WO2024133859A1

WO2024133859A1 - Malt1 inhibitors

Info

Publication number: WO2024133859A1
Application number: PCT/EP2023/087548
Authority: WO
Inventors: Jeffrey Stuart MOWAT; Johannes Wilhelmus J. Thuring; Fabian HULPIA; Susan LEPRI; Aldo Peschiulli; Yves Emiel Maria Van Roosbroeck; Adriana-Ingrid VELTER; Mikko Juhani Artturi MUURONEN; Berthold Wroblowski; Evelien RENDERS; Veronica TONA
Original assignee: Janssen Pharmaceutica Nv; Johnson & Johnson (China) Investment Ltd.
Priority date: 2022-12-23
Filing date: 2023-12-22
Publication date: 2024-06-27

Abstract

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

Description

MALT1 INHIBITORS

FIELD OF THE INVENTION

The present invention relates to a novel compound that is a MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) inhibitor. The compound may be useful for the treatment of a disease, syndrome, condition, or disorder, particularly a MALTl-related disease, syndrome, condition, or disorder, including but not limited to, cancer and immunological diseases. The invention also relates to pharmaceutical compositions comprising one or more of such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds or pharmaceutical compositions for the treatment of cancer and autoimmunological diseases, syndromes, disorders, or conditions associated with MALT1 inhibitors.

BACKGROUND OF THE INVENTION

MALT1 (mucosa-associated lymphoid tissue lymphoma translocation 1) is a key mediator of the classical NFKB signaling pathway. MALT1 is the only human paracaspase and transduces signals from the B cell receptor (BCR) and T cell receptor (TCR). MALT1 is the active subunit of the CBM complex which is formed upon receptor activation. The CBM complex consists of multiple subunits of three proteins: CARD 11 (caspase recruitment domain family member 11), BCL10 (B-cell CLL/Lymphoma 10) and MALT1. MALT1 affects NFKB signaling by two mechanisms: firstly, MALT1 functions as a scaffolding protein and recruits NFKB signaling proteins such as TRAF6, TAB-TAK1 or NEMO-IKKa/0; and secondly, MALT1, as a cysteine protease, cleaves and thereby deactivates negative regulators of NFKB signaling, such as RelB, A20 or CYLD. The ultimate endpoint of MALT1 activity is the nuclear translocation of the NFKB transcription factor complex and activation of NFKB signaling.

Constitutive activation of NFKB signaling is the hallmark of ABC-DLBCL (Diffuse Large B cell Lymphoma of the Activated B Cell-like subtype), the more aggressive form of DLBCL. DLBCL is the most common form of non-Hodgkin’s lymphoma (NHL), accounting for approximately 25% of lymphoma cases while ABC-DLBCL comprises approximately 40% of DLBCL. NFKB pathway activation is driven by mutations of signaling components, such as CD79A/B, CARD11, MYD88 or A20, in ABC-DLBCL patients.

The use of BTK inhibitors, for example Ibrutinib, provides clinical proof-of-concept that inhibiting NFKB signaling in ABC-DLBCL is efficacious. MALT1 is downstream of BTK in the NFKB signaling pathway and a MALT1 inhibitor could target ABC-DLBCL patients not responding to Ibrutinib, mainly patients with CARD 11 mutations, as well as treat patients that acquired resistance to Ibrutinib. Small molecule tool compound inhibitors of MALT1 protease have demonstrated efficacy in preclinical models of ABC-DLBCL. Interestingly, covalent catalytic site and allosteric inhibitors of MALT1 protease function have been described, suggesting that inhibitors of this protease may be useful as pharmaceutical agents.

The chromosomal translocation creating the API2-MALT1 fusion oncoprotein is the most common mutation identified in MALT (mucosa-associated lymphoid tissue) lymphoma. API2-MALT1 is a potent activator of the NFKB pathway. API2-MALT1 mimics ligand-bound TNF receptor, promotes TRAF2-dependent ubiquitination of RIP 1 which acts as a scaffold for activating canonical NFKB signaling. Furthermore, API2-MALT1 has been shown to cleave and generate a stable, constitutively active fragment of NFicB-inducing kinase (NIK) thereby activating the non-canonical NFKB pathway.

In addition to lymphomas, MALT1 has been shown to play a critical role in innate and adaptive immunity. MALT1 protease inhibitor can attenuate disease onset and progression of mouse experimental allergic encephalomyelitis, a mouse model of multiple sclerosis. Mice expressing catalytically inactive MALT1 mutant showed loss of marginal zone B cells and Bl B cells and general immune deficiency characterized as decreased T and B cell activation and proliferation. However, those mice also developed spontaneous multi-organ autoimmune inflammation at the age of 9 to 10 weeks. It is still poorly understood why MALT1 protease dead knock-in mice show a break of tolerance while conventional MALT1 KO mice do not. One hypothesis suggests the unbalanced immune homeostasis in MALT1 protease dead knock- in mice may be caused by incomplete deficiency in T and B cell but severe deficiency of immunoregulatory cells. Similarly, MALT deficiency in humans has been associated with combined immunodeficiency disorder. Given the difference between genetic mutation and pharmacological inhibition, a phenotype of MALT1 protease dead knock-in mice might not resemble that of patients treated with MALT1 protease inhibitors. A reduction of immunosuppressive T cells by MALT1 protease inhibition may be beneficial to cancer patients by potentially increasing antitumor immunity.

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

The present invention is directed to compounds of Formula (I)

and the tautomers and the stereoisomeric forms thereof, wherein

R¹ represents

R^x represents hydrogen; Ci-4alkyl; halo; or Ci-4alkyl substituted with one, two or three halo substituents;

R^y represents hydrogen; Ci-4alkyl; Cs-ecycloalkyl; or Ci-4alkyl substituted with one, two or three halo substituents;

R^z represents Ci-4alkyl; Cs-ecycloalkyl; or Ci-4alkyl substituted with one, two or three halo substituents; or R^y and R^z taken together with the carbon atom to which they are attached form a C3-6cycloalkyl; ring

represents phenyl or pyridyl;

R² represents halo; n is 0, 1 or 2;

R^3a represents hydrogen or Ci-4alkyl;

R^3b represents hydrogen; Ci-4alkyl; Cs-ecycloalkyl; adamantyl; Ce-iocarbobicyclic; Het¹;

Cs-ecycloalkyl substituted with one, two, three or four substituents each independently selected from the group consisting of oxo, halo, cyano, -OH, -OR⁷, -S(=O)2-R⁷, -S(=O)₂-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-R⁷, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-R⁷, -C(=O)-NR^4aR^4b, -S(=O)(=NH)-NR^4aR^4b, -P(=O)-R^4cR^4d, -O-Ci-₄alkyl-C(=O)-NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl-O-R⁷, -NH-S(=O)₂-R⁷, Het^3a, Het^3b, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-Ci-₄alkyl, -C(=O)-NR^4aR^4b, -S(=O)₂-NR^4aR^4b, and -S(=O)₂-Ci-₄alkyl;

Ce-iocarbobicyclic 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-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-R⁷, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-R⁷, -C(=O)-NR^4aR^4b, -S(=O)(=NH)-NR^4aR^4b, -P(=O)-R^4cR^4d, -O-Ci-₄alkyl-C(=O)-NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl-O-R⁷, -NH-S(=O)₂-R⁷, and Ci-₄alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-Ci-₄alkyl, -C(=O)-NR^4aR^4b, -S(=O)₂-NR^4aR^4b, and -S(=O)₂-Ci-₄alkyl; or

Ci-₄alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of cyano, halo, -OH, -OR⁷, -S(=O)₂-R⁷, -S(=O)₂-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-R⁷, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-R⁷, -C(=O)-NR^4aR^4b, -S(=O)(=NH)-NR^4aR^4b, -P(=O)-R^4cR^4d, -O-Ci-₄alkyl-C(=O)-NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl-O-R⁷, -NH-S(=O)₂-R⁷, -CF₃, Cy¹, Het^3a, Het^3b, -O-Het^3b, -C(=O)-Het^3a, -C(=O)-Het^3b, and

or R^3a and R^3b are taken together to form together with the nitrogen atom to which they are attached Het²;

Cy¹ represents 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-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-Ci-₄alkyl, -NH-(C=O)-C₃-6cycloalkyl, -C(=O)-NR^4aR^4b, and -NH-S(=O)₂-R⁷;

Het¹ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; or Het¹ represents a bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; 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-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-R⁷, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-R⁷, -C(=O)-NR^4aR^4b, -S(=O)(=NH)-NR^4aR^4b, -P(=O)-R^4cR^4d, -O-Ci-₄alkyl-C(=O)-NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl-O-R⁷, -NH-S(=O)₂-R⁷, and Ci-₄alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-Ci-₄alkyl, -C(=O)-NR^4aR^4b, -S(=O)₂-NR^4aR^4b, and -S(=O)₂-Ci-₄alkyl; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)₂, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-₄alkyl, Het⁵, -C(=O)-NR^4aR^4b, -C(=O)-Ci-₄alkyl, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, -C(=O)-C3-6cycloalkyl, or Ci-₄alkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH and halo;

Het² represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; or Het² represents a bicyclic N-linked 6- to 11 -membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; 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-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-R⁷, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-R⁷, -C(=O)-NR^4aR^4b, -S(=O)(=NH)-NR^4aR^4b, -P(=O)-R^4cR^4d, -O-Ci-₄alkyl-C(=O)-NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl-O-R⁷, -NH-S(=O)₂-R⁷, and Ci-₄alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-Ci-₄alkyl, -C(=O)-NR^4aR^4b, -S(=O)₂-NR^4aR^4b, Het⁴ and -S(=O)₂-Ci-₄alkyl; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)₂, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-₄alkyl, -C(=O)-NR^4aR^4b, -C(=O)-Ci-₄alkyl, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, Het⁴, or -C(=O)-C3-6cycloalkyl;

Het^3a represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; or Het^3a represents a bicyclic N-linked 6- to 11 -membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, halo, -OH, -OR⁷, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-Ci-₄alkyl, -NH-(C=O)-C₃-6cycloalkyl, -C(=O)-NR^4aR^4b, and -NH-S(=O)₂-R⁷; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)₂, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-₄alkyl, Het⁵, -C(=O)-NR^4aR^4b , -C(=O)-Ci-₄alkyl, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, -C(=O)-C3-6cycloalkyl, or Ci-₄alkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH and halo;

Het^3b represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; or Het^3b represents a bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, halo, -OH, Ci-₄alkyl, -OR⁷, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-Ci-₄alkyl, -NH-(C=O)-C₃-6cycloalkyl, -C(=O)-NR^4aR^4b, and -NH-S(=O)₂-R⁷; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)₂, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-₄alkyl, Het⁵, -C(=O)-NR^4aR^4b , -C(=O)-Ci-₄alkyl, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, -C(=O)-C₃-6cycloalkyl, or Ci-₄alkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH and halo;

Het⁴ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; 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);

Het⁵ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; 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);

Het⁶ represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=0)₂, or S(=O)(=NH);

R^4a and R^4b each independently represent hydrogen, Ci-4alkyl, Cs-ecycloalkyl, or Ci-4alkyl-O-Ci-4alkyl;

R^4C and R^4d each independently represent Ci-4alkyl or -O-Ci-4alkyl;

R⁶ represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH;

R⁷ represents Ci-4alkyl or Cs-ecycloalkyl, each optionally substituted with one, two or three halo substituents; pl and p2 each independently are 1, 2 or 3; and the pharmaceutically acceptable salts thereof.

The present invention is also directed to active intermediates of Formula (A)

and the tautomers and the stereoisomeric forms thereof, wherein

R¹ represents

R^y represents Ci-4alkyl; Cs-ecycloalkyl; or Ci-4alkyl substituted with one, two or three halo substituents;

represents phenyl or pyridyl;

R² represents halo; n is 0, 1 or 2;

R⁶ represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH; and the pharmaceutically acceptable salts thereof.

All references to “compound(s) of Formula (I)” and “intermediates 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).

The compounds of Formula (I) and intermediates 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 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 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 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 intermediates of Formula (A).

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 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 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: .

₉ , whereby X and X represent substituents, indicate that the substituents on the cyclobutyl moiety have trans-configuration.

It will be clear for a skilled person that the bold bonds on a 1,3 -di substituted cyclobutyl moiety as shown below: .

₉ , whereby X and X represent substituents, indicate that the substituents 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- disubstituted cyclohexyl moiety as shown below:

, whereby X¹ and X² represent substituents, 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-di substituted cyclohexyl moiety as shown below:

indicate that the substituents 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 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, trans isomers and mixtures thereof, whenever chemically possible. It will be clear this also applies to intermediates 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 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.

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 intermediates of Formula (A).

Also provided are processes for making a pharmaceutical composition comprising, consisting of, and/or consisting essentially of admixing a compound of Formula (I), and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent. It will be clear this also applies to intermediates of Formula (A).

The present invention further provides methods for treating or ameliorating a disease, syndrome, condition, or disorder in a subject, including a mammal and/or human in which the disease, syndrome, or condition is affected by the inhibition of MALT1, including but not limited to, cancer and/or immunological diseases, using a compound of Formula (I). It will be clear this also applies to intermediates 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 MALT 1, such as cancer and/or immunological diseases.

The present invention is also directed to the preparation of compounds of Formula (I) that act as an inhibitor of MALT 1. The present invention is also directed to the preparation of intermediates of Formula (A) that act as an inhibitor of MALT 1.

Exemplifying the invention are methods of treating a disease, syndrome, condition, or disorder mediated by MALT1, using a compound of Formula (I). In particular said disease, syndrome, condition, or disorder mediated by MALT1 is selected from the group consisting of lymphomas, leukemias, carcinomas, and sarcomas, e.g. non-Hodgkin’s lymphoma (NHL (including B-cell NHL)), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, Burkitt’s lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukemia, chronic myelogenous leukemia (CML), hairy-cell leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erytholeukemia, brain (gliomas), glioblastomas, breast cancer, colorectal/colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing’s sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, esophageal cancer, salivary gland cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, and GIST (gastrointestinal stromal tumor), comprising, consisting of, and/or consisting essentially of, administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described in the present invention.

In another embodiment, the disease, syndrome, condition, or disorder mediated by MALT1 is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma.

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 MALT 1, including but not limited to, autoimmune and inflammatory disorders, e.g. arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatits, Crohn’s disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplact rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet’s diseases, uveitis, myasthenia gravis, Grave’s disease, Hashimoto thyroiditis, Sjorgen’s syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis.

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 MALT 1, selected from the group consisting of rheumatoid arthritis (RA), psoritic arthritis (PsA), psorisis (Pso), ulcerative colitis (UC), Crohn’s disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

In an alternate embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is selected from non-Hodgkin’s lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL), transformed follicular lymphoma, chronic lymphocytic leukemia, and Waldenstrom macroglobulinemia.

In yet another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT 1 is lymphoma.

In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT 1 is the activated B cell like (ABC) subtype of diffuse large B- cell lymphoma (DLBCL).

In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT 1 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 affected by inhibition of MALT1 is non-germinal center B cell like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL).

In an additional embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT 1 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. In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT 1 is Waldenstrom 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 lymphoid tissue (MALT) lymphoma.

In an alternate embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT 1 is non-Hodgkin’s lymphoma (NHL). In a further embodiment, the nonHodgkin’s lymphoma (NHL) is B-cell NHL. In another embodiment, the non-Hodgkin’s lymphoma (NHL) is relapsed/refractory B-cell NHL.

In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is selected from the group consisting of relapsed/refractory non-germinal center B cell like (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL), relapsed/refractory Waldenstrom macroglobulinemia (WM), relapsed/refractory mantle cell lymphoma (MCL), relapsed/refractory follicular lymphoma (FL), and relapsed/refractory mucosa-associated lymphoid tissue (MALT) lymphoma.

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 affected by inhibition of MALT1 is relapsed/refractory Waldenstrom macroglobulinemia (WM).

In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT 1 is relapsed/refractory mantle cell lymphoma (MCL).

In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT 1 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 including, but not limited to, autoimmune and inflammatory disorders, e.g. sepsis-related acute lung injury (ALI), acute respiratory distress syndrome (ARDS), arthritis, rheumatoid arthritis (RA), psoriatic arthritis (PsA), inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatitis, Crohn’s disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplant rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet’s diseases, uveitis, myasthenia gravis, Grave’s disease, Hashimoto thyroiditis, Sjorgen’s syndrome, blistering disorders, antibody -mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis.

In another embodiment of the present invention, the compounds of the present invention may be employed in combination with one or more other medicinal agents, more particularly with other anti-cancer agents, e.g. chemotherapeutic, anti-proliferative or immunomodulating agents, or with adjuvants in cancer therapy, e.g. immunosuppressive or anti-inflammatory agents.

Possible combinations of the compounds of the present invention may include, but are not limited to, BTK (Bruton’s tyrosine kinase) inhibitors such as ibrutinib, SYK inhibitors, PKC inhibitors, PI3K pathway inhibitors, BCL family inhibitors, JAK inhibitors, PIM kinase inhibitors, rituximab or other B cell antigen-binding antibodies, as well as immune cell redirection agents (e.g. blinatumomab or CAR T-cells) and immunomodulatory agents such as daratumumab, anti-PDl antibodies, and anti-PD-Ll antibodies.

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.

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 MALT 1.

In another embodiment, the present invention is directed to a composition comprising a compound of Formula (I) for (use in) the treatment of said disease, syndrome, condition, or disorder affected by inhibition of MALT1.

In another embodiment, the present invention is directed to methods of treating said disease, syndrome, condition, or disorder mediated by MALT1. Another embodiment of the present invention is directed to a pharmaceutical composition comprising a compound of Formula (I) and uses thereof as described in any of the other embodiments.

DETAILED DESCRIPTION OF THE INVENTION

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 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 intended to connote their generally accepted meanings in the patent vernacular; that is, (i) “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) “consisting of’ excludes any element, step, or ingredient not specified in the claim; and (iii) “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel character! stic(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 ‘C_x-y’ (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, a Ci-4alkyl group contains from 1 to 4 carbon atoms, and so on.

The term ‘Ci-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, //-butyl, .s-butyl, /-butyl and the like.

The term ‘Cs-ecycloalkyl’ as used herein as a group or part of a group defines a saturated, cyclic hydrocarbon radical having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Fused bicycles or fused bicyclic groups, are two cycles that share two atoms and the bond between these atoms. Spiro bicycles or spiro bicyclic groups, are two cycles that are joined at a single atom.

