THAZOLYLPENYL-BENZENOSULPONAMIDE DERIVATIVES AS KINASE INHIBITORS

专利摘要:
thiazolylpenyl-benzenesulfonamido derivatives as kinase inhibitors the present invention relates to the thiazolylpenyl-benzenesulfonamido derivatives of formula (i) as defined in the specification and their pharmaceutically acceptable salts, process for their preparation and pharmaceutical compositions comprising these compounds; the compounds of the invention may be useful in the therapy and treatment of diseases associated with an unregulated protein kinase activity, such as cancer.
公开号:BR112013021537B1
申请号:R112013021537-2
申请日:2012-02-21
公开日:2021-08-10
发明作者:Maurizio Pulici；Gabriella Traquandi；Chiara Marchionni；Alessandra Scolaro；Nicoletta Colombo
申请人:Nerviano Medical Sciences S.R.L.；
IPC主号:

专利说明:

The present invention relates to some substituted thiazolylphenyl-benzenesulfonamido derivatives that modulate protein kinase activity. The compounds of this invention, therefore, are useful in treating diseases caused by unregulated protein kinase activity. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising such compounds, and methods for treating diseases using pharmaceutical compositions comprising such compounds.
The classical pathways Ras, Raf, MEK (Mitogen Activated Protein Kinase), ERK (Extracellular Signal Regulated Kinase), play an important role in the regulation of a variety of cellular context-dependent cellular functions, including cell proliferation, differentiation, survival, immortalization and angiogenesis (reviewed in Peyssonnaux and Eychene, Biology of the Cell 2001, 93.3-62). In this pathway, Raf family elements are recruited to the plasma membrane after the binding of charged Ras to guanosine triphosphate (GTP) resulting in the phosphorylation and activation of Raf proteins. Activated Rafs then phosphorylate and activate MERKs, which in turn phosphorylate and activate ERKs. After activation, ERKs translocate from the cytoplasm to the nucleus resulting in phosphorylation and regulation of the activity of transcription factors such as Elk-L and Myc. The Ras/Raf/MEK/ERK pathways are reported to contribute to the tumorigenic phenotype inducing immortalization, to the growth factor independent of growth, to generate insensitivity to inhibitory growth signals, to create the ability to invade and metastasize by stimulating the angiogenesis and for the inhibition of apoptosis (Kolch et al. Exp. Rev. Moi. Med. April 25, 2002 http://www.expertreviews.org/02004386h.htm). In fact, ERK phosphorylation is achieved in about 30% of all human tumors (Hoshino et al. Oncogene, 1999, 18. 813-822). This may be the result of overexpression and/or mutation of key pathway elements.
Three Raf isoforms of the serine/threonine protein kinase have been reported Raf-1/c-Raf, B-Raf and A-Raf (reviewed in Mercer and Pritchard, Biochim. Biophys. Acta, 2003, 1653, 2540), the genes for which are thought to have arisen by gene duplication. All three Raf genes are expressed in most tissues, but with differences: c-Raf is ubiquitously expressed at high levels, whereas high-level B-Raf expression is found in neuronal tissue and A-Raf in urogenital tissue . The high degree of familial Raf homology overlaps but is distinguished in biochemical activities and biological functions (Hagemann and Rapp, Expt. Cell Res. 1999, 253, 34-46). Expression of all three Raf genes is required for normal murine development, however both c-Raf and B-Raf are required to complete pregnancy. B-Raf -/- rats die at E12.5 due to vascular hemorrhage caused by increased endothelial cell apoptosis (Wojnowski et al, Nature Genet, 1997, 16, 293-297). B-Raf is reportedly the main isoform involved in cell proliferation and the main target of oncogenic Ras. Activation of the five somatic missen.se mutations has been identified exclusively for B-Raf, which occur at a frequency of 66% in cutaneous malignant melanomas (Davies et al, Nature, 2002, 417, 949-954) and are also present in a wide range of human cancers, including but not limited to papillary thyroid carcinoma (Cohen et al., J. Natl. Cancer Inst. 2003, 95, 625-627), cholangiocarcinomas (Tannapfel et al. Gut, 2003, 52, 706-712), ovarian and colon cancers (Davies et al. Nature, 10 2002, 417, 949-954). The most frequent mutation in B-Raf (80%) is a glutamic acid by valine substitution at position 600. These mutations increase the basal kinase activity of B-Raf and are thought to uncouple Raf/MEK/ERK signaling from proliferation amount including Ras and growth factor receptor activation, resulting in constitutive activation of ERK. Mutated B-Raf proteins are transforming into NIH3T3 cells (Davies et al., Nature, 2002, 15 417, 949-954) and melanocytes (Wellbrock et al. Cancer Res. 2004, 64, 2338-2342) and also shown essential for the viability and transformation of melanoma cells (Hingorani et al. Res, Cancer., 2003, 63, 5198-5202). As a key factor in the MEK/Raf/ERK signaling cascade, B-Raf represents a likely point of intervention in tumors dependent on this pathway.
Substituted thiazole derivatives for the treatment of protein kinase mediated diseases such as cancer are disclosed in WO2009/137391 in the name of SKB & Co, W02011/059610 in the name of Glaxosmithkline LLC and WO2011/161216 in the name of Novartis AG.
The present inventors have now found that the compounds of formula (I), described below, are kinase inhibitors and are therefore useful in therapy as antitumor agents.
Thus, a first object of the present invention is to provide a substituted tricyclic compound of formula (I).
where: neither are each independently 1 or 2;
R1 is hydrogen, halogen, cyano or an optionally substituted group selected from alkyl (C1-C8), alkenyl (C2-C8), alkynyl (C2-C8), cycloalkyl (C3-C8), cycloalkyl (C3-C8), heterocyclyl linear or branched , aryl and heteroaryl; or RI is NR7R8 or COR9 where: R7 and R8 are each independently hydrogen or an optionally substituted group selected from alkyl (C1-C8), alkenyl (C2-C8), alkynyl (C2-C8), cycloalkyl (C3-C8 ), linear or branched 5-cycloalkyl (C3-C8), heterocyclyl, aryl and heteroaryl; or taken together with the nitrogen atom to which they are attached, R7 and R8 can form an optionally substituted 3- to 8-membered heterocyclyl, optionally containing an additional heteroatom or a heteroatomic group selected from S, O, N and NH; or
R7 is hydrogen and R8 is CHORIO, where: R10 is OR11, NR12R13 or an optionally substituted group selected from (C1 -C8) alkyl, (C2 -C8) alkenyl, (C2 -Câ ) alkynyl, (C3 -Câ) cycloalkyl C8), cycloalkyl (C3-C8), linear or branched heterocyclyl, aryl and heteroaryl, where:
R11 is an optionally substituted group selected from (C 1 -C 8 )alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) alkynyl, (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, linear aryl and heteroaryl or branched; R12 and R13 are each independently hydrogen or an optionally substituted group selected from (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl ), linear or branched heterocyclyl, aryl and heteroaryl; or taken together with the nitrogen atom to which they are attached, R12 and R13 may form an optionally substituted 3- to 8-membered heterocyclyl or heteroaryl, optionally containing an additional heteroatom or heteroatomic group selected from S, O, N and NH;
R9 is OR14 or NR15R16 where: R14 is hydrogen or an optionally substituted group selected from (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl ), linear or branched heterocyclyl, aryl and heteroaryl; R 15 and R 16 are each independently hydrogen or an optionally substituted group selected from alkyl (C 1 -C 8 ), alkenyl (C 2 -C 8 ), alkynyl (C 2 -C 8 ), cycloalkyl (C 3 -C 8 ), cycloalkyl (C 3 -C 8 ) linear or branched, heterocyclyl, aryl and heteroaryl; or taken together with the nitrogen atom to which they are attached, R15 and R16 can form an optionally substituted 3- to 8-membered heterocyclyl or heteroaryl, optionally containing an additional heteroatom or heteroatomic group selected from S, O, N and NH;
R2 and R3 are each independently hydrogen, halogen, cyano or an optionally substituted group selected from alkyl (C1-C8), alkenyl (C2-C8), alkynyl (C2C8), cycloalkyl (C3-C8), cycloalkyl (C3- C8), linear or branched heterocyclyl, aryl and heteroaryl; or R2 and R3 are each independently NR17R18, CONR19R20, OR21, SR21 or SO2R21, wherein: R17 and R18 are independently hydrogen or an optionally substituted group selected from (C1 -C8) alkyl, (C2-C8) alkenyl linear or branched , (C 2 -C 6 ) alkynyl, (C 6 -C 6 ) cycloalkyl, (C 3 -C 6 ) cycloalkyl, heterocyclyl, aryl and heteroaryl; or taken together with the nitrogen atom to which they are attached, R17 and R18 can form an optionally substituted 3- to 8-membered heterocyclyl or heteroaryl, optionally containing an additional heteroatom or heteroatomic group selected from S, O, N and NH; or R17 is hydrogen and R18 is COR22, where:
R22 is OR23, NR24R25 or an optionally substituted group selected from alkyl (C1-C8), alkenyl (C2-C8), alkynyl (C2-C8), cycloalkyl (C3-C8), cycloalkyl (C3-C8), heterocyclyl, aryl and linear or branched heteroaryl, where:
R23 is an optionally substituted group selected from alkyl (C 1 -C 8 ), alkenyl (C 2 -C 8 ), alkynyl (C 2 -C 8 ), cycloalkyl (C 3 -C 8 ), cycloalkyl (C 3 -C 8 ), heterocyclyl, aryl and heteroaryl linear or branched, and
R24 and R25 are each independently hydrogen or an optionally substituted group selected from (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl linear or branched, heterocyclyl, aryl and heteroaryl; or taken together with the nitrogen atom to which they are attached, R24 and R25 can form an optionally substituted 3- to 8-membered heterocyclyl or heteroaryl, optionally containing an additional heteroatom or heteroatomic group selected from S, O, N and NH;
R19 and R20 are each independently hydrogen or an optionally substituted group selected from (C1-5C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl ), linear or branched heterocyclyl, aryl and heteroaryl; or taken together with the nitrogen atom to which they are attached, R19 and R20 may form an optionally substituted 3- to 8-membered heterocyclyl or heteroaryl, optionally containing an additional heteroatom or heteroatomic group selected from S, 0, N and NH;
R21 is hydrogen or an optionally substituted group selected from (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl, heterocyclyl, aryl and linear or branched heteroaryls; or, R2 and R3 together may be part of a heterocyclyl, aryl or heteroaryl when m is 1 and R3 is at the 3-position of the pyridine nucleus;
R4 and R5 are each independently hydrogen, halogen, trifluoromethyl, benzene, cyano, OR26 or an optionally substituted group selected from alkyl (C1-C8), alkenyl (C2-C8), alkynyl (C2-C8) and cycloalkyl ( C3-C8) linear or branched, where:
R26 is hydrogen or an optionally substituted group selected from linear or branched (C1-C8) alkyl, (C2-C8) alkenyl, (C2-25C8) alkynyl and (C3-C8) cycloalkyl;
RX is hydrogen, an optionally substituted straight or branched (C 1 -C 3 )alkyl, an optionally substituted (C 6 -C 2 ) acyl group or an optionally substituted (C 2 -C 6 )alkoxycarbonyl group;
R6 is a group selected from (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C8) cycloalkyl, (C3-C8) cycloalkyl, optionally substituted linear or branched heterocyclyl, aryl and heteroaryl; or pharmaceutically acceptable salts thereof.
The present invention also provides methods for preparing the substituted thiazolylphenyl-benzenesulfonamido compounds represented by formula (I) prepared by a process consisting of standard synthetic transformations. The present invention also provides a method for treating diseases caused by and/or associated with dysregulated protein kinase activity, particularly the Raf family, ABL, ACK1, AKT1, ALK, AUR1, AUR2, BRK, BUB1, CDC7/DBF4, CDK2/CYCA, CHK1, CK2, EEF2K, EGFR1, EphA2, EphB4, ERK2, FAK, FGFR1, FLT3, GSK3beta, Haspin, IGFR1, IKK2, IR, JAK1, JAK2, JAK3, KIT, LCK, LYN, MAPKAPK2, MELK, MET, MNK2, MPS1, MST4, NEK6, NIM1, P38alpha, PAK4, PDGFR, PDK1, PERK, PIM1, PIM2, PKAalpha, PKCbeta, PLK1, RET, ROS1, SULU1, Syk, TLK2, TRKA, TYK, VEGFR2, VEGFR3, ZAP70, more particularly the Raf family, which comprises administering to a mammal in need thereof an effective amount of a substituted thiazolylphenyl-benzenesulfonamido compound are represented by formula (I) as defined above.
A preferred method of the present invention is to treat a disease caused by and/or associated with dysregulated protein kinase activity selected from the group consisting of cancer, cell proliferation disorders, viral infections, autoimmune and neurodegenerative diseases.
Another preferred aspect of the present invention is a method of treating certain types of cancer, including but not limited to carcinomas such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gallbladder, ovary, pancreas, stomach, nape, thyroid, prostate and skin, including squamous cell carcinoma, lymphoid lineage hematopoietic tumors, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, B-cell lymphoma T, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hair cell lymphoma, and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcona; central and peripheral nervous system tumors, including astrocytoma and neuroblastoma, glioma and schwannomas; other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratocanthoma, thyroid follicular cancer, and Kaposi's sarcoma.
Another preferred aspect of the present invention is a method of treating certain cell proliferative disorders such as, for example, benign prostatic hyperplasia, familial adenomatosis polyposis, neurofibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis and post-surgical stenosis and restenosis.
Another preferred aspect of the present invention is a method of treating viral infections, in particular the prevention of AIDS developed in HIV-infected individuals.
Another preferred aspect of the present invention is a method to treat diseases and disorders associated with autoimmune cells and disorders such as autoimmune and inflammatory diseases, for examples, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease (IBD), Crohn's disease, heart syndrome. irritable bowel, pancreatitis, ulcerative colitis, diverticulosis, myasthenia gravis, vasculitis, psoriasis, scleroderma, asthma, allergies, systemic sclerosis, vitiligo, arthritis such as osteoarthritis, juvenile rheumatoid arthritis, ankylosing spondylitis.
Another preferred aspect of the present invention is a method to treat neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease.
Furthermore, the methods of the present invention also provide tumor angiogenesis and metastasis inhibition, as well as the treatment and rejection of transplanted organs, diseases due to graft versus host.
In a preferred embodiment, the methods of the present invention further comprise subjecting the mammal in need thereof to a regimen of radiation therapy or chemotherapy in combination with at least one cytostatic or cytotoxic agent.
Furthermore, the invention provides an in vitro method for inhibiting the activity of the Raf family protein comprising contacting said protein with an effective amount of a compound of formula (I).
The present invention also provides a pharmaceutical composition, comprising one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, carrier or diluent.
The present invention also includes pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient, which may be a carrier or a diluent.
The present invention further provides for a pharmaceutical composition comprising a compound of formula (I), in combination with known anticancer treatments such as radiation therapy or chemotherapy regimen in combination with cytostatic or cytotoxic agents, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-like agents, cyclooxygenase inhibitors (eg, COX-2 inhibitors), metalomatrixprotease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-agents -EGFR, antiangiogenesis agents, farnesyl transferase inhibitors, ras-raf signal transduction pathway inhibitors, cell cycle inhibitors, other cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, and the like. Furthermore, the invention provides a product or kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, or pharmaceutical compositions thereof and one or more chemotherapeutic agents, as preparation for simultaneous, separate or in anticancer therapy.
Another aspect of the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use as a medicine.
Furthermore, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt, as defined above, in the manufacture of a medicine with anticancer activity.
Finally, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use in a method of treating cancer.
Unless otherwise specified, when referring to the compounds of formula (I) themselves, as well as any pharmaceutical composition thereof, or any therapeutic treatment comprising them, the present invention includes all isomers, tautomers, hydrates, solvates, complexes , metabolites, prodrugs, vehicles, N-oxides and pharmaceutically acceptable salts of the compounds of the present invention.
A metabolite of a compound of formula (I) is any compound to which this same compound of formula (I) is converted in vivo, for example upon administration to a mammal in need thereof. Usually, however, without representing a limiting example, upon administration of the compound of formula (I), the same derivative can be converted into a variety of compounds, for example, including more soluble derivatives such as hydroxylated derivatives, which are easily excreted. Thus, depending on the metabolic pathway thus occurring, any of these hydroxylated derivatives can be considered as a metabolite of the compounds of formula (I). Prodrugs are any covalently linked compounds that release in vivo the active drug according to formula (I).
N-oxides are compounds of the formula (I), where nitrogen and oxygen are held together via a dative bond. If a stereogenic center or other form of an isomeric center is present in a compound of the present invention all forms of such an isomer or isomers, including enantiomers and diastereomers, are intended to be covered by them. Compounds containing a stereogenic center can be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture can be separated using well known techniques and a single enantiomer can be used alone. In cases where the compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of the present invention.
In cases where the compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is considered to be part of this invention if it exists predominantly in one form or in equilibrium.
In cases where m is 1 and R3 is in position 3 of the pyridine nucleus, R2 and R3 together may be part of a heterocyclyl, aryl or heteroaryl, so in such a case we intend a group as described below:

