EP4735430A1 - Malt1 inhibitors - Google Patents

Abstract

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

Description

MALT1 INHIBITORS FIELD OF THE INVENTION The present invention relates to a novel compound that is a MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1) inhibitor. The compound may be useful for the treatment of a disease, syndrome, condition, or disorder, particularly a MALT1-related disease, syndrome, condition, or disorder, including but not limited to, cancer and immunological diseases. The invention also relates to pharmaceutical compositions comprising one or more of such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds or pharmaceutical compositions for the treatment of cancer and autoimmunological diseases, syndromes, disorders, or conditions associated with MALT1 inhibitors. BACKGROUND OF THE INVENTION MALT1 (mucosa-associated lymphoid tissue lymphoma translocation 1) is a key mediator of the classical NF _^B signaling pathway. MALT1 is the only human paracaspase and transduces signals from the B cell receptor (BCR) and T cell receptor (TCR). MALT1 is the active subunit of the CBM complex which is formed upon receptor activation. The CBM complex consists of multiple subunits of three proteins: CARD11 (caspase recruitment domain family member 11), BCL10 (B-cell CLL/Lymphoma 10) and MALT1. MALT1 affects NF _^B signaling by two mechanisms: firstly, MALT1 functions as a scaffolding protein and recruits NF- _^B signaling proteins such as TRAF6, TAB-TAK1 or NEMO-IKKα/ ^; and secondly, MALT1, as a cysteine protease, cleaves and thereby deactivates negative regulators of NF- _^B signaling, such as RelB, A20 or CYLD. The ultimate endpoint of MALT1 activity is the nuclear translocation of the NF- _^B transcription factor complex and activation of NF- _^B signaling. Constitutive activation of NF- _^B signaling is the hallmark of ABC-DLBCL (Diffuse Large B cell Lymphoma of the Activated B Cell-like subtype), the more aggressive form of DLBCL. DLBCL is the most common form of non-Hodgkin’s lymphoma (NHL), accounting for approximately 25% of lymphoma cases while ABC-DLBCL comprises approximately 40% of DLBCL. NF- _^B pathway activation is driven by mutations of signaling components, such as CD79A/B, CARD11, MYD88 or A20, in ABC-DLBCL patients. The use of BTK inhibitors, for example Ibrutinib, provides clinical proof-of-concept that inhibiting NF- _^B signaling in ABC-DLBCL is efficacious. MALT1 is downstream of BTK in the NF- _^B signaling pathway and a MALT1 inhibitor could target ABC-DLBCL patients not responding to Ibrutinib, mainly patients with CARD11 mutations, as well as treat patients that acquired resistance to Ibrutinib. Small molecule tool compound inhibitors of MALT1 protease have demonstrated efficacy in preclinical models of ABC-DLBCL. Interestingly, covalent catalytic site and allosteric inhibitors of MALT1 protease function have been described, suggesting that inhibitors of this protease may be useful as pharmaceutical agents. The chromosomal translocation creating the API2-MALT1 fusion oncoprotein is the most common mutation identified in MALT (mucosa-associated lymphoid tissue) lymphoma. API2-MALT1 is a potent activator of the NF- _^B pathway. API2-MALT1 mimics ligand-bound TNF receptor, promotes TRAF2-dependent ubiquitination of RIP1 which acts as a scaffold for activating canonical NF- _^B signaling. Furthermore, API2-MALT1 has been shown to cleave and generate a stable, constitutively active fragment of NF- _^B-inducing kinase (NIK) thereby activating the non-canonical NF- _^B pathway. In addition to lymphomas, MALT1 has been shown to play a critical role in innate and adaptive immunity. MALT1 protease inhibitor can attenuate disease onset and progression of mouse experimental allergic encephalomyelitis, a mouse model of multiple sclerosis. Mice expressing catalytically inactive MALT1 mutant showed loss of marginal zone B cells and B1 B cells and general immune deficiency characterized as decreased T and B cell activation and proliferation. However, those mice also developed spontaneous multi-organ autoimmune inflammation at the age of 9 to 10 weeks. It is still poorly understood why MALT1 protease dead knock-in mice show a break of tolerance while conventional MALT1 KO mice do not. One hypothesis suggests the unbalanced immune homeostasis in MALT1 protease dead knock- in mice may be caused by incomplete deficiency in T and B cell but severe deficiency of immunoregulatory cells. Similarly, MALT deficiency in humans has been associated with combined immunodeficiency disorder. Given the difference between genetic mutation and pharmacological inhibition, a phenotype of MALT1 protease dead knock-in mice might not resemble that of patients treated with MALT1 protease inhibitors. A reduction of immunosuppressive T cells by MALT1 protease inhibition may be beneficial to cancer patients by potentially increasing antitumor immunity. WO2023192506 described MALT1 modulators. Thus, MALT1 inhibitors of the present invention may provide a 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 C1-4alkyl or C3-6cycloalkyl; each optionally substituted with 1, 2 or 3 substituents each independently selected from halo and -OH; ring represents phenyl or pyridyl; R^x represents halo; n is 0, 1 or 2; Ar represents phenyl, thiazolyl, 1,2,4-thiadiazolyl, isothiazolyl, oxazolyl, pyrazolyl, pyridinonyl or pyridinyl; R^4a and R^4b are each independently selected from the group consisting of hydrogen; halo; C1-4alkyl; -C(=O)-NR⁵R⁶; -O-C1-4alkyl; -CN; -NR^7aR^8a; -C(=O)-O-R⁹; C3-6cycloalkyl; -O-C1-4alkyl substituted with 1, 2 or 3 halo substituents; or C1-4alkyl substituted with 1, 2 or 3 halo substituents; R² represents C1-4alkyl; R³ represents C3-6cycloalkyl optionally substituted with one substituent selected from -NR^7bR^8b, 1-azetidinyl, 1-pyrrolidinyl and 1-piperidinyl; or R³ represents (a-1), (a-2), (a-3), (a-4) or (a-5):

(a-1) (a-4) (_a-2) ^(a-5) (a-3) X¹ represents O, NH or N-C_1-4alkyl; X² represents O, NH or N-C_1-4alkyl; n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, n12, and n14 are each independently 1, 2 or 3; n13 is 0, 1 or 2; R¹², R¹³ and R¹⁶ are each independently selected from the group consisting of hydrogen, C_1-4alkyl and -S(=O)₂-C_1-4alkyl; R¹⁴, R¹⁵ and R¹⁷ are substituents on a carbon atom of (a-1), (a-2), (a-3), (a-4) or (a-5) and are each independently selected from the group consisting of hydrogen, C_1-4alkyl and halo; which they are attached ; X³ represents CH or N; X⁴ represents CH or N; provided that at least one of X³ and X⁴ represents N; X⁵ represents CH or N; X⁶ represents CH or N; provided that at least one of X⁵ and X⁶ represents N; R¹⁰ and R¹¹ represent hydrogen or C_1-4alkyl optionally substituted with 1, 2 or 3 halo substituents; R⁵, R⁶, R^7a, R^7b, R^8a, R^8b and R⁹ are each independently selected from the group consisting of hydrogen and C1-4alkyl; and the pharmaceutically acceptable salts thereof. All references to “compound(s) of Formula (I)”, 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). The compounds of Formula (I) 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 or otherwise indicated as having a particular configuration (e.g. by a stereodescriptor such as R, S, ‘R or S’, ‘S or R’) 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 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). 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. 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. 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 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). 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. 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). The present invention also is directed to the use of any of the compounds described herein in the preparation of a medicament wherein the medicament is prepared for treating a disease, syndrome, condition, or disorder that is affected by the inhibition of MALT1, such as cancer and/or immunological diseases. The present invention is also directed to the preparation of Compounds of Formula (I) that act as an inhibitor of MALT1. 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), Waldenström macroglobulinemia, lymphoblastic T cell leukemia, chronic myelogenous leukemia (CML), hairy-cell leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, immunoblastic large cell leukemia, megakaryoblastic leukemia, acute megakaryocytic 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 MALT1, including but not limited to, autoimmune and inflammatory disorders, e.g. arthritis, inflammatory bowel disease, gastritis, ankylosing spondylitis, ulcerative colitis, pancreatits, Crohn’s disease, celiac disease, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, rheumatic fever, gout, organ or transplact rejection, chronic allograft rejection, acute or chronic graft-versus-host disease, dermatitis including atopic, dermatomyositis, psoriasis, Behcet’s diseases, uveitis, myasthenia gravis, Grave’s disease, Hashimoto thyroiditis, Sjorgen’s syndrome, blistering disorders, antibody-mediated vasculitis syndromes, immune-complex vasculitides, allergic disorders, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, pneumonia, pulmonary diseases including oedema, embolism, fibrosis, sarcoidosis, hypertension and emphysema, silicosis, respiratory failure, acute respiratory distress syndrome, BENTA disease, berylliosis, and polymyositis. In another embodiment, the present invention is directed to a compound of Formula (I) for (use in) the treatment of a disease, syndrome, condition, or disorder affected by inhibition of MALT1, selected from the group consisting of rheumatoid arthritis (RA), psoritic arthritis (PsA), psorisis (Pso), ulcerative colitis (UC), Crohn’s disease, systemic lupus erythematosus (SLE), asthma, and chronic obstructive pulmonary disease (COPD). 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 Waldenström macroglobulinemia. In yet another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is lymphoma. In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is the activated B cell like (ABC) subtype of diffuse large B- cell lymphoma (DLBCL). In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is germinal center B cell like (GCB) subtype of diffuse large B-cell lymphoma (DLBCL). In another embodiment of the invention, the disease, syndrome, condition, or disorder 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 MALT1 is chronic lymphocytic leukemia (CLL). In another embodiment, the disorder or condition small lymphocytic lymphoma (SLL). In another embodiment of the invention, the lymphoma is MALT lymphoma. In another embodiment of the invention, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is Waldenström macroglobulinemia (WM). In yet another embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and mucosa-associated lymphoid tissue (MALT) lymphoma. In an alternate embodiment, the disease, syndrome, condition, or disorder affected by inhibition of MALT1 is non-Hodgkin’s lymphoma (NHL). In a further embodiment, the non- Hodgkin’s lymphoma (NHL) is B-cell NHL. 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-PD1 antibodies, and anti-PD-L1 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 MALT1. 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 characteristic(s)” of the claimed invention. Embodiments described in terms of the phrase “comprising” (or its equivalents) also provide as embodiments those independently described in terms of “consisting of” and “consisting essentially of.” The prefix ‘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 C1-4alkyl group contains from 1 to 4 carbon atoms, and so on. The term ‘C_1-4alkyl’ as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 4 carbon atoms, such as methyl, ethyl, n- propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like. The term ‘C_3-6cycloalkyl’ 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. The term “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine atoms. It will be clear for the skilled person that S(=O)2 or SO2 represents a sulfonyl moiety. . Whenever substituents are represented by chemical structure, “---” represents the bond of attachment to the remainder of the molecule of Formula (I). 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 combinations of substituents and/or variables are permissible only if such combinations result in chemically stable compounds. ‘Stable compound’ is in this context meant to indicate 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). Unless otherwise specified or clear from the context, the R^4a and R^4b substituents on the Ar moiety, can be substituents on carbon and/or nitrogen atoms of the Ar moiety. Lines drawn from substituents into ring systems indicate that the bond may be attached to any of the suitable ring atoms. The stereodescriptor label “R” or “(R)” at a stereocenter designates that the stereocenter is purely of the R-configuration as defined in the art; likewise, the stereodescriptor label “S” or “(S)” means that the stereocenter is purely of the S-configuration. A compound containing one stereocenter drawn without a stereo bond designation is a mixture of two stereoisomers unless otherwise indicated (for example via a stereodescriptor). A compound containing two stereocenters both drawn without stereo bond designations is a mixture of four diastereomers unless otherwise indicated (for example via stereodescriptors). 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 MALT1; or (2) reduce or inhibit the activity of MALT1; or (3) reduce or inhibit the expression of MALT1; or (4) modify the protein levels of MALT1. The term “composition” refers to a product that includes the specified ingredients in therapeutically effective amounts, as well as any product that results, directly, or indirectly, from combinations of the specified ingredients in the specified amounts. Suitable examples of a disease, syndrome, condition, or disorder mediated by MALT1 include, but are not limited to, lymphomas, leukemias, carcinomas, and sarcomas, e.g. non- Hodgkin’s lymphoma (NHL (including B-cell NHL)), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, T-cell lymphoma, Hodgkin’s lymphoma, Burkitt’s lymphoma, multiple myeloma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström macroglobulinemia, lymphoblastic T cell leukemia, chronic myelogenous leukemia (CML), hairy-cell leukemia, acute lymphoblastic T 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 MALT1-mediated disease or condition in a subject in need thereof, including an animal, a mammal, and a human in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I). In another embodiment, the MALT1-dependent or MALT1-mediated disease or condition is selected from cancers of hematopoietic origin or solid tumors such as chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin lymphoma, and other B cell lymphomas. In particular, the compounds of Formula (I) may be useful for treating or ameliorating 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). 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 C_1-4alkyl or C_3-6cycloalkyl; each optionally substituted with 1, 2 or 3 substituents each independently selected from halo and -OH; ring represents phenyl or pyridyl; R^x represents halo; n is 0, 1 or 2; Ar represents phenyl, thiazolyl, 1,2,4-thiadiazolyl, isothiazolyl, oxazolyl, pyrazolyl, pyridinonyl or pyridinyl; R^4a and R^4b are each independently selected from the group consisting of hydrogen; halo; C1-4alkyl; -C(=O)-NR⁵R⁶; -O-C1-4alkyl; -CN; -NR^7aR^8a; -C(=O)-O-R⁹; C3-6cycloalkyl; -O-C1-4alkyl substituted with 1, 2 or 3 halo substituents; or C1-4alkyl substituted with 1, 2 or 3 halo substituents; R² represents C1-4alkyl; R³ represents C3-6cycloalkyl optionally substituted with one substituent selected from or X² represents O, NH or N-C_1-4alkyl; n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, n12, and n14 are each independently 1, 2 or 3; n13 is 0, 1 or 2; R¹², R¹³ and R¹⁶ are each independently selected from the group consisting of hydrogen, C_1-4alkyl and -S(=O)₂-C_1-4alkyl; R¹⁴, R¹⁵ and R¹⁷ are substituents on a carbon atom of (a-1), (a-2), (a-3), (a-4) or (a-5) and are each independently selected from the group consisting of hydrogen, C_1-4alkyl and halo; which they are attached ; X³ represents CH or N; X⁴ represents CH or N; provided that at least one of X³ and X⁴ represents N; X⁵ represents CH or N; X⁶ represents CH or N; provided that at least one of X⁵ and X⁶ represents N; R¹⁰ and R¹¹ represent hydrogen or C1-4alkyl optionally substituted with 1, 2 or 3 halo substituents; R⁵, R⁶, R^7a, R^7b, R^8a, R^8b and R⁹ are each independently selected from the group consisting of hydrogen and C_1-4alkyl; and the pharmaceutically acceptable salts thereof, provided that the following compounds

and are excluded. 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 C1-4alkyl or C3-6cycloalkyl; each optionally substituted with 1, 2 or 3 substituents each independently selected from halo and -OH; ring represents phenyl or pyridyl; R^x represents halo; n is 0, 1 or 2; Ar represents phenyl, thiazolyl, 1,2,4-thiadiazolyl, isothiazolyl, oxazolyl, pyrazolyl, pyridinonyl or pyridinyl; R^4a is selected from the group consisting of hydrogen; halo; C_1-4alkyl; -C(=O)-NR⁵R⁶; -O-C_{1- 4}alkyl; -CN; -NR^7aR^8a; -C(=O)-O-R⁹; C_3-6cycloalkyl;-O-C_1-4alkyl substituted with 1, 2 or 3 halo substituents; or C1-4alkyl substituted with 1, 2 or 3 halo substituents; R^4b is -C(=O)-NR⁵R⁶; R² represents C1-4alkyl; R³ represents C_3-6cycloalkyl optionally substituted with one substituent selected from or X² represents O, NH or N-C_1-4alkyl; n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, n12, and n14 are each independently 1, 2 or 3; n13 is 0, 1 or 2; R¹², R¹³ and R¹⁶ are each independently selected from the group consisting of hydrogen, C_1-4alkyl and -S(=O)₂-C_1-4alkyl; R¹⁴, R¹⁵ and R¹⁷ are substituents on a carbon atom of (a-1), (a-2), (a-3), (a-4) or (a-5) and are each independently selected from the group consisting of hydrogen, C_1-4alkyl and halo; or R² and R³ are taken together to form together with the atoms to which they are attached (b-1) or (b-2):

; X³ represents CH or N; X⁴ represents CH or N; provided that at least one of X³ and X⁴ represents N; X⁵ represents CH or N; X⁶ represents CH or N; provided that at least one of X⁵ and X⁶ represents N; R¹⁰ and R¹¹ represent hydrogen or C1-4alkyl optionally substituted with 1, 2 or 3 halo substituents; R⁵, R⁶, R^7a, R^7b, R^8a, R^8b and R⁹ are each independently selected from the group consisting of hydrogen and C_1-4alkyl; and the pharmaceutically acceptable salts thereof. The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein R¹ represents C1-4alkyl or C3-6cycloalkyl; each optionally substituted with 1, 2 or 3 substituents each independently selected from halo and -OH; ring represents phenyl or pyridyl; R^x represents halo; n is 0, 1 or 2; Ar represents phenyl, thiazolyl, 1,2,4-thiadiazolyl, isothiazolyl, oxazolyl, pyrazolyl, pyridinonyl or pyridinyl; R^4a and R^4b are each independently selected from the group consisting of hydrogen; halo; C_1-4alkyl; -C(=O)-NR⁵R⁶; -O-C_1-4alkyl; -CN; -NR^7aR^8a; -C(=O)-O-R⁹; C_3-6cycloalkyl; -O-C_1-4alkyl substituted with 1, 2 or 3 halo substituents; or C1-4alkyl substituted with 1, 2 or 3 halo substituents; they are attached ; X³ represents CH or N; X⁴ represents CH or N; provided that at least one of X³ and X⁴ represents N; X⁵ represents CH or N; X⁶ represents CH or N; provided that at least one of X⁵ and X⁶ represents N; R¹⁰ and R¹¹ represent hydrogen or C1-4alkyl optionally substituted with 1, 2 or 3 halo substituents; R⁵, R⁶, R^7a, R^7b, R^8a, R^8b and R⁹ are each independently selected from the group consisting of hydrogen and C_1-4alkyl; and the pharmaceutically acceptable salts thereof. The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein R¹ represents C1-4alkyl or C3-6cycloalkyl; each optionally substituted with 1, 2 or 3 substituents each independently selected from halo and -OH; ring represents phenyl; n is 0; Ar represents phenyl, thiazolyl, 1,2,4-thiadiazolyl, isothiazolyl, oxazolyl, pyrazolyl, pyridinonyl or pyridinyl; R^4a and R^4b are each independently selected from the group consisting of hydrogen; halo; C1-4alkyl; -C(=O)-NR⁵R⁶; -O-C1-4alkyl; -CN; -NR^7aR^8a; -C(=O)-O-R⁹; C3-6cycloalkyl; -O-C1-4alkyl substituted with 1, 2 or 3 halo substituents; or C1-4alkyl substituted with 1, 2 or 3 halo substituents; R² represents C1-4alkyl; R³ represents C3-6cycloalkyl optionally substituted with one substituent selected from -NR^7bR^8b, 1-azetidinyl, 1-pyrrolidinyl and 1-piperidinyl; or R³ represents (a-1), (a-2), (a-3), (a-4) or (a-5): (a-1) (a-4) (_a-2) ^(a-5) (a-3) X¹ represents O, NH or N-C1-4alkyl; X² represents O, NH or N-C1-4alkyl; n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, n12, and n14 are each independently 1, 2 or 3; n13 is 0, 1 or 2; R¹², R¹³ and R¹⁶ are each independently selected from the group consisting of hydrogen, C1-4alkyl and -S(=O)2-C1-4alkyl; R¹⁴, R¹⁵ and R¹⁷ are substituents on a carbon atom of (a-1), (a-2), (a-3), (a-4) or (a-5) and are each independently selected from the group consisting of hydrogen, C1-4alkyl and halo; which they are attached ; X³ represents CH or N; X⁴ represents CH or N; provided that at least one of X³ and X⁴ represents N; X⁵ represents CH or N; X⁶ represents CH or N; provided that at least one of X⁵ and X⁶ represents N; R¹⁰ and R¹¹ represent hydrogen or C1-4alkyl optionally substituted with 1, 2 or 3 halo substituents; R⁵, R⁶, R^7a, R^7b, R^8a, R^8b and R⁹ are each independently selected from the group consisting of hydrogen and C_1-4alkyl; and the pharmaceutically acceptable salts thereof. The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein R¹ represents C1-4alkyl or C3-6cycloalkyl; each optionally substituted with 1, 2 or 3 substituents each independently selected from halo and -OH; ring represents phenyl; n is 0; Ar represents phenyl, thiazolyl, 1,2,4-thiadiazolyl, isothiazolyl, oxazolyl, pyrazolyl, pyridinonyl or pyridinyl; R^4a and R^4b are each independently selected from the group consisting of hydrogen; halo; C_1-4alkyl; -C(=O)-NR⁵R⁶; -O-C_1-4alkyl; -CN; -NR^7aR^8a; -C(=O)-O-R⁹; C_3-6cycloalkyl; -O-C_1-4alkyl substituted with 1, 2 or 3 halo substituents; or C1- substituted with 1, 2 or 3 halo substituents; or n1, n2, and n14 are each independently 1 or 2; n13 is 2; R¹⁶ represents hydrogen; R¹⁴ and R¹⁷ are substituents on a carbon atom of (a-1) or (a-3) and represent hydrogen; which they are attached ; X³ represents CH or N; X⁴ represents CH or N; provided that at least one of X³ and X⁴ represents N; X⁵ represents N; X⁶ represents CH or N; R¹⁰ and R¹¹ represent hydrogen or C1-4alkyl optionally substituted with 1, 2 or 3 halo substituents; R⁵, R⁶, R^7a, R^8a, and R⁹ are each independently selected from the group consisting of hydrogen and C1-4alkyl; and the pharmaceutically acceptable salts thereof. The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein R¹ represents C1-4alkyl optionally substituted with 1, 2 or 3 halo substituents; n Ar represents thiazolyl or pyridinyl; R^4a and R^4b are each independently selected from the group consisting of hydrogen; C1-4alkyl; -C(=O)-NR⁵R⁶; or C1- substituted with 1, 2 or 3 halo substituents; or n1, n2, and n14 are each independently 1 or 2; n13 is 2; R¹⁶ represents hydrogen; R¹⁴ and R¹⁷ are substituents on a carbon atom of (a-1) or (a-3) and represent hydrogen; or R² and R³ are taken together to form together with the atoms to which they are attached (b-1) or (b-2):

; X³ represents N; X⁴ represents N; X⁵ represents N; X⁶ represents N; R¹⁰ and R¹¹ represent C_1-4alkyl; R⁵ and R⁶ are hydrogen; and the pharmaceutically acceptable salts thereof. The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein R¹ represents CF₃; ring represents phenyl; n is 0; Ar represents thiazolyl or pyridinyl; R^4a represents hydrogen; R^4b represents -C(=O)-NR⁵R⁶; R² represents C_1-4alkyl; R³ represents (a-1) or (a-3): X¹ represents NH; n1 and n2 are 2; n14 is 1; n13 is 2; R¹⁶ represents hydrogen; R¹⁴ and R¹⁷ are substituents on a carbon atom of (a-1) or (a-3) and represent hydrogen; which they are attached ; X³ represents N; X⁴ represents N; X⁵ represents N; X⁶ represents N; R¹⁰ and R¹¹ represent C1-4alkyl; R⁵ and R⁶ are hydrogen; and the pharmaceutically acceptable salts thereof. The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein R¹ represents CF3; ring represents phenyl; n is 0; Ar represents thiazolyl or pyridinyl; R^4a represents hydrogen; R^4b -C(=O)-NR⁵R⁶; n1 and n2 are 2; n14 is 1; n13 is 2; R¹⁶ represents hydrogen; R¹⁴ and R¹⁷ are substituents on a carbon atom of (a-1) or (a-3) and represent hydrogen; R⁵ and R⁶ are hydrogen; and the pharmaceutically acceptable salts thereof. The present invention relates in particular to compounds of Formula (I) as defined herein, and the tautomers and the stereoisomeric forms thereof, wherein R¹ represents CF₃; ring represents phenyl; n is 0; Ar represents thiazolyl or pyridinyl; R^4a represents hydrogen; R^4b represents -C(=O)-NR⁵R⁶; they are attached ; X³ represents N; X⁴ represents N; X⁵ represents N; X⁶ represents N; R¹⁰ and R¹¹ represent C_1-4alkyl; R⁵ and R⁶ are hydrogen; 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 R¹ represents CF₃. 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 Ar represents pyridinyl. 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 Ar represents thiazolyl. 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 Ar represents 1-pyridinyl. 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^4a represents hydrogen; and R^4b represents -C(=O)-NR⁵R⁶. 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 C1-4alkyl. In an embodiment, the present invention relates to those compounds of Formula (I) and the pharmaceutically acceptable salts thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R³ represents (a-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 R² represents C1-4alkyl; and R³ represents (a-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 R³ represents (a-2). 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 C1-4alkyl; and R³ represents (a-3). 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 R³ represents (a-3). 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 R³ represents (a-4). 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 R³ represents (a-5). 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 R³ represents C_3-6cycloalkyl optionally substituted with one substituent selected from -NR^7bR^8b, 1-azetidinyl, 1-pyrrolidinyl and 1-piperidinyl. 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 and R³ are taken together form together with the atoms to which they are attached (b-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 R² and R³ are taken together form together with the atoms to which they are attached (b-2). 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 and R³ are taken together form together with the atoms to which they are attached (b-1), wherein X³ represents CH and X⁴ represents N. 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 and R³ are taken together form together with the atoms to which they are attached (b-1), wherein X³ represents N and X⁴ represents CH. 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 and R³ are taken together form together with the atoms to which they are attached (b-2), wherein X⁵ represents N and X⁶ represents CH. 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 and R³ are taken together. 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 and R³ are not taken together. 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 X³, X⁴, X⁵ and X⁶ represent N. 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 n1 and n2 represent 2; and n14 represents 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 n13 represents 2. 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 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 Ar together with the R^4a and R^4b substituents is selected from: N N . 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 . 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 wherein ring represents phenyl; n is 0. The will understand that compounds of Formula (I) wherein ring represents phenyl; and wherein n is 0; have the following Formula: . 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 wherein ring represents phenyl; n is 0; and wherein the stereochemistry of the CF₃ moiety in Formula . 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 wherein ring represents phenyl; n is 0; and wherein the stereochemistry of the CF3 moiety in Formula . 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, any pharmaceutically acceptable salts thereof. In an embodiment the compound of Formula (I) is selected from the group consisting of compounds 11, 13, 52, 96, 98, 100, 101, 104, and 125. In an embodiment the compound of Formula (I) is selected from the group consisting of compounds 11, 13, 52, 96, 98, 100, 101, 104, and 125; tautomers and stereoisomeric forms thereof, and any 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 any 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 11, 13, 52, 96, 98, 100, 101, 104, and 125. 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 11, 13, 52, 96, 98, 100, 101, 104, and 125; tautomers and stereoisomeric forms thereof, and any pharmaceutically acceptable salts 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 13 or a pharmaceutically acceptable salt thereof. In an embodiment the compound of Formula (I) is compound 52 or a pharmaceutically acceptable salt thereof. In an embodiment the compound of Formula (I) is compound 96 or a pharmaceutically acceptable salt thereof. In an embodiment the compound of Formula (I) is compound 98 or a pharmaceutically acceptable salt thereof. In an embodiment the compound of Formula (I) is compound 100 or a pharmaceutically acceptable salt thereof. In an embodiment the compound of Formula (I) is compound 101 or a pharmaceutically acceptable salt thereof. In an embodiment the compound of Formula (I) is compound 104 or a pharmaceutically acceptable salt thereof. In an embodiment the compound of Formula (I) is compound 125 or a pharmaceutically acceptable salt thereof. In (I) is or a pharmaceutically acceptable salt thereof. In (I) is or a pharmaceutically acceptable salt thereof. In an embodiment the compound of Formula (I) is or a pharmaceutically acceptable salt thereof. In (I) is or a pharmaceutically acceptable salt thereof. Formula (I) is or a pharmaceutically acceptable salt thereof. 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 (I) is or a pharmaceutically acceptable salt thereof. In (I) is or a pharmaceutically acceptable salt thereof. In (I) 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. For use in medicine, salts of compounds of Formula (I) refer to non-toxic “pharmaceutically acceptable salts.” Other salts may, however, be useful in the preparation of compounds of Formula (I) or of their pharmaceutically acceptable salt forms thereof. Suitable pharmaceutically acceptable salts of compounds of Formula (I) include acid addition salts that can, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as, hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of Formula (I) carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts such as, sodium or potassium salts; alkaline earth metal salts such as, calcium or magnesium salts; and salts formed with suitable organic ligands such as, quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-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, (+)-(1S)-camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy- ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, ^-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-1,5-disulfonic acid, 1- hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine, tromethamine, and zinc hydroxide. Embodiments of the present invention include prodrugs of compounds of Formula (I). In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound. Thus, in the methods of treating or preventing 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 well-known to a skilled person. 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, ¹¹C, ¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, the isotope is selected from the group of ²H, ³H, ¹¹C 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 MALT1 by a provided compound may be useful in treating or preventing, in particular treating, the non-limiting list of cancers described herein. The invention relates to compounds of Formula (I) for use as a medicament. The invention relates to compounds of Formula (I) for use in the inhibition of MALT1 activity. The invention relates to compounds of Formula (I) for use in the treatment of diseases mentioned herein. The invention relates to compounds of Formula (I) for the treatment or prevention, in particular for the treatment, of said diseases. The invention relates to compounds of Formula (I) for the treatment or prevention, in particular in the treatment, of MALT1 mediated diseases or conditions. The invention relates to compounds of Formula (I) for the manufacture of a medicament. The invention relates to compounds of Formula (I) for the manufacture of a medicament for the inhibition of MALT1. The invention relates to compounds of Formula (I) for the manufacture of a medicament for the treatment or prevention, in particular for the treatment, of any one of the disease conditions mentioned herein. The invention relates to compounds of Formula (I) for the manufacture of a medicament for the treatment of any one of the disease conditions mentioned herein. The invention relates to compounds of Formula (I) 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 warm- blooded animals, including humans, to suffer from any one of the diseases mentioned herein. GENERAL SYNTHETIC METHODS In this section, as in all other sections unless the context indicates otherwise, references to Formula (I) also include all other sub-groups and examples thereof as defined herein. 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. Abbreviations used in the Schemes below are clarified therein, or alternatively can be checked in 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 acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyl (Bn), benzyloxycarbonyl (CBz) and 9- fluorenylmethyleneoxycarbonyl (Fmoc). 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: 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). This reaction may be performed in the presence of a suitable base, such as, for example, Cs₂CO_3, K₃PO₄ or K₂CO₃. This reaction can be performed in a reaction-inert solvent, such as, for example, tBuOH, toluene, or dioxane. The reaction is typically performed in the presence of a catalyst system comprising a suitable catalyst such as tBuXPhos 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 should be understood by the person skilled in the art that in some instances a Compound of Formula (I) can be prepared via late stage functionalization reactions, such as for example the ones described in General Scheme 2 wherein an intermediate of Formula (IV) is converted into a compound of Formula (I) wherein R¹ represents CF₃, hereby named a compound of Formula (Ia). All other variables are defined according to the scope of the present invention. 2 In General Scheme 2, an intermediate of Formula (IV) is reacted with a trifluoromethyl radical source, such as for example trifluoromethanesulfinate (CF₃SO₂Na or Langlois reagent), under photoredox conditions, in the presence of a radical initiator such as for example ammonium persulfate, a photocatalyst such as for example (Ir[dF(CF3)ppy]2(dtbpy))PF6, and solvent, such as, for example, a mixture of DMSO and water. In general, an intermediate of Formula (IV) can be synthesized as depicted in General Scheme 3 below. In General Scheme 3, all other variables are defined according to the scope of the present invention. In General Scheme 3, the following reaction conditions typically apply: Step 1. An intermediate of Formula (IIa), where Pg is a Protecting Group such as for example trimethylsilylethoxymethyl (SEM), 2-tetrahydropyranyl (THP), or any other protecting group known to one skilled in the art, is reacted with an intermediate of Formula (III), under C-N cross-coupling conditions, to provide an intermediate of Formula (V). 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, tBuOH, toluene, or dioxane. The reaction is typically performed in the presence of a catalyst system comprising a suitable catalyst such as tBuXPhos 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 (V) is reacted with a suitable acid, such as, for instance, HCl at a concentration of 4M, in a suitable solvent such as for instance dioxane, at a suitable temperature, such as for instance room temperature, to provide an intermediate of Formula (VI). Step 3. An intermediate of Formula (VI) is reacted with a suitable aryl halide under C-N cross- coupling conditions, to provide an intermediate of Formula (IV). This reaction may be performed in the presence of a suitable base, such as, for example, Cs₂CO_3, K₃PO₄ or K₂CO₃. This reaction can be performed in a reaction-inert solvent, such as, for example, tBuOH, toluene, dioxane or DMSO. The reaction is typically performed in the presence of a catalyst system comprising a suitable catalyst such as tBuXPhos Pd G3, BrettPhos Pd G3, or SPhos Pd G4 and a ligand such as BrettPhos. Alternatively, the reaction can be performed in the presence of a Cu catalyst, such as for instance bis[(tetrabutylammonium iodide)copper(I) iodide], and in the presence of a ligand, such as for instance trans-N,N’-dimethylcyclohexane-1,2-diamine. 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 100 °C, under conventional heating or microwave irradiation. Alternatively, this step can be performed under SNAr (nucleophilic aromatic substitution) conditions. In this case, this reaction may be performed in the presence of a suitable base, such as, for example, LiOH. This reaction can be performed in a reaction-inert solvent, such as, for example acetonitrile, and in a suitable temperature range, such as for instance room temperature to 100 °C. An intermediate of Formula (II) can be synthesized according to General Scheme 4 below. All variables are defined according to the scope of the present invention.

General Scheme 4 In General Scheme 4 the following conditions typically apply: Step 1. Saponification. An intermediate of Formula (VII) is reacted with a base, such as for instance LiOH, in the presence of water, to provide an intermediate of Formula (VIII). This reaction is carried out in a solvent, such as for instance THF, and at a suitable temperature, such as for example room temperature. Step 2. An intermediate of Formula (VIII) is reacted with an azide source, such as, for instance, diphenyl azidophosphate or trimethylsilyl azide, to afford an intermediate of Formula (IX). This reaction can be performed in the presence of a base, such as, for instance triethyl amine. Preferably, this reaction is carried out in a suitable solvent, such as for instance t-butanol and at a suitable temperature, such as for example 110 °C. Step 3. An intermediate of Formula (IX) or (XIII) is reacted with HCl at a concentration for instance of either 4M or 5M, in a suitable solvent such as for instance dioxane, or THF, at a suitable temperature, such as for instance 0 ° C to 100 °C, to provide an intermediate of Formula (II). Alternatively, an intermediate of Formula (IX) is reacted with a Lewis acid, such as for example ZnBr2, in a suitable solvent such as for instance DCM, at a suitable temperature, such as for instance room temperature, to provide an intermediate of Formula (II). Step 4. An intermediate of Formula (X) where Hlg is a halogen such as for example F, Cl, Br or I, is reacted with a commercially available pyrazole of Formula (XI) where Hlg = Cl, Br, I, to provide an intermediate of Formula (XII). This reaction is performed in the presence of a base, such as for instance Cs₂CO₃, in a suitale solvent, such as for instance DMSO. Preferably, this reaction is performed at a suitable temperature, such as for instance 100 °C. Step 5. An intermediate of Formula (XII) is reacted with diphenylmethanimine to provide an intermediate of Formula (XIII). This reaction is carried out in the presence of a base, such as for example Cs₂CO₃, K₂CO₃, or NaOtBu. This reaction can be performed in a reaction-inert solvent, such as, for example, toluene, dioxane or DME. The reaction is typically performed in the presence of a catalyst system comprising a suitable catalyst such as Pd₂dba₃, Pd (OAc)₂, [Dicyclohexyl(2′,6′-diisopropoxy-2-biphenylyl)phosphine-κP](methanesulfonatato-κO)[2′- (methylamino-κN)-2-biphenylyl-κC²]palladium (RuPhos PdG1) or [dicyclohexyl[3-(1- methylethoxy)-2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]phosphine- κP](methanesulfonato-κO)[2′-(methylamino-κN)[1,1′-biphenyl]-2-yl-κC]-palladium (EPhos Pd G4) and a suitable ligand such as BINAP, DPPF, Xantphos, RuPhos or dicyclohexyl[3-(1- methylethoxy)-2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl] phosphine (EPhos). Preferably this reaction is performed at a suitable temperature range, such as for example 60 °to 120 °C. An intermediate of Formula (VII) can be synthesized according to General Scheme 5 below, where R⁵ = H or Boc; Pg1 refers to a suitable protecting group, such as for instance Boc or benzophenone and Hlg refers to a halogen, such as F, Cl, Br, I. All other variables are defined according to the scope of the present invention. It can be understood by the people skilled in the art that for certain R^4a and/or R^4b substituents, a functional group interconversion can occur at any of below described steps, using methods known to those skilled in the art.