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

The term ‘Ce-iocarbobicyclic’ as used herein as a group or part of a group defines a saturated, bicyclic hydrocarbon radical having from 6 to 10 carbon atoms. Ce-iocarbobicyclic can be fused, spiro or bridged, such as spiro[3.3]heptanyl and bicyclo[l.l. l]pentanyl.

The term ‘monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one two or three heteroatoms each independently selected from O, S, and N’, defines a C-linked fully saturated, monocyclic radical having from 4 to 7 ring members in total (including the heteroatoms) containing one, two or three heteroatoms each independently selected from O, S, and N, such as for example C-linked azetidinyl, C-linked oxetanyl, C-linked pyrrolidinyl, C- linked tetrayhydrothiophenyl, C-linked tetrahydrofuranyl, C-linked morpholinyl, C-linked 1,4- oxathianyl, C-linked thiazinanyl, C-linked tetrahydropyranyl, C-linked tetrahydrothiopyranyl, C-linked pyrazolidinyl, C-linked isothiazolidinyl, C-linked oxazolidinyl, and C-linked piperidinyl.

Bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl groups can be fused, spiro 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, and N, such as for example:

The term ‘monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N’, defines a N-linked fully saturated, monocyclic radical having from 4 to 7 ring members in total (including the heteroatoms) containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N, such as for example N-linked azetidinyl, N-linked pyrrolidinyl, N-linked morpholinyl, N-linked thiazinanyl, N-linked pyrazolidinyl, N-linked isothiazolidinyl, N-linked oxazolidinyl, N-linked thiomorpholinyl, N-linked piperazinyl, N- linked thiazolidinyl, N-linked azepanyl, N-linked thiadiazepanyl, and N-linked piperidinyl.

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

The term ‘bicyclic N-linked 6- to 11 -membered fully saturated heterocyclyl containing one N- atom and optionally one or two heteroatoms each independently selected from O, S, and N’, defines a N-linked fully saturated, bicyclic radical having from 6 to 11 ring members in total (including the heteroatoms) containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N, such as for example:

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). 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.

A skilled person will understand R² is absent when n is 0.

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

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

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

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

C_1-4alkyl

— N=S=O

C|_₄alkyl

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

H O

— N—

Cj_₄ alkyl

It will be clear for the skilled person that a group such as -NH-(C=O)-C3-6cycloalkyl represents

H O

— N—

C_3.6cycloalkyl

It will be clear for the skilled person that a group such as -NH-(SO2)-Ci-4alkyl represents

In general, it will be clear for the skilled person that a group such as -NH-(S02)-R (with R being any substituent) represents

Whenever substituents are represented by chemical structure, “ — ” represents the bond of attachment to the remainder of the molecule of Formula (I) or Formula (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 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 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).

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).

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 “ K ” at a stereocenter designates that the stereocenter is purely of the K-configuration as defined in the art; likewise, the stereodescriptor label “S” or “(S)” means that the stereocenter is purely of the ^-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). 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 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 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.

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 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 least partially alleviate, inhibit, prevent, and/ or ameliorate a condition, or a disorder or a disease (i) mediated by MALT1; or (ii) associated with MALT1 activity; or (iii) characterized by activity (normal or abnormal) of MALT 1; or (2) reduce or inhibit the activity of MALT 1; or (3) reduce or inhibit the expression of MALT1; or (4) modify the protein levels of MALT1.

The term “composition” refers to a product that includes the specified ingredients in therapeutically effective amounts, as well as any product that results, directly, or indirectly, from combinations of the specified ingredients in the specified amounts.

The term “MALT 1 -mediated” refers to any disease, syndrome, condition, or disorder that might occur in the absence of MALT1 but can occur in the presence of MALT1. 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 (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, Burkitt’s lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, lymphoblastic T cell leukemia, chronic myelogenous leukemia (CML), hairy-cell leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erytholeukemia, brain (gliomas), glioblastomas, breast cancer, colorectal/colon cancer, prostate cancer, lung cancer including non-small-cell, gastric cancer, endometrial cancer, melanoma, pancreatic cancer, liver cancer, kidney cancer, squamous cell carcinoma, ovarian cancer, sarcoma, osteosarcoma, thyroid cancer, bladder cancer, head and neck cancer, testicular cancer, Ewing’s sarcoma, rhabdomyosarcoma, medulloblastoma, neuroblastoma, cervical cancer, renal cancer, urothelial cancer, vulval cancer, esophageal cancer, salivary gland cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, and GIST (gastrointestinal stromal tumor).

As used herein, the term "MALT1 inhibitor" refers to an agent that inhibits or reduces at least one condition, symptom, disorder, and/or disease of 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 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 least one of the clinical symptoms thereof). In another embodiment, “treat”, “treating”, or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In a further embodiment, “treat”, “treating”, or “treatment” refers to modulating the disease, condition, syndrome or disorder either physically (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both. In yet another embodiment, “treat”, “treating”, or “treatment” refers to preventing or delaying the onset or development or progression of the disease, condition, syndrome or disorder.

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 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 MALT 1 -mediated disease or condition in a subject in need thereof, including an animal, a mammal, and a human in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I).

In another embodiment, the MALT 1 -dependent or MALT 1 -mediated disease or condition is selected from cancers of hematopoietic origin or solid tumors such as chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin lymphoma, and other B cell lymphomas.

In particular, the compounds of Formula (I) may be useful for treating or ameliorating diseases, syndromes, conditions, or disorders such as diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma.

More particularly, the compounds of Formula (I) may be useful for treating or ameliorating diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) as herein defined.

Further, the compounds of Formula (I) may be useful for treating or ameliorating an immunological disease, syndrome, disorder, or condition selected from the group consisting of rheumatoid arthritis (RA), psoritic arthritis (PsA), psorisis (Pso), ulcerative colitis (UC), Crohn’s disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD).

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

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

R¹ represents

represents phenyl or pyridyl;

R² represents halo; n is 0, 1 or 2;

R^3a represents hydrogen; and

R^3b represents hydrogen; Ci-4alkyl; Cs-ecycloalkyl; -Ci^alkyl-Cy¹;

Cs-ecycloalkyl substituted with one substituent selected from the group consisting of halo, -OH, -O-Ci-₄alkyl, -OCF₃, -OCHF2, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-Ci-₄alkyl, -NH-(C=O)-C₃-6cycloalkyl, -C(=O)-NR^4aR^4b, and -NH-(SO₂)-Ci-₄alkyl;

Ci-4alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -O-Ci-4alkyl, -OCF3, -OCHF₂, -S(=O)₂-Ci-4alkyl, -S(=O)₂-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-Ci-₄alkyl, -NH-(C=O)-C₃-6cycloalkyl, -C(=O)-NR^4aR^4b, and -NH-(SO₂)-Ci-₄alkyl;

3- or 4-piperidinyl optionally substituted on the N-atom with Ci-4alkyl, -C(=O)-NR^4aR^4b ,

or R^3a and R^3b are taken together to form together with the nitrogen atom to which they are attached

Cy¹ represents Cs-ecycloalkyl; or Cs-ecycloalkyl substituted with one substituent selected from the group consisting of halo, -OH, -O-Ci-4alkyl, -OCF3, -OCHF2, -S(=O)2-Ci-4alkyl, -S(=O)₂-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-Ci-₄alkyl, -NH-(C=O)-C₃-6cycloalkyl, -C(=O)-NR^4aR^4b, and -NH-(SO₂)-Ci-₄alkyl;

R^4a and R^4b each independently represent hydrogen or Ci-4alkyl;

R⁵ represents hydrogen, -OH, -O-Ci-4alkyl, -S(=O)2-Ci-4alkyl, -S(=O)2-C3-6cycloalkyl, -S(=O)₂-NR^4aR^4b, or -C(=O)-NR^4aR^4b;

R⁶ represents methyl; nl, n2, n3, n4, n5, n6, n7 and n8 each independently are 1 or 2;

R¹ represents

R^x represents halo;

R^y represents hydrogen or Ci-4alkyl;

R^z represents Ci-4alkyl substituted with one, two or three halo substituents; or R^y and R^z taken together with the carbon atom to which they are attached form a C3-6cycloalkyl; ring

represents phenyl or pyridyl;

R² represents halo; n is 0, 1 or 2;

R^3a represents hydrogen or Ci-4alkyl;

Cs-ecycloalkyl substituted with one, two, three or four substituents each independently selected from the group consisting of oxo, -OH, -OR⁷, -S(=O)2-R⁷, -S(=O)2-NR^4aR^4b, - NR^4aR^4b, -S(=O)(=NH)-R⁷, -NH-(C=O)-R⁷, -S(=O)(=NH)-NR^4aR^4b, -P(=O)-R^4cR^4d, - NH-S(=O)2-R⁷, Het^3a, Het^3b, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, - S(=O)(=NH)-Ci-₄alkyl, -C(=O)-NR^4aR^4b, -S(=O)₂-NR^4aR^4b, and -S(=O)₂-Ci-₄alkyl;

Ce-iocarbobicyclic 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-NR^4aR^4b; or

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

NR^4aR^4b, -S(=O)(=NH)-R⁷, -N=S(=O)-(Ci-₄alkyl)₂, -C(=O)-NR^4aR^4b, -P(=O)-R^4cR^4d, -O- Ci-₄alkyl-C(=O)-NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl-O-R⁷, -NH-S(=O)₂-R⁷, - Cy¹, Het^3a, Het^3b, -O-Het^3b, -C(=O)-Het^3a, and

Cy¹ represents Cs-ecycloalkyl; or Cs-ecycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of -S(=O)2-Ci-4alkyl, and -S(=O)2- NR^4aR^4b;

Het¹ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; or Het¹ represents a bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; 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)-NR^4aR^4b, -S(=O)(=NH)-NR^4aR^4b, - P(=O)-R^4cR^4d, -O-Ci-4alkyl-C(=O)-NR^4aR^4b, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, and -C(=O)-NR^4aR^4b; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=0)₂, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-₄alkyl, Het⁵, -C(=O)-Ci-₄alkyl, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, -C(=O)-C_3.6cycloalkyl, or Ci- ₄al kyl substituted with one, two or three -OH;

Het² represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; or Het² represents a bicyclic N-linked 6- to 11 -membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of Het⁶, -S(=O)₂-NR^4aR^4b, -S(=O)(=NH)-R⁷, -N=S(=O)-(Ci-₄alkyl)₂, -C(=O)- NR^4aR^4b, and Ci-₄alkyl optionally substituted with one, two or three -S(=O)₂-Ci-₄alkyl; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)₂, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Het⁴;

Het^3a represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, and -OH; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)₂, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-₄alkyl, Het⁵, -C(=O)-Ci-₄alkyl, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, or -C(=O)-C_3.6cycloalkyl;

Het^3b represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; or Het^3b represents a bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, halo, -OH, Ci-₄alkyl, and -OR⁷; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)₂, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, Het⁵, or -S(=O)2-Ci-4alkyl;

Het⁴ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; 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);

Het⁵ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; 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);

Het⁶ represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; 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);

R^4a and R^4b each independently represent hydrogen, Ci-4alkyl, Cs-ecycloalkyl, or Ci-4alkyl-O- Ci-4alkyl;

R^4C and R^4d each independently represent Ci-4alkyl or -O-Ci-4alkyl;

R⁶ represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH;

R⁷ represents Ci-4alkyl or Cs-ecycloalkyl, each optionally substituted with one, two or three halo substituents; pl and p2 are 2; and the pharmaceutically acceptable salts thereof.

R¹ represents

R^x represents halo;

R^y represents hydrogen or Ci-4alkyl;

R^z represents Ci-4alkyl substituted with one, two or three halo substituents; or R^y and R^z taken together with the carbon atom to which they are attached form a Cs-ecycloalkyl; ring

represents phenyl or pyridyl;

R² represents halo; n is 0, 1 or 2;

R^3a represents hydrogen or Ci-4alkyl;

Ci-4alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of cyano, halo, -OH, -OR⁷, -S(=O)2-R⁷, -S(=O)2-NR^4aR^4b, - NR^4aR^4b, -S(=O)(=NH)-R⁷, -N=S(=O)-(Ci-₄alkyl)₂, -C(=O)-NR^4aR^4b, -P(=O)-R^4cR^4d, -O- Ci-₄alkyl-C(=O)-NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl-O-R⁷, -NH-S(=O)₂-R⁷, - Cy¹, Het^3a, Het^3b, -O-Het^3b, -C(=O)-Het^3a, and

Cy¹ represents Cs-ecycloalkyl; or Cs-ecycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of -S(=O)2-Ci-4alkyl, and -S(=O)2- NR^4aR^4b; Het¹ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; or Het¹ represents a bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; provided that the monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl and bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl, are selected from the following heterocyclyl s:

C-linked azetidinyl, C-linked oxetanyl, C-linked pyrrolidinyl, C-linked tetrayhydrothiophenyl, C-linked tetrahydrofuranyl, C-linked morpholinyl, C-linked 1,4- oxathianyl, C-linked thiazinanyl, C-linked tetrahydropyranyl, C-linked tetrahydrothiopyranyl, C-linked pyrazolidinyl, C-linked isothiazolidinyl, C-linked oxazolidinyl, C-linked piperidinyl,

wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, -OH, -OR⁷ -S(=O)₂-R⁷, -C(=O)-NR^4aR^4b, -S(=O)(=NH)-NR^4aR^4b, - P(=O)-R^4cR^4d, -O-Ci-4alkyl-C(=O)-NR^4aR^4b, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, and -C(=O)-NR^4aR^4b; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)₂, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, Het⁵, -C(=O)-Ci-₄alkyl, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, -C(=O)-C₃-6cycloalkyl, or Ci- 4alkyl substituted with one, two or three -OH;

Het² represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; or Het² represents a bicyclic N-linked 6- to 11 -membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; provided that the monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl and bicyclic N-linked 6- to 11 -membered fully saturated heterocyclyl, are selected from the following heterocyclyl s:

N-linked azetidinyl, N-linked pyrrolidinyl, N-linked morpholinyl, N-linked thiazinanyl, N- linked pyrazolidinyl, N-linked isothiazolidinyl, N-linked oxazolidinyl, N-linked thiomorpholinyl, N-linked piperazinyl, N-linked thiazolidinyl, N-linked azepanyl, N-linked thiadiazepanyl, N-linked piperidinyl,

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

Het^3a represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; provided that the monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl is selected from the following heterocyclyl s:

N-linked azetidinyl, N-linked pyrrolidinyl, N-linked morpholinyl, N-linked thiazinanyl, N- linked pyrazolidinyl, N-linked isothiazolidinyl, N-linked oxazolidinyl, N-linked thiomorpholinyl, N-linked piperazinyl, N-linked thiazolidinyl, N-linked azepanyl, N-linked thiadiazepanyl, and N-linked piperidinyl; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, and -OH; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)₂, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-₄alkyl,

Het^3b represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; or Het^3b represents a bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; provided that the monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl and bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl, are selected from the following heterocyclyl s:

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

Het⁴ represents C-linked oxetanyl;

Het⁵ represents C-linked oxetanyl;

R^4a and R^4b each independently represent hydrogen, Ci-₄alkyl, C₃-6cycloalkyl, or Ci-₄alkyl-O- Ci-₄alkyl;

R^4C and R^4d each independently represent Ci-₄alkyl or -O-Ci-₄alkyl; R⁶ represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH;

R¹ represents

R^x represents halo;

R^y represents Ci-4alkyl;

R^z represents Ci-4alkyl substituted with one, two or three halo substituents; ring

represents phenyl or pyridyl;

R² represents halo; n is 0 or 1;

R^3a represents hydrogen;

R^3b represents Ci-4alkyl; Cs-ecycloalkyl; or

Cs-ecycloalkyl substituted with one substituent selected from the group consisting of -S(=O)₂-R⁷ and -S(=O)(=NH)-R⁷;

R⁶ represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH;

R⁷ represents Ci-4alkyl; and the pharmaceutically acceptable salts thereof.

R¹ represents

R^x represents halo;

R^y represents Ci-4alkyl;

represents phenyl; n is 0;

R^3a represents hydrogen;

R^3b represents Cs-ecycloalkyl substituted with one -S(=O)2-R⁷;

R⁶ represents Ci-4alkyl;

R⁷ represents Ci-4alkyl; and the pharmaceutically acceptable salts thereof.

R¹ represents

R^x represents chloro;

R^y represents methyl;

R^z represents CF3; ring

represents phenyl; n is 0;

R^3a represents hydrogen;

R^3b represents Cs-ecycloalkyl substituted with one -S(=O)2-R⁷;

R⁶ represents methyl;

R⁷ represents methyl; and the pharmaceutically acceptable salts thereof.

R¹ represents

R^x represents hydrogen, Ci-4alkyl or halo;

R^z represents Ci-4alkyl; Cs-ecycloalkyl; or Ci-4alkyl substituted with one, two or three halo substituents; or R^y and R^z taken together with the carbon atom to which they are attached form a C3-6cycloalkyl;

R⁶ represents CH3; ring

represents phenyl or pyridyl;

R² represents halo; n is 0, 1 or 2;

R^3a represents hydrogen; and R^3b represents hydrogen; Ci-4alkyl; Cs-ecycloalkyl;

Cs-ecycloalkyl substituted with one substituent selected from the group consisting of -OH, -S(=O)₂-Ci-₄alkyl, -NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl, and -N=S(=O)-(Ci-₄alkyl)₂;

-Ci-₄alkyl-S(=O)₂-Ci-₄alkyl; Ci-₄alkyl substituted with one, two or three halo substituents; 3- or 4-piperidinyl optionally substituted on the N-atom with Ci-₄alkyl;

R^4a and R^4b each independently represent hydrogen or Ci-₄alkyl;

R⁵ represents hydrogen or -OH; nl, n2, n3, n4, n5, n6, n7 and n8 each independently are 1 or 2; and the pharmaceutically acceptable salts thereof.

R¹ represents

R^x represents halo;

R^y represents Ci-₄alkyl;

R^z represents Ci-₄alkyl substituted with one, two or three halo substituents;

R⁶ represents CH3; ring

represents phenyl; R² represents halo; n is 0, 1 or 2;

R^3a represents hydrogen; and

R^3b represents Ci-4alkyl; or Cs-ecycloalkyl substituted with one -S(=O)2-Ci-4alkyl; and the pharmaceutically acceptable salts thereof.

