to 10") refers to each integer in the given range; for example, "1 to 10 carbon atoms" means that the alkyl group is composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, etc., up to and including 10 carbon atoms, although the definition also covers the occurrence of the term "alkyl" without specifying a numerical range. In some embodiments, the alkyl group is a C1-C6 alkyl group. In one aspect, the alkyl group is a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl group. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl or hexyl.

[0035] "Alkylene" refers to a divalent alkyl group. Any of the above-mentioned monovalent alkyl groups can become an alkylene group by taking the second hydrogen atom from the alkyl group. In some embodiments, the alkylene group is a C1-C6 alkylene group. In other embodiments, the alkylene group is a C1-C4 alkylene group. In certain embodiments, the alkylene group contains one to four carbon atoms (e.g., C1-C4 alkylene group). In other embodiments, the alkylene group contains one to three carbon atoms (e.g., C1-C3 alkylene group). In other embodiments, the alkylene group contains one to two carbon atoms (e.g., C1-C2 alkylene group). In other embodiments, the alkylene group contains one carbon atom (e.g., C1 alkylene group). In other embodiments, the alkylene group contains two carbon atoms (e.g., C2 alkylene group). In other embodiments, the alkylene group contains two to four carbon atoms (e.g., C2-C4 alkylene group). 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.

[0036] The "deuterated alkyl group" refers to an alkyl group in which one or more hydrogen atoms in the alkyl group are replaced by deuterium.

[0037] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, the alkenyl group has the formula -C(R)=CR 2 , wherein R refers to the rest of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl group. In some embodiments, the alkenyl group is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, etc. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0038] The term "alkynyl" refers to a class of alkyl groups in which at least one carbon-carbon triple bond is present. In one embodiment, the alkenyl group has the formula -C≡CR, wherein R refers to the remainder of the alkynyl group. In some embodiments, R is H or an alkyl group. In some embodiments, the alkynyl group is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, -CH2C≡CH.

[0039] "Alkoxy" means an (alkyl)O- group where alkyl is as defined herein.

[0040] The term "alkylamine" refers to -N(alkyl) x H y A group wherein x is 0 and y is 2, or wherein x is 1 and y is 1, or wherein x is 2 and y is 0.

[0041] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. The term "aromatic" includes carbocyclic aromatic ("aryl", e.g., phenyl) and heterocyclic aromatic (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 atoms or nitrogen atoms) groups.

[0042] 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 carbocycles from "heterocyclic" rings or "heterocycles" in which the ring backbone contains at least one atom different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include cycloalkyl and aryl.

[0043] As used herein, the term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. In one aspect, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl. In some embodiments, aryl is C6-C 10 Depending on the structure, an aryl group is a monoradical or a diradical (ie, an arylene group).

[0044] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic non-aromatic group, in which each atom (i.e., skeleton atom) forming the ring is a carbon atom. In some embodiments, cycloalkyl is a spirocyclic or bridging compound. In some embodiments, cycloalkyl is optionally fused with an aromatic ring, and the point of attachment is located on the carbon of a non-aromatic ring carbon atom. Cycloalkyl includes a group with 3 to 10 ring atoms. In some embodiments, cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro [2.2] pentyl, norbornyl and bicyclo [1.1.1] pentyl. In some embodiments, cycloalkyl is C3-C6 cycloalkyl. In some embodiments, cycloalkyl is a monocyclic cycloalkyl. Monocyclic cycloalkyl includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Multicyclic cycloalkyl groups include, for example, adamantyl, norbornyl (ie, bicyclo[2.2.2]octyl and bicyclo[2.2.1]heptyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like.

[0045] The term "halo" or "halogen" or "halide" refers to fluorine, chlorine, bromine or iodine. In some embodiments, halo is fluoro, chloro or bromo.

[0046] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen atom. In one aspect, the fluoroalkyl group is a C1-C6 fluoroalkyl group.

[0047] The term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by fluorine atoms. In one aspect, the fluoroalkyl group is a C1-C6 fluoroalkyl group. In some embodiments, the fluoroalkyl group is selected from trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0048] The term "heteroalkyl" refers to an alkyl group in which one or more of the backbone atoms in the alkyl group are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, or a combination thereof. The heteroalkyl group is attached to the rest of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl group is a C1-C6 heteroalkyl group.

[0049] The term "heteroalkylene" refers to a divalent heteroalkyl group.

[0050] The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also referred to as heteroaryls) and heterocycloalkyl rings (also referred to as heteroalicyclic groups) containing one to four heteroatoms in the ring, wherein each heteroatom in the ring is selected from O, S and N, wherein each heterocyclic group has 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. In some embodiments, the heterocycle is a monocyclic, bicyclic, polycyclic, spirocyclic or bridged compound. Non-aromatic heterocyclic groups (also referred to as heterocycloalkyls) include rings having 3 to 10 atoms in their ring systems, and aromatic heterocyclic groups include rings having 5 to 10 atoms in their ring systems. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, oxazolidinyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine oxazepinyl, diazepine Thiazepine 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiophenyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 2-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, 5-azabicyclo[2. 1.1]hexyl, 6-azabicyclo[3.1.1]heptyl, 7-azabicyclo[2.2.1]heptyl, 8-azabicyclo[3.2.1]octyl, 3H-indolyl, indolin-2-one, isoindolyl-1-one, isoindolyl-1,3-dione, 3,4-dihydroisoquinolin-1(2H)-one, 3,4-dihydroquinolin-2(1H)-one, isoindolyl-1,3-disulfinyl, benzo[d]oxazol-2(3H)-one, 1H-benzo[d]imidazol-2(3H)-one, benzo[d]thiazol-2(3H)-one and quinolizinyl. Examples of aromatic heterocyclic groups are pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furanpyridinyl. Where possible, the above groups are C-connected (or C-linked) or N-connected. For example, groups derived from pyrrole include pyrrol-1-yl (N-connected) or pyrrol-3-yl (C-connected). In addition, the group derived from imidazoles includes imidazole-1-yl or imidazole-3-yl (all N connected) or imidazole-2-yl, imidazole-4-yl or imidazole-5-yl (all C connected). Heterocyclic groups include benzo fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of the bicyclic heterocycle is aromatic. In some embodiments, both rings of the bicyclic heterocycle are aromatic.

[0051] The term "heteroaryl" or "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl include monocyclic heteroaryl and bicyclic heteroaryl. Monocyclic heteroaryl includes pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl and furazanyl. Bicyclic heteroaryl includes indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine and pteridine. In some embodiments, heteroaryl contains 0-4 N atoms in the ring. In some embodiments, heteroaryl contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl group contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl group contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl group is a C1-C9 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a C1-C5 heteroaryl group. In some embodiments, the monocyclic heteroaryl group is a 5- or 6-membered heteroaryl group. In some embodiments, the bicyclic heteroaryl group is a C6-C9 heteroaryl group.

[0052] "Heterocycloalkyl" or "heteroalicyclic" groups refer to cycloalkyl groups containing at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, heterocycloalkyl is fused to aryl or heteroaryl. In some embodiments, heterocycloalkyl is oxazolidinone, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-one, pyrrolidine-2,5-disulfinyl, pyrrolidine-2,5-dione, pyrrolidinone, imidazolidinyl, imidazolidin-2-one or thiazolidin-2-one. The term heteroalicyclic also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. In one aspect, heterocycloalkyl is C2-C 10 In another aspect, the heterocycloalkyl group is C4-C 10 Heterocycloalkyl. In some embodiments, the heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0053] The term "oxo" refers to a =0 group.

