Malt1 inhibitors

Abstract

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

Description

[0001] MALT1 INHIBITORS

[0002] FIELD OF THE INVENTION

[0003] 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.

[0004] BACKGROUND OF THE INVENTION

[0005] 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. The ultimate endpoint of MALT1 activity is the nuclear translocation of the NFKB transcription factor complex and activation of NFKB signaling.

[0006] Constitutive activation of NFKB 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. NFKB pathway activation is driven by mutations of signaling components, such as CD79A / B, CARD11, MYD88 or A20, in ABC-DLBCL patients.

[0007] The use of BTK inhibitors, for example 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.

[0008] 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.

[0009] 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. Furthermore, 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.

[0010] 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 Bl 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.

[0011] Thus, MALT1 inhibitors of the present invention may provide a therapeutic benefit to patients suffering from cancer and / or immunological diseases.

[0012] SUMMARY OF THE INVENTION

[0013] The present invention is directed to compounds of Formula (I) and the tautomers and the stereoisomeric forms thereof, wherein

[0014] Ar represents phenyl, thiazolyl, 1,2,4-thiadiazolyl, isothiazolyl, oxazolyl, pyrazolyl, pyridinonyl or pyridinyl;

[0015] Raand Rbare each independently selected from the group consisting of hydrogen; halo;

[0016] Ci-4alkyl; -C(=O)-NR5aR5b; -O-Ci-4alkyl; -CN; -NR7aR8a; -C(=O)-O-R9; C3-6cycloalkyl;

[0017] -O-Ci-4alkyl substituted with 1, 2 or 3 halo substituents; or

[0018] Ci-4alkyl substituted with 1, 2 or 3 halo substituents;

[0019] Rlarepresents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents;

[0020] Rlbrepresents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents; or Rlaand Rlbare taken together to form together with the carbon atom to which they are attached a Cs-ecycloalkyl; ring represents phenyl or pyridyl;

[0021] R2represents halo; n is 0, 1 or 2;

[0022] R3arepresents hydrogen or Ci-4alkyl;

[0023] R3brepresents hydrogen; Ci-4alkyl; Cs-ecycloalkyl; adamantyl; Ce-iocarbobicyclic; Het1; Cs-ecycloalkyl substituted with one, two, three or four substituents each independently selected from the group consisting of oxo, halo, cyano, -OH, -OR7, -S(=O)2-R7, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(Ci-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-Ci-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-Ci-4alkyl-O-R7, -NH-S(=O)2-R7, Het3a, Het3b, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-Ci-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, and -S(=O)2-Ci-4alkyl;

[0024] Ce-iocarbobi cyclic substituted with one, two, three or four substituents each independently selected from the group consisting of oxo, halo, cyano, -OH, -OR7, -S(=O)2-R7, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(Ci-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-Ci-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-Ci-4alkyl-O-R7, -NH-S(=O)2-R7, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-Ci-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, and -S(=O)2-Ci-4alkyl; or

[0025] Ci-4alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of cyano, halo, -OH, -OR7, -S(=O)2-R7, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(Ci-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-Ci-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-Ci-4alkyl-O-R7, -NH-S(=O)2-R7, -CF3, Cy1, Het3a, Het3b, -O-Het3b, -C(=O)-Het3a, -C(=O)-Het3b, and or R3aand R3bare taken together to form together with the nitrogen atom to which they are attached Het2;

[0026] Cy1represents Cs-ecycloalkyl; or Cs-ecycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -OR7, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-Ci-4alkyl, -N=S(=O)-(Ci-4alkyl)2, -NH-(C=O)-Ci-4alkyl, -NH-(C=O)-C3-6cycloalkyl, -C(=O)-NR4aR4b, and -NH-S(=O)2-R7;

[0027] Het1represents 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 Het1represents a bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected fromO, S, and N; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, halo, cyano, -OH, -OR7-S(=O)2-R7, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(Ci-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-Ci-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-Ci-4alkyl-O-R7, -NH-S(=O)2-R7, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-Ci-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, and -S(=O)2-Ci-4alkyl; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, Het5, -C(=O)-NR4aR4b, -C(=O)-Ci-4alkyl, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, -C(=O)-C3-6cycloalkyl, or Ci-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH and halo;

[0028] Het2represents 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 Het2represents 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; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, halo, cyano, -OH, -OR7, Het6, -S(=O)2-R7, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(Ci-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-Ci-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-Ci-4alkyl-O-R7, -NH-S(=O)2-R7, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-Ci-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, Het4and -S(=O)2-Ci-4alkyl; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, -C(=O)-NR4aR4b, -C(=O)-Ci-4alkyl, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, Het4, or -C(=O)-C3-6cycloalkyl;

[0029] Het3arepresents 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 Het3arepresents 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; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, halo, -OH, -OR7, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-Ci-4alkyl, -N=S(=O)-(Ci-4alkyl)2, -NH-(C=O)-Ci-4alkyl, -NH-(C=O)-C3-6cycloalkyl, -C(=O)-NR4aR4b, and -NH-S(=O)2-R7; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, Het5, -C(=O)-NR4aR4b, -C(=O)-Ci-4alkyl, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, -C(=O)-C3-6cycloalkyl, or Ci-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH and halo;

[0030] Het3brepresents 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 Het3brepresents 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; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, halo, -OH, Ci-4alkyl, -OR7, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-Ci-4alkyl, -N=S(=O)-(Ci-4alkyl)2, -NH-(C=O)-Ci-4alkyl, -NH-(C=O)-C3-6cycloalkyl, -C(=O)-NR4aR4b, and -NH-S(=O)2-R7; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, Het5, -C(=O)-NR4aR4b, -C(=O)-Ci-4alkyl, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, -C(=O)-C3-6cycloalkyl, or Ci-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH and halo;

[0031] Het4represents 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; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH);

[0032] Het5represents 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; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH);

[0033] Het6represents 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; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH);

[0034] R4aand R4beach independently represent hydrogen, Ci-4alkyl, Cs-ecycloalkyl, or Ci-4alkyl-O-Ci-4alkyl;

[0035] R4Cand R4deach independently represent Ci-4alkyl or -O-Ci-4alkyl;

[0036] R5a, R5b, R7a, R8a, and R9are each independently selected from the group consisting of hydrogen and Ci-4alkyl; R6represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH;

[0037] R7represents Ci-4alkyl or Cs-ecycloalkyl, each optionally substituted with one, two or three halo substituents; pl and p2 each independently are 1, 2 or 3; and the pharmaceutically acceptable salts thereof.

[0038] The present invention is also directed to active compounds of Formula (A) and the tautomers and the stereoisomeric forms thereof, wherein

[0039] Ar represents phenyl, thiazolyl, 1,2,4-thiadiazolyl, isothiazolyl, oxazolyl, pyrazolyl, pyridinonyl or pyridinyl;

[0040] Raand Rbare each independently selected from the group consisting of hydrogen; halo;

[0041] Ci-4alkyl; -C(=O)-NR5aR5b; -O-Ci-4alkyl; -CN; -NR7aR8a; -C(=O)-O-R9; C3-6cycloalkyl;

[0042] -O-Ci-4alkyl substituted with 1, 2 or 3 halo substituents; or

[0043] Ci-4alkyl substituted with 1, 2 or 3 halo substituents;

[0044] Rlarepresents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents;

[0045] Rlbrepresents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents; or Rlaand Rlbare taken together to form together with the carbon atom to which they are attached a Cs-ecycloalkyl; ring represents phenyl or pyridyl;

[0046] R2represents halo; n is 0, 1 or 2; R5a, R5b, R7a, R8a, and R9are each independently selected from the group consisting of hydrogen and Ci-4alkyl;

[0047] R6represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH; and the pharmaceutically acceptable salts thereof.

[0048] All references to “compound(s) of Formula (I)” and “compound(s) of Formula (A)”, in the context of this invention, might also refer to a solvate or a pharmaceutically acceptable salt form thereof, even if not explicitly referred to, and are included in the scope of the present invention. It will be clear this also applies to subgroups of Formula (I) and Formula (A).

[0049] 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.

[0050] As used herein, bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, hashed or bold bonds, or otherwise indicated as having a particular configuration (e.g. by a stereodescriptor such as / . 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. Where 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.

[0051] Hereinbefore and hereinafter, 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. However, where 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).

[0052] In the context of this invention it should be understood that bonds shown as solid lines but indicated with a stereodescriptor, mean that such a stereocenter is specified and defined according to the stereodescriptor.

[0053] In the context of this invention it should be understood that 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 ’).

[0054] Substituents on bivalent cyclic saturated (for example a cyclopropyl moiety) or partially saturated radicals may have either the cis- or trans-configuration. Terms like ‘trans A’ or ‘trans B’ mean that one particular trans form was obtained but that the absolute stereochemistry was undetermined.

[0055] It will be clear for a skilled person that a hashed bond and a bold bond on a 1,3- disubstituted cyclobutyl moiety as shown below: , whereby X1and X2represent substituents, indicate that the substituents on the cyclobutyl moiety have trans-configuration.

[0056] It will be clear for a skilled person that the bold bonds on a 1,3-disubstituted cyclobutyl moiety as shown below: . ?

[0057] , whereby X and X represent substituents, indicate that the substituents on the cyclobutyl moiety have cis-configuration.

[0058] It will be clear for a skilled person that a hashed bond and a bold bond on a 1,4- disubstituted cyclohexyl moiety as shown below: , whereby X1and X represent substituents, indicate that the substituents on the cyclohexyl moiety have trans-configuration.

[0059] It will be clear for a skilled person that the bold bonds on a 1,4-disubstituted cyclohexyl moiety as shown below: , whereby X1and X2represent substituents, indicate that the substituents on the cyclohexyl moiety have cis-configuration.

[0060] Atropisomers (or atropoisomers) 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.

[0061] If a compound contains a double bond, the substituents may be in the E or the Z configuration.

[0062] Therefore, the invention and the term “compound(s) of Formula (I)” is also meant to include enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible. It will be clear this also applies to compounds of Formula (A).

[0063] The meaning of all those terms, i.e. enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person. The configuration is specified in line with standard priority rules according to the Cahn-Ingold-Prelog system.

[0064] The term “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.

[0065] The present invention also provides 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).

[0066] Also provided are processes for making 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).

[0067] 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).

[0068] 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.

[0069] 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.

[0070] Exemplifying the invention are methods of treating a disease, syndrome, condition, or disorder mediated by MALT1, using a compound of Formula (I). In particular 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)), 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, 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, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing’s sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, esophageal cancer, salivary gland cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, and GIST (gastrointestinal stromal tumor), comprising, consisting of, and / or consisting essentially of, administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described in the present invention.

[0071] In another embodiment, 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.

[0072] 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-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis.

[0073] In another embodiment, 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).

[0074] In an alternate embodiment, 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.

[0075] In yet another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is lymphoma.

[0076] In another embodiment of the invention, 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).

[0077] In another embodiment of the invention, 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).

[0078] In another embodiment of the invention, 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).

[0079] In an additional embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is chronic lymphocytic leukemia (CLL). In another embodiment, the disorder or condition small lymphocytic lymphoma (SLL).

[0080] In another embodiment of the invention, the lymphoma is MALT lymphoma.

[0081] In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is Waldenstrom macroglobulinemia (WM).

