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]JAB7225WOPCT1 MALT1 INHIBITORS FIELD OF THE INVENTION The present invention relates to a novel compound that is a MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) inhibitor. The compound may be useful for 5 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 10 and autoimmunological diseases, syndromes, disorders, or conditions associated with MALT1 inhibitors. BACKGROUND OF THE INVENTION MALT1 (mucosa-associated lymphoid tissue lymphoma translocation 1) is a key mediator of the classical NF^B signaling pathway. MALT1 is the only human paracaspase and 15 transduces signals from the B cell receptor (BCR) and T cell receptor (TCR). MALT1 is the active subunit of the CBM complex which is formed upon receptor activation. The CBM complex consists of multiple subunits of three proteins: CARD11 (caspase recruitment domain family member 11), BCL10 (B-cell CLL / Lymphoma 10) and MALT1. MALT1 affects NF^B signaling by two mechanisms: Firstly, MALT1 functions as a scaffolding protein and recruits 20 NF^B signaling proteins such as TRAF6, TAB-TAK1 or NEMO-IKKα / ^; and secondly, MALT1, as a cysteine protease, cleaves and thereby deactivates negative regulators of NF^B signaling, such as RelB, A20 or CYLD. The ultimate endpoint of MALT1 activity is the nuclear translocation of the NF^B transcription factor complex and activation of NF^B signaling. Constitutive activation of NF^B signaling is the hallmark of ABC-DLBCL (Diffuse 25 Large B cell Lymphoma of the Activated B Cell-like subtype), the more aggressive form of DLBCL. DLBCL is the most common form of non-Hodgkin’s lymphoma (NHL), accounting for approximately 25% of lymphoma cases while ABC-DLBCL comprises approximately 40% of DLBCL. NF^B pathway activation is driven by mutations of signaling components, such as CD79A / B, CARD11, MYD88 or A20, in ABC-DLBCL patients. 30 The use of BTK inhibitors, for example Ibrutinib, provides clinical proof-of-concept that inhibiting NF^B signaling in ABC-DLBCL is efficacious. MALT1 is downstream of BTK in the NF^B signaling pathway and a MALT1 inhibitor could target ABC-DLBCL patients not responding to Ibrutinib, mainly patients with CARD11 mutations, as well as treat patients that acquired resistance to Ibrutinib. 35 Small molecule tool compound inhibitors of MALT1 protease have demonstrated efficacy in preclinical models of ABC-DLBCL. Interestingly, covalent catalytic site and 1 JAB7225WOPCT1 allosteric inhibitors of MALT1 protease function have been described, suggesting that inhibitors of this protease may be useful as pharmaceutical agents. The chromosomal translocation creating the API2-MALT1 fusion oncoprotein is the most common mutation identified in MALT (mucosa-associated lymphoid tissue) lymphoma. 5 API2-MALT1 is a potent activator of the NF^B pathway. API2-MALT1 mimics ligand-bound TNF receptor, promotes TRAF2-dependent ubiquitination of RIP1 which acts as a scaffold for activating canonical NF^B signaling. Furthermore, API2-MALT1 has been shown to cleave and generate a stable, constitutively active fragment of NF^B-inducing kinase (NIK) thereby activating the non-canonical NF^B pathway. 10 In addition to lymphomas, MALT1 has been shown to play a critical role in innate and adaptive immunity. MALT1 protease inhibitor can attenuate disease onset and progression of mouse experimental allergic encephalomyelitis, a mouse model of multiple sclerosis. Mice expressing catalytically inactive MALT1 mutant showed loss of marginal zone B cells and B1 B cells and general immune deficiency characterized as decreased T and B cell activation and 15 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 20 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 25 by potentially increasing antitumor immunity. Thus, MALT1 inhibitors of the present invention may provide a therapeutic benefit to patients suffering from cancer and / or immunological diseases. SUMMARY OF THE INVENTION 30 The present invention is directed to compounds of Formula (I) 2 JAB7225WOPCT1 and the tautomers and the stereoisomeric forms thereof, wherein Het is a monocyclic or bicyclic heterocyclic radical selected from ; 5 Rarepresents C1-4alkyl, -C1-4alkyl-O-C1-4alkyl, or C1-4alkyl substituted with 1, 2 or 3 halo; R1brepresents cyano; R1crepresents hydrogen or C1-4alkyl; R1drepresents hydrogen or C1-4alkyl; 10 R1erepresents hydrogen or halo; R1frepresents hydrogen or halo; R1grepresents hydrogen or C1-4alkyl; rin represents phenyl or pyridyl; 15 R2represents halo; n is 0, 1 or 2; R3arepresents hydrogen or C1-4alkyl; R3brepresents hydrogen; C1-4alkyl; C3-6cycloalkyl; adamantyl; C6-10carbobicyclic; Het1; 20 C3-6cycloalkyl 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)-(C1-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, 3 JAB7225WOPCT1 -O-C1-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-C1-4alkyl-O-R7, -NH-S(=O)2-R7, Het3a, Het3b, and C1-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-C1-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, and -S(=O)2-C1-4alkyl; 5 C6-10carbobicyclic 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)-(C1-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-C1-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-C1-4alkyl-O-R7, -NH-S(=O)2-R7, and C1-4alkyl optionally substituted with 10 one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-C1-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, and -S(=O)2-C1-4alkyl; or C1-4alkyl 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, 15 -NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(C1-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-C1-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-C1-4alkyl-O-R7, -NH-S(=O)2-R7, -CF3, Cy1, Het3a, Het3b, -O-Het3b, -C(=O)-Het3a, -C(=O)-Het3b, and ; 20 or R aand R are taken together to form together with the nitrogen atom to which they are attached Het2; Cy1represents C3-6cycloalkyl; or C3-6cycloalkyl substituted with one, two or three substituents 25 each independently selected from the group consisting of halo, -OH, -OR7, -S(=O)2-C1-4alkyl, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-C1-4alkyl, -N=S(=O)-(C1-4alkyl)2, -NH-(C=O)-C1-4alkyl, -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 30 Het1represents 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, cyano, -OH, -OR7-S(=O)2-R7, -S(=O)2-NR4aR4b, -NR4aR4b, 35 -S(=O)(=NH)-R7, -N=S(=O)-(C1-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, 4 JAB7225WOPCT1 -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-C1-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-C1-4alkyl-O-R7, -NH-S(=O)2-R7, and C1-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-C1-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, and 5 -S(=O)2-C1-4alkyl; 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 C1-4alkyl, Het5, -C(=O)-NR4aR4b, -C(=O)-C1-4alkyl, -S(=O)2-C1-4alkyl, -S(=O)2-NR4aR4b, 10 -C(=O)-C3-6cycloalkyl, or C1-4alkyl 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 15 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 20 consisting of oxo, halo, cyano, -OH, -OR7, Het6, -S(=O)2-R7, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(C1-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-C1-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-C1-4alkyl-O-R7, -NH-S(=O)2-R7, and C1-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of 25 -OH, halo, -S(=O)(=NH)-C1-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, Het4and -S(=O)2-C1-4alkyl; 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 C1-4alkyl, 30 -C(=O)-NR4aR4b, -C(=O)-C1-4alkyl, -S(=O)2-C1-4alkyl, -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 35 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; 5 JAB7225WOPCT1 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-C1-4alkyl, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-C1-4alkyl, -N=S(=O)-(C1-4alkyl)2, -NH-(C=O)-C1-4alkyl, 5 -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 C1-4alkyl, Het5, -C(=O)-NR4aR4b, -C(=O)-C1-4alkyl, -S(=O)2-C1-4alkyl, -S(=O)2-NR4aR4b, 10 -C(=O)-C3-6cycloalkyl, or C1-4alkyl 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 15 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, C1-4alkyl, -OR7, -S(=O)2-C1-4alkyl, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-C1-4alkyl, -N=S(=O)-(C1-4alkyl)2, -NH-(C=O)-C1-4alkyl, 20 -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 C1-4alkyl, Het5, -C(=O)-NR4aR4b, -C(=O)-C1-4alkyl, -S(=O)2-C1-4alkyl, -S(=O)2-NR4aR4b, 25 -C(=O)-C3-6cycloalkyl, or C1-4alkyl 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; 30 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), 35 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 6 JAB7225WOPCT1 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); 5 R4aand R4beach independently represent hydrogen, C1-4alkyl, C3-6cycloalkyl, or C1-4alkyl-O-C1-4alkyl; R4cand R4deach independently represent C1-4alkyl or -O-C1-4alkyl; R6represents C1-4alkyl; or C1-4alkyl substituted with one -OH; R7represents C1-4alkyl or C3-6cycloalkyl, each optionally substituted with one, two or three 10 halo substituents; p1 and p2 each independently are 1, 2 or 3; and the pharmaceutically acceptable salts thereof. The present invention is also directed to compounds of Formula (A) 15 and the tautome Het is a monocyclic or bicyclic heterocyclic radical selected from ; 7 JAB7225WOPCT1 R1arepresents C1-4alkyl, -C1-4alkyl-O-C1-4alkyl, or C1-4alkyl substituted with 1, 2 or 3 halo; R1brepresents cyano; R1crepresents hydrogen or C1-4alkyl; R1drepresents hydrogen or C1-4alkyl; 5 R1erepresents hydrogen or halo; R1frepresents hydrogen or halo; R1grepresents hydrogen or C1-4alkyl; rin represents phenyl or pyridyl; 10 R2represents halo; n is 0, 1 or 2; R6represents C1-4alkyl; or C1-4alkyl substituted with one -OH; and the pharmaceutically acceptable salts thereof. 15 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). 20 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. 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 25 configuration (e.g. by a stereodescriptor such as R, S, ‘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 30 two or more stereoisomers. 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 8 JAB7225WOPCT1 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). 5 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. 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 10 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’). 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 15 undetermined. 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, indica s on the cyclobutyl moiety have trans-configuration. 20 It will be clear for a skilled person that the bold bonds on a 1,3-disubstituted cyclobutyl moiety as shown below: , whereby X1and X2represent substituents, indica s on the cyclobutyl moiety have cis-configuration. It will be clear for a skilled person that a hashed bond and a bold bond on a 1,4- 25 disubstituted cyclohexyl moiety as shown below: , whereby X1and X2represent substituents, 9 JAB7225WOPCT1 indicate that the substituents on the cyclohexyl moiety have trans-configuration. 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, 5 indica on the cyclohexyl moiety have cis-configuration. 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 10 within the scope of the present invention. If a compound contains a double bond, the substituents may be in the E or the Z configuration. 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, 15 trans isomers and mixtures thereof, whenever chemically possible. It will be clear this also applies to compounds of Formula (A). 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 20 to the Cahn-Ingold-Prelog system. 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. 25 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). Also provided are processes for making a pharmaceutical composition comprising, 30 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 10 JAB7225WOPCT1 (A). The present invention further provides methods for treating or ameliorating a disease, syndrome, condition, or disorder in a subject, including a mammal and / or human in which the disease, syndrome, or condition is affected by the inhibition of MALT1, including but not 5 limited to, cancer and / or immunological diseases, using a compound of Formula (I). It will be clear this also applies to compounds of Formula (A). The present invention also is directed to the use of any of the compounds described herein in the preparation of a medicament wherein the medicament is prepared for treating a disease, syndrome, condition, or disorder that is affected by the inhibition of MALT1, such as 10 cancer and / or immunological diseases. The present invention is also directed to the preparation of compounds of Formula (I) that act as an inhibitor of MALT1. The present invention is also directed to the preparation of compounds of Formula (A) that act as an inhibitor of MALT1. Exemplifying the invention are methods of treating a disease, syndrome, condition, or 15 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, 20 marginal zone lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, Burkitt’s lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström 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 25 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, 30 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 35 invention. 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), 11 JAB7225WOPCT1 mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma. An embodiment of the present invention is directed to a compound of Formula (I) for (use in) the treatment of immunological diseases that are affected by the inhibition of MALT1, 5 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, 10 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 15 distress syndrome, BENTA disease, berylliosis, and polymyositis. 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 20 (SLE), asthma, and chronic obstructive pulmonary disease (COPD). 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 25 Waldenström macroglobulinemia. In yet another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is lymphoma. 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- 30 cell lymphoma (DLBCL). 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). In another embodiment of the invention, the disease, syndrome, condition, or disorder 35 affected by inhibition of MALT1 is non-germinal center B cell like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL). 12 JAB7225WOPCT1 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). In another embodiment of the invention, the lymphoma is MALT lymphoma. 5 In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is Waldenström macroglobulinemia (WM). 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 10 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 non- Hodgkin’s lymphoma (NHL) is B-cell NHL. In another embodiment, the non-Hodgkin’s lymphoma (NHL) is relapsed / refractory B-cell NHL. 15 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 Waldenström macroglobulinemia (WM), relapsed / refractory mantle cell lymphoma (MCL), relapsed / refractory follicular lymphoma (FL), and 20 relapsed / refractory mucosa-associated lymphoid tissue (MALT) lymphoma. 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). In another embodiment of the invention, the disease, syndrome, condition, or disorder 25 affected by inhibition of MALT1 is relapsed / refractory Waldenström macroglobulinemia (WM). In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is relapsed / refractory mantle cell lymphoma (MCL). In another embodiment of the invention, the disease, syndrome, condition, or disorder 30 affected by inhibition of MALT1 is relapsed / refractory follicular lymphoma (FL). 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. Compounds of Formula (I) may be used for the treatment of immunological diseases 35 including, but not limited to, autoimmune and inflammatory disorders, e.g. sepsis-related acute 13 JAB7225WOPCT1 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, 5 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 10 diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis. In another embodiment of the present invention, the compounds of the present 15 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. Possible combinations of the compounds of the present invention may include, but are 20 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-PD1 antibodies, and anti-PD-L1 antibodies. 25 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. 30 All possible combinations of the above-indicated embodiments are considered to be embraced within the scope of this invention. 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 MALT1. 35 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 14 JAB7225WOPCT1 disorder affected by inhibition of MALT1. In another embodiment, the present invention is directed to methods of treating said disease, syndrome, condition, or disorder mediated by MALT1. 5 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 10 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. 