General Scheme 5 In general Scheme 5, the following reaction conditions typically apply. Step 1. (a) An intermediate of Formula (X) is reacted with a hydrazine source (PG is protecting group), such as, for instance, tert-butyl carbazate, di-tert-butyl hydrazodicarboxylate, diphenylmethanimine, to provide an intermediate of Formula (XIV). This reaction can be performed in the presence of a base, such as, for instance Cs₂CO_3, K₃PO₄ or K₂CO₃ or NaOtBu. This reaction can be performed in a reaction-inert solvent, such as, for example, toluene, dioxane or DMF. The reaction is typically performed in the presence of a catalyst system comprising a suitable catalyst such as XPhos Pd G3, EPhos Pd G4, or Pd₂(dba)₃, palladium(II)(pi-cinnamyl) chloride dimer ([(Cinnamyl)PdCl]₂) and a ligand such as EPhos or Di(1-adamantyl)-2-morpholinophenylphosphine (MorDalphos). 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 120 °C, under conventional heating or microwave irradiation. (b) Alternatively, an intermediate of Formula (X) is first metalated by treatment with for example BuLi, or iPrMgCl, optionally in the presence of additives such as for instance LiCl and then treated with diterbutylazodicarboxylate (DTAD) to provide an intermediate of Formula (XIV), where R⁵ = PG = Boc. The reaction is carried out at a suitable temperature range, such as for example 0 °C to RT (room temperature). (c) Alternatively, an intermediate of Formula (XV) is reacted with DTAD in the presence of a Cu catalyst, such as for instance copper (II) acetate. The reaction is performed in a suitable solvent, such as for instance MeOH, and in a suitable temperature range, such as for instance RT to 60 °C. (d) Alternatively, an intermediate of Formula (XVI) is reacted with a nitrate source, such as for example sodium nitrate, in the presence of an acid, such as HCl, and in a suitable solvent, such as water. Subsequent treatment with a reducing agent, such as for instance tin(II) chloride dihydrate in concentrated HCl provides an intermediate of Formula (XIV). Step 2. An Intermediate of Formula (XIV), which can be commercially available or prepared according to Step 1a -d, is reacted with HCl at a concentration of for instance 4M, in a suitable solvent such as for instance dioxane, at a suitable temperature, such as for instance room temperature to 60 °C, to provide an intermediate of Formula XVII. Step 3. Alternatively, an intermediate of Formula (X) is reacted with hydrazine hydrate, to provide an intermediate of Formula (XVII). The reaction is carried out in a suitable solvent, such as for instance dioxane, ethanol, or methanol and at a suitable temperature range, such as 0 °C to 120 °C. Step 4. An Intermediate of Formula (XVII), which can be commercially available or prepared according to steps 1-2, is reacted with a dicarbonylic reagent of Formula (XVIII). This reaction is carried out in a suitable solvent, such as for example ethanol or ethyl acetate. The reaction can be optionally in the presence of an acid, such as for instance acetic acid, or a base, such as for example triethylamine. The reaction can be carried out at a temperature range, such as for example 0 °C to 85 °C. Alternatively, an intermediate of Formula (XIV) can also be reacted under these conditions, to provide an intermediate of Formula (VII). Alternatively compounds of formula (VII) can be synthesized by late-stage functionalization as described in general scheme 6, wherein R¹ = C_1-4alkyl or C_3-6cycloalkyl optionally substituted with OH. All other variables are defined according to the scope of the present invention. General Scheme 6 In general Scheme 6, the following reaction conditions typically apply. Step 1. An intermediate of Formula (XIV) can be reacted with 1-pyrazole carboxylate in the presence of a copper (I) source, such as for instance CuI, to provide an Intermediate of Formula (VIIa), where R¹ = H. This reaction is carried out in the presence of a base, such as for instance K₂CO₃, Cs₂CO₃ or NaOtBu, and in a suitable solvent, such as for instance DMF or 1,4-dioxane. The recation is carried out in a suitable temperature range, such as for instance 100 °C to 120 °C. Step 2. An intermediate of Formula (VIIa) is reacted with a suitable base, such as nBuLi, and an appropriate electrophilic source, such as for example a ketone, to provide an intermediate of Formula (VII). This reaction is carried out in a suitable solvent, such as for example THF, and at a suitable temperature range, such as for example -78 °C to -70 °C. In general, an intermediate of Formula III, wherein R² represents CH₃, hereby named an intermediate of Formula (III-a), can be synthesized as depicted in the General Scheme 7 below: General In General Scheme 7, R³ represents C_3-6cycloalkyl optionally substituted with one substituent selected from -NR^7bR^8b, 1-azetidinyl, 1-pyrrolidinyl and 1-piperidinyl; or R³ represents (a-1), (a-2), (a-3), (a-4) or (a-5) as defined in the scope of the present invention. In General Scheme 7, the following reaction conditions typically apply: Step 1: An intermediate of Formula (XIX) is reacted with a base, such as, NaH, LDA, or the like, typically in a polar solvent, such as for example DMF, in a suitable temperature range such as for example between room temperature and the boiling point of the solvent, and in the presence of a methylating reagent, such as for example MeI. Step 2: An intermediate of Formula (XX) is reacted with an acid, typically in an aprotic solvent, such as for example dioxane, in a suitable temperature range such as for example 0 ^°C to room temperature. Step 3: An intermediate of Formula (XXI) is reacted with an appropriate acylating reagent R⁴-C(O)-X, where X is either Cl or Br, in the presence of an appropriate base such as for example DIPEA, typically in an aprotic solvent such as for example DCM, in a suitable temperature range such as for example 0 ^°C to room temperature. An intermediate of Formula (III), wherein R² and R³ are taken together to form together with the atoms to which they are attached (b-1) or (b-2) as defined in Formula (I), hereby named an intermediate of Formula (III-b), can be synthesized as depicted in the General Scheme 8 below: In General Scheme 8, the general the following reaction conditions typically apply: Step 1.1-(4-bromophenyl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (Formula (XXII)) is reacted with an intermediate of Formula (XXIII) to provide an intermediate of Formula (XXIV). This reaction is typically carried out in presence of a base, such as for example trithethylamine, DIPEA or K₂CO₃, in a suitable solvent, such as for instance DCE or THF, and in a suitable temperature range, such as for instance room temperature to 75 °C. Step 2. An intermediate of Formula XXIV is reacted with a suiatble oxidant system, such as iodine in the presence of a base, such as NaHCO₃, or ruthenium (IV) oxide hydrate and sodium periodate, to provide an intermediate of Formula (III-b). The reaction is typically performed in a solvent or a mixture of solvents such as for example DMSO, ACN, or CHCl₃ and water, and at a suitable temperature, such as for instance 0 °C to room temperature. Alternatively, an intermediate of Formula (III), where R² and R³ are taken together to form together with the atoms to which they are attached (b-2) as defined in Formula (I) but with both X⁵ and X⁶ representing N, hereby named an intermediate of Formula (III-c), can be synthesized according to the General Scheme 9 below. In General Scheme 9 the following reaction conditions typically apply: Step 1. An intermediate of Formula (XXII) is reacted with t-butyl-N-(2aminoethyl)carbamate to provide an intermediate of Formula (XXV). This reaction is typically performed in a solvent such as for example n-hexane, in the presence of a base, such as for example K₂CO₃, and at a suitable temperature, such as for example 70 °C. Step 2. An intermediate of Formula (XXV) is reacted with ethyl oxalylchloride to afford an intermediate of Formula (XXVI). This reaction is typically carried out in the presence of a base such as for example triethylamine, in a suitable solvent, such as for example DCM, and at a suitable temperature, such as for instance 0 °C. Step 3. An intermediate of Formula (XXVI) is reacted with an acid, typically in an aprotic solvent, such as for example ethyl acetate, in a suitable temperature range such as for example -50 ^°C to room temperature. Step 4 An intermediate of Formula (XXVII) is reacted with a base, such as for instance triethylamine, in a suitable solvent, such as for instance DCM, and at a suitable temperature, such as for instance room temperature, to afford an intermediate of Formula (XXVIII). Step 5. An intermediate of Formula (XXVIII) is reacted with a thiolating reagent, such as for instance phosphorous pentasulfide (P₂S₅), typically in a solvent such as for example THF, in a suitable temperature range, such as for example room temperature to 55 °C, to afford an intermediate of Formula (XXIX). Step 6. An intermediate of Formula (XXIX) is reacted with an appropriate acyl hydrazine source (XXX) to provide and intermediate of Formula (III). This reaction is typically performed in a solvent such as for instance nBuOH, and at a suitable temperature range, such as for example room temperature to 120 °C. 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 preparation’s methods. Suitable amino-protecting groups include but are not limited to t- butoxycarbonyl (Boc), and acetyl. Suitable alcohol protecting groups include t- butyldimethylsilyl or benzyl. 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. 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. Abbreviation Meaning °C Degrees ACN or CH₃CN Acetonitrile AcOH Acetic acid Ag₂CO₃ Silver carbonate Aq or aq. Aqueous BINAP (±)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene Bn Benzyl Boc tert-Butyloxycarbonyl Boc2O Di-tert-butyl dicarbonate Abbreviation Meaning 2-(Dicyclohexylphosphino)3,6-dimethoxy-2’,4’,6’- BrettPhos triisopropyl-1,1’-biphenyl [2-(Dicyclohexylphosphino)3,6-dimethoxy-2’,4’,6’- BrettPhos Pd G3 triisopropyl-1,1’-biphenyl]palladium(II) methanesulfonate Celite^® Diatomaceous earth Co Compound Co. No. Compound Number CHCl₃ Chloroform CF3SO2Na Sodium trifluoromethanesulfonate Co₂(CO)₈ Cobalt carbonyl CO2 Carbon dioxide Cs₂CO₃ Cesium carbonate CuI Copper iodide DAST (Diethylamino)sulfur trifluoride DCE or EDC Dichloroethane DCM Dichloromethane DIBAL-H Diisobutylaluminium hydride DIPEA N,N-Diisopropylethylamine DMA N,N-Dimethylacetamide DMAP 4-(Dimethylamino)pyridine DME 1,2-Dimethoxyethane DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide DPPF 1,1′-Ferrocenediyl-bis(diphenylphosphine) dicyclohexyl[3-(1-methylethoxy)-2',4',6'-tris(1- Ephos methylethyl)[1,1'-biphenyl]-2-yl]phosphine Ephos Pd G4 [dicyclohexyl[3-(1-methylethoxy)-2′,4′,6′-tris(1- methylethyl)[1,1′-biphenyl]-2-yl]phosphine- Abbreviation Meaning κP](methanesulfonato-κO)[2′-(methylamino-κN)[1,1′- biphenyl]-2-yl-κC]-palladium equiv Equivalent(s) Et2O Ethyl ether Et₃N or TEA Triethylamine EtOAc Ethyl acetate EtOH Ethanol h Hour(s) H₂ Hydrogen H2O Water 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate, N- HATU [(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1- ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide HCl Hydrochloric acid HPLC High performance liquid chromatography iPrNH2 Isopropylamine IPA or iPrOH Isopropanol K2CO3 Potassium carbonate KOH Potassium hydroxide LAH, LiAlH4 Lithium Aluminium Hydride LC Liquid chromatography LDA Lithium diisopropylamide LED Light-emitting diode LCMS Liquid chromatography- Mass spectrometry LiOH Lithium hydroxide Me Methyl Abbreviation Meaning MeI methyl iodide MeMgBr Methyl magnesium bromide MeOH Methanol MP Melting point Mor-DalPhos Di(1-adamantyl)-2-morpholinophenylphosphine MgSO₄ Magnesium sulphate MTBE Methyl tert-butyl ether MW Molecular weight µW Microwaves N₂ Nitrogen n-BuOH 1-butanol Na₂S₂O₃ Sodium sulfate NaBH4 Sodium borohydride NaH Sodium hydride NaHCO3 Sodium bicarbonate NaI Sodium iodide NaIO4 Sodium periodate NaOH Sodium hydroxide NaOtBu Sodium tert-butoxide NH₄Cl Ammonium chloride NH4HCO3 Ammonium bicarbonate NMP 1-Methyl-2-pyrrolidone NMR Nuclear magnetic resonance P₂S₅ Di-Phosphorus pentasulfide PE Petroleum ether Pd₂dba₃ Tris(dibenzylideneacetone)dipalladium(0) Pd/C Palladium on carbon Abbreviation Meaning Pd(OAc)2 Palladium acetate Pd(OH)₂ Palladium hydroxide on carbon Prep-HPLC Preparative high performance liquid chromatography Quant. Quantitative rac Racemic RP Reversed phase Rochelle's salt Potassium sodium tartrate tetrahydrate rt or RT Room temperature Rt Retention time RuCl₃.H₂O Ruthenium(III) chloride hydrate RuPhos 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl Chloro-(2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′- RuPhos Pd G1 biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) - methyl- tert-butyl ether adduct Sat or sat. Saturated SFC Supercritical fluid chromatography SiliaMetS DMT Dimercaptotriazine-functionalized silica gel SiOH Tris(trimethylsilyl)silanol SnCl Tin chloride SPhos 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl _{SPhos Pd G4} [(2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl)(2'- methylamino-1,1'-biphenyl-2-yl)] palladium(II) methanesulfonate t-BuOH or tBuOH Tert-butanol (tert-butyl alcohol) _{tBuXPhos Pd G3} [(2-Di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′- biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate TBAF Tetra-N-butylammonium fluoride Abbreviation Meaning TEMPO 2,2,6,6-Tetramethylpiperidine 1-oxyl, 2,2,6,6-Tetramethyl- 1-piperidinyloxy, free radical TFA Trifluoroacetic acid THF Tetrahydrofuran TMSCl Chlorotrimethylsilane UV Ultraviolet XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene Y Yield 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 ‘HCl salt’ without indication of the number of equivalents of HCl, this means that the number of equivalents of HCl 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. 1 A solution of thiazol-2-ylhydrazine [30216-51-4] (1.85 g, 15.95 mmol) in EtOH (100 mL) was stirred at room temperature for 15 minutes, then AcOH (1.82 ml, 31.9 mmol) and ethyl 2- (ehtoxymethylene)-4,4,4-trifluoro-3-oxobutyrate [571-55-1] (3.09 mL, 15.95 mmol) were added and mixture was stirred at room temperature for 1 h. The crude was poured into NaHCO3 (aq. sat) and extracted with EtOAc. Combined organic layers were washed with water, dried over dry MgSO4, solids were filtered, and the solvent concentrated in vacuo. The crude was purified by flash column chromatography (Heptane:EtOAc 100:0 to 50:50) to yield Intermediate 1 (2.2 g, 47%) as a white solid. 2 To a solution of Intermediate 1 (2.2 g, 7.55 mmol) in THF (22.5 mL), was added dropwise a solution of lithium hydroxide (362 mg, 15.12 mmol) in water (10.8 mL). The reaction was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc and water. The organic layer was separated, and the aqueous layer was added with DCM and cooled down to 0 °C. The mixture was treated with HCl (1N, dropwise) until pH 2-3. A white solid was formed and filtered to afford Intermediate 2 (1.16 g, 58%). To a solution of Intermediate 2 (1.06 g, 4.03 mmol) in toluene (40 mL) was added diphenyl azidophosphate [26386-88-9] (1.04 ml, 4.83 mmol), triethylamine (0.84 ml, 6.04 mmol) and tert-butanol (40 mL) and the mixture was heated to 110 °C for 16 hours. The mixture was diluted with water and extracted with EtOAc (three times). The combined organic layer was concentrated in vacuo, and the residue was purified by silica gel column chromatography (Heptane:EtOAc form 100:0 to 50:50) to give Intermediate 3 (1.2 g, 89%) as a white crystalline solid. To a solution of Intermediate 3 (50 mg, 0.15 mmol) in dioxane (1.5 mL) at 0 °C, was added HCl (4M in dioxane, 0.8 mL). The mixture was stirred for 24 hours at room temperature. The residue was diluted with NaHCO3 (aq. sat) and extracted with DCM (3 times). The combined organic layer was concentrated in vacuum to afford Intermediate 4 (40 mg, quantitative yield). Isopropylmagnesium chloride, lithium chloride complex solution (1.9 mL, 1.3 M in THF, 2.46 mmol) was added dropwise to a stirred solution of 3-bromo-1-methyl-1H-pyrazole [151049- 87-5] (306 mg, 1.9 mmol) in dry THF (3.1 mL) at 0 °C, under nitrogen. The mixture was stirred at room temperature for 30 minutes. A solution of di-tert-butyl azodicarboxylate [870-50-8] (590.82 mg, 2.57 mmol) in dry THF (1.1 mL) under nitrogen was added dropwise, and the mixture was stirred at room temperature overnight. The mixture was quenched with NH4Cl (sat.) and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over MgSO4, filtered and the solvent was removed in vacuo. The crude was purified by flash column chromatography (DCM:MeOH 100:0 to 98:2) to afford Intermediate 5 (237 mg, 20% yield) as a yellow residue. HCl (4 M in dioxane; 0.74 mL, 2.97 mmol) was added to a stirred solution of Intermediate 5 (231.9 mg, 0.74 mmol) in EtOH (2.2 mL) at room temperature and the mixture was stirred for 18 h. Ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate [571-55-1] (0.19 mL, 1.24 g/mL, 0.97 mmol) was added, and the mixture was stirred at 80 °C for 1 h. Solvents were evaporated under vacuo and the crude was first purified by flash column chromatography (100% DCM) then by Preparative HPLC to give Intermediate 6 (50 mg, 23.4% yield) as a yellow residue. 7 Intermediate 7 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 6 (50 mg, 0.17 mmol) instead of Intermediate 1, to give Intermediate 7 (59.6 mg, quantitative yield) as an off-yellow solid that was used in the following step without further purification. Intermediate 8 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 7 (50 mg, 0.19 mmol) instead of Intermediate 2, to give Intermediate 8 (74.6 mg, 90% yield) as a yellow residue that was used in the following step without further purification. Intermediate 9 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 8 (70 mg, 0.16 mmol) instead of Intermediate 3, to give Intermediate 9 (39.9 mg, 86% yield) as a yellow residue. Intermediate 10 was prepared by an analogous reaction protocol as Intermediate 1, starting from 3-chloro-2-hydrazineylpyridine [22841-92-5] (1.79 g, 12.5 mmol), to give Intermediate 10 (1.1 g, 80% yield) as a yellow oil. 11 Intermediate 11 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 10 (1.1 g, 3.4 mmol) instead of Intermediate 1, to give Intermediate 11 (1.0 g, 96.5% yield) as a white solid. 12 Intermediate 12 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 11 (0.9 g, 3.1 mmol) instead of Intermediate 2, to give Intermediate 12 (0.6 g, 53% yield) as a yellow solid. Intermediate 13 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 12 (0.2 g, 0.5 mmol) instead of Intermediate 3, to give Intermediate 13 (0.12 g, 72% yield) as a yellow oil. 14 5-Chloropyridin-3-amine [22353-34-0] (5.00 g, 38.9 mmol) was dissolved in 6 N HCl (98 mL, 589 mmol) and cooled with an ice bath. A solution of sodium nitrate [7632-00-0] (2.68 g, 38.9 mmol) in water (105 mL) was added dropwise. The reaction was stirred for 30 minutes under N2 atmosphere, then a solution of SnCl dihydrate [10025-69-1] (21.9 g, 97.2 mmol) dissolved in 6 N HCl (98 mL, 589 mmol) was added slowly, and the reaction was stirred for 1.5 hours at 0 °C. The reaction was quenched by dropwise addition of 40% aqueous KOH solution (150 ml) until the pH was adjusted to 12. The reaction was extracted three times with ethyl acetate. The combined organic layers were washed once with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give Intermediate 14 (5.1 g, 76 % yield) as red solid. Intermediate 15 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 14 (0.5 g, 3.48 mmol), to give Intermediate 15 (0.89 g, 80% yield) as a white solid. Intermediate 16 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 15 (7.78 g, 24.3 mmol), to give Intermediate 16 (6.92 g, 98% yield). 17 Intermediate 17 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 16 (6.92 g, 23.7 mmol), to give Intermediate 17 (6.04 g, 70% yield) as a white solid. Intermediate 18 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 17 (6.72 g, 18.5 mmol), to give Intermediate 18 (3.55 g, 71% yield) as a yellow solid. Intermediate 19 was prepared by an analogous reaction protocol as Intermediate 1, starting from 5-fluoro-2-hydrazinylpyridine [145934-90-3] (1.80 g, 9.91 mmol), to give Intermediate 19 (2.34 g, 78% yield) as a yellow oil. Intermediate 20 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 19 (2.62 g, 8.64 mmol), to give Intermediate 20 (2.22 g, 93% yield) as an off- white solid. 21 Intermediate 21 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 20 (2.22 g, 8.07 mmol), using trimethylsilylazide [4648-54-8] (2.18 ml, 24.2 mmol) instead of diphenyl azidophosphate [26386-88-9], to give Intermediate 21 (2.26 g, 74% yield) as white solid. 22 Intermediate 22 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 21 (2.03 g, 5.3 mmol), to give Intermediate 22 (1.38 g, quantitative yield) as a brown oil. Intermediate 23 was prepared by an analogous reaction protocol as Intermediate 1, starting from 3-fluoro-2-hydrazininylpyridine [887266-57-1] (3.06 mL, 15.7 mmol), to give Intermediate 23 (3.35 g, 70% yield) as a yellow solid. 24 Intermediate 24 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 23 (3.35 g, 11.1 mmol), to give Intermediate 24 (2.9 g, 96% yield). Intermediate 25 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 24 (2.9 g, 10.5 mmol), to give Intermediate 25 (0.88 g, 17% yield) as a yellow oil. Intermediate 26 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 25 (883 mg, 1.79 mmol), to give Intermediate 26 (255 mg, 58%) as a white solid. 27 To a solution of 2-chloropyridine [109-09-1] (1.0 g, 8.81 mmol) in dioxane (20 ml), was added hydrazine monohydrate [7803-57-8] (8.54 ml, 176.14 mmol). The mixture was stirred at 110 ºC overweekend. The solvent was removed, the crude was dissolved in DCM, washed with NaHCO3 (sat. solution), dried over MgSO4, filtered, and concentrated under reduced pressure to give Intermediate 27 (0.961 g, 84% yield). Intermediate 28 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 27 (10.9 g, 0.1 mol), to give Intermediate 28 (30.0 g, quantitative yield). I i 2 Intermediate 29 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 28 (10.0 g, 35.1 mmol), to give Intermediate 29 (7.7 g, 85% yield). Intermediate 30 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 29 (2.0 g, 7.78 mmol), to give Intermediate 30 (2.80 g, quantitative yield) as a white solid. Intermediate 31 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 30 (0.5 g, 1.46 mmol), to give Intermediate 31 (0.32 g, 96%) as a yellow solid. Intermediate 32 was prepared by an analogous reaction protocol as Intermediate 1, starting from 3-hydrazineylpyridine hydrochloride [30216-52-5] (1.6 g, 11.0 mmol), to give Intermediate 32 (1.0 g, 70% yield) as a brown oil. Intermediate 33 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 32 (1.0 g, 3.51 mmol), to give Intermediate 33 (0.70 g, 78% yield) as a yellow solid. Intermediate 34 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 33 (0.65 g, 2.53 mmol), to give Intermediate 34 (0.40 g, 48% yield) as a brown oil. Intermediate 35 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 34 (0.15 g, 0.457 mmol), to give Intermediate 35 (90 mg, 86% yield) as a brown oil. Intermediate 36 was prepared by an analogous reaction protocol as Intermediate 1, starting from 2-chloro-6-hydrazineylpyridine [5193-03-3] (2.2 g, 15.0 mmol), to give Intermediate 36 (3.5 g, 88% yield) as a yellow oil. To a mixture of Interemediate 36 (2.0 g, 6.3 mmol) and palladium (II) acetate [3375-31-3] (140.5 mg, 0.62 mmol) in 1,4-dioxane (20 mL) were added benzyl carbamate (1.42 mg, 9.38 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene [161265-03-8] (362.01 mg, 0.63 mmol) and cesium carbonate (4.08 g, 12.51 mmol). The resulting solution was stirred at 100 ºC for 3h. EtOAc (100 mL) and water (100 mL) were added. After separation, the aqueous phase was extracted with EtOAc (twice 150 mL). The combined organic phases were washed with brine (2x 300 mL), dried with Na2SO4, filtered, and concentrated. The obtained residue was purified (Eluent: Petroleum Ether:EtOAc from 100:0 to 0:100) to give Intermediate 37 (1.7 g, 58% yield) as a brown oil. Intermediate 38 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 37 (0.5 g, 1.15 mmol), to give Intermediate 38 (0.12 mg, 26% yield) as a yellow oil. Intermediate 39 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 38 (0.12 g, 0.3 mmol), to give Intermediate 39 (0.06 g, 43% yield) as a white solid. Intermediate 40 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 39 (60 mg, 0.13 mmol), to give Intermediate 40 (45 mg, 73% yield) as a yellow oil. 41 A solution of hydrazine monohydrate [10217-52-4] (5.27 mL, 70.4 mmol) in ethanol (50 mL) was added dropwise to a stirred solution of 3-fluoro-2-nitropyridine [54231-35-5] (5.00 g, 35.2 mmol) in ethanol (30 mL) at 0 °C for 1 hour. The reaction mixture was filtrated and washed with Ethanol/H₂O (50/50) to give Intermediate 41 (5.7 g, quantitative yield) as orange solid. Intermediate 42 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 41 (5.7 g, 37.0 mmol), to give Intermediate 42 (2.8 g, 23% yield) as a yellow solid. Intermediate 43 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 42 (2.61 g, 7.9 mmol), to give Intermediate 43 (2.3 g, 96% yield). 44 Intermediate 44 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 43 (2.5 g, 8.3 mmol), to give Intermediate 44 (1.75 g, 57% yield) as a yellow oil. Intermediate 45 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 44 (1.72 g, 4.61 mmol), to give Intermediate 45 (1.12 g, 89% yield) as an orange solid. Under nitrogen atmosphere, DAST [38078-09-0] (1.24 mL, 9.40 mmol) was added to a solution of 6-Chloro-3-fluoropicolinaldehyde [884494-77-3] (1.00 g, 6.27 mmol) in DCM (20 mL). The mixture was stirred at 0 °C for 1 hour, then warmed up to room temperature and stirred for 2 hours. Water and DCM were added, and the reaction mixture was basified with a saturated aqueous solution of NaHCO3. The reaction mixture was extracted with DCM (2 times), the organic layer was washed with brine and dried under vacuo to give Intermediate 46 (0.97 g, 85% yield) as a brown oil. A degassed mixture of [Pd(1-phenylallyl)Cl]₂ [12131-44-1] (285 mg, 0.55 mmol) and Mor- DalPhos [1237588-12-3] (511 mg, 1.10 mmol) in dry 1,4-dioxane (42 mL) was stirred at room temperature under nitrogen for 10 min. Then, Intermediate 46 (2.0 g, 11.0 mmol) and sodium tert-butoxide [865-48-5] (2.12 g, 22.0 mmol) were added, and the mixture was degassed (3 times). The resulting mixture was stirred at room temperature under nitrogen for 5 minutes, tert-butyl carbazate [870-46-2] (2.91 g, 22.0 mmol) was added and the mixture was degassed (3 times). The reaction mixture was stirred at 120 °C for 3 h. Water and DCM were added, and the reaction mixture was extracted with DCM (3 times). The layers were separated, and the organic phase was dried over MgSO₄, filtered and the organic solvents were evaporated under vacuo. The crude product was purified by normal phase (Eluent: Heptane:EtOAc from 100:0 to 60:40) to give Intermediate 47 (1.31 g, 43% yield) as a brown oil. Intermediate 47 (1.15 g, 4.15 mmol) was dissolved in EtOH (11 mL) and treated with HCl conc. (11 mL, 133 mmol). The mixture was stirred for 10 min at 50 °C. The reaction mixture was concentrated to dryness to give Intermediate 48 (0.80 g, quantitative yield) as an orange solid. Intermediate 49 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 48 (0.8 g, 4.53 mmol), to give Intermediate 49 (1.0 g, 63% yield) as an orange oil. Intermediate 50 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 49 (1.01 g, 2.86 mmol), to give Intermediate 50 (0.84 g, 90% yield) as a yellow solid. Intermediate 51 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 50 (0.84 g, 2.57 mmol), to give Intermediate 51 (1.32 g, quantitative yield) as a brown solid. Intermediate 52 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 51 (1.32 g, 3.16 mmol), to give Intermediate 52 (0.58 g, 62% yield) as a white solid. Hydrazine monohydrate [7803-57-8] (6.00 mL, 193 mmol) was added to a solution of 2-chloro- 6-trifluoromethylpyridine [39890-95-4] (5.00 g, 27.5 mmol) in EtOH (16 mL) and the reaction was stirred at 80 °C for 6 h. After the cooling down to room temperature, the mixture was evaporated in vacuo to give Intermediate 53 (3.06 g, 52% yield) as a yellow solid. Intermediate 54 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 53 (3.1 g, 17.3 mmol), to give Intermediate 54 (4.5 g, 74% yield) as a yellow solid. Intermediate 55 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 54 (5.1 g, 14.47 mmol), to give Intermediate 55 (4.62 g, 98% yield) as a yellow solid. Intermediate 56 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 55 (4.62 g, 14.21 mmol), to give Intermediate 56 (4.28 g, 76% yield) as a yellow solid. Intermediate 57 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 56 (2.0 g, 4.79 mmol), to give Intermediate 57 (1.46 g, quantitative yield) as a yellow oil. Hydrazine monohydrate [7803-57-8] (1.72 mL, 35.4 mmol) was added to a solution of 2-chloro- 6-(trifluoromethoxy)pyridine [1221171-70-5] (1.00 g, 5.06 mmol) in EtOH (3 mL) and the reaction was stirred at 120 °C for 18 h. After the cooling down to rt, the mixture was evaporated in vacuo to give Intermediate 58 (1.28 g, purity 50%) as an orange solid. Intermediate 59 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 58 (1.28 g, purity 50%, 3.31 mmol), to give Intermediate 59 (0.48 g, 39% yield) as a yellow solid. Intermediate 60 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 59 (0.47 g, 1.27 mmol), to give Intermediate 60 (0.42 g, 97% yield) as a white solid. F Intermediate 61 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 60 (0.42 g, 1.24 mmol), to give Intermediate 61 (0.17 g, 34% yield). Intermediate 62 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 61 (0.17 g, 0.42 mmol), to give Intermediate 62 (0.13 g, 98% yield) as a yellow solid. Copper (II) acetate [142-71-2] (245 mg, 1.35 mmol) was added to a mixture of 5-cyano-3- pyridinylboronic acid [497147-93-0] (2.00 g, 13.5 mmol) and di-tert-butyl azodicarboxylate [870-50-8] (3.11 g, 13.5 mmol) in MeOH (10 mL) at room temperature. The reaction mixture was heated at 60 °C for 1 h. After cooling down to room temperature, the mixture was evaporated in vacuo. The residue was solubilized in EtOAc and a 10% aqueous solution of NaHCO₃ was added. The mixture was extracted with EtOAc (3 times). The organics layers were combined, washed with brine, dried over MgSO₄, filtered and the solvent was evaporated in vacuo. The crude was purified by flash column chromatography (Eluent: Heptane/EtOAc from 80:20 to 70:30). The fractions containing compound were combined and evaporated in vacuo to give Intermediate 63 (2.32 g, 51% yield) as a white solid. HCl (4 M in 1,4-dioxane) (13.9 mL, 55.5 mmol) was added dropwise to a solution of Intermediate 63 (2.32 g, 6.94 mmol) in 1,4-dioxane (14.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 50 h. Additional HCl (4M in 1,4-dioxane) (20 mL, 80 mmol) was added dropwise and the suspension was stirred at room temperature for 6 h. The suspension was filtered, and the precipitate was washed with diethylether and dried in vacuo to give Intermediate 64 (1.35 g, 94% yield) as a yellow solid. Intermediate 65 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 64 (1.90 g, 7.91 mmol), to give Intermediate 65 (1.38 g, 56% yield) as an off- white solid. Intermediate 66 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 65 (0.85 g, 2.73 mmol), to give Intermediate 66 (0.80 g, 88% yield) as a white solid. Intermediate 67 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 66 (0.79 g, 2.38 mmol), to give Intermediate 67 (0.32 g, 65% purity, 25% yield). Intermediate 68 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 67 (0.23 g, 0.59 mmol), to give Intermediate 68 (0.11 g, 73% yield) as a white solid. Intermediate 69 was prepared by an analogous reaction protocol as Intermediate 1, starting from 3-bromo-2-hydrazineylpyridine [54231-41-3] (3.0 g, 15.95 mmol), to give Intermediate 69 (3.0 g, 51% yield) as a white solid. Intermediate 70 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 69 (3.0 g, 8.24 mmol), to give Intermediate 70 (2.2 g, 78% yield) as a white solid. 71 Intermediate 71 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 70 (2.2 g, 6.55 mmol), to give Intermediate 71 (1.6 g, 60% yield). 72 To a solution of Intermediate 71 (0.900 g, 2.210 mmol), dicyanozinc (389.4 mg, 3.315 mmol) and Pd(PPh3)4 (255.4 mg, 0.221 mmol) was added NMP (20 mL). The resulting mixture was maintained under nitrogen and stirred at 110 °C overnight. After cooling down to room temperature, the reaction was quenched with water (50 mL). The resulting mixture was extracted with EtOAc (3 times). The organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by silica gel chromatography (Eluent: petroleum ether/EtOAc 100:0 to 60:40) to give Intermediate 72 (0.31 g, 39% yield) as a white solid. Intermediate 73 Intermediate 73 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 72 (0.12 g, 0.34 mmol), to give Intermediate 73 (0.085 g, 99% yield). Intermediate 74 was prepared by an analogous reaction protocol as Intermediate 2, starting from Ethyl 2-(4-fluorophenyl)-3-(trifluoromethyl)pyrazole-4-carboxylate [175137-38-9] (1.0 g, 3.31 mmol), to give Intermediate 74 (1.15 g, quantitative yield) as a brown oil. Intermediate 75 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 74 (0.30 g, 1.09 mmol), to give Intermediate 75 (0.24 g, 64% yield). Intermediate 76 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 75 (0.24 g, 0.70 mmol), to give Intermediate 76 (0.17 g, 98% yield) as a yellow oil. Intermediate 77 was prepared by an analogous reaction protocol as Intermediate 63, starting from 2-fluorophenylboronic acid [1993-03-9] (2.0 g, 14.29 mmol), to give Intermediate 77 (4.37 g, 94% yield) as a colourless oil. Intermediate 78 was prepared by an analogous reaction protocol as Intermediate 64, starting from Intermediate 77 (4.37 g, 13.39 mmol), to give Intermediate 78 (2.40 g, quantitative yield) as a white solid. Intermediate 79 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 78 (2.4 g, 14.76 mmol), to give Intermediate 79 (3.0 g, 68% yield). Intermediate 80 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 79 (3.04 g, 10.06 mmol), to give Intermediate 80 (2.63 g, 95% yield) as a yellow solid. Intermediate 81 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 80 (1.95 g, 7.12 mmol), to give Intermediate 81 (1.26 g, 46% yield) as a yellow oil. Intermediate 82 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 81 (1.25 g, 3.27 mmol), to give Intermediate 82 (0.71 g, 89% yield) as a white solid. 83 To a solution of 2-Bromo-6-difluoromethylpyridine [872365-91-8] (2.47 mL, 20.2 mmol) in EtOH (9.9 mL) under nitrogen was added hydrazine hydrate 80% (18.5 mL, 302.4 mmol), and the reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under vacuum to give Intermediate 83 (5.60 g, quantitative yield) as a yellow solid. Intermediate 84 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 83 (0.35 g, 1.46 mmol), to give Intermediate 84 (0.51 g, quantitative yield). Intermediate 85 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 84 (5.95 g, 17.75 mmol), to give Intermediate 85 (4.43 g, 81% yield) as a yellow solid. Intermediate 86 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 85 (0.50 g, 1.63 mmol), to give Intermediate 86 (0.33 g, 54% yield) as an orange oil. Intermediate 87 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 86 (5.38 g, 14.22 mmol), to give Intermediate 87 (3.82 g, 95% yield) as an orange solid. In a sealed tube under nitrogen, a mixture of [Pd(1-phenylallyl)Cl]2 [12131-44-1] (413 mg, 0.798 mmol) and Mor-DalPhos [1237588-12-3] (740 mg, 1.60 mmol) in dry 1,4-dioxane (60 mL) was degassed 3 times. The solution was stirred at room temperature under nitrogen for 10 min. Then, 2-bromo-6-methoxypyridine [40473-07-2] (3.0 g, 16.0 mmol) and sodium tert- butoxide (3.07 g, 31.9 mmol) were added, and the mixture was degassed (3 times). The resulting mixture was stirred at room temperature under nitrogen for 5 min, tert-butyl carbazate [870-46- 2] (4.22 g, 31.9 mmol) was added and the mixture was degassed again (3 times). The reaction mixture was stirred at 120 °C for 5 h. Water and EtOAc were added. The layers were separated then the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give a residue which was purified by flash chromatography (Mobile phase: Heptane:EtOAc from 100:0 to 70:30) to give Intermediate 88 (1.87 g, 42% yield) as a brown oil. Intermediate 88 (1.87 g, 6.68 mmol) was dissolved in EtOH (20 mL) and treated with HCl conc. [7647-01-0] (17.9 mL, 214 mmol) then the mixture was stirred for 10 min at 50 °C. The reaction mixture was concentrated to dryness to give Intermediate 89 (1.4 g, quantitative yield) as an orange solid. Intermediate 90 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 89 (1.4 g, 6.70 mmol), to give Intermediate 90 (1.22 g, 58% yield) as a yellow oil. Intermediate 91 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 90 (4.0 g, 12.69 mmol), to give Intermediate 91 (3.56 g, 98% yield) as a white solid. Intermediate 92 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 91 (3.56 g, 12.40 mmol), to give Intermediate 92 (1.27 g, 28% yield) as a yellow solid. Intermediate 93 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 92 (1.1 g, 3.07 mmol), to give Intermediate 93 (0.67 g, 84% yield) as a yellow oil. TMSCl (1.85 mL, 14.6 mmol) was added dropwise to a solution of Intermediate 90 (574 mg, 1.82 mmol) and NaI (2.18 g, 14.6 mmol) in dry acetonitrile (7 mL) under nitrogen. The resulting mixture was stirred at room temperature for 16 h then a solution of saturated Na₂S₂O₃ and EtOAc were added. The layers were separated, and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography on silica gel (Mobile phase gradient: Heptane:EtOAc from 100:0 to 70:30). The fractions containing compound were combined and the solvent was evaporated in vacuo to give Intermediate 94 (0.36 g, 67% yield) as a white solid. NaH 60% in mineral oil (148 mg, 3.70 mmol) was added to a solution of Intermediate 94 (557 mg, 1.85 mmol) in CH3CN (10 mL) at 0 °C and stirred at 0 °C for 20 min. Then 2-difluoro-2- (fluorosulfonyl)acetic acid [1717-59-5] (0.353 mL, 4.62 mmol) was added dropwise and stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc and water, layers were separated, and the aqueous layer was 85hromatog with EtOAc (3 times), dried over MgSO4, filtered, concentrated, and purified by flash column chromatography on silica gel (Mobile phase gradient: Heptane:EtOAc from 100:0 to 80:20). The fractions containing product were combined, evaporated to give Intermediate 95 (0.31 g, 48% yield) as colorless oil. Intermediate 96 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 95 (0.31 g, 0.88 mmol), to give Intermediate 96 (0.29 g, quantitative yield). Intermediate 97 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 96 (0.29 g, 0.88 mmol), to give Intermediate 97 (0.32 g, 92% yield) as a white solid. Intermediate 98 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 97 (0.32 g, 0.81 mmol), to give Intermediate 98 (0.20 g, 84% yield) as a white solid. To a solution of Intermediate 94 (800 mg, 2.66 mmol) in DMF (8 mL) was added K2CO3 (734 mg, 5.31 mmol) followed by iodomethane [74-88-4] (198 µL, 3.19 mmol). The mixture was stirred at 100 °C for 16 h. The crude was cooled down to room temperature, then water and EtOAc were added, and the layers were separated. The aqueous layer was extracted with EtOAc (2 times). The combined organic layers were washed with brine, dried over MgSO₄, filtered, and concentrated in vacuo to give a residue which was purified by normal phase preparative LC (Mobile phase gradient: Heptane:EtOAc from 100:0 to 50:50). The fractions containing product were combined and evaporated to dryness to give Intermediate 99 (0.15 g, 18% yield) as a white solid. Intermediate 100 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 99 (0.15 g, 0.48 mmol), to give Intermediate 100 (70 mg, 51% yield). Intermediate 101 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 100 (70 mg, 0.24 mmol), to give Intermediate 101 (66 mg, 72% yield) as a colourless oil. Intermediate 102 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 101 (66 mg, 0.18 mmol), to give Intermediate 102 (35 mg, 77% yield) as a colourless oil. To a solution of Intermediate 94 in DMF (6 mL) was added Ag2CO3 (0.60 g, 3.98 mmol) followed by Iodomethane-D3 [865-50-9] (0.15 mL, 2.39 mmol). The mixture was stirred at 90°C for 2 h, then water and EtOAc were added, and mixture was filtered through a pad of Celite, and then extracted with EtOAc (3 times). The mixture was dryed with MgSO4 and concentrated under vacuum. The crude was purified by normal phase preparative LC (Mobile phase: Heptane: EtOAc from 100:0 to 70:30). The fractions containing compound were combined and the solvent was evaporated in vacuo to give Intermediate 103 (0.43 g, 68% yield) as a yellow solid. Intermediate 104 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 103 (0.43 g, 1.35 mmol), to give Intermediate 104 (0.35 g, 90% yield). Intermediate 105 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 104 (0.35 g, 1.22 mmol), to give Intermediate 105 (0.1 g, 23% yield) as a white solid. Intermediate 106 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 105 (0.1 g, 0.25 mmol), to give Intermediate 106 (60 mg, 92% yield) as a yellow oil. Intermediate 107 was prepared by an analogous reaction protocol as Intermediate 1, starting from phenylhydrazine [100-63-0] (0.92 ml, 9.25 mmol), to give Intermediate 107 (0.90 g, 33% yield) as a yellow solid. Intermediate 108 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 107 (0.90 g, 3.15 mmol), to give Intermediate 108 (0.63 g, 78% yield) as a grey solid. Intermediate 109 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 108 (0.63 g, 2.46 mmol), to give Intermediate 109 (0.47 g, 59% yield). Intermediate 110 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 109 (1.1 g, 3.45 mmol), to give Intermediate 110 (0.68 g, 87% yield) as a white solid. 111 3,6-Dichloro-2-methoxypyridine [1214391-95-3] (2.0 g, 11.2 mmol), di-tert-butyl hydrazodicarboxylate [16466-61-8] (5 g, 21.5 mmol), (2-dicyclohexylphosphino-2’,4’,6’- triisopropyl-1,1’-biphenyl)[2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate (Xphos Pd G3, 0.95 g, 1.1 mmol), Cs2CO3 (8.1 mg, 25 mmol) were loaded into a reaction vial. The vial was sealed, flushed with nitrogen, and toluene (50 mL) was added. The mixture was degassed and heated at 100°C for 16 h. The reaction mixture was cooled down to room temperature, filtered and concentrated under reduced pressure. The crude was purified throught silica gel column (Mobile phase: Heptane: EtOAc from 100:0 to 90:10) to give Intermediate 111 (1.34 g, yield 32%) as a clear oil. 112 Intermediate 111 (3.44 g, 9.20 mmol) was dissolved in DCM (15 mL) and treated with HCl (4M in dioxane, 17.9 mL, 214 mmol) then the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness to give Intermediate 112 (1.39 g, 87% yield) as a white solid. Intermediate 113 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 112 (1.25 g, 7.20 mmol), to give Intermediate 113 (1.73 g, 69% yield) as a yellow oil. 114 Intermediate 114 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 113 (1.70 g, 4.86 mmol), to give Intermediate 114 (1.48 g, 95% yield) as a yellow solid. Intermediate 115 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 114 (1.40 g, 4.35 mmol), to give Intermediate 115 (1.70 g, quantitative yield) as a pink solid. Intermediate 116 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 115 (1.70 g, 4.33 mmol), to give Intermediate 116 (1.48 g, 94% yield) as a yellow solid. 117 Intermediate 117 was prepared by an analogous reaction protocol as Intermediate 111, starting from 6-chloro-3-fluoro-2-methoxypyridine [1261473-36-2] (215 mg, 1.33 mmol), to give Intermediate 117 (0.42 g, 87% yield). Intermediate 118 was prepared by an analogous reaction protocol as Intermediate 112, starting from Intermediate 117 (0.44 g, 1.23 mmol), to give Intermediate 118 (0.20 g, 76% yield). Intermediate 119 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 118 (1.95 g, 0.93 mmol), to give Intermediate 119 (0.33 g, quantitative yield). Intermediate 120 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 119 (0.33 g, 0.99 mmol), to give Intermediate 120 (0.25 g, 83% yield). 121 Intermediate 121 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 120 (0.25 g, 0.82 mmol), to give Intermediate 121 (0.30 g, 97% yield). Intermediate 122 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 121 (0.30 g, 0.80 mmol), to give Intermediate 122 (0.12 g, 52% yield). Intermediate 123 was prepared by an analogous reaction protocol as Intermediate 88, starting from 2-bromo-3-fluoro-6-methoxypyridine [1161497-33-1] (0.50 g, 2.43 mmol), to give Intermediate 123 (0.11 g, 14% yield) as a black solid. 124 Intermediate 124 was prepared by an analogous reaction protocol as Intermediate 89, starting from Intermediate 123 (50.0 mg, 0.16 mmol), to give Intermediate 124 (23.5 mg, 84% yield) as an orange solid. Intermediate 125 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 124 (0.18 g, 1.13 mmol), to give Intermediate 125 (0.34 g, 85% yield) as a yellow oil. Intermediate 126 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 125 (0.22 g, 0.63 mmol), to give Intermediate 126 (0.20 g, quantitative yield) as a yellow solid. 127 Intermediate 127 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 126 (0.19 g, 0.63 mmol), to give Intermediate 127 (0.23 g, 94% yield) as a yellow solid. Intermediate 128 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 127 (0.18 g, 0.48 mmol), to give Intermediate 128 (0.14 g, quantitative yield) as a yellow oil. Intermediate 129 was prepared by an analogous reaction protocol as Intermediate 63, starting from 3-cyanophenylboronic acid [150255-96-2] (1.00 g, 6.81 mmol), to give Intermediate 129 (1.62 g, 59%) as a yellow oil. Intermediate 130 was prepared by an analogous reaction protocol as Intermediate 64, starting from Intermediate 129 (1.43 g, 3.56 mmol), to give Intermediate 130 (0.66 g, quantitative yield) as a yellow solid. Intermediate 131 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 130 (0.66 g, 3.83 mmol), to give Intermediate 131 (1.00 g, 79% yield) as a yellow solid. Intermediate 132 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 131 (0.90 g, 2.90 mmol), to give Intermediate 132 (0.62 g, 69% yield) as a yellow solid. Intermediate 133 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 132 (0.62 g, 2.21 mmol), to give Intermediate 133 (0.53 g, 68% yield) as a white solid. Intermediate 134 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 133 (0.53 g, 1.37 mmol), to give Intermediate 134 (0.28 g, 81% yield) as a white solid. Intermediate 135 was prepared by an analogous reaction protocol as Intermediate 1, starting from 3-methoxyphenylhydrazine hydrochloride [39232-91-2] (5 g, 27.8 mmol), to give Intermediate 135 (3.50 g, 40% yield) as an orange oil. Intermediate 136 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 135 (3.50 g, 11.14 mmol), to give Intermediate 136 (3.02 g, 95% yield). Intermediate 137 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 136 (3.02 g, 10.55 mmol), to give Intermediate 137 (2.76 g, 73% yield) as a yellow solid. Intermediate 138 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 137 (2.76 g, 7.72 mmol), to give Intermediate 138 (2.06 g, 88% yield). Intermediate 139 was prepared by an analogous reaction protocol as Intermediate 5, starting from 4-bromo-2-methylthiazole (3.3 g, 18.53 mmol). Upon addition of di-tert-butyl azodicarboxylate, the reaction was stirred at room temperature for 1 hour, instead of overnight, to give Intermediate 139 (6 g, 98% yield) as a brown oil. HCl (4M in dioxane) (18.55 mL, 4 M, 74.19 mmol) was added to a stirred solution of Intermediate 139 (6.11 g, 18.55 mmol) in EtOH (54 mL) at room temperature. The crude was stirred overnight, then ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (4.67 mL, 24.11 mmol) was added. The mixture was heated at 80 °C for 1 h. The solvents were evaporated under reduced pressure and the crude was purified by flash column chromatography (DCM: MeOH 100:0 to 98:2) to give Intermediate 140 (1.34 g, 24% yield) as an orange residue. 141 Intermediate 141 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 140 (0.65 g, 2.345 mmol), to give Intermediate 141 (0.61 g, 75% yield) as a yellow oil. 142 Intermediate 142 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 141 (0.61 g, 1.75 mmol), to give Intermediate 142 (0.44 g, quantitative yield) as an orange solid. A mixture of 3-aminopyrazole [1820-80-0] (10 g, 120 mmol) and phthalic anhydride (24.96 g, 168.49 mmol) in 1,4-dioxane (140 mL) was stirred at reflux overnight. The reaction was allowed to reach room temperature, the solvent was evaporated to dryness and the residue was stirred with EtOH and filtered to give Intermediate 143 (24.6 g, 96% yield) as an off white solid. NaH (60% dispersion in mineral oil; 0.90 g, 22.51 mmol) was added to a stirred solution of Intermediate 143 (4.0 g, 18.76 mmol) in dry DMF (60 mL) at 0 °C and under nitrogen. The mixture was stirred at the same temperature for 30 minutes, then a solution of benzyl bromide (3.1 mL, 28.1 mmol) in dry DMF (20 mL) was slowly added and crude was finally stirred at room temperature overnight. The reaction was partitioned between sat. NH4Cl and EtOAc, the phases separated, the aqueous layer extracted with EtOAc (2x) and combined organic layers were dried over MgSO4, filtered and solvents evaporated. The crude was purified by flash column chromatography (Mobile phase: n-heptane:EtOAc from 100:0 to 70:30) to give Intermediate 144 (5.24 g, crude, ~20% purity) as a yellow solid. Hydrazine hydrate [10217-52-4] (7.2 mL, 148.4 mmol) was added to a stirred solution of Intermediate 144 (15.0 g, crude, assumed 49.4 mmol) in EtOH (200 mL). The mixture was heated to 70 °C for 1 h, with formation of a white solid. The reaction was coold down to room temperature, filtered to remove the solid material, and the filtrate was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (Mobile phase: DCM:MeOH from 100:0 to 98:2) to give Intermediate 145 (4.15g, 48% yield) as a colorless oil. A solution of sodium nitrite [7632-00-0] (2.00 g, 29.0 mmol) in water (6.7 mL) was slowly added to a stirred solution of Intermediate 145 (3.35 g, 19.34 mmol) in HCl (6.0 M in H2O, 27 mL) stirring at at -15 °C. The mixture was stirred at -15 °C for 30 min, then a solution of tin(II) chloride dihydrate [10025-69-1] (6.55 g, 29.0 mmol) in conc. HCl (37% in H2O, 6.7 mL) was dropwise added. The reaction was allowed to warm up to room temperature and stirred for 1 h. The mixture was cooled down to 0 °C, treated dropwise with aq. NaOH (10%) until basic pH and then diluted with EtOAc (150 mL). The organic phase was separated and the aqueous one was extracted with EtOAc (2x). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (Mobile phase: DCM:MeOH from 100:0 to 96:4) to give Intermediate 146 (0.77 g, 21% yield) as a yellow solid. Intermediate 147 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 146 (1.47 g, 7.81 mmol), to give Intermediate 147 (2.36 g, 83% yield) as a yellow solid. A suspension of Intermediate 147 (1.29 g, 3.54 mmol) and Pd/C (10 wt. % loading) in MeOH (30 mL) under nitrogen atmosphere, was bubbled with H2 for 15 min and stirred under H2 atmosphere, at 50°C overnight. Then, Pd(OH)₂ (20 wt. % loading) was added and the reaction mixture was bubbled with H₂ for 15 min and stirred under H₂ atmosphere, at 50°C over weekend. The mixture was filtered on Dicalite and evaporated. The product was purified by flash column chromatography on silicagel (Mobile phase: DCM:MeOH from 100:0 to 95:5) to give Intermediate 148 (0.45 g, 46% yield) as a white solid. A mixture of Intermediate 148 (0.40 g, 1.46 mmol), Cs₂CO₃ (0.95 g, 2.93 mmol) and sodium chlorodifluoroacetate [1895-39-2] (0.29 g, 1.89 mmol) in DMA (4.0 mL), was stirred at 80 °C for 5 hours. The reaction mixture was poured into water and extracted with EtOAc (2x). The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo. The crude was purified by flash column chromatography (Mobile phase: Heptane:EtOAc from 100:0 to 60:40) to give Intermediate 149 (0.23 g, 48% yield) as a colorless oil. Intermediate 150 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 149 (0.14 g, 0.43 mmol), to give Intermediate 150 (0.13 g, quantitative yield) as a white solid. Intermediate 151 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 150 (0.13 g, 0.44 mmol), to give Intermediate 151 (80.0 mg, 49% yield) as a colourless oil. Intermediate 152 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 151 (80.0 mg, 0.22 mmol), to give Intermediate 152 (80.0 g, quantitative yield) as an orange oil. Intermediate 153 was prepared by an analogous reaction protocol as Intermediate 1, starting from 5-hydrazinyl-1,2,4-thiadiazole dihydrochloride [2230799-80-9] (0.90 g, 3.44 mmol), to give Intermediate 153 (0.83 g, 83% yield) as a white solid. Intermediate 154 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 153 (0.83 g, 2.84 mmol), to give Intermediate 154 (0.70 g, 93% yield) as a white solid. Intermediate 155 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 154 (0.60 g, 2.26 mmol), to give Intermediate 155 (0.25 g, 32% yield) as a colourless oil. Intermediate 156 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 155 (0.25 g, 0.73 mmol), to give Intermediate 156 (0.17 g, 99% yield) as a yellow solid. Intermediate 36 (0.55 g, 1.74 mmol), triethylborane 1 M in THF [97-94-9] (2.26 mL, 2.26 mmol) and potassium carbonate (0.48 g, 3.47 mmol) were dissolved in 1,4-dioxane (2.2 mL) and water (0.5 mL) then purged with nitrogen. Bis(triphenylphosphine)palladium(II) dichloride [13965-03-2] (0.10 g, 0.144 mmol) was added and the reaction mixture was stirred at 120 °C using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 20 min (fixed hold time). The mixture was diluted with EtOAc and water, the layers were separated, and the organic layer was washed with water (3x) and brine, dried over MgSO₄, filtered, concentrated, and purified by normal phase preparative LC (Mobile phase: Heptane:EtOAc from 100:0 to 70:30) to give Intermediate 157 (0.49 g, 89% yield) as a colorless oil. Intermediate 158 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 157 (0.49 g, 1.55 mmol), to give Intermediate 158 (0.41 g, 93% yield). Intermediate 159 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 158 (0.41 g, 1.45 mmol), to give Intermediate 159 (0.39 g, 76% yield) as a colourless oil. Intermediate 160 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 159 (0.38 g, 1.06 mmol), to give Intermediate 160 (0.20 g, 75% yield) as a yellow solid. Intermediate 161 was prepared by an analogous reaction protocol as Intermediate 47, starting from 2-bromo-6-isopropylpyridine [1037223-35-0] (1.00 g, 5.00 mmol), to give Intermediate 161 (0.82 g, 70% purity, 46% yield) as a brown oil. Intermediate 162 was prepared by an analogous reaction protocol as Intermediate 48, starting from Intermediate 161 (0.82 g, 2.28 mmol), to give Intermediate 162 (1.80 g, quantitative yield) as an orange solid. Intermediate 163 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 162 (1.8 g, 2.30 mmol), to give Intermediate 163 (0.83 g, quantitative yield) as a yellow oil. Intermediate 164 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 163 (0.83 g, 2.55 mmol), to give Intermediate 164 (0.66 g, 86% yield) as an off-white solid. Intermediate 165 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 164 (0.66 g, 2.20 mmol), to give Intermediate 165 (0.47 g, 57% yield) as a colourless oil. Intermediate 166 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 165 (0.47 g, 1.26 mmol), to give Intermediate 166 (0.32 g, 94% yield) as a colorless oil. Intermediate 167 was prepared by an analogous reaction protocol as Intermediate 157, starting from cyclopropylboronic acid [411235-57-9] (0.17 g, 2.03 mmol), to give Intermediate 167 (0.37 g, 72% yield) as a yellow oil. Intermediate 168 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 167 (0.37 g, 1.13 mmol), to give Intermediate 168 (0.30 g, 91% yield) as a yellow solid. Intermediate 169 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 168 (0.30 g, 1.03 mmol), to give Intermediate 169 (0.20 g, 53% yield) as a colourless oil. Intermediate 170 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 169 (0.20 g, 0.55 mmol), to give Intermediate 170 (0.13 g, 90% yield) as a yellow residue. Intermediate 171 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 147 (0.39 g, 23% purity, 0.24 mmol), to give Intermediate 171 (0.21 g, crude, 51% purity, quantitative yield) as a golden solid. 172 Intermediate 172 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 171 (0.21 g, 0.31 mmol), to give Intermediate 172 (36.6 mg, 62% purity, 18% yield) as a yellow residue. Intermediate 173 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 172 (36 mg, 0.05 mmol), to give Intermediate 173 (33.2 mg, 53% purity, quantitative yield) as a yellow residue. Intermediate 174 was prepared by an analogous reaction protocol as Intermediate 1, starting from 2-bromo-6-hydrazineylpyridine [26944-71-8] (11.7 g, 62.23 mmol), to give Intermediate 174 (4.30 g, 51% yield) as a yellow oil. Intermediate 175 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 174 (4.28 g, 11.76 mmol), to give Intermediate 175 (3.78 g, 76% yield) as an orange oil. Intermediate 176 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 175 (3.74 g, 11.12 mmol), to give Intermediate 176 (3.0 g, 60% yield) as a yellow solid. 177 A solution of Intermediate 176 (1.5 g, 3.684 mmol), Co2(CO)8 [10210-68-1] (0.31 g, 0.92 mmol), DMAP (0.90 g, 7.37 mmol), XantPhos (0.21 g, 0.37 mmol) and Pd(OAc)2 [3375-31-3] (30.66 mg, 0.18 mmol) in MeOH:Toluene (1:3 ratio, 14 ml) was stirred for 30 min at 90°C under nitrogen. The obtained residue was submitted to silica gel column chromatography (Mobile phase: Petroleum ether:EtOAc from 100:0 to 70:30) giving Intermediate 177 (0.50 g, 95% yield). Intermediate 178 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 177 (0.38 g, 0.94 mmol), to give Intermediate 178 (0.32 g, quantitative yield). Intermediate 179 was prepared by an analogous reaction protocol as Intermediate 1, starting from 2-hydrazino-4-methylpyridine [4931-00-4] (2.0 g, 16.24 mmol), to give Intermediate 179 (2.3 g, 47% yield) as a yellow oil. Intermediate 180 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 179 (2.30 g, 7.69 mmol), to give Intermediate 180 (2.0 g, 96% yield) as a white solid. Intermediate 181 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 180 (1.90 g, 7.00 mmol), to give Intermediate 181 (1.05 g, 44% yield) as a yellow solid. Intermediate 182 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 181 (0.20 g, 0.58 mmol), to give Intermediate 182 (0.12 g, 85% yield) as a yellow oil. Intermediate 179 was prepared by an analogous reaction protocol as Intermediate 1, starting from 1-(5-methylpyridine-2-yl)hydrazine [4931-01-5] (1.0 g, 8.12 mmol), to give Intermediate 183 (2.06 g, 85% yield) as an orange solid. Intermediate 184 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 183 (2.06 g, 6.88 mmol), to give Intermediate 184 (1.82 g, 97% yield). Intermediate 185 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 184 (1.82 g, 6.71 mmol), to give Intermediate 185 (1.77 g, 77% yield) as a white solid. Intermediate 186 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 185 (1.77 g, 5.17 mmol), to give Intermediate 186 (0.93 g, 74% yield) as a yellow oil. Intermediate 187 was prepared by an analogous reaction protocol as Intermediate 146, starting from 5-aminopicoline [3430-14-6], to give Intermediate 187 (3.19 g, 43% yield) as a brown solid. Intermediate 188 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 187 (2.91 g, 23.63 mmol), to give Intermediate 188 (3.14 g, 44% yield) as a yellow oil. Intermediate 189 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 188 (1.0 g, 3.34 mmol), to give Intermediate 189 (0.51 g, 57% yield) as yellow solid. Intermediate 190 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 189 (0.51 g, 1.90 mmol), to give Intermediate 190 (0.39 g, 53% yield) as a yellow solid. Intermediate 191 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 190 (0.39 g, 1.01 mmol), to give Intermediate 191 (0.21 g, 84% yield) as a colorless oil. Intermediate 192 was prepared by an analogous reaction protocol as Intermediate 1, starting from 2-hydrazineyl-6-methylpyridine (2.0 g, 16.24 mmol), to give Intermediate 192 (3.30 g, 76% yield) as a yellow oil. Intermediate 193 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 192 (3.3 g, 11.03 mmol), to give Intermediate 193 (1.64 g, 55% yield) as yellow oil. Intermediate 194 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 193 (1.64 g, 6.05 mmol), to give Intermediate 194 (0.50 g, 24% yield) as a white solid. Intermediate 195 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 194 (0.20 g, 0.58 mmol), to give Intermediate 195 (0.15 g, 87% yield) as a yellow oil. Intermediate 196 was prepared by an analogous reaction protocol as Intermediate 47, starting from 3-bromo-2-methylpyridine [38749-79-0] (2.0 g, 11.63 mmol), to give Intermediate 196 (1.56 g, 60% yield) as a yellow solid. 197 Intermediate 197 was prepared by an analogous reaction protocol as Intermediate 48, starting from Intermediate 196 (1.46 g, 6.54 mmol), to give Intermediate 197 (1.11 g, quantitative yield). Intermediate 198 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 197 (1.12 g, 6.99 mmol), to give Intermediate 198 (1.87 g, 89% yield) as a yellow oil. Intermediate 199 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 198 (1.86 g, 6.23 mmol), to give Intermediate 199 (0.72 g, 43% yield) as a yellow solid. Intermediate 200 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 199 (0.57 g, 2.10 mmol), to give Intermediate 200 (0.57 g, 79% yield) as a yellow solid. Intermediate 201 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 200 (0.57 g, 1.49 mmol), to give Intermediate 201 (0.57 g, 89% yield) as a yellow solid. Intermediate 202 was prepared by an analogous reaction protocol as Intermediate 63, starting from 5-methylpyridine-3-boronic acid [173999-18-3] (1.0 g, 7.30 mmol), to give Intermediate 202 (1.0 g, 36% yield) as a colourless oil. Intermediate 203 was prepared by an analogous reaction protocol as Intermediate 64, starting from Intermediate 202 (1.0 g, 2.63 mmol), to give Intermediate 203 (0.6 g, quantitative yield) as a yellow solid. Intermediate 204 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 203 (6.10 g, 29.7 mmol), to give Intermediate 204 (1.41 g, 16% yield) as a yellow solid. Intermediate 205 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 204 (1.4 g, 4.68 mmol), to give Intermediate 205 (1.02 g, 81% yield) as a white solid. Intermediate 206 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 205 (1.18 g, 3.45 mmol), to give Intermediate 206 (0.65 g, 44% yield) as a white solid. Intermediate 207 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 206 (0.10 g, 0.29 mmol), to give Intermediate 207 (81.4 mg, quantitative yield). Intermediate 208 was prepared by an analogous reaction protocol as Intermediate 47, starting from 3-bromo-4-methylpyridine [3430-22-6] (1.29 g, 11.63 mmol), to give Intermediate 208 (1.5 g, 40% yield) as a yellow solid. Intermediate 209 was prepared by an analogous reaction protocol as Intermediate 48, starting from Intermediate 208 (0.38 g, 1.39 mmol), to give Intermediate 209 (0.28 g, quantitative yield) as a white solid. Intermediate 210 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 209 (0.28 g, 1.43 mmol), to give Intermediate 210 (0.37 g, 83% yield) as a yellow solid. 211 Intermediate 211 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 210 (0.37 g, 1.18 mmol), to give Intermediate 211 (0.31 g, 95% yield) as a white solid. 212 Intermediate 212 was prepared by an analogous reaction protocol as Intermediate 21, starting from Intermediate 211 (0.31 g, 1.13 mmol), to give Intermediate 212 (0.32 g, 83% yield) as a yellow solid. Intermediate 213 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 212 (0.32 g, 0.92 mmol), to give Intermediate 213 (0.22 g, 85% yield) as a yellow solid. 214 Intermediate 214 was prepared by an analogous reaction protocol as Intermediate 1, starting from 2-hydrazineyl-3-methylpyridine (3.08 g, 24.98 mmol), to give Intermediate 214 (2.0 g, 59% yield) as a brown oil. Intermediate 215 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 214 (2.0 g, 6.68 mmol), to give Intermediate 215 (1.6 g, 88% yield) as a brown solid. Intermediate 216 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 215 (1.6 g, 5.90 mmol), to give Intermediate 216 (1.0 g, 50% yield) as a brown oil. 217 Intermediate 217 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 216 (0.20 g, 0.58 mmol), to give Intermediate 217 (0.16 g, 84% yield) as a brown oil. Intermediate 218 was prepared by an analogous reaction protocol as Intermediate 146, starting from 4-fluoro-2-methylaniline [452-71-1] (25.0 g, 199.77 mmol), to give Intermediate 218 (19.38 g, 62% yield). Intermediate 219 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 218 (19.8 g, 141.27 mmol), to give Intermediate 219 (32.0 g, 72% yield) as an orange oil. Intermediate 220 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 219 (1.20 g, 3.79 mmol), to give Intermediate 220 (1.10 g, 99% yield) as a brown solid. 221 Intermediate 221 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 220 (1.08 g, 3.75 mmol), to give Intermediate 221 (1.28 g, 48% yield) as an orange oil. Intermediate 222 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 221 (1.3 g, 3.62 mmol), to give Intermediate 222 (62.0 mg, 66% yield) as an orange solid. Intermediate 223 was prepared by an analogous reaction protocol as Intermediate 63, starting from 2-methoxypyridine-3-boronic acid [163105-90-6] (1.13 g, 7.39 mmol), to give Intermediate 223 (2.75 g, 88% yield) as a colourless oil. 224 Intermediate 224 was prepared by an analogous reaction protocol as Intermediate 64, starting from Intermediate 223 (2.75 g, 6.48 mmol), to give Intermediate 224 (0.82 g, 70% yield) as an orange oil. Intermediate 225 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 224 (1.09 g, 4.52 mmol), to give Intermediate 225 (0.74 g, 52% yield). Intermediate 226 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 225 (0.73 g, 2.32 mmol), to give Intermediate 226 (0.64 g, 97% yield) as an orange solid. 227 Intermediate 227 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 226 (0.62 g, 2.15 mmol), to give Intermediate 227 (0.45 g, 48% yield) as a yellow oil. Intermediate 228 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 227 (0.45 g, 1.26 mmol), to give Intermediate 228 (0.24 g, 73% yield) as a white solid. 229 A suspension of 2-fluoro-3-nitropyridine [1480-87-1] (3 g, 21.11 mmol), hydrazinium hydroxide solution [10217-52-4] (2.11 g, 42.23 mmol) and Ephos Pd G4 [2132978-44-8] (29.82 mg, 0.035 mmol) in methanol (30 mL) was stirred for 6 hours. The aqueous phase was washed with MeOH (2x), filtered and the solvents evaporated, to give Intermediate 229 (2.5 g, 68% yield) as a brown oil. Intermediate 230 was prepared by an analogous reaction protocol as Intermediate 1, starting from Intermediate 229 (2.40 g, 9.99 mmol), to give Intermediate 230 (1.80 g, 55% yield) as a brown oil. Intermediate 231 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 230 (1.80 g, 5.45 mmol), to give Intermediate 231 (0.50 g, 28% yield) as a yellor solid. Intermediate 232 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 231 (0.30 g, 0.99 mmol), to give Intermediate 232 (0.30 g, 80% yield) as a yellow solid. Intermediate 233 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 232 (0.15 g, 0.40 mmol), to give Intermediate 233 (0.11 g, quantitative yield). To a solution of 2-bromo-4-methyloxazole [1060816-11-6] (0.19 g, 1.06 mmol) in N,N- dimethylformamide (5 mL) were added ethyl 1H-pyrazole-4-carboxylate [37622-90-5] (0.13 g, 0.96 mmol), cuprous iodide [7681-65-4] (36 mg, 0.19 mmol), L-proline (44 mg, 0.38 mmol) and potassium carbonate (0.26 g, 1.92 mmol). The reaction mixture was set under nitrogen and stirred at 100°C for 12 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate (2x). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified with silica gel column chromatography (Mobile phase: petroleum ether: ethyl acetate from 100:0 to 40:60) to give Intermediate 234 (0.130 g, 58% yield) as a yellow oil. Intermediate 235 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 234 (0.13 g, 0.53 mmol), to give Intermediate 235 (80.0 mg, 70% yield) as a yellor solid. Intermediate 236 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 235 (80.0 mg, 0.37 mmol), to give Intermediate 236 (45.0 mg, 43% yield) as a yellow solid. Intermediate 237 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 236 (26.0 mg, 0.94 mmol), to give Intermediate 237 (50.0 mg, 31% yield) as a yellow solid. To a mixture of ethyl 1H-pyrazole-4-carboxylate [37622-90-5] (1.00 g, 6.42 mmol), cesium carbonate (4.19 g, 12.84 mmol) and 4-bromothiazole [34259-99-9] (1.16 g, 7.06 mmol) in 1,4- dioxane (20 mL) under nitrogen atmosphere, was added cuprous iodide [7681-65-4] (0.12 g, 0.64 mmol). The mixture was stirred overnight at 110°C under nitrogen atmosphere. The mixture was cooled to room temperature, filtered, and concentrated to obtain a residue, which was purified by silica gel column chromatography (Mobile phase: petroleum ether: ethyl acetate from 100:0 to 60:40) to give Intermediate 238 (0.32 g, 20% yield) as a white solid. N Intermediate 239 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 238 (0.32 g, 1.29 mmol), to give Intermediate 239 (0.20 g, 68% yield) as a yellor solid. Intermediate 240 Intermediate 240 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 239 (0.20 g, 0.87 mmol), to give Intermediate 240 (0.21 g, 81% yield) as a yellow solid. 241 Intermediate 241 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 240 (0.20 g, 0.68 mmol), to give Intermediate 241 (90.0 mg, 68% yield) as a yellow solid. 242 To a solution of 5-bromothiazole [3034-55-7] (1.0 g, 6.1 mmol) in N,N-dimethylformamide (15.0 ml) was added ethyl 1H-pyrazole-4-carboxylate [37622-90-5] (1.03 g, 7.32 mmol), cuprous iodide [7681-65-4] (116. 73 mg, 0.61 mmol) and sodium tert-butoxide (1.17 g, 12.2 mmol), the reaction mixture was stirred at 120°C overnight. The resulting mixture was extracted with ethyl acetate (3x 50 mL). The combined organic layers were washed with brine (2x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (Mobile phase: Petroleum ether : ethyl acetate = 5:1) to give Intermediate 242 (0.60 g, 44% yield) as a white solid. Intermediate 243 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 242 (0.60 g, 2.69 mmol), to give Intermediate 243 (0.35 g, 94%) as a white solid. 244 Intermediate 244 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 243 (0.25 g, 1.26 mmol), to give Intermediate 244 (0.24 g, 66% yield) as a white solid. Intermediate 245 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 244 (0.25 g, 0.90 mmol), to give Intermediate 245 (0.13 mg, 84% yield) as a white solid. 4-Bromo-5-methyl-1H-pyrazole [13808-64-5] (2.00 g, 12.42 mmol), 2- bromothiazole [3034-53-5] (3.06 g, 18.63 mmol) and Cs₂CO₃ (8.09 g, 24.85 mmol) were added with DMSO (15 mL) and the resulting solution was stirred at 100 °C overnight. The reaction mixture was cooled down to room temperature and diluted with ethyl acetate (20 mL) and brine (20 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate (3x 50 mL). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (Mobile phase: Petroleum ether : ethyl acetate from 100:0 to 80:20) to give Intermediate 246 (1.50 g, 48% yield) as a white solid. To a solution of Intermediate 246 (0.18 g, 0.74 mmol) in 1,4-dioxane (5 mL) was added diphenylmethanimine [1013-88-3] (0.20 g, 1.11 mmol), RuPhos Pd G1 [2361069-97-6] (60.0 mg, 0.07 mmol), RuPhos [787618-22-8] (69.0 mg, 0.147 mmol), Cs2CO3 (0.48 g, 1.47 mmol) at 120°C for 16 hours. The mixture was diluted with water (50mL) and extracted with ethyl acetate (3x). The combined organic layer was concentrated in vacuum. The residue was purified by silica gel column chromatography (Mobile phase: Petroleum ether : ethyl acetate 10:1) to give Intermediate 247 (0.14 g, 52% yield) as a yellow solid. To a solution of Intermediate 247 (0.14 g, 0.39 mmol) in THF (2 mL) was added 5M HCl (2 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the reside was diluted with NaHCO3(aq.) (50mL) and extracted with ethyl acetate (3x). The combined organic layer was concentrated in vacuum and the residue was purified by silica gel column chromatography (Mobile phase: DCM : MeOH = 10:1) to give Intermediate 248 (60.0 mg, 78% yield) as a yellow solid. A mixture of ethyl propionylacetate [4949-44-4] (1.00 g, 6.94 mmol), triethyl orthoformate [122-51-0] (2.06 g, 13.87 mmol) and acetic anhydride [108-24-7] (2.7 mL) was stirred at 150 °C for 7 h. The mixture was concentrated under vacuum to give Intermediate 249 (1.10 g, 79% yield) as a yellow oil. To a solution of 2-hydrazineylthiazole hydrochloride [30216-52-5] (2.50 g, 16.48 mmol) in ethyl acetate (30 mL), Intermediate 249 (1.50 g, 7.49 mmol) was added at 0°C. The resulting 127hromatogr was stirred at 85°C for 3 h. The reaction mixture was cooled down to room temperature and added with saturated NH₄Cl aqueous solution (30 mL). The aqueous phase was extracted with EtOAc (3x 50 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (Mobile phase: Petroleum ether : ethyl acetate from 100:0 to 50:50) to give Intermediate 250 (1.20 g, 64% yield) as a white solid. Intermediate 251 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 250 (1.11 g, 4.43 mmol), to give Intermediate 251 (0.60 g, 61%) as a yellow solid. Intermediate 252 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 251 (0.60 g, 2.69 mmol), to give Intermediate 252 (0.20 g, 25% yield) as a yellow solid. Intermediate 253 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 252 (0.19 g, 0.65 mmol), to give Intermediate 253 (0.11 g, 88% yield) as a brown oil. Intermediate 254 was prepared by an analogous reaction protocol as Intermediate 249, starting from ethyl 3-cyclopropyl-3-oxopropanoate [24922-02-9] (2.00 g, 12.81 mmol), to give Intermediate 254 (2.60 g, 42% yield) as a white solid. Intermediate 255 was prepared by an analogous reaction protocol as Intermediate 250, starting from Intermediate 254 (2.60 g, 12.25 mmol), to give Intermediate 255 (3.60 g, 75%) as an orange oil. Intermediate 256 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 255 (3.00 g, 11.39 mmol), to give Intermediate 256 (2.60 g, 50%) as an orange solid. Intermediate 257 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 256 (0.27 g, 1.14 mmol), to give Intermediate 257 (89.0 mg, 25% yield) as a yellow solid. Intermediate 258 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 257 (0.88 g, 0.29 mmol), to give Intermediate 258 (60.0 mg, 80% yield) as a yellow solid. Intermediate 259 was prepared by an analogous reaction protocol as Intermediate 250, starting from 2-hydrazineylpyridine [4930-98-7] (4.10 g, 37.60 mmol), to give Intermediate 259 (2.28 g, 65%) as an orange oil. Intermediate 260 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 259 (2.30 g, 8.94 mmol), to give Intermediate 260 (1.80 g, 79%) as an orange oil. Intermediate 261 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 260 (1.85 g, 8.07 mmol), to give Intermediate 261 (0.80 g, 31% yield) as a yellow oil. Intermediate 262 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 261 (0.20 g, 0.67 mmol), to give Intermediate 262 (0.10 g, 68% yield) as a yellow oil. Intermediate 263 was prepared by an analogous reaction protocol as Intermediate 249, starting from ethyl 4-methyl-3-oxopentanoate [7152-15-0] (3 g, 18.96 mmol), to give Intermediate 263 (3.50 g, 52% yield) as a yellow oil. Intermediate 264 was prepared by an analogous reaction protocol as Intermediate 250, starting from Intermediate 263 (1.50 g, 7.00 mmol), to give Intermediate 264 (0.70 g, 36%) as a white solid. Intermediate 265 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 264 (0.70 g, 2.64 mmol), to give Intermediate 265 (0.45 g, 66%) as a yellow solid. Intermediate 266 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 265 (0.35 g, 1.48 mmol), to give Intermediate 266 (0.15 g, 30% yield) as a yellow solid. Intermediate 267 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 266 (0.15 g, 0.49 mmol), to give Intermediate 267 (0.11 g, 92% yield) as a yellow oil. Intermediate 268 was prepared by an analogous reaction protocol as Intermediate 249, starting from ethyl 4,4-difluoro-3-oxopentanoate [51368-10-6] (1.00 g, 5.55 mmol), to give Intermediate 268 (1.47 g, quantitative yield) as a yellow oil. Intermediate 269 was prepared by an analogous reaction protocol as Intermediate 250, starting from Intermediate 268 (0.80 g, 3.39 mmol), to give Intermediate 269 (0.41 g, 41%) as a white solid. Intermediate 270 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 269 (0.41 g, 1.41 mmol), to give Intermediate 270 (0.36 g, 98%) as a white solid. 271 Intermediate 271 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 270 (0.36 g, 1.39 mmol), to give Intermediate 271 (0.25 g, 54% yield) as a white solid. 272 Intermediate 271 (0.10 g, 0.15 mmol) was dissolved in dry DCM (2 ml) and zinc bromide [7699-45-8] (0.340 g, 0.75 mmol) was added. The solution was stirred for 16 h, then washed with NaHCO3 sat. solution. The combined organics were dried over anhydrous MgSO4, filtered and evaporated to give Intermediate 272 (70.0 mg, quantitative yield) and used as such into the next step. Intermediate 273 was prepared by an analogous reaction protocol as Intermediate 249, starting from methyl 5,5,5-trifluoro-3-oxopentanoate [915213-24-0] (1.00 g, 5.43 mmol), to give Intermediate 273 (1.30 g, quantitative yield) as a yellow oil. 274 Intermediate 274 was prepared by an analogous reaction protocol as Intermediate 250, starting from Intermediate 273 (1.20 g, 5.00 mmol), to give Intermediate 274 (0.43 g, 26%) as a white solid. Intermediate 275 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 274 (0.41 g, 1.41 mmol), to give Intermediate 275 (0.34 g, 85%) as a white solid. Intermediate 276 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 275 (0.32 g, 1.15 mmol), to give Intermediate 276 (0.10 g, 23% yield) as a white solid. 277 Intermediate 277 was prepared by an analogous reaction protocol as Intermediate 4, starting from Intermediate 276 (90.0 mg, 0.26 mmol), to give Intermediate 277 (80.0 mg, 87% yield) yellow oil. To a solution of 4-fluorophenylhydrazine hydrochloride [823-85-8] (3 g; 15.07 mmol) and triethylamine (3.07 ml, 22.14 mmol) in EtOH (180 ml) at 0°C, was added ethyl 2-formyl-3- oxopropanoate [80370-42-9] (2.9 mL; 22.14 mmol). The reaction mixture was stirred at room temperature for 12 h. Water was added, and a precipitate was formed. The precipitate was filtered and washed with water to afford a yellow solid. The filtrate was concentrated and purified by flash column chromatography (Mobile phase: Heptane:EtOAc from 100:0 to 50:50) to give the desired product as an orange foam. The solid obtained by precipitation, and the one obtained after purification were merged to give Intermediate 278 (2.09 g, 60% yield) as orange solid. A solution of N,N-diisopropylamine (0.77 mL, 5.44 mmol) in dry THF (10 mL) was cooled to -78°C and n-BuLi (2.5M in hexane, 2.18 mL, 5.44 mmol) was added dropwise in ~15min. A premade solution of Intermediate 278 (0.85 g, 3.63 mmol) in THF (10mL) at -78°C was then added. The reaction mixture was stirred at -78°C for ~30min. Finally, cyclobutanone [1191-95- 3] (0.31 mL, 0.94 g/mL, 4.2 mmol) was slowly added at -70°C and the mixture was stirred at - 70°C for 1 h. The mixture was quenched with NH4Cl (sat. solution) and then diluted with EtOAc. The phases were separated, and the aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under vacuum. The crude was purified by flash column chromatography (Mobile phase: Heptane: EtOAc from 100:0 to 70:30) to give Intermediate 279 (0.70 g, 63% yield) as a clear oil. NaH (17.0 mg, 0.74 mmol) was added to a solution of Intermediate 279 (0.20 g, 0.66 mmol) in DMF (6 mL) and the resulting mixture was stirred at room temperature for 30 min. Benzyl bromide (86.0 µL, 0.72 mmol) was added and the reaction was stirred at 0°C for 1 h. The reaction mixture was 135hroma into water slowly and extracted with EtOAc (2x), the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The crude was purified by flash column chromatography (Mobile phase: Heptane:EtOAc from 100:0 to 70:30) to give Intermediate 280 (0.21 g, 66% yield) as a colorless oil. Intermediate 281 was prepared by an analogous reaction protocol as Intermediate 2, starting from Intermediate 280 (0.21 g, 0.43 mmol), to give Intermediate 281 (0.12 g, 78%) as a white solid. Intermediate 282 was prepared by an analogous reaction protocol as Intermediate 3, starting from Intermediate 281 (0.26 g, 0.71 mmol), to give Intermediate 282 (0.16 g, 53% yield) as a colourless oil. Intermediate 283 was prepared by an analogous reaction protocol as Intermediate 272, starting from Intermediate 282 (0.16 g, 0.37 mmol), to give Intermediate 283 (0.12 g, 80% yield). NaH (60% dispersion in oil) (0.84 g, 20.9 mmol) was added portionwise to a solution of I-N- [(1S)-1-(4-bromophenyl)-2,2,2-trifluoro-ethyl]-2-methyl-propane-2-sulfinamide [336105-31-8] (5.00 g, 14.0 mmol) in DMF (50 mL) at 0 °C and under nitrogen. The resulting suspension was stirred at 0 °C for 15 minutes, then a solution of MeI (1.74 mL, 27.9 mmol) in DMF (3 mL) was added. The resulting solution was stirred for 2 h at room temperature. Water (100 mL) was added and then EtOAc (100 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3x 100 mL). The combined organic layers were washed with water (3x 500 mL) and brine, dried over anhydrous MgSO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Mobile phase: Heptane:EtOAc from 90:10 to 70:30) to give Intermediate 284 (2.90 g, 56% yield) as a yellow oil. Alternatively (large scale): To a stirred solution of Intermediate 318 (250 g, 697.89 mmol, 1.00 equiv) and Cs₂CO₃ (682.16 g, 2093.68 mmol, 3.00 equiv) in THF (2.5 L) were added MeI (297.2 g, 2093.7 mmol) at room temperature. The resulting solution was stirred for 24 h at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Mobile phase: Petroleum ether: EtOAc from 100:0 to 90:10) to give Intermediate 284 (160 g, 62%) as a light-yellow oil. To a solution of Intermediate 284 (2.90 g, 7.80 mmol) in 1,4-dioxane (36 mL) at room temperature was added HCl (4M in dioxane, 9.74 mL, 39.0 mmol). The resulting solution was stirred at room temperature for 90 minutes. The precipitate was filtered, washed with Et₂O (20 mL), then air-dried on the frit to give Intermediate 285 (2.19 g, 92% yield), as a white powder. Alternatively (large scale): To a stirred solution of Intermediate 319 (160 g, 429.8 mmol) in EtOAc (160 mL) was added HCl (gas) in EtOAc (640 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The precipitated solids were collected by filtration and washed with MTBE (2x 100 mL) to give Intermediate 285 (100 g, 76%) as a white solid. To a solution of Intermediate 285 (1.59 g, 5.22 mmol) and DIPEA (2.66 mL, 15.7 mmol) in DCM (20 mL) at 0 °C under nitrogen, was added Tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide [841301-53-9] (1.54 g, 7.83 mmol) portionwise. The resulting mixture was stirred overnight at room temperature. DCM and water were added, the organic layer was separated by passing the mixture through a hydrophobic frit and concentrated under vacuum. The resulting residue was purified by flash chromatography (Mobile phase: Heptane:EtOAc from 70:30 to 50:50). The pure fractions were combined and evaporated under vacuum. The residue was crystallized from Et₂O and air-dried on the frit to give Intermediate 286 (1.66 g, 74% yield) as a white solid. To a solution o’ 4'-bromo-2,2,2-trifluoroacetophenone [16184-89-7] (25.0 g, 98.8 mmol) in THF [109-99-9] (500 mL) at 0° C under nitrogen, was added NaBH₄ [16940-66-2] (3.93 g, 104.0 mmol) and the mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was then diluted with EtOAc, and H₂O was added. The aqueous layer was separated and extracted with EtOAc, and the combined organic layers were dried over anhydrous Na₂SO₄, filtered and evaporated under vacuum to give Intermediate 287 (23.6 g, 93.6 % yield) as a colorless liquid. Trifluoromethanesulfonic anhydride [358-23-6] (10.0 mL, 59.2 mmol) was added dropwise to a solution of Intermediate 287 (11.0 g, 43.1 mmol) and 2,6-lutidine [108-48-5] (7.31 mL, 62.7 mmol) in cyclohexane (100 mL) at -10 °C. After 45 min, the mixture was diluted with water and EtOAc, the organic layer was washed with brine, dried over anhydrous Na₂SO₄, filtered and the solvents were evaporated under vacuum to give Intermediate 288 (16.0 g, crude) used as it for the next step. To a stirred solution of Intermediate 288 (3.80 g, 9.82 mmol) and 1-methyl-1H,4H,5H,6H,7H- imidazo[4,5-C]pyridine [87673-88-9] (1.60 g, 11.6 mmol) in DCE (17 mL) under nitrogen, was added Et3N (2.20 mL, 15.2 mmol). The mixture was heated at 50 °C for 1 h and left stirring overnight at room temperature. The mixture was washed with DCM and NaHCO3 (sat. solution), the aqueous phase was washed twice with DCM and the organic layers were dried over anhydrous Na2SO4 and evaporated to dryness. The crude was purified by reverse phase flash LC (Mobile phase gradient water:ACN from 50:50 to 25:75). The fractions containing product were combined and evaporated to give Intermediate 289 (1.60 g, 44% yield) as an orange solid. Iodine (18.0 g, 70.9 mmol) was added portionwise (over 60 minutes) to a mixture of Intermediate 289 (1.58 g, 4.22 mmol) and NaHCO3 (3.80 g, 45.2 mmol) in DMSO (100 mL) and water (50 mL) at 0 °C. The reaction mixture was allowed to warm-up to room temperature and stirred at the same temperature for 18 h. The mixture was added slowly into a mixture of Na2S2O3 (sat. solution, 100 mL) and NaHCO3 (100 mL), the water layer was extracted with ethyl acetate (2x 100 mL), the combined organic layers were washed with water, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude was purified by reverse phase flash chromatography (Mobile phase gradient: ACN: H2O (+ NH4HCO30.2 %) from 10:90 to 100:0). The pure fractions were combined and evaporated under vacuum to provide Intermediate 290 (0.92 g, 54% yield) as a yellow solid. Intermediate 291 and Intermediate 292 Intermediate 290 was purified by preparative chiral SFC. The fractions containing compound were combined and evaporated in vacuo to give two fractions which were taken-up with MeOH, ACN, extended with water and freeze-dried to give: Intermediate 291 (0.44 g, 26% yield) as white solids. Intermediate 292 (0.26 g, 16% yield) as white solids. A solution of Intermediate 288 (3.34 g, 8.64 mmol), 1-methyl-4,5,6,7-tetrahydropyrazolo[4,3- c]pyridine hydrochloride [1392271-80-5] (2.25 g, 13.0 mmol) and K2CO3 (1.91 g, 14.0 mmol) was stirred in THF (80.0 mL) at 75 °C for 1 h. Then, EtOAc (100 mL) and water (100 mL) were added, the organic phase was separated, dried, and evaporated under vacuum. The crude was purified by reverse preparative HPLC (Mobile phase gradient: ACN: H2O (+ NH4HCO3 0.2 %) from 25:75 to 100:0). The fractions containing compound were combined and evaporated under vacuum to give Intermediate 293 (1.84 g, 57% yield) as a yellow paste. Intermediate 294 was prepared by an analogous reaction protocol as Intermediate 290, starting from Intermediate 293 (1.90 g, 5.08 mmol), to give Intermediate 294 (1.47 g, 73% yield) as a yellow solid. Intermediate 295 and Intermediate 296 Intermediate 294 was purified by preparative chiral SFC (Chiralpak IG 30x250 mm, Mobile phase: CO₂ / MeOH 70/30, flow rate : 90 mL/min). The fractions containing compound were combined and evaporated under vacuum to give: Intermediate 295 (0.40 g, 20% yield) as an off-white solid. Intermediate 296 (0.35 g, 18% yield) as an off-white solid. * S Intermediate 297 was prepared by an analogous reaction protocol as Intermediate 289, starting from 1-methyl-1H,4H,5H,6H,7H-[1,2,3]triazolo[4,5-C]pyridine [160752-39-6] (5.00 g, 36.19 mmol) and stirring at 50 °C overnight, to give Intermediate 297 (5.30 g, 39% yield) as a brown oil. To a stirred solution of Intermediate 297 (5.30 g, 14.13 mmol) in chloroform (53.7 mL) and ACN (53.7 mL) was added a solution of ruthenium(IV) oxide hydrate [32740-79-7] (0.26 g, 1.74 mmol) and sodium periodate [7790-28-5] (13.90 g, 65.0 mmol) in distilled water (133 mL). The mixture was stirred for 2h at room temperature, then filtered on Dicalite. Water and DCM were added, the organic layer was dried over MgSO4, filtered, and evaporated to dryness. The crude was purified on flash column chromatography (Mobile phase: DCM: MeOH from 100:0 to 95:5) to give Intermediate 298 (2.53 g, 46% yield). Intermediate 299 and Intermediate 300 A purification was performed via Prep SFC (Stationary phase: Chiralcel Diacel IH 20 x 250 mm, Mobile phase: CO₂, EtOH + 0.4 iPrNH₂). The fractions containing compound were combined and evaporated under vacuum to give: Intermediate 299 (0.72 g, 13% yield) Intermediate 300 (0.70 g, 13% yield) To a mixture of Intermediate 288 (280.0 g, 723 mmol), n-hexane (2.0 L), K₂CO₃ (149.0 g, 1.08 mol) was added tert-butyl N-(2-aminoethyl)carbamate [57260-73-8] (151 g, 942 mmol, 148.04 mL) and the reaction was stirred at 70 °C for 12 hrs. The mixture was added with water (1.5 L) and the organic layer was separated, the aqueous phase was extracted with n-hexane (500 mL), the combined organic layers were washed with brine (1.0 L), dried over Na₂SO₄, filtered, and concentrated to give compound Intermediate 301 (233.0 g, 81.1% yield) as yellow oil. To a mixture of Intermediate 301 (233.0 g, 587.0 mmol) in DCM (1.50 L) and TEA (89.0 g, 879.53 mmol, 122.42 mL) at 0 °C was added ethyl oxalyl chloride [4755-77-5] (120.0 g, 879.0 mmol, 98.4 mL) and the mixture was stirred at 0 °C for 1 h Sat. citric acid (1.00 L) was added and the organic layer was separated, washed with sat. NaHCO₃ (500 mL) and brine (500 mL), dried over Na₂SO₄, filtered and concentrated to give compound Intermediate 302 (200.0 g, 402.17 mmol, 69% yield) as a yellow oil. Gas HCl (N/A) was bubbled into a mixture of Intermediate 302 (200.0 g, 402.17 mmol) in EtOAc (1000 mL) -50 °C for 20 min, then the reaction was stirred at 25 °C for 2 hours. The mixture was concentrated to give compound Intermediate 303 (189.0 g, crude, HCl) as a yellow gum. To a mixture of Intermediate 303 (189.0 g, 476 mmol) in DCM (1.30 L) was added TEA (193 g, 1.90 mol, 265 mL, 4 eq) at 25 °C, then the mixture was stirred at 25 °C for 3 hrs. Sat. citric acid (800 mL) was added, and the mixture was extracted with DCM (500 mL), the organic layer was washed with Sat.NaHCO₃ (800 mL) and brine (800 mL) and dried over Na₂SO₄, filtered, and concentrated to give Intermediate 304 (135.3 g, 385.34 mmol, 81% yield) as off-white solid. To a mixture of Intermediate 304 (103.0 g, 294 mmol) in THF (700 mL) was added P2S5 [19172- 47-5] (83.1 g, 206 mmol) at 25 °C, then the mixture was stirred at 55 °C for 12 hrs. The mixture was concentrated to give crude product. The crude product was purified by column chromatography on silica gel (Mobile phase: Dichloromethane : Methanol, from 100:1 to 10:1) to give Intermediate 305 (92.0 g, 248 mmol, 84% yield) as orange solid. Intermediate 306 To a solution of Intermediate 305 (92.0 g, 250.6 mmol) in n-BuOH (650 mL) was added acetyl hydrazine [1068-57-1] (27.8 g, 375.8 mmol) at 25 °C, then the mixture was stirred at 120 °C for 4 hrs. The mixture was cooled down to room temperature and filtered, and the filter-cake was washed with n-BuOH (2x 100 mL), collected, and dried under vacuum to give Intermediate 306 (50.0 g, 51% yield) as a light-yellow solid. purification was performed via Prep SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO₂, EtOH). The fractions containing compound were combined and evaporated under vacuum to give: Intermediate 307 (4.30 g, 43% yield) Intermediate 308 (4.45 g, 45% yield) 309 To a solution of hydrazine hydrate [10217-52-4] (3.68 mL, 49.1 mmol) in ethanol (20 mL) in a sealed tube was added ethyl difluoroacetate [454-31-9] (6.00 g, 48.4 mmol) dropwise, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum to give Intermediate 309 (5.57 g, quantitative yield) as a colorless oil. Intermediate 310 Intermediate 305 (30.0 g, 81.7 mmol) and Intermediate 309 (44.9 g, 408 mmol) were added with n-butanol (600 mL) and the reaction mixture was heated to 90 °C for 1 h. Ethyl 2,2- difluoroacetate [454-31-9] (101 g, 817 mmol) was added dropwise at 90 °C and the reaction was stirred at 90 °C for 1 h. The mixture was cooled to 25 °C and filtered, the filter cake was concentrated under reduced pressure to give Intermediate 310 (20.0 g, 57% yield). Intermediate 311 and Intermediate 312 Intermediate 310 (6.4 g, mmol) was purified by preparative chiral SFC (Stationary phase : Chiralpak AD-H 20x250 mm, Mobile phase: CO₂ / MeOH 80/20). The fractions containing compound were combined and evaporated to give: Intermediate 311 (1.89 g, 14% yield) as a yellow solid. Intermediate 312 (1.91 g, 15% yield) as 313 Intermediate 313 was prepared by an analogous reaction protocol as Intermediate 289, starting from 3-methyl-5,6,7,8-tetrahydroimidazo[1,5-A]pyrazine [734531-00-1] (3.65 g, 26.6 mmol). After purification the desired product was washed with DCM and 3 N aqueous solution of NaOH. The mixture was extracted with DCM (3x), the organics layers were combined, dried over MgSO4, filtered and the solvent was evaporated in vacuo to give Intermediate 313 (1.20 g, 14% yield) as a yellow oil. Intermediate 314 Intermediate 314 was prepared by an analogous reaction protocol as Intermediate 298, starting from Intermediate 313 (1.21 g, 3.23 mmol), to give Intermediate 314 (0.38 g, 31% yield) as brown foam. Intermediate 315 and Intermediate 316 Intermediate 314 was purified by preparative chiral SFC (Stationary phase: Chiralpak OJ-H 20x250 mm, Mobile phase: CO₂ / (MeOH + 0,3% iPrNH₂) 90/10). The fractions containing compound were combined and the solvent was evaporated under vacuum to give: Intermediate 315: (0.16 g, 13% yield) as grey oil. Intermediate 316: (0.15 g, 12% yield) as grey oil. A mixture of 4-bromo-benzaldehyde [1122-91-4] (400 g, 2161.92 mmol) aI(R)-2- methylpropane-2-sulfinamide (262.03 g, 2161.92 mmol) in toluene (1600 mL) was treated with NaOH (95.12 g, 2378.12 mmol, 1.10 equiv) at room temperature. The resulting mixture was stirred for 12 h at room temperature. Then Na₂SO₄ (40 g) was added and stirred for 10 min at room temperature. The resulting mixture was filtered. The filtrate was concentrated under vacuum to give Intermediate 317 (640 g, 90% yield) as a light-yellow solid. The crude product was used in the next step directly without further purification. I To a stirred solution of Intermediate 317 (500 g, 1561.41 mmol) and tetrabutylammonium acetate [10534-59-5] (470.78 g, 1561.41 mmol) in THF (2500 mL) were added trifluoromethyltrimethylsilane [81290-20-2] (555.07 g, 3903.54 mmol) dropwise over 2 h at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0 °C. The resulting mixture was poured into saturated NH₄Cl aqueous solution (5000 mL) at 0-10 °C and stirred at 0-10 °C for 10 min. The precipitated solids were collected by filtration and washed with H₂O (2x 1000 mL) to give Intermediate 318 (253.0 g, 45% yield) as a white solid. Intermediate 319 A solution of (S)-1-Boc-piperidine-3-carboxylic acid [88495-54-9] (145 g, 632.42 mmol) in EtOAc (2900 mL) was treated with H₂O (2900 mL) followed by the addition of NaIO₄ (541.08 g, 2529.70 mmol, 4.00 equiv) and RuCl₃.H₂O (1.43 g, 6.32 mmol, 0.01 equiv). The resulting mixture was stirred vigorously for 16 h at room temperature. The resulting mixture was diluted with water and extracted with EtOAc (3x 1 L). The combined organic layers were washed with brine (1 L), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure and the crude was purified by silica gel column chromatography (Mobile phase: DCM: MeOH from 100:0 to 95:5 to give Intermediate 319 (70 g, 46% yield) as a grey solid. Intermediate 320 A solution of Intermediate 285 (100 g, 328.36 mmol) and Intermediate 319 (95.85 g, 394.03 mmol) in dry DMF (1000 mL) was treated with pyridine (116.88 g, 1477.63 mmol) followed by the dropwise addition of propylphosphonic anhydride [68957-94-8] (313.44 g, 985.09 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 50 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and quenched by addition of water (2.0 L). The resulting mixture was extracted with EtOAc (3x 1000 mL). The combined organic layers were washed with brine (1000 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography (Mobile phase: petroleum ether: EtOAc from 100:0 to 70:30) to give Intermediate 320 (50.46 g, 31% yield) as a white solid. A solution of Intermediate 285 (12.0 g, 39.4 mmol) in anhydrous DCM (150 mL) was added to a solution of tetrahydro-2H-thiopyran-4-carbonyl chloride [121654-84-0] (10.5 g, 63.7 mmol) in anhydrous DCM (90 mL) and DIPEA (20.1 mL, 118 mmol) at 0 °C. The solution was stirred at rt for 3 h. Then water was added to the mixture, the layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO₄, filtered, evaporated and the crude was purified by normal phase preparative LC (Mobile phase: DCM:EtOAc from 100:0 to 93:07). The fractions containing compound were combined and evaporated under vacuum to give Intermediate 321 (11.9 g, 75% yield) as a yellowish oil. Under nitrogen, a solution of 3-chloroperbenzoic acid [937-14-4] (8.14 g, 33.0 mmol) in anhydrous DCM (140 mL) was added at -78 °C to a solution of Intermediate 321 (11.9 g, 30.0 mmol) in anhydrous DCM (60 mL). The reaction mixture was stirred at -78 °C for 4 h. A 10% aqueous solution of NaHCO₃ and DCM were added. The mixture was extracted with DCM (3x), the organics layers were combined, dried over MgSO₄, filtered, the solvent was evaporated under vacuum. The crude was purified by normal phase preparative LC (Mobile phase: DCM:iPrOH from 100:0 to 91:9) . The fractions containing product were combined and evaporated to give Intermediate 322 (9.82 g, 79% yield) as a white solid. In a sealed tube, iodobenzene diacetate [3240-34-4] (11.1 g, 34.5 mmol) was added to a suspension of Intermediate 322 (9.50 g, 23.0 mmol), tert-butyl carbamate [4248-19-5] (4.05 g, 34.5 mmol), magnesium oxide [1309-48-4] (3.71 g, 92.2 mmol) and rhodium(II) acetate dimer [15956-28-2] (509 mg, 1.15 mmol) in DCM (133 mL) at room temperature. The reaction mixture was stirred at 40 °C for 18 h. The mixture was filtered through a pad of Celite, and the filtrate was evaporated. The crude was purified by normal phase preparative LC (Mobile phase: heptane:EtOAc from 100:0 to 40:60). The fractions containing compound were combined and the solvent was evaporated under vacuum to give Intermediate 323 (9.50 g, 78% yield) as a white solid. Intermediate 237 (50 mg, 0.289 mmol, 95 % purity), Intermediate 286 (62 mg, 0.145 mmol), BrettPhos Pd G3 [1470372-59-8] (7 mg, 0.007 mmol), BrettPhos [1070663-78-3] (4 mg, 0.007 mmol) and cesium carbonate (71 mg, 0.217 mmol) were placed in a sealed tube. The tube was purged with nitrogen, and anhydrous 1,4-dioxane (5 mL) was added. The mixture was heated at 120 °C for 2 hours. The mixture was cooled to room temperature and concentrated in vacuum. The residue was purified by prep-HPLC (Column: Xbridge C18 (5 µm 19 *150 mm), Mobile Phase A: Water (0.1 % ammonium bicarbonate), Mobile Phase B: acetonitrile, UV: 214 nm, Flow rate: 15 mL / min, Gradient –: 30 - 70 % (%B) to give Intermediate 324 (27.3 mg, 37% yield) as an off-white solid. The following were synthesized by an analogous method as described for Intermediate 324, starting from Intermediate 286 and performing the reaction in toluene overnight. Starting Resulting Int. No. Structure material Intermediate Intermediate 325 241 Intermediate Intermediate 326 245 1- Phenylpyrazo Intermediate 351 le 4-amine [1128-53-6] 3,4-dihydro-2H-pyran (12.1 mL, 133.0 mmol) and p-toluenesulfonic acid monohydrate (0.42 g, 2.21 mmol) were added to a stirred solution of 4-nitro-1H-pyrazole (5.00 g, 44.2 mmol) in THF (14 mL) at room temperature and the mixture was stirred overnight. The solvent mixture was concentrated under vacuum and the was purified by flash column chromatography (Mobile phase: Heptane:EtOAc from 95:5 to 20:80) to give Intermediate 327 (8.65 g, 99% yield) as a yellow oil. Intermediate 327 (1.62 g, 8.21 mmol) was dissolved in EtOH (19 mL) and water (9.0 mL) was added. NH₄Cl (2.20 g, 41.1 mmol) and iron powder (2.30 g, 41.1 mmol) was added and the resulting mixture heated to 70 °C for 3 h. The mixture was cooled to room temperature, diluted with EtOAc and water, and the layers were separated. The water layer was washed once with EtOAc. Organic layers were combined, dried over Na₂SO₄, filtered, and evaporated to dryness to give Intermediate 328 (1.4 g, 76% yield) as a dark red oil. I i 2 Intermediate 329 was prepared by an analogous reaction protocol as Intermediate 324, starting from Intermediate 328 (1.4 g, 8.37 mmol) and heating the reaction at 115 °C for 90 minutes, to give Intermediate 329 (1.66 g, 57% yield) as a pink solid. HCl (4M in dioxane, 7.3 mL, 29.2 mmol) was added at room temperature to a stirred solution of Intermediate 329 (1.5 g, 2.92 mmol) in MeOH (10 mL) and the mixture was stirred at room temperature overnight. The solution was concentrated under vacuum, the residue was redissolved in DCM and added with NaHCO₃ (sat. solution). The layers were separated, and the aq. phase was extracted with DCM (2x). The combined organic phases were dried over sodium sulfate, filtered, and evaporated to dryness to give Intermediate 330 (0.989 g, 79% yield) as a beige solid. A solution containing Intermediate 330 (61.12 mg, 0.14 mmol), bis[(tetrabutylammonium iodide)copper(I) iodide] [81412-07-9] (6.7 mg, 5.81 umol), tra’s-N,N'-dimethylcyclohexane- 1,2-diamine [67579-81-1] (18.66 ul, 0.118 mmol) under nitrogen was added with 1,4-dioxane (1.3 mL), 4-bromo-5-methylthiazole [132221-51-3] (22.18 mg, 0.12 mmol) and Cs2CO3 (113.54 mg, 0.35 mmol). The reaction was stirred at 100 °C for 12 h. The reaction was cooled to room temperature and SiliaMetS DMT (54.63 mg) was added in each reaction, stirred for 2 hours, and filtered. Additional EtOAc (1mL) was used to wash the filters followed by 500 µl of DMSO. The crudes were concentrated in a Genevac until only DMSO remained.2.5 mL of a ACN/MeOH 1:1 mixture was added, and the solution was submitted to HTE purification, to give Intermediate 331 (26.06 mg, 35% yield). Intermediate 332 was prepared by an analogous reaction protocol as Intermediate 331, starting from 3-bromoisothiazole [55512-82-8] (19.42 mg, 0.12 mmol) and using K₂CO₃ (49.1 mg, 0.36 mmol) instead of Cs₂CO₃, to give Intermediate 332 (24.96 mg, 34% yield). ACN (3.8 mL) was added under nitrogen atmosphere to a mixture of Intermediate 330 (60 mg, 0.1 mmol), 5-bromo-1,2,4-thiadiazole [43201-13-4] (46 mg, 0.3 mmol) and LiOH (10 mg, 0.4 mmol). The resulting mixture was stirred at 100 °C for 12 h. After cooling to rt, the crude mixture was diluted with acetonitrile and filtered through Celite. The filtrate was purified by prep HPLC (Stationary phase: RP XBridge Prep C18 OBD- 5µm, 50x250mm, Mobile phase: 0.25% NH₄HCO₃ solution in water, CH3CN) to give Intermediate 333 (15 mg, 21% yield) as a pale yellow solid. Intermediate 334 was prepared by an analogous reaction protocol as Intermediate 320, starting from 1-(tert-butoxycarbonyl)-6-oxopiperidine-3-carboxylic acid [1779990-74-7] (1.00 g, 4.11 mmol) and using DIPEA (2.2 ml, 12.8 mmol) instead of Pyridine, to give Intermediate 334 (0.78 g, 35% yield, 71% purity). Compounds Compound 1 Intermediate 4, (120 mg, 0.51 mmol), Intermediate 286 (219 mg, 0.51 mmol), BrettPhos Pd G3 (23 mg, 0.025 mmol), BrettPhos (14 mg, 0.026 mmol) and Cs2CO3 (250 mg, 0.77 mmol) were placed in a microwave tube. The tube was sealed, anhydrous 1,4-dioxane (5 mL) was added and the resulting mixture was purged with nitrogen for 5 min, then heated to 120 °C for 2 hours. After this time, the reaction mixture was cooled to room temperature and concentrated in vacuum. The resulting residue was purified by flash column chromatography, using as eluent a gradient heptane/EtOAc, 100% to 50%, to provide the desired product as a solid. The solid was solubilized in ACN and evaporated in vacuo to afford compound 1 as a white foam (220 mg, 74 %). Table 1 below lists additional compounds that were prepared by analogy to the above examples, starting from Intermediate 4 and the appropriate bromoaryl intermediate, as indicated. If applicable, conventional protecting groups (such as Boc protecting group) were removed according to standard procedures known to the skilled person. To obtain some of the compounds, SFC separation was required. Reagents used in the synthesis of the compounds are either commercially available or can be made by procedures known to the skilled person. Table 1 Co.No. Structure Prepared from Yield (%) 2 Intermediate 33 334 Co.No. Structure Prepared from Yield (%) 10 Intermediate 22 323 11 Intermediate 42 299 Compounds 12-34. A mixture of Intermediate 248 (0.06 g, 0.3 mmol) added under nitrogen to Intermediate 286 (0.064 g, 0.15 mmol), BrettPhos Pd G3 (0.007 g, 0.0075 mmol), BrettPhos (0.004 g, 0.0075 mmol), and Cs₂CO₃ (73 mg, 0.22 mmol) was evacuated and back filled with nitrogen 3 times, and then anhydrous dioxane (5 mL) was added. The mixture was heated at 120 °C for 120 min. The mixture was allowed to cool down at rt and was concentrated in vacuum. The residue was purified by prep-HPLC (Column: Xbridge C18 (5 µm 19 *150 mm), Mobile Phase A: Water (0.1 % ammonium bicarbonate), Mobile Phase B: acetonitrile, UV: 214 nm, Flow rate: 15 mL / min, Gradient: 30 – 70 % (%B)) to give Compound 12 (70.4 mg, 85 % yield) as an off-white solid. Table 2 below lists additional compounds that were prepared by analogy to the above examples, starting from Intermediate 286 and the appropriate aminopyrazoles as indicated in the table. Reagents used in the synthesis of the compounds are either commercially available or can be made by procedures known to the skilled person. Table 2 Co.No. Structure Prepared from Yield (%) 13 Intermediate 31 52 14 Intermediate 222 9 15 Intermediate 258 23 16 Intermediate 267 46 17 Intermediate 253 26 18 Intermediate 277 25 Co.No. Structure Prepared from Yield (%) 26 Intermediate 217 2 27 Intermediate 13 8 28 Intermediate 182 2 29 Intermediate 186 52 30 Intermediate 228 59 31 Intermediate 207 40