[0082] In yet another embodiment, 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. In an alternate embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is non-Hodgkin’s lymphoma (NHL). In a further embodiment, the nonHodgkin’s lymphoma (NHL) is B-cell NHL. In another embodiment, the non-Hodgkin’s lymphoma (NHL) is relapsed / refractory B-cell NHL.

[0083] In another embodiment of the invention, 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.

[0084] In another embodiment of the invention, 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).

[0085] In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed / refractory Waldenstrom macroglobulinemia (WM).

[0086] In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed / refractory mantle cell lymphoma (MCL).

[0087] In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed / refractory follicular lymphoma (FL).

[0088] In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed / refractory mucosa-associated lymphoid tissue (MALT) lymphoma.

[0089] 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, Sjorgen’s syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis.

[0090] In another embodiment of the present invention, 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.

[0091] 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.

[0092] It will be appreciated that variations to the foregoing embodiments of the invention can be made while still falling within the scope of the invention. Each feature disclosed in this specification, unless stated otherwise, may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

[0093] All possible combinations of the above-indicated embodiments are considered to be embraced within the scope of this invention.

[0094] In another embodiment, 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

[0095] In another embodiment, 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

[0096] In another embodiment, the present invention is directed to methods of treating said disease, syndrome, condition, or disorder mediated by MALT1.

[0097] 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. DETAILED DESCRIPTION OF THE INVENTION

[0098] With reference to substituents, the term “independently” refers to the situation where several substituents are selected independently from each other and may be the same or different from each other.

[0099] The term “about” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. Unless explicitly stated otherwise within the Examples or elsewhere in the Specification in the context of a particular assay, result or embodiment, “about” means within one standard deviation per the practice in the art, or a range of up to 5%, whichever is larger.

[0100] The 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.”

[0101] The prefix ‘Cx-y’ (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, a Ci-4alkyl group contains from 1 to 4 carbon atoms, and so on.

[0102] The term ‘Cwalkyf 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.

[0103] The term ‘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.

[0104] Fused bicycles or fused bicyclic groups, are two cycles that share two atoms and the bond between these atoms.

[0105] Spiro bicycles or spiro bicyclic groups, are two cycles that are joined at a single atom.

[0106] Bridged bicycles or bridged bicyclic groups, are two cycles that share more than two atoms.

[0107] The term ‘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.

[0108] 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 oxazolidinyl, and C-linked piperidinyl.

[0109] Bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl groups can be fused, spiro or bridged.

[0110] The term ‘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:

[0111] 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.

[0112] Bicyclic N-linked 6- to 11 -membered fully saturated heterocyclyl groups can be fused, spiro or bridged.

[0113] The term ‘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:

[0114] Unless otherwise specified or clear from the context, 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).

[0115] C-linked means attached to the remainder of the molecule through any available carbon atom.

[0116] N-linked means attached to the remainder of the molecule through any available nitrogen atom. The term “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine atoms.

[0117] A skilled person will understand R2is absent when n is 0.

[0118] It will be clear for the skilled person that S(=O)2 or SO2 represents a sulfonyl moiety.

[0119] It will be clear for the skilled person that a group such as -S(=O)(=NH)-Ci-4alkyl represents

[0120] In general, it will be clear for the skilled person that a group such as -S(=O)(=NH)-R (with R being any substituent) represents

[0121] It will be clear for the skilled person that a group such as -N=S(=O)-(Ci-4alkyl)2 represents

[0122] It will be clear for the skilled person that a group such as -NH-(C=O)-Ci-4alkyl represents

[0123] It will be clear for the skilled person that a group such as -NH-(C=O)-C3-6cycloalkyl represents illed person that a group such as -NH-(SO2)-Ci-4alkyl represents

[0124] In general, it will be clear for the skilled person that a group such as -NH-(SO2)-R (with R being any substituent) represents

[0125] Whenever substituents are represented by chemical structure, ” represents the bond of attachment to the remainder of the molecule of Formula (I) or Formula (A).

[0126] When any variable occurs more than one time in any constituent, each definition is independent.

[0127] When any variable occurs more than one time in any formula (e.g. Formula (I)), each definition is independent.

[0128] The skilled person will understand that 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).

[0129] The skilled person will understand that the term ‘optionally substituted’ means that the atom or radical indicated in the expression using ‘optionally substituted’ may or may not be substituted (this means substituted or unsubstituted respectively).

[0130] Lines drawn from substituents into ring systems indicate that the bond may be attached to any of the suitable ring atoms.

[0131] The 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.

[0132] 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).

[0133] Unlabeled stereocenters drawn without stereo bond designations are mixtures of the R- and 5- configurations. For unlabeled stereocenters drawn with stereo bond designations, the absolute stereochemistry is as depicted.

[0134] Hereinbefore and hereinafter, the term “compound(s) of Formula (I)” is meant to include the stereoisomers thereof and the tautomeric forms thereof. However, where 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).

[0135] Unless otherwise noted, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable enough to isolate and that can be synthesized by methods set forth herein in combination with techniques known in the art.

[0136] The term “subject” refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

[0137] The term “therapeutically 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.

[0138] In one embodiment, 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.

[0139] The term “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.

[0140] 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, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocyte leukemia, promyelocytic leukemia, erytholeukemia, brain (gliomas), glioblastomas, breast cancer, colorectal / colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing’s sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, esophageal cancer, salivary gland cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, and GIST (gastrointestinal stromal tumor).

[0141] As used herein, the term "MALT1 inhibitor" refers to an agent that inhibits or reduces at least one condition, symptom, disorder, and / or disease of MALTl.

[0142] As used herein, unless otherwise noted, 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.

[0143] As used herein, 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). In another embodiment, “treat”, “treating”, or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In a further embodiment, “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. In yet another embodiment, “treat”, “treating”, or “treatment” refers to preventing or delaying the onset or development or progression of the disease, condition, syndrome or disorder.

[0144] 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).

[0145] 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). In another embodiment, 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.

[0146] In particular, 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.

[0147] More particularly, 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.

[0148] Further, 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).

[0149] Whenever possible, any embodiment for the compounds of Formula (I) as listed hereinabove or hereinafter, also holds for the compounds of Formula (A).

[0150] The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein

[0151] Ar represents thiazolyl or pyridinyl;

[0152] Raand Rbare each independently selected from the group consisting of hydrogen or -C(=O)-NR5aR5b;

[0153] Rlarepresents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents;

[0154] Rlbrepresents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents; ring represents phenyl; n is 0;

[0155] R3arepresents hydrogen or Ci-4alkyl;

[0156] R3brepresents hydrogen; Ci-4alkyl; Cs-ecycloalkyl; adamantyl; Ce-iocarbobicyclic; Het1;

[0157] C3-6cycloalkyl substituted with one, two, three or four substituents each independently selected from the group consisting of oxo, -OH, -OR7, -S(=O)2-R7, -S(=O)2-NR4aR4b, - NR4aR4b, -S(=O)(=NH)-R7, -NH-(C=O)-R7, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, - NH-S(=O)2-R7, Het3a, Het3b, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, - S(=O)(=NH)-Ci-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, and -S(=O)2-Ci-4alkyl;

[0158] Ce-iocarbobi cyclic substituted with one, two, three or four substituents each independently selected from the group consisting of -OR7, -S(=O)2-R7, and -S(=O)2-NR4aR4b; or

[0159] Ci-4alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of cyano, halo, -OH, -OR7, -S(=O)2-R7, -S(=O)2-NR4aR4b, - NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(Ci-4alkyl)2, -C(=O)-NR4aR4b, -P(=O)-R4cR4d, -O- Ci-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-Ci-4alkyl-O-R7, -NH-S(=O)2-R7, - Cy1, Het3a, Het3b, -O-Het3b, -C(=O)-Het3a, and or R3aand R3bare taken together to form together with the nitrogen atom to which they are attached Het2;

[0160] Cy1represents Cs-ecycloalkyl; or Cs-ecycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of -S(=O)2-Ci-4alkyl, and -S(=O)2- NR4aR4b;

[0161] Het1represents 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 Het1represents a bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected fromO, S, and N; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, -OH, -OR7-S(=O)2-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, - P(=O)-R4cR4d, -O-Ci-4alkyl-C(=O)-NR4aR4b, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, and -C(=O)-NR4aR4b; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, Het5, -C(=O)-Ci-4alkyl, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, -C(=O)-C3-6cycloalkyl, or Ci- 4alkyl substituted with one, two or three -OH;

[0162] Het2represents 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 Het2represents 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; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of Het6, -S(=O)2-NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(Ci-4alkyl)2, -C(=O)- NR4aR4b, and Ci-4alkyl optionally substituted with one, two or three -S(=O)2-Ci-4alkyl; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Het4;

[0163] Het3arepresents 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 Het3arepresents 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; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, and -OH; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, Het5, -C(=O)-Ci-4alkyl, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, or -C(=O)-C3-6cycloalkyl;

[0164] Het3brepresents 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 Het3brepresents 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; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, halo, -OH, Ci-4alkyl, and -OR7; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, Het5, or -S(=O)2-Ci-4alkyl;

[0165] Het4represents 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; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH);

[0166] Het5represents 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; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH);

[0167] Het6represents 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; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH);

[0168] R4aand R4beach independently represent hydrogen, Ci-4alkyl, Cs-ecycloalkyl, or Ci-4alkyl-O- Ci-4alkyl;

[0169] R4Cand R4deach independently represent Ci-4alkyl or -O-Ci-4alkyl;

[0170] R5aand R5bare each independently selected from the group consisting of hydrogen and Ci-4alkyl;

[0171] R6represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH;

[0172] R7represents Ci-4alkyl; pl and p2 are 2; and the pharmaceutically acceptable salts thereof.

[0173] The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein

[0174] Ar represents thiazolyl or pyridinyl; Raand Rbare each independently selected from the group consisting of hydrogen or -C(=O)-NR5aR5b;

[0175] Rlarepresents hydrogen or halo;

[0176] Rlbrepresents hydrogen, halo, or Ci-4alkyl; ring represents phenyl; n is 0;

[0177] R3arepresents hydrogen;

[0178] R3brepresents hydrogen; Ci-4alkyl; Cs-ecycloalkyl; or C3-6cycloalkyl substituted with one -S(=O)2-R7;

[0179] R5aand R5bare hydrogen ;

[0180] R6represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH;

[0181] R7represents Ci-4alkyl; and the pharmaceutically acceptable salts thereof.

[0182] The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein

[0183] Ar represents thiazolyl or pyridinyl;

[0184] Raand Rbare each independently selected from the group consisting of hydrogen or -C(=O)-NR5aR5b;

[0185] Rlarepresents hydrogen or halo;

[0186] Rlbrepresents hydrogen, halo, or Ci-4alkyl; ring represents phenyl; n is 0;

[0187] R3arepresents hydrogen;

[0188] R3brepresents hydrogen; Ci-4alkyl; Cs-ecycloalkyl; or

[0189] C3-6cycloalkyl substituted with one -S(=O)2-R7;

[0190] R5aand R5bare hydrogen ;

[0191] R6represents -CH3 or -CH2OH;

[0192] R7represents -CH3; and the pharmaceutically acceptable salts thereof.

