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US-20260124205-A1 - MODULATORS OF BETA CATENIN AND USES THEREOF

US20260124205A1US 20260124205 A1US20260124205 A1US 20260124205A1US-20260124205-A1

Abstract

Provided are compounds of the Formula I: or pharmaceutically acceptable salts thereof, which are useful for the modulation of beta catenin condensates and in the treatment of a variety of conditions or diseases associated therewith.

Inventors

  • Adam TALBOT
  • Thomas Durand-Reville

Assignees

  • DEWPOINT THERAPEUTICS, INC.

Dates

Publication Date
20260507
Application Date
20251021

Claims (20)

  1. 1 . A compound having the structural Formula I: or a pharmaceutically acceptable salt thereof, wherein: z 1 is N or —CR 3 ; z 2 is N or —CR 5 ; z 3 is N or —CR 4 ; R 1 is hydrogen, (C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylene(C 1 -C 4 )alkoxy, or (C 1 -C 4 )alkylene[OP(O)(OH) 2 ]; R 2 is aryl, heteroaryl, heterocyclyl, or cycloalkyl, each of which are optionally substituted with 1 to 3 groups selected from R 1A ; R 3 and R 4 are each independently hydrogen, halo, cyano, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, (C 2 -C 4 )alkenyl, (C 1 -C 4 )alkylence[heterocyclyl], (C 1 -C 4 )alkylene[aryl], (C 1 -C 4 )alkylene[heteroaryl], (C 1 -C 4 )alkylene[cycloalkyl], —S(O) 2 (C 1 -C 4 )alkyl, or —S(O)(C 1 -C 4 )alkyl, wherein said heterocyclyl, aryl, heteroaryl, and cycloalkyl are each optionally substituted with 1 to 3 groups selected from halo, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, and cyano; R 5 is hydrogen, halo, or (C 1 -C 4 )alkyl; X is —OR 6 or —NR 7 R 8 ; R 6 is cycloalkyl, heterocyclyl, (C 1 -C 4 )alkylene(C 1 -C 4 alkoxy), (C 1 -C 4 )alkylene[aryl], (C 1 -C 4 )alkylene[heteroaryl], (C 1 -C 4 )alkylene[heterocyclyl], or (C 1 -C 4 )alkylene[cycloalkyl], wherein the aryl, heteroaryl, and cycloalkyl are each optionally substituted with 1 to 3 groups selected from R 2A ; R 7 and R 8 are taken together to form a heterocyclyl optionally substituted with 1 to 3 groups selected from R 2A ; each R 1A is independently selected from halo, cyano, (C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, hydroxy[halo(C 1 -C 4 )alkyl], cyano(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, deuterated(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxyO(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxyO[deuterated(C 1 -C 4 )alkyl], halo(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxyO[halo(C 1 -C 4 )alkyl], oxo, hydroxy, —O[hydroxy(C 1 -C 4 )alkyl], —O[cycloalkyl], —O[heterocyclyl], —O[aryl], —O[heteroaryl], (C 1 -C 4 )alkylene[cycloalkyl], (C 1 -C 4 )alkylene[aryl], (C 1 -C 4 )alkylene[heterocyclyl], (C 1 -C 4 )alkylene[heteroaryl], —O(C 1 -C 4 )alkylene[NR a R b ], —O(C 1 -C 4 )alkylene[NR a C(O)R b ], —O(C 1 -C 4 )alkylene[cycloalkyl], —O(C 1 -C 4 )alkylene[aryl], —O(C 1 -C 4 )alkylene[heterocyclyl], —O(C 1 -C 4 )alkylene[heteroaryl], cycloalkyl, heterocyclyl, aryl, heteroaryl, (C 1 -C 4 )alkylene(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylene[deuterated(C 1 -C 4 )alkoxy], (C 1 -C 4 )alkylene[halo(C 1 -C 4 )alkoxy], (C 1 -C 4 )alkoxyO[cycloalkyl], (C 1 -C 4 )alkoxyO[heterocyclyl], (C 1 -C 4 )alkoxyO[heteroaryl], (C 1 -C 4 )alkoxyO[phenyl], —C(O)[heterocyclyl], —SR a , —S(O)R a , —SO 2 R a , —S(O)(NR a )R b , —NR b SO 2 R b , —SO 2 NR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —NR a C(O)R b , —NR a C(O)NR b , —NR a R b , —NH(C 1 -C 4 )alkylene[heterocyclyl], and (C 1 -C 4 )alkyleneNR a R b , where each occurrence of cycloalkyl, heterocyclyl, aryl, and heteroaryl alone, or as part of another group, is optionally substituted with 1 to 3 groups selected from halo, oxo, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, hydroxy, —NH 2 , —NH(C 1 -C 4 )alkyl, —N((C 1 -C 4 )alkyl) 2 , cycloalkyl, heterocyclyl, aryl, heteroaryl, and cyano; each R 2A is independently selected from