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WO2026003049A1 - Inhibiteurs de malt1 - Google Patents

Inhibiteurs de malt1

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Publication number
WO2026003049A1
WO2026003049A1 PCT/EP2025/067856 EP2025067856W WO2026003049A1 WO 2026003049 A1 WO2026003049 A1 WO 2026003049A1 EP 2025067856 W EP2025067856 W EP 2025067856W WO 2026003049 A1 WO2026003049 A1 WO 2026003049A1
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WO
WIPO (PCT)
Prior art keywords
4alkyl
substituted
alkyl
independently selected
het
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/067856
Other languages
English (en)
Inventor
Jeffrey Stuart MOWAT
Johannes Wilhelmus J. Thuring
Yves Emiel Maria Van Roosbroeck
Adriana-Ingrid VELTER
Aldo Peschiulli
Fabian HULPIA
Susan LEPRI
Berthold Wroblowski
Mikko Juhani Artturi Muuronen
Evelien RENDERS
Veronica TONA
Giulia ROAGNA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceutica NV
Original Assignee
Janssen Pharmaceutica NV
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Filing date
Publication date
Application filed by Janssen Pharmaceutica NV filed Critical Janssen Pharmaceutica NV
Publication of WO2026003049A1 publication Critical patent/WO2026003049A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • 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.
  • MALT1 (mucosa-associated lymphoid tissue lymphoma translocation 1) is a key mediator of the classical NFKB 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 NFKB signaling by two mechanisms: firstly, MALT1 functions as a scaffolding protein and recruits NFKB signaling proteins such as TRAF6, TAB-TAK1 or NEMO-IKKa/P; and secondly, MALT1, as a cysteine protease, cleaves and thereby deactivates negative regulators of NFKB signaling, such as RelB, A20 or CYLD.
  • NFKB signaling proteins such as TRAF6, TAB-TAK1 or NEMO-IKKa/P
  • MALT1 as a cysteine protease, cleaves and thereby deactivates negative regulators of NFKB signaling, such as RelB, A20 or CYLD.
  • the ultimate endpoint of MALT1 activity is the nuclear translocation of the NFKB transcription factor complex and activation of NFKB signaling.
  • DLBCL Diffuse Large B cell Lymphoma of the Activated B Cell-like subtype
  • DLBCL Diffuse Large B cell Lymphoma of the Activated B Cell-like subtype
  • NDL non-Hodgkin’s lymphoma
  • NFKB pathway activation is driven by mutations of signaling components, such as CD79A/B, CARD11, MYD88 or A20, in ABC-DLBCL patients.
  • BTK inhibitors for example Ibrutinib
  • Ibrutinib provides clinical proof-of-concept that inhibiting NFKB signaling in ABC-DLBCL is efficacious.
  • MALT1 is downstream of BTK in the NFKB signaling pathway and a MALT1 inhibitor could target ABC-DLBCL patients not responding to Ibrutinib, mainly patients with CARD 11 mutations, as well as treat patients that acquired resistance to Ibrutinib.
  • API2-MALT1 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 NFKB pathway.
  • API2-MALT1 mimics ligand-bound TNF receptor, promotes TRAF2-dependent ubiquitination of RIP 1 which acts as a scaffold for activating canonical NFKB signaling.
  • API2-MALT1 has been shown to cleave and generate a stable, constitutively active fragment of NFKB-inducing kinase (NIK) thereby activating the non-canonical NFKB pathway.
  • NIK NFKB-inducing kinase
  • 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 Bl B cells and general immune deficiency characterized as decreased T and B cell activation and proliferation.
  • 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.
  • MALT1 protease dead knock- in mice may be caused by incomplete deficiency in T and B cell but severe deficiency of immunoregulatory cells.
  • MALT deficiency in humans has been associated with combined immunodeficiency disorder.
  • 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.
  • MALT1 inhibitors of the present invention may provide a therapeutic benefit to patients suffering from cancer and/or immunological diseases.
  • the present invention is directed to compounds of Formula (I) and the tautomers and the stereoisomeric forms thereof, wherein
  • Ar represents phenyl, thiazolyl, 1,2,4-thiadiazolyl, isothiazolyl, oxazolyl, pyrazolyl, pyridinonyl or pyridinyl;
  • R a and R b are each independently selected from the group consisting of hydrogen; halo;
  • R la represents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents;
  • R 3a represents hydrogen or Ci-4alkyl
  • R 5a , R 5b , R 7a , R 8a , and R 9 are each independently selected from the group consisting of hydrogen and Ci-4alkyl;
  • R 6 represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH;
  • the present invention is also directed to active compounds of Formula (A) and the tautomers and the stereoisomeric forms thereof, wherein
  • R a and R b are each independently selected from the group consisting of hydrogen; halo;
  • R la represents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents;
  • R lb represents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents; or R la and R lb are taken together to form together with the carbon atom to which they are attached a Cs-ecycloalkyl; ring represents phenyl or pyridyl;
  • R 2 represents halo; n is 0, 1 or 2; R 5a , R 5b , R 7a , R 8a , and R 9 are each independently selected from the group consisting of hydrogen and Ci-4alkyl;
  • R 6 represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH; and the pharmaceutically acceptable salts thereof.
  • the compounds of Formula (I) and compounds of Formula (A) may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • a R or S’, ‘S or R ’, trans, cis) around one or more atoms contemplate each possible stereoisomer (stereoisomeric form), or mixture of two or more stereoisomers.
  • the stereochemistry of any particular chiral atom is not specified in the structures shown herein, then all possible stereoisomers are contemplated and included as the compounds of the invention, either as a pure stereoisomer or as a mixture of two or more stereoisomers.
  • the term “compound(s) of Formula (I)” is also meant to include the tautomers and the stereoisomeric forms (stereoisomers; for example enantiomers and diastereomers) thereof, even if not explicitly referred to.
  • stereochemistry as mentioned in the previous paragraph, is specified by bonds which are shown as solid wedged or hashed wedged bonds, hashed or bold bonds, or are otherwise indicated as having a particular configuration (e.g. R. S, R or S’, ‘S or R ’, trans, cis), then that stereoisomer is so specified and defined. It will be clear this also applies to subgroups of Formula (I). It will be clear this also applies to corresponding compounds of Formula (A).
  • bonds shown as solid lines but indicated with a stereodescriptor mean that such a stereocenter is specified and defined according to the stereodescriptor.
  • bonds shown as solid lines but indicated with R or S’ or ‘S or R ’ are used to indicate that such a stereocenter is chirally pure but with unknown configuration (pure stereoisomers and enantiomerically pure, but absolute stereochemistry undetermined on stereocenter indicated with R or S’ or ‘S or R ’).
  • Atropisomers are stereoisomers which have a particular spatial configuration, resulting from a restricted rotation about a single bond, due to large steric hindrance. All atropisomeric forms of the compounds of Formula (I) are intended to be included within the scope of the present invention.
  • the substituents may be in the E or the Z configuration.
  • compound(s) of the (present) invention or “compound(s) according to the (present) invention” as used herein, is meant to include the compounds of Formula (I) including tautomers and stereoisomeric forms, the pharmaceutically acceptable salt forms, and the solvates thereof.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising, consisting of and/or consisting essentially of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent and a compound of Formula (I). It will be clear this also applies to compounds of Formula (A).
  • a pharmaceutical composition comprising, consisting of, and/or consisting essentially of admixing a compound of Formula (I), and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent. It will be clear this also applies to compounds of Formula (A).
  • the present invention further provides methods for treating or ameliorating a disease, syndrome, condition, or disorder in a subject, including a mammal and/or human in which the disease, syndrome, or condition is affected by the inhibition of MALT1, including but not limited to, cancer and/or immunological diseases, using a compound of Formula (I). It will be clear this also applies to compounds of Formula (A).
  • the present invention also is directed to the use of any of the compounds described herein in the preparation of a medicament wherein the medicament is prepared for treating a disease, syndrome, condition, or disorder that is affected by the inhibition of MALT1, such as cancer and/or immunological diseases.