[0193] The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein

[0194] Ar represents thiazolyl or pyridinyl;

[0195] Raand Rbare each independently selected from the group consisting of hydrogen or -C(=O)-NR5aR5b;

[0196] Rlarepresents hydrogen or F;

[0197] Rlbrepresents hydrogen, F, or methyl; ring represents phenyl; n is 0;

[0198] R3arepresents hydrogen;

[0199] R3brepresents hydrogen; Ci-4alkyl; cyclobutyl; or cyclobutyl substituted with one -S(=O)2-R7;

[0200] R5aand R5bare hydrogen ;

[0201] R6represents -CH3 or -CH2OH;

[0202] R7represents -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

[0203] Ar represents thiazolyl or pyridinyl;

[0204] Raand Rbare each independently selected from the group consisting of hydrogen or -C(=O)-NR5aR5b;

[0205] Rlarepresents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents;

[0206] Rlbrepresents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents; ring represents phenyl; n is 0;

[0207] R3arepresents hydrogen or Ci-4alkyl;

[0208] R3brepresents hydrogen; Ci-4alkyl; Cs-ecycloalkyl; adamantyl; Ce-iocarbobicyclic; Het1;

[0209] Cs-ecycloalkyl substituted with one, two, three or four substituents each independently selected from the group consisting of oxo, -OH, -OR7, -S(=O)2-R7, -S(=O)2-NR4aR4b, - NR4aR4b, -S(=O)(=NH)-R7, -NH-(C=O)-R7, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, - NH-S(=O)2-R7, Het3a, Het3b, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, - S(=O)(=NH)-Ci-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, and -S(=O)2-Ci-4alkyl;

[0210] Ce-iocarbobi cyclic substituted with one, two, three or four substituents each independently selected from the group consisting of -OR7, -S(=O)2-R7, and -S(=O)2-NR4aR4b; or

[0211] Ci-4alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of cyano, halo, -OH, -OR7, -S(=O)2-R7, -S(=O)2-NR4aR4b, -

[0212] NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(Ci-4alkyl)2, -C(=O)-NR4aR4b, -P(=O)-R4cR4d, -O- Ci-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-Ci-4alkyl-O-R7, -NH-S(=O)2-R7, - Cy Het3a, Het3b, -O-Het3b, -C(=O)-Het3a, and or R3aand R3bare taken together to form together with the nitrogen atom to which they are attached Het2;

[0213] Cy1represents Cs-ecycloalkyl; or Cs-ecycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of -S(=O)2-Ci-4alkyl, and -S(=O)2- NR4aR4b;

[0214] Het1represents 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 Het1represents 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:

[0215] 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 oxazolidinyl, C-linked piperidinyl, wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, -OH, -OR7-S(=O)2-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, - P(=O)-R4cR4d, -O-Ci-4alkyl-C(=O)-NR4aR4b, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, and -C(=O)-NR4aR4b; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, Het5, -C(=O)-Ci-4alkyl, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, -C(=O)-C3-6cycloalkyl, or Ci- 4alkyl substituted with one, two or three -OH;

[0216] Het2represents 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 Het2represents 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:

[0217] 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, N-linked piperidinyl, wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of -S(=O)2-NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(Ci-4alkyl)2, -C(=O)- NR4aR4b, and Ci-4alkyl optionally substituted with one, two or three -S(=O)2-Ci-4alkyl; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Het4;

[0218] Het3arepresents 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:

[0219] 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; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, and -OH; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, Het5, -C(=O)-Ci-4alkyl, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, or -C(=O)-C3-6cycloalkyl;

[0220] Het3brepresents 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 Het3brepresents 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:

[0221] 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 oxazolidinyl, C-linked piperidinyl, wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, halo, -OH, Ci-4alkyl, and -OR7; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, Het5, or -S(=O)2-Ci-4alkyl; Het4represents C-linked oxetanyl;

[0222] Het5represents C-linked oxetanyl;

[0223] R4aand R4beach independently represent hydrogen, Ci-4alkyl, Cs-ecycloalkyl, or Ci-4alkyl-O- Ci-4alkyl;

[0224] R4Cand R4deach independently represent Ci-4alkyl or -O-Ci-4alkyl;

[0225] R5aand R5bare each independently selected from the group consisting of hydrogen and Ci-4alkyl;

[0226] R6represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH;

[0227] R7represents Ci-4alkyl; pl and p2 are 2; and the pharmaceutically acceptable salts thereof.

[0228] 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 R2represents fluoro.

[0229] 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 n is 0.

[0230] 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 n is i.

[0231] 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 ring represents phenyl.

[0232] 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 ring represents phenyl, and n is 0.

[0233] 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 ring represents phenyl, and R6represents methyl.

[0234] 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 ring represents phenyl, n is 0, and R6represents methyl.

[0235] 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 ring represents phenyl, and R6represents -CH2OH.

[0236] 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 ring represents phenyl, n is 0, and R6represents

[0237] -CH2OH.

[0238] 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

[0239] R3brepresents Ci-4alkyl; or Cs-ecycloalkyl substituted with one -S(=O)2-Ci-4alkyl. 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

[0240] R3brepresents Ci-4alkyl.

[0241] 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

[0242] R3brepresents Cs-ecycloalkyl substituted with one -S(=O)2-Ci-4alkyl; in particular cyclobutyl substituted with one -S(=O)2-Ci-4alkyl; more in particular cyclobutyl substituted with one - S(=O)2-CH3.

[0243] 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 substituent -S(=O)2-Ci-4alkyl is limited to -S(=O)2-CH3.

[0244] 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 R6represents CH3.

[0245] 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:

[0246] 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 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 R6represents methyl.

[0247] 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 cis: and wherein R6represents methyl.

[0248] 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 substituents on the cyclopropyl moiety in Formula (I) is as indicated below in Formula (I-a):

[0249] 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 substituents on the cyclopropyl moiety in Formula (I) is as indicated below in Formula (I-b):

[0250] 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 Formula (I) and the stereochemistry of the substituents on the cyclopropyl moiety are as indicated below in Formula (I-al ):

[0251] 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 Formula (I) and the stereochemistry of the substituents on the cyclopropyl moiety are as indicated below in Formula (I-bl ):

[0252] Whenever possible, any embodiment for the compounds of Formula (I) as listed hereinabove, also holds for the compounds of Formula (A).

[0253] In an embodiment, the present invention relates to a subgroup of Formula (I) as defined in the general reaction schemes.

[0254] In an embodiment 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.

[0255] In an embodiment the compound of Formula (I) is selected from the group consisting of compounds 32, 38, 48, 54, 61, 65, and 74.

[0256] In an embodiment 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.

[0257] In an embodiment 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.

[0258] In an embodiment 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.

[0259] In an embodiment 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.

[0260] In an embodiment 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.

[0261] The present invention also relates to 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.

[0262] The present invention also relates to 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.

[0263] The present invention also relates to 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.

[0264] The present invention also relates to 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.

[0265] In an embodiment the compound of Formula (I) is compound 32 or a pharmaceutically acceptable salt thereof.

[0266] In an embodiment the compound of Formula (I) is compound 38 or a pharmaceutically acceptable salt thereof.

[0267] In an embodiment the compound of Formula (I) is compound 48 or a pharmaceutically acceptable salt thereof.

[0268] In an embodiment the compound of Formula (I) is compound 54 or a pharmaceutically acceptable salt thereof.

[0269] In an embodiment the compound of Formula (I) is compound 61 or a pharmaceutically acceptable salt thereof.

[0270] In an embodiment the compound of Formula (I) is compound 65 or a pharmaceutically acceptable salt thereof.

[0271] In an embodiment the compound of Formula (I) is compound 74 or a pharmaceutically acceptable salt thereof.

[0272] In an embodiment the compound of Formula (I) is compound 32.

[0273] In an embodiment the compound of Formula (I) is compound 38.

[0274] In an embodiment the compound of Formula (I) is compound 48.

[0275] In an embodiment the compound of Formula (I) is compound 54.

[0276] In an embodiment the compound of Formula (I) is compound 61.

[0277] In an embodiment the compound of Formula (I) is compound 65.

[0278] In an embodiment the compound of Formula (I) is compound 74. In an embodiment 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.

[0279] In an embodiment the compound of Formula (I) is or a pharmaceutically acceptable salt thereof.

[0280] In an embodiment the compound of Formula (I) is

[0281] In an embodiment the compound of Formula (I) is or a pharmaceutically acceptable salt thereof.

[0282] In an embodiment the compound of Formula (I) is

[0283] In an embodiment the compound of Formula (I) is or a pharmaceutically acceptable salt thereof.

[0284] In an embodiment the compound of Formula (I) is

[0285] All possible combinations of the above indicated embodiments are considered to be embraced within the scope of the invention.

[0286] For use in medicine, 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. Furthermore, where the compounds of Formula (I) carry an acidic moiety, 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. Thus, 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, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.

[0287] Representative acids and bases that may be used in the preparation of pharmaceutically acceptable salts include acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(! S)-camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy- ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, a-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthal ene-2-sulfonic acid, naphthal ene-l,5-disulfonic acid, 1- hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, / V-methyl-glucamine, hydrabamine, / / / -imidazole. L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, l-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine, tromethamine, and zinc hydroxide.

[0288] Embodiments of the present invention include prodrugs of compounds of Formula (I). In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound. Thus, in the methods of treating or preventing embodiments of the present invention, 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.

[0289] The pharmaceutically acceptable salts as mentioned hereinabove or hereinafter 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.

[0290] A person of ordinary skill in the art would recognize that the compounds described herein may exist as tautomers and that other tautomeric arrangements of the structures depicted herein are possible. 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.

[0291] Where the compounds according to embodiments of this invention have at least one chiral center, they 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).

[0292] Where 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.

[0293] It is intended that within the scope of the present invention, 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. For example, a reference to hydrogen includes within its scope1H,2H (D), and3H (T). Similarly, references to carbon and oxygen include within their scope respectively12C,13C and14C and16O and18O. The isotopes may be radioactive or non-radioactive. Radiolabelled compounds of formula (I) may comprise one or more isotope(s) selected from the group of3H,nC,18F,122I,123I,125I,131I,75Br,76Br,77Br and82Br. Preferably, the isotope is selected from the group of2H,3H,nC and18F. In particular, deuterated compounds are intended to be included within the scope of the present invention.

[0294] During 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.

[0295] Even though the compounds of embodiments of the present invention (including their pharmaceutically acceptable salts and pharmaceutically acceptable solvates) can be administered alone, they will generally be administered in admixture with a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient and / or a pharmaceutically acceptable diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice. Thus, particular embodiments of the present invention are directed to pharmaceutical and veterinary compositions comprising compounds of Formula (I) and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, and / or pharmaceutically acceptable diluent.

[0296] By way of example, in the pharmaceutical compositions of embodiments of the present invention, 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.

[0297] 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.

[0298] 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.

[0299] It has been found that the compounds of the present invention inhibit MALT1 activity.

[0300] In some embodiments, 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.

[0301] The invention relates to compounds of Formula (I) for use as a medicament.

[0302] The invention relates to compounds of Formula (A) for use as a medicament.

[0303] The invention relates to compounds of Formula (I) for use in the inhibition of MALT1 activity.

[0304] The invention relates to compounds of Formula (A) for use in the inhibition of MALT1 activity.

[0305] The invention relates to compounds of Formula (I) for use in the treatment of diseases mentioned herein.