Non-limiting example
By the term "linear or branched (C 1 -C 6 )alkyl" we mean to refer to any groups, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec- butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like. By the term "linear or branched (C 1 -C 6 )alkyl" we mean to refer to any groups such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n- hexyl-sec-butyl, n-pentyl, and the like. By the term "linear or branched (C 1 -C 3 )alkyl" we mean any groups such as, for example, methyl, ethyl, n-propyl, isopropyl. By the term "C3-C6 cycloalkyl" it is our intention to refer to, unless otherwise noted, monocyclic carbon rings of 3 to 6 elements of all carbon elements that may contain one or more double bonds but do not have a system of fully conjugated n-electron bond. Examples of cycloalkyl groups, without limitation, are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene and cyclohexadiene. "heterocycloalkyl") is intended to refer to a 3- to 7-membered, saturated or partially unsaturated carbocyclic ring when one or more carbon atoms are replaced by heteroatoms, such as nitrogen, oxygen, and sulfur. Non-limiting examples of the heterocyclic group are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran (THF), 1,3-dioxolane, piperidine, piperazine, morpholine and the like.
By the term "alkenyl (C2-C')" we mean to refer to an aliphatic hydrocarbon chain (C2-CB) containing at least one carbon-carbon double bond and which may be straight or branched. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1 or 2-15 butenyl, and the like.
By the term "(C2-C8) alkynyl" we mean an aliphatic (C2-Cg) hydrocarbon chain containing at least one carbon-carbon double bond and which may be straight or branched. Representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1 or 2-butenyl, and the like.
The term "aryl" refers to mono-, bi- or poly-carbocyclic hydrocarbon, as well as a system of 1 to 4 rings, optionally further fused or linked together by a single bond, where at least one of the carbocyclic rings or heterocyclic is aromatic, wherein the term "aromatic" refers to the fully conjugated n-electron bonding system. Non-limiting examples of such aryl groups are phenyl, α- or β-naphthyl or biphenyl groups.
The term "heteroaryl" refers to aromatic heterocyclic rings, typically 5- to 8-membered heterocyclics with 1 to 3 heteroatoms selected from N, 0 or S; the heteroaryl ring may optionally be further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings. Non-limiting examples of such heteroaryl groups are pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indole, imidazoles, thiazolyl, isothiazolyl, pyrrolyl, phenyl-pyrrolyl, furyl, phenyl-furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzoimidazolyl, isothienyl quinolinyl, isoquinolinyl, 1,2,3-triazolyl, 1-phenyl-1,2,3-triazolyl, 2,3-dihydroindolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothiophenyl; benzopyranyl, 2,3-dihydrobenzoxazinyl, 2,3-dihydroquinoxalinyl and the like.
In accordance with the present invention and unless otherwise specified, any one of the group Rx, R1, R2, R3, R4, R5 and R6 above may optionally be substituted, at any of its free positions, by one or more groups, e.g. , groups from 1 to 6, independently selected from: halogen, nitro, oxo groups (=0), cyano, alkyl (C1-C6), perfluorinated alkyl, perfluorinated alkoxy, akenyl (C2-Ce), alkynyl (C2-Cg) , hydroxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, (C 3 -C 6 )cycloalkyl, hydroxy, alkoxy, aryloxy, heterocyclyloxy, methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, heterocyclylcarbonyloxy, cycloalkyloxycarbonyl, alkylidenealkylaminooxy heterocyclylalkyloxycarbonylamino, ureido, alkylamino, dialkylamino, arylamino, diarylamino, heterocyclylamino, formylamino, alkylcarbonylamino, arylcarbonylamino, heterocyclylcarbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminoc arbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, alkoxycarbonylamino, hydroxyaminocarbonyl alkoxyimino, alkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfonylamino, alkylsulfonylamino, alkylsulfonyl,aminocyclylamino, alkylsulfonyl, aminosulfonyl, alkylsulfonyl; In turn, where appropriate, each of the above substituents may be further substituted by one or more groups mentioned above.
The term "halogen" indicates fluorine, chlorine, bromine or iodine. By the term cyan we mean a -CN residue. By the term nitro we mean a -NO2 group.
By the term polyfluorinated alkyl or alkoxy we mean any of the above linear or branched alkoxy or C1 -C6 alkyl groups which are substituted by more fluorine atom, such as, for example, trifluoromethyl, trifluoroethyl, 1.1.1.3.3.3-hexafluoropropyl, trifluoromethoxy and the like .
By the term "hydroxyalkyl" we intend to refer to any (C 1 -C 6 )alkyl above having a hydroxyl group, such as, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like.
From all of the above, it is clear to a person skilled in the art that any group whose name is one of the compound names, such as, for example, arylamino has to be meant as conventionally interpreted by the parts from which they are derived, for example , by an amino group, which is also substituted by aryl, where aryl is as defined above.
Likewise, any of the terms, such as, for example, alkylthio, alkylamino, dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, cycloalkyloxycarbonyl and the like, includes groups where alkyl, alkoxy, aryl, (C3-C8) cycloalkyl and heterocyclic moieties are as defined above.
Pharmaceutically acceptable salts of compounds of formula (I) include acid addition salts with organic or inorganic acids, for example, nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric, acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, isethionic and salicylic.
The pharmaceutically acceptable salts of the compounds of formula (I) also include salts with organic or inorganic bases, for example alkali or alkaline earth metals, especially sodium, potassium, calcium or magnesium ammonium hydroxide, carbonates and bicarbonates, cyclic amines or acyclics, preferably methylamine, ethylamine, diethylamine, triethylamine, piperidine and the like. A preferred class of compounds of formula (I) are those compounds where: R1 is NR7R8 or an optionally substituted heterocyclyl, where R7 and R8 are as defined above.
A more preferred class of compounds of formula (I) are compounds, where: R2 is hydrogen or a group NR17R18, in which R17 and R18 are as defined above.
A still more preferred class of compounds of formula (I) are compounds, where: R2 is a group NR17R18, in which R17 is hydrogen and R18 is COR22, in which R22 is as defined above.
An even more preferred class of compounds of formula (I) are the compounds, where: R3 is hydrogen, R4 is halogen and R5 is hydrogen or halogen. A most preferred class of compounds of formula (I) are compounds, where: RX is hydrogen and R6 is an optionally substituted phenyl group.
Specific preferred compounds of formula (I) or a salt thereof are the compounds listed below: 1) N-{3-[2-amino-5-(pyridin-4-yl)-1,3-thiazol-4-yl ]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide; 2) N-{2,4-difluoro-3-[2-(methylamino)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide; 3) N-{3-[2-(diethylamino)-5-(pyridin-yl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide; 4) N-(2,4-difluoro-3-{2-[(2-methylpropyl)amino]-5-(pyridin-4-yl)-1,3-thiazol-4-yl}phenyl)-2, 5-difluorobenzenesulfonamide; 5) N-(2,4-difluoro-3-{2-[(2-methylethyl)amino]-5-(pyridin-4-yl)-1,3-thiazol-4-yl}phenyl)-2, 5-difluorobenzenesulfonamide; 6) N-{2,4-difluoro-3-[2-(piperidin-4-ylamino)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]phenyl}-2.5 -7) difluorobenzenesulfonamide; 7) ) N-(3-{2-[cyclohexyl(methyl)amino]-5-(pyridin-4-yl)-1,3-thiazol-4-yl}-2,4-difluorophenyl)-2,5 - difluorobenzenesulfonamide; 8) N-{2,4-difluoro-3-[2-(4-methylpiperazin-1-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]phenyl}-2 ,5-difluorobenzenesulfonamide; 9) N-{2,4-difluoro-3-[2-(pyridin-1-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]phenyl}-2,5 -difluorobenzenesulfonamide; 10) N-(3-{2 -[4-(dimethylamino)pipendin-1-yl]-5-(pyridin-4-yl)-1,3-thiazol-4-yl}-2,4-difluorophenyl) -2,5-difluorobenzenesulfonamide; 11) N-{3-[2-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5-(pyridin-4-yl)-1,3-thiazol-4- yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide; 12) N-{2,4-difluoro-3-[2-(4-oxopiperidin-1-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]phenyl}-2 ,5-difluorobenzenesulfonamide; 13) N-{2,4-difluoro-3-[2-(4-hydroxypiperidin-1-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]phenyl}-2 ,5-difluorobenzenesulfonamide; 14) N-{3-[2-(4,4-difluoropiperidin-1-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}- 2,5-benzenesulfonamide; 15) N-{2,4-difluoro-3-[2-(morpholin-4-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]phenyl}-2.5 - difluorobenzenesulfonamide; 16) N-{3-[2-(diethylamino)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide; 17) N-{3-[2-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5-(pyridin-4-yl)-1,3-thiazol-4- yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide; 18) N-{3-[2-(4,4-difluoropiperidin-1-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2, 5-difluorobenzenesulfonamide; 19) 2,5-difluoro-N-{2-fluoro-3-[2-(1-methylpiperidin-4-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl] phenyl}benzenesulfonamide 20) 2,5-difluoro-N-{2-fluoro-3-[5-(pyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazole -4-yl]phenyl}difluorobenzenesulfonamide; 21) N-{ 3-[2-(1-cyclopropylpiperidin-4-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5- difluorobenzenesulfonamide; 22) N-{3-[5-(2-aminopyridin-4-yl)-2-(1-cyclopropylpiperidin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}- 2,5-difluoro-benzenesulfonamide; 23) N-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1-methylpiperidin-4-yl)1,3-thiazol-5 -yl]pyridin-2-yl}acetamide; 24) N-{3 -[5-(2-aminopyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}- 2,5-difluorobenzenesulfonamide; 25) 2,5-difluoro-N-(2-fluoro-3-{5-[2-(methylamino)pyridin-4-yl]-2-(tetrahydro-2H-pyran-4-yl)-1,3 -thiazol-4-yl}phenyl)benzenesulfonamide; 26) 2,5-difluoro-N-{2-fluoro-3-[2-(1-methylpiperidin-4-yl)-5-(2-methylpyridin-4-yl)-1,-3-thiazol-4 -yl]phenyl}benzenesulfonamide; 27) 2,5-difluoro-N-{2-fluoro-3-[5-(2-fluoropyridin-4-yl)-2-(1-methylpiperidin-4-yl)-1,3-thiazol-4- yl]phenyl}benzenesulfonamide; 28) 2,5-difluoro-N-{2-fluoro-3-[5-(2-methylpyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol- 4-yl]phenyl}benzenesulfonamide; 29) N—{4 — [4 — (3—{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1-methylpiperidin-4-yl)-1,3-thiazol- 5-5yl]pyridin-2-yl}-2-methylpropanamide; 30) N-{4-[2-(1-cyclopropylpiperidin-4-yl)— 4— (3—{[(2,5 — difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol- 5-yl]pyridin-2-yl}acetamide; 31) N-{3-[2-(1-cyclopropylpiperidin-4-yl)-5-(2-10-methylpyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2 ,5-difluorobenzenesulfonamide; 32) N-{3-[2-(1-cyclopropylpiperidin-4-yl)-5-(2-fluoropyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2, 5-difluorobenzenesulfonamide; 15 33) N-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2,6-difluorophenyl)-5-(pyridin-4-yl)-1,3-thiazol-2- il] acetamide; 34) 2,5-difluoro-N-{2-fluoro-3-[5-(3-fluoropyridin-4-yl)-2-(tetrahydro-2h-pyran-4-yl)-1,3-thiazol- 4-4yl]phenyl}20 benzenesulfonamide; 35) N—{4—[4—(3—{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(tetrahydro-2h-pyran-4-yl)-1,3- thiazol-5-yl]pyridin-2-yl}acetamide; 36) N-[2-({4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino]-25 2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl) -1,3-thiazol-5-yl]pyridin-2-yl}amino)ethyl]acetamide; 37) N-(3-{2-(1-cyclopropylpiperidin-4-yl)-5-[2-(methylamino)pyridin-4-yl]-1,3-thiazol-4-yl}-2-fluorophenyl) -2,5-difluorobenzenesulfonamide; 38) 2,5-difluoro-N-(2-fluoro-3-{5-[2-(methylamino)pyridin-4-yl]-2-(1-methylpiperidin-4-yl)-1,3-thiazole -4-yl}phenyl)methyl-benzenesulfonamide; 39) N-{3-[5-(2-aminopyridin-4-yl)-2-(1-methylpiperidin-4-yl)-1,3-thiazol-4-yl)-2-fluorophenyl}-2, 5-difluorobenzenesulfonamide; 40) N-{3-[5-(2-{[2-(dimethylamino)ethyl]amino}pyridin-4-yl)-2-(tetrahydro-2h-pyram-4-yl)-1,3-thiazole -4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide; 41) methyl [(2S)-1-({4-[4-(3{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(tetrahydro-2Hpyran-4-yl)- 1,3-thiazol-5-yl]pyridin-2-2yl}amino)propane-2-yl]carbamate; 42) N-{4-[2-tert-butyl-4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-5-yl]pyridin- 2-yl}acetamide; 43) N-{3-[2-tert-butyl-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide; 44) N—{4—[4—(3—{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(piperidin-4-yl)-1,3-thiazol-5- yl]acetamide; 45) methyl[(2S)—1—({4—[4—(3—{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1-methylpiperidin-4-yl) -1,3-thiazol-5-yl]pyridin-2-yl}amino)propan-2-yl]carbamate; 46) 2,5-difluoro-N-{2-fluoro-3-[5-(3-fluoropyridin-4-yl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide; 5 47) N-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1-ethylpiperidin-4-yl)-1,3-thiazole -5-yl]pyridin-2-yl}acetamide; 48) methyl [(2S)-1-({4-[2-(1-cyclopropylpiperidin-4-yl)-4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl) -1,3-10 thiazol-5-yl]pyridin-2-yl}amino)propan-2-yl]carbamate; 49) N-{3-[2-(1-cyclopropylpiperidin-4-yl)-5-(3-fluoropyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2, 5-difluorobenzenesulfonamide; 50) N-{3-[5-(2-aminopyridin-4-yl)-2-tert-butyl-1,3-15-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide; 51) N-(3-{2-tert-butyl-5-[2-(methylamino)pyridin-4-yl]-51,3-iazol-4-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide; and 52) methyl [(2S)-1-({4-[2-tert-butyl-4-(3-{[(2,5-difluoro-phenyl)sulfonyl]amino}-2-fluorophenyl}-1 ,3-thiazol-5-yl]pyridin-2-yl}amino)propane-2yl}carbamate.
The present invention also provides a process for preparing the compounds of formula (I), as defined above, using reaction routes and synthetic schemes described below, employing techniques available in the art and available starting materials. Preparations of certain embodiments of the present invention are described in the examples which follow, but those skilled in the art will recognize that such preparations can be readily adapted to prepare other embodiments of the present invention. For example, the synthesis of the non-examplified compounds according to the invention can be carried out by modifications apparent to those skilled in the art, for example, by suitably protecting interfering groups, switching to other appropriate reagents known in the art or by making routine modifications of the conditions of reaction. Alternatively, other reactions referred to herein or known in the art will be recognized to have adaptability for preparing other compounds of the invention.
A compound of formula (I) can be prepared according to the general synthetic procedures described hereinafter in methods A, B, C, D, E and F.
Those skilled in the art will appreciate that any transformation performed in accordance with such methods may require standard modifications such as, for example, protecting interfering groups, switching to other appropriate reagents known in the art, or making routine modifications to the reaction conditions.
In a general synthetic process, a compound of formula (I)A, (I)B, (I)U1 or (I)VI is prepared according to the method shown below. METHOD A

R1' is like RI except NH2, PG' is a protecting group such as an acetyl, benzoyl or dimethylaminoimino group, Hal is a halogen such as iodine or bromine and M is Li, B(OH)2, B(OA1K)2 , Sn(Alk)3, ZnHal AlAlk)2, ZnHal, MgHal or ZrCp2Hal, where Alk bears an alkyl group and Cp bears cyclopentadiene.
In a general synthetic process for the preparation of a compound of formula (I)A, (I)B, (I)A1 and (I)B1, which is described in method A, in step "a" a compound of formula 1 reacts with a compound of formula 2 to produce a sulfonamide of formula 3. In step "b", optionally, a group is introduced into the sulfonamide portion, giving a compound of formula 4. In step "c" a methylketone of formula 6 is prepared in a two-step procedure involving a Heck-type reaction followed by acid hydrolysis. In step "cl" a methylketone of formula 5 is prepared from a compound of formula 3 in a two step procedure involving a Heck type reaction followed by acid hydrolysis. In step "bl", optionally, a group is introduced into the sulfonamide portion of a compound of formula 5, giving a compound of formula 6. In step "d" and "dl" a ketone of formula 5 or 6 is respectively transformed into corresponding α-bromo ketone of formula 7, by a suitable bromination method. In step "e" the generation of the thiazole system is carried out by condensation with a thiourea or thioamide derivative of formula 8 to produce a compound of formula 9. In step "f" the thiazole ring is halogenated to produce a compound of formula 10 .
In step "g", a compound of formula 10, where R1 is NH2 is protected at the amino group, giving rise to a compound of formula 11. In step "h" a compound of formula 10, where R1 is different from NH2, this is subjected to a suitable cross-coupling reaction for the formation of carbon-carbon bonds, to give a compound of formula (I)A; in step "H1" a compound of formula 11 is sent to the above-said cross-coupling reaction to give a compound of formula 13. Said reactions, which are well known in the art, involve coupling with a suitable organometallic reagent of formula. general 12, such as, for example, organoboron, organotin, organozinc, organoaluminium or organozinc compounds and the like. In step "i", a compound of formula 13 is reacted with a suitable hydrolyzing agent to give a compound of formula (I)U1. In step "j", a compound of formula (I)A, where Rx is as defined above, except that the hydrogen is transformed into the corresponding compound of formula (I)B. In step "jl", a compound of formula (I)U1, where Rx is as defined above, except the hydrogen which is transformed into the corresponding compound of formula (I)V1.
According to step "a" of method A, a compound of formula 1 is reacted with a sulfonyl chloride of formula 2 in the presence of a suitable base such as, for example, pyridine, N-methylmorpholine, diisopropylethylamine (DIPEA), triethylamine (TEA), in the appropriate solvent such as pyridine, dichloromethane (DCM) or THF at a temperature ranging from 0°C to reflux and for a time ranging from about 1 to 8 h.
According to step "b" of method A, a compound of formula 3 is optionally reacted with a suitable reagent such as tert-butoxycarbonyl anhydride, p-methoxybenzyl chloride, alkoxyalkyl chloride such as methoxymethyl chloride, acyl such as acetyl chloride, alkoxycarbonyl chloride such as ethyl chloroformate or the like, optionally in the presence of a suitable base such as dimethylaminopyridine, TEA, DIPEA, in the appropriate solvent such as DCM, acetonitrile, pyridine or THE at a temperature ranging from 0°C to room temperature and for a time ranging from 1 to about 6 h.
According to step "bl" of method A, the optional transformation of a compound of formula 5 into a compound of formula 6 is carried out as described in step "b" of method A.
According to step "c" of method A, a compound of formula 4 is reacted with a vinyl n-alkyl, preferably vinyl n-butyl ether, in the presence of a base such as TEA, a phosphine binder such as 1 ,3-bis(diphenylphosphino)propane (DPPP) and in the presence of a suitable catalyst such as palladium acetate in the appropriate solvent such as ethylene glycol at a temperature ranging from 80 to 150 °C in a closed flask under a nitrogen atmosphere and for a time ranging from 1 to about 12 h. The intermediate thus prepared is hydrolyzed under acidic conditions, for example, with aqueous hydrochloric acid (HC1), in the appropriate solvent such as dioxane or THF at room temperature and for a time ranging from 1 to about 6 h to form a compound of formula 6.
According to step "cl" of method A, the transformation 5 of a compound of formula 3 into a compound of formula 5 is carried out as described in step "c" of method A.
According to step "d" of method A, a compound of formula 5 is reacted with a suitable brominating agent, such as pyridinium bromide-perbromide or ammonium-tetrabutyl perbromide, in the appropriate solvent, such as THF or DCM at a temperature that ranges from 60 to 100°C in a microwave appliance or in classic thermal conditions and for a time ranging from 15 min to 3 h. Alternatively, bromination of a compound of formula 5 is achieved in a two-step procedure involving firstly reacting compounds 5 with trimethylsilyl trifluoromethanesulfonate in the presence of a base, such as TEA or DIPEA, in the appropriate solvent, such as DCM or THF at a temperature ranging from -10 to 0°C and for a time ranging from 10 to 30 min. The resulting trimethylsilyl enol ether is then treated with N-bromosuccinimide, in the appropriate solvent, such as DCM or THF at a temperature ranging from -10 to 0°C and for a time ranging from 30 min to 1 h.
According to step "d1" of method A, the transformation of a compound of formula 6 into a compound of formula 7 is carried out as described in step "d" of method A.
According to step "e" of method A, a compound of formula 7 is reacted with a thiourea or thioamide derivative of formula 8, in the appropriate solvent, such as ethanol or methanol (MeOH) at a temperature ranging from 60°C at reflux, in a microwave oven or in classic thermal conditions and for a time ranging from 15 min to 3 h. According to step "f" of method A, a compound of formula 9 is reacted with a suitable brominated agent, such as N-bromosuccinimide in the appropriate solvent, such as DCM or THF, or Br2 in the appropriate solvent, such as acetic acid , optionally, in the presence of KOAc, at room temperature and for a time ranging from 1 to about 6 h.
According to step "g" of method A, a compound of formula 10, where R 1 is NH 2 , is reacted with a suitable protecting agent. The preferred reaction is with dimethylformamide dimethyl acetal in the appropriate solvent such as dimethylformamide (DMF) at room temperature and for a time ranging from 1 to 16 h.
According to step "h" of method A, a compound of formula 10, where R1 is other than NH2, is coupled to an appropriate organometallic compound of general formula 12, such as, for example, an organoboron compound (reaction of Suzuki), an organotin compound (Stille reaction), an organozinc, organoaluminum or organozinc compound (Negishi reaction), and the like to produce a compound of formula (I)A. Said 25 reactions are well known among those skilled in the art. The preferred reaction is the Suzuki reaction, where an appropriate boron derivative is used in the presence of a palladium based catalyst such as, for example, palladium diphenylphosphinoferrocene dichloride complex with DCM and a suitable base such as Cs2C03 , Na2CO3, K2CO3, Rb2CO3, NaOH, CsF and the like. Said reactions can be carried out in a solvent such as DMF, dimethylsulfoxide, water, dimethoxyethane (DME), 1,4-dioxane, THF or similar and mixing them at a temperature ranging from 100 to 120°C, in a microwave or under classical thermal conditions for a time ranging from 1 to 16 h.
According to step "hi" of method A, the transformation of a compound of formula 11 into a compound of formula 13 is carried out as described in step "h" of method A.
According to step "i" of method A, a compound of formula 13 is reacted with a suitable hydrolyzing agent, depending on the nature of the protecting group PG', to form a compound of formula (I)U1. For example, when this protecting group is represented by a dimethylaminoimino group, deprotection is achieved using 7N ammonia in MeOH, ethylenediamine in ethanol, lithium hydrate or sodium hydrate in water/THF or MeOH or ethanol mixtures at a temperature that ranges from room temperature to reflux and for a time ranging from 8 to 96 h.
According to step "j" of method A, the compound of formula (I) A, where Rx is Rx', is transformed into a compound of formula (I)B, using conditions depending on the nature of such group Rx' . For example, when a group is represented by a methoxymethyl, benzyl, tert-butoxycarbonyl or the like group, removal can be carried out using strong acids such as trifluoroacetic acid (TFA) or HCl. Said reaction may optionally be carried out in the presence of an appropriate co-solvent such as water, THF or 1,4-dioxane at a temperature ranging from room temperature to 90°C and for a time ranging from 1 to about 8 h. When such group is represented, for example, by acetyl, an ethoxycarbonyl group or the like, removal can be carried out using a base such as TEA or DIPEA in MeOH or ethanol, or using an aqueous solution of inorganic base such as sodium or potassium carbonate, or sodium or potassium hydroxide or the like. Said reactions can be carried out at 15 temperatures ranging from 0°C to reflux and for a time ranging from 30 min to about 48 h.
According to step "jl" of method A, the compound of formula (I)U1 is transformed into a compound of formula (I)V1 as described in step "j" above.
A compound of formula (I), prepared according to method A described above, can also be transformed into another compound of formula (I) following procedures well known to those skilled in the art.
For example, when R1 is represented by an NH2 group (compound of formula (I)U1), said compound can be further transformed into another compound of formula (I)C, (I)D, (I)E, ( I)F, (I)G, (I)H, (1)1, (I)J, (I)K, (I)L, (I)M, (I)N, (1)0, Method B