  • the present invention is also directed to the preparation of compounds of Formula (I) that act as an inhibitor of MALT1.
  • the present invention is also directed to the preparation of compounds of Formula (A) that act as an inhibitor of MALT 1.
  • Exemplifying the invention are methods of treating a disease, syndrome, condition, or disorder mediated by MALT1, using a compound of Formula (I).
  • said disease, syndrome, condition, or disorder mediated by MALT1 is selected from the group consisting of lymphomas, leukemias, carcinomas, and sarcomas, e.g.
  • non-Hodgkin’s lymphoma NHL (including B-cell NHL)
  • DLBCL diffuse large B-cell lymphoma
  • MCL mantle cell lymphoma
  • FL follicular lymphoma
  • MALT mucosa-associated lymphoid tissue lymphoma
  • marginal zone lymphoma T-cell lymphoma
  • Hodgkin’s lymphoma Burkitt’s lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukemia, chronic myelogenous leukemia (CML), hairy-cell leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erytholeukemia,
  • the disease, syndrome, condition, or disorder mediated by MALT1 is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma.
  • DLBCL diffuse large B-cell lymphoma
  • MCL mantle cell lymphoma
  • FL follicular lymphoma
  • MALT mucosa-associated lymphoid tissue lymphoma
  • An embodiment of the present invention is directed to a compound of Formula (I) for (use in) the treatment of immunological diseases that are affected by the inhibition of MALT1, including but not limited to, autoimmune and inflammatory disorders, e.g. arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatits, Crohn’s disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplact rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet’s diseases, uveitis, myasthenia gravis, Grave’s disease, Hashimoto thyroiditis, Sjorgen’s syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-com
  • the present invention is directed to a compound of Formula (I) for (use in) the treatment of a disease, syndrome, condition, or disorder affected by inhibition of MALT1, selected from the group consisting of rheumatoid arthritis (RA), psoritic arthritis (PsA), psorisis (Pso), ulcerative colitis (UC), Crohn’s disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).
  • RA rheumatoid arthritis
  • PsA psoritic arthritis
  • Pso psorisis
  • UC ulcerative colitis
  • Crohn’s disease systemic lupus erythematosus
  • COPD chronic obstructive pulmonary disease
  • the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is selected from non-Hodgkin’s lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma, chronic lymphocytic leukemia, and Waldenstrom macroglobulinemia.
  • NHL non-Hodgkin’s lymphoma
  • DLBCL diffuse large B-cell lymphoma
  • MCL mantle cell lymphoma
  • FL follicular lymphoma
  • transformed follicular lymphoma chronic lymphocytic leukemia
  • Waldenstrom macroglobulinemia Waldenstrom macroglobulinemia
  • the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is lymphoma.
  • the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is the activated B cell like (ABC) subtype of diffuse large B- cell lymphoma (DLBCL).
  • the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is germinal center B cell like (GCB) subtype of diffuse large B-cell lymphoma (DLBCL).
  • GCB germinal center B cell like
  • DLBCL diffuse large B-cell lymphoma
  • the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is non-germinal center B cell like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL).
  • non-GCB non-germinal center B cell like
  • DLBCL diffuse large B-cell lymphoma
  • the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is chronic lymphocytic leukemia (CLL).
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • the lymphoma is MALT lymphoma.
  • the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is Waldenstrom macroglobulinemia (WM).
  • the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma.
  • the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is non-Hodgkin’s lymphoma (NHL).
  • the nonHodgkin’s lymphoma (NHL) is B-cell NHL.
  • the non-Hodgkin’s lymphoma (NHL) is relapsed/refractory B-cell NHL.
  • the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is selected from the group consisting of relapsed/refractory non-germinal center B cell like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL), relapsed/refractory Waldenstrom macroglobulinemia (WM), relapsed/refractory mantle cell lymphoma (MCL), relapsed/refractory follicular lymphoma (FL), and relapsed/refractory mucosa-associated lymphoid tissue (MALT) lymphoma.
  • non-GCB non-germinal center B cell like subtype of diffuse large B-cell lymphoma
  • WM relapsed/refractory Waldenstrom macroglobulinemia
  • MCL mantle cell lymphoma
  • FL relapsed/refractory follicular lymphoma
  • MALT mucosa-associated lymphoid tissue lymphoma
  • the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed/refractory non-germinal center B cell like (non- GCB) subtype of diffuse large B-cell lymphoma (DLBCL).
  • non- GCB non-germinal center B cell like subtype of diffuse large B-cell lymphoma
  • the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed/refractory Waldenstrom macroglobulinemia (WM).
  • the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed/refractory mantle cell lymphoma (MCL).
  • MCL mantle cell lymphoma
  • the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed/refractory follicular lymphoma (FL).
  • the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed/refractory mucosa-associated lymphoid tissue (MALT) lymphoma.
  • Compounds of Formula (I) may be used for the treatment of immunological diseases including, but not limited to, autoimmune and inflammatory disorders, e.g. sepsis-related acute lung injury (ALI), acute respiratory distress syndrome (ARDS), arthritis, rheumatoid arthritis (RA), psoriatic arthritis (PsA), inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn’s disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet’s diseases, uveitis, myasthenia gravis, Grave’s disease, Hashimoto thyroiditis, Sjor
  • the compounds of the present invention may be employed in combination with one or more other medicinal agents, more particularly with other anti-cancer agents, e.g. chemotherapeutic, anti-proliferative or immunomodulating agents, or with adjuvants in cancer therapy, e.g. immunosuppressive or anti-inflammatory agents.
  • other anti-cancer agents e.g. chemotherapeutic, anti-proliferative or immunomodulating agents
  • adjuvants in cancer therapy e.g. immunosuppressive or anti-inflammatory agents.
  • Possible combinations of the compounds of the present invention may include, but are not limited to, BTK (Bruton’s tyrosine kinase) inhibitors such as ibrutinib, SYK inhibitors, PKC inhibitors, PI3K pathway inhibitors, BCL family inhibitors, JAK inhibitors, PIM kinase inhibitors, rituximab or other B cell antigen-binding antibodies, as well as immune cell redirection agents (e.g. blinatumomab or CAR T-cells) and immunomodulatory agents such as daratumumab, anti-PDl antibodies, and anti-PD-Ll antibodies.
  • the present invention is directed to a compound of Formula (I) for (use in) the treatment of said disease, syndrome, condition, or disorder affected by the inhibition of MALTE
  • the present invention is directed to a composition comprising a compound of Formula (I) for (use in) the treatment of said disease, syndrome, condition, or disorder affected by inhibition of MALTE
  • the present invention is directed to methods of treating said disease, syndrome, condition, or disorder mediated by MALT1.
  • Another embodiment of the present invention is directed to a pharmaceutical composition comprising a compound of Formula (I) and uses thereof as described in any of the other embodiments.
  • transitional terms “comprising,” “consisting essentially of,” and “consisting of’ are intended to connote their generally accepted meanings in the patent vernacular; that is, (i) “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) “consisting of’ excludes any element, step, or ingredient not specified in the claim; and (iii) “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention.
  • Embodiments described in terms of the phrase “comprising” (or its equivalents) also provide as embodiments those independently described in terms of “consisting of’ and “consisting essentially of.”
  • Ci-4alkyl group contains from 1 to 4 carbon atoms, and so on.
  • Crosswalkyf as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 4 carbon atoms, such as methyl, ethyl, n- propyl, isopropyl, w-butyl. s-butyl, /-butyl and the like.
  • Cs-ecycloalkyl as used herein as a group or part of a group defines a saturated, cyclic hydrocarbon radical having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Fused bicycles or fused bicyclic groups are two cycles that share two atoms and the bond between these atoms.
  • Spiro bicycles or spiro bicyclic groups are two cycles that are joined at a single atom.
  • Bridged bicycles or bridged bicyclic groups are two cycles that share more than two atoms.