Co.No. Structure Prepared from Yield (%) 32 Intermediate 201 70 33 Intermediate40 11 34 Intermediate 213 40 Step 1 A solution of Intermediate 173 (0.026 g, 0.062 mmol) in anhydrous dioxane (0.3 mL) was added under nitrogen to Intermediate 286 (0.034 g, 0.058 mmol), Pd2dba3 (0.005 g, 0.005 mmol), EPhos (0.005 g, 0.010 mmol), and Cs2CO3 (35 mg, 0.11 mmol). The mixture was evacuated and back filled with nitrogen 3 times, and then it was heated at 100 °C for 120 min. The mixture was allowed to cool down at rt, it was diluted with EtOAc and filtered over Celite. The filtrate was evaporated under reduced, and the resulting residue was purified by flash column chromatography (4G SiO₂, MeOH in DCM, 0% to 2%) to give Intermediate 335 (29 mg, 84% purity, 64% yield) as a yellow foam. Step 2 A suspension of intermediate Intermediate 335 (29 mg, 0.044 mmol) and Pd/C (10%) (spatula spoon) in a MeOH (2 mL) was stirred at room temperature under H₂ atmosphere (1 atm) for 6 hours. Reaction was filtered through Dicalite, extra Pd/C (10%) was added, and reaction was stirred at 50 °C for 18 hours under H₂ atmosphere. The mixture was filtered through Dicalite, concentrated, and purified twice by flash column chromatography (Redisep CombiFlash, silica, 24 g; MeOH in DCM 0% to 5%) to yield Compound 35 (4.1 mg, yield 16.4%) as a transparent film. TMSCl (179 µL, 1.41 mmol) was added dropwise to a solution of Compound 30 (107 mg, 0.177 mmol) and NaI (212 mg, 1.41 mmol) in dry acetonitrile (0.8 mL) under nitrogen. The reaction mixture was stirred at rt for 1 h. A solution of saturated Na2S2O3 and EtOAc were added. The mixture was extracted with EtOAc (3x). The organics layers were combined, washed with brine, dried over MgSO4, filtered and the solvent was evaporated in vacuo. The resulting residue was purified (regular SiOH, 12 g, liquid loading (DCM), mobile phase: MeOH in DCM 0% to 5%) to give a first fraction of compound 37 which was further purified by prep-HPLC (Column YMC –Actus Triart Prep C18-S 150*30 mm 10 µm Flow rate 50 mL/min-Focused gradient MeCN/aq.NH4HCO30.2% pH=7.9 Focused gradient from 25/75 to 65/35) to give Compound 36 (46 mg, 44% yield) as a white solid. A thin tube was filled with Intermediate 333 (17 mg, 0.032 mmol), sodium trifluoromethanesulfinate (5.3 mg, 0.034 mmol), ammonium persulfate (8.2 mg, 0.036 mmol) and (Ir[dF(CF3)ppy]₂(dtbpy))PF6 (0.5 mg, 0.45 µmol), then DMSO (0.3 mL) and H₂O (31 µL) were added. The reaction mixture was degassed with nitrogen for 5 min, then reacted in a Penn Phororeactor UV-150 irradiating with blue LED 450nm for 1h at 300 rpm. The reaction mixture was poured into water and EtOAc, the resulting biphasic mixture separated, and the aqueous layer extracted with 2xEtOAc. The combined organic layer was washed 2xbrine, dried over Na₂SO₄, filtered, and evaporated in vacuo. The resulting residue was purified via Prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 50x150mm, Mobile phase: 0.25% NH₄HCO₃ solution in water, CH₃CN). The resulting material was further purified via Prep SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO₂, EtOH + 0.4 iPrNH₂), to provide Compound 37 (5 mg, 27% yield) Table 3 below lists additional compounds that were prepared by analogy to the above example, starting from the appropriate substituted aminopyrazoles as indicated in the table. Reagents used in the synthesis of the compounds are either commercially available or can be made by procedures known to the skilled person. Table 3 Co.No. Structure Prepared from Yield (%) 38 Intermediate 25 351 39 Intermediate 3 351 40 Intermediate 24 325 Co.No. Structure Prepared from Yield (%) 41 Intermediate 4 325 42 Intermediate 22 331 43 Intermediate 12 324 44 Intermediate 23 326 45 Intermediate 35 332

