COMPOUNDS THAT INHIBIT CYTIDINE TRIPHOSPHATE SYNTHASE 1 (CTPS1)

Abstract

Pyrimidin-2-yl-N-sulfonamide derivatives as CTPS1 inhibitors, pharmaceutical composition comprising them, intermediates for their synthesis and their use in the treatment of diseases such as various types of cancer including leukemia.

Description

COMPOUNDS field of invention The invention relates to novel compounds or processes for the manufacture of such compounds, related intermediates, compositions comprising such compounds and the use of such compounds as inhibitors of cytidine triphosphate synthase 1, particularly in the treatment or prophylaxis of disorders associated with 10 cell proliferation. Background of the invention Nucleotides are a key building block for cellular metabolic processes such as the synthesis of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). There are two classes of nucleotides, containing either purine or pyrimidine bases, both of which are important for metabolic processes. On this basis, many therapies have been developed to act selectively on different aspects of nucleotide synthesis, some inhibiting the generation of purine nucleotides and some of pyrimidine nucleotides, or both. The pyrimidine nucleotide cytidine 5'-triphosphate (CTP) is a precursor required not only for the anabolism of DNA and RNA, but also for phospholipids and the sialylation of proteins. CTP comes from two sources: a rescue pathway and a de novo synthesis pathway that depends on two enzymes, CTP synthases (or synthases) 1 and 2 (CTPS1 and CTPS2) (Evans and Guy 2004; Higgins, et al. . 2007; CTPS1 and CTPS2 catalyze the conversion of uridine triphosphate (UTP) and glutamine to cytidine triphosphate (CTP) and L-glutamate: 233,317 IF-2019-16749728-APN-ANf*#INPI Page 1 of 363 L-glutamine ΙΝθ L-glutamate \ X* Ο OPO31- ¡-y exogenQj NH2 J._! '1 HN” ”>N<?! 7.Ί1 I and ,------------------jj ----------------------'-™- .. ...........ha»· |J ATPf.t ADP + p.I R RJF? UTP 4-phospho-UTP CTP Both enzymes have two domains, an aminoterminai synthetase domain and a carboxyterminal glutaminase domain (Kursula, et al. 2006). The synthetase domain transfers a phosphate from adenosine triphosphate (ATP) to position 4 of the UTP to create an activated intermediate, 4-phospho-UTP. The glutaminase domain generates ammonia from glutamine, through a covalent thioester-type intermediate with a conserved active site cisterna, 10 generating glutamate. This ammonium is transferred from the glutaminase domain to the synthetase domain via a tunnel or can be derived from external ammonium. This ammonium is then used by the synthetase domain to generate CTP from 4-phospho-UTP (Lieberman, 1956). Although CTPS exists as two isozymes in humans and other eukaryotic organisms, CTPS1 and CTPS2, functional differences between the two isozymes have not yet been fully elucidated (van Kuilenburg, et al. 2000). The immune system provides protection against 20 infections and has therefore evolved to respond quickly to the wide variety of pathogens to which the individual may be exposed. This response can take many forms, but the expansion and differentiation of immune populations is a critical element and is therefore closely related to rapid cell proliferation. Within this context, CTP synthase activity appears to play an important role in DNA synthesis and rapid expansion of IF-2019-16749728-APN-AU2i#INPI Page 2 of 363 lymphocytes after activation (Fairbanks, et al. 1995; van den Berg, et al. 1995). The convincing clinical confirmation that CTPS1 is the essential enzyme in human lymphocyte proliferation was accompanied by the identification of a homozygous loss-of-function mutation (rs145092287) in this enzyme that causes an unmistakable and potentially fatal immunodeficiency, characterized by a diminished capacity of activated T and B lymphocytes to proliferate in response to antigen receptor-mediated activation. It was shown that activated CTPS1-deficient cells have decreased CTP levels. Normal T cell proliferation was restored in CTPS1-deficient cells by expression of wild-type CTPS1 or by addition of cytidine. It was found that CTPS1 expression was low in resting lymphocytes, but increased rapidly after activation of these cells. CTPS1 expression in other tissues was generally low. CTPS2 appears to be expressed predominantly in a variety of cells and tissues but at low levels, and the inability of CTPS2, which remains intact in patients, to compensate for mutated CTPS1, corroborates that CTPS1 is the essential enzyme for affected immune populations in patients (Martin, et al. 2014). Taken together, these findings suggest that CTPS1 is an essential enzyme necessary to meet the demands of CTP supply required by several important immune cell populations. Normally, the immune response is tightly regulated to ensure protection against infection, while controlling any response directed at host tissues. In certain situations, the control of IF-2019-16749728-APN-AN®#INPI Page 3 of 363 this process is not effective, which leads to pathology mediated by the immune system. A wide variety of human diseases are believed to be due to such inappropriate responses mediated by different elements of the immune system. Given the role that cell populations, such as T and B lymphocytes, are believed to play in a wide variety of autoimmune and other diseases, CTPS1 represents a target for a new class of immunosuppressive agents. Therefore, inhibition of CTPS1 provides a new strategy for the inhibition of activated lymphocytes and other selected immune cell populations such as cytotoxic lymphocytes, mucosa-associated invariant T lymphocytes 15 (MAIT) and cytotoxic invariant T lymphocytes, highlighted by the phenotype of human mutation patients (Martin, et al. 2014). Cancer can affect multiple types of cells and tissues but the main cause is a failure in the control of cell division. This process is extremely complicated, requiring careful coordination of multiple pathways, many of which have not yet been fully characterized. Cell division requires efficient replication of the cells' DNA and other constituents. Interfering with a cell's ability to replicate by altering nucleic acid synthesis has been a fundamental strategy in cancer therapy for many years. Examples of therapies that act in this way are 6-thioguanine, 6-mecaptopurine, 5~fluorouracil, cytonabine, gemcitabine, and pemetrexed. As noted above, the pathways involved in providing the key building blocks for nucleic acid replication are the pathways for IF-2019-16749728-APN-ANÍ#INPI Page 4 of 363 purine and pyrimidine synthesis, and pyrimidine biosynthesis has been observed to increase in tumors and neoplastic cells. CTPS activity increases in several types of tumors of both hematological and non-hematological origin, although heterogeneity is observed between patients. Relationships have also been established between high enzyme levels and resistance to guimotherapeutic agents. At present, the specific role that CTPS1 and CTPS 2 may play in cancer is not completely clear. Several non-selective CTPS inhibitors have been developed for oncologic indications up to phase I / II clinical trials, but were rejected due to toxicity and efficacy concerns. Most of the inhibitors developed are nucleoside analog prodrugs (3-deazauridine, CPEC, carbodine), which are converted into the active triphosphorylated metabolite by the action of kinases involved in pyrimidine biosynthesis: uridine / cytidine-kinase, nucleoside monophosphate. kinase (NMP-kinase) and nucleoside diphosphate kinase (NDP-kinase). The remaining inhibitors (acivicin, DON) are reactive glutamine analogues, which irreversibly inhibit the glutaminase domain of CTPS. Gemeitibine has also been reported to have some inhibitory activity against CTPS (McClusky et al., 2016). Therefore, CTPS appears to be an important target in the field of cancer. The nature of all of the above compounds is such that effects on 30 other pathways are likely to contribute to the efficacy they show in inhibiting tumors. Selective CTPS inhibitors therefore offer an attractive alternative strategy for tumor treatment. Compounds with different potencies against IF-2019-16749728-APN-AN^INPI Page 5 of 363 CTPS1 and CTPS2 may offer important opportunities to target different tumors depending on their relative dependence on these enzymes. CTPS1 has also been suggested to play a role in the proliferation of vascular smooth muscle cells following vascular injury or surgery (Tang, et al. 2013). To our knowledge, no selective CTPS1 inhibitor has been developed to date. Recently, the CTPS1-selective inhibitory peptide CTpep10 3 has been identified. However, the inhibitory effects of CTpep-3 were observed in cell-free assays but not in the cellular context. On the other hand, this was not unexpected, since the peptide is unlikely to enter the cell and, therefore, the possibility of its development as a therapeutic agent is not easy (Sakamoto, et al. 2017). In summary, the available information and data strongly suggest that CTPS1 inhibitors will reduce the proliferation of numerous immune cell populations, with the potential to exert an effect on other selected cell types, such as vascular smooth cells, as well. It is therefore expected that CTPS1 inhibitors will have utility for treatment or prophylaxis in a wide variety of indications in which the pathology is controlled by these populations. CTPS1 inhibitors represent a new strategy to inhibit selected components of the immune system in various tissues, and related pathologies or pathological conditions such as, broadly speaking, rejection of transplanted cells and tissues, graft-related diseases or disorders, allergies and autoimmune diseases. Additionally, CTPS1 inhibitors offer therapeutic potential in a variety of cancer indications and to promote recovery from vascular injury or surgery and reduce IF-2019-16749728-APN-ANefrlNPI Page 6 of 363 morbidity and mortality associated with neointima and restenosis. Compendium of invention The invention provides a compound of formula (I): where A is an amide linker that has the following structure: -C(=O)NH- or -NHC(=O)~; X is N or CH; Y is N or CR2; Z is N or CR3; provided that when at least one of X or Z is N, Y cannot be N; Ri is C0-2CÍcl alkylene alkyl or C.^5 alkyl whose cycloalkyl is optionally substituted with CH< or CF5; R¿ is H, halo, Ci^alkyl, OC1-2alkyl, Ci-2haloalkyl or OhaloCi^2alkyl; R3es H, halo, CH3, OCH3, CF3u OCF3; where at least one of R¿ and R3 is H; R4 and R5 are each independently that are linked form a C3-e cycloalkyl or C;·^ heterocycloalkyl; and when A is -NHC(=O)-: R.i and R5 may be further selected from halo, OhaloC3-t;, Oalkylene Cn?Cd-c cycloalkyl, Oalkylene Coaheterocycloalkyl C3-g, Oalkyl C|-c, and NR^iR^p; Arl is a 6-membered aryl or heteroaryl; IF-2019-16749728-APN-ANWiNPI Page 7 of 363 Ar2 is a 6-membered aryl or heteroaryl and is linked to Arl in the para position with respect to the amide; Rio is H, halo, Ci-3 alkyl, Ci-2 haloalkyl, C]-2 alkyl, Ci-2 Ohaloalkyl CN; R1Les H, F, Cl, alkyl Ci^zCF-OOCH3o CN; Ri2 is linked to Ar2 in the ortho or meta position with respect to Arl and R]2is H, halo, C ] _4 alkyl ΛC2-4 alkenyl ralkylene C)S-?cycloalkyl C j-r,, Oalkyl Ci- / ]fOalkylene C0-2cycloalkyl C.i-o, haloCi~4fOhaloC1-4alkyl, hydroxy, C1-4alkylOH, S02C.i2alkyl, C (O) N (Ci-2alkyl) 2fNHC(O)Ci~3alkyl NR23R24; and when A is -NHC(=O)-: Ri2 can be further selected from CN, OCH2CH2N (CH3) 2 and a C3-o heterocycloalkyl comprising a nitrogen located at the bonding point to Ar2, or R¡2 together with a nitrogen atom to which it is bonded forms an N-oxide (N+~O~) ; R]3 is H or halo; R2i is H, Ci-5 alkyl, C(O)Ci-5 alkyl, C(O)Oalkyl R22is H or CH3; R23is H or Ci.-2 alkyl; and R24 is H or Ci-2 alkyl. Conveniently, the invention provides a compound of formula (I): where R] is C>-5 alkyl or Cn-?Cb-cycloalkyl, which cycloalkyl is optionally substituted with CH3; R3 is H, halo or CH3; IF-2019-16749728-APN-ANftdNPI Page 8 of 363 R / i and R-, are each independently H, halo, Cm alkyl, C]-alkylene Ci-3 alkyl, or and R3 together with the carbon atom to which they are bonded form a C3-e cycloalkyl or C* heterocycloalkyl,- <p Arl is a 6-membered aryl or heteroaryl; Ar2 is a 6-membered aryl or heteroaryl and is linked to Arl in the para position with respect to the amide; Rin is H, halo, C1-2alkyl, OC1-2alkyl, OhaloC1-2alkyl or CN; Rnes H, F, CHj or OCH3; and R12 is linked to Ar2 in the ortho or meta position with respect to Arl and Ri2es H, halo, CL_^ alkyl, OC1-4alkyl, Oalkylene C0-2 cycloalkyl C3-3 rCN, haloC1-4alkyl, OhaloC1-4alkyl. The invention also provides a compound of formula (I): where Ri is C1-5alkyl or C0-2alkyleneC3_3cycloalkyl whose cycloalkyl is optionally substituted with CH3; R3 is H, halo or CH3; R / ι and R5 are each independently H, C16 alkyl, Ci^3 alkylene, or Ci-3 alkyl, or R4 and R3 together with the carbon atom to which they are bonded form a C3-c cycloalkyl; Arl is a 6-membered aryl or heteroaryl; Ar2 is a 6-membered aryl or heteroaryl and is linked to Arl in the para position with respect to the amide; R.L0 is H, halo, C1-2 alkyl, OC1-2 alkyl, C1-2 ohaloalkyl or CN; IF-2019-16749728-APN-AN^#INPI Page 9 of 363 ‘ Ri] is H, F, CH., or OCH.,; and R12 is linked to Ar2 in the ortho or meta position with respect to Arl and R12 is H, halo, Ci-4 alkyl, O Ci-4 alkyl, Oalkylene Co-pcycloalkyl C,-·,, CN, haloalkyl Ci-4, Ohaloalkyl Ci~4. The invention also provides a compound of formula (I): F?42R13 8l0 R11 R4R5V—á X—tk \ / π °0(I) where A is an amide linker that has the following structure: ~-C(=O)NH- or -NHC(=O)-; X is N oCH; And it is NOCR Z is N oCR3; provided that when at least one of X or Z is N, Y cannot be N; R-i is Ci-b alkyl or C0-2alkyleneCÍeloC3-3alkyl whose cycloalkyl is optionally substituted with CH3; R? is H, C1-2 alkyl or Ci-2 haloalkyl; R3 is H, halo or CH3; where at least one of R2 and R3 is H; R4 and R5 are each independently H, Ci-t·alkyl or Ci-^OC1-3 alkylene, or R4 and R5 together with the carbon atom to which they are bonded form a 5 C3-f·cycloalkyl, or C3-c heterocycloalkyl; and when A is -NHC(=0)-: R4 and R') can be additionally selected between halo and Oalkyl Cj-íP Arl is a 6-membered aryl or heteroaryl; 0 Ar2 is a 6-membered aryl or heteroaryl and is bonded to Arl in the para position with respect to the amide; IF-2019-16749728-APN-AMMNPI Page 10 of 363 Rio is Hfhalo, C 1.-3 alkyl, haloalkyl Ci-2} Oalkyl Οι-2λ Ohaloalkyl Ci-2o CN; Rn is H, F, CH3u OCH3; R12 is linked to Ar2 in the ortho or meta position with respect to Arl and R12 is H, halo, C,-4 alkyl, OC1-4alkyl, C1-4 haloalkyl, OhaloC1-4alkyl, C3-5 alkylene Co2cycloalkyl, Oalkylene C0- 2C3-5cycloalkyl, CN or C2- / ¡alkenyl; and Ru is H. A compound of formula (I) may be provided in the form of a salt and / or solvate thereof and / or derivative thereof. Conveniently, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable salt and / or solvate thereof and / or derivative thereof. In particular, the compound of formula (I) may be provided in the form of a pharmaceutically acceptable salt and / or solvate, such as a pharmaceutically acceptable salt. Also provided is a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof and / or derivative thereof, for use as a medicament, in particular for use in the inhibition of CTPS1 in a subject or the prophylaxis or treatment of associated diseases or disorders, such as those in which a reduction in the proliferation of T and / or B lymphocytes would be beneficial. Additionally, a method is provided for the inhibition of CTPS1 in a subject or the prophylaxis or treatment of associated diseases or disorders, such as those in which a reduction in the proliferation of T and / or B lymphocytes would be beneficial, by administering to a subject which is needed by a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof and / or derivative thereof. IF-2019- 16749728-APN-AíW#INPI Page 11 of 363 Further provided is the use of a compound of formula (X), or a pharmaceutically acceptable salt and / or solvate thereof and / or derivative thereof, in the manufacture of a medicament for the inhibition of CTPS1 in a subject or the prophylaxis or treatment of associated diseases or disorders, such as those in which a reduction in the proliferation of T and / or B lymphocytes would be beneficial. Conveniently, the disease or disorder is selected from: inflammatory skin diseases such as psoriasis or lichen planus; Acute and / or chronic GVHD such as spheroid-resistant acute GVHD; acute lymphoproliferative syndrome (ALPS); systemic lupus erythematosus, lupus nephritis or cutaneous lupus; and transplant. Furthermore, the disease or disorder can be selected from myasthenia gravis, multiple sclerosis and scleroderma / systemic sclerosis. Also provided is a compound of formula (I), or a pharmaceutically acceptable salt / or solvate thereof and / or derivative thereof, for use in the treatment of cancer. Furthermore, there is provided a method of treating cancer in a subject by administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof and / or derivative thereof. Additionally, the use of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof and / or derivative thereof, in the manufacture of a medicament for the treatment of cancer in a subject is provided. Also provided is a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof and / or derivative thereof, for use in promoting recovery from vascular injury or surgery and reducing morbidity and mortality associated with neointima and restenosis in a subject. IF-2019- 16749728-APN-Aítí$#INPI Page 12 of 363 It further provides a method of promoting recovery from a vascular injury or surgery and reducing the morbidity and mortality associated with neointima and restenosis in a subject, by administering to a subject in need thereof a compound of formula (I) or a salt and / or solvate thereof and / or pharmaceutically acceptable derivative thereof. Additionally, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof and / or derivative thereof, in the manufacture of a medicament to promote recovery from vascular injury or surgery and reduce the morbidity and mortality associated with neointima and restenosis in a subject. Also provided are pharmaceutical compositions containing a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof and / or derivative thereof, and a pharmaceutically acceptable carrier or excipient. Also provided are processes for preparing compounds of formula (I) and new intermediates for use in the preparation of compounds of formula (I). Detailed description of the invention The invention provides a compound of formula (I): where A is an amide linker that has the following structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; And is it N or CR?; Z is N or CR^; provided that when at least one of X or Z is N, Y cannot be N; IF-2019-16749728-ΑΡΝ-αΛ^ΙΝΡΙ Page 13 of 363 Ri is C1-5 alkyl, Co^C3-5 alkylene cycloalkyl whose cycloalkyl is optionally substituted with CH3 or CF3; R2 is H, halo, C1-2 alkyl, OC1-2alkyl, ha 1 oCi-2alkyl or OhaloCi-2alkyl; R-ses H, halo, CH3, OCH3, CF3u OCF3; where at least one of R2 and R3 is H; R / j and R5 are each independently H, alkyl C]_ 6, alkyl Ci-cOH, haloalkyl alkylene C·:.]2heteroicloalkyl alkylene Co-2heterocycloalkyl C3-6 alkylene, Ci _3O C1-3 alkyl or R4 and R.> together with the carbon atom to which they are bonded they form a C3-6 cycloalkyl or C3-6 heterocycloalkyl; and when A is “NHC(=O)-~: R4 and R5 can be further selected from halo, OhaloCi-g alkyl, OAlkylene Cordel oC3-C alkyl, Oalkylene C.j2heterocycloalkyl C3-c,, OCi-f)alkyl and NR21R22; Arl is a 6-membered aryl or heteroaryl; Ar2 is a 6-membered aryl or heteroaryl and is linked to Arl in the para position with respect to the amide; Rio is H, halo, Ct -3 alkyl, C1-2 haloalkyl, Oalkyl Ó1-2 / Ohaloalkyl Ci-2o CN; R-i i is H, F, 01, Ci-2 alkyl, CF3, OCH-j or CN; R12 is linked to Ar2 in the ortho or meta position to Arl and R12 is H, halo, C1-4 alkyl, C2-4 alkenyl / C3-3 alkylene Co-2cycloalkyl, OC1-4alkyl, Oalkylene Co-2C3-0cycloalkyl , C1-4 haloalkyl, OhaloC1-4Λhydroxy, C1-4alkylOH, SO2C5_ 2alkyl, C(O)N(C^d alkyl NHC(O)C1-3alkyl or NR2.3R24; and when A is -NHC( =O)-: R12 can be additionally selected from CN, OCH2CH2N (CH3) 2 and a C3-,i heterocycloalkyl which IF-2019-16749728-APN-AÍh*tINPI Page 14 of 363 comprises a nitrogen located at the point of bonding to Ar2, or R12 together with a nitrogen atom to which it is bonded forms an N-oxide (N+-0~); R]3 is H or halo; R?i is H, C1-5 alkyl, C(0)C1-5 alkyl, 0(O)OC1-5 alkyl; R22is H or CH3; R2.3 is Η or Ci-2 alkyl; and R24 is H or Cj_2 alkyl; or a salt and / or solvate thereof and / or derivative thereof. Conveniently, the invention provides a compound of formula (T): where R] is C1-5alkyl or Co-2C3-5alkylenecycloalkyl whose cycloalkyl is optionally substituted with CH3; R.i is H, halo or CH3; R4 and R5 are each independently H, halo, alkyl alkylene Ci-^O C1.-3 alkyl, or R4 and R5 together with the carbon atom to which they are bonded form a cycloalkyl or heterocycloalkyl C Arl is a 6-membered aryl or heteroaryl; Ar2 is a 6-membered aryl or heteroaryl and is linked to Arl in the para position with respect to the amide; Rio is H, halo, alkyl Oalkyl C1_?, Ohaloalkyl Ci-2o CN; R11 is H, F, CH3u OCH3; and R12 is linked to Ar2 in the ortho or meta position with respect to Arl and R12 is H, halo, Ci-4 alkyl, Oalkyl IF-2019-16749728-APN-A^INPI Page 15 of 363 Oalkylene C0-2cycloalkyl CN, haloalkyl Cd-4, C1-4 Ohaloalkyl. or a salt and / or solvate thereof and / or derivative thereof. The invention also provides a compound of formula (I): where Ri is Ci~5 alkyl or Co-alkylene cycloalkyl Cwhose cycloalkyl is optionally substituted with CHq R3 is Hfhalo or CHj; R4 and R5 are each independently H, Cialkylene C1-3O alkyl or C1-3 chyl, or R4 and R5j together with the carbon atom to which they are linked form a C3-6 cycloalkyl; Arl is a 6-membered aryl or heteroaryl; Ar2 is a 6-membered aryl or heteroaryl and is linked to Arl in the para position with respect to the amide; Rio is H, halo, C1-2 alkyl, OC]_2 alkyl, 0 Ohaloalkyl CV2o CN; R11 is H, F, CH3u OCH3; and R12is linked to Ar2 in the ortho or meta position with respect to Arl and Ri2es H, halo, C1-4 alkyl, OCi-4alkyl, Oalkylene Cn-2cycloalkyl C3-5, CN, haloCi-4alkyl, OhaloC1-4alkyl. or a salt and / or solvate thereof and / or derivative thereof. The invention also provides a compound of formula (I): where IF-2019-16749728-APN-A^INPI Page 16 of 363 A is an amide linker that has the following structure: -C(=O)NH- or ~NHC(=O)~·; X is N oCH; And it is NOCR Z is N or CR with the condition that when at least one of X or Z is N, Y cannot be N; Rt is C1-5alkyl or C0_2alkyleneC3-5cycloalkyl whose cycloalkyl is optionally substituted with CH3; R2 is H, C1-2 alkyl or ha 1 or C]~2 alkyl; R3 is H, halo or CH3; where at least one of R2 and R3 is H; R4 and Rh are each independently H, Ci-(· alkyl, or Ci-j alkylene Cj-j alkyl, or R4 and R5 together with the carbon atom to which they are bonded form a C3-6 cycloalkyl or heterocycloalkyl; and when A is -NHC¢=0)-: R4 and R5 can additionally be selected between halo and Oalkyl Arl is a 6-membered aryl or heteroaryl; Ar2 is a 6-membered aryl or heteroaryl and is linked to Arl in the para position with respect to the amide; Rio is H, halo, Cj-3 alkyl, Ci-2z haloalkylCi~2falkylOhoC1-2 alkyl or CN; R11 is H, F, CH3u OCHg R12 is linked to Ar2 in the ortho or meta position with respect to Arl and R]?is H, halo, C1 -4 alkyl< OCy~4alkylZhaloC1 -4alkyl, OhaloC1-4alkyl, C alkylene;> 2C3-5cycloalkyl, . Oalkylene Co-2C3-5cycloalkyl / ·CN or C2-4alkenyl; and R13es H; or a salt and / or solvate thereof and / or derivative thereof. IF-2019- 16749728-ΑΡΝ-αΛ?#ΙΝΡΙ Page 17 of 363 The term 'alkyl' as used herein such as in C'-? alkyl, C'-4 alkyl, C1-5 alkyl or alkyl either alone or forming part of a larger group such as an Oalkyl group (p eg, C]_Oalkyl, C1-4Oalkyl, and C1-5Oalkyl) is a linear or branched fully saturated hydrocarbon chain containing the specified number of carbon atoms. Examples of alkyl groups include the C1-5 alkyl groups methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, tert-butyl and n-pentyl, sec-pentyl and 3-pentyl, in particular the groups C1 _ 3 alkyl methyl, ethyl, npropyl and isopropyl. Reference to “propyl” includes npropyl and isopropyl, and reference to butyl” includes n~ butyl, isobutyl, sec-butyl and tert-butyl. Examples of Oalkyl groups include the C1-4 Oalkyl groups methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) and butoxy (including n-butoxy, isobutoxy, sec-butoxy and tert-butoxy). CP alkyl groups as used herein, either alone or as part of a larger group such as an Oalkyl C group, are a linear or branched fully saturated hydrocarbon chain containing six carbon atoms. Examples of C6 alkyl groups include n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl. The term 'alkylene', as used herein, such as in alkylene Cn_2cycloalkyl alkylene C]_ 20alkyl or Oalkylene Co^cycloalkyl is a bifunctional linear or branched fully saturated hydrocarbon chain containing the specified number of carbon atoms. Examples of Co-2 alkylene groups are where the group is absent (i.e. Co), methylene (CJ and ethylene (C2) The term 'alkenyl', as used herein, such as in C2-alkenyl 4, it is a hydrocarbon chain IF-2019-16749728-APN-AÍt^INPI Page 18 of 363 linear or branched that contains the specified number of carbon atoms and a carbon-carbon double bond. The term ''cycloalkyl'', as used herein, such as in C cycloalkyl or Cj-g cycloalkyl, either alone or as part of a larger group such as C3-5 ocycloalkyl or Co-2 alkylene cycloalkyl C3-5 is a fully saturated hydrocarbon ring containing the specified number of carbon atoms. Examples of cycloalkyl groups include the Cj-g cycloalkyl groups cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, in particular the C3-5 cycloalkyl groups cyclopropyl, cyclobutyl and cyclopentyl: A, A'r A I / \ ί ί i \ .. Λ-.z a'A Cycloalkyl €2-.. CIclosIquílDCi Cycloalkyl <0 The term 'heterocycloalkyl', as used herein, such as in C.j-g heterocycloalkyl or C3-6 alkylene Co2heterocycloalkyl is a fully saturated hydrocarbon ring containing the specified number of carbon atoms and may include the carbon atom through to which the cycloalkyl group is linked, where 0 at least one of the carbon atoms in the ring is replaced by a heteroatom such as N, S or O. As valence requires, the nitrogen atom(s) may be connected to a hydrogen atom to form an NH group. Alternatively, the nitrogen atom(s) may be substituted (just as a nitrogen atom is substituted), for example, with alkyl Ci4, C(O)H, C(0) C1-4alkyl, C(O)OC1-4alkyl, C(O)OalkylCy4aryl such as C(O)OBz, C(O)NHalkylC-]-4, C(O)NHalkylCy4aryl such as C(O) )NHBz, an Fmoc group, C(0)haloalkyl Ci~ IF-2019- 16749728-APN-aSP#INPI Page 19 of 363 4, C(0)OhaloC1-4alkyl or C(0)NHaloC1-4alkyl such as C(O)OtBu. Where a ring heteroatom is S, the term 'heterocycloalkyl' includes where the atom(s) of 3 is substituted (such as an S atom is substituted) with one or more oxygen atoms. (i.e. S(0) or 8(0)2). Alternatively, any sulfur atom(s) in the Cj-Ct heterocycloalkyl ring are unsubstituted. Examples of Cj-c heterocycloalkyl groups include those comprising one heteroatom such as those containing one heteroatom (e.g., oxygen) or containing two heteroatoms (e.g., two oxygen atoms or one oxygen atom and a nitrogen atom). Particular examples of C3-g heterocycloalkyl comprising an oxygen atom include oxiranyl, oxetanyl, 3-dioxolanyl, morpholinyl, 1,4-oxatianyl, tetrahydropyranyl, 1,4-thioxanyl and 1,3,5-trioxanyl. Examples of C3-g heterocycloalkyl include those comprising one oxygen atom such as containing one oxygen atom or containing two oxygen atoms. Particular examples of C3-g heterocycloalkyl comprising an oxygen atom include oxiranyl, oxetanyl, 3-dioxolanyl, morpholinyl, 1,4-oxatianyl, tetrahydropyranyl, 1,4-thioxanyl and 1,3,5-trioxanyl. In one embodiment, the term 'heterocycloalkyl1, as used herein, such as in Cw heterocyclolalkyl, is a fully saturated hydrocarbon ring containing the specified number of carbon atoms and may include the carbon atom through which The cycloalkyl group is attached, where at least one of the carbon atoms in the ring is replaced by a heteroatom such as N, S or 0. Examples of heterocycloalkyl groups include those that comprise a heteroatom such as those that contain a IF-2019-16749728-APN-A^INPI Page 20 of 363 heteroatom (e.g. oxygen or containing two heteroatoms (e.g. two oxygen atoms or one oxygen atom and one nitrogen atom), Heteroeichloalkyl groups can have the following structures: Hetero alkyl cycle·:;.; H ete spray it a leuílo c Heterocycloalkyl C.i H eterocycloa ¡kyl L;, H eterocycles lo uilü Lo Heterocycloatauyl C=, Hete re cycle a Ichylo Heterccycloalkyl C-, where each Q is a heteroatom independently selected from O, N or S. When Q is N, as valence requires, the atom(s) s) of nitrogen can (n) be connected to a hydrogen atom to form an NH group. Alternatively, the nitrogen atom(s) may be substituted (just as a nitrogen atom is substituted), for example, with alkyl Ci4, C(O)H, C(0) C1-4 alkyl, C(0)0C1.-4 alkyl, C(O)Oalkyl Cq_4aryl such as C(O)OBz, C (O) NHalkyl C1-4, C(O)MHalkyl Will mention such as C(O) )NHBz, an Fmoc group, C(O)Ci4haloalkyl, C(O)Cq-4ohaloalkyl or C(O)C1-4Nhaloalkyl such as C(O)OtBu. When any Q is S, the S atoms may be substituted (just as an S atom is substituted) with one or two oxygen atoms (i.e., S(O) or S(0)2) Alternatively, any (Any) sulfur atom(s) in the C3-6 heterocycloalkyl ring are / are unsubstituted. IF-2019- 16749728-APN-AÍWNPI Page 21 of 363 Heterocycloalkyl groups can also have the following structures: \ / \ / . / ' I ¿ \ / 4 : Ϊ s I ·' .·' 0' ... _Yo HíterocidOabuilo -,,3l· ehrt CKlúdqu 1’ u3H ateroocluab uüq '..i Hetercdcloa bu ib Meter ocictoabuilc ' । H e t e r c c icio a fc mó i; H eter o cyclic a fc tí ilo c H e t e r o :.icio a le t.í il o C where each Q is independently selected from O, N or S, such as O or N. When Q is N, as required by the valence, the nitrogen atom(s) may be connected to a hydrogen atom to form an NH group. Alternatively, the nitrogen atom(s) may be substituted (just as a nitrogen atom is substituted), for example, with alkyl ©4-4, C(O)H, C (O) Alkyl Ci_¿i, C(O)©alkyl Ci- / ,, C (0) Oalkyl Ci-4aryl such as C(O)OBz, C (0) NHalkyl C;.-4, C(O) NHalkyl Ci^aryl such as C(0)NHBz, an Fmoc group, C(0) haloalkyl Ci-4, C (0) Ohaloalkyl Ci-4o C (0) NHhaloalkyl C].-4such as C(O)OtBu. When any Q is Ξ, the S atoms can IF-2019-16749728-APN-AÍ^INPI Page 22 of 363 be substituted (just as a Ξ atom is substituted) with one or two oxygen atoms (i.e., S(0) or 8(0)2) · Alternatively, any atom(s) of sulfur in the C3-6 heterocycloalkyl ring is / are not 5 substituted(s). When A is -C (=0) NH and R4 and / or R5 is C3-t·alkylene Cnheterocycloalkyl, or when R4 and R·, together with the carbon atom to which they are bonded, form a heterocycloalkyl any heteroatom in the heterocycloalkyl it may not be directly connected to the carbon that R4 and R5 are connected to. Conveniently, the heterocycloalkyl is a fully saturated hydrocarbon ring containing the specified number of carbon atoms where at least one of the carbon atoms is replaced by a heteroatom such as N, S or 0, where, as valence requires, any Nitrogen atom is connected to a hydrogen atom, and where the S atom is not present as an oxide. The term 'halo' or 'halogen', as used herein, refers to fluorine, chlorine, bromine or iodine. Particular examples of halo are fluorine and chlorine, especially fluorine. The term 'haloalkyl', as used herein, such as in Ci-haloalkyl, such as in C1-4 haloalkyl, either alone or as part of a larger group such as an Ohal or alkyl group or , such as in Cj-6 Ohaloalkyl, such as in C1-4 Ohaloalkyl, is a linear or branched fully saturated hydrocarbon chain containing the specified number of carbon atoms and at least one halogen atom, such as fluoro or chlorine, especially fluoro. An example of haloalkyl is CF3. Other examples of haloalkyl are CHF2 and CH2CF3. Examples of Ohaloalkyl include OCF3, OCHF? and OCH?CF3. IF-2019-16749728-APN-A&&INPI Page 23 of 363 The term '6-membered aryl', as used herein, refers to a phenyl ring. The term '6-membered heteroaryl', as used herein, refers to 6-5 membered aromatic rings containing at least one heteroatom (e.g., nitrogen). Exemplary 6-membered heteroaryls include one nitrogen atom (pyridinyl), two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl), and three nitrogen atoms (triazinyl). The phrase 'in the para position with respect to the amide', as used herein, such as with respect to the Ar2 position, means that compounds with the following substructure are formed: where Wi may be N, CH, CR10, or CRn, and may be N, CH, or CRi2, as permitted by the definitions given for compounds of formula (I). may also be CR] 3 as permitted by the definitions given for compounds of formula (I). The terms 'ortho' and 'meta', as used herein, as when used with respect to defining the position of R]2 in Ar2 is with respect to Arl, means that structures: y---, / VAr2 Y'~Y' \ Ari p Οι'ΐΟ 25 can form the following -2019-16749728-APN-AÍ^INPI Page 24 of 363 The phrase Ά is an amide connector that has the following structure: -C (=0)NH~ or -NHC(=0) means that the following structures are formed: -NH(C=O)~ -(C=O)NHIn one embodiment, A is -C(=O)NH-, In another embodiment, A is -NHC (>O)-. In one embodiment, X is N. In another embodiment, X is CH. In one embodiment, Y is N. In another embodiment, Y is CR>. In one embodiment, Z is N. In another embodiment, Z is CR Conveniently, X is N, Y is CR? and Z is CR3,Alternatively, X is CH, Y is N and Z is CRj. Alternatively, X is CH, Y is CR2, and Z is CR3. Alternatively, X is CH, Y is CR2, and Z is N. Alternatively, X is N, Y is CR2, and Z is N. In one embodiment of the invention, Ri is C1-5 alkyl. When Ri is C1-5 alkyl, Ri may be methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl, sec-butyl or tert-butyl) or pentyl (e.g., npentyl, sec-pentyl or 3-pentyl). In a second embodiment of the invention, Ri is C3-5 alkylene Co-2cycloalkyl whose cycloalkyl is optionally substituted with CH-. In some embodiments, Ri is C3-5 alkylene Co-2cycloalkyl. In other embodiments, Ri is C0_2alkyleneC3_5cycloalkyl whose cycloalkyl is substituted with CH-. R3 may be C·^ cycloalkyl, whose cycloalkyl is optionally substituted with CH- R[ may be C-jcycloalkyl Ca-.nfwhose cycloalkyl is optionally substituted with CH-. Ri may be C3^5 C2cycloalkylene alkylene, which cycloalkyl is optionally substituted with CH.j. R1 may be Co~2cycloalkylC3 alkylene, whose cycloalkyl is substituted IF-2019-16749728-APN-AÍ^INPI Page 25 of 363 optionally with CH3. Ri may be alkylene Cr(Cq-cycloalkyl, whose cycloalkyl is optionally substituted with CH?. R? may be alkylene C(.i_2cycloalkyl C···,, whose cycloalkyl is optionally substituted with CH.3. Conveniently, where alkylene C[¡ -2cycloalkyl C ?<, is optionally substituted with CH.?, the CH? is at the bonding point of the cycloalkyl C.?-3alkylene Cn-2. In a third embodiment, R¡ is CF?. Conveniently, Ri is cyclopropyl, cyclopropyl substituted with CH·? at the point of attachment, cyclobutyl, CH.? or CH2CH? In particular, Rj is cyclopropyl, cyclobutyl, CH? or CH2CH3, especially cyclopropyl. In one embodiment, R2 is H. In a second embodiment, R2 is halo such as F, C1 or Br, e.g. e.g., C1 or Br. In a third embodiment, R2 is Ci~2 alkyl. When R2 is Ci-2 alkyl, R2 may be methyl or ethyl, such as methyl. In a fourth embodiment, R2 is OC5_2 alkyl. When R?is Oalkyl C^2, it can be OCH.? or OEt, such as OCH3. In a fifth embodiment, R2 is Ci-2 haloalkyl. When R2 is haloalkyl or Ci^2, can R2 be CF? or CH2CF3, such as CF·?, In a sixth embodiment, R2 is Ci-2 Ohaloalkyl. When R2 is Ohaloalkyl Ci~2> R? Could it be OCF? or OCH2CF3, such as OCF3. Conveniently, R2 is H, CH? or CF.?, such as H or CH·?, in particular H. In one embodiment, R? is H. In a second embodiment, R? is halo, in particular chloro or fluoro, especially fluoro. In a third embodiment, R·? is CH·?. In a fourth embodiment, R? Is it OCH·? In a fifth embodiment, R? Is it CE? In a sixth embodiment, R.? Is it OCR?, Conveniently, R? is H, halo in particular chloro or fluoro, especially fluoro, CH.? or CF.? More conveniently, R? is H or F, just like H. Conveniently, at least one of R2and R.