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 15 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. The transitional terms “comprising,” “consisting essentially of,” and “consisting of” are 20 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 25 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.” The prefix ‘Cx-y’ (where x and y are integers) as used herein refers to the number of carbon 30 atoms in a given group. Thus, a C1-4alkyl group contains from 1 to 4 carbon atoms, and so on. The term ‘C1-4alkyl’ 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, n-butyl, s-butyl, t-butyl and the like. The term ‘C3-6cycloalkyl’ as used herein as a group or part of a group defines a saturated, cyclic 35 hydrocarbon radical having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, 15 JAB7225WOPCT1 cyclopentyl and cyclohexyl. Fused bicycles or fused bicyclic groups, are two cycles that share two atoms and the bond between these atoms. Spiro bicycles or spiro bicyclic groups, are two cycles that are joined at a single atom. 5 Bridged bicycles or bridged bicyclic groups, are two cycles that share more than two atoms. The term ‘C6-10carbobicyclic’ as used herein as a group or part of a group defines a saturated, bicyclic hydrocarbon radical having from 6 to 10 carbon atoms. C6-10carbobicyclic can be fused, spiro or bridged, such as spiro[3.3]heptanyl and bicyclo[1.1.1]pentanyl. The term ‘monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one 10 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- 15 oxathianyl, C-linked thiazinanyl, C-linked tetrahydropyranyl, C-linked tetrahydrothiopyranyl, C-linked pyrazolidinyl, C-linked isothiazolidinyl, C-linked oxazolidinyl, and C-linked piperidinyl. Bicyclic C-linked 6- to 11-membered fully saturated heterocyclyl groups can be fused, spiro 20 or bridged. The term ‘bicyclic C-linked 6- to 11-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, 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, 25 and N, such as for example: , , 16 JAB7225WOPCT1 d 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 a N-linked fully saturated, monocyclic radical having from 4 to 7 ring members in total 5 (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. 10 Bicyclic N-linked 6- to 11-membered fully saturated heterocyclyl groups can be fused, spiro or bridged. 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’, 15 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: , , 17 JAB7225WOPCT1 . 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). 5 C-linked means attached to the remainder of the molecule through any available carbon atom. N-linked means attached to the remainder of the molecule through any available nitrogen atom. The term “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine atoms. 10 A skilled person will understand R2is absent when n is 0. It will be clear for the skilled person that S(=O)2or SO2represents a sulfonyl moiety. It will be clear for the skilled person that a group such as -S(=O)(=NH)-C1-4alkyl represents . ill be clear for the skilled person that a group such as -S(=O)(=NH)-R (with R 15 being any substituent) represents . It will be clear for the skilled person that a group such as -N=S(=O)-(C1-4alkyl)2 represents . 20 for the skilled person that a group such as -NH-(C=O)-C1-4alkyl represents 18 JAB7225WOPCT1 . r the skilled person that a group such as -NH-(C=O)-C3-6cycloalkyl represents . 5 It will be clear for the skilled person that a group such as -NH-(SO2)-C1-4alkyl represents . e clear for the skilled person that a group such as -NH-(SO2)-R (with R being any substituent) represents . 10 Whenever substituents are represented by chemical structure, “---” represents the bond of attachment to the remainder of the molecule of Formula (I) or F ormula (A). When any variable occurs more than one time in any constituent, each definition is independent. When any variable occurs more than one time in any formula (e.g. Formula (I)), each definition 15 is independent. 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 20 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). 25 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). 19 JAB7225WOPCT1 Lines drawn from substituents into ring systems indicate that the bond may be attached to any of the suitable ring atoms. The stereodescriptor label “R” or “(R)” at a stereocenter designates that the stereocenter is purely of the R-configuration as defined in the art; likewise, the stereodescriptor label “S” or 5 “(S)” means that the stereocenter is purely of the S-configuration. 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). 10 Unlabeled stereocenters drawn without stereo bond designations are mixtures of the R- and S- configurations. For unlabeled stereocenters drawn with stereo bond designations, the absolute stereochemistry is as depicted. 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 15 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). Unless otherwise noted, it is intended that the definition of any substituent or variable at a 20 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. 25 The term “subject” refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. 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 30 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. 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 35 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 20 JAB7225WOPCT1 activity (normal or abnormal) of MALT1; or (2) reduce or inhibit the activity of MALT1; or (3) reduce or inhibit the expression of MALT1; or (4) modify the protein levels of MALT1. The term “composition” refers to a product that includes the specified ingredients in 5 therapeutically effective amounts, as well as any product that results, directly, or indirectly, from combinations of the specified ingredients in the specified amounts. Suitable examples of a disease, syndrome, condition, or disorder mediated by MALT1 include, but are not limited to, lymphomas, leukemias, carcinomas, and sarcomas, e.g. non- Hodgkin’s lymphoma (NHL (including B-cell NHL)), diffuse large B-cell lymphoma 10 (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), Waldenström macroglobulinemia, lymphoblastic T cell leukemia, chronic myelogenous leukemia (CML), hairy-cell leukemia, acute lymphoblastic T 15 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 20 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). As used herein, the term "MALT1 inhibitor" refers to an agent that inhibits or reduces 25 at least one condition, symptom, disorder, and / or disease of MALT1. 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 MALT1) 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 30 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. 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 35 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 21 JAB7225WOPCT1 “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, 5 syndrome or disorder. The compounds of the instant invention may be useful in methods for treating or ameliorating a disease, a syndrome, a condition or a disorder that is affected by the inhibition of MALT1. 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 10 and / or prevention, a therapeutically effective amount of a compound of Formula (I). One embodiment of the present invention is directed to a method of treating a MALT1- dependent or MALT1-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). 15 In another embodiment, the MALT1-dependent or MALT1-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. In particular, the compounds of Formula (I) may be useful for treating or ameliorating 20 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. More particularly, the compounds of Formula (I) may be useful for treating or ameliorating diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), 25 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. 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 30 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). Whenever possible, any embodiment for the compounds of Formula (I) as listed hereinabove or hereinafter, also holds for the compounds of Formula (A). 35 22 JAB7225WOPCT1 The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein Het is a monocyclic or bicyclic heterocyclic radical selected from (a-1) and (a-4); 5 R1arepresents C1-4alkyl or -C1-4alkyl-O-C1-4alkyl; R1brepresents cyano; R1crepresents C1-4alkyl; R1frepresents halo; 10 rin represents phenyl; R2represents halo; n is 0, 1 or 2; R3arepresents hydrogen; 15 R3brepresents C1-4alkyl; C3-6cycloalkyl; or C3-6cycloalkyl substituted with one -S(=O)2-R7; R6represents C1-4alkyl; R7represents C1-4alkyl; and the pharmaceutically acceptable salts thereof. 20 The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein Het is a monocyclic or bicyclic heterocyclic radical selected from (a-1) and (a-4); 25 R1arepresents C1-4alkyl or -C1-4alkyl-O-C1-4alkyl; R1brepresents cyano; R1crepresents C1-4alkyl; R1frepresents Cl; 30 rin represents phenyl; 23 JAB7225WOPCT1 R2represents F; n is 0, 1 or 2; R3arepresents hydrogen; R3brepresents C1-4alkyl; or C3-6cycloalkyl substituted with one -S(=O)2-R7; 5 R6represents methyl; R7represents methyl; and the pharmaceutically acceptable salts thereof. The present invention relates in particular to compounds of Formula (I) as defined herein, and 10 the tautomers and the stereoisomeric forms thereof, wherein Het is a monocyclic or bicyclic heterocyclic radical selected from ; Rarepresents C1-4alkyl, -C1-4alkyl-O-C1-4alkyl, or C1-4alkyl substituted with 1, 2 or 3 halo; 15 R1brepresents cyano; R1crepresents hydrogen or C1-4alkyl; R1drepresents hydrogen or C1-4alkyl; R1erepresents hydrogen or halo; R1frepresents hydrogen or halo; 20 R1grepresents hydrogen or C1-4alkyl; rin represents phenyl; 24 JAB7225WOPCT1 R2represents halo; n is 0, 1 or 2; 5 R3arepresents hydrogen or C1-4alkyl; R3brepresents hydrogen; C1-4alkyl; C3-6cycloalkyl; adamantyl; C6-10carbobicyclic; 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, - 10 NH-S(=O)2-R7, Het3a, Het3b, and C1-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, - S(=O)(=NH)-C1-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, and -S(=O)2-C1-4alkyl; C6-10carbobicyclic 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 15 C1-4alkyl 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)-(C1-4alkyl)2, -C(=O)-NR4aR4b, -P(=O)-R4cR4d, -O- C1-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-C1-4alkyl-O-R7, -NH-S(=O)2-R7, - Cy1, Het3a, Het3b, -O-Het3b, -C(=O)-Het3a, and 20 ; or R aand R are taken together to form together with the nitrogen atom to which they are attached Het2; 25 Cy1represents C3-6cycloalkyl; or C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of -S(=O)2-C1-4alkyl, 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 30 Het1represents 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, -OH, -OR7-S(=O)2-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, - 35 P(=O)-R4cR4d, -O-C1-4alkyl-C(=O)-NR4aR4b, and C1-4alkyl optionally substituted with 25 JAB7225WOPCT1 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); 5 wherein one or more of the N-atoms in said heterocyclyl might be substituted with C1-4alkyl, Het5, -C(=O)-C1-4alkyl, -S(=O)2-C1-4alkyl, -S(=O)2-NR4aR4b, -C(=O)-C3-6cycloalkyl, or C1- 4alkyl substituted with one, two or three -OH; Het2represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl 10 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 15 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)-(C1-4alkyl)2, -C(=O)- NR4aR4b, and C1-4alkyl optionally substituted with one, two or three -S(=O)2-C1-4alkyl; 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); 20 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 25 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; 30 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 C1-4alkyl, Het5, -C(=O)-C1-4alkyl, -S(=O)2-C1-4alkyl, -S(=O)2-NR4aR4b, or -C(=O)-C3-6cycloalkyl; Het3brepresents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl 35 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; 26 JAB7225WOPCT1 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, C1-4alkyl, and -OR7; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), 5 S(=O)2, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with C1-4alkyl, Het5, or -S(=O)2-C1-4alkyl; Het4represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl 10 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; 15 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 20 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, C1-4alkyl, C3-6cycloalkyl, or C1-4alkyl-O- 25 C1-4alkyl; R4cand R4deach independently represent C1-4alkyl or -O-C1-4alkyl; R6represents C1-4alkyl; or C1-4alkyl substituted with one -OH; R7represents C1-4alkyl or C3-6cycloalkyl, each optionally substituted with one, two or three halo substituents; 30 p1 and p2 are 2; and the pharmaceutically acceptable salts thereof. The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein 35 Het is a monocyclic or bicyclic heterocyclic radical selected from 27 JAB7225WOPCT1 ; Rarepresents C1-4alkyl, -C1-4alkyl-O-C1-4alkyl, or C1-4alkyl substituted with 1, 2 or 3 halo; R1brepresents cyano; 5 R1crepresents hydrogen or C1-4alkyl; R1drepresents hydrogen or C1-4alkyl; R1erepresents hydrogen or halo; R1frepresents hydrogen or halo; R1grepresents hydrogen or C1-4alkyl; 10 rin represents phenyl; R2represents halo; n is 0, 1 or 2; 15 R3arepresents hydrogen or C1-4alkyl; R3brepresents hydrogen; C1-4alkyl; C3-6cycloalkyl; adamantyl; C6-10carbobicyclic; 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, -20 NR4aR4b, -S(=O)(=NH)-R7, -NH-(C=O)-R7, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, - NH-S(=O)2-R7, Het3a, Het3b, and C1-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, - S(=O)(=NH)-C1-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, and -S(=O)2-C1-4alkyl; 28 JAB7225WOPCT1 C6-10carbobicyclic 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 C1-4alkyl 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, - 5 NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(C1-4alkyl)2, -C(=O)-NR4aR4b, -P(=O)-R4cR4d, -O- C1-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-C1-4alkyl-O-R7, -NH-S(=O)2-R7, - Cy1, Het3a, Het3b, -O-Het3b, -C(=O)-Het3a, and ; 10 or R aand R are taken together to form together with the nitrogen atom to which they are attached Het2; Cy1represents C3-6cycloalkyl; or C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of -S(=O)2-C1-4alkyl, and -S(=O)2- 15 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 from O, S, and N; 20 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: C-linked azetidinyl, C-linked oxetanyl, C-linked pyrrolidinyl, C-linked tetrayhydrothiophenyl, C-linked tetrahydrofuranyl, C-linked morpholinyl, C-linked 1,4- 25 oxathianyl, C-linked thiazinanyl, C-linked tetrahydropyranyl, C-linked tetrahydrothiopyranyl, C-linked pyrazolidinyl, C-linked isothiazolidinyl, C-linked oxazolidinyl, C-linked piperidinyl, , , 29 JAB7225WOPCT1 ; erocyclyl 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-C1-4alkyl-C(=O)-NR4aR4b, and C1-4alkyl optionally substituted with 5 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 C1-4alkyl,10 Het5, -C(=O)-C1-4alkyl, -S(=O)2-C1-4alkyl, -S(=O)2-NR4aR4b, -C(=O)-C3-6cycloalkyl, or C1- 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 15 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 20 following heterocyclyls: 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, , , 30 JAB7225WOPCT1 ; w e 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)-(C1-4alkyl)2, -C(=O)- NR4aR4b, and C1-4alkyl optionally substituted with one, two or three -S(=O)2-C1-4alkyl; 5 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 10 from O, S, and N; provided that the monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl is selected from the following heterocyclyls: N-linked azetidinyl, N-linked pyrrolidinyl, N-linked morpholinyl, N-linked thiazinanyl, N- linked pyrazolidinyl, N-linked isothiazolidinyl, N-linked oxazolidinyl, N-linked 15 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; 20 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 C1-4alkyl, Het5, -C(=O)-C1-4alkyl, -S(=O)2-C1-4alkyl, -S(=O)2-NR4aR4b, or -C(=O)-C3-6cycloalkyl; Het3brepresents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl 25 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 30 following heterocyclyls: C-linked azetidinyl, C-linked oxetanyl, C-linked pyrrolidinyl, C-linked tetrayhydrothiophenyl, C-linked tetrahydrofuranyl, C-linked morpholinyl, C-linked 1,4- 31 JAB7225WOPCT1 oxathianyl, C-linked thiazinanyl, C-linked tetrahydropyranyl, C-linked tetrahydrothiopyranyl, C-linked pyrazolidinyl, C-linked isothiazolidinyl, C-linked oxazolidinyl, C-linked piperidinyl, ; the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group 5 consisting of oxo, halo, -OH, C1-4alkyl, 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 C1-4alkyl, Het5, or -S(=O)2-C1-4alkyl; 10 Het4represents C-linked oxetanyl; Het5represents C-linked oxetanyl; R4aand R4beach independently represent hydrogen, C1-4alkyl, C3-6cycloalkyl, or C1-4alkyl-O- C1-4alkyl; 15 R4cand R4deach independently represent C1-4alkyl or -O-C1-4alkyl; R6represents C1-4alkyl; or C1-4alkyl substituted with one -OH; R7represents C1-4alkyl or C3-6cycloalkyl, each optionally substituted with one, two or three halo substituents; p1 and p2 are 2; 20 and the pharmaceutically acceptable salts thereof. 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. 25 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. In an embodiment, the present invention relates to those compounds of Formula (I) and the 32 JAB7225WOPCT1 pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein n is 1. In an embodiment, the present invention relates to those compounds of Formula (I) and the 5 pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein rin represents phenyl. In an embodiment, the present i ates 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 rin represents phenyl and n is 0. 10 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 rin represents phenyl, and R6represents methyl. In an embodiment, the present i ates to those compounds of Formula (I) and the 15 pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein rin represents phenyl, n is 0, and R6represents methyl. 