[0306] The invention relates to compounds of Formula (A) for use in the treatment of diseases mentioned herein.

[0307] The invention relates to compounds of Formula (I) for the treatment or prevention, in particular for the treatment, of said diseases.

[0308] 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.

[0309] The invention relates to compounds of Formula (A) for the treatment or prevention, in particular in the treatment, of MALT1 mediated diseases or conditions.

[0310] The invention relates to compounds of Formula (I) for the manufacture of a medicament.

[0311] The invention relates to compounds of Formula (A) for the manufacture of a medicament.

[0312] The invention relates to compounds of Formula (I) for the manufacture of a medicament for the inhibition of MALT 1.

[0313] The invention relates to compounds of Formula (A) for the manufacture of a medicament for the inhibition of MALT1.

[0314] 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.

[0315] 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.

[0316] 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.

[0317] 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.

[0318] 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.

[0319] 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.

[0320] In view of the utility of the compounds of Formula (I), there is provided a method of treating warm-blooded animals, including humans, suffering from or a method of preventing warmblooded animals, including humans, to suffer from any one of the diseases mentioned herein.

[0321] In view of the utility of the compounds of Formula (A), there is provided a method of treating warm-blooded animals, including humans, suffering from or a method of preventing warmblooded animals, including humans, to suffer from any one of the diseases mentioned herein. GENERAL SYNTHETIC METHODS

[0322] In this section, as in all other sections unless the context indicates otherwise, references to Formula (I) also include all other sub-groups and examples thereof as defined herein.

[0323] The general preparation of some typical examples of the compounds of Formula (I) is described hereunder and in the specific examples and are generally prepared from starting materials which are either commercially available or prepared by standard synthetic processes commonly used by those skilled in the art of organic chemistry. The following schemes are only meant to represent examples of the invention and are in no way meant to be a limit of the invention.

[0324] Alternatively, 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.

[0325] The skilled person will realize that in the reactions described in the Schemes, although this is not always explicitly shown, it may be necessary to protect reactive functional groups (for example hydroxy, amino, or carboxy groups) where these are desired in the final product, to avoid their unwanted participation in the reactions. In general, conventional protecting groups can be used in accordance with standard practice. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

[0326] The skilled person will realize that in the reactions described in the Schemes, it may be advisable or necessary to perform the reaction under an inert atmosphere, such as for example under N2-gas atmosphere, for example when NaH, LDA or MeMgBr is used in the reaction.

[0327] It will be apparent for the skilled person that it may be necessary to cool the reaction mixture before 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).

[0328] The skilled person will realize that heating the reaction mixture under stirring may enhance the reaction outcome. In some reactions microwave heating may be used instead of conventional heating to shorten the overall reaction time.

[0329] The skilled person will realize that another sequence of the chemical reactions shown in the Schemes below, may also result in the desired compound of Formula (I).

[0330] The skilled person will realize that 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.

[0331] For abbreviations used in the Schemes below, check the table with abbreviations in the part ‘Examples’.

[0332] In the preparation of compounds of the present invention, protection of remote functionality (e.g., primary, or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups (NH-PG) 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.

[0333] In general, compounds of Formula (I) can be prepared as exemplified below in General Scheme 1, wherein the variables are described as hereabove:

[0334] In General Scheme 1, 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). It is understood by the persons skilled in the art that prior to the reaction, 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.

[0335] General Scheme 2

[0336] In general, compounds of Formula (II) can be prepared as exemplified below in General Scheme 2, wherein the variables are described as hereabove:

[0337] 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).

[0338] Step 2. An intermediate of Formula (V) is reacted with an appropriate commercially available hydrazine (VI), wherein the variables are described as hereabove. Alternatively, 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). Alternatively, the reaction is carried out in a suitable acid as solvent, such as AcOH, at a suitable temperature, such as for instance 120 °C, to provide an intermediate of Formula (VII).

[0339] 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). Alternatively, an intermediate of Formula (VII) is reacted with a suitable oxidant, such as for instance, potassium permanganate, in a suitable solvent, such as pyridine, at a suitable temperature, such as 95 °C, to provide an intermediate of Formula (VIII). Alternatively, 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).

[0340] 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. 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).

[0341] 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).

[0342] Specifically, compounds of Formula (II), wherein Rla, Rlb=F, can be prepared as exemplified below in General Scheme 3, wherein all other variables are described as hereabove:

[0343] General Scheme 3

[0344] 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).

[0345] 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).

[0346] 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). Alternatively, the reaction is carried out in a suitable acid as solvent, such as AcOH, at a suitable temperature, such as for instance 120 °C, to provide an intermediate of Formula (XIV).

[0347] 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).

[0348] 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).

[0349] Step 6. An intermediate of Formula (XVI) is reacted with a fluorinating agent, such as for instance hydrogen fluoride-pyridine, in the presence of an additive such as NIS, in a suitable solvent, such as for instance dichlorometane, at an appropriate temperate range, such as 0 °C to room temperature, to provide an intermediate of Formula (II), wherein Rla, Rlb=F.

[0350] In general, compounds of Formula (III) can be prepared as exemplified below in General Scheme 4, wherein the variables are described as hereabove:

[0351] General Scheme 4

[0352] 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). Alternatively, a compound of Formula (XIX), in which R6is 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). A person skilled in the art will understand that for compounds of Formula (XIX), in which R6is 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.

[0353] 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). An intermediate of Formula (XXa) is protected with a suitable protecting group, such as triisopropylsilyl ether or acetyl, by reaction with a suitable reagent, such as triisopropylsilyl chloride or acetic anhydride, in the presence of a base such as imidazole, pyridine or triethylamine (TEA), in a suitable solvent, such as for instance DCM, and at a suitable temperature, such as, for instance, 25 °C, to provide an intermediate of Formula (XXb) where PG= triisopropylsilyl or acetyl.

[0354] 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). Alternatively, 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). An intermediate of Formula (XXIa) where PG= triisopropylsilyl, is reacted with an appropriate deprotecting reagent / procedure, such as for instance, tetrabutylammonium fluoride, at a suitable temperature range, such as for instance 0 °C to 25 °C, to provide an intermediate of Formula (XXIb).

[0355] 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).

[0356] Step 5. An intermediate of Formula (XXII) is reacted with an appropriate amine R3aR3bNH, 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).

[0357] 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).

[0358] 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). Alternatively, 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 R3aR3bNH, as exemplified below in General Scheme 5.

[0359] General Scheme 5

[0360] In General Scheme 5, an intermediate of Formula (XXIVa) is reacted with an appropriate amine R3aR3bNH, wherein the variables are described as hereabove. This reaction is carried out in the presence of a suitable reagent, such as HATU, an appropriate base such as for example TEA, in a solvent such as acetonitrile, at a suitable temperature, such as for example room temperature, to provide an intermediate of Formula (I). It is understood by the persons skilled in the art that an additional deprotection step might be carried out, when R6= Ci-4alkyl substituted with a OH, wherein the hydroxy is protected with a suitable protecting group.

[0361] In general, an intermediate of Formula (XXIVa) can be prepared as exemplified below in General Scheme 6, wherein the variables are described as hereabove:

[0362] General Scheme 6

[0363] 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. . It is understood by the persons skilled in the art that prior to the reaction 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. An intermediate of Formula (XXIVb) where R=Et, is hydrolyzed in the presence of a suitable base, such as for instance LiOH, at a suitable temperature, such as for instance room temperature, to provide an intermediate of Formula (XXIV a).

[0364] Alternatively, an intermediate of Formula (XXIVa) can be prepared as exemplified below in General Scheme 7, wherein the variables are described as hereabove:

[0365] General Scheme 7

[0366] 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).

[0367] 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).

[0368] 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).

[0369] 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. The reaction is carried out in the presence of a suitable acid, such as AcOH, or HC1, in an appropriate solvent, such as for instance EtOH, and a suitable temperature, such as for instance 60 °C, to provide an intermediate of Formula (XXIVb), where R=Et. An intermediate of Formula (XXIVb) where R=Et, is hydrolyzed in the presence of a suitable base, such as for instance, LiOH, at a suitable temperature, such as for instance room temperature, to provide an intermediate of Formula (XXIV a).

[0370] Specific Examples

[0371] The following examples further illustrate the present invention. EXAMPLES

[0372] Several methods for preparing the intermediates and Compounds of this invention are illustrated in the following examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification, or alternatively can be synthesized by a skilled person by using well-known methods.

[0373]

[0374]

[0375] As understood by a person skilled in the art, Compounds synthesized using the protocols as indicated may contain residual solvent or minor impurities.

[0376] A skilled person will realize that, even where not mentioned explicitly in the experimental protocols below, typically after a column chromatography purification, the desired fractions were collected, and the solvent was evaporated.

[0377] In case no stereochemistry is indicated, this means it is a mixture of stereoisomers, unless otherwise is indicated or is clear from the context.

[0378] As understood by a person skilled in the art, 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. When an intermediate or compound in the experimental part below is indicated as ‘a HC1 salt’ without indication of the number of equivalents of HC1, this means that the number of equivalents of HC1 was not determined.

[0379] Preparation of intermediates

[0380] For intermediates that were used in a next reaction step as a crude or as a partially purified intermediate, in some cases no mol amounts are mentioned for such intermediate in the next reaction step or alternatively estimated mol amounts or theoretical mol amounts for such intermediate in the next reaction step are indicated in the reaction protocols described below. Intermediate 1

[0381] To a cooled (0 °C) suspension of NaH (60% in mineral oil, 2.59 g, 64.85 mmol) in THF (100 mL) was added triethylphosphonopropionate (13.9 mL, 64.85 mmol) dropwise. The reaction was stirred for 30 minutes, then a solution of 4-bromobenzaldehyde [1122-91-4] (10 g, 54 mmol) in THF (20 mL) was added dropwise, keeping the internal temperature between 0 °C and 5 °C. The mixture was allowed to warm to RT and stirred for 16 h. The reaction was quenched with a saturated aqueous solution of NH4CI (60 mL), and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (Eluent: heptane:EtOAc up to 90:10). The fractions containing compound were combined and concentrated in vacuo to give Intermediate 1 (12.30 g, 84% yield) as a colorless oil.

[0382] Intermediate 2

[0383] To a cooled (0 °C) solution of Intermediate 1 (12.30 g, 45.70 mmol) in dry THF (230 mL) under nitrogen, was added DIBAL-H (IM in THF, 115 mL, 115.0 mmol) dropwise. The mixture was then allowed to slowly warm up to RT and stirred for 1 h. The reaction was cooled down to 0 °C, diluted with EtOAc (100 mL) and quenched with a saturated aqueous solution of Rochelle's salt (250 mL). After stirring for 1 h, the reaction was allowed to warm up to RT, the organic layer was separated, and the aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give Intermediate 2 (9.80 g, 94%) as a white solid.

[0384] Intermediate 3

[0385] To a solution of Intermediate 2 (8.70 g, 38.30 mmol) and imidazole (3.13 g, 46.00 mmol) in DCM (100 mL) pre-cooled to 0 °C, was added triisopropylsilyl chloride (9.0 mL, 42.10 mmol) dropwise. The mixture was allowed to warm up to RT and stirred for 16 h. The mixture was diluted with water (100 mL) and DCM (100 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous MgSO-i. filtered, and concentrated in vacuo. The crude was purified by flash column chromatography over silica gel (eluent: heptane / DCM up to 90 / 10) to obtain Intermediate 3 (14.0 g, 95% yield) as a colorless oil.