R¹ represents

R^x represents halo;

R^y represents Ci-4alkyl;

R^z represents Ci-4alkyl substituted with one, two or three halo substituents;

R⁶ represents CH3; ring

represents phenyl; n is 0;

R^3a represents hydrogen; and

R^3b represents Cs-ecycloalkyl substituted with one -S(=O)2-Ci-4alkyl; and the pharmaceutically acceptable salts thereof.

R¹ represents

R^x represents halo;

R^y represents Ci-4alkyl;

R^z represents Ci-4alkyl substituted with one, two or three halo substituents;

R⁶ represents CH3; ring

represents phenyl; n is 1;

R^3a represents hydrogen; and

R¹ represents

R^x represents halo;

R^y represents Ci-4alkyl;

R^z represents Ci-4alkyl substituted with one, two or three halo substituents;

R⁶ represents CH3; ring

represents phenyl; n is 1; R^3a represents hydrogen; and

R^3b represents Ci-4alkyl; 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

R^z represents Ci-4alkyl; Cs-ecycloalkyl; or Ci-4alkyl substituted with one, two or three halo substituents.

R^x represents Ci-4alkyl; halo; or Ci-4alkyl substituted with one, two or three halo substituents;

R^z represents Ci-4alkyl; Cs-ecycloalkyl; or Ci-4alkyl substituted with one, two or three halo substituents; or R^y and R^z taken together with the carbon atom to which they are attached form a Cs-ecycloalkyl.

R^y and R^z taken together with the carbon atom to which they are attached form a C3-6cycloalkyl.

R^x represents Ci-4alkyl; halo; or Ci-4alkyl substituted with one, two or three halo substituents; R^y and R^z taken together with the carbon atom to which they are attached form a Cs-ecycloalkyl.

R^x represents chloro;

R^y represents methyl;

R^z represents trifluoromethyl.

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 R^x represents chloro.

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 R^z represents trifluorom ethyl.

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 R^y represents Ci-4alkyl; Cs-ecycloalkyl; or Ci-4alkyl substituted with one, two or three halo substituents.

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 R² represents fluoro.

R¹ represents

R^x represents halo;

R^y represents Ci-4alkyl;

R^z represents Ci-4alkyl substituted with one, two or three halo substituents;

R^3a represents hydrogen;

R^3b represents Ci-4alkyl; Cs-ecycloalkyl; or

R⁷ represents Ci-4alkyl.

R¹ represents

R^x represents halo;

R^y represents Ci-4alkyl;

R^z represents Ci-4alkyl substituted with one, two or three halo substituents;

R^3a represents hydrogen;

R^3b represents Ci-4alkyl; Cs-ecycloalkyl; or

Cs-ecycloalkyl substituted with one substituent selected from the group consisting of -S(=O)₂-R⁷ and -S(=O)(=NH)-R⁷

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 R¹ represents

R^x represents halo;

R^y represents Ci-4alkyl;

R^z represents Ci-4alkyl substituted with one, two or three halo substituents;

R^3a represents hydrogen;

R^3b represents Cs-ecycloalkyl substituted with one substituent selected from the group consisting of -S(=O)2-R⁷ and -S(=O)(=NH)-R⁷;

R⁷ represents Ci-4alkyl.

R¹ represents

R^x represents chloro;

R^y represents methyl;

R^z represents trifluoromethyl;

R^3a represents hydrogen;

R⁷ represents 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 n is 0.

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 1.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein ring

represents phenyl.

represents phenyl, and R⁶ represents 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 R^3b represents Ci-4alkyl; or Cs-ecycloalkyl substituted with one -S(=O)2-Ci-4alkyl.

R^3b represents Ci-4alkyl.

R^3b represents Cs-ecycloalkyl substituted with one -S(=O)2-Ci-4alkyl; in particular cyclobutyl substituted with one -S(=O)2-Ci-4alkyl; more in particular cyclobutyl substituted with one - S(=O)₂-CH₃.

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein substituent -S(=O)2-Ci-4alkyl is limited to -S(=O)2-CH3.

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 R⁶ represents 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 trans:

trans

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the stereochemistry of the cyclopropyl moiety in Formula (I) is cis:

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the stereochemistry of the cyclopropyl moiety in Formula (I) is

, and wherein R⁶ represents methyl.

, and wherein R⁶ represents 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 in Formula (I) is as indicated below in Formula (I-a):

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the stereochemistry of the substituents on the cyclopropyl moiety in Formula (I) is as indicated below in Formula (I-b):

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Formula (I) and the stereochemistry of the substituents on the cyclopropyl moiety are as indicated below in Formula (Lal):

In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Formula (I) and the stereochemistry of the substituents on the cyclopropyl moiety are as indicated below in Formula ( bl):

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

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

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.

In an embodiment the compound of Formula (I) is selected from the group consisting of compounds 1, 2, 3, 7, 8, 9, 10, 11, 12, 14, 15, 16, and 17.

In an embodiment the compound of Formula (I) is selected from the group consisting of compounds 1, 2, 3, 7, 8, 9, 10, 11, 12, 14, 15, 16, and 17; 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 1, 2, 3, 7, 8, 9, 10, 11, 12, 14, 15, 16, and 17; and the pharmaceutically acceptable salts thereof.

In an embodiment the compound of Formula (I) is selected from the group consisting of compounds 22, 28, 33, 34, 36, 37, 39, 40, 41, 129, 131, 132, 148, 178, 191, 193, 201, 204, 267, 294, and 318.

In an embodiment the compound of Formula (I) is selected from the group consisting of compounds 22, 28, 33, 34, 36, 37, 39, 40, 41, 129, 131, 132, 148, 178, 191, 193, 201, 204, 267, 294, and 318; 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 22, 28, 33, 34, 36, 37, 39, 40, 41, 129, 131, 132, 148, 178, 191, 193, 201, 204, 267, 294, and 318; 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, 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, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176,

177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195,

196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214,

215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233,

234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252,

253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271,

272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290,

291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309,

310, 311, 312, 313, 314, 315, 316, 317, 318, 319 and 320.

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, 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, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319 and 320; tautomers and stereoisomeric forms thereof, and the pharmaceutically acceptable salts thereof.

310, 311, 312, 313, 314, 315, 316, 317, 318, 319 and 320; and the pharmaceutically acceptable salts thereof.

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.

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.

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 1, 2, 3, 7, 8, 9, 10, 11, 12, 14, 15, 16, and 17.

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 1, 2, 3, 7, 8, 9, 10, 11, 12, 14, 15, 16, and 17; tautomers and stereoisomeric forms thereof, and the pharmaceutically acceptable salts thereof.

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 22, 28, 33, 34, 36, 37, 39, 40, 41, 129, 131, 132, 148, 178, 191, 193, 201, 204, 267, 294, and 318.

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 22, 28, 33, 34, 36, 37, 39, 40, 41, 129, 131, 132, 148, 178, 191, 193, 201, 204, 267, 294, and 318; tautomers and stereoisomeric forms thereof, and the pharmaceutically acceptable salts thereof.

In an embodiment the compound of Formula (I) is compound 1 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 2 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 3 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 7 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 8 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 9 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 10 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 11 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 12 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 14 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 15 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 16 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 17 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 22 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 28 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 34 or a pharmaceutically acceptable salt thereof. In an embodiment the compound of Formula (I) is compound 36 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 37 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 39 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 40 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 41 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 129 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 131 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 132 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 148 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 178 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 191 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 193 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 201 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 204 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 267 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 294 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is compound 318 or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is

a stereoisomeric form thereof, or a pharmaceutically acceptable salt thereof. In particular wherein the stereochemistry of the cyclopropyl moiety is trans. In an embodiment the compound of Formula (I) is

a stereoisomeric form thereof, or a pharmaceutically acceptable salt thereof. In particular wherein the stereochemistry of the cyclopropyl moiety is trans.

In an embodiment the compound of Formula (I) is

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

or a pharmaceutically acceptable salt thereof.

5 In an embodiment the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is

In an embodiment the compound of Formula (I) is

In an embodiment the compound of Formula (I) is

In an embodiment the compound of Formula (I) is

In an embodiment the compound of Formula (I) is

In an embodiment the compound of Formula (I) is

In an embodiment the compound of Formula (I) is

In an embodiment the compound of Formula (I) is

In an embodiment the compound of Formula (I) is

In an embodiment the compound of Formula (I) is

In an embodiment the compound of Formula (I) is (lR,3S)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[l,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2- difluoro-l-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-l -carboxamide, or a pharmaceutically acceptable salt thereof. In an embodiment the compound of Formula (I) is (lS,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[l,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2- difluoro- l-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-l -carboxamide, or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is (lS,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[l,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2- difluoro-l-methyl-N-((trans)-3-(-S-methylsulfonimidoyl)cyclobutyl)cyclopropane-l- carboxamide, or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is (lS,3R)-2,2-difluoro-l-methyl-3-(4-((R)-8- methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[l,5-a]pyrrolo[2,3-e]pyrimidin-6- yl)phenyl)-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-l -carboxamide, or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is (lS,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[l,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2- difluoro-l-methyl-N-(2-sulfamoylethyl)cyclopropane-l -carboxamide, or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is (lS,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[l,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-N- ((dimethylphosphoryl)methyl)-2,2-difluoro-l -methylcyclopropane- 1 -carboxamide, or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is (lS,3R)-N-((trans)-3- acetamidocyclobutyl)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolof 1 , 5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1 -methylcyclopropane- 1 - carboxamide, or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is (lS,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[l,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2- difluoro-l-methyl-N-(((trans)-3-((S)-S- methylsulfonimidoyl)cyclobutyl)methyl)cyclopropane-l -carboxamide, or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is (lS,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[l,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-N-(3- (cyclopropanesulfonamido)propyl)-2,2-difluoro- 1 -methylcyclopropane- 1 -carboxamide, or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is (lS,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[l,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2- difluoro- l-methyl-N-(3-(methylamino)cyclobutyl)cyclopropane-l -carboxamide, or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of Formula (I) is (lR,3S)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[l,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2- difluoro-l-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-l -carboxamide.

In an embodiment the compound of Formula (I) is (lS,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[l,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2- difluoro-l-methyl-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-l -carboxamide.

In an embodiment the compound of Formula (I) is (lS,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[l,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2- difluoro-l-methyl-N-((trans)-3-(-S-methylsulfonimidoyl)cyclobutyl)cyclopropane-l- carb oxami de.

In an embodiment the compound of Formula (I) is (lS,3R)-2,2-difluoro-l-methyl-3-(4-((R)-8- methyl-8-(trifluoromethyl)-7,8-dihydro-6H-pyrazolo[l,5-a]pyrrolo[2,3-e]pyrimidin-6- yl)phenyl)-N-((trans)-3-(methylsulfonyl)cyclobutyl)cyclopropane-l -carboxamide.

In an embodiment the compound of Formula (I) is (lS,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[l,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2- difluoro- 1 -methyl-N-(2-sulfamoylethyl)cyclopropane- 1 -carboxamide.

In an embodiment the compound of Formula (I) is (lS,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[l,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-N- ((dimethylphosphoryl)methyl)-2,2-difluoro-l -methylcyclopropane- 1 -carboxamide.

In an embodiment the compound of Formula (I) is (lS,3R)-N-((trans)-3- acetamidocyclobutyl)-3-(4-((R)-2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6H- pyrazolof 1 , 5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2-difluoro- 1 -methylcyclopropane- 1 - carboxamide.

In an embodiment the compound of Formula (I) is (lS,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[l,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2- difluoro-l-methyl-N-(((trans)-3-((S)-S- methylsulfonimidoyl)cyclobutyl)methyl)cyclopropane-l-carboxamide.

In an embodiment the compound of Formula (I) is (lS,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[l,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-N-(3- (cyclopropanesulfonamido)propyl)-2,2-difluoro- 1 -methylcyclopropane- 1 -carboxamide.

In an embodiment the compound of Formula (I) is (lS,3R)-3-(4-((R)-2-chloro-8-methyl-8- (trifluoromethyl)-7,8-dihydro-6H-pyrazolo[l,5-a]pyrrolo[2,3-e]pyrimidin-6-yl)phenyl)-2,2- difluoro- l-methyl-N-(3-(methylamino)cy cl obutyl)cy cl opropane-1 -carboxamide.

In an embodiment the active intermediate of Formula (A) is

or a pharmaceutically acceptable salt thereof.

In an embodiment the active intermediate of Formula (A) is

or a pharmaceutically acceptable salt thereof.

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

The compounds of Formula (I) may be prepared according to a process comprising the following reaction steps:

The reaction conditions in each of the reaction steps described above, may be as described in the General Synthetic Methods (General Schemes).

For use in medicine, salts of compounds of Formula (I) refer to non-toxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the preparation of compounds of Formula (I) or of their pharmaceutically acceptable salt forms thereof. Suitable pharmaceutically acceptable salts of compounds of Formula (I) include acid addition salts that can, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as, hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of Formula (I) carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts such as, sodium or potassium salts; alkaline earth metal salts such as, calcium or magnesium salts; and salts formed with suitable organic ligands such as, quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methyl sulfate, mucate, napsylate, nitrate, /'/-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.

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, (+)-(lS)-camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy- ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, a-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-l,5-disulfonic acid, 1- hydroxy -2 -naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, 7V-methyl-glucamine, hydrabamine, 777-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, l-(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 embodiments of the present invention, the term “administering” encompasses the treatment or prevention of the various diseases, conditions, syndromes and disorders described with the compound specifically disclosed or with a compound that may not be specifically disclosed, but which converts to the specified compound in vivo after administration to a patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

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 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.

Where the compounds according to embodiments of this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorph and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. The skilled artisan will understand that the term compound as used herein, can also include solvated compounds of Formula (I).

Where the processes for the preparation of the compounds according to certain embodiments of the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as, preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques such as, the formation of diastereomeric pairs by salt formation with an optically active acid such as, (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chomatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

It is intended that within the scope of the present invention, any one or more element(s), in particular when mentioned in relation to a compound of Formula (I), shall comprise all isotopes and isotopic mixtures of said element(s), either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, a reference to hydrogen includes within its scope ¹H, ²H (D), and ³H (T). Similarly, references to carbon and oxygen include within their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O. The isotopes may be radioactive or non-radioactive. Radiolabelled compounds of formula (I) may comprise one or more isotope(s) selected from the group of ³H, ⁿC, ¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, the isotope is selected from the group of ²H, ³H, ⁿC and ¹⁸F. 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 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 pharmaceutically acceptable salts and pharmaceutically acceptable solvates) can be administered alone, they will generally be administered in admixture with a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient and/or a pharmaceutically acceptable diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice. Thus, particular embodiments of the present invention are directed to pharmaceutical and veterinary compositions comprising compounds of Formula (I) and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, and/or pharmaceutically acceptable diluent.

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.

Solid oral dosage forms such as, tablets or capsules, containing the compounds of the present invention may be administered in at least one dosage form at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.

A therapeutically effective amount of a compound of Formula (I) or a pharmaceutical composition thereof includes a dose range from about 0.1 mg to about 3000 mg, or any particular amount or range therein; although, it is apparent to one skilled in the art that the therapeutically effective amount for a compound of Formula (I) will vary as will the diseases, syndromes, conditions, and disorders being treated.

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

In some embodiments, the inhibition of MALT 1 by a provided compound may be useful in treating or preventing, in particular treating, the non-limiting list of cancers described herein. The invention relates to compounds of Formula (I) for use as a medicament.

The invention relates to intermediates of Formula (A) for use as a medicament.

The invention relates to compounds of Formula (I) for use in the inhibition of MALT 1 activity.

The invention relates to intermediates 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 intermediates of Formula (A) for use in the treatment of diseases mentioned herein.

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

The invention relates to intermediates of Formula (A) for the treatment or prevention, in particular for the treatment, of said diseases.

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

The invention relates to intermediates of Formula (A) for the treatment or prevention, in particular in the treatment, of MALT 1 mediated diseases or conditions.

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

The invention relates to intermediates of Formula (A) for the manufacture of a medicament.

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

The invention relates to intermediates of Formula (A) for the manufacture of a medicament for the inhibition of MALT 1.

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 intermediates of Formula (A) for the manufacture of a medicament for the treatment or prevention, in particular for the treatment, of any one of the disease conditions mentioned herein.

The invention relates to compounds of Formula (I) for the manufacture of a medicament for the treatment of any one of the disease conditions mentioned herein. The invention relates to intermediates of Formula (A) for the manufacture of a medicament for the treatment of any one of the disease conditions mentioned herein.

The invention relates to compounds of Formula (I) that can be administered to mammals, preferably humans, for the treatment or prevention of any one of the diseases mentioned herein.

The invention relates to intermediates of Formula (A) that can be administered to mammals, preferably humans, for the treatment or prevention of any one of the diseases mentioned herein.

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

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

GENERAL SYNTHETIC METHODS

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.

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.

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.

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

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

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

In the preparation of compounds of the present invention, protection of remote functionality (e.g., primary, or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups (NH-PG) include but are not limited to acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyl (Bn), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Suitable hydroxy-protecting groups include but are not limited to triisopropyl silyl and acetyl. The need for such protection is readily determined by one skilled in the art.

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

General Scheme 1

In General Scheme 1, Compounds of Formula (I) can be prepared via a coupling reaction between an intermediate of Formula (II) and Formula (III), where X represents a suitable leaving group, such as for instance a halogen, in particular Cl, Br, I. This reaction may be performed in the presence of a suitable base, such as, for example, CS2CO3, K3PO4 or K2CO3. This reaction can be performed in a reaction-inert solvent, such as, for example, ZBuOH, toluene, or dioxane. The reaction is typically performed in the presence of a catalyst system comprising a suitable catalyst such as /BuXPhos Pd G3, BrettPhos Pd G3, or SPhos Pd G4 and a ligand such as BrettPhos. Preferably, 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 60 °C, under conventional heating or microwave irradiation. It is understood by the persons skilled in the art that an additional deprotection step might be carried out, when R⁶ = Ci-4alkyl substituted with a OH, wherein the hydroxy group may be protected with a suitable protecting group.

In general, an intermediate of Formula (II) can be synthesized as depicted in General Scheme 2 below.

General Scheme 2

In General Scheme 2, the following reaction conditions typically apply:

Step 1. A commercially available intermediate of Formula (IV) or an intermediate of Formula (IV) prepared according General Scheme 3 (for q=l) is reacted with, for instance, DMF-DMA, at a suitable temperature, such as for instance 35 °C, to provide an intermediate of Formula (V).

