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JP-2026514377-A - Inhibitors of Spinster homolog 2 (SPNS2) for therapeutic use

JP2026514377AJP 2026514377 AJP2026514377 AJP 2026514377AJP-2026514377-A

Abstract

This disclosure provides SPNS2 inhibitor compounds of formula I, where T, U, V, W, X, R1 , R2 , and m are defined herein. This disclosure also provides pharmaceutically acceptable salts and/or tautomers of the compounds of formula I described herein. Methods of using them in the treatment of diseases requiring immunomodulatory and/or antifibrotic activity are also provided.

Inventors

  • リンチ ケビン アール．
  • カレル ユゲシュ
  • ホアン タオ
  • サントス ウェブスター エル．
  • シュレーダー クリストファー
  • ダナヴァント カイル
  • ブルジオ アリエル ルイーズ
  • ベイジ アンドリュー ディー．

Assignees

  • ユニバーシティ オブ バージニア パテント ファンデーション
  • バージニア テック インテレクチュアル プロパティーズ， インコーポレイテッド
  • リンチ ケビン アール．
  • カレル ユゲシュ
  • ホアン タオ
  • サントス ウェブスター エル．
  • シュレーダー クリストファー
  • ダナヴァント カイル
  • ブルジオ アリエル ルイーズ
  • ベイジ アンドリュー ディー．

Dates

Publication Date
20260511
Application Date
20240322
Priority Date
20230324

Claims (20)