-? it's H. IF-20 19-16749728-APN-AM^INPI Page 26 of 363 In one embodiment, R4 and R<, together with the carbon atom to which they are bonded form a C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl, in particular cyclopropyl or cyclopentyl. In a second embodiment, R4 and R5 together with the carbon atom to which they are bonded form a C3-6 heterocycloalkyl, such as a heterocyclohexyl, in particular a tetrahydropyranyl. Any nitrogen atom, such as a nitrogen atom in the C4-0 heterocycloalkyl ring may be substituted, for example, with C1-4 alkyl, C(O)H, C(O)C1-4 alkyl, C(0) 0Ci-4alkyl, C(O)OCy-4alkylaryl such as C(O)OBz, C(O)NCi-4alkyl, C(O)NHalkylC4-4aryl such as C(O)NHBz, an Fmoc group, C(O)C1-4haloalkyl, C(O)OhaloCi-4alkyl or C(O)NHhaloCi-4alkylsuch as C(O)OtBu. Conveniently, any nitrogen atom in the Cj-c» heterocycloalkyl ring is unsubstituted. In a third embodiment, R4 is Ci_c alkyl, in particular C1-4 alkyl such as methyl, ethyl, propal (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a fourth embodiment, R4 is CiOalkyleneC1-3alkylene, in particular Ci^OalkyleneC1-2alkylene such as CiOalkyleneC^alkylene, CoOalkylCt alkylene, C-jOalkyleneC2alkylene or C2OalkyleneC2alkylene. In a fifth embodiment, it is H. In a sixth embodiment, R4 is halo, such as chloro or fluoro, especially fluoro. In a seventh embodiment, R4 is C^haloalkyl, such as CFj or CH^CFj, In an eighth embodiment, R4 is Cn2 alkylene C3-6 cycloalkyl such as C-m cycloalkyl;, alkylene Cycloalkylene C2Cycloalkyl C5-67 alkylene Cn-^C3-cycloalkyl, Co-^C4-cycloalkyl, C<-alkylene Covcycloalkyl, or Cn.-Cg-cycloalkyl. In a ninth embodiment, R4 is C3g alkylene Co-2heterocycloalkyl such as Cj-g heterocycloalkyl, Coheterokyloalkylene alkylene C2heterocycloalkyl or C3g alkylIF-2019- 16749728-APN-AÍWNPI Page 27 of 363υ, alkylene Co^heterocycloalkyl C, a heterocyclohexyl ring. Conveniently, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Conveniently, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom, such as a nitrogen atom in the C3-heterocycloalkyl ring, may be substituted, for example. with C1-4 alkyl, C(O)H, C(0)C]_-4 alkyl, C(0)0C1-4 alkyl, C(O)OalkylCy-^aryl such as C(O)OBz, C (O) C1-4NHalkyl, C(O)NHalkylCy-4aryl such as C(O)NHBz, an Fmoc group, C(O)C1-4haloalkyl, C(O)OhaloC1-4alkyl or C(O) NHhaloC1-4alkyl such as C(O)OtBu. Conveniently, any nitrogen atom in the CÓ-í heterocycloalkyl ring is unsubstituted. In a tenth embodiment, R4 is Ci-V1OH alkyl, such as CH2OH or CH2CH2OH. In an eleventh embodiment, R4 is Ci-G Ohaloalkyl, such as C-1-4 Ohaloalkyl, such as OCF3 or OCHF2. In a twelfth embodiment, R is C3, Oalkylene Co-2cycloalkyl C4, Oalkylene Co-zCYcloalkyl C5 or Oalkylene Co~2cycloalkyl CG. In a thirteenth embodiment, R4 is Ci-c Oalkyl, in particular Ci4 Oalkyl such as methoxy, ethoxy, propoxy (n-propoxy or isopropoxy) or butoxy (n-butoxy, isobutoxy, sec-butoxy or tert-butoxy). In a fourteenth embodiment, R is C2heterocytioalkyl C3-t;, . Oalkylene C0-2heterocycloalkyl C3, Oalkylene Co-rheterocycloalkyl C4, Oalkylene Cn IF-2019-16749728-APN-A^INPI Page 28 of 3632heterocycloalkyl C5u Oalkylene Cr^iheterocycloalkyl Co. Conveniently, the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Conveniently, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Conveniently, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom such as a nitrogen atom in the C.w, 10 heterocycloalkyl ring may be substituted, for example, with Ci-4 alkyl, C(0)H, C(0)alkyl Ci-4, C(0)OalkylC1-4, C(0)Oalkyl·Cy~4aryl such as C(O)OBz, C(0)NHalkylCi-4 , C(O)NHalkyl C]_4aryl such as C(O)NHBz, an Fmoc group, C(0)haloCi4alkyl, C(0)OhaloC1-4alkyl or C(0)NHhaloC4-4alkylsuch as 15 C(O )OtBu. Conveniently, any nitrogen atom in the C-j-c heterocycloalkyl ring. is not replaced. In a fifteenth embodiment, R4 is NR2iR22 When A is -NHC(=0)- or -C (=0)NH~, conveniently, R4 is H, C-4-(-, alkyl, C^ haloalkyl, Ci-gOH alkyl, Cp202 alkylene Cj-c cycloalkyl, alkylene Cn-2heterocycloalkyl C4-í:,, alkylene Ci-jaalkyl OC1-3, or R,j and R5 together with the carbon atom to which they are bonded form a cycloalkyl C3_(·, or heterocycloalkyl C3_6. When A is -NHC (= 0) -, conveniently R4 may be additionally selected from halo, Oalkylene C1 -c-c, Oalkylene Co-^cycloalkyl C3g, Oalkylene Co-2heterocycloalkyl C3-f--,, Oalkyl C1 _fc-, or NR21R22 Conveniently, R4 is H, fluoro, CH3, ethyl, OCH3 or CH2CH2OCH3, such as fluoro, ethyl, OCH3 or CH2CH2OCH3. 0 Conveniently, R4 is H, CH3, ethyl or CH2CH2OCH3, in particular CH3o ethyl. Conveniently, R4 and R5 together with the carbon atom to which they are bonded form a cyclopropyl or cyclopentyl, in particular a cyclopentyl. IF-2019-16749728-APN-A^INPI Page 29 of 363 Conveniently, R4 and R5 together with the carbon atom to which they are bonded form a heterocyclohexyl, such as tetrahydropyranyl or piperidinyl, especially tetrahydropyranyl. Any nitrogen atom in the heterocyclohexyl ring may be substituted, for example, with C1-4 alkyl, C(0)H, C(0)Cl-4 alkyl, C(0) or C1-4 alkyl, C(0) OalkylCy^aryl such as C(0)OBz, C(0)NHalkylC1-4, C(0)HalkylCy^aryl such as C(0)NHBz, an Fmoc group, C(0)haloalkylC1-4, C(0)OhaloC1-4alkyl or C(0)NHhaloC1-4alkyl such as C(O)OtBu. Conveniently, any nitrogen atom in the heterocyclohexyl ring is unsubstituted. Conveniently, R4 and R5 together with the carbon atom to which they are bonded form a heterocyclobutyl, such as 15-azetidinyl. Any nitrogen atom in the heterocyclobutyl ring may be substituted, for example, with Ci-4 alkyl, C(O)H, C(0)C1-4 alkyl, C(0)0C>4alkyl, C(0)0alkyl Ci-^aryl such as C(O)OBz, C (0)NHalkyl C1-0 C (0) NHalkyl Cy^aryl such as C (0) NHBz, a group Fmoc, 20 C (0) ha lo to chyl Ci ^, C(0)OhaloC1-4alkyl or C(0)NHhaloC1-4alkyl such as C(0)0tBu. Conveniently, any nitrogen atom on the heterocyclobutyl ring is unsubstituted. When R4 is NR2iR22 / in one embodiment R2i is H. In a second embodiment, R2i is C1-5 alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment, R2i is C(0)C1-?>alkyl such as C(0)CFR. In a fourth embodiment, R21 is C(0)OCi-5alkyl, such as C(O)OCH?>or C(0)Otert-butyl. When R4 is NR2]R22, in one embodiment R22 is H. In a second embodiment, R22 is methyl. For example, R4 is NH?, N(CH-J2, NHC(0)CH3, NHC(0)OCH3, NHC(0)Otert-butyl and CH2CH2OH, especially, N(CH3)2, NHC(O)CH3, NHC (O)OCH3. IF-2019-16749728-APN-A^INPI Page 30 of 363 Conveniently, R2] is C (0) OCH3 and R22 is H. Conveniently, R2i is C(O)CH3 and R22 is H. Conveniently, R2i and R22 are both CH3. Conveniently, R21 and R22 are both H. In one embodiment, R5 is Ci-13 alkyl, in particular C1-4 alkyl such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl). In a second embodiment, R is , is H. In a fourth embodiment, R¡;, is halo, such as chloro or fluoro, especially fluoro. In a fifth embodiment, R5 is Ci-e haloalkyl, such as CF3 or CH2CF3. In a sixth embodiment, R5 is Cd2C3-c alkylenecycloalkyl such as C.3m cycloalkyl, C3m alkylenecycloalkyl C3-g alkylenecycloalkyl, Co-2C3-cycloalkyl, C-2cycloalkyl, Conveniently, heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl ring. or heterocyclohexyl such as a heterocyclohexyl ring. Conveniently, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Conveniently, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom in the C3m heterocycloalkyl ring may be substituted, for example, with C1-4 alkyl. C(O)H, C(0)C1.4alkyl, C(0)0C^alkyl, IF-2019-16749728-APN-A^INPI Page 31 of 363 C(O)Oalqurl Ci-4aryl such as C(O)OBz, C(O)NHalkylC1-4, C(O)NHalkyl Ci-^aryl such as C(O)NHBz, an Fmoc group, C(0) Ci-4 haloalkyl, C (O)OhoC1-4 alkyl 0 C(0)NHhaloC1-4alkyl such as C(O)OtBu. Conveniently, any nitrogen atom in the C3-6 heterocycloalkyl ring is unsubstituted. In an eighth embodiment, Rr is alkyl Ci-6OH, such as CH?OH or CH2CH2OH. In a ninth embodiment, R5 is Ohaloalkyl such as Ohaloalkyl Ci, such as OCF3 or OCHF2. In a tenth embodiment, R3 is Oalkylene Co-2C3-6cycloalkyl such as OalkyleneC3-ccycloalkyl, OalkyleneCicycloalkylC^-ñ, OalkyleneC?cycloalkylCj-6, OalkyleneCo-2cycloalkylC3, OalkyleneCo-2cicloa1chyloC4 In an eleventh embodiment, ) or butoxy (n-butoxy, isobutoxy, sec-butoxy or tert-butoxy). C2heterocycloalkyl C3-C, Oalkylene Co-2heterocycloalkyl C-,, Oalkylene Co-hetero c i oalkyl C4, Oalkylene 0.Ί_ ¿heterocycloalkyl C5 or Oalkylene C0_2heterocycloalkyl Cf;. Conveniently, the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. Conveniently, the heterocyclopentyl ring is tetrahydrofuranyl or pyrrolidinyl. Conveniently, the heterocyclohexyl ring is tetrahydropyranyl or piperidinyl. Any nitrogen atom, such as a nitrogen atom in the heterocycloalkyl ring Cj..^ may be substituted, for example, with C1-4alkyl, C(O)H, C(OC1-4alkyl, C(0)Oalkyl C1-4, C(0)Oalkyl C24aryl such as C(O)OBz, C(0)NHalkyl Ci-4, C(O)NHalkyl Cj IF-2019-16749728-APN-A^INPI Page 32 of 363 ¿aryl such as C(O)NHBz, an Fmoc group, C (O)haloalkyl ΟΊ_ 4, C (O) Ohaloalkyl C¡-¿ or C (O) NHhaloalkyl Cj - 4 such as C(O )OtBu. Conveniently, any nitrogen atom in the C3-c heterocycloalkyl ring is unsubstituted. In a thirteenth embodiment, Rr>is NR21R22. When A is -NHC(=O)- or -C(=O)NH-, conveniently, R3 is H, Ci~g alkyl, Ci-g haloalkyl, Ci-¿alkyl OH, Cn2 alkylene C3-gzalkylene Cn-pheterocycloal C3-6 alkyl, Ci-3 alkylene 0C]-3 alkyl, or R4 and R5 together with the atom of carbon to which they are bonded form a C3-t-cycloalkyl, or C3-6 heterocycloalkyl. When A is -NHC (=0) -, R3 can conveniently be further selected from halo, OhaloCi-f, Oalkylene Co-2cycloalkyl C36, Oalkylene C0~2hete rocal loa 1 chylo C3_fj, Oalkylene Ci-3o NR21R22. When R5 is NR2iR22, in one embodiment R2is H. In a second embodiment, R2¡ is Cj_5 alkyl, such as methyl, ethyl or propyl, especially methyl. In a third embodiment, R21 is C(0)C1-.5 alkyl such as C(O)CH3. In a fourth embodiment, R21 is C(0)C1-5alkyl, such as C(O)OCH3or C(0)Otert-butyl. When R., is NR21R22, in one embodiment R22 is H. In a second embodiment, R22 is methyl. For example, R5 is NH2, N(CH3)2, NHC(O)CH3, NHC(O)OCH3, NHC (0) Otert-butyl and CH2CH2OH, especially, N(CHj)2, NHC(O)CH3, NHC( O)OCH3. Conveniently, Reí is C (0) 0CH.3 and R22 is H. Conveniently, R2| is C(O)CH3 and R22 is H. Conveniently, R21 and R22 are both CH3. Conveniently, R2i and R22 are both H. Conveniently, R5 is H, F, CH3o ethyl such as H, CH3o ethyl. Conveniently, R4 is H, CH3, ethyl or CH2CH2OCH3 and R$ is H, CH3o ethyl, in particular R4 is CH3o ethyl and R3 is H, IF-2019-16749728-APN-A^PtINPI Page 33 of 363 methyl or ethyl. For example, R4 and R3 are H, R4 and Rr-, are methyl, R / | and R5 are ethyl or R4 is CH2CH2OCH3 and R5 is H. Conveniently, R4 is F and Rr is ethyl. Conveniently, R4is F and R3is F. Conveniently, R4 is ethyl and R5 is H. Conveniently, R4 and Rr are arranged in the following configuration: R4r5 In one embodiment, Arl is a 6-membered aryl, i.e., phenyl. In a second embodiment, Arl is a 6-membered heteroaryl, in particular containing one nitrogen atom (pyridyl) or two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl). In particular Arl is phenyl, 2-pyridyl or 3-pyridyl, such as phenyl or 2-pyridyl. The position numbering for Arl is with respect to the amide, with the carbon at the bonding point called position 1 and other numbers providing the relative location of the nitrogen atoms, for example: 2-pyridyl. 3-pyridyl In one embodiment, Rio is H. In a second embodiment, Rio is halo, for example, fluoro or chloro. In a third embodiment, RK) is C1-3 alkyl such as Ci-2 alkyl, such as CH3o ethyl. In a fourth embodiment, Rio is OC1-2alkyl, such as OCH3o ethoxy. In a fifth embodiment, R10 is C1-2 Ohaloalkyl, such as OCF3. In a sixth embodiment, Rio is CN. In a seventh embodiment, R1(i is Ci-2 haloalkyl such as CF3. IF-2019-16749728-APN-aSAtNPI Page 34 of 363 Conveniently, Rio is H, fluoro, chloro, CH3, CFj, OCH3, OCF3 or CN, such as H, fluoro, chloro, CH3, OCH3, OCF3 or CN, in particular H, fluoro, chloro, OCH3, OCF-, or CN especially Η or fluoro. Conveniently, Rin is H, F or CH?,. In one embodiment, Rn is H. In a second embodiment, Ri 1 is F. In a third embodiment, Ru is Cm alkyl such as CH? or Et, such as CH3. In a fourth embodiment, Ri i is OCH3. In a fifth embodiment, Ru is C1. In a sixth embodiment, Ru is Et. In a seventh embodiment, Rn is CFj. In an eighth embodiment, Ru is CN. Conveniently, Rn is H, F, CH3 or OCH3, such as H, F or CH.or such as H or F, such as H. In one embodiment, RI(j is in the ortho position with respect to the amide. In another embodiment, Rio is in the meta position with respect to the amide. Conveniently, Rio is in the ortho position with respect to the amide. In one embodiment, Rn is in the ortho position with respect to the amide. In another embodiment, Rn is in the meta position with respect to the amide. Conveniently, R11 is in the ortho position with respect to the amide. In one embodiment, Ar2 is a 6-membered aryl, i.e., phenyl. In a second embodiment, Ar2 is a 6-membered heteroaryl, in particular containing one nitrogen atom (pyridyl) or two nitrogen atoms (pyridazinyl, pyrimidinyl or pyrazinyl). The position numbering for Ar2 is with respect to the attachment point to Arl, for example: 3-pyridyl 2,5-pyrazinyl IF-2019- 16749728-APN-A$f#INPI Page 35 of 363 In particular, Ar2 is 3-pyridyl or 2,5-pyrazinyl, especially 2,5-pyrazinyl. In one embodiment, R12 is H. In a second embodiment, Ri2 is halo, for example, fluoro or chloro. In a third embodiment, R]2 is C1-4 alkyl, such as methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl, sec-butyl or tert-butyl), In a fourth embodiment, R12 is OC^alkyl, such as OCH3, ethoxy, isopropoxy or n-propoxy. In a fifth embodiment, R12 is Oalkylene Co-2C3-5cycloalkyl, such as OalkyleneC3-3cycloalkyl (e.g., cyclopropoxy or cyclobutoxy), OalkyleneC3-5Cycycloalkyl or OalkyleneC3-5cycloalkyl. In a sixth embodiment, R22 is CN. In a seventh embodiment, R12 is C1-4 haloalkyl, such as CF3. In an eighth embodiment, R12 is OhaloC1-4alkyl, such as OCF3, OCHF2u OCH2.CF3. In a ninth embodiment, R]2 is C2-4 alkenyl such as C(=CH2)CH3. In a tenth embodiment, R]2 is C3-5 alkylene C-2cycloalkyl such as C3-5 cycloalkyl, C3-5 alkylene C-cycloalkyl, Cn-2C5 alkylene. In an eleventh embodiment, Rj2 is hydroxy. In a twelfth embodiment, R12 is C]-4OH alkyl such as CH2OH. In a thirteenth embodiment, R12 is S02Ci-2alkyl such as SO2CH3. O) N (C3_2 chyl)2 such as C(O)N(CHj) 2 In a fifteenth embodiment, Rt2 is NHC (O) C1-3 alkyl · In a sixteenth embodiment, R12 is NR23R24. In a seventeenth embodiment, Rv is OCH2CH2N. (CH3)2. In an eighteenth embodiment, Ri2 is a C3-6 heterocycloalkyl comprising a nitrogen located at the bonding point to Ar2. Conveniently, the heterocycloalkyl is a heterocyclopropyl, heterocyclobutyl, heterocyclopentyl or heterocyclohexyl ring such as a heterocyclohexyl ring. , he IF-2019-16749728-APN-AJ$f^INPI Page 36 of 363 heterocyclopentyl ring is pyrrolidinyl. Conveniently, the heterocyclohexyl ring is piperidinyl or piperazinyl. Any nitrogen atom in the C3-g heterocycloalkyl ring may be substituted, for example, with C1-4 alkyl, C(O)H, C(O)C1-4 alkyl, C(O)OC1-4 alkyl, C( O) Oalkyl·Cy-4aryl such as C].4 alkyl, C(O)OBz, C(O)NHalkylC1-4, C(O)NHalkyl Chlaryl such as C(O)NHBz, an Fmoc group, C( O)C1-4haloalkyl, C(O)OhaloC1-4alkyl or C(O)NHhaloCj-áalkyl such as (O)OtBu. Conveniently, any nitrogen atom on the Cno heterocycloalkyl ring is substituted. In a nineteenth embodiment, Ri¿ together with the nitrogen atom to which it is bonded forms an N-oxide (Ν'-O”). When A is -NHC (=0) - or -C (=0) NH-, conveniently, R-]¿ is bonded to Ar2 in the ortho or meta position with respect to Arl and R12 is H, halo, C1-4 alkyl , C¿- / ¡ alkenyl, Cq-2 alkylene C3-5 cycloalkyl, OC1-4alkyl, Oalkylene C(> ¿C3-5cycloalkyl, Ci~4 haloalkyl, OhaloC1-4alkyl, hydroxy, C1-4alkylOH, S02alkyl C1-2, C(O)N(C1-2 alkyl)2, NHC(O)Cí-j alkyl or NR23R24. When A is -NHC(=0)-, Ri¿ can conveniently be further selected from CN, OCH2CH7N (CH3)¿ and a C3-g heterocycloalkyl comprising a nitrogen located at the bonding point to Ar2, or Ri¿ together with a nitrogen atom to which it is bonded forms an N-oxide (N+-O“). The present invention provides N~oxides of the compound of formula (I). Conveniently, when Ri¿ together with a nitrogen atom to which it is bonded forms an N-oxide (N1—0), the following example structures are formed: IF-2019- 16749728-APN-aS?#INPI Page 37 of 363 R12 is conveniently H, F, Cl, CH3, OCH5, OEt, OiPr, OCyclopropyl, CN, CF;i, OCHF2u OCH2CF3. In particular, R12 is Cl, CN, CF3, OCHF?, OCH2CF3, 0CHoOEt, OiPr, OCyclopropyl, such as CF3, OCHF2, OCH2CF3, OCHj, OEt, OiPr, OCyclopropyl, p. e.g., Oet. Ri¿ is conveniently H, F, Cl, CH3, iPr, OCH3, OEt, OiPr, OCyclopropyl, CN, CF?, OCHF2, OCH2CF3, C3o cycloalkyl C(=CH2)CH3. In particular, R12es Cl, iPr, OCH3, OEt, OiPr, OCyclopropyl, CN, CF3, OCHF2, OCH?CFi, C3o cycloalkyl C(=CH2)CH3, such as Cl, OCH3, OEt, OiPr, OCyclopropyl, CF3, OCHF2, OCH2CF3 or C3 cycloalkyl, e.g. e j . , Oet. When A is -C(=O)NH-, conveniently R12 is CFi, OEt or OiPr, such as OEt or OiPr. Conveniently, R:2 is in the target position of Ar2. Alternatively, Ri2 is in the ortho position of Ar2. In one embodiment, R13 is H. In another embodiment, R13 is halo such as F or Cl, conveniently F. In one embodiment, R13 is ortho position with respect to Arl. In another embodiment, R13 is in position para with respect to Arl. In another embodiment, R(1) is in the meta position with respect to Arl. In one embodiment, R23 is H. In another embodiment, R23 is Ci-2 alkyl such as methyl. In one embodiment, R24 is H. In another embodiment, R24 is Ci-2 alkyl such as methyl. Conveniently, R23 is H and R24 is ethyl. Conveniently, R23 is CH.3 and R2¿ is CH3. Desirably, a compound of formula (I) does not include 2—(6—(methi1suIfonamido)pyrazin-2-yl)-N-(4-(pyridin-3yl)phenyl)acetamide. In one embodiment, when R3 is methyl, at least one of Rzi, R3, R10, R-| 1, R12and r13is different from H. Conveniently, at least one of R4, R5, R-m, Rn, R12and Ri 3 is different from H. IF-2019-16749728-APN-AÍÍftlNPI Page 38 of 363 More conveniently, at least one of R1(J, Rn, R]2and Ri:i is different from H. Throughout the specification, Arl and Ar2 can be represented as follows: Ar1 All representations referring to Arl are equivalent and all representations referring to Ar2 are equivalent, unless the context requires otherwise, the representations of Arl and Ar2 should not be considered as excluding the presence of heteroatoms or substitutions. The present invention provides the compounds described in any of Examples Pl to Pili. The present invention also provides the compounds described in any of Examples P112 to P115. The present invention also provides the compounds described in any of Examples P116 to P225. The present invention provides the following compounds: 1 / -(4-(5-chloropyridin-3-yl)phenyl)~2-(2(cyclopropanesulfonamido)pyrimidin-4-yl)butanamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)phenyl)cyclopentanecarboxamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6methoxypyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4(5-(trifluoromethyl)pyridin-3-yl)phenyl)propanamide; 2-methyl-N-(2-methyl-4-(6-methylpyrazin-2-yl)phenyl)-2-(2(methylsulfonamido)pyrimidin-4-yl)propanamide; IF-2019-16749728-APN-aS^INPI Page 39 of 363 2-(2-(cyclopropanesulfonamido)pyrimidin-4-i1)-N- (2-fluoro 4- (pyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin~4-yl)-N-(4-(5(trifluoromethyl)pyridin-3-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6(trifluoromethyl)pyrazin-2-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6isopropoxypyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)phenyl)-2-ethylbutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro~ 4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro4-(6-isopropoxypyrazin-2-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5(trifluoromethyl)pyridin-3-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5(2,2f2-trifluoroethoxy)pyridin-3-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)-5-fluoropyrimidin-4-yl)-7V(4-(pyridin-3-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4(pyridin-3-yl)phenyl)acetamide; N-([1,1'-biphenyl]-4-yl)-2-(2(cyclopropanesulfonamido)pyrimidin-4-yl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N~ (4-feet oxypyr az in-2-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)~N~ (4-(6methoxypyrazin-2-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N~(4-(6(2r2,2-trifluoroethoxy)pyrazin-2-yl)phenyl)acetamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6isopropoxypyrazin-2-yl)phenyl)acetamide; 2-(2-(cyclobutanesulfonamido)pyrimidin-4-yl)~N~ (5-(6ethoxypyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide; IF-2019-16749728-APN-A^INPI Page 40 of 363 2-(2-(cyclobutanesulfonamido)pyrimidin-4-yl)-N-(2“fluoro-4(6-isopropoxypyrazin-2-yl)phenyl)“2-methylpropanamide; 2-(2-(cyclobutanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)-2-methylphenyl)-2-methylpropanamide; 2-(2-(cyclobutanesulfonamido)pyrimidin-4-yl)~N~(4-(6methoxypyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclobutanesulfonamido)pyrimidin-4-yl)~N-(4-(6ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)-2methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)~N~(5'-ethoxy[3,3'-bipyridin]-6-yl)-2-methylpropanamide; N-([3,3'-bipyridin]-6-yl)-2-(2(cyclopropanesulfonamide)pyrimidin-4-yl)-2methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(5(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)propanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6cyclopropoxypyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide; N-(2-chloro-4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2(cyclopropanesulfonamide)pyrimidin-4-yl)-2methylpropanamide; N-(2-cyano-4-(6-ethoxypyrazin~2-yl)phenyl)-2-(2(cyclopropanesulfonamide)pyrimidin-4-yl)-2methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro4-(5-isopropoxypyridin-3-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamide)pyrimidin-4-yl)~N~ (2-fluoro4-(pyridin-3-yl)phenyl)-2-methylpropanamide; IF-2019-16749728-APN-A^INPI Page 41 of 363 2~(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)-2methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)-2-fluorophenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)(2-fluoro4-(6-isopropoxypyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)-2-fluoro-5-methylphenyl)-2methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N~(4-(6ethoxypyrazin-2-yl)-2,6-difluorophenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)(2-fluoro4-(pyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(2methyl-4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)-2,3-dimethylphenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)~N~(4-(6ethoxypyrazin-2-yl)-5-fluoro-2-methylphenyl)-2methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)-2,5-dimethylphenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)-2-(trifluoromethoxy)phenyl)-2methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)-5-fluoro-2-methoxyphenyl)-2methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)-2-methoxyphenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4(pyrimidin-5-yl)phenyl)propanamide; IF-2019-16749728-APN-Al^INPI Page 42 of 363 N-(4-(5-chloropyridin-3-yl)phenyl)-2-(2(cyclopropanesulfonamido)pyrimidin-4-yl)-2methylpropanamide; N-(4-(5~cyanopyridin-3-yl)phenyl)-2-(2(cyclopropanesulfonamido)pyrimidin-4-yl)-2methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5fluoropyridin-3-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4(5-methylpyridin-3-yl)phenyl)propan amide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5(difluoromethoxy)pyridin-3-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N~(4-(5methoxypyridin-3-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)(4-(5ethoxypyridin-3-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5isopropoxypyridin-3-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4(pyridin-3-yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N(31-(trifluoromethyl)-[1,1'-biphenyl]—4—i1)propanamide; N~ (3'-chloro-[l,l'-biphenyl]-4-yl)-2-(2(cyclopropanesulfonamido)pyrimidin-4-yl)-2methylIpropanamide; N-(3'-cyano-[1,1'-biphenyl]-4-yl)-2-(2(cyclopropanesulfonamido)pyrimidin-4-yl)-2methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(3'-ethoxy[1,1'-biphenyl]-4-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide; IF-2019-16749728-APN-AÍ^9#INPI Page 43 of 363 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6cyclopropoxypyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6isopropoxypyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-5-fluoropyrimidin-4-yl)~N(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide; N~ (4- (6-ethoxypyrazin-2-yl)phenyl)-2-methyl-2-(2-((1methylcyclopropane)-1-sulfonamido)pyrimidin-4yl)propanamide; 2-(2-(cyclopropanesulfonamido)-5-methylpyrimidin-4-yl)-N-(4(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4(pyrazin-2-yl)phenyl)propanamide; N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2-(2(ethylsulfonamido)pyrimidin-4-yl)-2-methylpropanamide; 2-(2-(ethylsulfonamido)pyrimidin-4-yl)-2-methyl-N-(4-(6(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide; N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-(2(ethylsulfonamido)pyrimidin-4-yl)-2-methylpropanamide; N-(5-(6-ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)-2-methyl-2(2-(methylsulfonamido)pyrimidin-4-yl)propanamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methyl-2-(2(methylsulfonamido)pyrimidin-4-yl)propanamide; N-(2-fluoro-4-(5-isopropoxypyridin-3-yl)phenyl)-2-methyl-2(2-(methylsulfonamido)pyrimidin-4-yl)propanamide; N-(2-fluoro-4-(6-isopropoxypyrazin-2-yl)phenyl)-2-methyl-2(2-(methylsulfonamido)pyrimidin-4-yl)propanamide; 2-methyl-N-(2-methyl-4-(6-(trifluoromethyl)pyrazin-2yl)phenyl)-2-(2-(methylsulfonamido)pyrimidin-4yl)propanamide; 2-methyl-2-(2-(methylsulfonamido)pyrimidin-4-yl)-N-(4-(6(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide; N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methyl~2-(2(methylsulfonamido)pyrimidin-4-yl)propanamide; IF-2019-16749728-ΑΡΝ-αΛ^ΙΝΡΙ Page 44 of 363 2-(2~((1f1-dimethylethyl)sulfonamide)pyrimidin-4-yl)-N- (4-(6ethoxypyrazin-2-i1)phenyl)-2-methylpropanamide; 1-(2-(cyclopropanesulfonamido)pyrimidln-4-yl)-N-(4-(6ethoxypyrazin-2-yl)phenyl)cyclopropanecarboxamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)—W—(5'—(trifluoromethyl)-[3,3'-bipyridin]-6-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-i 1)-N~(5'-(2,2,2trifluoroethoxy)-[3,3'-bipyridin]-6-yl)butanamide; N-([3,3'-bipyridin]-6-yl)-2-(2(cyclopropanesulfonamido)pyrimidin-4-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6-(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6ethoxypyraz in-2-yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6isopropoxypyrazin-2-yl)pyridin-2-yl)butanamide; N-(4-(5-chloropyridin-3-yl)-2-fluorophenyl)-2- (2(cyclopropanesulfonamido)pyrimidin-4-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro4-(5-(2,2,2-trifluoroethoxy)pyridin-3-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro4-(5-isopropoxypyridin-3-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro4-(pyridin-3-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro4-(6-(trifluoromethyl)pyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro4-(6-methoxypyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-W-(4-(6ethoxypyrazin-2-yl)-2-fluorophenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro4-(6-isopropoxypyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(2-fluoro4-(6-(2,2,2-trifluoroethoxy)pyrazin-2-yl)phenyl)butanamide; IF-2019-16749728-APN-A^INPI Page 45 of 363 j N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(2(cyclopropanesulfonamido)pyrimidin-4-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5(2,2r2-trifluoroethoxy)pyridin-3-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(5isopropoxypyridin-3-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4(pyridin-3-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(610(trifluoromethyl)pyrazin-2-yl)phenyl)butanamide; ΛΓ-(4-(6-chloropyrazin-2-yl)phenyl)-2-(2(cyclopropanesulfonamido)pyrimidin-4-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6methoxypyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6isopropoxypyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(620(2,2,2-trifluoroethoxy)pyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4(pyrazin-2-yl)phenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)phenyl)-4-methoxybutanamide; and 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4(pyridin-3-yl)phenyl)propanamide; The present invention also provides the following compounds: 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(630 ethoxypyrazin-2-yl)pyridin-2-yl)-2-(R)-fluorobutanamide; - (2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)-2-(S)-fluorobutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluorobutanamide; and IF-2019-16749728-APN-A4^INPI Page 46 of 363 ) 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N- (5-(6ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2Jf-pyran-4carboxamide. The present invention also provides the following 5 compounds: 2- (2- (cyclopropanesulfonamido)pyrimidin-4-yl) -N-(5- (6isopropylpyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide —(2 — (cyclopropanesulfonamido)pyrimidin-4-yl) -N-(4-(6ethoxypyrazin-2-yl)-2-fluorophenyl)-2,2-difluoroacetamide; N-((2-(cyclopropanesulfonamido)pyrimidin-4-yl)methyl)-4-(6ethoxypyrazin-2-yl)benzamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(5(6-(prop-l-en-2-yl)pyrazin-2-yl)pyridin-2-yl)propanamide ; 2-(2-(cyclopropanesulfonamido)-6-methylpyrimidin-4~yl)-N-(515 (6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-(trifluoromethyl)pyrimidin4-yl)-N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2methylpropanamide; - (2-(cyclopropanesulfonamido)pyrimidin-4-yl)~N-(5-(62 0 cyclopropylpyrazin-2-yl)pyridin-2-yl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(6-(6ethoxypyrazin-2-yl)pyridin-3-yl)-2-methylpropanamide; - (2-(cyclopropanesulfonamido)pyrimidin-4-i1)-N-(4-(6cyclopropylpyrazin-2-yl)-2-fluorophenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-methylpyrimidin-4-yl)-N-(4(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2-methylpropanamide; - (2-(cyclopropanesulfonamido)-6-(trifluoromethyl)pyrimidin4-yl)-N-(4-(6-ethoxypyrazin-2-yl)-2-fluorophenyl)-2methylpropanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-methyl-N-(4(6-(prop-l-en-2-yl)pyrazin-2-yl)phenyl)propanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6isopropylpyrazin-2-yl)phenyl)-2-methylpropanamide; IF-2019- 16749728-APN-AJ$F#INPI Page 47 of 363 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(Οι dimethyl lamino)pyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-methylpyrimidin-4-yl)-N-(4(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-(trifluoromethyl)pyrimidin4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(2-(cyclopropanesulfonamido)-6-methoxypyrimidin-4-yl·)-2methyl-N-(4-(pyridin-3-yl)phenyl)propanamide; 1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)cyclopentane-l-carboxamide; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carboxamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-(2(methylsulfonamido)pyrimidin-4-yl)piperidine-4-carboxamide; tert-butyl 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl·)-4-((5-(6ethoxypyrazin-2-yl)pyridin-2-yl)carbamoyl)piperidine-1carboxylate; 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)piperidine-4-carboxamide; tert-butyl 3-(2-(cyclopropanesulfonamido)pyrimidin-4-yl·)-3-((5-(6ethoxypyrazin-2-yl)pyridin-2-yl)carbamoyl)azetidine-1carboxylate; tert-butyl 4-((5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)carbamoyl)-4-(2(methylsulfonamido)pyrimidin-4-yl)piperidin-l-carboxylate 4-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)-2-fluorophenyl)tetrahydro-2H-pyran-4carboxamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)-4methoxybutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxybutanamide; IF-2019-16749728-APN-A^ft / INPI Page 48 of 363 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)-2-fluorophenyl)-4-methoxybutanamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxy-2-methyl-2(2-(methylsulfonamido)pyrimidin-4-yl)butanamide; N-(5'-chloro-[3,3'-bipyridin]-6-yl)-2-(2(cyclopropanesulfonamido)pyrimidin-4-yl)butanamide; N-(5'-chloro-[3,3'-bipyridin]-6-yl)-2-(2(cyclopropanesulfonamido)pyrimidin-4-i1)-2fluorobutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6cyclopropylpyrazin-2-yl)pyridin-2-yl)-2-fluorobutanamide; N-(5-(6-ethoxypyrazin~2-yl)pyridin-2-yl)-2-fluoro-2-(2(methylsulfonamido)pyrimidin-4-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6ethoxypyrazin-2-yl)-3-methylpyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6cyclopropylpyrazin-2-yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6(2,2,2-trifluoroethoxy)pyrazin-2-yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(3-fluoro5-(6-methoxypyrazin-2-yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6methoxypyrazin-2-yl)pyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-i1)-N-(4-(6cyclopropylpyrazin-2-yl)-2-fluorophenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)-2-methylphenyl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6ethoxypyrazin-2-yl)-3-fluoropyridin-2-yl)butanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)-2-methylbutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-3-methylbutanamide; IF-2019-16749728-APN-A4^INPI Page 49 of 363 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)-2-fluorophenyl)-3-methylbutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)-3-methylbutanamide; 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)phenyl)-2-methoxyacetamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2(methylsulfonamido)pyrimidin-4-yl)-(R)-butanamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluoro-2-(2(methylsulfonamido)pyrimidin-4-yl)-(S)-butanamide; N~(4-(5-chloropyridin-3-yl)phenyl)-2- (6(cyclopropanesulfonamido)pyridin-2-yl)acetamide; N-(4-(5-cyanopyridin-3-yl)phenyl)-2-(6(cyclopropanesulfonamido)pyridin-2-yl)acetamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(5fluoropyridin-3-yl)phenyl)acetamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(5methoxypyridin-3-yl)phenyl)acetamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N~ (4-(pyridin3-yl)phenyl)acetamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6(trifluoromethyl)pyrazin-2-yl)phenyl)acetamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6methoxypyrazin-2-yl)phenyl)acetamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(pyrazin2-yl)phenyl)acetamide; N-([3,3'-bipyridin]—6—i1)-2-(6(cyclopropanesulfonamido)pyridin-2-yl)-2-methylpropanamide; N-(4-(5-chloropyridin-3-yl)phenyl)-2-(6(cyclopropanesulfonamido)pyridin-2-yl)-2-methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(5fluoropyridin-3-yl)phenyl)-2-methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(5ethoxypyridin-3-yl)phenyl)-2-methylpropanamide; IF-2019-16749728-APN-AS04INPI Page 50 of 363 j 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-2-methyl-N-(4(pyridin-3-yl)phenyl)propanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(2-fluoro-4(pyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(6-(cyclopropanesulfonamide)pyridin-2-yl)-2-methyl-N-(4(6-(trifluoromethyl)pyrazin-2-yl)phenyl)propanamide; N-(4-(6-chloropyrazin-2-yl)phenyl)-2-(6(cyclopropanesulfonamido)pyridin-2-yl)-2-methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(610 ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6methoxypyrazin-2-yl)phenyl)-2-methylpropanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-2-methyl-N-(4(pyrazin-2-yl)phenyl)propanamide; 4-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4carboxamide. 