20 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 R3brepresents C1-4alkyl; or C3-6cycloalkyl substituted with one -S(=O)2-C1-4alkyl. In an embodiment, the present invention relates to those compounds of Formula (I) and the 33 JAB7225WOPCT1 pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3brepresents C1-4alkyl. In an embodiment, the present invention relates to those compounds of Formula (I) and the 5 pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R3brepresents C3-6cycloalkyl substituted with one -S(=O)2-C1-4alkyl; in particular cyclobutyl substituted with one -S(=O)2-C1-4alkyl; more in particular cyclobutyl substituted with one - S(=O)2-CH3. 10 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-C1-4alkyl is limited to -S(=O)2-CH3. 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 15 other embodiments, wherein R6represents CH3. 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 20 trans: (R2)nR6O I) . 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 25 cis: (R2)nR6O I) . 34 JAB7225WOPCT1 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: (R2)nR6O I) 5 , and wherein R6represents methyl. , ose 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: (R2)nR6O I) 10 , and wherein R6represents methyl. 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 15 in Formula (I) is as indicated below in Formula (I-a): . In an embodimen t, 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 20 other embodiments, wherein the stereochemistry of the substituents on the cyclopropyl moiety in Formula (I) is as indicated below in Formula (I-b): 35 JAB7225WOPCT1 . 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 5 other embodiments, wherein Formula (I) and the stereochemistry of the substituents on the cyclopropyl moiety are as indicated below in Formula (I-a1): . In an embodime nt, the present invention relates to those compounds of Formula (I) and the 10 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-b1): . 15 Whenever possible, any embodiment for the compounds of Formula (I) as listed hereinabove, also holds for the compounds of Formula (A). In an embodiment, the present invention relates to a subgroup of Formula (I) as defined in the general reaction schemes. 20 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. 25 In an embodiment the compound of Formula (I) is selected from the group consisting of 36 JAB7225WOPCT1 compounds 4, 7, 57, 64, 67, 71, 73, 77, and 96. In an embodiment the compound of Formula (I) is selected from the group consisting of compounds 4, 7, 57, 64, 67, 71, 73, 77, and 96; 5 tautomers and stereoisomeric forms thereof, and the pharmaceutically acceptable salts thereof. In an embodiment the compound of Formula (I) is selected from the group consisting of compounds 4, 7, 57, 64, 67, 71, 73, 77, and 96; 10 and the pharmaceutically acceptable salts thereof. 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, 15 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, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134 and 135. 20 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, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 25 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134 and 135; tautomers and stereoisomeric forms thereof, and the pharmaceutically acceptable salts thereof. 30 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, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 35 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134 and 135; and the pharmaceutically acceptable salts thereof. 37 JAB7225WOPCT1 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. 5 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. 10 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 4, 7, 57, 64, 67, 71, 73, 77, and 96. 15 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 4, 7, 57, 64, 67, 71, 73, 77, and 96; 20 tautomers and stereoisomeric forms thereof, and the pharmaceutically acceptable salts thereof. In an embodiment the compound of Formula (I) is compound 4 or a pharmaceutically acceptable salt thereof. In an embodiment the compound of Formula (I) is compound 7 or a pharmaceutically 25 acceptable salt thereof. In an embodiment the compound of Formula (I) is compound 57 or a pharmaceutically acceptable salt thereof. In an embodiment the compound of Formula (I) is compound 64 or a pharmaceutically acceptable salt thereof. 30 In an embodiment the compound of Formula (I) is compound 67 or a pharmaceutically acceptable salt thereof. In an embodiment the compound of Formula (I) is compound 71 or a pharmaceutically acceptable salt thereof. In an embodiment the compound of Formula (I) is compound 73 or a pharmaceutically 35 acceptable salt thereof. In an embodiment the compound of Formula (I) is compound 77 or a pharmaceutically acceptable salt thereof. In an embodiment the compound of Formula (I) is compound 96 or a pharmaceutically 38 JAB7225WOPCT1 acceptable salt thereof. In an embodiment the compound of Formula (I) is compound 4. In an embodiment the compound of Formula (I) is compound 7. 5 In an embodiment the compound of Formula (I) is compound 57. In an embodiment the compound of Formula (I) is compound 64. In an embodiment the compound of Formula (I) is compound 67. In an embodiment the compound of Formula (I) is compound 71. In an embodiment the compound of Formula (I) is compound 73. 10 In an embodiment the compound of Formula (I) is compound 77. In an embodiment the compound of Formula (I) is compound 96. In an embodiment the compound of Formula (I) is 15 harmaceutically acceptable salt thereof. In particular wherein the stereochemistry of the cyclopropyl moiety is trans, in particular trans A. In an embodiment the compound of Formula (I) is 20 thereof. In an embodiment the compound of Formula (I) is . 39 JAB7225WOPCT1 In an embodiment the compound of Formula (I) is lt thereof. 5 In an embodiment the compound of Formula (I) is lt thereof. 10 In an embodiment the compound of Formula (I) is . In an embodiment the compound of Formula (I) is 15 lt thereof. 40 JAB7225WOPCT1 In an embodiment the compound of Formula (I) is . 5 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 10 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 15 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, 20 hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate. 25 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, (+)-(1S)-camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic30 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, ^-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, 41 JAB7225WOPCT1 lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-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, 5 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, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, 10 potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine, tromethamine, and zinc hydroxide. 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 15 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 20 described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985. 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. A person of ordinary skill in the art would recognize that the compounds described 25 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. 30 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 35 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 42 JAB7225WOPCT1 compounds of Formula (I). 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 5 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 10 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. 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 15 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 and 18O. The isotopes may be radioactive or non-radioactive. Radiolabelled compounds of formula 20 (I) may comprise one or more isotope(s) selected from the group of3H,11C,18F,122I,123I,125I, 131I,75Br,76Br,77Br and82Br. Preferably, the isotope is selected from the group of2H,3H,11C and18F. In particular, deuterated compounds are intended to be included within the scope of the present invention. During any of the processes for preparation of the compounds of the various 25 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. Even though the compounds of embodiments of the present invention (including their 30 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 35 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. 43 JAB7225WOPCT1 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. 5 Solid oral dosage forms such as, tablets or capsules, containing the compounds of the present invention may be administered in at least one dosage form at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations. A therapeutically effective amount of a compound of Formula (I) or a pharmaceutical composition thereof includes a dose range from about 0.1 mg to about 3000 mg, or any 10 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. It has been found that the compounds of the present invention inhibit MALT1 activity. In some embodiments, the inhibition of MALT1 by a provided compound may be useful 15 in treating or preventing, in particular treating, the non-limiting list of cancers described herein. The invention relates to compounds of Formula (I) for use as a medicament. The invention relates to compounds of Formula (A) for use as a medicament. The invention relates to compounds of Formula (I) for use in the inhibition of MALT1 activity. 20 The invention relates to compounds of Formula (A) for use in the inhibition of MALT1 activity. The invention relates to compounds of Formula (I) for use in the treatment of diseases mentioned herein. The invention relates to compounds of Formula (A) for use in the treatment of diseases mentioned herein. 25 The invention relates to compounds of Formula (I) for the treatment or prevention, in particular for the treatment, of said diseases. The invention relates to compounds of Formula (A) for the treatment or prevention, in particular for the treatment, of said diseases. The invention relates to compounds of Formula (I) for the treatment or prevention, in particular 30 in the treatment, of MALT1 mediated diseases or conditions. The invention relates to compounds of Formula (A) for the treatment or prevention, in particular in the treatment, of MALT1 mediated diseases or conditions. The invention relates to compounds of Formula (I) for the manufacture of a medicament. 44 JAB7225WOPCT1 The invention relates to compounds of Formula (A) for the manufacture of a medicament. The invention relates to compounds of Formula (I) for the manufacture of a medicament for the inhibition of MALT1. The invention relates to compounds of Formula (A) for the manufacture of a medicament for 5 the inhibition of MALT1. The invention relates to compounds of Formula (I) for the manufacture of a medicament for the treatment or prevention, in particular for the treatment, of any one of the disease conditions mentioned herein. The invention relates to compounds of Formula (A) for the manufacture of a medicament for 10 the treatment or prevention, in particular for the treatment, of any one of the disease conditions mentioned herein. The invention relates to compounds of Formula (I) for the manufacture of a medicament for the treatment of any one of the disease conditions mentioned herein. The invention relates to compounds of Formula (A) for the manufacture of a medicament for 15 the treatment of any one of the disease conditions mentioned herein. The invention relates to compounds of Formula (I) that can be administered to mammals, preferably humans, for the treatment or prevention of any one of the diseases mentioned herein. The invention relates to compounds of Formula (A) that can be administered to mammals, preferably humans, for the treatment or prevention of any one of the diseases mentioned herein. 20 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 warm- blooded animals, including humans, to suffer from any one of the diseases mentioned herein. 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 warm- 25 blooded animals, including humans, to suffer from any one of the diseases mentioned herein. GENERAL SYNTHETIC METHODS 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. 30 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. 45 JAB7225WOPCT1 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. 5 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 10 convenient subsequent stage using methods known from the art. 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 sodium hydride, lithium diisopropyl amide, or methyl magnesium bromide is used in the reaction. 15 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). The skilled person will realize that heating the reaction mixture under stirring may enhance the 20 reaction outcome. In some reactions microwave heating may be used instead of conventional heating to shorten the overall reaction time. 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). The skilled person will realize that intermediates and final compounds shown in the Schemes 25 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. 30 For abbreviations used in the Schemes below, check the table with abbreviations in the part ‘Examples’. In general, compounds of Formula I can be prepared as exemplified below in General Scheme 1, wherein the variables are described as hereabove: 46 JAB7225WOPCT1 General Scheme 1 Compounds of general formula (I) can be prepared via a coupling reaction between an 5 intermediate of formula (II) and formula (III). This reaction may be performed in the presence of a suitable base, such as, for example, Cs2CO3, K2CO3or K3PO4. This reaction can be performed in a reaction-inert solvent, such as, for example, tBuOH, toluene, or dioxane. The reaction is typically performed in the presence of a catalyst system comprising a suitable catalyst such as BrettPhos PdG3, or SPhos PdG4 and a ligand such as BrettPhos. Preferably, 10 this reaction is carried out under an inert atmosphere, such as nitrogen or argon atmosphere, and in a suitable temperature range, such as for instance room temperature to 120 °C, under conventional heating or microwave irradiation. An intermediate of Formula II can be synthesized according to the general Schemes below, if not commercially available. 15 An intermediate of general Formula (II-a1), where Het is described by the general formula (a- 1), can be prepared according to General Scheme 2. General Scheme 2 l; 20 47 JAB7225WOPCT1 Step 1. An intermediate of Formula (IV), where Hlg = Cl, Br, is reacted with an amine source, such as for instance diphenylmethylamine, typically in a solvent such as for instance toluene. This reaction is typically performed in the presence of a palladium catalyst, such as for instance Pd2(dba)3, a ligand, such as for instance rac-BINAP and a base such as NaOtBu, in a suitable 5 temperature range, such as for example 100 °C to 120 °C, to provide an intermediate of general Formula (V). Step 2. An intermediate of Formula (V) is reacted with a suitable acid, such as for instance aqueous HCl at a concentration of 6M, or with a solution of HCl in DCM at a concentration of 1 M, in a suitable solvent, such as for instance MeOH or DCM, and at a suitable temperature, 10 such as for instance room temperature, to provide an intermediate of general Formula (VI). Step 3. An intermediate of Formula (VI) is reacted with a cyanide source, such as zinc cyanide, in the presence of Zn, typically in a solvent such as for instance DMF or DMA, in the presence of a palladium catalyst such as for instance Pd2(dba)3, in the presence of a ligand, such as dppf, in a suitable temperature range such as for instance 120 °C to 180 °C, to provide an intermediate 15 of Formula (II-(a-1)). Step 4. Alternatively, an intermediate of Formula (V) is reacted with a cyanide source, such as zinc cyanide, in the presence of Zn, typically in a solvent such as for instance DMF or DMA, in the presence of a palladium catalyst such as for instance Pd2(dba)3, in the presence of a ligand, such as dppf, in a suitable temperature range such as for instance 120 °C to 180 °C, to provide 20 an intermediate of Formula (VII). Step 5. An intermediate of Formula (VII) is reacted with a suitable acid, such as for instance aqueous HCl at a concentration of 6M, or with a solution of HCl in DCM at a concentration of 1 M, in a suitable solvent, such as for instance MeOH or DCM, and at a suitable temperature, such as for instance room temperature, to provide an intermediate of general Formula (II-(a- 25 1)). An intermediate of Formula (IV) can be obtained from commercial sources, or, alternatively, can be prepared according to General Scheme 3. 48 JAB7225WOPCT1 General Scheme 3. 5 In general Scheme 3, Hlg represents Cl or Br, whereas R1ais further detailed in text where appropriate. In general Scheme 3, the following reaction conditions typically apply. Step 1. An intermediate of Formula (VIII), where Hlg = Cl or Br, is reacted with a suitable base, such as lithium diisopropyl amide (LDA), typically in an aprotic solvent, such as for instance anhydrous THF, in a suitable temperature range, such as -78 °C to RT, and in the 10 presence of an alkylating agent, such as R1a-I to provide an intermediate of Formula (IV), where R1arepresents C1-4alkyl, and Hlg = Cl or Br. Step 2. Alternatively, an intermediate of Formula (VIII) is reacted with a base, such as LDA, typically in an aprotic solvent, such as for example anhydrous THF, in a suitable temperature range such as for example -70°C to RT, and in the presence of a formyl donor, such as DMF, 15 to provide an intermediate of Formula (IX). Step 3. An intermediate of Formula (IX) is reacted with an appropriate fluorinating agent, such as diethylaminosulfur trifluride (DAST), in an appropriate solvent, such as DCM, in a suitable temperature, such as 0 °C, to provide an intermediate of Formula (IV) where R1arepresents CHF2. 