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US-20260125372-A1 - DYNAMIN-1-LIKE PROTEIN INHIBITORS AND USES THEREOF

US20260125372A1US 20260125372 A1US20260125372 A1US 20260125372A1US-20260125372-A1

Abstract

Provided are compounds of the Formula (I); or pharmaceutically acceptable salts thereof, which can be useful for the inhibition of Drp 1 and in the treatment of a variety of Drp 11 mediated conditions or diseases.

Inventors

  • Bin Ma
  • Takeru Furuya

Assignees

  • Astellas Engineered Small Molecules US, Incorporated

Dates

Publication Date
20260507
Application Date
20231024

Claims (20)

  1. 1 . A compound represented by Formula (I): or a pharmaceutically acceptable salt thereof, wherein: X 1 is CH or N; R 1 is a 5- to 10-membered monocyclic or bicyclic heteroaryl optionally substituted with one more R 1a ; each R 1a is independently selected from the group consisting of halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; R 2 is C 1-6 alkyl, C 3-6 cycloalkyl, bridged C 5-12 cycloalkyl, phenyl, 3- to 10-membered monocyclic or bicyclic heterocyclyl, or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which is optionally substituted by one or more R 2a ; each R 2a is independently selected from halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OH, C 1-6 alkoxy, C 1-6 haloalkoxy, —C(O)R 2b , —C(O)OR 2b , —C(O)NR N2a R N2b , and —NR N2a R N2b ; R 2b , R N2a , and R N2b are each independently H, C 1-6 alkyl, or C 1-6 haloalkyl; R 3 is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, 3- to 10-membered monocyclic or bicyclic heterocyclyl, or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which is optionally substituted with one or more R 3a ; each R 3a is independently selected from the group consisting of halo, C 1-6 alkyl, OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; R 4 is H, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl; and R 5 is H, C 1-6 alkyl, or C 1-6 haloalkyl.
  2. 2 . The compound of claim 1 , wherein the compound is represented by Formula (IA): or a pharmaceutically acceptable salt thereof.
  3. 3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H or C 1-3 alkyl.
  4. 4 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H or —CH 3 .
  5. 5 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein: R 1 is a 5- or 6-membered monocyclic heteroaryl, wherein the 5- or 6-membered monocyclic heteroaryl is optionally substituted by 1 or 2 R 1a ; each R 1a is independently selected from the group consisting of halo, cyano, C 1-4 alkyl, C 3-4 cycloalkyl, and C 1-3 alkoxy.
  6. 6 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of imidazoyl, pyrazoyl, triazoyl, and thiazoyl, each of which is optionally substituted by 1 or 2 R 1a .
  7. 7 . The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is represented by the following structural formula: each of which is optionally substituted by 1 or 2 R 1a , and wherein each R 1a is independently selected from the group consisting of —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —C(CH 3 ) 3 , cyclopropyl, —OCH 3 , —Cl, and cyano.
  8. 8 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of imidazoyl and thiazoyl, each of which is optionally substituted by 1 or 2 R 1a , and wherein each R 1a is independently selected from the group consisting of —CH 3 , cyclopropyl, and —OCH 3 .
  9. 9 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein: R 2 is C 1-3 alkyl, C 3-6 cycloalkyl, bridged C 5-8 cycloalkyl, 3- to 6-membered monocyclic heterocyclyl, or 5- or 6-membered monocyclic heteroaryl, each of which is optionally substituted by 1 to 3 R 2a ; each R 2a is independently selected from the group consisting of halo, cyano, C 1-3 alkyl, C 1-3 haloalkyl, —OH and C 1-3 alkoxy.
  10. 10 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-3 alkyl, cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentanyl, oxetanyl, tetrahydropyranyl, or isoxazoyl, each of which is optionally substituted by 1 to 3 R 2a .
  11. 11 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-3 alkyl optionally substituted by 1 to 3 R 2a , or R 2 is represented by the following structural formula: each of which is optionally substituted by 1 or 2 R 2a , and wherein each R 2a is selected from the group consisting of —F, cyano, —CH 3 , —CF 3 , —OH, —OCH 3 , —OCH 2 CH 3 , and —OCH 2 CH 2 CH 3 .
  12. 12 . The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —CF 3 , —CH 2 CH 2 OCH 3 , —CH 2 OCH 3 , —CH 2 OH, —CH(OH)CH 3 , —CH(CH 3 )CH 2 OCH 3 , —CH(CH 3 )CN, —CH(CH 3 )OCH 3 , —CH(CH 3 )OCH 2 CH 3 , —CH(CH 3 )OCH 2 CH 2 CH 3 , —CF 2 CH 2 OH, or R 2 is represented by the following structural formula:
  13. 13 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-3 alkyl, cyclopropyl, cyclobutyl, oxetanyl, or tetrahydropyranyl, wherein the C 1-3 alkyl, cyclopropyl, and cyclobutyl are each optionally substituted with 1 to 3 R 2a .
  14. 14 . The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —CH(CH 3 )CN, —CH(CH 3 )OCH 3 , —CH(CH 3 )OCH 2 CH 3 , —CH(CH 3 )OCH 2 CH 2 CH 3 , or R 2 is represented by the following structural formula:
  15. 15 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein: R 3 is C 1-4 alkyl or C 3-4 cycloalkyl, each of which is optionally substituted with 1 to 3 R 3a ; each R 3a is independently selected from the group consisting of C 1-3 alkyl, —OH, and C 1-3 alkoxy.
  16. 16 . The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein: R 3 is C 1-4 alkyl or cyclopropyl, and wherein the C 1-3 alkyl is optionally substituted with 1 to 3 R 3a ; each R 3a is independently selected from —CH 3 , OH, and —OCH 3 .
  17. 17 . The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 3 is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , —CH(CH 3 )CH 2 OCH 3 , —C(CH 3 ) 2 CH 2 OCH 3 , or cyclopropyl.
  18. 18 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.
  19. 19 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  20. 20 . A method of treating a Dynamin-1-like protein (Drp1) mediated disease or disorder in a subject, comprising administering to the subject an effective amount of a compound, or pharmaceutically acceptable salt thereof, of claim 1 .