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6(trifluoromethyl)pyrazin-2-yl)pyridin-2-yl)butanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)butanamide; N-(4-(5-chloropyridin-3-yl)phenyl)-2-(6(cyclopropanesulfonamido)pyridin-2-yl)butanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(625ethoxypyrazin-2-yl)-2-fluorophenyl)butanamide; 2-(6-(cyclopropanesulfonamido)pyridin-2-yl)-N-(4-(6ethoxypyrazin-2-yl)phenyl)butanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(pyridin3-yl)phenyl)acetamide; 2-(6-(ethylsulfonamido)pyrazin-2-yl)-N-(4-(pyridin-3yl)phenyl)acetamide; 2-(6-(methylsulfonamido)pyrazin-2-ii)-N-(4-(pyridin-3ii)phenyl)acetamide; IF-2019-16749728-APN-AÍ5Fl#INPI Page 51 of 363 2(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(fist oxypyra zin-2-yl)pyridin-2-yl)-2-methylpropanamide; 2-(6-(cyclopropanesulfonamide)pyrazin-2-yl)-N-(4-(6ethoxypyrazin-2-yl)phenyl)-2-methylpropanamide; 4-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)tetrahydro-2H-pyran-4carboxamide. 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxy-2-methylbutanamide; N-(5-(6-ethoxypyrazin-2-yl)pyridin-2-yl)-4-methoxy-2-methyl-2(6-(methylsulfonamido)pyrazin-2-yl)butanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)-2-fluorobutanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)butanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6ethoxypyrazin-2-yl)phenyl)butanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)-2-methoxyacetamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-(6ethoxypyrazin-2-yl)phenyl)-2-methoxyacetamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6ethoxypyrazin-2“yl)pyridin-2-yl)-2-methoxyacetamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)-2-(R)-fluorobutanamide; 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)-2-(5)-fluorobutanamide; 2-(4-(cyclopropanesulfonamido)pyrimidin-2-yl)-N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)butanamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4yl)cyclopropyl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-5(6-ethoxypyrazin-2-yl)picolinamide; IF-2019-16749728-APN-Afi^INPI Page 52 of 363 N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-2fluoro-4-(5-(trifluoromethyl)pyridin-3-yl)benzamide; 4” (5-chloropyridin-3-yl) -N~ (1- (2(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-2fluorobenzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4(5-(trifluoromethyl)pyridin-3-yl)benzamide; - (5-chloropyridin-3-yl)-N-(1-(2(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)benzamide; N-(1~(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4(6-ethoxypyrazin-2-yl)-2-(trifluoromethyl)benzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4~yl)propyl)-4(6-ethoxypyrazin-2-yl)-2-fluorobenzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4(6-(trifluoromethyl)pyrazin-2-yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4(6-isopropoxypyrazin-2-yl)benzamide; N-(1-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)propyl)-4(6-ethoxypyrazin-2-yl)benzamide; N-(2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butan-2yl)-4-(6-ethoxypyrazin-2-yl)-2-fluorobenzamide; N-(2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)propan-2-ii)2-fluoro-4-(6-isopropoxypyrazin-2-yl)benzamide; N-(2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)propan-2-yl)4-(6-(trifluoromethyl)pyrazin-2-yl)benzamide; N-(1-(6-(cyclopropanesulfonamido)pyrazin—2—i1)propyl)-4-(6ethoxypyrazin-2-yl)-2-fluorobenzamide; N-(1-(6-(cyclopropanesulfonamido)pyrazin-2-yl)propyl)-4-(6ethoxypyrazin-2-yl)-2-(R)-fluorobenzamide; and N-(1-(6-(cyclopropanesulfonamido)pyrazin-2-yl)propyl)-4-(6ethoxypyrazin-2-yl)-2-(S)-fluorobenzamide. The compounds of the invention may be provided in the form of a pharmaceutically acceptable salt and / or solvate thereof and / or derivative thereof. In particular, the compound of IF-2019-16749728-APN-Afi^INPI Page 53 of 363 Formula (I) may be provided in the form of a pharmaceutically acceptable salt and / or soivate, such as a pharmaceutically acceptable salt. The compounds of the invention of particular interest are those that have an IC>;,o of 1 uM or less, especially 100 nM or less, with respect to the CTPS1 enzyme, using the methods of the examples (or similar methods). Compounds of the invention of particular interest are those that exhibit a selectivity for CTPS1 over CTPS2 that is 2-30 times greater, conveniently >30-60 times greater, or more conveniently >60 times greater, using the methods of the examples ( or similar methods). Desirably, the selectivity is for human CTPS1 versus human CTPS2. It will be appreciated that for use in medicine, the salts of the compounds of formula (I) must be pharmaceutically acceptable. Non-pharmaceutically acceptable salts of the compounds of formula (I) may be useful in other contexts such as during the preparation of the compounds of formula (I). Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge et al. (1977). Such pharmaceutically acceptable salts include acid and base addition salts. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids, e.g. e.g. , hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid, and organic acids, e.g. e.g., succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other salts can be used, e.g. e.g. , oxalates or formates, for example, in the insulation IF-2019-16749728-APN-A^INPI Page 54 of 363 i of compounds of formula (I) and are included within the scope of this invention. Some of the compounds of formula (I) may form acid or base addition salts with one or more equivalents of the acid or base. The present invention includes within its scope all possible stoichiometric and non-stoichiometric shapes. The compounds of formula (I) may be prepared in crystalline or non-crystalline form and, if crystalline, may be optionally solvated, e.g. e.g. , like the hydrate. The invention includes within its scope stoichiometric solvates (e.g., hydrates) as well as compounds containing variable amounts of solvent (e.g., water). It will be understood that the invention includes pharmaceutically acceptable derivatives of compounds of formula (I) and that these are included within the scope of the invention. As used herein, pharmaceutically acceptable derivative includes any pharmaceutically acceptable prodrug such as an ester or salt of such ester of a compound of formula (I) that, when administered to the recipient, is capable of providing (directly or indirectly ) a compound of formula (I) or a metabolite or active residue thereof. It is to be understood that the present invention encompasses all isomers of formula (I) and their pharmaceutically acceptable derivatives, including all geometric, tautomeric and optical forms, and mixtures thereof (e.g., racemic mixtures). Where additional quinal centers are present in compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms can be separated or IF-2019-16749728-APN-A®^INPI Page 55 of 363 redissolve from each other by conventional methods, or any given isomer can be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. The present disclosure includes all isotopic forms of the compounds of the invention provided herein, either in a form (i) in which all atoms of a given atomic number have a mass number (or mixture of mass numbers) that predominates in nature (herein referred to as the natural isotopic form) or (ii) in which one or more atoms are replaced by atoms that have the same atomic number, but a mass number different from the mass number of atoms that predominates in nature (herein referred to as a non-natural variant isotopic form). It is understood that an atom can exist naturally as a mixture of mass numbers. The term non-natural variant isotopic form also includes embodiments in which the proportion of an atom of a given atomic number that has a mass number less common in nature (referred to herein as a rare isotope) has been increased relative to the found in nature, e.g. e.g., up to the level of >203, >501, >751, >901, >951 or >991 in the number of atoms of that atomic number (this latter embodiment referred to as an isotopically enriched variant form). The term non-natural variant isotope form also includes embodiments in which the proportion of a rare isotope has been reduced from that found in nature. The 30 isotopic forms may include radioactive forms (i.e., they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will normally be isotopically enriched variant forms. IF-2019-16749728-APN-AS^INPI Page 56 of 363 A non-natural variant isotopic form of a compound may therefore contain one or more artificial or rare isotopes such as deuterium (2H or D), carbon-11 (lIC), carbon-13 (13C), carbon-14 ( 14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (±5O), oxygen-17 (170), oxygen-18 (υιΟ), phosphorus-32 ('2Ρ), sulfur-35 (^'S), chlorine-36 ChCl), chlorine-37 (37C1), fluorine-18 Í^'F) iodine-123 (123I), iodine-125 (12jI) on one or more atoms, or may contain a higher proportion of said isotopes compared to the proportion that predominates in nature in one or more atoms. Unnatural variant isotopic forms comprising radioisotopes can be used, for example, for studies of the distribution of drugs and / or substrates in tissues. The radioactive isotopes tritium, i.e.,3H, and carbon-14, i.e.,1^C, are particularly useful for this purpose in view of their ease of incorporation and means of immediate detection. Unnatural variant isotopic forms incorporating deuterium, i.e., 2H or D, may offer certain therapeutic advantages as a result of their increased metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. , and, therefore, may be preferred in some circumstances. Additionally, unnatural variant isotopic forms incorporating positron-emitting isotopes, such as 1'c,niF,1,:,0 and i3N, can be prepared and would be useful in positron emission tomography (PET) studies to examine the occupancy of substrate receptors. In one embodiment, the compounds of the invention are provided in a natural isotopic form. In one embodiment, the compounds of the invention are provided in a non-natural variant isotopic form. In a specific embodiment, the variant isotopic form IF-2019- 16749728-APN-AI^#INPI Page 57 of 363) non-natural is a form in which deuterium (i.e., 2H or D) is incorporated where hydrogen is specified in the chemical structure on one or more atoms of a compound of the invention. In one embodiment, the atoms of the compounds of the invention are in an isotopic form that is not radioactive. In one embodiment, one or more atoms of the compounds of the invention are in an isotopic form that is radioactive. Conveniently, radioactive isotopes are stable isotopes. Conveniently, the non-natural variant isotopic form is a pharmaceutically acceptable form. In one embodiment, a compound of the invention is provided such that a single atom of the compound exists in a non-natural variant isotopic form. In another embodiment, a compound of the invention is provided such that two or more atoms exist in a non-natural variant isotopic form. Non-natural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein, e.g. e.g., processes analogous to those described in the attached Examples for the preparation of natural isotopic forms. Therefore, unnatural isotopic variant forms could be prepared using appropriate isotopically variant (or labeled) reagents instead of the normal reagents used in the Examples. Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will be readily understood that each is preferably provided in substantially pure form, for example, at least a pure 601, more conveniently at least a pure 751 and preferably at least 851, especially at least 98% pure (% are expressed in terms of weight for weight). Impure preparations can be used IF-2019-16749728-APN-ASWiNPI Page 58 of 363 the compounds to prepare the purest forms used in pharmaceutical compositions. In general, the compounds of formula (I) can be prepared according to the organic synthesis techniques known to those skilled in the art, as well as by the representative methods set forth below, those of the Examples and modifications thereof. General routes: Generic routes by which examples of compounds of the invention can be conveniently prepared are summarized below. Outline the Scheme Ib IF-2019- 16749728-APN-A^#INPI Page 59 of 363 Ease I rent Ύ' Akjü Ar-.. Ar Rj = H U OMe Alkyl => Alkyl r3-' and r£(VIII) r3(VIII I rent Rs (V| Coupling conditions χ O (VI) «,· ΓΗ 1. “M5OK and / or Μ eO, 2. Activating agent, N If I rent ® ll J.j 1. H.T. Alkyl' (H where R5is H A';..,, .NHí Af 4 mu 1111 1. Activating agent A»;, ,NH¡> (tut In general and as illustrated in the is H or Et) where Rj, R3 / Arl and Ar2 above or Scheme Ib (where MeC, .O l .Rj H Q _O, >1, TI, t íl K |f / r, S' k M íl ’ R-,' (IV) If Alquíh = Me CIO,. U.C. Λ _.N (XXVI) Scheme (where R4 are as defined Rzi is H or OMe) where Ri, R¿, R3, Arl and Ar2 are as defined above, the compounds of formula (I) can be prepared in four or five steps starting from a 2,4~ dichloropyrimidine derivative of general formula (VIII). Derivative (VIII) can be reacted with an asymmetric ester malonate derivative to displace the more reactive chloride and form intermediate compounds of formula (VII). Such reactions can be carried out in the presence of a strong base such as sodium hydride and in a polar solvent such as DMF. If monoalkylation is desired then treatment of intermediate (VII) with an inorganic base, such as sodium hydroxide, in the presence of an alkylating agent, such as iodoethane (EtI), provides compounds of the general formula (V). If you want a IF-2019-16749728-APN-AÍ?W[NPI Page 60 of 363!desmethyl linker (R4= H), compounds of general formula (VII) can be converted directly to compounds of general formula (IV) (see below). Palladium-catalyzed suitamination of the chloropyrimidine derivative (VII) and (V) can be carried out using a catalyst such as [ t-BuXPhos Pd (alii)]OTf and substituted sulfonamide nucleophile (VI), in the presence of a inorganic base, for example, potassium carbonate, to form the intermediate derivative (IV). This compound can then be deprotected through decarboxylation, initiated by the use of a strong acid such as TEA to provide the intermediate derivative (II). Such reactions are carried out in DCM at temperatures from 0 °C to room temperature. Compounds of general formula (I) can be prepared by conversion of intermediate (II) by a one- or two-step process. First, saponification using an agent such as TMSOK provides the intermediate carboxylic acid derivative followed by reaction with an activating agent, to generate an electrophilic, reactive carboxylic acid derivative followed by subsequent reaction with an amine of formula ( III), or a conveniently protected derivative thereof. 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinan 2,4,6-trioxide (T3P) is a suitable reagent for activation of the carboxylate group. An alternative strategy involves activation of the ester moiety directly using trimethylaiuminium (usually a 2.0 M solution in toluene or heptane) and the addition of amine (III). These reactions are typically heated to 80-100°C for a few hours in a solvent such as toluene. If an alkoxy type linker is needed (R4= OMe), the compounds can be prepared in four steps starting from a 2,4-dichloropyrimidine derivative of general formula IF-2019-16749728-APN-Afií#INPI Page 61 of 363 (VIII) (Scheme lb) . The derivative (VIII) can be reacted with a symmetric malonate ester to form intermediate compounds of formula (VII) where = OMe. Compounds such as (VII) can then be coupled with a primary sulfonamide under the conditions described previously. Next, compounds of formula (IV) where both alkyl groups are methyl can be deprotected through decarboxylation, initiated by the use of an alkali metal base to provide the intermediate derivative (XXVI). The intermediate carboxylate derivative (XXVI) can be subjected to amide coupling as previously described to obtain the final compounds of formula (I). Scheme 2a IVIIIJ 1. Base 2. Alkye halide Yo. Active agent or μ --—zΪ Y 1 o JR. r Ar,.. hlH,Ri (Illi 411) Scheme 2b ill Conditions of 1. coupling n = ;,2.3 T R;,Ri ,N IX) IF-2019-16749728-APN-Afi^INPI Page 62 of 363 R?<i) 1. κκ2* activating agent (il!j ¢11) “ Conditions of 1- coupling ¿fb (VI) I'l (viii) (XXVII) Conveniently, R2 is H, (IX) using a base and where n becomes (X) alkyl halide or X-CH2- (CH2) n-X 1,2,3, and the compounds of general formula (I) are obtained by a five-step process. In general and as illustrated in Schemes 2a and 2b, compounds of general formula (I) can be obtained by a five or six step process from a 2,4-dichloropyrimidine derivative of general formula (VIII). First, the derivative (VIII) can be reacted with an asymmetric malonate aster as shown in Schemes la, Ib, 2a or 2b. This intermediate compound can then be deprotected at this time through a decarboxylation, initiated by the use of a strong acid such as TEA to provide the intermediate derivative (IX). Certain intermediates are commercially available such as (IX) where R3= H. The reaction of a 2-(2chloropyr irnidin-4-yl) methyl acetate derivative of general formula (IX) with an inorganic base, such as carbonate IF-2019-16749728-ΑΡΝ-Αί?β#ΙΝΡΙ Page 63 of 363 potassium, in the presence of an alkylating agent leads to alpha alkylation with respect to the ester. Those skilled in the art will understand that both mono- and dialkylation can be achieved with careful control of the reaction conditions, but for a more reliable synthesis of the monoalkylated product, an alternative procedure (as in Scheme la) should be considered. R4 and R^, can be connected to form a C.-q-r cycloalkyl ring as defined above ((IX) to (X)). Such compounds can be prepared by double alkylation with a dihaloalkane, such as 1,2-dibromoethane or 1,3-dibromobutane, in the presence of an inorganic base such as sodium hydroxide. Palladium-catalyzed sulfamination of intermediate (X) can be achieved using a catalyst such as [tBuXPhosPd(allyl)]OTf or t~BuXPhos-Pd-G3 and the substituted sulfonamide nucleophile (VI), in the presence of an inorganic base, by example, potassium carbonate, to form the intermediate derivative (II). The final transformation to compounds of general formula (I) can be prepared by conversion of the intermediate (II) by activation of the ester moiety using trimethylaluminum (usually a 2.0 M solution in toluene or heptane) and the addition of the amine (III) ( marketed or prepared as in Schemes 6a, 6b, 7a or 7b). Compounds of general formula (VII) where R2 is 0alkyl can be obtained in two steps from commercial 2,4,6-trichloropyrimidine derivatives such as (VIII) where R2 is C1. The reaction of an asymmetric malonate ester can provide compounds such as (VII) that can be treated with an alkoxide type base such as sodium methoxide in order to displace the more reactive chloride to obtain compounds of general formula (VII) where R2= O-alkyl. Such compounds can IF-2019-16749728-APN-AJ^INPI Page 64 of 363 become final compounds of formula (I) following the steps previously described in Schemes 2a or 2b. Compounds of general formula (I), where Rt, Arl and Ar2 are defined above and and R3 together with the carbon to which they are bonded form a C3-(j) heterocycloalkyl, can be prepared in four steps starting from the intermediate of general formula (VIII) First, alkyl esters of general formula (XXVII) can be treated with a strong base such as LHMDS, followed by reaction with 2,4-dichloropyrimidines such as the derivative (VIII). Such compounds can then be converted to final compounds using the methods. in Scheme 2b. If any of the protecting groups are still present after amide coupling, treatment with a strong acid such as TEA can provide final compounds of formula (I). For compounds where RI} is halo, such as F, and R^ is Ci-6Z alkyl, a two-step procedure can be carried out to convert the intermediates of formula (IX) to (X), see Scheme 2b. First, alpha monoagulation with respect to the ester can be achieved by treatment with an inorganic base such as potassium carbonate, in the presence of an alkylating agent. Reaction of these products with a strong base such as LHMDS followed by exposure to a fluorinating agent such as N-fluoro-N-(phenylsulfonyl)benzenesulfonamide can produce compounds of formula (X). Scheme 3 IF-2019-16749728-APN-AtfiSSHNPI Page 65 of 363 ,MH. Ah, 1. Protection of amine ,NH 1. Activating agent 0^0 (IHi Or JL A Her (XIV) II 1. Base '[[ (XV) or P o „ „ 1, Base, *.. p R5Rj ________ Arix. .r-L,,CI Λίί.,.Ν. X ,Ν. XI z HalurodeMr’ Y ¡I 'Γ Λίι γΐ alkylO or J-L xjj1,3’ (XIX) Ri (XVIII) (xvi) 1. Coupling conditions Au. (VI) oÍJ 1. Coupling conditions (XVII) In general and as illustrated in Scheme 3, compounds of general formula (I) where R3 is H can be obtained by a seven-step process when R4 and / or R3 = alkyl (or five-step process when R4 = Re = H) from the anilines of formula (III) defined in the Scheme 4 and 5. First, aniline (III) can be protected with a suitable nitrogen protecting group such as a para-methoxybenzyl ether group by the reaction of aniline (III) with 4-methoxybenzaldehyde followed by reduction in situ with reducing agents such as sodium tlacetoxyborohydride. The protected aniline of formula (XIII) can then be reacted with 3-(tert-butoxy)“3-oxopropanoic acid (XIV) in the presence of a coupling agent such as HATU to obtain intermediates (XV). Such intermediates (XV) can undergo Sb¡Ar with 2, 4-dichloropyrimidine (VIII) (R, = H) in the presence of a strong base such as NaH to obtain IF-2019-16749728-APN-A^INPI Page 66 of 363 i pyrimidines of formula (XVI). The intermediates (XVI) can then undergo two transformations. First, decarboxylation with a strong acid such as TEA to obtain intermediates of formula (XVIII) followed by alkylation in the presence of a base such as K2CO3 results in the formation of compounds of formula (XIX). Palladium-catalyzed sulfonamideation of intermediate (XIX) can be achieved using a catalyst system such as Pd-174 in the presence of a sulfonamide of type (VI) to obtain compounds of formula (XX) - Compounds of formula (I) can be obtained by deprotecting the aniline nitrogen using a strong acid system such as TEA / triflic acid. Alternatively, compounds of formula (XVI) can undergo sulfonamideation using a type (VI) sulfonamide followed by double deprotection using a strong acid system such as TFA / triflic acid to provide compounds of formula 20 Scheme 4a 0 0 Y ipAll, H .0.. Aun ,ci A. αιολ Ί1' 1| Ί -O ' ]f 1| Ύ λ ° Catalyst $ A·--·N 0 ° (x) Base (II) RI( = alkyl Cf.f u F, Re P r ... f p Αη.,Κχ .N rpP rXn rp^R-j ap K , .Ri Reactrzode A á A O k-. N 0 coupling J <XXIV} 7 Ar2.AfNH2 (xxhd I {III) H 'A II 0 Αγ?..λ N X N „N f ΛΓ Y JA o 0 ( i) Scheme 4b (I) . I 0 ^0 PMB-Ci Y ------·“ A A. Ai ϊ X A (XXI) Q 0 0 O AsH <v.· LHMD5 phA-.rrS-.ph 1 t F 1 0·. A Íia:;<J J<F ΙΑ -<> Ai iV >r q- 'su 1 tAb (XXII) IF-2019- 16749728-APN-A^?#INPI Page 67 of 363 PMtJCI .H ¡XXIVI H Ftb Ar,.... ,HtX. "either. I rent 'jj' Or, :n 0‘ 'Ri I rent .0 R* I rent 'AlquiloC,.. if alkyl = IBu f-í(XXVIII) if alkyl - Me 1.LiCI P.L. H n n,(.j PMI5 a .Ι< „R¡ '0 t d' ,N Η, H,, · rent,..- or ' CH?CtlsOMií 'R;' txo LF Ό. „-0 1. Base Coupling reagent Ar?^k.NH, illl) r,. .NH, ~ 'Art“ OH) yes RjesH 1.salt formation 1. itosc if Rj = F 1. LHMDS 0 or °0 ΡΙν^'Ι'Γ^Ρΐι 1, Base R=· p db ¡XXIII) ¡XXII) Rj'y i Conveniently H, R3is H, R4es F and R3 are alkyl In general and as illustrated in the Scheme 4a, the compounds of general formula (I), where Ri, Arl and Ar2 are defined above, P is a nitrogen protecting group such as PMB, R4 is halo such as F and R>;, Ci-β alkyl can be prepared from the methyl ester (II) which can be subjected to protection, such as as PMB-C1, to provide intermediate (XXI) which can then be subjected to fluorination using a fluorinating agent such as N-fluoro-N-(phenylsulfonyl)benzenesulfonamide after being treated with an appropriate base such as LHMDS. Intermediate (XXII) can undergo salt formation using an inorganic base such as LiOH to provide intermediate (XXIII) which can be activated with a coupling agent such as T3P in the presence of a base and coupled with an aniline such as IF-2019-16749728-ΑΡΝ-Αβ^ΙΝΡΙ Page 68 of 363 i (III) to obtain the final protected compound (XXIV). Next is the final deprotection step under strongly acidic conditions such as TFA in DCM to obtain the desired final compounds of general formula (I). As shown in Scheme 4b, intermediates of formula (XXI) can also be prepared starting from pyrimidine (IV) which can be subjected to protection such as with PMB-C1 to obtain intermediate (XXVIII). Decarboxylation when the alkyl ester is tBu can be carried out with a strong acid such as TFA to provide derivatives of formula (XXI). Alternatively, if the alkyl group is methyl, decarboxylation can be carried out under Krapcho conditions using a chloride ion source such as LiCl, in a polar aprotic solvent such as DMSO at elevated temperatures such as 140 IJC to provide derivatives of general formula (XXI). For compounds where Ci-p is alkyl, but where R4A R5, derivatives of general formula (XXI) can be reacted with an inorganic base, such as potassium carbonate, in the presence of an alkylating agent to obtain compounds of formula ( XXII). Such compounds can be converted into final compounds using methods previously described in Scheme 4a. For compounds where R4=H is desired, compounds of formula (XXI) can be converted directly to carboxylate salts such as (XXIII) by treatment with a suitable agent, such as TMSOK, as previously described. Intermediates (XXIII) can be converted to compounds of formula (I) as described above, or in two steps by direct coupling of (XXII) with amines of formula (III) in the presence of an activating agent such as AlMe3 , followed by the IF-2019-16749728-APN-A^INPI Page 69 of 363 conversion of (XXIV) into compounds of formula (I) as described above. Scheme 5a Scheme 5b Yr. , .0. Jf ;N ,NI1;«iQUíta· γ γ n l··.. X y * A.|qui!o ’Alquiiocv- (χχιχ) 1. Bne-is 2, pz or Bí 8í (XXV) t CL tv (XXX) or > when Fg and R? ’ 11 „0. I rent ......Rent'' u yes ~ F 1. RX Catalyst ¡?po;íN¡i| θ ,(Ίa^°' y r y / x V % Αν.χ· Rf'^'NH,<lh' 2. ñ<ue Agent (Inorant (VI} e,. MH A(j(lili r 2, E 'ff. / l3CiK and / or Acting agent U) (IX) Conveniently, X is N, Y is CH, R? is H, convert to (X) using a base and compounds of formula (XXV) where ni=n2~2, hal is Cl, alkyl is methyl, Rd and Rb together with the carbon atom to which they are bonded form a tetrahydropyranyl ring, and the IF-2019-16749728-APN-YEAR^INPI Page 70 of 363 compounds of formula (II) are converted to compounds of formula (I) using AlMe3 and compounds of formula (III). Compounds of general formula (I), where Rj, Arl and Ar2 are defined above and R,j and R3 together with the carbon to which they are bonded form a C3-c heterocycloalkyl, can be prepared in three steps starting from the intermediate of general formula (IX), see Scheme 5a. First, the derivative (IX) can be reacted with a symmetric dibromoether of general formula (XXV) as shown in Scheme 5a to obtain an alphacyclic compound of formula (X). The intermediate obtained in this way can be further reacted with sulfonamides of general formula (VI) to obtain compounds of formula (II). Finally, subjecting the derivatives (II) to AlMe3 in the presence of anilines of type (III) provided compounds of general formula (I). Compounds of general formula (I), where Ri, R3, Arl and Ar2 are defined above, H or Ci^c alkyl, can be prepared in three or four steps starting from the intermediate of general formula (IX). The reaction of a derivative of general formula (IX) with an inorganic base, such as potassium carbonate, in the presence of an alkylating agent leads to alpha-alkylation with respect to the ester to provide compounds of formula (X). Those skilled in the art will understand that both mono- and dialkylation can be achieved with careful control of the reaction conditions. The compounds of formula (X) can then be converted to final compounds of formula (I) by following the steps described above in Scheme 5b. Compounds of general formula (I), where , R3, Arl and Ar2 are defined above, X=Y=CHoX=CHeY=Ny R^ and R5 together with the carbon atom to which they are IF-2019-16749728-APN-AM^INPI Page 71 of 363 linked to form a heterocycloalkyl can be prepared in the same way as described above for compounds when X = N and Y = CH. Compounds of general formula (II) when Ri and R3 are as described above, = R5 = H and X and Y = CH, can also be obtained by sulfonylation of commercial amines of formula (XXIX) with a sulfonyl chloride (XXX ) suitable in pyridine. Intermediate (II) can then undergo hydrolysis and amide coupling using previously described methods. Compounds of general formula (I), where Ri, R3, Arl and Ar2 are defined above, of the intermediate of general formula (IX). First, alpha monoalkylation with respect to the ester can be achieved by treatment with an inorganic base such as potassium carbonate, in the presence of an alkylating agent. Reaction of these products with a strong base such as LHMDS followed by exposure to a fluorinating agent such as 17-fluoro-N(phenylsulfonyl)benzenesulfonamide can produce compound of formula (X). Compounds of formula (X) can then be converted to compounds of formula (I) by following the steps described in Scheme 5b. Scheme 6a R12 (XII) Z = B(OH)2, B(pin>2 X = Br, Cl IF-2019-16749728-APN-AJ^INPI Page 72 of 363 Scheme 6b Z = B(OH)2, B(pin)2X = Br, C! Intermediates of formula (III) where Arl, R10, Rii and Ri2 are defined above and Ar2 is a substituted or unsubstituted 3-pyridyl ring, can be synthesized by coupling under Suzuki conditions of a boronate of general formula (XII ), where R-12 is as defined above and Z represents a dihydroxyboryl or dialkyloxyboryl group, usually a 4,4,5,5tetramethyl-1,3,3,2-dioxaborolan-2-yl group, with a substituted pyridine of formula (XI) where X denotes a halide. Couplings according to the Suzuki method are carried out, for example, by heating in the presence of a catalyst such as a complex of [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium (II) with dichloromethane and a base inorganic such as potassium carbonate in a mixture of the solvents dioxane and water. Scheme 7a (xii) Z = Br, Cl X = B(OH)2, B(pin)2 (xi) (neither) IF-2019-16749728-APN-AÍ^INPI Page 73 of 363 Scheme 7b Z = Br, Cl Conveniently, R13is H. Intermediates of formula (III) where Arl, Rio, Rn and Ri>> are defined above and Ar2 is a substituted or unsubstituted 2,5-pyrazinyl ring, can be synthesized by coupling under Suzuki conditions of an aromatic halide of general formula (XII) and Z represents a halide, with a boronate of general formula (XI) where 2dioxaborolan-2-yl. Couplings according to the Suzuki method are carried out, for example, by heating in the presence of a catalyst such as 15 tetrakis(triphenylphosphine)palladium or [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium (II) and an inorganic base such as potassium carbonate in a mixture of the solvents dioxane and water. IF-2019-16749728-APN-A^INPI Page 74 of 363 Scheme 8 i XXXI) I.Activating agent, NH2ΜΓ|(III) In general and as illustrated in Scheme 8, the compounds of formula (I), where R], R3, Arl and Ar2 are defined above, where X = N and Y = CH, where R4= H, alkyl Cj- í-, or CH2CH2OMe and where Rfl= H, can be prepared in four or five steps starting from an intermediate of general formula (VII). Alkylation can be achieved by treatment of intermediate (VII) with an inorganic base, such as sodium hydroxide, in the presence of an alkylating agent, such as iodoethane, to provide compounds of the general formula (V). Decarboxylation can then be initiated with a strong acid such as TFA to obtain intermediates of formula (X). Such intermediates can then be subjected to saponification and amide coupling according to methods described in Scheme 1 to obtain compounds of formula (XXXI). The final compounds of formula (I) can be obtained by coupling intermediates of formula IF-2019-16749728-APN-AMS^INPI Page 75 of 363 (') (XXXI) with a primary sulfonamide as previously described in Scheme 1. In general and as illustrated in Scheme 8, the compounds of formula (I), where Ri, R3, Arl and Ar2 are defined above, where X = CH and Y = N, where R<: = H or CH2CH20Me and where = H or Me, can be prepared starting from an intermediate of general formula (VIII) following methods similar to those described for when X = N and Y = CH in Scheme 8. If a connector is needed, where R5 = 10 Me, the alkylating intermediates of formula (X) can be treated with an alkylating agent in the presence of a base to generate intermediates such as (Xa). Compounds of formula (Xa) can then be converted to final compounds through a three-step procedure such as that described in Scheme 8. Compounds of general formula (XXXI) when R4 = R3 = H and X = CH and Y = N can also be obtained by coupling commercial acids of formula (XXXII) with anilines of formula (III) under amide coupling conditions previously described. Compounds of this type can then be converted into compounds of formula (I) using the sulfamidation conditions described previously. Scheme 9 R F F F C1e ε NX^S^' 1, I!»-,!» HO.. V N-, JP lí Y 1 Π T ilxy s,^ (ΧΧΧΙΠ) (XXXÍV) O - 4XXXVI Ar£.^.NH2i. Activating agent {111} (EITHER IF-2019-16749728-APN-AÍ^INPI Page 76 of 363 In general and as illustrated in Scheme 9, compounds of general formula (I) where Ri, Arl and Ar2 are defined above can be prepared in 3 steps from the literature compound 2,2-difluoro-2- Ethyl (2(methylthio)pyrimidin-4-yl)acetate (XXXIII). Thioethers of the general formula (XXXIII) can be transformed into sulfones (XXXIV) in the presence of an oxidizing agent such as Oxone® at room temperature in a polar protic solvent such as MeOH. Displacement of the sulfone group with a primary sulfonamide (VI) and subsequent hydrolysis of the ester to obtain acids of the general formula (XXXV) can be carried out in a one-pot process in the presence of a strong base such as NaH and in a polar aprotic solvent such as DMF. The acid derivative (XXXV) can then be activated with a coupling agent such as HATU in the presence of a base and coupled with an aniline such as (III) to obtain the final compounds of formula (I). Scheme 10 R4- OMe (VIII) In general and as illustrated in Scheme 10, compounds of general formula (X) where RirR3, Arl and Ar2 are defined above and where R4- OMe can be prepared in four, five or six steps starting from a derivative of 2 ,4-dichloropyrazine of general formula (VIII). The derivative (VIII) can be reacted with a symmetrical malonate ester when R4=OMe in the presence of a strong base such as sodium hydride in a polar solvent such as DMF to form intermediate compounds of formula (V). Then a two-step procedure can be carried out to obtain compounds of structure IF-2019- 16749728-APN-A^?#INPI Page 77 of 363 general (X). Firstly, saponification using an alkali metal hydroxide such as NaOH can generate biscarboxylic acid which once acidified can undergo spontaneous decarboxylation. The resulting 5-carboxylic acid can then be converted to esters of general formula (X) by treatment with an activating agent such as thionyl chloride in the presence of an alcoholic solvent such as methanol. Derivatives of formula (X) can be converted to final compounds of formula (I) using methods previously described in the Scheme 5. Scheme 11 H 0 T 0 Clx^N^^CI 1. Base 1 PMB-CI Cl N H2N Fq N-3, j ORlORl Á'V) (VI) (VIII) orυ(XXXVI) (XXXVII) Me / Et Me / Et Me / Et (XXVIII) (XXXVIII) In general and as illustrated in Scheme 11, compounds of formula (XXVIII), where R| defined above and where R4= H or Et, can be prepared in seven steps starting from a 2,4dichloropyrimidine derivative of general formula (VIII). The derivative (VIII) can be reacted with a sulfonamide of 0 type (VI) in the presence of an inorganic base such as potassium carbonate to displace the more reactive chloride and form intermediate compounds of formula (XXXVI). Compounds of formula (XXXVI) can be protected, e.g. e.g., using PMB-CI to obtain compounds of formula 5 (XXXVII) . IF-2019-16749728-APN-AÍWdNPI Page 78 of 363 This compound can then be converted to compounds of general formula (XXXVIII) by treatment with an asymmetric malonate in the presence of a base such as cesium carbonate in a solvent such as dimethoxyethane. If monoalkylation is desired then treatment of the intermediate (XXXVIII) with an inorganic base, such as potassium carbonate, in the presence of an alkylating agent, such as EtI, provides compounds of the general formula (XXVIII). This compound can then be converted to final compounds of formula (I) using methods previously described in Scheme 4. Where R4= H, compounds of general formula (XXXVIII) can be directly transformed into compounds of general formula (I) (as described above). Benzamide pyrimidines Scheme 12 XXXIX] Coupling conditions |XXXX) (XXXXl) íÍ'q <vi] 1, Activating agent ’ H,A EITHER Al· fXXXXIH) H* (XXXX1I] Compounds of general formula (I) can be obtained by a four-step process, as shown in Scheme 12. 