R10, R11, R12, R13, Rx and Hal are as described above and R1" is an optionally substituted (C2-C8) alkynyl, (C3-C8) cycloalkenyl, heterocyclyl, aryl or heteroaryl.
In a synthetic process for the preparation of compounds of formula (I)C, (I)D, (I)E, (I)F, (I)G, (I)H, (1)1, (I) J , (I)K, (I)L, (I)M, (I)N, (1)0, (I)P, (I)U or I (V), which is described in method B, in step "a", a compound of formula (I)U1 prepared as described in method A is subjected to a Sandmeyer-type reaction followed by reduction of the intermediate diazonium salt to give a compound of general formula (I)D. In step "b", the compound of formula (I)D wherein Rx is as defined above, except hydrogen, is converted to the corresponding compound of formula (I)E. In step "C", a compound of formula (I)U1 is subjected to a Sandmeyer-type reaction followed by reaction with a suitable halogenating agent to obtain a halo-derivative of formula (I)F. In step "bl" , the compound of formula (I)F, wherein Rx is as defined above, except hydrogen, is converted to the corresponding compound of formula (I)G. In step "d", a compound of formula (I)F is transformed into a compound of formula (I)H exploiting any of the suitable cross-coupling reactions for the formation of carbon-carbon bonds. The reactions, which are well known in the art, involve coupling with an appropriate organometallic reagent of formula 22, such as , for example, an organoboron, organotin, organozinc, organoaluminium or organozirconium compound and the like. In step "b2", a compound of formula (I)H, wherein Rx is as defined above, except hydrogen is converted to the corresponding compound of formula (1)1. In step "e" of a compound of formula (I)F is converted to a compound of formula (I)U by reaction with an amine of formula 14. In step "b3", a compound of formula (I)U, wherein Rx is as defined above, except hydrogen is converted to the corresponding compound of formula (I)V. In step "f", a compound of formula (I)U1 is condensed with an isocyanate of formula 15 to obtain a urea derivative of general formula (I)J. In step "B4", a compound of formula (I)J, wherein Rx is as defined above, except hydrogen, is converted to the corresponding compound of formula (I)K. In step "g", a compound of formula (I)U1 is condensed with a compound of general formula 16 or 17 to obtain an imido derivative of general formula 18 or directly a compound of formula (I)L. The latter can be obtained otherwise in step "h" from a compound of formula 18 by selective hydrolysis of an acyl group, which can be achieved under basic conditions. In step "B5", a compound of formula (I)L, wherein Rx is as defined above, except hydrogen, is converted to the corresponding compound of formula (I)M. In step "i", a compound of formula (I)U1 is reacted with an appropriate chloroformate of formula 19 to obtain a carbamate derivative of formula (I)N. In step "j", the latter is converted to a urea derivative of formula (1)0, by reaction with an amine of formula 20. In step "b6", a compound of formula (1)0, where Rx is as defined above, except hydrogen, is converted to the corresponding compound of formula (I)P. In step "b7", a compound of formula (I)N, wherein Rx is as defined above, except hydrogen, is converted to the compound corresponding formula (I)C.
According to step "a" of method B, the synthesis of a compound of formula (I)D from a compound of formula (I)U1 is obtained by preparing a diazonium salt, which can be done using nitrite. sodium in water or aqueous solvents, in the presence of a mineral acid such as HCl, sulfuric acid and the like, after reduction of said salt, which can be done using an alcohol such as ethanol, or a suitable reducing agent such as hypophosphorous acid. Alternatively, the diazonium salt can be obtained using isoamyl nitrite in a suitable solvent such as DCM, DME, THF and the like at a temperature ranging from 0°C to reflux and for a time ranging from 30 minutes to about 30 minutes. 24 h.
According to step "b" of method B, the conversion of a compound of formula (I)D into the corresponding compound of formula (I)E is carried out as described in step "j" of method A.
According to step "c" of method B, the transformation of a compound of formula (I)U1 into a compound of formula (I)F is carried out by means of a Sandmeyer protocol. This is achieved by preparing a diazonium salt, which can be made using sodium nitrite in water or aqueous solvents, in the presence of a mineral acid such as HCl, sulfuric acid and the like, after treatment with a halide salt. Bromination is preferred, and therefore the preferred salt is CuBr halide. Alternatively, iodination can be performed,
This is achieved using Kl, Nal, Csl, Cul, optionally in the presence of iodine. Alternatively, the diazonium salt can be obtained using isoamyl nitrite or tert-butyl nitrite in a suitable solvent such as acetonitrile, DCM, 10 DME, THF and the like at a temperature ranging from 0°C to reflux and for a time between 30 minutes and about 3 days. According to step "bl" of method B, the conversion of a compound of formula (I)F into the corresponding compound of formula (I)L is carried out as described in step "j" of method A.
According to step "d" of method B, a compound of formula (I)F is cross-coupled with an appropriate organometallic compound of general formula 22, such as, for example, an organoboro compound (Suzuki reaction), a 20 an organotin compound (Stille reaction), an organozinc, organoaluminum or organozinc compound (Negishi reaction), and the like. The reactions are well known among those skilled in the art. The preferred reaction is the Suzuki reaction, where an appropriate aryl or heteroaryl boronate is used in the presence of a palladium-based catalyst such as, for example, Tetrakis (triphenylphosphine)-palladium (Pd (PPh3) dz θ a suitable base such as CS2CO3, Na2CO3, K2CO3, Rb2C03 NaOH, CsF, and the like. The reactions can be carried out in a solvent such as DMF, dimethylsulfoxide, water, DME, 1,4-dioxane, THF or the like and the like mixtures at a temperature ranging from 20°C to reflux and for a time ranging from 30 min to about 24 h. According to step "b2" of method B, the conversion of a compound of formula (I) H, on the corresponding compound of formula (1)1 is carried out as described in step "j" of method A.
According to step "e" of method B, the reaction of a compound of formula (I)F with a compound of formula 14 can be carried out in an appropriate solvent, such as dimethylacetamide, DMF, acetonitrile or the like, optionally in the presence of a suitable base such as TEA or DIPEA. The reaction can be carried out in a microwave device or under classical thermal conditions at a temperature ranging from 80 to 120°C and for a time between 1 hour and 2 days. According to step "b3'' of method B, the conversion of a compound of formula (I)L to the corresponding compound of formula (I)V is carried out as described in step "j" of method A.
According to step "f" of method B, the reaction of a compound of formula (I)U1 with a compound of formula 15 can be carried out in a suitable solvent, such as 1,4-dioxane, THF, DME in a temperature ranging from room temperature to reflux and for a time ranging from 2 to 5 days. According to step "b4" of method B, the conversion of a compound of formula (I)J to the corresponding compound of formula (I)K is carried out as described in step "j" of method A.
According to step "g" of method B, the reaction of a compound of formula (I)U1 with a compound of formula 16 or 17 can be carried out in the presence of a suitable base such as TEA or DIPEA or pyridine, in the appropriate solvent such as DCM, THE, 1,4-dioxane or acetonitrile at room temperature and for a time ranging from 1 to about 8 h.
According to step "h" of method B, the conversion of a compound of formula 18 to a compound of formula (I)L is carried out by selective hydrolysis using basic hydrolytic conditions such as TEA in MeOH or dilute aqueous solution of NaOH or LiOH in a suitable solvent such as ethanol, MeOH or THE at room temperature and for a period of time ranging from 1 to about 6 h. According to step "b5" of method B, the conversion of a compound of formula (I)L to the corresponding compound of formula (I) M is carried out as described in step "j" of method A.
According to step "i" of method B, the conversion of a compound of formula (I)U1 into a compound of formula (I)N is achieved by reaction with a chloroformate of formula 19 in the appropriate solvent, such as THE, DME, DCM, chloroform, acetonitrile, toluene or mixtures thereof at a temperature ranging from approximately -10°C to reflux and for a time ranging from about 30 minutes to about 96 h. The reaction is usually carried out in the presence of an opportune scavenger proton such as TEA, DIPEA or pyridine.
According to step "b7" of method B, the conversion of a compound of formula (I)N to the corresponding compound of formula (I)C is carried out as described in step "j" of method A.
According to step "j" of method B, a compound of formula (1)0 is obtained from a compound of formula (I)N by reaction with a suitable amine of formula 20. Said reaction is normally carried out in a suitable solvent such as dimethylsulfoxide, THE, DMF, N,N-dimethylacetamide, acetonitrile, toluene or mixture thereof, optionally in the presence of an additional base such as TEA, DIPEA, diazabicycloundecene or an organometallic reagent such as a Grignard reagent or trimethyl aluminum at a temperature ranging from about -10°C to reflux and for a time ranging from about 30 min to about 96 h. According to step "b6" of method B, the conversion of a compound of formula (1)0 to the corresponding compound of formula (I)P is carried out as described in step "j" of method A.
In another general synthetic process, described in method C shown below, the synthesis of a compound of formula (I), where R1 is a heterocyclyl group is described; in particular, a compound of formula (I)H1 is prepared and further elaborated into a compound of formula (I)Q, (I)R, (I)R1 or (I)R2. Method C

In the above scheme m, n, R2, R3, R4, R5, R6, Rx and Hal are 5 as defined above; R2" is like R2 or NR18COR22, where R18 and R22 are as defined above.
X is S, O, NH or NR', where R' is a straight or branched (C 1 -C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, heterocyclyl, aryl, heteroaryl or a PG" group, in which PG" is a suitable nitrogen protecting group such as, for example, tert-butoxycarbonyl, benzyl or benzyloxycarbonyl;
R" is a linear or branched (C 1 -C 8 )alkyl or (C 3 -C 8 )cycloalkyl; Y is S, 0, NH or an NR'" group, where R'" is a (C 1 -C 8 )alkyl, cycloalkyl ( C3-C8), heterocyclyl, aryl or linear or branched heteroaryl.
In a synthetic process for the preparation of a compound of formula (I)H1, (I)Q, (I)R, (I)R1 and (I)R2 which is described in method C, in step "A" a compound of formula (I)F is reacted with a compound of formula 23, according to a Suzuki protocol, to produce a compound of formula (I) HI. In step "b", a compound of formula (I) HI is subjected to catalytic hydrogenation to produce a compound of formula (I)Q. In step "c", when X is S, 0, NH or NR', a compound of formula (I)R is obtained. In step "d", when X is an NPG group, a compound of formula 47 is obtained by selectively gently removing the PG" group. In step "e" a compound of formula 47 is subjected to reductive amination to generate a compound of formula 48. In step "cl" or "c2" a compound of formula (I) R1 or (I)R2 is respectively obtained.
According to step "a" of method C, a heterocycloalkenyl derivative of formula 23 is coupled to a compound of formula (I)F according to a Suzuki reaction protocol. Said reaction may be carried out in the presence of a suitable base such as cesium carbonate or potassium carbonate or phosphate and in the presence of a suitable catalyst such as palladium dichloride diphenylphosphinoferrocene complex with 25 DCM using water/DME mixtures or 1 ,4-dioxane/water, such as
The solvent system. The reaction is carried out in an appropriate solvent, such as DME/water or 1,4-dioxane/water mixtures, in a microwave apparatus or under classical thermal conditions at a temperature ranging from 90 to 120°C and for a time ranging from 1 h to about 16 h.
According to step "b" of method C, the reduction of a compound of formula (I)H1 to give a compound of formula (I)Q is carried out using any of the methods known in the art for reducing a double bond carbon-carbon, for example, with ammonium formate in the presence of a catalyst such as 10% palladium on charcoal or 10% palladium carbonate supported on charcoal in a suitable solvent such as MeOH or ethanol at reflux and for a period that ranges from 4 am to about 4 pm. Alternatively, the reduction can be accomplished through hydrogenation in a Parr apparatus at a pressure ranging from 20 to 50 psi in the presence of a catalyst such as palladium supported on carbon 5 or 10% at room temperature for a time that varies. from 2 to about 6 h.
According to step "c" of method C, the conversion of a compound of formula (I)Q to the formula of the corresponding compound (I)R is carried out as described in step "j" of method A.
According to step "d" of method C, selective removal of the PG" group from a compound of formula (I)Q generates a compound of formula 47 which can be carried out using acidic or reducing conditions. For example, the reaction is made with strong acids such as TEA, optionally in the presence of a suitable co-solvent such as DCM at temperatures ranging from 20°C to reflux and for a period ranging from 30 min to about 48 h. when PG" is a benzylic or benzyloxy group, said reaction is carried out using reducing conditions such as H2 in the presence of an appropriate hydrogenation catalyst. The hydrogenation catalyst is generally a metal, most often palladium, which can be used as such or supported on carbon in a suitable solvent such as, for example, THF, 1,4-dioxane, DMF, MeOH, acetate. ethyl or a mixture of these.
According to step "cl" of method C, the conversion of a compound of formula 47 into a corresponding compound of formula (I)R 1 is carried out as described in step "j" of method A.
According to step "e" of method C, the reductive amination of a compound of formula 47 to produce a compound of formula 48 is carried out by reaction with the appropriate carbonyl derivative, such as an aldehyde, a ketone or its derivatives of corresponding acetal. The reaction is carried out in the presence of an appropriate reducing agent, such as sodium cyanoborohydride or sodium triacetoxyborohydride, in the appropriate solvent, such as MeOH or an acetic acid-MeOH mixture at a temperature ranging from room temperature to reflux and for a time ranging from one to about 24 h.
According to step "c2" of method C, the conversion of a compound of formula 48 to the corresponding compound of formula (I)R2 is carried out as described in step "j" of method A.
In another general synthetic process, a compound of general formula (I)S or (I)T is prepared according to method D shown below. Method D