Compound 46 was prepared according to the procedure for Compound 1, starting from Intermediate 31 (0.12 g, 0.53 mmol) and Intermediate 334 (0.22 g, 0.44 mmol), followed by a Boc deprotection, to give Compound 46 as a white solid (0.043 g, 11% yield). Table 4 below lists additional compounds that were prepared by analogy to the above example, starting from Intermediate 31 and the appropriate bromoaryl intermediate, as indicated. If applicable, conventional protecting groups (such as Boc protecting group) were removed according to standard procedures known to the skilled person. To obtain some of the compounds, SFC separation was required. Reagents used in the synthesis of the compounds are either commercially available or can be made by procedures known to the skilled person. Table 4 Co.No. Structure Prepared from Yield (%) 47 Intermediate 334 19 48 Intermediate 307 32 49 Intermediate 320 58 Co.No. Structure Prepared from Yield (%) 50 Intermediate 311 10 51 Intermediate 312 10 52 Intermediate 299 25 53 Intermediate 300 25 Compound 54 was prepared according to the procedure for Compound 1, starting from Intermediate 272 (0.07 g, 0.3 mmol) and Intermediate 334 (0.154 g, 0.3 mmol), followed by a Boc deprotection as described for Compound 91, to give Compound 54 as a yellow solid (0.055 g, 32% yield). Table 5 below lists additional compounds that were prepared by analogy to the above example, starting from Intermediate 334 (or intermediate 320 enantiopure) and the appropriate aminopyrazole, as indicated. If applicable, conventional protecting groups (such as Boc protecting group) were removed according to standard procedures known to the skilled person. To obtain some of the compounds, SFC separation was required. Reagents used in the synthesis of the compounds are either commercially available or can be made by procedures known to the skilled person. Table 5 Co. Structure Prepared from Yield (%) No. 55 Intermediate 272 32 with Intermediate 334 56 Intermediate 272 32 with Intermediate 334 57 Intermediate 9 42 (yield over with Intermediate 2 steps – 334 Buchwald and deprotection) 58 Intermediate 9 42 with Intermediate 334 Co. Structure Prepared from Yield (%) No. 59 Intermediate 142 64 with Intermediate 320 60 Intermediate 195 66 with Intermediate 320 61 Intermediate 68 98 with Intermediate 334 62 Intermediate 68 98 with Intermediate 334 63 Intermediate 93 30 with Intermediate 320 64 Intermediate 57 56 with Intermediate 320 65 Intermediate 110 40 with Intermediate 334 Co. Structure Prepared from Yield (%) No. 66 Intermediate 76 36 with Intermediate 320 67 Intermediate 110 14 with Intermediate 334 68 Intermediate 166 30 with Intermediate 320 69 Intermediate 134 78 with Intermediate 320 70 Intermediate 22 75 Combined with Intermediate 320 71 Intermediate 73 73 with Intermediate 320 72 Intermediate 160 73 with Intermediate 320 Co. Structure Prepared from Yield (%) No. 73 Intermediate 102 53 with Intermediate 320 74 Intermediate 87 73 with Intermediate 320 75 Intermediate 35 60 with Intermediate 320 76 Intermediate 170 24 with Intermediate 320 77 Intermediate 82 72 with Intermediate 320 78 Intermediate 26 54 with Intermediate 320 79 Intermediate 156 91 with Intermediate 320 Co. Structure Prepared from Yield (%) No. 80 Intermediate 106 28 with Intermediate 320 81 Intermediate 138 58 with Intermediate 320 82 Intermdiate 98 72 Combined with Intermediate 320 83 Intermediate 128 86 with Intermediate 320 84 Intermediate 62 15 with Intermediate 320 85 Intermediate 178 44 with Intermediate 320 86 Intermediate 152 49 with Intermediate 320 Co. Structure Prepared from Yield (%) No. 87 Intermediate 262 40 with Intermediate 320 88 Intermediate 116 100 with Intermediate 320 89 Intermediate 52 50 with Intermediate 320 90 Intermediate 122 100 with Intermediate 320 Intermediate 233(0.11 g, 0.40 mmol), Intermediate 320 (0.2 g, 0.403 mmol), Pd G3 BrettPhos (37 mg, 0.040 mmol), Brettphos (22 mg, 0.040 mmol) and Cs₂CO₃ (200 mg, 0.60 mmol) were added to a 40 mL vial. Next, 1,4-dioxane (6.8 mL) was added, and the mixture was bubbled with nitrogen for 5min. Then, the mixture was heated to 110°C for 1.5h, after which it was cooled to room temperature. Then, ethyl acetate was added, and the mixture was filtered over Dicalite. The filtrate was evaporated and purified by silica (24g, DCM loading, MeOH in DCM 0 to 7%) to give the Intermediate 336 (200 mg, 72% yield). Step 2 Intermediate 336 (200 mg, 0.29 mmol) was dissolved in 1,4-dioxane (2.7 mL), after which 4N HCl in 1,4-dioxane (0.37 mL, 1.5 mmol) was added. The resulting mixture was stirred at ambient temperature. Next, saturated aqueous solution of NaHCO₃ and ethyl acetate were added. The layers were separated, and the water layer extracted once more with ethyl acetate. Organic layers were combined, dried over Na2SO4, filtered, and evaporated. The residue was purified by silica (24g, DCM loading, MeOH in DCM 0 to 8%) to give Intermediate 337 (0.16 g, 94% yield). Step 3 Intermediate 337 (80 mg, 0.14 mmol) was dissolved in MeOH (5 mL) and the mixture was purged with nitrogen. After 5min, Pd/C (10%) was added under nitrogen. Then, nitrogen atmosphere was exchanged for hydrogen (balloon), and the resulting mixture stirred at ambient temperature for 2h. Then, the mixture was filtered, and purified via RP-prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 50x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH₃CN) to give Compound 91 (25 mg, 33% yield). Compound 92