Step 2. An intermediate of Formula (V) is reacted with a commercially available UT-pyrazol- 5-amine of Formula (VI), in the presence of acid, for instance, AcOH, in a suitable solvent, such as for instance toluene and at a suitable temperature range, such as, for instance room temperature to 95 °C, to provide an intermediate of Formula (VII).

Step 3. An intermediate of Formula (VII) where, for instance, PG¹⁼Boc, is reacted with an appropriate acid, such as HC1 or TFA, in a suitable solvent, such as dichloromethane or dioxane, at a suitable temperature range, such as, for instance 0 °C to room temperature, to provide an intermediate of Formula (II). Alternatively, intermediate of Formula (IVa), where q=l, can be synthesized as depicted in General Scheme 3 below, wherein the variables are described as hereabove.

General Scheme 3

In General Scheme 3, the following reaction conditions typically apply:

Step 1. An intermediate of Formula (VIII) is reacted with an acylating agent, such as an acylchloride of Formula (IX), in the presence of base, for instance, triethylamine in a suitable solvent, such as for instance chloroform and at a suitable temperature, such as, for instance 0 °C, to provide an intermediate of Formula (X).

Step 2. An intermediate of Formula (X) is reacted with a suitable base, such as for instance, NaH, in a suitable solvent, such as for instance THF, and a suitable temperature range, such as for instance 75 °C, to provide an intermediate of Formula (XI).

Step 3. An intermediate of Formula (XI) is reacted with an alkylating reagent, such as for instance 5-(trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate or other alkylating agents known to one skilled in the art, in the presence of a suitable base, such as NaH, in a suitable solvent, such as for instance DMF and at a suitable temperature, such as, for instance 0 °C to room temperature, to provide an intermediate of Formula (XII).

Step 4. An intermediate of Formula (XII) is reacted with a suitable reductant, such as for instance, lithium aluminum hydride, in a suitable solvent, such as for instance THF, and a suitable temperature range, such as for instance 25 °C to 80 °C, to provide an intermediate of Formula (XIII).

Step 5. An intermediate of formula (XIII) where PG² is a suitable protecting group such as for example benzyl is deprotected under appropriate conditions known to one skilled in the art, such as metal catalysed hydrogenation in a suitable solvent, such EtOH, at a suitable temperature, such as, for instance 25 °C, to provide an intermediate of Formula (XlVa). An intermediate of Formula (XlVa) is protected with an alternative protecting group by reaction with a suitable reagent, such as for example di-te/7-butyl dicarbonate for PG¹⁼Boc, in the presence of a suitable base, such as, for instance, triethylamine (TEA), in a suitable solvent, such as, for instance, THF, and at a suitable temperature, such as for instance 25 °C, to provide an intermediate of Formula (XlVb) where PG¹ is a suitable protecting group such as for example Boc.

Step 6. An intermediate of formula (XlVb) is oxidized in the presence of a suitable oxidant, such as for instance, pyridinium chlorochromate, in a suitable solvent, such as for instance DCM, and a suitable temperature, such as for instance 40 °C, to provide an intermediate of Formula (IVa). In general, intermediates of Formula (III), wherein X is a leaving group such as for instance a halogen, in particular Cl, Br, I as described above in Scheme 1, can be prepared as exemplified below in General Scheme 4, wherein the variables are described as hereabove:

General Scheme 4

Step 1. An intermediate of Formula (XV) is reacted with a phosphonate of Formula (XVI) according to Horner-Wadsworth-Emmon’s reaction conditions. A person skilled in the art will understand that the choice of the R’ substituent in intermediate (XVI) will enable the formation of either Z- or E- forms of intermediate (XVII). 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 to 25 °C, to provide an intermediate of Formula (XVII). Alternatively, an intermediate of Formula (XVII), in which R⁶ is Ci-4alkyl substituted with one -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 (XVII), in which R⁶ is Ci-4alkyl substituted with one -OH, the alcohol moiety may be protected with a suitable protecting group, such as triisopropylsilyl, which was kept throughout the synthetic scheme.

Step 2. An intermediate of Formula (XVII) 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 range, such as for instance 0 °C to 25 °C, to provide an intermediate of Formula (XVIIIa). An intermediate of Formula (XVIIIa) is protected with a suitable protecting group, such as triisopropylsilyl ether or acetyl, by reaction with a suitable reagent, such as triisopropyl silyl chloride, or acetic anhydride in the presence of a base such as imidazole, pyridine, or triethylamine (TEA) in a suitable solvent, such as for instance DCM, and at a suitable temperature, such as, for instance, 25 °C, to provide an intermediate of Formula (XVIIIb) where PG= triisopropylsilyl or acetyl.

Step 3. An intermediate of Formula (XVIIIb) is reacted with a suitable difluorocyclopropanation reagent, such as methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, in the presence of additives such as for instance, potassium iodide and trimethylchlorosilane, in a suitable solvent, such bis(2 -methoxy ethyl)ether, at a suitable temperature, such as, for instance, 120 °C, to provide an intermediate of Formula (XIXa). Alternatively, an intermediate of Formula (XVIIIb) is reacted with a suitable difluorocyclopropanation reagent, such as (bromodifluoromethyl)trimethylsilane, in a suitable solvent such as, for instance, toluene, at a suitable temperature, such as, for instance 110 °C, optionally in the presence of a catalyst such as tetrabutylammonium bromide, to provide an intermediate of Formula (XIXa). An intermediate of Formula (XIXa) where PG is a suitable protecting group such as for example triisopropylsilyl or acetyl, is reacted with an appropriate deprotecting reagent/procedure, such as for instance, tetrabutylammonium fluoride (in suitable solvent such as for example THF) or potassium carbonate (in a suitable solvent such as methanol), at a suitable temperature range, such as for instance 0 °C to 25 °C, to provide an intermediate of Formula (XlXb).

Step 4. An intermediate of formula (XlXb) is reacted with a suitable oxidant, such as for instance, (di acetoxy iodo)benzene in the presence of a catalyst, such as for instance TEMPO, and a suitable base, such as NaHCOs, in an appropriate solvent, such as for instance a mixture of water and ACN, and a suitable temperature, such as for instance 25 °C, to provide an intermediate of Formula (XX).

Step 5. An intermediate of Formula (XX) is reacted with an appropriate amine R^3aR^3bNH, wherein the variables are described as hereabove, in the presence of a suitable coupling reagent, such as HATU, and an appropriate base such as for example triethylamine, typically in a solvent such as ACN, at a suitable temperature, such as for example room temperature, to provide an intermediate of Formula (III).

Step 6. Alternatively, an intermediate of Formula (XVI) is reacted with a suitable difluorocyclopropanation reagent, such as (bromodifluoromethyl)trimethylsilane, in a suitable solvent such as, for instance, toluene, at a suitable temperature, such as, for instance 110 °C, optionally in the presence of a catalyst such as tetrabutylammonium bromide, to provide an intermediate of Formula (XXI).

Step 7. An intermediate of Formula (XXI) is reacted under hydrolysis conditions to provide an intermediate of Formula (XX). This reaction can be performed in the presence of a 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.

Alternatively, a compound of Formula (I) can be prepared via a coupling reaction between an active intermediate of Formula (A) and an amine of R^3aR^3bNH (commercially available or can be prepared by skilled person), as exemplified below in General Scheme 5.

General Scheme 5

In General Scheme 5, an active intermediate of Formula (A) is reacted with an appropriate amine R^3aR^3bNH, wherein the variables are described as hereabove. This reaction is carried out in the presence of a suitable reagent, such as HATU, an appropriate base such as for example TEA, typically in a solvent such as ACN, at a suitable temperature, such as for example room temperature, to provide an intermediate of Formula (I). It is understood by the persons skilled in the art that an additional deprotection step might be carried out, when R⁶ = Ci-4alkyl substituted with a OH, wherein the hydroxy is protected with a suitable protecting group.

In general, an active intermediate of Formula (A) can be prepared as exemplified below in General Scheme 6, wherein the variables are described as hereabove. General Scheme 6

Step 1. An intermediate of Formula (XXI), wherein X is a leaving group such as for instance halogen, in particular Cl, Br, I as described above in Scheme 1, is reacted with an intermediate of Formula (II) under coupling reaction conditions, to provide an intermediate of Formula (XXII). This reaction may be performed in the presence of a suitable base, such as, for example, CS2CO3, K3PO4 or K2CO3. This reaction can be performed in a reaction-inert solvent, such as, for example, ZBuOH, toluene, DMA or dioxane. The reaction is typically performed in the presence of a catalyst system comprising a suitable catalyst such as /BuXPhos Pd G3, BrettPhos Pd G3, or SPhos Pd G4 and a ligand such as BrettPhos. Preferably, 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 60 °C, under conventional heating or microwave irradiation.

Step 2. An intermediate of Formula (XXII) is reacted hydrolyzed to provide an active intermediate of Formula (A). This reaction can be performed in the presence of a suitable base, such as LiOH, in a suitable solvent system, such as water/THF, and at a suitable temperature range, such as room temperature.

In the preparation of compounds of the present invention, protection of remote functionality (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- butoxy carbonyl (Boc), and acetyl. Suitable alcohol protecting groups include t- butyldimethylsilyl. The need for such protection is readily determined by one skilled in the art.

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 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 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 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, 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

The following examples further illustrate the present invention.

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 be synthesized by a skilled person by using well-known methods.

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 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.

As understood by a person skilled in the art, compounds synthesized using the protocols as indicated may exist as a solvate e.g. hydrate, and/or contain residual solvent or minor impurities.

Compounds or intermediates isolated as a salt form, may be integer stoichiometric i.e. mono- or di-salts, or of intermediate stoichiometry. When an intermediate or compound in the experimental part below is indicated as ‘a HC1 salt’ without indication of the number of equivalents of HC1, this means that the number of equivalents of HC1 was not determined. 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 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

Into a 10 L 3-necked flask was placed ethyl 2-(benzylamino)acetate (550 g, 2.85 mol, 1.00 equiv), CHCh (5.5 L), TEA (576 g, 5.70 mmol, 2.00 equiv). Propanoyl chloride (290 g, 3.13 mol, 1.10 equiv) in CHCI3 (300 mL) was added dropwise at 0 °C. The mixture was stirred for 1 h at 25 °C. The mixture was poured into H2O (6 L). The resulting solution was extracted with DCM (2x 2 L). The organic layers were combined, dried over anhydrous MgSCU, and concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc/PE 1 :2) to give Intermediate 1 (561 g, 79% yield) as a light-yellow oil.

Intermediate 2

Intermediate 1 (561 g, 2.25 mol, 1.00 equiv) in THF (2 L) was added dropwise at 75 °C to a mixture of NaH (108 g, 2.70 mol, 1.20 equiv, 60%) and THF (10 L). After 12 h at 75 °C, the reaction was cooled to 20 °C, water (100 mL) was added, and the mixture was concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: MeOH/DCM 1 :30) to give Intermediate 2 (231 g, 50% yield) as an off-white solid.

Intermediate 3

NaH (45.5 g, 1.14 mol, 1.00 equiv, 60%) was added portionwise at 0 °C to Intermediate 2 (231 g, 1.14 mol, 1.00 equiv) in DMF (4.6 L). The mixture was stirred for 0.5 h at 25 °C. 5- (Trifluoromethyl)dibenzothiophenium trifluoromethanesulfonate (457 g, 1.14 mol, 1.00 equiv) was added to the mixture at -55 °C. The mixture was gradually warmed up to 25 °C and stirred for 1 h. The mixture was poured into a mixture of ice/water (10 L) and extracted with EtOAc (2x 5 L). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc/PE 1 :4) to give Intermediate 3 (275 g, 89% yield) as a light-yellow oil.

Intermediate 4

LAH (154 g, 4.10 mol, 4.00 equiv) was added at 0 °C to a mixture of Intermediate 3 (275 g, 1.01 mol, 1.00 equiv) in THF (5.5 L). The mixture was warmed up to 80 °C and stirred at this temperature for 15 h. The mixture was cooled to 0 °C, and were added 154 g of water, 154 g of aqueous of NaOH solution (10%), and 154 g of H2O. The mixture was stirred for 30 min at 25 °C and the precipitate was filtered off. The filtrate was concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: MeOH/DCM 1 :50) to give Intermediate 4 (204 g, 78% yield) as a colorless oil.

Intermediate 5

HC1 (787 mL, 1 M) and Pd/C (8.37 g, 78.7 mmol, 0.10 equiv) were added to a solution of Intermediate 4 (204 g, 787 mmol, 1.00 equiv) in EtOH (2 L). The mixture was degassed and flushed with hydrogen. The mixture was stirred for 18 h at 25 °C under an atmosphere of hydrogen (balloon). Then was added HC1 (787 mL, 1 M) and the mixture was stirred for 30 min at 25 °C. The solid was filtered out and the filtrate was concentrated under vacuum to give Intermediate 5 (106 g, 66% yield; as a HC1 salt, number of equivalents not determined) as a yellow solid which was used without further purifications. Intermediate 6

di-Zc/V-butyl dicarbonate (169 g, 773 mmol, 1.50 equiv) was added to a mixture of Intermediate 5 (106 g, 515 mmol, 1.00 equiv), THF (2 L), and TEA (2089 g, 2.06 mol, 4.00 equiv). The flask was stirred for 2 h at 25 °C. The mixture was concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc/PE 1 :4) to give Intermediate 6 (134 g, 96% yield) as a white solid.

Intermediate 7

A mixture of Intermediate 6 (134 g, 0.496 mol, 1.00 equiv), DCM (2.6 L), PCC (534 g, 2.48 mol, 5.00 equiv) and silica gel (268 g, 4.46 mol, 9.00 equiv) was stirred for 12 h at 40 °C. The mixture was concentrated under vacuum and the resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc/PE 1 : 10) to give Intermediate 7 (79 g, 60% yield) as a white solid.

Intermediate 8

Intermediate 7 (79 g, 296 mmol, 1.00 equiv) and DMF-DMA (790 mL) were stirred for 1 h at 35 °C. The mixture was concentrated to give Intermediate 8 (100 g, crude) as a light-yellow oil which was used without any further purification. Intermediate 9

A mixture of Intermediate 8 (100 g, 310 mmol, 1.00 equiv), 5-chloro-2J/-pyrazol-3-amine [CAS: 916211-79-5] (36.5 g, 310 mmol, 1.00 equiv), toluene (1 L) and AcOH (100 mL) was stirred for 15 h at 95 °C. The reaction was cooled to 25 °C and concentrated under vacuum. NaHCCL (1000 mL) was added to the mixture, and the resulting solution was extracted with EtOAc (2x 1 L). The organic layers were combined, dried over anhydrous MgSCU, and concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc/PE 15:85) to give Intermediate 9 (39.7 g, 34% yield) as a yellow oil.

Intermediate 10

A mixture of Intermediate 9 (39.7 g, 105 mmol, 1.00 equiv), DCM (400 mL) and TFA (80 mL) was stirred for 1 h at 25 °C. The mixture was concentrated under vacuum and NaHCCL (500 mL) was added. The resulting mixture was extracted with DCM (3x300 mL). The organic layers were combined, dried over anhydrous MgSCU. and concentrated under vacuum. The resulting residue was purified by flash column chromatography over silica gel (eluent: EtOAc:PE (1 : 1). This resulted in 2-chloro-8-methyl-8-(trifluoromethyl)-7,8-dihydro-6J/-pyrazolo[l,5- a]pyrrolo[2,3-e]pyrimidine (Intermediate 10, [CAS: 2661482-67-1], 15.2 g, 51% yield) as a yellow solid.

Intermediate 11 and 12

Intermediate 10 (5.0 g) was separated in enantiomers via chiral SFC, using as stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 z'PrNEE to provide two fractions as follows:

Fraction 1 : Intermediate 11 (2.35 g, 47% yield)

Fraction 2: Intermediate 12 (2.35 g, 47% yield)

Intermediate 13

To a cooled (0 °C) suspension of NaH (60% in mineral oil, 2.59 g, 64.85 mmol) in THF (100 mL) was added triethylphosphonopropionate (13.9 mL, 64.85 mmol) dropwise. The reaction was stirred for 30 minutes, then a solution of 4-bromobenzaldehyde [1122-91-4] (10.0 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 NH4CI (60 mL), and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (eluent: heptane/EtOAc up to 90/10). The fractions containing compound were combined and concentrated in vacuo to give Intermediate 13 (12.3 g, 84% yield) as a colorless oil.

Intermediate 14

To a cooled (0 °C) solution of Intermediate 13 (12.3 g, 45.7 mmol) in dry THF (230 mL) under nitrogen, was added DIBAL-H (IM 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 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 14 (9.8 g, 94% yield) as a white solid. Intermediate 15

To a solution of Intermediate 14 (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 triisopropyl silyl 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 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 MgSCU, 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 15 (14 g, 95% yield) as a colorless oil.

In a 20 mL pressure tube charged with Intermediate 15 (1.15 g, 3.0 mmol) and tetrabutylammonium bromide (48.3 mg, 0.15 mmol), were added toluene (6 mL) and (bromodifluoromethyl)trimethylsilane (1.4 mL, 9 mmol). The reaction was stirred at 110 °C for 6 h. Six identical reactions were run in parallel and combined before work-up and purification. The reactions were cooled down to RT, each diluted with water (10-15 mL), EtOAc (20-25 mL), and combined. The organic layer was separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in anhydrous THF (50 mL), cooled to 0 °C and TBAF (IM in THF, 27 mL, 27 mmol) was added. The reaction was allowed to warm up to RT and stirred for 1 h. Volatiles were removed under reduced pressure and the residue was diluted with water (50 mL) and EtOAc (100 mL). The aqueous layer was separated, and the organic layer was washed with brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (eluent: heptane/EtOAc 70/30) to obtain Intermediate 16 (4.6 g, 92% yield) as a yellowish oil. Intermediate 17

To a solution of Intermediate 16 (3.81 g, 13.75 mmol) in water/MeCN (87 mL/87 mL), were added TEMPO (1.07 g, 6.87 mmol), (Diacetoxyiodo)benzene (13.29 g, 41.25 mmol) and NaHCOs (2.89 g, 34.37 mmol). The mixture was stirred for 6 h at RT, the mixture was diluted with water, and aq HC1 (I M) was added until the pH reached approximately 2. EtOAc was added and the organic layer was separated. The aqueous layer was extracted with 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 MgSO4 to give Intermediate 17 (3.46 g, 86% yield) as white solid.