halo, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, deuterated(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, deuterated(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylene(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylene[deuterated(C 1 -C 4 )alkoxy], (C 1 -C 4 )alkylene[halo(C 1 -C 4 )alkoxy], oxo, —O[cycloalkyl], cyano, hydroxy, S(O)(C 1 -C 4 )alkyl, —S(O) 2 (C 1 -C 4 )alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, (C 1 -C 4 )alkylene[cycloalkyl], (C 1 -C 4 )alkylene[aryl], (C 1 -C 4 )alkylene[heterocyclyl], (C 1 -C 4 )alkylene[heteroaryl], —C(O)R a1 , —C(O)OR a1 , —C(O)NR a1 R b1 , —NR a1 C(O)R b1 , —NR a1 C(O)NR b1 , wherein said heterocyclyl, aryl, heteroaryl, and cycloalkyl are each optionally substituted with 1 to 3 groups selected from halo, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, and cyano; and each R a , R a1 , R b , and R b1 is each independently selected from hydrogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylene(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkyleneNH 2 , (C 1 -C 4 )alkyleneNH((C 1 -C 4 alkyl), (C 1 -C 4 )alkyleneN((C 1 -C 4 alkyl) 2 , cycloalkyl, and heterocyclyl, wherein the cycloalkyl and heterocyclyl are each optionally substituted with (C 1 -C 4 )alkyl, hydroxy, or hydroxy(C 1 -C 4 )alkyl; provided that: (i) if R 7 and R 8 , taken together with the N to which they are attached, form pyrrolidinyl, then R 2A is not —C(O)NH 2 ; (ii) if R 7 and R 8 , taken together with the N to which they are attached, form piperidinyl, then R 2A is not benzyl; and (iii) if R 7 and R 8 , taken together with the N to which they are attached, form 6- to 12-membered heterocyclyl, then R 2 is substituted by 1 to 3 groups selected from R 1A .
  2. 2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: z 3 is —CR 4 ; and each R 2A is independently selected from halo, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, deuterated(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, deuterated(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylene(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylene[deuterated(C 1 -C 4 )alkoxy], (C 1 -C 4 )alkylene[halo(C 1 -C 4 )alkoxy], oxo, cyano, hydroxy, S(O)(C 1 -C 4 )alkyl, —S(O) 2 (C 1 -C 4 )alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, (C 1 -C 4 )alkylene[cycloalkyl], (C 1 -C 4 )alkylene[heterocyclyl], (C 1 -C 4 )alkylene[heteroaryl], —C(O)Rai, —C(O)OR a1 , —NR a1 C(O)R b1 , —NR a1 C(O)NR b1 , wherein said heterocyclyl, aryl, heteroaryl, and cycloalkyl are each optionally substituted with 1 to 3 groups selected from halo, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, and cyano.
  3. 3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: (i) z 1 is N, z 2 is —CR 5 , and z 3 is —CR 4 ; (ii) z 1 is —CR 3 , z 3 is —CR 4 , and z 2 is N; or (iii) z 1 is —CR 3 , z 2 is —CR 5 , and z 3 is —CR 4 .
  4. 4 . (canceled)
  5. 5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is: (i) hydrogen, halo, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 1 -C 4 )alkoxy, cyano, —S(O) 2 (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkylene[heterocyclyl], wherein said heterocyclyl is optionally substituted by 1 halo; or (ii) hydrogen, —F, —Cl, —CH 3 , —CF 3 , —CH═CH 2 , —OCH 3 , cyano, —S(O) 2 CH 3 ,
  6. 6 . (canceled)
  7. 7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is: (i) hydrogen, halo, or (C 1 -C 4 )alkyl; or (ii) hydrogen, —F, or —CH 3 .
  8. 8 . (canceled)
  9. 9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is: (i) hydrogen, halo, or (C 1 -C 4 )alkyl; or (ii) hydrogen, —F, or —CH.
  10. 10 . (canceled)
  11. 11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is: (i) hydrogen or (C 1 -C 4 )alkylene[OP(O)(OH) 2 ]; or (ii) hydrogen.
  12. 12 . (canceled)
  13. 13 . The compound of claim 1 , having the structural Formula II: or a pharmaceutically acceptable salt thereof.