Intermediate 339 Compound 92 Step 1 Intermediate 40 (0.24 g, 0.62 mmol), Intermediate 320 (310 mg, 0.62 mmol), Pd G3 BrettPhos (56 mg, 0.062 mmol), Brettphos (33 mg, 0.062 mmol) and Cs2CO3 (304 mg, 0.93 mmol) were added to a 40 mL vial. Next, 1,4-dioxane (11 mL) was added, and the mixture was bubbled with nitrogen for 5min. Then, the mixture was heated to 110 °C for 3 h, after which it was cooled to ambient temperature. Then, ethyl acetate was added, and the mixture was filtered over Dicalite. The filtrate was evaporated, purified twice by flash column chromatography on silica (MeOH in DCM 0 to 8% first time, EtOAc in heptane 0 to 80% second time) to give Intermediate 338 (0.11 g, 22%). Step 2 A mixture of Intermediate 338 (110 mg, 0.13 mmol) and Pd/C (10%) were hydrogenated at rt for 2.5 h. Then, the mixture was filtered through Dicalite, and the filtrate evaporated. The residue was purified by silica (24g, DCM loading, MeOH in DCM 0 to 5%) to give Intermediate 339 (42 mg, 31%, 61% purity). Step 3 Intermediate 339 (42 mg, 0.064 mmol) was dissolved in 1,4-dioxane (1.5 mL) after which 4 N HCl in 1,4-dioxane (0.10 mL, 0.4 mmol) was added. The resulting mixture was stirred at ambient temperature for 2 h. Next, the mixture was poured in a saturated solution of NaHCO3 solution and ethyl acetate was added. The layers were separated, and the water layer extracted once more with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered, and evaporated. The residue was purified via RP-prep HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 50x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to give Compound 92 (14 mg, 0.025 mmol, Y=39%). Compound 93 Step 1 Intermediate 283 (crude from previous step, 85% purity, 116 mg, 0.29 mmol), Intermediate 320 (144 mg, 0.29 mmol), Pd G3 BrettPhos (13 mg, 0.014 mmol), BrettPhos (8 mg, 0.015 mmol) and cesium carbonate (141 mg, 0.43 mmol) were placed in a vial. The vial was closed and anhydrous 1,4-dioxane (3.5 mL) was added. The mixture was purged with nitrogen for 5 min. The mixture was heated at 100°C for 2 hours. The reaction mixture was filtered over Dicalite and washed with EtOAc. The filtrate was evaporated in vacuo. The crude was purfied by flash chromatography (EtOAc in Heptane 0% to 100%) to afford intermediate 340 (159 mg, 73%) as a white foam. Step 2 Intermediate 340 (25 mg, 0.033 mmol) was dissolved in dry DCM (1 ml) and zinc bromide (37 mg, 0.16 mmol) was added. The mixture was stirred at room temperature for 16 h. The solution in DCM was washed with a saturated solution of NaHCO3. The organic layer was dried on sodium sulfate, filtered, and evaporated in vacuo to give Intermediate 341 (30 mg, crude pure at 76%) and used as such into the next step. Step 3 Intermediate 341 (30 mg, 0.035 mmol) in MeOH (12.5 ml) under nitrogen atmosphere was added Pd/C 5% (20 mg, 0.0094 mmol). The mixture was stirred for 12h. The mixture was filtered on Dicalite and evaporated in vacuo. The crude was purified by flash chromatography (MeOH in DCM 0% to 5%) to afford Compound 93 (9 mg, yield 46%) as a light-yellow solid. Step 1 In a sealed vessel, a suspension of Intermediate 45 (300 mg, 1.10 mmol), Intermediate 320 (650 mg, 1.32 mmol), BrettPhos (59.0 mg, 0.110 mmol) and Cs2CO3 (537 mg, 1.65 mmol) in dry 1,4-dioxane (11 mL) was bubbled under nitrogen for 5 min. Then, Pd G3 BrettPhos (99.6 mg, 0.110 mmol) was added, and the reaction mixture was degassed under nitrogen (3 x draining/filling) and heated at 120 °C using one single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400 W for 15 min [fixed hold time]. The reaction mixture was filtered through a pad of Dicalite and washed with EtOAc (3 x 20 mL). The filtrate was washed with a saturated solution of NaHCO3 and extracted with ethyl acetate. The organics layers were combined, washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The resulting residue was purified twice by flash column chromatography on silica (MeOH in DCM 0 to 10%, followed by a second purification with EtOAc in heptane 0 to 80%) to give Intermediate 342 (310 mg, 41%) as a yellow oil. Step 2 To a mixture of Intermediatte 342 (280 mg, 408 µmol) in dichloromethane (2.6 mL) was added TFA (482 µL, 613 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under vacuum and the residue was taken up in DCM and 10% aqueous solution of K2CO3 then, was extracted with DCM. The organic layers were collected, dried over MgSO4, filtered, and concentrated under vacuum to give Intermediate 343 (198 mg, 83%) as a yellow solid. Step 3 A solution of Intermediate 343 (198 mg, 338 µmol), Zinc dust (177 mg, 2.71 mmol) and ammonium chloride (145 mg, 2.71 mmol) in water (841 µL) and THF (850 µL) was stirred at room temperature for 2 h. The mixture was filtered off on a pad of Dicalite and washed with DCM (20 mL). The filtrate was extracted with 10 % aqueous solution of K₂CO₃ (10 mL). The organic layers were collected, dried over MgSO₄, filtered, and concentrated under vacuum. The resulting residue was taken-up with CH₃CN (2 mL), extended with water (4 mL) then freeze-dried to give 116 mg as a white solid. The resulting solid was purified via Reverse phase (Stationary phase: YMC-actus Triart C18 10 µm 30*150 mm, Mobile phase: Gradient from 40% (aq. NH₄HCO₃0.2% pH=7.9)/CH₃CN from 95/5 to 70/30). The fractions containing product were combined and concentrated under vacuum then taken-up with CH₃CN (2 mL), extended with water (4 mL) then freeze-dried to give Compound 94 (85 mg, 45% yield) as a white solid. To a solution of Compound 86 (50 mg, 0.084 mmol) in MeOH (0.6 mL) and THF (2 mL), was added a solution of LiOH (6.002 mg, 0.251 mmol) in H2O (0.6 mL). The mixture was stirred at room temperature for 2 h. The residue was submitted to Prep-HPLC with the following Column: XSelect CSH C18 Column, 30*150 mm, 5µm; Mobile Phase A: Water (0.1% TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient: 29% B to 59% B in 7 min; Wave Length: 254nm nm; Rt1(min): 5.33. After the product was lyophilized, it provided Compound 95 (17mg, 40) as a yellow solid. Compound 96 was prepared according to the following procedure. Step 1 Intermediate 178 (0.466 g, 1.50 mmol), Intermediate 320 (0.780 g, 1.58 mmol), BrettPhos Pd G3 (0.184 g, 0.2 mmol), BrettPhos (0.110 g, 0.20 mmol), Cesium carbonate (0.772 g, 2.37 mmol) and 1,4-dioxane (28 mL) were purged with nitrogen for 5 minutes, and then heated at 110 °C for 2 h under nitrogen. The reaction mixture was cooled down at room temperature, filtered through Dicalite, rinsed with ethyl acetate and the filtrate was concentrated under vacuo. The residue was purified by flash column chromatography (Redisep CombiFlash, silica, 120 g; EtOAc in n-heptane 0% to 40%, then to 70%) to afford Intermediate 344 (1.03 g, yield 94%) as light brown foam. Step 2 HCl (4 M in dioxane; 0.5 mL, 2 mmol) was added to a stirred solution of Intermediate 344 (0.17 g, 0.2 mmol) in 1,4-dioxane (1.6 mL). The reaction was stirred at room temperature for 3.5 h, then diluted with water and sat. NaHCO₃ solution was added, followed by ethyl acetate. Phases were separated, aqueous mixture extracted with EtOAc (x3) and combined organic layers were dried over MgSO₄, solids filtered, and solvents removed. Crude was then purified by flash column chromatogrpahy (Redisep CombiFlash, silica, 40 g; MeOH/NH₃7 N in DCM 0% to 2%, then to 5%) to yield compound 153 (0.13 g, 96% yield) as a light-yellow residue that was used in the following step without further purification. Step 3 Compound 153 (3.13 g, 5.23 mmol) was dissolved in MeOH/NH₃ (7N; 36 mL) in a round- bottom flask, and the resulting mixture was stirred at room temperature for 1 h. Crude was then diluted with EtOAc and mixture evaporated to dryness under vacuo. Crude was purified by flash column chromatography (Redisep CombiFlash, silica; MeOH in DCM 0% to 4%, then to 7%). The residue was crystallized iPrOH to afford Compound 96 (2.3 g, yield 75 %) as a white, crystalline solid. Table 6 below lists additional compounds that were prepared by analogy to the above example, starting from Intermediate 178 and the appropriate bromoaryl intermediate, as indicated. In general, conventional protecting groups (such as Boc protecting group) can be removed accordance with standard practice known to the skilled person. Reagents used in the synthesis of the compounds are either commercially available or can be made by procedures known to the skilled person. Table 6 Co.No. Structure Prepared from Yield (%) Intermediate 312 51 over two steps 97 Intermediate 299 56 over two steps 98 Intermediate 300 61 99 Intermediate 307 52 100 Compound 101 Step 1 Intermediate 178 (90 mg, 0.31 mmol), Intermediate 286 (112 mg, 0.26 mmol), BrettPhosPdG3 (24 mg, 0.026 mmol), Brettphos (14 mg, 0.026 mmol) and Cs₂CO₃ (128 mg, 0.39 mmol) were added to a 40 mL vial. 1,4-dioxane (4.4 mL) was added, and the mixture was bubbled with nitrogen for 5 min. Then, the mixture was heated to 110 °C for 1.5 h, after which it was cooled to ambient temperature. Ethyl acetate was added, and the mixture was filtered over Dicalite. The filtrate was evaporated and purified via flash column chromatography (Gradient: 0-10% MeOH/DCM) to give Compound 154 (0.17 g, 0.25 mmol, 94% yield, 92% purity), which was used without further purification. Step 2 Compound 154 (170 mg, 0.25 mmol, 92% purity) was dissolved in THF (2.0 mL) and LiOH (12 mg, 0.49 mmol) in water (1.0 mL) was added. The resulting mixture was stirred at 50 °C for 5 h. Next, the mixture was cooled to ambient temperature and neutralized by the addition of sat. aq. NH₄Cl solution. Then, the mixture was evaporated to dryness. The residue was taken up into a mixture of ethyl acetate and water and the water layer was acidified by the addition of 1M aq. HCl solution. The layers were separated, and the water layer extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over Na₂SO₄, filtered, and evaporated to give Compound 155 (160 mg, 0.26 mmol), which was used in the next step without further purification. Step 3 Compound 155 (80 mg, 0.13 mmol), NH₄Cl (14 mg, 0.26 mmol) and HATU (98 mg, 0.26 mmol) were placed in a 20 mL vial, after which CH₃CN (3.0 mL) was added, followed by DIPEA (67 µL, 0.39 mmol). The resulting mixture was stirred at room temperature overnight. Next, water was added, and the resulting mixture stirred at room temperature for ~5min. Then, the mixture was diluted with ethyl acetate and transferred into a separatory funnel. The layers were separated, and the aqueous phase extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over Na₂SO₄, filtered, and evaporated to dryness. The residue was purified via reverse phase preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 50x150mm, Mobile phase: 0.25% NH₄HCO₃ solution in water, CH₃CN) to give Compound 101 (51 mg, 0.080 mmol, 62% yield). Compound 102 Compound 103 was prepared according to the procedure for Compound 102, starting from Compound 155 (0.040 g, 0.065 mmol) and methylamine hydrochloride (0.009 g, 0.13 mmol), to give Compound 102 as a solid (16 mg, 39% yield). Compound 103 Compound 104 was prepared according to the procedure for Compound 102, starting from Compound 155 (0.040 g, 0.065 mmol) and dimethylamine hydrochloride (0.011 g, 0.13 mmol), to give compound 103 as a solid (18 mg, 43% yield). Step 1 Intermediate 178 (90 mg, 0.31 mmol), Intermediate 323 (161 mg, 0.26 mmol), BrettPhos PdG3 (24 mg, 0.026 mmol), Brettphos (14 mg, 0.026 mmol) and Cs2CO3 (128 mg, 0.39 mmol) were added to a 40 mL vial. Next, 1,4-dioxane (4.4 mL) was added, and the mixture was bubbled with nitrogen for 5 min. Then, the mixture was heated to 60 °C for 2.5 h, after which it was cooled to ambient temperature. Then, ethyl acetate was added, and the mixture was filtered over dicalite. The filtrate was evaporated and purified via reverse phase preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD-10µm, 50x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to give the Intermediate 348 (250 mg, 0.34 mmol), which was used in the next step without further purification. Step 2 Intermediate 348 (250 mg, 0.34 mmol) was dissolved in 7N NH3/MeOH (10 mL) and the resulting mixture was heated to 35 °C for 1 h. Next, the mixture was evaporated to dryness. The residue was purified via flash column chromatography over silica gel (Gradient: 0-10% MeOH/DCM). Product containing fractions were pooled and evaporated. The residue was purified via reverse phase preparative HPLC (Stationary phase: RP XBridge Prep C18 OBD- 10µm, 50x150mm, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to give Intermediate 349 (0.18 g, 74% yield). Step 3 Intermediate 349 (180 mg, 0.25 mmol) was dissolved in DCM (2.5 mL), after which TFA (270 ^L) was added. The mixture was stirred at room temperature for 1.5h. Next, the mixture was evaporated to dryness. The residue was partitioned between a saturated solution of NaHCO₃ and ethyl acetate. The layers were separated, and the water layer was extracted once more with ethyl acetate. The organic layers were then combined, washed with brine, dried over Na₂SO₄, filtered, and evaporated. The residue was purified by preparative SFC (Stationary phase: Chiralpak Diacel AD 20 x 250 mm, Mobile phase: CO₂, EtOH + 0.4 iPrNH₂) to give Compound 104 (61 mg, 39% yield) and Compound 105 (42 mg, 27% yield). Compounds 106-147 Compounds in Table 7 were prepared by analogy to the above example, starting from the appropriate aniline intermediate and bromide intermediate as described in example 11. Table 7 Co. Structure Bromide Aniline Yield No. Intermediate intermediate (%) 106 Intermediate Intermediate 23 307 195 F 107 O F F Intermediate Intermediate 19 N H N N N 307 93 N N N N O F F F R or S 108 Intermediate Intermediate 63 307 134 Co. Structure Bromide Aniline Yield No. Intermediate intermediate (%) 109 Intermediate Intermediate 50 307 82 110 Intermediate Intermediate 86 307 26 111 Intermediate Intermediate 56 307 110 112 Intermediate Intermediate 6 307 156 113 Intermediate Intermediate 20 307 106 114 Intermediate Intermediate 56 307 98 115 Intermediate Intermediate 17 307 138 116 Intermediate Intermediate 41 307 87 Co. Structure Bromide Aniline Yield No. Intermediate intermediate (%) 117 Intermediate Intermediate 32 312 93 118 Intermediate Intermediate 4 311 93 119 Intermediate Intermediate 50 307 122 120 Intermediate Intermediate 40 312 87 121 Intermediate Intermediate 10 307 116 122 Intermediate Intermediate 35 307 62 123 Intermediate Intermediate 2 311 87 124 Intermediate Intermediate 59 307 57 F 125 F F H _N ^N N Intermediate Intermediate 61 N O N N _N N 299 87 F F R or S F F F Co. Structure Bromide Aniline Yield No. Intermediate intermediate (%) 126 Intermediate Intermediate 29 299 156 127 Intermediate Intermediate 2 299 195 128 Intermediate Intermediate 14 299 93 129 Intermediate Intermediate 53 300 93 130 intermediate intermediate 31 299 152 131 intermediate intermediate 59 299 122 132 Intermediate Intermediate 16 300 262 133 Intermediate Intermediate 8 299 262 Co. Structure Bromide Aniline Yield No. Intermediate intermediate (%) 134 Intermediate Intermediate 61 299 57 135 Intermediate Intermediate 58 300 57 136 Intermediate Intermediate 31 294 87 137 Intermediate Intermediate 45 295 87 138 Intermediate Intermediate 33 291 87 139 Intermediate Intermediate 84 315 87 140 Intermediate Intermediate 41 292 87 141 Intermediate Intermediate 53 296 93 142 Intermediate Intermediate 80 295 93 Co. Structure Bromide Aniline Yield No. Intermediate intermediate (%) 143 Intermediate Intermediate 23 292 93 144 Intermediate Intermediate 55 291 93 145 Intermediate Intermediate 76 315 93 146 Intermediate Intermediate 32 316 93 147 Intermediate Intermediate 43 316 87

