Search

EP-4735430-A1 - MALT1 INHIBITORS

EP4735430A1EP 4735430 A1EP4735430 A1EP 4735430A1EP-4735430-A1

Abstract

Disclosed are compounds of formula (I), compositions and methods for treating of diseases, syndromes, conditions, and disorders that are affected by the inhibition of MALT1.

Inventors

  • MOWAT, Jeffrey, Stuart
  • LEPRI, Susan
  • VELTER, Adriana-Ingrid
  • HULPIA, Fabian
  • THURING, Johannes Wilhelmus J
  • ROAGNA, Giulia
  • HAHN, David Friedrich

Assignees

  • Janssen Pharmaceutica NV

Dates

Publication Date
20260506
Application Date
20240628

Claims (14)

  1. CLAIMS 1. A Formula (I) or a tautomer or a stereoisomeric form thereof, wherein R 1 represents C1-4alkyl or C3-6cycloalkyl; each optionally substituted with 1, 2 or 3 substituents each independently selected from halo and -OH; ring represents phenyl or pyridyl; R x represents halo; n is 0, 1 or 2; Ar represents phenyl, thiazolyl, 1,2,4-thiadiazolyl, isothiazolyl, oxazolyl, pyrazolyl, pyridinonyl or pyridinyl; R 4a and R 4b are each independently selected from the group consisting of hydrogen; halo; C1-4alkyl; -C(=O)-NR 5 R 6 ; -O-C1-4alkyl; -CN; -NR 7a R 8a ; -C(=O)-O-R 9 ; C3-6cycloalkyl; -O-C1-4alkyl substituted with 1, 2 or 3 halo substituents; or C1-4alkyl substituted with 1, 2 or 3 halo substituents; R 2 represents C1-4alkyl; R 3 represents C3-6cycloalkyl optionally substituted with one substituent selected from -NR 7b R 8b , 1-azetidinyl, 1-pyrrolidinyl and 1-piperidinyl; or R 3 represents (a-1), (a-2), (a-3), (a-4) or (a-5): (a-1) (a-4) ( a-2) (a-5) (a-3) X 1 represents O, NH or N-C 1-4 alkyl; X 2 represents O, NH or N-C 1-4 alkyl; n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, n12, and n14 are each independently 1, 2 or 3; n13 is 0, 1 or 2; R 12 , R 13 and R 16 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl and -S(=O) 2 -C 1-4 alkyl; R 14 , R 15 and R 17 are substituents on a carbon atom of (a-1), (a-2), (a-3), (a-4) or (a-5) and are each independently selected from the group consisting of hydrogen, C 1-4 alkyl and halo; which they are attached ; X 3 represents CH or N; X 4 represents CH or N; provided that at least one of X 3 and X 4 represents N; X 5 represents CH or N; X 6 represents CH or N; provided that at least one of X 5 and X 6 represents N; R 10 and R 11 represent hydrogen or C 1-4 alkyl optionally substituted with 1, 2 or 3 halo substituents; R 5 , R 6 , R 7a , R 7b , R 8a , R 8b and R 9 are each independently selected from the group consisting of hydrogen and C1-4alkyl; or a pharmaceutically acceptable salt thereof.
  2. 2. The compound according to claim 1 provided that the following compounds and are excluded.
  3. 3. The compound according to claim 1 wherein R 4b is -C(=O)-NR 5 R 6 .
  4. 4. The compound according to claim 1 or 3 wherein R 2 and R 3 are taken together to form together with the atoms to which they are attached (b-1) or (b-2).
  5. 5. according to any one of the previous claims wherein ring represents phenyl; and n is 0.
  6. 6. The compound according to any one of the previous claims wherein R 4a and R 4b are each independently selected from the group consisting of hydrogen; halo; C 1-4 alkyl; -C(=O)-NR 5 R 6 ; -O-C 1-4 alkyl; -CN; -NR 7a R 8a ; -C(=O)-O-R 9 ; C 3-6 cycloalkyl; -O-C 1-4 alkyl substituted with 1, 2 or 3 halo substituents; or C1-4alkyl substituted with 1, 2 or 3 halo substituents; R 2 represents C1-4alkyl; R 3 represents (a-1) or (a-3); X 1 represents O or NH; n1, n2, and n14 are each independently 1 or 2; n13 is 2; R 16 represents hydrogen; R 14 and R 17 are substituents on a carbon atom of (a-1) or (a-3) and represent hydrogen; or R 2 and R 3 are taken together to form together with the atoms to which they are attached (b-1) or (b-2); X 5 represents N; X 6 represents CH or N; R 5 , R 6 , R 7a , R 8a , and R 9 are each independently selected from the group consisting of hydrogen and C1-4alkyl.
  7. 7. The compound according to any one of the previous claims wherein R 1 represents C1-4alkyl optionally substituted with 1, 2 or 3 halo substituents; Ar represents thiazolyl or pyridinyl; R 4a and R 4b are each independently selected from the group consisting of hydrogen; C 1-4 alkyl; -C(=O)-NR 5 R 6 ; or C1-4alkyl substituted with 1, 2 or 3 halo substituents; R 2 represents C1-4alkyl; R 3 represents (a-1) or (a-3); X 1 represents O or NH; n1, n2, and n14 are each independently 1 or 2; n13 is 2; R 16 represents hydrogen; R 14 and R 17 are substituents on a carbon atom of (a-1) or (a-3) and represent hydrogen; or R 2 and R 3 are taken together to form together with the atoms to which they are attached (b-1) or (b-2); X 3 represents N; X 4 represents N; X 5 represents N; X 6 represents N; R 10 and R 11 represent C1-4alkyl; R 5 and R 6 are hydrogen.
  8. 8. The compound according to any one of the preceding claims wherein R 2 and R 3 are taken together.
  9. 9. The compound according to any one of the preceding claims wherein X 1 represents NH;
  10. 10. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 9 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.
  11. 11. A compound as claimed in any one of claims 1 to 9 or a pharmaceutical composition as claimed in claim 10 for use as a medicament.
  12. 12. A compound as claimed in any one of claims 1 to 9 or a pharmaceutical composition as claimed in claim 10 for use in the treatment or prevention of cancer.
  13. 13. A compound as claimed in any one of claims 1 to 9 or a pharmaceutical composition as claimed in claim 10 for use for use in the treatment or prevention of a disease, syndrome, condition, or disorder, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT1.
  14. 14. A method of treating a disease, syndrome, condition, or disorder, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as claimed in any one of claims 1 to 9 or a pharmaceutical composition as claimed in claim 10.