  • Ce-iocarbobi cyclic as used herein as a group or part of a group defines a saturated, bicyclic hydrocarbon radical having from 6 to 10 carbon atoms. Ce-iocarbobi cyclic can be fused, spiro or bridged, such as spiro[3.3]heptanyl and bicyclo[l.l.l]pentanyl.
  • the term ‘monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one two or three heteroatoms each independently selected from O, S, and N’ defines a C-linked fully saturated, monocyclic radical having from 4 to 7 ring members in total (including the heteroatoms) containing one, two or three heteroatoms each independently selected from O, S, and N, such as for example C-linked azetidinyl, C-linked oxetanyl, C-linked pyrrolidinyl, C- linked tetrayhydrothiophenyl, C-linked tetrahydrofuranyl, C-linked morpholinyl, C-linked 1,4- oxathianyl, C-linked thiazinanyl, C-linked tetrahydropyranyl, C-linked tetrahydrothiopyranyl, C-linked pyrazolidinyl, C-linked isothiazolidinyl, C-linked oxazolidin
  • Bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl groups can be fused, spiro or bridged.
  • bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected fromO, S, and N defines a C-linked fully saturated, bicyclic radical having from 6 to 11 ring members in total (including the heteroatoms) containing one, two or three heteroatoms each independently selected from O, S, and N, such as for example:
  • the term ‘monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N’ defines aN-linked fully saturated, monocyclic radical having from 4 to 7 ring members in total (including the heteroatoms) containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N, such as for example N-linked azetidinyl, N-linked pyrrolidinyl, N-linked morpholinyl, N-linked thiazinanyl, N-linked pyrazolidinyl, N-linked isothiazolidinyl, N-linked oxazolidinyl, N-linked thiomorpholinyl, N-linked piperazinyl, N- linked thiazolidinyl, N-linked azepanyl, N-linked thiadiazepanyl, and N-linked piperidinyl.
  • Bicyclic N-linked 6- to 11 -membered fully saturated heterocyclyl groups can be fused, spiro or bridged.
  • bicyclic N-linked 6- to 11-membered fully saturated heterocyclyl containing one N- atom and optionally one or two heteroatoms each independently selected from O, S, and N defines a N-linked fully saturated, bicyclic radical having from 6 to 11 ring members in total (including the heteroatoms) containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N, such as for example:
  • cyclic moieties such as fully saturated heterocyclyl goups, can be attached to the remainder of the molecule of Formula (I) through any available ring carbon atom (C -linked) or nitrogen atom (N-linked).
  • C-linked means attached to the remainder of the molecule through any available carbon atom.
  • N-linked means attached to the remainder of the molecule through any available nitrogen atom.
  • halogen or “halo” refers to fluorine, chlorine, bromine and iodine atoms.
  • R 2 is absent when n is 0.
  • each definition is independent.
  • substituted in general, whenever the term ‘substituted’ is used in the present invention, it is meant, unless otherwise indicated or clear from the context, to indicate that one or more hydrogens, in particular from 1 to 4 hydrogens, more in particular from 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using ‘substituted’ are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture (isolation after a reaction e.g. purification by silica gel chromatography).
  • stereodescriptor label “R” or “(R ” at a stereocenter designates that the stereocenter is purely of the ⁇ -configuration as defined in the art; likewise, the stereodescriptor label “S” or “(5)” means that the stereocenter is purely of the A'-con figuration.
  • a compound containing one stereocenter drawn without a stereo bond designation is a mixture of two stereoisomers unless otherwise indicated (for example via a stereodescriptor).
  • a compound containing two stereocenters both drawn without stereo bond designations is a mixture of four diastereomers unless otherwise indicated (for example via stereodescriptors).
  • Unlabeled stereocenters drawn without stereo bond designations are mixtures of the R- and 5- configurations.
  • the absolute stereochemistry is as depicted.
  • stereoisomers of Formula (I) are meant to include the stereoisomers thereof and the tautomeric forms thereof.
  • stereochemistry as mentioned in the previous paragraph, is specified by bonds which are shown as solid wedged or hashed wedged bonds, or are otherwise indicated as having a particular configuration (e.g. R. S). then that stereoisomer is so specified and defined. It will be clear this also applies to subgroups of Formula (I).
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • terapéuticaally effective amount refers to an amount of an active compound or pharmaceutical agent, including a compound of the present invention, which elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, including reduction or inhibition of an enzyme or a protein activity, or ameliorating symptioms, alleviating conditions, slowing or delaying disease progression, or preventing a disease.
  • the term “therapeutically effective amount” refers to the amount of a compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent, and/ or ameliorate a condition, or a disorder or a disease (i) mediated by MALT1; or (ii) associated with MALT1 activity; or (iii) characterized by activity (normal or abnormal) of MALT 1; or (2) reduce or inhibit the activity of MALT 1; or (3) reduce or inhibit the expression of MALT1; or (4) modify the protein levels of MALT1.
  • composition refers to a product that includes the specified ingredients in therapeutically effective amounts, as well as any product that results, directly, or indirectly, from combinations of the specified ingredients in the specified amounts.
  • Suitable examples of a disease, syndrome, condition, or disorder mediated by MALT1 include, but are not limited to, lymphomas, leukemias, carcinomas, and sarcomas, e.g. nonHodgkin’s lymphoma (NHL (including B-cell NHL)), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, Burkit’s lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukemia, chronic myelogenous leukemia (CML), hairy-cell leukemia, acute lymphoblastic T cell leukemia, plasma
  • MALT1 inhibitor refers to an agent that inhibits or reduces at least one condition, symptom, disorder, and/or disease of MALTl.
  • the term “affect” or “affected” when referring to a disease, syndrome, condition or disorder that is affected by the inhibition of MALTl) includes a reduction in the frequency and / or severity of one or more symptoms or manifestations of said disease, syndrome, condition or disorder; and / or includes the prevention of the development of one or more symptoms or manifestations of said disease, syndrome, condition or disorder or the development of the disease, condition, syndrome or disorder.
  • the term “treat”, “treating”, or “treatment” of any disease, condition, syndrome or disorder refers, in one embodiment, to ameliorating the disease, condition, syndrome or disorder (i.e. slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat”, “treating”, or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat”, “treating”, or “treatment” refers to modulating the disease, condition, syndrome or disorder either physically (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both.
  • “treat”, “treating”, or “treatment” refers to preventing or delaying the onset or development or progression of the disease, condition, syndrome or disorder.
  • the compounds of the instant invention may be useful in methods for treating or ameliorating a disease, a syndrome, a condition or a disorder that is affected by the inhibition of MALTl.
  • Such methods comprise, consist of and/or consist essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment, amelioration and / or prevention, a therapeutically effective amount of a compound of Formula (I).
  • One embodiment of the present invention is directed to a method of treating a MALTl - dependent or MALTl -mediated disease or condition in a subject in need thereof, including an animal, a mammal, and a human in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I).
  • the M ALT 1 -dependent or MALT 1 -mediated disease or condition is selected from cancers of hematopoietic origin or solid tumors such as chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin lymphoma, and other B cell lymphomas.
  • the compounds of Formula (I) may be useful for treating or ameliorating diseases, syndromes, conditions, or disorders such as diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma.
  • DLBCL diffuse large B-cell lymphoma
  • MCL mantle cell lymphoma
  • FL follicular lymphoma
  • MALT mucosa-associated lymphoid tissue lymphoma
  • the compounds of Formula (I) may be useful for treating or ameliorating diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) as herein defined.
  • DLBCL diffuse large B-cell lymphoma
  • MCL mantle cell lymphoma
  • FL follicular lymphoma
  • MALT mucosa-associated lymphoid tissue
  • the compounds of Formula (I) may be useful for treating or ameliorating an immunological disease, syndrome, disorder, or condition selected from the group consisting of rheumatoid arthritis (RA), psoritic arthritis (PsA), psorisis (Pso), ulcerative colitis (UC), Crohn’s disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).