C F cis and trans Intermediate 87 Intermediate 323 o_r Step 1 To a microwave vial of Intermediate 87 (132 mg, 0.474 mmol), Intermediate 323 (300 mg, 0.569 mmol), potassium phosphate tribasic (221 mg, 1.04 mmol) was added tBuOH (3.5 mL) and purged with nitrogen. BrettPhos [1070663-78-3] (25.5 mg, 0.048 mmol), and BrettPhos Pd G3 [1470372-59-8] (43.1 mg, 0.048 mmol) were added. The reaction mixture was heated at 120 °C for 1 h using one single mode microwave with power output ranging from 0 to 800 W. The reaction mixture was diluted with EtOAc and water. The layers were separated, and the organic layer was washed with water (3 times) and brine, dried over MgSO4, filtered, and concentrated in vacuo to give a residue which was purified by flash column chromatography over silica gel (mobile phase gradient Heptane/EtOAc 100/0 to 40/60). The fractions containing product were combined and evaporated to dryness to give 347 mg of Intermediate 350 as a pale- yellow foam (98%). Step 2 To a solution of Intermediate 350 (347 mg, 0.469 mmol) in DCM (4.5 mL) was added TFA (503 µL, 6.57 mmol). The resulting mixture was stirred at rt for 1 h. A saturated aqueous solution of potassium carbonate was added, and the layers were separated. The aqueous phase was extracted with dichloromethane. The combined organic layers were dried over MgSO₄, filtered, and the solvents were removed in vacuo to give a residue which was purified by flash column chromatography over silica gel (gradient DCM/MeOH: 100/0 to 97/3). The fractions containing product were combined and evaporated to give Compound 148 (217 mg, mixture of isomers) as a white foam. Step 3 Compound 148 was purified via chiral SFC (Stationary phase: Chiralpak AD-34.6x100 mm, Mobile phase: CO₂ / EtOH 65/35) to obtain two fractions. Both fractions were taken-up with MeCN (2 mL), diluted with water (10 mL) then freeze-dried to give compound 149 as a white solid (141 mg, 48% yield) and compound 150 as a white solid (46 mg, 16% yield). The following compounds were synthesized in analogy to compounds 149 and compound 150 starting with intermediate 323 and the specified aniline intermediate. Table 8 Co.No. Structure Prepared from Yield (%) Intermediate 93 60 151 Intermediate 93 14 152 Table 9: 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). Co. No. LCMS results 1 confirms the MW (Rt: 1.91, [M+H]+: 582, Method: 3) 2 confirms the MW (Rt: 1.83, [M+H]+: 547, LCMS Method: 20) 3 confirms the MW (Rt: 1.82, [M+H]+: 547, LCMS Method: 3) 4 confirms the MW (Rt: 1.9, [M+H]+: 547.3, LCMS Method: 1) Co. No. LCMS results 5 confirms the MW (Rt: 1.78, [M+H]+: 543, LCMS Method: 20) 6 confirms the MW (Rt: 0.94, [M+H]+: 543, LCMS Method: 21) 7 confirms the MW (Rt: 1.78, [M+H]+: 543, LCMS Method: 20) 8 confirms the MW, (Rt: 0.95, [M+H]⁺: 581, LCMS Method: 21 9 confirms the MW, (Rt: 1.93, [M+H]⁺: 581, LCMS Method: 3) 10 confirms the MW,( Rt: 1.78, [M+H]⁺: 581, LCMS Method: 3) 11 confirms the MW, (Rt: 0.99, [M+H]⁺: 543, LCMS Method: 22) 12 confirms the MW, (Rt: 3.54, [M+H]⁺: 528.1, LCMS Method:11) 13 confirms the MW (Rt: 1.84, [M+H]⁺: 576, LCMS Method: 3) 14 confirms the MW, (Rt: 2.06, [M+H]⁺: 607.5, LCMS Method: 23) 15 confirms the MW, (Rt: 1.04, [M+H]⁺: 554, LCMS Method: 21) 16 confirms the MW, (Rt = 1.529 min, [M+H]⁺: 556.20, LCMS Method: 5) 17 confirms the MW (Rt: 0.977, [M+H]+: 542.15, LCMS Method: 4) 18 confirms the MW (Rt: 1.727 min, [M+H]+: 596.15, LCMS Method: 7) 19 confirms the MW (Rt: 1.146, [M+H]+: 576.20, LCMS Method: 10) 20 confirms the MW (Rt: 1.89, [M+H]+: 578.5, LCMS Method: 3) 21 confirms the MW (Rt: 1.86, [M+H]+: 579, LCMS Method: 1) 22 confirms the MW (Rt: 1.01, [M+H]+: 596.4, LCMS Method: 21) 23 confirms the MW (Rt: 2.85, [M+H]+: 590.2, LCMS Method: 15) 24 confirms the MW (Rt: 7.10, [M+H]+: 609.9, LCMS Method: 17) 25 confirms the MW (Rt: 1.482 min, [M+H]+: 590.15, LCMS Method: 9) 26 confirms the MW (Rt: 0.922, [M+H]+: 590.05, LCMS Method: 4) 27 confirms the MW (Rt: 0.936 min, [M+H]+: 609.95, LCMS Method: 4) 28 confirms the MW (Rt: 0.985, [M+H]+: 590.20, LCMS Method: 4) 29 confirms the MW (Rt: 3.11, [M+H]+: 590.2, LCMS Method: 15 ) 30 confirms the MW (Rt: 6.80, [M+H]+: 605.9, LCMS Method: 17) 31 confirms the MW (Rt: 2.87, [M+H]+: 590.2, LCMS Method: 15) Co. No. LCMS results 32 confirms the MW (Rt: 2.78, [M+H]+: 590.2, LCMS Method: 15 ) 33 confirms the MW (Rt: 0.869 min, [M+H]+: 591.05, LCMS Method: 4) 34 confirms the MW (Rt: 2.80, [M+H]+: 590.2, LCMS Method: 15) 35 confirms the MW (Rt: 0.86, [M+H]+: 565, LCMS Method: 21) 36 confirms the MW (Rt: 2.43, [M+H]+: 592.2, , LCMS Method: 15) 37 confirms the MW,. (Rt: 1.97, [M+NH₄]⁺: 600.4, LCMS Method: 13) 38 confirms the MW (Rt: 2.01, [M+H]+: 575.3, LCMS Method: 13) 39 confirms the MW (Rt: 2.20, [M+H]+: 643.3, LCMS Method: 1) 40 confirms the MW (Rt: 1.80, [M+H]+: 582.3, LCMS Method: 13) 41 confirms the MW (Rt: 2.03, [M+H]+: 650.4, LCMS Method: 1) 42 confirms the MW (Rt: 1.85, [M+H]+: 596.3, LCMS Method: 13) 43 confirms the MW (Rt: 1.89, [M+H]+: 580.4, LCMS Method: 13) 44 confirms the MW (Rt: 1.78, [M+H]+: 582.3, LCMS Method: 20) 45 confirms the MW (Rt: 1.99, [M+H]+: 582.3, LCMS Method: 1) 46 confirms the MW (Rt: 1.80, [M+H]+: 541.4, LCMS Method: 2) 47 confirms the MW (Rt: 1.86, [M+H]+: 541.4, LCMS Method: 1) 48 confirms the MW (Rt: 1.75, [M+H]+: 537.3, LCMS Method: 2) 49 confirms the MW (Rt: 1.78, [M+H]+: 541.3, LCMS Method: 3) 50 confirms the MW (Rt: 1.88, [M+H]+: 573.3, LCMS Method: 3) 51 confirms the MW (Rt: 1.88, [M+H]+: 573.3, LCMS Method: 3) 52 confirms the MW (Rt: 1.86, [M+H]+: 537.4, LCMS Method: 13) 53 confirms the MW (Rt: 1.86, [M+H]+: 537.4, LCMS Method: 13) 54 confirms the MW (Rt: 1.78, [M+H]+: 543, LCMS Method: 20) 55 confirms the MW (Rt: 1.78, [M+H]+: 543.5, LCMS Method: 23) 56 confirms the MW (Rt: 1.79, [M+H]+: 543.4, LCMS Method: 23) 57 confirms the MW (Rt: 1.62, [M+H]+: 544.5, LCMS Method: 23) 58 confirms the MW (Rt: 1.64, [M+H]+: 544.5, LCMS Method: 23) Co. No. LCMS results 59 confirms the MW (Rt: 0.93, [M+H]+: 561, LCMS Method: 21) 60 confirms the MW (Rt: 1.89, [M+H]+: 555.4, LCMS Method: 3) 61 confirms the MW (Rt: 1.26, [M+H]+: 566.2, LCMS Method: 14) 62 confirms the MW (Rt: 2.66, [M+H]+: 566.2, LCMS Method: 15 ) 63 confirms the MW (Rt: 3.08, [M+H]+: 571.2, LCMS Method: 15 ) 64 confirms the MW (Rt: 3.09, [M+H]+: 609.2, LCMS Method: 15 ) 66 confirms the MW (Rt: 2.96, [M+H]+: 558.3, LCMS Method: 15) 67 confirms the MW (Rt: 2.94, [M+H]+: 540.2 , LCMS Method: 15) 68 confirms the MW (Rt: 3.32, [M+H]+: 583.4, LCMS Method: 15) 69 confirms the MW (Rt: 2.81, [M+H]+: 565.3, LCMS Method: 15 ) 70 confirms the MW (Rt: 2.89, [M+H]+: 559.2, LCMS Method: 15) 71 confirms the MW (Rt: 1.80, [M+H]+: 566.5, LCMS Method: 24) 72 confirms the MW (Rt: 3.14, [M+H]+: 569.3, LCMS Method: 15 ) 73 confirms the MW (Rt: 2.40, [M+H]+: 571.2, LCMS Method: 15 ) 74 confirms the MW (Rt: 3.14, [M+H]+: 569.3, LCMS Method: 15 ) 75 confirms the MW (Rt: 2.54, [M+H]+: 541.2, LCMS Method: 15 ) 76 confirms the MW (Rt: 3.21, [M+H]+: 581.3, LCMS Method: 15) 77 confirms the MW (Rt: 1.25, [M+H]+: 558.3, LCMS Method: 16) 78 confirms the MW (Rt: 1.25, [M+H]+: 558.3, LCMS Method: 16) 79 confirms the MW (Rt: 1.84, [M+H]+: 548.3, LCMS Method: 3) 80 confirms the MW (Rt: 3.26, [M+H]+: 574.3, LCMS Method: 15) 81 confirms the MW (Rt: 3.14, [M+H]+: 570.3, LCMS Method: 15) 82 confirms the MW (Rt: 3.25, [M+H]+: 607.2, LCMS Method: 15 ) 83 confirms the MW (Rt: 1.89, [M+H]+: 589.3, LCMS Method: 20) 84 confirms the MW (Rt: 7.28, [M+H]+: 624.8, LCMS Method: 17) 85 confirms the MW (Rt: 0.872, [M+H]+: 599.15, LCMS Method: 4) 86 confirms the MW (Rt: 0.94, [M+H]+: 580, LCMS Method: 21) Co. No. LCMS results 87 confirms the MW (Rt: 0.822, [M+H]+: 513.20, LCMS Method: 4) 88 confirms the MW (Rt: 2.12, [M+H]+: 605.3, LCMS Method: 20) 89 confirms the MW (Rt: 3.09, [M+H]+: 609.3, LCMS Method: 16) 90 confirms the MW (Rt: 1.97, [M+H]+: 589.3, LCMS Method: 3) 91 confirms the MW (Rt: 2.89, [M+H]+: 559.2, LCMS Method: 15 ) 92 confirms the MW (Rt: 1.64, [M+H]+: 556.4, LCMS Method: 2) 93 confirms the MW (Rt: 1.77, [M+H]+: 560, LCMS Method: 3) 94 confirms the MW (Rt: 2.59, [M+H]+: 556.3, LCMS Method: 15 ) 95 confirms the MW (Rt: 1.410, [M+H]+: 585.10, LCMS Method: 6) 96 confirms the MW (Rt: 9.12, [M+H]+: 584.2, LCMS Method: 8) 97 confirms the MW (Rt: 1.69, [M+H]+: 616.3, LCMS Method: 20) 98 confirms the MW (Rt: 1.66, [M+H]+: 580.3, LCMS Method: 20) 99 confirms the MW (Rt: 0.825, [M+H]+: 580.10 LCMS Method: 4) 100 confirms the MW (Rt: 1.54, [M+H]+: 580.3, LCMS Method: 20) 101 confirms the MW (Rt: 1.71, [M+H]+: 619.3, LCMS Method: 20) 102 confirms the MW (Rt: 1.89, [M+H]+: 633.5, LCMS Method: 24) 103 confirms the MW (Rt: 1.85, [M+H]+: 647.5, LCMS Method: 24) 104 confirms the MW (Rt: 1.54, [M+H]+: 618.3, LCMS Method: 3) 105 confirms the MW (Rt: 1.54, [M+H]+: 618.3, LCMS Method: 3) 106 confirms the MW (Rt: 1.85, [M+H]+: 551.4, LCMS Method: 20) 107 confirms the MW (Rt: 3.02, [M+H]+: 567.2, , LCMS Method: 15 ) 108 confirms the MW (Rt: 2.78, [M+H]+: 561.3, LCMS Method: 15 ) 109 confirms the MW (Rt: 2.85, Area %: 100, MH+: 554.2, Method: 15) 110 confirms the MW (Rt: 1.15, [M+H]+: 555.2, LCMS Method: 16) 111 confirms the MW (Rt: 2.88, [M+H]+: 536.2, LCMS Method: 15) 112 confirms the MW (Rt: 1.78, [M+H]+: 544, LCMS Method: 3) 113 confirms the MW (Rt: 1.37, [M+H]+: 570.3, LCMS Method: 14) Co. No. LCMS results 114 confirms the MW (Rt: 3.20, [M+H]+: 603.2, LCMS Method: 15) 115 confirms the MW (Rt: 3.09, [M+H]+: 566.2, LCMS Method: 15) 116 confirms the MW (Rt: 6.57, [M+H]+: 587, LCMS Method: 17) 117 confirms the MW (Rt 3.34, [M+H]+: 603.3, LCMS Method: 15 ) 118 confirms the MW (Rt: 3.33, [M+H]+: 603.3, LCMS Method: 15) 119 confirms the MW (Rt: 1.95, [M+H]+: 585, LCMS Method: 20) 120 confirms the MW (Rt: 1.95, [M+H]+: 585, LCMS Method: 20) 121 confirms the MW (Rt: 2.08, [M+H]+: 601, LCMS Method: 13) 122 confirms the MW (Rt: 3.10, [M+H]+: 621.4, LCMS Method: 15 ) 123 confirms the MW (Rt: 3.09, [M+H]+: 623.3, LCMS Method: 15) 124 confirms the MW (Rt: 6.96, [M+H]+: 604.8, LCMS Method: 18) 125 confirms the MW (Rt: 7.14, [M+H]+: 586.9, LCMS Method: 17) 126 confirms the MW (Rt: 1.08, [M+H]+: 544, LCMS Method: 22) 127 confirms the MW (Rt: 1.94, [M+H]+: 551.2, LCMS Method: 3) 128 confirms the MW (Rt: 3.37, [M+H]+: 567.3, LCMS Method: 15 ) 129 confirms the MW (Rt: 3.31, [M+H]+: 567.3, LCMS Method: 15) 130 confirms the MW (Rt: 1.83, [M+H]+: 576, LCMS Method: 20) 131 confirms the MW (Rt: 2.05, [M+H]+: 585, LCMS Method:20) 132 confirms the MW (Rt: 1.833, [M+H]+: 509.20, LCMS Method: 12) 133 confirms the MW (Rt: 0.853, [M+H]+: 509.15, LCMS Method: 4) 134 confirms the MW, Rt: 7.55, [M+H]⁺: 604.8, LCMS Method:18) 135 confirms the MW (Rt: 7.53, [M+H]⁺: 604.8, LCMS Method: 18 136 confirms the MW (Rt: 3.26, [M+H]^+: 586.3, LCMS Method: 15) 137 confirms the MW (Rt: 3.27, [M+H]^+: 586.3, LCMS Method: 15 ) 138 confirm the MW (Rt: 3.12, [M+H]⁺: 586.2, LCMS Method: 16) 139 confirms the MW (Rt: 3.01, [M+H]⁺: 586.4, LCMS Method: 15) 140 confirms the MW (Rt: 3.12, [M+H]⁺: 586.3, LCMS Method: 15) Co. No. LCMS results 141 confirms the MW (Rt: 3.39, [M+H]+: 566.3, LCMS Method: 15 ) 142 confirms the MW (Rt: 3.45, [M+H]+: 566.3, LCMS Method: 15 ) 143 confirms the MW (Rt: 3.10, [M+H]+: 566.4, LCMS Method: 15) 144 confirms the MW (Rt: 3.22, [M+H]+: 566.3, LCMS Method: 15) 145 confirms the MW (Rt: 3.12, [M+H]+: 566.4, LCMS Method: 15) 146 confirms the MW (Rt 3.12, [M+H]+: 566.3, LCMS Method: 15) 147 confirms the MW (Rt: 3.02, M+H]+: 586.4, LCMS Method: 15 ) 149 confirms the MW (Rt: 2.90, [M+H]+: 625.4, LCMS Method: 15) 150 confirms the MW (Rt: 2.90, [M+H]+: 625.4, , LCMS Method: 15) 151 confirms the MW (Rt: 3.01, [M+H]+: 605.4, LCMS Method: 15 ) 152 confirms the MW (Rt: 3.01, [M+H]+: 605.4, LCMS Method: 15 ) Table 10: Analytical SFC data – Rt means retention time (in minutes), method referse method used for (SFC)MS analysis of enantiomerically pure compounds. Co. No. SFC Method Rt UV Area (%) 3 26 4.30 100 4 26 6.09 100 6 27 4.79 98.28 7 27 6.24 100 9 27 4.95 100 10 27 5.47 100 26 7 1.737 100 27 37 1.356 100 44 26 4.78 100 45 28 5.04 100 5.88min isomer 1, 15.35% isomer 1, 46 29 6.56min isomer 2 80.81% isomer 2 47 29 6.54 100 49 29 5.85 98.86 50 28 4.10 100 51 28 4.76 100 52 27 4.76 99 Co. No. SFC Method Rt UV Area (%) 53 27 5.81 100 54 4.58min isomer 1, 56.77% isomer 1, 30 4.92min isomer 2 38.93% isomer 2 55 30 4.57 100 56 30 4.92 100 57 29 5.42 96.39 58 29 5.99 100 60 30 3.98 92.15 61 36 1.19 100 62 36 1.74 100 63 24 1.29 95.8 65 25 1.43 100 66 8 2.27 95.88 67 25 1.43 100 69 9 1.23 96.5 70 3 1.40 98 72 4 1.47 96.24 73 13 1.61 97.8 74 4 1.47 96.24 75 24 1.00 93.2 76 22 1.25 100 77 16 1.49 97.18 78 11 2.65 99.7 80 23 1.81 100 81 9 1.40 97 82 10 1.19 97.3 84 2 1.09 99.04 85 5 1.7 95.02 87 38 2.28 100 89 2 1.40 98 94 12 1.31 98.8 95 39 1.39 97.19 96 31 7.74 99.7 104 28 6.22 100.0 ₁₀₅ ²⁸ _{6.92 100.00} 133 1 4.36 99.7 Co. No. SFC Method Rt UV Area (%) 134 19 0.86 100% 135 19 1.41 99 136 15 1.85 99.3 137 18 0.97 100 138 19 1.45 98 140 17 0.98 100 141 32 1.39 99.45 142 35 2.74 100 143 19 1.72 98.3 144 17 2.74 100 145 33 1.51 98.9 146 33 1.13 98.9 147 34 2.29 100 149 21 2.18 99.8 150 21 1.54 98.8 151 20 1.86 98.5 152 20 1.46 100 NMR ¹H NMR spectra were recorded on a spectrometer such as for example a Bruker Avance III 400MHz or an Avance NEO 400MHz. CDCl3 was used as solvent, unless otherwise mentioned. The chemical shifts are expressed in ppm relative to tetramethylsilane. Table 11: 1H-NMR Data, decreasing order ppm Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 1 1H NMR (400 MHz, CHLOROFORM-d) 7.83 (s, 1 H) 7.64 (d, J=3.52 Hz, 1 H) 7.28 (d, J=8.36 Hz, 2 H) 7.22 (d, J=3.52 Hz, 1 H) 6.98 (d, J=8.80 Hz, 2 H) 6.58 (q, J=8.88 Hz, 1 H) 5.75 (s, 1 H) 3.30 - 3.52 (m, 2 H) 2.86 - 3.04 (m, 6 H) 2.19 - 2.49 (m, 4 H) 2 1H NMR (400 MHz, CHLOROFORM-d) 7.84 (s, 1 H) 7.64 (d, J=3.55 Hz, 1 H) 7.29 (br d, J=3.14 Hz, 2 H) 7.22 (d, J=3.45 Hz, 1 H) 6.99 (d, J=7.94 Hz, 2 H) 6.50 - 6.63 (m, 1 H) 5.66 - 5.78 (m, 2 H) 3.62 - 3.76 (m, 1 H) 3.34 - 3.51 (m, 1 H) 3.01 - 3.11 (m, 1 H) 2.96 (s, 3 H) 2.33 - 2.63 (m, 2 H) 1.97 - 2.16 (m, 2 H) 3 1H NMR (CHLOROFORM-d, 400 MHz) 7.85 (s, 1H), 7.65 (d, J = 3.5 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 3.5 Hz, 1H), 7.00 (d, J = 8.6 Hz, 2H), 6.58 (q, J = 8.9 Hz, 1H), 5.78 (br s, 1H), 5.76 (s, 1H), 3.64-3.73 (m, 1H), 3.43-3.52 (m, 1H), 3.07 (tt, Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) J = 10.1, 5.0 Hz, 1H), 2.96 (s, 3H), 2.52-2.63 (m, 1H), 2.35-2.48 (m, 1H), 1.98-2.15 (m, 2H) 4 1H NMR (400 MHz, CHLOROFORM-d) 7.83 (s, 1 H) 7.64 (d, J=3.52 Hz, 1 H) 7.30 (br d, J=8.80 Hz, 2 H) 7.22 (d, J=3.52 Hz, 1 H) 6.99 (d, J=8.36 Hz, 2 H) 6.58 (q, J=8.88 Hz, 1 H) 5.68 - 5.79 (m, 2 H) 3.66 - 3.75 (m, 1 H) 3.35 - 3.44 (m, 1 H) 2.99 - 3.11 (m, 1 H) 2.96 (s, 3 H) 2.53 - 2.63 (m, 1 H) 2.38 - 2.49 (m, 1 H) 2.02 - 2.15 (m, 2 H) 5 1H NMR (400 MHz, CHLOROFORM-d) 7.84 (s, 1 H) 7.64 (d, J=3.5 Hz, 1 H) 7.39 (d, J=8.6 Hz, 2 H) 7.22 (d, J=3.5 Hz, 1 H) 6.96 - 7.03 (m, 2 H) 6.64 (q, J=8.6 Hz, 1 H) 5.80 (s, 1 H) 3.94 - 4.19 (m, 2 H) 3.46 - 3.87 (m, 2 H) 2.49 (s, 3 H) 6 1H NMR (400 MHz, CHLOROFORM-d) 7.84 (s, 1 H) 7.64 (d, J=3.55 Hz, 1 H) 7.40 (d, J=8.47 Hz, 2 H) 7.23 (d, J=3.55 Hz, 1 H) 7.00 (d, J=8.78 Hz, 2 H) 6.63 (q, J=8.64 Hz, 1 H) 5.83 (s, 1 H) 3.94 - 4.19 (m, 2 H) 3.47 - 3.86 (m, 2 H) 2.48 (s, 3 H) 7 1H NMR (400 MHz, CHLOROFORM-d) 7.84 (s, 1 H) 7.64 (d, J=3.5 Hz, 1 H) 7.39 (d, J=8.6 Hz, 2 H) 7.22 (d, J=3.5 Hz, 1 H) 6.96 - 7.03 (m, 2 H) 6.64 (q, J=8.6 Hz, 1 H) 5.80 (s, 1 H) 3.94 - 4.19 (m, 2 H) 3.46 - 3.87 (m, 2 H) 2.49 (s, 3 H) 8 1H NMR (400 MHz, CHLOROFORM-d) 7.83 (s, 1 H) 7.64 (d, J=3.4 Hz, 1 H) 7.29 (br d, J=8.2 Hz, 2 H) 7.22 (d, J=3.4 Hz, 1 H) 6.98 (d, J=8.6 Hz, 2 H) 6.54 - 6.64 (m, 1 H) 5.74 (s, 1 H) 3.30 - 3.51 (m, 2 H) 2.99 - 3.12 (m, 2 H) 2.92 (s, 3 H) 2.86 - 2.90 (m, 1 H) 2.35 - 2.49 (m, 2 H) 2.26 - 2.35 (m, 1 H) 2.15 - 2.25 (m, 1 H) ₉ 1H NMR (400 MHz, CHLOROFORM-d) 7.83 (s, 1 H) 7.64 (d, J=3.45 Hz, 1 H) 7.29 (br d, J=8.47 Hz, 2 H) 7.22 (d, J=3.55 Hz, 1 H) 6.98 (d, J=8.67 Hz, 2 H) 6.59 (q, J=8.85 Hz, 1 H) 5.75 (s, 1 H) 3.32 - 3.52 (m, 2 H) 2.98 - 3.10 (m, 2 H) 2.84 - 2.94 (m, 4 H) 2.15 - 2.49 (m, 5 H) 10 1H NMR (400 MHz, CHLOROFORM-d) 7.83 (s, 1 H) 7.64 (d, J=3.45 Hz, 1 H) 7.28 (d, J=8.47 Hz, 2 H) 7.22 (d, J=3.45 Hz, 1 H) 6.98 (d, J=8.67 Hz, 2 H) 6.58 (q, J=9.06 Hz, 1 H) 5.75 (s, 1 H) 3.30 - 3.49 (m, 2 H) 3.00 - 3.12 (m, 2 H) 2.86 - 2.95 (m, 4 H) 2.36 - 2.53 (m, 3 H) 2.13 - 2.35 (m, 2 H) ₁₁ 1H NMR (600 MHz, DMSO-d6) 8.23 (s, 1 H) 8.08 (s, 1 H) 7.68 (d, J=3.7 Hz, 1 H) 7.61 (d, J=3.3 Hz, 1 H) 6.95 - 7.31 (m, 4 H) 6.43 (q, J=9.3 Hz, 1 H) 3.89 - 3.92 (m, 3 H) 3.27 - 3.66 (m, 2 H) 2.87 - 3.04 (m, 2 H) 12 1H NMR (400 MHz, DMSO) 7.80 – 7.79 (m, 1H), 7.73 – 7.69 (m, 1H), 7.66 – 7.65 (m, 1H), 7.52 (d, J = 3.2 Hz, 1H), 7.22 – 7.12 (m, 2H), 6.78 – 6.71 (m, 2H), 6.39 – Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 6.34 (m, 1H), 3.27 – 3.08 (m,5H), 2.88 – 2.64 (m, 3H), 2.52 (s,3H), 2.10 – 1.98 (m, 4H). 13 1H NMR (400 MHz, CHLOROFORM-d) 8.52 (dd, J=4.8, 1.9 Hz, 1 H) 7.88 (td, J=7.8, 1.8 Hz, 1 H), 7.82 (s, 1 H), 7.74 (d, J=8.2 Hz, 1 H), 7.30 - 7.38 (m, 1 H), 7.27 (s, 2 H), 6.96 (d, J=8.4 Hz, 2 H), 6.57 (q, J=9.0 Hz, 1 H), 5.65 (s, 1 H), 3.31 - 3.52 (m, 2 H), 2.87 - 3.05 (m, 6 H), 2.19 - 2.49 (m, 4 H), 14 1H NMR (400 MHz, CHLOROFORM-d) 7.80 (s, 1H), 7.26-7.31 (m, 3H), 6.97-7.09 (m, 2H), 6.93 (d, J = 8.6 Hz, 2H), 6.57 (q, J = 9.1 Hz, 1H), 5.52 (s, 1H), 3.28-3.59 (m, 2H), 2.85-3.10 (m, 6H), 2.14-2.53 (m, 4H), 2.06 ppm (s, 3H) 15 1H NMR (400 MHz, DMSO-d6) 7.66 – 7.74 (m, 2H), 7.49 – 7.61 (m, 2H), 7.01 – 7.25 (m, 2H), 6.61 – 6.79 (m, 2H), 6.05 – 6.45 (m, 1H), 3.05 – 3.30 (m, 5H), 2.60 – 2.95 (m, 3H), 2.52 – 2.60 (m, 1H), 1.91 – 2.15 (m, 4H), 0.78 – 0.93 (m, 4H). 16 1H NMR (400 MHz, CHLOROFORM-d) 7.58 - 7.57 (m, 2H), 7.18 - 7.14 (m, 3H), 6.67 (d, J = 8.4 Hz, 2H), 6.52 (q, J = 9.2 Hz, 1H), 4.97 (s, 1H), 4.33 - 4.26 (m, 1H), 3.48 - 3.32 (m, 2H), 3.01 - 2.81 (m, 6H), 2.43 - 2.21 (m, 4H), 1.35 (d, J = 6.8 Hz, 6H). 17 1H NMR (300 MHz, DMSO-d6) 7.78 - 7.82 (m, 1H), 7.61 - 7.71 (m, 3H), 7.17 - 7. 44 (m, 2H), 6.70 - 6.85 (m, 2H), 6.32 - 6.43 (m, 1H), 2.98 - 3.23 (m, 10H), 1.89 - 2.13 (m, 4H), 1.09 - 1.18 (m, 3H). ₁₈ 1H NMR (400 MHz, DMSO-d6) 8.03 - 8.04 (m, 1H), 7.87 - 7.91 (m, 1H), 7.69 - 7.70 (m, 1H), 7.47 - 7.58 (m, 1H), 7.16 - 7.26 (m, 2H), 6.87 - 6.92 (m, 2H), 6.38 - 6.45 (m, 1H), 4.45 - 4.53 (m, 2H), 3.09 - 3.29 (m, 5H), 2.65 - 2.90 (m, 3H), 1.95 - 2.11 (m, 4H) 19F NMR (376 MHz, DMSO-d6) d ppm: -63.32, -67.42. 19 1H NMR (400 MHz, DMSO-d6) 8.70 – 8.82 (m, 2H), 8.02 – 8.24 (m, 3H), 7.59 – 7.74 (m, 1H), 7.17 – 7.31 (m, 2H), 6.87 – 7.09 (m, 2H), 6.36 – 6.56 (m, 1H), 3.13 – 3.33 (m, 5H), 2.63 – 2.96 (m, 3H), 1.91 – 2.13 (m, 4H). ₂₀ 1H NMR (400 MHz, CHLOROFORM-d) 7.80 (s, 1 H) 7.60 (d, J=3.55 Hz, 1 H) 7.20 - 7.25 (m, 2 H) 6.92 (d, J=8.57 Hz, 2 H) 6.56 (q, J=8.81 Hz, 1 H) 5.79 (br s, 1 H) 3.30 - 3.53 (m, 2 H) 2.88 - 3.04 (m, 6 H) 2.20 - 2.49 (m, 7 H) 21 1H NMR (CHLOROFORM-d, 400 MHz) 7.79 (s, 1H), 7.43 (d, J = 2.3 Hz, 1H), 7.24 (s, 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.53-6.62 (m, 1H), 6.43 (d, J = 2.3 Hz, 1H), 5.52 (s, 1H), 3.97 (s, 3H), 3.44-3.54 (m, 1H), 3.30-3.42 (m, 1H), 2.88-3.06 (m, 6H), 2.31-2.51 (m, 3H), 2.18-2.31 (m, 1H) Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 22 1H NMR (400 MHz, CHLOROFORM-d) 7.79 (s, 1 H) 7.29 (s, 1 H) 7.25 (br d, J=8.36 Hz, 2 H) 6.93 (d, J=8.67 Hz, 2 H) 6.56 (q, J=8.92 Hz, 1 H) 5.59 (s, 1 H) 3.26 - 3.56 (m, 2 H) 2.95 - 3.05 (m, 2 H) 2.94 (br d, J=3.76 Hz, 1 H) 2.91 (s, 3 H) 2.76 (s, 3 H) 2.18 - 2.49 (m, 4 H) 23 1H NMR (500 MHz, CHLOROFORM-d) 8.63 (d, J = 2.6 Hz, 1H), 7.83 (s, 1H), 7.69 (dd, J = 8.3, 2.7 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.29 – 7.26 (m, 2H), 7.00 – 6.92 (m, 2H), 6.57 (q, J = 8.9 Hz, 1H), 5.54 (s, 1H), 3.56 – 3.28 (m, 2H), 3.04 – 2.88 (m, 6H), 2.66 (s, 3H), 2.50 – 2.17 (m, 4H). 24 1H NMR (500 MHz, CHLOROFORM-d) 8.68 (dd, J = 8.7, 2.2 Hz, 2H), 7.86 (d, J = 2.7 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 7.00 – 6.94 (m, 2H), 6.58 (q, J = 8.9 Hz, 1H), 5.60 (s, 1H), 3.47 (ddd, J = 14.2, 8.4, 3.3 Hz, 1H), 3.40 – 3.30 (m, 1H), 3.04 – 2.88 (m, 3H), 2.92 (s, 3H), 2.48 – 2.31 (m, 2H), 2.30 – 2.20 (m, 2H). 25 1H NMR (400 MHz, DMSO-d6) 8.03 - 8.12 (m, 2H), 7.93 - 7.97 (m, 1H), 7.58 - 7.61 (m, 1H), 7.36 - 7.38 (m, 1H), 7.19 - 7.21 (m, 2H), 6.93 - 6.95 (m, 2H), 6.41 - 6.44 (m, 1H), 3.01 - 3.30 (m, 5H), 2.65 - 2.91 (m, 3H), 2.55 (s, 3H), 1.92 - 2.14 (m, 4H) 19F NMR (376 MHz, DMSO-d6) d ppm: -55.51, -67.35. 26 1H NMR (300 MHz, DMSO-d6) 8.40 - 8.49 (m, 1H), 7.95 - 8.09 (m, 3H), 7.52 - 7.62 (m, 1H), 7.16 - 7.32 (m, 2H), 6.87 - 6.99 (m, 2H), 6.05 - 6.50 (m, 1H), 3.00 - 3.33 (m, 5H), 2.59 - 2.98 (m, 3H), 2.18 (s, 3H), 1.96 - 2.10 (m, 4H). 19F NMR (282MHz, DMSO-d6) d (ppm): -56.70,67.36. 27 1H NMR (400 MHz, DMSO-d6) 8.58 - 8.67 (m, 1H), 8.30 - 8.39 (m, 1H), 8.00 - 8.22 (m, 2H), 7.70 - 7.82 (m, 1H), 7.35 - 7.54 (m, 1H), 7.25 - 7.32 (m, 1H), 6.86 - 7.01 (m, 2H), 6.35 - 6.51 (m, 1H), 3.20 - 3.41 (m, 5H), 2.87 - 2.95 (m, 2H), 2.70 - 2.80(m, 1H), 1.96 - 2.26 (m, 3H) 19F NMR (376 MHz, DMSO-d6) d (ppm): -57.0090, -67.3542. ₂₈ (400 MHz, DMSO-d6) 8.34 – 8.45 (m, 1H), 8.09 – 8.18 (m, 2H), 8.02 – 8.07 (m, 1H), 8.04 (s, 2H), 7.62 – 7.71 (m, 1H), 7.31 – 7.50 (m, 3H), 7.07 – 7.28 (m, 3H), 6.84 – 6.99 (m, 1H), 4.03 – 4.15 (m, 2H), 3.18 – 3.45 (m, 5H), 2.87 – 2.95 (m, 3H), 2.62– 2.71 (m, 1H), 2.41 – 2.55 (m, 3H), 1.95 – 2.16 (m, 4H)./ 29 1H NMR (500 MHz, CHLOROFORM-d) 8.34 (d, J = 2.3 Hz, 1H), 7.80 (s, 1H), 7.68 (dd, J = 8.2, 2.3 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.24 (s, 2H), 6.98 – 6.90 (m, 2H), 6.56 (q, J = 8.9 Hz, 1H), 5.62 (s, 1H), 3.52 – 3.41 (m, 1H), 3.35 (ddt, J = 14.1, 8.1, Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 3.0 Hz, 1H), 3.05 – 2.93 (m, 2H), 2.91 (s, 3H), 2.41 (s, 6H), 2.29 – 2.20 (m, 1H), 2.00 (s, 1H). 30 1H NMR (500 MHz, DMSO) 8.39 (dd, J = 5.0, 1.8 Hz, 1H), 8.03 – 7.95 (m, 3H), 7.30 – 7.17 (m, 3H), 6.96 – 6.87 (m, 2H), 6.42 (q, J = 9.3 Hz, 1H), 3.89 (s, 3H), 3.27 – 3.04 (m, 5H), 2.90 (s, 3H), 2.17 – 1.89 (m, 4H). 31 1H NMR (500 MHz, CHLOROFORM-d) 8.60 – 8.54 (m, 2H), 7.84 (s, 1H), 7.65 – 7.61 (m, 1H), 7.28 (s, 2H), 6.99 – 6.93 (m, 2H), 6.58 (q, J = 8.9 Hz, 1H), 5.55 (s, 1H), 3.51 – 3.44 (m, 1H), 3.38 – 3.32 (m, 1H), 3.03 – 2.96 (m, 2H), 2.96 – 2.89 (m, 4H), 2.45 (s, 3H), 2.44 – 2.31 (m, 3H), 2.29 – 2.21 (m, 1H). 19F NMR (471 MHz, CHLOROFORM-d) d -55.72, -68.16. 32 1H NMR (500 MHz, CHLOROFORM-d) 8.67 (dd, J = 4.8, 1.7 Hz, 1H), 7.85 (s, 1H), 7.68 – 7.60 (m, 1H), 7.31 (dd, J = 7.9, 4.8 Hz, 1H), 7.29 – 7.26 (m, 2H), 7.00 – 6.93 (m, 2H), 6.58 (q, J = 9.0 Hz, 1H), 5.55 (s, 1H), 3.48 (d, J = 8.2 Hz, 1H), 3.41 – 3.29 (m, 1H), 3.05 – 2.94 (m, 2H), 2.92 (s, 4H), 2.47 – 2.34 (m, 3H), 2.32 (s, 3H), 2.25 (t, J = 11.6 Hz, 1H). 33 1H NMR (400 MHz, DMSO-d6) 8.00 - 8.04 (m, 1H), 7.90 - 7.97 (m, 1H), 7.56 - 7.61 (m, 1H), 7.17 - 7.31 (m, 2H), 6.88 - 6.94 (m, 2H), 6.75 - 6.77 (m, 1H), 6.50 - 6.53 (m, 1H), 6.38 - 6.45 (m, 1H), 6.09 - 6.23 (m, 2H), 3.10 - 3.30 (m, 5H), 2.65 - 2.91 (m, 3H), 1.99 - 2.19 (m, 4H) 19F NMR (376 MHz, DMSO-d6) d ppm: -55.50, -67.35. 34 1H NMR (500 MHz, CHLOROFORM-d) 8.61 (d, J = 5.0 Hz, 1H), 8.54 (s, 1H), 7.86 (s, 1H), 7.31 (d, J = 5.0 Hz, 1H), 7.27 (d, J = 8.5 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 6.57 (q, J = 8.9 Hz, 1H), 5.54 (s, 1H), 3.51 – 3.42 (m, 1H), 3.39 – 3.30 (m, 1H), 3.04 – 2.93 (m, 2H), 2.93 (m, 4H), 2.48 – 2.30 (m, 3H), 2.28 – 2.19 (m, 1H), 2.14 (s, 3H). ₃₅ 1H NMR (CHLOROFORM-d, 400 MHz) 7.82 (s, 1H), 7.67 (br s, 1H), 7.25 (br s, 2H), 6.95 (d, J = 8.6 Hz, 2H), 6.52-6.62 (m, 2H), 5.57 (s, 1H), 3.43-3.54 (m, 1H), 3.31-3.42 (m, 1H), 2.88-3.06 (m, 6H), 2.20-2.49 (m, 4H) 36 1H NMR (500 MHz, CHLOROFORM-d) 12.93 (s, 1H), 7.84 (s, 1H), 7.69 (d, J = 7.1 Hz, 1H), 7.49 (d, J = 6.5 Hz, 1H), 7.24 (s, 2H), 6.94 (d, J = 8.2 Hz, 2H), 6.56 (q, J = 9.0 Hz, 1H), 6.41 (t, J = 6.8 Hz, 1H), 5.56 (s, 1H), 3.46 (t, J = 11.2 Hz, 1H), 3.39 – 3.31 (m, 1H), 3.00 (t, J = 11.0 Hz, 3H), 2.91 (s, 3H), 2.50 – 2.16 (m, 4H). Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 37 1H NMR (400 MHz, CHLOROFORM-d) 8.44 (s, 1 H) 7.94 (s, 1 H) 7.32 (m, J=8.5 Hz, 2 H) 7.04 (m, J=8.6 Hz, 2 H) 6.60 (q, J=9.0 Hz, 1 H) 5.90 (s, 1 H) 3.31 - 3.51 (m, 2 H) 2.93 - 3.03 (m, 3 H) 2.93 (s, 4 H) 2.32 - 2.48 (m, 3 H) 2.17 - 2.29 (m, 2 H) 38 1H NMR (400 MHz, CHLOROFORM-d) 7.79 (s, 1 H) 7.46 - 7.61 (m, 5 H) 7.23 - 7.29 (m, 2 H) 6.94 (d, J=8.6 Hz, 2 H) 6.57 (q, J=9.0 Hz, 1 H) 5.56 (s, 1 H) 3.30 - 3.49 (m, 2 H) 2.86 - 3.04 (m, 6 H) 2.21 - 2.47 (m, 4 H) 39 1H NMR (400 MHz, CHLOROFORM-d) 7.77 (s, 1 H) 7.46 - 7.55 (m, 6 H) 7.38 - 7.42 (m, 1 H) 7.08 (d, J=8.8 Hz, 1 H) 6.60 (q, J=8.8 Hz, 1 H) 6.01 (br s, 1 H) 3.29 - 3.52 (m, 2 H) 2.93 - 3.03 (m, 3 H) 2.93 (s, 3 H) 2.32 - 2.48 (m, 3 H) 2.22 - 2.30 (m, 1 H) 2.17 (s, 2 H) 40 1H NMR (400 MHz, CHLOROFORM-d) 8.83 (d, J=2.2 Hz, 1 H) 7.82 (s, 1 H) 7.54 (d, J=2.2 Hz, 1 H) 7.21 - 7.32 (m, 3 H) 6.95 (d, J=8.8 Hz, 2 H) 6.57 (q, J=8.9 Hz, 1 H) 5.57 - 5.68 (m, 1 H) 3.27 - 3.53 (m, 2 H) 2.86 - 3.03 (m, 6 H) 2.21 - 2.47 (m, 4 H) 41 1H NMR (400 MHz, CHLOROFORM-d) 8.82 - 8.88 (m, 1 H) 7.77 - 7.84 (m, 1 H) 7.48 - 7.59 (m, 2 H) 7.37 - 7.42 (m, 1 H) 7.05 - 7.11 (m, 1 H) 6.53 - 6.64 (m, 1 H) 6.01 - 6.07 (m, 1 H) 3.29 - 3.52 (m, 2 H) 2.86 - 3.04 (m, 7 H) 2.32 - 2.46 (m, 4 H) 2.17 - 2.30 (m, 2 H) 42 1H NMR (400 MHz, CHLOROFORM-d) 8.62 (s, 1 H) 7.84 (s, 1 H) 7.36 (s, 2 H) 6.95 (d, J=8.7 Hz, 2 H) 6.51 - 6.63 (m, 1 H) 5.56 (s, 1 H) 3.93 - 4.08 (m, 1 H) 3.24 - 3.51 (m, 3 H) 2.96 - 3.05 (m, 2 H) 2.91 (s, 4 H) 2.30 - 2.47 (m, 7 H) 2.17 - 2.28 (m, 2 H) 1.81 - 2.08 (m, 7 H) ₄₃ 1H NMR (400 MHz, CHLOROFORM-d) 7.89 (s, 1 H) 7.42 (d, J=1.3 Hz, 1 H) 7.29 (br d, J=8.5 Hz, 2 H) 6.98 (d, J=8.7 Hz, 2 H) 6.58 (q, J=8.9 Hz, 1 H) 5.70 (s, 1 H) 3.30 - 3.52 (m, 3 H) 2.86 - 3.04 (m, 7 H) 2.31 - 2.46 (m, 4 H) 2.22 - 2.29 (m, 4 H) 44 1H NMR (400 MHz, CHLOROFORM-d) 9.00 (br d, J=25.7 Hz, 1 H) 8.06 (br s, 1 H) 7.85 (s, 1 H) 7.25 - 7.30 (m, 3 H) 6.97 (d, J=8.7 Hz, 2 H) 6.58 (q, J=9.0 Hz, 1 H) 5.62 (s, 1 H) 3.31 - 3.50 (m, 2 H) 2.86 - 3.04 (m, 7 H) 2.21 - 2.48 (m, 5 H) ₄₅ 1H NMR (400 MHz, CHLOROFORM-d) 8.75 (br s, 1 H) 7.84 (br s, 1 H) 7.47 - 7.66 (m, 1 H) 7.28 (s, 2 H) 6.97 (d, J=8.7 Hz, 2 H) 6.57 (q, J=9.0 Hz, 1 H) 5.70 (s, 1 H) 3.31 - 3.50 (m, 2 H) 2.86 - 3.04 (m, 7 H) 2.21 - 2.48 (m, 5 H) 46 1H NMR (400 MHz, CHLOROFORM-d) 8.5-8.5 (m, 1H), 7.8-7.9 (m, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.3-7.4 (m, 2H), 7.3-7.3 (m, 1H), 6.9-7.0 (m, 2H), 6.5-6.6 (m, 1H), Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 5.66 (s, 2H), 3.7-3.8 (m, 1H), 3.4-3.4 (m, 1H), 3.0-3.1 (m, 1H), 2.96 (s, 3H), 2.5-2.6 (m, 1H), 2.4-2.5 (m, 1H), 2.0-2.1 (m, 2H) 47 1H NMR (400 MHz, CHLOROFORM-d) 8.5-8.5 (m, 1H), 7.88 (q, 1H, J=1.0 Hz), 7.83 (s, 1H), 7.7-7.8 (m, 1H), 7.3-7.4 (m, 1H), 7.2-7.3 (m, 1H), 6.9-7.0 (m, 2H), 6.55 (q, 1H, J=1.0 Hz), 6.09 (s, 1H), 5.68 (s, 1H), 5.30 (s, 1H), 3.6-3.8 (m, 1H), 3.4-3.5 (m, 1H), 3.0-3.1 (m, 1H), 2.95 (s, 3H), 2.5-2.6 (m, 1H), 2.3-2.5 (m, 1H), 2.0-2.1 (m, 2H) 48 1H NMR (400 MHz, CHLOROFORM-d) 8.49 - 8.56 (m, 1 H) 7.86 - 7.94 (m, 1 H) 7.83 (s, 1 H) 7.71 - 7.79 (m, 1 H) 7.31 - 7.41 (m, 3 H) 6.93 - 7.00 (m, 2 H) 6.59 - 6.71 (m, 1 H) 5.68 (br s, 1 H) 4.09 - 4.18 (m, 1 H) 3.92 - 4.03 (m, 1 H) 3.77 - 3.87 (m, 1 H) 3.44 - 3.59 (m, 1 H) 2.50 (s, 3 H) 49 1H NMR (400 MHz, CHLOROFORM-d) 8.50 - 8.56 (m, 1 H) 7.86 - 7.95 (m, 1 H) 7.84 (s, 1 H) 7.75 (d, J=8.1 Hz, 1 H) 7.31 - 7.39 (m, 1 H) 7.27 (s, 2 H) 6.97 (m, J=8.8 Hz, 2 H) 6.46 - 6.66 (m, 1 H) 5.59 - 5.79 (m, 2 H) 3.61 - 3.72 (m, 1 H) 3.40 - 3.51 (m, 1 H) 2.99 - 3.15 (m, 1 H) 2.96 (s, 3 H) 2.48 - 2.68 (m, 1 H) 2.32 - 2.48 (m, 1 H) 1.91 - 2.15 (m, 2 H) 50 1H NMR (400 MHz, CHLOROFORM-d) 8.49 - 8.58 (m, 1 H) 7.86 - 7.93 (m, 1 H) 7.76 (m, J=8.2 Hz, 1 H) 7.33 - 7.39 (m, 3 H) 6.96 - 7.03 (m, 3 H) 6.53 - 6.71 (m, 1 H) 5.68 (s, 1 H) 4.41 - 4.52 (m, 1 H) 4.27 - 4.37 (m, 1 H) 3.83 - 3.96 (m, 1 H) 3.46 - 3.70 (m, 1 H) 51 1H NMR (400 MHz, CHLOROFORM-d) 8.51 - 8.55 (m, 1 H) 7.87 - 7.93 (m, 1 H) 7.84 (s, 1 H) 7.76 (d, J=8.2 Hz, 1 H) 7.34 - 7.40 (m, 3 H) 6.96 - 7.03 (m, 3 H) 6.59 - 6.68 (m, 1 H) 5.68 (s, 1 H) 4.41 - 4.55 (m, 1 H) 4.25 - 4.36 (m, 1 H) 3.84 - 3.94 (m, 1 H) 3.48 - 3.65 (m, 1 H) ₅₂ 1H NMR (400 MHz, CHLOROFORM-d) 8.48 - 8.56 (m, 1 H) 7.85 - 7.92 (m, 1 H) 7.83 (s, 1 H) 7.75 (m, J=8.1 Hz, 1 H) 7.32 - 7.40 (m, 3 H) 6.94 - 7.00 (m, 2 H) 6.61 - 6.73 (m, 1 H) 5.67 (s, 1 H) 4.03 (s, 3 H) 3.65 - 3.79 (m, 1 H) 3.34 - 3.46 (m, 1 H) 2.95 - 3.06 (m, 1 H) 2.79 - 2.90 (m, 1 H) 53 1H NMR (400 MHz, CHLOROFORM-d) 8.50 - 8.55 (m, 1 H) 7.86 - 7.91 (m, 1 H) 7.83 (s, 1 H) 7.73 - 7.77 (m, 1 H) 7.32 - 7.40 (m, 3 H) 6.93 - 7.00 (m, 2 H) 6.62 - 6.72 (m, 1 H) 5.67 (s, 1 H) 4.03 (s, 3 H) 3.68 - 3.80 (m, 1 H) 3.36 - 3.46 (m, 1 H) 2.95 - 3.05 (m, 1 H) 2.78 - 2.89 (m, 1 H) ₅₄ 1H NMR (400 MHz, CHLOROFORM-d) 7.81 (s, 1 H) 7.60 (d, J=3.6 Hz, 1 H) 7.20 - 7.26 (m, 3 H) 6.92 (d, J=8.5 Hz, 2 H) 6.49 - 6.61 (m, 1 H) 5.74 - 5.83 (m, 2 H) 3.63 - Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 3.73 (m, 1 H) 3.35 - 3.49 (m, 1 H) 2.99 - 3.10 (m, 1 H) 2.95 (s, 3 H) 2.52 - 2.61 (m, 1 H) 2.35 - 2.49 (m, 1 H) 2.29 (t, J=18.9 Hz, 3 H) 2.00 - 2.13 (m, 2 H) 55 1H NMR (400 MHz, CHLOROFORM-d) 7.81 (s, 1 H) 7.60 (d, J=3.55 Hz, 1 H) 7.20 - 7.26 (m, 3 H) 6.92 (d, J=8.57 Hz, 2 H) 6.55 (q, J=9.09 Hz, 1 H) 5.72 - 5.82 (m, 2 H) 3.63 - 3.71 (m, 1 H) 3.42 - 3.50 (m, 1 H) 3.01 - 3.10 (m, 1 H) 2.95 (s, 3 H) 2.52 - 2.60 (m, 1 H) 2.35 - 2.46 (m, 1 H) 2.29 (t, J=18.92 Hz, 3 H) 1.99 - 2.13 (m, 2 H) 56 1H NMR (400 MHz, CHLOROFORM-d) 7.80 (s, 1 H) 7.60 (d, J=3.55 Hz, 1 H) 7.25 (s, 2 H) 7.22 (d, J=3.55 Hz, 1 H) 6.92 (d, J=8.67 Hz, 2 H) 6.56 (q, J=8.99 Hz, 1 H) 5.78 (br d, J=15.15 Hz, 2 H) 3.65 - 3.75 (m, 1 H) 3.35 - 3.43 (m, 1 H) 2.99 - 3.08 (m, 1 H) 2.96 (s, 3 H) 2.59 (dd, J=5.80, 3.61 Hz, 1 H) 2.55 (dd, J=5.70, 3.61 Hz, 1 H) 2.38 - 2.49 (m, 1 H) 2.29 (t, J=18.92 Hz, 3 H) 2.03 - 2.17 (m, 2 H) 57 1H NMR (CHLOROFORM-d, 400 MHz) 7.80 (s, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.24 (s, 2H), 6.93 (d, J = 8.7 Hz, 2H), 6.55 (q, J = 8.8 Hz, 1H), 6.43 (d, J = 2.2 Hz, 1H), 5.73 (br d, J = 1.5 Hz, 1H), 5.53 (s, 1H), 3.97 (s, 3H), 3.63-3.73 (m, 1H), 3.46 (dt, J = 12.5, 4.1 Hz, 1H), 3.01-3.11 (m, 1H), 2.96 (s, 3H), 2.52-2.64 (m, 1H), 2.33-2.48 (m, 1H), 1.97-2.15 (m, 2H) 58 1H NMR (CHLOROFORM-d, 400 MHz) 7.80 (s, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.25 (br s, 2H), 6.93 (d, J = 8.6 Hz, 2H), 6.57 (q, J = 9.0 Hz, 1H), 6.43 (d, J = 2.3 Hz, 1H), 5.73 (br s, 1H), 5.53 (s, 1H), 3.97 (s, 3H), 3.65-3.76 (m, 1H), 3.36-3.45 (m, 1H), 3.00- 3.10 (m, 1H), 2.96 (s, 3H), 2.53-2.64 (m, 1H), 2.38-2.51 (m, 1H), 1.99-2.19 (m, 2H) 59 1H NMR (400 MHz, CHLOROFORM-d) 7.80 (s, 1 H) 7.28 (s, 1 H) 7.25 (br d, J=8.36 Hz, 2 H) 6.94 (d, J=8.67 Hz, 2 H) 6.55 (q, J=8.95 Hz, 1 H) 6.19 (br d, J=2.30 Hz, 1 H) 5.63 (s, 1 H) 3.59 - 3.70 (m, 1 H) 3.38 - 3.51 (m, 1 H) 2.98 - 3.12 (m, 1 H) 2.94 (s, 3 H) 2.76 (s, 3 H) 2.33 - 2.62 (m, 2 H) 1.95 - 2.17 (m, 2 H) ₆₀ 1H NMR (400 MHz, CHLOROFORM-d) 7.82 (s, 1 H) 7.76 (s, 1 H) 7.52 (d, J=7.9 Hz, 1 H) 7.24 - 7.29 (m, 2 H) 7.17 - 7.21 (m, 1 H) 6.94 - 6.99 (m, 2 H) 6.50 - 6.63 (m, 1 H) 5.84 (br s, 1 H) 5.66 (br s, 1 H) 3.61 - 3.71 (m, 1 H) 3.42 - 3.51 (m, 1 H) 3.01 - 3.11 (m, 1 H) 2.96 (s, 3 H) 2.52 - 2.61 (m, 4 H) 2.35 - 2.47 (m, 1 H) 1.99 - 2.15 (m, 2 H) 61 1H NMR (500 MHz, CHLOROFORM-d) 9.02 – 8.89 (m, 2H), 8.12 (t, J = 2.3 Hz, 1H), 7.91 (s, 1H), 7.30 (d, J = 8.3 Hz, 2H), 6.99 (d, J = 8.3 Hz, 2H), 6.57 (q, J = 8.9 Hz, 1H), 5.95 (s, 1H), 5.68 (s, 1H), 3.66 (t, J = 11.2 Hz, 1H), 3.46 (d, J = 11.8 Hz, 1H), 3.06 (tt, J = 10.4, 4.5 Hz, 1H), 2.56 (ddd, J = 17.8, 5.8, 3.2 Hz, 1H), 2.45 – 2.34 (m, 1H), 2.03 (s, 2H). Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 62 1H NMR (500 MHz, CHLOROFORM-d) 8.98 (dd, J = 17.9, 2.2 Hz, 2H), 8.12 (t, J = 2.2 Hz, 1H), 7.91 (s, 1H), 7.31 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 8.2 Hz, 2H), 6.58 (q, J = 8.8 Hz, 1H), 5.88 (s, 1H), 5.66 (s, 1H), 3.69 (t, J = 11.0 Hz, 1H), 3.39 (d, J = 11.9 Hz, 1H), 3.04 (dt, J = 10.1, 5.6 Hz, 1H), 2.96 (s, 3H), 2.62 – 2.53 (m, 1H), 2.44 (ddd, J = 18.0, 11.1, 6.7 Hz, 1H), 2.15 – 2.03 (m, 2H). 63 1H NMR (500 MHz, CHLOROFORM-d) 7.81 (s, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.29 – 7.26 (m, 2H), 7.00 – 6.93 (m, 2H), 6.75 (d, J = 8.2 Hz, 1H), 6.56 (q, J = 8.9 Hz, 1H), 5.76 (d, J = 3.9 Hz, 1H), 5.67 (s, 1H), 3.95 (s, 3H), 3.71 – 3.63 (m, 1H), 3.50 – 3.42 (m, 1H), 3.05 (tt, J = 10.5, 4.4 Hz, 1H), 2.95 (s, 3H), 2.56 (ddd, J = 17.9, 5.8, 3.2 Hz, 1H), 2.45 – 2.35 (m, 1H), 2.13 – 1.99 (m, 2H). 64 1H NMR (500 MHz, CHLOROFORM-d) 8.08 – 8.00 (m, 2H), 7.87 (s, 1H), 7.66 (dd, J = 6.2, 2.2 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.01 – 6.96 (m, 2H), 6.56 (q, J = 8.9 Hz, 1H), 5.81 (s, 1H), 5.78 (s, 1H), 3.71 – 3.63 (m, 1H), 3.50 – 3.42 (m, 1H), 3.06 (tt, J = 10.6, 4.5 Hz, 1H), 2.95 (s, 3H), 2.56 (ddd, J = 17.9, 5.8, 3.2 Hz, 1H), 2.46 – 2.35 (m, 1H), 2.13 – 1.97 (m, 2H). 65 1H NMR (500 MHz, CHLOROFORM-d) 7.73 (s, 1H), 7.42 (qd, J = 7.0, 3.4 Hz, 5H), 7.19 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.5 Hz, 2H), 6.49 (q, J = 8.8 Hz, 1H), 5.67 (s, 1H), 5.46 (s, 1H), 3.60 (t, J = 11.2 Hz, 1H), 3.39 (dd, J = 11.4, 5.8 Hz, 1H), 2.99 (tt, J = 10.4, 4.5 Hz, 1H), 2.88 (s, 3H), 2.49 (ddd, J = 17.9, 5.8, 3.2 Hz, 1H), 2.33 (ddd, J = 18.1, 11.3, 7.0 Hz, 1H), 2.06 – 1.91 (m, 2H). 66 1H NMR (500 MHz, CHLOROFORM-d) 7.79 (s, 1H), 7.48 – 7.42 (m, 2H), 7.29 – 7.25 (m, 2H), 7.23 – 7.14 (m, 2H), 6.97 – 6.91 (m, 2H), 6.55 (q, J = 8.9 Hz, 1H), 5.70 (s, 1H), 5.52 (s, 1H), 3.72 – 3.63 (m, 1H), 3.50 – 3.42 (m, 1H), 3.05 (tt, J = 10.4, 4.4 Hz, 1H), 2.95 (s, 3H), 2.56 (ddd, J = 17.8, 5.8, 3.2 Hz, 1H), 2.45 – 2.34 (m, 1H), 2.13 – 1.98 (m, 2H). 67 1H NMR (500 MHz, CHLOROFORM-d) 7.79 (s, 1H), 7.49 (qd, J = 6.9, 3.5 Hz, 5H), 7.30 – 7.22 (m, 2H), 6.99 – 6.90 (m, 2H), 6.57 (q, J = 8.9 Hz, 1H), 5.94 – 5.79 (m, 1H), 5.53 (s, 1H), 3.74 – 3.64 (m, 1H), 3.43 – 3.36 (m, 1H), 3.04 (dq, J = 10.3, 4.9 Hz, 1H), 2.96 (s, 3H), 2.57 (ddd, J = 17.9, 5.8, 3.5 Hz, 1H), 2.44 (ddd, J = 17.9, 11.2, 6.8 Hz, 1H), 2.15 – 2.02 (m, 2H), 1.26 (d, J = 2.4 Hz, 6H). ₆₈ 1H NMR (400 MHz, CHLOROFORM-d) 7.81 (s, 1H), 7.77 (t, J = 7.9 Hz, 1H), 7.56 (dd, J = 8.1, 0.9 Hz, 1H), 7.26 – 7.23 (m, 2H), 7.17 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 6.55 (q, J = 8.9 Hz, 1H), 5.73 (s, 1H), 5.67 (s, 1H), 3.72 – 3.62 (m, 1H), Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 3.50 – 3.41 (m, 1H), 3.14 – 3.00 (m, 2H), 2.95 (s, 3H), 2.56 (ddd, J = 17.9, 5.6, 3.3 Hz, 1H), 2.47 – 2.33 (m, 1H), 2.14 – 1.98 (m, 2H), 1.31 (d, J = 6.9 Hz, 6H). 69 1H NMR (500 MHz, CHLOROFORM-d) 7.95 – 7.79 (m, 2H), 7.75 (t, J = 9.3 Hz, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 8.2 Hz, 2H), 6.96 (d, J = 8.2 Hz, 2H), 6.55 (q, J = 8.9 Hz, 1H), 6.28 (s, 1H), 5.68 (s, 1H), 3.64 (t, J = 11.2 Hz, 1H), 3.45 (d, J = 12.0 Hz, 1H), 3.10 – 3.01 (m, 1H), 2.95 (s, 3H), 2.53 (t, J = 11.0 Hz, 1H), 2.39 (tt, J = 11.1, 7.0 Hz, 1H), 2.12 – 1.93 (m, 2H). 70 1H NMR (500 MHz, CHLOROFORM-d) 8.34 (d, J = 3.0 Hz, 1H), 7.81 (s, 1H), 7.74 (dd, J = 9.0, 3.8 Hz, 1H), 7.59 (td, J = 8.2, 3.0 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.3 Hz, 2H), 6.54 (q, J = 8.9 Hz, 1H), 6.37 – 6.33 (m, 1H), 5.75 (s, 1H), 3.63 (t, J = 11.2 Hz, 1H), 3.45 (dt, J = 11.3, 4.5 Hz, 1H), 3.04 (tt, J = 10.2, 4.5 Hz, 1H), 2.94 (s, 3H), 2.54 (ddd, J = 17.8, 5.9, 3.2 Hz, 1H), 2.47 – 2.33 (m, 1H), 2.12 – 1.96 (m, 2H). 71 1H NMR (400 MHz, CHLOROFORM-d) 2.03 - 2.17 (m, 2 H) 2.34 - 2.47 (m, 1 H) 2.51 - 2.66 (m, 1 H) 2.97 (s, 3 H) 3.02 - 3.12 (m, 1 H) 3.43 - 3.52 (m, 1 H) 3.64 - 3.71 (m, 1 H) 5.65 - 5.87 (m, 2 H) 6.52 - 6.65 (m, 1 H) 6.96 - 7.10 (m, 2 H) 7.30 (d, J=8.6 Hz, 2 H) 7.47 - 7.55 (m, 1 H) 7.97 (s, 1 H) 8.22 (dd, J=7.9, 1.8 Hz, 1 H) 8.73 (dd, J=4.8, 1.8 Hz, 1 H) 72 1H NMR (500 MHz, CHLOROFORM-d) 7.81 (s, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 6.99 – 6.92 (m, 2H), 6.55 (q, J = 8.9 Hz, 1H), 6.11 (s, 1H), 5.70 (s, 1H), 3.65 (t, J = 11.0 Hz, 1H), 3.49 – 3.41 (m, 1H), 3.08 – 3.00 (m, 1H), 2.94 (s, 3H), 2.84 (q, J = 7.6 Hz, 2H), 2.60 – 2.49 (m, 1H), 2.45 – 2.34 (m, 1H), 2.13 – 1.97 (m, 2H), 1.32 (t, J = 7.6 Hz, 3H). 73 1H NMR (500 MHz, CHLOROFORM-d) 7.91 (s, 1H), 7.41 (dd, J = 9.3, 6.9 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.01 – 6.96 (m, 2H), 6.78 (dd, J = 9.3, 1.3 Hz, 1H), 6.57 (q, J = 8.9 Hz, 1H), 6.34 (d, J = 6.9 Hz, 1H), 5.73 (s, 1H), 5.61 (s, 1H), 3.71 – 3.63 (m, 1H), 3.50 – 3.42 (m, 1H), 3.15 (s, 3H), 3.11 – 3.01 (m, 1H), 2.96 (s, 3H), 2.56 (ddd, J = 17.9, 5.8, 3.2 Hz, 1H), 2.40 (ddd, J = 18.0, 11.3, 7.0 Hz, 1H), 2.13 – 1.99 (m, 2H). ₇₄ 1H NMR (500 MHz, CHLOROFORM-d) 7.81 (s, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 6.99 – 6.92 (m, 2H), 6.55 (q, J = 8.9 Hz, 1H), 6.11 (s, 1H), 5.70 (s, 1H), 3.65 (t, J = 11.0 Hz, 1H), 3.49 – 3.41 (m, 1H), 3.08 – 3.00 (m, 1H), 2.94 (s, 3H), 2.84 (q, J = 7.6 Hz, 2H), 2.60 – 2.49 (m, 1H), 2.45 – 2.34 (m, 1H), 2.13 – 1.97 (m, 2H), 1.32 (t, J = 7.6 Hz, 3H). Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 75 1H NMR (400 MHz, CHLOROFORM-d) 8.78 (d, J = 2.6 Hz, 1H), 8.73 (dd, J = 4.9, 1.5 Hz, 1H), 7.86 (s, 1H), 7.85 – 7.81 (m, 1H), 7.47 (ddd, J = 8.1, 4.8, 0.8 Hz, 1H), 7.30 – 7.26 (m, 2H), 7.03 – 6.93 (m, 2H), 6.56 (q, J = 8.9 Hz, 1H), 5.85 (s, 1H), 5.59 (s, 1H), 3.72 – 3.62 (m, 1H), 3.51 – 3.41 (m, 1H), 3.06 (tt, J = 10.1, 4.6 Hz, 1H), 2.96 (s, 3H), 2.56 (ddd, J = 17.9, 5.7, 3.3 Hz, 1H), 2.47 – 2.33 (m, 1H), 2.15 – 1.94 (m, 2H). 76 1H NMR (500 MHz, CHLOROFORM-d) 7.79 (s, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.50 (dd, J = 8.0, 0.8 Hz, 1H), 7.26 – 7.24 (m, 2H), 7.21 (d, J = 7.6 Hz, 1H), 6.98 – 6.93 (m, 2H), 6.55 (q, J = 8.9 Hz, 1H), 5.70 (s, 1H), 5.65 (s, 1H), 3.71 – 3.63 (m, 1H), 3.50 – 3.43 (m, 1H), 3.05 (tt, J = 10.2, 4.5 Hz, 1H), 2.95 (s, 3H), 2.56 (ddd, J = 17.8, 5.7, 3.1 Hz, 1H), 2.40 (ddd, J = 17.9, 11.3, 7.0 Hz, 1H), 2.13 – 1.97 (m, 3H), 1.17 – 1.10 (m, 2H), 1.01 – 0.94 (m, 2H). 77 1H NMR (500 MHz, CHLOROFORM-d) 7.84 (s, 1H), 7.56 – 7.44 (m, 2H), 7.35 – 7.21 (m, 4H), 6.97 – 6.92 (m, 2H), 6.56 (q, J = 8.9 Hz, 1H), 5.72 (s, 1H), 5.51 (s, 1H), 3.71 – 3.64 (m, 1H), 3.50 – 3.41 (m, 1H), 3.06 (tt, J = 10.4, 4.6 Hz, 1H), 2.95 (s, 3H), 2.56 (ddd, J = 17.8, 5.6, 3.1 Hz, 1H), 2.41 (td, J = 11.1, 5.7 Hz, 1H), 2.13 – 2.00 (m, 2H). 78 1H NMR (400 MHz, CHLOROFORM-d) 8.36 (dd, J = 4.7, 1.5 Hz, 1H), 7.83 (s, 1H), 7.63 (td, J = 8.7, 1.5 Hz, 1H), 7.44 (ddd, J = 8.3, 4.7, 3.6 Hz, 1H), 6.98 – 6.81 (m, 2H), 6.49 (q, J = 8.9 Hz, 1H), 5.91 (s, 1H), 5.55 (s, 1H), 3.59 (t, J = 11.2 Hz, 1H), 3.46 – 3.36 (m, 1H), 2.99 (dq, J = 10.5, 5.1 Hz, 1H), 2.88 (s, 3H), 2.49 (ddd, J = 17.9, 5.6, 3.2 Hz, 1H), 2.33 (ddd, J = 18.0, 11.0, 7.3 Hz, 1H), 2.14 – 1.88 (m, 2H). 79 1H NMR (400 MHz, CHLOROFORM-d) 8.45 (s, 1H), 7.95 (s, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H), 6.59 (q, J = 9.0 Hz, 1H), 5.91 (s, 1H), 5.80 (br s, 1H), 3.64-3.73 (m, 1H), 3.43-3.52 (m, 1H), 3.02-3.12 (m, 1H), 2.97 (s, 3H), 2.53-2.62 (m, 1H), 2.35-2.48 (m, 1H), 1.98-2.15 (m, 2H) 80 1H NMR (500 MHz, CHLOROFORM-d) 7.74 (s, 1H), 7.66 (t, J = 7.9 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.20 (s, 2H), 6.90 (d, J = 8.3 Hz, 2H), 6.68 (d, J = 8.2 Hz, 1H), 6.49 (q, J = 8.9 Hz, 1H), 5.62 (d, J = 28.2 Hz, 2H), 3.60 (t, J = 11.2 Hz, 1H), 3.39 (d, J = 12.0 Hz, 1H), 3.04 – 2.94 (m, 1H), 2.88 (s, 3H), 2.55 – 2.44 (m, 1H), 2.33 (ddd, J = 18.1, 11.4, 7.1 Hz, 1H), 2.06 – 1.91 (m, 2H). ₈₁ 1H NMR (500 MHz, CHLOROFORM-d) 7.78 (s, 1H), 7.39 (t, J = 8.0 Hz, 1H), 7.25 (s, 2H), 7.11 – 6.99 (m, 3H), 6.94 (d, J = 8.2 Hz, 2H), 6.55 (q, J = 8.9 Hz, 1H), 5.91 (s, 1H), 5.54 (s, 1H), 3.85 (s, 3H), 3.66 (t, J = 11.2 Hz, 1H), 3.45 (d, J = 12.0 Hz, 1H), Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 3.05 (dt, J = 10.8, 6.0 Hz, 1H), 2.95 (s, 3H), 2.55 (dt, J = 17.6, 5.2 Hz, 1H), 2.45 – 2.34 (m, 1H), 2.24 – 1.93 (m, 2H). 82 1H NMR (500 MHz, DMSO) 8.27 – 8.14 (m, 2H), 8.11 (s, 1H), 7.73 – 7.35 (m, 3H), 7.19 (t, J = 8.8 Hz, 3H), 6.97 (d, J = 8.6 Hz, 2H), 6.49 – 6.14 (m, 1H), 3.27 – 3.09 (m, 3H), 2.98 – 2.65 (m, 3H), 2.31 – 2.14 (m, 2H), 1.92 – 1.70 (m, 2H). 83 1H NMR (400 MHz, CHLOROFORM-d) 8.19 (s, 1H), 7.57 (dd, 1H, J=8.0, 8.9 Hz), 6.91 (dd, 1H, J=2.8, 8.9 Hz), 4.38 (q, 2H, J=7.2 Hz), 3.89 (s, 3H), 1.38 (t, 3H, J=7.2 Hz) 84 1H NMR (500 MHz, CHLOROFORM-d) 7.88 (t, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.1 Hz, 2H), 6.92 (t, J = 8.4 Hz, 3H), 6.49 (q, J = 8.9 Hz, 1H), 5.67 (d, J = 8.3 Hz, 2H), 3.61 (t, J = 11.2 Hz, 1H), 3.47 – 3.36 (m, 1H), 2.99 (tt, J = 10.5, 4.6 Hz, 1H), 2.88 (s, 3H), 2.49 (ddd, J = 17.9, 5.7, 3.2 Hz, 1H), 2.34 (ddd, J = 18.1, 11.3, 7.1 Hz, 1H), 2.00 (dtd, J = 28.7, 11.7, 5.2 Hz, 2H). 85 1H-NMR (300 MHz, DMSO-d6) 8.18 - 8.35 (m, 1H), 7.89 - 8.19 (m, 3H), 7.12 - 7.40 (m, 2H), 6.89 - 7.07 (m, 2H), 6.27 - 6.67 (m, 1H), 3.81 - 4.12 (m, 3H), 3.02 - 3.32 (m, 3H), 2.91 - 2.97 (m, 2H), 2.65 - 2.71 (m, 1H), 2.18 - 2.31 (m, 2H), 1.65 - 2.02 (m, 2H). 19F NMR (282 MHz, DMSO-d6) d -55.67, 67.25. 86 1H NMR (400 MHz, CHLOROFORM-d) 7.89 (d, J=2.7 Hz, 1 H) 7.84 (s, 1 H) 7.27 - 7.36 (m, 1 H) 6.95 (d, J=8.7 Hz, 2 H) 6.71 (d, J=2.7 Hz, 1 H) 6.56 (q, J=8.9 Hz, 1 H) 5.78 (br s, 1 H) 5.61 (s, 1 H) 3.63 - 3.71 (m, 1 H) 3.42 - 3.50 (m, 1 H) 3.00 - 3.11 (m, 1 H) 2.95 (s, 3 H) 2.52 - 2.61 (m, 1 H) 2.33 - 2.47 (m, 1 H) 1.96 - 2.16 (m, 2 H) ₈₇ 1H-NMR (400 MHz, DMSO-d6) 8.51 - 8.58 (m, 1H), 7.98 - 8.06 (m, 1H), 7.75 - 7.82 (m, 1H), 7.63 (s, 1H), 7.49 - 7.54 (m, 2H), 7.38 - 7.46 (m, 1H), 7.07 - 7.23 (m, 2H), 6.65 - 6.78 (m, 2H), 6.32 - 6.45 (m, 1H), 3.12 - 3.29 (m, 3H), 2.91(s, 3H), 2.16 - 2.41 (m, 3H), 1.72 - 1.90(m, 2H), 0.68 - 0.78 (m, 2H), 0.53 - 0.63 (m, 2H). 19F-NMR (400 MHz, DMSO-d6) d (ppm): - 67.19 88 1H NMR (400 MHz, CHLOROFORM-d) 7.81 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.28 (s, 2H), 6.97 (d, J = 8.7 Hz, 2H), 6.63 - 6.48 (m, 1H), 5.91 (br s, 1H), 5.71 (s, 1H), 4.04 (s, 3H), 3.72 - 3.62 (m, 1H), 3.51 - 3.42 (m, 1H), 3.11 - 3.00 (m, 1H), 2.95 (s, 3H), 2.61 - 2.51 (m, 1H), 2.46 - 2.33 (m, 1H), 2.14 - 1.96 (m, 2H) Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 89 1H NMR (500 MHz, CHLOROFORM-d) 7.97 (d, 1H), 7.84 (s, 1H), 7.71 (t, J = 8.8 Hz, 1H), 7.27 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H), 6.86 – 6.61 (m, 1H), 6.56 (q, J = 8.9 Hz, 1H), 6.08 – 6.04 (m, 1H), 5.77 (s, 1H), 3.65 (t, J = 11.2 Hz, 1H), 3.50 – 3.42 (m, 1H), 3.09 – 3.00 (m, 1H), 2.95 (s, 3H), 2.60 – 2.51 (m, 1H), 2.45 – 2.34 (m, 1H), 2.13 – 1.97 (m, 2H). 90 1H NMR (400 MHz, CHLOROFORM-d) 7.80 (s, 1 H) 7.51 (dd, J=9.2, 8.4 Hz, 1 H) 7.32 (dd, J=8.4, 2.4 Hz, 1 H) 7.25 - 7.30 (m, 3 H) 6.97 (d, J=8.8 Hz, 2 H) 6.56 (q, J=8.9 Hz, 1 H) 5.94 (br s, 1 H) 5.68 (s, 1 H) 4.05 (s, 3 H) 3.67 (t, J=11.2 Hz, 1 H) 3.42 - 3.51 (m, 1 H) 2.86 - 3.13 (m, 4 H) 2.35 - 2.61 (m, 2 H) 1.98 - 2.14 (m, 2 H) 91 1H NMR (400 MHz, CHLOROFORM-d) 7.93 - 7.97 (m, 1 H) 7.27 (s, 2 H) 7.85 (s, 1 H) 7.20 - 7.23 (m, 2 H) 6.92 - 7.00 (m, 2 H) 6.47 - 6.64 (m, 1 H) 5.84 (br s, 1 H) 5.60 (br s, 1 H) 4.42 (br s, 2 H) 3.61 - 3.75 (m, 1 H) 3.39 - 3.50 (m, 1 H) 3.00 - 3.11 (m, 1 H) 2.96 (s, 3 H) 2.52 - 2.61 (m, 1 H) 2.35 - 2.47 (m, 1 H) 2.03 - 2.14 (m, 2 H) 19F NMR (377 MHz, CHLOROFORM-d) d ppm -68.27 - -67.93 (m, 3 F) -56.91 (s, 3 F) 92 1H NMR (400 MHz, CHLOROFORM-d) 7.79 (s, 1 H) 7.60 (t, J=7.9 Hz, 1 H) 7.23 - 7.28 (m, 2 H) 6.99 - 7.06 (m, 1 H) 6.95 (d, J=8.6 Hz, 2 H) 6.49 - 6.62 (m, 2 H) 5.77 (br s, 1 H) 5.63 (br s, 1 H) 4.54 (br s, 2 H) 3.60 - 3.74 (m, 1 H) 3.40 - 3.53 (m, 1 H) 3.01 - 3.11 (m, 1 H) 2.96 (s, 3 H) 2.52 - 2.65 (m, 1 H) 2.31 - 2.46 (m, 1 H) 1.99 - 2.16 (m, 2 H) 19F NMR (377 MHz, CHLOROFORM-d) d ppm -68.09 (d, J=9.0 Hz, 3 F) -55.65 (s, 3 F) 93 1H NMR (400 MHz, CHLOROFORM-d) 7.54 - 7.71 (m, 3 H) 7.11 - 7.20 (m, 4 H) 6.75 (d, J=8.6 Hz, 2 H) 6.51 (q, J=9.0 Hz, 1 H) 5.84 (br s, 1 H) 5.27 (s, 1 H) 3.61 - 3.71 (m, 1 H) 3.40 - 3.50 (m, 1 H) 3.00 - 3.11 (m, 1 H) 2.94 (s, 3 H) 2.55 (ddd, J=17.9, 5.7, 3.6 Hz, 1 H) 2.34 - 2.44 (m, 4 H) 1.95 - 2.14 (m, 6 H) 1.65 - 1.70 (m, 1 H) 94 1H NMR (500 MHz, CHLOROFORM-d) 8.20 (dd, J = 5.1, 1.7 Hz, 1H), 7.88 (s, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.31 – 7.25 (m, 2H), 7.00 – 6.92 (m, 2H), 6.78 (dd, J = 7.8, 4.9 Hz, 1H), 6.55 (q, J = 8.9 Hz, 1H), 6.20 (s, 1H), 5.63 (s, 1H), 4.75 (s, 2H), 3.74 – 3.57 (m, 1H), 3.50 – 3.42 (m, 1H), 3.11 – 3.01 (m, 1H), 2.95 (s, 3H), 2.62 – 2.48 (m, 1H), 2.48 – 2.33 (m, 1H), 2.13 – 1.96 (m, 2H). 