  1. Compounds of formula I or pharmaceutically acceptable salts thereof: During the ceremony X is a C6 - C10 aryl or a 5-10 membered heteroaryl (where 1-4 heteroaryl ring members are independently selected from N, O, and S); R1 and R2 are independently selected from the group consisting of H, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkoxy, C3 - C8 cycloalkyl, C1 - C6 haloalkyl, CN, and halo; W is a bond, O, NH, -NHC(O)-, or -O-(N=)C(R)- (where R is H or C1 - C6 alkyl); U is (A) A 6- to 8-membered heterocycloalkyl group having two ring atoms that are N, which may be condensed, crosslinked, or spirocondensed, where V is selected from the group consisting of H, C1 - C14 alkyl, C2 - C12 alkenyl, ( C6 - C10 ) aryl, ( C6 - C10 ) heteroaryl, -C1 - C10 alkyl-( C6 - C10 ) aryl, -C2 - C12 alkenyl-( C6 - C10 ) aryl, -C1 - C10 alkyl-( C3 - C8 ) cycloalkyl, -(3-14 member heterocycloalkyl) (where 1-4 heterocycloalkyl members are independently selected from N, O, and S), and -( C1 - C10 ) alkyl-(3-14 member heterocycloalkyl) (where 1-4 heterocycloalkyl members are independently selected from N, O, and S). or (B) Monocyclic 4-7 membered heterocycloalkyl (where 1-4 heterocycloalkyl members are independently selected from N, O, and S), where V includes H, -C1 - C14 alkyl, -C1 - C10 alkyl-O-( C3 - C14 ) cycloalkyl, -C1 - C10 alkyl-O-( C6 - C10 ) aryl, -C1 - C10 alkyl- NRx- ( C6 - C10 ) aryl, -C1 - C10 alkyl- NRxC (O)( C6 - C10 ) aryl, -C1 - C10 alkyl-C(O) NRx ( C6 - C10 ) aryl, -C2 - C12 alkenyl-O-( C6 - C10 ) aryl, -C1 - C10 alkyl-O-( C6 - C10 ) heteroaryl (where 1-4 heteroaryl ring members are independently selected from N, O, and S), and -C2 -C It is one of the groups consisting of 12- alkenyl-O-( C6 - C10 ) heteroaryls (where 1-4 heteroaryl ring members are independently selected from N, O, and S); T is -C(O)- or -NR x C(O)-; R x is H or C1 - C6 alkyl; m is an integer selected from 0, 1, 2, 3, 4, 5, and 6; Here, each alkyl, alkoxy, alkenyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl are defined as hydroxy, halo, C1 - C6 alkyl, C1 - C6 haloalkoxy, C1 - C6 haloalkyl, -NR'2 , -NHC(O)( OC1 - C6 alkyl), -NO2 , -CN, oxo, -C(O)OH, -C(O)O( C1 - C6 alkyl), -C1 - C6 alkyl( C1 - C6 alkoxy), -C(O) NH2 , C1 - C6 alkoxy, C3 - C14 cycloalkyl, -C(O) C1 - C6 alkyl, -OC1- C6 alkyl, -Si( C1 - C6 alkyl) 3 , -S(O) O-2 -( C1 - C6 alkyl), C6 - C10 aryl, -(C It may also be substituted with 1 to 5 substituents independently selected from the group consisting of 1 - C6 alkyl ( C6 - C10 aryl), 3-14 member heterocycloalkyl and -( C1 - C6 alkyl)-(3-14 member heterocycle) (where 1-4 heterocycle members are independently selected from N, O, and S), and -O( C6 - C14 aryl); Here, each R' is independently selected from the group consisting of C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C6 -C10 aryl, 3-14 member heterocycloalkyl and -( C1 - C6 alkyl)-(3-14 member heterocycloalkyl) (where 1-4 ring members are independently selected from N, O, and S), and 5-10 member heteroaryl (where 1-4 heteroaryl members are independently selected from N, O, and S).
  2. U is a 6- to 8-membered heterocycloalkyl group in which (A) two ring atoms are N, and which may be substituted and may be condensed, crosslinked, or spirocondensed. V is selected from the group consisting of H, C1 - C14 alkyl, C2 - C12 alkenyl, ( C6 - C10 ) aryl, ( C6 - C10 ) heteroaryl, -C1 - C10 alkyl-( C6 - C10 ) aryl, -C2 - C12 alkenyl-( C6 - C10 ) aryl, -C1 - C10 alkyl-( C3 - C8 ) cycloalkyl, -(3-14 member heterocycloalkyl) (where 1-4 heterocycloalkyl members are independently selected from N, O, and S), -( C1 - C10 ) alkyl-(3-14 member heterocycloalkyl) (where 1-4 heterocycloalkyl members are independently selected from N, O, and S). The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein V is a C1 - C14 alkyl group.
  4. The compound according to claim 2 or 3, wherein V is a C8 - C12 alkyl group, or a pharmaceutically acceptable salt thereof.
  5. Even if U is substituted A compound according to any one of claims 2 to 4, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.
  6. U is a (B) optionally substituted monocyclic 4- to 7-membered heterocycloalkyl (where 1 to 4 heterocycloalkyl members are independently selected from N, O, and S), V is a -C1 - C10 alkyl-O-( C6 - C10 )aryl, -C1 - C10 alkyl-NR x- ( C6 - C10 )aryl, -C1 - C10 alkyl-NR x C(O)( C6 - C10 )aryl, -C1 - C10 alkyl-C(O)NR x ( C6 - C10 )aryl, -C2 - C12 alkenyl-O-( C6 - C10 )aryl, -C1 - C10 alkyl-O-( C6 - C10 ) heteroaryl (where 1-4 heteroaryl ring members are independently selected from N, O, and S), and -C2 - C12 alkenyl-O-( C6 - C10 ) heteroaryl (where 1-4 heteroaryl ring members are independently selected from N, O, and S). Selected from the group consisting of, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein U is a monocyclic 5- to 7-membered heterocycloalkyl (where one or two heterocycloalkyl members are independently selected from N and O).
  8. The compound according to claim 6 or 7 or a pharmaceutically acceptable salt thereof, wherein U is selected from pyrrolidinyl, oxazolidinyl, isoxazolidinyl, imidazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl, which may be substituted.
  9. A compound according to any one of claims 6 to 8, wherein U is piperazinyl, or a pharmaceutically acceptable salt thereof.
  10. A compound according to any one of claims 6 to 9 or a pharmaceutically acceptable salt thereof, wherein V is -C1 to C10 alkyl-O-( C6 to C10 )aryl.
  11. A compound according to any one of claims 6 to 10 or a pharmaceutically acceptable salt thereof, wherein V is a C3 - C8 alkyl-O-phenyl.
  12. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein X is a C6 - C10 aryl compound.
  13. A compound according to any one of claims 1 to 12, wherein X is phenyl, or a pharmaceutically acceptable salt thereof.
  14. A compound according to any one of claims 1 to 13, wherein W is a bond or O, or a pharmaceutically acceptable salt thereof.
  15. A compound according to any one of claims 1 to 14, wherein W is a bond, or a pharmaceutically acceptable salt thereof.
  16. A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein T is -NR x C(O)-.
  17. A compound according to any one of claims 1 to 15, wherein T is -C(O)-, or a pharmaceutically acceptable salt thereof.
  18. A compound according to any one of claims 1 to 17, wherein m is 0, or a pharmaceutically acceptable salt thereof.
  19. U is a 6-8 member heterocycloalkyl group, (A) having two ring atoms that are N, which may be substituted, condensed, crosslinked, or spirocondensed. X is C6 to C10 aryl, T is -NR x C(O)- where R x is H, V is C8 - C12 alkyl, W is a bond, m is 0, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  20. U is a (B) optionally substituted 5- to 7-membered heterocycloalkyl (where one or two heterocycloalkyl members are independently selected from N and O), X is C6 to C10 aryl, T is -NR x C(O)- where R x is H, V is a -C1 - C10 alkyl-O-( C6 - C10 )aryl, W is a bond, m is 0, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