  • RA rheumatoid arthritis
  • PsA psoritic arthritis
  • Pso psorisis
  • UC ulcerative colitis
  • Crohn’s disease systemic lupus erythematosus
  • COPD chronic obstructive pulmonary disease
  • the present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • Ar represents thiazolyl or pyridinyl
  • R la represents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents;
  • R lb represents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents;
  • ring represents phenyl; n is 0;
  • R 3a represents hydrogen or Ci-4alkyl
  • R 3b represents hydrogen; Ci-4alkyl; Cs-ecycloalkyl; adamantyl; Ce-iocarbobicyclic; Het 1 ;
  • R 4a and R 4b each independently represent hydrogen, Ci-4alkyl, Cs-ecycloalkyl, or Ci-4alkyl-O- Ci-4alkyl;
  • R 4C and R 4d each independently represent Ci-4alkyl or -O-Ci-4alkyl
  • R 5a and R 5b are each independently selected from the group consisting of hydrogen and Ci-4alkyl
  • R 6 represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH;
  • R 7 represents Ci-4alkyl; pl and p2 are 2; and the pharmaceutically acceptable salts thereof.
  • the present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • Ar represents thiazolyl or pyridinyl
  • R la represents hydrogen or halo
  • R lb represents hydrogen, halo, or Ci-4alkyl; ring represents phenyl; n is 0;
  • R 3a represents hydrogen
  • R 5a and R 5b are hydrogen ;
  • R 6 represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH;
  • R 7 represents Ci-4alkyl; and the pharmaceutically acceptable salts thereof.
  • the present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • Ar represents thiazolyl or pyridinyl
  • R la represents hydrogen or halo
  • R lb represents hydrogen, halo, or Ci-4alkyl; ring represents phenyl; n is 0;
  • R 3a represents hydrogen
  • R 3b represents hydrogen; Ci-4alkyl; Cs-ecycloalkyl; or
  • R 5a and R 5b are hydrogen ;
  • R 6 represents -CH3 or -CH2OH
  • R 7 represents -CH3; and the pharmaceutically acceptable salts thereof.
  • the present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • Ar represents thiazolyl or pyridinyl
  • R la represents hydrogen or F
  • R lb represents hydrogen, F, or methyl; ring represents phenyl; n is 0;
  • R 3a represents hydrogen
  • R 5a and R 5b are hydrogen ;
  • R 6 represents -CH3 or -CH2OH
  • R 7 represents -CH3; and the pharmaceutically acceptable salts thereof.
  • the present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein
  • Ar represents thiazolyl or pyridinyl
  • R la represents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents;
  • R lb represents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents;
  • ring represents phenyl; n is 0;
  • R 3a represents hydrogen or Ci-4alkyl
  • R 3b represents hydrogen; Ci-4alkyl; Cs-ecycloalkyl; adamantyl; Ce-iocarbobicyclic; Het 1 ;
  • Het 1 represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; or Het 1 represents a bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected fromO, S, and N; provided that the monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl and bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl, are selected from the following heterocyclyls:
  • Het 2 represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; or Het 2 represents a bicyclic N-linked 6- to 11-membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; provided that the monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl and bicyclic N-linked 6- to 11 -membered fully saturated heterocyclyl, are selected from the following heterocyclyls:
  • Het 3a represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; provided that the monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl is selected from the following heterocyclyls:
  • Het 3b represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; or Het 3b represents a bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; provided that the monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl and bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl, are selected from the following heterocyclyls:
  • Het 5 represents C-linked oxetanyl
  • R 4a and R 4b each independently represent hydrogen, Ci-4alkyl, Cs-ecycloalkyl, or Ci-4alkyl-O- Ci-4alkyl;
  • R 4C and R 4d each independently represent Ci-4alkyl or -O-Ci-4alkyl
  • R 5a and R 5b are each independently selected from the group consisting of hydrogen and Ci-4alkyl
  • R 6 represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH;
  • R 7 represents Ci-4alkyl; pl and p2 are 2; and the pharmaceutically acceptable salts thereof.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 2 represents fluoro.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein n is 0.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein n is i.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ring represents phenyl.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ring represents phenyl, and n is 0.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ring represents phenyl, and R 6 represents methyl.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ring represents phenyl, n is 0, and R 6 represents methyl.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ring represents phenyl, and R 6 represents -CH2OH.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ring represents phenyl, n is 0, and R 6 represents
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • R 3b represents Ci-4alkyl.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 6 represents CH3.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the stereochemistry of the cyclopropyl moiety in Formula (I) is trans:
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the stereochemistry of the cyclopropyl moiety in Formula (I) is cis: In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the stereochemistry of the cyclopropyl moiety in Formula (I) is trans: trans and wherein R 6 represents methyl.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the stereochemistry of the cyclopropyl moiety in Formula (I) is cis: and wherein R 6 represents methyl.
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the stereochemistry of the substituents on the cyclopropyl moiety in Formula (I) is as indicated below in Formula (I-a):
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the stereochemistry of the substituents on the cyclopropyl moiety in Formula (I) is as indicated below in Formula (I-b):
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Formula (I) and the stereochemistry of the substituents on the cyclopropyl moiety are as indicated below in Formula (I-al ):
  • the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Formula (I) and the stereochemistry of the substituents on the cyclopropyl moiety are as indicated below in Formula (I-bl ):
  • the present invention relates to a subgroup of Formula (I) as defined in the general reaction schemes.
  • the compound of Formula (I) is selected from the group consisting of any of the exemplified compounds, tautomers and stereoisomeric forms thereof, and the free bases, and the pharmaceutically acceptable salts thereof.
  • the compound of Formula (I) is selected from the group consisting of compounds 32, 38, 48, 54, 61, 65, and 74.
  • the compound of Formula (I) is selected from the group consisting of compounds 32, 38, 48, 54, 61, 65, and 74; tautomers and stereoisomeric forms thereof, and the pharmaceutically acceptable salts thereof.
  • the compound of Formula (I) is selected from the group consisting of compounds 32, 38, 48, 54, 61, 65, and 74; and the pharmaceutically acceptable salts thereof.
  • the compound of Formula (I) is selected from the group consisting of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 and 81.
  • the compound of Formula (I) is selected from the group consisting of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 and 81; tautomers and stereoisomeric forms thereof, and the pharmaceutically acceptable salts thereof.
  • the compound of Formula (I) is selected from the group consisting of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 and 81; and the pharmaceutically acceptable salts thereof.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or excipient, wherein the compound of Formula (I) is selected from the group consisting of any of the exemplified compounds.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or excipient, wherein the compound of Formula (I) is selected from the group consisting of any of the exemplified compounds, tautomers and stereoisomeric forms thereof, and the pharmaceutically acceptable salts thereof.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or excipient, wherein the compound of Formula (I) is selected from the group consisting of compounds 32, 38, 48, 54, 61, 65, and 74.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or excipient, wherein the compound of Formula (I) is selected from the group consisting of compounds 32, 38, 48, 54, 61, 65, and 74; tautomers and stereoisomeric forms thereof, and the pharmaceutically acceptable salts thereof.
  • the compound of Formula (I) is compound 32 or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is compound 38 or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is compound 48 or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is compound 54 or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is compound 61 or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is compound 65 or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is compound 74 or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is compound 32.
  • the compound of Formula (I) is compound 38.
  • the compound of Formula (I) is compound 48.
  • the compound of Formula (I) is compound 54.
  • the compound of Formula (I) is compound 61.
  • the compound of Formula (I) is compound 65.
  • the compound of Formula (I) is compound 74.
  • the compound of Formula (I) is a stereoisomeric form thereof, or a pharmaceutically acceptable salt thereof. In particular wherein the stereochemistry of the cyclopropyl moiety is trans.
  • the compound of Formula (I) is or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I) is or a pharmaceutically acceptable salt thereof.
  • salts of compounds of Formula (I) refer to non-toxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the preparation of compounds of Formula (I) or of their pharmaceutically acceptable salt forms thereof.
  • Suitable pharmaceutically acceptable salts of compounds of Formula (I) include acid addition salts that can, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as, hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts such as, sodium or potassium salts; alkaline earth metal salts such as, calcium or magnesium salts; and salts formed with suitable organic ligands such as, quaternary ammonium salts.