20 Step 4. Alternatively, an intermediate of Formula (VIII) is reacted with a base, such as LDA, typically in an aprotic solvent, such as for example anhydrous THF, in a suitable temperature range such as for example -78°C to room temperature, and in the presence of an aldehyde of 49 JAB7225WOPCT1 general formula Rx-CHO, wherein Rxis represented by C1-4alkyl, to provide an intermediate of Formula (X). Step 5. An intermediate of Formula (X) is reacted with an alkylating agent Ry-Hlg, wherein Ryis represented by C1-4alkyl, typically in an aprotic solvent, such as for example anhydrous THF, 5 and in the presence of a suitable base such as sodium hydride (NaH), in a suitable temperature range such as for example 0°C to room temperature, to provide an intermediate of Formula (IV), where R1ais represented by C1-4alkyl-O-C1-4alkyl. An intermediate of general Formula (II-a2), where Het is described by the general formula (a- 2), can be prepared according to General Scheme 4. 10 General Scheme 4. In General Scheme 4, R1drepresents hydrogen or C1-4alkyl. Step 1. An intermediate of Formula (XI) (known in the art or can be prepared by a skilled person) is reacted with a chlorinating agent such as for instance phosphorous oxychloride 15 (POCl3), neat or in an appropriate solvent, such as DCM, optionally in the presence of a base, such as for instance triethylamine (Et3N) or DIPEA, in a suitable temperature range, such as 70 °C to 95 °C, to provide a compound of Formula (XII). Step 2. An intermediate of Formula (XII) is reacted with a suitable base, such as LiOH, in a suitable solvent, such as water or a mixture of water and a suitable organic solvent such as 50 JAB7225WOPCT1 dioxane or THF, in a suitable temperature range, such as 0 °C to 40 °C, to provide an intermediate of Formula (XIII). Step 3. An intermediate of Formula (XIII) is reacted with an azide source, such as diphenyl phosphorylazide, in the presence of a suitable base, such as Et3N or DIPEA, in a suitable 5 solvent, such as toluene or tBuOH, and in the presence of tBuOH. This reaction is performed at a suitable temperature, for instance 90 °C, to provide an intermediate of Formula (XIV). Step 4. An intermediate of Formula (XIV) is reacted under inert atmosphere with an appropriate boronic acid or boronic acid derivative, such as, for instance potassium trifluoro(vinyl)borate, in a suitable solvent, such as for instance DMF, in the presence of a suitable base, such as 10 K2CO3and a suitable Pd catalyst, such as, for instance, AmPhos PdCl2, and at a suitable temperature, such as, for instance 100 °C, to provide an intermediate of general Formula (XV). Step 5. An intermediate of Formula (XV) is reacted with H2 in a suitable solvent, such as for instance MeOH, in the presence of a suitable catalyst, such as for instance Pd / C, and in a suitable temperature range, such as RT to 30 °C, to provide an intermediate of Formula (XVI). 15 Step 6. An intermediate of Formula (XVI) is reacted with a suitable acid, such as for instance TFA, in a suitable solvent, such as DCM and at a suitable temperature ranging from 0 °C to RT, to provide an intermediate of Formula (II-a2), where R1a= Et. A skilled person will understand that starting from (XIV) or (XV), intermediates with other definitions in the position R1acan be prepared. 20 An intermediate of general Formula (II-a3), where Het is described by the general Formula (a- 3), can be prepared according to General Scheme 5. 51 JAB7225WOPCT1 General Scheme 5 Step 1. An intermediate of Formula (XVII) is reacted with H2in a suitable solvent, such as for 5 instance acetic acid (AcOH), in the presence of a suitable catalyst, such as for instance iron powder (Fe), and at a suitable temperature, such as 60 °C, to provide an intermediate of Formula (XVIII). Step 2. An intermediate of Formula (XVIII) is reacted under inert atmosphere with an appropriate organoborane source, such as triethyl borane (BEt3), in a suitable solvent, such as 10 a mixture of dioxane and water, in the presence of a suitable base, such as K2CO3 and a suitable Pd catalyst, such as, for instance, Bis(triphenylphosphine)palladium(II) dichloride, (PPh3)2PdCl2, and at a suitable temperature, such as, for instance 75 °C, to provide an intermediate of Formula (II-a3), where R1ais represented by an ethyl group. 52 JAB7225WOPCT1 Step 3. Alternatively, an intermediate of formula (XVIII) can be protected with a suitable protecting group, such as for instance Boc. This reaction can be performed with, for instance, with Boc anhydride, typically in a solvent such as THF or DCM, in the presence of a base such as for instance triethyl amine, and catalytical amounts of DMAP, at a suitable temperature 5 ranging from RT to 70 °C, to provide an intermediate of Formula (XIX), where PG = Boc. Step 4. An intermediate of formula (XIX) is reacted, for instance, under Stille coupling conditions with an appropriate tin derivative, such as for instance, tributylvinyltin, in a suitable solvent, such as for instance toluene in the presence of a suitable Pd catalyst, such as, for instance, tetrakis(triphenylphosphine)palladium(0), Pd(PPh3)4, and at a suitable temperature, 10 such as, for instance 90 °C, to provide an intermediate of Formula (XX). Step 5. An intermediate of Formula (XX) is reacted under appropriate oxidative cleavage conditions, such as, for instance with N-methylmorpholine N-oxide-monohydrate (NMO), sodium periodate and osmium tetraoxide (OsO4), in an appropriate solvent, such as for instance a mixture of dioxane and water, at a suitable temperature range, such as, for instance 0 °C to 15 RT, to provide an intermediate of Formula (XXI). Step 6. An intermediate of Formula (XXI) is reacted with an appropriate fluorinating agent, such as diethylaminosulfur trifluride (DAST), in an appropriate solvent, such as DCM, in a suitable temperature range, such as 0 °C, to provide an intermediate of Formula (II-a3) where R1arepresents CHF2. 20 Step7. Alternatively, an intermediate of Formula (XVIII) is reacted with, for instance, tributyl(1-ethoxyvinyl)tin in a suitable solvent, such as for instance toluene or 1,4-dioxane and in the presence of a suitable Pd catalyst, such as, for instance, tetrakis(triphenylphosphine)- palladium(0), Pd(PPh3)4, at a suitable temperature, such as, for instance 90 °C, to provide an intermediate of general formula (XXII). 25 Step 8. An intermediate of Formula (XXII) is reacted with a suitable acid, such as for instance, aqueous HCl at a concentration of 3M, in a suitable solvent, such as for instance THF or 1,4- dioxane, and a suitable temperature range, such as for instance room temperature to 60 °C, to provide an intermediate of Formula (XXIII). Step 9. An intermediate of Formula (XXIII) is reacted with a reducing agent, such as for 30 instance NaBH4or LiAlH4, in a suitable solvent, such as MeOH, THF or Me-THF, at an appropriate temperature, such as, for instance 0 °C o RT, to provide an intermediate of Formula (XXIV). Step 10. An intermediate of Formula (XXIV) is reacted with an alkylating agent of Formula (XXXIV), wherein Rxis represented by C1-4alkyl and Hlg = Cl, Br, I. The reaction is carried out 35 in the presence of a suitable base, such as NaH, in a suitable solvent, such as THF, and in a suitable temperature range, such as, for instance 0 °C to RT to provide an intermediate of Formula (II-a3,) where R1ais represented by CH3-CH-ORx, and Rxis represented by C1-4alkyl. 53 JAB7225WOPCT1 An intermediate of general Formula (II-a4), where Het is described by the general Formula (a- 4), can be prepared according to General Scheme 6 General Scheme 6 5 In General Scheme 6, R1frepresents hydrogen or halo. 10 Step 1. An intermediate of Formula (XXV) is reacted with a 1,3-dicarbonyl derivative of Formula (XXVI), in the presence of N,N-dimethylformamide dimethyl acetal (DMF-DMA), at a suitable temperature, such as 120 °C, to provide an intermediate of Formula (XXVII). Step 2. An intermediate of Formula (XXVII) is reacted with a suitable acid, such as for instance TFA, in a suitable solvent, such as DCM and at a suitable temperature, such as RT, to provide 15 an intermediate of Formula (XXVIII). Step 3. A compound of Formula (XXVIII) is reacted with an azide source, such as diphenyl phosphorylazide, in the presence of a suitable base, such as Et3N or DIPEA, in a suitable solvent, such as tBuOH, or a mixture of toluene and tBuOH. This reaction is performed at a suitable temperature, for instance 90 °C, to provide an intermediate of Formula (XXIX). 20 Step 4. An intermediate of Formula (XXIX) is reacted with a suitable acid, such as for instance TFA, in a suitable solvent, such as DCM and at a suitable temperature ranging from 0 °C to RT, to provide an intermediate of Formula (II-a2), where R1ais defined as in the general descriptions. 25 An intermediate of general (Formula II-a5), where Het is described by the general Formula (a- 5), can be prepared according to General Scheme 7. 54 JAB7225WOPCT1 Scheme 7 OEt OEt O 2 where Ra= CH3-CH-OR and Rx= C1-4alkylIn General Scheme 7, R1grepresents hydrogen or C1-4alkyl, and R1ais as defined in the Scheme. Step 1. A known intermediate of Formula (XXX) is reacted with, for instance, tributyl(1- 5 ethoxyvinyl)tin in a suitable solvent, such as for instance toluene or 1,4-dioxane and in the presence of a suitable Pd catalyst, such as, for instance Pd(PPh3)4, or Pd(PPh3)2Cl2, at a suitable temperature, such as, for instance 80 °C, to provide an intermediate of general Formula (XXXI) Step 2. An intermediate of Formula (XXXI) is reacted with a suitable acid, such as for instance, aqueous HCl at a concentration of 3M, in a suitable solvent, such as for instance THF or 1,4- 10 dioxane, and a suitable temperature range, such as for instance room temperature to 60 °C, to provide an intermediate of Formula (XXXII). Step 3. An intermediate of Formula (XXXII) is reacted with a reducing agent, such as for instance NaBH4or LiAlH4, in a suitable solvent, such as MeOH, THF or Me-THF, at an appropriate temperature, such as, for instance 0 °C o RT, to provide an intermediate of Formula 15 (XXXIII). Step 4. An intermediate of Formula (XXXIII) is reacted with an alkylating agent of Formula (XXXIV), where Rxis represented by C1-4alkyl and Hlg = Cl, Br I. The reaction is carried out in the presence of a suitable base, such as NaH, in a suitable solvent, such as THF, and in a suitable temperature range, such as, for instance 0 °C to RT, to provide an intermediate of Formula (II- 20 a5,) where R1ais represented by CH3-CH-ORx, and Rxis represented by C1-4alkyl. 55 JAB7225WOPCT1 An intermediate of general Formula (II-a6), where Het is described by the general formula (a- 6), can be prepared according to General Scheme 8. Scheme 8 with 1, 2 or 3 halo, and R1frepresents hydrogen or halo. Step 1. A known amino-imidazole of Formula (XXXV) [1008130-15-1] can be protected with a suitable protecting group, such as for instance Boc. This reaction can be performed with, for instance, with Boc anhydride, typically in a solvent such as THF or DCM, in the presence of a 56 JAB7225WOPCT1 base such as for instance triethyl amine, and catalytical amounts of DMAP, at a suitable temperature ranging from RT to 70 °C, to provide an intermediate of Formula (XXXV). Step 2. An intermediate of Formula (XXXV) is halogenated with an appropriate halogen source, such as for instance NCS, NBS, NIS, or Selectfluor, in an appropriate solvent, such as, 5 for instance, DMF, and at a suitable temperature, such as, for instance, RT, to provide an intermediate of Formula (XXXVI). Step 3. An intermediate of Formula (XXXV) or Formula (XXXVI) is condensed with an appropriate ester, such as, for instance, ethyl acetate, in the presence of an appropriate base, such as for instance KOtBu, in an appropriate solvent, such as THF, and at an appropriate 10 temperature, such as for instance RT, to afford an intermediate of Formula (XXXVII). Step 4. An intermediate of Formula (XXXVII) is condensed with a suitable reagent, such as, for instance, DMF-DMA, in an appropriate solvent, such as, for instance DCM, and at a suitable temperature, such as, for instance RT, to provide an intermediate of Formula (XXXVIII). Step 5. An intermediate of Formula (XXXVIII) is reacted with an appropriate halogenating 15 reagent, such as phosphorus(V)oxybromide (POBr3), in a suitable solvent, such as, for instance, acetonitrile, and at a suitable temperature range, such as RT to 90 °C, to provide an intermediate of Formula (XXXIX). Step 6. An intermediate of Formula (XXXIX) is reacted with an appropriate boronic acid or derivative, such as, for instance triethylborane, in a suitable solvent, such as for instance DMF, 20 dioxane, or THF, in the presence of a suitable base, such as K2CO3and a suitable Pd catalyst, such as, for instance, Pd(PPh3)2Cl2, and at a suitable temperature, such as, for instance 120 °C, optionally under microwave irradiation, to provide an intermediate of Formula (XL). Step 7. An intermediate of Formula (XL) is reacted with a suitable base, such as LiOH, in a suitable solvent, such as water or a mixture of water and a suitable organic solvent such as 25 dioxane or THF, in a suitable temperature range, such as 0 °C to 40 °C, to provide an intermediate of Formula (XLI). Step 8. A compound of Formula (XLI) is reacted with an azide source, such as diphenyl phosphorylazide, in the presence of a suitable base, such as Et3N or DIPEA, in a suitable solvent, such as tBuOH, or a mixture of toluene and tBuOH. This reaction is performed at a 30 suitable temperature, for instance 90 °C, to provide an intermediate of Formula (XLII). Step 9. An intermediate of Formula (XLII) is reacted with a suitable acid, such as for instance TFA, in a suitable solvent, such as DCM and at a suitable temperature ranging from 0 °C to RT, to provide an intermediate of Formula (II-a6). 35 In general, compounds of Formula (III) can be prepared as exemplified below in General Scheme 9, wherein the variables are described as hereabove: 57 JAB7225WOPCT1 General Scheme 9 LIV) according to Horner-Wadsworth-Emmon’s reaction conditions. A person skilled in the art will 5 understand that the choice of the R’ substituent in intermediate (XLIV) will enable the formation of either Z- or E- forms of intermediate (XLV). For example, when R’ represents - CH2CF3, typically a Z isomer is obtained. For example, when R’ represents ethyl, typically a E isomer is obtained. The reaction is performed 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 10 to 25 °C, to provide an intermediate of Formula (XLV). Alternatively, an intermediate of Formula (XLV), in which R6is C1-4alkyl 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 (XLV), in which R6is C1-4alkyl substituted 15 with -OH, the alcohol moiety may be protected with a suitable protecting group, such as triisopropylsilyl. which could be kept throughout the synthetic scheme. Step 2. An intermediate of Formula (XLV) is reacted with a suitable reductant, such as for instance, DIBAL-H, in a suitable solvent, such as for instance THF, and a suitable temperature 58 JAB7225WOPCT1 range, such as for instance 0 °C to 25 °C, to provide an intermediate of Formula (XLVIa). An intermediate of Formula (XLVIa) 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 5 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 (XLVIb) where PG= triisopropylsilyl or acetyl. Step 3. An intermediate of Formula (XLVIb) is reacted with a suitable difluorocyclopropanation reagent, such as methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, in the 10 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 (XLVIIa). Alternatively, intermediate of Formula (XLVIb) is reacted with a suitable difluorocyclopropanation reagent, such as (bromodifluoromethyl)trimethylsilane, in a suitable solvent such as, for instance, toluene, at a 15 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 (XLVIIa). An intermediate of Formula (XLVIIa) 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 20 (XLVIIb). Step 4. An intermediate of formula (XLVIIb) 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 NaHCO3, 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 25 intermediate of Formula (XLVIII). Step 5. An intermediate of Formula (XLVIII) 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 TEA, typically in a solvent such as ACN, at a suitable temperature, such as for example room temperature, to provide an intermediate of 30 Formula (III). Step 6. Alternatively, an intermediate of Formula (XLV) 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 35 intermediate of Formula (XLIX). Step 7. An intermediate of Formula (XLIX) is reacted under hydrolysis conditions to provide an intermediate of Formula (XLVIII). This reaction can be performed in the presence of a 59 JAB7225WOPCT1 suitable base, such as LiOH, in a suitable solvent system, such as water / THF optionally containing EtOH or MeOH, and at a suitable temperature range, such as room temperature. In the preparation of compounds of the present invention, protection of remote functionality 5 (e.g., primary amine or alcohol) 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 preparations methods. Suitable amino-protecting groups include but are not limited to t- butoxycarbonyl (Boc), and acetyl. Suitable alcohol protecting groups include t- butyldimethylsilyl. The need for such protection is readily determined by one skilled in the art. 10 It will be appreciated that where appropriate functional groups exist, compounds of various formulae or any intermediates used in their preparation may be further derivatised by one or more standard synthetic methods employing condensation, substitution, oxidation, reduction, or cleavage reactions. