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EP-4739397-A1 - FUSED PYRAZOLE DERIVATIVES AS USP1 INHIBITORS

EP4739397A1EP 4739397 A1EP4739397 A1EP 4739397A1EP-4739397-A1

Abstract

The present disclosure provides fused pyrazole derivatives of formula (I), which are therapeutically useful as USP1 inhibitors. These compounds are useful in the treatment and/or prevention of diseases and/or disorders responsive to the inhibition of USP1 protein expression and USP1 activity. Compounds of the present disclosure are especially useful for treating cancer. The present disclosure also provides processes for preparation of the compounds and pharmaceutical formulations comprising at least one of the compounds of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof.

Inventors

  • ABBINENI, Chandrasekhar
  • SAMAJDAR, SUSANTA
  • AELURI, Madhu
  • SIMONOVICH, Scott

Assignees

  • Exelixis, Inc.

Dates

Publication Date
20260513
Application Date
20240702

Claims (20)

  1. WHAT IS CLAIMED IS: 1. A compound of formula (I): or a pharmaceutical wherein: ; ring Y is C3-C8 cycloalkyl, C5-C10 cycloalkeny , wherein the asterisk marks the point of attachment to rin ring Z is 3- to 15-membered heterocycloalkyl or 5- to 14-membered heteroaryl; X 1 , X 2 and X 3 are independently N or C; Y 1 to Y 4 are independently N or C, wherein 0-2 of Y 1 to Y 4 are N; Y 5 and Y 6 are independently N, C, O or S; each R X is independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 8 cycloalkyl; R Y is halo, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 alkylamino; each R Z is independently hydrogen, halo, C 1 -C 6 alkyl, halo(C 1 -C 6 )alkyl, C 1 -C 6 alkoxy, C3-C8 cycloalkyl, (C1-C6)alkylamino-(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, unsubstituted 3- to 15-membered heterocycloalkyl or (C 1 -C 6 alkyl)-substituted 3- to 15-membered heterocycloalkyl, wherein halo and C1-C6 alkoxy are bonded to carbon atoms in the Z ring; G is -O-, -N(R G1 )-, *-C(R G2 R G3 )-N(R G1 )-, *-N(R G1 )-C(R G2 R G3 )-, *-C(R G2 R G3 )-O-, -[C(R G2 R G3 )] q - or -C(R 4 R 4 ^)-, wherein the asterisk marks the point of attachment to the pyrazole ring; R G1 , each R G2 and each R G3 are independently hydrogen or C1-C6 alkyl; R 1 is hydrogen, C1-C6 alkyl, halo(C1-C6)alkyl, C3-C8 cycloalkyl, (C1-C6)alkylamino- (C 1 -C 6 )alkyl, unsubstituted 3- to 15-membered heterocycloalkyl, (C 1 -C 6 )alkyl-substituted 3- to 15-membered heterocycloalkyl, optionally substituted (C6-C14)aryl(C1-C6)alkyl, or optionally substituted (5- to 14-membered heteroaryl)-(C1-C6)alkyl, wherein the substituents on (C6- C14)aryl(C1-C6)alkyl and (5- to 14-membered heteroaryl)-(C1-C6 )alkyl are independently halo, C1-C6 alkyl or C1-C6 alkoxy; R 2 , R 2 ^, R 3 and R 3 ^ are independently hydrogen, C 1 -C 6 alkyl, halo, cyano or amino; or R 2 and R 2 ^, taken together, form an oxo group; or R 2 and R 2 ^, taken together along with the carbon atom to which they are attached, form C3-C8 cycloalkyl; or R 2 and R 3 are taken together to form