[0054] The term "bond" or "single bond" refers to a chemical bond between two atoms or moieties when the atoms connected by the bond are considered part of a larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent, thereby allowing bonds to form between the remaining identified groups.

[0055] The term "moiety" refers to a specific fragment or functional group of a molecule. A chemical moiety is typically a recognized chemical entity embedded in or attached to a molecule.

[0056] The terms "optionally substituted" or "substituted" mean that the referenced group is optionally substituted by one or more additional groups individually and independently selected from D, halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -C02H, -C02alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, alkenyl, alkynyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone and aryl sulfone. In some other embodiments, the optional substituents are independently selected from D, halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4 alkyl), -S(=O)2N(C1-C4 alkyl)2, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, C1-C4 heteroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, -SC1-C4 alkyl, -S(=O)C1-C4 alkyl and -S(=O)2C1-C4 alkyl. In some embodiments, the optional substituents are independently selected from D, halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3 and -OCF3. In some embodiments, the substituent groups are substituted by one or two of the aforementioned groups. In some embodiments, the optional substituents on aliphatic carbon atoms (non-cyclic or cyclic) include oxo (=O).

[0057] The term "acceptable" as used herein, with respect to a formulation, composition or ingredient, means having no persistent detrimental effect on the general health of the subject being treated.

[0058] As used herein, the term "modulate" refers to interacting directly or indirectly with a target 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 prolonging the activity of the target.

[0059] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, interactions of agonists, partial agonists, inverse agonists, antagonists, degraders, or combinations thereof. In some embodiments, the modulator is an agonist.

[0060] As used herein, the terms "administer", "administering", "administration", etc. refer to methods that can be used to deliver a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (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.

[0061] As used herein, the terms "administered in combination with," "administered in combination with," and the like are intended to encompass administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration, or at the same or different times.

[0062] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of an agent or compound administered that will alleviate to some extent one or more symptoms of the disease or condition being treated. Results include reduction and / or alleviation of signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. In any individual case, an appropriate "effective" amount is optionally determined using techniques such as dose escalation studies.

[0063] As used herein, the terms "enhance" or "enhancing" refer to increasing or prolonging the potency or duration of a desired effect. Thus, with respect to enhancing the effect of a therapeutic agent, the term "enhancing" refers to the ability to increase or prolong the potency or duration of the effect of another therapeutic agent on a system. As used herein, an "enhancing-effective amount" refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0064] The term "drug combination" as used herein refers to a product produced by mixing or combining more than one active ingredient, and includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to active ingredients (e.g., compounds described herein or pharmaceutically acceptable salts thereof and co-agents) that are administered to patients simultaneously in the form of a single entity or dosage. The term "non-fixed combination" refers to active ingredients (e.g., compounds described herein or pharmaceutically acceptable salts thereof and co-agents) that are administered to patients simultaneously, jointly, or sequentially as separate entities without specific intermediate time limits, wherein such administration provides effective levels of two compounds in the patient's body. The latter is also applicable to cocktail therapy, such as the administration of three or more active ingredients.

[0065] The terms "kit" and "article of manufacture" are used synonymously.

[0066] The term "subject" or "patient" encompasses mammals. Examples of mammals include, but are not limited to, any member of the class mammals: humans, non-human primates such as chimpanzees and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, pigs; livestock such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs, etc. In one aspect, the mammal is a human.

[0067] As used herein, the terms "treat," "treating," or "treatment" include alleviating, alleviating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, such as arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or prophylactically and / or therapeutically arresting the symptoms of the disease or condition.

[0068] Compound

[0069] 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.

[0070] In some embodiments, described herein are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof:

[0071]

[0072] in,

[0073] R 1 Selected from 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, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 One or more groups in are substituted;

[0074] R 2 Selected from -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, wherein 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 optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 or R 1 With R 2 Combination forms C2-C9 heterocycloalkyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 One or more groups in are substituted;

[0075] R 3 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, C6-10 Aryl and C 1-9 Heteroaryl, wherein 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 selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted;

[0076] Each R 4 are independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )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 )(R11 )-、-S(=O)(=NH)N(R 10 )(R 11 )、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 and -CH2S(O)2N(R 10 )(R 11 ), where 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 optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted;

[0077] R 5 and R 6 Independently selected from hydrogen and C1-C6 alkyl;

[0078] Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl;

[0079] R 9a and R 9b are independently selected from 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 ), where 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 optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted;

[0080] R 9c Selected from 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 ), where 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 optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted;

[0081] Each R 10 are independently selected from 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, wherein C1-6 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 optionally selected from 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 One, two or three groups of heteroaryl are substituted;

[0082] Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0083] Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl;

[0084] Each R 13 C is independently selected 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, wherein 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 optionally selected from 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 One, two or three groups of heteroaryl are substituted; and

[0085] m is 0, 1, 2 or 3.

[0086] For any and all embodiments, the substituents are selected from a subset of the listed alternatives. For example, in some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 C 1-6 Alkyl and R 6 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 C 1-6 alkyl.

[0087] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b are independently selected from hydrogen and C 1-6 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a is hydrogen, and R 9b It is C 1-6 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a is hydrogen, and R 9b In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b C 1-6 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b For hydrogen.

[0088] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 9c C 1-6 Alkyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 9c For unsubstituted C 1-6 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 9c In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 9c It is -CH2CH3.

[0089] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 Selected from C 1-6 Alkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3C 6-10 Aryl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is phenyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is phenyl, which is optionally selected from C 1-6 Alkyl and -OR 10 One, two or three groups are substituted, wherein R 10 Selected from hydrogen, C 1-6 Alkyl and C 1-6 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is phenyl, which is optionally selected from C 1-6 Alkyl and -OR 10 One, two or three groups are substituted, wherein R 10 C 1-6 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is a phenyl group selected from C 1-6 Alkyl and -OR 10 One or two groups are substituted, wherein R 10 C 1-6 alkyl.

[0090] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 C 1-9 Heteroaryl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is pyridinyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is pyridinyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR 10 One, two or three groups are substituted, wherein R 10 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0091] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 C 1-6 Alkyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 C 1-6 Alkyl, which is optionally selected from halogen, -OR 10 and -N(R 10 )(R 11 ) is substituted with one, two or three groups. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 For unsubstituted C 1-6 alkyl.

[0092] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 for

[0093] In some embodiments is a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

[0094] In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein m is 2. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein m is 3. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 are independently selected from halogen, -CN, C 1-6 Alkyl, -OR 10 、-SR 10 、-N(R 10 )(R 11 )、-C(O)OR 10 、-C(O)R 13 、-C(O)N(R 10 )(R 11 )、-S(O)2R 13 and -S(O)2N(R 10 )(R 11 )-, where C 1-6 Alkyl is optionally selected from halogen, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 are independently selected from halogen, -CN, C 1-6 Alkyl, -OR 10 and -N(R 10 )(R 11 ), where C 1-6 Alkyl is optionally selected from halogen, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 independently selected from halogen, C 1-6 Alkyl, -OR 10 , where C 1-6 Alkyl is optionally selected from halogen, C 1-6 Haloalkyl and -OR 10 One, two or three groups are substituted.

[0095] In some embodiments, the 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, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is a C1-C6 alkyl group. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -CH3.