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation and 15 coupling procedures. The compounds of Formula (I) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of Formula (I) containing a basic nitrogen atom may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral 20 acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of Formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the 25 appropriate starting materials, provided that the reaction occurs stereospecifically. 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 acetyl,30 trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz) and 9- fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. Specific Examples 35 The following examples further illustrate the present invention. 60 JAB7225WOPCT1 EXAMPLES 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 5 be synthesized by a skilled person by using well-known methods. Abbreviation Meaning 61 JAB7225WOPCT1 Abbreviation Meaning 62 JAB7225WOPCT1 Abbreviation Meaning 63 JAB7225WOPCT1 Abbreviation Meaning As understood by a person skilled in the art, Compounds synthesized using the protocols as indicated may contain residual solvent or minor impurities. A skilled person will realize that, even where not mentioned explicitly in the experimental 5 protocols below, typically after a column chromatography purification, the desired fractions were collected, and the solvent was evaporated. In case no stereochemistry is indicated, this means it is a mixture of stereoisomers, unless otherwise is indicated or is clear from the context. 10 Preparation of intermediates 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 64 JAB7225WOPCT1 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 5 xture of 3,5-dibromo-4-ethylpyridine [125419-80-9] (9.60 g, 35.87 mmol), benzophenone imine [1013-88-3] (7.12 g, 39.31 mmol) and cesium carbonate (24.22 g, 74.34 mmol) in 1,4-dioxane (240 ml) was purged with nitrogen. Pd2(dba)3(1.65 g, 1.80 mmol) and Xantphos [161265-03-8] (2.08 g, 3.59 mmol) were added. The mixture was purged with 10 nitrogen then heated at 90 ºC for 4 hours. After cooling down to room temperature the reaction was diluted with 20 ml of EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (eluent: heptane:EtOAc 95:5 to 80:20). The desired fractions were combined, and the solvent was removed in vacuo to yield Intermediate 15 1 (12.35 g, 84% yield) as a yellow solid. Intermediate 2 diate 1 (23.46 g, 64.23 mmol) and zinc dust [7440-66-6] (1.29 g, 19.7120 mmol) in dry DMA (200 mL) under nitrogen was stirred for 10 min. Then zinc cyanide [557- 21-1] (9.02 g, 76.80 mmol) and Pd(dppf)Cl2^CH2Cl2[95464-05-4] (5.28 g, 6.45 mmol) were added and the mixture was heated to 130 ºC for 2 h. The mixture was cooled to room temperature, then filtered over celite. An aqueous saturated solution of NaHCO3 was added and the organic phase was extracted with ethyl acetate, washed with brine, dried over MgSO4, 25 filtered, and concentrated in vacuo to give the crude product. The crude product was purified by flash column chromatography over silica gel (eluent: Heptane:EtOAc 95:5 to 65:35). Pure fractions were combined and concentrated in vacuum to yield Intermediate 2 (20.00 g, 90% yield) as a yellow solid. 65 JAB7225WOPCT1 Intermediate 3 of Intermediate 2 (20.00 g, 57.81 mmol) in MeOH (280 mL), HCl aqueous solution 6M (175 ml, 1050 mmol) was added and the mixture was stirred at room temperature 5 for 2 h. The mixture was diluted with water and extracted with DCM (3 x). The aqueous phase was quenched with NaHCO3and extracted with DCM (3 x). Finally, the organic layer was concentrated in vacuo to yield Intermediate 3 (6.77 g, 77% yield) as a white crystalline solid. Intermediate 4 10 (-78°C) solution of 3,5-dibromo-2-methylpyridine [38749-87-0] (1.00 g, 3.99 mmol) in THF (10 mL) was added LDA [4111-54-0] (2M in THF / heptane / ethylbenzene, 2.39 mL, 4.78 mmol). The resulting mixture was stirred for 30 min at -78°C at which time ethyl iodide [74-88-4] (0.32 mL, 3.99 mmol) was added. The mixture was stirred for 1 h at -78 °C at 15 which time a saturated aqueous solution of NH4Cl was added (5 mL) was added. The mixture was diluted with EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc (2 x) and the combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by flash column chromatography over silica gel (eluent: Cyclohexane:EtOAc 100:0 to 85:15). 20 The fractions containing compound were combined and concentrated in vacuo to give Intermediate 4 (0.81 g, 73% yield) as a yellow oil. Intermediate 5 25 f Intermediate 4 (0.70 g, 2.51 mmol) in toluene (15 mL) were added benzophenone imine [1013-88-3] (0.58 mL, 3.01 mmol) and NaOtBu (0.48 g, 5.02 mmol). The mixture was purged with N2at which time Pd2(dba)3[51364-51-3] (0.12 g, 0.13 mmol) and rac-BINAP [98327-87-8] (0.16 mg, 0.25 mmol) were added. The mixture was purged again 66 JAB7225WOPCT1 with N2 for 5 min then heated at 120 °C for 2 h. After cooling to RT, the reaction was diluted with 20 mL of EtOAc. The organic layer was washed with water (3 x 15 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by flash column chromatography over silica gel (eluent: 5 cyclohexane:EtOAc 100:0 to 80:20).The fractions containing compound were combined and concentrated in vacuo to give Intermediate 2 (0.82 g, 86% yield) as a colorless solid. Intermediate 6 10 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 5 (0.70 g, 1.85 mmol) instead of Intermediate 2, to give Intermediate 6 (0.33 g, 88% yield) as a yellow solid. Intermediate 7 15 ution of Intermediate 6 (0.30 g, 1.40 mmol) in DMA (7.0 mL) were added Zn(CN)2[557-21-1] (0.15 mg, 1.26 mmol) and Zn [7440-66-6] (22.8 mg, 0.35 mmol). The mixture was purged with N2for 5 min at which time Pd2(dba)3[51364-51-3] (63.9 mg, 0.07 mmol) and dppf [12150-46-8] (77.3 mg, 0.14 mmol) were added. The mixture was purged with 20 N2for 5 min then heated at 180 °C for 2 h. After cooling to RT, the mixture was diluted with EtOAc (10 mL) and a 10% aqueous solution of NaHCO3(5 mL) was added. The mixture was filtered through a pad of Celite, and the phases were separated. The aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated in vacuo to give the crude product. The crude product was purified by 25 flash column chromatography over silica gel (eluent: cyclohexane:EtOAc from 80:20 to 50:50). The fractions containing compound were combined and concentrated in vacuo to give Intermediate 7 (0.20 g, 89% yield) as a yellow solid. 67 JAB7225WOPCT1 Intermediate 8 repared by an analogous reaction protocol as Intermediate 1, starting from commercially available 3,5-dibromo-4-(difluoromethyl)pyridine [1805252-89-4] (15.90 g, 5 54.86 mmol) instead of 3,5-dibromo-4-ethylpyridine, to give Intermediate 8 (14.50 g, 68% yield) as a yellow solid. Intermediate 9 10 repared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 8 (27.45 g, 70.89 mmol) instead of Intermediate 1 to give Intermediate 9 (30.76 g, 73% yield) as a yellow solid. Intermediate 10 15 0 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 9 (28.26 g, 76.31 mmol) instead of Intermediate 2, to give Intermediate 10 (10.30 g, 80% yield) as a yellow solid. 20 Intermediate 11 .0 mL, 150.00 mmol) was added dropwise to a solution of diisopropylamine (22.9 ml, 162.5 mmol) in anhydrous THF (325 ml) under nitrogen at -78 ºC. The mixture was stirred for 30 minutes. Commercially available 3,5-dibromo-2-methylpyridine [38749-87-0] (31.36 g, 68 JAB7225WOPCT1 125.0 mmol) was diluted in anhydrous THF (50 ml) and added dropwise to the solution that was then stirred for 30 min at -78 ºC. DMF (14.5 mL, 187.5 mmol) was added dropwise, and the mixture was stirred for 1 h at -78 ºC. The reaction mixture was carefully added onto a stirred saturated aqueous solution of NH4Cl , the mixture then extracted with EtOAc. The organic layer 5 was washed with brine, dried over MgSO4, and filtered. Solvent was evaporated to dryness under reduced pressure. The crude was purified by flash column chromatography over silica gel (eluent: Heptane:EtOAc from 95:5 to 75:25). The desired fractions were combined and concentrated under vacuo to afford Intermediate 11 (20.40 g, 59% yield) as a yellow pale solid. 10 Intermediate 12 9 ml, 218.29 mmol) was added dropwise to a solution of Intermediate 11 (20.30 g, 72.77 mmol) in 364 ml of dry DCM at 0 ºC under nitrogen and the mixture was stirred at rt for 20 h. The reaction mixture was carefully poured in ice-water with NaHCO3 (400 ml). The 15 mixture was extracted with DCM (300 ml). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography (Heptane:EtOAc up to 50:50). The desired fractions were combined, and the solvent was removed in vacuo to yield Intermediate 12 (20.50 g, 97% yield) as an off-white solid. 20 Intermediate 13 prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 12 (10.00 g, 33.21 mmol) instead of 3,5-dibromo-4-ethylpyridine, and heating to 25 90 ºC for 20 hours, to give Intermediate 13 (10.11 g, 99% yield) as a yellow solid. 69 JAB7225WOPCT1 Intermediate 14 prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 13 (4.00 g, 9.97 mmol) instead of Intermediate 1, to give Intermediate 14 (3.65 g, 5 95% yield) as a yellow solid. Intermediate 15 5 was prepared by an analogous reaction protocol as Intermediate 3, starting from 10 Intermediate 14 (1.00 g, 2.88 mmol) instead of Intermediate 2, to give Intermediate 15 (0.53 g, 99% yield) as a brown solid. Intermediate 16 15 .4 mL, 103.62 mmol) was added dropwise to a solution of diisopropylamine (10.5 ml, 103.62 mmol) in anhydrous THF (230 ml) under nitrogen at -78 ºC. The mixture was stirred for 30 minutes. Commercially available 3,5-dibromo-2-methylpyridine [38749-87-0] (20.00 g, 79.71 mmol) was diluted in anhydrous THF (10 ml) and added dropwise to the solution that was then stirred for 1 h at -78 ºC. Then acetaldehyde [75-07-0] (8.9 mL, 159.41 mmol) was 20 added dropwise and the mixture was stirred for 1 h at -78 ºC. The reaction was quenched with 250 ml of saturated aqueous solution of NH4Cl , the mixture then extracted with EtOAc (3x200 ml). The organic layer was washed with brine (200 ml), dried over MgSO4, and filtered. Solvent was evaporated to dryness under reduced pressure. The crude was purified by flash column chromatography over silica gel (eluent: Heptane:EtOAc up to 0:100). The desired fractions 25 were combined and concentrated under vacuo to afford Intermediate 16 (16.90 g, 72% yield) as an orange oil. 70 JAB7225WOPCT1 Intermediate 17 ride (7.8 g, 195.3 mmol) was added to a stirred suspension of Intermediate 16 (38.4 g, 130.2 mmol) in anhydrous THF (500 mL) at 0 ºC under nitrogen. The mixture was stirred at 5 0 ºC for 30 min. Then, iodomethane [74-88-4] (32.4 mL, 520.7 mmol) was added dropwise at 0 ºC and the mixture stirred at rt for 3.5 h. The mixture was quenched with water (600 mL) and extracted with EtOAc. The organic layer was separated and washed with brine. Then, the organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography over silica gel (eluent: 10 Heptane:EtOAc up to 0:100). The desired fractions were collected and concentrated in vacuo to yield Intermediate 17 (33.1 g, 82% yield) as a colorless oil. Intermediate 18 15 prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 17 (22.9 g, 74.1 mmol) instead of 3,5-dibromo-4-ethylpyridine, and heating to 100 ºC for 16 hours, to give Intermediate 18 (8.6 g, 28% yield) as an orange oil. Intermediate 19 20 9 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 18 (12.6 g, 30.8 mmol) instead of Intermediate 2, to give Intermediate 19 (4.42 g, 59% yield) as a yellow solid. 71 JAB7225WOPCT1 Intermediate 20 20 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 19 (4.90 g, 20.0 mmol) instead of Intermediate 1, and heating to 160 ºC for 2 h, to 5 give Intermediate 20 (3.52 g, 92% yield) as a yellow solid. Intermediate 21 s performed in eight separate batches. For each batch, a solution of 4-amino-2- 10 chloropyridine [14432-12-3] (5.0 g, 38.9 mmol) in H2SO4 (50 mL) at 0 °C was added KNO3 [7757-79-1] (15.7 g, 156 mmol). The reaction mixture was stirred at 0 °C for 30 min and then was stirred at 20 °C for 30 min, then heated to 60 °C for 12 h. The reaction mixture was cooled to 0 °C and poured onto crushed ice. The eight mixtures were merged and extracted with diethyl ether (4 x 150 mL). The combined organic layers were washed with a saturated solution of 15 NaHCO3 (50 mL), dried over Na2SO4 and evaporated in vacuo to give Intermediate 21 (30.0 g, 44% yield) as a brown solid. Intermediate 22 20 termediate 21 (47.5 g, 218.3 mmol) and thioacetamide [62-55-5] (65.3 g, 869.2 mmol) in sulfolane [126-33-0] (169 mL, 2.17 mol) was stirred at 100 °C for 3 h. The reaction mixture was cooled to room temperature, the solid obtained was filtered and washed with water (x 3) to give Intermediate 22 (36.0 g, 78% yield) as a brown solid. 25 Intermediate 23 72 JAB7225WOPCT1 To a 0 °C cooled suspension of tert-butyl nitrite [540-80-7] (29.4 mL, 247 mmol) and copper bromide [7789-45-9] (55.2 g, 247 mmol) in acetonitrile (840 mL) was added dropwise Intermediate 22 (26 g, 124 mmol). The reaction mixture was stirred at 0 °C for 30 min, then stirred for 18 h at room temperature. The reaction mixture was cooled to 0 °C and quenched 5 with an aq. saturated solution of NH4Cl. EtOAc was added, the resulting layers were separated, and the aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was removed under vacuo to give Intermediate 23 (20.0 g, 59% yield) as a yellow solid. 10 Intermediate 24 8 g, 730 mmol) and ammonium chloride (39.0 g, 730 mmol) were added to a solution of Intermediate 23 (20.0 g, 73.0 mmol) in EtOH (701 mL) and water (3004 mL). The reaction was stirred at 80 °C for 4 h. The crude was filtered through celite, and the filter cake 15 was washed EtOAc (3200 mL). Brine (200 mL), and EtOAc (200 mL) were added, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 150 mL), the combined organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give Intermediate 24 (12.0 g, 49.2 mmol, 67% yield) as a brown solid. 20 Intermediate 25 mixture of Intermediate 24 (12.0 g, 49.2 mmol) and tributyl(1-ethoxyvinyl)tin [97674-02-7] (18.3 mL, 54.1 mmol) in 1,4-dioxane (300 mL) was degassed for 10 min. Bis(triphenylphosphine) palladium (II) chloride [13965-03-2] (3.45 g, 4.92 mmol) was added 25 and the reaction mixture was stirred at 80 °C for 18 h. The reaction was poured out into an aqueous solution of KF (10 wt%) and extracted with EtOAc (4 x 150 mL). The organic layer was washed again with an aqueous solution of KF (10 wt%), dried over Na2SO4, filtered and solvents were evaporated in vacuo. The crude was purified by flash column chromatography over silica gel (eluent: Heptane:EtOAc from 80:20 to 50:50). The pure fractions were combined 30 and evaporated in vacuo to give Intermediate 25 (6.8 g, 59% yield) as a yellow solid. 73 JAB7225WOPCT1 Intermediate 26 ermediate 25(11.3 g, 48.0 mmol) in HCl 3M (160 mL, 480 mmol) and THF (452 mL) was stirred at 60 °C for 2 h. Volatiles were evaporated in vacuo, and the residue was 5 dissolved in DCM (300 mL), and a K2CO310% aq solution (150 mL) was added. The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 150 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated in vacuo to give Intermediate 26 (9.2 g, 92% yield) as a yellow solid. 10 Intermediate 27 ermediate 26 (9.2 g, 44.4 mmol) in MeOH (259 mL) at 0 °C was added NaBH4 (5.04 mg, 133 mmol). The mixture was stirred at 20 °C for 30 min, then cooled to 0 °C, and water was added. The resulting mixture was evaporated in vacuo till dryness and the residue 15 was taken up into EtOAc and washed with H2O. The organic layer was separated, washed with water and brine, dried over Na2SO4, and evaporated in vacuo to give Intermediate 27 (8.8 g, 95% yield) as a slightly yellow solid. Intermediate 28 20 was prepared by an analogous reaction protocol as Intermediate 17, starting from Intermediate 27 (8.8 g, 42.1 mmol) instead of Intermediate 16, to give Intermediate 28 (5.23 g, 56% yield) as an off-white solid. 25 Intermediate 29 74 JAB7225WOPCT1 A mixture of commercially available tert-butyl (S)-4-methoxy-3-oxopentanoate [1832579-72- 2] (22.45 g, 111.0 mmol) and N,N-dimethylformamide dimethyl acetal [4637-24-5] (22.1 mL, 166.5 mmol) was stirred at 120 ºC for 2 h. The solvent was evaporated in vacuo. A solution of 3-pyrazolamine [1820-80-0] (9.69 g, 116.55 mmol) in EtOH (115 ml) was added and the 5 reaction mixture was stirred at 85 ºC for 18 h. The solvent was evaporated in vacuo and the crude was purified by flash column chromatography over silica gel (eluent: Petroleum ether:EtOAc from 100:0 to 50:50). The desired fractions were collected and concentrated in vacuo to give Intermediate 29 (20.1 g, 65% yield) as a white solid. 10 Intermediate 30 865.86 mmol) was added to a solution of Intermediate 29 (20.0 g, 72.16 mmol) in 350 ml DCM and the mixture was stirred at room temperature for 16 h. Water was added, and the reaction mixture was extracted with DCM. The combined organic layers were dried 15 over MgSO4and concentrated to afford Intermediate 30 (15.4 g, 96% yield) as a pale-yellow solid. Intermediate 31 20 rmediate 30 (15.4 g, 66.14 mmol) in tert-Butanol (250 mL), diphenyl phosporyl azide [26386-88-9] (14.8 mL, 66.62 mmol) and DIPEA [7087-68-5] (11.8 mL, 67.07 mmol) were added and the reaction mixture was stirred at 90 ºC for 18 hours under nitrogen atmosphere. EtOAc was added to the reaction mixture and was washed with water. The crude was purified by flash column chromatography over silica gel (eluent: Heptane:EtOAc from 25 90:10 to 60:40). The desired fractions were collected, combined, and concentrated under vacuum to give Intermediate 31 (13.57 g, 70% yield) as a pale-yellow solid. 