[0386] Intermediate 4

[0387] In a 20 mL pressure tube charged with Intermediate 3 (1.15 g, 3.00 mmol) and tetrabutylammonium bromide (48.3 mg, 0.15 mmol), were added toluene (6 mL) and (bromodifluoromethyl)trimethylsilane (1.4 mL, 9 mmol). The reaction was stirred at 110 °C for 6 h. Six identical reactions were run in parallel and combined before work-up and purification. The reactions were cooled down to RT, each diluted with water (10-15 mL), EtOAc (20-25 mL), and combined. The organic layer was separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in anhydrous THF (50 mL), cooled to 0 °C and TBAF (IM in THF, 27 mL, 27 mmol) was added. The reaction was allowed to warm up to RT and stirred for 1 h. Volatiles were removed under reduced pressure and the residue was diluted with water (50 mL) and EtOAc (100 mL). The aqueous layer was separated, and the organic layer was washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (Eluent: heptane:EtOAc 70:30) to obtain Intermediate 4 (4.60 g, 92% yield) as a yellowish oil.

[0388] Intermediate 5 and Intermediate 6

[0389] Intermediate 4 was purified by preparative chiral SFC (Column: Chiralpak Daicel IG (20 x 250 mm), Mobile phase: CO2, EtOH + 0.4 zPrlkTh). The fractions containing compound were combined and evaporated in vacuo to give Intermediate 5 (5.66 g, 47% yield) and Intermediate 6 (5.50 g, 46%yield) as transparent, yellowish oils.

[0390] Intermediate 7

[0391] To a solution of Intermediate 5 (5.65 g, 20.39 mmol) in ACN (100 mL), were added water (100 mL), TEMPO [2564-83-2] (1.59 g, 10.19 mmol), (diacetoxyiodo)benzene [3240-34-4] (19.70 g, 61.17 mmol) and NaHCOs (4.28 g, 50.97 mmol). The resulting mixture was stirred at room temperature for 18 h, then diluted with water and acidified with aq HC1 (1 M). EtOAc was added, the phases separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated. The crude was purified by flash column chromatography (Mobile phase: DCM:MeOH from 100:0 to 96:5) to yield Intermediate 7 (6.16 g, quantitative yield) as a yellow residue.

[0392] Intermediate 8

[0393] To a solution of Intermediate 7 (2.00 g, 6.87 mmol), EtsN (3.8 mL, 0.73 g / mL, 27.34 mmol) and HATU (5.22 g, 13.74 mmol) in ACN (50 mL) was added MeNH2(5.15 mL, 2 M in THF, 10.31 mmol). The reaction was stirred at room temperature overnight, then diluted with EtOAc and water. The phases were separated, the aqueous layer was extracted with EtOAc (2x) and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was then purified by flash column chromatography (Redisep CombiFlash, silica; MeOH / NFh 7N in DCM 0% to 2%) to yield Intermediate 8 (1.80 g, 86% yield) as a yellow residue.

[0394] The following Intermediates were synthesized by analogous reaction protocol as described for Intermediate 8, starting from Intermediate 7.

[0395] Intermediate 12 was prepared by an analogous reaction protocol as Intermediate 7 starting from Intermediate 4 (3.81 g, 13.75 mmol) to give Intermediate 12 (3.46 g, 86% yield) as white solid.

[0396] To a mixture of Intermediate 1 (118.00 g, 438.40 mmol), toluene (826 mL) and tetrabutylaminyl bromide [1643-19-2] (4.24 g, 13.15 mmol), was added (bromodifluoromethyl)trimethylsilane [115262-01-6] (1424.76 g, 7014.99 mmol) dropwise over 24 h at 110 °C (with a syringe pump). The resulting mixture was stirred for additional 5 h at 110 °C. The reaction was poured into ice water (1.5 L). The resulting mixture was extracted with PE (3 x 1 L). The combined organic layers were washed with brine (3 x 0.5 L) and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (Eluent: PE:EtOAc 30:1) to afford Intermediate 13 (92 g, 66% yield) as a light-yellow oil. Intermediate 14 and Intermediate 15

[0397] Intermediate 14 Intermediate 15

[0398] Intermediate 13 (100.00 g, 313.34 mmol) was purified by preparative chiral HPLC (Stationary phase: Chiralpak IG 5x25 cm, 10 pm, Mobile Phase: Hexane:EtOH 99:1). The fractions containing compound were combined and evaporated in vacuo to give Intermediate 14 (23.80 g, 23% yield) as a brown oil and Intermediate 15 (48.70 g, 47% yield) as a brown oil.

[0399] Intermediate 16

[0400] 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. The reaction was stirred for 24 h, then extra triisopropylsilyl chloride (0.4 mL, 1.87 mmol) and imidazole (111.50 mg, 1.64 mmol) were added and resulting mixture stirred for 24 h more. The mixture was diluted with water and DCM, the phases separated and the aqueous layer extracted once with DCM. The combined organic layers were dried over MgSO-i. the solids filtered and the solvent evaporated under vacuo. The crude was purified by flash column chromatography over silica gel (Eluent: Hexane:EtOAc from 100:0 to 90:10) to give Intermediate 16 (2.0 g, 71% yield) as a colourless oil.

[0401] Intermediate 17

[0402] A mixture of Intermediate 16 (1.00 g, 2.34 mmol), tetrabutylammonium bromide [1643-19-2] (37.71 mg, 0.17 mmol) in toluene (2 mL), was added TMSCF2Br [115262-01-6] (7.27 mL, 46.79 mmol). The resulting mixture was stirred at 110 °C for 72 h, then concentrated under reduced pressure. The crude was purified by flash column chromatography over silica gel (Eluent: Hexane:EtOAc from 100:0 to 90: 10) to give Intermediate 17 (0.93 g; 33% purity, 27% yield).

[0403] Intermediate 18

[0404] LiOH (2.0 M in water; 1.8 mL, 3.60 mmol) was added to a stirred solution of Intermediate 17 (570.40 mg; mixture) in THF (3.4 mL). The reaction was stirred at room temperature ovenright, then diluted with aq. HC1 1.0M until pH < 2. EtOAc was added, the phases separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give Intermediate 18 as a brown oil, which was used in the next step without further purification (assumed quantitative yield).

[0405] The following Intermediates were synthesized by analogous reaction protocol as described for

[0406] Intermediate 8, starting from Intermediate 18 and the indicated reagents.

[0407] Intermediate 21

[0408] 2 -Methylcyclopentanone [1120-72-5] (5.00 g, 0.92 g / mL, 50.95 mmol) and N.N- dimethylformamidedimethylacetal [4637-24-5] (10.15 mL, 0.9 g / mL, 76.42 mmol) were heated at 150 °C for 40 min in a microwave reactor. The mixture was evaporated to give Intermediate 21 (7.17 g, 92% yield).

[0409] Intermediate 22

[0410] 2-Bromo-6-hydrazinopyridine [26944-71-8] (7.61 g, 40.46 mmol) in AcOH (9 mL) was added dropwise to Intermediate 21 (6.20 g, 40.46 mmol) and the resulting mixture was heated at 120°C in an oil bath for 1 h. The reaction mixture was diluted with DCM and quenched with a saturated aqueous solution of NaHCCh. The organic layer was separated, dried over MgSCfi, filtered, and evaporated. The product was purified by flash column chromatography over silica gel (Eluent DCM:MeOH from 100:0 to 98:2). The fractions containing compound were combined and evaporated in vacuo to give Intermediate 22 (4.56 g, 41% yield) as a brown oil.

[0411] Intermediate 23

[0412] Intermediate 22 (4.56 g, 16.39 mmol) was dissolved in pyridine (115 mL), after which water (82 mL) was added. The resulting mixture was heated to near reflux temperature (~95 °C set temperature on heating block), after which potassium permanganate [7722-64-7] (25.91 g, 163.94 mmol) was added in portions over a period of 30 min. The resulting mixture was kept at 95 °C for ~45 min to 1 h. The mixture was cooled to ambient temperature and diluted with ethyl acetate. The resulting suspension was filtered over Decalite®. The filtrate was transferred into a separatory funnel and the product extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and evaporated to give Intermediate 23 (3.32 g, 69% yield) as a yellow solid.

[0413] Intermediate 24

[0414] Intermediate 23 (3.32 g, 11.36 mmol) was dissolved in MeOH (116 mL) and the resulting solution cooled to 0 °C in an ice bath. Sodium borohydride [16940-66-2] (0.43 g, 11.36 mmol) was added and the resulting mixture was stirred at 0 °C for 10 min, then at RT for ~2 h. Water was added, and the product was extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and evaporated. The product was purified by flash column chromatography over silica gel (Eluent: DCM:MeOH, from 100:0 to 98:2). The pure fractions were evaporated to give Intermediate 24 (0.47 g, 14% yield) as a yellow oil.

[0415] Intermediate 25

[0416] To a solution of EtsN (0.95 mL) in degassed MeOH:THF(l:l, 20 mL) was added a mixture of Intermediate 24 (0.80 g, 2.72 mmol), palladium(II) acetate [3375-31-3] (24.42 mg, 0.11 mmol), and Xant Phos [161265-03-8] (125.90 mg, 0.22 mmol). Then the mixture was stirring at 100 °C under 30 bar of CO for 24 h. The solvent was evaporated, the residue was dissolved in water, NaHCOs (0.50 g) was added, and the mixture extracted with DCM. The organic layer was dried over MgSO4, filtered, and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (Eluent: DCM:MeOH from 100:0 to 96:4). The pure fractions were evaporated to give Intermediate 25 (0.65 g, 87% yield) as a colorless oil.

[0417] The following Intermediates were synthesized by analogous reaction protocol as described for

[0418] Intermediate 22, starting from Intermediate 21 and the indicated reagents.

[0419] Intermediate 28

[0420] In a vial containing NFSI [133745-75-2] (2.37 g, 7.53 mmol), lithium carbonate [554-13-2] (0.67 g, 9.03 mmol), methylboronic acid [13061-96-6] (0.36 g, 6.02 mmol) and Intermediate 26 (0.60 g, 3.01 mmol), was added via syringe a pre-stirred mixture of 4,7-diphenyl-l,10- phenanthroline [1662-01-7] (0.20 g, 0.6 mmol), CuOAc [598-54-9] (73.83 mg, 0.60 mmol), and chlorobenzene (15 mL) (pre-stirred at ambient temperature for 5 min). The resulting mixture was stirred at 45 °C overnight, at which time the reaction mixture was allowed to cool to ambient temperature and sodium dithionite [7775-14-6] (1.31 g, 7.53 mmol) was added, together with water (868 pL, 48.2 mmol). The resulting mixture was stirred at ambient temperature for 10 min, after which time DCM (10 mL) was added, and the mixture was filtered over celite. To the filtrate was added MgSO-i. the mixture was stirred at ambient temperature for 5-10 min, and it was filtered and washed with DCM (20 mL). The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (Eluent: heptane:EtOAc from 90:10 to 30:70). The fractions containing product were combined and concentrated under vacuum to give Intermediate 28 (0.28 g, 44% yield) as a light-yellow solid.

