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US-12624003-B2 - Carboxylic acid containing indanyl compounds for the treatment of neurodegenerative diseases

US12624003B2US 12624003 B2US12624003 B2US 12624003B2US-12624003-B2

Abstract

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

Inventors

  • Jeffrey M. Schkeryantz
  • Julie Selkirk
  • Philip Stewart TURNBULL
  • Junko Tamiya
  • Patrick W. Papa
  • Jean-Francois Brazeau
  • Karin Worm

Assignees

  • CELGENE CORPORATION

Dates

Publication Date
20260512
Application Date
20211222

Claims (19)

  1. 1 . A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: L is —C(Y) C(X)— or a bond; X and Y are independently H, O, H 2 , or absent; is a single, double, or triple bond; R 1 is C 6 -C 10 aryl, fused bicyclic 8- to 10-membered heteroaryl, or fused bicyclic 8- to 10-membered heterocyclyl, each of which is optionally substituted by 1-5 R′ groups, wherein the heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from nitrogen and oxygen; each R′ is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 3 -C 6 cycloalkyl; R 2 is H or C 1 -C 6 alkyl; R 3 is —(CH 2 ) x —CO 2 H or or the dashed line between R 2 and R 3 represents a ring structure where R 2 and R 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 4 groups, wherein at least one R 4 group is —CO 2 H or contains a —CO 2 H moiety; x is 1-5; and each R 4 is independently —CO 2 H, halo, or C 1 -C 6 alkyl, or two R 4 groups are taken together with the carbon atoms to which they are attached to form a fused, bridged, or spiro C 3 -C 5 cycloalkyl optionally substituted by —CO 2 H.
  2. 2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: L is —C≡C—, —HC═CH—, —CH 2 CH 2 —, —C(O)—CH 2 —, or —CH 2 —C(O)—.
  3. 3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: L is a bond.
  4. 4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R 1 is phenyl, phenyl fused to a cycloalkyl, fused bicyclic 9-membered heteroaryl, or fused bicyclic 9-membered heterocyclyl, each of which is optionally substituted by 1-3 R′ groups, wherein the heterocyclyl and heteroaryl contain 1-2 heteroatoms selected from nitrogen and oxygen.
  5. 5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: each R′ is independently halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, or C 3 -C 6 cycloalkyl.
  6. 6 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein: each R′ is independently Cl, F, methyl, ethyl, isopropyl, —CF 3 , —OCH 3 , or cyclopropyl.
  7. 7 . The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein: R 1 is
  8. 8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R 2 is H or C 1 -C 3 alkyl; R 3 is —(CH 2 ) x —CO 2 H or and x is 1-3.
  9. 9 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein:
  10. 10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R 2 and R 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 4 groups, wherein at least one R 4 group is —CO 2 H or contains a —CO 2 H moiety.
  11. 11 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein: R 2 and R 3 are taken together with the nitrogen atom to which they are attached to form azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted by 1-3 R 4 groups, wherein at least one R 4 group is —CO 2 H or contains a —CO 2 H moiety.
  12. 12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: each R 4 is independently —CO 2 H, halo, or C 1 -C 3 alkyl, or two R 4 groups are taken together with the carbon atoms to which they are attached to form a fused, bridged, or spiro C 3 -C 5 cycloalkyl optionally substituted by —CO 2 H, wherein at least one R 4 group is —CO 2 H or contains a —CO 2 H moiety.
  13. 13 . The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein: each R 4 is independently —CO 2 H, F, or methyl, or two R 4 groups are taken together with the carbon atoms to which they are attached to form a fused cyclopropyl, a spiro cyclopropyl, a spiro cyclobutyl, or a bridged cyclopentyl, each of which is optionally substituted by —CO 2 H, wherein at least one R 4 group is —CO 2 H or contains a —CO 2 H moiety.
  14. 14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
  15. 15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II):
  16. 16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (IIIa) or (IIIb):
  17. 17 . A compound selected from: or a pharmaceutically acceptable salt thereof.
  18. 18 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  19. 19 . A method of modulating sphingosine 1-phosphate receptor 5 (S1P5) comprising contacting S1P5 with an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a national stage entry pursuant to 35 U.S.C. § 371 of International Application No. PCT/US2021/064881, filed Dec. 22, 2021, which claims priority to U.S. Provisional Application No. 63/130,023, filed on Dec. 23, 2020, each of which is incorporated herein by reference in its entirety for any purpose. FIELD 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 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. 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. Accordingly, in one aspect, provided herein are compounds that modulate S1P5 for use in treating neurodegenerative diseases. SUMMARY 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. The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments. Exemplary embodiments include the following. Embodiment 1. In some embodiments, provided herein are compounds of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:L is —C(Y)C(X)— or a bond;X and Y are independently H, O, H2, or absent; is a single, double, or triple bond;R1 is C6-C10 aryl, fused bicyclic 8- to 10-membered heteroaryl, or fused bicyclic 8- to 10-membered heterocyclyl, each of which is optionally substituted by 1-5 R′ groups, wherein the heterocyclyl and heteroaryl contain 1-3 heteroatoms selected from nitrogen and oxygen;each R′ is independently halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl;R2 is H or C1-C6 alkyl;R3 is —(CH2)x—CO2H or or the dashed line between R2 and R3 represents a ring structure where R2 and R3 are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclyl substituted by 1-5 R4 groups, wherein at least one R4 group is —CO2H or contains a —CO2H moiety;x is 1-5; andeach R4 is independently —CO2H, halo, or C1-C6 alkyl,or two R4 groups are taken together with the carbon atoms to which they are attached to form a fused, bridged, or spiro C3-C5 cycloalkyl optionally substituted by —CO2H. Embodiment 2. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein: L is —C(Y)C(X)—. Embodiment 3. The compound of embodiment 2, or a pharmaceutically acceptable salt thereof, wherein: L is —C≡C—, —HC═CH—, or —CH2CH2—. Embodiment 4. The compound of embodiment 2, or a pharmaceutically acceptable salt thereof, wherein: L is —C(O)—CH2— or —CH2—C(O)—. Embodiment 5. The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein: L is a bond. Embodiment 6. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein: R1 is phenyl, phenyl fused to a cycloalkyl, fused bicyclic 9-membered heteroaryl, or fused bicyclic 9-membered heterocyclyl, each of which is optionally substituted by 1-3 R′ groups, wherein the heterocyclyl and heteroaryl contain 1-2 heteroatoms selected from nitrogen and oxygen. Embodiment 7. The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein: each R′ is independently halo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C3-C6 cycloalkyl. Embodiment 8. The compound of embodiment 7, or a pharmaceutically acceptable salt thereof, wherein: each R is independently Cl, F, methyl, ethyl, isopropyl, —CF3, —OCH3, or cyclopropyl. Embodiment 9. The compound of any one of embodiments 6-8, or a pharmaceutically acceptable salt thereof, wherein: R1 is Embodiment 10. The compound of any one of embodi