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CN-122003418-A - Cyclopenta [ E ] pyrazolo [1,5-A ] pyrimidine derivatives as MALT1 inhibitors

CN122003418ACN 122003418 ACN122003418 ACN 122003418ACN-122003418-A

Abstract

The present application relates to compounds of formula (I) as defined herein and pharmaceutically acceptable salts thereof. The application also describes pharmaceutical compositions comprising compounds of formula (I) and pharmaceutically acceptable salts thereof, as well as methods of using the compounds and compositions for treating diseases such as cancer, autoimmune disorders, and inflammatory disorders.

Inventors

  • FENG SHULU
  • GUO JIAYE
  • Goran Krilov
  • Anna Negri
  • NIE ZHE
  • Andrew Plazek
  • Manz swensen
  • Michael Tezos

Assignees

  • 薛定谔公司

Dates

Publication Date
20260508
Application Date
20240910
Priority Date
20230911

Claims (20)

  1. 1. A compound of formula (I): , (I) Or a pharmaceutically acceptable salt thereof, wherein: X is CH, CF or N; y is CH, CF or N; R 1 is H, halo or C 1 -C 3 alkyl; R 2 is H, halo or C 1 -C 3 alkyl; r 0 、R 3 and R 4 are defined as follows: (i) R 0 is H; R 3 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or 4-7 membered heteroaryl, wherein the heteroaryl is optionally substituted with 1C 1 -C 6 haloalkyl, and R 4 is C 1 -C 6 alkyl, or (Ii) R 0 is H, and R 3 and R 4 together with the carbon atom to which they are attached form a C 3 -C 7 cycloalkyl group or a 4-7 membered heterocyclyl group, or (Iii) R 0 and R 3 together with the carbon atom to which they are attached form a C 3 -C 7 cycloalkyl radical, and R 4 is C 1 -C 6 alkyl; r 5 is H or halo; r 6 is H or halo, and R 7 and R 8 are defined as follows: (i) R 7 is C 1 -C 6 alkyl, and R 8 is C 3 -C 6 cycloalkyl or a 4-7 membered heterocyclyl, wherein the heterocyclyl is optionally substituted with 1-2 oxo groups, or (Ii) R 7 and R 8 together with the atoms to which they are attached form a 5-12 membered heterocyclyl, wherein the heterocyclyl is optionally substituted with 1-2 oxo groups; Provided that no more than one of X and Y is N.
  2. 2. The compound of claim 1, wherein the compound is of formula (I-1): , (I-1) Or a pharmaceutically acceptable salt thereof.
  3. 3. The compound of claim 1 or 2, wherein the compound is of formula (I-2 a): , (I-2a) Or a pharmaceutically acceptable salt thereof.
  4. 4. The compound of claim 1 or 2, wherein the compound is of formula (I-2 b): , (I-2b) Or a pharmaceutically acceptable salt thereof.
  5. 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is CH.
  6. 6. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is CF.
  7. 7. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is N.
  8. 8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is CH.
  9. 9. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is CF.
  10. 10. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is N.
  11. 11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 1 is H.
  12. 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 2 is F.
  13. 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or 4-7 membered heteroaryl, wherein the heteroaryl is optionally substituted with 1C 1 -C 6 haloalkyl.
  14. 14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R 3 is CH 3 、CF 3 or 。
  15. 15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 4 is CH 3 .
  16. 16. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the carbon atom to which they are attached form a C 3 -C 7 cycloalkyl group.
  17. 17. The compound of claim 16, wherein R 3 and R 4 , or a pharmaceutically acceptable salt thereof, form, together with the carbon atom to which they are attached, cyclopropyl or cyclobutyl.
  18. 18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R 0 is H.
  19. 19. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 0 and R 3 together with the carbon atom to which they are attached form a C 3 -C 7 cycloalkyl group.
  20. 20. The compound of claim 19, wherein R 0 and R 3 , or pharmaceutically acceptable salts thereof, form, together with the carbon atom to which they are attached, a cyclobutyl, and R 4 is CH 3 .