[0421] Intermediate 29

[0422] To a pre-stirred solution of Intermediate 27 (4.00 g, 19.49 mmol) in DCM (40 mL) was added chromium(VI) oxide [1333-82-0] (0.98 g, 9.76 mmol). Then, tert-butyl hydroperoxide solution [75-91-2] (25.00 g, 0.7 M, 277.41 mmol) was added at 0 °C, under nitrogen. The resulting mixture was stirred at 27 °C for 4 h. The resulting mixture was diluted with water (120 mL) and extracted with EtOAc (3 x 120 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a yellow oil. The yellow oil was subjected to flash column chromatography over silica gel to yield Intermediate 29 (1.20 g, 5.47 mmol) as a yellow solid.

[0423] Intermediate 30

[0424] 5,6-Hydrocyclopenta[c]pyrazol-4(lH)-one [596844-18-7] (5.00 g, 40.94 mmol), 2- bromothiazole (8.06 g, 49.13 mmol), Cui (1.56 g, 8.19 mmol), K2CO3 (11.32 g, 81.88 mmol) and AMimethylglycine (2.53 g, 24.56 mmol) were stirred in 50 mL DMSO under N2 at 120 °C overnight. The reaction was diluted with water (300 mL) and EtOAc (300 mL). The reaction was then filtered twice over dicalite. The layers were separated, and the organic layer was washed with brine (100 mL). The organic layer was then dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography over silica gel (Mobile phase: DCM:MeOH from 100:0 to 99:1) to give Intermediate 30 (1.60 g, 19% yield).

[0425] Intermediate 31

[0426] To a mixture of cyclopentanone (10.00 g, 118.88 mmol) and 4-chlorobenzaldehyde (13.93 g, 99.07 mmol) in ether (120 ml) was added an aqueous solution of NaOH (IM, 120 mL) at 25 °C. The obtained suspension was stirred at room temperature for 48 h. The reaction mixture was diluted with water (200 mL), and the obtained mixture was extracted with EtOAc (2 x 200 mL). The combined organic phases were washed with a saturated aqueous solution of NH4CI (100 mL), dried with Na2SO4, filtered, and concentrated. The crude was purified by flash column chromatography over silica gel (Mobile phase: PE:EtOAc 10:1) to afford Intermediate 31 (10.00 g, 49% yield) as a yellow solid.

[0427] Intermediate 32

[0428] Intermediate 32 was prepared by an analogous reaction protocol as Intermediate 21 starting from Intermediate 31 (3.00 g, 14.52 mmol) to give Intermediate 32 (4.00 g, 84% yield) as a brown solid.

[0429] Intermediate 33

[0430] To a solution of 2-aminothiazole [96-50-4] (10.03 g, 100.16 mmol) in HC1 (80 mL) was added dropwise a solution of NaNCh (6.91 g, 100.16 mmol) in H2O (50 mL) at -30 °C. After stirring for 10 min, SnCh [7772-99-8] (37.98 g, 200.32 mmol) in HC1 (20 mL) was added dropwise at -30 °C. The reaction was stirred at -30 °C for 30 min and then allowed to warm to room temperature. Once at room temperature, the reaction was filtered and washed with Et20 to give Intermediate 33 (10.80 g, 71% yield) as a yellow solid. The following Intermediates were synthesized by analogous reaction protocol as described for

[0431] Intermediate 36

[0432] To a solution of Intermediate 34 (5.00 g, 12.93 mmol) in DCM (20 mL) was added water (40 mL) and MeCN (20 ml) under air atmosphere. Sodium periodate (13.96 g, 64.65 mmol) and ruthenium (III) chloride (53.64 mg, 0.26 mmol) were added, and the resulting mixture was stirred vigorously at room temperature for 12 h, at which time the mixture was filtered, and concentrated. The mixture was extracted with EtOAc (3 x 200 mL). The combined organic phases were washed with brine (2 x 200 mL), dried with Na2SO4, filtered and concentrated. The crude was purified by flash column chromatography over silica gel (Mobile phase: PE:EtOAc from 100:0 to 60:40) to give Intermediate 36 (1.00 g, 28% yield) as a yellow solid.

[0433] Intermediate 37

[0434] Intermediate 37 was prepared by an analogous reaction protocol as Intermediate 36 starting from Intermediate 35 (3.00 g, 9.56 mmol) to give Intermediate 37 (0.70 g, 36% yield) as a yellow solid. Intermediate 38

[0435] To a suspension of Intermediate 36 (6.00 g, 21.57 mmol) in DCM (60 mL) was added 1,2- ethanedithiol [540-63-6] (3.62 ml, 43.15 mmol) and BF3«Et2O [109-63-7] (1.33 mL, 10.79 mol). The mixture was stirred at 25 °C overnight. The reaction was diluted with water (100 mL), and the obtained mixture was extracted with DCM (2 x 150 mL). The combined organic phases were washed with water (200 mL), dried with Na2SO4, filtered, and concentrated. The crude was purified by flash column chromatography over silica gel (Mobile phase: PE:EtOAc from 100:0 to 60:40) to give Intermediate 38 (5.20 g, 68% yield) as a yellow solid.

[0436] Intermediate 39

[0437] Intermediate 39 was prepared by an analogous reaction protocol as Intermediate 38 starting from Intermediate 37 (0.70 g, 3.41 mmol) to give Intermediate 39 (0.30 g, 31% yield) as a yellow solid.

[0438] Intermediate 40

[0439] A suspension of NIS [516-12-1] (1.00 g, 4.44 mmol) in DCM (7 mL) was cooled to -70 °C. Hydrogen fluoride-pyridine [62778-11-4] (5.0 mL, 38.85 mmol) was added dropwise under N2and stirred for 30 min. A solution of Intermediate 38 (0.50 g, 1.41 mmol) in DCM (7 mL) was added dropwise and the mixture was stirred at -70 °C for 30 minutes. The resulting mixture was stirred vigorously at room temperature for 2.5 h. The residue was slowly added to a saturated aqueous solution of NaHCCL (800 mL), and the obtained mixture was adjusted to pH 2~3 and extracted with DCM. The combined organic phases were concentrated, and the crude was purified by flash column chromatography over silica gel (Mobile phase: PE:EtOAc from 100:0 to 60:40) to give Intermediate 40 (0.16 g, 38% yield) as a white solid. Intermediate 41

[0440] Intermediate 41 was prepared by an analogous reaction protocol as Intermediate 40 starting from Intermediate 39 (1.50 g, 5.33 mmol) to give Intermediate 41 (0.40 g, 27% yield) as a yellow solid.

[0441] The following Intermediates were synthesized by analogous reaction protocol as described for

[0442] Intermediate 29, starting from the indicated intermediate.

[0443] Intermediate 44

[0444] A mixture of Intermediate 42 (1.20 g, 3.82 mmol), palladium (II) acetate [3375-31-3] (43 mg, 0.19 mmol), Xant Phos [161265-03-8] (221 mg, 0.38 mmol), MAMiisopropylethylamine [7087-68-5] (0.99 g, 7.641 mmol), and phenyl formate [1864-94-4] (933 mg, 7.64 mmol) in toluene (24 mL) was stirred for 24 h at 90 °C under N2. EtOAc (100 mL) and water (100 mL) were added. After separation of the biphasic solution, the aqueous phase was extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with brine (2 x 10 mL), dried with Na2SO4, filtered and concentrated. The crude was purified by flash column chromatography over silica gel (Mobile phase: PE:EtOAc from 100:0 to 30:70) to give Intermediate 44 (0.68 g, 50% yield) as a white solid. Intermediate 45 o

[0445] To a solution of Intermediate 42 (1.40 g, 4.46 mmol) in MeOH (55 ml) was added Pd / C [7440- 05-3] (0.95 g, 8.93 mmol) under N2. The suspension was stirred at rt for 3 h under an atmosphere of H2, then filtered and concentrated to obtain Intermediate 45 (1.30 g, 87% yield) as a light- yellow solid.

[0446] The following Intermediates were synthesized by analogous reaction protocol as described for

[0447] Intermediate 24, starting from the indicated intermediates.

[0448] Intermediate 52 A mixture of Intermediate 14 (0.50 g, 1.57 mmol), bis(pinacolato)diboron [73183-34-3] (0.56 g, 2.19 mmol), Xphos Pd G4 [1599466-81-5] (0.13 g, 0.16 mmol) and potassium pivalate [19455-23-3] (0.66 g, 4.70 mmol) in 1,4-dioxane (10 mL) was stirred at 90 °C for 1 h under N2. The mixture was cooled to ambient temperature, diluted with EtOAc and water, the layers were separated, and the water layer extracted with EtOAc (2x). The organic layers were combined and washed with brine, dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by flash column chromatography over silica gel (Mobile phase: Heptane:EtOAc from 100:0 to 70:30) to give Intermediate 52 (0.40 g, 70% yield) as ayellow oil.

[0449] Intermediate 53

[0450] Under nitrogen, a reaction vial was charged with Intermediate 52 (0.43 g, 1.17 mmol), chloro(1.5-cyclooctadiene)rhodium (I) dimer [12092-47-6] (0.17 g, 0.35 mmol), and a degassed mixture of dioxane / water (6: 1 ratio, 7.8 / 1.1 mL), followed by EtsN (1.70 mL, 12.23 mmol), and 2-cyclopentene-l-one (489 uL, 5.84 mmol). The resulting mixture was stirred at room temperature for 16 h, then a saturate aqueous solution of NH4CI solution and EtOAc were added. The layers were separated, and the organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by flash column chromatography over silica gel (Mobile phase: EtOAc in Heptane:EtOAc from 100:0 to 50:50) to give Intermediate 53 (0.31 g, 83% yield) as ayellow oil.

[0451] To a solution of Intermediate 53 (0.63 g, 0.93 mmol) in toluene (16 mL) was added Bredereck's reagent [5815-08-7] (2.7 mL, 11.45 mmol). The resulting mixture was heated to 50 °C for 90 min. The mixture was cooled to ambient temperature, concentrated under vacuo, and purified by flash column chromatography over silica gel (Mobile phase: DCM:MeOH from 100:0 to 95:5) to give Intermediate 54 (0.62 g, 97% purity, quantitative yield) as ayellow oil. Intermediate 55

[0452] Intermediate 55 was prepared by an analogous reaction protocol as Intermediate 22 starting from Intermediate 54 (0.62 g, 1.59 mmol) to give Intermediate 55 (0.38 g, 43% yield).

[0453] Intermediate 56

[0454] Intermediate 56 was prepared by an analogous reaction protocol as Intermediate 25 starting from Intermediate 55 (0.34 g, 0.67 mmol) to give Intermediate 56 (0.32 g, 98% yield).

[0455] Intermediate 57

[0456] Intermediate 56 (0.32 g, 0.66 mmol) was dissolved in MeOH / NHs (7N; 20 mL) and the resulting mixture was stirred at room temperature for 3.5 hours. The solvents were evaporated under reduced pressure to give Intermediate 57 (0.31 g, 88% yield) as a white solid.