[0096] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C2-C6 alkyl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C2-C6 alkyl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C2-C6 alkyl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group selected from halogen, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11) is substituted with one or more groups. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group selected from halogen, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with one, two or three groups. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group substituted with one, two or three halogens. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group, which is replaced by one, two or three C 1-6 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group, which is substituted by one, two or three -OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group substituted with one, two or three -OH groups. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group, which is substituted by one, two or three -N(R 10 )(R 11 )replace.

[0097] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted C2-C6 alkyl group.

[0098] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group selected from halogen, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with one or more groups. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group selected from halogen, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with one, two or three groups. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group substituted by one, two or three halogens. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group, which is replaced by one, two or three C 1-6 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group, which is substituted by one, two or three -OR 10 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group substituted with one, two or three -OH groups. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group, which is substituted by one, two or three -N(R 10 )(R 11 )replace.

[0099] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an unsubstituted C3-C6 cycloalkyl. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an unsubstituted cyclopropyl. In some embodiments, is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an unsubstituted cyclobutyl. In some embodiments, is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an unsubstituted cyclopentyl. In some embodiments, is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted cyclohexyl group.

[0100] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -C1-C6 alkyl-C3-C6 cycloalkyl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an unsubstituted -C1-C6 alkyl-C3-C6 cycloalkyl. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -CH2-C3-C6 cycloalkyl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted -CH2-C3-C6 cycloalkyl group.

[0101] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 C 1-9 Heteroaryl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 C 1-9 Heteroaryl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 One or more groups are substituted, wherein C 1-9 The heteroaryl group is selected from pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is pyridyl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a pyridazinyl group, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a pyrimidinyl group, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a pyrazinyl group, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R11 ) and -S(O)2R 13 One or more groups are substituted.

[0102] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is selected from unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl and unsubstituted pyrazinyl. In some embodiments, it is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an unsubstituted pyrazinyl group.

[0103] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 Combination forms C2-C9 heterocycloalkyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 Combination forms C2-C9 heterocycloalkyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 Combine to form an unsubstituted C2-C9 heterocycloalkyl group.

[0104] In some embodiments, described herein are compounds of Formula (Ia), or pharmaceutically acceptable salts or solvates thereof:

[0105]

[0106] in,

[0107] R 1 Selected from 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, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 One or more groups in are substituted;

[0108] R 2 Selected from -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, wherein 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 optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 or R 1 With R 2 Combination forms C2-C9 heterocycloalkyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 One or more groups in are substituted;

[0109] Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl;

[0110] Each R 10 are independently selected from 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, wherein 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 optionally selected from 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 One, two or three groups of heteroaryl are substituted;

[0111] Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; and

[0112] Each R 13 C is independently selected 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein 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 optionally selected from 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 One, two or three groups in the heteroaryl group are substituted.

[0113] In some embodiments 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, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is a C1-C6 alkyl group. In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is -CH3.

[0114] In some embodiments is a compound of Formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C2-C6 alkyl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C2-C6 alkyl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R13 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C2-C6 alkyl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group selected from halogen, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with one or more groups. In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group selected from halogen, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with one, two or three groups. In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group substituted with one, two or three halogens. In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group, which is replaced by one, two or three C 1-6 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group, which is substituted by one, two or three -OR 10 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group substituted with one, two or three -OH groups. In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group, which is substituted by one, two or three -N(R 10 )(R 11 )replace.

[0115] In some embodiments is a compound of Formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted C2-C6 alkyl group.

[0116] In some embodiments is a compound of Formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group selected from halogen, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with one or more groups. In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group selected from halogen, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with one, two or three groups. In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2is a C3-C6 cycloalkyl group substituted by one, two or three halogens. In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group, which is replaced by one, two or three C 1-6 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group, which is substituted by one, two or three -OR 10 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group substituted with one, two or three -OH groups. In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group, which is substituted by one, two or three -N(R 10 )(R 11 )replace.

[0117] In some embodiments is a compound of Formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an unsubstituted C3-C6 cycloalkyl. In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an unsubstituted cyclopropyl. In some embodiments, is a compound of Formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an unsubstituted cyclobutyl. In some embodiments is a compound of Formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an unsubstituted cyclopentyl. In some embodiments, is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted cyclohexyl group.

[0118] In some embodiments is a compound of Formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -C1-C6 alkyl-C3-C6 cycloalkyl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2is an unsubstituted -C1-C6 alkyl-C3-C6 cycloalkyl. In some embodiments, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -CH2-C3-C6 cycloalkyl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted -CH2-C3-C6 cycloalkyl group.

[0119] In some embodiments is a compound of Formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 C 1-9 Heteroaryl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 C 1-9 Heteroaryl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 One or more groups are substituted, wherein C 1-9 The heteroaryl group is selected from pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is pyridyl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a pyridazinyl group, which is optionally selected from halogen, C1-C6 alkyl, C 1-6Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a pyrimidinyl group, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a pyrazinyl group, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 One or more groups are substituted.

[0120] In some embodiments 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, it is a compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is an unsubstituted pyrazinyl group.

[0121] In some embodiments is a compound of Formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 Combination forms C2-C9 heterocycloalkyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11) and -S(O)2R 13 In some embodiments, the compound of formula (Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 Combination forms C2-C9 heterocycloalkyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 Combine to form an unsubstituted C2-C9 heterocycloalkyl group.

[0122] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are selected by one skilled in the art to provide stable moieties and compounds.

[0123] In some embodiments is a compound or a pharmaceutically acceptable salt or solvate thereof selected from:

[0124]

[0125] In some embodiments is a compound or a pharmaceutically acceptable salt or solvate thereof selected from:

[0126]

[0127] or a pharmaceutically acceptable salt or solvate thereof.

[0128] In some embodiments, the compounds described herein are in the form of pharmaceutically acceptable salts. Likewise, active metabolites of these compounds having the same active type are also included within the scope of the present disclosure. In addition, the compounds described herein may exist in unsolvated forms as well as solvated forms formed with pharmaceutically acceptable solvents (such as water, ethanol, etc.). The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0129] As used herein, "pharmaceutically acceptable" 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 nontoxic, i.e., the material does not cause adverse biological effects when administered to an individual or interact in a deleterious manner with any component of the composition in which it is contained.

[0130] The term "pharmaceutically acceptable salt" refers to a therapeutically active agent in the form of a cationic therapeutic agent combined with a suitable anion, or in an alternative embodiment, a therapeutically active agent in the form of an anionic therapeutic agent combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bighley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PH Stahl and CG Wermuth, eds., Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich: Wiley-VCH / VHCA, 2002. Pharmaceutically acceptable salts are generally more soluble and dissolve faster in gastric and intestinal fluids than non-ionic substances and can therefore be used in solid dosage forms. In addition, because their solubility is generally a function of pH, it is possible to selectively dissolve in one or another part of the digestive tract, and this ability can be manipulated as an aspect of delayed and sustained release behavior. Furthermore, because salt-forming molecules can be in equilibrium with the neutral form, passage through biological membranes can be modulated.

[0131] In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound described herein with an acid to provide a "pharmaceutically acceptable acid addition salt." In some embodiments, the compounds described herein (i.e., the free base form) are basic and react 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 (+); decanoic acid (capric acid / decanoic acid); caproic acid (caproic acid / hexanoic acid); octanoic acid (caprylic acid / octanoic acid) acid); carbonic acid; cinnamic acid; citric acid; cyclohexanesulfamic acid; dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; propionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

[0132] In some embodiments, the compounds described herein are prepared as chloride, sulfate, bromide, methanesulfonate, maleate, citrate, or phosphate salts.