2-Chloropyrimidin-4-carbonitrile (XXXIX) can be converted to the corresponding sulfonamide (XXXX) using the conditions of palladium-catalyzed sulfamination processes previously reported in Scheme 1. Reduction of the nitrile group using sodium borohydride in the presence of nickel(II) chloride and ditert-butyl dicarbonate can provide the protected benzylamine derivative of general formula (XXXXI). Deprotection can be carried out by acid hydrolysis IF-2019-16749728-APN-A^INPI Page 79 of 363 using HC1 in dioxane to benzylamine of general formula provide the derivative of (XXXXII). Amide coupling conditions can subsequently be employed to convert the benzylamine derivative (XXXXII) to amides of general formula (I) using a coupling reagent together with a biarylcarboxylic acid (XXXXIII) (commercially or prepared as in Scheme Scheme 13 .0 (ÍXI = N, Y = CR.j = CRi, Y = N Btu s·-. Έιo N.. .ClA>qUÍkX RsR_| No. XI1'υ0Η, R5Rj X. .N base (X) (XXXII) 1. Coupling conditions 1.DPPA ERN tBuOH O' “N H FL (Vil 'cr* N hi χι (XXXXI) (XXXXI V) Compounds of general formula (I), where Rj, Ari and Ar? are defined above, the carbon atom to which they are bonded form a C3^c skyalkyl, can be obtained by a six-step process, as shown in Scheme 13 (and Scheme 12 for certain steps). First, the derivative (IX) can be reacted with an alkyl halide to obtain compounds of general formula (X) where R4= alkyl and R>?= H. Alternatively, the derivative (IX) can be reacted with an alkyl bis-halide to obtain compounds of general formula (X) where R4 and R.a can be connected to form a C heterocycloalkyl ring as defined above. He IF-2019-16749728-APN-Afl^INPI Page 80 of 363 Carboxylic acid (XXXII) can be obtained by hydrolysis of methyl ester (X) using an alkali metal base, such as lithium hydroxide, in a solvent mixture such as THF / MeOH. A Curtius rearrangement can be carried out, for example, using diphenylphosphorylazide in the presence of triethylamine and tert-butanol to provide carbamates such as (XXXXIV). The corresponding sulfonamide (XXXXI) can then be obtained by a palladium-catalyzed sulfamination using conditions previously reported in Scheme 1. The carbamates of formula (XXXXI) can subsequently be converted to final compounds of formula (I) following the Scheme 12. Compounds of general formula (I) where Ri, ArT and Ar2 are defined above CH and Y N, R4es C]-f alkyl, es H can be obtained by a four-step process starting from a marketed acid of formula (XXXII) following the subsequent steps described in Scheme 13. Scheme 14 1. TMPMrjCILiCI VIA B ΠΙΡ (XXXXV} (XXXXVIJ □ .Br R / (XXXXVtl) VIA A 1. NH¿OCOCF, NaBHj H1 H.N. RAÍ EITHER N NHBH., Br ÍM X = Cl c Br R; (XXXXVIII) Activating agent or Aru A ' 'Ar. OH (XXXXlilJ IF-2019- 16749728-APN-Aftí#INPI Page 81 of 363 The pyrimidin-4--i 1 (propan-2-yl) benzamide derivatives of formula (I)fen in which Ri, R^, Arl and Ar2 are defined above fR4= alkyl and Rh= Hrse can be prepared by two different routes as as shown in Scheme 14, The two pathways both begin by converting 2-bromopyrimidine to the corresponding ketone (XXXXVI) by treatment with a suitable base such as TMPMgCl LiCl, followed by exposure to the Weinreb amide derivative. The two pathways then converge to compounds of general formula (L) where they are then converted to the final analogues through a two-step process. PATHWAY A: Treatment of ketone derivatives (XXXXVI) with ammonium trifluoroacetate, followed by reduction using sodium borohydride can provide the benzylamine (L). PATH B: The. Ketone of the general formula (XXXXVI) is converted to sulfinamide (XXXXVII) by treatment with a Lewis acid, such as titanium isopropoxide, followed by exposure to a sulfinamine such as 2-methylpropane2-sulfinamide. Reduction using sodium borohydride can provide sulfinamide (XXXXVIII). The intermediate of formula (XXXXVIII) can then be deprotected using a strong acid, such as HC1, which can also lead to halogen exchange to obtain amines of general formula (L) where X = C1. Amide coupling conditions reported in Scheme 12 can then be used to convert the benzylamine derivatives (L) to amides of general formula (LI). A palladium-catalyzed sulfamination as described in Scheme 12 can provide compounds of the general formula (I). IF-2019-16749728-APN-Afl^INPI Page 82 of 363 Scheme 15 (XXXXVI) X = Chlo Br Coupling conditions HZN R, ¿TO (VI) 1. H2ra'-fiJH- H0 2.ÍH] bJ / 'P (XXXXll) In general and as illustrated in Scheme 15, compounds of general formula (XXXXII) can be obtained by a three-step process from a ketone derivative of general formula (XXXXVI). Sulfamidation of the derivative (XXXXVI) can be carried out using conditions described in Scheme 12 to obtain compounds of formula (LII). Oxime formation with methoxyamine may be followed by reduction in the presence of a suitable catalyst such as Pd / C in an atmosphere of H2 gas in a polar protic solvent such as MeOH to provide amine derivatives of general formula (XXXXII). Amines of this type can be converted into final compounds following Scheme 12. Scheme 16 (XXXXVII) (XXXXVIii) Conditions of 1 coupling n’b (VI) (YO !) 1KXXXIII Alternatively, compounds of general formula (XXXXII) can be obtained by a three-step process, as shown in Scheme 16. N-(2-(2bromopyrimidin-“4-yl) butan-2-yl ) -2-methylpropane-2sulfinamide (XXXXVII) can be synthesized as described above (Scheme 14). The imine can then be exposed to a nucleophile such as MeMgBr to provide intermediates such as (XXXXVIII). The corresponding sulfonamide (LUI) can then be obtained by a sulfamination catalyzed by IF-2019-16749728-APN-A^INPI Page 83 of 363 palladium as described in Scheme 1. Deprotection by acid hydrolysis can be carried out using HC1 to provide the benzylamine derivatives of general formula (XXXXII) which can then be converted to final compounds following Scheme 12 . Scheme 17 Yo. Conditions of n । here plamiento Et / fvle 1. RUgB.hvj ¿pb (V!) XCN Yo. Activating agent H S| 1. Deprotection 'N(XXX XIII) (XXXXIÍJ The benzamide derivatives of formula (I) in which Ri, R3, Arl and Ar2 are as defined above and R4= R^ = alkyl can be prepared in 5 steps as described in Scheme 17 by coupling an aromatic chloride commercial such as (LIV) with a primary sulfonamide using the sulfamidation conditions described in Scheme 1. A double addition of Grignard in an aprotic solvent such as THF to form intermediates of formula (LVI). They can then be subjected to a Ritter type reaction using an alkylnitrile, such as 2-chloroacetonitrile, in the presence of an acid such as H2SO4. The intermediate of formula (LVII) can be deprotected by reaction with thiourea in a protic solvent such as ethanol in the presence of acetic acid and heated to reflux to provide the benzylamine derivatives (XXXXII). The final compounds of formula (I) can be obtained using amide coupling conditions in Scheme 12. IF-2019-16749728-APN-A^^INPI Page 84 of 363 Scheme 18 In general and as illustrated in Scheme 18, compounds of general formula (I) can be prepared by conversion of intermediate (II) via a three-step process. First, saponification of (II) using an agent such as TMSOK provides the carboxylic acid derivative intermediate, which may be followed by reaction with an activating agent such as T3P and a bromoaniline of formula (XI) - The intermediates of formula (LVIII) are then converted into a compound of the invention of general formula (I) by coupling under Suzuki conditions with a boronate ester of general formula (XII). Boronate is typically a dihydroxyboryl or dialkyloxyboryl group, typically a 4,4,5,5-tetramethyl-l,3,3,2-dioxaborolan-2-yl. Couplings according to the Suzuki method are carried out, for example, by heating in the presence of a catalyst such as [1,1'20 bis(diphenylphosphino)ferrocene]dichloropalladium (II) and an inorganic base such as carbonate of potassium in a mixture of the solvents dioxane and water. Those skilled in the art will understand that many catalysts and conditions can be used for such couplings. IF-2019-16749728-APN-A&^INPI Page 85 of 363 j Scheme 19: Synthesis of the carboxylic derivative (XXXXIII) Rl 3 1 Coupling [¡Α,ΐΐ R„ H' / 0H jé IiaÓ l ?ii x i· R12 XsP> | --------------- Ri2 Ar1 VaL . .OH yl W-Y r·^ p r (Xíí) River 0 Fio 2 = Br, Cl (X|) y „ X - í5(OH)2. B(pin)2 (LVIX) = COyHu, CO2Me, CN (XXXXIII) Intermediates of formula (XXXXIII), where Ar2 is a substituted or unsubstituted 2-pyrazine ring or 3-pyridyl ring, can be synthesized as shown in Scheme 19 by coupling under Suzuki conditions of an aromatic halide of general formula (XII), of which R12 and Ria are defined above and Z represents Br or Cl, with a boronate of general formula (XI) where Rjr} and Rnse defined above, ,5,5-tetramethyl~ 1,3,3,2-dioxaborolan-2-yl . Couplings according to the Suzuki method are carried out, for example, by heating in the presence of a catalyst such as the [1,1r~bis(diphenylphosphino)ferrocene]dichloropalladium(II) adduct. CH2C12and an inorganic base such as cesium carbonate in a solvent mixture of dioxane and water in an inert atmosphere such as a nitrogen atmosphere to obtain compounds of formula (LVIX). Carboxylic acids of general formula (XXXXIII) are obtained either by deprotection of the t-butyl ester using a strong acid, such as TFA, in a CH2C12 solvent, hydrolysis of the methyl ester using an alkali metal hydroxide such as NaOH in a solvent mixture such as THE / MeOH, or hydrolysis of the nitrile using a strong acid such as concentrated HC1. IF-2019-16749728-APN-AMfrINPI Page 86 of 363 f) Intermediates of the invention The present invention also relates to new intermediates in the synthesis of compounds of formula (I) such as compounds of formula (II) to (LVIX) such as compounds of formula (II) to (XXV), such as compounds of formula (II)-(XX). The particular intermediates of interest are those of the following general formulas, where the variable groups and associated preferences are as previously defined for compounds of formula ίο(I): a compound of formula (II): R4,R5 RC where R is H, C alkyl; benzyl; )V,ZN N Ri ΪΙ |¡ T / / \\ o ^A^.n o o R3 (II) -6 (e.g. methyl and ethyl) o 15 - a compound of formula (III): pQ í11r NH2 (III); a compound of formula (XX): R12 rio (Ar21 / -pyRl1 Ap *) R4 yR5 |_| n„c / Π I I / / p o A-n or a compound of formula (XXIV): R12 \ AL / ''“'X H R4R5 R ( ArXN.( yv T η / R R °D'ZAN 0 2Q R10 R11 R3 .Ai (xx); Page 87 of 363 where P is a nitrogen protecting group such as paramethoxybenzyl. Also of interest are the following compounds, where the variable groups and associated preferences are as previously defined for compounds of formula (I): a compound of formula (II): R4«5 R where R is H, C alkyl, benzyl; WyT 0 Ζ.,λΧ 0 0 Y (II) í-6 (e.g. methyl and ethyl) or 10 - a compound of formula (III): ®R12 R -i or NH2 (III); a compound of formula (XX): / ¿'Y R< / Rs H .n n r, / Y Y Y Y p 0 Z. 4X 0 0 a compound of formula (XXIV): Rl2 (XX); ^3γΥ\ C Ar21 / ~x H 15 River R11 a compound of formula ^4^5 ? \z 1 n 1 T 'S Ri Z. X O γ (XXIV) ; (XXXI): IF-2019-16749728-APN-aS^INPI Page 88 of 363 Cl (XXXI); a compound of formula (XXXXII): N^R1 / / \\ O O (XXXXII); a compound of formula (XXXXIII): (XXXXIII); a compound of formula (LI): a compound of formula (LVIII): (LVIII). Included as an aspect of the invention are all new intermediates described in the examples, including: intermediates 1NTC1 to INTC47; and the intermediates INTD1 to INTD51. Also provided Intermediates INTC48 to INTC53 are also provided. the intermediates INTC54 to INTC177 the intermediates INTD52 to INTD86. IF-2019-16749728-APN-ASftlNPI Page 89 of 363 j Salts such as pharmaceutically acceptable salts of any of the intermediates described herein, such as any of the compounds of formulas (II)-(LVIX), are included as one aspect of the invention. therapeutic methods The compounds of formula (I) of the present invention are useful as CTPS1 inhibitors. Accordingly, the invention also provides a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g., salt) and / or derivative thereof, for use as a medicament, in particular in the treatment or prophylaxis of a disease or disorder where a CTPS1 inhibitor is beneficial, for example, those diseases and disorders mentioned below. The invention provides a method for the treatment or prophylaxis of a disease or disorder where a CTPS1 inhibitor is beneficial, for example, those diseases and disorders mentioned below, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., salt) and / or derivative thereof. The invention also provides the use of a compound of formula (I), or a salt and / or solvate thereof (e.g., salt) and / or pharmaceutically acceptable derivative, in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder where a CTPS1 inhibitor is beneficial, for example, those diseases and disorders mentioned below. More conveniently, the disease or disorder where a CTPS1 inhibitor is beneficial is a disease or disorder where a reduction in the proliferation of T lymphocytes and / or B lymphocytes would be beneficial. The invention also provides a compound of formula (I) or a salt and / or solvate (e.g., salt) and / or derivative of IF-2019-16749728-APN-A^INPI Page 90 of 363 is pharmaceutically acceptable, for use in the inhibition of CTPS1 in a subject. The invention provides a method for the inhibition of CTPS1 in a subject, comprising administering to the subject an effective amount of a compound of formula (I) or a salt and / or solvate (e.g., salt) and / or derivative of is pharmaceutically acceptable. The invention also provides the use of a compound of formula (I) or a salt and / or solvate thereof (e.g., salt) and / or pharmaceutically acceptable derivative, in the manufacture of a medicament for the inhibition of CTPS1 in a subject. The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate (e.g., salt) and / or derivative thereof, for use in reducing the proliferation of T lymphocytes and / or B lymphocytes in a subject. The invention provides a method for reducing the proliferation of T lymphocytes and / or B lymphocytes in a subject, comprising administering to the subject an effective amount of a compound of formula (I) or a salt and / or solvate (e.g. ., salt) and / or pharmaceutically acceptable derivative thereof. The invention also provides the use of a compound of formula (I) or a salt and / or solvate thereof (e.g., salt) and / or pharmaceutically acceptable derivative, in the manufacture of a medicament for the reduction of proliferation of T lymphocytes and / or B lymphocytes in a subject. More conveniently, the disease or disorder where a CTPS1 inhibitor is beneficial is a disease or disorder where a reduction in the proliferation of T lymphocytes and / or B lymphocytes would be beneficial. The term 'treatment' or 'treat', as used herein, includes the control, mitigation, reduction or modulation of the disease state or its symptoms. IF-2019-16749728-APN-ASMflNPI Page 91 of 363 The term "prophylaxis" or "prevent" is used herein to mean preventing symptoms of a disease or disorder in a subject or preventing the recurrence of symptoms of a disease or disorder in an affected subject and is not limited to complete prevention of the condition. . Conveniently, the disease or disorder is selected from rejection of transplanted cells and tissues, graft-related diseases or disorders, allergies and autoimmune diseases. In one embodiment, the disease or disorder is rejection of transplanted cells and tissues. The subject may have undergone a transplant with a graft selected from the group consisting of heart, kidney, lung, liver, pancreas, pancreatic islets, brain tissue, stomach, large intestine, small intestine, cornea, skin, trachea, bone, bone marrow (or any other source of hematopoietic precursor cells and hemocytoblasts including hematopoietic cells mobilized from bone marrow in the form of peripheral blood or umbilical cord blood cells), muscle or bladder. The compounds of the invention may be useful in preventing or suppressing an immune response associated with the rejection of a donated tissue, cell, graft or organ transplant in a subject. In a further embodiment, the disease or disorder is a graft-related disease or disorder. Graft-related diseases or disorders include graft versus host disease (GVHD), such as GVHD associated with a bone marrow transplant, and immune disorders resulting from or associated with rejection of an organ graft transplant. , tissues or cells (e.g. allografts or xenografts of tissues or cells) including, e.g. e j . , IF-2019-16749728-APN-A^INPI Page 92 of 363 grafts of skin, muscle, neurons, islets, organs, parenchymal cells of the liver, etc., and host versus graft disease (HCDI). The compounds of the invention may be useful in preventing or suppressing acute rejection of such a transplant in the recipient and / or, in long-term maintenance therapy, in preventing rejection of such a transplant in the recipient (e.g., inhibit the rejection of a transplant of insulin-producing islet cells from a donor in the recipient subject suffering from diabetes). Thus, the compounds of the invention are useful for preventing host versus graft disease (GVHD) and graft versus host disease (GVHD). A CTPS1 inhibitor may be administered to the subject before, after transplant, and / or during transplant. In some embodiments, the CTPS1 inhibitor may be administered to the subject periodically before and / or after transplantation. In another embodiment, the disease or disorder is an allergy. In further embodiments, the immune system-related disease or disorder is an autoimmune disease. As used herein, an autoimmune disease is a disease or disorder that attacks a subject's own tissues. Examples of autoimmune diseases include, but are not limited to, Addison's disease, adult-onset Still's disease, alopecia areata, Alzheimer's disease, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. , ankylosing spondylitis, antiphospholipid syndrome (Hughes syndrome), aplastic anemia, arthritis, asthma, atherosclerosis, atherosclerotic plaque, atopic dermatitis, autoimmune hemolytic anemia, hepatitis IF-2019-16749728-APN-A^INPI Page 93 of 363 autoimmune, autoimmune hypophysitis (lymphocytic hypophysitis), autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis, autoimmune orchitis, autoinflammatory diseases requiring immunosuppressive treatment, azoospermia, Behcet's disease, disease Berger's disease, bullous pemphigoid, cardiomyopathy, cardiovascular disease, celiac disease including refractory celiac disease (type I and type II), chronic immune dysfunction fatigue syndrome (CFIDS), chronic idiopathic polyneuritis, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing polyneuropathy (Guillain-Barré syndrome), Churg-Strauss syndrome (CSS), cicatricial pemphigoid, cold agglutinin disease (CGA), chronic obstructive pulmonary disease (COPD), CREST syndrome, cryoglobulinemic syndromes, lupus cutaneous, dermatitis herpetiformis, dermatomyositis, eczema, epidermolysis bullosa acquisita, essential mixed cryoglobulinemia, Evan's syndrome, exophthalmos, fibromyalgia, Goodpasture syndrome, Grave's disease, hemophagocytic lymphohistiocytosis (HLH) (including hemophagocytic lymphohistiocytosis type 1), histiocytosis / histiocytic disorders, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, immunoproliterative diseases or disorders, inflammatory bowel disease (ILD), interstitial lung disease, juvenile arthritis, juvenile idiopathic arthritis (JIA), Kawasaki, Lambert-Eaton myasthenic syndrome, lichen planus, localized scleroderma, lupus nephritis, Meniere's disease, microangiopathic hemolytic anemia, microscopic polyangiitis, Miller Fischer syndrome / seminated encephalomyeloradiculopathy IF-2019-16749728-APN-AS4#INPI Page 94 of 363 acute, mixed connective tissue disease, multiple sclerosis (MS), muscular rheumatism, myalgic encephalomyelitis (ME), myasthenia gravis, ocular inflammation, pemphigus foliaceus, pemphigus vulgaris, pernicious anemia, nodular polyarteritis, polychondritis, polyglandular syndromes ( Whitaker syndrome), polymyalgia rheumatica, polymyositis, primary agammaglobulinemia, primary biliary cirrhosis / autoimmune cholangiopathy, primary glomerulonephritis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, pure red series anemia, Raynaud's phenomenon, Reiter syndrome / reactive arthritis, Relapsing polychondritis, restenosis, rheumatic fever, rheumatic disease, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleroderma / systemic sclerosis, Sjógren's syndrome, stiff man syndrome, Sweet syndrome (acute febrile neutrophilic dermatosis), systemic lupus erythematosus (SLE) , systemic scleroderma, Takayasu arteritis, temporal arteritis / giant cell arteritis, thyroiditis, type 1 diabetes, type 2 diabetes, uveitis, vasculitis, vitiligo, Wegener's granulomatosis and X-linked 1infoproliferative disease. Of particular interest are diseases and disorders that are caused primarily by the activation and proliferation of T lymphocytes, including: diseases and disorders that are not associated with alloreactivity including: Alopecia areata, atopic dermatitis, eczema, psoriasis, lichen planus, psoriatic arthritis, vitiligo; Uveitis; Ankylosing spondylitis, syndrome Reiter / reactive arthritis; IF-2019-16749728-APN-A29BINPI Page 95 of 363 Η 'ι Aplastic anemia, autoimmune lymphoproliferative syndrome / disorders, hemophagocytic lymphohistiocytosis; type 1 diabetes; and Refractory BCeliacism; Acute rejection of grafted tissues and transplanted organs; Acute graft-versus-host disease (GVHD) after transplantation of bone marrow cells or any other source of allogeneic cells including hematopoietic precursor cells and / or hemocytoblasts. Also of interest are diseases and disorders that are caused by the activation and proliferation of both T and B lymphocytes, with a significant participation of B lymphocytes, including: diseases and disorders for which the involvement of pathogenic autoantibodies is well characterized, including: • Allergy; · Cicatricial pemphigoid, bullous pemphigoid, epidermolysis bullosa acquisita, pemphigus foliaceus, pemphigus vulgaris, dermatitis herpetiformis; • Vasculitis associated with ANCA and microscopic polyangiitis, vasculitis, granulomatosis of Wegener; Churg-Strauss syndrome (CSS), nodular polyarteritis, cryoglobulinemic syndromes and essential mixed cryoglobulinemia; • Systemic lupus erythematosus (SLE), antiphospholipid syndrome (Hughes syndrome), lupus IF-2019-16749728-APN-AJ9MNPI Page 96 of 363 cutaneous, lupus nephritis, mixed connective tissue disease; • Thyroiditis, Hashimoto's thyroiditis, Grave's disease, exophthalmos; ® Autoimmune hemolytic anemia, autoimmune neutropenia, ITP, pernicious anemia, pure red series anemia, microangiopathic hemolytic anemia; * Primary glomerulonephritis, Berger's disease, Goodpasture syndrome, IgA nephropathy; and ® Chronic idiopathic polyneuritis, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic relapsing polyneuropathy (Guillain-Barré syndrome), Miller Fischer syndrome, rigid man syndrome, Lambert-Eaton myasthenic syndrome, myasthenia gravis. diseases and disorders for which B cell involvement is less clearly characterized (although sometimes illustrated by the effectiveness of intravenous infusions of anti-CD20 monoclonal antibodies or immunoglobulins) and may not correspond to or be limited to antibody production pathogens (however, non-pathogenic antibodies are sometimes described or are even usually present and used as a diagnostic biomarker), including: ® Addison's disease, autoimmune oophoritis and azoospermia, polyglandular syndromes (Whitaker syndrome), Schmidt syndrome; IF-2019- 16749728-APN-A^álNPI Page 97 of 363 • Autoimmune myocarditis, cardiomyopathy, Kawasaki disease; • Rheumatoid arthritis, Sjógren's syndrome, mixed connective tissue disease, polymyositis and dermatomyositis; polychondritis; ® Primary glomerulonephritis; • Multiple sclerosis; ® Autoimmune hepatitis, primary biliary cirrhosis / autoimmune cholangiopathy, Hyperacute rejection of transplanted organs; Chronic graft or transplant rejection; Chronic graft-versus-host / disease reaction after transplantation of bone marrow cells or hematopoietic precursor cells. Additionally of interest are diseases and disorders for which the mechanism is shared between the activation / proliferation of T lymphocytes and the activation / proliferation of innate immune cells and other inflammatory cell subpopulations (including myeloid cells such as macrophages or granulocytes) and cells. residents (such as fibroblasts and endothelial cells), including: COPD, idiopathic pulmonary fibrosis, interstitial lung disease, sarcoidosis; Adult Still's disease, juvenile idiopathic arthritis, systemic sclerosis, CREST syndrome where pathogenic B lymphocytes and antibodies may also play a role; he IF-2019-16749728-APN-AÍfflfINPI Page 98 of 363 Sweet syndrome; Takayasu arteritis, temporal arteritis / giant cell arteritis; Ulcerative cholangitis, inflammatory bowel disease (ILD) including Crohn's and ulcerative colitis, primary sclerosing cholangitis. Also of interest are diseases and disorders for which the mechanism remains poorly characterized but involves the activation and proliferation of T lymphocytes, 10 including: HAlzheimer's disease, cardiovascular syndrome, type 2 diabetes, restenosis, chronic fatigue immune dysfunction syndrome (CFIDS). Autoimmune lymphoproliferative disorders, which include: HSautoimmune lymphoproliferative syndrome and X-linked lymphoproliferative disease. Conveniently, the disease or disorder is selected from: inflammatory skin diseases such as psoriasis or lichen planus; Acute and / or chronic GVHD such as spheroid-resistant acute GVHD; acute lymphoproliferative syndrome; systemic lupus erythematosus, lupus nephritis or cutaneous lupus; or transplant. Furthermore, the disease or disorder can be selected from myasthenia gravis, multiple sclerosis and systemic scleroderma / eslerosis. The compounds of formula (I) can be used in the treatment of cancer. Thus, in one embodiment, a compound of formula (I), or a salt / or solvate thereof and / or derivative thereof, is provided. IF-2019-16749728-APN-AÍWlNPI Page 99 of 363 is pharmaceutically acceptable, for use in the treatment of cancer. Furthermore, there is provided a method of treating cancer in a subject by administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt / or solvate thereof and / or derivative thereof. Additionally, the use of a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof and / or derivative thereof, in the manufacture of a medicament for the treatment of cancer in a subject is provided. Conveniently, the cancer is a hematological cancer, such as acute myeloid leukemia, angioimmunoblastic T-cell lymphoma, B-cell acute lymphoblastic leukemia, Sweet syndrome, T-cell non-Hodgkin lymphoma (including T-cell / cytolytic lymphoma, leukemia / 1reports adult T-cell lymphoma, enteropathic-type T-cell lymphoma, hepatosplenic T-cell lymphoma, and cutaneous T-cell lymphoma), T-cell acute lymphoblastic leukemia, B-cell non-Hodgkin lymphoma (including Burkitt lymphoma, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma), tricholeukemia, Hodgkin lymphoma, lymphoblastic lymphoma, lymphoplasmacytic lymphoma, mucosa-associated lymphoid tissue lymphoma, multiple myeloma, myelodysplastic syndrome, myeloma of plasma cells, primary mediastinal lymphocyte B lymphocytes, chronic myeloprolifenative disorders (such as chronic myeloid leukemia, primary myelofibrosis, essential thrombocythemia, polycythemia vera) or chronic lymphocytic leukemia. Alternatively, the cancer is a non-hematological cancer, such as selected from the group consisting of bladder cancer, breast cancer, melanoma, neuroblastoma, malignant pleuric mesothelioma and sarcoma. IF-2019-16749728-APN-4WINPI Page 100 of 363 Additionally, compounds of formula (I) may be used to promote recovery from vascular injury or surgery and reduce the morbidity and mortality associated with neointima and restenosis in a subject. For example, compounds of formula (I) can be used to prevent, reduce or inhibit neointima formation. A medical device may be treated prior to insertion or implantation with an effective amount of a composition comprising a compound of formula (I) in order to prevent, reduce or inhibit neointima formation following insertion or implantation of the device or graft. in the subject. The device may be a device that is inserted into the subject temporarily or a device that is permanently implanted. In some embodiments, the device is a surgical device. Examples of medical devices include, but are not limited to, needles, cannulas, catheters, shunts, balloons, and implants such as stents and valves. Conveniently, the subject is a mammal, in particular the subject is a human being. Pharmaceutical compositions For use in therapy, the compounds of the invention are usually administered as a pharmaceutical composition. The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g., salt) and / or derivative thereof, and a pharmaceutically acceptable carrier or excipient. In one embodiment, a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g., salt) and / or derivative thereof, is provided for use in the treatment or prophylaxis of a disease or disorder as described herein. IF-2019-16749728-APN-AIM#INPI Page 101 of 363 In a further embodiment, there is provided a method for the prophylaxis or treatment of a disease or disorder as described herein, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I ) or a pharmaceutically acceptable salt and / or solvate (e.g., salt) and / or derivative thereof. The invention also provides the use of a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate (e.g., salt) and / or derivative thereof, in the manufacture of a medicament. for the treatment or prophylaxis of a disease or disorder as described herein. The compounds of formula (I) or their pharmaceutically acceptable salts and / or solvates and / or derivatives thereof may be administered by any convenient method, e.g. e.g., by oral, parenteral, jugal, sublingual, nasal, rectal or transdermal administration, and correspondingly adapted pharmaceutical compositions. The compounds of formula (I) or their pharmaceutically acceptable salts and / or solvates and / or derivatives thereof may be administered topically, for example, to the eye, intestine or skin. Thus, in one embodiment, a pharmaceutical composition is provided comprising a compound of the invention optionally combined with one or more topically acceptable diluents or carriers. A pharmaceutical composition of the invention can be delivered topically to the skin. Compositions suitable for transdermal administration include ointments, gels and patches. A pharmaceutical composition of this type may also be suitable in the form of a cream, lotion, foam, powder, paste or tincture. IF-2019-16749728-APN-ÁOWlNPI Page 102 of 363 The pharmaceutical composition may conveniently include vitamin D3 analogs (e.g., calcipotriol and maxacalcitol), spheroids (e.g., fluticasone propionate, betamethasone valerate and clobetasol propionate), retinoids (e.g., Tazarotene). ), mineral tar and dithranol. Topical medications are typically used in combination with each other (e.g., a vitamin D3 and a spheroid) or with additional agents such as salicylic acid. A pharmaceutical composition of the invention can be delivered topically to the eye. Such a pharmaceutical composition may conveniently be in the form of eye drops or an ointment. A pharmaceutical composition of the invention can be delivered topically to the intestine. Such a pharmaceutical composition may conveniently be supplied orally, such as in the form of a tablet or capsule, or rectally, such as in the form of a suppository. Conveniently, the delayed release formulations are in the form of a capsule. The compounds of formula (I) or their pharmaceutically acceptable salts and / or solvates and / or derivatives thereof that are active when administered orally may be formulated as liquids or solids, e.g., as syrups, suspensions, emulsions. , tablets, capsules or dragees. A liquid formulation will generally consist of a suspension or solution of the active ingredient (such as a compound of formula (I) or a salt and / or solvate (e.g., salt) and / or pharmaceutically acceptable derivative thereof) in a ( Suitable liquid carrier(s), e.g. e.g., an aqueous solvent such as water, ethanol or glycerin, or a non-aqueous solvent, such as polyethylene glycol or a IF-2019- 16749728-APN-1ÍWNPI Page 103 of 363 oil. The formulation may also contain a suspending agent, preservative, flavoring agent and / or colorant. A composition in the form of a tablet can be prepared using any pharmaceutically suitable carrier(s) routinely used to prepare solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose. . A composition in the form of a capsule can be prepared using routine encapsulation procedures, ρ. e.g. , pellets containing the active ingredient (such as a compound of formula (I) or a salt and / or solvate (e.g., salt) and / or pharmaceutically acceptable derivative thereof) can be prepared using standard carriers and then introduced in a hard gelatin capsule; Alternatively, a dispersion or suspension can be prepared using any pharmaceutically suitable carrier(s), e.g. e.g. , aqueous gums, celluloses, silicates or oils, and the dispersion or suspension is then introduced into a soft gelatin capsule. Typical parenteral compositions consist of a solution or suspension of the active ingredient (such as a compound of formula (I) or a salt and / or solvate (e.g., salt) and / or pharmaceutically acceptable derivative thereof) in a Sterile aqueous carrier or acceptable oil for the parental route, e.g. e.g., polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just before administration. Compositions for nasal administration can conveniently be formulated as sprays, drops, gels and powders. Aerosol formulations typically comprise a fine solution or suspension of the ingredient. IF-2019- 16749728-ΑΡΝ-4]<Μ / ΙΝΡΙ Page 104 of 363 active in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single- or multidose quantities in sterile form in a sealed container that may be in the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a disposable dosing device such as a single-dose nasal inhaler or an aerosol dispenser equipped with a dosing valve. Where the dosage form comprises an aerosol dispenser, this will contain a propellant which may be a compressed gas, e.g. e.g., air, or an organic propellant such as fluoro-chloro-hydrocarbon or hydrofluorocarbon. Aerosol dosage forms may also be in the form of pump atomizers. Compositions suitable for buccal or sublingual administration include tablets, dragees and lozenges where the active ingredient is formulated with a carrier such as sugar and gum arabic, tragacanth or gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter. Conveniently, the composition is in a unit dosage form such as a tablet, capsule or capsule. The composition may contain, for example, from 0.11 to 100% by weight, for example, from 10 to 60% by weight, of the active material, depending on the method of administration. The composition may contain from 0% to 9% by weight, for example, from 40 to 90% by weight, of the carrier, depending on the method of administration. The composition may contain from 0.05 mg to 2000 mg, for example from 1.0 mg to 500 mg, of the active material, depending on the method of administration. The composition may contain from 50 mg to IF-2019-16749728-APN-^QÉ^INPI Page 105 of 363 1000 mg, for example, of 100 mg to 4 00 mg, from the carrier, depending on the method of administration. The dose of the compound used in the treatment or prophylaxis of the aforementioned disorders will vary in the usual way with the severity of the disorders, the weight of the patient and