[0457] Intermediate 58

[0458] An oven-dried 20 mL vial was charged with Intermediate 48 (0.17 g, 0.82 mmol), 5,7-ditert- butyl-3-phenyl-l,3-benzoxazol-3-ium tetrafluoroborate [1207294-92-5] (231.31 mg, 0.75 mmol), and an X-shaped magnetic stir bar. The vial was evacuated and refilled with nitrogen gas twice, methyl tert-butyl ether (5 mL) was added, and the reaction stirred at r.t. for 5 min. Then, a pyridine solution (59.3 mg, 0.75 mmol in 1 ml methyl tert-butyl ether) was added dropwise at room temperature. The resulting mixture was stirred at r.t. for 60 min. Another oven-dried 20 mL vial was charged with (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2- pyridinyl)phenyl]iridium(III) hexafluorophosphate [676525-77-2] (6.42 mg, 0.007 mmol), [4,4'-Bis(tert-butyl)-2,2'-bipyridine]nickel dibromide [1894189-67-3] (11.41 mg, 0.023 mmol), quinuclidine [100-76-5] (91.2 mg, 0.82 mmol) and Intermediate 14 (149.59 mg, 0.47 mmol). 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. The mixture was then diluted with a saturated aqueous solution of NH4CI, water, and EtOAc. The phases were separated, the aqueous layer extracted with EtOAc (2x), and the combined organic layers were washed with water, brine, dried over MgSO-i. filtered, and concentrated under vacuo. The residue was purified by flash column chromatography over silica gel (Mobile phase: DCM:MeOH from 100:0 to 98:2) to give Intermediate 58 (0.14 g, 69% yield).

[0459] The following Intermediate was synthesized by analogous reaction protocol as described for

[0460] Intermediate 58, starting from Intermediate 14 and the indicated intermediate.

[0461] The following Intermediates were synthesized by analogous reaction protocol as described for

[0462] Intermediate 18, starting from the indicated intermediate. Intermediate 63 and Intermediate 64

[0463] Intermediate 63 Intermediate 64

[0464] Intermediate 61 (1.51 g, 3.57 mmol) was purified via Prep HPLC (Stationary phase: RP XBridge Prep Cl 8 OBD-lOpm, 50x150mm, Mobile phase: 0.25%NH4HCC>3 solution in water,

[0465] CH3CN) and then separated via Prep SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 zPrNEh). The fractions containing compound were combined and evaporated in vacuo to give Intermediate 63 (0.33 g, 22% yield) and Intermediate 64 (39 g, 26% yield).

[0466] The following Intermediates were synthesized by analogous reaction protocol as described for

[0467] Intermediate 58, starting from Intermediate 25 and the indicated intermediate.

[0468] The following Intermediate was synthesized by analogous reaction protocol as described for Intermediate 58, starting from Intermediate 50 and the indicated intermediate.

[0469] The following Intermediates were synthesized by analogous reaction protocol as described for

[0470] Intermediate 58, starting from Intermediate 48 and the indicated intermediate. COMPOUNDS

[0471] Compound 1

[0472] To a mixture of Intermediate 64 (32.5 mg, 0.08 mmol), HATU (61.57 mg, 0.16 mmol), and EtsN (0.045 mL, 0.73 g / mL, 0.32 mmol) in ACN (1 mL) was added trans-3- methylsulfonylcyclobutylamine hydrochloride [1408075-97-7] (22.55 mg, 0.12 mmol). The reaction was stirred at rt for 2 h. The solvent was removed, and the crude was purified by Prep HPLC (Stationary phase: Torus Diol 30 x 150 mm, Mobile phase: CO2, MeOH + 20mM NH4OH) to give Compound 1 (24.5 mg, 57% yield). The following Compounds were synthesized by analogous reaction protocol as described for

[0473] Compound 1, starting from the indicated Intermediates (Int.) and reagents.

[0474]

[0475]

[0476] The following Compounds were synthesized by analogous reaction protocol as described for

[0477] Intermediate 58, starting from Intermediate 46 and the indicated intermediates.

[0478] The following Compounds were synthesized by analogous reaction protocol as described for

[0479] Intermediate 58, starting from Intermediate 48 and the indicated intermediates.

[0480] The following Compounds were synthesized by analogous reaction protocol as described for

[0481] Intermediate 58, starting from Intermediate 49 and the indicated intermediates. The following Compounds were synthesized by analogous reaction protocol as described for The following Intermediates were synthesized by analogous reaction protocol as described for

[0482] Intermediate 57, from the indicated intermediates.

[0483]

[0484]

[0485]

[0486] Compound 72

[0487] TBAF (IM in THF, 0.14 mL, 0.14 mmol) was added to a solution of Intermediate 70 (74.0 mg, 0.095 mmol) in anhydrous THF (2 mL). The reaction was stirred at rt for 1 h. Volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (150 mL) and water (10 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (Mobile phase: Heptane:EtOAc from 70:30 to 0:100) to give Compound 72 (45.0 mg, 87% yield) as a white solid. Compound 73, 74, 75, and 76

[0488] Compound 75 Compound 76

[0489] Compound 72 (45.0 mg, 87% yield) was separated via Prep SFC (Stationary phase: Chiralpak Daicel IG 20 x 250 mm, Mobile phase: CO2, zPrOH + 0.4 zPrNEb) to give Compound 73(10.5 mg, 20% yield), Compound 74 (10.0 mg, 19% yield) and a mixture of 75 and 76. This latest was separated via Prep SFC (Stationary phase: Chiralpak Daicel ID 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 zPrNEb) to give Compound 75 (9.5 mg, 18% yield) and Compound 76 (8.5 mg, 16% yield) .

[0490] Compound 77

[0491] 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

[0492] Compound 80 Compound 81

[0493] 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).

[0494] Analytical Analysis

[0495] The high performance liquid chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below).

[0496] If configured with a Mass Spectrometer (MS) the flow from the column was brought to the (MS) which was configured with an atmospheric pressure ion source. 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.

[0497] Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H]+(protonated molecule) and / or [M-H]' (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH4]+, [M+HCOO]', etc... ). For molecules with multiple isotopic patterns (Br, Cl), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.

[0498] Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” Mass Selective Detector, “RT” room temperature, “BEH” bridged ethylsiloxane / silica hybrid, “DAD” Diode Array Detector, “HSS” High Strength silica.

[0499] LC and LCMS Method Codes (Flow expressed in mL / min, column temperature (T) in °C, Run time in minutes)

[0500] LC and LC-MS methods:

[0501]

[0502] Table: LC and LCMS results. Rt means retention time, in minutes (min.); [M+H]+means the protonated mass of the compound; method refers to the method used for LC and LCMS analysis of compounds; No. means number. Rt means retention time (in minutes). SFC-MS methods:

[0503] 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. Analytical SFC-MS Methods (Flow expressed in mL / min, column temperature (Col T) in °C, Run time in minutes, Backpressure (BPR) in bars. “zPrNFb” means isopropylamine, “zPrOH” means 2-propanol, “EtOH” means ethanol, “min” mean minutes. SFC methods:

[0504] Table: 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.

[0505] NMR

[0506] 1H NMR spectra were recorded on Bruker Avance III 400MHz and Avance NEO 400MHz spectrometers. CHLOROFORM-d was used as solvent, unless otherwise mentioned. The chemical shifts are expressed in ppm relative to tetramethylsilane.

[0507] Pharmacological Analysis

[0508] Biological Examples

[0509] 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.

[0510] 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.

[0511] Alternatively, or additionally, 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.

[0512] Such assays are exemplary and not intended to limit the scope of the invention. The skilled practitioner can appreciate that modifications can be made to conventional assays to develop equivalent or other assays that can be employed to comparably assess activity or otherwise characterize compounds and / or compositions as described herein.

[0513] In Vitro Assays Biological Example 1 MALT1 Biochemical Protease Assay

[0514] 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.

[0515] ICso values were calculated using the following formula (Z prime should be >0.5):

[0516] LC = Median of the low control values

[0517] = Low control: Reaction without enzyme

[0518] HC = Median of the High control values

[0519] = High Control: Reaction with enzyme %Effect = 100-[((sample-LC) / (HC-LC)) x 100]

[0520] %Control = (sample / HC) x 100

[0521] %Controlmin = ((sample-LC) / (HC-LC)) x 100 A best-fit curve was fitted by a minimum sum of squares method to the plot of %Controlmin vs. compound concentration. From this an ICso value (inhibitory concentration causing 50 % inhibition) can be obtained. An estimate of the slope of the plot in terms of the Hill coefficient was also obtained. ICso Calculation: With y = estimated response UB = upper bound LB = lower bound h = Hill slope of curve CONC = concentration

[0522] Used in “Lexis Dose Response Curve Fitting” Version 1.0. Resultant data are shown in Table 2 (Cpd No. means Compound number).

[0523] Biological Example 2

[0524] GloSensor reporter MALT 1 -mediated cleavage In Jurkat Cells

[0525] MALT1 GloSensor™ 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 GloSensor™ 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.

[0526] Jurkat MALT1 GloSensor™ 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% GloSensor™ 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 GloSensor™ cells (1 x 105cells) were seeded in each well of 384-well plate. Next, 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. After incubation at 37 °C in 5% CO2 incubator for 4 h, luminescence was measured on the Envision (Perkin Elmer) at 37 °C.

[0527] IC50 values were calculated using SmartFit in GeneData Screenerd:

[0528] . SmartFit uses the 4p curve fit equation seen below:

[0529] Where: x = concentration y = activity So = activity at bottom plateau of curve

[0530] Sinf = activity at top plateau of curve

[0531] S50 = inflection point, halfway between SO and Sinf h = Hill slope of curve Resultant data are shown in Table 3.

[0532] Biological Example 3 Human IL-6 / IL-10 Mesoscale Assay

[0533] 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.

[0534] For the Mesoscale assay, 100,000 OCI-Ly3 cells were seeded per well into black-colored 96- well plates with clear bottom (Coming® #3904) and test compounds were added in 9 dilution steps (1:2) ranging from 15 pM to 58.6 nM (final DMSO concentration 0.3%). DMSO control wells were used to determine the maximum signal (High Control (HC)). Treatment with reference compounds at an appropriate dose served as positive control for MALT1 inhibition and was used to determine the maximum inhibition (Low Control (LC)). Compounds and cells were incubated for 24 h at 37 °C and 5% CO2 (assay volume is 150 pL). After 24 h of incubation 50 pL of the supernatant was transferred to an MSD plate (V-Plex Proinflammation Panel 1 (human) kit, Mesoscale (MSD)) and incubated for 2 h with vigorous shaking (600 rpm) at room temperature. Following incubation, plates were washed 3x with phosphate-buffered saline (PBS) + 0.05% Tween-20 and 25 pL detection antibody solution (IL-6 & IL-10 antibodies in diluent 3 (MSD)) was added per well followed by 2 h of incubation with vigorous shaking (600 rpm) at room temperature. After 3x washes with PBS + 0.05% Tween-20, plates were incubated with 150 pL 2x Read Buffer T and read on SECTOR imager. Resultant data are shown in Table 4.

[0535] Biological Example 4 Proliferation Assays

[0536] 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.

[0537] To assess anti-proliferative effects, 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. After 8 days of incubation, 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) were added to each well and luminescence was measured on Envision (Perkin Elmer) after 10 minutes shaking at 300 rpm followed by 10 minutes of incubation at room temperature in the dark.