In the above scheme m, n, R1, R2, R3, R4, R5, R6, Rx and Hal are as described above; J is a halogen such as chloride, bromide, an O-alkyl group or an -N(CH 3 )O-alkyl group, where alkyl is as defined above; E is hydrogen or an alkoxycarbonyl group;
In a synthetic process for the preparation of a compound of formula (I)S and (I)T, which is described in method D, in step "a" a compound of formula 36, which, when Rx is hydrogen corresponds to a compound of formula 3 or when Rx is Rx' corresponds to a compound of formula 4 described in scheme A, it is subjected to a Sonogashira-type reaction with trimethylsilylacetylene to form an intermediate of formula 24. In step "b" the distillation of the latter yields another intermediate of formula 25, which, after a second Sonogashira-type coupling with a compound of formula 26 in step "c", yields an acetylene derivative of formula 27. Hydration of the latter is carried out in step "d" to form a key intermediate ketone of formula 28. Alternatively, in step "e" a compound of formula 36 is transformed into a compound of formula 29 by metallation, for example, with isopropyl magnesium chloride or butyl lithium and reduced with a suitable reagent of the formula Hal-CO- J. Alternatively, reducing with CO2 followed by carboxylic acid activation or palladium catalyzed carboxylation can produce the same compound of formula 29. In step "f", the latter is reacted with a compound of formula 30, which is first normally transformed into the metal anion correspondingly, to give the key intermediate of formula 28. Alternatively, in step "g" a compound of formula 36 is directly transformed into a compound of formula 28 by a palladium catalyzed coupled cross with an appropriate aldehyde of formula 31. Alternatively, in step "h", a compound of formula 36 is transformed into a compound of formula 37, which in step "i" is reacted according to a Heck-type reaction with an appropriate compound of formula 26 to produce key intermediate 28 Alternatively, in step "j", a compound of formula 36 is transformed into an organometal derivative of formula 32, such as, for example, organolithium, organoboron or organomagnesium compounds, which may be used. in turn, in step "k" it is put to react with a suitable electrophile of formula 33 to form a compound of formula 28. This transformation can be carried out according to various methodologies depending on the nature of M and J like any other person. versed in the art you can easily appreciate it. In step "I", halogenation of intermediate 28 yields a compound of formula 34, which in step "m" is reacted with a suitable thiourea or thioamide derivative of formula 8 to produce a thiazole compound of formula (I)S. In step "n" the latter is converted to the corresponding compound of formula (I)T.
According to step "a" of method D, a compound of formula 36 is reacted with trimethylsilylacetylene in the presence of an appropriate palladium catalyst such as PdCl2 (PPh3) 2, Pd(PPh3)4 and the like, and a palladium catalyst. suitable copper such as Cul. Said reaction is carried out in the presence of a suitable base such as TEA, diethylamine, diisopropylamine and the like, optionally in the presence of a phosphine binder such as triphenylphosphine. The reaction is usually carried out at temperatures ranging from -20°C to reflux and for a time ranging from 30 min to about 48 h. According to step "b" of method D, the trimethylsilyl group is removed using a base such as KOH, NaOH, K2CO3, in a solvent such as MeOH, ethanol or the like or using a suitable fluorine salt such as n- Bu4NF in solvents such as THF, DME, DMF or similar. According to step "c" of method D, a compound of formula 25 is transformed into a compound of formula 27 by reaction with an appropriate aromatic halide of formula 26 following the conditions described in step "a" of method D. with step "d" of method D, hydration of the formula 27 alkyne generates a formula 28 compound using, for example, acetic acid, TFA, trifluoromethanesulfonic acid, sulfuric acid, Hg(OTf)2, HgSO4, NaHSO3 and the like , in a suitable aqueous aqueous solvent such as acetonitrile, 1,4-dioxane, acetone, ethanol or the like at a temperature ranging from 0°C to reflux and for a time ranging from 1 to 72 h.
According to step "e" of method D, the transformation of a compound of formula 36 into a compound of formula 29 can be carried out in various ways. One involves metallation with a suitable organometallic compound, such as, for example, isopropyl magnesium chloride or butyl lithium, followed by reduction with a reagent of the formula Hal-CO-J. Such reactions are usually carried out in an inert atmosphere using a suitable solvent such as, for example, THF, 1,4-dioxane, DME or the like at a temperature ranging from -80°C to room temperature. Alternatively, the reduction can be carried out with dry ice, and the resulting carboxylic acid activated to form a compound of formula 29 following any of the methods known in the art. According to step "f" of method D, a compound of formula 30 is reacted with a strong base, such as sodium hexamethyldisilazane (NaHMDS), lithium hexamethyldisilazane (LiHMDS), lithium diisopropylamide (LDA), a Grignard reagent. and the like, following condensation with a compound of formula 29. Said reaction is generally carried out using a variety of solvents such as toluene, THF, 1,4-dioxane, DME or the like at a temperature ranging from 0°C to reflux and for a time ranging from 30 min to about 24 h.
According to step "g" of method D, the transformation of a compound of formula 36 into a compound of formula 28 can be carried out by reaction with an appropriate aldehyde of formula 31. Such reaction is normally carried out in the presence of a suitable catalyst , such as Pd(dba) 2 or Pd(OAc) 2 , and base such as for example pyrrolidine, optionally in the presence of an additional binder such as DPPP and molecular sieves. Said reaction is usually carried out in solvents such as, for example, DME at a temperature ranging from 80°C to reflux, for a time ranging from 1 h to 10 h. According to step "h" of method D, the transformation of a compound of formula 36 into a compound of formula 37 can be carried out by reaction with vinyl n-alkylether, preferably vinyl n-butylether, in the presence of a base, such as TEA, a phosphine binder such as DPPP and in the presence of a suitable catalyst such as palladium acetate in the appropriate solvent such as ethylene glycol at a temperature ranging from 80 to 120°C, in a closed bottle, under nitrogen atmosphere and for a time ranging from 1 to about 6 h.
According to step "i" of method D, the transformation of a compound of formula 37 into a compound of formula 28 can be carried out using a Mizoroki-Heck protocol, where the olefin derivative 37 is reacted with a halide of aryl of formula 26 in the presence of a palladium based catalyst such as, for example, Pd(PPh 3 ) 4 and a suitable base such as TEA and the like. Such reaction is usually carried out in solvents such as DMF, THF, 1,4-dioxane, DME or the like at a temperature ranging from 0°C to reflux and for a time ranging from 30 min to about 24 h.
According to step "j" of method D, a compound of formula 36 is transformed into an organometallic derivative of formula 32, such as an organolithium, organoboron, organomagnesium or the like. Such a compound can be obtained in several ways, depending on the nature of the organometallic itself. For example, organolithium compounds can be obtained by reacting a compound of formula 36 with butyl lithium or tert-butyl lithium. Organoboron compounds can be obtained by reacting a compound of formula 36 with an appropriate boron compound such as bis(pinacolato)diboron, pinacolborane or the like in the presence of an appropriate palladium catalyst such as palladium acetate, PdCl 2 (dppf) chloride palladium(II)[1,1-bis(diphenylphosphine)ferrocene] and a suitable base such as KOAc, TEA and the like in solvents such as DMF, dimethylsulfoxide, DME, 1,4-dioxane, THF or the like in a temperature ranging from 20°C to reflux and for a time ranging from 30 minutes to approximately 24 h. Organomagnesium compounds can be obtained by reacting a compound of formula 36 with a suitable magnesium derivative, such as isopropyl magnesium chloride, or metallic magnesium in solvents such as DME, 1,4-dioxane, THF or the like at a temperature ranging from -78 °C at reflux and for a time ranging from 30 minutes to about 24 h.
According to step "k" of method D, a compound of formula 32 is transformed into a compound of formula 28 by coupling with a suitable reagent of formula 33. The conditions for such coupling depend on the nature of the organometallic compounds 32 and the reagent of formula 33. For example, when the compound of formula 32 is an organoboron compound, coupling can be achieved with a compound of the formula 33. Such a reaction is normally carried out in the presence of a palladium-based catalyst such as, for example , PdCl2 or Pd(OAc)2 and a suitable base such as K3PO4, CS2CO3, K2CO3, Rb2CC>3, NaOH, CsF, or the like, in a solvent like DME, 1,4-dioxane, THF or the like at one temperature ranging from 20°C to reflux and for a time ranging from 30 minutes to about 24 h. When compound 32 is an organomagnesium, coupling can conveniently be accomplished with a Weinreb ester or amide of formula 33. Such reactions are normally carried out in a solvent such as DME, 1,4-dioxane, THF or the like at one temperature ranging from -20°C to reflux and for a time ranging from 30 minutes to about 24 h.
According to step "I" of method D, a compound of formula 28 is reacted with a suitable brominated agent, such as Br2, N-Bromosuccinimide, pyridinium bromide-perbromide or tetrabutyl ammonium perbromide, in a suitable solvent , such as THF or DCM at a temperature ranging from 60 to 100°C in a microwave oven or under classical thermal conditions and for a time ranging from 15 min to 3 h.
Alternatively, bromination of a compound of formula 28 is achieved in a two-step procedure, first involving the reaction of a compound of formula 28 with trimethylsilyl trifluoromethansulfonate in the presence of a base, such as TEA or DIPEA, in the appropriate solvent, such as DCM or THF 20 at a temperature ranging from -10 to 0°C and for a time ranging from 10 to 30 min. The resulting trimethylsilyl enol ether is then treated with N-Bromosuccinimide, in the appropriate solvent, such as DCM or THF at a temperature ranging from -10 to 0°C and for a time ranging from 30 min to 1 h.
According to step "m" of method D, a compound of formula 34 is reacted with a compound of formula 8 in the appropriate solvent, such as ethanol or MeOH at a temperature ranging from 60°C to reflux in a microwave or under classical thermal conditions for a time ranging from 15 min to 3 h. According to step "n" of method D the conversion of a compound of formula (I)S to the corresponding compound of formula (I)T is carried out as described in step "j" of method A.
In another general synthetic process, a compound of general formula (I)T is prepared according to method E 10 shown below. Method E
In the above scheme, m, n, R1, R2, R3, R4, R5, R6, M and Hal are as described above.
In a synthetic process for the preparation of a compound of formula (I)T, which is described in method E, step "a", a compound of formula 38 is transformed into the corresponding α-bromo ketone of formula 39 by a method of suitable bromination. In step "b", generation of the thiazole system is carried out by condensation with a thiourea or thioamide derivative of formula 8 to produce a compound of formula 40. In step "c", the thiazole ring is halogenated to produce a compound of formula 41. In step "d", a compound of formula 41 is subjected to a suitable cross-coupling reaction for the formation of carbon-carbon bonds to give a compound of formula 42. Said reactions, which are well known in the art , involve coupling with a suitable organometallic reagent of general formula 12, such as, for example, an organoboron, organotin, organozinc, organoaluminium or organozirconium compound and the like. In step "e" a compound of formula 42 is treated with a suitable reducing agent to produce an amino derivative of formula 43, which, in step "f" is reacted with a compound of formula 2 to produce a compound of formula (I)T.
According to step "a" of method E, the synthesis of a compound of general formula 39 from a compound of general formula 38 is carried out as described in step "d" of method A.
According to step "b" of method E, the synthesis of a thiazole derivative of general formula 40 from a compound of general formula 39 is carried out as described in step "e" of method A.
According to step "c" of method E, the halogenation of a thiazole derivative of general formula 40 to produce a compound of general formula 41 is carried out as described in step "f" of method A.
According to step "d" of method E, the coupling reaction between a derivative of general formula 41 and an organometallic compound of general formula 12 to produce a compound of general formula 42 is carried out as described in step "h" of method THE.
According to step "e" of method E, the nitro group of a compound of formula 42 is reduced to the amino group to produce a compound of formula 43. The reaction can be carried out by various methods and operating conditions, widely known in the art. to reduce a nitro to an amino group. Preferably, this reaction is carried out in a suitable solvent such as, for example, water, MeOH, THF, 1,4-dioxane, DME, ethyl acetate or a mixture thereof, in the presence of a suitable reducing agent such as, for example, hydrogen and a hydrogenation catalyst, or by treatment with cyclohexene or cyclohexadiene and a hydrogenation catalyst or by treatment with tin(II) chloride, or by treatment with zinc(II) chloride or zinc and aqueous or acidic HCl acetic or ammonium chloride at a temperature ranging from 0°C to reflux and for a time ranging from about 1 h to about 96 h. The hydrogenation catalyst is generally a metal, most often palladium, which can be used as such or supported on carbon.
According to step "f" of method E, the synthesis of a compound of general formula (I)T from a compound of general formula 43 is carried out as described in step "a" of method A.
A compound of formula (I) prepared according to methods A, B, C, D and E above can be further transformed into another compound of formula (I) following procedures known to those skilled in the art.
For example, when R2 is represented by a hydrogen (compound of formula (I)W) or when R2 is a halogen (compound of formula (I)Y), said compounds can be further transformed into other compounds of formula (I )X, (I)Z (I)Z1 and (I)Z2. Furthermore, a compound of formula (I)Y can be further transformed into another compound of Method F
R17' is like R17 or COR22, in which R22 is as defined above.
In a synthetic process for the preparation of a compound of formula (I)X, (I)Z (I)Z1, (I)Z2, (I)AB and (I)AC, which is described in method F, in step "a", the nitrogen of the IO pyridine of a compound of formula (I)W is oxidized to form an N-oxide derivative of the formula 44. In step "b" and "bl" the reaction of the latter with an appropriate electrophilic species as a tosyl anhydride in the presence of, or followed by treatment with a suitable nucleophile, such as a compound of formula NHR17'R18 (45) or a primary amine of formula NH2RI8 (46), yields a compound of formula 49 or ( I)X 5 respectively. In step "d" and "dl", the last compounds, where Rx is as defined above, except hydrogen, are converted to the corresponding compound of formula (I)Z or (I)Z1 respectively. Optionally in step "e", a compound of formula 49, where R17' is represented by a tert-butyl group, a benzyl group, a tert-butoxycarbonyl group or the like, is treated with an acid or under reducing conditions to remove said group producing a compound of formula (I)X. Similarly, in step "el", a compound of formula (I)X, where R18 is represented by a tert-butyl group, a benzyl group, a tert-butoxycarbonyl group or the like, is treated with an acid or under reducing conditions to remove said group producing a compound of formula (I)Z2. In step "f", a compound of formula (I)X is optionally treated with an electrophile of general formula R17'Hal to form a compound of formula 49. In steps "c" and "cl", the compounds of general formula 49 and (I)X, respectively, can be obtained from a compound of general formula (I)Y by palladium catalyzed cross-coupling reaction with an appropriate compound of general formula NHR17'R18 (45) or NH2R18 (46), respectively .
In step "g" a compound of formula (I)Y is transformed into a compound of general formula (I)AB by a palladium catalyzed coupling reaction with an appropriate organometallic derivative, such as an organoaluminium compound; in step "d2" the latter, where Rx is as defined above, except hydrogen, is converted to the corresponding compound of formula (I)AC.
According to step "a" of method F, the oxidation of pyridine nitrogen can be carried out using oxidizing agents known to those skilled in the art, such as, for example, hydrogen peroxide in a solvent such as acetic acid or m-acid. -chloroperbenzoic acid in solvents such as DCM, acetone, THF or similar at temperatures ranging from 0°C, to reflux and for a time ranging from 30 minutes to about 48 h.
According to step "b" of method F, the transformation of a compound of formula 44 into a compound of formula 49 is achieved by activating the pyridine N-oxide and reacting it with a compound of general formula NHR17'R18 (45). Activation is usually carried out using a suitable electrophilic reagent such as oxychloride, trifluoromethanesulfonyl chloride, tosyl chloride, benzoyl chloride, acetic anhydride, tosyl anhydride, PyBroP (bromo-tris-pyrrolidine-phosphonium hexafluorophosphate), BroP (bromo-tris-(dimethylamino)-phosphonium hexafluorophosphate), PyBOP (benzotriazole-1-yl-oxy-tris-pyrrolidine-phosphonium hexafluorophosphate), BOP (benzotriazole-1-yl-oxy-tris(dimethylamino) hexafluorophosphate -phosphonium) and the like, in a solvent such as DCM, THF, dichloroethane, ethyl acetate, acetonitrile, toluene, trifluoromethylbenzene and the like, in the presence of a base such as TEA, DIPEA, 2,6-lutidine and the like. PyBroP and DIPEA in DCM are preferably used. The reaction is usually carried out in the presence of secondary amine and can be carried out at temperatures ranging from 20°C to reflux and for a time ranging from 30 minutes to about 48 h.
According to step "bl" of method F, the conversion of a compound of formula 44 to a compound of general formula (I)X is carried out as described in step "b" of method F, but using an appropriate primary amine of general formula 46.
According to step "c" of method F, a compound of formula (I)Y is cross-coupled with suitable amine, amide or carbamoyl compounds of general formula 45 (Buchwald-Hartwig reaction). This reaction is well known among those skilled in the art. This is carried out using a palladium-based catalyst such as, for example, palladium chloride, palladium acetate, Pd(dba)2, Pd2 (dba)3 or the like, in the presence of a suitable base such as t- sodium butoxide, CS2CO3, Na2 CO3, K2CO3, K3PO4, LiHMDS, and the like, optionally, in the presence of a phosphine-based binder such as P(o-tol)3, P(t-Bu)3 DPPP, DPPF, BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene or monophosphinobiphenyl linkers. Said reactions can be carried out in a solvent such as DMF, dimethylsulfoxide, water, DME, 1,4-dioxane, THF or similar and mixing them at a temperature ranging from 20°C to reflux and for a time ranging from 30 minutes to about 24 h.
According to step "cl" of method F, the conversion of a compound of formula (I)Y into a compound of general formula (I)X is carried out as described in step "c" of method F, but using suitable compounds of amine, amide or carbamoyl of general formula 46.
According to step "d" of method F, the conversion of a compound of formula 49 to the corresponding compound of formula (I)Z is carried out as described in step "j" of method A.
According to step "dl" of method F, the conversion of a compound of formula (I)X to the corresponding compound of formula (I)Z1 is carried out as described in step "j" of method A.
According to step "e" of method F, a compound of formula 49 where R17' is represented by a group such as tert-butyl, benzyl, tert-butoxycarbonyl or the like, such as a group R17' can be removed for produce a compound of general formula (I)X. The reaction is normally carried out using strong acids, such as TFA, optionally, in the presence of suitable co-solvents, such as DCM or water, at temperatures ranging from 20°C to reflux and for a time ranging from 30 minutes to about 48 h. Alternatively, this reaction is carried out using reducing conditions such as H2 in the presence of a suitable hydrogenation catalyst. The hydrogenation catalyst is generally a metal, most often palladium, it can be used as such or supported on carbon, in a suitable solvent such as, for example, THF, 1,4-dioxane, DMF, MeOH, ethyl acetate or a mixture of these.
According to step "el" of method F, the conversion of a compound of formula (I)X to a compound of formula (I)Z2 is carried out as described in step "e" of method F.
According to step "f" of method F, a compound of formula (I) X can be converted to another compound of formula 49 by reaction with an appropriate electrophile of general formula R17'Hal. It is obvious to a person skilled in the art that this reaction can be carried out in various ways and operating conditions, widely known in the art for the preparation of amines, carboxamides or carbamates. Such reactions can be carried out in a suitable solvent such as, for example, DCM, chloroform, THF, diethyl ether, 1,4-dioxane, acetonitrile, toluene, or DMF in the presence of a suitable base such as TEA, DIPEA, DBU and the like over a temperature range from about -10°C to reflux and for a suitable time, for example, from about 30 minutes to approximately 96 h.
According to step "g" of method F, a compound of formula (I)Y can be converted to a compound of formula (I)AB, where R 2' is an alkyl group. The reaction is usually carried out by means of an organometallic reagent such as R2'MgBr, R2'ZnCl, R2'2CuMgBr or R2'3A1 and the like, in the presence of a coordinating agent such as Fe(acac)3, NlBr2, CuBr, ZnBr2, Ni(acac)2 and the like, in a solvent such as THF or n-methylpyrrolidone and the like at a temperature ranging from 0°C to reflux. Alternatively, coupling of the organometallic reagent with the substrate can be mediated by a palladium catalyst such as Pd(PPh3)4 and the like, in a solvent such as dioxane or toluene at a temperature ranging from room temperature to reflux. Reaction with R2'3A1 and Pd(PPh3)4 in dioxane is preferred. According to step "d2" of method F, the conversion of a compound of formula (I)AB into the corresponding compound of formula (I)AC is carried out as described in step "j" of method A.
During the preparation of the compounds of formula (I) according to any process variant, all of which are intended to be within the scope of the invention, optional functional groups within the starting materials, the reagents or their intermediates, which may give origin of undesirable side reactions, need to be properly protected according to conventional techniques.
The starting materials of the process object of the present invention encompass all possible variants, as well as any reagents thereof, are known compounds and, if not commercially available per se, can be prepared according to well-known methods. PHARMACOLOGY Assays In vitro cell proliferation assay
Exponentially growing A375 human melanoma cells (with mutated B-RAF) and Mewo human melanoma cells (with wild-type B-RAT) were seeded and incubated at 37°C in a CO2 atmosphere with 5% humidity. After 24 hours, scalar doses of the compound were added to the medium and the cells incubated for 72 hours. At the end of treatment, cells were washed and counted. Cell number was determined by a cellular adenosine triphosphate monitoring system. Cell proliferation was compared to cell control and cell growth inhibition concentration was calculated to be 50%. ArrayScan p-MAPK Assay (T202/Y204)
A375 human melanoma cells, having a B-RAF mutation were seeded into 384 wells of polylysine coated plates (Matrix) at a density of 1000 cells/well in a suitable medium, supplemented with 10% FCS and incubated for 16 to 24 hours. Cells were treated for 1.5 or 2 hours with increasing doses of compounds (initial dose 10 µM, dilution factor 2.5) . At the end of treatment, cells were fixed with 3.7% p-formaldehyde for 15 to 30 minutes, washed twice with D-PBS (80 µL/well) and permeabilized with D-PBS containing 0.1% Triton X -100 and 1% BSA (Sigma-Aldrich) for 15 minutes at room temperature (staining solution). Anti-phospho-MAPK (T202/Y204) monoclonal antibody ELO (Cell Signaling, cat. #9106) diluted 1:100 is added to the staining solution and incubated for 1 hour at 37°C. After removing the primary antibody solution, anti-mouse conjugate Cy™ 2 (Green), a secondary antibody (Amersham) diluted 1:500 in dye solution containing 2 µ/ml DAPI was added. The plate was incubated for 1 hour at 37°C, washed twice and then stained red with Cellomics' ArrayScan VTI (4 fields/well, CytoNucTrans algorithm).
The parameter "MEAN_RingAvglntenCh2", which measures the mean intensity of cytoplasmic fluorescence associated with p-MAPK staining, is reported as a final result.
B-RAF mutations, which constitutively activate the kinase, have been identified in most melanomas and in a large fraction of colorectal and papillary thyroid carcinoma. The growth of B-RAF activated cells is strictly dependent on B-RAF activity.
Given the above assay, the compounds of formula (I) result in having a strong activity to inhibit cell proliferation, with IC50 values lower than 10 mM in cell line with mutant B-Raf (A375), and higher in cell line with wild-type B-Raf (Mewo), as reported in the table below. In the same table, data obtained with compounds of formula (I) in the ArrayScan assay are also reported and demonstrate the ability of compounds of formula (I) to inhibit the signal transduction pathway controlled by B-Raf activation in the A375 cell line with mutant B-RAF. IC50 values are always below 10μM and are in agreement with the IC50 values obtained in the proliferation assay of the same cell line, 5 confirming that the antiproliferative activity of the compounds occurs due to the inhibition of the B-RAF activity. Table 1.