[0133] 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."

[0134] In some embodiments, the compounds described herein are acidic and react with a base. In this case, the acidic protons of the compounds described herein are replaced by metal ions (e.g., lithium ions, sodium ions, potassium ions, magnesium ions, calcium ions, or aluminum ions). In some cases, the compounds described herein are coordinated with organic bases such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids (such as, but not limited to, arginine, lysine, etc.). Acceptable inorganic bases for forming salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, etc. In some embodiments, provided herein are compounds prepared as sodium salts, calcium salts, potassium salts, magnesium salts, meglumine salts, N-methylglucamine salts, or ammonium salts.

[0135] It should be understood that reference to pharmaceutically acceptable salts includes solvent addition forms. In some embodiments, solvates contain stoichiometric or non-stoichiometric amounts of solvents and are formed during the separation or purification of compounds with pharmaceutically acceptable solvents (such as water, ethanol, etc.). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein are optionally present in unsolvated forms as well as solvated forms.

[0136] The methods and formulations described herein include the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of the compounds described herein, as well as active metabolites of these compounds having the same type of activity.

[0137] In some embodiments, sites on the organic radicals (e.g., alkyl, aromatic rings) of the compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize, or eliminate the metabolic pathway. In specific embodiments, suitable substituents that reduce or eliminate the sensitivity of the aromatic ring to metabolic reactions are, by way of example only, halogens, deuterium, alkyls, haloalkyls, or deuterated alkyls.

[0138] In another embodiment, the compounds described herein are isotopically labeled (eg, with a radioisotope) or labeled by another other means, including but not limited to the use of a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0139] The compounds described herein include isotopically labeled compounds, which are identical to those recited in the various formulas and structures presented herein, except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as, for example, 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 35 S. 18 F. 36 In one aspect, an isotopically labeled compound described herein, for example one in which a radioactive isotope (such as 3 H and 14 C) for drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium provides certain therapeutic advantages resulting from greater metabolic stability, such as, 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 substituted with deuterium.

[0140] In some embodiments, the compounds described herein have one or more stereocenters, and each stereocenter exists independently in the R or S configuration. The compounds presented herein include all diastereoisomers, enantiomers, atropisomers and epimers, and suitable mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers and suitable mixtures thereof.

[0141] If desired, a single stereoisomer is obtained 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 single stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds / salts, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, the resolution of enantiomers is performed using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based on solubility differences. In other embodiments, separation of stereoisomers is performed by chromatography or by forming diastereomeric salts and separating by recrystallization or chromatography 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.

[0142] Compound synthesis

[0143] The compounds described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with the methods described herein.

[0144] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are employed.

[0145] 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 be employed, such as varying solvents, reaction temperatures, reaction times, and different chemical reagents and other reaction conditions. Starting materials are available from commercial sources or are readily prepared.

[0146] Suitable reference books and papers that describe in detail the synthesis of the reactants used to prepare the compounds described herein, or provide references to articles describing such preparations, include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; SR Sandler et al., "Organic Functional Group Preparations," 2nd edition, Academic Press, New York, 1983; H O House, "Modern Synthetic Reactions," 2nd edition, WA Benjamin, Inc. Menlo Park, Calif. 1972; TL Gilchrist, "Heterocyclic Chemistry," 2nd edition, John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure," 4th edition, Wiley-Interscience, New York, 1992. Additional suitable reference books and papers that describe in detail the synthesis of the reactants used to prepare the compounds described herein or provide references to articles describing such preparations 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 1992Guide 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; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, more than 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, 73 volumes.

[0147] In some embodiments, the compounds are prepared as described in the Examples.

[0148] Treatment

[0149] In some embodiments, described herein are methods of treating a CNS disease or condition in a patient in need thereof, comprising administering to the patient a compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods of treating a CNS disease or condition in a patient in need thereof, 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 condition is selected from acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHL or AHLE), adult Refsum's disease, infantile Refsum's disease, Alexander disease, Alzheimer's disease, Balo concentric sclerosis, Canavan disease, central pontine myelinolysis (CPM), cerebral palsy, cerebrotendinous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic syndrome, diffuse demyelinating sclerosis, encephalomyelitis, Guillain-Barré syndrome, Henry Tinton disease (HD), idiopathic inflammatory demyelinating disease (HDD), Krabbe disease, Leber hereditary optic neuropathy, leukodystrophy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy (MLD), multifocal motor neuropathy (MMN), multiple sclerosis (MS), Niemann-Pick type C, paraproteinemic demyelinating polyneuropathy, Parkinson's disease (PD), Pelizaeus-Merzheimer 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, a method of treating a CNS disease or disorder in a patient in need thereof comprises 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 are methods of treating a CNS disease or disorder in a patient in need thereof, 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.

[0150] In some embodiments, described herein are methods of treating a CNS disease or disorder in a patient in need thereof, 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, a method of treating a CNS disease or disorder in a patient in need thereof comprises 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 acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalitis (AHL or AHLE), adult Refsum's disease, infantile Refsum's disease, Alexander disease, Alzheimer's disease, Balo concentric sclerosis, Canavan disease, central pontine myelinolysis (CPM), cerebral palsy, cerebrotendinous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic syndrome, diffuse demyelinating sclerosis, encephalomyelitis, Guillain-Barre syndrome, Huntington's disease (HD), idiopathic inflammatory demyelinating polyneuropathy (CIDP), disease (HDD), Krabbe disease, Leber hereditary optic neuropathy, leukodystrophy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy (MLD), multifocal motor neuropathy (MMN), multiple sclerosis (MS), Niemann-Pick type C, paraproteinemic demyelinating polyneuropathy, Parkinson's disease (PD), Pelizaeus-Merzheimer disease (PMD), progressive multifocal leukoencephalopathy (PML), tropical spastic paraplegia (TSP), X-linked adrenoleukodystrophy (X-ALD, ALO or X-linked ALO) and Zellweger syndrome, further comprising administering to the patient a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments, a method of treating a CNS disease or condition in a patient in need thereof, 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 condition is selected from multiple sclerosis, and further comprising administering to the patient a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments, a method of treating a CNS disease or condition in a patient in need thereof, 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 condition is X-linked adrenoleukodystrophy, and further comprising administering to the patient a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor.

[0151] In some embodiments of the methods described herein, the peripherally restricted FAAH inhibitor is ASP-3652.

[0152] Pharmaceutical composition

[0153] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients, which assist in processing the active compound into a pharmaceutically useful product. The appropriate formulation depends on the selected route of administration. A summary of the pharmaceutical compositions described herein is found in, for example, Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., ed., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for such disclosures.

[0154] In some embodiments, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent as a pharmaceutical composition. In some embodiments disclosed herein, the pharmaceutical composition further comprises a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments, the pharmaceutical composition further comprises a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

[0155] The administration of the compounds and compositions described herein can be achieved by any method capable of delivering the compounds to the site of action. These methods include, but are not limited to, administration by enteral routes (including oral, gastric or duodenal feeding tubes, rectal suppositories and rectal enemas), parenteral routes (injection or infusion, including intra-arterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal and topical (including epidermal, dermal, enema, eye drops, ear drops, intranasal, vaginal) for delivery, although the most appropriate route may depend on, for example, the condition and illness of the recipient.

