Provided herein are compounds and compositions thereof for modulating S1P5. In some embodiments, the compounds and compositions are provided for treatment of neurological diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63/211,313, filed on Jun. 16, 2021, the disclosure of which is incorporated herein by reference in its entirety for any purpose.

FIELD

[0002] The present disclosure relates generally to compounds, compositions, and methods for their preparation and use of the compounds and compositions for treating neurodegenerative diseases.

BACKGROUND

[0003] Sphingosine-1-phosphate (S1P; (2S,3R,4E)-2-amino-3-hydroxyoctadec-4-enyl-1-phosphate) is a bioactive sphingolipid that is synthesized by metabolic turnover of sphingolipids in cells and by the extracellular action of a secreted sphingosine kinase. S1P binds to and stimulates members of the endothelial cell differentiation gene family (EDG receptors), which are plasma membrane-localized G protein-coupled receptors. The five members of this family of receptors are S1P1 (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6), and S1P5 (EDG-8). S1P mediates a wide variety of cellular responses including proliferation, cytoskeletal organization and migration, adherence- and tight junction assembly, and morphogenesis.

[0004] S1P5 is primarily expressed in the central nervous system. Specifically, S1P5 is highly expressed in oligodendrocytes (oligodendroglia) and oligodendrocyte progenitor cells (Jaillard, C. et al., J. Neuroscience, 2005, 25(6), 1459-1469; Novgorodov, A. S. et al., FASEB J., 2007, 21, 1503-1514). Oligodendrocytes are glial cells that form myelin sheaths (myelin) by binding to the axons of nerve cells. Compounds that bind to S1P5 can modulate the function of S1P5 and may be useful for treating neurodegenerative diseases.

[0005] Accordingly, in one aspect, provided herein are compounds that modulate S1P5 for use in treating neurodegenerative diseases.

SUMMARY

[0006] Described herein, in certain embodiments, are compounds and compositions thereof for modulating S1P5. In various embodiments, the compounds and compositions thereof may be used for treatment of neurodegenerative diseases.

[0007] The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments.

[0008] Embodiment 1 is a compound of Formula (I):

##STR00001##

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is

[0009] ##STR00002## [0010] Z.sub.1 and Z.sub.2 are independently CR.sub.0 or N; [0011] L is azetidinyl optionally substituted with 1-5 substituents independently selected from halo and C.sub.1-C.sub.6 alkyl; [0012] each R.sub.0 is independently H, —CN, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, halo, C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6 alkoxy, [0013] or two R.sub.0 groups are taken together with the carbon atoms to which they are attached to form a fused phenylene; [0014] R.sub.1 is C.sub.6-C.sub.10 aryl or 5- to 6-membered heteroaryl, each of which is optionally substituted by 1-5 R′ groups, wherein the heteroaryl contains 1-3 heteroatoms selected from nitrogen and oxygen; [0015] each R′ is independently halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 alkoxy, or C.sub.3-C.sub.6 cycloalkyl, [0016] or two R′ groups are taken together with the carbon atoms to which they are attached to form a fused phenylene; [0017] R.sub.2 is H or C.sub.1-C.sub.6 alkyl; [0018] R.sub.3 is —(CH.sub.2).sub.x—CO.sub.2H; [0019] or the dashed line between R.sub.2 and R.sub.3 represents a ring structure where R.sub.2 and R.sub.3 are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl substituted by 1-5 R.sub.4 groups, wherein at least one R.sub.4 group is —CO.sub.2H; [0020] x is 1-5; [0021] each R.sub.4 is independently —CO.sub.2H, halo, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, or C.sub.1-C.sub.6 alkoxy; [0022] R.sub.5 and R.sub.6 are independently H or C.sub.1-C.sub.6 alkyl; and [0023] n is 0 or 1.

[0024] Embodiment 2 is the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein:

Ring A is

[0025] ##STR00003##

[0026] Embodiment 3 is the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein:

Ring A is

[0027] ##STR00004##

[0028] Embodiment 4 is the compound of embodiment 3, or a pharmaceutically acceptable salt thereof, wherein:

Z.sub.1 and Z.sub.2 are each independently CR.sub.0.

[0029] Embodiment 5 is the compound of embodiment 3, or a pharmaceutically acceptable salt thereof, wherein:

Z.SUB.1 .is N; and

[0030] Z.sub.2 is CR.sub.0.

[0031] Embodiment 6 is the compound of embodiment 3, or a pharmaceutically acceptable salt thereof, wherein:

Z.sub.1 is CR.sub.0; and

Z.SUB.2 .is N.

[0032] Embodiment 7 is the compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein:

each R.sub.0 is independently H, —CN, C.sub.1-C.sub.3 alkyl, C.sub.3-C.sub.5 cycloalkyl, halo, C.sub.1-C.sub.3 haloalkyl, or C.sub.1-C.sub.3 alkoxy, or two R.sub.0 groups are taken together with the carbon atoms to which they are attached to form a fused phenylene.

[0033] Embodiment 8 is the compound of embodiment 7, or a pharmaceutically acceptable salt thereof, wherein:

each R.sub.0 is independently H, —CN, methyl, ethyl, isopropyl, cyclopropyl, Cl, F, —CF.sub.3, or —OCH.sub.3, or two R.sub.0 groups are taken together with the carbon atoms to which they are attached to form a fused phenylene.