Description

Cyclopenta [ E ] pyrazolo [1,5-A ] pyrimidine derivatives as MALT1 inhibitors Cross Reference to Related Applications The present application claims the benefit of U.S. provisional patent application No. 63/537,637, filed on 9/11 of 2023, which is incorporated herein by reference in its entirety. Technical Field The present application relates to tricyclic and other polycyclic compounds that are useful for treating proliferative disorders, such as cancer, as well as autoimmune and inflammatory disorders. Background MALT1 (mucosa-associated lymphoid tissue lymphoma translocator 1) is an intracellular protein that is involved in lymphocyte proliferation through NF- κb upstream signaling to control lymphocyte activation, survival, proliferation and differentiation. MALT1 is one of the three subunits of the CBM complex formed upon activation of cell surface antigen receptors, together with CARMA or CARD scaffold proteins (e.g., CARD11 (caspase recruitment domain family member 11, also referred to as CARMA 1), CARD14 (caspase recruitment domain family member 14, also referred to as CARMA 2), CARD10 (caspase recruitment domain family member 10, also referred to as CARMA 3), or CARD9 (caspase recruitment domain family member 9)) and BCL10 (B cell CLL/lymphoma 10). See jaworth et al, cell Mol LIFE SCIENCE 2016, 73, 459-473 and Juilland and thome Frontiers in Immunology 2018, 9, 1927. MALT1 is known to mediate NF-. Kappa.B signaling by at least two mechanisms, firstly, MALT1 acts as a scaffold protein, recruiting NF-. Kappa.B signaling proteins such as TRAF6, TAB (e.g., TAB1, TAB2, TAB 3), TAK1 and NEMO-IKKK alpha/beta, and secondly, as a cysteine protease, it cleaves and inactivates negative regulators of NF-. Kappa.B signaling such as RelB, A20 or CYLD. See Rosebeck et al, science, 2011, 331, 468-472. The protease activity of MALT1 has become a potential therapeutic target, especially where NF- κb and related pathways are thought to play an important role. Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is an invasive lymphoma, which is often characterized by NF- κb overactivation, and studies have shown that MALT1 protease inhibition can significantly inhibit the growth of and promote apoptosis of highly invasive ABC-type DLBCL. See Ferch U et al, J Exp Med 2009, 206, 2313-2320, see also HAILFINGER S et al, proc NATL ACAD SCI USA 2009, 106, 19946-19951. Known peptide substrates for MALT1 or fusion protein API2-MALT1 include A20, CYLD, BCL10, relB, regnase-1, roquin-1, NIK and LIMA la. See Rebeaud et al, nat Immunol 2008, 9, 272-281; see also Coornaert et al, nat Immunol 20008, 9, 263-271; staal et al, EMBO J2011, 30, 1742-1752; hailfinger et al, PNAS 2011, 108, 14596-14601; jeltsch et al, nat Immunol 2014, 15, 1079-1089; uehata et al, cell 2013, 153, 1036-1049; nie et al, nat Commun 2015, 6, 5908; and Baens et al, PLoS ONE 2014, 9, e103774. A general overview of MALT1 substrates is described in Kasperkiewicz et al SCIENTIFIC REPORTS 8.1.1 (2018): 1-10. Additionally, several chromosomal translocations have been identified in ABC-DLBCL that result in the production of constitutively active MALT1, and the identification of MALT1 fusion protein API2-MALT1/IgH-MALT1 that results in NF- κb activation independent of upstream stimulation further highlights the importance of this protein in cancer and various diseases. See Farinha et al, J Clinical Oncology 2005, 23, 6370-6378. Further, MALT1 has been shown to be associated with several different types of cancer, such as hematological malignancies (e.g., mantle cell lymphoma), chronic Lymphocytic Leukemia (CLL), and solid tumors (e.g., lung adenocarcinoma, breast cancer, pancreatic cancer, and glioblastoma). See Jiang et al, CANCER RESEARCH 2011, 71, 2183-2192; see also Pan et al, mol CANCER RES 2016, 14, 93-102, penas et al, blood 2010, 115, 2214-2219 and J Cell Mol Med.2020, 7 months; 24 (13): 7550-7562.MALT1, as an immunomodulatory protein, also participates in innate and adaptive immunity and may have an impact on several inflammatory disorders, such as psoriasis, multiple sclerosis, rheumatoid arthritis, sjogren's syndrome, ulcerative colitis and different types of allergic disorders caused by chronic inflammation. See Afofina et al, FEBS Journal 2015, DOI: 10.1/febs.13325, see also Lowes et al, ANN REVIEW Immunology 2014, 32, 227-255, jabara et al, J ALLERGY CLIN Immunology 2013, 132, 151-158, streubel et al, CLIN CANCER RESEARCH 2004, 10, 476-480, and Liu et al, oncotarget 2016, 1-14. Recently, the results of the study also demonstrate the importance of MALT1 in controlling regulatory T cell (Treg) function and homeostasis. Studies are underway to confirm the potential of MALT1 inhibitors alone or in combination with immune checkpoint mechanisms to treat solid tumor patients. However, no MALT1 inhibitors are currently approved for therapeutic use. Disclosure of Invention Accordingly, provided herein is a compound of formula (I): , (I) Or a pharmaceu