19F NMR (471 MHz, CHLOROFORM-d) d -56.98, -68.07. Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 95 1H-NMR (400 MHz, DMSO-d6) 8.21-8.29(m, 1H), 8.03-8.12 (m, 2H), 7.98- 8.05 (m, 1H), 7.13 - 7.31 (m, 2H), 6.90 - 7.08 (m, 2H), 6.25 - 6.52 (m, 1H), 3.12 - 3.29 (m, 3H), 2.70 - 2.98 (m, 3H), 2.13- 2.29 (m, 2H), 1.72 - 1.98(m, 2H) 19F NMR (376 MHz, DMSO-d6) d -55.6671, -67.2767. 96 1H NMR (CHLOROFORM-d, 400 MHz) 8.17-8.24 (m, 1H), 8.02-8.09 (m, 2H), 7.88 (s, 1H), 7.65 (br s, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 6.58 (q, J = 8.8 Hz, 1H), 6.16 (br d, J = 2.4 Hz, 1H), 5.92 (br s, 1H), 5.82 (s, 1H), 3.61-3.72 (m, 1H), 3.42-3.52 (m, 1H), 3.01-3.12 (m, 1H), 2.97 (s, 3H), 2.50-2.64 (m, 1H), 2.34-2.48 (m, 1H), 1.97-2.16 (m, 2H). 97 1H NMR (400 MHz, CHLOROFORM-d) 8.19 - 8.26 (m, 1 H) 8.04 - 8.10 (m, 2 H) 7.88 (s, 1 H) 7.60 - 7.68 (m, 1 H) 7.36 - 7.45 (m, 2 H) 6.87 - 7.16 (m, 3 H) 6.57 - 6.72 (m, 1 H) 5.79 (br s, 1 H) 5.55 - 5.69 (m, 1 H) 4.41 - 4.52 (m, 1 H) 4.27 - 4.39 (m, 1 H) 3.84 - 4.00 (m, 1 H) 3.55 - 3.66 (m, 1 H) 98 1H NMR (400 MHz, CHLOROFORM-d) 8.20 (t, J=4.3 Hz, 1 H) 8.05 (s, 1 H) 8.04 (d, J=0.9 Hz, 1 H) 7.87 (s, 1 H) 7.52 - 7.71 (m, 1 H) 7.39 (m, J=8.6 Hz, 2 H) 6.97 - 7.03 (m, 2 H) 6.68 (q, J=8.9 Hz, 1 H) 5.59 - 5.80 (m, 2 H)m 4.03 (s, 3 H) 3.73 (dt, J=12.9, 6.2 Hz, 1 H) 3.35 - 3.44 (m, 1 H) 3.01 (ddd, J=16.2, 8.7, 5.5 Hz, 1 H) 2.80 - 2.88 (m, 1 H) 99 1H-NMR (400 MHz, DMSO-d6) 8.21 - 8.41 (m, 1H), 8.02 - 8.20 (m, 3H), 7.21 - 7.39 (m, 2H), 6.97 - 7.05 (m, 2H), 6.41 - 6.57 (m, 1H), 3.92 - 4.01 (m, 3H), 3.55 - 3.74 (m, 1H), 3.29 - 3.39 (m, 1H), 2.93 - 3.10 (m, 2H) 100 1H NMR (400 MHz, DMSO-d6) 8.21 - 8.32 (m, 2 H) 8.12 (s, 1 H) 8.08 (ddd, J=13.9, 7.9, 0.9 Hz, 2 H) 7.97 (s, 1 H) 7.43 (br s, 1 H) 7.29 - 7.39 (m, 2 H) 6.95 - 7.08 (m, 2 H) 6.41 - 6.55 (m, 1 H) 4.01 - 4.20 (m, 2 H) 3.69 - 3.84 (m, 1 H) 3.47 (br d, J=5.1 Hz, 1 H) 2.37 (s, 3 H) ₁₀₁ 1H NMR (400 MHz, CHLOROFORM-d) 8.19 - 8.24 (m, 1 H) 8.02 - 8.09 (m, 2 H) 7.88 (s, 1 H) 7.61 - 7.70 (m, 1 H) 7.28 - 7.32 (m, 2 H) 6.94 - 7.08 (m, 2 H) 6.50 - 6.67 (m, 1 H) 5.79 (br s, 1 H) 5.65 (br s, 1 H) 3.43 - 3.54 (m, 1 H) 3.31 - 3.42 (m, 1 H) 2.88 - 3.06 (m, 6 H) 2.19 - 2.51 (m, 4 H) 102 1H NMR (400 MHz, CHLOROFORM-d) 8.17 - 8.25 (m, 1 H) 7.97 - 8.08 (m, 2 H) 7.87 (s, 1 H) 7.74 - 7.85 (m, 1 H) 7.28 - 7.33 (m, 2 H) 6.98 - 7.04 (m, 2 H) 6.49 - 6.66 (m, 1 H) 5.64 - 5.87 (m, 1 H) 3.42 - 3.54 (m, 1 H) 3.26 - 3.41 (m, 1 H) 3.06 (d, J=5.0 Hz, 3 H) 2.89 - 3.05 (m, 6 H) 2.19 - 2.53 (m, 4 H) Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 103 1H NMR (400 MHz, CHLOROFORM-d) 7.94 - 8.04 (m, 1 H) 7.81 - 7.86 (m, 2 H) 7.68 (dd, J=7.6, 0.8 Hz, 1 H) 7.27 - 7.31 (m, 2 H) 6.93 - 7.03 (m, 2 H) 6.52 - 6.64 (m, 1 H) 5.69 (s, 1 H) 3.44 - 3.53 (m, 1 H) 3.33 - 3.42 (m, 1 H) 3.16 (s, 3 H) 3.09 (s, 3 H) 2.90 - 3.04 (m, 6 H) 22.18 - 2.51 (m, 4 H).18 - 2.51 (m, 4 H). 104 1H NMR (400 MHz, CHLOROFORM-d) 2.16 - 2.49 (m, 4 H) 2.49 - 2.55 (m, 1 H) 2.84 - 2.92 (m, 1 H) 2.93 (s, 3 H) 2.99 - 3.12 (m, 2 H) 3.34 - 3.52 (m, 2 H) 5.57 (br s, 1 H) 5.79 (br s, 1 H) 6.52 - 6.70 (m, 1 H) 6.93 - 7.07 (m, 2 H) 7.28 - 7.33 (m, 2 H) 7.64 (br s, 1 H) 7.88 (s, 1 H) 8.02 - 8.11 (m, 2 H) 8.18 - 8.27 (m, 1 H) 105 1H NMR (400 MHz, CHLOROFORM-d) 2.13 - 2.52 (m, 5 H) 2.86 - 2.96 (m, 4 H) 3.01 - 3.14 (m, 2 H) 3.31 - 3.50 (m, 2 H) 5.58 (br s, 1 H) 5.76 (s, 1 H) 6.53 - 6.66 (m, 1 H) 6.97 - 7.05 (m, 2 H) 7.28 - 7.33 (m, 2 H) 7.57 - 7.74 (m, 1 H) 7.88 (s, 1 H) 8.00 - 8.11 (m, 2 H) 8.17 - 8.25 (m, 1 H) 106 1H NMR (400 MHz, CHLOROFORM-d) 7.81 (s, 1 H), 7.72 - 7.79 (m, 1 H), 7.50 - 7.56 (m, 1 H), 7.33 - 7.40 (m, 2 H), 7.17 - 7.23 (m, 1 H), 6.92 - 7.01 (m, 2 H), 6.57 - 6.71 (m, 1 H), 4.08 - 4.17 (m, 1 H), 3.94 - 4.02 (m, 1 H), 3.77 - 3.85 (m, 1 H), 3.69 - 3.77 (m, 1 H), 3.46 - 3.58 (m, 1 H), 2.59 (s, 3 H), 2.50 (s, 3 H). 19F NMR (377 MHz, CHLOROFORM-d) d -55.77 (s, 3 F), -68.54 (d, J=9.0 Hz, 1 F) 107 1H NMR (500 MHz, CHLOROFORM-d) 7.80 (s, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 8.2 Hz, 3H), 7.00 – 6.94 (m, 2H), 6.76 (d, J = 8.2 Hz, 1H), 6.64 (q, J = 8.6 Hz, 1H), 5.68 (s, 1H), 4.16 – 4.05 (m, 1H), 4.03 – 3.89 (m, 4H), 3.85 – 3.76 (m, 1H), 3.56 – 3.47 (m, 1H), 2.49 (s, 3H). 108 1H NMR (500 MHz, CHLOROFORM-d) 7.84 (s, 1H), 7.79 (s, 1H), 7.75 (t, J = 8.0 Hz, 2H), 7.63 (t, J = 7.9 Hz, 1H), 7.39 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 8.2 Hz, 2H), 6.58 (q, J = 8.5 Hz, 1H), 5.86 (s, 1H), 4.13 (ddd, J = 12.5, 7.9, 4.3 Hz, 1H), 4.08 – 3.97 (m, 1H), 3.80 (dt, J = 11.7, 4.9 Hz, 1H), 3.55 (ddd, J = 13.2, 8.0, 4.1 Hz, 1H), 2.45 (s, 3H). ₁₀₉ 1H NMR (500 MHz, DMSO) 8.04 (d, J = 8.9 Hz, 2H), 7.75 – 7.63 (m, 2H), 7.52 (ddd, J = 9.8, 8.3, 1.3 Hz, 1H), 7.42 (td, J = 7.7, 1.3 Hz, 1H), 7.33 (d, J = 8.3 Hz, 2H), 6.98 – 6.91 (m, 2H), 6.47 (q, J = 8.9 Hz, 1H), 4.17 (ddd, J = 12.3, 7.5, 4.4 Hz, 1H), 4.07 (ddd, J = 13.0, 7.1, 4.4 Hz, 1H), 3.77 (ddd, J = 12.1, 7.1, 4.5 Hz, 1H), 3.47 (ddd, J = 12.6, 7.5, 4.4 Hz, 1H), 2.37 (s, 3H). 110 1H NMR (500 MHz, CHLOROFORM-d) 8.35 (dd, J = 4.6, 1.4 Hz, 1H), 7.82 (s, 1H), 7.62 (td, J = 8.7, 1.5 Hz, 1H), 7.44 (ddd, J = 8.3, 4.7, 3.6 Hz, 1H), 7.30 (d, J = 8.3 Hz, 2H), 6.95 – 6.85 (m, 2H), 6.56 (q, J = 8.6 Hz, 1H), 5.55 (s, 1H), 4.05 (ddd, J = 12.5, Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 8.1, 4.2 Hz, 1H), 3.91 (ddd, J = 12.8, 6.8, 4.2 Hz, 1H), 3.74 (ddd, J = 13.6, 6.9, 4.4 Hz, 1H), 3.45 (ddd, J = 12.8, 8.1, 4.2 Hz, 1H), 2.42 (s, 3H). 111 1H NMR (400 MHz, CHLOROFORM-d) 7.72 (s, 1H), 7.47 – 7.39 (m, 5H), 7.29 (d, J = 8.3 Hz, 2H), 6.93 – 6.84 (m, 2H), 6.57 (q, J = 8.7 Hz, 1H), 5.49 (s, 1H), 4.06 (ddd, J = 12.5, 8.1, 4.2 Hz, 1H), 3.95 – 3.86 (m, 1H), 3.74 (dt, J = 11.6, 5.3 Hz, 1H), 3.45 (ddd, J = 12.9, 8.1, 4.2 Hz, 1H), 2.42 (s, 3H). 112 1H NMR (400 MHz, CHLOROFORM-d) 8.44 (s, 1 H) 7.95 (s, 1 H) 7.43 (d, J=8.5 Hz, 2 H) 7.05 (d, J=8.7 Hz, 2 H) 6.66 (q, J=8.7 Hz, 1 H) 5.94 (s, 1 H) 4.14 (ddd, J=12.8, 8.4, 4.2 Hz, 1 H) 3.95 - 4.03 (m, 1 H) 3.78 - 3.85 (m, 1 H) 3.51 (ddd, J=13.2, 8.6, 4.3 Hz, 1 H) 2.49 (s, 3 H) 113 1H NMR (400 MHz, CHLOROFORM-d) d 7.82 (s, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.38 (dd, J = 10.4, 7.9 Hz, 3H), 7.00 (d, J = 8.2 Hz, 2H), 6.78 (d, J = 8.2 Hz, 1H), 6.65 (q, J = 8.7 Hz, 1H), 5.75 (s, 1H), 4.14 (td, J = 9.9, 4.2 Hz, 1H), 4.05 – 3.96 (m, 1H), 3.89 – 3.77 (m, 1H), 3.62 – 3.47 (m, 1H), 2.51 (s, 3H). 114 1H NMR (500 MHz, DMSO) 8.25 (s, 1H), 8.17 (t, J = 8.0 Hz, 1H), 8.11 (s, 1H), 7.73 – 7.37 (m, 2H), 7.33 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.1 Hz, 1H), 7.01 – 6.95 (m, 2H), 6.48 (q, J = 9.0 Hz, 1H), 4.21 – 4.12 (m, 1H), 4.11 – 4.02 (m, 1H), 3.81 – 3.72 (m, 1H), 3.51 – 3.42 (m, 1H), 2.37 (s, 3H). 115 1H NMR (500 MHz, CHLOROFORM-d) 7.78 (s, 1H), 7.43 – 7.32 (m, 3H), 7.09 – 6.99 (m, 3H), 6.95 (d, J = 8.4 Hz, 2H), 6.63 (q, J = 8.7 Hz, 1H), 5.56 (s, 1H), 4.12 (ddd, J = 12.5, 8.1, 4.2 Hz, 1H), 3.97 (ddd, J = 12.3, 6.7, 4.3 Hz, 1H), 3.85 (s, 3H), 3.84 – 3.76 (m, 1H), 3.52 (ddd, J = 13.1, 8.1, 4.2 Hz, 1H), 2.49 (s, 3H). ₁₁₆ 1H NMR (500 MHz, CHLOROFORM-d) 8.03 (t, J = 7.9 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.85 (s, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.37 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H), 6.65 (q, J = 8.5 Hz, 1H), 6.60 (t, J = 55.3 Hz, 1H), 5.74 (s, 1H), 4.12 (ddd, J = 12.7, 8.3, 4.3 Hz, 1H), 3.97 (ddd, J = 12.0, 7.0, 4.0 Hz, 1H), 3.81 (dt, J = 12.0, 7.0 Hz, 1H), 3.51 (ddd, J = 12.9, 8.1, 4.0 Hz, 1H), 2.50 (s, 3H). 117 1H NMR (400 MHz, CHLOROFORM-d) 7.72 (s, 1H), 7.70 – 7.61 (m, 1H), 7.31 – 7.23 (m, 3H), 7.08 – 6.78 (m, 1H), 6.92 – 6.87 (m, 2H), 6.68 (dd, J = 8.2, 0.7 Hz, 1H), 6.54 (q, J = 8.6 Hz, 1H), 5.61 (s, 1H), 4.36 (ddd, J = 12.7, 8.1, 4.2 Hz, 1H), 4.23 (ddd, J = 13.3, 6.8, 4.2 Hz, 1H), 3.87 (s, 3H), 3.80 (ddd, J = 13.7, 6.7, 4.3 Hz, 1H), 3.51 (ddd, J = 13.1, 8.1, 4.2 Hz, 1H). ₁₁₈ 1H NMR (400 MHz, DMSO) 7.80 (s, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.35 (dd, J = 8.0, 5.3 Hz, 3H), 7.15 – 6.85 (m, 3H), 6.76 (d, J = 8.2 Hz, 1H), 6.62 (q, J = 8.6 Hz, 1H), Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 5.69 (s, 1H), 4.44 (ddd, J = 12.6, 8.1, 4.3 Hz, 1H), 4.36 – 4.26 (m, 1H), 3.95 (s, 3H), 3.93 – 3.82 (m, 1H), 3.59 (ddd, J = 13.1, 8.2, 4.2 Hz, 1H). 119 1H NMR (400 MHz, CHLOROFORM-d) 7.80 (s, 1 H) 7.28 - 7.53 (m, 4 H) 6.98 (br d, J=8.1 Hz, 2 H) 6.53 - 6.68 (m, 1 H) 5.77 (br s, 1 H) 4.08 - 4.16 (m, 1 H) 4.04 (s, 4 H) 3.75 - 3.86 (m, 1 H) 3.54 (br s, 1 H) 2.47 (s, 3 H) 120 1H NMR (500 MHz, CHLOROFORM-d) 7.96 (t, J = 7.9 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.78 (s, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.30 (d, J = 8.3 Hz, 2H), 7.07 – 6.79 (m, 3H), 6.67 – 6.39 (m, 2H), 5.70 (s, 1H), 4.42 – 4.33 (m, 1H), 4.29 – 4.20 (m, 1H), 3.85 – 3.77 (m, 1H), 3.56 – 3.47 (m, 1H). 121 1H NMR (400 MHz, CHLOROFORM-d) 7.81 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.41 - 7.32 (m, 3H), 6.98 (d, J = 8.6 Hz, 2H), 6.64 (q, J = 8.7 Hz, 1H), 5.71 (br s, 1H), 4.17 - 4.08 (m, 1H), 4.04 (s, 3H), 4.02 - 3.93 (m, 1H), 3.87 - 3.76 (m, 1H), 3.51 (ddd, J = 4.4, 8.5, 13.3 Hz, 1H), 2.49 (s, 3H) 19F NMR (377 MHz, CHLOROFORM-d) -55.62 (s), -68.53 (d, J = 9.0 Hz) 122 1H NMR (500 MHz, CHLOROFORM-d) 7.94 (t, J = 8.0 Hz, 1H), 7.84 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 8.3 Hz, 2H), 7.05 – 6.93 (m, 3H), 6.60 (q, J = 8.6 Hz, 1H), 5.88 (s, 1H), 4.12 (ddd, J = 12.5, 8.1, 4.3 Hz, 1H), 4.00 (ddd, J = 12.7, 6.7, 4.2 Hz, 1H), 3.80 (ddd, J = 13.4, 6.8, 4.3 Hz, 1H), 3.53 (ddd, J = 13.2, 8.0, 4.2 Hz, 1H), 2.46 (s, 3H). 123 1H NMR (500 MHz, CHLOROFORM-d) 7.96 (t, J = 7.9 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.78 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.3 Hz, 2H), 7.06 – 6.79 (m, 3H), 6.64 – 6.36 (m, 2H), 5.68 (s, 1H), 4.37 (ddd, J = 12.8, 8.1, 4.1 Hz, 1H), 4.24 (dt, J = 13.7, 5.9 Hz, 1H), 3.80 (dd, J = 13.1, 6.7 Hz, 1H), 3.51 (ddd, J = 13.1, 8.3, 4.3 Hz, 1H). ₁₂₄ 1H NMR (500 MHz, CHLOROFORM-d) 8.09 – 7.99 (m, 2H), 7.87 (s, 1H), 7.70 – 7.61 (m, 1H), 7.38 (d, J = 8.3 Hz, 2H), 7.03 – 6.96 (m, 2H), 6.64 (q, J = 8.6 Hz, 1H), 5.82 (s, 1H), 4.17 – 4.08 (m, 1H), 4.02 – 3.94 (m, 1H), 3.85 – 3.76 (m, 1H), 3.56 – 3.47 (m, 1H), 2.48 (s, 3H). 125 1H NMR (400 MHz, CHLOROFORM-d) 8.02 (t, J = 7.9 Hz, 1H), 7.93 (dd, J = 8.3, 1.0 Hz, 1H), 7.85 (s, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.01 – 6.94 (m, 2H), 6.67 (q, J = 8.8 Hz, 1H), 6.73 – 6.34 (m, 1H), 5.75 (s, 1H), 4.03 (s, 3H), 3.72 (dt, J = 12.7, 6.2 Hz, 1H), 3.39 (ddd, J = 13.3, 8.6, 5.4 Hz, 1H), 3.00 (ddd, J = 16.3, 8.6, 5.6 Hz, 1H), 2.84 (ddd, J = 16.3, 7.0, 5.4 Hz, 1H). Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 126 1H NMR (600 MHz, DMSO-d6) 2.90 - 3.08 (m, 2 H) 3.30 - 3.68 (m, 2 H) 3.98 (s, 3 H) 6.51 (q, J=9.0 Hz, 1 H) 7.05 - 7.36 (m, 4 H) 8.39 (s, 1 H) 8.48 (s, 1 H) 8.75 (s, 1 H) 127 1H NMR (600 MHz, DMSO-d6) 1.34 (s, 3 H) 3.90 (dd, J=11.0, 7.0 Hz, 2 H) 3.98 (s, 3 H) 4.04 (dd, J=11.2, 3.9 Hz, 2 H) 6.45 - 6.50 (m, 1 H) 6.95 (d, J=8.4 Hz, 2 H) 7.29 (br d, J=8.8 Hz, 2 H) 7.36 (d, J=8.1 Hz, 1 H) 7.59 (d, J=8.1 Hz, 1 H) 7.92 - 7.96 (m, 1 H) 8.02 (s, 1 H) 8.13 (s, 1 H) 128 1H NMR (500 MHz, CHLOROFORM-d) 7.80 (s, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.40 – 7.31 (m, 3H), 6.96 (d, J = 8.2 Hz, 2H), 6.75 (d, J = 8.2 Hz, 1H), 6.66 (q, J = 8.8 Hz, 1H), 5.68 (s, 1H), 4.02 (s, 3H), 3.94 (s, 3H), 3.72 (dt, J = 12.8, 6.2 Hz, 1H), 3.39 (ddd, J = 13.3, 8.5, 5.4 Hz, 1H), 2.99 (ddd, J = 14.7, 8.6, 5.6 Hz, 1H), 2.83 (dt, J = 16.4, 6.2 Hz, 1H). 129 1H NMR (500 MHz, DMSO) 8.14 (s, 1H), 8.04 (s, 1H), 7.94 (t, J = 7.9 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.2 Hz, 1H), 6.48 (q, J = 9.2 Hz, 1H), 3.97 (s, 3H), 3.88 (s, 3H), 3.63 (dt, J = 13.1, 6.5 Hz, 1H), 3.37 – 3.33 (m, 1H), 3.08 – 2.90 (m, 2H). ¹³⁰ 1H NMR (400 MHz, CHLOROFORM-d) 7.89 (d, J=2.7 Hz, 1 H) 7.83 (s, 1 H)^ 7.33 - 7.38 (m, 2 H) 7.16 - 7.22 (m, 1 H) 6.95 (d, J=8.7 Hz, 2 H) 6.63 - 6.71 (m, 2 H) 5.60 (s, 1 H) 4.02 (s, 3 H) 3.67 - 3.76 (m, 1 H) 3.35 - 3.43 (m, 1 H) 2.79 - 3.03 (m, 2 H) ₁₃₁ 1H NMR (400 MHz, CHLOROFORM-d) 7.80 (s, 1 H) 7.51 (t, J=8.5 Hz, 1 H) 7.37 (d, J=8.4 Hz, 2 H) 7.32 (dd, J=8.3, 2.6 Hz, 1 H) 6.97 (d, J=8.7 Hz, 2 H) 6.67 (q, J=9.0 Hz, 1 H) 5.67 (s, 1 H) 4.05 (s, 3 H) 4.03 (s, 3 H) 3.73 (dt, J=12.9, 6.3 Hz, 1 H) 3.36 - 3.44 (m, 1 H) 2.96 - 3.05 (m, 1 H) 2.80 - 2.88 (m, 1 H) 132 1H NMR (400 MHz, DMSO-d6) 8.53 (m, 1H), 8.01 (m, 1H), 7.78 (m, 1H), 7.62 (s, 1H), 7.52 (s, 1H), 7.37-7.45(m, 1H), 7.21 (m, 2H), 6.72 (m, 2H), 6.44 (m, 1H), 3.97 (s, 3H), 3.63 (m, 1H), 3.31 (m, 1H), 2.87-3.09 (m, 2H), 2.33 (m, 1H), 0.63-0.76 (m, 2H), 0.54 - 0.62 (m, 2H). ₁₃₃ 1H NMR (400 MHz, DMSO-d6) 8.53 (m, 1H), 8.01 (m, 1H), 7.78 (m, 1H), 7.62 (s, 1H), 7.52 (s, 1H), 7.37-7.45(m, 1H), 7.21 (m, 2H), 6.72 (m, 2H), 6.44 (m, 1H), 3.97 (s, 3H), 3.63 (m, 1H), 3.31 (m, 1H), 2.87-3.09 (m, 2H), 2.33 (m, 1H), 0.63-0.76 (m, 2H), 0.54 - 0.62 (m, 2H) 134 1H NMR (500 MHz, CHLOROFORM-d) 8.08 – 7.99 (m, 2H), 7.86 (s, 1H), 7.67 – 7.62 (m, 1H), 7.36 (d, J = 8.3 Hz, 2H), 7.02 – 6.95 (m, 2H), 6.65 (q, J = 8.8 Hz, 1H), Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 5.83 (s, 1H), 4.01 (s, 3H), 3.75 – 3.67 (m, 1H), 3.43 – 3.34 (m, 1H), 3.04 – 2.95 (m, 1H), 2.89 – 2.79 (m, 1H). 135 1H NMR (500 MHz, CHLOROFORM-d) 8.08 – 8.00 (m, 2H), 7.86 (s, 1H), 7.68 – 7.62 (m, 1H), 7.37 (d, J = 8.3 Hz, 2H), 7.02 – 6.95 (m, 2H), 6.66 (q, J = 8.8 Hz, 1H), 5.80 (s, 1H), 4.02 (s, 3H), 3.76 – 3.67 (m, 1H), 3.43 – 3.34 (m, 1H), 3.04 – 2.95 (m, 1H), 2.88 – 2.79 (m, 1H). 136 1H NMR (400 MHz, CHLOROFORM-d) 8.01 (t, J = 7.9 Hz, 1H), 7.98 – 7.90 (m, 2H), 7.85 (s, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.02 – 6.95 (m, 2H), 6.75 – 6.44 (m, 2H), 5.73 (s, 1H), 3.80 (s, 3H), 3.66 (dt, J = 12.8, 6.4 Hz, 1H), 3.34 (ddd, J = 13.2, 8.4, 5.4 Hz, 1H), 2.96 – 2.86 (m, 1H), 2.75 (ddd, J = 16.1, 7.3, 5.4 Hz, 1H). 137 1H NMR (500 MHz, CHLOROFORM-d) 8.01 (t, J = 7.9 Hz, 1H), 7.93 (d, J = 7.6 Hz, 2H), 7.85 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 8.1 Hz, 2H), 6.76 – 6.44 (m, 2H), 5.74 (s, 1H), 3.79 (s, 3H), 3.66 (dt, J = 13.1, 6.5 Hz, 1H), 3.34 (ddd, J = 13.5, 8.3, 5.3 Hz, 1H), 2.96 – 2.71 (m, 2H). 138 1H NMR (500 MHz, CHLOROFORM-d) 8.01 (t, J = 7.9 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.85 (s, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.47 (s, 1H), 7.38 (d, J = 8.2 Hz, 2H), 6.97 (d, J = 8.3 Hz, 2H), 6.78 – 6.44 (m, 2H), 5.74 (s, 1H), 3.72 – 3.63 (m, 1H), 3.60 (s, 3H), 3.39 – 3.30 (m, 1H), 2.92 – 2.83 (m, 1H), 2.75 – 2.66 (m, 1H). 139 1H NMR (400 MHz, CHLOROFORM-d) 8.06 – 7.90 (m, 2H), 7.85 (s, 1H), 7.74 (s, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 8.2 Hz, 2H), 7.02 – 6.94 (m, 2H), 6.76 – 6.41 (m, 2H), 5.82 (s, 1H), 4.05 (ddd, J = 12.2, 7.9, 4.1 Hz, 1H), 3.91 (ddd, J = 12.3, 6.8, 4.1 Hz, 1H), 3.76 – 3.66 (m, 1H), 3.41 (ddd, J = 12.6, 7.8, 4.1 Hz, 1H), 2.39 (s, 3H). ₁₄₀ 1H NMR (500 MHz, CHLOROFORM-d) 8.00 (t, J = 7.9 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.84 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.35 (d, J = 8.2 Hz, 2H), 6.97 (d, J = 8.2 Hz, 2H), 6.77 – 6.38 (m, 2H), 5.85 (s, 1H), 3.66 (dt, J = 12.8, 6.3 Hz, 1H), 3.59 (s, 3H), 3.33 (ddd, J = 13.2, 8.8, 5.4 Hz, 1H), 2.86 (ddd, J = 15.0, 8.9, 5.6 Hz, 1H), 2.70 (dt, J = 16.1, 6.2 Hz, 1H). 141 1H NMR (400 MHz, CHLOROFORM-d) 7.85 (s, 1H), 7.73 (s, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.34 – 7.23 (m, 3H), 6.94 – 6.83 (m, 2H), 6.68 (dd, J = 8.2, 0.7 Hz, 1H), 6.55 (q, J = 9.0 Hz, 1H), 5.61 (s, 1H), 3.88 (s, 3H), 3.72 (s, 3H), 3.59 (dt, J = 12.7, 6.2 Hz, 1H), 3.27 (ddd, J = 13.1, 8.4, 5.4 Hz, 1H), 2.83 (ddd, J = 16.1, 8.4, 5.5 Hz, 1H), 2.68 (ddd, J = 16.0, 7.3, 5.4 Hz, 1H). Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 142 1H NMR (500 MHz, CHLOROFORM-d) 7.83 (s, 1H), 7.71 (s, 1H), 7.62 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 6.87 (d, J = 8.2 Hz, 2H), 6.74 – 6.46 (m, 2H), 5.59 (s, 1H), 3.85 (s, 3H), 3.70 (s, 3H), 3.56 (s, 1H), 3.26 (d, J = 13.1 Hz, 1H), 2.88 – 2.58 (m, 2H), 1.53 (s, 1H). 19F NMR (471 MHz, CHLOROFORM-d) d -55.53, -68.53 (d, J = 9.1 Hz). 143 1H NMR (500 MHz, CHLOROFORM-d) 7.72 (s, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.39 (s, 1H), 7.27 (dd, J = 15.2, 8.0 Hz, 3H), 6.87 (d, J = 8.6 Hz, 2H), 6.66 (d, J = 8.2 Hz, 1H), 6.61 (q, J = 9.0 Hz, 1H), 5.57 (s, 1H), 3.87 (s, 3H), 3.60 (dt, J = 12.6, 6.2 Hz, 1H), 3.52 (s, 3H), 3.27 (ddd, J = 13.2, 8.9, 5.4 Hz, 1H), 2.79 (ddd, J = 14.9, 8.9, 5.6 Hz, 1H), 2.62 (ddd, J = 16.0, 6.9, 5.4 Hz, 1H) 19F NMR (471 MHz, CHLOROFORM-d) d -55.49 (s, 3F), -68.53 (s, 3F). 144 1H NMR (500 MHz, CHLOROFORM-d) 7.80 (s, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.49 (s, 1H), 7.35 (dd, J = 15.1, 7.9 Hz, 3H), 6.96 (d, J = 8.3 Hz, 2H), 6.74 (d, J = 8.2 Hz, 1H), 6.69 (q, J = 9.1 Hz, 1H), 5.65 (s, 1H), 3.95 (s, 3H), 3.68 (dt, J = 12.8, 6.3 Hz, 1H), 3.60 (s, 3H), 3.35 (t, J = 13.4 Hz, 1H), 2.92 – 2.83 (m, 1H), 2.75 – 2.66 (m, 1H). 145 1H NMR (500 MHz, CHLOROFORM-d) 7.80 (s, 1H), 7.76 – 7.69 (m, 2H), 7.39 – 7.30 (m, 3H), 6.96 (d, J = 8.1 Hz, 2H), 6.75 (d, J = 8.2 Hz, 1H), 6.60 (q, J = 8.8 Hz, 1H), 5.72 (s, 1H), 4.05 (ddd, J = 12.4, 7.4, 3.8 Hz, 1H), 3.94 (s, 3H), 3.92 – 3.86 (m, 1H), 3.75 – 3.67 (m, 1H), 3.42 (ddd, J = 12.8, 7.8, 3.9 Hz, 1H), 2.39 (s, 3H). 146 1H NMR (500 MHz, CHLOROFORM-d) 7.79 (s, 1H), 7.77 – 7.65 (m, 2H), 7.45 – 7.32 (m, 3H), 6.96 (d, J = 8.2 Hz, 2H), 6.75 (d, J = 8.1 Hz, 1H), 6.60 (q, J = 8.8 Hz, 1H), 5.74 (s, 1H), 4.05 (ddd, J = 12.3, 7.8, 4.0 Hz, 1H), 3.94 (s, 4H), 3.71 (ddd, J = 11.6, 6.7, 4.1 Hz, 1H), 3.42 (ddd, J = 12.7, 7.8, 4.0 Hz, 1H), 2.39 (s, 3H). 147 1H NMR (400 MHz, CHLOROFORM-d) 8.01 (t, J = 7.9 Hz, 1H), 7.92 (dd, J = 8.2, 1.1 Hz, 1H), 7.85 (s, 1H), 7.73 (s, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 8.3 Hz, 2H), 7.02 – 6.92 (m, 2H), 6.77 – 6.31 (m, 2H), 5.87 (s, 1H), 4.05 (ddd, J = 12.2, 7.9, 4.1 Hz, 1H), 3.91 (ddd, J = 12.6, 6.8, 4.0 Hz, 1H), 3.71 (ddd, J = 13.3, 6.9, 4.2 Hz, 1H), 3.41 (ddd, J = 12.5, 7.9, 4.1 Hz, 1H), 2.38 (s, 3H). ₁₄₉ 1H NMR (500 MHz, CHLOROFORM-d) 8.02 (t, J = 7.9 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.85 (s, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.30 – 7.26 (m, 2H), 6.98 (d, J = 8.5 Hz, 2H), 6.77 – 6.44 (m, 2H), 5.72 (s, 1H), 3.52 – 3.29 (m, 2H), 3.14 – 2.99 (m, 2H), 2.95 – 2.86 (m, 4H), 2.48 (s, 1H), 2.46 – 2.36 (m, 2H), 2.35 – 2.14 (m, 2H). Co. No. 1H-NMR and 19F-NMR (if available) : solvent, δ (ppm) 19F NMR (471 MHz, CHLOROFORM-d) 55.53 (s, 3F), -68.10 (s, 3F), -116.21 (s, 2F). 150 1H NMR (500 MHz, CHLOROFORM-d) 8.02 (t, J = 7.9 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.85 (s, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.5 Hz, 2H), 6.75 – 6.46 (m, 2H), 5.72 (s, 1H), 3.52 – 3.32 (m, 2H), 3.04 (q, J = 8.9 Hz, 2H), 2.94 – 2.85 (m, 4H), 2.49 (s, 1H), 2.42 (dd, J = 13.6, 7.5 Hz, 2H), 2.35 – 2.15 (m, 2H). 19F NMR (471 MHz, CHLOROFORM-d) 55.50 (s, 3F), -68.07 (s, 3F), -116.21 (s, 2F). 151 1H NMR (500 MHz, CHLOROFORM-d) 7.80 (s, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.37 – 7.31 (m, 1H), 7.30 – 7.23 (m, 2H), 6.96 (d, J = 8.3 Hz, 2H), 6.75 (d, J = 8.2 Hz, 1H), 6.57 (q, J = 8.9 Hz, 1H), 5.66 (s, 1H), 3.95 (s, 3H), 3.50 – 3.40 (m, 1H), 3.40 – 3.30 (m, 1H), 3.12 – 3.00 (m, 2H), 2.96 – 2.86 (m, 4H), 2.51 – 2.37 (m, 3H), 2.35 – 2.24 (m, 1H), 2.24 – 2.13 (m, 1H). 152 1H NMR (500 MHz, CHLOROFORM-d) 7.80 (s, 1H), 7.73 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.30 – 7.26 (m, 2H), 7.00 – 6.94 (m, 2H), 6.75 (d, J = 8.1 Hz, 1H), 6.58 (q, J = 8.9 Hz, 1H), 5.66 (s, 1H), 3.95 (s, 3H), 3.52 – 3.43 (m, 1H), 3.43 – 3.31 (m, 1H), 3.09 – 2.98 (m, 2H), 2.94 – 2.85 (m, 4H), 2.50 (s, 1H), 2.47 – 2.35 (m, 2H), 2.35 – 2.26 (m, 1H), 2.22 (s, 1H). 19F NMR (471 MHz, CHLOROFORM-d) -55.56, -68.13. 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 lowst isotope mass. All results were obtainedwith 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): Table 12 Method Instrument column mobile phase gradient Flow Run Code ------- time Col T ₁ ^Waters: Waters :BEH A: 10mM From 100% A 0.6 3.5 Acquity^® (1.7µm, CH3COONH4 to ------- UPLC^® - 2.1*100mm) in 95% H2O + 5% 5% A in 55 DAD and CH₃CN 2.10min, SQD B: CH3CN to 0% A in 0.90min, to 5% A in 0.5min Waters: Waters :BEH A: 0.1% From 100% A 0.6 3.5 Acquity^® (1.7µm, NH₄HCO3 to ------- UPLC^® - 2.1*100mm) in 95% H2O + 5% 5% A in 55 DAD and CH₃CN 2.10min, 2 SQD B: CH3CN to 0% A in 0.9min, to 5% A in 0.5min 3 Waters: Waters :BEH A: 0.1% From 100% A 0.6 3.5 Acquity^® (1.7µm, NH4HCO3 to ------- UPLC^® - 2.1*100mm) in 95% H2O + 5% 5% A in 55 DAD and CH3CN 2.10min, SQD B: CH3CN to 0% A in 0.9min, to 5% A in 0.5min 4 Shimadzu HALO C18 A:Water/0.05%TF From 95% A to 1.5 2.0 A LCMS‐2020 (2.0µm, 0% A in 1.2 ------- B:Acetonitrile/0.0 3.0*30mm) min, 40 5%TFA to 0% A in 1.7 min, Method Instrument column mobile phase gradient Flow Run Code ------- time Col T to 5% A in 1.75 min ₅ Shimadzu Shim‐Pack Mobile Phase A: From 70% A to 1.2 3.0 Water/5mM LCMS‐2020 C18 (3.0µm, NH4HCO3 0% A in 2 min, ------- 3.0*33mm) Mobile Phase B: to 5% A in 2.7 40 Acetonitrile min, to 90% A in 2.75 min 6 Shimadzu HALO C18 A:Water/0.05%TF From 95% A to 1.5 3.0 A LCMS‐2020 (2.0µm, B:Acetonitrile/0.0 40% A in 1.7 ------- 3.0*30mm) 5%TFA min, 40 to 5% A in 2.3 min, to 5% A in 2.8 min, to 95% A in 2.83 min ₇ Shimadzu Shim‐Pack Mobile Phase A: From 80% A to 1.5 3.0 Water/5mM LCMS‐2020 C18 (3.0µm, NH4HCO3 20% A in 1.7 ------- 3.0*33mm) Mobile Phase B: min, 40 Acetonitrile to 5% A in 2.3 min, to 5% A in 2.8 min, to 90% A in 3.0 min 8 Shimadzu A:Water/0.05%TF From 95% A to 1.5 2.0 A LCMS‐2020 B:Acetonitrile/0.0 0% A in 1.2 ------- 5%TFA min, 40 to 0% A in 1.7 min, to 5% A in 1.75 min Method Instrument column mobile phase gradient Flow Run Code ------- time Col T 9 Shimadzu Poroshell Mobile Phase A: From 70% A to 1.2 3.0 Water/5mM LCMS‐2020 HPH‐C18 NH4HCO3 5% A in 2.0 ------- (2.7µm, Mobile Phase B: min, 40 3.0*50mm) Acetonitrile to 5% A in 2.7 min, to 90% A in 2.75 min 10 Shimadzu Shim‐Pack Mobile Phase A: From 90% A to 1.2 2.0 Water/5mM LCMS‐2020 C18 (3.0µm, NH4HCO3 5% A in 1.20 ------- 3.0*33mm) Mobile Phase B: min, 40 Acetonitrile to 5% A in 1.8 min, to 90% A in 1.85 min 11 95% A for 1.5 6.5 0.50min, to ------- 50% A in 40 4.00min, then Agilent Xbridge C18 to 5% A in Technologies ,5um A:0.05% TFA; B: 0.50min, held 1200 Series, CH3CN 4.6*50mm for 1.00min, G6110A back to 95% A in 0.10min, held for 0.40min. 12 Shimadzu Shim‐Pack Mobile Phase A: From 70% A to 1.2 4.0 Water/5mM LCMS‐2020 C18 (3.0µm, NH4HCO3 35% A in 3.0 ------- 3.0*33mm) Mobile Phase B: min, 40 Acetonitrile to 5% A in 3.30 min, to 5% A in 3.30 min, to 90% A in 4.00 Method Instrument column mobile phase gradient Flow Run Code ------- time Col T ₁₃ ^Waters: Waters :BEH A: 10mM From 100% A 0.6 3.5 Acquity^® (1.7µm, NH4HCO3 to ------- UPLC^® - 2.1*100mm) in 95% H2O + 5% 5% A in 55 DAD and CH3CN 2.10min, SQD B: CH3CN to 0% A in 0.9min, to 5% A in 0.5min ₁₄ ^Waters: Waters A: CH3COONH4 95% A/5% B 0.5 3.5 Acquity® BEH® 7mM 95%/ for 0.2min, to ------- UPLC - C18 (1.7µm, CH3CN 5%, B: 5% A in 1min, 40 DAD and 2.1x50mm) CH3CN held for QuattroTM 1.6min, back to 95% A/5% B in 0.2min, held for 0.4min. ₁₅ Waters: Waters BEH A: CH3COONH4 84.2% 0.343 6.07 ® 7mM 95%/ ------- Acquity® C18 (1.7µm, CH3CN 5%, B: A/15.8% B for 40 UPLC - 2.1x100mm) CH3CN 0.49min, to DAD and 10.5% A in QuattroTM 2.18min, held for 1.94min, back to 84.2% A/15.8% B in 0.73min, held for 0.73min 16 Waters: Waters BEH® A: 95% From 95% 0.5/ 3.3 C18 (1.7µm, CH3COONH4 40 Acquity 2.1x50mm) 7mM / 5% A/5% B to 5% UPLC® H- CH3CN, B: A in 1min, held Class - DAD CH3CN for 1.6min, and QDa back to 95% A/5% B in 0.2min, held for 0.5min. Method Instrument column mobile phase gradient Flow Run Code ------- time Col T ¹⁷ _Waters YMC C18 A : 0,2% 90% A / 10% B 15 7,5cm*4,6mm Alliance 5 µm NH4HCO3 in to 100% B in HPLC – water (pH = 7,9) 13min, held for 1 DAD & ZQ B : CH3CN 0.5 min, back mL/m to 90% A / in 10% B in 0.3 30 °C min, held for 1.2 min 18 Waters Xbridge C18 A : 0,2% 80% A / 20% B 0.8 12 100mm*4,6 Alliance mm 5µm NH4HCO3 in for 0.5 min, to mL/m HPLC – water (pH = 7,9) 90% B in 4.5 in DAD & ZQ B : CH3CN min, held for 4 min, back to 30 °C 80% A / 20% B in 1.5 min, held for 1.5 min ¹⁹ _Waters: A: 0.1% From 100% A 0.6 3.5 Waters :BEH NH4HCO3 ------- Acquity® (1.7µm, in 95% H2O + 5% to 55 UPLC® - 2.1*100mm) CH3CN 5% A in B: CH3CN DAD and 2.10min, SQD2 to 0% A in 1.4min 20 Waters: Waters :BEH A: 10mM From 100% A 0.6 3.5 Acquity^® (1.7µm, ------- UPLC^® - 2.1*100mm) NH4HCO3 in 95% to 55 DAD and H2O + 5% 5% A in SQD CH3CN 2.10min, B: CH3CN to 0% A in 0.9min, to 5% A in 0.5min Method Instrument column mobile phase gradient Flow Run Code ------- time Col T 21 Waters: Waters :BEH A: 10mM From 95 % A 0.8 2 Acquity^® (1.7µm, CH3COONH4 and 5 % B to 5 ------- UPLC^® - 2.1*50mm) in 95% H2O + 5% % A and 95 % 55 DAD and CH3CN B in 1.3 min, SQD B: CH3CN hold for 0.7 min 22 Waters: Waters :BEH A: 10mM From 100% A 0.8 2 Acquity^® (1.7µm, CH3COONH4 to ------- UPLC^® - 2.1*50mm) in 95% H2O + 5% 5% A in 1.3 55 DAD and CH3CN min, SQD2 B: CH3CN hold 0.7min ₂₃ ^Waters: Waters :BEH A: 10mM From 100% A 0.6 3.5 Acquity^® (1.7µm, CH3COONH4 to ------- UPLC^® - 2.1*100mm) in 95% H2O + 5% 5% A in 55 DAD and CH₃CN 2.10min, SQD2 B: CH3CN to 0% A in 0.9min, to 5% A in 0.5min ₂₄ ^Waters: Waters :BEH A: 0.1% From 100% A 0.6 3.5 Acquity^® (1.7µm, NH4HCO3 to ------- UPLC^® - 2.1*100mm) in 95% H2O + 5% 5% A in 55 DAD and CH₃CN 2.10min, SQD2 B: CH3CN to 0% A in 0.9min, to 5% A in 0.5min 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 unless mentioned otherwise. “iPrNH_2” means isopropylamine, “iPrOH” means 2-propanol, “EtOH” means ethanol, “min” mean minutes, “DEA” means diethylamine, “Hex” means hexanes, “IPA” means isopropylamine. Table 13: SFC methods Flow Run time SFC Column mobile phase gradient ------- ------- Method Col T BPR ¹ 1.0 6.0 CHIRALPAK IA‐ (Hex:DCM=3:1)(0.1 isocratic ------- ------- 3: 4.6*50 mm,3 um %DEA):EtOH=90:10 25 103 ² 3.5 3 Chiralcel OD-3 CO2 75%+ (MeOH isocratic ------- ------- 3µm 25%+0.3% iPrNH2) 35 103.4 ³ 3.5 3 Chiralpak IG-3 CO2 65%+ (EtOH isocratic ------- ------- 3µm 35%+0.3% iPrNH2) 35 103.4 4 3.5 3 Chiralpak AD-3 CO2 70%+(MeOH isocratic ------- ------- 3µm 30%+0.3% iPrNH2) 35 103.4 2.0 3.5 CHIRALPAK IA‐3 CO250%+ MeOH(1% 5 isocratic ------- ------- 3.0*50 mm,3 μm 2M NH3‐MeOH) 35 100 Flow Run time SFC Column mobile phase gradient ------- ------- Method Col T BPR CHIRALCellulose- 1.0 5.0 6 SB4.6*100mm3, MTBE(0.1%DEA): isocratic ------- ------- IPA = 60:40 μm 25 100 10% to 50% in 2 4 2 Chiral Pak IB-N 7 MeOH (0.1% DEA) min, hold ------- ------- 4.6*100 mm, 3 μm 1.0 min 35 103.4 at 50% 3.5 3 ₈ Chiralpak OD-3 CO285% / (MeOH + isocratic ------- ------- 3µm 0.3 % iPrNH2) 15% 35 103.4 3.5 3 ₉ Chiralpak OD-3 CO275% / (MeOH + isocratic ------- ------- 3µm 0.3 % iPrNH2) 25% 35 103.4 3.5 3 ₁₀ Chiralpak OD-3 CO275% / (EtOH + isocratic ------- ------- 3µm 0.3 % iPrNH2) 25% 35 103.4 3.5 3 ₁₁ Chiralpak OD-3 CO280% / (EtOH + isocratic ------- ------- 3µm 0.3 % iPrNH2) 20% 35 103.4 3.5 3 ₁₂ Chiralpak OD-3 CO270% / (EtOH + isocratic ------- ------- 3µm 0.3 % iPrNH2) 30% 35 103.4 Flow Run time SFC Column mobile phase gradient ------- ------- Method Col T BPR 3.5 3 ₁₃ ^{Chiralpak IG-3} CO260% / (MeOH + isocratic ------- ------- 3µm 0.3 % iPrNH2) 40% 35 103.4 3.5 3 ₁₄ Chiralpak IG-3 CO265% / (iPrOH + isocratic ------- ------- 3µm 0.3 % iPrNH2) 35% 35 103.4 3.5 3 ₁₅ Chiralpak IG-3 CO255% / (MeOH + isocratic ------- ------- 3µm 0.3 % iPrNH2) 45% 35 103.4 3.5 3 ₁₆ Chiralpak IG-3 CO265% / (MeOH + isocratic ------- ------- 3µm 0.3 % iPrNH2) 35% 35 103.4 ¹⁷ _{Chiralpak AS-3} 3.5 3 min CO2 75% / (MeOH + isocratic ------- P=1500 3µm 0.3 % iPrNH2) 25% 35 PSI 3.5 3 min ₁₈ Chiralpak AS-3 CO280% / (EtOH + isocratic ------- P=1500 3µm 0.3 % iPrNH2) 20% 35 PSI 3.5 3 min ₁₉ Chiralpak AS-3 CO275% / (MeOH + isocratic ------- P=1500 3µm 0.3 % iPrNH2) 25% 35 PSI 3.5 3 min ₂₀ Chiralpak AD-3 CO260% / (EtOH + isocratic ------- P=1500 3µm 0.3 % iPrNH2) 40% 35 PSI Flow Run time SFC Column mobile phase gradient ------- ------- Method Col T BPR 3.5 3 min ₂₁ ^{Chiralpak AD-3} CO265% / (EtOH + isocratic ------- P=1500 3µm 0.3 % iPrNH2) 35% 35 PSI 3.5 3 min ₂₂ Chiralpak OJ-3 CO275% / (EtOH + isocratic ------- P=1500 3µm 0.3 % iPrNH2) 25% 35 PSI 3.5 3 min ₂₃ Chiralpak OJ-3 CO265% / (MeOH + isocratic ------- P=1500 3µm 0.3 % iPrNH2) 35% 35 PSI 3.5 3 min ₂₄ Chiralpak OJ-3 CO280% / (MeOH + isocratic ------- P=1500 3µm 0.3 % iPrNH2) 20% 35 PSI 3.5 3 min ₂₅ Chiralpak AD-3 CO270% / (MeOH + isocratic ------- P=1500 3µm 0.3 % iPrNH2) 30% 35 PSI 10%- Daicel Chiralpak® A:CO 50% B in 2.5 9.5 OJ3 column (3.0 ₂ B: EtOH+0.2 6 min, ------- ------- 26 % μm, 150 x 4.6 mm) iPrNH2 hold 3.5 40 130 min 10%- Daicel Chiralpak® A:CO2 50% B in 2.5 9.5 IH3 column (3.0 B: E 6 min, ------- ------- 27 tOH +0.2% μm, 150 x 4.6 mm) iPrNH₂ hold 3.5 40 130 min Flow Run time SFC Column mobile phase gradient ------- ------- Method Col T BPR 10%- Daicel Chiralpak® A:CO 50% B in 2.5 9.5 AD3 column (3.0 ₂ B: EtOH 6 min, ------- ------- 28 +0.2% μm, 150 x 4.6 mm) iPrNH2 hold 3.5 40 130 min 10%- Daicel Chiralpak® A:CO 50% B in 2.5 9.5 IG3 column (3.0 ₂ B: EtOH +0 6 min, ------- ------- 29 .2% μm, 150 x 4.6 mm) iPrNH₂ hold 3.5 40 130 min 10%- Daicel Chiralpak® A:CO 50% B in 2.5 9.5 OD3 column (3.0 ₂ B: EtOH +0.2% 6 min, ------- ------- 30 μm, 150 x 4.6 mm) iPrNH2 hold 3.5 40 130 min Daicel Chiralpak® A:CO 10%- ID3 column (3.0 ₂ 2.5 9.5 B: MeO 50% B in ------- ------- 31 H +0.2% μm, 150 x 4.6 mm) iPrNH₂ 6 min, 40 130 hold 3.5 min 3.5 3 Chiralpak AS-3 32 CO2 75% / iPrOH isocratic ------- ------- 3µm 25% 35 103.4 3.5 3 Chiralpak AS-3 33 CO2 80% / (MeOH + isocratic ------- ------- 3µm 0.3 % iPrNH2) 20% 35 103.4 3.5 3 Chiralpak IG-3 CO265%+ (iPrOH+ isocratic ------- ------- 34 3µm 0.3% iPrNH2) 35% 35 103.4 Flow Run time SFC Column mobile phase gradient ------- ------- Method Col T BPR CO2 / (MeOH + 0 3.5 3 min Chiralpak OD-3 .3 35 % iPrNH2) 95/5 to gradient ------- P=1500 3µm 40/60 35 PSI 3.5 3 min ₃₆ Chiralpak OJ-3 CO280% / MeOH isocratic ------- P=1500 3µm 20% 35 PSI CO2 50% 2.0 3.5 CHIRALPAK IH‐3 + 37 MeOH(1% 2M NH3‐ isocratic ------- ------- 3.0*50 mm,3 μm MeOH) 35 100 B: 10% to 50% in CHIRALPAK IB‐ A: CO2; 2.0 3.5 2.0 38 N 4.6*100 mm,3 B:MeOH(0.1% ------- ------- Diethylamin min,hold μm e) 35 100 1.0 min at 50% B: 10% to 50% in A: CO 2.0 3.5 CHIRALPAK AS‐ 2; 2.0 39 B:MeOH(0.1% ------- ------- 33.0*50 mm,3 μm Diethylamine) min,hold 35 100 1.0 min at 50% 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-MALT1(1-824)-His) purified from baculovirus-infected insect cells. The tetrapeptide LRSR is coupled to AMC (7-amino-4-methylcoumarin) and provides a quenched, fluorescent substrate for the MALT1 protease (SM Biochemicals). Cleavage of AMC from the Arginine residue results in an increase in coumarin fluorescence measured at 460 nm (excitation 355 nm). The final assay buffer consisted of 10 nM FL MALT1 protein, 200 µM Ac-LRSR-AMC, 50 mM Tris pH 7.5, 0.6 M Citrate, 1 mM dithiothreitol (DTT), 1 mM ethylenediaminetetraacetic acid (EDTA), 0.05% bovine serum albumin (BSA) and 1.5% dimethyl sulfoxide (DMSO). Test compounds were spotted at 50 nL in 100% DMSO per well of a black 384-Proxiplate (Perkin Elmer). Test compound concentrations ranged from 30 µM to 0.5 nM using 11 dilution steps (1:3). Background signal was measured from control wells containing assay buffer without enzyme which functions as low control (LC). High control (HC) values were generated using the reaction with enzyme but no compound treatment. Compounds were pre-incubated with MALT1 enzyme for 50 minutes at RT. Substrate was added subsequently, and fluorescence was measured in 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 µM. 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: yi = LB + UB – LB 1 +10^{(h*(pCONCi-pIC50))} With y = estimated response UB = upper bound LB = lower bound h = Hill slope of curve CONC = concentration in “Lexis Dose Response Curve Fitting” Version 1.0. Resultant data are shown in Table MALT1_Biochemical MALT1_Biochemical Co. Co. activity (Ac-LRSR-AMC) activity (Ac-LRSR-AMC) No. No. IC50 (μM) IC50 (μM) 1 0.0074 4 0.0145 2 0.0151 5 0.0096 3 0.0081 6 0.0063 MALT1_Biochemical MALT1_Biochemical Co. Co. activity (Ac-LRSR-AMC) activity (Ac-LRSR-AMC) No. No. IC50 (μM) IC50 (μM) 7 2.69 33 0.0183 8 0.0108 34 1.36 9 0.0077 35 0.0900 10 0.0057 36 0.0785 11 0.0106 37 0.0218 12 0.0098 38 0.0580 13 0.0379 39 >4.87 14 0.4248 40 0.0396 15 0.0153 41 >7.33 16 0.0327 42 0.379 17 0.0164 43 0.0293 18 0.0122 44 0.0204 19 0.0312 45 0.0239 20 0.0117 46 0.0289 21 0.0407 47 0.0500 22 0.0303 48 0.0434 23 1.78 49 0.0283 24 0.375 50 >30 25 0.0179 51 0.137 26 0.0617 52 0.0182 27 0.185 53 >30 28 1.09 54 0.0136 29 0.2903 55 0.0100 30 0.0482 56 0.0207 31 1.20 57 0.0402 32 0.226 58 0.0585 MALT1_Biochemical MALT1_Biochemical Co. Co. activity (Ac-LRSR-AMC) activity (Ac-LRSR-AMC) No. No. IC50 (μM) IC50 (μM) 59 0.0282 85 0.0286 60 0.0218 86 0.0584 61 0.520 87 0.0439 62 1.16 88 0.340 63 0.0127 89 0.0420 64 0.0275 90 0.0296 65 0.0383 91 0.0220 66 0.0747 92 0.0213 67 0.109 93 0.0761 68 0.0580 94 0.113 69 0.0192 95 0.513 70 0.0714 96 0.0073 71 0.5325 97 0.0117 72 0.0387 98 0.0085 73 4.23 99 1.33 74 0.0176 100 0.0110 75 0.0576 101 0.0051 76 0.0616 102 0.0115 77 0.143 103 0.140 78 0.0911 104 0.0076 79 0.0228 105 0.0072 80 0.0178 106 0.0220 81 0.0614 107 0.0122 82 0.0429 108 0.0173 83 0.0322 109 0.0906 84 0.0771 110 0.149 MALT1_Biochemical MALT1_Biochemical Co. Co. activity (Ac-LRSR-AMC) activity (Ac-LRSR-AMC) No. No. IC50 (μM) IC50 (μM) 111 0.0563 132 0.0301 112 0.0230 133 2.83 113 0.0092 134 0.0286 114 0.0372 135 >1.13 115 0.0575 136 2.77 116 0.0155 137 0.0400 117 0.0289 138 1.09 118 0.0731 139 3.10 119 0.0298 140 0.0311 120 0.0340 141 3.13 121 1.01 142 0.0397 122 0.0406 143 >0.621 123 >2.59 144 0.0282 124 0.0208 145 1.59 125 0.0197 146 0.0239 126 0.0124 147 0.0211 127 0.0295 148 n.d. 128 0.0348 149 0.0074 129 0.555 150 0.0114 130 0.0311 151 0.0072 131 0.0335 152 0.0130 Biological Example 2 GloSensor reporter MALT1-mediated cleavage In Jurkat Cells MALT1 GloSensor^TM is a split luciferase reporter, which utilizes a genetically modified form of firefly luciferase (CP UltraGlo) split into 2 distinct domains by insertion of a RelB MALT1 cleavage site sequence PRLVSRGA. MALT1-induced cleavage allows for a conformational 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^TM 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^TM cells were maintained in complete RPMI 1640 media containing 10% fetal bovine serum, 10mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), 100 units/mL of penicillin, 100 µg/mL of streptomycin and 0.5 mg/mL Geneticin. Prior to the assay, compounds were made 2.5-fold serial dilutions in DMSO. 100 nL of of test compounds were spotted per well of 384-well plates (Perkin Elmer, catalogue number 6007688). Jurkat cells were harvested by centrifuge at 1200 RPM for 5 min and suspended in 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^TM cells (1 x 10⁵ cells) were seeded in each well of 384-well plate. Next, a volume 2 µL of diluted PMA / Ionomycin (2.5 ^g/mL / 25 µM respectively, Sigma, catalog 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 ^: Where: x = concentration y = activity S₀ = activity at bottom plateau of curve S_inf = activity at top plateau of curve S₅₀ = inflection point, halfway between S0 and Sinf h = Hill slope of curve Resultant data are shown in Table 15. n.d. means not determined Table 15 Jurkat Jurkat MALT1 MALT1 Co. No. ^T Co. No. GloSensor ^M GloSensor^TM IC50 (μM) IC50 (μM) 1 0.0033 25 0.0090 2 0.0078 26 0.0461 3 0.0043 27 0.0603 4 0.0058 28 0.101 5 0.0081 29 0.0353 6 0.0047 30 0.0173 7 0.430 31 0.137 8 0.0046 32 0.0685 9 0.0051 33 0.0142 10 0.0039 34 0.300 11 0.0034 35 0.0560 12 0.0041 36 0.3650 13 0.0108 37 0.0066 14 0.0422 38 0.0078 15 0.0064 39 0.3781 16 0.0055 40 0.0232 17 0.0043 41 >1.01 18 0.0023 42 0.0725 19 0.0120 43 0.0151 20 0.0064 44 0.0143 21 0.0285 45 0.0068 22 0.0199 46 0.0098 23 0.213 47 0.0126 24 0.0459 48 0.0182 Jurkat Jurkat MALT1 MALT1 Co. No. C nsor^TM o. No. GloSe GloSensor^TM IC50 (μM) IC50 (μM) 49 0.0103 74 0.0054 50 >0.229 75 0.0157 51 0.0176 76 0.0234 52 0.0071 77 0.0203 53 >0.397 78 0.0370 54 0.0077 79 0.0043 55 0.0071 80 0.0072 56 0.0151 81 0.0146 57 0.0447 82 0.0166 58 0.0496 83 0.0120 59 0.0191 84 0.0201 60 0.0148 85 0.0208 61 0.257 86 0.0187 62 0.234 87 0.0334 63 0.0067 88 0.0660 64 0.0066 89 0.0127 65 0.0087 90 0.0100 66 0.0094 91 0.0297 67 0.0131 92 0.0192 68 0.0395 93 0.0759 69 0.0145 94 0.0769 70 0.0106 95 >0.820 71 0.193 96 0.0034 72 0.0162 97 0.0071 73 >0.684 98 0.0028 Jurkat Jurkat MALT1 MALT1 Co. No. Co. N oSensor^TM o. Gl GloSensor^TM IC50 (μM) IC50 (μM) 99 0.2495 124 0.0092 100 0.0207 125 0.0052 101 0.0029 126 0.0034 102 0.0091 127 0.0090 103 0.135 128 0.0080 104 0.0052 129 0.131 105 0.0053 130 0.0123 106 0.0130 131 0.0071 107 0.0045 132 0.0194 108 0.0140 133 >0.602 109 0.0179 134 0.0082 110 0.0427 135 0.446 111 0.0108 137 0.0060 112 0.0076 138 0.278 113 0.0051 139 0.527 114 0.0124 140 0.0061 115 0.0102 141 0.514 116 0.0055 142 0.0057 117 0.0114 143 0.238 118 0.0222 144 0.0076 119 0.0085 145 0.257 120 0.0089 146 0.0076 121 0.0846 147 0.0079 122 0.0183 149 0.0048 123 >0.419 150 0.0068 Jurkat Jurkat MALT1 MALT1 Co. No. ^TM Co. No. GloSensor GloSensor^TM IC50 (μM) IC50 (μM) 151 0.0039 152 0.0049 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 µM to 58.6 nM (final DMSO concentration 0.3%). DMSO control wells were used to determine the maximum signal (High Control (HC)). Treatment with reference compounds at an appropriate dose served as positive control for MALT1 inhibition and was used to determine the maximum inhibition (Low Control (LC)). Compounds and cells were incubated for 24 h at 37 °C and 5% CO₂ (assay volume is 150 µL). After 24 h of incubation 50 µL of the supernatant was transferred to an MSD plate (V-Plex Proinflammation Panel 1 (human) kit, Mesoscale (MSD)) and incubated for 2 h with vigorous shaking (600 rpm) at room temperature. Following incubation, plates were washed 3x with phosphate-buffered saline (PBS) + 0.05% Tween-20 and 25 µL detection antibody solution (IL-6 & IL-10 antibodies in diluent 3 (MSD)) was added per well followed by 2 h of incubation with vigorous shaking (600 rpm) at room temperature. After 3x washes with PBS + 0.05% Tween-20, plates were incubated with 150 µL 2x Read Buffer T and read on SECTOR imager. Resultant data are shown in Table 16. n.d. means not determined Table 16 Human IL6 Mesoscale assay Human IL10 Mesoscale assay Co. (OCI-Ly3) (OCI-Ly3) No. IC50 (µM) IC50 (µM) 1 0.0191 0.0135 3 0.0115 0.0089 Human IL6 Mesoscale assay Human IL10 Mesoscale assay Co. (OCI-Ly3) (OCI-Ly3) No. IC50 (µM) IC50 (µM) 4 0.0158 0.0100 5 0.0083 0.0055 6 0.0123 0.0120 8 0.0155 0.0105 9 0.0229 0.0129 10 0.0160 0.0110 11 0.0120 0.0055 12 0.0229 0.0100 13 0.0513 0.0288 15 0.0048 0.0100 16 0.0269 0.0200 17 0.0302 0.0178 18 0.0214 0.0158 19 0.0955 0.0661 20 0.112 0.0589 21 0.275 0.200 22 0.118 0.0603 24 0.166 0.0933 25 0.046 0.0309 26 0.182 0.120 30 0.120 0.0537 33 0.0776 0.0417 36 >0.562 0.692 37 0.0407 0.0174 38 0.0245 0.0120 40 0.0631 0.0282 43 0.0813 0.0468 44 0.0631 0.0234 45 0.0525 0.0269 46 0.0501 0.0316 47 0.112 0.0501 48 0.144 0.0355 49 0.0617 0.0288 51 0.135 0.0813 52 0.0501 0.0339 54 0.110 0.0525 Human IL6 Mesoscale assay Human IL10 Mesoscale assay Co. (OCI-Ly3) (OCI-Ly3) No. IC50 (µM) IC50 (µM) 55 0.0661 0.0447 56 0.105 0.0562 57 0.339 0.155 58 0.309 0.282 59 0.138 0.0891 60 0.0562 0.0398 63 0.0288 0.0209 64 0.0380 0.0219 65 0.0331 0.0214 66 0.126 0.0468 67 0.0813 0.0447 68 0.339 0.224 69 0.0724 0.0437 70 0.0912 0.0468 72 0.0692 0.0302 74 0.0295 0.0170 75 0.0891 0.0380 76 0.155 0.0977 77 0.251 0.107 79 0.0692 0.0200 80 0.0389 0.0245 81 0.141 0.0234 82 0.115 0.0295 83 0.0501 0.0525 86 0.0891 0.0447 90 0.0331 0.0135 91 0.209 0.0708 92 0.170 0.123 93 0.724 0.324 94 0.457 0.263 96 0.0083 0.0058 97 0.0145 0.0105 98 0.0035 0.0034 100 0.0288 0.0282 101 0.0072 0.0068 102 0.0479 0.0324 Human IL6 Mesoscale assay Human IL10 Mesoscale assay Co. (OCI-Ly3) (OCI-Ly3) No. IC50 (µM) IC50 (µM) 104 0.0126 0.0110 105 0.0066 0.0055 106 0.0447 0.0269 107 0.0275 0.0141 108 0.1047 0.0550 109 0.1349 0.0550 111 0.0832 0.0257 112 0.0603 0.0275 113 0.0204 0.0135 114 0.0871 0.0331 116 0.0240 0.0093 124 0.0269 0.0158 125 0.0148 0.0091 126 0.0151 0.0085 128 0.0132 0.0071 130 0.0447 0.0229 131 0.0269 0.0123 132 0.0708 0.0316 134 0.0195 0.0115 144 0.0148 0.0074 146 0.0166 0.0102 147 0.0229 0.0138 149 0.0158 0.0079 150 0.0162 0.0076 151 0.0182 0.0145 152 0.0240 0.0186 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 µg/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 µL media per well and incubated for 8 days at 37 °C and 5% CO₂. Cell plating numbers were chosen based on growth curves to ensure linear cell growth. After 8 days of incubation, 100 µL of the plated cells were resuspended up and down by pipette and transferred to a flat bottom black plate (Corning, #3904).50 µL CellTiterGLO reagent (Promega) were added to each well and luminescence was measured on Envision (Perkin Elmer) after 10 minutes shaking at 300 rpm followed by 10 minutes of incubation at room temperature in the dark. IC₅₀ values were calculated using SmartFit in GeneData Screener ^: Where: x = concentration y = activity S₀ = activity at bottom plateau of curve S_inf = activity at top plateau of curve S₅₀ = inflection point, halfway between S0 and Sinf h = Hill slope of curve Resultant data are shown in Table 17. n.d. means not determined. Table 17 Anti-proliferation: Anti-proliferation: Co. No. OCI-Ly3 IC50 Co. No. OCI-Ly3 IC50 (μM) (μM) 1 0.119 6 0.100 2 n.d. 8 0.065 3 0.104 9 0.108 4 0.108 10 0.058 5 0.187 11 0.042 Anti-proliferation: Anti-proliferation: Co. No. OCI-Ly3 IC50 Co. No. OCI-Ly3 IC50 (μM) (μM) 12 0.250 51 2.20 13 0.226 52 0.180 15 0.077 54 0.544 16 0.099 55 0.414 17 0.246 56 0.787 18 0.087 57 1.47 19 0.301 58 0.523 20 0.679 59 0.659 21 0.776 60 0.787 22 0.333 63 0.114 24 1.13 64 0.318 25 0.187 65 0.498 26 0.809 66 1.22 30 0.779 67 0.126 33 0.786 68 1.40 36 10.654 69 0.596 37 0.686 70 1.43 38 0.196 72 0.886 40 1.077 74 0.213 43 0.393 75 1.97 44 0.607 76 0.705 45 0.856 77 1.09 46 0.507 79 0.527 47 0.317 80 0.155 48 1.08 81 0.460 49 0.421 82 0.313 Anti-proliferation: Anti-proliferation: Co. No. OCI-Ly3 IC50 Co. No. OCI-Ly3 IC50 (μM) (μM) 83 0.225 116 0.108 84 0.098 119 0.219 86 0.458 120 0.280 89 0.299 122 0.477 90 0.231 124 0.127 91 1.95 125 0.070 92 1.43 126 0.097 93 3.44 127 0.398 94 0.460 128 0.073 96 0.047 129 1.85 97 0.103 130 0.235 98 0.018 131 0.143 100 0.099 132 0.879 101 0.043 134 0.092 102 0.261 137 0.107 104 0.050 140 0.082 105 0.030 142 0.123 106 0.719 144 0.052 107 0.140 146 0.097 108 1.06 147 0.121 109 2.31 149 0.140 111 0.651 150 0.155 112 0.079 151 0.052 113 0.114 152 0.097 114 0.314 115 n.d.