Anti-Tumor Efficacy in a Human Melanoma Transplant Model
Male Balb Nu/Nu mice, from Harlan (Italy), were kept in cages lined with filter paper, sterilized food and bedding, and acidified water. 3 x 10 6 A375 human melanoma cells (from the American Type Culture Collection) were injected subcutaneously. Compounds were administered orally in a volume of 10 mL/kg for 10 consecutive days. Tumor growth and body weight were measured every 3 days. Tumor growth was assessed by forceps. Tumor mass was calculated as follows: Tumor weight (mg) = length (mm) • width2 (mm2) /2'd (mg/mm3) , assuming tumor tissue density is d = 1 mg/ mm3. Tumor growth inhibition (TGI) was determined according to the equation %TGI = 100 - (mean tumor weight of treated group/mean tumor weight of control group) X 100. Toxicity was evaluated based on the reduction in body weight. Based on the above assay, a selection of compounds of the present invention showed a TGI greater than 90% with no reduction in body weight. Bioavailability
In addition to in vitro methods, in vivo methods such as pharmacokinetic studies can be performed on a variety of animals. A compound of formula (I) of the present invention can be administered to animals, for example rats or mice, at different dosages and by a different route of administration, preferably orally. Blood samples can be collected at serial time points and the samples tested for the presence of said compounds of formula (I).
A compound of formula (I) of the present invention, formulated in 0.5% Methocel®, was administered orally to rats (10 to 100 mg/kg) in pharmacokinetic studies and its concentration was monitored in blood by HPLC/ MS at 15 and 30 min, 1.6 and 24 h post-dose. All blood samples were taken from the saphenous vein.
Oral bioavailability (Fos) was calculated as the percent ratio of the mean oral AUC value of the compound to the mean of the AUC IV value of the compound following compound dose normalization. Based on the above assay, a selection of compounds of the present invention showed an oral bioavailability greater than 20%.
From all above, the novel compounds of formula (I) of the invention appear to be particularly advantageous in the therapy of diseases caused by unregulated protein kinase activity such as cancer.
The compounds of the present invention can be administered as sole agents or alternatively in combination with known anticancer treatments such as radiotherapy or chemotherapy in combination with, for example, anti-hormonal agents such as antiestrogens, antiandrogens and aromatase inhibitors, topoisomerase I protease inhibitors, topoisomerase II inhibitors, microtubule-targeting agents, platinum-based agents, alkylating agents, damaged DNA or intercalating agents, antineoplastic antimetabolites, other kinase inhibitors, other anti-angiogenic agents, kinesin inhibitors, therapeutic monoclonal antibodies , mTOR inhibitors, histone deacetylase inhibitors, famesyl transferase inhibitors and hypoxic response inhibitors.
If formulated as a fixed dose, these product combinations employ compounds of this invention within the dose range described below and another pharmaceutically active agent within the approved dose range.
Compounds of formula (I) can be used sequentially with known anticancer agents when a combination formulation is inadequate.
The compounds of formula (I) of the present invention, suitable for administration to a mammal, e.g. humans, can be administered by the normal routes, the dosage level depending on the age, weight, conditions of the patient and the route of administration. .
For example, a suitable dosage adopted for oral administration of a compound of formula (I) may range from about 10 to about 1 g per dose, from 1 to 5 times a day. The compounds of the invention can be administered in various dosage forms, for example, orally, in the form of tablets, capsules, film-coated or sugar-coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, for example, intramuscularly, or by intravenous and/or intrathecal and/or intraspinal injection or infusion.
The present invention also includes pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient, which may be a carrier or a diluent.
Pharmaceutical compositions containing the compounds of the invention are normally prepared following conventional methods and are administered in a pharmaceutically suitable form.
For example, solid oral forms may contain, together with the active compound, diluents, for example lactose, dextrose, sucrose, sucrose, cellulose, corn starch or potato starch; lubricants, for example, silica, talcum, stearic acid, calcium or magnesium stearate, and/or polyethylene glycols; binding agents, for example starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disintegrating agents, for example a starch, alginics, alginates or sodium starch glycolate; effervescent mixtures; dyes; sweeteners, wetting agents such as lecithin, polysorbates, lauryl sulfates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. These pharmaceutical preparations can be manufactured in a known manner, for example by means of mixing, granulating, tabletting, sugar coating or film coating processes. Liquid dispersions for oral administration can be, for example, syrups, emulsions and suspensions.
As an example, syrups may contain a vehicle such as sucrose or sucrose with glycerin and/or mannitol and/or sorbitol. Suspensions and emulsions may contain as a vehicle, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.
Suspensions or solutions for intramuscular injections may contain, together with the active compound, a carrier which is pharmaceutically acceptable, for example, sterile water, olive oil, ethyl oleate, glycols, for example, propylene glycol, and, if desired, a adequate amount of lidocaine hydrochloride.
Solutions for intravenous injections or infusions may contain as the vehicle, for example, sterile water, or preferably they may be in the form of sterile aqueous isotonic saline solutions, or they may contain as the vehicle a propylene glycol.
Suppositories may contain together with the active compound a pharmaceutically acceptable carrier, for example cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty ester surfactant or lecithin. EXPERIMENTAL SECTION
For reference any specific compound of formula (I) of the invention, optionally in the form of a pharmaceutically acceptable salt, see the experimental section and claims. Referring to the examples below, the compounds of the present invention were synthesized using the methods described herein, or other methods known in the art.
In these examples and elsewhere, abbreviations have the following meanings g (grams) mg (milligrams) ml (milliliters) mM (millimolar) μM (micromolar) mmol (millimoles) h (hours) Rt Retention time MHz (Mega Hertz) mm (millimeters) Hz (Hertz) M (molar) min (minutes) mol (moles) TLC (thin layer chromatography) ta (room temperature) TEA (triethylamine) DMAP (dimethylaminopyridine) DME (dimethoxyethane) DIPEA (N,N-diisopropyl-N-ethylamine) DCM (dichloroethane) TEA (trifluoroacetic acid) DMF (N,N-dimethyl formamide) DIPEA (N, N-disopropyl-N-ethylamine) DCM (dichloromethane) THF (tetrahydrofuran) Hex (hexane) MeOH (methanol) DMSO (dimethylsulfoxide) DPPP (1,3-bis(diphenylphosphino)propane) acac (acetylacetone) Dppf (1.1' -bis (diphenylphosphine) ferrocene) ESI = electrospray ionization RP-HPLC (reverse phase high performance liquid chromatography) In order to better illustrate the present invention, without representing any limitation thereto, examples are given below.
As used herein the symbols and conventions used in the processes, schemes and examples are consistent with those used in contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry.
Unless otherwise noted, all materials were obtained from top-rated commercial suppliers and used without further purification. Anhydrous solvents such as DMF, THF, CH2 Cl2 and toluene were obtained from Aldrich Chemical Company. All reactions involving compounds sensitive to moisture or air were carried out under nitrogen or argon atmosphere. General purification and analytical methods
Flash chromatography was performed with silica gel (Merck grade 9385, 60A). HPLC/MS was performed on a Waters X Terra RP 18 column (4.6 x 50 mm, 3.5 µm) using a Waters 2790 HPLC system equipped with a 996 Waters PDA detector and a single quadrupole mass spectrometer mod. Model ZQ Micromass, equipped with an electrospray ionization (ESI) source. Mobile phase A was 5mM ammonium acetate buffer (pH 5.5 with acetic acid/acetonitrile 95:5), and Mobile phase B was H20/acetonitrile (5:95), gradient was 10 to 90% B in 8 minutes, retaining 90% B in 2 min. UV detection was 220 nm and 254 nm. The flow rate was 1 ml/min. The injection volume was 10 µl. Full scan, mass range was between 100 to 800 amu. Capillary voltage was 2.5 KV; the source temperature was 120°C; cone was 10 V. Retention time (HPLC T.A.) was determined in minutes at 220 nm or 254 nm. Mass was determined by the m/z ratio.
When necessary, compounds were purified by preparative HPLC on a Waters C18 Symmetry column (19 x 50 mm, 5 µm) or on a Waters X Terra RP 18 column (30 x 150 mm, 5 µm) using a Waters HPLC 600 preparative equipped with a Waters PDA 996 detector and a single quadrupole mass spectrometer mod. of Model ZQ Micromass, an ionization electrospray, in positive mode. Mobile phase A was 0.01% TEA water, and mobile phase B was acetonitrile. Gradient was 10 to 90% B in 8 min, retained at 90% B in 2 min. Flow rate 20 ml/min. Alternatively, mobile phase A was water at 0.01% NH3 and mobile phase B was acetonitrile. The gradient was from 10 to 100% B in 8 min, retained at 100% B for 2 min. The flow rate was 20 ml/min.
The 1H-NMR spectrum was recorded at a constant temperature of 28 °C, in a Varian INOVA 400 spectrometer operating at 400.50 MHz and equipped with a PEG indirect detection probe with a 5 mm axis (*H {15N-31P}) ) .
Chemical changes were referenced in relation to residual solvent signals (DMSO-c^: 2.50 ppm to 1H, if not otherwise specified). Data are reported as follows: chemical shift (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br. s = broad singlet, td - doublet triplet, dd = doublet doublet , ddd = double doublet of doublet, m = multiplet, spt = septet), coupling constants (J, Hz) and number of protons.
As previously reported (M. Colombo, FR Sirtori, V. Rizzo, Rapid Commun Mass Spectrom 2004, 18(4), 511-517), ESI(+) high resolution mass spectra (HRMS) were obtained on a spectrometer. Last mass Q-Tof (Waters
Manchester, UK), mass spectra directly connected to an Agilent 1100 micron HPLC system (Paio Alto, USA).
Preparation of N-(3-acetyl-2-fluorophenyl)-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide, cmpd. of formula 6 [n = 1; R4 = F; R5 = H; R6 = 2,5-difluorophenyl; RX'-methoxymethyl] (Preparation 1, Method A) N-(3-bromo-2-fluorophenyl)-2,5-difluorobenzenesulfonamide, cmpd. from the formula 3 [n — 1; R4 = F; R5=H; R6=2,5-difluorophenyl] Method A, step a 3-Bromo-2-fluoroaniline (10g, 52.63 mmol) was dissolved in DCM (100 mL) under nitrogen atmosphere. Dry pyridine was added (6ml, 73.68mmol), followed by 2,5-difluorobenzenesulfonyl chloride (7.08ml, 52.63mmol) and the mixture was stirred at rt. for 2 h. Then the mixture was diluted with DCM and washed with 0.5 N aqueous HCl (3 x 80 mL) and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The solid was taken up in diethyl ether and stirred for 30 min, then filtered and dried at 40°C under reduced pressure to yield 17.8 g of N-(3-bromo-2-fluoro-phenyl)-2.5 -difluorobenzenesulfonamide as a pale yellow solid (92%). HPLC: Rt: 6.28 min
NMR (401 MHz, DMSO-dβ) δ ppm 10.86 (s, 1H), 7.50-7.73 (m, 4H), 7.23-7.31 (m, 1H), 7. 12 (dt, J = 1.3, 8.1 Hz, 1H) N-(3-bromo-2-fluorophenyl)-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide, cmpd. of formula 4 [n=1; R4=F; R5=H; R6=2,5-difluorophenyl; RX’ = methoxymethyl] Method A, step b
To a solution of N-(3-bromo-2-fluoro-phenyl)-2,5-difluoro-benzenesulfonamide (17.8 g, 48.61 mmol) in anhydrous DCM (160 mL) at 0°C, DIPEA (12.5 mL, 73 mmol) was added, followed by methoxymethyl chloride (5.7 mL, 73 mmol). The reaction mixture was stirred at 0°C for 10 min and then allowed to warm to room temperature. After 2 h a saturated ammonium chloride solution was added and the mixture was stirred at rt. for 10 min. It was then diluted with DCM and washed with water and brine, dried over Na2SO4 and evaporated to dryness. The residue was treated with Hex and stirred for 30 min. The solid was filtered and dried to yield 18.52 g (93%) of the title compound as a white powder. HPLC: Rt: 6.88 min rH NMR (401 MHz, DMSO-d6) δ ppm 7.78 (ddd, J = 1.7, 6.4, 8.1 Hz, 1H), 7.67- 7.73 (m, 1H), 7.61 (dt, J = 4.3, 9.6, 1H), 7.49-7.55 (m, 1H), 7.28-7.34 (m, 1H), 7.17-7.23 (m, 1H), 5.06 (s, 2H), 3.35 (s, 3H)
HRMS (ESI) calcd for C11HuBrFaNOgSNa [M+Na] + 431.9487, found 431.9487, N-(3-acetyl-2-fluorophenyl)-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide, cmpd. of formula 6 [n = 1; R4 = F; R5 = H; R6 = 2,5-difluorophenyl; RX' = methoxymethyl] Method A, step c
To a solution of 6.15 g (15 mmol) of N-(3-bromo-2-fluorophenyl)-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide in 35 mL of ethylene glycol in a flask equipped with a rubber septum, through which nitrogen passes through a needle, 37.5 mg (0.15 mmol) palladium acetate, 129 mg (0.30 mmol) DPPP, 5.4 mL (37.5 mmol) TEA and 5.9 mL (45 mmol) of n-butylvinylether were added consecutively. The mixture was heated to 120°C, stirring for 6 h and then diluted with DCM and washed with brine. The organic layer was dried over Na 2 SO 4 and evaporated, giving N-[3-(1-butoxyethenyl)-2-fluorophenyl]-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide as a brown oil. The latter, without any further purification, was dissolved in 65 ml of 1,4-dioxane and 11 ml of 1N HCl were added to the resulting solution. After 1 h under stirring at RT, the reaction was completed. The solvent was then removed, the residue re-dissolved with DCM and washed with aqueous NaHCO 3 . The organic layer was dried over anhydrous Na2SO4 and evaporated. After trituration with diethyl ether 4.82 g (86%) of the title compound were collected by filtration. HPLC: Rt: 6.28 min
NMR (401 MHz, DMSO-d6) δ ppm 7.81-7.89 (m, H 1), 7.47-7.73 (m, 5 H), 7.36 (t, J = 7.8 Hz, 1H), 5.05 - 5.10 (m, 2H), 3.35-3.38 (m, 3H), 2.48-2.49 (m, 3H) HRMS (ESI ) calculated for C16Hi4F3NO4SNA [M+Na]+ 396.0488, found 396.0488.
Preparation of 3-{[(2,5-Difluorophenyl)sulfonyl](methoxymethyl)amino)-2-fluoro-N-methoxy-N-methylbenzamide, cmpd. of formula 29 [n=1; R4=F; R5=H; RX = methoxymethyl; R6=2,5-difluorophenyl; J= NMe(OMe)] (Preparation 2, Method D) 3-{[(2,5-Difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorobenzoic acid N-(3-bromo-2-fluorophenyl)-2 ,5-difluoro-N-(methoxymethyl)benzenesulfonamide (prepared as described in Preparation 1, 10.92 g, 26.62 mmol) was dissolved in anhydrous THF (53 mL) and cooled to 0°C. A solution of isopropylmagnesium chloride (2N in THF) (13.3 mL, 26.62 mmol, 1 eq) was added dropwise. At the end of the addition the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The yellow solution was cooled, then cooled again to 0°C and gaseous carbonic anhydride (generated from solid carbonic anhydride and dried by concentrated sulfuric acid) bubbled through the solution for 20 min. A 0.5N HCl solution (50ml) was then added and the mixture was extracted with diisopropyl ether (3x130ml). The desired product was then extracted from the organic phase with a 1N sodium hydroxide solution (3 x 100ml). Under vigorous stirring 2N HCl (150 ml) was then added. The precipitate was collected by filtration, washed with water and Hex and dried in the oven, giving 9.07 g (91%) of the title compound as a white solid. HPLC: Rt: 3.67 min
ÃH NMR (600 MHz, DMSO-d6) δ ppm 7.88 (t, J = 6.7 Hz, 1H), 7.71-7.64 (m, 1H), 7.61 (dt, J = 4.1, 9.4 Hz, 1H), 7.53-7.44 (m, 2H), 7.32 (t, J = 7.2 Hz, 1H), 5.06 (s , 2H). HRMS (ESI) calculated for C15H12NO5F3SNa [M+Na]+ 398.0280, found 398.0280. 3-{[(2,5-Difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluoro-N-methoxy-N-methylbenzamide, cmpd. of formula 29 [n=1; R4=F; R5=H; RX=methoxymethyl; R6=2,5-difluorophenyl; J= NMe (OMe) ] 3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorobenzoic acid (8.86 g, 23.61 mmol) was dissolved in DCM (73 mL) under nitrogen atmosphere. Dry DMF (14 mL) was added, followed by N-methoxy-N-methyl amine hydrochloride (3.72 g, 38.13 mmol, 1.6 eq), N-methylmorpholine (4.1 mL, 37.3 mmol, 1.6 eq) and DMAP (293 mg, 2.4 mmol, 0.1 eq). The reaction mixture was then cooled to 0°C and EDC hydrochloride (5.38 g, 28.06 mmol, eq 1.2) was added in portions. The mixture was allowed to warm to room temperature and stirred for 4 h. This was then cooled to 0°C and a cold 1N HCl solution (100 mL) was added. The mixture was extracted with diisopropyl ether and the organic phase was washed with saturated aqueous NaHCOa and brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by silica gel flash chromatography (98:2 DCM/MeOH) to yield 8.97 g (91%) of the title compound as a colorless amorphous solid. HPLC: Rt: min 5.25 NMR (600 MHz, DMSO-dg) δ ppm 7.70-7.64 (m, 1H), 7.61 (dt, J = 3.9, 9.4 Hz, 1H), 7.54-7.44(m, 2H), 7.42(t,J=7.2Hz, 1H), 7.31(t,J=7.9Hz, 1H) ), 5.07 (s, 2H) 3.36 (s, 3H), 3.29 (s, 3H), 3.21 (br.s., 1H). HRMS (ESI) calculated for C17H18N2θ5F3S [M+H]+ 419.0883, found 419.0893.
Preparation of tert-butyl-4-carbamothioylpiperidine-1-carboxylate, cmpd. of formula 8 [R1 = 1-tert-butoxycarbonyl-piperidin-4-yl] (Preparation 3, methods A, D and E) Tert-butyl-4-carbamoylpiperidine-1-carboxylate For a solution of piperidine-4-carboxamides ( 2 g, 15.6 mmol), in acetonitrile (30 mL), tert-butyldicarbonate (4.4 g, 10 20.2 mmol, 1.3 eq) and DMAP (190 mg, 1.56 mmol, 0.1 eq) were added and the mixture was stirred at rt. during the night. This was then concentrated under reduced pressure, along with DCM and washed with saturated aqueous NaHCO3, saturated aqueous NH4Cl, brine and water. The organic phase was dried over 15 Na2SO4 and evaporated to dryness. The residue was triturated with diethyl ether and the white solid was filtered and dried to yield 2.65 g (74%) of the title product.
HPLC: Rt: 4.23 min XH NMR (401 MHz, DMSO-d6) δ ppm 7.24 (br.s., 1H), 6.75 20 (br.s., 1H), 4.06 -3.73 (m, 2H), 2.71 (br.s., 2H), 2.23 (tt, J = 3.8, 11.5Hz, 1H), 1.66 (dd , J = 2.7, 13.2 Hz, 2H), 1.44-1.26 (m, 2H), 1.36 (s, 9H). Tert-butyl-4-carbamothioylpiperidine-1-carboxylate, cmpd. of the formula 8 [R1 = 1-tert-butoxycarbonyl-piperidin-4-yl]
For a solution of tert-butyl-4-carbamoylpiperidine-1-carboxylate (2.65 g, 11.62 mmol) in DME/DCM 2:1 mixture (78 mL), Lawesson's reagent (2.35 g, 5.81 mmol, 0.5 eq) was added and the mixture was stirred at rt. during the night. The solvent was removed and the residue was taken up with ethyl acetate and washed with saturated aqueous K 2 CO 3 . The organic layer was separated, dried over Na2SO4 and concentrated to dryness. The residue was triturated with diethyl ether and dried to yield 2.65 g (92%) of the title compound as a white solid. HPLC: Rt: 5.06 min
NMR (401 MHz, DMSO-d6) δ ppm 9.39 (br.s., 1H), 9.09 (br.s., 1H), 4.00 (d, J = 12.6 Hz, 2H), 2.77-2.61 (m, 3H), 1.71-1.51 (m, 4H), 1.39 (br.s., 9H) Preparation of benzyl-4- carbamothioylpiperidine-1-carboxylate, cmpd. of formula 8 [R1 = 1-benzyloxycarbonyl-piperidin-4-yl] (Preparation 4, methods A, D and E) Benzyl-4-carbamoylpiperidine-1-carboxylate
To a solution of piperidine-4-carboxamides (5g, 39 mmol) and benzylchloroformate (5.54 mL, 39 mmol) in a mixture of water (30 mL) and acetone (40 mL), 1N NaOH (39 mL, 39) mmol) was added dropwise, keeping the pH between 6 and 8. The mixture was stirred at rt. for 3 h; then, acetone was evaporated and the resulting precipitate filtered and dried at 70°C under reduced pressure, giving 7.75 g of benzyl-4-carbamoylpiperidine-1-carboxylate (76%). HPLC: Rt: 4.54 min TH NMR (600 MHz, DMSO-d6) δ ppm 7.41-7.29 (m, 5H), 7.25 (br.s., 1H), 6.76 (br.s., 1H), 5.07 (s, 2H), 4.06-3.81 (m, J = 13.2 Hz, 2H), 2.92-2.72 (m , 2H), 2.27 (tt, J=3.7, 11.5Hz, 1H), 1.75-1.64 (m, 2H), 1.40 (dq, J=4, 3, 12.4 Hz, 2H) HRMS (ESI) [M+H]+ calculated for C14H18O3N2 263.1390, found 263.1390.
Benzyl-4-carbamothioylpiperidine-1-carboxylate, cmpd. of formula 8 [R 1 = 1-benzyloxycarbonyl-piperidin-4-yl] Benzyl-4-carbamoylpiperidine-1-carboxylate (7.5 g, 38.6 mmol) was dissolved in THF (160 mL) and Lawesson's reagent ( 6.9 g, 17.1 mmol) was added. After 4 h the solvent was evaporated and the residue purified by flash chromatography on silica gel (DCM-MeOH 95/5) affording 1.8 g (23%) of the title compound, crystallized from MeOH.
HPLC: Rt: 5.28 min XH NMR (600 MHz, DMSO-d6) δ ppm 9.40 (br.s., 1H), 9.11 (br.s., 1H), 7.42- 7.24 (m, 5H), 5.07 (s, 2H), 4.07 (d, J= 13.2 Hz, 2H), 2.90-2.73 (m, 2H) , 2.69 (tt, J=3.8, 11.6 Hz, 1H), 1.70-1.64 (m, 2H), 1.64-1.55 (m, 2H) HRMS (ESI) [M+H]+ calcd for C14H18O2N2S 279, 1162, found 279.1163.
Preparation of 1-methylpiperidine-4-carbothioamide, cmpd. of formula 8 [R1 = 1-methyl-piperidin-4-yl] (Preparation 5, Methods A, D and E)
To a suspension of tert-butyl-4-carbamothioylpiperidine-1-carboxylate (prepared as described in preparation 3, 2.65 g, 10.86 mmol) in dry dioxane (40 mL) a 4 M solution of HCl in dioxane was added. (16 mL, 64 mmol, 5.9 eq) and the mixture was stirred at rt After 1 h, an addition of HCl (10 mL) was made and stirring was continued for a further 2 h. The solvent was evaporated to dryness and the residue taken up with toluene and evaporated to dryness twice.
The residue was dissolved in MeOH (64 mL) and aqueous formaldehyde (2 mL, 26.86 mmol, 2.5 eq) was added, followed by acetic acid (2.24 mL, 39.17 mmol, 3.6 eq) and sodium cyanoborohydride (2.08 g, 28.24 mmol, 2.6 eq) and the mixture was stirred at rt. for 2 h. The solvent was then concentrated under reduced pressure and the residue taken up in ethyl acetate, washed with saturated aqueous NaHCO3 and brine, dried over Na∑SO^ and evaporated to dryness to yield 2.2 g of the title compound as a white solid.
XH NMR (401 MHz, DMSO-d6) δ ppm 9.35 (br.s., 1H), 9.08 (br.s., 1H), 3.44-3.19 (m, 2H) ), 2.86 (br.s., 2H), 2.44 (t, J = 10.2 Hz, 1H), 2.21 (br.s., 3H), 1.82-1 .73 (m, 2H), 1.63 (d, J = 11.9 Hz, 2H) HRMS (ESI) calculated for C7H15N2S [M+H]+ 159.0951, found 159.0944.
Preparation of tetrahydro-2H-pyran-4-carbothioamide, cmpd. of formula 8 [R1 = tetrahydropyran-4-yl] (Preparation 6, Methods A, D and E) Tetrahydro-2H-pyran-4-carboxamide
A mixture of methyl tetrahydro-2H-pyran-4-carboxylate (7g, 48.6 mmol) and 30% aqueous ammonia (20 mL) was stirred in a closed flask at rt. for 18 h. Excess ammonia was removed under reduced pressure and the residue was crystallized from ethanol yielding 5.6 g (89%) of tetrahydro-2H-pyran-4-carboxamide.
XH NMR (401 MHz, DMSO-d6) δ ppm 7.21 (br.s., 1H), 6.73 (br.s., 1H), 3.90-3.80 (m, 2H) ), 3.30-3.23 (m, 2H), 2.36-2.24 (m, 1H), 1.66-1.47 (m, 4H)
Tetrahydro-2H-pyran-4-carbothioamide. of formula 8 [R1 = Tetrahydropyran-4-yl] Tetrahydro-2H-pyran-4-carboxamide (2 g, 15.5 mmol) was suspended in dry THF (20 mL) and Lawesson's reagent (3.13 g, 7 .75 mmol) was added. After refluxing for 4 h the mixture was poured into a saturated aqueous solution of NaHCO3 (200 mL) and then extracted with diethyl ether (4 x 100 mL). The organic layer was dried over Na2SO4 and evaporated to dryness, yielding 1.2 g (54%) of the title compound.
HPLC: Rt: min 2.79 XH NMR (401 MHz, DMSO-d6) δ ppm 9.37 (br.s., 1H), 9.08 (br.s., 1H), 3.87 ( dd, J = 4.0, 11.0Hz, 2H), 3.37-3.23 (m, 2H), 2.78m - 2.67 (m, 1H), 1.75 (dq , J=4.5, 12.5Hz, 2H), 1.63-1.52 (m, 2H) HRMS (ESI) calculated for CieHuNOS [M+H]+ 146.0634, found 146.0634 .
Preparation of 1-Cyclopropylpiperidine-4-carbothioamide, cmpd. of formula 8 [R 1 = 1-cyclopropyl-piperidin-4-yl] (Preparation 7, methods A, D and E) To a solution of piperidine-4-carboxamide (1 g, 7.8 mmol) in MeOH (80 mL) 1-ethoxy-1-trimethylsilyloxycyclopropane (2.35 mL, 11.7 mmol, 1.5 eq) was added, followed by acetic acid (1.34 mL, 23.4 mmol, 3 eq) and sodium cyanoborohydride (923 mg, 12.48 mmol, 1.6 eq) and the mixture was stirred at 60°C overnight. The solvent was then concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (DCM/MeOH/7N NH3 in 90:9:1 MeOH) affording 1.6 g of 1-cyclopropylpiperidine-4-carboxamide. 1-Cyclopropylpiperidine-4-carboxamide was suspended in dry THF (20 mL) and Lawesson's reagent (2.7 g, 6.67 mmol) was added. After refluxing for 6 h, the solvent was concentrated under reduced pressure. The residue was dissolved in an ethyl acetate/MeOH mixture and washed with saturated aqueous NaHCO 3 . The aqueous phase was extracted again with ethyl acetate and evaporated to dryness. The crude product was treated with ethanol and filtered. The solid white was dried under high vacuum providing 2.7 g of the title compound. TH NMR (600 MHz, DMSO-dg) δ ppm 9.32 (br.s., 1H), 9.04 (br.s., 1H), 2.95 (br.s., 2H) , 2.54-2.43 (m, 1H), 2.20-2.04 (m, 2H), 1.75-1.38 (m, 5H), 0.39 (br.s. ., 2H), 0.27 (br.s., 2H) HRMS (ESI) calcd for C9H17N2S [M+H]+ 185.1107, found 185.1104.
Preparation of tert-butyl-methylcarbamate, cmpd. of formula 45 [R17* = tert-butoxycarbonyl; R18=methyl] (Preparation 8, Method F) 2M methylamine in THF (15ml, 33mmol) and TEA (4.35ml) were added to dry DCM (25ml), cooled to -20°C, with stirring . A solution of tert-butyl-dicarbonate (7.2 g, 33 mmol) in DCM (25 mL) was dropped into the reaction mixture, keeping the temperature between -20 and -10°C. The temperature then rose to room temperature overnight. The mixture was then washed with brine and the organic layer dried over Na 2 SO 4 and evaporated to dryness, giving 2.83 g (66%) of the title compound as a colorless oil. NMR (600 MHz, DMSO-dg) δppm 6.63 (br.s., 1H), 2.49 (br.s., 3H), 1.37 (s., 9H). Example 1
Synthesis of N-{2,4-difluoro-3-[2-(4-methylpiperazin-1-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]phenyl)-2 ,5 difluorobenzenesulfonamide, cmpd. of formula (I)A (cmpd. 8) [m, n=1; R2, R3, Rx=H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R1' = 4-methylpiperazin-1-yl]