[0156] 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 liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary, or paste.

[0157] Pharmaceutical compositions that can be used orally include tablets, push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers (such as glycerol or sorbitol). Tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing an active ingredient in a free-flowing form (such as powder or granules) optionally mixed with a binder, an inert diluent or lubricant, a surfactant or a dispersant in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. In some embodiments, the tablets are coated or scored and are formulated to provide a slow or controlled release of the active ingredient therein. All preparations for oral administration should be suitable for such administration in terms of dosage. Push-fit capsules may contain active ingredients blended with fillers (such as lactose), binders (such as starches) and / or lubricants (such as talc or magnesium stearate) and optionally stabilizers. In soft capsules, the active compound can be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin or liquid polyethylene glycol. In some embodiments, stabilizers are added. The dragee core is equipped with suitable coatings. For this purpose, concentrated sugar solution can be used, which can optionally comprise gum arabic, talcum powder, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture. Dye or pigment can be added to tablet or dragee coating to identify or characterize the different combinations of active compound dosage.

[0158] In some embodiments, the pharmaceutical composition is formulated for parenteral administration by injection, for example, by push injection or continuous infusion. Injection preparations can be presented in unit dosage form, for example, in ampoules or in multi-dose containers with the addition of preservatives. The composition can be in the form of a suspension, solution or emulsion, for example, in an oily or aqueous vehicle, and can include a preparaton, such as a suspending agent, a stabilizer and / or a dispersant. The composition can be presented in unit dose or multi-dose containers (for example, sealed ampoules and vials), and can be stored in powder form or freeze-dried (lyophilized) state, only needing to add sterile liquid carriers, for example saline or sterile pyrogen-free water, immediately before use. The injection solution and suspension prepared before use can be prepared by sterile powders, granules and tablets of the types described above.

[0159] 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 preparation isotonic with the blood of the intended recipient; and 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 also contain a suitable stabilizer or an agent that increases the solubility of the compound to allow the preparation of a high concentration solution.

[0160] Pharmaceutical compositions can also be formulated into depot preparations. Such long-acting preparations can be administered by implantation (e.g., subcutaneous or intramuscular implantation) or by intramuscular injection. Thus, for example, the compound can be formulated with a suitable polymer or hydrophobic material (e.g., formulated into an emulsion in an acceptable oil) or an ion exchange resin, or formulated into a sparingly soluble derivative, e.g., formulated into a sparingly soluble salt.

[0161] For buccal or sublingual administration, the composition may take the form of tablets, lozenges, troches or gels formulated in conventional manner.Such compositions may include the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0162] 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.

[0163] The pharmaceutical composition can be administered topically, i.e., by non-systemic administration. This includes applying the compound of the invention externally to the epidermis or oral cavity, and dropping such compound into the ears, eyes, and nose, so that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0164] Pharmaceutical compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin into the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes and drops suitable for application to the eyes, ears or noses. For topical administration, the active ingredient may comprise 0.001% to 10%, for example 1% to 2%, of the weight of the formulation.

[0165] Pharmaceutical compositions for administration by inhalation are conveniently delivered from an insufflator, a nebulizer pressurized pack, or other convenient device for delivering an aerosol spray. The pressurized pack may contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the pharmaceutical preparation may take the form of a dry powder composition, such as a powder mixture of a compound and a suitable powder matrix, such as lactose or starch. The powder composition may be presented in unit dosage form, such as in a capsule, cartridge, gelatin, or blister pack, from which the powder may be administered by means of an inhaler or insufflator.

[0166] In some embodiments, the compounds disclosed herein are formulated in such a way that the compounds are delivered to specific regions of the gastrointestinal tract. For example, the compounds disclosed herein are formulated for oral delivery with bioadhesive polymers, pH sensitive coatings, time-dependent, biodegradable polymers, microbiota activation systems, etc., so as to achieve delivery of the compounds to specific regions of the gastrointestinal tract.

[0167] 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 the dosage form into which they are incorporated according to a desired curve over an extended period of time. Controlled release curves include, for example, sustained release, extended release, pulsed release, and delayed release curves. Compared to immediate release compositions, controlled release compositions allow the delivery of medicaments to the subject over an extended period of time according to a predetermined curve. Compared to conventional rapid release dosage forms, this release rate can provide therapeutically effective levels of medicaments over an extended period of time, and thereby provide a longer pharmacological response time while minimizing side effects. This longer response time provides many inherent benefits that cannot be achieved with corresponding short-acting immediate release products.

[0168] Methods for delivering intact therapeutic compounds to specific areas of the gastrointestinal tract, such as the colon, include:

[0169] (i) Coating with polymers: By coating the drug molecule with a suitable polymer, which degrades only in the colon, the intact molecule can be delivered to the colon without being absorbed in the upper intestinal tract.

[0170] (ii) Coating with pH-sensitive polymers: Most enteric and colon-targeted delivery systems are based on coating of tablets or pills that are filled into conventional hard gelatin capsules. The most commonly used pH-dependent coating polymers are methacrylic acid copolymers, commonly known as S, more specifically L and S. L100 and S100 are copolymers of methacrylic acid and methyl methacrylate.

[0171] (iii) coating with a biodegradable polymer;

[0172] (iv) embedded in a matrix;

[0173] (v) embedded in biodegradable matrices and hydrogels;

[0174] (vi) embedded in a pH-sensitive matrix;

[0175] (vii) Timed release system;

[0176] (viii) redox-sensitive polymers;

[0177] (ix) bioadhesive systems;

[0178] (x) coating with microparticles;

[0179] (xi) osmotic controlled drug delivery;

[0180] Another method of colon targeted drug delivery or controlled release system includes embedding the drug into a polymer matrix to embed the drug and release it into the colon. These matrices can be pH sensitive or biodegradable. Matrix-based systems (such as delayed release tablets based on multimatrix (MMX)) ensure that the drug is released in the colon.

[0181] Additional pharmaceutical approaches are known for targeting the delivery of therapeutic agents to specific regions of the gastrointestinal tract. Chourasia MK,Jain SK,Pharmaceutical approaches to colon targeted drug delivery systems.,JPharm Sci.2003 Jan-April;6(1):33-66.Patel M,Shah T,Amin A.Therapeuticopportunities in colon-specific drug-delivery systems Crit Rev Ther DrugCarrier 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.

[0182] It should be understood that in addition to the ingredients particularly 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 those suitable for oral administration may include flavoring agents.

[0183] Dosage and treatment regimen

[0184] In one embodiment, the compounds described herein, or pharmaceutically acceptable salts thereof, are used in the preparation of a medicament for treating a disease or condition in a mammal that may benefit from administration of a dual S1P1 and S1P5 receptor agonist. The method for treating any disease or condition described herein in a mammal in need of such treatment involves administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof.

[0185] In some embodiments disclosed herein are methods of administering a dual S1P1 and S1P5 receptor agonist in combination with an additional therapeutic agent. In some embodiments are methods of administering a dual S1P1 and S1P5 receptor agonist in combination with a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor. In some embodiments are methods of administering a dual S1P1 and S1P5 receptor agonist in combination with a peripherally restricted FAAH inhibitor, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

[0186] In certain embodiments, compositions containing compounds described herein are administered for preventive and / or therapeutic treatment. In certain therapeutic applications, the composition is 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 treatment, the patient's health, body 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 range clinical trials.