other similar factors. However, as a general rule, suitable unit doses may be from 0.05 mg to 1000 mg, more conveniently from 1.0 mg to 500 mg, and such unit doses may be administered more than once a day, for example, two or three a day. day. Such therapy can last for several weeks or months. The invention provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate and / or derivative thereof (e.g., a combination comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof) together with an additional pharmaceutically acceptable active ingredient or ingredients. The invention provides a compound of formula (1), for use in combination with a further pharmaceutically acceptable active ingredient(s). When the compounds are used in combination with other therapeutic agents, the compounds can be administered separately, sequentially or simultaneously by any convenient route. Optimal combinations depend on the disease or disorder. Possible combinations include those with one or more active agents selected from the list consisting of: 5-aminosalicylic acid or a prodrug thereof (such as sulfasalazine, olsalazine or bisalazide); corticosteroids (eg, prednisolone, methylprednisolone, or budesonide); immunosuppressants (eg, cyclosporine, tacrolimus, sirolimus, methotrexate, mycophenolate mofetil IF-2019-16749728-APN-ÁOf^INPI Page 106 of 363 of azathioprine, leflunomide, cyclophosphamide, 6~ mercaptopurine or antilymphocytic (or antithymocyte) globulins); anti-TNF-alpha antibodies (eg, infliximab, adalimumab, certolizumab pegol, or golimumab); anti-IL12 / IL23 antibodies (eg, ustekinumab); anti-IL6 or anti-IL6R antibodies, anti-IL17 antibodies or low molecular weight IL12 / IL23 inhibitors (eg, apilimod); anti-alpha-4-beta-7 antibodies (e.g., vedolizumab); MAdCAM-1 blockers (eg, PF00547659); antibodies against the cell adhesion molecule alpha-4-integrin (eg, natalizumab); antibodies against the alpha subunit of the IL2 receptor (eg, daciizumab or basiliximab); JAK inhibitors including JAKI and JAK3 inhibitors (eg, tofacitinib, baricitinib, R348); Syk inhibitors and prodrugs thereof (eg, fostamatinib and R-406); phosphodiesterase-4 inhibitors (eg, tetomilast); HMPL-004; probiotics; dersalazine; semapimod / CPSI-2 364; and protein-cmase C inhibitors (eg, AEB-071). For cancer, the pharmaceutically acceptable active ingredient can be selected from antimitotic agents such as vinblastine, paclitaxel and docetaxel; alkylating agents, for example, cisplatin, carboplatin, dacarbazine and cyclophosphamide; antimetabolites, for example, 5-fluorouracil, cytosine arabinoside and hydroxyurea; intercalating agents, for example, adriamycin and biomycin; topoisomerase inhibitors, for example, etoposide, topotecan and irinotecan; thymidylate-synthase inhibitors, for example, raltitrexed; PI3 kinase inhibitors, e.g. idelalisib; mTor inhibitors, for example, everolimus and temsirolimus; proteasome inhibitors, e.g. bortezomib; histone deacetylase inhibitors, e.g. panobinostat or IF-2019- 16749728-APN-JtfWNPI Page 107 of 363 vorinostat; and Hedgehog pathway blockers such as vismodegib. The additional pharmaceutically acceptable active ingredient can be selected from tyrosine kinase inhibitors such as, for example, axitinib, dasatinib, erlotinib, imatinib, nilotinib, pazopanib and sunitinib. Antineoplastic antibodies can be included in a combination therapy and are selected from the group consisting of olaratumab, daratumumab, necítumumab, dinutuximab, traztuzumab emtansine, pertuzumab, obinutuzumab, brentuximab, ofatumumab, panitumumab, catumaxomab, bevacizumab, cetuximab, tositumomab, traztuzumab, gentuzumab ozogamicin and rituximab. The compounds or pharmaceutical compositions of the invention can also be used in combination with radiotherapy. Some of the combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and, therefore, pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient constitute a further aspect of the invention. The individual components of such combinations can be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. The individual components of the combinations can also be administered separately, by the same or different routes. When a compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state, the dose of each compound may differ from the dose when the compound is used alone. The dose IF-2019-16749728-APN-ÁOf^INPI Page 108 of 363 appropriate will be easily estimated by those skilled in the art. Medical devices In one embodiment, the compounds of the invention or pharmaceutical compositions comprising such compounds may be formulated to allow their incorporation into the medical device, thereby providing for application of the compound or composition directly to the site to prevent or treat conditions mentioned herein. . In one embodiment, the compounds of the invention or the pharmaceutical composition thereof are formulated by including them in a coating on the medical device. There are various coatings that can be used such as, for example, polymeric coatings that can release the compound over a prescribed period of time. The compound or a pharmaceutical composition thereof can be embedded directly into the medical device. In some embodiments, the compound is coated on or within the device in a delivery vehicle such as a microparticle or liposome that facilitates its release and delivery. In some embodiments, the compound or pharmaceutical composition is miscible in the coating. In some embodiments, the medical device is a vascular implant such as a stent. Stents are used in medicine to prevent or eliminate vascular restrictions. Implants can be inserted into a restricted blood vessel in such a way that the vessel widens. Excessive growth of adjacent cells after a vascular implant results in vessel restriction particularly at the ends of the implants, resulting in reduced effectiveness of the implants. If a vascular implant is inserted into a IF-2019-16749728-APN-ÁQWlNPI Page 109 of 363 human artery to eliminate, for example, an atherosclerotic stenosis, intimal hyperplasia can occur within a year at the ends of the implant \mscular and causes renewed stenosis (restenosis). Accordingly, in some embodiments, the stents are coated or loaded with a composition that includes a compound of the invention or pharmaceutical composition thereof and optionally a targeting signal, a delivery vehicle, or a combination of these. Many stents are commercially available or known in the art. In some embodiments, the stent is a drug eluting stent. Various drug eluting stents are known in the art that simultaneously deliver a therapeutic substance to the treatment site while providing artificial radial support to the pread tissue. Endoluminal devices, including stents, are sometimes coated on their external surfaces with a substance such as a drug-releasing agent, growth factor, or the like. Stents have also been developed that have a hollow tubular structure with holes or ports cut through the side wall to allow elution of drug from a central lumen. Although the hollow nature of the stent allows the central lumen to be loaded with a drug solution that is delivered through ports or holes in the side wall of the stent, the hollow tubular structure may not have adequate mechanical strength to provide the scaffolding. suitable in the artery. In some embodiments, the devices are also coated or impregnated with a compound of the invention or a pharmaceutical composition thereof and one or more additional therapeutic agents, including, but not limited to, antiplatelet agents, anticoagulant agents, agents. anti-inflammatory agents IF-2019-16749728-APN-AlfÉ^INPI Page 110 of 363 j antimicrobials, antimetabolic agents, additional anti-neointimal agents, additional antiproliferatives agents, immunomodulators, antiproliferatives agents, agents affecting migration and extracellular matrix production, agents affecting platelet deposition or formation of thrombi, and agents that promote vascular healing and reendothelialization, such as those described in Sousa et al. (2003) and Salu et al. (2004) and others. Examples of antithrombotic agents include, but are not limited to, Heparin (including low molecular weight heparin), R-Hirudin, Hirulog, Argatroban, Efegatran, tick anticoagulant peptide and Ppack. Examples of antiproliferative agents include, but are not limited to, Paclitaxel (Taxol), QP-2 Vincristine, Methotrexate, Angiopeptin, Mitomycin, BCP 678, c-myc antisense, ABT 578, Actinomycin-D, RestenASE, 1-chlorodeoxyadenosine, PCNA Ribozyme and Celecoxib. Examples of anti-restenosis agents include, 20 but are not limited to, immunomodulators such as Sirolimus (Rapamycin), Tacrolimus, Biorest, Mizoribine, Cyclosporin, Interferon-y Ib, Leflunomid, Tranilast, Corticosteroid, Mycophenolic Acid and Bisphosphonate. Examples of anti-migratory agents and extracellular matrix modulators include, but are not limited to, Halofuginone, Propyl hydroxylase inhibitors, Proteinase C inhibitors, MMP inhibitors, Batimastat, Probucol. Examples of antiplatelet agents include, but are not limited to, heparin. Examples of wound healing agents and endothelialization promoters include vascular epithelial growth factor (VEGF), 17-Estradiol, Tkase Inhibitors, BCP 671, Statins, Nitric Oxide (NO) Donors IF-2019-16749728-APN-4fWlNPI Page 111 of 363 and antibodies against endothelial progenitor cells (EPC). Apart from coronary applications, drugs and active agents can be incorporated into the stent or stent coating for other indications. For example, in urological applications, antibiotic agents can be incorporated into the stent or stent coating for the prevention of infection. In gastroenterological and urological applications, active agents can be incorporated into the stent or stent coating for local treatment of carcinoma. It may also be advantageous to incorporate in or on the stent a contrast agent, radiopaque markers or other additives to allow imaging of the stent in vivo for tracking, localization and other purposes. Such additives may be added to the absorbent composition used to manufacture the stent or stent coating, or absorbed into, melted onto, or sprayed onto the surface of part or all of the stent. Preferred additives for this purpose include silver, iodine and iodine-labeled compounds, barium sulfate, gadolinium oxide, bismuth derivatives, zirconium oxide, cadmium, tungsten, gold, tantalum, bismuth, platinum, iridium and roclium. These additives may be, but are not limited to, micro- or nanometric particles, or nanoparticles. Radioopacity can be determined by fluoroscopy or by x-ray analysis. A compound of the invention and one or more additional agents, or pharmaceutical composition thereof, may be incorporated into the stent, either by loading the compound and one or more additional agents, or pharmaceutical composition thereof, into the absorbable material prior to processing and / or coat the surface of the stent with the agent or agents. Agent release rate can be controlled IF-2019- 16749728-APN-jW^INPI Page 112 of 363 by numerous methods including varying the following: the ratio of the absorbable material to the compound and one or more additional agents or the pharmaceutical composition, the molecular weight of the absorbable material, the composition of the compound and one or more additional agents or the pharmaceutical composition, the composition of the absorbed polymer, the thickness of the coating, the number of coating layers and their relative thicknesses, and / or the concentration of the compound and one or more additional agents or the pharmaceutical composition. Topcoats of polymers and other materials, including absorbable polymers, can also be applied to active agent coatings to control the release rate. For example, P4HB can be applied as a topcoat on a P4HB-coated metal stent that includes an active agent to delay the release of the active agent. The invention is further illustrated by the following non-limiting examples. EXAMPLES The abbreviations used herein are defined below. Any undefined abbreviations are intended to express the generally accepted meaning. Abbreviations Ac acetyl (C(0)CHJ AcOH glacial acetic acid AlMe.3 trimethylaluminum aqueous Ar aromatic ring BEH ethylene-bridged hybrid particles Bispin Bis(pinacolato)diboron; 4,4,4',4r,5,5,5r, 5' Octamethyl-2,2 f-bi-1,3,2-dioxaborolane Bz benzyl (CH2-phenyl) Boc tert-butyloxycarbonyl protecting group IF-2019-16749728-APN-Á^INPI Page 113 of 363 CS2CO3 cesium carbonate CSH surface charged hybrid particles d doublet adduct of trimethylaluminum and 1,4- DABAL-Me 3 diazabicyclo[2.2.2]octane DCM dielorornetan DI PEA N, N-diisopropylethylamine dioxane 1,4-dioxane DMAP 4-dimethylaminopyridine DME dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DP PA diphenylphosphorylazide dppf 1,1'-bis(diphenylphosphino)ferrocene (ES+) electrospray ionization, positive mode electrospray ionization, negative (ES“) mode ESI electrospray ionization Et ethyl Etl ethyl iodide EtOAc ethyl acetate EtOH ethanol g grams 1-HATU [bis(dimethylamino)methylene]-1H-1f 2,3triazolo[4,5-b]pyridinium 3-oxide halogen halogen hexafluorophosphate HPLC liquid chromatography high resolution h (s) hour (s) IC50 inhibitory concentration of 50'1 iPr isopropyl K2CO3 potassium carbonate IF-2019-16749728-ΑΡΝ-Α11%ΙΝΡΙ Page 114 of 363 LCMS liquid chromatography-mass spectrometry LHMDS lithium hexamethyldisilazide LiOH lithium hydroxide (M+H) 1 protonated molecular ion (M-H) “ deprotonated molecular ion M molar concentration mL milliliter mm millimeter mmol millimole Me methyl MeCN acetonitrile Mel iodomethane MeOH methanol MHz megahertz min (s) minute (s) MSD mass selector detector m / z ratio of mass to charge n2 nitrogen gas nh3 ammonia NH4C1 ammonium chloride NaH sodium hydride NaHCO3 sodium bicarbonate nm nenometer NMR nuclear magnetic resonance (spectroscopy) NSFI ΛΖ-f lu or obenzene su 1fonimide P4HB poly-4-hydroxybutyrate PDA photodiode beam Pd 170 chloro(crotyl) (2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl)palladium(II) 0 XPhos Pd(crotyl )C1 Pd 174 allyl(2-di-tert-butylphosphino- triflate IF-2019-16749728-APN-Jt^INPI Page 115 of 363 2 ', 4 ' , 6 '-triisopropyl-l, 1 ' - biphenyl)palladium (11) or [ tBuXPhosPd (alii)]OTf [Rd (alii) Cl2) 2 bis(alii)dichlorodipalladium [i,i PdCl2(dppf ) bis(diphenylphosphine)ferrocene]dichloropalladium (ID Pd (PPh3) 4 tetrakis(triphenylphosphine)palladium (0) PMB 4-methoxybenzyl high performance liquid chromatography HPLC prep preparative Ph phenyl pos / neg positive / negative q quadruplet RF / MS spectrometry mass test coupled with RapidFire TA room temperature tR retention time RP reverse phase s singlet SNAr aromatic nucleophilic substitution sat saturated cation exchange with solid support sex (resin) bis (tetrafluoroborate) of N-chloromethyl-N'- Selectfluor fluorotriethylenediammonium t triplet tBu tert -butyl T3P 2,4,6-trioxide 2,4,6~tripropyl- 1,3,5,2,4,6-trioxatriphosphorinane TBME tert-butyl methyl ether TFA trifluoroacetic acid allyl(2-di-tert triflate -butylphosphine- t-BuXPhos Pd(allyl)]OTf 2',41,6'-triisopropyl-1,1'-biphenyl)palladium (II) IF-2019-16749728-APN-ÁltffelNPI Page 116 of 363 THE tetrahydrofuran TMP 2,2,6,6-tetramethylpiperidinyl TMSOK potassium trimethylsilanolate TTIP titanium tetraisopropoxide ultrahigh resolution liquid chromatography UPLC UV ultraviolet v / v volume / volume VWD variable wave detector p weight um micrometer uL microliter '' C degrees Celsius General procedures All starting materials and solvents were obtained from commercial suppliers or prepared according to the literature. Unless otherwise indicated, all reactions are shaken. Organic solutions were routinely dried with anhydrous magnesium sulfate. Hydrogenations were carried out in a Thales H-cube flow reactor under the indicated conditions. Column chromatography was carried out on prepacked silica cartridges (230-400 mesh, 40-63 um) using the indicated amount. SCX was purchased from Supelco and treated with 1M hydrochloric acid before use. Unless otherwise indicated, the reaction mixture to be purified was first diluted with MeOH and acidified with a few drops of AcOH. This solution was placed directly on the SCX and washed with MeOH. The desired material was then eluted by washing with 0.7 M NHj in MeOH. Preparative reversed-phase high-performance liquid chromatography IF-2019- 16749728-APN-MF#INPI Page 117 of 363 HPLC prep acid prep Waters Cl8 X-Select CSH column, 5 urn (19 254nm. Basic prep Waters C18 X-Bridge Prep column, 5 um (19 Analytical methods Reversed Phase HPLC Conditions for LCMS Analytical Methods Acid HPLC: Acid LCMS 4 minutes (5-951) Analytical LCMS was carried out using a Waters CIS X-Select CSH column, 2.5 um, 4.6x30 mm, eluting with a gradient of 0.11 formic acid in MeCN in 0.11 formic acid in water. The 5-951 gradient of 0.1% formic acid in MeCN occurs between 0.00-3.00 minutes at 2.5 mL / min with a purge from 3.01-3.5 minutes at 4.5 mL / min. A re-equilibration of the column to 5% MeCN is from 3.60-4.00 minutes at 2.5 mL / min. The UV spectra of the eluted peaks were measured using an Agilent VWD 1260 Infinity at 254 nm. Mass spectra were measured using an Agilent MSD 6120 operating with positive / negative shift. Basic HPLC: Basic LCMS 4 minutes (5-95%) Analytical LCMS was carried out using a Waters CIS The 5-95% MeCN gradient occurs between 0.00-3.00 minutes at 2.5 mL / min with a purge from 3.01-3.5 minutes at 4.5 mL / min. A re-equilibration of the column to 5?, MeCN is from 3.60-4.00 minutes at 2.5 mL / min. IF-2019-16749728-APN-ÁftfkíNPI Page 118 of 363 The UV spectra of the luid peaks were measured using an Agilent VWD 12 60 Infinity at 25 4 nm. Mass spectra were measured using an Agilent MSD 6120 operating with positive / negative shift. Reversed Phase HPLC Conditions for UPLC Analytical Methods Acid UPLC: Acid UPLC 3 minutes Analytical UPLC / MS was carried out using a Waters CIS Acquity CSH, 1.7 uro, 2.1x30 mm column, eluting with a gradient of 0.15 formic acid in MeCN in 0.15 formic acid in water. The gradient was structured with a starting point of 5% MeCN maintained from 0.0-0.11 minutes. The 5-95% gradient takes place between 0.11-2.15 minutes with a purge from 2.15-2.56 minutes. A column reequilibration to 5% MeCN is from 2.56-2.83 minutes. UV spectra of the eluted peaks were measured using an Acquity PDA and mass spectra were recorded using an Acquity QDa detector with pos / neg ESI shift. Acid UPLC 2 Acid UPLC 1 minute Analytical UPLC / MS was carried out using a Waters C18 Acquity CSH column, 1.7 um, 2.1x30 mm, eluting with a gradient of 0.1% formic acid in MeCN in 0.1% formic acid in water. The gradient was structured with a starting point of 5% MeCN maintained from 0.0-0.08 minutes. The 5-95% gradient takes place between 0.08-0.70 minutes with a purge from 0.7-0.8 minutes. A column rebalance to 5% MeCN is from 0.8-0. 9 minutes. UV spectra of the eluted peaks were measured using an Acquity PDA and mass spectra were recorded using an Acquity QDa detector with ESIpos / neg shift. Basic UPLC: Basic UPLC 3 minutes IF-2019-16749728-APN-ÁSft^INPI Page 119 of 363 Analytical UPLC / MS was carried out using a Waters C18 Acquity BEH column, 1.7 um, 2.1x30 mm, eluting with a gradient of MeCN in aqueous 10 mM ammonium bicarbonate. The gradient was structured with a starting point of 5% MeCN maintained from 0.0-0.11 minutes. The 5-951 gradient takes place between 0.11-2.15 minutes with a blowdown from 2.15-2.56 minutes. A column rebalance to 51 MeCN is from 2.56-2.83 minutes. UV spectra of the eluted peaks were measured using an Acquity PDA and mass spectra were recorded using an Acquity QDa detector with pos / neg ESI shift. Basic UPLC 2 Basic UPLC 1 minute Analytical UPLC / MS was carried out using a column Waters C18 Acquity BEH, 1.7 um, 2.1x30 mm, eluting with a gradient of MeCN in 10 mM aqueous ammonium bicarbonate. The gradient was structured with a starting point of 5% MeCN maintained from 0.0-0.08 minutes. The 5-95 gradient takes place between 0.08-0.70 minutes with a blowdown from 0.7-0.8 minutes. A column reequilibration to 51 MeCN is from 0.8-0.9 minutes. The UV spectra of the eluted peaks were measured using an Acquity PDA and the mass spectra were recorded using an Acquity QDa detector with shift ESIpos / neg. The column temperature is 40 C in all developments. The injection volume is 3 uL and the flow rate is 0.77 mL / min. The PDA performs a scan of 210-400 nm in all developments. Normal phase HPLC conditions for quinal analytical methods Chiral IC3 Method: Chiral HPLC (Diacel Chiralpak IC, 5 um, 4.6x250 mm, 1.0 mL / min, 25-70% EtOH (0.2%: TEA) in isohexane (0.2% TFA) IF-2019-16749728-APN- / WfclNPI Page 120 of 363 Chiral IC4 Method: Chiral HPLC (Diacel Chiralpak IC, 5 um, 4.6x250 mm, 1.0 mL / min, 401 EtOH (0.21 TFA) in heptane / chloroform 4:1 (0.21 TEA). Chiral IC5 Method: Quinal HPLC (Diacel Chiralpak IC, 5 um, 4.6x250 mm, 1.0 mL / min, 20% EtOH (0.2% TFA) in isohexane (0.21 TFA). Reversed Phase HPLC Conditions for Quinal Analytical Methods Chiral IC6 Method: Chiral HPLC (Diacel Chiralpak IC, 5 um, 4.6x250 mm, 1.0 mL / min, 50% MeCN (0.1% formic acid) in water (0.1% formic acid). Chiral IC7 Method: Chiral HPLC (Diacel Chiralpak IC, 5 um, 4.6x250 mm, 1.0 mL / min, 5-95% MeCN (0.1¾ formic acid) in water (0.1% formic acid). 1H NMR spectroscopy 1H NMR spectra were acquired on a Bruker Avance III spectrometer at 400 MHz or a Bruker Avance III HD spectrometer at 500 MHz using residual undeuterated solvent as a reference and, unless otherwise specified, processed in DMSOch . Preparation of intermediates Known synthetic intermediates were purchased from commercial suppliers or obtained using procedures published in the literature. Additional intermediates were prepared by the representative synthetic processes described herein. Any of Methods 1-10 (referred to below) or A-N can be used in the synthesis of the compounds of formula (I). For example, a scheme shown in which a compound where X = N, Y = CR2 and Z = CR?5 is used in the synthesis of compounds where X, Y and Z are as defined in the claims. IF-2019- 16749728-AP\-.1^1I\PI Page 121 of 363 Preparation of biester intermediates 1-(tert-butyl)3methyl 2-(2-Chloropyrimidin-4-yl)malonate INTC1 Yo either. x NaH (601 p in mineral oil, 5.10 g, 128 mmol) was added portionwise to a stirred, ice-cold solution of tert-butyl methyl malonate (20.5 mL, 121 mmol) in THF (160 mL). It was stirred at 0°C for 20 min, then at RT for 60 min until hydrogen was no longer evolved. 2,4-Dichloropyrimidine (10 g, 67.1 mmol) was then added and the resulting mixture was stirred at 70 C for 3 h. The reaction was allowed to cool, partitioned between NH4C1 (sat. ac, 500 mL) and EtOAc (500 mL), the two phases were separated and the organic layer was passed through a phase separator. The crude product was purified by silica gel chromatography (220 g column, 0-30% EtOAc / isohexane) to provide 1-tert-butyl 3-methyl 2-(2-chloropyrimidin-4-yl)malonate (13.1 g, 44.3 mmol, 66% yield) as a transparent pale yellow oil; tR 2.09 min (acid HPLC); m / z 230 (M+H-tBu)+(ES+) and 287 (M+H)((ESf) ; NMR (400 Mhz, DMSO-d6) δ 8.83 (d, J = 5.1 Hz, 1H), 7.65 (d, J - 5.1 Hz, 1H), 5.21 (s, 1H), 3.73 (s, 3H), 1.42 (s, 9H). 1-(tert-butyl)-3-methyl 2-(2-Chloro-5~fluoropyrimidin-4-yl)malonate INTC2 NaH (60% wt in mineral oil, 0.575 g, 14.4 mmol) was added portionwise to a stirred solution of tert-butyl methyl malonate (2.23 mL, 13.2 mmol) in DMF (20 mL). The IF-2019-16749728-APN-jW^INPI Page 122 of 363 reaction was stirred at RT in an atmosphere for 10 min until hydrogen was no longer evolved. The reaction was cooled to 0 °C and 2,4-dichloro-5fluoropyrimidine (2.0 g, 12.0 mmol) was added. The resulting mixture was stirred slowly at RT for 18 hours. The reaction mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography (4 0 g column, 0-50% EtOAc / isohexane) to provide 2 —(Ιο lo ro— 5— f luoropi r imidin— 4 — i 1) malonate 1-tert-butyl and 3methyl (1.96 g, 5.47 mmol, 46% yield) as a transparent colorless oil; tR 1.42 min (acid HPLC); m / z 305 (M+H) ' (ES4) ; NMR (400 Mhz, DMSO-d6) δ 9.08 - 8.90 (m, 1H), 5.47 - 5.38 (m, 1H), 3.75 (s, 3H), 1.43 (s, 9H). 1-(tert-butyl)3-methyl 2-(2-Chloro-5-methylpyrimidin-4-yl)malonate INTC3 NaH (60 wt% dispersion in mineral oil, 0.466 g, 11.7 mmol) was added portionwise to a stirred, ice-cold solution of tert-butyl methyl malonate (1.97 mL, 11.7 mmol) in THF (10 mL). . The reaction was stirred at RT for 10 min. 2,4-Dichloro-5-methylpyrimidine (1.0 g, 6.13 mmol) was then added and the resulting mixture was stirred at 70 °C for 2 h. The reaction was allowed to cool, partitioned between saturated NH4C1 (aq, 10 mL) and EtOAc (10 mL), the two phases were separated and the organic layer was passed through a phase separator. The crude product was purified by silica gel chromatography (12 g column, 0-30% EtOAc / isohexane) to provide 1-tert-butyl 2-(2~chloro-5methylpyrimidin-4-yl)malonate and 3 -methyl (1.40 g, 4.41 mmol, 72% yield) as a colorless oil; tR 1.39 min (acid HPLC); m / z 201 (M-Boc+H)1(ES1);XH NMR (500 Mhz, DMSO-d6) δ 8.66 (d, J = 0.8 Hz, IF-2019- 16749728-APN-l^INPI Page 123 of 363 1H), 5.38 (s, 1H), 3.74 (s, 3H), 2.19 (d, J = 0.7 Hz, 3H), 1.44 (s, 9H). 1-tert-butyl 3-methyl 2-(2-Chloro-6-methylpyrimidin-4-yl)malonate INTC54 l\k / Cl Prepared as for INTC1 using commercial 2,4-dichloro-6-methylpyrimidine and 3-methyl tert-butyl malonate to provide 1-tert-butyl 3-methyl 2-(2-chloro-6-methylpyrimidin-4yljmalonate (617; from yield) as a transparent oil. tR 1.39 (basic UPLC); m / z 301 (35C1 M+H)f(ES!); ), 3.70 (s, 3H), 2.52 (s, 3H), 1.40 (s, 9H). 1I 2-(2-Chloro-6-(trifluoromethyl)pyrimidin-4-yl)malonate Ck / -O Nk .Cl tert-butyl and 3-methyl INTC55 Prepared as for INTCl using 2,4-dichloro-6(trifluoromethyl)pyrimidine and commercial methyl tert-butyl malonate to provide 1-tert 2-(2-chloro-6(trifluoromethyl)pyrimidin-4-i1)malonate -butyl and 3-methyl (671 yield) as a transparent oil. tR 1.34 (basic UPLC); no m / z;!H NMR (500 Mhz, DMSO-d6) was observed δ 8.21 (s, 1H), 5.39 (s, 1H), 3.74 (s, 3H), 1.42 (s, 9H). Dimethyl 2-(2-Chloropyrimidin-4-yl)-2-methoxymalonate IF-2019-16749728-APN-1&&INPI Page 124 of 363 INTC56 EITHER . O'Oj EITHER Prepared as for INTC1 using 2,4-dichloropyrimidine and dimethyl 2-methoxymalonate to provide dimethyl 2-(2-chloropyrimidin-4-yl)-2-methoxymalonate (79¾ yield) as a clear colorless oil. tR 1.55 (acidic HPLC); m / z 275 (31C1 M+H)+(ES+) ; ¥ MRI not recorded. Material used directly in the next step without additional purification. Dimethyl 2-(2-Chloropyrimidin-4-yl)-2-isopropylrnaionate INTC57 Prepared as using dichloropyrimidine and dimethyl 2-isopropylmalonate to provide dimethyl 2-(2-chloropyrimidin-4-yl)-2-isopropylmalonate (981 yield) as a red gum. tR 0.64 (acidic UPLC 2) ; m / z 2 86 (J5C1 M+H)!(ES1) ; ¥ MRI not recorded. Material used directly in the next step without additional purification. Decarboxylation of chloropyrimidines Methyl 2-(2-Chloropyrimidin-4-yl)acetate INTC4 ¥ T ¥ O A>,.. N TFA (55.3 mL, 717 mmol) was added dropwise to a stirred, ice-cold solution of 1-tert-butyl 3-methyl 2-(2-chloropyrimidin4-yl)malonate INTC1 (12.1 g, 42.2 mmol). in DCM (50 mL). The reaction was stirred at 25 °C for 1 h and then concentrated in vacuo. The residue is IF-2019-16749728-APN-ÁKS1INPI Page 125 of 363 dissolved in EtOAc (200 mL) and basified with NaHCO? (200 mL), the organic layer was isolated and passed through a phase separator, the solvent was removed in vacuo. The crude product was purified by silica gel chromatography (220 g cartridge, 0-50.1 EtOAc / isohexane) to provide methyl 2-(2-chloropyrimidin-4-yl)acetate (7.12 g, 37.8 mmol, 901 yield) as a pale yellow oil. tR 1.16 min (acid HPLC); m / z 187 (M+H)1(ES1) ; 1H NMR (500 Mhz, DMSO-d6) δ 8.76 (d, J = 5.0 Hz, 1H), 7.60 (d, J = 5.0 Hz, 1H), 3.96 (s, 2H), 3.66 (s, 3H). Method A: Decarboxylation of chloroheterocycles such as chloropyrimidines X= CH, N Y = CR2, N Z = CRJtN TEA (10 eq) was added dropwise to a stirred, ice-cold solution of malonate derivative (1 eq) in DCM (15 volumes). The reaction vessel was stirred at RT for 18 h and then concentrated. The crude product was purified by normal phase chromatography. IF-2019-16749728-APN-Mf#INPI Page 126 of 363 Table 1: The following intermediates were prepared according to Method A. INTC Name / Structure (All examples containing chiral centers are racemates unless otherwise noted) Synthesis method, [LCMS Method]r m / z (M+H)+ , (tR / min) Displacement data NMR chemicals of A (DMSO-dg unless otherwise indicated) INTC5 methyl 2- (2~chloro-5-fluoropyrimidin-4-yl)acetate A'. .-N-. ^-ci «T Y Method A using INTC2, [acidic HPLC], 205 (0.85). 3.91 (d, J = 1.4 Hz, 1H), 4.04 (d, J = 1.9 Hz, 2H), 3 .68 (s, 3H) . INTC6 methyl 2-(2~chloro~5methylpyrimidin-4yl)acetate n YCI ° / N Method A using INTC3, [acidic HPLC], 201 (0 .82) . 8.60 (s, 1H), 3.96 (s, 2H), 3.66 (s, 3H), 2.24 (s, 3H). INTC58 2- (2-chloro~6~ methylpyrimidin~4~ yl)methyl acetate Αγ-'χζ ΝΎci Method A using INTC54, [basic UPLC], no m / z (0.78) . 7.45 (s, 1H), 3.88 (s, 2H), 3.65 (s, 3H), 2.47 (sf 3H). INTC59 2~ (2-chloro-6- (trifluoromethyl)pyrimidin4-yl)methyl acetate,. Ν-ϊγ-·010 T,F p' A Method A using INTC55, [Basic UPLC], without m / z (1.22) . 8.19 (s, 1H), 4.12 (s, 2H), 3.67 (s, 3H). IF-2019- 16749728-APN-ÁS?#INPI Page 127 of 363 INTC60 2- (2“-chloropyrimidin-4-yl) methyl 4-methoxybutanoate O''*’ or Method A using INTC16, [UPLC acid], M+Na isotope 3'Ο1 2 67 (0.94). 8.76 (d, J = 5.0 Hz, 1H), 7.60 (d, J = 5.0 Hz, 1H), 3.98 - 3.94 (m, 1H), 3.63 (s, 3H), 3.37 - 3.20 (m, 2H) , 3.16 (s, 3H), 2.31 - 2.21 (m, 1H), 2.14 - 2.03 (m, 1H). INTC61 2-(2-chloropyrimidin~4yl)butanoate methyl N'íy·c!0 Method A using INTC15, [acid HPLC], M+H isotope ^'Cl 215 (1.68). 8.76 (d, J = 5.1 Hz, 1H), 7 .60 (d, J = 5.1 Hz, 1H)t 3.87 (t, J = 7.5 H z, 1H), 3.63 (s, 3H), 2.08 - 1.98 ( m, 1H), 1.93 - 1.83 (m, 1H), 0.83 (t, J - 7.4 Hz, 3H). Rental Methyl 2-(2-Chloropyrimidin-4-yl)-2-methylpropanoate INTC7 Mel (0.24 mL, 3.89 mmol) was added to a stirred suspension of methyl 2-(2“Chloropyrimidin-4~yl)acetate INTC4 (0.29 g, 1.55 mmol) and K2CO3 (0.644 g, 4.66 mmol) in acetone (5 mL). The reaction vessel was sealed and stirred at 60 °C for 18 h. The reaction mixture was concentrated in vacuo, water (40 mL) was added and extracted with DCM (2 x 40 mL). The organic phase was dried (phase separator) and concentrated in vacuo. The crude product was purified by silica gel chromatography (2 4 g column, 0-501 EtOAc / isohexane) to provide 2-(2-chloropyrimidin-4IF-2019-16749728-APN-ASft / INPI Page 128 of 363 Methyl il)-2-methylpropanoate (0.25 g, 1.11 mmol, 71¾ yield) as a clear, pale yellow liquid; tR 1.70 min (acid HPLC); m / z 215 (M+H)* (ES*); NMR (400 Mhz, DMSO“d6) δ 8.78 (d, J = 5.2 Hz, 1H), 7.66 (d, J = 5.2 Hz, 1H), 3.63 (s, 3H), 1.53 (s, 6H). Methyl 2-(2“Chloropyrimidin-4-yl)propanoate INTC8 MeT (14.1 mL, 225 mmol) was added to a stirred suspension of 2-(2-chloropyrinidin-4-yl) methyl acetate INTC4 (10.37 g, 45.0 mmol) and K2CO3 (31.1 g, 225 mmol) in acetone (150 mL). The reaction mixture was stirred at 60 °C for 40 h under N2 atmosphere. The reaction mixture was concentrated in vacuo, the resulting mixture was diluted in EtOAc and filtered. The inorganic phases were washed with EtOAc and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (220 g column, 0-301 EtOAc / isohexane) to provide methyl 2~(2-chloropyrimidin-4yl)propanoate (1.27 g, 5.00 mmol, 111 yield) as the by-product; tR 0.89 min (acidic UPLC); m / z 201 (M+H)r(ES*) . ^H-PMN data were not recorded. Method B: Alkylation π = 1Λ3 n = 1,2,3 IF-2019-16749728-APN-A$&HNPI Page 129 of 363 Base (2.5 - 5 eq) was added to a stirred, ice-cold mixture of methyl 2-(2-chloropyrimidin™4-yl)acetate (1 eq) in an appropriate polar aprotic solvent such as DMF or acetone (10 volumes ). After 20 min, 5 alkyl halide (1-5 eq) was added. The reaction vessel was stirred at 0 °C for 30 min, then at RT for 2 h. The reaction was quenched with NH^Cl (aq) or 1M HC1 (aq), stirred for 20 min, then extracted with EtOAc. The organic phases were dried (phase separator) and concentrated. The crude product was purified by normal phase chromatography. Table 2: The following intermediates were prepared according to Method B. INTC Name / Structure (All examples containing chiral centers are racemates unless otherwise indicated) Synthesis method, [LCMS Method], m / z (M+H) + , (tR / min) Data NMR chemical shifts of TH (DMSO-da unless otherwise indicated) Base, RX, solvent and INTC 9 methyl 2-(2-chloro-5-fluoropyrimidin-4~yl)~2~ methylpropanoate O .JL F Method B using INTC5, [acidic UPLC], 233 (1.31) . 8.88 (d, J = 2.5 Hz, 1H), 3.66 (s, 3H), 1.52 (s, 6H). K2CO:1, Mel, acetone INTC10 methyl 2-(2-chloro-5- methylpyrimidin~4~ yl)propanoate / λ Αχ N<yCi o XXa Method B using INTC6, [acidic UPLC], 215 (1.03). 8.60 (s, 1H), 4.25 (q, J = 7.0 Hz, 1H), 3.61 (s, 3H), 2.29 (d, J = 0.8 Hz, 3H), 1.40 (d, J = 7.0 Hz, 3H). K2CO3, Mel, acetone INTC11 methyl 2-(2-chloro-5~ methylpyrimidin-4-yl)-2methylpropanoate 0 'Ύ τ Method B using INTC6, [acidic UPLC], 228 / 231 (1.26). 8.57 (d, J = 0.8 HZ, 1H), 3.66 (s, 3H), 2.13 (d, J = 0.8 Hz, 3H), 1.50 (s, 6H). K2CO?, Mel, acetone IF-2019-16749728-APN-ÁSWlNPI Page 130 of 363 INTC12 methyl 2-(2-chloropyrimidin-4yl)-2-ethylbutanoate O Method B using INTC4, [acidic UPLC], 243 (1.38). 8.83 - 3.67 (m, 1H), 7.65 - 7.52 (m, 1H), 3. 63 (s, 3H), 2.07 1.99 (m, 4H), 0.730.59 (m, 6H). NaOH, EtA, DMF INTC13 methyl 1-(2-chloropyrimidin-4yl)cyclopropane-1carboxylate 0 kA Method B using INTC4, (acidic UPLC], 213, (1.05). 8.78 - 8.62 (m, 1H), 7.94 - 7.81 (m, 1H), 3.68 (s, 3H), 1.70 1.56 (m, 4H). Na OH, BrCH,CH?B r DMF INTC14 methyl 1-(2-chloropyrimidin~4yl)cyclopentane-1carboxylate _.O <. m, 2H), 2.21 - 2.06 (m, 2H), 1.31- 1.57 (m, 4H), B r - (n Bu)-Br DMF INTC15 2- (2-chloropyrimidin-4yl)-2-ethylmalonate 1(teut-butyl) y 3-methyl i O=Z J ,-O-, JX. ...N, .C1 TY Y 0 '-e--N Method B using INTC1, [acidic UPLC], 315 (1.58 ). (t, J = 7.4 Hz, 3H) ! / °4Y to I or Y<.--N Method B using INTC1, [acidic UPLC], 345 (1.48) . 8.83 (dd, J = 5.2, 1.0 Hz, 1H), 7.83 (d, J = 5.3 Hz, 1H), 3.72 (s, 3H), 3.31 3.24 (m, 2H), 3.11 (s, 3H), 2.47 - 2.40 (m, 2H), 1.39 (s, 9H) . NaOH, BrCH / CH-O Me, DMF INTC62 methyl 2-(2~chloro-6-methylpyrimidin-4-yl)-2methylpropanoate or ,>N Method B using INTC58 No LCMS data 7.53 (s, 1H), 3.62 (s, 3H), 2.50 (s, 3H), 1.51 (s, 6H). K2CO;, _MeI, acetone IF-2019-16749728-APN-ÁM#INPI Page 131 of 363 INTC63 methyl 2- (2-chloro-6- (trifluoromethyl)pyrimidi n-4-yl)-2- methylpropanoate F'T'F F Method B using INTC59 No LCMS data S . 17 (s, 1H), 3.64 (s, 3H), 1.59 (s, 6H). KzCOíf Mel, acetone INTC64 methyl 2-(2,6-dichloropyrimidin4-yl)-2-methylpropanoate fg· Cl Method B using commercial pyrimidine [acidic UPLC], isotope 3jCl 249 (1.39). 7.90 (s, 1H), 3.63 (s, 3H), 1.53 (s, 6H). tBuOK, Mel, THE SnAR in 2,6-dichloropyrimidines Methyl 2-(2-Chloro-6-methoxypyrimidin-4-yl)-2-methylpropanoate INTC65 To a stirred solution of methyl 2-(2,6~dichloropyrimidin-4-yl)-2methylpropanoate INTC64 (0.77 g, 2.78 mmol) in MeOH (10 mL) at 0 °C was added 5.4 M sodium methanolate (MeOH) (0.6 mL, 3.24 mmol). The mixture was stirred at 0°C for 30 min, then at RT for a further 30 min. The reaction was then concentrated in vacuo. The crude product was purified by silica gel chromatography (40 g column, 0-50% EtOAc / isohexane) to provide methyl 2-(2-chloro-6-methoxypyrimidin-4-yl)-215 methylpropanoate ( 0.54 g, 1.72 mmol, 62% yield) as a white solid. tR 1.35 min (UPLC, acidic); m / z 245 (^Cl M+H)+(ES1); 1H NMR (400 Mhz, DMSO-d6) δ 6.99 (s, 1H), 3.96 (s, 3H), 3.61 (s, 3H), 1.48 (s, 6H). IF-2019-16749728-APN-Á$?