N-[3-(2-bromo-acetyl)-2,4-difluoro-phenyl]-2,5-difluoro benzenesulfonamide, cmpd. of formula 7 [n=1; Rx=H; R4=F; R5=4-F; R6= 2,5-difluorophenyl] Method A, step d
N-(3-acetyl-2,4-difluoro-phenyl)-2,5-difluoro-benzenesulfonamide (7.6 g, 21.88 mmol) prepared as described in WO2010/10154, was dissolved in acetic acid (30 mL) ). Then a solution of 1.12 ml (26.25 mmol) of bromine in 2 ml of acetic acid was added in three portions. 48% aqueous hydrogen bromide (0.248 ml, 2.19 mmol) dissolved in 1 ml acetic acid was then added and the mixture was stirred at rt. by 21 h. 5% aqueous NaHCO3 was added dropwise (50 mL) and the mixture was extracted with methyl tert-butyl ether (2 x 30 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness. The crude was recrystallized from a mixture of ethyl acetate/toluene/cyclohexane giving 5.79 g (61%) of the title compound as a light brown solid. HPLC: Rt: 6.10 min 1H-NMR (401 MHz, DMSO-d6) δ ppm 10.75 (br.s., 1H), 7.68-7.39 (m, 4H), 7. 29-7.17 (m, 1H), 4.34 (s, 2H).
N-{2,4-Difluoro-3-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-phenyl}-2,5-difluoro-benzenesulfonamide, cmpd. of formula 9 [n=1; Rx=H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R 1 = 4-methylpiperazin-1-yl] Method A, step e 50 mg (0.31 mmol) of 4-methylpiperazine-1-carbothioamide (prepared as described in Heterocyclics, 1989, 29, 1601) was dissolved in 15 mL of ethanol and 134 mg (0.31 mmol) of the N-[3-(bromoacetyl)-2,4-difluorophenyl]-2,5-difluorobenzenesulfonamide were added to the resulting solution. The mixture was stirred at 60°C for 20 min in a microwave oven. The solvent was evaporated, then the residue was triturated with diisopropyl ether, giving 140 mg (97%) of the title compound. HPLC: Rt: 5.51 min
XH NMR (401 MHz, DMSO-d6) δ ppm 10.50 (s, 1H), 7.60-7.66 (m, 1H), 7.53-7.60 (m, 1H), 7 .46-7.53 (m, 1H), 7.27 (td, J = 5.7, 8.7 Hz, 1H), 7.15 (td, J = 1.5, 9.2 Hz , 1H), 7.11 (s, 1H), 2.80 (br.s., 3H) HRMS (ESI) calcd for C20H19F4N4O2S2 [M+H]+ 487.0880, found 487.0857. The following intermediate was similarly obtained: N-[3-(2-amino-1,3-thiazol-4-yl)-2,4-difluorophenyl]-2,5-difluorobenzenesulfonamide, empd. of formula 9 [n=1; Rx=H; R1 = NH2; R4=F; R5=4-F; R6= 2,5-difluorophenyl] HPLC: Rt: 5.50 min
NMR (401 MHz, DMSO-d6) δppm 10.60 (s, 1H), (m, 3H), 7.46-7.65 7.24 (td, J = 5.7, 8.8 Hz) , 1H), 7.11 (td, J = 1.6, 9.3Hz, 1H), 7.07 (br.s., 2H), 6.69 (s, 7H) HRMS ( ESI) calculated for C15H10F4N3O2S2 [M+H]+ 404.0145, found 404.0142.
N-{3-[5-bromo-2-(4-methyl-piperazin-1-yl)-thiazol-4yl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide, empd. of formula 10 [n=1; Rx=H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R1 = 4-methylpiperazin-1-yl; Hal=Br] Method A, step f 150 mg (0.31 mmol) of N-2,4-difluoro-3-[2-(4-methylpiperazin-1-yl)-thiazol-4-yl]-phenyl} -2,5-difluorobenzenesulfonamide was suspended in 15 mL of dry DCM and 103 mg (0.62 mmol) of N-bromosuccinimide was added. The reaction was kept at room temperature for 1h and then diluted with the same solvent and washed with aqueous NaHCO3 . The organic layer was dried over Na2SO4 and evaporated. The residue was triturated with petroleum ether and filtered yielding 128 mg (73%) of N-{3-[5-bromo-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4-yl] -2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide. HPLC: Rt: 6.33 min HRMS (ESI) calculated for C20Hi8BrF4N402S2 [M+H]+ 564, 9985, found 564.9982.
The following intermediate was similarly obtained: N-[3-(2-amino-5-bromo-1,3-thiazol-4-yl)-2,4-difluorophenyl]-2,5-difluorobenzenesulfonamide cmpd. of formula 10 [n=1; Rx=H; R1 = NH2; R4=F; R5=4-F; R6=2,5-difluorophenyl; Hal = Br] HPLC: Rt:5.91 min
XH NMR (401 MHz, DMSO-d6) δ ppm 10.67 (s, 1H), (m, 3H), 7.43-7.65 7.36-7.42 (m, 1H), 7 .35 (br.s., 2H), 7.17 (td, J =1.5, 8.9 Hz, 1H). HRMS (ESI) calculated for C15H9BrF4N302S2 [M+H]+ 481, 9250, found 481.9232.
N-{2,4-difluoro-3-[2-(4-methylpiperazin-1-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]phenyl}-2.5 -difluorobenzenesulfonamide, cmpd. of formula (I) A (cmpd. 8) [m, n=1; R2, R3, Rx=H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R1'= 4-methylpiperazin-1-yl] Method A, step h 100 mg (0.18 mmol) of N-{3-[5-Bromo-2-(4-methyl piperazin-1-yl)-thiazol- 4-yl]-2,4-difluoro-phenyl}-2,5-difluorobenzenesulfonamide were dissolved in 9 ml of DME and 1 ml of water. 170 mg (0.54 mmol) of CS2CO3, 116 mg (0.35 mmol) of 4-pyridyl-boropinacolate and 42 mg (0.05 mmol) of
PdC12(dppf)2 CH2Cl2 were added to the mixture, which was subjected to microwave irradiation at 110°C for 1 h. The crude was filtered through a celite pad and the filtrate evaporated. The residue was taken up with DCM and washed with 15% NH4OH. The organic layer was dried over Na2SO4 and evaporated. The product was finally purified by flash chromatography on a pre-coated silica gel column, eluting with DCM-MeOH 95/5, affording 30 mg (30%) of the title compound. HPLC: Rt: 5.44 min NMR (401 MHz, DMSO-d6) δ ppm 8.38-8.44 (m, 2H), 7.53-7.62 (m, 1H), 7.38 -7.52 (m, 3H), 7.19 (td, J = 1.4, 8.8Hz, 1H), 6.79-6.96 (m, 2H), 3.64 ( br.s., 4H), 3.15 (br.s., 4H), 2.73 (br.s., 3H) HRMS (ESI) calcd for C25H2iF4N5O2S2 [M+H]+ 523.0516 , found 523.0508.
Analogously, the following compounds were obtained: N-{2,4-difluoro-3-[2-(methylamino)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]phenyl}-2 ,5-difluorobenzenesulfonamide empd. of formula (I)A (empd. 2) [m, n=1; R2, R3, Rx=H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R1'=methylamino]