Claims

CLAIMS 1. A Formula (I) or a tautomer or a stereoisomeric form thereof, wherein R¹ represents C1-4alkyl or C3-6cycloalkyl; each optionally substituted with 1, 2 or 3 substituents each independently selected from halo and -OH; ring represents phenyl or pyridyl; R^x represents halo; n is 0, 1 or 2; Ar represents phenyl, thiazolyl, 1,2,4-thiadiazolyl, isothiazolyl, oxazolyl, pyrazolyl, pyridinonyl or pyridinyl; R^4a and R^4b are each independently selected from the group consisting of hydrogen; halo; C1-4alkyl; -C(=O)-NR⁵R⁶; -O-C1-4alkyl; -CN; -NR^7aR^8a; -C(=O)-O-R⁹; C3-6cycloalkyl; -O-C1-4alkyl substituted with 1, 2 or 3 halo substituents; or C1-4alkyl substituted with 1, 2 or 3 halo substituents; R² represents C1-4alkyl; R³ represents C3-6cycloalkyl optionally substituted with one substituent selected from -NR^7bR^8b, 1-azetidinyl, 1-pyrrolidinyl and 1-piperidinyl; or R³ represents (a-1), (a-2), (a-3), (a-4) or (a-5): (a-1) (a-4) (_a-2) ^(a-5) (a-3) X¹ represents O, NH or N-C_1-4alkyl; X² represents O, NH or N-C_1-4alkyl; n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, n11, n12, and n14 are each independently 1, 2 or 3; n13 is 0, 1 or 2; R¹², R¹³ and R¹⁶ are each independently selected from the group consisting of hydrogen, C_1-4alkyl and -S(=O)₂-C_1-4alkyl; R¹⁴, R¹⁵ and R¹⁷ are substituents on a carbon atom of (a-1), (a-2), (a-3), (a-4) or (a-5) and are each independently selected from the group consisting of hydrogen, C_1-4alkyl and halo; which they are attached ; X³ represents CH or N; X⁴ represents CH or N; provided that at least one of X³ and X⁴ represents N; X⁵ represents CH or N; X⁶ represents CH or N; provided that at least one of X⁵ and X⁶ represents N; R¹⁰ and R¹¹ represent hydrogen or C_1-4alkyl optionally substituted with 1, 2 or 3 halo substituents; R⁵, R⁶, R^7a, R^7b, R^8a, R^8b and R⁹ are each independently selected from the group consisting of hydrogen and C1-4alkyl; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 provided that the following compounds

and are excluded.

3. The compound according to claim 1 wherein R^4b is -C(=O)-NR⁵R⁶.

4. The compound according to claim 1 or 3 wherein R² and R³ are taken together to form together with the atoms to which they are attached (b-1) or (b-2).

5. according to any one of the previous claims wherein ring represents phenyl; and n is 0.

6. The compound according to any one of the previous claims wherein R^4a and R^4b are each independently selected from the group consisting of hydrogen; halo; C_1-4alkyl; -C(=O)-NR⁵R⁶; -O-C_1-4alkyl; -CN; -NR^7aR^8a; -C(=O)-O-R⁹; C_3-6cycloalkyl; -O-C_1-4alkyl substituted with 1, 2 or 3 halo substituents; or C1-4alkyl substituted with 1, 2 or 3 halo substituents; R² represents C1-4alkyl; R³ represents (a-1) or (a-3); X¹ represents O or NH; n1, n2, and n14 are each independently 1 or 2; n13 is 2; R¹⁶ represents hydrogen; R¹⁴ and R¹⁷ are substituents on a carbon atom of (a-1) or (a-3) and represent hydrogen; or R² and R³ are taken together to form together with the atoms to which they are attached (b-1) or (b-2); X⁵ represents N; X⁶ represents CH or N; R⁵, R⁶, R^7a, R^8a, and R⁹ are each independently selected from the group consisting of hydrogen and C1-4alkyl.

7. The compound according to any one of the previous claims wherein R¹ represents C1-4alkyl optionally substituted with 1, 2 or 3 halo substituents; Ar represents thiazolyl or pyridinyl; R^4a and R^4b are each independently selected from the group consisting of hydrogen; C_1-4alkyl; -C(=O)-NR⁵R⁶; or C1-4alkyl substituted with 1, 2 or 3 halo substituents; R² represents C1-4alkyl; R³ represents (a-1) or (a-3); X¹ represents O or NH; n1, n2, and n14 are each independently 1 or 2; n13 is 2; R¹⁶ represents hydrogen; R¹⁴ and R¹⁷ are substituents on a carbon atom of (a-1) or (a-3) and represent hydrogen; or R² and R³ are taken together to form together with the atoms to which they are attached (b-1) or (b-2); X³ represents N; X⁴ represents N; X⁵ represents N; X⁶ represents N; R¹⁰ and R¹¹ represent C1-4alkyl; R⁵ and R⁶ are hydrogen.

8. The compound according to any one of the preceding claims wherein R² and R³ are taken together.

9. The compound according to any one of the preceding claims wherein X¹ represents NH;

10. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 9 and at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.

11. A compound as claimed in any one of claims 1 to 9 or a pharmaceutical composition as claimed in claim 10 for use as a medicament.

12. A compound as claimed in any one of claims 1 to 9 or a pharmaceutical composition as claimed in claim 10 for use in the treatment or prevention of cancer.

13. A compound as claimed in any one of claims 1 to 9 or a pharmaceutical composition as claimed in claim 10 for use for use in the treatment or prevention of a disease, syndrome, condition, or disorder, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT1.

14. A method of treating a disease, syndrome, condition, or disorder, wherein said disease, syndrome, condition, or disorder is affected by the inhibition of MALT1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as claimed in any one of claims 1 to 9 or a pharmaceutical composition as claimed in claim 10.