  14. 14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is: (i) phenyl, cyclohexyl, azetidinyl, morpholinyl, tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, piperdinyl, azaspirohexanyl, azaspiroheptanyl, oxaazaspiroheptanyl, oxaazaspirooctanyl, oxaazaspirononanyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoindolinyl, dihydropyrazolooxazinyl, dihydrodioxinopyridinyl, or hexahydropyrazinopyridooxazinyl, each of which is optionally substituted with 1 to 3 groups selected from R 1A ; (ii) each of which is optionally substituted with 1 or 2 groups selected from R 1A ; or (iii) and wherein (a) each R 1A is independently halo, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, hydroxy[halo(C 1 -C 4 )alkyl], (1-C 4 )alkylene(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylene[deuterated(C 1 -C 4 )alkoxy], (C 1 -C 4 )alkylene[halo(C 1 -C 4 )alkoxy], hydroxy, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxyO(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxyO[deuterated(C 1 -C 4 )alkyl], (C 1 -C 4 )alkoxyO[halo(C 1 -C 4 )alkyl], —O(C 1 -C 4 )alkylene[NR a R b ], —NR a R b , —NH(C 1 -C 4 )alkylene[heterocyclyl], cyano, —C(O)R a , —C(O)NR a R b , —SO 2 R a , cycloalkyl, heterocyclyl, (C 1 -C 4 )alkylene[heterocyclyl], —O(C 1 -C 4 )alkylene[cycloalkyl], —O(C 1 -C 4 )alkylene[heterocyclyl], (C 1 -C 4 )alkoxyO[cycloalkyl], —O[cycloalkyl], or —O[heterocyclyl], where each occurrence of cycloalkyl and heterocyclyl, alone, or as part of another group, is optionally substituted with 1 to 3 groups selected from oxo, (C 1 -C 4 )alkyl, hydroxy, —NH(C 1 -C 4 alkyl), and heterocyclyl; and wherein R a and R b are each independently hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkylene(C 1 -C 4 )alkoxy, cycloalkyl, or heterocyclyl, wherein the cycloalkyl and heterocyclyl are each optionally substituted with (C 1 -C 4 )alkyl, hydroxy, or hydroxy(C 1 -C 4 )alkyl; or (b) each R 1A is independently —F, —Cl, —CH 3 , —CH(CH 3 ) 2 , —CH 2 F, —CHF 2 , —CF 3 , —CF 2 CH 3 , —CH 2 CF 3 , —CF 2 CH 2 OH, —CH 2 OCH 3 , —CH 2 OCD 3 , —CH 2 OCHF 2 , —CH 2 OCF 3 , —CH 2 CH 2 OCH 3 , —C(OH)(CH 3 ) 2 , —CH 2 C(OH)(CH 3 ) 2 , hydroxy, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCHF 2 , —OCF 3 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 OCD 3 , —OCH 2 CH 2 OCHF 2 , —OCH 2 CH 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , cyano, —C(O)CH 3 , —C(O)NH 2 , —C(O)NHCH 3 , —C(O)N(CH 3 ) 2 , —C(O)NHCH 2 CH 2 OCH 3 , —S(O) 2 CH 3 , cyclopropyl,
  15. 15 .- 19 . (canceled)
  16. 20 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: (i) X is —OR 6 ; and (ii) R 6 is: (a) (C 1 -C 4 )alkylene[heteroaryl]; or (b)
  17. 21 .- 23 . (canceled)
  18. 24 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: (i) X is —NR 7 R 8 ; and (ii) R 7 and R 8 , together with the N to which they are attached, form: (a) azetidinyl, azaspirohexanyl, azaspiroheptanyl, oxaazaspiroheptanyl, thiaazaspiroheptanyl, diazaspirooctanyl, oxaazaspirooctanyl, oxaazaspirononanyl, diazaspirononanyl, oxadiazaspirononanyl, or dioxaazaspirononanyl, each of which are optionally substituted with 1 to 3 groups selected from R 2A ; (b) each of which are optionally substituted with 1 to 3 groups selected from R 2A ; or (c) and wherein: each R 2A is independently: (I) halo, (C 1 -C 4 )alkyl, deuterated(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylene(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylene[deuterated(C 1 -C 4 )alkoxy], (C 1 -C 4 )alkylene[halo(C 1 -C 4 )alkoxyl, hydroxy(C 1 -C 4 )alkyl, hydroxy, (C 1 -C 4 )alkoxy, deuterated(C 1 -C 4 )alkoxy, —S(O) 2 (C 1 -C 4 )alkyl, cyano, or cycloalkyl; or (II) —F, —CH 3 , —CD 3 , —CH 2 F, —CF 3 , —CH 2 CF 3 , —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —CH 2 OCD 3 , —CH 2 OCHF 2 , —CH 2 OCF 3 , —C(OH)(CH 3 ) 2 , —C(CH 3 ) 2 OCH 3 , hydroxy, —OCH 3 , —OCD 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —S(O) 2 CH 3 , cyano, or cyclopropyl.
  19. 25 .- 28 . (canceled)
  20. 29 . The compound of claim 1 , having the structural Formula III: or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5- to 6-membered nitrogen containing heteroaryl.

