Search

EP-4734976-A2 - AGENTS FOR TREATING DISORDERS INVOLVING RYANODINE RECEPTORS

EP4734976A2EP 4734976 A2EP4734976 A2EP 4734976A2EP-4734976-A2

Abstract

The present disclosure relates to 1,4-oxazepane and 1,4-thiazepane derivatives and their use to treat disorders and diseases associated with ryanodine receptors (RyRs) that regulate calcium channel signaling in cells. The present disclosure also discloses pharmaceutical compositions comprising these compounds and uses thereof to treat diseases and conditions associated with RyR dysfunction, in particular cardiac, musculoskeletal and central nervous system (CNS) disorders.

Inventors

  • BELVEDERE, SANDRO
  • KONTES, FERENC
  • CHENG, ZHENZHUANG

Assignees

  • RyCarma Therapeutics, Inc.

Dates

Publication Date
20260506
Application Date
20240626

Claims (20)

  1. 1. A compound of F ormula (I) : wherein ring A is aryl or a 5 or 6 membered heteroaryl, each of which is unsubstituted or substituted; - X is O, S, S(O), or S(O) 2 ; - Y is CH 2 or C(O); Z is alkyl or aryl, each of which is unsubstituted or substituted, or hydrogen; R' and R" are each hydrogen, or together with the carbon atom to which R' and R" are bound form C(O); R 1 and R 2 are each independently alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen, C(O)R a , C(O)OR b , or S(O) 2 R b ; or R 1 and R 2 together with the nitrogen atom to which they are bound form a heterocycloalkyl moiety; each R 3 is independently alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino, each of which is unsubstituted or substituted, or hydrogen, halogen, NHC(O)R b , C(O)NHR b or S(O) 2 R b ; or two adjacent R 3 groups, together with the carbon atoms to which they are bound, form a fused cycloalkyl or heterocycloalkyl ring, each of which is unsubstituted or substituted; R 4 is alkyl that is unsubstituted or substituted, or hydrogen; R a is alkyl, aryl, heteroaryl, cycloalkyl, or heterocyloalkyl, each of which is unsubstituted or substituted, or hydroxy, carboxy, or NHR C , wherein R c is alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen; R b is alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, each of which is unsubstituted or substituted, or hydrogen; and n is 0, 1, 2, 3, 4 or 5; or a pharmaceutically-acceptable salt thereof.
  2. 2. The compound of claim 1, wherein X is sulphur.
  3. 3. The compound of claim 1, wherein Y is C(O).
  4. 4. The compound of claim 1, wherein the compound is of formula (I a ):
  5. The compound of claim 4, wherein Z is hydrogen.
  6. The compound of claim 1, wherein the compound is of formula (lb):
  7. The compound of claim 1, wherein n is 1.
  8. The compound of claim 1, wherein R' and R" are each hydrogen.
  9. 9. The compound of claim 1, wherein R 1 and R 2 are each hydrogen.
  10. 10. The compound of claim 1, wherein R 1 is hydrogen.
  11. 11. The compound of claim 1, wherein R 1 is methyl.