[0538] IC50 values were calculated using SmartFit in GeneData Screenerd:

[0539] . SmartFit uses the 4p curve fit equation seen below: Where: x = concentration y = activity

[0540] So = activity at bottom plateau of curve

[0541] Sinf = activity at top plateau of curve S50 = inflection point, halfway between SO and Sinf h = Hill slope of curve

[0542] Resultant data are shown in Table 5:

[0543]

Claims

CLAIMS1. A compound of F ormula (I)or a tautomer or a stereoisomeric form thereof, whereinAr represents phenyl, thiazolyl, 1,2,4-thiadiazolyl, isothiazolyl, oxazolyl, pyrazolyl, pyridinonyl or pyridinyl;Raand Rbare each independently selected from the group consisting of hydrogen; halo;Ci-4alkyl; -C(=O)-NR5aR5b; -O-Ci-4alkyl; -CN; -NR7aR8a; -C(=O)-O-R9; C3-6cycloalkyl;-O-Ci-4alkyl substituted with 1, 2 or 3 halo substituents; orCi-4alkyl substituted with 1, 2 or 3 halo substituents;Rlarepresents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents;Rlbrepresents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents; or Rlaand Rlbare taken together to form together with the carbon atom to which they are attached a Cs-ecycloalkyl; ringrepresents phenyl or pyridyl;R2represents halo; n is 0, 1 or 2;R3arepresents hydrogen or Ci-4alkyl;R3brepresents hydrogen; Ci-4alkyl; Cs-ecycloalkyl; adamantyl; Ce-iocarbobicyclic; Het1;Cs-ecycloalkyl substituted with one, two, three or four substituents each independently selected from the group consisting of oxo, halo, cyano, -OH, -OR7, -S(=O)2-R7,-S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(Ci-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-Ci-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-Ci-4alkyl-O-R7, -NH-S(=O)2-R7, Het3a, Het3b, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-Ci-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, and -S(=O)2-Ci-4alkyl;Ce-iocarbobi cyclic substituted with one, two, three or four substituents each independently selected from the group consisting of oxo, halo, cyano, -OH, -OR7, -S(=O)2-R7, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(Ci-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-Ci-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-Ci-4alkyl-O-R7, -NH-S(=O)2-R7, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-Ci-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, and -S(=O)2-Ci-4alkyl; orCi-4alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of cyano, halo, -OH, -OR7, -S(=O)2-R7, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(Ci-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-Ci-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-Ci-4alkyl-O-R7, -NH-S(=O)2-R7, -CF3, Cy1, Het3a, Het3b, -O-Het3b, -C(=O)-Het3a, -C(=O)-Het3b, andor R3aand R3bare taken together to form together with the nitrogen atom to which they are attached Het2;Cy1represents Cs-ecycloalkyl; or Cs-ecycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -OR7, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-Ci-4alkyl, -N=S(=O)-(Ci-4alkyl)2, -NH-(C=O)-Ci-4alkyl, -NH-(C=O)-C3-6cycloalkyl, -C(=O)-NR4aR4b, and -NH-S(=O)2-R7;Het1represents 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 Het1represents a bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected fromO, S, and N; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the groupconsisting of oxo, halo, cyano, -OH, -OR7-S(=O)2-R7, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(Ci-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-Ci-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-Ci-4alkyl-O-R7, -NH-S(=O)2-R7, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-Ci-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, and -S(=O)2-Ci-4alkyl; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, Het5, -C(=O)-NR4aR4b, -C(=O)-Ci-4alkyl, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, -C(=O)-C3-6cycloalkyl, or Ci-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH and halo;Het2represents 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 Het2represents 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; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, halo, cyano, -OH, -OR7, Het6, -S(=O)2-R7, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(Ci-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-Ci-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-Ci-4alkyl-O-R7, -NH-S(=O)2-R7, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-Ci-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, Het4and -S(=O)2-Ci-4alkyl; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, -C(=O)-NR4aR4b, -C(=O)-Ci-4alkyl, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, Het4, or -C(=O)-C3-6cycloalkyl;Het3arepresents 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 Het3arepresents a bicyclic N-linked 6- to 11 -membered fully saturatedheterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, halo, -OH, -OR7, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-Ci-4alkyl, -N=S(=O)-(Ci-4alkyl)2, -NH-(C=O)-Ci-4alkyl, -NH-(C=O)-C3-6cycloalkyl, -C(=O)-NR4aR4b, and -NH-S(=O)2-R7; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, Het5, -C(=O)-NR4aR4b, -C(=O)-Ci-4alkyl, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, -C(=O)-C3-6cycloalkyl, or Ci-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH and halo;Het3brepresents 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 Het3brepresents 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; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, halo, -OH, Ci-4alkyl, -OR7, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-Ci-4alkyl, -N=S(=O)-(Ci-4alkyl)2, -NH-(C=O)-Ci-4alkyl, -NH-(C=O)-C3-6cycloalkyl, -C(=O)-NR4aR4b, and -NH-S(=O)2-R7; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, Het5, -C(=O)-NR4aR4b, -C(=O)-Ci-4alkyl, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, -C(=O)-C3-6cycloalkyl, or Ci-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH and halo;Het4represents 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; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH);Het5represents 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; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH);Het6represents 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; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O),S(=O)2, or S(=O)(=NH);R4aand R4beach independently represent hydrogen, Ci-4alkyl, Cs-ecycloalkyl, or Ci-4alkyl-O-Ci-4alkyl;R4Cand R4deach independently represent Ci-4alkyl or -O-Ci-4alkyl;R5a, R5b, R7a, R8a, and R9are each independently selected from the group consisting of hydrogen and Ci-4alkyl;R6represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH;R7represents Ci-4alkyl or Cs-ecycloalkyl, each optionally substituted with one, two or three halo substituents; pl and p2 each independently are 1, 2 or 3; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 whereinAr represents thiazolyl or pyridinyl;Raand Rbare each independently selected from the group consisting of hydrogen or -C(=O)-NR5aR5b;Rlarepresents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents;Rlbrepresents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents;represents phenyl; n is 0;R3arepresents hydrogen or Ci-4alkyl;R3brepresents hydrogen; Ci-4alkyl; Cs-ecycloalkyl; adamantyl; Ce-iocarbobicyclic; Het1;C3-6cycloalkyl substituted with one, two, three or four substituents each independently selected from the group consisting of oxo, -OH, -OR7, -S(=O)2-R7, -S(=O)2-NR4aR4b, - NR4aR4b, -S(=O)(=NH)-R7, -NH-(C=O)-R7, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, - NH-S(=O)2-R7, Het3a, Het3b, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, - S(=O)(=NH)-Ci-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, and -S(=O)2-Ci-4alkyl;Ce-iocarbobi cyclic substituted with one, two, three or four substituents each independently selected from the group consisting of -OR7, -S(=O)2-R7, and -S(=O)2-NR4aR4b; orCi-4alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of cyano, halo, -OH, -OR7, -S(=O)2-R7, -S(=O)2-NR4aR4b, - NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(Ci-4alkyl)2, -C(=O)-NR4aR4b, -P(=O)-R4cR4d, -O- Ci-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-Ci-4alkyl-O-R7, -NH-S(=O)2-R7, - Cy1, Het3a, Het3b, -O-Het3b, -C(=O)-Het3a, andor R3aand R3bare taken together to form together with the nitrogen atom to which they are attached Het2;Cy1represents Cs-ecycloalkyl; or Cs-ecycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of -S(=O)2-Ci-4alkyl, and -S(=O)2- NR4aR4b;Het1represents 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 Het1represents a bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected fromO, S, and N; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, -OH, -OR7-S(=O)2-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, - P(=O)-R4cR4d, -O-Ci-4alkyl-C(=O)-NR4aR4b, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, and -C(=O)-NR4aR4b; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl,Het5, -C(=O)-Ci-4alkyl, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, -C(=O)-C3-6cycloalkyl, or Ci- 4alkyl substituted with one, two or three -OH;Het2represents 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 Het2represents 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; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of Het6, -S(=O)2-NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(Ci-4alkyl)2, -C(=O)- NR4aR4b, and Ci-4alkyl optionally substituted with one, two or three -S(=O)2-Ci-4alkyl; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Het4;Het3arepresents 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 Het3arepresents 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; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, and -OH; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, Het5, -C(=O)-Ci-4alkyl, -S(=O)2-Ci-4alkyl, -S(=O)2-NR4aR4b, or -C(=O)-C3-6cycloalkyl;Het3brepresents 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 Het3brepresents 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; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, halo, -OH, Ci-4alkyl, and -OR7; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH);wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, Het5, or -S(=O)2-Ci-4alkyl;Het4represents 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; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH);Het5represents 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; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH);Het6represents 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; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)2, or S(=O)(=NH); pl and p2 are 2.

3. The compound according to claim 1 or 2 whereinAr represents thiazolyl or pyridinyl;Raand Rbare each independently selected from the group consisting of hydrogen or -C(=O)-NR5aR5b;Rlarepresents hydrogen or halo;Rlbrepresents hydrogen, halo, or Ci-4alkyl; ringrepresents phenyl; n is 0;R3arepresents hydrogen;R3brepresents hydrogen; Ci-4alkyl; Cs-ecycloalkyl; or C3-6cycloalkyl substituted with one -S(=O)2-R7;R5aand R5bare hydrogen ;R6represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH;R7represents Ci-4alkyl.

4. The compound according to any one of claims 1-3 wherein n is 0.

5. The compound according to any one of claims 1-3 wherein n is 1.

6. The compound according to any one of the preceding claims wherein ringrepresents phenyl, and R6represents methyl.

7. The compound according to any one of the preceding claims wherein R3arepresents hydrogen.

8. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 7 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.

9. A compound as claimed in any one of claims 1 to 7 or a pharmaceutical composition as claimed in claim 8 for use as a medicament.

10. A compound as claimed in any one of claims 1 to 7 or a pharmaceutical composition as claimed in claim 8 for use in the treatment or prevention of cancer.

11. A compound as claimed in any one of claims 1 to 7 or a pharmaceutical composition as claimed in claim 18 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.

12. 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 7 or a pharmaceutical composition as claimed in claim 8.

13. A compound of F ormula (A)Formula (A) or a tautomer or a stereoisomeric form thereof, whereinAr represents phenyl, thiazolyl, 1,2,4-thiadiazolyl, isothiazolyl, oxazolyl, pyrazolyl, pyridinonyl or pyridinyl;Raand Rbare each independently selected from the group consisting of hydrogen; halo;Ci-4alkyl; -C(=O)-NR5aR5b; -O-Ci-4alkyl; -CN; -NR7aR8a; -C(=O)-O-R9; C3-6cycloalkyl;-O-Ci-4alkyl substituted with 1, 2 or 3 halo substituents; orCi-4alkyl substituted with 1, 2 or 3 halo substituents;Rlarepresents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents;Rlbrepresents hydrogen, halo, Ci-4alkyl, Cs-ecycloalkyl, -OH, or Ci-4alkyl substituted with 1, 2 or 3 halo substituents; or Rlaand Rlbare taken together to form together with the carbon atom to which they are attached a Cs-ecycloalkyl; ringrepresents phenyl or pyridyl;R2represents halo; n is 0, 1 or 2;R5a, R5b, R7a, R8a, and R9are each independently selected from the group consisting of hydrogen and Ci-4alkyl;R6represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH; or a pharmaceutically acceptable salt thereof.

Images