HPLC: Rt: 5.55 min NMR (401 MHz, DMSO-d6) δ ppm 10.67 (br.s., 1H), (m, 2H), 8.29-8.44 8.14 ( q, J = 4.8 Hz, 1H), 7.52-7.61 (m, 1H), 7.38-7.52 (m, 3H), 7.19 (td, J = 1 .5.5, 8.8Hz, 1H), 6.83-6.91 (m, 2H), 2.85 (d, J = 4.8Hz, 3H) HRMS (ESI) calculated for C2iHi4F4N4θ2S2 [ M+H]+ 495.0567, found 495.0548.
N-{3-[2-amino-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide empd. of the formula (IJU1 (empd. 1) [m, n= 1; R2, R3, Rx=H; R4=F; R5=4-F; R6=2,5-difluorophenyl]

HPLC: Rt: 5.15 min NMR (401 MHz, DMSO-d5) δ ppm 10.67 (br.s., 1H), 8.33 (d, J = 5.7Hz, 2H), 7 .59-7.51 (m, 3H), 7.50-7.35 (m, 3H), 7.20-7.11 (m, 1H), 6.82 (d, J = 5 0.9 Hz, 2H) HRMS (ESI) calculated for C20H12F4N4O2S2 [M+H]+ 481.0411, found 481.0394. Example 2
Synthesis of N-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2,6-difluorophenyl)-5-(pyridin-4-yl)-1,3-thiazol-2-yl ] acetamide, cmpd. of the formula (I)M (cmpd. 33) [m, n=1; R2, R3 = H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R10 = methyl] Method B, steps g and b5
50 mg (0.104 mmol) of 27-{ 3-[2-amino-5-(pyridin-4-yl) - 1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide were dissolved in 5 ml of acetic anhydride and the solution was stirred at rt for 3 days. The mixture was poured into a saturated aqueous solution of NaHCO3 and extracted several times with DCM. The organic layer was dried over Na2SO4 and evaporated. The crude was dissolved in 5 mL of MeOH and 2 mL of TEA was added. The solution was stirred for 3 days at room temperature. The solvent was then removed, the residue taken up with DCM and washed with water. The organic layer was dried over Na 2 SO 4 and evaporated to yield 30 mg (58%) of the title compound, triturated with petroleum ether diisopropyl ether. HPLC: Rt: 5.23 min rH NMR (401 MHz, DMSO-d6) δ ppm 12.48 (s, 1H), 8.40-8.48 (πi, 2H), 7.30-7.62 (m, 4H), 7.12 (br.s., 1H), 7.02-7.07 (m, 2H), 2.19 (s, 3H) 5 HRMS (ESI) calcd for C22H14F4N4O3S2 [M+H]+ 523.0516, found 523.0497. Example 3
Synthesis of 2,5-difluoro-N-{2-fluoro-3-[2-(1-methylpiperidin-4-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl] phenylbenzenesulfonamide, cmpd. of the formula (I)R2 (cmpd.19) [m, n=1; R2, R3, R5=H; R4=F, R6=2,5-difluorophenyl; R" = methyl]