75 JAB7225WOPCT1 Intermediate 32 753.5 mmol) was added to a solution of Intermediate 31 (13.57 g, 44.10 mmol) in 350 ml DCM, and the mixture was stirred at room temperature for 3 h. The reaction mixture 5 was quenched with Na2CO3 and extracted with DCM (x3). The combined organic layers were dried over MgSO4, concentrated, and the crude was purified by flash column chromatography over silica gel (eluent: Heptane:EtOAc from 95:5 to 70:30). The desired fractions were combined, and the solvent was removed in vacuo to give Intermediate 32 (5.42 g, 64% yield) as a red solid. 10 Intermediate 33 epared by an analogous reaction protocol as Intermediate 29, starting from commercially available 5-chloro-1H-pyrazol-3-amine (7.50 g, 63.78 mmol) instead of 3- 15 pyrazolamine [1820-80-0], to give Intermediate 33 (14.2 g, 71% yield) as a white solid. Intermediate 34 prepared by an analogous reaction protocol as Intermediate 30, starting 20 from Intermediate 33 (14.5 g, 46.51 mmol) instead of Intermediate 29, to give Intermediate 34 (10.1 g, 85% yield) as a white solid. 76 JAB7225WOPCT1 Intermediate 35 red by an analogous reaction protocol as Intermediate 31, starting from Intermediate 34 (5.05 g, 19.8 mmol) instead of Intermediate 30, to give Intermediate 35 5 (5.96 g, 92% yield) as a white solid. Intermediate 36 10 Intermediate 36 was prepared by an analogous reaction protocol as Intermediate 32, starting from Intermediate 35 (5.95 g, 18.2 mmol) instead of Intermediate 31, to give Intermediate 36 (4.11 g, quantitative yield) as pale-yellow solid. Intermediate 37 15 as prepared by an analogous reaction protocol as the (S)- enantiomer Intermediate 36, following the synthetic sequence from Intermediate 29 to Intermediate 32 starting from tert-butyl (R)-4-methoxy-3-oxopentanoate [1832579-91-5] instead of tert-butyl (S)-4-methoxy-3-oxopentanoate [1832579-72-2], to give Intermediate 37 (89 mg, 83% yield) 20 as an off white solid. 77 JAB7225WOPCT1 Intermediate 38 rt-butyl 3-oxopentanoate (10.5 g, 61.0 mmol) in N,N- dimethylformamidedimethylacetate [4637-24-5] (8.91 mL, 67.1 mmol) was stirred at 120 °C 5 for 1.5 h. Then a solution of 3-chloro-1H-pyrazol-5-amine [916211-79-5] (7.17 g, 61.0 mmol) in ethanol (62 mL) was added dropwise at 85 °C and the resulting mixture was stirred at 85 °C for 1 h. The reaction mixture was concentrated to dryness under reduced pressure. The crude was purified by flash column chromatography over silica gel (eluent: cyclohexane:EtOAc from 100:0 to 80:20). The fractions containing compound were combined and concentrated under 10 reduced pressure to give Intermediate 38 (13.4 g, 78% yield) as a white solid. Intermediate 39 prepared by an analogous reaction protocol as Intermediate 30, starting 15 from Intermediate 38 (13.4 g, 47.6 mmol) instead of Intermediate 29, to give Intermediate 39 (10.3 g, 96% yield) as an off-white solid. Intermediate 40 20 red by an analogous reaction protocol as Intermediate 31, starting from Intermediate 39 (10.3 g, 45.6 mmol) instead of Intermediate 30, to give Intermediate 40 (8.6 g, 55% yield) as a pale-yellow solid. Intermediate 41 25 78 JAB7225WOPCT1 Intermediate 41 was prepared by an analogous reaction protocol as Intermediate 32, starting from Intermediate 40 (27.7 g, 122.2 mmol) instead of Intermediate 31, to give Intermediate 41(23.8 g, 99% yield) as an orange solid. 5 Intermediate 42 on of ethyl 1-amino-1H-imidazole-2-carboxylate [1008130-15-1] (19.8 g, 128 mmol) in DCM (100 mL) and DMF (30 mL) was added 4-dimethylaminopyridine (19.5 g, 160 mmol). The solution was cooled with an ice bath and di-tert-butyl dicarbonate [24424-99-5] 10 (69.6 g, 319 mmol) in DCM (60 mL) was carefully added. The reaction mixture was stirred at room temperature for 3 h, then quenched with a 10% aqueous solution of NH4Cl (100 mL). The mixture was brought to pH 6-7 with a 3N aqueous solution of HCl, then the aqueous layer was separated and extracted with DCM (2x). The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude was purified by flash column 15 chromatography over silica gel (eluent: DCM:(DCM / MeOH, 8 / 2) from 100:0 to 90:10). The fractions containing compound were combined and evaporated in vacuo to give Intermediate 42 (38.0 g, 84% yield) as a white solid. Intermediate 43 20 ntermediate 42 (20.0 g, 56.3 mmol) in DMF (420 mL) was added slowly N-chlorosuccinimide [128-09-6] (7.5 g, 56.3 mmol) in DMF [68-12-2] (140 mL). The reaction mixture was stirred at room temperature for 36 h. A saturated aqueous solution of NaHCO3 was added, and the mixture extracted with EtOAc (3 x 200 mL). The combined organic phases were 25 concentrated in vacuo, then co-evaporated with heptane (2 x 50 mL). The crude was purified 79 JAB7225WOPCT1 by flash column chromatography over silica gel (eluent: cyclohexane:EtOAc from 100:0 to 60:40). The pure fractions were combined and concentrated in vacuo to give Intermediate 43 (8.9 g, 40.5% yield) as a white solid. 5 Intermediate 44 mediate 43 (3.5 g, 8.98 mmol) in THF (34 mL) at 0 °C was added potassium tert-butoxide (dropwise, 1M in THF, 19.8 mL, 19.8 mmol) and dry ethyl acetate (2.14 mL, 22.45 mmol). The resulting solution was pre-stirred at 0 °C for 15 minutes, then at 10 room temperature for 2 h. The reaction mixture was cooled to 0 °C, an aqueous solution of HCl (1M, 38.2 mL, 38.2 mmol) was added dropwise and the resulting mixture was extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give Intermediate 44 (2.77 g, 67% yield). 15 Intermediate 45 ediate 44 (2.77 g, 8.35 mmol) in dry DCM (24 mL) was added N,N- dimethylformamide dimethyl acetal [4637-24-5] (1.33 mL, 10.0 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in 20 vacuo to give Intermediate 45 (2.8 g, 100% yield), which was used without further purification in the next step. Intermediate 46 80 JAB7225WOPCT1 To a solution of Intermediate 45 (5.74 g, 23.8 mmol) in acetonitrile (37 mL) at room temperature was added phosphorus oxybromide [7789-59-5] (16.7 g, 58.2 mmol) and the mixture was stirred for 2 h at 90 °C under N2. The mixture was cooled to room temperature and ice water was added. The mixture was neutralized with a saturated aqueous solution of NaHCO35 and extracted with EtOAc (3x). Combined organic layers were washed with water, brine, and dried over MgSO4, filtered and the solvent was removed in vacuo. The crude was purified by flash column chromatography over silica gel (eluent: Heptane:EtOAc from 100:0 to 70:30). The fractions containing compound were combined and evaporated in vacuo to give Intermediate 46 (1.5 g, 21% yield) as a yellow solid. 10 Intermediate 47 p med in 4 batches of 1.9 g. For each batch: a microwave tube was charged with Intermediate 46 (1.9 g, 6.24 mmol) and K2CO3(1.73 g, 12.5 mmol). The mixture was 15 purged with N2, then 1.4-dioxane (5.9 mL) and water (1.5 mL) were added. Then triethyl borane 1M in THF [97-94-9] (8.11 mL, 8.11 mmol) and bis(triphenylphosphine)palladium (II) chloride [13965-03-2] (0.35 g, 0.50 mmol) were added. The reaction mixture was heated at 120 °C using one single mode microwave with a power output ranging from 0 to 800 W for 1 h. The batches were combined then water was added, and the mixture was extracted with EtOAc (2x). The 20 combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a residue which was purified by flash column chromatography over silica gel (eluent: Heptane:EtOAc from 100:0 to 80:20). The fractions containing compound were combined and evaporated to dryness to give Intermediate 47 (4.6 g, 74% yield) as a colorless oil. 25 Intermediate 48 ermediate 47 (2.93 g, 11.6 mmol) in THF (34 mL), MeOH (34 mL), and water (34 mL) was added NaOH (1.85 g, 46.2 mmol) and the reaction mixture was stirred at 45 81 JAB7225WOPCT1 °C for 1 h. The reaction mixture was allowed to reach room temperature, diluted with water, and acidified with a 3 M aqueous solution of HCl before being extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered and the solvent removed in vacuo to give Intermediate 48 (2.69 g, quant.) as a white solid. 5 Intermediate 49 ared by an analogous reaction protocol as Intermediate 31, starting from Intermediate 48(2.69 g, 11.9 mmol) instead of Intermediate 30, to give Intermediate 49 10 (2.42 g, 68% yield) as a white solid. Intermediate 50 as prepared by an analogous reaction protocol as Intermediate 32, starting 15 from Intermediate 49 (2.42 g, 8.15 mmol) instead of Intermediate 31, to give Intermediate 50 (0.75 g, 47% yield). Intermediate 51 20 methyl-4amino-1-methyl-1H-pyrazole-3-carboxylate [637336-53-9] (37.6 g, 230.2 mmol) in N,N-dimethylformamide (50 mL) at room temperature was added di-tert-butyl dicarbonate [24424-99-5] (60.9 g, 276.9 mmol). The reaction was heated to 60 °C for 5 hours. The mixture was poured into water and extracted with EtOAc (2x). The combined organic phases were dried over Na2SO4, washed with brine, filtered, and concentrated under reduced 82 JAB7225WOPCT1 pressure. The resulting residue was purified by flash column chromatography over silica gel (eluent: petroleum ether:EtOAc from 100:0 to 50:50) to give Intermediate 51 (50 g, 82% yield) as a white solid. 5 Intermediate 52 ntermediate 51(50.0 g, 188.9 mmol) in THF (100 mL) was added a solution of LiOH (20.8 g, 472.3 mmol) in water (20 mL). The reaction was stirred at room temperature for 4 hours. The mixture was concentrated and acidified with HCl 1 N to pH = 3~4. The mixture 10 was then filtered and the solid collected was washed with water and then dried in vacuo to give Intermediate 52 (45.8 g, quantitative yield) as a white solid. Intermediate 53 15 mediate 87 (30.5 g, 95.1 mmol) in DCM (50 mL) at room temperature was added N,N-dimethylformamide dimethyl acetal (91.6 g, 761.0 mmol) dropwise. The reaction was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by flash column chromatography over silica gel (eluent: DCM:MeOH from 100:0 to 90:10) to give Intermediate 53 (14.2 g, 61% yield) as a white solid. 20 Intermediate 54 diate 53 (14.2 g, 58.2 mmol) in phosphorus oxychloride (30 mL) was heated to 80 °C for 3 hours. The reaction mixture was concentrated, and the residue was purified 25 by flash column chromatography over silica gel (eluent: petroleum ether:EtOAc from 100:0 to 50:50) to give Intermediate 54 (7.1 g, 49% yield). 83 JAB7225WOPCT1 Intermediate 55 termediate 54 (10.4 g, 41.2 mmol) in THF (200 mL) and water (80 mL) at 0 5 °C was added lithium hydroxide monohydrate (3.46 g, 82.4 mmol). The reaction was stirred at 40 °C for 30 minutes. The mixture was acidified to pH < 2 with aqueous HCl (1 M, 42 mL), the organic volatiles were removed in vacuo, and the mixture was filtered. The filter cake was washed with water (2x) and dried in vacuo to give Intermediate 55 (8.8 g, 96% yield) as a light- yellow solid. 10 Intermediate 56 pared by an analogous reaction protocol as Intermediate 31, starting from Intermediate 55 (12.8 g, 57.5 mmol) instead of Intermediate 30, and stirring at 90 ºC for 15 12 hours to give Intermediate 56 (4.15 g, 24% yield) as a yellow oil. Intermediate 57 termediate 56 (2.4 g, 8.06 mmol) in N,N-dimethylformamide (26 mL) was 20 added potassium trifluoro(vinyl)borate [13682-77-4] (1.62 g, 12.1 mmol) and K2CO3 (1.78 g, 12.9 mmol). The mixture was degassed under a flow of nitrogen, and AmPhos PdCl2[887919- 35-9] (286 mg, 0.40 mmol) was added. The reaction was heated to 100 ºC for 12 hours. The mixture was cooled to room temperature, then poured into water and extracted with EtOAc (2x 30 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and 25 concentrated to afford the crude product, which was purified by flash column chromatography 84 JAB7225WOPCT1 over silica gel (eluent: petroleum ether:EtOAc from 100:0 to 0:100) to give Intermediate 57 (1.5 g, 64% yield) as a yellow oil. Intermediate 58 5 termediate 57 (2.8 g, 9.7 mmol) in MeOH (90 mL) was added palladium on charcoal [7440-05-3] (1.4 g) under H2atmosphere. The reaction mixture was stirred at 30 ºC for 2 hours, then filtered and concentrated in vacuo. The crude product was purified by flash column chromatography over silica gel (eluent: DCM:MeOH up to 90:10) to give Intermediate 10 58 (2.8 g, 99% yield) as a colorless oil. Intermediate 59 was prepared by an analogous reaction protocol as Intermediate 32, starting 15 from Intermediate 58 (2.8 g, 9.6 mmol) instead of Intermediate 31, to give Intermediate 59 (1.4 g, 76% yield) as an off-white solid. Intermediate 60 20 xybromide [7789-59-5] (10.3 g, 36.0 mmol) and DIPEA [7087-68-5] (8.37 mL, 48.0 mmol) were added to a suspension of 6-fluoro-4-hydroxy-3-nitroquinoline [628284- 75-3] (5.00 g, 24.0 mmol) in acetonitrile (70 mL). The resulting solution was heated to reflux 85 JAB7225WOPCT1 for 2 hours. Upon cooling the resulting solution was filtered through a pad of silica gel and eluted with DCM to give Intermediate 60 (5.18 g, 80% yield). Intermediate 61 5 39-89-6] (23.4 g, 419 mmol) was added to a suspension of Intermediate 60 (11.4 g, 41.9 mmol) in acetic acid (228 mL) and the mixture was stirred at 60 °C for 3 h. The mixture was diluted with EtOAc and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and the residue was purified by flash column 10 chromatography over silica gel (eluent: Cyclohexane:EtOAc from 90:10 to 50:50). The pure fractions were combined, and the solvents were removed in vacuo to give Intermediate 61 (8.83 g, 87% yield). Intermediate 62 15 13.11 g, 54.39 mmol), triethylborane 1 M in THF [97-94-9] (70.7 mL, 70.7 mmol) and K2CO3(15.0 g, 109 mmol) were dissolved in 1,4-dioxane (51 mL) and water (13 mL), and the solution was purged with N2. Bis(triphenylphosphine)palladium(II) dichloride [13965-03-2] (3.17 g, 4.51 mmol) was added and the reaction mixture was stirred at 75 °C for 20 3 hours. The solvents were removed in vacuo and the residue purified by flash column chromatography over silica gel (eluent: Heptane:(Heptane / MeOH / EtOAc 40 / 7 / 53) from 100:0 to 50:50). The fractions containing product were collected and the solvent was evaporated. The product was further purified by reverse phase chromatography (Cartridge YMC -DispoPack AT ODS_25µm_300g Flow rate 75ml / min-Focused gradient MeCN / aq.NH4HCO3 0.2% pH=7.9 25 Focused gradient from 20 / 80 to 55 / 45). The pure fractions were combined to give Intermediate 62 (6.79 g, 66% yield) as an off-white solid. 86 JAB7225WOPCT1 Intermediate 63 ediate 61 (8.88 g, 36.84 mmol) in THF (160 mL), were added triethylamine (17.76 mL, 127.42 mmol), 4-dimethylaminopyridine [1122-58-3] (901 mg, 7.38 5 mmol) and di-tert-butyl dicarbonate [24424-99-5] (19.86 mL, 38.17 mmol) and the mixture was stirred at 70 ºC for 4h. The mixture was diluted with dichloromethane and water. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated in vacuo to afford Intermediate 63 (16.02 g, 98% yield) as a brown solid. 10 Intermediate 64 ine)-palladium (0) [14221-01-3] (4.19 g, 3.63 mmol) and tributyl(vinyl)tin [7486-35-3] (11.15 mL, 38.16 mmol) were added to a solution of Intermediate 63 (16.02 g, 36.30 mmol) in toluene (400 mL) under N2. The reaction mixture was stirred at 90 15 ºC for 18 h. The mixture was diluted with a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography over silica gel (eluent: heptane:EtOAc up to 85:15). The desired fractions were collected and concentrated in vacuo to yield Intermediate 64 (10.56 g, 75% yield) as a yellowish solid. 20 Intermediate 65 87 JAB7225WOPCT1 Na2CO3 (8.20g, 77.37 mmol) was added to a solution of Intermediate 64 (10.53 g, 27.11 mmol) in methanol (100 mL) and the mixture was stirred at room temperature for 16 h. The crude was concentrated in vacuo, stirred with a 1M aqueous solution of KHSO4, and extracted with DCM (x3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo 5 to yield Intermediate 65 (8.22 g, 100% yield) as a brown oil. Intermediate 66 ntermediate 65 (8.22 g, 28.51 mmol) in dioxane (110 ml) and water 10 (19 mL) at 0 ºC were added 4-methylmorpholine-N-oxide-monohydrate [70187-32-5] (5.88 g, 43.47 mmol) and sodium periodate [7790-28-5] (18.29 g, 85.53 mmol) followed by osmium tetroxide [20816-12-0] (146 mg, 0.57 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was quenched with a 1M aqueous solution of Na2SO3and then diluted with water and brine. The mixture was extracted with DCM. The combined organic layers were 15 dried over MgSO4, filtered, and concentrated in vacuo. The crude was purified by flash column chromatography over silica gel (eluent: heptane:EtOAc up to 0:100). The fractions were combined and concentrated in vacuo to give Intermediate 66 (5.64 g, 68% yield) as a yellow solid. 20 Intermediate 67 -0] (8.06 mL, 60.98 mmol) was added to a solution of Intermediate 66 (5.64 g, 19.43 mmol) in DCM (70 mL) under nitrogen, and the mixture was stirred at room temperature for 16 h. The reaction mixture was poured onto ice water and a saturated aqueous 25 solution of NaHCO3 and extracted with dichloromethane (3x). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude was purified by flash column chromatography over silica gel (Heptane:EtOAC up to 0:100). Fractions containing 88 JAB7225WOPCT1 product were combined and concentrated in vacuo to afford Intermediate 67 (0.85 g, 20% yield) as a brown solid. Intermediate 68 5 as prepared by an analogous reaction protocol as Intermediate 60, starting from 6-chloro-3-nitroquinolin-4-ol [101861-61-4] (8 g, 35.62 mmol) instead of 6-fluoro-4- hydroxy-3-nitroquinoline [628284-75-3], to give Intermediate 68 (7.6 g, 74% yield). 10 Intermediate 69 as prepared by an analogous reaction protocol as Intermediate 61, starting from Intermediate 68 (25.5 g, 88.7 mmol) instead of Intermediate 60, to give Intermediate 69 (25.0 g, 89% yield) as an orange solid. 15 Intermediate 70 ared by an analogous reaction protocol as Intermediate 63, starting from Intermediate 69 (7.5 g, 29.1 mmol) instead of Intermediate 61, to give Intermediate 70 20 (13.3 g, 100% yield) as a brown solid. 