  • representative pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, JV-methylglucamine ammonium salt, oleate, pam
  • Embodiments of the present invention include prodrugs of compounds of Formula (I).
  • such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound.
  • the term “administering” encompasses the treatment or prevention of the various diseases, conditions, syndromes and disorders described with the compound specifically disclosed or with a compound that may not be specifically disclosed, but which converts to the specified compound in vivo after administration to a patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
  • compositions of Formula (I) and solvates thereof are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which compounds of Formula (I) and solvates thereof, are able to form.
  • Tautomers are constitutional isomers that readily interconvert. It is understood that all tautomeric forms are encompassed by a structure where one possible tautomeric arrangement of the groups of the compound is described, even if not specifically indicated.
  • the compounds according to embodiments of this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorph and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. The skilled artisan will understand that the term compound as used herein, can also include solvated compounds of Formula (I).
  • the processes for the preparation of the compounds according to certain embodiments of the invention give rise to mixture of stereoisomers
  • these isomers may be separated by conventional techniques such as, preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques such as, the formation of diastereomeric pairs by salt formation with an optically active acid such as, (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chomatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • any one or more element(s), in particular when mentioned in relation to a compound of Formula (I), shall comprise all isotopes and isotopic mixtures of said element(s), either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
  • a reference to hydrogen includes within its scope 1 H, 2 H (D), and 3 H (T).
  • references to carbon and oxygen include within their scope respectively 12 C, 13 C and 14 C and 16 O and 18 O.
  • the isotopes may be radioactive or non-radioactive.
  • Radiolabelled compounds of formula (I) may comprise one or more isotope(s) selected from the group of 3 H, n C, 18 F, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 Br.
  • the isotope is selected from the group of 2 H, 3 H, n C and 18 F.
  • deuterated compounds are intended to be included within the scope of the present invention.
  • any of the processes for preparation of the compounds of the various embodiments of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • compositions comprising compounds of Formula (I) and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, and/or pharmaceutically acceptable diluent.
  • the compounds of Formula (I) may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s), and combinations thereof.
  • Solid oral dosage forms such as, tablets or capsules, containing the compounds of the present invention may be administered in at least one dosage form at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.
  • a therapeutically effective amount of a compound of Formula (I) or a pharmaceutical composition thereof includes a dose range from about 0.1 mg to about 3000 mg, or any particular amount or range therein; although, it is apparent to one skilled in the art that the therapeutically effective amount for a compound of Formula (I) will vary as will the diseases, syndromes, conditions, and disorders being treated.
  • the inhibition of MALT1 by a provided compound may be useful in treating or preventing, in particular treating, the non-limiting list of cancers described herein.
  • the invention relates to compounds of Formula (I) for use as a medicament.
  • the invention relates to compounds of Formula (A) for use as a medicament.
  • the invention relates to compounds of Formula (I) for use in the inhibition of MALT1 activity.
  • the invention relates to compounds of Formula (A) for use in the inhibition of MALT1 activity.
  • the invention relates to compounds of Formula (I) for use in the treatment of diseases mentioned herein.
  • the invention relates to compounds of Formula (A) for use in the treatment of diseases mentioned herein.
  • the invention relates to compounds of Formula (I) for the treatment or prevention, in particular for the treatment, of said diseases.
  • the invention relates to compounds of Formula (A) for the treatment or prevention, in particular for the treatment, of said diseases.
  • the invention relates to compounds of Formula (I) for the treatment or prevention, in particular in the treatment, of MALT1 mediated diseases or conditions.
  • the invention relates to compounds of Formula (A) for the treatment or prevention, in particular in the treatment, of MALT1 mediated diseases or conditions.
  • the invention relates to compounds of Formula (I) for the manufacture of a medicament.
  • the invention relates to compounds of Formula (A) for the manufacture of a medicament.
  • the invention relates to compounds of Formula (I) for the manufacture of a medicament for the inhibition of MALT 1.
  • the invention relates to compounds of Formula (A) for the manufacture of a medicament for the inhibition of MALT1.
  • the invention relates to compounds of Formula (I) for the manufacture of a medicament for the treatment or prevention, in particular for the treatment, of any one of the disease conditions mentioned herein.
  • the invention relates to compounds of Formula (A) for the manufacture of a medicament for the treatment or prevention, in particular for the treatment, of any one of the disease conditions mentioned herein.
  • the invention relates to compounds of Formula (I) for the manufacture of a medicament for the treatment of any one of the disease conditions mentioned herein.
  • the invention relates to compounds of Formula (A) for the manufacture of a medicament for the treatment of any one of the disease conditions mentioned herein.
  • the invention relates to compounds of Formula (I) that can be administered to mammals, preferably humans, for the treatment or prevention of any one of the diseases mentioned herein.
  • the invention relates to compounds of Formula (A) that can be administered to mammals, preferably humans, for the treatment or prevention of any one of the diseases mentioned herein.
  • intermediates or compounds of the present invention may also be prepared by analogous reaction protocols as described in the general schemes below and the specific examples, combined with standard synthetic processes commonly used by those skilled in the art.
  • reaction work-up refers to the series of manipulations required to isolate and purify the product(s) of a chemical reaction such as for example quenching, column chromatography, extraction).
  • microwave heating may be used instead of conventional heating to shorten the overall reaction time.
  • intermediates and final compounds shown in the Schemes below may be further functionalized according to methods well-known by the person skilled in the art.
  • the intermediates and compounds described herein can be isolated in free form or as a salt, or a solvate thereof.
  • the intermediates and compounds described herein may be synthesized in the form of mixtures of tautomers and stereoisomeric forms that can be separated from one another following art-known resolution procedures.
  • Suitable amino-protecting groups include but are not limited to acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyl (Bn), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxy carbonyl (Fmoc).
  • Suitable hydroxy -protecting groups include but are not limited to triisopropylsilyl and acetyl. The need for such protection is readily determined by one skilled in the art.
  • compounds of Formula (I) can be prepared via a coupling between an intermediate of Formula (II) and an intermediate of Formula (III), where X represents a suitable leaving group, such as for instance a halogen, in particular Cl, Br, I.
  • This reaction may be performed in the presence of metal catalysts such as 4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2- pyridinyl)phenyl]iridium(III) hexafluorophosphate and 2,2'-bipyridine)nickel(II) dibromide, in the presence of additives, such as quinuclidine, in a suitable solvent such as DMA, under an inert atmosphere, such as nitrogen or argon atmosphere, under photo-irradiation to afford compounds of Formula (I).
  • metal catalysts such as 4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2- pyridinyl)phenyl]iridium
  • an intermediate of Formula (II) requires pre-activation with a reagent such as 5,7- ditert-butyl-3-phenyl-l,3-benzoxazol-3-ium tetrafluoroborate, in the presence of a base, such as pyridine, in a suitable solvent such as TBME, 1,4-di oxane, CPME or CPME/DMA, under an inert atmosphere, such as nitrogen or argon atmosphere, in a suitable temperature range, such as for instance room temperature.
  • a reagent such as 5,7- ditert-butyl-3-phenyl-l,3-benzoxazol-3-ium tetrafluoroborate
  • a base such as pyridine
  • a suitable solvent such as TBME, 1,4-di oxane, CPME or CPME/DMA
  • an inert atmosphere such as nitrogen or argon atmosphere
  • Step 1 An intermediate of Formula (IV), that usually is commercially available or alternatively prepared according to methods well-known by the person skilled in the art, is reacted with the appropriate aminal ester, such as for instance V.V-dimethy 1 formamide dimethylacetal, at a suitable temperature, such as for instance 100 or 150 °C, to provide an intermediate of Formula (V).
  • the appropriate aminal ester such as for instance V.V-dimethy 1 formamide dimethylacetal
  • Step 2 An intermediate of Formula (V) is reacted with an appropriate commercially available hydrazine (VI), wherein the variables are described as hereabove.
  • hydrazine (VI) can be prepared according to methods well-known by the person skilled in the art.