Intermediate 18

To a mixture of Intermediate 17 (315 mg, 1.08 mmol), A-[(Dimethylamino)-U/-l,2,3-triazolo- [4,5-b]pyridin-l-ylmethylene]-A-methylmethanaminium hexafluorophosphate A -ox ide (823 mg, 2.16 mmol) and A-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 acqueous layer was separated and extracted with EtOAc (30 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (eluent: heptane/EtOAc up to 50/50) to obtain Intermediate 18 (320 mg, 97% yield) as colorless oil.

Intermediate 19 and 20

Intermediate 19 Intermediate 20 Intermediate 18 (1 g, 3.29 mmol) was purified by preparative chiral SFC (Stationary phase: Chiralpak AS-H 30x250 mm, Mobile phase: CO2:zPrOH 85: 15). The fractions containing compound were combined and evaporated in vacuo to give Intermediate 19 (447 mg, 44% yield) and Intermediate 20 (480 mg, 48% yield).

Intermediate 21

To a mixture of Intermediate 17 (200.0 mg, 0.687 mmol) and A-[(Dirnethylarnino)-lJ/-l,2,3- triazolo-[4,5-b]pyridin-l-ylmethylene]-A-methylmethanaminium hexafluorophosphate N- oxide (522.5 mg, 1.37 mmol) and A A -Di ethyl ethanamine (0.38 mL, 2.75 mmol) in MeCN (5.2 mL) was added 3-(methylsulfonyl)cyclobutan-l-amine hydrochloride [2639792-63-3] (205.0 mg, 1.37 mmol). The reaction was stirred at RT for 1 h. The reaction was diluted with EtOAc and water. The water layer was separated, and the acqueouse phase was extracted with EtOAc. The combined organic layers were then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography over silica gel (eluent: MeOH/DCM 0 to 7%) to give Intermediate 21 (264 mg, 91% yield) as a white solid.

Intermediate 22 was prepared by an analogous reaction protocol as Intermediate 21, starting from trans-3-methylsulfonylcyclobutylamine hydrochloride [1408075-97-7] (1.25 g, 6.73 mmol) instead of 3-(methylsulfonyl)cyclobutan-l-amine hydrochloride [2639792-63-3] to give Intermediate 22 (1.16 g, 73% yield) as a light-yellow solid.

Intermediate 23

Intermediate 23 was prepared by an analogous reaction protocol as Intermediate 13, starting from 4-bromo-2,3-difluorobenzaldehyde [644985-24-0] (5 g, 22.6 mmol) instead of 4- bromobenzaldehyde [1122-91-4] to give Intermediate 23 (3.5 g, 51% yield).

Intermediate 24

Intermediate 24 was prepared by an analogous reaction protocol as Intermediate 14, starting from Intermediate 23 (3.2 g, 10.5 mmol) instead of Intermediate 13, to give Intermediate 24 (2.3 g, 83% yield).

Intermediate 25

Intermediate 25 was prepared by an analogous reaction protocol as Intermediate 15, starting from Intermediate 24 (2.3 g, 8.7 mmol) instead of Intermediate 14 to give Intermediate 25 (3.3 g, 90% yield).

Intermediate 26

Intermediate 26 was prepared by an analogous reaction protocol as Intermediate 16, starting from Intermediate 25 (3 g, 6.4 mmol) instead of Intermediate 15 to give Intermediate 26 (1.65 g, 67% yield). Intermediate 27

Intermediate 27 was prepared by an analogous reaction protocol as Intermediate 17, starting from Intermediate 26 (1.65 g, 5.27 mmol) instead of Intermediate 16 to give Intermediate 27 (1.1 g, 30% yield).

Intermediate 28

Intermediate 28 was prepared by analogous reaction protocol as Intermediate 21, starting from Intermediate 27 (1.1 g, 3.36 mmol) instead of Intermediate 17 to give Intermediate 28 (1.16 g, 74% yield) as a light-yellow solid.

Intermediate 29

Intermediate 29 was prepared by an analogous reaction protocol as Intermediate 13, starting from 4-bromo-2 -fluorobenzaldehyde [57848-46-1] (5 g, 1.2 mmol) instead of 4- bromobenzaldehyde [1122-91-4] to give Intermediate 29 (7 g, 84% yield).

Intermediate 30

Intermediate 30 was prepared by an analogous reaction protocol as Intermediate 14, starting from Intermediate 29 (5 g, 17.4 mmol) instead of Intermediate 13, to give Intermediate 30 (6 g, 93% yield). Intermediate 31

Intermediate 31 was prepared by an analogous reaction protocol as Intermediate 15, starting from Intermediate 30 (5 g, 20.4 mmol) instead of Intermediate 14 to give Intermediate 31 (6 g, 72% yield).

Intermediate 32

Intermediate 32 was prepared by an analogous reaction protocol as Intermediate 16, starting from Intermediate 31 (3.5 g, 8.7 mmol) instead of Intermediate 15 to give Intermediate 32 (1.8 g, 55% yield).

Intermediate 33

Intermediate 33 was prepared by an analogous reaction protocol as Intermediate 17, starting from Intermediate 32 (1.8 g, 6.1mmol) instead of Intermediate 16 to give Intermediate 33 (1.6 g, 51% yield).

Intermediate 34

Intermediate 34 was prepared by analogous reaction protocol as Intermediate 21, starting from Intermediate 33 (1.6 g, 5.18 mmol) instead of Intermediate 17 to give Intermediate 34 (1.09 g, 47% yield) as a white solid.

Intermediate 35

Intermediate 35 was prepared by an analogous reaction protocol as Intermediate 13, starting from 4-bromo-3 -fluorobenzaldehyde [133059-43-5] (10 g, 1.2 mmol) instead of 4- bromobenzaldehyde [1122-91-4] to give Intermediate 35 (11 g, 74% yield).

Intermediate 36

Intermediate 36 was prepared by an analogous reaction protocol as Intermediate 14, starting from Intermediate 35 (11 g, 38.3 mmol) instead of Intermediate 13 to give Intermediate 36 (9 g, 93% yield).

Intermediate 37

Intermediate 37 was prepared by an analogous reaction protocol as Intermediate 15, starting from Intermediate 36 (9 g, 36.7 mmol) instead of Intermediate 14 to give Intermediate 37 (11 g, 75% yield).

Intermediate 38

Intermediate 38 was prepared by an analogous reaction protocol as Intermediate 16, starting from Intermediate 37 (3.5 g, 7.7 mmol) instead of Intermediate 15 to give Intermediate 38 (2.1 g, 92% yield).

Intermediate 39

Intermediate 39 was prepared by an analogous reaction protocol as Intermediate 17, starting from Intermediate 38 (2.1 g, 7.1 mmol) instead of Intermediate 16 to give Intermediate 39 (2.0 g, 91% yield).

Intermediate 40

Intermediate 40 was prepared by analogous reaction protocol as Intermediate 21, starting from Intermediate 39 (2.0 g, 6.47 mmol) instead of Intermediate 17 to give Intermediate 40 (1.13 g, 40% yield) as a white solid.

Intermediate 41 and 42

Intermediate 41 Intermediate 42

Intermediate 17 (63 g, 216.42 mmol) was purified by preparative chiral SFC (Stationary phase: Chiralpak IG 5x30 cm, 10 pm, Mobile Phase: CO2/ MeOH: 85/15). The fractions containing compound were combined and evaporated in vacuo to give Intermediate 41 (25.8 g, 41% yield) and Intermediate 42 (25.8 g, 41% yield) as white solids. The following Intermediates were synthesized by analogous reaction protocol as described for Intermediate 21, starting from Intermediate 41 and indicated reagent.

To a mixture of Intermediate 13 (118 g, 438.43 mmol), toluene (826 mL) and tetrabutylammonium bromide [1643-19-2] (4.24 g, 13.15 mmol) was added (bromodifluoromethyl)trimethylsilane [115262-01-6] (1424.76 g, 7014.99 mmol) dropwise over 24 h at 110 °C (with a syringe pump). The resulting mixture was stirred for additional 5 h at 110 °C. The reaction was poured into ice water (1.5 L). The resulting mixture was extracted with PE (3x1 L). The combined organic layers were washed with brine (3x0.5 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (30: 1) to afford Intermediate 47 (92 g, 66% yield) as a light-yellow oil.

Intermediate 48 and 49

Intermediate 48 Intermediate 49

Intermediate 47 (100 g, 313.34 mmol) was purified by preparative chiral HPLC (Stationary phase: Chiralpak IG 5x25 cm, 10 pm, Mobile Phase: Hexane/ EtOH: 99/1). The fractions containing compound were combined and evaporated in vacuo to give Intermediate 48 (23.8 g, 23% yield,) as a brown oil and Intermediate 49 (48.7 g, 47% yield) as a brown oil.

Intermediate 50

Intermediate 11 (3.0 g, 10.84 mmol), Intermediate 48 (3.46 g, 10.84 mmol), CS2CO3 (5.3 g, 16.27 mmol) and [(2-Di-tert-butylphosphino-2',4',6'-triisopropyl-l,r-biphenyl)-2-(2'-amino- 1, l'-biphenyl)] palladium(II) methanesulfonate [1447963-75-8] (948.0 mg, 1.19 mmol) were placed in a reaction vessel. Then dry DMA (120 mL) was added, and the reaction mixture was degassed for 10 min by bubbling nitrogen. The mixture was stirred at 60 °C for 2 hours. Then, the crude was cooled down to room temperature, diluted with brine, water and EtOAc. The phases were separated, the aqueous layer extracted twice with EtOAc and combined organic layers were dried over MgSO4, solids were filtered, and solvents removed under vacuo. The crude was then purified by flash column chromatography (Mobile phase: DCM 100% yield) to give Intermediate 50 (3.32 g, 59% yield) as a yellow solid.

Intermediate 51 (active intermediate)

LiOH in water (30.44 mL, 2 M, 60.89 mmol) was added to a solution of Intermediate 50 (10.45 g, 20.3 mmol) in THF (150 mL) at room temperature. The reaction was stirred at room temperature for 12 h. The solvent was evaporated, and the residue was acidified to pH 2 and extracted with EtOAc (3x). The combined organic layers were dried over MgSCU, filtered, and concentrated under reduced pressure to give Intermediate 51 (9.96 g, 100% yield) as a yellow solid. 'H NMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.60 (s, 1 H), 7.31 (d, J=8.6 Hz, 2 H), 7.12-7.18 (m, 2 H), 6.72 (s, 1 H), 4.34 (d, J= 11.0 Hz, 1 H), 4.02-4.10 (m, 1 H), 3.72 (dd, J= 15.1 , 2.8 Hz, 1 H), 2.01 (s, 3 H), 1.25 (t, J=2.2 Hz, 3 H). Confirms the MW, Rt: 2.28, [M+H]⁺: 487.1, Method: 6.

Intermediate 52

mCPBA [937-14-4 ] (58.36 mg, 0.26 mmol) was added to a stirred solution of Intermediate 45 (96.8 mg, 0.25 mmol) in dry DCM (2 mL) at 0 °C. The reaction was stirred for 3.5 h, while allowed to reach room temperature, and then diluted with sat. NaHCCL and DCM. The phases were separated, the aqueous layer was extracted with DCM and the combined organic layers were dried over MgSCU, filtered and concentrated under reduced pressure to give Intermediate 52 (99.2 mg, yield 84% yield) as a white solid without further purification.

Intermediate 53

A mixture of Intermediate 52 (99 mg, 0.24 mmol), tert-butyl carbamate (42.84 mg, 0.37 mmol), magnesium oxide [1309-48-4] (39.29 mg, 0.97 mmol) and rhodium(II) acetate dimer [15956-28-2] (5.66 mg, 0.013 mmol) was degassed and dry DCM (2.5 mL) was added, followed by (diacetoxyiodo)benzene [3240-34-4] (117.73 mg, 0.37 mmol). The reaction mixture was stirred at 40 °C for 5 h, then allowed to reach room temperature, filtered through a pad of dicalite and rinsed with DCM. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (Mobile phase: Heptane:EtOAc from 100:0 to 20:80) to afford Intermediate 53 (120.3 mg, 80% yield) as a colourless film.

Intermediate 54

Intermediate 54 was prepared by analogous reaction protocol as Intermediate 50, starting from Intermediate 11 (24.3 mg, 0.088 mmol) and Intermediate 53 (60.0 mg, 0.097 mmol) to give Intermediate 54 (59.4 g, 72% yield) as a yellow film.

Intermediate 55

Triisopropyl silyl chloride [13154-24-0] (1.7 mL, 0.9 g/mL, 7.94 mmol) was added to a stirred solution of methyl (2E)-3-(4-bromophenyl)-2-(hydroxymethyl)-2-propenoate [1505472-36-5] (1.79 g, 6.6 mmol), DMAP [1122-58-3] (87 mg, 0.71 mmol) and imidazole [288-32-4] (582.6 mg, 8.56 mmol) in dry DCM (35 mL) at room temperature. The reaction was stirred for 24 h, then extra triisopropylsilyl chloride (0.4 mL, 1.87 mmol) and imidazole (111.5 mg, 1.64 mmol) were added and resulting mixture stirred for 24 h more. The crude was diluted with water and DCM, the phases separated and the aqueous layer extracted once with DCM. The combined organic layers were dried over MgSCU, the solids filtered and the solvent evaporated under vacuo. The crude was purified by flash column chromatography (Mobile phase: Hexane:EtOAc from 100:0 to 90: 10) to give Intermediate 55 (2.0 g, 71% yield) as a colourless oil.

Intermediate 56

A mixture of Intermediate 55 (1.0 g, 2.34 mmol), tetrabutylammonium bromide [1643-19-2] (37.7 mg, 0.17 mmol), dry toluene (2 mL) and TMSCF₂Br [115262-01-6] (7.3 mL, 46.8 mmol) was stirred at 110 °C for 72 h, then concentrated under reduced pressure. The crude was purified by flash column chromatography (Mobile phase: Hexane:EtOAc from 100:0 to 90: 10) to give Intermediate 56 (930 mg; 33% purity, 27% yield).

Intermediate 57

LiOH (2.0 M in H2O; 1.8 mL, 3.6 mmol) was added to a stirred solution of Intermediate 56 (570.4 mg; mixture) in THF (3.4 mL). The reaction was stirred at room temperature overnight, then diluted with aq. HC1 1.0 M until acidid pH. EtOAc was added, the phases separated and the aqueous layer extracted twice with EtOAc. The combined organic layers were dried over MgSO4, solids filtered and concentrated under reduced pressure to give Intermediate 57 as a brown oil, which was used as such in the next without further purification (assumed quantitative yield).

Intermediate 58

Ammonium chloride [12125-02-9] (169.7 mg, 3.17 mmol) was added to a stirred solution of Intermediate 57 (crude), HATU [148893-10-1] (903.9 mg, 2.38 mmol) and TEA (0.66 mL, 0.73 g/mL, 4.78 mmol) in ACN (11 mL). The reaction was stirred at room temperature for 2 days, then diluted with EtOAc and water. Phases were separated, aqueous layer extracted twice with EtOAc and combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography (Mobile phase: Hexane:EtOAc from 100:0 to 70:30) to give Intermediate 58 (112.6 mg, 20% yield) as a yellow film.

Intermediate 59

To a solution of Intermediate 55 (140 g, 328 mmol) in THF (750 mL) was added DIBALH [1191-15-7] (1 M, 983 mL) at -70 ° C (dry ice / EtOH) dropwise for 30 minutes. The mixture was stirred at 25 °C for 3 hours. The reaction mixture was quenched by addition sat. potassium sodium tartrate (100 mL) at -70 °C, and then diluted with water (1000 mL) and extracted with EtOAc (3x700 mL). The combined organic layers were washed with brine (800 mL), dried over ISfeSCL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Mobile phase: Petroleum ether: EtOAc from 100: 1 to 8: 1) to give Intermediate 59 (89.3 g, 68% yield) as a colorless oil.

Intermediate 60

To a solution of Intermediate 59 (89.0 g, 223 mmol) in DCM (450 mL) was added TEA (45.1 g, 446 mmol, 62.0 mL) and acetic anhydride [108-24-7] (34.1 g, 334 mmol, 31.3 mL). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated to give the crude product. The residue was purified by column chromatography (Mobile phase: Petroleum ether:EtOAc from 100: 1 to 8: 1) to give Intermediate 60 (78 g, 177 mmol, 79% yield) as a colorless oil.

Intermediate 61

To a solution of Intermediate 60 (17.0 g, 38.5 mmol) in diglyme (20 mL) was added dropwise bis(trimethylsilyl)acetamide [10416-59-8] (783 mg, 3.85 mmol, 951 pL, 0.1 eq) at 170 °C and was added dropwise slowly sodium 2-bromo-2,2-difluoroacetate [84349-27-9] (75.8 g, 385 mmol, 10 eq) in diglyme (240 mL) at 170 °C for 5-8 h. The resulting mixture was stirred at 170 °C for 2 h. The reaction mixture was quenched by addition H2O (500 mL), and then extracted with EtOAc (3x200 mL). Dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Mobile phase: Petroleum ether:EtOAc from 100: 1 to 10: 1) to give Intermediate 61 (30.0 g, 55% yield, 70% purity) as a yellow oil. Intermediate 62

A mixture of Intermediate 61 (30.0 g, 61.0 mmol), K2CO3 (16.8 g, 122 mmol) in MeOH (150 mL) was degassed and purged with nitrogen, and then the mixture was stirred at 25 °C for 1 hour under N2 atmosphere. The reaction mixture was quenched by adding water (10 mL), and then extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Mobile phase: Petroleum ether: EtOAc from 100: 1 to 10: 1) to give Intermediate 62 (30.0 g, crude) as a colorless oil.

Intermediate 63 and 64

Intermediate 63 Intermediate 64

Intermediate 62 was purified by preparative chiral SFC (Column: DAICEL CHIRALCEL OJ (250mm*50mm, lOum); Mobile phase: [CCL-EtOH (0.1% NH3H2O)]; B%:20%, isocratic elution mode). The fractions containing compound were combined and evaporated in vacuo to give Intermediate 63 (14.6 g, 98% purity) and Intermediate 64 (13.2 g, 98% purity) as yellow oils.

