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US-12617785-B2 - Pyrrolo[2,3-b]pyridine-3-carboxamide compositions and methods for ameliorating hearing loss

US12617785B2US 12617785 B2US12617785 B2US 12617785B2US-12617785-B2

Abstract

N-(3-Substituted thiazol-2(3H)-ylidene)-1H-pyrrolo[2,3-b]pyridine-3-carboxamides and N-(3-substituted oxazol-2(3H)-ylidene)-1H-pyrrolo[2,3-b]pyridine-3-carboxamides are disclosed. The compounds activate Yap and inhibit Lats kinases. They are therefore useful for treating hearing loss.

Inventors

  • Ksenia GNEDEVA
  • Robert Walter MYERS
  • A. James HUDSPETH
  • Nathaniel KASTAN
  • Rui Liang
  • Peter T. Meinke
  • David John HUGGINS
  • Nigel John Liverton
  • Leigh Ashley BAXT
  • John David Ginn

Assignees

  • THE ROCKEFELLER UNIVERSITY

Dates

Publication Date
20260505
Application Date
20210205

Claims (20)

  1. 1 . A compound of formula I: wherein: R 1 is selected from the group consisting of (C 1 -C 6 )alkyl, carboxy, (C 3 -C 7 )carbomonocyclyl, (C 9 -C 11 )carbobicyclyl, heteromonocyclyl, and heterobicyclyl, wherein said (C 1 -C 6 )alkyl, (C 3 -C 7 )carbomonocyclyl, (C 9 -C 11 )carbobicyclyl, heteromonocyclyl, and heterobicyclyl may be optionally substituted with from one to three substituents selected independently from the group consisting of halogen, cyano, hydroxy, nitro, amino, acetoxy, carboxy, (C 1 -C 7 )hydrocarbyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )acyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, heteroaryl, benzenesulfonyl, (C 1 -C 3 )alkoxycarbonyl, aminocarbonyl, (C 1 -C 3 )alkylaminocarbonyl, di(C 1 -C 3 )alkylaminocarbonyl, (C 1 -C 3 )alkylamino, di(C 1 -C 3 )alkylamino, amino(C 1 -C 3 )alkyl, (C 1 -C 3 )alkylamino(C 1 -C 3 )alkyl (C 1 -C 3 )dialkylamino(C 1 -C 3 )alkyl, (C 1 -C 3 )alkylthio, (C 1 -C 3 )alkylsulfonylamino, (C 1 -C 3 )alkylsulfinyl, (C 1 -C 3 )alkylsulfonyl, phenoxy, and benzyloxy; R 2 is selected from the group consisting of hydrogen, halogen, (C 1 -C 7 )hydrocarbyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )acyl, hydroxy(C 1 -C 3 )alkyl, —C(═O)O(C 1 -C 6 )alkyl, —C(═O)NR 20 R 21 , and (C 1 -C 6 )oxaalkyl; R 3 is selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )hydrocarbyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )acyl, and (C 1 -C 3 )alkoxy; R 4 is selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )hydrocarbyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )acyl, and (C 1 -C 3 )alkoxy; R 10 is selected independently in each instance from the group consisting of hydrogen and methyl; R 20 is selected from the group consisting of hydrogen and (C 1 -C 6 )hydrocarbyl; R 21 is selected from the group consisting of hydrogen, (C 1 -C 6 )hydrocarbyl, (C 1 -C 6 )oxaalkyl, amino(C 1 -C 6 )alkyl, (C 1 -C 3 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 3 )alkylamino(C 1 -C 6 )alkyl, and —(CH 2 ) m -Het, wherein Het is an aliphatic mono- or bicyclic heterocycle, optionally substituted with a substituent selected from the group consisting hydroxy, amino, acetoxy, carboxy, (C 1 -C 7 )hydrocarbyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )acyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, aminocarbonyl, (C 1 -C 3 )alkylaminocarbonyl, di(C 1 -C 3 )alkylaminocarbonyl, (C 1 -C 3 )alkylamino, and di(C 1 -C 3 )alkylamino; or, taken together with the nitrogen to which they are attached, R 20 and R 21 form an aliphatic heterocyle; n is zero, one or two; m is zero, one or two; and X is S; or, when n is 1 and R 1 is optionally substituted phenyl, X is S or O; with the proviso that, when R 1 is phenyl, X is sulfur, and n is one, at least one of R 2 , R 3 , R 4 , and R 10 is other than hydrogen.
  2. 2 . A compound according to claim 1 wherein R 2 is selected from the group consisting of —C(═O)O(C 1 -C 6 )alkyl, —C(═O)NR 20 R 21 , and (C 1 -C 6 )oxaalkyl.
  3. 3 . A compound according to claim 2 wherein R 20 is chosen from hydrogen and methyl, and and R 21 is chosen from hydrogen, methyl, (C 1 -C 6 )oxaalkyl, dimethylamino(C 1 -C 6 )alkyl, and —(CH 2 ) m -Het.
  4. 4 . A compound according to claim 1 wherein R 20 and R 21 taken together with the nitrogen to which they are attached form a 4-7-membered aliphatic heterocycle.