  • the reaction is carried out in the presence of a suitable acid, such as AcOH, in an appropriate solvent, such as for instance EtOH, and a suitable temperature, such as for instance 65 °C, to provide an intermediate of Formula (VII).
  • a suitable acid as solvent such as AcOH
  • a suitable temperature such as for instance 120 °C
  • Step 3 An intermediate of Formula (VII) is reacted with a suitable oxidant, such as for instance, chromium(VI) oxide in the presence of tert-butyl hydroperoxide solution, at a suitable temperature, such as 0 °C, to provide an intermediate of Formula (VIII).
  • a suitable oxidant such as for instance, potassium permanganate
  • a suitable solvent such as pyridine
  • a suitable temperature such as 95 °C
  • an intermediate of Formula (VII) is reacted with a suitable oxidant, such as for instance, NFSI, in the presence of methylboronic acid and a suitable base, such as lithium carbonate, in the presence of additives such as 4,7- diphenyl-l,10-phenanthroline and copper acetate, in an appropriate solvent, such as for instance chlorobenzene, and at a suitable temperature, such as for instance 45 °C, to provide an intermediate of Formula (VIII).
  • a suitable oxidant such as for instance, NFSI
  • methylboronic acid and a suitable base such as lithium carbonate
  • additives such as 4,7- diphenyl-l,10-phenanthroline and copper acetate
  • an appropriate solvent such as for instance chlorobenzene
  • Step 4 An intermediate of Formula (IX), that is commercially available or alternatively prepared according to methods well-known by the person skilled in the art, is reacted with an intermediate of formula (X), where X represents a suitable leaving group, such as for instance a halogen, in particular Cl, Br, I.
  • X represents a suitable leaving group, such as for instance a halogen, in particular Cl, Br, I.
  • This reaction may be performed in the presence of suitable additives, such as Cui and MAMimethylgl cine. and an appropriate base, such as, for example, K2CO3.
  • This reaction can be performed in an appropriate solvent, such as, for example, acetonitrile or DMSO, at a suitable temperature, such as for instance 120 °C, to provide an intermediate of Formula (VIII).
  • Step 5 An intermediate of Formula (VIII) is reacted with a suitable reductant, such as for instance, sodium borohydride, in an appropriate solvent, such as for instance, MeOH, and a suitable temperature range, such as for instance 0 °C to room temperature, to provide an intermediate of Formula (II).
  • a suitable reductant such as for instance, sodium borohydride
  • Step 1 An intermediate of Formula (XI) is reacted with 4-chlorobenzaldehyde, in the presence of a base, such as for instance NaOH, in a suitable solvent, such as ether, at an appropriate temperature, such as 25 °C, to provide an intermediate of Formula (XII).
  • a base such as for instance NaOH
  • a suitable solvent such as ether
  • Step 2 An intermediate of Formula (XII) is reacted with the appropriate aminal ester, such as for instance A,A-di methyl form ami dedi methyl acetal, at a suitable temperature, such as for instance 100 °C, to provide an intermediate of Formula (XIII).
  • the appropriate aminal ester such as for instance A,A-di methyl form ami dedi methyl acetal
  • Step 3 An intermediate of Formula (XIII) is reacted with an appropriate hydrazine (VI), wherein the variables are described as hereabove, that is commercially available or alternatively prepared according to methods well-known by the person skilled in the art.
  • the reaction is carried out in the presence of a suitable acid, such as AcOH, in an appropriate solvent, such as for instance EtOH, and at a suitable temperature, such as for instance 65 °C, to provide an intermediate of Formula (XIV).
  • a suitable acid as solvent such as AcOH
  • a suitable temperature such as for instance 120 °C
  • Step 4 An intermediate of Formula (XIV) is reacted with a suitable oxidant, such as for instance, sodium periodate, in the presence of a catalyst, such as ruthenium(III) chloride, in an appropriate solvent mixture, such as for instance a mixture of DCM, water, and acetonitrile, at an appropriate temperature, such as for instance room temperature, to provide an intermediate of Formula (XV).
  • a suitable oxidant such as for instance, sodium periodate
  • a catalyst such as ruthenium(III) chloride
  • an appropriate solvent mixture such as for instance a mixture of DCM, water, and acetonitrile
  • Step 5 An intermediate of Formula (XV) is reacted with 1 ,2-ethanedithiol, in the presence of a Lewis acid, such as for instance boron trifluoride etherate complex, in a suitable solvent, such as dichloromethane, at a suitable temperature, such as for instance 25 °C, to provide an intermediate of Formula (XVI).
  • a Lewis acid such as for instance boron trifluoride etherate complex
  • a suitable solvent such as dichloromethane
  • a fluorinating agent such as for instance hydrogen fluoride-pyridine
  • NIS an additive
  • suitable solvent such as for instance dichlorometane
  • Step 1 An intermediate of Formula (XVII) is reacted according to Homer-Wadsworth- Emmon’s reaction conditions, with the appropriate known phosphonate of Formula (XVIII), such as, for instance, triethyl-2-phosphonopropionate or ethyl 2-(diethoxyphosphoryl)-4- methylpentanoate, in the presence of an appropriate base, such as NaH, in a suitable solvent, such THF, at a suitable temperature range, such as for instance 0 °C to 25 °C, to provide an intermediate of Formula (XIX).
  • an appropriate known phosphonate of Formula (XVIII) such as, for instance, triethyl-2-phosphonopropionate or ethyl 2-(diethoxyphosphoryl)-4- methylpentanoate
  • a compound of Formula (XIX), in which R 6 is Ci-4alkyl substituted with -OH could be prepared by a person skilled in the art according to described literature procedures (for instance, Pereire, A.A. et al, Eur. J. Org. Chem. 2017, 12, 1578-1582).
  • R 6 is Ci-4alkyl substituted with -OH
  • the alcohol moiety might be protected with a suitable protecting group, such as triisopropylsilyl, which is kept throughout the synthetic scheme.
  • Step 2 An intermediate of Formula (XIX) is reacted with a suitable reductant, such as for instance, DIBAL-H, in a suitable solvent, such as for instance THF, and at a suitable temperature range, such as for instance 0 °C to 25 °C, to provide an intermediate of Formula (XXa).
  • a suitable reductant such as for instance, DIBAL-H
  • THF a suitable solvent
  • a suitable temperature range such as for instance 0 °C to 25 °C
  • a suitable protecting group such as triisopropylsilyl ether or acetyl
  • Step 3 An intermediate of Formula (XXb) is reacted with a suitable difluorocyclopropanation reagent, such as methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, in the presence of additives such as for instance, potassium iodide and trimethylchlorosilane, in a suitable solvent, such bis(2- methoxyethyl)ether, at a suitable temperature, such as, for instance, 120 °C, to provide an intermediate of Formula (XXIa).
  • a suitable difluorocyclopropanation reagent such as methyl 2,2-difluoro-2-(fluorosulfonyl)acetate
  • additives such as for instance, potassium iodide and trimethylchlorosilane
  • an intermediate of Formula (XXb) is reacted with a suitable difluorocyclopropanation reagent, such as (bromodifluoromethyl)trimethylsilane, in a suitable solvent such as, for instance, toluene, at a suitable temperature, such as, for instance 110 °C, optionally in the presence of a catalyst such as tetrabutylammonium bromide, to provide an intermediate of Formula (XXIa).
  • a suitable difluorocyclopropanation reagent such as (bromodifluoromethyl)trimethylsilane
  • a suitable solvent such as, for instance, toluene
  • a suitable temperature such as, for instance 110 °C
  • a catalyst such as tetrabutylammonium bromide
  • Step 4 An intermediate of Formula (XXIb) is reacted with a suitable oxidant, such as for instance, (diacetoxyiodo)benzene in the presence of a catalyst, such as for instance TEMPO, and a suitable base, such as NaHCOs, in an appropriate solvent, such as for instance a mixture of water and ACN, and a suitable temperature, such as for instance 25 °C, to provide an intermediate of Formula (XXII).