[0187] In preventive applications, compositions containing the compounds described herein are administered to patients susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such amounts are defined as "prophylactically effective amounts or doses". In this use, the exact amount also depends on the patient's health, weight, etc. When used in a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous treatment, the patient's health and response to drugs, and the judgment of the treating physician. In one aspect, preventive treatment includes administering a pharmaceutical composition comprising 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 currently in remission to prevent the recurrence of symptoms of the disease or condition.

[0188] 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 throughout the patient's life, at the physician's discretion, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0189] In certain embodiments, where the patient's condition does improve, the dose of the administered drug is temporarily reduced or temporarily stopped for a period of time (i.e., a "drug holiday"). In specific 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%-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%.

[0190] Once the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dose or frequency of administration, or both, is reduced to a level that maintains the improvement in the disease, disorder, or condition, depending on the change in symptoms. However, in certain embodiments, patients require long-term intermittent treatment upon any recurrence of symptoms.

[0191] The amount of a given agent corresponding to such an amount varies depending on factors such as the specific compound, the disease state and its severity, the characteristics of the subject or host in need of treatment (e.g., weight, sex), but will still be determined according to the specific circumstances of the case, including, for example, the specific agent administered, the route of administration, the condition being treated, and the subject or host being treated.

[0192] However, in general, dosages for adult treatment are generally in the range of 0.01 mg / day to 5000 mg / day. In one aspect, dosages for adult treatment are from about 1 mg / day to about 1000 mg / day. In one embodiment, the desired dose is conveniently presented in a single dose or divided doses, which are administered simultaneously or at appropriate intervals, for example, twice, three times, four times or more per day.

[0193] In one embodiment, the daily dose suitable for the compound described herein or its pharmaceutically acceptable salt is about 0.01 mg / kg body weight to about 50 mg / kg / body weight. In some embodiments, based on multiple variables related to individual treatment regimens, the amount of active substance in the daily dose or dosage form is lower or higher than the range shown herein. In various embodiments, the daily dose and unit dose are changed according to multiple variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition to be treated, and the judgment of the practitioner.

[0194] The toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to determining the LD 50and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, and it is denoted LD 50 and ED 50 In certain embodiments, the data obtained from cell culture assays and animal studies are used to formulate therapeutically effective daily dose ranges and / or therapeutically effective unit doses for mammals (including humans). In some embodiments, the daily dose amount of the compounds described herein is within the range of ED 50 In certain embodiments, the daily dosage range and / or unit dosage amount varies within this range, which range depends on the dosage form employed and the route of administration employed.

[0195] Within any of the foregoing aspects are further embodiments wherein 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.

[0196] Within any of the above aspects are further embodiments comprising a single administration of an effective amount of the compound, including further embodiments wherein (i) the compound is administered once daily; or (ii) the compound is administered to the mammal multiple times over the course of a day.

[0197] In any of the above aspects are further embodiments comprising multiple administrations of an effective amount of the compound, including further embodiments wherein (i) the compound is administered continuously or intermittently: such as a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal once every 8 hours; (iv) the compound is administered to the mammal once every 12 hours; (v) the compound is administered to the mammal once every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein administration of the compound is temporarily stopped or the dose of the administered compound is temporarily reduced; at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday ranges from 2 days to 1 year.

[0198] In certain cases, it may be appropriate to administer at least one compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents.

[0199] In one embodiment, the therapeutic effect of one of the compounds described herein is enhanced by administering an adjuvant (i.e., the adjuvant has minimal therapeutic benefit on its own, but when used in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, in some embodiments, the benefit experienced by the patient is increased by administering one of the compounds described herein with another agent (also including a therapeutic regimen) that also has therapeutic benefit.

[0200] In a specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is administered in combination 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 administration of either therapeutic agent alone.

[0201] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may be additive of the two therapeutic agents or the patient may experience a synergistic benefit.

[0202] In certain embodiments, when the compounds disclosed herein are administered in combination with one or more additional agents (such as additional therapeutically effective drugs, adjuvants, etc.), different therapeutically effective doses of the compounds disclosed herein will be used to prepare pharmaceutical compositions and / or treatment regimens. The therapeutically effective doses of the drugs and other agents used in the combined treatment regimen are optionally determined by methods similar to those described above for the active substance itself. In addition, the prevention / treatment methods described herein include the use of metronomic administration, i.e., providing more frequent, lower doses to minimize toxic side effects. In some embodiments, the combined treatment regimen includes a treatment regimen in which the compounds described herein or their pharmaceutically acceptable salts are administered before, during, or after treatment with the second agent described herein, and continue to any time during treatment with the second agent or after treatment with the second agent is terminated. It also includes the treatment of administering the compounds described herein or their pharmaceutically acceptable salts and the second agent used in combination at the same time or at different times and / or at intervals that are gradually reduced or increased during treatment. Combination therapy also includes periodic treatments that start and stop at different times to assist in the clinical management of patients.

[0203] It should be understood that the dosage regimen for treating, preventing or improving the condition being sought to be alleviated is modified according to a variety of factors (e.g., the disease, disorder or condition suffered by the subject; the age, weight, sex, diet and medical condition of the subject). Therefore, in some cases, the dosage regimen actually adopted will be different, and in some embodiments deviate from the dosage regimen described herein.

[0204] For the combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, the specific drug employed, the disease or condition being treated, etc. In additional embodiments, when administered in combination with one or more additional therapeutic agents, the compounds provided herein are administered simultaneously or sequentially with the one or more additional therapeutic agents.

[0205] In combination therapy, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents are provided, by way of example only, in a single unified form or in multiple forms (e.g., as a single tablet or as two separate tablets).

[0206] The compounds described herein or their pharmaceutically acceptable salts and combination therapies are administered before, during or after the occurrence of a disease or condition, and the time for administering the composition containing the compound is different. Therefore, in one embodiment, the compounds described herein are used as prophylactics and are continuously administered to objects with a tendency to develop a condition or disease to prevent the occurrence of a disease or condition. In another embodiment, the compounds and compositions are administered to the object as quickly as possible during or after the onset of symptoms. In a specific embodiment, after the onset of a disease or condition is detected or suspected, the compounds described herein are administered as soon as possible, and for the duration required for the treatment of the disease. In some embodiments, the duration required for treatment is different, and the duration of treatment is adjusted to suit the specific needs of each object. For example, in a specific embodiment, the compound described herein or a preparation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.

[0207] Example

[0208] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0209] As used above, and throughout the description of the present invention, unless otherwise indicated, the following abbreviations shall be understood to have the following meanings:

[0210] ACN or MeCN Acetonitrile

[0211] AcOH Acetic acid

[0212] Ac Acetyl

[0213] BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene

[0214] Bn Benzyl

[0215] BOC or Boc tert-butyl carbamate

[0216] t-Bu tert-butyl

[0217] Cy Cyclohexyl

[0218] DBA or dba dibenzylideneacetone

[0219] DCE Dichloroethane (ClCH2CH2Cl)

[0220] DCM Dichloromethane (CH2Cl2)

[0221] DIPEA or DIEA diisopropylethylamine

[0222] DMAP 4-(N,N-dimethylamino)pyridine

[0223] DME 1,2-Dimethoxyethane

[0224] DMF N,N-Dimethylformamide

[0225] DMA N,N-Dimethylacetamide

[0226] DMSO Dimethyl sulfoxide

[0227] Dppf or dppf 1,1'-bis(diphenylphosphino)ferrocene

[0228] EEDQ 2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline

[0229] eq equivalent

[0230] Et Ethyl

[0231] Et2O Ether

[0232] EtOH

[0233] EtOAc Ethyl acetate

[0234] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0236] HMPA Hexamethylphosphoramide