Intermediate 65

To a solution of Intermediate 63 (13.2 g, 29.4 mmol) in DCM (130 mL) was added Dess-Martin periodinane [87413-09-0] (15.0 g, 35.2 mmol, 10.9 mL) at 0 °C and the mixture was stirred at 20 °C for 1 hour under nitrogen atmosphere. The resulting mixture was quenched by sat., aq., NaHCCL (50 mL) and sat., aq., Na2SOs (50 mL), the phases were separated and the organic layer was concentrated. The crude product was used into the next step without further purification. To a solution of crude (12.9 g, 28.8 mmol) 2-methyl-2 -butene [513-35-9] (4.04 g, 57.7 mmol, 6.11 mL) in THF (50 mL) and acetone (50mL), was added a solution of sodium chlorite [7758-19-2] (3.91 g, 43.3 mmol, 1.5 eq) and NaH₂PO₄ [7558-80-7] (10.4 g, 86.5 mmol) in water (50 mL) at 0 °C. The mixture was stirred at 20 °C for 1 hr, then quenched by sat., aq., NaHCCh (50 mL) and sat., aq., Na₂SOs (50 mL), the phases were separated and the organic layer was concentrated. The residue was purified by column chromatography (Mobile phase: Petroleum ether:EtOAc from 100: 1 to 10: 1) to give Intermediate 65 (10.0 g, 74% yield) as a colorless oil.

Intermediate 66

Intermediate 66 was prepared by an analogous reaction protocol as Intermediate 13, starting from ethyl 2-(diethoxyphosphoryl)-4-methylpentanoate [17145-91-4] (2.12 g, 7.56 mmol) and 4-bromo-benzaldehyde [1122-91-4] (1.16 mg, 6.30 mmol) to give Intermediate 66 (861 mg, 44% yield).

Intermediate 67

Intermediate 67 was prepared by analogous reaction protocol as Intermediate 56, starting from Intermediate 66 (861 mg, 2.767 mmol) to give Intermediate 67 (1.36 g, assumed quantitative yield) as an orange residue.

Intermediate 68

Intermediate 68 was prepared by analogous reaction protocol as Intermediate 57, starting from Intermediate 67 (1.36 g, crude from previous step, assumed 3.765 mmol) to give Intermediate 68 (196 mg, 15% yield). Intermediate 69

Intermediate 69 was prepared by an analogous reaction protocol as Intermediate 18, starting from Intermediate 68 (196 mg, 0.588 mmol) to give Intermediate 69(19 mg, 9% yield) as a white solid.

Intermediate 70

Intermediate 70 was prepared by an analogous reaction protocol as Intermediate 13, starting from ethyl 2-(diethoxyphosphoryl)propanoate [3699-66-9] (35.22 g, 147.845 mmol) and 5- bromopicolinaldehyde [31181-90-5] (25 g, 134.404 mmol) to give Intermediate 70 (21.3 g, 56% yield) as a light-yellow solid.

Intermediate 71

Intermediate 71 was prepared by an analogous reaction protocol as Intermediate 14, starting from Intermediate 70 (21.3 g, 74.91 mmol) to give Intermediate 71 (16 g, 89% yield) as a lightyellow oil.

Intermediate 72

Intermediate 72 was prepared by an analogous reaction protocol as Intermediate 15, starting from Intermediate 71 (16 g, 66.64 mmol) to give Intermediate 72 (20 g, 77% yield) as a lightyellow oil.

Intermediate 73

Intermediate 73 was prepared by an analogous reaction protocol as Intermediate 16, starting from Intermediate 72 (1.0 g, 2.58 mmol) to give Intermediate 73 (300 mg, 42% yield) as a brown paste.

Intermediate 74

Intermediate 73 (300 mg, 1.08 mmol) was dissolved in water/MeCN (5 mL/5 mL). TEMPO [2564-83-2] (84 mg, 0.54 mmol), (diacetoxyiodo)benzene [3240-34-4] (1.04 g, 3.24 mmol) and NaHCOs (227 mg, 2.70 mmol) were added. The resulting mixture was stirred at room temperature for 72 h. The mixture was concentrated under reduced pressure to give Intermediate 74 (160 mg, 51% yield).

The following Intermediates were synthesized by analogous reaction protocol as described for Intermediate 21, starting from the indicated Intermediate and trans-3- methylsulfonylcyclobutylamine hydrochloride [1408075-97-7].

Intermediate 77

/c/V-Butyl 3,3-dimethyl-4-oxopyrrolidine-l-carboxylate [1824385-39-8] (900 mg, 4.22 mmol) and -di methyl form ami dedi methyl acetate [4637-24-5] (617 pL, 4.64 mmol) were stirred at 90 °C for 1 h. Then a solution of 3 -chloro- lJT-pyrazol-5 -amine [916211-79-5] (496 mg, 4.22 mmol) in AcOH (4.2 mL) was added dropwise at 85 °C and the resulting mixture was stirred at 85 °C for 15 h. The reaction mixture was concentrated to dryness to give a residue which was purified by normal phase preparative liquid chromatography (Mobile phase gradient: heptane:EtOAc from 100:0 to 50:50). The fractions containing product were combined and concentrated under vacuum to give Intermediate 77 (782 mg, 57% yield) as a pale-yellow solid.

The following Intermediates were synthesized by analogous reaction protocol as described for Intermediate 8, starting from the indicated reagents.

The following Intermediates were synthesized by analogous reaction protocol as described for Intermediate 9, starting from the indicated Intermediates.

The following Intermediates were synthesized by analogous reaction protocol as described for Intermediate 10, starting from the indicated Intermediates.

The following Intermediates were synthesized by analogous reaction protocol as described for Intermediate 50, starting from Intermediate 11 and the indicated reagent.

Intermediate 90

A solution of tert-butyl (3-oxocyclobutyl)carbamate [154748-49-9] (2.0 g, 10.80 mmol), dimethylphosphine oxide [7211-39-4] (1.69 g, 21.60 mmol) and HMDS [999-97-3] (3.48 g, 21.60 mmol) was stirred at 90 °C overnight under nitrogen atmosphere. After cooled down to rt, the reaction mixture was diluted with DCM (50 mL) and brine (50 mL). The phases were separated, and the aqueous phase was extracted with DCM (3 x 50 mL). The combined organic phases were washed with saturated brine (3x 50 mL), dried over Na2SO4, filtered and concentrated to afford Intermediate 90 (3 g, crude) as a white solid.

Intermediate 91

To a mixture of Intermediate 90 (300 mg, 0.894 mmol) in ACN (3 mL) was added EtsN 3HF [73602-61-6] (72.09 mg, 0.45 mmol). The resulting solution was stirred at rt for 1 h. The reaction mixture was diluted with DCM (30 mL) and brine (30 mL). After separation of phases, the aqueous phase was extracted with DCM (3x 50 mL). The combined organic phases were washed with saturated NaHCCL (3x 30 mL), dried over Na2SO4, filtered and concentrated to give Intermediate 91 (90 mg, crude) as a white solid.

Intermediate 92 and Intermediate 93

Intermediate 92 Intermediate 93

A suspension of Intermediate 91 (1.2 g, 4.56 mmol) and 4-dimethylaminopyridine [1122-58-3] (1.11 g, 9.12 mmol) in ACN (36 mL) was stirred at 0 °C under nitrogen atmosphere. Then methyl oxalyl chloride [5781-53-3] (837.59 mg, 6.84 mmol) was added and the mixture was allowed to warm to rt and stirred an addditional 2.5 h. After addition of EtOAc (50 mL), the mixture was washed with saturated NaHCCL (50 mL) and brine (50 mL). The organic phases were dried over Na2SO4 and concentrated to give a yellow oil. The obtained yellow oil was dissolved in toluene (36 mL). To this solution, azobisisobutyronitrile [78-67-1] (187.11 mg, 1.140 mmol) and BusSnH [688-73-3] (1.99 g, 6.84 mmol) were added. The resulting solution was stirred at 90 °C overnight. After cooled down to rt, the resulting solution was concentrated. The residue was purified by flash column chromatography (Mobile phase: DCM:MeOH from 100:0 to 80:20) to give:

Fraction 1 : Intermediate 92 (136.3 mg, 12% yield) as yellow solid. Fraction 2: Intermediate 93 (73.3 mg, 6% yield) as yellow solid.

Intermediate 94

A mixture of tert-butyl cis-3-sulfamoylcyclobutyl)carbamate [2567498-52-4] (6.5 g, 25.97 mmol), DCM (60 mL) and UT-imidazole [288-32-4] (20.0 g, 293.78 mmol) was stirred at rt for 15 min. Then, tert-butyldimethylsilyl chloride [18162-48-6] (78.27 g, 3.99 mmol) was added and the mixture was stirred at rt overnight. The reaction mixture was diluted with DCM (150 mL) and water (150 mL). After separation of phases, the aqueous phase was extracted with DCM (2x 100 mL) and washed with brine (2x 150 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue purified by flash column chromatography (Mobile phase: PE:EtOAc from 100:0 to 50:50) to give Intermediate 94 (2.5 g, 26% yield) as a yellow oil.

Intermediate 95

Dry EtsN (1.28 mL, 9.02 mmol) was added dropwise into a colorless suspension of fresh made dichlorotriphenylphosphorane [2526-64-9] (3.66 g, 11.0 mmol) in CHCh (30 mL) at -5 °C and stirred at -5 °C for 10 min. To this suspension, a solution of Intermediate 94 (800 mg, 2.20 mmol) in CHCI3 (5 mL) was added dropwise and stirred at 5 °C for 1 h. The reaction mixture was dropped into methylamine [74-89-5] (tetrahydrofuran solution 1.96 M, 160.0 mL) at 0 °C. The reaction mixture was diluted with EtOAc (150 mL) and water (150 mL). After separation of phases, the aqueous phase was extracted with EtOAc (2 x 100 mL) and washed with brine (2 x 150 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (Mobile phase: PE:EtOAc from 100:0 to 50:50) to give Intermediate 95 (240 mg, 29% yield) as a yellow solid. Intermediate 96

To a stirred solution of Intermediate 95 (200 mg, 0.53 mmol) in DCM (20 mL) at rt was added AcOH (30 mL, 524.04 mmol). To this mixture, a 3: 1 mixture of chloroform and isopropyl alcohol (100 mL) and water (30 mL) were added. The solution was basified to PH 7~8 with ammonia water and the phases separated. The combined organic phases were dried over Na2SC>4, filtered and concentrated. The residue was s purified by flash column chromatography (Mobile phase: DCM :MeOH from 100 :0 to 80 :20) to give Intermediate 96 (132.7 mg, 79% yield) as an off-white solid.

Intermediate 100

Intermediate 100 was prepared by an analogous reaction protocol as Intermediate 47, starting from Intermediate 35 (60.0 g, 208.96 mmol) to give Intermediate 100 (36.0 g, 48% yield) as a brown oil. Intermediate 101 and 102

Intermediate 101 Intermediate 102

Intermediate 100 (42.0 g, 124.58 mmol) was purified by preparative chiral SFC (Column: CHIRAL Cellulose-SB, 4.6*100mm, 3um; Mobile Phase A: Hex: IPA= 99: 1; Gradient: isocratic; Injection Volume: 0.1 mL). The fractions containing compound were combined and evaporated in vacuo to give Intermediate 101 (19.2 g, 45% yield ) as a light-yellow oil and Intermediate 102 (16.2 g, 38% yield) as a brown oil.

Intermediate 103

Intermediate 103 was prepared by an analogous reaction protocol as Intermediate 50, starting from Intermediate 102 (163.9 mg, 0.48 mmol) to give Intermediate 103 (184.8 mg, 80% yield) as a yellow film.

Intermediate 104 (active intermediate)

Intermediate 104 was prepared by an analogous reaction protocol as Intermediate 51, starting from Intermediate 103 (176.3 mg, 0.32 mmol) to give Intermediate 104 (175.9 mg, 98% purity, quantitative yield) as a yellow foam. ^JH NMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.29 (d, J =1.3 Hz, 1H), 7.24-7.31 (m, 1H), 7.16 (dd, J =12.0, 1.0 Hz, 1H), 7.09 (d, J= 8.3 Hz, 1H), 6.70-6.75 (m, 1H), 4.27 (dd, J= 11.4, 1.2 Hz, 1H), 4.08 (br d, J= 11.5 Hz, 1H), 3.71 (dd, J= 14.5, 2.5 Hz, 1H), 1.98-2.04 (m, 3H), 1.26-1.29 (m, 3H). Confirms the MW, Rt: 0.91, [M+H]⁺: 505.2, Method: 5. Preparation of compounds

Compound 1

A pressure tube was charged with Intermediate 22 (175 mg, 0.41 mmol), Intermediate 11 (126.11 mg, 0.46 mmol), BrettPhos Pd G3 (37.57 mg, 0.041 mmol), BrettPhos (22.24 mg, 0.041 mmol), CS2CO3 (202.53 mg, 0.62 mmol), and 1,4-dioxane (4.05 mL). The mixture was degassed, then stirred at 60 °C for 8 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 Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-lOpm, 30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to obtain Compound 1 as a yellow solid (147 mg, 58% yield).

‘H NMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.29 - 8.25 (m, IH), 7.26 - 7.23 (m, IH), 7.18 - 7.06 (m, 2H), 6.70 (s, IH), 6.08 (d, J=6.2 Hz, IH), 4.55 (sxt, 7=7.6 Hz, IH), 4.25 (d, 7=12.3 Hz, IH), 4.06 (d, 7=11.7 Hz, IH), 3.80 (tt, 7=4.6, 9.5 Hz, IH), 3.62 (d, 7=15.6 Hz, IH), 3.04 - 2.90 (m, 2H), 2.87 (s, 3H), 2.70 - 2.60 (m, 2H), 2.00 (s, 3H), 1.25 (s, 3H).

Compound 2 and Compound 3

Compound 2 Compound 3

Compound 1 (147 mg) was separated via chiral SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 zPrNHz). The fractions containing compound were combined and the solvent was concentrated in vacuo to provide two fractions as follows:

Fraction 1 : Compound 2 (61 mg, 24% yield starting from intermediate 22)

'HNMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.26 (d, 7=1.3 Hz, IH), 7.26 - 7.22 (m, IH), 7.15 (d, 7=11.9 Hz, IH), 7.08 (d, 7=8.3 Hz, IH), 6.71 (s, IH), 6.08 (br d, 7=6.4 Hz, IH), 4.55 (sxt, 7=7.6 Hz, IH), 4.26 (d, 7=10.5 Hz, IH), 4.06 (d, J=11.4 Hz, IH), 3.79 (tt, 7=4.7, 9.5 Hz, IH), 3.64 - 3.59 (m, IH), 3.00 - 2.92 (m, 2H), 2.87 (s, 3H), 2.70 - 2.61 (m, 2H), 2.00 (s, 3H), 1.25 (s, 3H).

Fraction 2: Compound 3 (63 mg, 25% yield starting from intermediate 22)

'HNMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.26 (d, J=1.3 Hz, 1H), 7.25 - 7.05 (m, 3H), 6.70 (s, 1H), 6.06 (d, .7=6, 2Hz, 1H), 4.59 - 4.50 (m, 1H), 4.24 (d, J=10.5 Hz, 1H), 4.06 (d, .7=11.5 Hz, 1H), 3.83 - 3.75 (m, 1H), 3.61 (d, 7=16.0 Hz, 1H), 2.99 - 2.92 (m, 2H), 2.86 (s, 3H), 2.69 - 2.60 (m, 2H), 1.99 (s, 3H), 1.24 (s, 3H).

Compound 4 was prepared by an analogous reaction protocol as Compound 1, starting from Intermediate 28 (0.1 g, 0.22 mmol) instead of Intermediate 22 to give Compound 4 (63.4 mg, 44% yield).

'HNMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.32 (s, IH), 7.11 - 6.98 (m, 2H), 6.72 (s, IH), 6.10 (br d, 7=6.2 Hz, IH), 4.54 (sxt, 7=7.5 Hz, IH), 4.32 - 4.22 (m, IH), 4.11 (t, J=11.7 Hz, IH), 3.80 (tt, J=9.5, 4.5 Hz, IH), 3.57 (br d, 7=14.3 Hz, IH), 3.03 - 2.81 (m, 5H), 2.72 - 2.62 (m, 2H), 2.01 (s, 3H), 1.27 (s, 3H).

Compound 4 (63.4 mg) was separated via chiral SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 zPrNHz). The fractions containing compound were combined and the solvent was concentrated in vacuo to provide two fractions as follows:

Fraction 1 : Compound 5 (29.6 mg, 21% yield starting from intermediate 28)

'HNMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.31 (d, 7=1.1 Hz, 1H), 7.10 - 6.99 (m, 2H), 6.72 (s, 1H), 6.08 (br d, 7=6.2 Hz, 1H), 4.53 (sxt, 7=7.7 Hz, 1H), 4.28 (dd, J=11.4, 1.5 Hz, 1H), 4.10 (d, J=11.4 Hz, 1H), 3.80 (tt, J=9.5, 4.7 Hz, 1H), 3.57 (br d, 7=14.3 Hz, 1H), 2.99 - 2.92 (m, 2H), 2.86 (s, 3H), 2.71 - 2.63 (m, 2H), 2.00 (s, 3H), 1.27 (s, 3H)

Fraction 2: Compound 6 (32.8 mg, 23% yield starting from intermediate 28)

'H NMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.32 (d, J=l.l Hz, 1H), 7.09 - 6.98 (m, 2H), 6.72 (s, 1H), 6.07 (br d, J=6.2 Hz, 1H), 4.53 (sxt, J=7.7 Hz, 1H), 4.25 (dd, J=11.4, 1.5 Hz, 1H), 4.13 (d, J= 11.7 Hz, 1H), 3.80 (tt, .7=9.5, 4.6 Hz, 1H), 3.56 (br d, J=14.5 Hz, 1H), 2.99 - 2.92 (m, 2H), 2.86 (s, 3H), 2.67 (ddd, J=14.4, 9.6, 7.3 Hz, 2H), 2.01 (s, 3H), 1.27 (s, 3H).

Compound 7 was prepared by an analogous reaction protocol as Compound 1, starting from Intermediate 34 (175.0 g, 0.40 mmol) instead of Intermediate 22 to give Compound 7 (165.0 mg, 65% yield).

'H NMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.62 (s, 1H), 7.32 (t, J=8.1 Hz, 1H), 6.94 - 6.85 (m, 2H), 6.72 (s, 1H), 6.09 (br d, J=6.2 Hz, 1H), 4.52 (sxt, ./ 7.5 Hz, 1H), 4.32 (dd, J=11.2, 2.6 Hz, 1H), 4.05 (dd, J=10.9, 5.8 Hz, 1H), 3.80 (tt, J=9.6, 4.6 Hz, 1H), 3.49 (br d, J= 15.2 Hz, 1H), 3.03 - 2.89 (m, 2H), 2.86 (s, 3H), 2.66 (ddd, J=14.5, 9.6, 7.2 Hz, 2H), 2.00 (s, 3H), 1.24 (br s, 3H).