  • a suitable oxidant such as for instance, (diacetoxyiodo)benzene in the presence of a catalyst, such as for instance TEMPO, and a suitable base, such as NaHCOs
  • an appropriate solvent such as for instance a mixture of water and ACN
  • a suitable temperature such as for instance 25 °C
  • Step 5 An intermediate of Formula (XXII) is reacted with an appropriate amine R 3a R 3b NH, wherein the variables are described as hereabove, in the presence of a suitable reagent, such as HATU, and an appropriate base such as for example triethylamine, in a suitable solvent, such as ACN, at a suitable temperature, such as for example room temperature, to provide an intermediate of Formula (III).
  • a suitable reagent such as HATU
  • an appropriate base such as for example triethylamine
  • Step 6 An intermediate of Formula (XIX) is reacted with a suitable difluorocyclopropanation reagent, such as (bromodifluoromethyl)trimethylsilane, in a suitable solvent, such as for instance toluene, at a suitable temperature, such as, for instance 110 °C, optionally in the presence of a catalyst such as tetrabutylammonium bromide, to provide an intermediate of Formula (XXIII).
  • a suitable difluorocyclopropanation reagent such as (bromodifluoromethyl)trimethylsilane
  • a suitable solvent such as for instance toluene
  • a suitable temperature such as, for instance 110 °C
  • a catalyst such as tetrabutylammonium bromide
  • Step 7 An intermediate of Formula (XXIII) is reacted under hydrolysis conditions to provide an intermediate of Formula (XXII).
  • This reaction can be performed in the presence of a suitable base, such as LiOH, in a suitable solvent system, such as water and THF, optionally containing EtOH or MeOH, at a suitable temperature range, such as room temperature, to afford an intermediate of Formula (XXII).
  • a suitable base such as LiOH
  • a suitable solvent system such as water and THF, optionally containing EtOH or MeOH
  • a suitable temperature range such as room temperature
  • a compound of Formula (I) can be prepared via a coupling reaction between an intermediate of Formula (XXIV a) and a commercially available amine of R 3a R 3b NH, as exemplified below in General Scheme 5.
  • an intermediate of Formula (XXIVb) wherein R is an ethyl group can be prepared via a coupling between an intermediate of Formula (II) and an intermediate of Formula (XXIII), where X represents a suitable leaving group, such as for instance a halogen, in particular Cl, Br, I.
  • This reaction may be performed in the presence of metal catalysts such as 4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridinyl)phenyl]iridium(III) hexafluorophosphate and 2,2'-bipyridine)nickel(II) dibromide in the presence of additives, in a suitable solvent such as DMA, under an inert atmosphere, such as nitrogen or argon atmosphere under photoirradiation. .
  • metal catalysts such as 4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridinyl)phenyl]iridium(III) hexafluorophosphate and 2,2'-bipyridine)nickel(II) dibromide
  • additives in a suitable solvent such as DMA, under an inert atmosphere, such as nitrogen or argon atmosphere under photoirradiation.
  • an intermediate of Formula (II) requires pre-activation with a reagent such as 5,7-ditert-butyl-3- phenyl-l,3-benzoxazol-3-ium tetrafluoroborate, in the presence of a base, such as pyridine, in a suitable solvent such as TBME, under an inert atmosphere, such as nitrogen or argon atmosphere, in a suitable temperature range, such as for instance room temperature.
  • a suitable base such as for instance LiOH
  • Step 1 An intermediate of Formula (XXIII) where X represents a suitable leaving group, such as for instance a halogen, in particular Cl, Br, I, is reacted with bis(pinacolato)diboron, in the presence of a catalyst, such as for instance Xphos Pd G4, and in the presence of an additive, such as for instance potassium pivalate, in a suitable solvent, such as 1,4-di oxane, at an appropriate temperature, such as 90 °C, to provide an intermediate of Formula (XXV).
  • a suitable leaving group such as for instance a halogen, in particular Cl, Br, I
  • Step 2 An intermediate of Formula (XXV) is reacted with 2-cyclopentene-l-one, in the presence of a catalyst, such as for instance chloro(1.5-cyclooctadiene)rhodium (I) dimer or [Rh((S)-BINAP)(nbd)]BF4, and a suitable base, such as triethylamine, in a suitable solvent mixture, such as dioxane/water, at a suitable temperature, such as room temperature, to provide an intermediate of Formula (XXVI).
  • a catalyst such as for instance chloro(1.5-cyclooctadiene)rhodium (I) dimer or [Rh((S)-BINAP)(nbd)]BF4
  • a suitable base such as triethylamine
  • Step 3 An intermediate of Formula (XXVI) is reacted with an appropriate aminal ester, such as for instance the Bredereck’s reagent, in an appropriate solvent, such as toluene, at a suitable temperature, such as for instance 50 °C, to provide an intermediate of Formula (XXVII).
  • an appropriate aminal ester such as for instance the Bredereck’s reagent
  • an appropriate solvent such as toluene
  • Step 4 An intermediate of Formula (XXVII) is reacted with an appropriate hydrazine (VI), wherein the variables are described as hereabove, which is commercially available or alternatively prepared according to methods well-known by the person skilled in the art.
  • a suitable base such as for instance, LiOH
  • compounds synthesized using the protocols as indicated may exist as a solvate e.g. hydrate, and/or contain residual solvent or minor impurities.
  • Compounds or intermediates isolated as a salt form may be integer stoichiometric i.e. mono- or di-salts, or of intermediate stoichiometry.
  • a HC1 salt without indication of the number of equivalents of HC1
  • Triisopropylsilyl chloride [13154-24-0] (1.70 mL, 0.9 g/mL, 7.94 mmol) was added to a stirred solution of methyl (2E)-3-(4-bromophenyl)-2-(hydroxymethyl)-2-propenoate [1505472-36-5] (1.79 g, 6.60 mmol), DMAP [1122-58-3] (87.00 mg, 0.71 mmol) and imidazole [288-32-4] (582.60 mg, 8.56 mmol) in dry DCM (35 mL) at room temperature.
  • Dimethylacetamide [127-19-5] (4.5 mL) was added to this vial under an atmosphere of nitrogen.
  • the methyl tert-butyl ether suspension was drawn into a 12 mL syringe under air and the needle was replaced with a syringe filter and a new needle was installed.
  • the methyl tertbutyl ether mixture was injected through the filter into the dimethylacetamide solution and the subsequent reaction mixture was sparged with nitrogen for 15 minutes before being sealed with parafilm.
  • the vial was stirred in a PennOC Integrated Photoreactor for 18 hours while being irradiated under 450 nm LED modules at 100% light intensity with maximum fan speed of 6800 rpm.
  • Compound 77 was prepared by an analogous reaction protocol as Compound 72, starting from Intermediate 71 (56.0 mg, 0.095 mmol) to give Compound 77 (40.0 mg, 97% yield) as a white solid.
  • Compound 78, 79, 80, and 81
  • Compound 77 (40.0 mg, 97% yield) was separated via Prep SFC (Stationary phase: Chiralpak Daicel IC 20 x 250 mm, Mobile phase: CO2, zPrOH + 0.4 zPrNFb) to give Compound 78 (8.5 mg, 21% yield), Compound 79 (8.5 mg, 21% yield), Compound 80 (7.5 mg, 18% yield) and Compound 81 (4.5 mg, 11% yield).
  • HPLC high performance liquid chromatography
  • MS Mass Spectrometer
  • SQL Single Quadrupole Detector
  • MSD Mass Selective Detector
  • RT room temperature
  • BEH bridged ethylsiloxane/silica hybrid
  • DAD Diode Array Detector
  • HSS High Strength silica
  • the SFC measurement was performed using an Analytical Supercritical fluid chromatography (SFC) system composed by a binary pump for delivering carbon dioxide (CO2) and modifier, an autosampler, a column oven, a diode array detector equipped with a high-pressure flow cell standing up to 400 bars. If configured with a Mass Spectrometer (MS) the flow from the column was brought to the (MS). It is within the knowledge of the skilled person to set the tune parameters (e.g., scanning range, dwell time... ) to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software.