a C 1 -C 3 alkylene bridge, wherein 1 to 2 carbon atom(s) of the alkylene bridge is/are optionally replaced by heteroatom(s) independently selected from N, O and S; or R 3 and R G2 are taken together to form a C 1 -C 3 alkylene bridge, wherein 1 to 2 carbon atom(s) of the alkylene bridge is/are optionally replaced by heteroatom(s) independently selected from N, O and S; R 4 and R 4 ^ are: i. taken together along with the carbon atom to which they are attached to form a C3-C8 cycloalkyl, or ii. independently hydroxy or C 1 -C 6 alkoxy, or iii. independently hydrogen or C1-C6 alkyl, with the proviso that R 4 and R 4 ^ are not hydrogen or alkyl when: (a) each of R 2 , R 2 ^, R 3 , R 3 ^ is hydrogen, (b) ring Y is phenyl, thiophenyl, thiazolyl, 6-membered heteroaryl or cubanyl, and (c) ring Z is imidazolyl; or R 4 and R 3 are taken together to form a C 1 -C 3 alkylene bridge, wherein 1 to 2 carbon atom(s) of the alkylene bridge is/are optionally replaced by heteroatom(s) independently selected from N, O and S; subscript p is 1,
  2. 2 or 3; subscript q is 2,
  3. 3 or 4; subscript m is 0 or 1; and subscript n is 1, 2 or 3. 2. The compound of claim 1, having a formula (IA): or a pharmaceutica 3. The compound of claim 1, having a formula (IB): or a pharmaceutically f.
  4. 4. The compound of claim 1, having a formula (IC): or a pharmaceut
  5. 5. The compound of claim 1, having a formula (ID): or a pharmaceut .
  6. 6. The compound of claim 1, having a formula (IE): or a pharmaceut
  7. 7. The compound of claim 1, having a formula (IF): or a pharmaceuti
  8. 8. The compound of claim 1, having a formula (IG): or pharma f, wherein the bridge L G is -(CH 2 ) 1-3 - or -CH 2 -O-CH 2 -.
  9. 9. The compound of claim 1, having a formula (IH): or pharm f, wherein the G bridge L is -(CH2)1-3- or -CH2-O-CH2-.
  10. 10. The compound of any one of claims 1 to 9, wherein ring Z is a 5-membered heteroaryl.
  11. 11. The compound of any one of claims 1 to 10, wherein ring Z is imidazolyl or pyrazolyl.
  12. 12. The compound of any one of claims 1 to 9, wherein at least one R X is C1-C6 alkyl.
  13. 13. The compound of any one of claims 1 to 9, wherein each R X is independently C1-C6 alkoxy or C 3 -C 8 cycloalkyl.
  14. 14. The compound of any one of claims 1 to 9, wherein G is -C(R 4 R 4 ^)-.
  15. 15. The compound of any one of claims 1 to 9, wherein G is -[C(R G2 R G3 )] q - or -C(R 4 R 4 ^)-, and q is 2.
  16. 16. The compound of any one of claims 1 to 9, wherein R 1 is C 1 -C 6 alkyl.
  17. 17. The compound of any one of claims 1 to 9, wherein both R 4 and R 4 ^ are hydrogen.
  18. 18. The compound of any one of claims 1 to 9, wherein R 2 is C1-C6 alkyl.
  19. 19. The compound of any one of claims 1 to 9, wherein R 3 is C1-C6 alkyl.
  20. 20. The compound of any one of claims 1 to 9, wherein R 2 and R 3 are taken together to form a C1-C3 alkylene bridge, wherein 1 to 2 carbon atom(s) of the alkylene bridge is/are optionally replaced by heteroatom(s) independently selected from N, O and S.