Compound 7 (165 mg) was separated via chiral SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 zPrNHz). The fractions containing compound were combined and the solvent was concentrated in vacuo to provide two fractions as follows:

Fraction 1 : Compound 8 (72.0 mg, 29% yield starting from intermediate 34)

'H NMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.62 (s, 1H), 7.32 (t, J=8.3 Hz, 1H), 6.94 - 6.85 (m, 2H), 6.72 (s, 1H), 6.09 (br d, J=6.1 Hz, 1H), 4.57 - 4.48 (m, 1H), 4.32 (d, J=11.2 Hz, 1H), 4.05 (d, J=l l. l Hz, 1H), 3.80 (tt, J=9.5, 4.7 Hz, 1H), 3.49 (br d, .7=15.0 Hz, 1H), 2.99 - 2.91 (m, 2 H), 2.86 (s, 3 H), 2.67 (ddd, 7=14.5, 9.6, 7.1 Hz, 2 H), 2.00 (s, 3 H), 1.24 (s, 3 H).

Fraction 2: Compound 9 (76.0 mg, 30% yield starting from intermediate 34)

'H NMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.62 (s, 1H), 7.32 (t, 7=8.2 Hz, 1H), 6.93 - 6.85 (m, 2H), 6.72 (s, 1H), 6.08 (br d, J=6.3 Hz, 1H), 4.57 - 4.47 (m, 1H), 4.31 (d, J=11.2 Hz, 1H), 4.06 (d, 7=11.3 Hz, 1H), 3.80 (tt, J=9.6, 4.6 Hz, 1H), 3.49 (br d, 7=15.3 Hz, 1H), 2.99 - 2.91 (m, 2H), 2.86 (s, 3 H), 2.67 (ddd, 7=14.4, 9.6, 7.2 Hz, 2H), 2.00 (s, 3H), 1.24 (s, 3H).

Compound 10 was prepared by an analogous reaction protocol as Compound 1, starting from Intermediate 40 (0.17 mg, 0.40 mmol) instead of Intermediate 22 to give Compound 10 (151 mg, 59% yield).

'H NMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.29 - 8.25 (m, IH), 7.26 - 7.23 (m, IH), 7.18 - 7.06 (m, 2H), 6.70 (s, IH), 6.08 (br d, 7=6.2 Hz, IH), 4.55 (sxt, 7=7.6 Hz, IH), 4.25 (br d, 7=12.3 Hz, IH), 4.06 (br d, J=11.7 Hz, IH), 3.80 (tt, J=9.5, 4.6 Hz, IH), 3.62 (br d, 7=15.6 Hz, IH), 3.04 - 2.90 (m, 2H), 2.87 (s, 3H), 2.70 - 2.60 (m, 2H), 2.00 (s, 3H), 1.25 (s, 3H).

Compound 11 and Compound 12

Compound 10 (151 mg) was separated via chiral SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 z'PrMHE). The fractions containing compound were combined and the solvent was concentrated in vacuo to provide two fractions as follows:

Fraction 1 : Compound 11 (70.0 mg, 28% yield starting from intermediate 40)

'HNMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.26 (d, 7=1.3 Hz, 1H), 7.26 - 7.22 (m, 1H), 7.15 (d, 7=11.9 Hz, 1H), 7.08 (d, 7=8.3 Hz, 1H), 6.71 (s, 1H), 6.08 (br d, 7=6.4 Hz, 1H), 4.55 (sxt, 7=7.6 Hz, 1H), 4.26 (d, 7=10.5 Hz, 1H), 4.06 (d, J=11.4 Hz, 1H), 3.79 (tt, J=9.5, 4.7 Hz, 1H), 3.62 (br d, J= 15.8 Hz, 1H), 3.00 - 2.92 (m, 2H), 2.87 (s, 3H), 2.70 - 2.61 (m, 2H), 2.00 (s, 3H), 1.25 (s, 3H).

Fraction 2: Compound 12 (71.0 mg, 28% yield starting from intermediate 40)

'H NMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.26 (d, J=1.3 Hz, 1H), 7.26 (s, 2H), 7.25 - 7.05 (m, 3H), 6.70 (s, 1H), 6.06 (br d, J=6.2 Hz, 1H), 4.59 - 4.50 (m, 1H), 4.24 (d, J=10.5 Hz, 1H), 4.06 (d, .7=11.5 Hz, 1H), 3.79 (tt, J=9.5, 4.7 Hz, 1H), 3.61 (br d, 7=16.0 Hz, 1H), 2.99 - 2.92 (m, 2H), 2.86 (s, 3H), 2.64 (ddd, 7=14.4, 9.6, 7.2 Hz, 2H), 1.99 (s, 3H), 1.24 (s, 3H).

Compound 13

A 20 mL vessel was charged with Intermediate 10 (204.67 mg, 0.74 mmol), 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl (30.37 mg, 0.074 mmol), palladium(II) acetate (11.07 mg, 0.049 mmol) and potassium carbonate (170.41 mg, 1.23 mmol). The vessel was sealed and degassed. Then, a solution of Intermediate 18 (150 mg, 0.49 mmol) in dry toluene (5.0 mL) was syringed into the vessel which was then again degassed by bubbling N2. The mixture was stirred at 60 °C for 12 h, then the reaction was cooled down to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the crude was purified by Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-lOpm, 30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to obtain Compound 13 (125 mg, 51% yield).

'H NMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.57 (d, 7=1.1 Hz, 1H), 7.30 (m, 7=8.3 Hz, 2H), 7.12 (m, 7=8.4 Hz, 2H), 6.69 (s, 1H), 5.83 (s, 1H), 4.31 (dd, J=11.1, 2.0 Hz, 1H), 4.03 (dd, J=11.0, 4.0 Hz, 1H), 3.66 - 3.59 (m, 1H), 2.93 (d, 7=4.8 Hz, 3H), 1.99 (s, 3H), 1.69 - 1.65 (m, 1H), 1.21 (d, J=2.0 Hz, 3H).

Compound 14, 15, 16 and 17

Compound 14 Compound 15

Compound 16 Compound 17

Compound 13 (125 mg) was separated via chiral SFC (Stationary phase: Chiralcel Diacel OJ 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 zPrNFE). The fractions containing compound were combined and the solvent was concentrated in vacuo to provide four fractions as follows:

Fraction 1 : Compound 14 (23.3 mg, 9% yield starting from intermediate 18)

'H NMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.57 (d, 7=1.1 Hz, 1H), 7.33 - 7.27 (m, 7=8.3 Hz, 2H), 7.15 - 7.10 (m, 7=8.4 Hz, 2H), 6.69 (s, 1H), 5.83 (br s, 1H), 4.31 (dd, 7=2.0, 11.1 Hz, 1H), 4.03 (dd, 7=4.0, 11.0 Hz, 1H), 3.66 - 3.59 (m, 1H), 2.93 (d, 7=4.8 Hz, 3H), 1.99 (s, 3H), 1.69 - 1.65 (m, 1H), 1.25 - 1.16 (m, 3H).

Fraction 2: Compound 15 (23.0 mg, 9.3% yield starting from intermediate 18)

'H NMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.57 (s, 1H), 7.34 - 7.28 (m, 2H), 7.17 - 7.10 (m, 2H), 6.70 (s, 1H), 5.83 (br s, 1H), 4.33 (d, 7=11.0 Hz, 1H), 4.07 - 4.01 (m, 1H), 3.63 (dd, 7=2.5, 15.7 Hz, 1H), 2.94 (d, 7=4.8 Hz, 3H), 2.00 (s, 3H), 1.30 - 1.13 (m, 3H).

Fraction 3: Compound 16 (21.5 mg, 9% yield starting from intermediate 18)

'H NMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.58 (s, 1H), 7.33 - 7.28 (m, 7=8.6 Hz, 2H), 7.16 - 7.11 (m, 7=8.6 Hz, 2H), 6.70 (s, 1H), 5.83 (br s, 1H), 4.32 (d, 7=11.2 Hz, 1H), 4.05 (d, 7=11.2 Hz, 1H), 3.63 (dd, 7=2.3, 15.7 Hz, 1H), 2.94 (d, 7=4.8 Hz, 3H), 2.00 (s, 3H), 1.26 - 1.16 (m, 3H).

Fraction 4: Compound 17 (22.0 mg, 9% yield starting from intermediate 18)

'H NMR (CHLOROFORM-d, 400 MHz) 5 ppm: 8.58 (s, 1H), 7.31 (d, 7=8.4 Hz, 2H), 7.13 (d, 7=8.6 Hz, 2H), 6.70 (s, 1H), 5.83 (br s, 1H), 4.32 (d, 7=11.0 Hz, 1H), 4.05 (d, 7=11.2 Hz, 1H), 3.63 (dd, 7=2.4, 15.6 Hz, 1H), 2.94 (d, 7=4.6 Hz, 3H), 2.00 (s, 3H), 1.27 - 1.16 (m, 3H).

The following Compounds were synthesized by analogous reaction protocol as described for Compound 1, starting from Intermediate 43 and the indicated Intermediates.

The following Compounds were synthesized by analogous reaction protocol as described for Compound 1, starting from Intermediate 11 and the indicated Intermediates.

Intermediate 54 (59 mg, 0.063 mmol) was dissolved in MeOH (0.8 mL), HC1 (4M in dioxane; 0.3 mL, 1.2 mmol) was added and the mixture was stirred at room temperature for 4 hours. The mixture was dried under vacuum, and the residue was diluted with DCM. Sat. NaHCCL was added and the phases were separated. The aqueous layer was extracted with DCM and the combined organic layers were dried over MgSCU, filtered and evaporated. The residue was purified by flash column chromatography (Mobile phase: DCM : MeOH/NHs 7N from 100:0 to 96:4) to give Compound 33 (33.3 mg, 77% yield) as a yellow film. Compound 34 and 35

Compound 34 Compound 35

Compound 33 (33 mg) was separated via chiral SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 zPrNFE). The fractions containing compound were combined and the solvent was concentrated in vacuo to provide four fractions as follows:

Fraction 1 : Compound 34 (8.4 mg, 22% yield) as a yellow solid

Fraction 2: Compound 35 (8.4 mg, 22% yield) as a yellow solid

TBAF (IM in THF, 0.10 mL, 0.10 mmol) was added to a solution of Intermediate 87 (52 mg, 0.066 mmol) in anhydrous THF (2 mL). The reaction was stirred at rt for 1 h. Volatiles were removed under reduced pressure. The residue was dissolved in EtOAc (15 mL) and water (10 mL). The organic layer was separated and the aqueous one was extracted with EtOAc (10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column cromatography (Mobile phase: heptane:EtOAc from 100:0 to 0: 100) to obtain Compound 36 (35 mg, 80% yield) as a yellow solid.

Compound 37

A 20 mL vial was charged with Compound 3(150 mg, 0.24 mmol) and formic acid (0.018 mL, 1.22 g/mL, 0.49 mmol) and CS2CO3 (94.89 mg, 0.29 mmol) and BrettPhos Pd G3 (66.01 mg, 0.073 mmol) in 4 mL 1,4-dioxane. The mixture was degassed with N2 and stirred Ih at 55 °C. NaHCCh sat. sol. was added and the product was extracted with EtOAc. The organic layer was washed with brine and dried on MgSCU, filtered, and evaporated. The product was purified by flash column chromatography (Mobile phase: DMC:MeOH from 100:0 to 97:3). The pure fractions were evaporated and repurified via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-lOpm, 50x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to give Compound 37 (23.2 mg, 16% yield).

Compound 38

A solution of Intermediate 51 (49 mg, 0.10 mmol) and A-ethyl-A-isopropylpropan-2-amine (39 mg, 52 pL, 0.30 mmol) in ACN (1 mL) was added to 2-(dimethylphosphoryl)ethan-l -amine hydrochloride [1003315-34-1] (3.0 mg, 0.20 mmol). 2,4,6-tripropyl-l,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide [68957-94-8] (0.13 g, 0.12 mL, 50% Wt, 0.20 mmol) was added. The resulting mixtures were stirred at room temperature for 16h. The solvent was removed under reduced pressure, the crudes were redissolved in 2 mL DCM/EtOAc (2/1) and washed with 1 mL IM citric acid. The solvent was removed under reduced pressure and the crude mixtures was purified via Prep HPLC (Stationary phase: RP XBridge Prep Cl 8 OBD- 10pm, 30x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to give Compound 38 (34.0 mg, 58% yield).

The following Compounds were synthesized by analogous reaction protocol as described for Compound 38, from the indicated reagents.

Compound 318

HC1 (4M in dioxane, 0.1 mL, 0.4 mmol) was added to a solution of Intermediate 89 (42 mg, 0.06 mmol) in 1,4-dioxane (0.6 mL). The reaction was stirred at rt for 3 h. The mixture was pourred into a saturated solution of bicarbonate and extracted with DCM twice, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by flash chromatography (Mobile phase: DCM:MeOH from 100:0 to 95:5) to give Compound 318 (28 mg, 78% yield) as a white solid. Compound 319 and 320

Compound 319 Compound 320

Compound 318 (28.0 mg) was separated via chiral SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO2, EtOH + 0.4 zPrNFE). The fractions containing compound were combined and the solvent was concentrated in vacuo to provide two fractions as follows:

Fraction 1 : Compound 319 (4.5 mg, 13% yield starting from intermediate 89)

Fraction 2: Compound 320 (10.0 mg, 30% yield starting from intermediate 89) Table: 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. R_t means retention time (in minutes).

Table: Analytical SFC data - Rt means retention time (in minutes), method refers to the method used for (SFC)MS analysis of enantiomerically pure compounds. No. means number.

Analytical Analysis

The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in the respective methods. If necessary, additional detectors were included (see table of methods below).

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. . .) to obtain ions allowing the 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]⁺ (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.

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

LCMS Method Codes (Flow expressed in mL/min, column temperature (T) in °C, Run time in minutes, ‘ACN¹ means acetonitrile)

LC-MS methods:

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 standing up to 400 bars. If configured with a Mass Spectrometer (MS) the flow from the column was brought to the (MS). It is within the knowledge of the skilled person to set the tune parameters (e.g., scanning range, dwell time. . .) to obtain ions allowing the identification of the compound’s nominal monoisotopic molecular weight (MW). Data acquisition was performed with appropriate software. Analytical SFC-MS Methods (Flow expressed in mL/min, column temperature (Col T) in °C, Run time in minutes, Backpressure (BPR) in bars. “zPrN h” means isopropylamine, “zPrOH” means 2-propanol, “EtOH” means ethanol, “min” mean minutes.

SFC methods:

NMR

¹ H NMR spectra were recorded on Bruker Avance III 400MHz and Avance NEO 400MHz spectrometers. CHLOROFORM-d was used as solvent, unless otherwise mentioned. The chemical shifts are expressed in ppm relative to tetramethyl silane. ‘Cpd No.’ means Compound Number.

Pharmacological Analysis

Biological Examples

In vitro assays include assays that determine cell morphology, protein expression, and/or the cytotoxicity, enzyme inhibitory activity, and/or the subsequent functional consequences of treatment of cells with compounds of the invention. Alternate or additional in vitro assays may be used to quantitate the ability of the inhibitor to bind to protein or nucleic acid molecules within the cell.

Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/target molecule complex and determining the amount of radiolabel bound. Alternatively or additionally, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with purified proteins or nucleic acids bound to known radioligands. Detailed conditions of exemplary systems for assaying a compound of Formula (I) of the present invention as MALT1 inhibitors are set forth in the Biological Examples below.

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.

In Vitro Assays Biological Example 1

MALT1 Biochemical Protease Assay

MALT1 protease activity was assessed in an in vitro assay using a tetrapeptide as substrate and full-length MALT1 protein (Strep-MALTl(l-824)-His) purified from baculovirus-infected insect cells. The tetrapeptide LRSR is coupled to AMC (7-amino-4-methylcoumarin) and provides a quenched, fluorescent substrate for the MALT1 protease (SM Biochemicals). Cleavage of AMC from the Arginine residue results in an increase in coumarin fluorescence measured at 460 nm (excitation 355 nm). The final assay buffer consisted of 10 nM FL MALT1 protein, 200 pM Ac-LRSR-AMC, 50 mM Tris pH 7.5, 0.6 M Citrate, 1 mM dithiothreitol (DTT), 1 mM ethylenediaminetetraacetic acid (EDTA), 0.05% bovine serum albumin (BSA) and 1.5% dimethyl sulfoxide (DMSO). Test compounds were spotted at 50 nL in 100% DMSO per well of a black 384-Proxiplate (Perkin Elmer). Test compound concentrations ranged from 30 pM to 0.5 nM using 11 dilution steps (1 :3). Background signal was measured from control wells containing assay buffer without enzyme which functions as low control (LC). High control (HC) values were generated using the reaction with enzyme but no compound treatment. Compounds were pre-incubated with MALT1 enzyme for 50 minutes at RT. Substrate was added subsequently, and fluorescence was measured in Labsystems fluoroskan at excitation 355 nm and emission 460 nm to determine time 0. The reaction was subsequently incubated for 4 h at RT and fluorescence was measured. For IC50 calculations, timepoint 0 was subtracted from the 4 h timepoint to correct for any potential autofluorescence of the compounds. The enzyme reaction was linear during the 4 h incubation period. Characterization of the substrate Ac-LRSR-AMC determined the Michaelis constant KM at 200 pM.

IC50 values were calculated using the following formula (Z prime should be >0.5):

LC = Median of the low control values

= 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]

%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 IC50 value (inhibitory concentration causing 50 % inhibition) can be obtained. An estimate of the slope of the plot in terms of the Hill coefficient was also obtained.

IC50 Calculation:

With y = estimated response

UB = upper bound

LB = lower bound h = Hill slope of curve CONC = concentration

Used in “Lexis Dose Response Curve Fitting” Version 1.0. Resultant data are shown in Table 2 (‘Cpd No.’ means Compound Number, ‘n.d.’ means not determined, ‘Int’ means intermediate).