89 JAB7225WOPCT1 Intermediate 71 ared by an analogous reaction protocol as Intermediate 64, starting from Intermediate 70 (13.6 g, 26.8 mmol) instead of Intermediate 63, to give Intermediate 71 5 (2.8 g, 49% yield) as a yellow solid. Intermediate 72 red by an analogous reaction protocol as Intermediate 65, starting 10 from Intermediate 71 (5.34 g, 12.5 mmol) instead of Intermediate 64, to give Intermediate 72 (3.8 g, quant. yield) as a yellow solid. Intermediate 73 15 red by an analogous reaction protocol as Intermediate 66, starting from Intermediate 72 (8.56 g, 28.1 mmol) instead of Intermediate 65, to give Intermediate 73 (4.5 g, 52% yield) as a green solid. Intermediate 74 20 90 JAB7225WOPCT1 Intermediate 74 was prepared by an analogous reaction protocol as Intermediate 67, starting from Intermediate 73 (4.5 g, 14.7 mmol) instead of Intermediate 66, to give Intermediate 74 (4.3 g, 89% yield) as a brown oil. 5 Intermediate 75 mmol) was added in a solution of Intermediate 74 (4.3 g, 12.43 mmol) in 140 ml DCM and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with NaHCO3and extracted with DCM (x3). The combined organic layers were 10 dried over MgSO4, filtered, and concentrated. The mixture was purified by flash column chromatography over silica gel (eluent: heptane:EtOAc from 95:5 to 70:30). The desired fractions were combined and concentrated in vacuo to yield Intermediate 75 (0.34 g, 11% yield) as a yellow solid. 15 Intermediate 76 phine)palladium(II) dichloride [13965-03-2] (528 mg, 0.75 mmol) was added to a solution of Intermediate 61 (3.63 g, 15.1 mmol) and tributyl(1-ethoxyvinyl)tin [97674-02- 7] (6.11 mL, 18.1 mmol) in 1,4-dioxane (75 mL) under nitrogen atmosphere. The reaction was 20 heated at 90 °C for 20 h. The mixture was filtered through a pad of celite, the filtrate poured into an aqueous solution of KF (10% w / w) and filtered again through a pad of celite. The organic layer was washed with an aqueous solution of KF (10%), dried over MgSO4, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel (eluent: Heptane:EtOAc from 90:10 to 70:30). The pure 25 fractions were combined, and the solvent removed in vacuo to give Intermediate 76 (2.49 g, 71% yield). 91 JAB7225WOPCT1 Intermediate 77 ntermediate 76 (9.29 g, 31.6 mmol) in 1,4-dioxane (517 mL) was added an aqueous solution of HCl 3 M [7647-01-0] (105 mL, 316 mmol) and the mixture was stirred at 5 60°C for 3 h. The solvent was evaporated, and the residue was dissolved in EtOAc. K2CO310% aq. was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and the solvents were removed in vacuo to give Intermediate 77 (8.21 g, quant. yield), which was used without further purification. 10 Intermediate 78 was prepared by an analogous reaction protocol as Intermediate 27, starting from Intermediate 77 (8.21 g, 32.6 mmol), instead of Intermediate 26, to give Intermediate 78 (4.63 g, 69% yield). 15 Intermediate 79 was prepared by an analogous reaction protocol as Intermediate 17, starting from Intermediate 78 (5.5 g, 26.7 mmol) instead of Intermediate 16, to give Intermediate 79 20 (4.77 g, 81% yield). 92 JAB7225WOPCT1 Intermediate 80 and 81 81 For both intermediates, pure stereoisomers but absolute stereochemistry undetermined on 5 stereocenter indicated with arrow. Intermediate 79 (4.77 g) was purified by preparative chiral SFC (Stationary phase: Chiralpak IC, 250 x 30mm; Mobile phase: CO2 85% + iPrOH 15% + 0,6% iPrNH2). The fractions containing compoundwere combined and evaporated in vacuo to give Intermediate 80 (2.37 g, 40% yield) and Intermediate 81 (2.30 g, 39% yield). 10 Intermediate 82 pension 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 15 was stirred for 30 minutes, then a solution of 4-bromobenzaldehyde [1122-91-4] (10.0 g, 54.0 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 NH4Cl (60 mL), and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous 20 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 82 (12.3 g, 84% yield) as a colorless oil. 25 Intermediate 83 93 JAB7225WOPCT1 To a cooled (0 °C) solution of Intermediate 82 (12.3 g, 45.7 mmol) in dry THF (230 mL) under nitrogen, was added DIBAL-H (1M in THF, 115 mL, 115 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 5 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 83(9.8 g, 94% yield) as a white solid. 10 Intermediate 84 iate 83 (8.70 g, 38.3 mmol) and imidazole (3.13 g, 46.0 mmol) in DCM (100 mL) pre-cooled to 0 °C, was added triisopropylsilyl chloride (9.0 mL, 42.1 mmol) dropwise. The mixture was allowed to warm up to RT and stirred for 16 h. The mixture was 15 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 MgSO4, 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 84 (14 g, 95% yield) as a colorless oil. 20 Intermediate 85 ressure tube charged with Intermediate 84 (1.15 g, 3.0 mmol) and tetrabutylammonium bromide (48.3 mg, 0.15 mmol), were added toluene (6 mL) and 25 (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) and EtOAc (20-25 mL), and then 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, 30 and concentrated under reduced pressure. The residue was dissolved in anhydrous THF (50 mL), cooled to 0 °C and TBAF (1M in THF, 27 mL, 27 mmol) was added. The reaction was 94 JAB7225WOPCT1 allowed to warm up to RT and stirred for 1 h. The 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 5 flash column chromatography over silica gel (eluent: heptane / EtOAc 70 / 30) to obtain Intermediate 85 (4.6 g, 92% yield) as a yellowish oil. Intermediate 86 10 ermediate 85 (3.81 g, 13.75 mmol) in water / MeCN (87 mL / 87 mL), was added TEMPO (1.07 g, 6.87 mmol), (diacetoxyiodo)benzene (13.29 g, 41.25 mmol) and NaHCO3 (2.89 g, 34.37 mmol). The mixture was stirred for 6 h at RT, the mixture was diluted with water, and an aqueous solution of HCl (1 M) was added until the pH reached approximately 2. EtOAc was added and the organic layer was separated. The aqueous layer was extracted with 15 EtOAc, and the combined organic layers were dried over anhydrous MgSO4, filtered, and evaporated. The product was stirred in diisopropyl ether and filtered. The filtrate was evaporated and stirred in heptane to obtain a precipitate that was filtered and dried over anhydrous MgSO4to give Intermediate 86 (3.46 g, 86% yield) as white solid. 20 Intermediate 87 e 52 (46.1 g, 189.8 mmol) in ACN (200 mL) and THF (200 mL) was added 1,1'-carbonyldiimidazole [530-62-1] (46.9 g, 284.8 mmol). The mixture was stirred at room temperature for 2 hours and ethyl potassium malonate (34.0 g, 189.8 mmol), MgCl225 (18.4 g, 189.8 mmol) and triethylamine (58.2 g, 569.5 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with EtOAc (2x). The combined organic phase was dried over Na2SO4, washed with brine, filtered, and concentrated. The resulting residue was purified by flash column chromatography over silica gel (eluent: petroleum ether:EtOAc from 100:0 to 70:30) to give 30 Intermediate 87 (41.2 g, 67% yield) as a white solid. 95 JAB7225WOPCT1 The following Intermediates were synthesized by analogous reaction protocol as described for Intermediate 82, starting from the indicated reagents. Reagent Resulting Int. No. Structure 5 The following Intermediates were synthesized by analogous reaction protocol as described for Intermediate 83, starting from the indicated reagents. Reagent Resulting Int. No. Structure The following Intermediates were synthesized by analogous reaction protocol as described for Intermediate 84, starting from the indicated reagents. Reagent Resulting Int. No. Structure 96 JAB7225WOPCT1 Reagent Resulting Int. No. Structure The following Intermediates were synthesized by analogous reaction protocol as described for Intermediate 85, starting from the indicated reagents. Reagent Resulting Int. No. Structure 5 The following Intermediates were synthesized by analogous reaction protocol as described for Intermediate 86, starting from the indicated reagents. Reagent Resulting Int. No. Structure 97 JAB7225WOPCT1 Reagent Resulting Int. No. Structure Intermediate 103 rmediate 86 (315 mg, 1.08 mmol), N-[(dimethylamino)-1H-1,2,3-triazolo- 5 [4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (823 mg, 2.16 mmol) and N,N-diethylethanamine (0.60 mL, 4.33 mmol) in ACN (9 mL), was added methylamine (2 M in THF, 1.35 mL, 2.70 mmol). The mixture was stirred at RT for 1 h, then diluted with EtOAc (30 mL) and water (15 mL). The aqueous layer was separated and extracted with EtOAc (30 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, 10 and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (eluent: heptane:EtOAc up to 50:50) to obtain Intermediate 103 (320 mg, 97% yield) as colorless oil. Intermediate 104 and 105 15 Intermediate 103 (1.00 g, 3.29 mmol) was purified by preparative chiral SFC (Stationary phase: Chiralpak AS-H 30x250 mm, Mobile phase: CO2 / iPrOH 85 / 15). The fractions containing compound were combined and evaporated in vacuo to give Intermediate 104 (447.0 mg, 44% 98 JAB7225WOPCT1 yield) and Intermediate 105 (480.0 mg, 48% yield). The following Intermediates were synthesized by analogous reaction protocol as described for Intermediate 103 starting from the indicated reagents and methylamine (2 M in THF). Reagent Resulting Int. No. Structure 5 The following Intermediates were synthesized by analogous reaction protocol as described for Intermediate 103, starting from the indicated reagents and 3-(methylsulfonyl)cyclobutan-1- amine hydrochloride [2639792-63-3]. Reagent Resulting Int. No. Structure 99 JAB7225WOPCT1 Reagent Resulting Int. No. Structure The following Intermediates were synthesized by analogous reaction protocol as described for Intermediate 103, starting from Intermediate 86 and the indicated reagents. Reagent Resulting Int. No. Structure 100 JAB7225WOPCT1 Reagent Resulting Int. No. Structure 101 JAB7225WOPCT1 Reagent Resulting Int. No. Structure Intermediate 128 and 129 129 5 For both intermediates, pure stereoisomers but absolute stereochemistry undetermined on stereocenter indicated with arrow. Intermediate 20 (695 mg) was purified by preparative chiral SFC (Stationary phase: Chiralpak IG, 250x30mm; Mobile phase: CO290% + iPrOH 10% + 0.3% iPrNH2). The fractions containing compound were combined and evaporated in vacuo to give Intermediate 128 (304 10 mg, 39% yield) and Intermediate 129 (301 mg, 37% yield). Intermediate 130 and 131 131 15 For both intermediates, pure stereoisomers but absolute stereochemistry undetermined on stereocenter indicated with arrow. Intermediate 28 (3.5 g) was purified by preparative chiral SFC (Stationary phase: Chiralpak Daicel IC, 250 x 20mm; Mobile phase: CO2,iPrOH + 0,4% iPrNH2). The fractions containing 102 JAB7225WOPCT1 compound were combined and evaporated in vacuo to give Intermediate 130 (1.70 g, 49% yield) and Intermediate 131 (1.70 g, 49% yield). COMPOUNDS 5 Compound 1 ediate 7 (100.8 mg, 0.63 mmol), Intermediate 110 (264 mg, 0.63 mmol), Cs2CO3 (244.4 mg, 0.75 mmol) and BrettPhos Pd G3 [1470372-59-8] (170.0 mg, 0.19 mmol). The vessel was sealed and 1,4-dioxane (10 mL) was added via syringe. The 10 mixture was degassed by bubbling N2 for a few minutes and then stirred at 60 °C for 3 h. The reaction was cooled down to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the crude was purified by flash column chromatography on silica gel (eluent: DCM:MeOH up to 95:5) to obtain Compound 1 as a yellow oil (276 mg). 15 Compound 2, Compound 3, Compound 4 and Compound 5 For both compounds, pure stereoisomers but absolute stereochemistry undetermined on stereocenters. 20 103 JAB7225WOPCT1 For both compounds, pure stereoisomers but absolute stereochemistry undetermined on stereocenter Compound 1 (276 mg) was separated via chiral SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH2). The fractions containing compound were 5 combined and the solvent was concentrated in vacuo to provide four fractions as follows: Fraction 1: Compound 2 (13.6 mg, 4%) 1H NMR (400 MHz, CDCl3) δ ppm: 8.41 (s, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 6.41 (d, J = 8.1 Hz, 1H), 5.40 (s, 1H), 4.49 (sxt, J = 7.9 Hz, 1H), 3.57 - 3.42 (m, 2H), 2.78 - 2.77 (m, 7H), 2.60 (s, 3H), 2.45 - 2.22 (m, 2H), 1.87 - 1.50 (m, 3H), 1.18 - 1.11 (m, 3H). 10 Fraction 2: Compound 3 (13.3 mg, 4% yield) 1H NMR (400 MHz, CDCl3) δ ppm: 8.41 (s, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 6.41 (d, J = 8.1 Hz, 1H), 5.40 (s, 1H), 4.61 - 4.37 (m, 1H), 3.56 - 3.40 (m, 2H), 2.80 - 2.70 (m, 7H), 2.60 (s, 3H), 2.40 - 2.26 (m, 2H), 1.14 (t, J = 7.6 Hz, 3H), 1.11 - 1.06 (m, 1H), 1.11 - 1.06 (m, 1H), 1.11 - 1.05 (m, 1H). 15 Fraction 3: Compound 4 (85.4 mg, 27% yield) 1H NMR (400 MHz, CDCl3) δ ppm: 8.40 (s, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 6.18 (d, J = 6.6 Hz, 1H), 5.47 (s, 1H), 4.46 (sxt, J = 7.7 Hz, 1H), 3.70 – 3.36 (m, 1H), 3.47 (dd, J = 2.0, 16.1 Hz, 1H), 2.82 - 2.69 (m, 7H), 2.60 (s, 3H), 2.51 - 2.39 (m, 2H), 1.14 (t, J = 7.6 Hz, 3H), 1.11 – 1.06 (m, 3H). 20 Fraction 4: Compound 5 (93.5 mg, 30% yield) 1H NMR (400 MHz, CDCl3) δ ppm: 8.41 (s, 1H), 7.07 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 6.07 (d, J = 6.2 Hz, 1H), 5.41 (s, 1H), 4.45 (sxt, J = 7.7 Hz, 1H), 3.72 - 3.59 (m, 1H), 3.47 (dd, J = 2.3, 16.0 Hz, 1H), 2.86 - 2.70 (m, 7H), 2.60 (s, 3H), 2.52 - 2.40 (m, 2H), 1.18 - 1.12 (m, 3H), 1.11 - 1.07 (m, 3H). 25 The following compounds were synthesized by an analogous method as described for Compound 1, starting from Intermediate 7 and the indicated intermediates. 104 JAB7225WOPCT1 Int. No. Compound No. Comment a : , 4 d a : , 4 2 105 JAB7225WOPCT1 Int. No. Compound No. Comment ) l 106 JAB7225WOPCT1 Int. No. Compound No. Comment l e ) 0 d l e ) d 107 JAB7225WOPCT1 Int. No. Compound No. Comment l e ) d l e ) 108 JAB7225WOPCT1 Int. No. Compound No. Comment k e ) d l e ) d 109 JAB7225WOPCT1 Int. No. Compound No. Comment l e ) d k e ) d 110 JAB7225WOPCT1 Int. No. Compound No. Comment k e ) d l e ) 111 JAB7225WOPCT1 Int. No. Compound No. Comment k e ) l e ) 112 JAB7225WOPCT1 Int. No. Compound No. Comment Compound 56 54644-66-9] (35.8 mg, 0.16 mmol), Intermediate 103 (53.1 mg, 0.17 mmol), BrettPhos Pd G3 [1470372-59-8] (11.9 mg, 0.013 mmol), Cs2CO3[534-17-8] 5 (51.4 mg, 0.16 mmol) in 1,4-dioxane (2.0 mL) was degassed by bubbling N2and stirred at 60 °C for 12 h. The reaction was cooled down to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the crude was purified by flash column chromatography (Eluent: EtOAc:DCM up to 20:80) to obtain Compound 56 (15.6 mg, 21.5%) as a yellow film. 10 Compound 57 and Compound 58 cel AD 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 iPrNH2). The fractions containing compound 15 were combined and the solvent was concentrated in vacuo to provide two fractions as follows: Fraction 1: Compound 57 (4.7 mg, 7% yield) as yellow film. Fraction 2: Compound 58 (4.0 mg, 6% yield) as yellow film. 113 JAB7225WOPCT1 The following compounds were synthesized by an analogous method as described for Compound 1, starting from Intermediate 36. Int. No. Compound No. Comment a s 4 . . a l e o s 114 JAB7225WOPCT1 Int. No. Compound No. Comment l . l , ) . 115 JAB7225WOPCT1 Int. No. Compound No. Comment l , . l , ) 116 JAB7225WOPCT1 Int. No. Compound No. Comment The following compounds were synthesized by an analogous method as described for Compound 1, starting from intermediate 103 and the indicated intermediates. Int. No. Compound No. Comment l , : ) ) l , : ) ) 117 JAB7225WOPCT1 Int. No. Compound No. Comment a : , 4 : ) l , : ) 118 JAB7225WOPCT1 Int. No. Compound No. Comment l , : ) p l e o ) ) 119 JAB7225WOPCT1 Int. No. Compound No. Comment y , o ) l , : ) 120 JAB7225WOPCT1 Int. No. Compound No. Comment l , : ) l , : ) ) 121 JAB7225WOPCT1 Int. No. Compound No. Comment l , : d s l , ) 122 JAB7225WOPCT1 Int. No. Compound No. Comment l , : d l , ) . 123 JAB7225WOPCT1 Int. No. Compound No. Comment l , ) ) l , ) 124 JAB7225WOPCT1 Int. No. Compound No. Comment l , : d The following compounds were synthesized by an analogous method as described for Compound 1, starting from Intermediate 3 and the indicated intermediates. Int. No. Compound No. Comment : ) 125 JAB7225WOPCT1 Int. No. Compound No. Comment s The following compounds were synthesized by an analogous method as described for Compound 1, starting from the indicated intermediates. Int. No. Compound No. Comment 5 LCMS (Liquid chromatography / Mass spectrometry) General procedure 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 10 methods. If necessary, additional detectors were included (see table of methods below). Flow from the column was brought to the Mass Spectrometer (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…) in order to obtain ions allowing the 126 JAB7225WOPCT1 identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. 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]+5 (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. 