  5. 5 . A compound according to claim 1 of formula: wherein: R 1 is selected from the group consisting of (C 1 -C 6 )alkyl, carboxy, (C 3 -C 7 )carbomonocyclyl, (C 9 -C 11 )carbobicyclyl, heteromonocyclyl, and heterobicyclyl, wherein said (C 1 -C 6 )alkyl, (C 3 -C 7 )carbomonocyclyl, (C 9 -C 11 )carbobicyclyl, heteromonocyclyl, and heterobicyclyl may be optionally substituted with from one to three substituents selected independently from the group consisting of halogen, cyano, hydroxy, nitro, amino, acetoxy, carboxy, (C 1 -C 7 )hydrocarbyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, (C 1 -C 6 )acyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, hydroxy(C 1 -C 3 )alkyl, heteroaryl, benzenesulfonyl, (C 1 -C 3 )alkoxycarbonyl, aminocarbonyl, (C 1 -C 3 )alkylaminocarbonyl, (C 1 -C 3 )alkylamino, di(C 1 -C 3 )alkylamino, amino(C 1 -C 3 )alkyl, (C 1 -C 3 )alkylamino(C 1 -C 3 )alkyl (C 1 -C 3 )dialkylamino(C 1 -C 3 )alkyl, (C 1 -C 3 )alkylthio, (C 1 -C 3 )alkylsulfonylamino, (C 1 -C 3 )alkylsulfinyl, (C 1 -C 3 )alkylsulfonyl, phenoxy, and benzyloxy; R 2 is selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )hydrocarbyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )acyl, hydroxy(C 1 -C 3 )alkyl, and (C 1 -C 3 )alkoxy; R 3 is selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )hydrocarbyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )acyl, and (C 1 -C 3 )alkoxy; R 4 is selected from the group consisting of hydrogen, halogen, (C 1 -C 6 )hydrocarbyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )acyl, and (C 1 -C 3 )alkoxy; R 10 is selected independently in each instance from the group consisting of hydrogen and methyl; n is zero, one or two; and X is O or S; with the proviso that, when R 1 is phenyl, X is sulfur, and n is one, at least one of R 2 , R 3 , R 4 , and R 10 is other than hydrogen.
  6. 6 . A compound according to claim 1 wherein n is zero.
  7. 7 . A compound according to claim 1 wherein n is one.
  8. 8 . A compound according to claim 7 wherein R 10 is hydrogen.
  9. 9 . A compound according to claim 1 wherein R 1 is selected from the group consisting of carboxy and optionally substituted (C 1 -C 4 )alkyl, phenyl, cyclohexyl, 5-membered heterocyclyl, 6-membered heterocyclyl and heterobicyclyl.
  10. 10 . A compound according to claim 9 wherein R 1 is selected from the group consisting of methyl, ethyl, aminobutyl, and carboxyethyl.
  11. 11 . A compound according to claim 9 wherein R 1 is optionally substituted cyclohexyl.
  12. 12 . A compound according to claim 9 wherein R 1 is optionally substituted phenyl.
  13. 13 . A compound according to claim 9 wherein R 1 is optionally substituted heterocyclyl.
  14. 14 . A compound according to claim 13 wherein R 1 is selected from the group consisting of pyridinyl, pyrazolyl, piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, and tetrahydroisoquinolinyl, each optionally substituted.
  15. 15 . A compound according to claim 12 wherein R 1 is phenyl or phenyl substituted with one or two substituents selected independently from the group consisting of halogen, cyano, hydroxy, amino, carboxy, (C 1 -C 6 )hydrocarbyl, trifluoromethyl, methoxy, acetyl, formyl, hydroxy(C 1 -C 3 )alkyl, methoxycarbonyl, carboxamido, methanesulfonylamino, and amino(C 1 -C 3 )alkyl.
  16. 16 . A compound according to claim 15 wherein R 1 is phenyl substituted at the ortho position and n is zero.
  17. 17 . A compound according to claim 14 wherein R 1 is selected from the group consisting of pyridinyl, pyrazolyl, piperidinyl, tetrahydropyranyl, and tetrahydroisoquinolinyl, each optionally substituted with one or two substituents selected independently from the group consisting of amino, hydroxy and (C 1 -C 6 )hydrocarbyl.
  18. 18 . A compound according to claim 9 wherein X is S.
  19. 19 . A compound according to claim 9 wherein X is O.
  20. 20 . A compound according to claim 9 wherein R 3 and R 4 are selected independently from the group consisting of hydrogen, chloro and methyl.