#INPI Page 132 of 363 Formation of heterocycles through alkylation Methyl 4-(2-Chloropyrimidin-4-yl)tetrahydro-2H-pyran-4-carboxylate INTC52 To a solution of INTC4 methyl 2-(2-chloropyrimidin-4-yl)acetate (2.0 gf10.1 mmol) in DM.F (10 mL, 10.7 mmol) at 0 °C was added NaOH (0.986 g, 24.6 mmol ). The reaction mixture was stirred at 0 °C for 20 min, then l-bromo-2-(2-bromoethoxy)ethane (1.8 mL, 12.9 mmol) was added. The reaction was stirred at RT for 23 h. The reaction mixture was acidified using 1M HC1 (aq, 53.6 mL, 53.6 mmol) before extracting with DCM (70 mL). The phases were separated using a phase separator cartridge and the aqueous was extracted with more DCM (2 x 50 mL). The combined organic phases were concentrated in vacuo. The crude product was purified by silica gel chromatography (8 0 g column, 0-5 0% EtOAc / isohexane) to provide methyl 4-(2-chloropyrimidin-4-yl)tetrahydro~2fl-pyran4-carboxylate. (1.83 g, 5.57 mmol, 52% yield) as a yellow oil. tR 1.56 min (HPLC, acidic); 257 m / z (3!?C1 M+H)+(ES*) ;]H NMR (500 Mhz, DMSOd6) δ 8.80 (d, J = 5.3 Hz, 1H), 7.69 (d, J = 5.3 Hz, 1H), 3.72-3.67 (m, 2H), 3.66 (s, 3H), 3.55-3.50 (m, 2H), 2.33 2.22 (m, 2H), 2.16 - 2.06 (m, 2H). Heterocycle formation via enolate SNAR 1-tert-butyl 4-methyl 4-(2-chloropyrimidin-4-yl)piperidine-1,4-dicarboxylate INTC66 Boc i IF-2019-16749728-APN-l^INPI Page 133 of 363 LiHMDS (1.61 mL, 1.61 mmol) was added in one portion to a stirred, ice-cold solution of 1-tert-butyl 4-methyl piperidine-l,4dicarboxylate (340 mg, 1.40 mmol) and 2,4-dichloropyrimidine (200 mg, 1.34 mmol) in THF (10 mL). The reaction mixture was allowed to warm to RT and stirred for 2 h. The reaction was quenched by the addition of NaH^PCq (aq, 1M, 3 mL). The product was extracted with DCM (2 x 10 mL). The combined organic extracts were dried using a hydrophobic phase separator and concentrated in vacuo. The crude product was purified by silica gel chromatography (24 g column, 0-50% EtOAc / isohexane) to provide 1-tert-butyl 4-(Ιοί oropyrimidin-4-i1)piperidine-l,4-dicarboxylate and 4-methyl (315 mg, 0.66 mmol, 49% yield) as a colorless oil. tR 2.29 min (HPLC, acid); m / z 255 (35C1 M-Boc+H)+(ES’) ; NMR (500 Mhz, DMSO-d6) δ 8.79 (d, J = 5.3 Hz, 1H), 7.68 (d, J = 5.3 Hz, 1H), 3.69 - 3.59 (m, 5H), 3.13 (s, 2H), 2.26 - 2.22 (m, 2H), 2.06 - 2.00 (m, 2H), 1.40 (s, 9H). 3-Methyl 1-tert-butyl 3-(2-Chloropyrimidin-4-yl)azetidine-1,3-dicarboxylate INTC67 boc Prepared as for INTC66 using 3-methyl 1-tert-butyl azetidine-1,3-dicarboxylate and 2,4-dichloropyrimidine in toluene to provide 1-tert-butyl 3-(2-chloropyrimidin-4-yl)azetidin-1,3-dicarboxylate and 3-methyl (7¾ yield) as a pale yellow oil. tR 2.12 min (HPLC, basic); m / z 272 (JbCl M-tBu+H)+(ES+) ;ΊΗ NMR (500 Mhz, DMSO-d6) δ 8.83 (d, J = 5.2 Hz, 1H), 7.72 (d, J = 5.2 Hz, 1H ), 4.39 - 4.35 (m, 2H), 4.34 - 4.28 (m, 2H), 3.71 (s, 3H), 1.39 (s, 9H). IF-2019-16749728-APN-Á3^INPI Page 134 of 363 Hydrolysis of chloropyrimidines Lithium 2-(2-Chloropyrimidin-4-yl)-4-methoxybutanoate INTC68 O'' UO-^AyN^CI To a solution of methyl 2-(2-chloropyrimidin~4“yl)-4methoxybutanoate INTC60 (479 mg, 1.96 mmol) in THE (5 mL) and MeOH (2.5 mL) was added a solution of LiOH (56 mg, 2.35 mmol) in water (3 mL). The reaction mixture was stirred at ΤΆ for 72 h. The reaction mixture was concentrated in vacuo to obtain lithium 2-(2-chloropyrimidin-4-yl)-4methoxybutanoate (441 mg, 1.49 mmol, 767 yield) as a colorless solid. tR 1.34 min (acid HPLC); m / z 231 (as free acid5SC1 M+H)!(ES1-) ;JH NMR (500 Mhz, DMSO-d6) δ 8.64 (d, J - 5.1 Hz, 1H), 7.48 (d, J = 5.1 Hz, 1H), 3.39 - 3.33 (m, 1H), 3.22 (s, 3H), 2.82 - 2.75 (m, 2H), 1.96 - 1.85 (m, 2H). Coupling (sulfonamideation) 1(tert-butyl) 3-methyl 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-i1)malonate INTC17 (L / Ό In a 2 0 mL vial, cyclopropanesulfonamide (0.254 g, 2.09 mmol); 0.50 g, 1.74 mmol) and dioxane (2 mL). The mixture was degassed (N2, 5 min). In a separate 20 mL vial, [Pd(allyl)C1]2 (16 mg, 0.044 mmol), tBuXPhos (74 mg, 0.174 mmol), and dioxane (1 mL) were stirred under N2 atmosphere for 5 min, then They added to the first vial. The resulting reaction mixture was heated in an NIF-2019-16749728-APN-ÁÍJ&INPI atmosphere. Page 135 from 363 to 60 °C for 2.5 h. The mixture was allowed to cool to ΤΑ, diluted with H2O (2 mL) and then carefully acidified with 1M HC1 (aq, 5 mL) to pH 4. The residue was extracted with EtOAc (2 x 20 mL), the organic phase It was filtered through a phase separator and the solvent was removed in vacuo. The yellow residue was purified by solvation of impurities with TBME (10 mL), filtered and washed with TBME (10 mL) to obtain 1-tert10-butyl 2-(2(cyclopropanesulfonamido)pyrimidin-4-yl)malonate and 3-methyl (0.394 g, 1.05 mmol, 60% yield) as a white solid; tR 1.87 min (acid HPLC); m / z 372 (M+H)+(ES+) ; NMR (400 Mhz, DMSOd6) δ 12.57 (s, 1H), 11.61 (s, 1H), 7.28 - 7.21 (m, 1H), 6.10 (s, 1H), 3.67 (s, 3H), 2.75 - 2.65 (m, 1H), 1.44 (s, 9H), 1.18 - 0.83 ( m, 15 4H). 8:2 mixture of tautomers. Method C: Formation of sulfonamides from aromatic halides The 2-chloropyrimidine intermediate (1 eq), sulfonamide (1.2 eq) and base (2 eq) were dissolved in dioxane (40 volumes). The mixture was degassed (N2, 5 min), then catalyst (5 mol%) was added. The resulting mixture was heated under a nitrogen atmosphere at 90 °C for 2 h. The mixture was filtered, washed with EtOAc or DCM and the resulting filtrate was concentrated. The crude product was purified by normal phase chromatography or by adding a suitable solvent to solubilize impurities. IF-2019-16749728-APN-1M#INPI Page 136 of 363 Table 3: The following intermediates were prepared according to Method C. INTC Name / Structure (All examples containing quinal centers are racemates unless otherwise indicated) Method of synthesis, [LCMS Method], m / z (M+H)* r (tR / min) Data NMR chemical shifts of A (DMSO-cf unless otherwise noted) Catalyst, Base, Solvent INTC18 methyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4yl)propanoate i h o A A. ,N. .njiX-' ΪΎ ¥ 5 o A.A o Method C using INTC8, [UPLC acidic], 2 8 6 (0.86), None recorded. tBuXPhos Pd G3, K?CO.(, dioxane INTC19 methyl 2-methyl-2-(2- (methylsulfonamido)pyrimidin-4yl)propanoate HO ,O. AI .N. J¥ li / π Ύ ® o o Method C using INTC7, [acid HPLC], 274 (1.35). ), 3.35 (s, 3H), 1.50 (s, 6H) [Pd(allyl)Cl] 2 tBuXPhos, CS2CO3, dioxane INTC20 methyl 2-(2-(ethylsulfonamido)pyrimidin-4-yl)-2-methylpropanoate. A H 0 AC Π U- A s II II h o A,,-N 0 Method C using INTC7, [acidic UPLC], 288 (0.92) 11.20 (s, 1H) , 3.58 (d, J = 5.3 Hz, 1H) , 7.17 (d, J = 5.2 Hz, 1H), 3.62 (s, 3H), 3.53 (q, J = 7.4 Hz, 2H)t 1.49 (s, 6H), 1.21 (t, J = 7.3 Hz, 3H) . Pd 174, Cs-;COS, dioxane INTC21 (cyclopropanesulfonamido)pyrimidin-4yl)-2-methylpropanoate methyl or JcA N vz n YA Y ? or A.A ° Method C using INTC7, [acid HPLC], 300 (1.55). 11.28 (s, 1H), 8.55 (d, J = 5.3 HZ, 1H), 7.11 (d, J = 5.3 Hz, 1H), 3.61 (s, 3H), 3.22 - 3.11 (m, 1H), 1.49 (s , 6H) , 1.14 0.93 (m, 4H). Pd 174, κχ, dioxane INTC22 methyl 2-(2-(cyclopropanesulfonamido)-5-fluoropyrimidin-4-yl)-2-methylpropanoate A H o Δ AC -Y ,nj A^ Π Έ V s11 I 11 o A.. ,-N O F Method C using INTC9, [acidic UPLC], 318 (1.12) . 11.38 (s, 1H), 8.64 (d, J = 2.8 Hz, 1H), 3.66 (s, 3H), 3.19 (tt, J = 7.9, 4.9 Hz, 1H), 1.52 (s, 6H), 1.14 - 1.03 (m, 4H) . [Pd(alii)Cl]2 tBuXPhos, Cs2CO3, dioxane IF-2019- 16749728-ΑΡΝ-Λ3?#ΙΝΡΙ Page 137 of 363 K PC 2 3 methyl 2-(2- (cyclopropanesulfonamido)-5methylpyrimidin-4-yl)-2-methylpropanoate A H ° A XC A< A All π ti V 3 II 1 li 0 AAi· N O Method C using INTC11, [ UPLC acid], 313 (1.07). 11.07 (s, 1H), 8.36 (s, 1H), 3.66 (s, 3H), 3.26 - 3.19 (m, 1H), 2.05 (s, 3H), 1.50 (s, 6H), 1.13 - 1.00 ( m, 4H). [Pd(alii)Cl] tBuXPhos, CsAA, dioxane INTC24 methyl 2-(2 - (cyclobutanesulfonamido)pyrimidin4-yl)“2-methylpropanoate A ho A? X ,, N. ^N.11, .- A / π n v s □ Ax ° Method C using INTC7, [HPLC ACID], 314 (1.74). 11.11 (s, 1H), 8.56 (d, J = 5.3 Hz, 1H), 7.16 (d, J = 5.3 Hz, 1H), 4.55 (p, J = 8.4 Hz, 1H), 3.63 (s, 3H), 2.45 - 2.31 (m, 2H), 2.30 - 2.15 (m, 2H), 2.01 1.84 (m, 2H), 1.49 (s, 6H). [Pd(allyl)C1 ] ¿ tBuXPhos, CS;CO3, dioxane INTC25 2- (2- (1,1- dimethylethylsulfonamido)pyrimidin-4-yl) - methyl 2-methylpropanoate A η o A ,.0-. .-A A xnX ' AY Y S □ A-A ° Method C using INTC7, [acid UPLC], 316 (1.0 9 ) . 10.73 (s, 1H), 8.55 (d, J = 5.3 Hz, 1H), 7.14 (d, J = 5.2 Hz, 1H), 3.59 (s, 3H), 1.48 (s, 6H), 1.37 (s, 9H) ). Pd 174, Cs-AO.,, dioxane INTC26 methyl 2-methyl-2- (2- (I-methylcyclopropanesulfonamido)pyrimidin- 4-yl)propanoate A HO ,0. * 11 .04 (s, 1H), 8.57 (d, J = 5.2 HZ, 1H), 7.15 (d, J = 5.2 Hz, 1H), 3.60 (s, 3H), 1.55 - 1.45 (m, 8H), 1.43 (s, 3H), 0.89 0.83 (m, 2H). Pd 174, Cs2CO.?, dioxane INTC27 methyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2-ethylpropanoate O A„-N 0 Method C using INTC12, [acidic UPLC], 328 (1.22). 11.24 (s, 1H), 8.66 ~ 8.43 (m, 1H), 7.17 - 7.01 (m, 1H), 3.60 (s, 3H), 3.23 3.06 (m, 1H), 2.11 - 1.84 (m, 4H), 1.15 -0.96 (m, 4H) , 0.P 9 0.57 (ni, 6H) . Pd 174, CSjCO;, dioxane INTC28 1- (2- (cyclopropanesulfonamido)pyrimidin-4yl)cyclopropane-l-carboxylate methyl V7 H o A ,.o._ ,A „N.. ,νηιΑ X A A s II II it o Ax ° Method C using INTC13, [UPLC acid], 298 (0.93). 11.19 (s, 1H), 8.57 - 8.43 (m, 1H), 7.52 - 7.32 (m, 1H), 3.67 (s, 3H), 3.20 3 . OS (m, 1H), 1.68 - 1.52 (m, 4H), 1.15 - 0.98 (m, 4H). Methyl cyclopentane-l-carboxylate Ci H o A A A. 'Yr r s or AA or Method C using INTC14, [UPLC acid], 326 (1.17). 11.23 (s, 1H), 8.59 - 8.45 (m, 1H), 7.17 - 7.05 (m, 1H), 3.61 (s, 3H), 3.253.12 (m, 1H) r 2.40-2.24 (m, 2H), 2.21 - 2.08 (m, 2H), 1.73 1.59 (m, 4H), 1.18 - 0.96 (m, 4H) . Pd 174, Cs2CO.,, INTC30 2-(2-(cyclopropanesulfonamido)pyrimidin-4i1)-2-ethylmalonate of 1-(tert-butyl) and 3-methyl i oAJ h 0 A n .X. A. Α,!Α^ n r V s il II ii o Aa 0 Method C using INTC15, [acid UPLC], 400 (1.40) . 11.30 (s, 1H), 8.62 (d, J = 5.3 Hz, 1H), 7.35 (d, J = 5.3 Hz, 1H), 3.71 (s, 3H), 3.21 - 3.10 (m, 1H), 2.302 .10 (m, 2H), 1.41 (s, 9H), 1.18 - 0.97 (m, 4H), 0.83 (t, J = 7.4 Hz, 3H). Pd 174, Cs2CO3, dioxane INTC31 2-(2- (cyclopropanesulfonamido)pyrimidin-4yl)-2-(2-methoxyethyl)malonate of 1- (tert-butyl) and 3-methyl i o o- rj' / .A n / ,° o4 T Y r-A / 1 Ya ° V Method C using INTC16, [UPLC acid], 430 (1.31) . 11.31 (s, 1H), 8.63 (d, J = 5.3 Hz, 1H), 7.33 (d, J = 5.3 Hz, 1H), 3.70 (s, 3H), 3.32 - 3.24 (m, 2H), 3.20 3 . 14 (m, 1H), 3.13 (s, 3H), 2.49-2.32 (m, 2H), 1.39 (s, 9H), 1.15- 0.98 (m, 4H). Pd 174, Cs2C0.u dioxane INTC32 1-(tert-butyl)-3-methyl 2-(2-(cyclopropanesulfonamido)-5fluoropyrimidin-4-yl)malonate γΧνΎ 1 0 f,-'Aa 0 Method C using INTC2, [UPLC acid], 390 (1.27). 11.47 (s, 1H), 8.81 - 8.72 (m, 1H), 5.31 - 5.20 (m, 1H), 3.75 (s, 3H), 3.20 3.12 (m, 1H), 1.43 (s, 9H), 1.17 - 0.99 (m, 4H) . Pd 174, K?CO,y, dioxane IF-2019-16749728-APN-AS^INPI Page 139 of 363 T-RC53 4- (2- (cyclopropanesulfonamido)pyrimidin-4yl)tetrahydro-2H-pyran-4~carboxylate methyl,0. 1 L J H or 0..X.N N,H J XX or' >7 Method C using INTC52 ​​[UPLC, acid], 342 (0.88). 11.30 (s, 1H), 8.61 (d, J = 5.3 Hz, 1H), 7.20 (d, J = 5.3 Hz, 1H), 3.79 - 3.71 (m, 2H), 3.67 (s, 3H), 3.523.48 (m, 2H), 3.25 - 3.15 (m, 1H), 2 .24-2.21 (m, 2H), 2.13 2.03 (m, 2H), 1.08 - 1.01 (m, 2H), 0.91 - 0.87 (m, 2H) ). Pd 174, Cs;-CO3, dioxane INTC69 methyl 2-(2-(cyclopropanesulfonamido)-6methylpyrimidin-4-yl)-2-methylpropanoate V H O A .0. >< . Μ Π ¥ 11.09 (s, 1H), 7.05 (s, 1H), 3.59 (s, 3H), 3.21 - 3.11 (m, 1H), 2.40 (s, 3H), 1.48 (s, 6H), 1.15 - 1.07 (m, 2H), 1.07 0 . 96 (m, 2H) .[Pd(allyl)C1 ] 2 tBuXPhos, Cs2CO3, dioxane INTC70 methyl 2-(2-(cyclopropanesulfonamido)-6(trifluoromethyl)pyrimidin-4-yl)-2- methylpropanoate or ° F'T'F F Method C using INTC63, [acidic UPLC], 368 (1.37). 11.87 (s, 1H) t 7 . 64 (s, 1H), 3.63 (s, 3H), 3.15 - 3.05 (m, 1H), 1.56 (s, 6H) f 1.20 - 1.04 (m, 4H). [Pd(allyl)C1 ]tBuXPhos, Cs2CO3, dioxane INTC71 2-(2-(cyclopropanesulfonamido)-6methoxypyrimidin-4-yl)-2~methylpropanoate methyl -°XrNY>'L 0 X,-N ° V °x. Method C using INTC65, [acid HPLC], 330 (1.86). 11.11 (s, 1H), 6 . 53 (s, 1H) , 3.91 (s, 3H), 3.59 (s, 3H), 3.25 - 3.17 (m, 1H) , 1.46 (s, 6H)f 1.17 - 0.90 (m, 4H) . Pd-174 dioxane INTC72 3-(2-(cyclopropanesulfonamido)pyrimidin-4yl)azetidine-1,3-dicarboxylate 1-tert-butyl and 3-methyl Boc 1 N H o .O. >< _,bt N t / ' IT Ti ''Y S. o °* X7 Method C using INTC67 , [UPLC acid], 313 (MBoc + H) (1.22). 11.40 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 7.24 (d, J = 5.2 Hz, 1H), 4.38 - 4.34 (m, 2H), 4.32 4.26 (m, 2H), 3.71 ( s, 3H), 3.20 - 3.11 (m, 1H), 1.39 (s, 9H), 1.16 - 1.05 (m, 2H), 1,081.00 (m, 2H). Pd-174 Cs2CO3, dioxane. IF-2019-16749728-APN-Á140¥INPI Page 140 of 363 1-tert-butyl 3-methyl 2- (2-methoxyethyl)~2~ (2- (methylsulfonamido)pyrimidin-4-yl)malonate 0A / ° Η O / X / — ' fl —O ° Method C using INTC16, [acid HPLC], 404 (1.91). 11.33 (s, 1H), S.63 (d, J - 5.3 Hz, 1H), 7. 33 (d, , 2.41 - 2.34 (m, 1H), 1.40 (ξ, 9H) . Pd-174 Cs;CO-, dioxane INTC74 methyl 2-fluoro-2-(2- (methylsulfonamido)pyrimidin-4yl)butanoate F ) \Z Η O .o. pt .XX - π n X s Η 1 ii 0 0 Method C using INTC85, [acid HPLC], 292 (1.52) . 11.56 (s, 1H), 3.74 (d, J = 5 . 1 Hz, 1H), 7.31 (d, J = 5.1 Hz, 1H), 3.74 (s, 3H), 3.37 (s, 3H), 2.43 - 2.17 (m, 2H), 0.38 (t, J = 7.3 Hz, 3H). Pd-174 Cs2CO3, dioxane INTC75 (cyclopropanesulfonamido)pyrimidin-4yl)-2-dimethyl methoxylonate ''O / 0 / 3·NN -< / Y Y ü Method C using INTC56, [acid HPLC], 360 (1.49). 11.48 (s, 1H), 8.70 (d, J = 5.2 Hz, 1H), 7.26 (d, J = 5.2 Hz, 1H), 3.77 (,s, 6H), 3.49 (s, 3H), 3.23 - 3.10 ( m, 1H) , 1.16 1.01 (m, 4H). Pd-174 CssCO3, dioxane INTC76 1-tert-butyl 4-raethyl 4-(2-(methylsuIfonamido)pyrimidin-4yl)piperidine-1,4-dicarboxylate BOC X L J Η o .0. * 11.36 (s, 1H), 8.60 (d, J = 5 . 3 Hz, 1H), 7.20 (d, J = 5.3 Hz, 1H), 3.72 - 3.62 (m, 7H), 3.35 (s, 3H), 2.25 2.19 (m, 2H), 1.98-1.92 (m, 2H), 1.40 (s, 9H) . Pd-174 Cs?CO3, dioxane IF-2019-16749728-APN-41^INPI Page 141 of 363 PAC 7 7 4- (2- Method C 11.30 (s, 1H) (cyclopropanesulfonamido)pyrimidine~4~ using 8.59 (d, J = 11)piperidine-1,4-dicarboxylate of 1 tert-butyl and 4-methyl Boc 1 ó ó H o TA .n. δ 5A ti Ά m O A^n o \7 1NTC66 [acid HPLC] 395 (M tBulH) (2.08) f F Hz, 1H) , 7.19 (d, J = 5.3 H 1H), 3.74 - 3 (m, 1H), 3.67 (s, 3H), 3.24 3 . 15 (m, 1H), 2.53-2.48 (2H), 2.26 - 2 (m, 3H), 2.03 1.92 (m, 2H), 1.4 0 (s, 9H), 1.15-1.08 (2H), 1.08 - 1 ( m, 2H). INTC7 8 2- (2- Method c A NMR dimethyl no (cyclopropanesulfonamido)pyrimidin-4yl)-2~isopropylmalonate o \ A ° / o U 0 V using INTC57, [UPLC acidic 2], 372 (0.58) . registered. Pd-174. 3 tBuXPhos, dioxane m, :. 19m, . 00 CS-COyi, dioxane Decarboxylation Methyl 2-(2(cyclopropanesulfonamido)pyrimidin-4-yl)acetate 2,2,2-Trifluoroacetate INTC33Ho A AA Y ®0An oTFA TFA (1 mL, 13.0 mmol) was added dropwise to a stirred, ice-cold solution of 1-tert-butyl 3-methyl 2—(2—(cyclopropanesulfonamido)pyrimidin-4-yl)malonate INTC17 ( 0.27 g, 0.73 mmol) in DCM (2 mL). The reaction vessel was stirred at RT for 2 h and concentrated in vacuo to provide methyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)acetate 2,2,2-trifluoroacetate (0.29 g, 0.68 mmol, 93 % yield) as a yellow solid 15; tR 0.79 min (basic HPLC); m / z 272 (M+H)+(ES+) ; A NMR (400 Mhz, DMSO-d,-.) δ 12.19 (s, 1H), 11.39 10.93 (m, 2H), 8.57 (d, J - 5.1 Hz, 1H), 7.13 (d, J = 5.1 Hz, 1H), 7.00 (dd, J = 7.6, 5.1 Hz, 1H), 5.95 - 5.87 (m, IF-2019- 16749728-APN-ÍA?#INPI Page 142 of 363 1H), 4.92 (s, 1H) , 3.84 (s, 2H) , 3.65 (s, 3H) , 3.61 (s, 3H) , 3.29 - 3.10 (m, 1H) , 2.72 - 2.60 (m, 1H) , 1.17 - 0.85 (m, 8H). 1:1 mixture of tautomers. Method D: Decarboxylation of sulfonamide-substituted pyrimidines TFA (10 eq) was added dropwise to a stirred, ice-cold solution of malonate derivative (1 eq) in DCM (15 volumes). The reaction vessel was stirred at RT for 10 18 h and then concentrated. The crude product was purified by normal phase chromatography. Table 4: The following intermediates were prepared according to Method D. INTC Name / Structure (All examples containing chiral centers are racemates unless otherwise indicated) Synthesis method, [LCMS Method], m / z ÍM+H) +, (tR / min) Data of the NMR chemical shifts of *Η (DMSO-d6 unless otherwise stated) INTC34 methyl 2-(2-(cyclopropanesulfonamido)-5fluoropyrimidin-4-yl)acetate H o A .X XJi π r V s II II ii O 1X O F Method D using INTC32, [acid HPLC], 290 (0.83). 11.37 (s, 1H), 8.76 8.63 (m, 1H), 3.983.89 (m, 2H), 3.67 (s, 3H), 3.26 - 3.12 (m, 1H), 1.16 - 0.98 (m, 4H). IF-2019- 16749728-ΑΡΝ-ΙΛ^ΙΝΡΙ Page 143 of 363 INTO35 Method D (cyclopropanesulfonamido)pyrimidin- using methyl 4-yl)butanoate INTC30, [acid UPLC], 300 (0.99). 11.26 (s, 1H), 8.57 (d, J = 5.1 Hz, 1H), 7.13 (d, J = 5 . 1 Hz, 1H) 3.74 (t, J = 7 . 5 Hz, 1H) , 3 .62 (s, 3H) 3.26 - 3.15 (m, 1H) 2.06 -1.93 (m, 1H) 1.92 -1.77 (m, 1H) 1 . 19 -0.96 (m, 4H) 0 . 85 (t, J = 7 . 4 Hz, 3H) . INTC36 Method D 11.27 (s, 1H), 8.57 (cyclopropanesulfonamido)pyrimidin- using Methyl 4-yl)-4-methoxybutanoate INTC31, [UPLC basic]r330 (0.60). (d, J = 5 .1 Hz, 1H), 7 . 13 (d f J = 5.1 HZ, 1H) , 3 . 91 (t, J = 7 . 4 Hz, 1H) r 3.62 (s, 3H) , . 33 - 3.20 (m, 3H), 3. 19 (s, 3H), 2.23 - 2. 18 (m, 1H), 2.11 - 2. 01 (m, 1H), 1.16 - 0 . 99 (m, 4H). Hydrolysis Potassium 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)butanoate INTC37 A solution of methyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4yl)butanoate INTC35 (2.4 g, 7.22 mmol) in THF (80 mL) was treated with TMSOK (2.26 g, 15.9 mmol). The reaction mixture was allowed to stir at RT for 18 h. The resulting suspension was concentrated in vacuo to provide potassium 2—(2—(cyclopropanesulfonamido)pyrimidin-4-yl)butanoate (3 g, 6.49 mmol, 901 yield) as a pale yellow solid; tR 0.19 min (basic UPLC); m / z 286 (M+H)1(ES+), ionizes as the free acid;ΣΗ NMR (500 Mhz, DMSO-cu) δ 7.97 (d, J= 5.0 Hz, 1H) , 6.35 (d, J= 5.0 Hz, 1H), 3.01 IF-2019-16749728-APN-ΑΛΛίΝΡΙ Page 144 of 363 (tt, J= 8.2, 5.0 Hz, 1H), 2.88 (dd, J- 8.0, 6.9 Hz, 1H), 1.88 - 1.79 (m, 1H), 1.61 - 1.50 (m, 1H), 0.84 - 0.74 (m, 5H), 0.65 - 0.55 (m, 2H), NH proton was not observed. Potassium 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-4methoxybutanoate INTC38 θ' A solution of methyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4yl)-4-methoxybutanoate INTC36 (0.23 g, 0.69 mmol) in THF (5 mL) was treated with ΤΜΞΟΚ (0.22 g, 1.54 mmol). The reaction mixture was allowed to stir at RT for 18 h. The resulting suspension was quenched with MeOH (2 mL), then concentrated in vacuo to give potassium 2-(2(cyclopropanesulfonamido)pyrimidin-4-yl)-4-methoxybutanoate (0.33 g, 0.65 mmol, 941 yield) as a pale red solid; tR 0.14 min (basic UPLC); m / z 316 (M+H)+(ES+), ionizes as the free acid; NMR (500 Mhz, DMSO-ct) δ 8.03 (dd, J = 5.0, 2.9 Hz, 1H, minority), 7.97 (d, J = 5.0 Hz, 1H, majority), 6.59 (d, J = 5.1 Hz, 1H , minority), 6.33 (d, J - 5.0 Hz, 1H, majority), 3.28 - 3.13 (m, 7H), 3.12 - 2.96 (m, 1H), 2.22 - 1.99 (m, 1H), 1.83 - 1.77 (m , 1H), 0.84 - 0.75 (m, 2H), 0.63 - 0.57 (m, 2H). Mixture of tautomers. Potassium 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)acetate INTC39 A solution of methyl 2-(2-(cyclopropanesulfonamido)pyrimidin-4yl)acetate (600 mg, 2.212 mmol) INTC33 in THE (12 mL) was treated with TMSOK (624 mg, 4.87 mmol). The reaction mixture was allowed to stir at RT for 18 h. The resulting suspension was concentrated in vacuo to provide 2 — (2~ IF-2019-16749728-APN-414&INPI Page 145 of 363 Potassium (cyclopropanesulfonamido)pyrimidin-4-yl) acetate (1.069 g, 2.208 mmol, quantitative yield) as a pale yellow solid. tR 0.14 min (acidic UPLC); m / z 258 (M+H)1(ES*) ( ionizes as the free acid.1H NMR (500 Mhz, DMSO-d6) δ 7.97 (d, J - 4.9 Hz, 1H), 6.33 (d, J = 4.9 Hz, 1H), 2.99 - 2.92 (m, 1H)f 0.82 - 0.76 (m, 2H), 0.66 - 0.57 (m, 2H) . 2- (2- (cyclopropanesulfonamido) -5-~fluoropyrimidin-4H°NN - <2° , . o Yn θ V rl)acetic acid INTC40F LiOH (0.105 g, 4.37 mmol) was added to a solution of methyl 2-(2(cyclopropanesulfonamido)-5-fluoropyrimidin-4-yl)acetate (0.49 gr1.457 mmol) INTC34 in MeOH (5 mL) and water ( 2 mL), and stirred at RT for 18 h. The reaction mixture was concentrated in vacuo and the crude product was purified by flash 018 RP column chromatography (40 g column, 0-501 MeCN / water with 0.11 formic acid) to provide 2-(2-(cyclopropanesulfonamido) acid. )-5fluoropyrimidin-4-yl)acetic acid (0.44 g, 0.991 mmol, 681 yield) as a yellow solid. tR 0.65 min (acidic UPLC); m / z 276 (M+H}+(ES+) ; ¥ NMR (400 Mhz, DMSO-d6) δ 8.49 (s, 1H) , 4.15 (s, 1H) , 2.97 - 2.85 (m, 1H) , 2.22 2.15 (m, 2H), 0.86 - 0.69 (m, 2H), 0.69 - 0.52 (m, 2H), CO2H not observed. 4- (6-Ethoxypyrazin-2-yl)-N- (4-methoxybenzyl)aniline INTC41 Sodium triacetoxyborohydride (0.148 g, 0.697 mmol) was added to a solution of 4-(6-ethoxypyrazin-2-yl)aniline INTD18 (0.1 g, 0.465 mmol) and 4-methoxybenzaldehyde (0.085 mL, 0.697 mmol) in DCM ( 3 mL). The reaction was stirred at RT IF-2019-16749728-APN-JH&INPI Page 146 of 363 for 16 hours. Saturated NaHCCq (aq) (20 mL) was added to the reaction, the aqueous phase was extracted with DCM (3 x 20 mL) and the combined organic layers were concentrated in vacuo. The crude product was purified by silica gel chromatography (24 g cartridge, 0-50% EtOAc / isohexane) to provide 4-(6-ethoxypyrazin-2-í1)-N-(4methoxybenzyl)aniline (0.174 g, 0.467 mmol, quantitative yield) as a white solid. tR 1.68 min (UPLC, basic) ; m / z 336 (M+H)!(ES+) .ΊΗ NMR (500 Mhz, DMSO-d6) δ 8.59 (s, 1H) , 8.00 (s, 1H) , 7.88 - 7.83 (m, 2H) , 7.32 7.26 (m, 2H), 6.93 - 6.86 (m, 2H), 6.71 (t, J = 6.0 Hz, 1H), 6.70 - 6.65 (m, 2H), 4.43 (q, J - 7.0 Hz, 2H), 4.27 (d, J - 5.8 Hz, 2H), 3.73 (s, 3H), 1.37 (t, J - 7.0 Hz, 3H). Tert-Butyl 3-((4-(6-Ethoxypyrazin-2-yl)phenyl)(4-methoxybenzyl)amino)-3oxopropanoate INTC42 HATU (0.289 g, 0.760 mmol) was added to a stirred solution of 4-(6-ethoxypyrazin-2-yl)-N-(4-methoxybenzyl)aniline INTC41 (0.17 g, 0.507 mmol), 3-(tert- butoxy)-3-oxopropanoic acid (0.1 mL, 0.649 mmol) and TEA (0.21 mL, 1.507 mmol) in DCM (5 mL). The resulting reaction was stirred at RT for 1 h. The reaction mixture was diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic extracts were dried (phase separator) and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (24 g column, 0-100% EtOAc / isohexane) to provide 3-((4-(6-ethoxypyrazin-2yl)phenyl)(4-methoxybenzyl)amino tert-butyl-3-oxopropanoate (0.2 g, 0.377 mmol, 74% yield) as a IF-2019- 16749728-APN-1#?#INPI Page 147 of 363 colorless, transparent gum. tR 1.74 min (UPLC, basic); m / z 478 (M+H)+(ES+) ; NMR (500 Mhz, DMSO-d6) δ 8.81 (s,1H), 8.25 (s, 1H) , 8.15 - 8.09 (m, 2H) , 7.34 - 7.27 (m,2H) , 7.18 - 7.11 (m, 2H) , 6.8 8 - 6.82 (m, 2H) , 4.8 7 (s,2H) , 4.47 (q, J = 7.0 Hz, 2H), 3.72 (s, 3H), 3.20 (s, 2H),1.39 (t, J - 7.1 Hz, 3H), 1.35 (s, 9H). Tert-Butyl 2-(2-Chloropyrimidin-4-yl)-3-((4-(6-ethoxypyrazin-2yl)phenyl)(4-methoxybenzyl)amino)-3-oxopropanoate INTC43 NaH (601 dispersion in mineral oil) (0.034 g, 0.838 mmol) was added to a stirred solution of tert-3-((4-(6ethoxypyrazin-2-yl)phenyl)(4-methoxybenzyl)amino)-3oxopropanoate. INTC42 butyl (0.2 g, 0.419 mmol) in THF (4 mL, 0.419 mmol). The reaction was stirred at ΤΆ for 10 min, then 2,4-dichloropyrimidine (0.087 g, 0.586 mmol) was added. The resulting mixture was stirred at 70 °C for 2 h under N2 atmosphere. The reaction mixture was quenched with brine (20 mL). The aqueous phase was extracted with DCM (3 x 50 mL), dried (phase separator) and concentrated in vacuo. The crude product was purified by silica gel chromatography (24 g column, 0-100% EtOAc / isohexane) to provide 2-(2-chloropyrimidin-411)-3-((4-(6-ethoxypyrazin-2 tert-butyl -yl)phenyl) (4methoxybenzyl)amino)-3-oxopropanoate (0.13 g, 0.189 mmol, 45% yield) as a colorless, transparent gum. tR 1.86 min (UPLC, basic) ; m / z 591 (M+H) (ES'1);ςΗ NMR (500 Mhz, DMSO-d6) δ 8.81 (s, 1H) , 8.77 (d, J - 5.1 Hz, 1H) , 8.26 (s, 1H) ), 8.15 - 8.12 (m, 2H) , 7.66 IF-2019- 16749728-APN- 14Pl\PI Page 148 of 363 7.63 (m, 1H), 7.22 - 7.16 (m, 4H), 6.90 - 6.85 (m, 2H), 5.02 (d, J - 14.7 Hz, 1H), 4.84 (s, 1H), 4.74 ( d, J = 14.6 Hz, 1H), 4.47 (q, J - 7.0 Hz, 2H), 3.73 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.37 (s, 9H). 2-(2-Chloropyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)N-(4-methoxybenzyl)acetamide INTC44 TFA (0.234 mL, 3.03 mmol) was added dropwise to a stirred, ice-cold solution of 2-(2-chloropyrimidin4-yl)-3-((4-(6-ethoxypyrazin-2-yl)phenyl) ( tert-butyl 4methoxybenzyl)amino)-3-oxopropanoate INTC43 (0.13 g, 0.189 mmol) in DCM (20 mL). The reaction flask was shaken at 25 °C for 7 h and then basified with NaHCO3 (20 mL). The aqueous phase was extracted with DCM (2 x 20 mL), dried (phase separator) and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (24 g column, 0-100% EtOAc / isohexane) to provide 2-(2-chloropyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2- yl)phenyl)-N-(4methoxybenzyl)acetamide (0.05 g, 0.092 mmol, 49% yield) as a colorless, transparent gum. tR 1.62 min (UPLC, acidic) ; m / z 490 (M+H)+(ES+) ; NMR (500 Mhz, DMSO-d6) δ 8.81 (s, 1H), 8.66 (d, J - 5.0 Hz, 1H), 8.25 (s, 1H), 8.14 - 8.10 (m, 2H), 7.45 (d, J - 5.1 Hz, 1H), 7.39 7.34 (m, 2H), 7.17 (d, U = 8.2 Hz, 2H), 6.89 - 6.82 (m, 2H), 4.89 (s, 2H), 4.46 (q, J = 7.1 Hz, 2H), 3.76 (s, 2H), 3.72 (s, 3H), 1.39 (t, J = 7.0 Hz, 3H). 2-(2-Chloropyrimidin-4-yl)-N-(4-(6-ethoxypyrazin-2-yl)phenyl)N-(4-methoxybenzyl)butanamide INTC45 IF-2019- 16749728-APN-lftP#INPI Page 149 of 363 Iodoethane (0.410 mL, 5.10 mmol) was added to a stirred mixture of 2-(2-chloropyrimidin--4~yl)-N-(4-(6-ethoxypyrazin2~yl)phenyl)-N-(4-methoxybenzyl) INTC44 acetamide (0.5 g, 1.021 mmol) and potassium carbonate (0.705 g, 5.10 mmol) in acetone (5 mL). The reaction vessel was heated to 60 °C and stirred for 18 h at tp atmosphere. The reaction mixture was concentrated, diluted in water (40 mL) and extracted into DCM (3 x 40 mL). The organic phases were combined, dried (phase separator) and concentrated in vacuo. The crude product was purified by silica gel chromatography (40 g column, 0-100% EtOAc / isohexane) to provide 2—(2—chloropyrimidin-4-yl)-N-(4-(6-ethoxypyrazin- 2-yl)phenyl)-N-(415 methoxybenzyl)butanamide (0.31 g, 0.539 mmol, 537 yield) as a pale yellow, transparent gum. tR 2.73 min (HPLC, acidic); m / z 519 (M+H)1(ES!) ;ΤΗ NMR(500 Mhz, DMSO-d6) δ 8.80 (s, 1H) , 8.63 (d, J - 5.1 Hz,1H) , 8.25 (s, 1H), 8.07 (d, J = 8.3 Hz, 2H), 7.32 (d, J -5.2 Hz, 1H), 7.17 - 7.08 (m, 4H), 6.88 - 6.81 (m, 2H), 4.92(d, J = 14.7 Hz, 1H), 4.82 (d, J = 14.6 Hz, 1H), 4.50 - 4.43 (m, 2H), 3.73 - 3.69 (m, 4H), 2.09 - 2.00 (m, 1H), 1.83 1.74 ( m, 1H), 1.39 (t, J - 7.0 Hz, 3H), 0.82 (t, J = 7.3 Hz, 3H). 2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2-yl)phenyl)-N~ (4-methoxybenzyl)butanamide INTC46 IF-2019-16749728-APN-ÁSfi^INPI Page 150 of 363 Cyclopropanesulfonamide (0.078 g, 0.646 mmol), CS2CO3 (0.351 g, 1.08 mmol), 2-(2chloropyrimidin-4-yl)-V-(4-(6-ethoxypyrazin-2-yl) were introduced into a 20 mL vial. phenyl)-N-- (4methoxybenzyl)butanamide INTC45 (0.31 g, 0.539 mmol) and dioxane (10 mL). The mixture was purged with N2 for 5 min. Pd-174 (0.012 g, 0.016 mmol) was added, and the mixture was then heated to 80 °C for 1 h and then to 100 °C for 7 h. More cyclopropanesulfonamide (0.078 g, 0.646 mmol) and Pd-174 (0.012 g, 0.016 mmol) were added, and the mixture was heated at 100 °C for an additional 3 h. The reaction mixture was quenched with NH / jCl (aq, 40 mL), extracted with DCM (3 x 40 mL), dried (phase separator) and concentrated in vacuo. The crude product was purified by silica gel chromatography (40 g cartridge, 0-1001 EtOAc / isohexane) to provide 2-(2(cyclopropanesulfonamido)pyrimidin-4-yl)-N-(4-(6ethoxypyrazin-2 -yl)phenyl)-N-(4-methoxybenzyl)butanamide (0.18 g, 0.269 mmol, 501 yield) as a thick yellow gum. tR 1.65 min (UPLC, acidic) ; 603.6 (M+H)+(ES+) ; ¡H NMR (500 Mhz, DMSO-d6) δ 11.22 (s, 1H), 8.80 (s, 1H), 8.49 - 8.42 (m, 1H), 8.25 (s, 1H), 8.08 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 7.14 - 7.03 (m, 2H), 6.96 - 6.89 (m, 1H), 6.87 - 6.81 (m , 2H) , 4.99 (d, J = 14.6 Hz, 1H) , 4.76 (d, J = 14.7 Hz, 1H) , 4.47 (q, J - 7.0 Hz, 2H) , 3.71 (s, 3H) , 3.65 (t, J = 7.3 Hz, 1H) , 3.22 - 3.13 (m , 1 HOUR) , 2.10 - 1.96 (m, 1H), 1.83 - 1.72 (m, 1H), 1.39 (t, J = 7.0 Hz, 3H), 1.12 - 1.06 (m, 2H), 0.93 - 0.87 (m, 2H), 0, 83 (t, J = 7.3 Hz, 3H). IF-2019-16749728-APN-ÁStf #INPI Page 151 of 363 Tert-Butyl 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-í1)-3-((4-(6ethoxypyrazin-2-yl)phenyl)(4-methoxybenzyl)amino)-3oxopropanoate INTC47 Cyclopropanesulfonamide (0.074 g, 0.610 mmol), Cs2COs (0.331 g, 1.017 mmol), 2-(2chloropyrimidin-4-yl)-3-((4-(6-ethoxypyrazin-2-) were introduced into a 2 0 mL vial. tert-butyl yl)phenyl)(4methoxybenzyl)amino)-3-oxopropanoate INTC43 (0.3 g, 0.508 mmol) and dioxane (10 mL). The mixture was purged with N2 for 5 min. [Pd(allyl)C1]2(4.68 mg, 0.013 mmol), tBuXPhos (0.022 g, 0.051 mmol) and dioxane (2 mL) were added to a separate 20 mL vial. The mixture was stirred under N2 atmosphere for 5 min, then added to the first mixture. The resulting mixture was heated in a N2 atmosphere at 60 °C for 4 h. More cyclopropanesulfonamide (0.074 g, 0.610 mmol) was added followed by Pd-174 (11.00 mg, 0.015 mmol). The mixture was then heated at 80 °C for 1 h. The reaction mixture was quenched with NH4C1 (aq, 40 mL), extracted with DCM (3 x 20 mL), dried (phase separator) and concentrated in vacuo. The crude product was purified by silica gel chromatography (40 g column, 0-100¾ EtOAc / isohexane) to provide 2- (2- (cyclopropanesulfonamido)pyrimidin-4-i 1.) 3- ( (4-( Tert-butyl 6-ethoxypyrazin-2-yl)phenyl) (4-methoxybenzyl)amino)-3oxopropanoate (0.1 g, 0.130 mmol, 265 yield) as a white solid. tR 2.51 min (HPLC, basic); m / z 675 (M+H) (ES1). Protection with PMB Methyl 2-(2-(N-(4-Methoxybenzyl)cyclopropanesulfonamido)pyrimidin4-yl)butanoate INTC48 IF-2019-16749728-APN-Á^tINPI Page 152 of 363 1-(Bromomethyl)-4-methoxybenzene (0.470 mL, 3.34 mmol) was added to a stirred heterogeneous mixture of methyl 2(2-(cyclopropanesulfonamido)pyrimidin-4-yl)butanoate (1 g, 3.34 mmol) INTC35 and K2CO3(0.46 g, 3.34 mmol) in DMF (20 mL). The resulting reaction mixture was stirred at RT for 18 h, then poured into water (200 mL) and extracted with EtOAc (3 x 50 mL). The organic extract was washed with water (100 mL) and brine (10 0 mL), dried with MgSCg, filtered and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography (40 g column, 0-501 EtOAc / isohexane) to provide methyl 2-(2-(N-(4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4yl)butanoate (844 mg , 1.95 mmol, 581 yield) as a colorless oil. tR 2.43 min (HPLC, acidic); 420 m / z (M+H)k(ES+) ; NMR (500 Mhz, DMSO-d6) δ 8.64 (d, J = 5.1 Hz, 1H), 7.25 (d, J = 8.3 Hz, 2H), 7.19 (d, J - 5.1 Hz, 1H), 6.86 (d, J - 8.3 Hz, 2H), 5.17 - 5.02 (m, 2H), 3.71 (s, 3H), 3.64-3.55 (m, 4H), 2.05 - 1.93 (m, 2H), 1.89-1.76 (m, 1H) , 1.10 - 0.96 (m, 4H) , 0.82 (t, J = 7.3 Hz, 3H) . 1-tert-butyl 3-methyl 2-(2-(N-(4-methoxybenzyl)methylsulfonamido)pyrimidin-4-yl)-2(2-methoxyethyl)malonate INTC79 Prepared as for INTC48 using 1-tertIF-2019-16749728-APN-Áfi^INPI 2-(2-methoxyethyl)2-(2-(methylsulfonamido)pyrimidin-4-yl)malonate Page 153 of 363 butyl and 3-methyl INTC73 and 1-(chloromethyl)-4-methoxybenzene to provide 2-(2-(N-(4methoxybenzyl)methyl1sulfonamido)pyrimidin-4-yl)~2~ (2methoxyethyl)malonate of 1 -tert-butyl and 3-methyl (65% yield) as a colorless oil. tR 2.55 min (HPLC, acidic); m / z 524 (M+H)1(ES+) ; NMR (500 Mhz, DMSO-d6) δ 8.72 (d, J = 5.3 Hz, 1H), 7.47 (d, J = 5.3 Hz, 1H), 7.27 7.21 (m, 2H), 6.9 2 - 6.8 2 (m, 2H), 5.17 - 5.10 (m, 2H), 3.71 (s, 3H) , 3.67 (s, 3H) , 3.4 4 (s, 3H) , 3.2 9-3.22 (m, 1H), 3.22 - 3.15 (m, 1H), 3.09 (s, 3H), 2.48 - 2.29 (m, 2H), 1.37 (s, 9H). Dimethyl 2-Isopropyl-2-(2-(N-(4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4yl)malonate INTC80 Prepared as for INTC48 using dimethyl 2-(2(cyclopropanesulfonamido)pyrimidin-4-yl)-2isopropylmalonate INTC78 and 1-(chloromethyl)-4methoxybenzene to provide 2-isopropyl-2-(2-(N-(420 methoxybenzyl) dimethyl cyclopropanesulfonamido)pyrimidin-4yl)malonate (28% yield) as a colorless oil. tR 0.72 min (UPLC, acidic 2); m / z 492 (M+H)+ (ES+);1H NMR not recorded. Decarboxylation of PMB-protected sulfonamides 5 Methyl 4-Methoxy-2-(2-(N-(4methoxybenzyl)methyl1sulfonamido)pyrimidin-4-yl)butanoate INTC81 IF-2019-16749728-ΑΡΝ-ΛΒΛΐΝΡΙ Page 154 of 363 HC1 (4M in dioxane) (0.44 mL, 14.51 mmol) was added to a stirred solution of 2-(2-(A / -(4methoxybenzyl)methylsulfonamido)pyrimidin-4-yl)-2-(2methoxyethyl)malonate. 1-tert-butyl and 3-methyl INTC79 (8.0 g, 14.5 mmol) in DCM (100 mL) and the resulting reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was concentrated in vacuo and the crude product was purified by silica gel chromatography (220 g column, 0-1001 EtOAc / isohexane) to provide 4methoxy-2-(2-(N-(4-methoxybenzyl Methyl )methyl Isulfonamido)pyrimidin4-yl)butanoate (2.47 g, 5.54 mmol, 381 yield) as a colorless oil. tR 2.13 min (HPLC, acidic); m / z 424 (M+H)' (ES+) ;ΊΗ NMR (500 Mhz, DMSO~d6) δ 8.64 (d, J = 5.1 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.19 (d, J = 5.1 Hz, 1H), 6.90 - 6.84 (m, 2H), 5.20 - 5.07 (m, 2H), 3.97 (t, J - 7.4 Hz, 1H), 3.72 (s, 3H), 3.59 (s, 3H) ), 3.50 (s, 3H), 3.37 - 3.26 (m, 2H), 3.16 (s, 3H), 2.29 - 2.19 (m, 1H), 2.09 - 2.00 (m, 1H). Methyl 2-(2-(N-(4-Methoxybenzyl)cyclopropanesulfonamido)pyrimidin4-yl)methylbutanoate INTC82 To a solution of dimethyl 2-isopropyl-2-(2-(N-(4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4yl)malonate INTC80 (2.79 g, 5.68 mmol), in water (0.11 mL, 6.11 mmol) in DMSO (7 mL) chloride was added IF-2019-16749728-APN-Á®#INPI Page 155 of 363 lithium (0.29 g, 6.81 mmol). The reaction mixture was heated to 140 °C for 1 h. The reaction mixture was cooled to RT and diluted with EtOAc (100 mL) and water (100 mL). The phases were separated and the organic phase was further washed with water (100 mL), water / brine (1:1, 50 mL), and sat brine. (50 mL). The organic phase was dried with MgSCg, filtered and concentrated on silica (10 g). The crude product was purified by silica gel chromatography (40 g cartridge, 0-30% EtOAc / isohexane) to provide 2-(2-(N-(4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4-i1)-3methylbutanoate. methyl (2.00 g, 3.69 mmol, 65% yield) as a colorless gum. tR 0.70 min (UPLC, acidic 2); m / z 434 (M+H)1(ES+) ;lH NMR not recorded. Alkylation of PMB-protected sulfonamides Methyl 4-Methoxy-2-(2-(N-(4methoxybenzyl)methylsulfonamido)pyrimidin-4-yl)-2methylbutanoate INTC83 Prepared using Method B using methyl 4-methoxy-2-(2(N-(4-methoxybenzyl)methylsulfonamido)pyrimidin-4yl)butanoate INTC81 with NaH and Mel in DMF to give 4-methoxy-2-(2-( Methyl N-(4methoxybenzyl)methylsulfonamido)pyrimidin-4-yl)-2methylbutanoate (89% yield) as a colorless oil. tR 2.20 min (HPLC, acidic); τη / ζ 438 (M+H)+(ES1) ; A NMR (50 0 Mhz, DMSO-d6) δ 8.66 (d, J = 5.2 Hz, 1H), 7.29 - 7.19 (m, 3H), 6.91 - 6.81 (m, 2H), 5.13 (s, 2H), 3.72 (s, 3H), 3.57 (s, 3H), 3.47 (s, 3H), 3.33 - 3.25 (m, 2H), 3.12 (s, 3H), 2.29 - 2.13 (m, 2H), 1.48 (s, 3H) ). IF-2019-16749728-APN-ÍK^INPI Page 156 of 363 Methyl 2“(2-(N-(4-Methoxybenzyl)cyclopropanesulfonamido)pyrimidin4-yl)-2-methylbutanoate INTC84 Prepared using Method B using methyl 2-(2-(N-(4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4yl)butanoate INTC48 with K2CO3y Mel in DMF to give 2-(2-(N-(4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4 -i1)-methyl-2methylbutanoate (391 yield) as a colorless gum. tR 2.57 min (HPLC, acidic); m / z 434 (M+H)+(ES+) ;lH NMR (500 Mhz, DMSO~d6) δ 8.66 (d, J = 5.3 Hz, 1H), 7.26 - 7.17 (m, 3H), 6.90 - 6.82 ( m, 2H), 5.10 (s, 2H), 3.71 (s, 3H), 3.64 (s, 3H), 2.05 - 1.88 (m, 2H), 1.44 (s, 3H), 1.04 - 0.97 (m, 4H) , 0.76 (t, J = 7.4 Hz, 3H) . (1H hidden by DMSO). Fluorination Methyl 2-Fluoro-2-(2-(N-(4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4yl)butanoate INTC49 Methyl methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4yl)butanoate INTC48 (400 mg, 0.95 mmol) in THE (10 mL) at -78 °C LHMDS (1.19 mL, 1.19 mmol, 1 M in THF) was added dropwise in 5 min. The resulting mixture was warmed to RT and stirred for 1 h. The solution was cooled to -78 °C again and a solution of NIF-2019-16749728-APN-lfi?#INPI was added Page 157 of 363 fluoro-M- (phenylsulfonyl)benzenesulfonamide (376 mg, 1.19 mmol) in THF (3 mL) dropwise in 5 min. The resulting mixture was heated to ΤΑ and stirred for 1 h. The solution was diluted with sat. NaHCCg. (aq, 100 mL) and EtOAc (100 mL), and the phases were separated. The aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na¿SO.