Description

RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63/419,132, filed on Oct. 25, 2022. The entire contents of the foregoing application are expressly incorporated herein by reference. FIELD OF THE INVENTION The present disclosure relates to inhibitors of dynamin-1-like protein (Drp1), and pharmaceutically acceptable salts thereof, compositions of these compounds, processes for their preparation, and their use in the treatment of diseases. BACKGROUND OF THE INVENTION Dynamin-1-like protein is a GTPase that regulates mitochondrial fission. In humans, dynamin-1-like protein, which is typically referred to as dynamin-related protein 1 (Drp1), is encoded by the DNM1L gene. Inhibitors of Drp1 blocks cell death, implicating mitochondrial fission as an important step in apoptosis. Drp1 sequences (OMIM 603850) are publically available, for example, from GenBank® sequence database (e.g., BAA22193 (human, protein, AB006965 (human, nucleic acid)). In healthy cells, fusion and fission events participate in regulating mitochondrial morphology. Drp1, a dynamin-related protein, mediates outer mitochondrial membrane fission and typically activated during cell division. Specifically during the M phase, Drp1 is activated which induces mitochondrial fission to ensure equal distribution of mitochondria to each daughter cell. Mitochondrial fission creates smaller mitochondria which are more capable of generating reaction oxygen species, facilitating mitophagy, or accelerating cell proliferation compared to their larger counterparts (Archer S L. Mitochondrial dynamics—mitochondrial fission and fusion in human diseases. N Engl J Med. 2013 369(23):2236-51). Upon induction of apoptosis, Drp1 translocates from the cytosol to mitochondria, where it preferentially localizes to potential sites of organelle division. Drp1 is regulated by phosphorylation, with phosphorylation at serine 616 increasing activity and phosphorylation at serine 637 decreasing activity. Inhibition of Drp1 prevents the loss of the mitochondrial membrane potential and the release of cytochrome c, and reveals a reproducible swelling of the organelles. Remarkably, inhibition of Drp1 blocks cell death, implicating mitochondrial fission as an important step in cellular apoptosis. Further, inhibition of Drp1 has been shown to decrease reactive oxygen species due to a reduction in mitochondrial fission. Thus, modulation Drp1 activity is effective in the treatment of a variety of conditions, such as, for example, cardiovascular disease, kidney disease, ophthalmic conditions, cancer, ischemia-reperfusion injury, and neurodegenerative and cognitive diseases. Indeed, Drp1 is an important biological target for compounds used to help treat and prevent diseases such as cardiovascular disease, kidney disease, ophthalmic conditions, cancer, cognitive disease, and other related conditions. Thus, there is a need for Drp1 inhibitors as potential therapeutic agents for treating diseases or disorders that are responsive to Drp1 inhibition. SUMMARY OF THE INVENTION The present disclosure provides compounds that are Drp1 inhibitors. In a first aspect, the present disclosure relates to compounds having the Formula I: or a pharmaceutically acceptable salt thereof, wherein: X1 is CH or N;R1 is a 5- to 10-membered monocyclic or bicyclic heteroaryl optionally substituted with one more R1a;each R1a is independently selected from the group consisting of halo, cyano, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, OH, C1-6alkoxy, and C1-6haloalkoxy;R2 is C1-6alkyl, C3-6cycloalkyl, bridged C5-12cycloalkyl, phenyl, 3- to 10-membered monocyclic or bicyclic heterocyclyl, or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which is optionally substituted by one or more R2a;each R2a is independently selected from halo, cyano, C1-6alkyl, C1-6haloalkyl, OH, C1-6alkoxy, C1-6haloalkoxy, —C(O)R2b, —C(O)OR2b, —C(O)NRN2aRN2b, and —NRN2aRN2b;R2b, RN2a, and RN2b are each independently H, C1-6alkyl, or C1-6haloalkyl;R3 is C1-6alkyl, C3-6cycloalkyl, phenyl, 3- to 10-membered monocyclic or bicyclic heterocyclyl, or 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which is optionally substituted with one or more R3a;each R3a is independently selected from the group consisting of halo, C1-6alkyl, OH, C1-6alkoxy, and C1-6haloalkoxy;R4 is H, C1-6alkyl, C1-6haloalkyl, or C3-6cycloalkyl; andR5 is H, C1-6alkyl, or C1-6haloalkyl. Another aspect of the disclosure relates to pharmaceutical compositions comprising compounds of Formula (I) or pharmaceutically acceptable salts thereof, and a pharmaceutical carrier. In yet another aspect, the present disclosure provides a method of treating a Drp1 mediated disease or disorder in a subject comprising administering to said subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof or pharmaceutical compositions comprising a compound described herein or pharmaceutically accept