[0237] HPLC High Performance Liquid Chromatography

[0238] KHMDS Potassium bis(trimethylsilyl)amide

[0239] NaHMDS Sodium bis(trimethylsilyl)amide

[0240] LiHMDS Lithium bis(trimethylsilyl)amide

[0241] LAH Lithium Aluminium Anhydride

[0242] LCMS Liquid chromatography mass spectrometry

[0243] Me Methyl

[0244] MeOH Methanol

[0245] MS mass spectrometry

[0246] Ms Methanesulfonyl

[0247] NBS N-bromosuccinimide

[0248] NMM N-Methyl-morpholine

[0249] NMP N-Methyl-2-pyrrolidinone

[0250] NMR Nuclear Magnetic Resonance

[0251] PCC Pyridinium Chlorochromate

[0252] Ph Phenyl

[0253] PPTS pyridium p-toluenesulfonate

[0254] iPr / i-Pr Isopropyl

[0255] rt room temperature

[0256] TBS tert-Butyldimethylsilyl

[0257] RP-HPLC Reverse Phase-High Pressure Liquid Chromatography

[0258] TFA Trifluoroacetic acid

[0259] TEA Triethylamine

[0260] THF Tetrahydrofuran

[0261] TLC Thin layer chromatography

[0262] 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)

[0263]

[0264] 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 flash chromatography over silica gel (petroleum ether / EtOAc=100 / 1, v / v) to give A-2 (20.7 g, 89% yield) as a yellow oil.

[0265] MeMgBr (9.78 g, 82 mmol) was slowly added to a mixture of A-2 (20.7 g, 82 mmol) in THF (200 mL) 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 extracted with EtOAc (200 mL*3). The organic phase was concentrated and stirred for 3 hours at room temperature in 1N HCl (130 mL) and THF (100 mL). The mixture was extracted with EtOAc (100 mL×3), and the organic phase was washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel to obtain A-3 (13 g, yield 73%) as a yellow solid.

[0266] POCl3 (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 hours. A solution of A-3 (13 g, 51.9 mmol) in DCM (30 mL) was added and stirred at room temperature for 3 hours. The reaction mixture was poured into ice and extracted with EtOAc (20 mL×3). The combined organic phases were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography over silica gel to give A-4 (8.2 g, 57% yield) as a yellow solid.

[0267] To a mixture of A-4 (5 g, 18 mmol) in DCM (50 mL) was added BCl3 (4.21 g, 35.9 mmol) at 0 ° C. The mixture was stirred at 0 ° C for 4 hours. The mixture was quenched with water and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography over silica gel (petroleum ether / EtOAc=20 / 1 to 3 / 1, v / v) to obtain A-5 (2.0 g, 59% yield) as a yellow solid.

[0268] To a mixture of A-6 (3 g, 22 mmol) and MgCl2 (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 at room temperature for 0.5 hours. 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 phases were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel to obtain A-7 (3.1 g, yield 86%) as a colorless oil.

[0269] A mixture of A-7 (3.1 g, 18.9 mmol), MeI (4.02 g, 28.3 mmol) and K2CO3 (7.83 g, 56.6 mmol) in DMF (20 mL) was stirred at 40 ° C for 2 hours. The mixture was poured into water and extracted with EtOAc (30 mL * 3). The combined organic phase was washed with water and brine, dried over Na2SO4 and concentrated to give A-8 (3.1 g, yield 92%) as a colorless oil.

[0270] To a mixture of A-8 (3.1 g, 17.4 mmol) in MeOH (30 mL) was added NaBH4 (1.32 g, 34.8 mmol) at 0°C. The mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with EtOAc (30 mL*3). The combined organic phases were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography over silica gel to give A-9 (3.0 g, yield 96%) as a colorless oil.

[0271] To a solution of A-5 (2.2 g, 11.7 mmol) and PPh3 (3.99 g, 15.2 mmol) in THF (30 mL) was added A-9 (2.11 g, 11.7 mmol) and DIAD (2.99 mL, 15.2 mmol) at 0°C. The mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with EtOAc (20 mL*3). The combined organic phases were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography over silica gel to give A-10 (1.6 g, 39% yield) as a yellow solid.

[0272] 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 hours. The mixture was quenched with NH4Cl aqueous solution and poured into water, and extracted with EtOAc (50 mL * 3). The combined organic phases were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel to obtain A-12 (1.08 g, 53% yield) as a yellow solid.

[0273] To a mixture of A-12 (1.08 g, 2.4 mmol) in THF (6 mL) and water (3 mL) was added LiOH.H2O (115 mg, 4.8 mmol). The mixture was stirred at room temperature overnight. Water (10 mL) was added and the pH of the mixture was adjusted to 4-5 with 1N HCl. The mixture was extracted with EtOAc (20 mL×3), and the combined organic phases were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to give compound 1 (670 mg, yield 64%) as a white solid. LCMS: 434.2 [M-1] + .

[0274] Compound 1 (ceralifimod) had S1P1 EC50 = 11.8 nM and S1P5 EC50 = 1 nM.

[0275] 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)

[0276]

[0277] At 0°C, HATU (65.5 mg, 172 μmol) was added to a mixture of compound 1 (50 mg, 115 μmol) and DIEA (44.5 mg, 344 μmol) in DMF (5 mL). The mixture was stirred at 0°C for 1 hour, and methylamine (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).

[0278] 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)

[0279]

[0280] 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 starting from Compound 1 and pyridin-3-amine as described in Example 2. MS (ESI): 510.2 (M+H).

[0281] 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)

[0282]

[0283] 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 starting from Compound 1 and pyridazin-3-amine as described in Example 2. MS (ESI): 511.2 (M+H).

[0284] 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)

[0285]

[0286] 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 starting from Compound 1 and 3-fluoropropane-1-amine as described in Example 2. MS (ESI): 495.3 (M+H).

[0287] 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)

[0288]

[0289] 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 starting from Compound 1 and 2,2,2-trifluoroethane-1-amine as described in Example 2. MS (ESI): 517.3 (M+H).

[0290] 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)

[0291]

[0292] N-(Cyclopropylmethyl)-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 7) was prepared starting from Compound 1 and 1-cyclopropylmethanamin as described in Example 2. MS (ESI): 489.4 (M+H).

[0293] 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)

[0294]

[0295] N-Cyclopropyl-1-((6-((2-methoxy-4-propylbenzyl)oxy)-1-methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxamide (Compound 8) was prepared starting from Compound 1 cyclopropylamine as described in Example 2. MS (ESI): 475.4 (M+H).

[0296] 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)

[0297]

[0298] (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 starting from Compound 1 and (2R)-butan-2-amine as described in Example 2. MS (ESI): 491.4 (M+H).

[0299] 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)

[0300]

[0301] (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 starting from Compound 1 and (2S)-butan-2-amine as described in Example 2. MS (ESI): 491.4 (M+H).

[0302] 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)

[0303]

[0304] 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 starting from Compound 1 and 3,3,3-trifluoropropane-1-amine as described in Example 2.

[0305] 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)

[0306]

[0307] 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 starting from Compound 1 and azetidine as described in Example 2. MS (ESI): 475.2 (M+H).

[0308] Compounds 13-23 were prepared in a similar manner as described in previous examples.