Description

RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63/710,194, filed Oct. 22, 2024, the entire contents of which are incorporated herein by reference. BACKGROUND Biomolecular condensates are ubiquitous spatiotemporal organizers of biology, compartmentalizing and integrating a wide variety of regulatory pathways within cells. See Banani, S. F. et al. Nat Rev Mol Cell Bio 18, 285-298 (2017); and Hyman, A. A. et al. Annu Rev Cell Dev Bi 30, 39-58 (2014). Aberrant condensates, or condensatopathies, act as central nodes of dysfunction in disease, representing a new class of targets for drug discovery. See Alberti, S. et al. Nat Rev Mol Cell Bio 22, 196-213 (2021); Boija, A. et al. Cancer Cell 39, 174-192 (2021); Mitrea, D. M. et al. Nat Rev Drug Discov 1-22 (2022); Martin, E. W. et al. J. Mol. Biol. 168380 (2023); and Patel, A. et al. Frontiers Mol Biosci 9, 1007744 (2022). This new perspective expands the target space and enables new strategies for pursuing targets historically considered ‘undruggable’; these strategies include but are not limited to modifying the condensates these targets associate to, or targeting structural states that are selectively adopted by the ‘undruggable’ target inside the condensate. See Mitrea, D. et al. Nat Rev Drug Discov 1-22 (2022). Due to their integrative role, dysfunction of condensates leads to complex defects in multiple biological processes, explaining the root cause of complex diseases, such as cancer and neurodegeneration. This central role in pathophysiology also opens opportunities to discover broad-acting drugs that are active across large patient populations with a shared condensatopathy but of diverse genetic background. Beta catenin is a validated anti-neoplastic target, known to be a driver of over-proliferation and aberrant transcriptional programming in a broad spectrum of cancers, including, but not limited to colorectal, breast, skin and pancreatic cancer. See Liu, J. et al. Signal Transduct Target Ther. (2022); and Zhang, Y. et al. J Hematol Oncol 13, 165 (2020). The cancer-driving activity of beta catenin is attributed to its constitutively active transcriptional promoting function, which results from several mutations and other aberrations along the dysregulated Wnt-pathway. Transcriptionally active beta catenin drives the expression of dozens of genes including NOTUM, MYC, AXIN2 and LEF1. See Nusse, R. et al. Nature 519, 163 (2015) and Herbst, A. et al. BMC Genomics 15, 74 (2014). Thus, what is needed is novel small molecules that modulate beta catenin's aberrant transcriptional activation and cell proliferation through its sequestration into nuclear condensates. SUMMARY Provided herein are compounds having the Formula I: and pharmaceutically acceptable salts and compositions thereof, wherein R1, R2, X, z1, z2, and z3 are as described herein. In one aspect, the described compounds of Formula I and pharmaceutically acceptable salts thereof modulate beta catenin (e.g., sequester beta catenin in nuclear condensates), and are useful in a variety of therapeutic applications such as, for example, in treating cancer. See for example the cancer cell-line derived xenograft study and related data shown in the exemplification section below. Pharmaceutical compositions comprising the described compounds and pharmaceutically acceptable salts of the described compounds, as well as methods for their preparation are also included. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the beta catenin condensate modulation in DLD-1 cells treated with Example 1 or DMSO. FIG. 2 shows tumor volumes for mice treated with Example 1 and mice provided vehicle. FIG. 3 shows the gene expression changes in DLD-1 cells treated with Example 1 or DMSO. DETAILED DESCRIPTION 1. General Description of Compounds In a first embodiment, provided herein are compounds having the Formula I: or a pharmaceutically acceptable salt thereof, wherein: z1 is N or —CR3;z2 is N or —CR5;z3 is N or —CR4;R1 is hydrogen, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkylene(C1-C4)alkoxy, or (C1-C4)alkylene[OP(O)(OH)2];R2 is aryl, heteroaryl, heterocyclyl, or cycloalkyl, each of which are optionally substituted with 1 to 3 groups selected from R1A;R3 and R4 are each independently hydrogen, halo, cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C2-C4)alkenyl, (C1-C4)alkylene[heterocyclyl], (C1-C4)alkylene[aryl], (C1-C4)alkylene[heteroaryl], (C1-C4)alkylene[cycloalkyl], —S(O)2(C1-C4)alkyl, or —S(O)(C1-C4)alkyl, wherein said heterocyclyl, aryl, heteroaryl, and cycloalkyl are each optionally substituted with 1 to 3 groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, and cyano;R5 is hydrogen, halo, or (C1-C4)alkyl;X is —OR6 or —NR7R8;R6 is cycloalkyl, heterocyclyl, (C1-C4)alkylene(C1-C4alkoxy), (C1-C4)alkylene[aryl], (C1-C4)alkylene[heteroaryl], (C1-C4)alkylene[heterocyclyl], or (C1-C4)alkylene[cycloalky