  12. 12. The compound of claim 1, wherein R 2 is hydrogen.
  13. 13. The compound of claim 1, wherein R 2 is alkyl.
  14. 14. The compound of claim 1, wherein R 2 is C(O)R a .
  15. 15. The compound of claim 1, wherein R 2 is C(O)R a , wherein R a is aryl or heteroaryl, each of which is substituted or unsubstituted.
  16. 16. The compound of claim 1, wherein R 2 is C(O)R a , wherein R a is pyrimidinyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridyl, thiazolyl, isoxazolyl, oxazolyl, tetrazolyl, imidazolyl, pyridazinyl, triazolyl, oxadiazolyl, or pyrazinyl, each of which is substituted or unsubstituted.
  17. 17. The compound of claim 1, wherein R 2 is C(O)R a , wherein R a is pyrimidin-2-yl, pyrimidin- 5-yl, 5-amino-pyrimidin-2-yl, 5-methoxy-pyrimidin-2-yl, lJT-pyrazol-3-yl, 2-methyl-lJT- pyrazole-3-yl, pyridin-2-yl, 2-chloro-pyridin-2-yl, 6-chloro-pyridin-2-yl, 5-chloro-pyridin-2-yl, 6-hydroxy-pyridin-2-yl, pyridin-3-yl, 6-amino-pyri din-3 -yl, 2-chloro-pyridin-3-yl, pyridin-4-yl, 3-phenyl-17/-pyrazol-5-yl, lJ/-imidazol-4-yl, lJ/-imidazol-2-yl, 1 -methyl- IJT-imidazol -4-yl, 1- methyl-lJT-imidazol-2-yl, thiazol-2-yl, thiazol-4-yl, 4-methyl-l,2,3-thiadiazol-5-yl, 5- phenylisoxazol-3-yl, 5-(4-chlorophenyl)isoxazole-3-yl, 5-methyl-3-phenylisoxazol-4-yl, 4- phenylthiazol-2-yl, lJT-tetrazol-5-yl, pyridazin-2-yl, pyridazin-3-yl,pyridazin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazin-4-yl, 3 -hydroxy -pyrazinyl, 4-isopropyl-l,2,3-thiadiazolyl, 3-methyl- isoxazole-5-yl, 4,4-difluoro-piperidin-l-yl, l,2,4-triazin-3-yl, 4-methylpyrid-2-ylamino, 3- oxopiperazin-l-yl, 5-(4-fluorophenyl)-l,3,4-oxadiazol-2-yl, or piperazin- 1-yl.
  18. 18. The compound of claim 1, wherein R 1 and R 2 are each independently hydrogen, methyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3 -hydroxy cyclobutyl, 3, 3 -difluorocyclobutyl, cyclohexyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, pyrimidin-2-yl, pyrimidin-2-ylmethyl, pyrimidin-3-ylmethyl, pyrimidin-4-ylmethyl, oxalyl, 2-methoxy ethyl, benzyl, 4-carboxybenzyl, 4-carboxymethylbenzyl, tetrahydro-2//-pyran-4-yl, oxetan-3-yl, 1,2,4- thiadiazol-5-yl, 4-aminom ethyl- 1,2, 3 -triazol- 1-ylmethyl, 4-methyl-l,2,3-thiadiazolyl-5-ylmethyl, benzo[d]thiazol-2-yl, 4-carboxylethyl-l,2,3-thiadiazolyl-5-ylmethyl, 4-carboxy- 1,2,3- thiadiazolyl-5-ylmethyl, isoindoline- 1, 3-dion-2-yl, and acetyl; or wherein Ri and R2 together with the nitrogen atom to which they are bound form an optionally substituted heterocycle or heteroaryl selected from the group consisting of pyrazolidinonyl, piperazinyl, 2-oxopiperazinyl, triazolyl, benzotri azolyl, morpholinyl, pyrrolidinyl, or piperidinyl.
  19. 19. The compound of claim 1, wherein R 3 is alkoxy, cycloalkyloxy, or aryloxy, each of which is substituted or unsubstituted, or halogen.
  20. 20. The compound of claim 1, wherein R 3 is phenyloxy, which is substituted or unsubstituted.