  • SFC Analytical Supercritical fluid chromatography
  • Analytical SFC data - Rt means retention time (in minutes)
  • method refers to the method used for (SFC)MS analysis of enantiomerically pure compounds. No. means number.
  • In vitro assays include assays that determine cell morphology, protein expression, and/or the cytotoxicity, enzyme inhibitory activity, and/or the subsequent functional consequences of treatment of cells with compounds of the invention. Alternate or additional in vitro assays may be used to quantitate the ability of the inhibitor to bind to protein or nucleic acid molecules within the cell.
  • Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/target molecule complex and determining the amount of radiolabel bound.
  • inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with purified proteins or nucleic acids bound to known radioligands.
  • Detailed conditions of exemplary systems for assaying a compound of Formula (I) of the present invention as MALT1 inhibitors are set forth in the Biological Examples below.
  • MALT1 protease activity was assessed in an in vitro assay using a tetrapeptide as substrate and full-length MALT1 protein (Strep-MALTl(l-824)-His) purified from baculovirus-infected insect cells.
  • the tetrapeptide LRSR is coupled to AMC (7-amino-4-methylcoumarin) and provides a quenched, fluorescent substrate for the MALT1 protease (SM Biochemicals). Cleavage of AMC from the Arginine residue results in an increase in coumarin fluorescence measured at 460 nm (excitation 355 nm).
  • the final assay buffer consisted of 10 nM FL MALT1 protein, 200 pM Ac-LRSR-AMC, 50 mM Tris pH 7.5, 0.6 M Citrate, 1 mM dithiothreitol (DTT), 1 mM ethylenediaminetetraacetic acid (EDTA), 0.05% bovine serum albumin (BSA) and 1.5% dimethyl sulfoxide (DMSO).
  • Test compounds were spotted at 50 nL in 100% DMSO per well of a black 384-Proxiplate (Perkin Elmer). Test compound concentrations ranged from 30 pM to 0.5 nM using 11 dilution steps (1:3). Background signal was measured from control wells containing assay buffer without enzyme which functions as low control (LC).
  • High control (HC) values were generated using the reaction with enzyme but no compound treatment.
  • Compounds were pre-incubated with MALT1 enzyme for 50 minutes at RT. Substrate was added subsequently, and fluorescence was measured in Labsystems fluoroskan at excitation 355 nm and emission 460 nmto determine time 0. The reaction was subsequently incubated for 4 h at RT and fluorescence was measured. For ICso calculations, timepoint 0 was subtracted from the 4 h timepoint to correct for any potential autofluorescence of the compounds. The enzyme reaction was linear during the 4 h incubation period. Characterization of the substrate Ac-LRSR-AMC determined the Michaelis constant KM at 200 pM.
  • %Controlmin ((sample-LC) / (HC-LC)) x 100
  • ICso value inhibitor concentration causing 50 % inhibition
  • MALT1 GloSensorTM is a split luciferase reporter, which utilizes a genetically modified form of firefly luciferase (CP UltraGio) split into 2 distinct domains by insertion of a RelB MALT1 cleavage site sequence PRLVSRGA. MALTl-induced cleavage allows for a conformational change that reestablishes a functional luciferase protein resulting in luminescence, and hence luciferase activity would be a surrogate of endogenous MALT1 protease activity.
  • Jurkat MALT1 GloSensorTM were generated by electroporation and selected and maintained in the presence of 0.5 mg/mL Geneticin.
  • MALT1 protease is basally inactive in Jurkat cells and can be activated by treatment with PMA/Ionomycin. Small molecule MALT1 inhibitors added prior to PMA/Ionomycin addition prevent MALT1 protease activation and, therefore, the cleavage of the MALT1 GloSensor split luciferase reporter in a dose-dependent manner.
  • Jurkat MALT1 GloSensorTM cells were maintained in complete RPMI 1640 media containing 10% fetal bovine serum, lOmM 4-(2-hydroxyethyl)-l -piperazineethanesulfonic acid (HEPES), 100 units/mL of penicillin, 100 pg/mL of streptomycin and 0.5 mg/mL Geneticin. Prior to the assay, compounds were made 2.5-fold serial dilutions in DMSO. 100 nL of of test compounds were spotted per well of 384-well plates (Perkin Elmer, catalogue number 6007688).
  • Jurkat cells were harvested by centrifuge at 1200 RPM for 5 min and suspended in fresh complete RPMI 1640 media with 2% GloSensorTM cAMP Reagent and preincubated for 45-60 minutes at 37 °C in a 5% CO2 incubator.
  • a volume of 50 uL of preincubated Jurkat MALT1 GloSensorTM cells (1 x 10 5 cells) were seeded in each well of 384-well plate.
  • a volume 2 pL of diluted PMA / lonomycin (2.5 mg/mL / 25 pM respectively, Sigma, catalogue number P1585 and 407953) in DMSO were added to each well.
  • luminescence was measured on the Envision (Perkin Elmer) at 37 °C.
  • OCI-Ly3 cells were propagated in RPMI-1640 (Sigma Aldrich) supplemented with 10% fetal bovine serum (Hy Clone), 2 mM L-glutamine (Sigma Aldrich) and 1% PenStrep (Sigma Aldrich). Cell passage number should not exceed 30. Cells should be kept between 0.5 - 1.5 million cells per mL during culturing.
  • OCI-Ly3 cells were propagated in RPMI-1640 with Glutamax (ThermoFisher) supplemented with 10% heat inactivated fetal bovine serum (ThermoFisher). Cells should be kept between 0.2 - 1.5 million cells per mL and passed every 3-4 days during culturing.
  • OCI- Ly7 cells were propagated in IMDM (ThermoFisher) supplemented with 10% fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich) and 50 pg/mL Gentamycin. Cells should be kept between 0.15 - 3 million cells per mL and passed every 3-4 days during culturing. Cell passage numbers should not exceed 20.
  • test compounds 450 nL of test compounds were spotted per well of in U-bottom 96-well plates (Coming®, #3975).
  • 500 OCI-Ly3 or OCI-Ly7 cells were seeded in 150 pL media per well and incubated for 8 days at 37 °C and 5% CO2.
  • Cell plating numbers were chosen based on growth curves to ensure linear cell growth.
  • 100 pL of the plated cells were resuspended up and down by pipette and transferred to a flat bottom black plate (Coming®, #3904).
  • 50 pL CellTiterGLO reagent Promega

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Abstract

L'invention concerne des composés, des compositions et des méthodes de traitement de maladies, de syndromes, d'états et de troubles qui sont modifiés par l'inhibition de MALT1.
PCT/EP2025/067856 2024-06-26 2025-06-25 Inhibiteurs de malt1 Pending WO2026003049A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016174079A1 (fr) * 2015-04-28 2016-11-03 Janssen Sciences Ireland Uc Composés de pyrazolo- et triazolo-pyrimidine antiviraux du virus respiratoire syncytial (vrs)
WO2018210729A1 (fr) * 2017-05-18 2018-11-22 Bayer Pharma Aktiengesellschaft Dérivés de sulfonamide aromatiques utilisés en tant qu'antagonistes ou modulateurs allostériques négatifs du récepteur p2x4
WO2022106857A1 (fr) * 2020-11-23 2022-05-27 Exscientia Limited Modulateurs de malt-1

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016174079A1 (fr) * 2015-04-28 2016-11-03 Janssen Sciences Ireland Uc Composés de pyrazolo- et triazolo-pyrimidine antiviraux du virus respiratoire syncytial (vrs)
WO2018210729A1 (fr) * 2017-05-18 2018-11-22 Bayer Pharma Aktiengesellschaft Dérivés de sulfonamide aromatiques utilisés en tant qu'antagonistes ou modulateurs allostériques négatifs du récepteur p2x4
WO2022106857A1 (fr) * 2020-11-23 2022-05-27 Exscientia Limited Modulateurs de malt-1

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Design of Prodrugs", 1985, ELSEVIER
PEREIRE, A.A. ET AL., EUR. J. ORG. CHEM., vol. 12, 2017, pages 1578 - 1582

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