^, filtered and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography (24 g column, 0-50% EtOAc / isohexane) to provide methyl 2fluoro-2-(2-(N-(4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4yl)butanoate. (390 mg, 0.865 mmol, 91% yield) as a transparent oil. tR 2.48 min (HPLC, acidic); 438 m / z (M+H)+(ES+);λΗ NMR (500 Mhz, DMSO-d6) δ 8.81 (d, J = 5.1 Hz, 1H), 7.37 (dd, J = 5.1, 1.5 Hz, 1H), 7.29 - 7.19 (m, 2H), 6.90 - 6.83 (m, 2H), 5.17 - 5.03 (m, 2H), 3.72 (s, 3H), 3.69 (s, 3H) 3.65-3.57 (m, 1H), 2.40 2.14 (m, 2H), 1.11 - 0.97 (m, 4H), 0.84 (t, J = 7.4Hz, 3H). INTC49, which is enantiomerically enriched, can be prepared using the following method: LHMDS (0.189 mL, 0.189 mmol) drop by drop in 5 min. The resulting mixture was warmed to RT and stirred for 1 h. A second solution of (−)-Cinconidine (0.069 g, 0.236 mmol) and Selectfluorine (0.072 g, 0.205 mmol) in MeCN (2.5 mL) was prepared, which was stirred at RT for 30 min. The fluorinating agent solution was subsequently cooled to −40 °C and added to the deprotominated ester solution dropwise over 5 min. The reaction mixture was stirred at -40 °C for 1 h and warmed to IF-2019- 16749728-APN-1S?#INPI Page 158 of 363 TA as the cooling bath lost effectiveness in z. h. The reaction mixture was stirred at RT for 20 h. The reaction mixture was diluted with sat. NaHCOj. (aq, 10 mL) and EtOAc (20 mL). The phases were separated and the organic phases were further washed with sat. NaHCCh. (aq, 10 mL), followed by 1 M HC1 (aq, 10 mL). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (4 g cartridge, 0-501 EtOAc / fsohexane) to provide 2-fluoro-2-(2{N-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4yl)butanoate. of methyl (0.024 g, 0.052 mmol, 331 yield) as a colorless oil. tR 0.70 min (UPLC 2, acidic); 438 m / z (M+H)+(ES*); ¥ NMR (500 Mhz, DMSO-d6) δ 8.81 (d, J - 5.1 Hz, 1H), 7.37 (dd, J = 5.1, 1.5 Hz, 1H), 7.29 - 7.19 (m, 2H), 6.90 - 6.83 ( m, 2H), 5.17 - 5.03 (m, 2H), 3.72 (s, 3H), 3.69 (s, 3H) 3.65-3.57 (m, 1H), 2.40 2.14 (m, 2H), 1.11 - 0.97 (m, 4H), 0.84 (t, J = 7.4 Hz, 3H). Methyl 2-(2-(Cyclopropanesulfonamido)pyrimidin-4-yl)-2fluorobutanoate INTC177 To a solution of methyl 2-fluoro-2-(2-(N-(4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4yl)butanoate INTC49 (24 mg, 0.055 mmol) in DCM (5 mL) was added TEA (0.5 mL, 6.4 9 mmol). The reaction mixture was stirred at RT for 3 h. The reaction mixture was concentrated in vacuo and the resulting brown residue was purified by silica gel chromatography (4 g cartridge, 0-501 EtOAc / fsohexane) to provide 2-(2(cyclopropanesulfonamido)pyrimidin-4-yl) Methyl-2-fluorobutanoate (18 mg, 0.053 mmol, 97% yield) as a IF-2019- 16749728-ΑΡΝ-1£Φ#ΙΝΡΙ Page 159 of 363 Colorless oil. tR 0.55 min (UPLC 2, acidic); 318 m / z (M+H)1. NMR (500 Mhz, DMSO-d6) δ 11.50 (s, 1H), 8.73 (d, J - 5.2 Hz, 1H), 7.31 (d, J - 5.2 Hz, 1H), 3.73 (s, 3H), 3.25 - 3.16 (m, 1H), 2.45 - 2.18 (m, 2H), 1.22 - 1.01 (m, 5 4H), 0.89 (t, J = 7.4 Hz, 3H). The product was analyzed as a mixture of enantiomers by the IC7 quinal HPLC method; tR - 29.08 min (10%) and 2 9.75 min (90%) . Lithium salt formation Lithium 2-Fluoro-2- (2- (ΛΖ- (4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4yl)butanoate INTC50 \ EITHER To a solution of methyl 2-fluoro-2-(2-(N~(4~ methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4yl)butanoate INTC49 (1.45 g, 3.31 mmol) in THF (15 mL) and Me OH (7, 5 mL) a solution of LiOH (0.091 g, 3.81 mmol) in water (5 mL) was added. The reaction mixture was stirred at RT for 3 h. The reaction mixture was concentrated in vacuo, and the resulting yellow oil was dissolved in MeCN (10 mL) and concentrated in vacuo to obtain 2-fluoro~2-(2-(N-(4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4yl )lithium butanoate (1.46 g, 3.30 mmol, quant. yield) as a pale yellow foam which was used without further purification. tR 0.95 min (UPLC, basic); 424 m / z (ionizes as COOH, M+H)* (ES+);LH NMR (500 Mhz, DMSO-d6) δ 8.57 - 8.52 (m, 1H), 7.34 - 7.28 (m, 2H), 7.20 - 7.14 (m, 1H), 6.90 - 6.83 (m, 2H), 5.19 - 5.04 (m, 2H), 4.14 - 4.10 (m, 1H), 3.71 (s, 3H), 2.33 - 2.20 (m, 1H), 2.17 - 2.08 (m, IF-2019-16749728-APN-M©%INPI Page 160 of 363 ’i 1H), 1.15 - 1.04 (m, 1H) , 1.06 - 0.97 (m, 1H) , 0.93 - 0.80 (m, 2H)f0.80 - 0.73 (m, 3H). Method H: Benzyl fluorination of heteroaromatic esters Μ’4,0.. A -W (] X N w Rent || y jf ----------Rent” ''|f y or ZVX or ZVX X = CH:N Y = CR2>N Z = CR21N W-Hal. N(PMB)SO-Aiquik) A solution of heteroaromatic ester (1 eq) in THF (10 volumes) was cooled to -78 °C, to which LiHMDS (1M, 1.25 eq in THF) was added. The reaction mixture was subsequently heated to RT for 1 h. The solution was cooled to -78 °C and a solution (in THF) of, or solid, NSFI (1.25 eq) was added dropwise, then heated to RT for 2 h. The solution was diluted with sat. NaHCCg. (aq) and the product was extracted with EtOAc. The crude product was purified by normal phase chromatography. Table 5: The following intermediates were prepared according to Method H. INTC Name / Structure (All examples containing quinal centers are racemates unless otherwise indicated) Synthesis method, [LCMS Method], m / z (M+H) +, (tR / min) Data NMR chemical shifts of ΤΗ (DMSO-d6 unless otherwise stated) INTC85 methyl 2-(2-chloropyrimidin-4yl)-2-fluorobutanoate F 3 O s,N Method H using INTC61, [Basic HPLC], 233 isotope -C1 (1.85). 8.92 (d, J = 5.1 Hz, 1H), 7.78 (d, J - 5.1 Hz, 1H), 3.75 (s, 3H), 2.45 - 2.18 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H ). IF-2019-16749728-APN-Α^ΛίΝΡΙ Page 161 of 363 Methyl 2-Fluoro-2-(2-(N-thyoxybenzyl)cyclopropanesulfonamido)pyrimidin-4-11)-3methylbutanoate INTC86 To a solution of methyl 2-(2-(1 / -(4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4-yl)-3methylbutanoate INTC82 (1.50 g, 3.46 mmol) in anhydrous THE (30 mL) at -78 °C was added Li HMDS (1 M in THF) (4.15 mL, 4.15 mmol) dropwise. The reaction mixture was stirred at − 78 °C for 5 min, then warmed to room temperature for 1 h before being cooled again to − 78 °C. Next, a solution of Selectfluor (1.90 g, 5.10 mmol) in MeCN (30 mL) was added dropwise to the reaction mixture over 5 min. The reaction mixture was warmed to RT and stirred for 1 h before adding sat. NaHCCp. (aq, 5 mL). The reaction mixture was partly concentrated in vacuo (to ca. 10 mL), then EtOAc (100 mL) and sat. NaHCOj were added. (aq, 100 mL). The phases were separated and the organic phase was washed with sat. brine. (50 mL). The organic layer was dried with MgSCh, filtered and concentrated on silica (15 g). The crude product was purified by silica gel chromatography (40 g cartridge, 0-601 EtOAc / rsohexane) to provide 2-fluoro-2-(2-(N-(4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4-yl) Methyl-3methylbutanoate (680 mg, 1.48 mmol, 4 37. yield) as a yellow gum. tR 0.72 min (UPLC, acidic 2); m / z 452 (M+H)+(ES+) ; NMR (500 Mhz, DMSO-d6) δ 8.79 (d, J = 5.1 Hz, 1H), 7.33 (dd, J = 5.1, 2.2 Hz, 1H), 7.29 - 7.22 (m, 2H), 6.91 - 6.84 (m , 2H), 5.19 - 5.07 (m, IF-2019-16749728-APN-lfi^INPI Page 162 of 363 j 2H), 3.74 - 3.66 (m, 7H) , 2.93 - 2.77 (m, 1H), 1.17 - 1.05 (m, 2H), 1.06-0.97 (m, 5H) , 0.67 (d, J - 6.8Hz, 3H). Potassium salt formation Potassium 2-(2-(N-(4-Methoxybenzyl)cyclopropanesulfonamido)pyrimidin5 4—yl)-3-methylbutanoate INTC87 KCL ,NX'90° V Prepared as for INTC37 using methyl 2 — (2 — < ΛΖ — (4 — (4 — methoxybenzyl) cyclopropanesulfonamido)pyrimidin-4~yl) -3~ methylbutanoate INTC82 and potassium trimethylsilanolate to provide 2-(2-( Potassium N-(4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-4-yl)-3methylbutanoate (997; yield) as a pale yellow solid. tR 1.59 min (HPLC, basic); m / z 420 (M+H) * (ES + ) ;ίΗ NMR not recorded, Difluoroderivative via thioether Ethyl 2,2-Difluoro-2-(2-(methyisuifonyl)pyrimidin-4-yl)acetate INTC100 EITHER A suspension of ethyl 2,2-difluoro-2-(2-(methylthio)pyrimidin-420yl) acetate (240 mg, 0.97 mmol) in MeOH (8 mL) and water (5 mL) was treated with Oxone (1.19 g, 1.93 mmol) and stirred vigorously for 3 h. DCM (10 mL) was added and the phases were separated with a phase separator, further extracting with DCM (2x5 mL). The combined organic phases were concentrated on silica (1 g) and the crude product was purified by silica gel chromatography (12 g column, 0 - 50.5 EtOAc / isohexane) to provide 2,2-difluoro-2 -(2-(methyisuifonyl)pyrimidin-4yl)ethyl acetate (80 mg, 0.28 mmol, 295 yield) IF-2019-16749728-ΑΡΝ-Λβ3ΉΝΡΙ Page 163 of 363 like a colorless rubber that solidified at rest. tR 0.52 (acidic UPLC); m / z 281 (M+H)+(ES+) ; NMR (500 Mhz, DMSOd6) δ 9.42 (d, J = 5.1 Hz, 1H), 8.34 (d, J = 5.1 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.46 (s, 3H) , 1.25 (t, J = 7.1 Hz, 3H). 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,2difluoroacetic acid INTC101 A solution of cyclopropanesulfonamide (40 mg, 0.33 mmol) and ethyl 2,2-difluoro-2-(2-(methylsulfonyl)pyrimidin-4-yl)acetate INTC100 (80 mg, 0.29 mmol) in DMF (1 mL) was treated with NaH (601 p in mineral oil) (14 mg, 0.35 mmol) and stirred at RT for 5 min before heating to 60r'C for 6 h. 1M HC1 (10 mL) was added and the reaction mixture was extracted with EtOAc (4 x 10 mL). The organic phases were combined, dried with Na2SO4, filtered and concentrated on silica (500 mg). The crude product was purified by silica gel chromatography (4 g column, 0-51 MeOH / DCM) to provide 2-(2-(cyclopropanesulfonamido)pyrimidin-4-yl)-2,2difluoroacetic acid (80 g, 0.136 mmol, 481 yield) as a brown solid. tR 0.49 (acidic UPLC); m / z 294 (M+H) (ES*); No MRI data were collected. IF-2019- 16749728-ΑΡΝ-ΑΦΛΐΝΡΙ Page 164 of 363 Amide formation of selected building blocks Table 6: The following intermediates were prepared according to Methods 1-4 described below for the synthesis of the compound of formula (I). INTC Name / Structure (All examples containing chiral centers are racemates unless otherwise noted) Synthesis method r [LCMS Method], m / z (M+H)\ (tR / min) Displacement data 'Ή NMR chemicals (DMSO-dg unless otherwise stated) INTC88 2- (2-chloropyrimidin-4~ yl)-N~ (5-(6-ethoxypyrazin2--11) -3-fluoropyridin-2yl )-4-methoxybutanamide Η f N Method 4 using INTC6S and INTD31 [Basic HPLC], 447 isotope 35C1 (2.05). 10.89 (s, 1H), 9.03 - 8.98 (m, 1H), 8.92 (s, 1H), 8.78 (d, J = 5.1 Hz, 1H), 8.44 (dd, J = 11.1, 1.9 Hz, 1H), 8.32 (s, 1H), 7.65 (d, J = 5.1 HZ, 1H), 4.50 (q, J = 7.0 Hz, 2H), 4.26 - 4.19 (m, 1H), 3.44 - 3.33 (m, 2H), 3.23 ( s, 3H), 2.36 2.25 (m, 1H), 2.21 - 2.11 (m, 1H), 1.40 (t, J = 7.0 Hz, 3H). INTC89 2~ (2“chloropyrinidin-4-yl)-N-(5-(6-ethoxypyrazin2-yl)pyridin-2-yl)-4methoxybutanamide Η Γ N N 'V'gx Αγ-' Cl Method 4 using INTC68 and INTD33 [acidic UPLC], 429 isotope 35ci (1.38). 11.12 (s, 1H), 9.10 - 9.05 (m, 1H), 8.84 (s, 1H), 8.75 (d, J = 5.2 Hz, 1H), 8.53 - 3.47 (m, 1H), 8.25 (s, 1H) , 8.20 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 5.2 Hz, 1H), 4.52 - 4.44 (m, 2H), 4.34 - 4.27 (m, 1H), 3.42 - 3.32 (m, 2H ), 3.20 (s, 3H), 2.37 - 2.26 (m, 1H), 2.20 2.09 (m, 1H), 1.43 - 1.37 (m, 3H). IF-2019- 16749728-APN-l^f #INPI Page 165 of 363 INTC90 2~ (2-chloropyrimidin-4-yl)-N-(4-(6-ethoxypyrazin2—i1)-2-fluorophenyl)-4methoxybutanamide Η I λ . n Y' Y \ .0. .hk yL.-X o li N Method 4 using INTC6S and INTD24 [acidic UPLC], 446 isotope Xl (1.54). 10.34 (s, 1H), 8.83 (s, 1H)f 8.76 (d, J = 4.9 HZ, 1H), 8.24 (s, 1H), 8.07 - 7.95 (m, 3H), 7.67 (d, J = 5.1 Hz, 1H), 4.54 -4.45 (m, 2H), 4.34 - 4.27 (m, 1H), 3.42 - 3.36 (m, 1H), 3.33 (s, 3H), 2.89 - 2.86 (m, 1H), 2.34 - 2.25 (m, 1H), 2.19 -2.09 (m, 1H), 1.41 (t, J = 6.8 Hz, 3H). INTC91 N- (5-(6-ethoxypyrazin-2yl)pyridin-2-yl)-4methoxy-2- (2- (jV~ (4methoxybenzyl)methylsulfone mido)pyrimidin-4-yl) - 2methylbutanamide r X P'ArY / II N Method 2 using INTC83 and INTD33, No LCMS data 10.23 (s, 1H), 9 .03 (dd, J = 2.4, 0.8 Hz, 1H), 8.84 (s, 1H), 8.67 (d, J == 5.3 Hz, 1H), 8.48 (dd, J = 8.8, 2.4 Hz, 1H), 8.25 (s, 1H), 8.19 (dd, J = 8.8, 0.8 Hz, 1H), 7,287.18 (m, 3H), 6.76 - 6.67 (m, 2H), 5.12 (s, 2H), 4.48 (q, J =7.0 Hz, 2H), 3.62 (s, 3H), 3.43 (s, 3H), 3.12 (s, 3H), 2.45-2.36 (m, 2H), 2.30-2.21 (m, 2H), 1.60 (s, 3H), 1.41 (t, J = 7.0 Hz, 3H). INTC92 N- (51-chloro-[3,3'bipyridin]-6-yl) -2fluoro-2-(2-(N-(4methoxybenzyl)cyclopropane sulfonamido)pyrimidin-4yl)butanamide rj H F\ / ,-Y y .and. Y-~ .ct A YIT T J N Method 4 using INTC50 e 1NTD57 [acidic HPLC], 612 isotope 3 Al (2.70) . 10. 67 (s, 1H), 3.94 (d, J = 2.0 Hz, 1H), 8. S3 - 8.81 (m, 2H), 8.66 (d, J = 2.3 Hz, 1H), 8.36 (t, J = 2.2 Hz , 1H), 8.29 (dd, J = 8.7, 2.6 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.52 (dd, J = 5.2, 1.3 Hz, 1H), 7.32 - 7.24 (m, 2H), 6.82 6.75 (m, 2H), 5.20 - 5.07 (m, 2H), 3.78-3.70 (m, 1H), 3.66 (s, 3H), 2.47 - 2.26 (m, 2H), 1.13 - 0.85 (m , 7H). IF-2019-16749728-APN-lfifelNPI Page 166 of 363 INTC93 N- (5-(6-ethoxypyrazin-2yl)pyridin-2-yl)~2~(2~(N(4- methoxybenzyl) cyclopropa.no sulfonamido)pyrimidin-4yl)“2-methylbutanamide H (j Γ o Method 2 using INTC84 and INTD33, [acid HPLC], 618, (2.79). J = 5.3 Hz, 1H), 8.48 (dd, J = 8.8, 2.5 Hz, 1H), 8.25 (s, 1H), 8.20 (dd, J =8.8, 0.6 Hz, 1H), 7.24 (d, J = 5.3 Hz, 1H), 7.21 - 7.18 (m 2H), 6.76 - 6.68 (m, 2H), 5.09 (s, 2H), 4.48 (q, J = 7.0 Hz, 2H), 3.62 (s, 3H), 3.61 - 3.52 (m, 1H), 3.17 (d, J = 5.2 Hz, 2H), 1.55 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H), 0.96-0.91 (m, 2H), 0.83-0.74 (m, 5H) INTC94 N~ (5-bromo-3-fluoropyridin-2-yl)-2-(2~ (cyclopropanesulfonamido)pyriinidin-4-yl) butanamide Br / O or °V Method 3 using INTC37 No data of LCMS 11.25 (s, 1H), 10.70 (s, 1H), 8.57 (d, J = 5.2 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 8.23 ​​(dd, J = 9.4, 2.0 Hz , 1H) , 7.17 (d, J = 5.2 Hz, 1H), 3.84 (dd, J = 8.7, 6.3 Hz, 1H) , 2.10 - 1.98 (m, 1H) , 1.98 - 1.87 (m, 1H) , 1.15 - 1.10 (m, 2H), 1.07 - 0.99 (m, 2H), 0.99 - 0.39 (m, 3H). 1H hidden by R.O INTC95 W- (5-bromopyridin-2-yl)2-(2- (cyclopropanesulfonamido)pyrimidin-4-yl) butanamide U,XX TXJ ° Az Method 3 using INTC37 [acidic UPLC], 440 isotope 7< >Br, (1.26). 11.23 (s, 1H), 10.97 (s, 1H), 8.55 (d, J = 5.2 Hz, 1H), 3.45 (d, J = 2.5 Hz, 1H), 8.06 (d, J = 8.9 Hz, 1H) ), 8.01 (dd, J = 8.9, 2.5 Hz, 1H), 7.19 (d, J = 5.2 Hz, 1H), 3.98 - 3.93 (m, 1H), 3.30 - 3.26 (m, 1H), 2.09 - 2.00 ( m, 1H), 1.97 - 1.87 (m, 1H), 1.15 - 1.02 (m, 2H), 1.02 - 0.36 (m, 5H). IF-2019-16749728-APN-lft?#INPI Page 167 of 363 INTC96 N- (5- (6--ethoxypyrazin-2~ il)pyridin-2-yl)-2fluoro-2-(2-(jV-(4methoxybenzyl)cyclopropane sulfonamido)pyrimidin-4yl) -3-methylbutanamide V rU Η \X“ í or .N. YY t if Method 2 using INTCS6 and INTD33, [acid UPLC, 2], 636, (0.79), lH NMR not recorded. INTO97 N-(4-(6-ethoxypyrazin-2yl)-2”fluorophenyl)-2-(2(N-(4- methoxybenzyl)cyclopropane sulfonamido)pyrimidin-4~ yl)-3-methylbutanamide F „ Y χθ^χ -Ο ο INTC98 N- (5-(6-ethoxypyrazin-2yl)pyridin-2-yl) ~2~ (2 - (IV(4-methoxybenzyl)cyclopropane sulfonamido)pyrimidin-4yl)-3- methylbutanamide xX-'0' XJ H Γ Io X X X. ..n. / , V Yif Y ·- -X .N. X. J 0 IF-2019- 16749728-APN-lfi?#INPI Page 168 of 363 INTC176 N- ¢5-(6- cyclopropylpyrazin-2yl)pyridin-2-yl)-2fluoro-2-(2-(N-(4methoxybenzyl) cyclopropane sulfonamido)pyrimidin-4i1)butanamide : '> ΓΎ Vt ¥ / χ z+ x / j o x m ​​° V N X X' 10.67 (s, 1H), 9.06 (d, J = 2.4 Hz, 1H), 9.03 (s, 1H), 8.83 (d, J = 5.2 Hz, 1H), 8.61 (s, 1H), 8.49 (dd, J = 8.7, 2.5 Hz, 1H), 8.09 (d, J - 8.8 Hz, 1H), 7. 52 (dd, J = 5.2, 1.3 Hz, 1H), 7.29 - 7.23 (m, 2H), 6.81 - 6.75 ( m, 2H), 5.20 - 5.08 (m, 2H), 3.77 - 3.69 (m, 1H), 3.65 (s, 3H), 2.39 2.24 (m, 3H), 1.14 ~ 1.06 (m, 5H), 1.05-0.98 (m, 2H), 0.97 ~ 0.85 (m, 4H). Formation of lithium salt (lithium 4-(Carboxylate(methoxy)methyl)pyrimidin-iyl)(cyclopropylsulfonyl)amide INTC99 A stirred mixture of dimethyl 2-(2(cyclopropanesulfonamido)pyrimidin-4-i1)~2~methoxylonate (0.50 g, 1.25 mmol) INTC75 in MeOH (15 mL) was treated with LiOH solution (0.10 g, 4.18 mmol ) in water (5 mL). The reaction mixture was allowed to stir at RT for 2 h. The reaction mixture was concentrated in vacuo to provide lithium (4-(carboxylate(methoxy)methyl)pyrimidin-2yl)(cyclopropylsulfonyl)amide (0.4 g, 1.19 mmol, 95% yield) as a brown solid. tR 0.18 min (basic UPLC); m / z 288 as the free acid (M+H)* (ES');TH NMR not collected. Pyridine core section Sulfonation via sulfonyl chloride Ethyl 2-(6-(Cyclopropanesulfonamido)pyridin-2-i1)acetate INTC102 IF-2019-16749728-APN-ÁfíWlNPI Page 169 of 363 A solution of ethyl 2-(6-aminopyridin-2-yl)acetate (2 g, 11.10 mmol) and DMAP (0.136 g, 1.11 mmol) in pyridine (9.0 mL) was cooled to 0 °C. Cyclopropanesulfonyl chloride (1.12 mL, 11.10 mmol) was then added dropwise. The solution was allowed to warm slowly to RT and stirred for 18 h. The reaction mixture was quenched with MeOH (10 mL) and concentrated in vacuo. The crude product was purified by chromatography on C18-RP silica gel (80 g column, 0-50% MeCN / water with 0.1% formic acid to provide 2-(6(cyclopropanesulfonamido)pyridin-2-yl)acetate. ethyl (1.35 g, 4.70 mmol, 42% yield) as a pale brown oil; tR 0.95 min (acidic UPLC); Rental Ethyl 2-(6-Bromopyridin~2-yl)-2-methylpropanoate INTC103 or Xv t-BuOK (0.115 g, 1.02 mmol) was added to a stirred, ice-cold solution of ethyl 2-(6-bromopyridin-2yl)acetate (0.100 g, 0.41 mmol) in THF (1.5 mL). After 30 min, Niel (2M in TBME, 0.82 mL, 1.64 mmol) was added dropwise. The reaction vessel was heated to RT and stirred for 18 h. The reaction mixture was quenched with MeOH (1 mL) and concentrated in vacuo. The crude product was purified by silica gel chromatography (24 g column, 0-50% EtOAc / isohexane) to provide ethyl 2-(6-bromopyridin-2-yl)-2-methylpropanoate (0.06 g, 0.21 mmol, 51% yield) as a colorless, transparent liquid; tR 1.54 min (acidic UPLC); m / z 273 (?CiBr M+H)+(ES4);ÁH NMR (400 Mhz, DMSO-d6) δ 7.79 IF-2019-16749728-APN-ME^INPI Page 170 of 363 7.71 (m, 1H), 7.56 - 7.51 (m, 1H), 7.49 - 7.43 (m, 1H), 4.15 - 3.99 (m, 2H), 1.50 (s, 6H), 1.19 - 1.05 (m, 3H) . Ethyl 2-(6-Bromopyridin-2-yl)butanoate INTC104 N _ Br o LiHMDS (IM in THF) (2.25 mL, 2.25 mmol) was added to a stirred solution of ethyl 2~(6-bromopyridin-2-yl)acetate (0.5 g, 2.05 mmol) in THF (10 mL) at -78 °C. After 1 h, Etl (0.182 mL, 2.25 mmol) was added dropwise at the same temperature and the reaction was warmed to RT and stirred for 18 h. The reaction was partitioned between EtOAc (20 mL) and sat. NH4CI. (aq, 20 mL), the organic phase was passed through a phase separator and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography (40 g cartridge, 0-501 EtOAc / isohexane) to provide ethyl 2-(6-bromopyridin-2yl) butanoate (0.35 g, 1.27 mmol, 621 yield). like a pale yellow liquid. tR 2.30 min (acid HPLC); m / z 272 (7íiBr M+H)+(ES*) ;2H ​​NMR (400 Mhz, DMSO-d6) δ 7.76 - 7.72 (m, 1H), 7.55 (dd, J = 7.9, 0.9 Hz, 1H), 7.42 (dd, J = 7.6, 0.9 Hz, 1H), 4.12 - 4.05 (m, 2H), 3.74 (t, J - 7.5 Hz, 1H), 2.05 - 1.94 (m, 1H), 1.89 - 1.76 (m, 1H), 1.13 (t, J = 7.1 Hz, 3H), 0.83 (t, J - 7.4 Hz, 3H). Formation of heterocycles through alkylation Ethyl 4-(6-Bromopyridin-2-yl)tetrahydro-2H-pyran-4-carboxylate INTC105 Prepared as for INTC52 ​​using commercial ethyl 2-(6-bromopyridin2-yl)acetate (2.51 g, 10.28 mmol) and 1-bromo-2-(2-bromoethoxy)ethane to provide 4-(6IF-2019-16749728-APN- Á^íálNPI Page 171 of 363 % ethyl bromopyridin-2-yl)tetrahydro-2H-pyran-4-carboxylate (52% yield) as a transparent oil. tR 1.42 min (basic UPLC) ; m / z 314 (Ar M+H)+(ES+) ; At NMR (400 Mhz, DMSO-d6) δ 7.80 - 7.76 (m, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.49 (d, J - 7.7 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.77 - 3.70 (m, 2H), 3.52 - 3.45 (m, 2H), 2.30 - 2.23 (m, 2H), 2.07 - 2.01 (m, 2H), 1.12 (t, J - 7.1 Hz, 3H) . Method I: Buchwald coupling - sulfonylation H2A ¥ R5R4 or '° r5r4h „ rri ir r Y Y X = CH, N Y = CR2, N Z = CR2, N The 2-bromopyrimidine intermediate (1 eq), sulfonamide (1.2 eq), and base (2 eq) were dissolved in dioxane (40 volumes). The mixture was degassed (N2, 5 min), then catalyst (5 mol%) was added. The resulting mixture was heated under a nitrogen atmosphere at 90 °C for 2 h. The mixture was filtered, washed with EtOAc or DCM and the resulting filtrate was concentrated. The crude product was purified by normal phase chromatography. IF-2019-16749728-APN-K?^INPI Page 172 of 363 Table 7: The following intermediates were prepared according to Method I. INTC Name / Structure (All examples containing chiral centers are racemates unless otherwise indicated) Synthesis method, [LCMS Method], m / z (M+H) + , (tR / min) Data NMR chemical shifts of :H (DMSO-d^ unless otherwise stated) Catalyst, Base, Solvent INTC106 ethyl 2-(6-(cyclopropanesulfonamido)pyridin2—yl)-2-methylpropanoate otr Method I using INTC103, [UPLC acid], 313 (1.27). 10.48 (s, 1H), 7 .75 - 7.61 (m, 1H), 7.03 - 6.95 (m, 1H), 6 . 85 - 6.74 (m, 1H), 4.12 - 3.97 (m, 2H), 3.19 - 3.07 (m, 1H), 1.49 (s, 6H), 1.14 - 0.95 (m, 7H). Pd 174, ICCCu, dioxane INTC107 ethyl 2-(6-(cyclopropanesulfonamido)pyridin- 2—yl)-2-butanoate 1 H ° A \ ,-0., A, „N„ N II M—1 YY Y ' s^ fl u o A,,- ° Method I using INTC104, [acid HPLC], 313 (1.97). 10.50 (s, 1H), 7.69 (dd, J = 8.2, 7.5 Hz, 1H), 6.99 (d, J = 7.5 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 4.12 - 3.97 (m , 2H), 3.68 - 3.59 (m, 1H), 3.18 - 3.08 (m, IR), 1.99 - 1.93 (m, 1H), 1.88 - 1.77 (m, 1H), 1.13 (t, J = 7.1 Hz, 3H ), 1.10 1.05 (m, 2H) , 1.03 - 0.94 (m, 2H) , 0 . 84 (t, J = 7.4 Hz, 3H). Pd 174, Cs2CO3, dioxane IF-2019-16749728-APN-íWft / INPI Page 173 of 363 INT 08 ethyl 4~ (6- (cyclopropanesulfonamido)pyridin2-yl)tetrahydro-2H-pyran-4carboxylate .o L J Η Λ \ e Pe --V jf Ά' 0 0 ° Method I using INTC105, [acid HPLC], 355 (1.78) . 10.55 (s, 1H), 7.74 - 7 .70 (m, 1H), 7.05 (d, J = 7.7 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 4. 10 (q, J = 7.1 Hz, 2H), 3 .S2-3.72 (m, 2H), 3.53-3.43 (m, 2H), 3.24-3.16 (m, 1H), 2.33-2.25 (m, 2H), 2.11-2.00 (m, 2H), 1.15 ~ 1.06 (m, 5H), 1.05 0.98 (m, 2H). Pd 174, Cs2CO3, dioxane Method J: Hydrolysis X = CH, N Y = CR2iN z = cr2, n 2M LiOH (acf2 eq) was added to a solution of esten (1 eq) in MeOH (3 volumes) and THF (3 volumes), and the resulting reaction mixture was stirred at 50 °C for 2 h. The solvent was removed under reduced pressure and then acidified with 1M HC1 (aq) to pH 3. The solution was extracted with EtOAc, the organic phase was passed to. through a phase separator and the solvent was removed. The compound was used crude or purified by reverse phase chromatography. IF-2019- 16749728-ΑΡΝ-ΜΛΐΝΡΙ Page 174 of 363 Table 8: The following intermediates were prepared according to Method J. INT Name / Structure (All examples containing chiral centers are racemates unless otherwise indicated) Synthesis method, [LCMS Method], m / z (M+H) + , (tR / min) Data NMR chemical shifts of A (DMSO-dg unless otherwise stated) INTC109 2-(6-(cyclopropanesulfonamido)pyridin- 2-yl)-2-methylpropanoic acid A h ° A hcl X „.rt T K A s II n or AA ° Method J using INTC106, [UPLC acid], 285 (0.94). 12.25 (s, 1H), 10 .46 (s, 1H), 7.71 - 7.66 (m, 1H), 7.03 - 6.98 (m 1H), 6.82 - 6.77 (m, 1H), 3.20 - 3.17 (m, 1H) , 1.48 (s, 6H), 1.14 - 0.94 (m, 4H) . INTC110 2-(6-(cyclopropanesulfonamido)pyridin2-yl)acetic acid H0 , N Y°A-X Yf ¥ u ° ti 0 Method J using INTC102, [UPLC acid], 257 (0.61). None registered. INTC111 2-(6-(cyclopropanesulfonamido)pyridin- 2-yl)butanoic acid HO N N Y n¥ ¥ h o A ° Method J using INTC107, [acidic HPLC], 285 (0.90). 12.34 (s, 1H) f 10.49 (s, 1H), 7.72 - 7.65 (m, 1H), 6.99 - 6.95 (m, 1H), 6.89 - 6.83 (m, 1H), 3.56 - 3.52 (m, 1H) ), 3.17 - 3.07 (m, 1H), 1.99 - 1.93 (m, 1H), 1.86 - 1.75 (m, 1H), 1.13 - 0.91 (m, 4H), 0.86 - 0.81 (m 3H). IF-2019-16749728-APN-Á^INPI Page 175 of 363 Section of the pyrazine nucleus Ester formation Methyl 2-(6-Chloropyrazin-2-yl)acetate INTC112 Thionyl chloride (1.15 mL, 15.65 mmol) was added dropwise to a cold stirred solution of 2(6-chloropyrazin-2-yl)acetic acid (2.70 g, 15.65 mmol) in MeOH (50 mL) at 0 °C. After addition, the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo, and the crude residue was diluted with DCM (100 mL) and washed sequentially with sat. NaHCCg. (aq, 2 x 100 mL) and brine (100 mL). The organic extract was dried (MgSO4), filtered and the solvent removed in vacuo to provide methyl 2-(6~chloropyrazin-2-yl)acetate (2.63 g, 13.67 mmol, 87% yield) as a brown oil. . tR 1.25 min (HPLC, acidic); m / z 187 (¥1 M+H)+(ES+) ; ¥ NMR (500 Mhz, DMSO-d6) δ 8.74 (s, 1H), 8.68 (s, 1H), 4.00 (s, 2H), 3.66 (s, 3H). Methyl 2-(6-Chloropyrazin-2-yl)-2-methoxyacetate INTC121 O ,.n. ,ci ju N Prepared as for INTC112 using 2-(6-chloropyrazin-2-yl)-2-methoxyacetic acid INTC120 to provide methyl 2-(6-chloropyrazin-2-yl)-2-methoxyacetic acid (3.35 g, 15.31 mmol, 96% performance) as a transparent yellow oil. tR 1.33 min (HPLC, basic); in / z 217 (Ύ1 M+H)+(ES*), NMR data not recorded. Preparation of biester intermediates 1-tert-butyl 3-methyl 2-(6-Chloropyrazin-2-yl)malonate INTC113 IF-2019-16749728-APN-417WINPI Page 176 of 363 Prepared as for INTC1 using commercial 2,6-dichloropyrazine to provide 1-tert-butyl 3-methyl 2-(6-chloropyrazin-2-yl)malonate (7-8% yield) as a clear colorless oil. tR 2.18 min (HPLC, acidic); m / z 286 (35C1 M+H)1(ES+) ; 'h NMR (500 Mhz, DMSO-d6) δ 8.82 (s, 1H) , 8.72 (s, 1H) , 5.2 8 (s, 1H) , 3.7 3 (s, 3H) , 1.4 4-1.37 (m , 9H). Dimethyl 2-(6-Chloropyrazin-2-yl)-2-methoxymalonate INTC114 Prepared as for INTC1 using dimethyl 2-methoxymalonate and 2,6-dichloropyrazine to provide dimethyl 2-(6chloropyrazin-2-yl)-2-methoxymalonate (3%; yield) as a clear colorless oil. tR 1.65 min (HPLC, acidic); m / z 275 (3SC1 M+H) ” (ESf); A NMR (500 Mhz, DMSO-d6) δ 8.89 (d, J = 0.6 Hz, 1H), 8.86 (d, J - 0.6 Hz, 1H), 3.79 (s, 6H), 3.46 (s, 3H). IF-2019- 16749728-APN-M?#INPI Page 177 of 363 Alkylation of pyrazine intermediates Table 9: The following intermediates were prepared according to Method B described above. INTC Name / Structure (All examples containing chiral centers are racemates unless otherwise indicated) Synthesis method, [LCMS Method], m / z (M+H)+, (tR / min) Data NMR chemical shifts of (DMSO-de unless otherwise indicated) Base, RX, solvent INTC115 ethyl Method B using INTC113 [UPLC basic 2], 359 isotope ''Cl (0.72) , 8.88 (s, 1H) , 8.77 (s, 1H), 4.28 4.13 (m, 2H) , 3.29 (td, J = 6.4, 2.2 Hz, 2H), 3.10 (s, 3H), 2.46 (td, J = 6.3, 2.1 Hz, 2H), 1.40 (s, 9H), 1.20 (t, J = 7.1 Hz, 3H) . , MeOCH,C H2A, DMF INTC116 methyl 2-(6-Chloropyrazin2-yl)-2methylpropanoate xcl V Method B using INTC112 [acidic HPLC], 215 isotope J''C1 (1.88) 8.79 (s, 1H), 8.73. (s, 1H), 3.63 (s, 3H), 1.58 (s, 6H) K2CO?, MeL, acetone INTC117 methyl 2-(6-Chloropyrazin2-yl)butanoate Method B using 2-(6-chloropyrazin2-yl). )commercial methyl acetate [acidic HPLC], 215 isotope L<'C1 (1.84). 8.73 (s, 1H), 8.70 (s, 1H), 3.95 (dd, J = 8.1, 7.0 Hz, 1H), 3.62 (s, 3H), 2.13 - 2.01 (m, 1H), 1.96-1.84 (m, 1H), 0.83 (t, J 7.4 Hz, 3H). K.CO·-., EtBr, acetone IF-2019-16749728-APN-ffl^INPI Page 178 of 363 INTC119 2-(6-Chloropyrazin~ Method B using 8 . 74 (s, 1H), 8.71 NaH, 2-yl) -4-methoxy-~2~ INTC118, (A 1H), 4.08 (q, Mel, methylbutancate ethyl / 0 \ Λ, X N _,CI SU N [UPLC, basic], 273 isotope ;5C1 (1.32) . 12 Hz, 7.1 Hz, 2H), - 3.29 (m, 3.11 (s, 3H), -2.25 (m, 1.56 (s, 3H), (t, J - 7 . 1 3H). THF INTC122 2- (6 -Chloropyrazin- Method B using 8 . 84 (s, 1H), S . 61 NaH, 2-iI)-2- INTC121, (s, 1H), 3.68 (s, Mel, methyl methoxypropanoate or '°ny° [ Acid HPLC], 230 isotope 3DC1 (1, 67), 3H), 1 . 3.30 (s, 3H), (s, 3H). TFA decarboxylation Ethyl 2-(6-Chloropyrazin-2-yl)-4-methoxybutanoate INTC118 Prepared by Method A using 1-tert-butyl 2-(6chloropyrazin-2-yl)-2-(2-methoxyethyl)malonate and 3-ethyl INTC115 to provide ethyl 2-(6chloropyrazin-2-yl)-4-methoxybutanoate (2.49 g, 8.65 mmol, 711 yield) as a purple oil. tR 0.59 min (UPLC, basic 2); m / z 259 (35C1 M+H)+(ES+) ; and NMR (500 Mhz, DMSO-d6) δ 8.73 (s, 1H), 8.69 (s, 1H), 4.16 - 4.05 (m, 3H), 3.37 - 3.29 (m, 1H), 3.28 - 3.20 (m, 1H), 3.16 ( s, 3H), 2.35 - 2.24 (m, 1H), 2.16 - 2.07 (m, 1H), 1.13 (t, J = 7.1 Hz, 3H). Hydrolysis 2-(6-chloropyrazin-2-yl)-2-methoxyacetic acid INTC120 IF-2019- 16749728-APN-4ÍÍ&INPI Page 179 of 363 EITHER A stirred mixture of INTC114 dimethyl 2-(6-chloropyrazin-2-yl)-2methoxymalonate (4.54 g, 16.53 mmol) in THF (40 mL) and water (10 mL) was treated with 2M NaOH (aq, 4 mL, 8.00 mmol). The reaction mixture was allowed to stir at RT for 66 h. More 2M NaOH (aq, 5 eq) was added and the mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by flash C18 RP column chromatography (80 g column, 5-501 MeCN / 10 mM ammonium bicarbonate) to provide 2-(6-chloropyrazin-2 acid). -yl)-2-methoxyacetic acid (3.67 g, 16.30 mmol, 991 yield) as a white solid. tR 1.06 min (acid HPLC); m / z 203 (j:;íC1 M+H)4(ES1) ;]H NMR (500 Mhz, DMSO-d6) δ 8.63 (s, 2H), 4.45 (s, 1H), 3.26 (s, 3H). An exchangeable proton was not observed. 2-(6-chloropyrazin-2-yl)-4-methoxy-2-methylbutanoic acid INTC131 'O N^CI s IT N To a solution of ethyl 2-(6-chloropyrazin-2-yl)-4-methoxy-2methylbutanoate INTC119 (1.93 g, 7.08 mmol) in EtOH (2 mL) and THF (15 mL) was added a solution of LiOH ( 0.203 g, 8.49 mmol) in water (5 mL). The reaction was stirred at RT for 18 h. More LiOH (0.068 g, 2.83 mmol) in water (5 mL) was added and the reaction mixture was stirred at RT for 4 h. The reaction mixture was concentrated in vacuo and the resulting residue was acidified using 1M HC1 (50 mL). The product was extracted using EtOAc (3 x 50 mL), the combined organic extracts were dried (MgSCb) and concentrated in vacuo to obtain the acid 2-(6 IF-2019- 16749728-APN- IPPlNPI Page 180 of 363 chloropyrazin-2-yl)-4-methoxy-2-methylbutanoic acid (1.92 g, 5.98 mmol, 847 yield) as a dark brown oil that was used without further purification. tR 0.95 min (UPLC, acidic); m / z 245 (35C1 M+H)1(ES+) ;]H NMR (500 Mhz, DMSO-d6) δ 12.59 (s, 1H) , 8.74 (s, 1H) , 8.70 (s, 1H) , 3.36 - 3.27 (m, 2H), 3.11 (s, 3H), 2.34 - 2.18 (m, 2H), 1.56 (s, 3H). 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)butanoic acid INTC132 Prepared as for INTC131 using methyl 2—(6—(cyclopropanesulfonamido)pyrazin-2-yl)butanoate INTC126 to provide 2-(6(cyclopropanesulfonamido)pyrazin-2-yl)butanoic acid (597 yield) as a gum colorless tR 1.35 min (HPLC, acidic); m / z 286 (M+H)+(ES+) ;!H NMR (500 Mhz, DMSO-d6) δ 12.54 (s, 1H) , 11.00 (s, 1H) , 8.27 (s, 1H) , 8.21 (s , 1H), 3.70-3.65 (m, 1H), 3.10-3.03 (m, 1H), 2.09 - 1.98 (m, 1H), 1.91 - 1.79 (m, 1H), 1.21 - 0.98 (m, 4H), 0.84 (t, J = 7.4 Hz, 3H) . 2~(6-(cyclopropanesulfonamido)pyrazin-2-yl)-2fluorobutanoic acid INTC133 Prepared as for INTC131 using methyl 2-(6(cyclopropanesulfonamido)pyrazin-2-i1)-2-fluorobutanoate INTC130 to provide 2-(6(cyclopropanesulfonamido)pyrazin-2-yl)-2-fluorobutanoic acid (957 performance) as a thick red paste. tR 0.89 min (UPLC, acidic); m / z 304 (M+H)4(ES1);]H NMR (500 Mhz, DMSO-d6) δ 13.74 (s, 1H), 11.23 (s, 1H), 8.45 (s, 1H), 8.33 (s , 1H) , 3.15 3.09 (m, 1H) , 2.45 - 2.21 (m, 2H) , 1.21 IF-2019-16749728-APN-ÁÍW#INPI Page 181 of 363 1.15 (m, 1H), 1.15 - 0.97 (m, 3H), 0.92 (t, J = 7.4 Hz, 3H). 2-(6-(cyclopropanesulfonamido)pyrazin-2-yl)-2methoxyacetic acid INTC134 Prepared as INTC131 using methyl 2-(6(cyclopropanesulfonamido)pyrazin-2-yl)-2-methoxylacetate INTC128 to provide 2—(6—(cyclopropanesulfonamido)pyrazin-2-yl)-2-methoxyacetic acid (241 yield) like a solid brown. tR 1.06 min (HPLC, acidic); ixi / z 288 (M+H)' (ES+) ;]H NMR (500 Mhz, DMSO-d6) δ 11.13 (s, 1H) , 8.3 6 (s, 1H) , 8.32 (s, 1H) , 6.7 8 (s, 1H), 4.94 (s, 1H), 3.40 (s, 3H), 3.12-3.02 (m, 1H), 1.16 - 1.10 (m, 2H), 1.07-0.98 (m, 2H). Formation of heterocycles through alkylation Methyl 4-(6-Chloropyrazin-2-yl)tetrahydro-2H-pyran-4-carboxylate INTC123 aVa / I o k Y N Prepared as for INTC52 ​​using methyl 2-(6-chloropyrazin-2-yl)acetate INTC112 to give methyl 4-(6-chloropyrazin-2-yl)tetrahydro-2H-pyran-4-carboxylate (121 yield) as a yellow oil . tR 1.05 min (UPLC, acidic); m / z 257 (3-'Cl· M+H)+(ESÁ ; Y NMR (500 Mhz, DMSO-d6) δ 8.81 (s, 1H), 8.76 (s, 1H), 3.77 3.62 (m, 5H) , 3.58 - 3.49 (m, 2H), 2.38 - 2.26 (m, 2H), 2.21 - 2.10 (m, 2H). IF-2019-16749728-APN-1R&HNPI Page 182 of 363 Fluorination of pyrazine intermediates Table 10: The following intermediates were prepared according to Method H described above. INTC Name / Structure (All examples containing chiral centers are racemates unless otherwise indicated) Synthesis method, [LCMS Method], m / z (M+H)+, (tR / min) NMR chemical shifts of (DMSO-d^ unless otherwise noted) INTC124 2 - Methyl (6-chloropyrazin-2-yl)2-fluorobutanoate FU 1 ΠΓ N Method H using INTC117, [Basic UPLC], m / z not collected (1.22) . 8.91 (s, 1H), 8.90 (s, 1H), 3.76 (s, 3H), 2.43 -2.24 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). Formation of amides of selected building blocks Table 11: The following intermediates were prepared using methods analogous to Methods 1-10 described below for the synthesis of the compound of formula (I). INTC Name / Structure (All examples containing chiral centers are racemates unless otherwise indicated) Synthesis method, [LCMS Method], m / z (M+H) +, (tR / min) Data of XH NMR chemical shifts (DMSO-dg unless otherwise stated) INTC135 2 - (6doropyrazin-2“yl) - N-(4-(pyridin-3yl)phenyl)acetamide H Γ1 Method 1 using materials commercial starting material, [acidic HPLC],325 isotope jrjCl (1.11). 10.48 (s, 1.H), 8.89 (dd, J = 2.5, 0.9 Hz, 1H), 3.73 (s, 1H), 8.71 (s, 1H), 8.54 (dd, J = 4.3, 1.6 Hz, 1H), 8.06 (ddd, J = 3.1, 2.5, 1.6 Hz, 1H), 7.79 - 7.60 (m, 4H), 7.47 (ddd, J =8.1, 4.8, 0.9 Hz, 1H), 4 .01 (s, 2H). IF-2019- 16749728-APN-lfiftflNPI Page 183 of 363 INTC136 2(6-chloropyrazin-2-yl)- N- (5- (6-ethoxypyrazin-211)pyridin-2-yl) -4methoxy-2-methylbutanamide 0^ ΓΎ ΤΑΓ ¥ -x. ..m ΑλΝ o t p A Method S using INTC131 and INTD33 [UPLC acidic 2], 443 isotope Al (0.69). 10.32 (s, 1H), 9.02 (dd, J =2.5, 0.8 Hz, 1H), 8.84 (s, 1H), 8.74 (s, 1H), 3.72 (s, 1H), 8.50 (dd, J = 8.8, 2.5 Hz, 1H), 8.25 (s, 1H), 8.22 (dd, J = 8.8, 0.8 Hz, 1H), 4.48 (q, J = 7.0 Hz, 2H), 3.403.33 (m, 2H), 3.10 ( s, 3H), 2.47 - 2.32 (m, 2H), 1 . 68 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H). INTC137 2-(6-chloropyrazin-2-yl)N- (5- (6-ethoxypyrazin-2“ yl)pyridin-2-yl) -2methoxyacetamide A H ! N N χ N Cl \ .O. .N. JL J O L, J 1 ~'N' Method 3 using INTC120 and INTD33 [acid HPLC], 401 isotope Al (2.20). 10.85 (s, 1H), 9.12 (dd, J =2.4, 0.8 Hz, 1H), 8.91S.81 (m, 3H), 8.54 (dd, J = 8.7f 2.5 Hz, 1H), 8.27 (s, 1H) ), 8.24 - 8.16 (m, 1H), 5.33 (s, 1H), 4.49 (q, J = LI Hz, 2H), 3.48 (s, 3H), 1.40 (t, J = 7.0 Hz, 3H) . 2,6-pyrimidine core N-(2-Chloropyrimidin-4-yl)cyclopropanesulfonamide INTC138 Ck ,Ν. TO-. r s I rr N^A0 0 To a suspension of 2,4-dichloropyrimidine (15 g, 101 mmol) in acetonitrile (250 mL) cyclopropanesulfonamide (14.64 g, 121 mmol) and K2CO3 (27.8 g, 201 mmol) were added. The resulting mixture was allowed to stir at reflux for 18 h. The mixture was slowly poured onto ice-cold 6M HC1 (aq, 100 mL) subjected to vigorous stirring, then diluted with EtOAc (100 mL). The two-phase mixture was filtered, the phases were separated and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated on silica, then purified by IF-2019-16749728-APN-ÁS^INPI Page 184 of 363 silica gel chromatography (column 50-100 EtOAc / isohexane) to provide a white solid. The solid was purified by Solubilization of impurities with water (50 mL), then azeotroped with MeCN (30 mL) under vacuum to provide (2-chloropyrimidin-4yl)cyclopropanesulfonamide (11.68 g, 49.5 mmol, 49% yield) as a white solid. tR 0.79 min (UPLC, acidic); m / z 234 (ír'Cl M+H)1(ES'*');LH NMR (500 Mhz, DMSO-d6) δ 11.68 (s, 1H), 8.60 (d, J = 5.3 Hz, 1H), 7.32 (d, J = 5.3 Hz, 1H), 3.11-3.06 (m, 1H), 1.30 - 0.94 (m, 4H). N-(2-Chloropyrimidin-4-yl)-TV-(4methoxybenzyl)cyclopropanesulfonamide INTC139 To a stirred solution of N-(2-chloropyrimidin-4yl)cyclopropanesulfonamide INTC138 (11.68 g, 50.0 mmol) in DMF (50 mL), K2CO3 (13.82 g, 100 mmol) and 1-(chloromethyl)-4-methoxybenzene were successively added. (8.13 mL, 60.0 mmol) at RT. The reaction mixture was stirred at RT for 3 h, then heated to 40°C for 18 h. Additional 1-(chloromethyl)-4-methoxybenzene (2.03 mL, 15.0 mmol) was added and the resulting mixture was stirred at 40°C for 18 h. The mixture was cooled to RT, and poured into water (200 mL) and diluted with EtOAc (100 mL). The phases were separated and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO.5, filtered and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography (330 g column, 0-50% EtOAc / sohexane) to provide a white solid. The solid was purified by IF-2019-16749728-APN-ÁSf#INPI Page 185 of 363 solubilization of impurities with MeCN (20 mL) to provide N-(2-chloropyrimidin-4-yl)-N-(4methoxybenzyl)cyclopropanesulfonamide (8.4 g, 23.50 mmol, 47¾ yield) as a white powder. tR 1.41 min (UPLC, basic); m / z 354 (3rjCl M+H)+(ES+) ;rH NMR (500 Mhz, DMSO-d6) δ 8.54 (d, J = 5.9 Hz, 1H), 7.42 (d, J - 5.9 Hz, 1H) , 7.28 (d, J = 8.7 Hz, 2H) , 6.91 (d, J = 8.7 Hz, 2H) , 5.11 (s, 2H) , 3.7 3 (s, 3H) , 3.32 - 3.2 6 (m, 1H) , 1.2 3 1.08 (m, 4H) . 