[0309]

[0310]

[0311] Example 13: FAAH substrate evaluation

[0312] Purified recombinant human FAAH (rhFAAH) was purchased from Cayman Chemical (Ann Arbor, MI, USA). The total volume of each incubation was 400 μL, which contained a final 0.5 ng / μL rhFAAH, 1 μM test compound, 1.25% ethanol or 1 μM PF-3845 (FAAH inhibitor) and 0.1% bovine serum albumin in Tris-EDTA buffer at pH 8.0). The incubation was performed at room temperature. At 0, 5, 15, 30 and 60 minutes, aliquots of 30 μL of the reaction mixture were taken out 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, 4°C for 15 minutes, and 100 μL of the supernatant was prepared for LC-MS / MS analysis to measure the formation of acidic metabolites.

[0313] LC-MS / MS analysis

[0314] The samples were analyzed using a Waters Acquity Ultra Performance LC system. Chromatographic analysis was performed on a reverse phase Kinetex 2.6 μm C18 column (2.1 × 30 mm, ). Mobile phase A consisted of 0.1% formic acid in water, and mobile phase B consisted of 0.1% formic acid in acetonitrile, with a run time of 1.5 minutes and a flow rate of 0.9 mL / min for the acidic metabolites of the test compound. The mass spectrometer (API-5500 and API Q Trap 4000 Applied Biosystems / MDSSCIEX Instruments, Framingham, MA, USA) was operated in ESI positive or negative MRM mode.

[0315] Data analysis

[0316] The formation of acidic metabolites was monitored and quantified using one calibration point of 1 μM. The observed rate constants (ke) for the formation of acidic metabolites were calculated by plotting metabolite concentration versus incubation time (slope is ke) and are shown in Table 1.

[0317] Table 1

[0318] Compound ke Compound ke Compound ke 2 B 3 B 4 A 5 A 6 A 7 A 8 A 9 A 10 B 11 A 12 A 13 A 14 C 15 A 16 C 17 C 18 A 19 A 20 A 21 A 22 A 23 B

[0319] Where A = ke greater than or equal to 1.0; B = ke less than 1.0 and greater than 0; C = ke is 0

[0320] The examples and embodiments described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are intended to be included within the spirit and scope of this application and the scope of the appended claims.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: in: R 1 Selected from 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, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C2-C9 heterocycloalkyl, C 1-9 Heteroaryl, phenyl and -C1-C6 alkyl-phenyl are optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, C3-C6 cycloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 One or more groups are substituted; R 2 Selected from -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, wherein 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 optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 or R 1 With R 2 Combination forms C2-C9 heterocycloalkyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 One or more groups in are substituted; R 3 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, wherein 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 selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted; Each R 4 are independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )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(R 10 )(R 11 )、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 and -CH2S(O)2N(R 10 )(R 11 ), where 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 optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted; R 5 and R 6 Independently selected from hydrogen and C1-C6 alkyl; Each R 7 and each R 8 Independently selected from hydrogen and C1-C6 alkyl; R 9a and R 9b are independently selected from 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 ), where 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 optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted; R 9c Selected from 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 ), where 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 optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted; Each R 10 are independently selected from 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, wherein 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 optionally selected from 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 One, two or three groups of heteroaryl are substituted; Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; Each R 13 C is independently selected 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, wherein 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 optionally selected from 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 One, two or three groups of heteroaryl are substituted; and m is 0, 1, 2 or 3.

2. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 and R 6 For hydrogen.

3. The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b are independently selected from hydrogen and C 1-6 alkyl.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a and R 9b For hydrogen.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9c C 1-6 Alkyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9c For unsubstituted C 1-6 alkyl.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9c It is -CH3.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 Selected from C 1-6 Alkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 C 6-10 Aryl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is phenyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is phenyl, which is optionally selected from C 1-6 Alkyl and -OR 10 One, two or three groups are substituted, wherein R 10 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

13. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 C 1-9 Heteroaryl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted.

14. The compound according to claim 13, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is pyridinyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted.

15. The compound according to claim 14, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is pyridinyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl and -OR 10 One, two or three groups are substituted, wherein R 10 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

16. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 C 1-6 Alkyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -C(O)OR 10 One, two or three groups are substituted.

17. The compound according to claim 16, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 C 1-6 Alkyl, which is optionally selected from halogen, -OR 10 and -N(R 10 )(R 11 ) is substituted by one, two or three groups.

18. The compound according to claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 For unsubstituted C 1-6 alkyl.

19. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 for 20. The compound according to claim 19, or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 for 21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, wherein m is 0.

22. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (Ia):

23. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 For hydrogen.

24. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 It is a C1-C6 alkyl group.

25. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C2-C6 alkyl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 One or more groups are substituted.

26. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group selected from halogen, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted by one or more groups.

27. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group substituted by one or more -OH groups.

28. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C2-C6 alkyl group which is substituted by one or more halogens.

29. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted C2-C6 alkyl group.

30. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is a C3-C6 cycloalkyl group, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted by one or more groups.

31. The compound according to claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 It is an unsubstituted C3-C6 cycloalkyl group.

32. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 C 1-9 Heteroaryl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 One or more groups are substituted.

33. The compound according to claim 32, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 C 1-9 Heteroaryl, which is optionally selected from halogen, C1-C6 alkyl, C 1-6 Haloalkyl, -CN, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 One or more groups are substituted, wherein C 1-9 The heteroaryl group is selected from pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl.

34. The compound according to claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is selected from the group consisting of unsubstituted pyridyl, unsubstituted pyridazinyl, unsubstituted pyrimidinyl and unsubstituted pyrazinyl.

35. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 Combination forms C2-C9 heterocycloalkyl, which is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 、-N(R 10 )(R 11 ) and -S(O)2R 13 One or more groups are substituted.

36. The compound according to claim 35, or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 Combine to form an unsubstituted C2-C9 heterocycloalkyl group.

37. A compound selected from: or a pharmaceutically acceptable salt or solvate thereof.

38. A compound selected from: or a pharmaceutically acceptable salt or solvate thereof.

39. A pharmaceutical composition comprising a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

40. The pharmaceutical composition of claim 39, further comprising a peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor.

41. The pharmaceutical composition of claim 40, wherein the peripherally restricted FAAH inhibitor is ASP-3652.

42. A method of treating a CNS disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-38, or a pharmaceutically acceptable salt or solvate thereof.

43. A method of treating a CNS disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to any one of claims 39-41, or a pharmaceutically acceptable salt or solvate thereof.

44. The method of claim 42 or claim 43, 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 disease, Alzheimer's disease, Balo concentric sclerosis, Canavan disease, central pontine myelinolysis (CPM), cerebral palsy, cerebrotendinous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic syndrome, diffuse demyelinating sclerosis, encephalomyelitis, Guillain-Barré syndrome, idiopathic inflammatory demyelinating disease (HDD), Krabbe disease, Leber hereditary optic neuropathy, leukodystrophy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy (MLD), multifocal motor neuropathy (MMN), multiple sclerosis (MS), paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzheimer disease (PMD), progressive multifocal leukoencephalopathy (PML), tropical spastic paraplegia (TSP), X-linked adrenoleukodystrophy (X-ALD, ALO, or X-linked ALO), and Zellweger syndrome.

45. The method of claim 44, wherein the CNS disease or disorder is selected from multiple sclerosis and X-linked adrenoleukodystrophy.

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