Biological Example 2 GloSensor reporter MALT 1 -mediated cleavage In Jurkat Cells

MALT1 GloSensor™ is a split luciferase reporter, which utilizes a genetically modified form of firefly luciferase (CP UltraGio) split into 2 distinct domains by insertion of a RelB MALT1 cleavage site sequence PRLVSRGA. MALT 1 -induced cleavage allows for a conformational change that reestablishes a functional luciferase protein resulting in luminescence, and hence luciferase activity would be a surrogate of endogenous MALT1 protease activity. Jurkat MALT1 GloSensor™ were generated by electroporation and selected and maintained in the presence of 0.5 mg/mL Geneticin. MALT1 protease is basally inactive in Jurkat cells and can be activated by treatment with PMA/Ionomycin. Small molecule MALT1 inhibitors added prior to PMA/Ionomycin addition prevent MALT1 protease activation and, therefore, the cleavage of the MALT1 GloSensor split luciferase reporter in a dose-dependent manner.

Jurkat MALT1 GloSensor™ cells were maintained in complete RPMI 1640 media containing 10% fetal bovine serum, lOmM 4-(2 -hydroxy ethyl)- 1 -piperazineethanesulfonic acid (HEPES), 100 units/mL of penicillin, 100 pg/mL of streptomycin and 0.5 mg/mL Geneticin. Prior to the assay, compounds were made 2.5-fold serial dilutions in DMSO. 100 nL of of test compounds were spotted per well of 384-well plates (Perkin Elmer, catalogue number 6007688). Jurkat cells were harvested by centrifuge at 1200 RPM for 5 min and suspended in fresh complete RPMI 1640 media with 2% GloSensor™ cAMP Reagent and preincubated for 45-60 minutes at 37 °C in a 5% CO2 incubator. A volume of 50 uL of preincubated Jurkat MALT1 GloSensor™ cells (1 x 10⁵ cells) were seeded in each well of 384-well plate. Next, a volume 2 pL of diluted PMA / lonomycin (2.5 pg/mL / 25 pM respectively, Sigma, catalogue number P1585 and 407953) in DMSO were added to each well. After incubation at 37 °C in 5% CO2 incubator for 4 h, luminescence was measured on the Envision (Perkin Elmer) at 37 °C.

IC50 values were calculated using SmartFit in GeneData Screener®:

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

Where: x = concentration y = activity

So = activity at bottom plateau of curve

Sinf = activity at top plateau of curve

S50 = inflection point, halfway between SO and Sinf h = Hill slope of curve

Resultant data are shown in Table 3 (‘Cpd No.’ means Compound Number, ‘Int’ means intermediate).

Biological Example 3 Human IL-6/IL- 10 Mesoscale Assay

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.

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 pM to 58.6 nM (final DMSO concentration 0.3%). DMSO control wells were used to determine the maximum signal (High Control (HC)). Treatment with reference compounds at an appropriate dose served as positive control for MALT1 inhibition and was used to determine the maximum inhibition (Low Control (LC)). Compounds and cells were incubated for 24 h at 37 °C and 5% CO2 (assay volume is 150 pL). After 24 h of incubation 50 pL of the supernatant was transferred to an MSD plate (V-Plex Proinflammation Panel 1 (human) kit, Mesoscale (MSD)) and incubated for 2 h with vigorous shaking (600 rpm) at room temperature. Following incubation, plates were washed 3x with phosphate-buffered saline (PBS) + 0.05% Tween-20 and 25 pL detection antibody solution (IL-6 & IL-10 antibodies in diluent 3 (MSD)) was added per well followed by 2 h of incubation with vigorous shaking (600 rpm) at room temperature. After 3x washes with PBS + 0.05% Tween-20, plates were incubated with 150 pL 2x Read Buffer T and read on SECTOR imager. Resultant data are shown in Table 4 (‘Cpd No.’ means Compound Number, ‘Int’ means intermediate, ‘n.d.’ means not determined).

Biological Example 4

Proliferation Assays OCI-Ly3 cells were propagated in RPMI-1640 with Glutamax (ThermoFisher) supplemented with 10% heat inactivated fetal bovine serum (ThermoFisher). Cells should be kept between 0.2 - 1.5 million cells per mL and passed every 3-4 days during culturing. OCI- Ly7 cells were propagated in IMDM (ThermoFisher) supplemented with 10% fetal bovine serum (HyClone), 2 mM L-glutamine (Sigma Aldrich) and 50 pg/mL Gentamycin. Cells should be kept between 0.15 - 3 million cells per mL and passed every 3-4 days during culturing. Cell passage numbers should not exceed 20.

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 pL media per well and incubated for 8 days at 37 °C and 5% CO2. Cell plating numbers were chosen based on growth curves to ensure linear cell growth. After 8 days of incubation, 100 pL of the plated cells were resuspended up and down by pipette and transferred to a flat bottom black plate (Corning®, #3904). 50 pL CellTiterGLO reagent (Promega) were added to each well and luminescence was measured on Envision (Perkin Elmer) after 10 minutes shaking at 300 rpm followed by 10 minutes of incubation at room temperature in the dark.

IC50 values were calculated using SmartFit in GeneData Screener®:

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

Where: x = concentration y = activity

So = activity at bottom plateau of curve

Sinf = activity at top plateau of curve

S50 = inflection point, halfway between SO and Sinf h = Hill slope of curve

Resultant data are shown in Table 5 (‘Cpd No.’ means Compound Number, ‘n.d.’ means not determined, ‘Int’ means intermediate) :

Claims

1. A compound of Formula (I)

or a tautomer or a stereoisomeric form thereof, wherein

R¹ represents

represents phenyl or pyridyl;

R² represents halo; n is 0, 1 or 2; R^3a represents hydrogen or Ci-4alkyl;

R^3b represents hydrogen; Ci-4alkyl; C₃-6cycloalkyl; adamantyl; Ce-iocarbobicyclic; Het¹; Cs-ecycloalkyl substituted with one, two, three or four substituents each independently selected from the group consisting of oxo, halo, cyano, -OH, -OR⁷, -S(=O)2-R⁷, -S(=O)₂-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-R⁷, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-R⁷, -C(=O)-NR^4aR^4b, -S(=O)(=NH)-NR^4aR^4b, -P(=O)-R^4cR^4d, -O-Ci-₄alkyl-C(=O)-NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl-O-R⁷, -NH-S(=O)₂-R⁷, Het^3a, Het^3b, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-Ci-₄alkyl, -C(=O)-NR^4aR^4b, -S(=O)₂-NR^4aR^4b, and -S(=O)₂-Ci-₄alkyl;

Ce-iocarbobicyclic 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-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-R⁷, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-R⁷, -C(=O)-NR^4aR^4b, -S(=O)(=NH)-NR^4aR^4b, -P(=O)-R^4cR^4d, -O-Ci-₄alkyl-C(=O)-NR^4aR^4b, -S(=O)(=NH)-Ci-4alkyl-O-R⁷, -NH-S(=O)₂-R⁷, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-Ci-₄alkyl, -C(=O)-NR^4aR^4b, -S(=O)₂-NR^4aR^4b, and -S(=O)₂-Ci-4alkyl; or

Ci-4alkyl substituted with one, two, three or four substituents each independently selected from the group consisting of cyano, halo, -OH, -OR⁷, -S(=O)₂-R⁷, -S(=O)₂-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-R⁷, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-R⁷, -C(=O)-NR^4aR^4b, -S(=O)(=NH)-NR^4aR^4b, -P(=O)-R^4cR^4d, -O-Ci-₄alkyl-C(=O)-NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl-O-R⁷, -NH-S(=O)₂-R⁷, -CF₃, Cy¹, Het^3a, Het^3b, -O-Het^3b, -C(=O)-Het^3a, -C(=O)-Het^3b, and

Cy¹ represents 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-Ci-4alkyl, -S(=O)₂-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-Ci-₄alkyl, -NH-(C=O)-C₃-6cycloalkyl, -C(=O)-NR^4aR^4b, and -NH-S(=O)₂-R⁷;

Het¹ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; or Het¹ represents a bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; 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-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-R⁷, -N=S(=O)-(Ci-₄alkyl)2, -NH-(C=O)-R⁷, -C(=O)-NR^4aR^4b, -S(=O)(=NH)-NR^4aR^4b, -P(=O)-R^4cR^4d, -O-Ci-₄alkyl-C(=O)-NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl-O-R⁷, -NH-S(=O)2-R⁷, and Ci-₄alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-Ci-₄alkyl, -C(=O)-NR^4aR^4b, -S(=O)₂-NR^4aR^4b, and -S(=O)₂-Ci-₄alkyl; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)₂, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-₄alkyl, Het⁵, -C(=O)-NR^4aR^4b, -C(=O)-Ci-₄alkyl, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, -C(=O)-C3-6cycloalkyl, or Ci-₄alkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH and halo;

Het² represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; or Het² represents a bicyclic N-linked 6- to 11 -membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; 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-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-R⁷, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-R⁷, -C(=O)-NR^4aR^4b, -S(=O)(=NH)-NR^4aR^4b, -P(=O)-R^4cR^4d, -O-Ci-₄alkyl-C(=O)-NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl-O-R⁷, -NH-S(=O)2-R⁷, and Ci-₄alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, -S(=O)(=NH)-Ci-₄alkyl, -C(=O)-NR^4aR^4b, -S(=O)₂-NR^4aR^4b, Het⁴ and -S(=O)₂-Ci-₄alkyl; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)₂, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-₄alkyl, -C(=O)-NR^4aR^4b , -C(=O)-Ci-₄alkyl, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, Het⁴, or -C(=O)-C3-6cycloalkyl; Het^3a represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; or Het^3a represents a bicyclic N-linked 6- to 11 -membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, halo, -OH, -OR⁷, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-Ci-₄alkyl, -NH-(C=O)-C₃-6cycloalkyl, -C(=O)-NR^4aR^4b, and -NH-S(=O)₂-R⁷; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)₂, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-₄alkyl, Het⁵, -C(=O)-NR^4aR^4b , -C(=O)-Ci-₄alkyl, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, -C(=O)-C3-6cycloalkyl, or Ci-₄alkyl substituted with one, two or three substituents each independently selected from the group consisting of -OH and halo;

Het⁴ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; 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); Het⁵ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; 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);

R^4C and R^4d each independently represent Ci-4alkyl or -O-Ci-4alkyl;

R⁶ represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH;

R⁷ represents Ci-4alkyl or Cs-ecycloalkyl, each optionally substituted with one, two or three halo substituents; pl and p2 each independently are 1, 2 or 3; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein

R^x represents halo;

R^y represents hydrogen or Ci-4alkyl;

R^z represents Ci-4alkyl substituted with one, two or three halo substituents; or R^y and R^z taken together with the carbon atom to which they are attached form a Cs-ecycloalkyl;

Cs-ecycloalkyl substituted with one, two, three or four substituents each independently selected from the group consisting of oxo, -OH, -OR⁷, -S(=O)₂-R⁷, -S(=O)₂-NR^4aR^4b, - NR^4aR^4b, -S(=O)(=NH)-R⁷, -NH-(C=O)-R⁷, -S(=O)(=NH)-NR^4aR^4b, -P(=O)-R^4cR^4d, - NH-S(=O)₂-R⁷, Het^3a, Het^3b, and Ci-4alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, halo, - S(=O)(=NH)-Ci-₄alkyl, -C(=O)-NR^4aR^4b, -S(=O)₂-NR^4aR^4b, and -S(=O)₂-Ci-₄alkyl;

Ce-iocarbobicyclic 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-NR^4aR^4b; or

Cy¹ represents Cs-ecycloalkyl; or Cs-ecycloalkyl substituted with one, two or three substituents each independently selected from the group consisting of -S(=O)2-Ci-₄alkyl, and -S(=O)2- NR^4aR^4b;

Het¹ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; or Het¹ represents a bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; 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)-NR^4aR^4b, -S(=O)(=NH)-NR^4aR^4b, - P(=O)-R^4cR^4d, -O-Ci-₄alkyl-C(=O)-NR^4aR^4b, and Ci-₄alkyl optionally substituted with one, two or three substituents each independently selected from the group consisting of -OH, and -C(=O)-NR^4aR^4b; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)₂, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-₄alkyl, Het⁵, -C(=O)-Ci-₄alkyl, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, -C(=O)-C₃-6cycloalkyl, or Ci- ₄alkyl substituted with one, two or three -OH;

Het² represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; or Het² represents a bicyclic N-linked 6- to 11 -membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of Het⁶, -S(=O)₂-NR^4aR^4b, -S(=O)(=NH)-R⁷, -N=S(=O)-(Ci-₄alkyl)₂, -C(=O)- NR4aR4b, and Ci-4alkyl optionally substituted with one, two or three -S(=O)₂-Ci-4alkyl; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)₂, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Het⁴;

Het^3a represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, and -OH; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)₂, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, Het⁵, -C(=O)-Ci-₄alkyl, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, or -C(=O)-C_3-6cycloalkyl;

Het^3b represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; or Het^3b represents a bicyclic C-linked 6- to 11 -membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; wherein one or more of the carbon atoms in said heterocyclyl might be substituted with in total one, two or three substituents each independently selected from the group consisting of oxo, halo, -OH, Ci-4alkyl, and -OR⁷; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O), S(=O)₂, or S(=O)(=NH); wherein one or more of the N-atoms in said heterocyclyl might be substituted with Ci-4alkyl, Het⁵, or -S(=O)₂-Ci-4alkyl;

Het⁵ represents a monocyclic C-linked 4- to 7-membered fully saturated heterocyclyl containing one, two or three heteroatoms each independently selected from O, S, and N; 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); Het⁶ represents a monocyclic N-linked 4- to 7-membered fully saturated heterocyclyl containing one N-atom and optionally one or two heteroatoms each independently selected from O, S, and N; wherein one or more of the S-atoms in said heterocyclyl might be substituted to form S(=O),

S(=O)₂, or S(=O)(=NH); pl and p2 are 2.

3. The compound according to claim 1 or 2 wherein q is 1;

R^x represents halo;

R^y represents Ci-4alkyl;

R^z represents Ci-4alkyl substituted with one, two or three halo substituents; n is 0 or 1;

R^3a represents hydrogen;

R^3b represents Ci-4alkyl; Cs-ecycloalkyl; or

R⁶ represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH;

R⁷ represents Ci-4alkyl.

4. The compound according to claim 1 wherein

R¹ represents

R^z represents Ci-4alkyl; Cs-ecycloalkyl; or Ci-4alkyl substituted with one, two or three halo substituents; or R^y and R^z taken together with the carbon atom to which they are attached form a Cs-ecycloalkyl;

R^3a represents hydrogen; and

R^3b represents hydrogen; Ci-4alkyl; Cs-ecycloalkyl; -Ci^alkyl-Cy¹; Cs-ecycloalkyl substituted with one substituent selected from the group consisting of halo, -OH, -O-Ci-₄alkyl, -OCF₃, -OCHF2, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-Ci-₄alkyl, -NH-(C=O)-C₃-6cycloalkyl, -C(=O)-NR^4aR^4b, and -NH-S(=O)₂-Ci-₄alkyl;

Ci-₄alkyl substituted with one, two or three substituents each independently selected from the group consisting of halo, -OH, -O-Ci-₄alkyl, -OCF3, -OCHF₂, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-Ci-₄alkyl, -NH-(C=O)-C₃-6cycloalkyl, -C(=O)-NR^4aR^4b, and -NH-S(=O)₂-Ci-₄alkyl;

3- or 4-piperidinyl optionally substituted on the N-atom with Ci-₄alkyl, -C(=O)-NR^4aR^4b ,

Cy¹ represents Cs-ecycloalkyl; or Cs-ecycloalkyl substituted with one substituent selected from the group consisting of halo, -OH, -O-Ci-₄alkyl, -OCF3, -OCHF₂, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-NR^4aR^4b, -NR^4aR^4b, -S(=O)(=NH)-Ci-₄alkyl, -N=S(=O)-(Ci-₄alkyl)₂, -NH-(C=O)-Ci-₄alkyl, -NH-(C=O)-C₃-6cycloalkyl, -C(=O)-NR^4aR^4b, and -NH-S(=O)₂-Ci-₄alkyl;

R^4a and R^4b each independently represent hydrogen or Ci-₄alkyl;

R⁵ represents hydrogen, -OH, -O-Ci-₄alkyl, -S(=O)₂-Ci-₄alkyl, -S(=O)₂-C3-6cycloalkyl, -S(=O)₂-NR^4aR^4b, or -C(=O)-NR^4aR^4b; nl, n2, n3, n4, n5, n6, n7 and n8 each independently are 1 or 2;

R⁶ represents methyl.

5. The compound according to claim 4 wherein R^x represents hydrogen, Ci-₄alkyl or halo;

6. The compound according to claim 4 or 5 wherein

R^x represents halo;

R^y represents Ci-₄alkyl;

R^z represents Ci-₄alkyl substituted with one, two or three halo substituents; ring

represents phenyl;

R² represents halo;

R^3a represents hydrogen; and

R^3b represents Ci-₄alkyl; or Cs-ecycloalkyl substituted with one -S(=O)₂-Ci-₄alkyl.

7. The compound according to any one of the preceding claims wherein n is 0.

8. The compound according to any one of the preceding claims wherein n is i.

9. The compound according to any one of the preceding claims wherein ring

represents phenyl, and R⁶ represents methyl.

10. The compound according to any one of the preceding claims wherein Formula (I) and the stereochemistry of the substituents on the cyclopropyl moiety are as indicated below in

Formula (Lal):

11. The compound according to any one of the preceding claims wherein Formula (I) and the stereochemistry of the substituents on the cyclopropyl moiety are as indicated below in Formula ( bl):

12. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 11 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.

13. A compound as claimed in any one of claims 1 to 11 or a pharmaceutical composition as claimed in claim 12 for use as a medicament.

14. A compound as claimed in any one of claims 1 to 11 or a pharmaceutical composition as claimed in claim 12 for use in the treatment or prevention of cancer.

15. A compound as claimed in any one of claims 1 to 11 or a pharmaceutical composition as claimed in claim 12 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 MALT 1.

16. A method of treating a disease, syndrome, condition, or disorder, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT 1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as claimed in any one of claims 1 to 11 or a pharmaceutical composition as claimed in claim 12.

17. An active intermediate of Formula (A)

or a tautomer or a stereoisomeric form thereof, wherein

R¹ represents

represents phenyl or pyridyl;

R² represents halo; n is 0, 1 or 2;

R⁶ represents Ci-4alkyl; or Ci-4alkyl substituted with one -OH; or a pharmaceutically acceptable salt thereof.