Description

FUSED PYRAZOLE DERIVATIVES AS USP1 INHIBITORS CROSS-REFERENCES TO RELATED APPLICATIONS [0001] The present application claims priority to Indian provisional application no. 202341045361, filed July 6, 2023, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD [0002] The present application is directed to fused pyrazole derivatives of formula (I) as USP1 inhibitors, useful for the treatment of cancer and inflammatory diseases or disorders. The disclosure also provides pharmaceutically acceptable compositions comprising compounds of the present application and methods of using said compositions in the treatment of diseases associated with USP1. BACKGROUND [0003] Deubiquitinases (DUBs) are a class of enzymes that act on ubiquitinated substrates to catalyze the removal of ubiquitin moieties. The human genome contains approximately 100 genes that encode DUBs. Human DUBs are classified into five different families (Nijman, S.M. et al. (2005) Cell 123, 773-86, Nalepa, G. et al. (2006) Nat Rev Drug Discov 5, 596-613). USP1 (ubiquitin specific protease 1) belongs to the USP subfamily of DUBs. The USP1 gene encodes a 785 amino acid protein having a conserved USP domain amino-terminal Cys box motif and a carboxy-terminal His box motif (Nijman, S.M. et al. (2005) Mol Cell 17, 331-9). The interaction of USP1 with UAF1, a WD40 repeat-containing protein, leads to formation of an activated USP1/UAF1 complex, which is required for the deubiquitinase activity of USP1 (Cohn, M.A. et al. (2007) Mol Cell 28, 786-97, Cohn, M.A. et al. (2009) J Biol Chem 284, 5343-51). USP1 gene transcription is regulated in a cell cycle- dependent manner. mRNA levels of USP1 remain low during G1 phase and reach a peak during S phase (Nijman, S.M. et al. (2005) Mol Cell 17, 331-9). The expression of USP1 is also regulated at the protein level by proteasomal degradation (Cataldo F, Mol Cell Biol (2013), 33(12):2485–2496). [0004] USP1 is a nuclear protein and localizes to chromatin where it is specifically associated with Fanconi anemia protein FANCD2. USP1 regulates several important steps in the DNA damage response pathway, including the Fanconi anemia (FA) pathway and the process of translesion synthesis (TLS). USP1 deubiquitinates monoubiquitinated FANCD2, which plays an important role in DNA damage repair (Nijman, S.M. et al. (2005) Mol Cell 17, 331-9, Guervilly, J.H. et al. (2011) Hum Mol Genet). While DNA-dependent mono- ubiquitination of FANCD2 facilitates DNA repair, it is deubiquitinated by USP1 to block the DNA-repairing response. USP1 is also critical for the deubiquitination of monoubiquitinated PCNA and thus negatively regulates PCNA-mediated TLS during DNA repair (Huang TT. et al. Nat Cell Biol (2006), 8(4):339–347). The expression of USP1 is significantly increased in several cancers (Das DS. et al. Clin Cancer Res. (2017) 23:4280–9, Xin Xu, et al. Front Oncol. (2019) 9:1406). Inhibition of USP1 inhibited DNA repair and induced cell death in multiple myeloma cells (Das DS. Et al. Clin Cancer Res. (2017) 23:4280–9). Lung cancer cells are sensitized to cisplatin upon inhibition of USP1 activity (Chen J, et al. Chem Biol. (2011) 18:1390–400). The results from these studies indicate that USP1 is a promising anti-cancer target. [0005] Certain USP1 inhibitors are reported in the literature, including compounds described in WO2007/149484, WO2011/137320, WO2014/105952, WO2017/087837, WO2019/089216, WO2020/132269, WO2020/139988, WO2021/163530, WO2021/247606, WO2022/174184, WO2022/197892, WO2022/199652, WO2022/214053, WO2022/216820, WO2022/228399, WO2022/233263, WO2022/253188, WO2023/066299, WO2023/030295, WO2023/083285, WO2023/083286, and WO2023/083297. SUMMARY [0006] Inhibition of USP1 with small molecule inhibitors has the potential to be a treatment for cancers and other disorders. It is, therefore, an object of this disclosure to provide compounds useful in the treatment of such diseases and/or disorders responsive to the inhibition of USP1 protein expression and USP1 activity. [0007] Provided herein are fused pyrazole derivatives of formula (I) and pharmaceutical compositions thereof, which are capable of inhibiting USP1. [0008] In compounds of formula (I) and pharmaceutically acceptable salts or stereoisomers thereof ; ring Y is C3-C8 cycloalkyl, C5-C10 cycloalkeny , wherein the asterisk marks the point of attachment to rin ring Z is 3- to 15-membered heterocycloalkyl or 5- to 14-membered heteroaryl; X1, X2 and X3 are independently N or C; Y1 to Y4 are independently N or C, wherein 0-2 of Y1 to Y4 are N; Y5 and Y6 are independently N, C, O or S; each RX is independently C1-C6 alkyl, C1-C6 alkoxy or C3-C8 cycloalkyl; RY is halo, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 alkylamino; each RZ is independently hydrogen, halo, C1-C6 alkyl, halo(C1-C6)alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, (C1-C6)alkylamino-(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, unsubstituted 3- to 15-membered heterocycloalkyl or (C1-C6 a