1-tert-Butyl 3-ethyl 2-(4-(N-(4-Methoxybenzyl)cyclopropanesulfonamido)pyrimidin2-yl)malonate INTC140 To a solution of tert-butyl ethyl malonate (1.41 mL, 7.46 mmol) in DME (25 mL), Cs¿CO.? (4.86 g, 14.92 mmol) and N- (2-chloropyrimidin-4- il)-N-(4methoxybenzyl)cyclopropanesulfonamide INTC139 (2.4 g, 6.78 mmol) and the resulting mixture was heated at 90°C for 24 h. The reaction mixture was cooled to RT and poured into sat. NH4CI. (aq, 100 mL) and diluted with EtOAc (50 mL). The phases were separated and the aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent removed in vacuo. The crude product was purified by silica gel chromatography (220 g column, 0-701 EtOAc / isohexane) to provide 1-tert-2-(4-(W-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidin-2yl)malonate. butyl and 3-ethyl (1.67 g, 3.14 mmol, 46% yield) as a yellow oil. tR 1.67 min (UPLC, acidic); m / z 507 (M+H)+(ES1);!H NMR (500 Mhz, DMSOd6) δ 8.59 (d, J - 6.0 Hz, 1H), 7.33 (d, J = 6.0 Hz, 1H) , IF-2019-16749728-APN-ÍSftflNPI Page 186 of 363 7.29 - 7.22 m, 2H)r6.89 - 6.84 (m, 2H)f5.17 - 5.07 (m, 2H) , 4.99 (s, 1H) , 4.14 (q, J - 7.2 Hz, 2H) , 3.71 (s , 3H) , 3.31 - 3.2 6 (m, 1H) , 1.3 9 (s, 9H) , 1.19 - 1.14 (m, 3H) , 1.14-0.98 (m, 4H). 1-tert-Butyl 3-ethyl 2-Ethyl-2-(4-(77-(4methoxybenzyl)cyclopropanesulfonamido)pinimidin-2yl)maIonate INTC141 to one solution of 1-tert-butyl 3-ethyl 2-(4-(77-(4-methoxybenzyl)cyclopropanesulfonamido)pyrimidin-2-yl)malonate INTC140 (2.96 g, 5.85 mmol) in DMF (40 mL) was successively added K2CO; (1.780 g, 12.88 mmol) and EtT (0.52 mL, 6.44 mmol). The resulting mixture was stirred vigorously at 60°C for 2 h. The reaction mixture was cooled to RT and poured into sat. NH4CI. (aq, 150 mL) and diluted with EtOAc (50 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with semisaturated brine (50 mL), dried with Na2SOq, filtered and the solvent removed in vacuo. The crude product was purified by silica gel chromatography (120 g column, 0-507 EtOAc / isohexane) to provide 2-ethyl-2-(4-(N-(4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-2yl)malonate. 1-tert-butyl and 3-ethyl (2.63 g, 4.39 mmol, 75% yield) as a light yellow oil. tR 1.82 min (UPLC, acidic); m / z 534 (M+H)1(ES1);TH NMR (500 Mhz, DMSO-d6) δ 8.59 (d, J - 5.9 Hz, 1H) , 7.30 (d, J - 5.9 Hz, 1H) , 7.25 -7.00 (m, 2H), 6.89-6.84 (m, 2H), 5.16-5.07 (m, 2H), 4.18 - 4.11 (m, 1H), 4.11 - 4.01 (m, 1H), 3.71 (s, 3H), 3.3 0 - 3.25 (m, 1H), 2.27 - 2.13 (m, 2H), 1.35 (s, IF-2019- 16749728-APN-lft?#INPI Page 187 of 363 9H), 1.13 (t, J = 7.1 Hz, 3H), 1.10 - 0.97 (m, 4H), 0.92 (t, J - 7.3 Hz, 3H). Ethyl 2-(4-(N-(4-Methoxybenzyl)cyclopropanesulfonamido)pyrimidin2-yl)butanoate INTC142 To a solution of 1-tert-butyl 3-ethyl 2-ethyl-2-(4-(N-(4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-2yl)malonate INTC141 (3.0 g, 5.06 mmol) in DCM (40 mL) TFA (15.59 mL, 202 mmol) was added. The resulting solution was allowed to stir at RT for 18 h. The solution was poured into sat NaHCCg. (aq, 200 mL) and diluted with DCM (50 mL). The phases were separated and the aqueous layer was extracted with DCM (2 x 50 mL). The pH was readjusted to 4 with 12 M HC1 and the aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent removed in vacuo. The crude product was purified by silica gel chromatography (120 g column, 0-1003 EtOAc / isohexane) to provide ethyl 2-(4-(N-(4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-2yl)butanoate (1.74 g , 3.85 mmol, 763 yield) as a colorless oil. tR 1.56 min (UPLC, acidic); m / z 434 (M+H)+(ES+) ;2H ​​NMR (500 Mhz, DMSO-d6) δ 8.55 (d, J = 5.9 Hz, 1H) , 7.34 - 7.21 (m, 3H) , 6.90-6.86 ( m, 2H), 5.15-5.06 (m, 2H), 4.05 - 4.00 (m, 2H), 3.78 (t, J - 7.4 Hz, 1H), 3.71 (s, 3H), 1.98 - 1.87 (m, 2H) , 1.13 1.01 (m, 7H), 0.82 (t, J = 7.4 Hz, 3H). A CH proton hidden by the DMSO peak. N- (5 - (6-Ethoxypyrazin-2-yl)pyridin-2-yl)-2-(4-(N-(4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-2yl)butanamide INTC143 IF-2019- 16749728-APN-1S$#INPI Page 188 of 363 Prepared using Method 2 using 5 —(6 — ethoxypyrazin-2-yl)pyridin-2-amine INTD33 (449 mg, 2.08 mmol) and 2-(4-(77-(45-methoxybenzyl)cyclopropanesulfonamido)pyrimidin-2yl)butanoate of ethyl INTC142 to provide N-(5-(6ethoxypyrazin-2-yl)pyridin-2-yl)-2-(4-(7V-(4methoxybenzyl)cyclopropanesulfonamido)pyrimidin-2yl)butanamide (111 yield) as an oil colorless. tR 1.70 min (UPLC, acidic); m / z 604 (M+H)+(ES'1'); 41 NMR (500 Mhz, DMSO-d6) δ 10.99 (s, 1H) , 9.07 (d, J = 2.5 Hz,1H) , 8.85 (s, 1H), 8.58 (d, J = 5.9 Hz, 1H), 8.49 (dd, J -8.8, 2.5 Hz, 1H), 8.25 (s, 1H), 8.24 (d, J = 8.8 Hz, 1H), 7.26 7.21 (m, 3H), 6.79 - 6.74 (m, 2H), 5.12 (d, J = 16.3 Hz , 1H), 5.08 (d, J - 16.3 Hz, 1H), 4.49 (q, J = 7.0 Hz,2H), 4.24 - 4.15 (m, 1H), 3.64 (s, 3H), 3.42 - 3.37 (m, 1H), 2.15 - 2.02 (m, 2H), 1.41 (t, J - 7.0 Hz, 3H), 1.10 - 1.05 (m, 2H), 1.00-0.96 (m, 2H), 0.94 (t, J - 7.4 Hz, 3H). Benzamide Pyrimidine Intermediates Sulfonylation N-(4-Cyanopyrimidin-2-yl)cyclopropanesulfonamide INTC144 Prepared following Method C using 2chloropyrimidin-4-carbonitrile, cyclopropanesulfonamide with CS2CO3, tBuXPhos and [Pd(allyl)Cl] 2 in dioxane to provide N-(4-cyanopyrimidin-2yl)cyclopropanesulfonamide (881 yield) as an orange solid pale. tR 0.70 min (acidic UPLC); m / z 225 IF-2019- 16749728-APN-1$?#INPI Page 189 of 363 (M)1(ES+) ; NMR (500 Mhz, DMSO-d6) δ 11.87 (s, 1H), 8.95 (d, J = 4.9 Hz, 1H), 7.75 (d, J = 4.9 Hz, 1H), 3.23 - 3.14 (m, 1H), 1.19 - 1.04 (m, 4H). Reduction of tert-butyl nitrile ((2-(Cyclopropanesulfonamido)pyrimidin-4-yl)methyl)carbamate INTC145 To a suspension of N-(4-cyanopyrimidin-2yl)cyclopropanesulfonamide INTC144 (0.5 g, 2.23 mmol) in MeOH (20 mL) at 0 °C was added di-tert-butyl dicarbonate (0.973 g, 4.46 mmol) followed by nickel(II) chloride hexahydrate (0.029 g, 0.223 mmol). Next, NaBH4 (0.675 g, 17.8 mmol) was added in portions over 30 min, adding each portion only once the previous one had stopped effervescing. The reaction mixture was stirred at RT for 18 h. The reaction was quenched by the addition of N-(2-aminoethyl)-1,2-ethanediamine (0.5 mL, 4.50 mmol) and stirred for 1.5 h at RT. The reaction mixture was concentrated to dryness and the resulting orange residue was dissolved in EtOAc (50 mL) and water (50 mL). The phases were separated, the aqueous (pH 8) was neutralized using sat. NH4C1. (aq, 50 mL) and the product was extracted using EtOAc (50 mL). The aqueous was further acidified to pH 4 by adding 1M HC1 (aq) in portions. The product was extracted using EtOAc (50 mL). The combined organic extracts were dried (phase separator) and concentrated in vacuo. The crude product was concentrated on silica and purified by silica gel chromatography (24 g column, 0-100% EtOAc / isohexane) to provide ((2-(cyclopropanesulfonamido)pyrimidin-4yl)methyl)tert-carbamate. butyl (85 mg, 0.207 mmol, 9% yield) as a transparent colorless glass; tR 0.98 IF-2019- 16749728-APN-1SP#INPI Page 190 of 363 min (acidic UPLC); m / z 350 (M+Na)4(ΕΞ4); NMR (500 Mhz, DMSO-d6) δ 8.62 (d, J = 4.9 Hz, 1H), 8.55 (d, J - 5.2 Hz, 1H), 7.52 -7.48 (m, 1H), 6.96 (d, J = 5.2 Hz, 1H), 4.14 (d, J - 6.1 Hz, 2H), 3.30 - 3.19 (m, 1H), 1.41 (s, 9H), 1.15 1.05 (m, 2H), 1.08 - 1.00 (m, 2H). Rental Methyl I-(2-Chloropyrimidin-4-yl)cyclopropanecarboxylate INTC146 To a solution of methyl 2-(2-chloropyrimidin-4-yl)acetate (3 g, 16.08 mmol) in DMF (40 mL) was added NaOH (1.93 g, 48.2 mmol). The resulting mixture was allowed to stir for 15 min at RT before adding 1,2-dibromoethane (2.77 mL, 32.2 mmol) dropwise and allowing it to stir at RT for 3 h. The mixture was poured into sat. NH4C1. (aq, 100 mL) and diluted with EtOAc (40 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2 x 40 mL). The combined organic layers were dried (Na2SO4), filtered and the solvent removed in vacuo. The crude product was purified by silica gel chromatography (120 g column, 0-501 EtOAc / fsohexane) to provide methyl 1-(2chloropyrimidin-4-yl)cyclopropanecarboxylate (1.78 g, 8.12 mmol, 51% yield ) as a colorless oil. tR 1.05 min (UPLC, basic); m / z 213 (M+H)4(ES1); Y NMR (500 Mhz, DMSO-d6) δ 8.70 (d, J = 5.2 Hz, 1H), 7.88 (d, J = 5.2 Hz, 1H), 3.67 (s, 3H), 1.68 - 1.63 (m, 2H), 1.59 (dt, J = 5.1, 2.9 Hz, 2H). Hydrolysis 1-(2-Chloropyrimidin-4-yl)cyclopropanecarboxylic acid INTC147 ht ^Cl IF-2019- 16749728-APN-W>#INPI Page 191 of 363 Prepared by Method J using methyl 1-(Ιοί oropyrimidin-4-i1)cyclopropanecarboxylate INTC146 to provide 1-(2-chloropyrimidin-4yl)cyclopropanecarboxylic acid (quantitative yield) as a colorless solid. tR 0.83 min (acidic UPLC); m / z 199 (M+H)+(ES4-). No MRI data were recorded. Curtius (1-(2~Chloropyrimidin-4-yl)cyclopropyl)tert-butyl carbamate INTC148 in To a solution of 1-(2-chloropyrimidin-4yl)cyclopropanecarboxylic acid INTC147 (1.85 g, 9.31 mmol) in tert-butanol (15 mL) and toluene (15 mL), Et3N (1.49 mL, 10.3 mmol) and DPPA were successively added. (2.23 mL, 9.78 mmol). The resulting mixture was allowed to stir at 90°C for 4 h. The mixture was cooled to RT and diluted with sat. NaHCOj. (aq, 50 mL) and EtOAc (30 mL). The phases were separated and the aqueous layer was extracted with EtOAc (3 x 2 0 mL). The combined organic layers were dried (Na2SO), filtered and the solvent removed in vacuo. The crude product was purified by silica gel chromatography (12 0 g column, 0-501 EtOAc / isohexane) to provide tert-butyl (1-(2-chloropyrimidin-4yl)cyclopropyl)carbamate (1.02 g, 3.33 mmol, 361 yield) as a colorless solid. tR 1.26 min (acidic UPLC); m / z 270 (M+H)!(ES+) .qH NMR (500 Mhz, DMSOd6) δ 8.63 (d, J - 5.3 Hz, 1H), 7.91 (s, 1H), 7.38 (d, J 5.3 Hz, 1H), 1.42 (s, 9H), 1.35 - 1.21 (m, 4H). 1- (2-Bromopyrimidin-4-yl)propan-1-one INTC149 O A solution of 2-bromopyrimidine (17.91 g, 113 mmol) in IF-2019-16749728-APN-1R?#INPI Page 192 of 363 Anhydrous THF (150 mL) cooled to -60 added 1M lithium magnesium 2,2,6,6-tetramethylpiperidin-l-ide dichloride (in THF / Toluene) (180 mL, 16 9 mmol) dropwise in 1 hour. The resulting solution was stirred at -55 °C for 3 h then a solution of Nmethoxy-N-methylpropionamide (11 g, 94 mmol) in anhydrous THF (20 mL) was added dropwise to the resulting suspension. The reaction mixture was warmed to -40 °C, then after 3 0 min it was allowed to warm slowly from -40 °C to RT in 18 h. The reaction mixture was cooled in an ice bath, then carefully quenched with the dropwise addition of 51% citric acid (aq, 80 mL). The mixture was diluted with brine (150 mL) and the organic phase was separated. The aqueous phase was further extracted with DCM (3 x 100 mL), the combined organic phases were dried (MgSO4), filtered, then concentrated in vacuo. The crude product was purified by silica gel chromatography (330 g column, 0-101 EtOAc / fsohexane) to provide 1-(2-bromopyrimidin-4-yl)propan-1-one (11.39 g, 50.8 mmol, 541 yield) as a yellow solid. tR 1.74 min (basic HPLC); m / z 215 (7C>Br M+H)1(ES1). NMR (500 Mhz, DMSO-d6) δ 8.97 (d, J = 4.9 Hz, 1H), 7.95 (d, J = 4.9 Hz, 1H), 3.12 (q, J - 7.1 Hz, 2H), 1.09 (t, J = 7.1 Hz, 3H). N-(1-(2-Bromopyrimidin-4-yl)propylidene)-2-methylpropan-2sulfinamide INTC150 Ti(O-i-Pr)λ (30.1 ml, 103 mmol) was added to a mixture of (R)-2-methylpropan-2-sulfinamide (7.3 g, 60.2 mmol), (S)-2methylpropan-2-sulfinamide (5.9 g, 48.7 mmol) and l-(2bromopyrimidin-4-yl·)propan-l-one INTC149 (11.5 g, 51.3 mmol). The reaction mixture was then heated to 70 IF-2019-16749728-APN-Á^INPI Page 193 of 363 °C for 10 h. The reaction mixture was cooled in an ice bath, diluted in THF (200 mL), and treated dropwise with brine (50 mL). The mixture was stirred for 15 min, then filtered over Celite (80 g) eluting with THF (1 L). The filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (330 g column, 0-100% EtOAc / isohexane) to provide N-(1-(2-bromopyrimidin-4-yl)propylidene) ~~2~ methylpropan- 2-sulfinamide (12.87 g, 39.6 mmol, 77% yield) (a mixture of E and Z isomers) as a pale yellow solid. tR 1.79 and 2.12 min (basic HPLC); m / z 318 (79Br M+H)+(ES+) . No MRI data were collected. Reduction of sulfoximines N-(1-(2-Bromopyrimidin-4-yl)propyl)-2-methylpropan-2sulfinamide INTC151 A solution of N-(1-(2-bromopyrimidin-4-yl)propylidene)-2methylpropan-2-sulfinamide INTC150 (10 g, 30.8 mmol) in THF (200 mL) and water (2 mL) was cooled to − 50 °C (temp, external bath), then treated with sodium borohydride (1.2 g, 31.7 mmol). The reaction mixture was stirred for 10 min, then allowed to warm to RT. After 1 h, sat NaHCOj was added. (aq, 20 mL) and the reaction mixture was stirred for 20 min. The mixture was acidified to pH 5 with 1 N HC1 (aq), then concentrated in vacuo. The aqueous phase was extracted with DCM (3 x 80 mL), the combined organic phases were dried (phase separator) and concentrated in vacuo to provide N-(1-(2-bromopyrimidin-4~yl)propyl) ~2 ~ methylpropan-2-sulfinamide (7.2 g, 20.9 mmol, 68% yield) as an orange gum, as a 1:3 mixture of IF-2019-16749728-ΑΡΝ-ΛΜΉΝΡΙ Page 194 of 363 diastereomers. tR 1.63 and 1.77 min (basic HPLC); m / z 320 (M+H)+(ES+) . No No MRI data were collected. Grignard to add a second R4 / R5 group TV-(2-(2-Bromopyrimidin-4-yl)butan-2-yl)-2-methylpropan-2sulfinamide INTC152 MeMgBr ( 0.13 mL, 0.38 mmol) drop by drop in 5 min. The resulting mixture was allowed to warm to room temperature and stirred for 1 h, then quenched by the addition of sat. NH4CI. (aq, 50 mL). The product was extracted with EtOAc (2 x 100 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The crude product was purified by silica gel chromatography (40 g column, 0-100¾ EtOAc / isohexane) to provide N-(2-(2-bromopyrimidin4-yl)butan-2-yl)-2-methylpropan- 2-sulfinamide (0.107 g, 0.321 mmol, quantitative yield) as a colorless transparent gum, as a single diastereomer. tR 1.95 min (acid HPLC); m / z 332 (73Br Μ +H)+(ES+) .]H NMR (500 Mhz, DMSO-d6) δ 8.70 (d, J = 5.2 Hz, 1H), 7.85 (d, J - 5.2 Hz, 1H) , 5.63 (s, 1H), 1.97 - 1.82 (m, 2H), 1.54 (s, 3H), 1.17 (s, 9H), 0.75 (t, J = 7.4 Hz, 3H). IF-2019-16749728-APN-4J9BINPI Page 195 of 363 Formation of sulfonamides from aromatic halides Table 12: The following intermediates were prepared according to Method C described above. INTC Name / Structure (All examples containing chiral centers are racemates unless otherwise indicated) Synthesis method, [LCMS Method], m / z (M+H) + , (tR / min) Data Catalyst, Base shifts, Solvent NMR chemicals (DMSO-de unless otherwise noted) INTC153 ((2-(Cyclopropanesulfonamido)pyrimidin4-i1)cyclopropyl)tert-butyl carbamate >L X a ' 0 N A^ A Method C using INTC143, [UPLC acid], 355 (1.11). 11.07 (s, 1H), 8.45 Pd 174, (s, 1H), 7.83 (s, Cs?CO3, 1H), 6.99 (s, 1H), dioxane 3.16-3.03 (m, 1H), 1.42 (s , 9H), 1.12- 1.01 (m, 4H), 0.95 - 0.84 (m, 4H). INTC154 N- (4- (2-(1,1- dimethylethylsulfinamido)butan-2~ yl)pyrimidin-2- yl)cyclopropanesulfonamide 0 / , Λ h \ / h A \ .-A,., AW X n A^ A > H íl W 1 aa ° 0 Method C using INTC152, [UPLC acid], 375 (1.10). 11.26 (s, 1H), 8.58 Pd 174, (d, J = 5.3 Hz, 1H), Cs2CO?, 7.36 (d, J = 5.3 Hz, dioxane 1H), 5.54 (s, 1H), 3.30 - 3.20 (m , 1H), 1.95 - 1.85 (m, 2H), 1.56 (s, 3H), 1.19 (s, 9H), 1.16 - 0.99 (m, 4H), 0.71 (t, J = 7.3 Hz, 3H). INTC155 A (4-propionylpyrimidin-2yl)cyclopropanesulfonamide 0 Λ 11 h A \ Af X s 6° ° Method C using INTC149, [UPLC acid 2], 256 (0.50). No [Pd(alii)Cl] data were recorded. tBuXPhos, cs2co3, dioxane INTC125 2- (β- ίοι opropanesulf onamido) methyl pyrazin- 2-yl)-2-methylpropanoate ”Λυ / N Method C using INTC116, [acidic HPLC], 300 11.04 (s, 1H), 8.36 Pd-174, (s, 1H), 8.19 (s, Cs2CO;¿, 1H), 3.60 (s, 3H), dioxane 3.08-2.98 (m, 1H), 1.55 (s, 6H), 1.23 -1.00 ( m, 4H). IF-2019-16749728-APN-4WINPI Page 196 of 363 Í ' '1 (1.65). INTC126 Methyl 2-(6-(cyclopropanesulfonamido)pyrazin- 2-yl)butanoate Ί η A .0..,. V. N A—1 ÁI ¡Í y γ o U b o 0 N Method C using INTC117, [acid HPLC], 300 (1.62). 11.04 (s, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 3.82 (t, J = 7.5 Hz, 1H), 3.60 (s, 3H), 3.08-3.01 (m, 1H) , 2 . 09 2 .01 (m, 1H) , 1 . 91 1.82 (m, 1H), 1.18 (t, J = 7.1 Hz, 3H), 1.07 1.02 (m, 2H), 0.92 - 0.86 (m, 2H). Pd-174, Cs:íCO3, dioxane INTC127 methyl 4-(6- (cyclopropanesulfonamido)pyrazin2-yl)tetrahydro-2H-pyran-4carboxylate ,.,.ο, \ H 0 >< ,N, / , ' hr if hr A / / 'V-7 0 If P ° V N Method C using INTC123, [Acid HPLC], 342 (1.45) . 11.11 (s, 1H), 8.34 7.68 (m, 2H), 3.78 - 3.67 (m, 2H), 3.63 (s, 3H), 3.52 - 3.44 (m, 2H), 3.02 - 2.98 (m, 1H), 2.25 (s, 2H) , 2.09 (s, 2H) , 1.09 - 0.85 (m, 4H) . Pd-174, Cs2CO3, dioxane INTC128 2- (β- ίοι cl opr opanosulf onamido)pyrazin- 2-yl)-2~methyl methoxyacetate ~^O Λ ,Ο. Λ, ,N. .N, >-4 Π X A N Method C using INTC121, [Acid HPLC], 302 (1.25) . 11.17 (s, 1H), 8.38 (s, 1H), S.31 (s, 1H), 5.12 (s, 1H), 3.68 (s, 3H), 3.41 (s, 3H), 3.08-2.99 (m , 1H) , 1.17 1.01 (m, 4H). Pd-174, Cs?CO:3, dioxane INTC129 methyl 2-(6-(cyclopropanesulfonamido)pyrazin2-yl)-2-methoxypropanoate aAaAA IIJ Λ N Method C using INTC122, [acid HPLC], 316 (1.46). 11.14 (s, 1H), 8.44 (s, 1H), 8.25 (s, 1H), 3.66 (s, 3H), 3.29 (s, 3H), 3,062.96 (m, 1H), 1.70 (s, 3H) , 1.18 0.99 (m, 4H). Pd-174, Cs. CO3, dioxane INTC130 methyl 2-(6-(cyclopropanesulfonamido)pyrazin- 2-yl)-2-fluorobutanoate Method C using INTC124, [UPLC 11.29 (s, 1H), 8.48 (s, 1H), 8.33 (s, 1H ), 3.73 (s, 3H), 3.10-3.04 (m, 1H), Pd-174, Cs2CO3, dioxane IF-2019-16749728-APN-AWINPI Page 197 of 363 F\X H A ,-c\ A. ,.Ν^ ,ιν Xa ΥιΓ Y o U J ° ° N acid], 318 (1.08). 2.45 - 2.27 (m, 2H), 1.24 - 1.00 (m, 4H), 0.91 (t, J = 7.4 Hz, 3H). INTC170 methyl 6- (cyclopropanesulfonamido)pyrazine- 2-carboxylate ''O Λ 1 H A 2 n,n, Xa U J o o N Method C using commercial SM, [acidic HPLC], 2 53 (1.25). 11.40 (s, 1H), 8.85 (s, 1H), 8.58 (s, 1H), 3.92 (s, 3H), 3.14 - 3.03 (m, 1H), 1.26 - 1.18 (m, 2H), 1.12 1.03 (m , 2H). Pd 174, Cs2C0.3, dioxane INTC171 ((6- (Cyclopropanesulfonamido)pyrazin2-yl)propyl) tert-butyl carbamate tX JL 0 T Λ n o o N Method C using INTC169, [acid HPLC], 357 (1.89). 10.98 (s, 1H), 8.22 (s, 1H), 8.19 (s, 1H), 7.39 (d, J = 8.2 Hz, 1H), 4.49 4.39 (m, 1H), 3.20 3.06 (m, 1H), 1.85 - 1.74 (m, 1H), 1.74 - 1.63 (m, 1H), 1.38 (s, 9H), 1.15 - 1.08 (m, 2H), 1.08 1.02 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H). [Pd(allyl)Cl]? tBuXPhos, Cs.CCP, dioxane Deprotection: Boc W-(4-(1-aminocyclopropyl)pyrimidin-2yl)cyclopropanesulfonamide hydrochloride INTC156 To a solution of tert-butyl (1-(2-(cyclopropanesulfonamido)pyrimidin4-yl)cyclopropyl)carbamate INTC153 (200 mg, 0.564 mmol) in dioxane (2 mL) was added HC1 (4 M in dioxane) (1.41 mL). , 5.64 mmol) and the resulting solution was stirred at RT for 18 h. The solvent was removed in vacuo IF-2019-16749728-APN-Jt&WíNPI Page 198 of 363 to provide N-(4-(.1aminocyclopropyl)pyrimidin-2-yl)cyclopropanesulfonamide hydrochloride (164 mg, 0.564 mmol, quantitative yield) as a slightly yellow solid which was used without any further purification. tR 0.39 min (acidic UPLC); m / z 255 (M+H)+(ES+) . No MRI data were collected. N-(4-(aminomethyl)pyrimidin-2yl)cyclopropanesulfonamide hydrochloride INTC157 Prepared as for INTC156 using ((2(cyclopropanesulfonamido)pyrimidin-4-yl)methyl)tert-butyl carbamate INTC145 to provide N~ (4(aminomethyl)pyrimidin-2-yl)cyclopropanesulfonamide, HC1 (70 mg, 0.225 mmol , 88% yield) as a pale yellow solid; tR 0.13 min (acidic UPLC); m / z 229 (M+H)* (ES). No MRI data were recorded. Sulfoximine deprotection 1-(2~Chloropyrimidin-4-yl)propan-1-amine INTC158 A solution of N-(1-(2-bromopyrimidin-4-yl)propyl)-2methylpropan-2-sulfinamide INTC151 (7.2 g, 22.48 mmol) in THE (30 mL) was treated with 4 N HC1 in dioxane (2. 9 mL, 95 mmol) and MeOH (1.0 mL), then stirred at RT for 3 h. The reaction mixture was concentrated in vacuo then basified with sat. NaHCCy. (aq, 100 mL). The product was extracted with DCM (3 x 80 mL), the combined organic phases were dried (phase separator) and concentrated in vacuo. The crude product was purified by silica gel chromatography (80 g column, 0-10% (0.7 M Ammonia / MeOH) / DCM) to provide 1-(2chloropyrimidin-4-yl)propan-l-amine (1.34 g , 6.01 mmol, 27% IF-2019-16749728-ΑΡΝ-τΦθ^ΙΝΡΙ Page 199 of 363 performance) as a transparent brown oil. tR 0.75 min (basic UPLC); m / z 172 (J'C1 Μ + H)!(ES1).ΣΗ NMR (500 Mhz, DMSO-d6) δ 8.71 (d, J = 5.1 Hz, 1H), 7.64 (d, J = 5.1 Hz, 1H ), 3.77 - 3.64 (m, 1H), 2.03 (s, 2H), 1.74 - 1.63 (m, 1H), 1.62 - 1.49 (m, 1H), 0.84 (t, J -- 7.4 Hz, 3H). Br-Cl exchange reaction was observed. N-(4-(2-aminobutan-2-yl)pyrimidin-2yl)cyclopropanesulfonamide hydrochloride INTC159 H O Η2Ν^γΝγΝ / ^.N O V ,HCI Prepared as for INTC158 using N-(4-(2-(l,ldimethylethylsulfinamido)butan-2-yl)pyrimidin-2yl)cyclopropanesulfonamide INTC154 to provide N~(4-(2~aminobutan-2-yl)pyrimidin hydrochloride -2yl)cyclopropanesulfonamide (921 yield) as a yellow solid. tR 0.41 min (basic UPLC); m / z 271 (M+H)+(ΕΞ+) .:Η NMR (500 Mhz, DMSO-d6) δ 11.39 (s, 1H) , 8.79 8.51 (m, 4H) , 7.37 (d, J = 5.0 Hz , 1H) , 3.38 (s, 1H) , 2.05 - 1.85 (m, 2H) , 1.61 (s, 3H) , 1.19 - 0.99 (m, 4H) , 0.84 0 . 68 (m, 3H) . reductive amination 1~(2-Bromopyrimidin-4-yl)propan-l-amine INTC160 A suspension of the ammonium salt of 2,2,2trifluoroacetic acid (6.09 g, 46.5 mmol) and 1~(2-bromopyrimidin4-yl) propan-1-one INTC149 (500 mg, 2.32 mmol) in THF (20 mL, 244 mmol) was stirred at 45 °C for 15 min to obtain a transparent yellow solution, which was cooled to RT. More ammonium salt of 2,2,2-trifluoroacetic acid (1.8 g, 13.7 mmol) was added. NaHB(OAc)3 (985 mg, 4.65 mmol) was added and the reaction mixture was stirred at RT for 3 h. The IF-2019-16749728-APN-£taBHNPI Page 200 of 363 reaction mixture was reduced in vacuo to ca. 10 mL and diluted with EtOAc (50 mL) and washed with 2 M Na2CO3 (aq, 2 x 50 mL). The organic layer was then shaken with tosic acid (10 g), washed on a filter with EtOAc (2 x 50 mL) and MeOH (2 x 50 mL), and eluted with 30.7 M NH in MeOH to provide 1 -(2-bromopyrimidin-4-yl)propan-l-amine (22 7 mg, 0.99 mmol, 4 3 7 yield) as an orange oil. tR 0.69 min (basic UPLC); m / z 216 (?r'Br Μ +H)+(ES+) . A NMR (500 Mhz, DMSO-d6) δ 8.64 (d, J = 5.1 Hz, 1H), 7.67 (d, J = 5.1 Hz, 1H), 3.72 (t, J - 6.6 Hz, 1H), 1.73 - 1.62 (m, 1H), 1.62 - 1.51 (m, 1H), 0.84 (t, J - 7.4 Hz, 3H), NH2 was not observed. Oxime formation N~~(4-(1-(Methoxyimino)propyl)pyrimidin-2yl)cyclopropanesulfonamide INTC161 A suspension of O-methylhydroxylamine hydrochloride (170 mg, 2.04 mmol), N-(4-propionylpyrimidin-2~yl)cyclopropanesulfonamide INTC155 (500 mg, 1.96 mmol), and pyridine (0.35 mL, 4.33 mmol) in EtOH ( 4 mL) was heated at reflux for 18 h. The reaction mixture was concentrated, then dissolved in EtOAc (20 mL) and washed with 1 M HC1 (15 mL) and brine (15 mL). The organic phase was dried (Na2SO¿¡), filtered and concentrated on silica (3 g). The crude product was purified by silica gel chromatography (12 g column, 0-1007 EtOAc / i sohexane) to provide N~(4-(1-(methoxyimino)propyl)pyrimidin-2yl)cyclopropanesulfonamide (428 mg, 1.43 mmol, 707 yield) like a yellow rubber. tR 0.60 min (UPLC, basic 2); m / z 285 (M+H)1(ES+) . At NMR (500 Mhz, DMSO-d6) δ 11.35 (s, 1H), 8.60 (d, J = 5.2 Hz, 1H), 7.45 (d, J - 5.2 IF-2019- 16749728-APN-&Cflf#INPI Page 201 of 363 Hz, 1H), 4 .02 (s, 3H), 3.25 3.15 (m, 1H), 2.76 (q, J 7.5 Hz, 2H), 1.15 - 1.01 (m, 7H) . N-(4-(l~Aminopropyl)pyrimidin-2-yl)cyclopropanesulfonamide INTC162 hXy / I Jj A O O A solution of N-(4-(1-(methoxyimino)propyl)pyrimidin-2yl)cyclopropanesulfonamide (428 mg, 1.51 mmol) INTC161 in NH37M in MeOH (4 mL) was treated with 10% Pd-C on carbon (10 mg) and hydrogenated at 5 bar for 1 h. The reaction mixture was filtered through Celite eluting with DCM (30 mL), then concentrated in vacuo to provide N-(4-(l-aminopropyl)pyrimidin-2-yl)cyclopropanesulfonamide (38 0 mg, 1.19 mmol , 7 9% yield) as a whitish solid. tR 0.44 min (basic HPLC); m / z 257 (M+H) (ES). No NMR data were collected. IF-2019-16749728-ΑΡΝ-2ΪΚ^ΙΝΡΙ Page 202 of 363 Amide coupling with HATU Table 13: The following intermediates were prepared according to Method 1 described below for the synthesis of the compound of formula (I). INTC Name / Structure (All examples containing chiral centers are racemates unless otherwise indicated) Synthesis method, [LCMS Method], m / z (M+H) + , (tR / min) Data 1H NMR chemical shifts (DMSO-dg unless otherwise stated) INTC163 N~ (1- (2- chloropyrimidin-4- yl)propyl)~5~(6- ethoxypyrazin-2- yl)picolinamide 0 < As As ifY n -g rp 1 η II \ / O A,-'N l J Ar Method 1 using INTC158 and INTD86, [UPLC acidic], 398 isotope '“JC1 (1.52). 9.44 - 9.39 (m, 1H), 9.29 (d, J = 8.2 Hz, 1H), 9.01 (s, 1H), 8.75 (d, J = 5.1 Hz, 1H), 8.72 -8.67 (m, 1H), S .38 (s, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 5.1 Hz, 1H), 5.10- 4. 96 (mr 1H), 4.52 (q, J = 7 .1 Hz, 2H), 2.06 - 1.90 (m, 2H), 1.42 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H). INTC164 N~ (1-(2- (chloropyrimidin-4-yl)propyl)-4- ( 6- ethoxypyrazin-2-yl)~2~ (trifluoromethyl)benzam ida FtF ° o ÍJ s L Y<: -γΑΑ Aa' Method 1 using INTC158 and INTD80, [acidic UPLC], 466 isotope Al (1.55) 9.25 (d, J = 7.7 Hz, 1H), 9.00 (s, 1H), 8.80 (d, J = 5.1 Hz, 1H), 8.53-8.46 (m, 2H), 8.36 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 5.1 Hz, 1H), 4.93 - 4.82 (m, 1H), 4.51 (q, J = 7.0 Hz, 2H), 1.96-1.85 (m, 1H), 1.85-1.73 (m, 1H), 1.42 (t, J = 7.0 Hz, 3H), 0.99 (t, J = 7.3 Hz, 3H) . O nAJY AA Ά Method 1 using INTC160 and I14TD74, [acid HPLC], 460 isotope Ar (2.44) 9.02 (d, J = 1.5 HZ, 1H), 8.93 (s, 1H), 8.70 (d, J =). 5.1 Hz, 1H), 8.33 (s, 1H), 8.09-8.05 (m, 2H), 7.77-7.73 (m, 1H), 7.62 (d, J = 5.1 Hz, 1H), 4.93 -4.83 (m, 1H) ), 4.50 (q, J = 7.0 Hz, 2H), 1.96 - 1.86 (m, 1H), 1.86-1.74 (m, 1H), 1.41 (t, J = 7.0 Hz, 3H), 0.99 (t, J = 7.3Hz, 3H). IF-2019-16749728-APN-^£OINPI Page 203 of 363 INTC166 N-(1-fl- dor opyr imidin-4yl)propyl)-4-(6(trifluorornetyl)pyraz n-2-yl)benzamide q-jiiAí· XN' Method 1 using INTC158 and INTD75, [UPLC acid], 422 isotope 'Λ'Ρ1 (1.47) . 9.71 (s, 1H), 9.21 (s, 1H), 9.13 (d, J = 7.4 Hz, 1H), 8.75 (d, J = 5.1 Hz, 1H), 8.33 (d, J = 8.3 Hz, 2H), 8.13 (d, J = 8.3Hz, 2H), 7.61 (d, J = 5.1 Hz, 1H), 4.98 - 4.87 (m, 1H), 1.98 - 1.84 (τη, 2H), 1 .00 (t, J = 7.3Hz, 3H). INTC167 V-(l-(2- chloropyrimidin-4- yl)propyl)-4 - (6- isoproρoxypyrazin-2- yl)benzamide rrYdV1 Ά Method 1 using IMTC15S and INTD82, [acidic UPLC], 412 isotope ''JC1 ( 1.54). 9.05 (d, J = 7.5 Hz, 1H), 8.88 (s, 1H), 8.74 (d, J = 5.1 Hz, 1H), 8.26-8.20 (m, 3H), 8.06 (d, J = 8.2 Hz, 2H ), 7.60 (d, J = 5.1 Hz, 1H), 5.48 - 5.34 (m, 1H), 4.98 - 4.88 (m, 1H), 1.99 - 1.83 (m, 2H), 1.40 (d, J = 6.1 Hz, 6H), 1.00 (t, J = 7.3 Hz, 3H). INTC168 N- (1- (2chloropyrimidin-4yl)propyl)-4-(6ethoxypyrazin-211)benzamide χΑ Method 1 using INTC158 and INTD83, [acidic UPLC], 398 isotope ’ti (1.45). 9.06 (d, J = 7.6 Hz, 1H), 3.90 (s, 1H), 8.74 (d, J = 5.1 Hz, 1H), 8.30 (s, 1H), 8.25 (d, J = 8.2 Hz, 2H), 8.06 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 5.1 Hz, 1H), 4.98 - 4.82 (m, 1H), 4.50 (q, J = 7.0 Hz, 2H), 1.98 - 1.83 (m , 2H), 1.42 (t, J = 7.0 Hz, 3H), 1.00 (t, J = 7.3 Hz, 3H). Benzamide pyrazines Curtius tert-butyl (1-(6-Chloropyrazin-2-yl)propyl)carbamate INTC169 Prepared as for INTC148 using commercial 2-(6-chloropyrazin-2-ii)butanoic acid to provide tert-butyl (1(6-chloropyrazin-2-yl)propyl)carbamate (61 of IF-2019- 16749728-AP\'-.2Q41\'PI Page 204 of 363 performance) as a colorless solid. tR 2 . 15 min (acid HPLC); ni / z 272 (35C1 M+H)¡(ES1') .AH NMR (4:1 rotamer mixture) (500 Mhz, DMSO-d6) δ 8.68 (s, 1H), 8.61 (s, 1H), 7.52 (d, J = 7.9 Hz, 1H), 4.55 - 4.44 (m, 1H), 1.85 - 1.57 (m, 2H), 1.37 (s, 9H, majority), 1.22 (s, 9H, minority), 0.87 (t , J = 7.3 Hz, 3H). Grignard N-(6-(2-Hydroxypropan-2-yl)pyrazin-2yl)cyclopropanesulfonamide INTC172 A solution of methyl 6-(cyclopropanesulfonamido)pyrazine-2~ carboxylate INTC170 (3.00 g, 11.7 mmol) in THF (30 mL) was cooled to 0 °C, then added MeMgBr (3.0 M in Et2O) (18 mL, 54.0 mmol) dropwise over 15 min, then warmed to RT. The reaction mixture was stirred at RT for 18 h. The reaction mixture was heated to 4 0 °C for an additional 24 h. The reaction mixture was cooled with an ice bath and 1M HC1 (aq, 60 mL) was added carefully. The aqueous phase was extracted with EtOAc (4 x 500 mL). The organic phases were combined, dried (Na2SO / ¡), filtered and concentrated on silica (10 g). The crude product was purified by silica gel chromatography (40 g column, 0-1001 EtOAc / isohexane) to provide N-(6-(2-hydroxypropan~2-i1)pyrazin-2yl)cyclopropanesulfonamide (340 mg, 1.30 mmol, 11% yield) as a brown gum. tR 0.24 min (UPLC, acidic 2); m / z 258 (M+H)4(ES4), 1H NMR (500 Mhz, DMSO-d6) δ 10.92 (s, 1H), 8.51 (s, 1H), 8.16 (s, 1H), 5.40 (s, 1H), 3.11 3.01 (m, 1H), 1.45 (s, 6H), 1.14 - 1.02 (m, 4H), Ritter 2-Chloro-Al-(2-(6-(cyclopropanesulfonamido)pyrazin-2yl)propan-2-yl)acetamide INTC173 IF-2019-16749728-APN-JKQWINPI Page 205 of 363 A mixture of N-(6-(2-hydroxypropan-2-yl)pyrazin-2yl)cyclopropanesulfonamide INTC172 (330 mg, 1.28 mmol) and Ιοί or oace tonitril (0.65 mL, 10.3 mmol) in AcOH (0.75 mL, 13.1 mmol) was cooled in an ice bath before adding H2SO4 (0.82 mL, 15.4 mmol) dropwise. The vessel was then heated to 50°C and stirred for 18 h. The solution was poured into ice water (30 mL) and extracted with EtOAc (3 x 30 mL), the organic phases were combined, dried (Na^SOí), filtered and concentrated on silica (2 g). The crude product was purified by silica gel chromatography (12 g column, 0-100% EtOAc / isohexane) to provide 2-chloro-N-(2-(6(cyclopropanesulfonamido)pyrazin-2-yl)propan- 2-yl)acetamide (100 mg, 0.294 mmol, 19% yield) as a yellow gum. tR 0.98 min (acid HPLC); m / z 333 (35C1 M+H) ’ (ES+). Y NMR (500 Mhz, DMSO-d6) δ 10.94 (s, 1H), 8.63 (s, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 4.08 (s, 2H), 3.16 - 3.08 (m, 1H), 1.58 (s, 6H), 1.14 - 1.03 (m, 4H). Elimination of Boc jV- (6-(1-Aminopropyl)pyrazin-2yl)cyclopropanesulfonamide.HC1 INTC174 Prepared as for INTC156 using tert-butyl (1-(6(cyclopropanesulfonamido)pyrazin-2-yl)propyl)carbamate INTC171 to provide N-(6-(laminopropyl)pyrazin-2-yl)cyclopropanesulfonamide, HC1 (85 mg , 0.276 mmol, 42% yield) as a colorless solid. tR 0.58 min (basic HPLC); m / z 25 7 (M+H)+(ES+) .ίΗ NMR (500 Mhz, DMSO-d6) 611.25 (s, 1H) , 8.77 - 8.66 (m, IF-2019-16749728-APN-£t(jl^INPI Page 206 of 363 3H), 8.45 (s, 1H), 8.31 (s, 1H), 4.37 - 4.23 (m, 1H), - 3.45 (m, 1H), 2.09 - 1.83 (m, 2H), 1.20 - 0.99 (m, 4H), 0.83 (t, J = 7.4 Hz, 3H). Thiourea deprotection N-(6-(2-Aminopropan-2-yl)pyrazin-2yl)cyclopropanesulfonamide INTC175 A suspension of 2-chloro- / V-(2-(6(cyclopropanesulfonamido)pyrazin-2-yl)propan-2-yl)acetamide (100 mg, 0.30 mmol) INTC173 in EtOH (1.3 mL) was treated with thiourea ( 23 mg, 0.302 mmol) followed by AcOH (0.35 mL, 6.11 mmol), then heated at reflux for 1 h. The reaction mixture was allowed to cool to ΤΑ, then concentrated in vacuo. This was then carefully treated with NH30.7M in MeOH (5 mL) and concentrated. The crude product was purified by flash C18 RP chromatography (12 g column, 0-25% MeCN / 10 mM Ammonium Bicarbonate) to provide N-(6-(2-aminopropan-2yl)pyrazin-2-yl) cyclopropanesulfonamide (63 mg, 0.23 mmol, 78% yield) as a colorless solid. tR 0.37 min (basic HPLC); m / z 257 (M+H)* (ΕΞ*).ΊΗ NMR (500 Mhz, DMSOd6) δ 8.03 (s, 1H), 7.82 (s, 1H), 2.77 - 2.64 (m, 1H), 1.53 (s , 6H), 0.91 - 0.77 (m, 2H), 0.77 - 0.66 (m, 2H), 3 x exchangeable Hs was not observed. Preparation of the amino intermediate Method E: Suzuki coupling of haloanilines with heteroaromatic boronates IF-2019-16749728-ΑΡΝ-£®0$ΙΝΡΙ Page 207 of 363 X = Br, Cl A solution of Arl-X (1 eq) and Ar2-Z (1 eq) in solvent (3 volumes) and base (2.5 eq) was degassed (N2, 5 min) and heated to 40 °C, after which it was Pd catalyst 5 (3 mol %) was added and the reaction mixture was further degassed (N2.5 rain) before heating to 90 °C for 90 min. The reaction mixture was allowed to cool to RT. Generally, the desired compound was purified by column chromatography. Method F: Suzuki coupling of heteroaromatic halides with aniline boronates Z = Br, Cl X = B(OH)2, B(pin)2 Pd catalyst (57 mol) was added to a degassed solution (N2, 5 min) of Arl-X (1 eq), Ar2-Z (1 eq) and base (3 eq, 6.85 mmol) in solvent (3 volumes ). The solution was then further degassed (N?, 5 min) and then heated to 90 °C for 2 h, then allowed to cool to RT. Generally, the desired compound was purified by column chromatography. Method G: Telescopic Boronate Forming and Suzuki Coupling IF-2019-16749728-APN-JW^INPI Page 208 of 363 . pjΧλΛ 1. Suzuki Terms 7. Suzuki Conditions Bispin (1.1 eq) and KOAc (4 eq) were added to Arl-Hal (1 eq) in dioxane (5 volumes). The reaction was heated to 60°C and degassed (N2, 5 min). PdCl2(dppf) (5 mol %) was added to the reaction mixture and the temperature was increased to 90 °C for 1 h. The reaction mixture was then cooled to RT and a solution of Ar2-Hal (1 eq) in dioxane (3 volumes) was added, followed by a solution of K2CO3 (4 eq) in water (2 volumes). The temperature was then increased to 90°C for 18 h. The reaction was cooled to RT, aqueous workup was performed and the crude compound was purified by normal phase chromatography. Anilines Table 14: The following intermediates were prepared according to Methods E, F or G. INTD Name / Structure Synthesis method, . [LCMS Method], (M+H) +, (tR / min) NMR chemical shift data of ;'H (DMSO-unless otherwise stated) Catalyst, Base, Solvent INTD1 4-( 6-methoxypyrazin- 2-yl)aniline N i X Y YUYA, 'NH2 Method F, [Basic HPLC], 202, (1.63). 8.61 (s, 1H), 8.04 (s, 1H), 7.94 - 7.75 (m, 2H), 6.75 - 6.54 (m, 2H), 5.59 (s, 2H), 3.98 (s, 3H). Pd (PPh:<) 4, NaHCOj, MeCN IF-2019-16749728-APN-£WINPI Page 209 of 363 INTD2 5- (6- (trifluoromethyl)pyr azin-2-yl)pyridin- 2-amine r3U N T| N NH2 Method F, [acidic UPLC], 241, (0.52). 9.52 - 9.41 (m, 1H), 8.95 (t, J = 0.6 Hz, 1H), 8.81 (dd, J = 2.5, 0.8 Hz, 1H), 8.16 (dd, J = 8.8, 2.5 Hz, 1H), 6.66 (s, 2H), 6.59 (dd, J = 8.8, 0.8 Hz, 1H). Pd(PPh3) NaHCO;, EtOH, toluene INTO 3 3-(4-aminophenyl) -5(difluoro-13methoxy)pyridine FX<-F / 'χΛ 'Ν' Method E, [Basic UPLC], 237, (1.05) . 8.74 - 8.66 (m, 1H), 8.36 - 8.24 (m, 1H), 7.81 - 7.74 (m, 1H), 7.53 - 7.43 (m, 2H), 7.61 - 7.15 (m, 1H), 6.72 - 6.58 (m , 2H), 5.44 (s, 2H). PdCl··.; (dppf), K--CCL, dioxane I NTD 4 4...

Claims

1. A compound, characterized in that it is a compound of formula (I): (FORMULA I) where A is an amide linker having the following structure: -C(=O)NH- or -NHC(=O)-; X is N or CH; Y is N or CR2; Z is N or CR3; provided that when at least one of X or Z is N, Y cannot be N; R1 is CF3, C1-5 alkyl, or C3-5 cycloalkyl whose cycloalkyl is optionally substituted with CH3; R2 is H, halo, C1-2 alkyl, C1-2 alkyl, C1-2 haloalkyl or C1-2 haloalkyl; R3 is H, halo, CH3, OCH3, CF3 or OCF3; where at least one of R2 and R3 is H; R4 and R5 are each independently H, C1-6 alkyl, C1-6 alkylOH, C1-6 haloalkyl, C0-2 alkylene, C3-6 cycloalkyl, C0-2 alkylene, C3-6 heterocycloalkyl, C1-3 alkylene, or C1-3 alkyl or R4 and R5 together with the carbon atom to which they are bonded form a C3-6 cycloalkyl or C3-6 heterocycloalkyl;and when A is -NHC(=O)-: R 4 and R 5 can be further selected from halo, C1-6 O-aloalkyl, C3-6 O-alkylene C0-2cycloalkyl, C3-6 O-alkylene C0-2heterocycloalkyl, C1-6 O-alkyl and NR 21 R 22 ; Ar 1 is a 6-membered aryl or heteroaryl; Ar 2 is a 6-membered aryl or heteroaryl and is bonded to Ar 1 at the para position with respect to the amide; R 10 is H, halo, C1-3 alkyl, C1-2 haloalkyl, C1-2 O-alkyl, C1-2 O-aloalkyl or CN; R 11 is H, F, Cl, C1-2 alkyl, CF3, OCH3 or CN; R 12 is bonded to Ar 2 in the ortho or meta position with respect to Ar 1 and R 12 is H, halo, C1-4 alkyl, C2-4 alkenyl, C0-2 alkyl C3-5 cycloalkyl, O C1-4 alkyl, O C0-2 cycloalkyl C3-5 alkyl, C1-4 haloalkyl, Oh C1-4 haloalkyl, hydroxy, C1-4 alkyl OH, SO2 C1-2 alkyl, C(O)N(C1-2)2, NHC(O)C1-3 alkyl or NR 23 R 24 ;and when A is -NHC(=O)-: R12 may be further selected from CN, OCH2CH2N(CH3)2 and a C3-6 heterocycloalkyl comprising a nitrogen located at the point of attachment to Ar2, or R12 together with a nitrogen atom to which it is bonded forms an N-oxide (N+-O-); R13 is H or halo; R21 is H, C1-5 alkyl, C(O)C1-5 alkyl, C(O)OC1-5 alkyl; R22 is H or CH3; R23 is H or C1-2 alkyl; and R24 is H or C1-2 alkyl; or a salt and / or solvate thereof. 50 Claims follow;