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CN-122029151-A - Statin derivatives and methods of use thereof

CN122029151ACN 122029151 ACN122029151 ACN 122029151ACN-122029151-A

Abstract

The present disclosure relates to compounds of formula (I ') or formula (II'): (I') or (II'), as well as prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods of preparation thereof. The compounds disclosed herein are useful for modulating stathmin-2 (STMN 2) activity and for treating disorders involving STMN2 activity, such as neurodegenerative diseases and disorders or axonal lesions.

Inventors

  • C. Rajiye Turen
  • M. Nolan
  • R. D. Hubbard

Assignees

  • 通用医疗公司

Dates

Publication Date
20260512
Application Date
20240612
Priority Date
20230612

Claims (20)

  1. 1. A compound of formula (I'): (I’), or a pharmaceutically acceptable salt thereof, wherein: is a single bond or a double bond, as long as the valence bond permits; Is a single bond or a double bond, wherein the double bond is an (E) isomer; x 1 is CH or N; A 1 is CR A1 , N, O or S; A 2 is CR A2 , N, O or S; A 3 is CR A3 , N, O, or S, wherein at least one of a 1 、A 2 or a 3 is S; R 1 is C 6 -C 10 aryl or 5 to 10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more halo, -CN, -OH, -NH 2 、C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl; r 2 is C 3 -C 10 cycloalkyl; B 1 is H or-OH; b 2 is H or-OH; Y is H, -C (O) OR 3 、-C(O)N(R 3 ) 2 , Each R 3 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl; R A1 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 3 -C 10 cycloalkyl; R A2 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl or 5 to 10 membered heteroaryl, and R A3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, 3 to 10 membered heterocyclyl optionally substituted with one or more C 1 -C 6 alkyl, C 6 -C 10 aryl, or 5 to 10 membered heteroaryl optionally substituted with one or more C 1 -C 6 alkyl, The conditions are as follows: (a) When R 2 is cyclopropyl, X 1 is N, A 1 is CR A1 , and A 2 is CR A2 , then at least one of R A1 and R A2 is not H, and (B) When R 2 is cyclopropyl, X 1 is N, A 1 is CR A1 , and A 2 is CH, then R A1 is not ethyl.
  2. 2. The compound of claim 1, wherein Is a single bond or a double bond, as long as the valence bond permits; x 1 is CH or N; A 1 is CR A1 , N, O or S; A 2 is CR A2 , N, O or S; A 3 is CR A3 , N, O, or S, wherein at least one of a 1 、A 2 or a 3 is S; R 1 is C 6 -C 10 aryl or 5 to 10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more halo, -CN, -OH, -NH 2 、C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl; r 2 is C 3 -C 10 cycloalkyl; R 3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl; R A1 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl; R A2 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl, and R A3 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl, The conditions are as follows: (a) When R 2 is cyclopropyl, X 1 is N, A 1 is CR A1 , and A 2 is CR A2 , then at least one of R A1 and R A2 is not H, and (B) When R 2 is cyclopropyl, X 1 is N, A 1 is CR A1 , and A 2 is CH, then R A1 is not ethyl.
  3. 3. The compound of claim 1 or claim 2, wherein X 1 is N.
  4. 4. The compound of any one of the preceding claims, wherein a 1 is CR A1 , N, or S.
  5. 5. The compound of any one of the preceding claims, wherein a 2 is CR A2 .
  6. 6. The compound of any one of the preceding claims, wherein a 3 is CR A3 , N, or S.
  7. 7. The compound of any one of the preceding claims, wherein R 1 is C 6 aryl substituted with one or more halo, -CN, -OH, -NH 2 、C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl.
  8. 8. The compound of any one of the preceding claims, wherein R 1 is , , , , , , Or (b) 。
  9. 9. The compound of any one of the preceding claims, wherein R 2 is 。
  10. 10. A compound according to any one of the preceding claims wherein R 3 is H or methyl.
  11. 11. A compound according to any one of the preceding claims wherein R A1 is H, methyl or cyclopropyl.
  12. 12. A compound according to any one of the preceding claims wherein R A2 is H, methyl or cyclopropyl.
  13. 13. The compound of any one of the preceding claims, wherein R A3 is H, methyl, phenyl, cyclopropyl, cyclobutyl, cyclohexyl, 、 、 Or (b) 。
  14. 14. The compound of any one of the preceding claims, wherein the compound of formula (I ') is of formula (I'): (I’), Or a pharmaceutically acceptable salt thereof.
  15. 15. The compound of any one of the preceding claims, wherein the compound of formula (I') is of formula (I-a), (I-b), (I-c) or (I-d): (I-a), (I-b), (I-c), or (I-d), Or a pharmaceutically acceptable salt thereof.
  16. 16. The compound of any one of the preceding claims, wherein the compound of formula (I ') is of formula (I ' -a), (I ' -b), (I ' -c) or (I ' -d): (I’-a), (I’-b), (I' -c), or (I’-d), Or a pharmaceutically acceptable salt thereof.
  17. 17. The compound of any one of claims 1-15, wherein the compound of formula (I') is of formula (I-d), (I-e), (I-f), or (I-g): (I-d), (I-e), (I-f), or (I-g), Or a pharmaceutically acceptable salt thereof.
  18. 18. The compound of any one of the preceding claims, wherein the compound of formula (I ') is of formula (I ' -d), (I ' -e), (I ' -f) or (I ' -g): (I’-d), (I’-e), (I' -f), or (I’-g), Or a pharmaceutically acceptable salt thereof.
  19. 19. The compound of any one of claims 1-15, wherein the compound of formula (I') is of formula (I-h), (I-I), (I-j), or (I-k): (I-h), (I-i), (I-j), or (I-k), Or a pharmaceutically acceptable salt thereof, wherein R 1a is halogen, -CN, -OH, -NH 2 、C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl, and n is 0,1, 2, 3, or 4.
  20. 20. The compound of any one of the preceding claims, wherein the compound of formula (I ') is of formula (I ' -h), (I ' -I), (I ' -j) or (I ' -k): (I’-h), (I’-i), (I' -j), or (I’-k), Or a pharmaceutically acceptable salt thereof, wherein R 1a is halogen, -CN, -OH, -NH 2 、C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl, and n is 0,1, 2, 3, or 4.