[0034] Embodiment 9 is the compound of any one of embodiments 1, 2, 7, and 8, or a pharmaceutically acceptable salt thereof, wherein:

Ring A is

[0035] ##STR00005##

[0036] Embodiment 10 is the compound of any one of embodiments 1 and 3-8, or a pharmaceutically acceptable salt thereof, wherein:

Ring A is

[0037] ##STR00006## ##STR00007##

[0038] Embodiment 11 is the compound of any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, wherein:

L is

[0039] ##STR00008##

each of which is optionally substituted with 1-2 substituents independently selected from halo and C.sub.1-C.sub.3 alkyl.

[0040] Embodiment 12 is the compound of embodiment 11, or a pharmaceutically acceptable salt thereof, wherein:

L is

[0041] ##STR00009##

each of which is optionally substituted with one F, Cl, or methyl.

[0042] Embodiment 13 is the compound of embodiment 12, or a pharmaceutically acceptable salt thereof, wherein:

L is

[0043] ##STR00010##

[0044] Embodiment 14 is the compound of any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein:

R.sub.1 is phenyl or 5- to 6-membered heteroaryl, each of which is optionally substituted by 1-3 R′ groups, wherein the heteroaryl contains 1-2 heteroatoms selected from nitrogen and oxygen.

[0045] Embodiment 15 is the compound of embodiment 14, or a pharmaceutically acceptable salt thereof, wherein:

R.sub.1 is phenyl optionally substituted by 1-3 R′ groups.

[0046] Embodiment 16 is the compound of any one of embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein:

each R′ is independently halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.3 alkoxy, or C.sub.3-C.sub.6 cycloalkyl,

or two R′ groups are taken together with the carbon atoms to which they are attached to form a fused phenylene.

[0047] Embodiment 17 is the compound of embodiment 16, or a pharmaceutically acceptable salt thereof, wherein:

each R′ is independently halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, or C.sub.3-C.sub.6 cycloalkyl,

or two R′ groups are taken together with the carbon atoms to which they are attached to form a fused phenylene.

[0048] Embodiment 18 is the compound of embodiment 17, or a pharmaceutically acceptable salt thereof, wherein:

each R′ is independently F, Cl, methyl, ethyl, isopropyl, —CHF.sub.2, or cyclopropyl,

or two R′ groups are taken together with the carbon atoms to which they are attached to form a fused phenylene.

[0049] Embodiment 19 is the compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, wherein:

R.SUB.1 .is

[0050] ##STR00011## ##STR00012##

[0051] Embodiment 20 is the compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein:

R.sub.2 is H or C.sub.1-C.sub.3 alkyl;

R.sub.3 is —(CH.sub.2).sub.x—CO.sub.2H; and

x is 1-3.

[0052] Embodiment 21 is the compound of embodiment 20, or a pharmaceutically acceptable salt thereof, wherein:

##STR00013##

[0053] Embodiment 22 is the compound of any one of embodiments 1-19, or a pharmaceutically acceptable salt thereof, wherein:

R.sub.2 and R.sub.3 are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl substituted by 1-3 R.sub.4 groups, wherein at least one R.sub.4 group is —CO.sub.2H.

[0054] Embodiment 23 is the compound of embodiment 22, or a pharmaceutically acceptable salt thereof, wherein:

each R.sub.4 is independently —CO.sub.2H, halo, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, or C.sub.1-C.sub.3 alkoxy.

[0055] Embodiment 24 is the compound of embodiment 23, or a pharmaceutically acceptable salt thereof, wherein:

each R.sub.4 is independently —CO.sub.2H, methyl, F, Cl, —CF.sub.3, or —OCH.sub.3.

[0056] Embodiment 25 is the compound of any one of embodiments 1-19 and 22-24, or a pharmaceutically acceptable salt thereof, wherein:

##STR00014##

[0057] Embodiment 26 is the compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein:

n is 0.

[0058] Embodiment 27 is the compound of any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein:

n is 1.

[0059] Embodiment 28 is the compound of embodiment 27, or a pharmaceutically acceptable salt thereof, wherein:

R.sub.5 and R.sub.6 are independently H or C.sub.1-C.sub.3 alkyl.

[0060] Embodiment 29 is the compound of embodiment 28, or a pharmaceutically acceptable salt thereof, wherein:

R.sub.5 and R.sub.6 are independently H or methyl.

[0061] Embodiment 30 is the compound of embodiment 29, or a pharmaceutically acceptable salt thereof, wherein:

—CR.sub.5R.sub.6— is —CH.sub.2—, —CH(CH.sub.3)—, or —C(CH.sub.3).sub.2—.

[0062] Embodiment 31 is the compound of any one of embodiments 1, 2, and 7-9, and 11-26, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II):

##STR00015##

[0063] Embodiment 32 is the compound of any one of embodiments 1, 3-8, 10-19, 22-25, and 27-30, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (III):

##STR00016##

and

##STR00017##

is a 4- to 6-membered heterocyclyl, wherein at least one R.sub.4 group is —CO.sub.2H.

[0064] Embodiment 33 is a compound selected from the compounds of Table 1 and pharmaceutically acceptable salts thereof.

[0065] Embodiment 34 is a pharmaceutical composition comprising the compound of any one of embodiments 1-33, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0066] Embodiment 35 is a method of modulating sphingosine 1-phosphate receptor 5 (S1P5) comprising contacting S1P5 with an effective amount of the compound of any one of embodiments 1-33, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 34.

[0067] Embodiment 36 is a method of treating a neurological disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of embodiments 1-33, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 34.

[0068] Embodiment 37 is the method of embodiment 36, wherein the neurological disease is Alzheimer's disease or multiple sclerosis.