Description

This application claims priority to U.S. Provisional Patent Application No. 63/492,062, filed March 24, 2023, and U.S. Provisional Patent Application No. 63/512,698, filed July 10, 2023, which are incorporated as if they were entirely contained herein. Government Licensing Rights: This invention was made with government support under grant number R01 AI144026, awarded by the National Institutes of Health. The government has certain rights to the invention. Background: Sphingosine 1-phosphate (S1P) is a chemotactic lipid. This role requires compartmentalization, which is partially provided by S1P transporters on the cell surface. There are two distinct types of S1P transporters: SPNS2 (endothelial cells, microglial cells) and MFSD2B (erythrocytes, platelets). When S1P release is linked to S1P degradation in tissue parenchyma, a difference in S1P concentration arises between extracellular (high) and intracellular (low) regions. In blood, the S1P gradient helps maintain the integrity of the endothelial barrier, while other S1P concentration gradients control the placement of immune cells. S1P is particularly important for the release of lymphocytes from secondary lymphoid tissues to efferent lymphoid cells. S1P receptor modulators (SRMs) shield lymphocytes from S1P by desensitizing the S1P1 receptor. However, SRM agonist activity at endothelial and cardiac S1P1 receptors causes adverse events such as bradycardia and macular edema upon initial administration. Therefore, other methods are needed to modulate the migration of immune cells by blocking S1P signaling. Summary This disclosure satisfies this and other needs by providing compounds conforming to Formula I and pharmaceutically acceptable salts thereof as SPNS2 inhibitors that avoid adverse effects on targets in various embodiments: X is a C6 – C10 aryl or a 5–10 membered heteroaryl (where 1–4 heteroaryl ring members are independently selected from N, O, and S). R1 and R2 are independently selected from the group consisting of H, C1 - C6 alkyl, C1 - C6 alkoxy, C1 - C6 haloalkoxy, C3 - C8 cycloalkyl, C1 - C6 haloalkyl, CN, and halo. W is a bond, O, NH, -NHC(O)-, or -O-(N=)C(R)- (where R is H or C1 - C6 alkyl). In some embodiments, U is a 6- to 8-membered heterocycloalkyl group which may be condensed, crosslinked, or spirocondensed, having (A) two ring atoms that are nitrogen. In these embodiments, V is selected from the group consisting of H, C1 - C14 alkyl, C2 - C12 alkenyl, ( C6 - C10 ) aryl, ( C6 - C10 ) heteroaryl, -C1 - C10 alkyl-( C6 - C10 ) aryl, -C2 - C12 alkenyl-( C6 - C10 ) aryl, -C1 - C10 alkyl-( C3 - C8 ) cycloalkyl, -(3-14 member heterocycloalkyl) (where 1-4 heterocycloalkyl members are independently selected from N, O, and S), and -( C1 - C10 ) alkyl-(3-14 member heterocycloalkyl) (where 1-4 heterocycloalkyl members are independently selected from N, O, and S). In another embodiment, U is (B) a monocyclic 4- to 7-membered heterocycloalkyl (where 1 to 4 heterocycloalkyl members are independently selected from N, O, and S). In these embodiments, V is H, -C1 - C14 alkyl, -C1 - C10 alkyl-O-( C3 - C14 ) cycloalkyl, -C1 - C10 alkyl-O-( C6 - C10 ) aryl, -C1 - C10 alkyl- NRx- ( C6 - C10 ) aryl, -C1 - C10 alkyl- NRxC (O)( C6 - C10 ) aryl, -C1 - C10 alkyl-C(O) NRx ( C6 - C10 ) aryl, -C2 - C12 alkenyl-O-( C6 - C10 ) aryl, -C1 - C10 alkyl-O-( C6 - C10 ) heteroaryl (where 1-4 heteroaryl ring members are independently selected from N, O, and S), and -C2 -C Selected from the group consisting of 12- alkenyl-O-( C6 - C10 ) heteroaryls (where 1-4 heteroaryl ring members are independently selected from N, O, and S). T is -C(O)- or -NR x C(O)-. Rx is either H or C1 - C6 alkyl. m is an integer selected from 0, 1, 2, 3, 4, 5, and 6. In Formula I, each alkyl, alkoxy, alkenyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl are hydroxy, halo, C1 - C6 alkyl, C1 - C6 haloalkoxy, C1 - C6 haloalkyl, -NR'2 , -NHC(O)( OC1 - C6 alkyl), -NO2 , -CN, oxo, -C(O)OH, -C(O)O( C1 - C6 alkyl), -C1 - C6 alkyl( C1 - C6 alkoxy), -C(O) NH2 , C1 - C6 alkoxy, C3 - C14 cycloalkyl, -C(O) C1 - C6 alkyl , -OC1- C6 alkyl, -Si( C1 - C6 alkyl) 3 , -S(O) O-2- ( C1 - C6 alkyl), C6 -C The molecules may be substituted with 1 to 5 substituents independently selected from the group consisting of 10- aryl, -( C1 - C6 alkyl)( C6 - C10 aryl), 3-14 member heterocycloalkyl and -( C1 - C6 alkyl)-(3-14 member heterocycle) (where 1 to 4 heterocycle members are independently selected from N, O, and S), and -O( C6 - C14 aryl). Each R' is independently selected from the group consisting of C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C6 - C10 aryl, 3-14 member heterocycloalkyl and -( C1 - C6 alkyl)-(3-14 member heterocycloalkyl) (where 1-4 ring members are independently selected from N, O, and S), and 5-10 member heteroaryl (where 1-4 heteroaryl members are independently selected from N, O, and S). Another aspect of this disclosure is a pharmaceutical composition comprising a compound described herein or