Description

AGENTS FOR TREATING DISORDERS INVOLVING RYANODINE RECEPTORS CROSS-REFERENCE TO RELATED APPLICATIONS [001] This application claims the benefit of U.S. Provisional Application No. 63/523,439, filed June 27, 2023, which is incorporated herein by reference in its entirety. BACKGROUND [002] The sarcoplasmic reticulum (SR) is a structure in cells that functions, among other things, as a specialized intracellular calcium (Ca2+) store. Ryanodine receptors (RyRs) are channels in the SR that open and close to regulate the release of Ca2+ from the SR into the intracellular cytoplasm of the cell. Release of Ca2+into the cytoplasm from the SR increases cytoplasmic Ca2+ concentration. Open probability of RyRs refers to the likelihood that a RyR is open at any given moment, and therefore capable of releasing Ca2+ into the cytoplasm from the SR. Three RyR isoforms are known. RyRl is the predominant isoform expressed in mammalian skeletal muscle, RyR2 is predominantly found in cardiac muscle, whereas RyR3 expression is low in skeletal muscle. [003] Mutations in RYR1 or RYR2 are characterized by inappropriate channel opening not related to contraction signals. This channel opening is further exacerbated by post-translational modifications such as PKA-phosphorylation, oxidation, or nitrosylation of the RyR channel. The resulting leaky channels exhibit a pathologic increase in the open probability under resting conditions. The SR Ca2+ leak leads to a reduction in SR Ca2+ content, with less Ca2+ available for release and consequently weaker muscle contractions. INCORPORATION BY REFERENCE [004] Each patent, publication, and non-patent literature cited in the application is hereby incorporated by reference in its entirety as if each was incorporated by reference individually. SUMMARY OF THE INVENTION [005] In some embodiments, the disclosure provides compounds of formula (I): ring A is aryl or a 5- or 6- membered heteroaryl, each of which is unsubstituted or substituted; - X is O, S, S(O), or S(O)2; - Y is CH2 or C(O); Z is alkyl or aryl, each of which is unsubstituted or substituted, or hydrogen; R' and R" are each hydrogen, or together with the carbon atom to which R' and R" are bound form C(O); R1 and R2 are each independently alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen, C(O)Ra, C(O)ORb, or S(O)2Rb; or R1 and R2 together with the nitrogen atom to which they are bound form a heterocycloalkyl moiety; each R3 is independently alkyl, alkoxy, alkylamino, cycloalkyl, cycloalkyloxy, cycloalkylamino, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylamino, aryl, aryloxy, arylamino, heteroaryl, heteroaryloxy, or heteroarylamino, each of which is unsubstituted or substituted, or hydrogen, halogen, NHC(O)Rb, C(O)NHRb or S(O)2Rb; or two adjacent R3 groups, together with the carbon atoms to which they are bound, form a fused cycloalkyl or heterocycloalkyl ring, each of which is unsubstituted or substituted; R4 is alkyl that is unsubstituted or substituted, or hydrogen; Ra is alkyl, aryl, heteroaryl, cycloalkyl, or heterocyloalkyl, each of which is unsubstituted or substituted, or hydroxy, carboxy, or NHRC, wherein Rc is alkyl, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is unsubstituted or substituted, or hydrogen; Rb is alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, each of which is unsubstituted or substituted, or hydrogen; and n is 0, 1, 2, 3, 4 or 5; or a pharmaceutically-acceptable salt thereof. [006] The present disclosure further provides pharmaceutical compositions comprising a compound of formula (I) in combination with one or more pharmaceutically-acceptable excipients or carriers. [007] The present disclosure further relates to a compound of formula (I), or a pharmaceutically- acceptable salt thereof, or a pharmaceutical composition comprising such compound, for use in the treatment or reduction of a likelihood of occurrence of a condition. [008] The present disclosure further provides a method of treating a condition, the method comprising administering a pharmaceutical composition comprising a compound of formula (I) in combination with one or more pharmaceutically-acceptable excipients or carriers. [009] In some embodiments, the condition is a cardiac disorder or disease, muscle fatigue, a musculoskeletal disorder or disease, a CNS disorder or disease, cognitive dysfunction, a neuromuscular disorder or diseases, a bone disorder or disease, cancer cachexia, malignant hyperthermia, diabetes, sudden cardiac death, and sudden infant death syndrome, or cognitive dysfunction. [0010] The present disclosure further provides methods of making compounds of formula (I) and their intermediates. DETAILED DESCRIPTION [0011] In some embodiments, the disclosure provides a compound of formula (I): wherein ring A is aryl or a 5- or 6- membered heteroaryl, each of which is unsubstituted or substituted; - X is O, S, S(O), or S