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a national phase filing under 35 U.S.C. § 371 of PCT International Application PCT/US2021/016848, filed Feb. 5, 2021. PCT/US2021/016848 claimed priority from U.S. Provisional Application No. 62/970,425, filed Feb. 5, 2020. The contents of the prior applications are incorporated by reference herein in their entirety. GOVERNMENT RIGHTS STATEMENT This invention was made with government support under grant number T32GM007739 awarded by National Institutes of Health. The government has certain rights in the invention. BACKGROUND OF THE INVENTION Technical Field The present application relates generally to N-(3-substituted thiazol-2(3H)-ylidene)-1H-pyrrolo[2,3-b]pyridine-3-carboxamides and N-(3-substituted oxazol-2(3H)-ylidene)-1H-pyrrolo[2,3-b]pyridine-3-carboxamides that inhibit Lats kinases and thus increase Yap activity. The compounds are useful for inducing the proliferation of supporting cells in the inner ear, and thus potentially for treating hearing loss. Background Information Initiated in response to injury, regeneration is a complex process that can restore the structure and function of damaged tissue. Some adult mammalian tissues retain a gradually declining regenerative capability beyond development. Regeneration occurs either by activation and amplification of resident stem cells, as in the epithelia of the skin and intestine, or through cellular dedifferentiation and proliferation, as in the liver. In other instances, such as central nervous and cardiac-muscle tissues, cells exhibit little or no potential for regeneration after injury. In view of its fundamental roles in development, proliferation, stem-cell maintenance, and dedifferentiation, Hippo signaling is an inviting target for driving regeneration. The regenerative potential of the Hippo pathway has become abundantly clear in numerous organs, including the heart, retina, liver, and intestine. Hippo signaling limits the size of the developing murine utricle, a sensory organ in the vestibular portion of the inner ear, and the Yap-Tead complex is active during—and necessary for—proliferative regeneration in the neonatal utricle. These observations suggest that chemical activation of Yap signaling might engender supporting-cell proliferation in adult tissue, a key missing step in the regeneration of the mammalian inner ear. In an effort to identify activators of Yap, we conducted a small-molecule screen on cultured cells. We identified the compound, which we found to function as an inhibitor of Lats kinases. To test our original hypothesis, we treated utricles explanted from adult mice with the substance and found that a few days' exposure caused supporting cells to reenter the cell cycle, a critical step towards robust hair-cell regeneration. SUMMARY OF THE INVENTION The invention is directed to N-(3-substituted azol-2(3H)-ylidene)-1H-pyrrolo[2,3-b]pyridine-3-carboxamides, pharmaceutical compositions and methods for inhibiting Lats or activating Yap, and thereby stimulating regeneration of target cells, particularly hair-cells. The present invention relates, in a first aspect, to compounds of formula I: wherein:R1 is selected from the group consisting of (C1-C6)alkyl, carboxy, (C3-C7)carbomonocyclyl, (C9-C11)carbobicyclyl, heteromonocyclyl, and heterobicyclyl, wherein said (C1-C6)alkyl, (C3-C7)carbomonocyclyl, (C9-C11)carbobicyclyl, heteromonocyclyl, and heterobicyclyl may be optionally substituted with from one to three substituents selected independently from the group consisting of halogen, cyano, hydroxy, nitro, amino, acetoxy, carboxy, (C1-C7)hydrocarbyl, halo(C1-C6)alkyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy, (C1-C6)acyl, (C1-C3)alkoxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, heteroaryl, benzenesulfonyl, (C1-C3)alkoxycarbonyl, aminocarbonyl, (C1-C3)alkylaminocarbonyl, di(C1-C3)alkylaminocarbonyl, (C1-C3)alkylamino, di(C1-C3)alkylamino, amino(C1-C3)alkyl, (C1-C3)alkylamino(C1-C3)alkyl (C1-C3)dialkylamino(C1-C3)alkyl, (C1-C3)alkylthio, (C1-C3)alkylsulfonylamino, (C1-C3)alkylsulfinyl, (C1-C3)alkylsulfonyl, phenoxy, and benzyloxy;R2 is selected from the group consisting of hydrogen, halogen, (C1-C7)hydrocarbyl, halo(C1-C6)alkyl, (C1-C6)acyl, hydroxy(C1-C3)alkyl, —C(═O)O(C1-C6)alkyl, —C(═O)NR20R21, and (C1-C6)oxaalkyl;R3 is selected from the group consisting of hydrogen, halogen, (C1-C6)hydrocarbyl, halo(C1-C6)alkyl, (C1-C6)acyl, and (C1-C3)alkoxy;R4 is selected from the group consisting of hydrogen, halogen, (C1-C6)hydrocarbyl, halo(C1-C6)alkyl, (C1-C6)acyl, and (C1-C3)alkoxy;R10 is selected independently in each instance from the group consisting of hydrogen and methyl;R20 is selected from the group consisting of hydrogen and (C1-C6)hydrocarbyl;R21 is selected from the group consisting of hydrogen, (C1-C6)hydrocarbyl, (C1-C6)oxaalkyl, amino(C1-C6)alkyl, (C1-C3)alkylamino(C1-C6)alkyl, di(C1-C3)alkylamino(C1-C6)alkyl, and —(CH2)m-Het, wherein Het is an aliphatic mono- or bicyclic heterocycle,