10 Hereinafter, “SQD” means Single Quadrupole Detector, “RT” room temperature, “BEH” bridged ethylsiloxane / silica hybrid, “HSS” High Strength Silica, “DAD” Diode Array Detector. Table 1a: LCMS Method codes (Flow expressed in mL / min; column temperature (T) in °C; Run time in minutes). “TFA” means trifluoroacetic acid; “FA” means formic acid Flow e 127 JAB7225WOPCT1 Flow e 128 JAB7225WOPCT1 Flow e Table 1b: 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 LCMS analysis of compounds; No. means number. Rt means retention time (in minutes). Compound No. 129 JAB7225WOPCT1 Compound No. 130 JAB7225WOPCT1 Compound No. 131 JAB7225WOPCT1 Compound No. 132 JAB7225WOPCT1 Compound No. 133 JAB7225WOPCT1 Compound No. 134 JAB7225WOPCT1 SFC-MS methods: 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 5 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 10 temperature (Col T) in °C, Run time in minutes, Backpressure (BPR) in bars. “iPrNH2” means isopropylamine, “iPrOH” means 2-propanol, “EtOH” means ethanol, “min” mean minutes. SFC methods: Run Flow 135 JAB7225WOPCT1 Run Flow Table: Analytical SFC data – Rtmeans retention time (in minutes), method refers to the method used for (SFC)MS analysis of enantiomerically pure compounds. No. means number. Compound UV Area SFC Method Rt 136 JAB7225WOPCT1 Compound UV Area SFC Method Rt 137 JAB7225WOPCT1 Compound UV Area SFC Method Rt 138 JAB7225WOPCT1 Compound UV Area SFC Method Rt 139 JAB7225WOPCT1 Compound UV Area SFC Method Rt NMR: NMR-Methods Some NMR experiments were carried out using a Bruker Avance III 400 spectrometer at 5 ambient temperature (298.6 K), using internal deuterium lock, and equipped with BBO 400MHz S15 mm probe head with z gradients and operating at 400 MHz for the proton and 100MHz for carbon. Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz. Some NMR experiments were carried out using a Varian 400-MR spectrometer at ambient 10 temperature (298.6 K), using internal deuterium lock, and equipped with Varian 4004NUC PFG probe head with z gradients and operating at 400 MHz for the proton and 100MHz for carbon. Chemical shifts (δ) are reported in parts per million (ppm). J values are expressed in Hz. Some NMR experiments were carried out using a Varian 400-VNMRS spectrometer at ambient 15 temperature (298.6 K), using internal deuterium lock, and equipped with Varian 400 ASW PFG probe head with z gradients and operating at 400 MHz for the proton and 100MHz for carbon. Chemical shifts (d) are reported in parts per million (ppm). J values are expressed in Hz. Compoud Number NMR 140 JAB7225WOPCT1 Compoud Number NMR , , , , - , , , , 141 JAB7225WOPCT1 Compoud Number NMR , Biological Examples In vitro assays include assays that determine cell morphology, protein expression, and / or the 5 cytotoxicity, enzyme inhibitory activity, and / or the subsequent functional consequences of treatment of cells with compounds of the invention. Alternate or additional in vitro assays may be used to quantitate the ability of the inhibitor to bind to protein or nucleic acid molecules within the cell. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating 10 the inhibitor / target molecule complex and determining the amount of radiolabel bound. 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 15 Examples below. 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. 20 In Vitro Assays Biological Example 1 MALT1 Biochemical Protease Assay MALT1 protease activity was assessed in an in vitro assay using a tetrapeptide as substrate25 and full-length MALT1 protein (Strep-MALT1(1-824)-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 142 JAB7225WOPCT1 MALT1 protein, 200 µM 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 5 concentrations ranged from 30 µM 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 10 Labsystems fluoroskan at excitation 355 nm and emission 460 nm to determine time 0. The reaction was subsequently incubated for 4 h at RT and fluorescence was measured. For IC50calculations, 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 15 KM at 200 µM. IC50values were calculated using the following formula (Z prime should be >0.5): LC = Median of the low control values 20 = Low control: Reaction without enzyme HC = Median of the High control values = High Control: Reaction with enzyme %Effect = 100-[(sample-LC) / (HC-LC) x 100] 25 %Control = (sample / HC) x 100 %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 IC50value (inhibitory concentration causing 50 % 30 inhibition) can be obtained. An estimate of the slope of the plot in terms of the Hill coefficient was also obtained. IC50Calculation: 143 JAB7225WOPCT1 yi= LB + UB – LB 1 +10(h*(pCONCi-pIC50))5 With y = estimated response UB = upper bound LB = lower bound h = Hill slope of curve 10 CONC = concentration Used in “Lexis Dose Response Curve Fitting” Version 1.0. Resultant data are shown in Table 2. MALT1_Biochemical MALT1_Biochemical 144 JAB7225WOPCT1 MALT1_Biochemical MALT1_Biochemical Biological Example 2 GloSensor reporter MALT1-mediated cleavage In Jurkat Cells 5 MALT1 GloSensorTMis a split luciferase reporter, which utilizes a genetically modified form of firefly luciferase (CP UltraGlo) split into 2 distinct domains by insertion of a RelB MALT1 cleavage site sequence PRLVSRGA. MALT1-induced cleavage allows for a conformational 145 JAB7225WOPCT1 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 GloSensorTMwere 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 5 be activated by treatment with PMA / Ionomycin. Small molecule MALT1 inhibitors added prior to PMA / Ionomycin addition prevent MALT1 protease activation and, therefore, the cleavage of the MALT1 GloSensor split luciferase reporter in a dose-dependent manner. Jurkat MALT1 GloSensorTMcells were maintained in complete RPMI 1640 media containing 10 10% fetal bovine serum, 10mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 100 units / mL of penicillin, 100 µg / 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 15 fresh complete RPMI 1640 media with 2% GloSensor™ cAMP Reagent and preincubated for 45-60 minutes at 37 °C in a 5% CO2incubator. A volume of 50 uL of preincubated Jurkat MALT1 GloSensorTMcells (1 x 105cells) were seeded in each well of 384-well plate. Next, a volume 2 µL of diluted PMA / Ionomycin (2.5 mg / mL / 25 µM respectively, Sigma, catalog number P1585 and 407953) in DMSO were added to each well. After incubation at 37 °C in 20 5% CO2 incubator for 4 h, luminescence was measured on the Envision (Perkin Elmer) at 37 °C. IC50values were calculated using SmartFit in GeneData ScreenerÒ: 25 Where: x = concentration y = activity S0= activity at bottom plateau of curve Sinf= activity at top plateau of curve 30 S50 = inflection point, halfway between S0 and Sinf h = Hill slope of curve 146 JAB7225WOPCT1 Resultant data are shown in Table 3. n.d. means not determined Jurkat Jurkat Jurkat 147 JAB7225WOPCT1 Jurkat Jurkat Jurkat Biological Example 3 Human IL-6 / IL-10 Mesoscale Assay 5 OCI-Ly3 cells were propagated in RPMI-1640 (Sigma Aldrich) supplemented with 10% fetal bovine serum (HyClone), 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. 10 For the Mesoscale assay, 100,000 OCI-Ly3 cells were seeded per well into black-colored 96- well plates with clear bottom (Corning #3904) and test compounds were added in 9 dilution steps (1:2) ranging from 15 µM 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 15 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 µL). After 24 h of incubation 50 µL 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 20 saline (PBS) + 0.05% Tween-20 and 25 µL 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 µL 2x Read Buffer T and read on SECTOR imager. Resultant data are shown in Table 4. 148 JAB7225WOPCT1 Human IL6 Mesoscale Human IL10 Mesoscale 149 JAB7225WOPCT1 101 0.052 0.048 Biological Example 4 Proliferation Assays OCI-Ly3 cells were propagated in RPMI-1640 with Glutamax (ThermoFisher) 5 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 µg / mL Gentamycin. Cells should be kept between 0.15 – 3 million cells per mL and passed every 3-4 days during 10 culturing. Cell passage numbers should not exceed 20. To assess anti-proliferative effects, 450 nL of test compounds were spotted per well of U-bottom 96-well plates (Corning, #3975).500 OCI-Ly3 or OCI-Ly7 cells were seeded in 150 µL 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, 15 100 µL of the plated cells were resuspended up and down by pipette and transferred to a flat bottom black plate (Corning, #3904).50 µL 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. IC50 values were calculated using SmartFit in GeneData ScreenerÒ: 20 Where: x = concentration y = activity 150 JAB7225WOPCT1 S0 = activity at bottom plateau of curve Sinf= activity at top plateau of curve S50 = inflection point, halfway between S0 and Sinf h = Hill slope of curve 5 Resultant data are shown in Table 5: 151 JAB7225WOPCT1 Anti-proliferation: Anti-proliferation: 152 JAB7225WOPCT1 98 0.13 >17.60 153

Claims

JAB7225WOPCT1 CLAIMS 1. A compound of Formula (I) 5 or a tautomer or aHet is a monocyclic or bicyclic heterocyclic radical selected from ; 10Rarepresents C1-4alkyl, -C1-4alkyl-O-C1-4alkyl, or C1-4alkyl substituted with 1, 2 or 3 halo; R1brepresents cyano; R1crepresents hydrogen or C1-4alkyl; R1drepresents hydrogen or C1-4alkyl; 15 R1erepresents hydrogen or halo; R1frepresents hydrogen or halo; R1grepresents hydrogen or C1-4alkyl; 154JAB7225WOPCT1 rin represents phenyl or pyridyl;R2represents halo; n is 0, 1 or 2; 5 R3arepresents hydrogen or C1-4alkyl; R3brepresents hydrogen; C1-4alkyl; C3-6cycloalkyl; adamantyl; C6-10carbobicyclic; Het1; C3-6cycloalkyl 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)-(C1-4alkyl)2, -NH-(C=O)-R7, 10 -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-C1-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-C1-4alkyl-O-R7, -NH-S(=O)2-R7, Het3a, Het3b, and C1-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-C1-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, and -S(=O)2-C1-4alkyl; 15 C6-10carbobicyclic 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)-(C1-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-C1-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-C1-4alkyl-O-R7, -NH-S(=O)2-R7, and C1-4alkyl optionally substituted with 20 one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-C1-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, and -S(=O)2-C1-4alkyl; or C1-4alkyl 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, 25 -NR4aR4b, -S(=O)(=NH)-R7, -N=S(=O)-(C1-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-C1-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-C1-4alkyl-O-R7, -NH-S(=O)2-R7, -CF3, Cy1, Het3a, Het3b, -O-Het3b, -C(=O)-Het3a, -C(=O)-Het3b, and ; 30 or Raand R are taken together to form together with the nitrogen atom to which they are attached Het2; 155JAB7225WOPCT1 Cy1represents C3-6cycloalkyl; or C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -OR7, -S(=O)2-C1-4alkyl, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-C1-4alkyl, -N=S(=O)-(C1-4alkyl)2, -NH-(C=O)-C1-4alkyl, -NH-(C=O)-C3-6cycloalkyl, -C(=O)-NR4aR4b, and -NH-S(=O)2-R7; 5 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 from O, S, and N; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in 10 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)-(C1-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-C1-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-C1-4alkyl-O-R7, -NH-S(=O)2-R7, and C1-4alkyl optionally substituted with 15 one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-C1-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, and -S(=O)2-C1-4alkyl; 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); 20 wherein one or more of the N-atoms in said heterocyclyl might be substituted with C1-4alkyl, Het5, -C(=O)-NR4aR4b, -C(=O)-C1-4alkyl, -S(=O)2-C1-4alkyl, -S(=O)2-NR4aR4b, -C(=O)-C3-6cycloalkyl, or C1-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH and halo; 25 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; 30 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)-(C1-4alkyl)2, -NH-(C=O)-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, -P(=O)-R4cR4d, -O-C1-4alkyl-C(=O)-NR4aR4b, 35 -S(=O)(=NH)-C1-4alkyl-O-R7, -NH-S(=O)2-R7, and C1-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-C1-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, Het4and 156JAB7225WOPCT1 -S(=O)2-C1-4alkyl; 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 C1-4alkyl, 5 -C(=O)-NR4aR4b, -C(=O)-C1-4alkyl, -S(=O)2-C1-4alkyl, -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 10 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 15 consisting of oxo, halo, -OH, -OR7, -S(=O)2-C1-4alkyl, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-C1-4alkyl, -N=S(=O)-(C1-4alkyl)2, -NH-(C=O)-C1-4alkyl, -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); 20 wherein one or more of the N-atoms in said heterocyclyl might be substituted with C1-4alkyl, Het5, -C(=O)-NR4aR4b, -C(=O)-C1-4alkyl, -S(=O)2-C1-4alkyl, -S(=O)2-NR4aR4b, -C(=O)-C3-6cycloalkyl, or C1-4alkyl 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 25 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 30 consisting of oxo, halo, -OH, C1-4alkyl, -OR7, -S(=O)2-C1-4alkyl, -S(=O)2-NR4aR4b, -NR4aR4b, -S(=O)(=NH)-C1-4alkyl, -N=S(=O)-(C1-4alkyl)2, -NH-(C=O)-C1-4alkyl, -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); 35 wherein one or more of the N-atoms in said heterocyclyl might be substituted with C1-4alkyl, Het5, -C(=O)-NR4aR4b, -C(=O)-C1-4alkyl, -S(=O)2-C1-4alkyl, -S(=O)2-NR4aR4b, -C(=O)-C3-6cycloalkyl, or C1-4alkyl substituted with one, two or three substituents each 157JAB7225WOPCT1 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; 5 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), 10 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; 15 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, C1-4alkyl, C3-6cycloalkyl, or C1-4alkyl-O-C1-4alkyl; 20 R4cand R4deach independently represent C1-4alkyl or -O-C1-4alkyl; R6represents C1-4alkyl; or C1-4alkyl substituted with one -OH; R7represents C1-4alkyl or C3-6cycloalkyl, each optionally substituted with one, two or three halo substituents; p1 and p2 each independently are 1, 2 or 3; 25 or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein rin represents phenyl;30 R2represents halo; n is 0, 1 or 2; R3arepresents hydrogen or C1-4alkyl; 158JAB7225WOPCT1 R3brepresents hydrogen; C1-4alkyl; C3-6cycloalkyl; adamantyl; C6-10carbobicyclic; 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, - 5 NH-S(=O)2-R7, Het3a, Het3b, and C1-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, - S(=O)(=NH)-C1-4alkyl, -C(=O)-NR4aR4b, -S(=O)2-NR4aR4b, and -S(=O)2-C1-4alkyl; C6-10carbobicyclic 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 10 C1-4alkyl 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)-(C1-4alkyl)2, -C(=O)-NR4aR4b, -P(=O)-R4cR4d, -O- C1-4alkyl-C(=O)-NR4aR4b, -S(=O)(=NH)-C1-4alkyl-O-R7, -NH-S(=O)2-R7, - Cy1, Het3a, Het3b, -O-Het3b, -C(=O)-Het3a, and 15 ; or Raand R are taken together to form together with the nitrogen atom to which they are attached Het2; 20 Cy1represents C3-6cycloalkyl; or C3-6cycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of -S(=O)2-C1-4alkyl, 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 25 Het1represents 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, -OH, -OR7-S(=O)2-R7, -C(=O)-NR4aR4b, -S(=O)(=NH)-NR4aR4b, - 30 P(=O)-R4cR4d, -O-C1-4alkyl-C(=O)-NR4aR4b, and C1-4alkyl 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); 35 wherein one or more of the N-atoms in said heterocyclyl might be substituted with C1-4alkyl, 159JAB7225WOPCT1 Het5, -C(=O)-C1-4alkyl, -S(=O)2-C1-4alkyl, -S(=O)2-NR4aR4b, -C(=O)-C3-6cycloalkyl, or C1- 4alkyl substituted with one, two or three -OH; Het2represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl 5 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 10 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)-(C1-4alkyl)2, -C(=O)-NR4aR4b, and C1-4alkyl optionally substituted with one, two or three -S(=O)2-C1-4alkyl; 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); 15 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 20 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; 25 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 C1-4alkyl, Het5, -C(=O)-C1-4alkyl, -S(=O)2-C1-4alkyl, -S(=O)2-NR4aR4b, or -C(=O)-C3-6cycloalkyl; Het3brepresents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl 30 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 35 consisting of oxo, halo, -OH, C1-4alkyl, 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); 160JAB7225WOPCT1 wherein one or more of the N-atoms in said heterocyclyl might be substituted with C1-4alkyl, Het5, or -S(=O)2-C1-4alkyl; Het4represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl 5 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; 10 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 15 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); p1 and p2 are 2. 20 3. The compound according to claim 1 or 2 wherein Het is a monocyclic or bicyclic heterocyclic radical selected from (a-1) and (a-4); R1arepresents C1-4alkyl or -C1-4alkyl-O-C1-4alkyl; R1brepresents cyano; R1crepresents C1-4alkyl; 25 R1frepresents halo; rin represents phenyl;R2represents halo; 30 n is 0, 1 or 2; R3arepresents hydrogen; R3brepresents C1-4alkyl; C3-6cycloalkyl; or C3-6cycloalkyl substituted with one -S(=O)2-R7; R6represents C1-4alkyl; 161JAB7225WOPCT1 R7represents C1-4alkyl.

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

7. The compound according to any one of the preceding claims wherein R3arepresents hydrogen. 10 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. 15 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. 20 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. 25 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. 30 13. A Compound of Formula (A) 162JAB7225WOPCT1or a tautomer or a stereoisomeric form thereof, wherein Het is a monocyclic or bicyclic heterocyclic radical selected from 5 ;Rarepresents C1-4alkyl, -C1-4alkyl-O-C1-4alkyl, or C1-4alkyl substituted with 1, 2 or 3 halo; R1brepresents cyano; R1crepresents hydrogen or C1-4alkyl; 10 R1drepresents hydrogen or C1-4alkyl; R1erepresents hydrogen or halo; R1frepresents hydrogen or halo; R1grepresents hydrogen or C1-4alkyl; 15 rin represents phenyl or pyridyl;R2represents halo; n is 0, 1 or 2; R6represents C1-4alkyl; or C1-4alkyl substituted with one -OH; 20 or a pharmaceutically acceptable salt thereof. 163

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