Description

Statin derivatives and methods of use thereof RELATED APPLICATIONS The present application claims priority and benefit from U.S. provisional application No. 63/472,434 filed on 12, 6, 2023, and U.S. provisional application No. 63/611,822 filed on 19, 12, 2023, the entire contents of which are incorporated herein by reference. Background The present disclosure relates to statin derivatives and their use as modulators of stathmin (e.g., stathmin-2) for treating diseases or disorders (e.g., neurodegenerative diseases). About 97% of cases of Amyotrophic Lateral Sclerosis (ALS) and almost half of frontotemporal dementia (FTD) patients are pathologically associated with cytoplasmic mislocalization and aggregation of the neuronal and glial internal RNA binding protein TDP-43 (ALS-TDP and FTD-TDP). Furthermore, the mutation of its coding gene TARDBP is a rare cause of ALS and FTD, suggesting that TDP-43 may be the core of ALS/FTD pathogenesis. Human mRNAs have been determined to be affected by a decrease in TDP-43, such as the neuronal growth related protein Stathmin-2 (STMN 2; also known as SCG 10). Aberrant splicing (including aberrant "hidden" exon 2 a) and premature polyadenylation of STMN2 results in reduced levels of STMN2 protein in response to nuclear loss of TDP-43 in cultured neurons, such hidden exon markers are also detectable in tissues of patients with sporadic and familial ALS and FTD, as well as patients with alzheimer's disease associated with TDP-43 pathology. STMN2 is a binding partner for tubulin heterodimers, and is involved in neurite outgrowth and axon regeneration. Thus, modulation of STMN2 is a therapeutic target for ALS treatment. Currently available ALS therapies are non-target driven and have limited efficacy. There is a need for effective therapies directed against specific factors of disease pathophysiology, wherein STMN2 is a target for which therapeutic modulation of ease has been demonstrated. HMG-CoA reductase inhibitors (e.g., statins) are compounds that are capable of increasing STMN 2. The present disclosure stems from the need to provide additional compounds with improved therapeutic potential for modulating STMN2 activity. In particular compounds having improved physicochemical, pharmacological and/or pharmaceutical properties. Disclosure of Invention In some aspects, the invention provides compounds of formula (I'): (I’), or a pharmaceutically acceptable salt thereof, wherein: is a single bond or a double bond, as long as the valence bond permits; Is a single bond or a double bond, wherein the double bond is an (E) isomer; x 1 is CH or N; A 1 is CR A1, N, O or S; A 2 is CR A2, N, O or S; A 3 is CR A3, N, O, or S, wherein at least one of a 1、A2 or a 3 is S; R 1 is C 6-C10 aryl or 5 to 10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more halo, -CN, -OH, -NH 2、C1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy or C 1-C6 haloalkyl; r 2 is C 3-C10 cycloalkyl; B 1 is H or-OH; b 2 is H or-OH; Y is H, -C (O) OR 3、-C(O)N(R3)2, Each R 3 is independently H, C 1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, or C 1-C6 haloalkyl; R A1 is H, C 1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 1-C6 haloalkyl or C 3-C10 cycloalkyl; R A2 is H, C 1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 1-C6 haloalkyl, C 3-C10 cycloalkyl, C 6-C10 aryl, or 5 to 10 membered heteroaryl, and R A3 is H, C 1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 1-C6 haloalkyl, C 3-C10 cycloalkyl, 3 to 10 membered heterocyclyl optionally substituted with one or more C 1-C6 alkyl, C 6-C10 aryl, or 5 to 10 membered heteroaryl optionally substituted with one or more C 1-C6 alkyl, The conditions are as follows: When R 2 is cyclopropyl, X 1 is N, A 1 is CR A1, and A 2 is CR A2, then at least one of R A1 and R A2 is not H, and When R 2 is cyclopropyl, X 1 is N, A 1 is CR A1, and A 2 is CH, then R A1 is not ethyl. In some aspects, the invention provides compounds of formula (II'): (II’), or a pharmaceutically acceptable salt thereof, wherein: Is a double bond, wherein the double bond is the (E) or (Z) isomer; R 1 is C 6-C10 aryl or 5 to 10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R 1a; Each R 1a is independently halogen, -CN, -OH, -NH 2、C1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, or C 1-C6 haloalkyl; R 2 is C 3-C10 cycloalkyl or methyl; R 3 is H, C 1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy or C 1-C6 haloalkyl; r 4 is H, C 3-C10 cycloalkyl, 3 to 10 membered heterocyclyl, C 1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy or C 1-C6 haloalkyl; R 5 is H, C 1-C6 alkyl, C 2-C6 alkenyl, C 2-C6 alkynyl, C 1-C6 alkoxy, C 1-C6 haloalkyl or C 3-C10 cycloalkyl, wherein said alkyl, alkenyl, alkynyl, alkoxy, haloalkyl or C 3-C10 cycloalkyl is optionally substituted with one or more C 1-C6 alkoxy or-O (C 3-C10 cycloalkyl), or R 5 and one R 1a toge