Description

MALT1 INHIBITORS FIELD OF THE INVENTION The present invention relates to a novel compound that is a MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) inhibitor. The compound may be useful for the treatment of a disease, syndrome, condition, or disorder, particularly a MALT1-related disease, syndrome, condition, or disorder, including but not limited to, cancer and immunological diseases. The invention also relates to pharmaceutical compositions comprising one or more of such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds or pharmaceutical compositions for the treatment of cancer and autoimmunological diseases, syndromes, disorders, or conditions associated with MALT1 inhibitors. BACKGROUND OF THE INVENTION MALT1 (mucosa-associated lymphoid tissue lymphoma translocation 1) is a key mediator of the classical NF ^B signaling pathway. MALT1 is the only human paracaspase and transduces signals from the B cell receptor (BCR) and T cell receptor (TCR). MALT1 is the active subunit of the CBM complex which is formed upon receptor activation. The CBM complex consists of multiple subunits of three proteins: CARD11 (caspase recruitment domain family member 11), BCL10 (B-cell CLL/Lymphoma 10) and MALT1. MALT1 affects NF ^B signaling by two mechanisms: firstly, MALT1 functions as a scaffolding protein and recruits NF- ^B signaling proteins such as TRAF6, TAB-TAK1 or NEMO-IKKα/ ^; and secondly, MALT1, as a cysteine protease, cleaves and thereby deactivates negative regulators of NF- ^B signaling, such as RelB, A20 or CYLD. The ultimate endpoint of MALT1 activity is the nuclear translocation of the NF- ^B transcription factor complex and activation of NF- ^B signaling. Constitutive activation of NF- ^B signaling is the hallmark of ABC-DLBCL (Diffuse Large B cell Lymphoma of the Activated B Cell-like subtype), the more aggressive form of DLBCL. DLBCL is the most common form of non-Hodgkin’s lymphoma (NHL), accounting for approximately 25% of lymphoma cases while ABC-DLBCL comprises approximately 40% of DLBCL. NF- ^B pathway activation is driven by mutations of signaling components, such as CD79A/B, CARD11, MYD88 or A20, in ABC-DLBCL patients. The use of BTK inhibitors, for example Ibrutinib, provides clinical proof-of-concept that inhibiting NF- ^B signaling in ABC-DLBCL is efficacious. MALT1 is downstream of BTK in the NF- ^B signaling pathway and a MALT1 inhibitor could target ABC-DLBCL patients not responding to Ibrutinib, mainly patients with CARD11 mutations, as well as treat patients that acquired resistance to Ibrutinib. Small molecule tool compound inhibitors of MALT1 protease have demonstrated efficacy in preclinical models of ABC-DLBCL. Interestingly, covalent catalytic site and allosteric inhibitors of MALT1 protease function have been described, suggesting that inhibitors of this protease may be useful as pharmaceutical agents. The chromosomal translocation creating the API2-MALT1 fusion oncoprotein is the most common mutation identified in MALT (mucosa-associated lymphoid tissue) lymphoma. API2-MALT1 is a potent activator of the NF- ^B pathway. API2-MALT1 mimics ligand-bound TNF receptor, promotes TRAF2-dependent ubiquitination of RIP1 which acts as a scaffold for activating canonical NF- ^B signaling. Furthermore, API2-MALT1 has been shown to cleave and generate a stable, constitutively active fragment of NF- ^B-inducing kinase (NIK) thereby activating the non-canonical NF- ^B pathway. In addition to lymphomas, MALT1 has been shown to play a critical role in innate and adaptive immunity. MALT1 protease inhibitor can attenuate disease onset and progression of mouse experimental allergic encephalomyelitis, a mouse model of multiple sclerosis. Mice expressing catalytically inactive MALT1 mutant showed loss of marginal zone B cells and B1 B cells and general immune deficiency characterized as decreased T and B cell activation and proliferation. However, those mice also developed spontaneous multi-organ autoimmune inflammation at the age of 9 to 10 weeks. It is still poorly understood why MALT1 protease dead knock-in mice show a break of tolerance while conventional MALT1 KO mice do not. One hypothesis suggests the unbalanced immune homeostasis in MALT1 protease dead knock- in mice may be caused by incomplete deficiency in T and B cell but severe deficiency of immunoregulatory cells. Similarly, MALT deficiency in humans has been associated with combined immunodeficiency disorder. Given the difference between genetic mutation and pharmacological inhibition, a phenotype of MALT1 protease dead knock-in mice might not resemble that of patients treated with MALT1 protease inhibitors. A reduction of immunosuppressive T cells by MALT1 protease inhibition may be beneficial to cancer patients by potentially increasing antitumor immunity. WO2023192506 described MALT1 modulators. Thus, MALT1 inhibitors of the present invention may provide a ther