N-[3-(bromoacetyl)-2-fluorophenyl]-2,5-difluoro-N-15(methoxymethyl)benzenesulfonamide, cmpd. of formula 7 [n=1; R5=H; R4=F; R6=2,5-difluorophenyl; Rx = methoxymethyl] Method A, step dl
Condition 1 100mg (0.27mmol) of N-(3-acetyl-2-fluorophenyl)-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide was dissolved in mL of dry THF and 100mg (0.3mmol) ) of pyridinium bromide-perbromide were added. The resulting solution was heated in a microwave apparatus at 80°C for 15 min. The solvent was then evaporated, the residue taken up with DCM and washed with 0.5 N HCl. The organic layer was then dried over Na2SO4 and evaporated to yield the title compound as an oil.
Condition 2 100 mg (0.27 mmol) of N-(3-acetyl-2-fluorophenyl)-2,5-difluoro-W-(methoxymethyl)benzenesulfonamide was dissolved in 4 ml of dry DCM under nitrogen atmosphere. The solution was cooled to 0°C and 94 µL (0.65 mmol) of TEA and 106 µL (0.54 mmol) of trimethylsilyl trifluoromethane sulfonate were added. The solution was stirred for 15 minutes at the same temperature and then diluted with DCM and washed quickly with brine. The organic layer was dried over Na2SO4 and evaporated, yielding 2,5-difluoro-N-(2-fluor-3-{1-[(trimethylsilyl)oxy]ethenyl}phenyl)-N-(methoxymethyl)benzenesulfonamide as a clear oil. . The latter was re-dissolved in 4 ml of dry DCM under nitrogen atmosphere and 58 mg (0.32 mmol) of N-bromosuccinimide was added at 0°C. After 30 min, the reaction was completed. The mixture was diluted with DCM and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated to yield the title compound, which was used without further purification.
HPLC: Rt: 6.77 min. HPLC/MS (ESI): 469-471 [M+NH4]+ N-[3-(2-amino-1,3-thiazol-4-yl)-2-fluorophenyl]-2,5-difluoro-N- (methoxymethyl)benzenesulfonamide, empd. of formula 9 [n=1; R1 = NH2; R4=F; R5=H; R6=2,5-difluorophenyl; Rx=methoxymethyl] Method A, step and 21 mg (0.27 mmol) of thiourea were added to a solution of 122 mg (0.27 mmol) of N-[3-(bromoacetyl)-2-fluorophenyl]-2. 5-difluoro-N-(methoxymethyl)benzenesulfonamide in 5 mL of ethanol. The mixture was heated at 60°C for 20 min in a microwave oven. The solvent was then removed, the residue was taken up in DCM and washed with water. The organic layer was separated, dried over Na2SO4 and evaporated. The crude was purified by flash chromatography eluting with DCM-CH 3 OH 95/5, giving 92 mg (80%) of the title compound. HPLC: Rt: 6.26 min.
NMR (401 MHz, DMSO-d6) δppm 7.97 (td, J = 1.8, 7.5Hz, 1H), 7.57-7.76 (m, 2H), 7.40- 7.54 (m, 1H), 7.21-7.30 (m, 1H), 7.13-7.19 (m, 1H), 7.11 (s, 2H), 6 .82 (d, J = 2.6 Hz, 1H), 5.09 (s, 2H), 3.37 (s, 3H). HRMS (ESI) calculated for C17H15F3N3O3S2 [M+H]+ 430.0505, found 430.0493.
N-[3-(2-amino-5-bromo-1,3-thiazol-4-yl)-2-fluorophenyl]-2,5-difluoro-N-(methoxymethyl]benzenesulfonamide, cmpd. of formula 10 [n=1 ; R1 = NH2; R4 = F; R5 = H; R6 = 2,5-difluorophenyl; Rx = methoxymethyl; Hal = Br] Method A, step f 1.26 g (2.94 mmol) of N-[3- (2-amino-1,3-thiazol-4-yl)-2-25-fluorophenyl]-2,5-difluoro-N-(methoxymethyl)-benzenesulfonamide were dissolved in 30 ml of dry DCM and 523 mg (2.94 mmol) of N-bromosuccinimide were added. The resulting solution was stirred at rt for 30 min. The mixture was diluted with the same solvent and washed with aqueous NaHCCb. The organic layer was dried over Na2SO4 and evaporated. The residue was triturated with ether diisopropyl and filtered to yield 1.4 g (93%) of the title compound HPLC: Rt: 6.52 min.
NMR (401 MHz, DMSO-d6) δppm 7.57-7.71 (m, 2H), 7.44-7.55 (m, 2H), 7.31-7.42 (m, 2H) H), 7.24-7.32 (m, 1H), 4.96-5.21 (m, 2H), 3.36-3.39 (m, 3H). N-[3-(5-bromo-2-{[(E)-dimethylamino)methylidene]amino}-1,3-thiazol-4-yl)-2-fluorophenyl]-2,5-difluoro-N- (methoxymethyl)benzenesulfonamide), cmpd. of formula 11 [n=1; R4=F; R5=H; R6=2,5-difluorophenyl; Rx=methoxymethyl; PG'=dimethylaminomethylene; Hal = Br] Method A, step g 1.4 g (2.75 mmol) of N-[3-(2-amino-5-bromo-1,3-thiazol-4-yl)-2-fluorophenyl]- 2,5-difluoro-N-(methoxymethyl)benzenesulfonamide was dissolved in 30 mL of dry DMF and 448 µL (2.75 mmol) of dimethylformamide dimethylacetal was added to the mixture. The reaction was stirred at rt. overnight, and then the solvent was removed under reduced pressure. The residue was taken up with DCM and washed with brine. The organic layer was then dried over Na2SO4 and evaporated. The crude was finally purified by flash chromatography eluting with cyclohexane ethanol 9/1, affording 0.8 g (52%) of the title compound.
HPLC: Rt: min 7.18, NMR (401 MHz, DMSO-d6) δ ppm 8.25 (s, 1H), 7.72-7.57 (m, 2H), 7.57-7.52 (m, 1H), 7.52-7.45 (m, 1H), 7.45-7.37 (m, 1H), 7.34-7.28 (m, 1H), 5.09 (s, 2H), 3.38 (s, 3H), 3.11 (s, 3H), 2.97 (s, 3H). HRMS (ESI) calculated for C2oHi9BrF3N4O3S2 [M+H]+ 563.0029, found 563.0049. Working in an analogous way, but from derivatives of the suitable aminothiazole, the following compounds were obtained:
N-[3-(5-bromo-2-{[(E)-(dimethylamino)methylidene]amino} 1,3-thiazol-4-yl)-2,4-difluorophenyl-2,5-difluoro-N- (methoxymethyl)benzenesulfonamide, empd. of formula 11 [n=1; 15 R4=F; R5=4-F; R6=2,5-difluorophenyl; Rx=methoxymethyl; PG' = dimethylaminomethylene; Hal=Br] HPLC: Rt: 7.00 min.
TH NMR (401 MHz, DMSO-d6) δ ppm 8.25 (s, 1H), 7.57-7.71 (m, 2H), 7.45-7.56 (m, 2H), 7 .25-7.34 (m, 1H), 5.07 (s, 2 20H), 3.37 (s, 3H), 3.11 (s, 3H), 2.97, (s , 3H). HRMS (ESI) calculated for C2oHi8BrF4N403S2 [M+H]+ 580, 9935, found 580.9921.
N-[3-(5-bromo-2-{[(E)-dimethylamino)methylidene]amino}-1,3-thiazol-4-yl)-2,4-difluorophenyl]-2,5-difluorobenzenesulfo-25 namida, empd. of formula 11 [n=1; R4=F; R5=4-F; R6=2,5-difluorophenyl; Rx=H; PG'=dimethylaminomethylene; Hal = Br] HPLC: Rt: 6.47 min.
∑H NMR (401MHz, DMSO-d6) δppm 10.70 (s, 1H), 8.24 (s, 1H), 7.65-7.59 (m, 1H), 7.59-7 .52 (m, 1H), 7.51-7.46 (m, 1H), 7.42 (dt, J = 5.9, 8.9 Hz, 1H), 7.24-7, 17 (m, 1H), 3.11 (s, 3H), 2.97 (s, 3H) HRMS (ESI) calculated for C18H14BrF4N4θ2S2 [M+H]+ 536, 9672, found 536.9646.
N-{3-[2-{[(E)-(dimethylamino)methylidene]amino}-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl)- 2,5-difluoro-N-(methoxymethyl)benzenesulfonamide, cmpd. of formula 13 [m, n=1; R2, R3, R5=H; R4=F; R6=2,5-difluorophenyl; Rx=methoxymethyl; PG' = dimethylaminomethylene] Method A, step hi For 342 mg (0.61 mmol) of a solution of N-[3-(5-bromo-2-{[(E)-(dimethylamino)methylidene]amino}-1 ,3-thiazol-4-yl)-2-fluorophenyl]-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide in a mixture of 12 mL of DME and 2 mL of water, 596 mg (1.83 mmol ) of Cs2CO3, 160 mg (0.2 mmol) of PdCl2(dppf)2 CH2Cl2 and 244 mg (1.22 mmol) of 4-pyridyl-boropinacolate were consecutively added. The mixture was heated in a microwave oven at 110°C for 1 h and then filtered through a pad of celite. The filtrate was evaporated under reduced pressure, the crude taken up with DCM and washed with brine. The organic layer was separated, dried over Na2SO4 and the solvent removed. The product was purified by flash chromatography eluted by DCM-MeOH 98/2 giving 240 mg (70%) of the title compound. HPLC: Rt: 6.30 min.
XH NMR (401 MHz, DMSO-d6) δ ppm 8.39 (s, 1H), 8.40-8.37 (m, 2H), 7.68-7.59 (m, 1H), 7 .59-7.52 (m, 2H), 7.50-7.45 (m, 1H), 7.38-7.25 (m, 2H), 7.03-6.90 (m) , 2H), 4.98 (s, 25H), 3.27 (s, 3H), 3.14, (s, 3H), 3.01 (s, 3H). HRMS (ESI) calculated for C25H23F3N5O3S2 [M+H]+ 562.1189, found 562.1183.
Working analogously, but starting from the appropriate bromothiazole derivative, the following compound was obtained: 10 N-{3-[2-{[(E)-(dimethylamino)methylidene]amino)-5-(pyridin-4- yl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide, cmpd. of formula 13 [m, n=1; R2, R3, =H; R4=F; R5=4-F; R6=2,5-difluorophenyl; Rx=methoxymethyl; PG'=dimethylaminomethylene] 15 HPLC: Rt: 6.20 min.
XH NMR (401 MHz, DMSO-d6) δ ppm 8.40-8.44 (m, 2H), 8.38 (s, 1H), 7.58-7.68 (m, 1H), 7 .42-7.58 (m, 4H), 7.22-7.30 (m, 1H), 6.93-6.99 (m, 2H), 5.01-5.04 (m) , 2H), 5.03 (s, 2H), 3.14, (s, 3H), 3.01 (s, 3H). 20 HRMS (ESI) calcd for C25H22F4N5O3S2 [M+H]+ 580.1095, found 580.1072.
N-{3-[2-amino-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide, cmpd . of the formula (I)U1 [m, n=1; R2, R3, R5=H; R4=F; R6 25 difluorophenyl; Rx=methoxymethyl] Method A, step i
(dimethylamino)methylidene]amino}-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2,4-fluorophenyl}-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide were suspended in 15 mL of ethanol and 460 µL (6.86 mmol) of ethylenediamine were added. The mixture was refluxed giving a clear solution. After 8 h the solvent was removed under reduced pressure and the residue was re-dissolved in DCM and washed with brine. The organic phase was dried over Na2SO4 and the solvent evaporated. The crude was triturated with diethyl ether, yielding, after filtration, 450 mg (90%) of the title compound. HPLC: Rt: 5.68 min.
NMR (401 MHz, DMSO-d6) δppm 8.15-8.35 (m, 2H), 7.58-7.66 (m, 1H), 7.42-7.57 (m, 5 H), 7.24-7.36 (m, 2H), 6.84-6.91 (m, 2H), 4.99 (s, 2H), 3.27 (s, 3H) . HRMS (ESI) calcd for Ca∑H^NqOaSa [M+H]+ 507.0767, found 507.0769.
Working analogously, but starting from the appropriate imino derivative, the following compound was obtained: N-{3-[2-amino-5-(pyridin-4-yl)-1,3-thiazol-4-yl]- 2,4-difluorophenyl}-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide cmpd. of the formula (I)U1 [m, n=1; R2, R3, =H; R4=F; R5=4-F; R6=2,5-difluorophenyl; Rx=methoxymethyl]
HPLC: Rt: 5.62 min.
NMR (401 MHz, DMSO-dg) δ ppm 8.34-8.38 (m, 2H), 7.59-7.67 (m, 2H), 7.49-7.59 (m, 5 H), 7.41-7.49 (m, 1H), 7.20-7.27 (m, 1H), 6.85-6.90 (m, 2H), 5.02 (s , 2H) HRMS (ESI) calcd for C22H17F4N4O3S2 [M+H]+ 525.0673, found 525.0659.
N-{3-[2-bromo-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide , cmpd. of the formula (I)F [m, n=1; R2, R3, R5=H; R4=F; R6=2,5-difluorophenyl; Rx=methoxymethyl; Hal = Br] Method B, step c
450 mg (0.89 mmol) of N-{3-[2-amino-5-(pyridin-4-yl)-1,3-thiazol-4-yl)-2-fluorophenyl}-2,5-difluoro -N-(methoxymethyl)benzenesulfonamide was suspended in 45 mL of dry acetonitrile and 298 mg (1.34 mmol) of CuBr2 and 2 mL (16.8 mmol) of tert-butyl nitrite were added. The mixture was stirred at 85°C for 8 h. After this time the reaction was filtered through a pad of celite and the filtrate evaporated. The residue was taken up with DCM and washed with aqueous NaHCO 3 . The organic layer was separated, over Na2SO4, dried and evaporated. The crude was purified by flash chromatography, eluting with DCM-MeOH 98/2, affording 350 mg (69%) of the title compound. HPLC: Rt: 7.14 min.
NMR (401 MHz, DMSO-d6) δ ppm 8.52 (d, J = 5.2 Hz, 2H), 7.57-7.70 (m, 2H), 7.42-7.57 ( m, 2H), 7.25-7.42 (m, 2H), 7.14 (d, J=6.0 Hz, 2H), 4.97 (s, 2H), 3.23 (s, 3H) HRMS (ESI) calcd for C22Hi6BrF3N3O3S2 [M+H]+ 569.9763, found 569.9789. Working analogously, but starting from the corresponding aminothiazole derivative, the following compound was obtained: N-{3-[2-bromo-5-(pyridin-4-yl)-1,3-thiazol-4-yl] -2,4-difluorophenyl} -2,5-difluoro-N-(methoxymethyl)benzenesulfonamide, cmpd. of the formula (I)F [m, n=1; R2, R3, =H; R4=F; R5=4-F; R6=2,5-difluorophenyl; Rx=methoxymethyl; Hal = Br]
HPLC: Rt: 6.95 min.
TH NMR (401 MHz, DMSO-d6) δ ppm 8.53-8.59 (m, 2H), (m, 1H), 7.60-7, 68 7.45-7.59 (m, 3H), 7.26-7.34 (m, 1H), 7.12-7.18 (m, 2H), 5.01 (s, 2H), 3.27 (s, 3H ) HRMS (ESI) calcd for C22Hi5BrF4N3O3S3 [M+H]+ 587.9669, found 587.9645. Tert-butyl-4-[4-(3-{[(2,5-difluorophenyl)sulfonyl] (methoxymethyl)amino}-2-fluorophenyl)-5-(pyridin-4-yl)-1,3-thiazol- 2-yl]-3,6-dihydropyridine-1(2H)-carboxylate, empd. of formula (I) HI [m, n=1; R2, R3, R5=H; R4=F; R6=2,5-difluorophenyl; Rx=methoxymethyl; X = NCOOt-Bu] Method C, step a
200 mg (0.35 mmol) of N-{3-[2-bromo-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluoro -N-(methoxymethyl)benzenesulfonamide were dissolved in a mixture of 7.8 mL of DME and 1.2 mL of water. 344 mg (1.05 mmol) of Cs2CO3, 216 mg (0.70 mmol) of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6 -dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester and 96 mg (0.12 mmol) of PdCl2(dppf)2 CH2C12 were added and the resulting mixture heated in a microwave oven at 100°C for an hour. The reaction was filtered through a pad of celite and the filtrate evaporated. The residue was taken up with DCM and then washed with brine. The organic layer was dried over Na2SO4 and evaporated. The crude was finally purified by flash chromatography, eluting with 4/1/0.5 cyclohexane-ethylacetate-ethanol, giving, after trituration with diethyl ether and filtration, 225 mg (85%) of the title compound. HPLC: Rt: 7.91 min.
NMR (401 MHz, DMSO-d6) δppm 8.28-8.65 (m, 2H), 7.49-7.73 (m, 4H), 7.46 (ddd, J = 3.2 , 5.1, 7.9 Hz, 1H), 7.24-7.40 (m, 2H), 7.03-7.19 (m, 2H), 4.97 (s, 2H) ), 3.96-4.08 (m, J = 12.8Hz, 2H), 3.21-3.24 (m, 3H), 2.92 (br.s. 2H), 2 .08 (dd, J = 3.4, 14.1 Hz, 2 H), 1.60 (qd, J = 4.3, 12.1 Hz, 2 H), 1.41 (s, 9 H) HRMS (ESI) calculated for C32H32F3N4O5S22 [M+H]+ 673, 1761, found 673.1771.
Working analogously, but using the appropriate boropinacolate derivative, the following compound was obtained: N-{3-[2-(3,6-dihydro-2H-pyran-4-yl)-5-(pyridin-4-yl )- 1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide, cmpd. of the formula (I)H1 [m, n=1; R2, R3, R5=H; R4=F; R6=2,5-difluorophenyl; Rx=methoxymethyl; X=O]
HPLC: Rt: 6.12 min.
XH NMR (401 MHz, DMSO-d6) δ ppm 8.49 (d, J = 6.1 Hz, 2H), 7.57-7.69 (m, 2H), 7.50-7.57 (m, 1H), 7.42-7.49 (m, 1H), 7.28-7.41 (m, 2H), 7.07-7.17 (m, 2H), 6 .79 (s, 1H), 4.98 (s, 2H), 4.29 (d, J = 2.8Hz, 2H), 3.79-3.87 (m, 2H), 3 .24 (s, 3H), 2.57 (br.s., 2H), 2.10-2.02 (m, 1H) HRMS (ESI) calculated for C27H23F3N3O4S2 [M+H]+ 574, 1077, found 574,1086. tert-butyl-4-[4-(3 — {[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino]-2-fluorophenyl)-5-(pyridin-4-yl)-1,3-thiazol- 2-yl]piperidine-1-carboxylate, cmpd. of the formula (I)Q [m, n=1; R2, R3, R5=H; R4=F; R6=2,5-difluorophenyl; Rx=methoxymethyl; X = NCOOt-Bu] Method C, step b
220 mg (0.33 mmol) of tert-butyl 4-[4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-5-(pyridin-4-yl ) -1,3-thiazol-2-yl] -3,6-dihydropyridine-1 (2/1) -carboxylate were suspended in 30 mL of MeOH and 880 mg (14 mmol) of ammonium formate and 50 mg of Pd -C 10% has been added. The reaction was stirred under reflux for 2 days. After this time, the mixture was filtered through a pad of celite and the filtrate evaporated. The crude was taken up with DCM and washed with brine. The organic layer was dried over Na2SO4 and evaporated. The crude then was triturated with petroleum ether-diethyl ether and collected by filtration, affording 200 mg (91%) of the title compound. HPLC: Rt: 7.72 min. XH NMR (401 MHz, DMSO-d6) δ ppm 8.28-8.65 (m, 2H), 7.49-7.73 (m, 4H), 7.46 (ddd, J=3, 2.5.1, 7.9 Hz, 1H), 7.24-7.40 (m, 2H), 7.03-7.19 (m, 2H), 4.97 (s, 2 H), 3.96-4.08 (m, J = 12.8Hz, 2H), 3.21-3.24 (m, 3H), 2.92 (br.s. 2H), 2.08 (dd, J = 3.4, 14.1 Hz, 2 H), 1.60 (qd, J = 4.3, 12.1 Hz, 2 H), 1.41 (s, 9 H) ) HRMS (ESI) calculated for C32H34F3N4O5S2 [M+H]+ 675.1917, found 675.1938.
By working analogously, the following compound was obtained from the appropriate unsaturated derivative: 2,5-difluoro-N-{2-fluoro-3-[5-(pxridin-4-yl)-1,3-thiazol-4 -yl]phenyl}-N-(methoxymethyl)benzenesulfonamide, cmpd. of the formula (I)Q [m, n=1; R2, R3, R5=H; R4=F; R6=2,5-difluorophenyl; Rx=methoxymethyl; X=O]
HPLC: Rt: 5.83 min.
XH NMR (401 MHz, DMSO-d6) δ ppm 8.46-8.50 (m, J = 4.9 Hz, 2H), 7.41-7.67 (m, 4H), 7.28 -7.38 (m, 2H), 7.07-7.17 (m, 3H), 4.97 (s, 2H), 3.91-3.99 (m, 1H), 3 1.44-3.52 (m, 1H), 1.98-2.06 (m, 2H), 1.70-1.84 (m, 2H) HRMS (ESI) calculated for C27H25F3N3O4S2 [M+ H]+ 576, 1233, found 576.1252. 2,5-difluoro-N-{2-fluoro-3-[2-(piperidin-4-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]phenyl}- N-(methoxymethyl)benzenesulfonamide, empd. of formula 47 [m, n=1; R2", R3, R5=H; R4=F; R6=2,5-difluorophenyl; Rx=methoxymethyl], corresponding to a compound of formula (I), in which m, n=1; R1=4-piperidinyl; R2, R3, R5=H; R4=F; R6=2,5-difluorophenyl; Rx=methoxymethyl. Method C, step d
200 mg (0.3 mmol) of tert-butyl-4-[4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-5-(pyridin-4- yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate were dissolved in 20 ml of dry DCM and 2 ml of TFA was added. After 3 h at rt the solvent was removed at 30°C. The residue was taken up in DCM, washed with 15% NH4OH and extracted several times with a mixture of DCM-MeOH 9/1. The organic layer was separated, dried over Na2SO4 and evaporated. The residue was triturated with diethyl ether, giving after filtration 155 mg (91%) of the title compound. HPLC: Rt: 4.82 min.
XH NMR (401 MHz, DMSO-d6) δppm 8.48 (d, J = 6.1Hz, 2H), 7.42-7.69 (m, 5H), 7.27-7.39 (m, 2H), 7.04-7.15 (m, 2H), 4.97 (s, 2H), 3.23 (s, 3H), 3.15 (tt, J = 3 0.6, 11.6 Hz, 1H), 2.96-3.08 (m, J = 8.9Hz, 2H), 2.60-2.69 (m, 2H), 1.97 -2.06 (m, J = 11.1 Hz, 2 H), 1.63 (qd, J = 3.8, 12.1 Hz, 2 H) HRMS (ESI) calculated for C27H26F3N4O3S2 [M+H] + 575.1393, found 575.1418. 2,5-difluoro-N-{2-fluoro-3-[2-(1-methylpiperidin-4-yl)-1,3-thiazol-4-yl]phenyl}-N-(methoxymethyl)benzenesulfonamide, cmpd. of formula 48 [m, n=1; R2" , R3 , R5 = H; R4 = F; R6 = 2,5-difluorophenyl; Rx = methoxymethyl; R" = methyl], corresponding to a compound of formula (I), in which m, n = 1; R1 = 1-methyl-4-piperidinyl; R2, R3, R5=H; R4=F; R6=2,5-difluorophenyl; Rx = methoxymethyl. Method C, step e
150 mg (0.26 mmol) of 2,5-difluoro-N-{2-fluoro-3-[2-(piperidin-4-yl)-5-(pyridin-4-yl)-1,3-thiazole -4-yl]phenyl}-N-(methoxymethyl)benzenesulfonamide were dissolved in 15 mL of MeOH and 45 µL (0.78 mmol) of glacial acetic acid, 26 mg (0.52 mmol) of NaBH3CN and 20 µL (0 .39 mmol) of 37% formaldehyde were added. The resulting solution was stirred at rt for two hours and then the solvent evaporated. The residue was taken up with DCM, washed with 15% NH4OH and extracted several times with a mixture of DCM-MeOH 9/1. The organic layer was dried over Na2SO4 and evaporated, giving 145 mg (94%) of the title compound. HPLC: Rt: 4.91 min ÃH NMR (401 MHz, DMSO-d6) δ ppm 8.48 (d, <J = 6.0 Hz, 2H), 7.41-7.71 (m, 5H) ), 7.27-7.39 (m, 2H), 6.97-7.18 (m, 2H), 4.97 (s, 2H), 3.23 (s, 3H), 3.01 (tt, J = 3.6, 11.5 Hz, 1 H), 2.73 2.91 (m, J = 11.5 Hz, 2 H), 2.20 (s, 3 H) , 2.12-1.90 (m, 4H), 1.60-1.87 (m, 2H) HRMS (ESI) calculated for C28H28F3N4O3S2 [M+H]+ 589.1549, found 589.1551. 2,5-difluoro-N-{2-fluoro-3-[2-(1-methylpiperidin-4-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]phenyl} benzenesulfonamide, cmpd. of the formula (I)R2 (cmpd.19) [m, n=1; R2, R3, R5=H; R4=F; R6=2,5-difluorophenyl; R"= methyl] Method C, step c2 A solution of 140 mg (0.24 mmol) of 2,5-difluoro-N-{2-fluoro-3-[2-(1-methylpiperidin-4-yl)- 5-(pyridin-4-yl)-1,3-thiazol-4-yl]phenyl}-N-(methoxymethyl)benzenesulfonamide in 9 mL of TEA and 1 mL of water was heated under stirring at 80°C for 1, 5 h Then the solvent was evaporated, and the residue was re-dissolved in DCM, washed with 15% NH4OH and extracted several times with a mixture of DCM-MeOH 9/1. The organic layer was dried over Na2SO4 and evaporated. The product was finally purified by preparative RP-HPLC eluting with 0.05% NH4OH-CH3CN 95/5, yielding, after trituration with diethyl ether-diisopropyl ether, 70 mg (54%) of the title compound. , DMSO-d6) δ ppm 8.46 (d, J = 5.9 Hz, 2H), 7.35-7.43 (m, 2H), 7.21-7.34 (m, 2H) ), 7.07-7.16 (m, 2H), 7.00 (t, J = 7.9Hz, 1H), 6.80-6.95 (m, 1H), 2.97 -3.17 (m, 4H), 2.42 (s, 4H), 2.10-2.21 (m, 2H), 1.68-1.96 (m, 2H) HRMS ( ESI) calculated for C26H23F3N4O2S2 [M+H]+ 545.1287, found 545,1298.
Working analogously, but starting from the suitable protected sulfonamide derivative, the following compound was obtained: 2,5-difluoro-N-{2-fluoro-3-[5-(pyridin-4-yl)-2-(tetrahydro -2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl]benzenesulfonamide, empd. of the formula (I)R (empd. 20) [m, n=1; R2, R3, R5=H; R4=F; R6= 2,5-difluorophenyl] Method C, step c

HPLC: Rt: 5.38 min rH NMR (401 MHz, DMSO-d6) δ ppm 10.66 (br.s., 1H), 8.46 (d, J = 6.0Hz, 2H), 7.51-7.61 (m, 1H), 7.27-7.49 (m, 4H), 7.17-7.26 (m, 1H), 7.07 (d, J = 6.1Hz, 2H), 3.94 (dt, J = 2.3, 9.4Hz, 2H), 3.47 (td, J = 1.9, 11.6Hz, 2H) , 1.94-2.05 (m, J = 1,912.8 Hz, 2H), 1.76 (qd, J = 4.2, 12.2 Hz, 2 HRMS (ESI) calculated for C25H20F3N3O3S2 [M+ H] 532.0971, found 532.0991. Example 4
N-{3-[2-bromo-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide, cmpd. of the formula (I)G [m, n=1; R2, R3, R5=H; R4=F; R6=2,5-difluorophenyl; Hal = Br] Method B, step bl

N-{3-[2-bromo-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide (prepared as described in example 3, 174 mg, 0.305 mmol) was dissolved in 6 mL of TEA. Water (0.5ml) was added and the mixture was stirred at 80°C for 6h. The solvent was concentrated under reduced pressure and the residue was taken up in DCM and washed with saturated aqueous NaHCOs and brine. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude product was treated with petroleum ether, filtered and dried under high vacuum affording 130 mg (80%) of the title compound as a white solid. HPLC: Rt: 5.81 min
XH NMR (401 MHz, DMSO-dg) δ ppm 10.71 (s, 1H), 8.53 (d, N = 4.8 Hz, 2H), 7.32-7.72 (m, 5H) ), 7.26 (q, J = 7.7 Hz, 1H), 7.11-7.19 (m, 2H) HRMS (ESI) calculated for C2oHnBrF3N3θ2S2 [M+H] + 525.9501, found 525.9508. Example 5
Synthesis of N-{3-[2-(4,4-difluoropiperidin-1-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2, 5-difluorobenzenesulfonamide, cmpd. of the formula (I)U (cmpd. 18) [m, n=1; R2, R3, R5, Rx=H; R4=F; R6=2,5-difluorophenyl; R7-R8 = - (CH2CH2)2CF2] Method B, step e
47 mg (0.09 mmol) of N-{3-[2-bromo-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide were dissolved in 3 ml of dimethylacetamide and 100 µl (1.39 mmol) of TEA and 100 mg (0.6 mmol) of 4,4-difluoropiperidine hydrochloride were added to the mixture.
The solution was heated in a microwave oven at 120°C for 3 h. After that time, the solvent was removed under reduced pressure, the residue was taken up with DCM and washed with aqueous NaHCCb. The organic phase was dried over Na2SO4 and evaporated. The crude was then purified by preparative RP-HPLC, eluting with 0.05% NH4OH-CH3CN 95/5, affording 30 mg (59%) of the title compound.
XH NMR (401 MHz, DMSO-d6) δppm 10.66 (br.s., 1H), 8.35 (d, J = 5.7Hz, 2H), 7.55 (br.s., 1H), , 1H), 7.39-7.49 (m, 2H), 7.32-7.37 (m, 1H), 7.10-7.30 (m, 2H), 6.73 -6.96 (m, 2H), 3.59-3.73 (m, 4H), 2.03-2.19 (m, 4H) HRMS (ESI) calculated for C25H19F5N4O2S2 [M+H] + 567.0943, found 567.0963.
Working in an analogous way, but using the appropriate commercial amino acid derivatives, the following compounds were obtained:
N-{3-[2-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl] -2-fluorophenyl}-2,5-difluorobenzenesulfonamide, cmpd. of the formula (I)U (cmpd. 17) [m, n=1; R2, R3, R5, Rx=H; R4=F; R6=2,5-difluorophenyl; R7- R8 = - (CH2CH2) 2C (OCH2CH2O)]
HPLC: Rt: 5.7 6 min
XH NMR (401 MHz, DMSO-d6) δppm 10.66 (br.s., 1H), 8.18-8.40 (m, 2H), 7.52-7.61 (m, 1 H), 7.40-7.48 (m, 2H), 7.36 (td, J = 1.8, 7.6Hz, 1H), 7.25-7.31 (m, 1H) ), 7.17-7.24 (m, 1H), 6.83-6.90 (m, 2H), 3.93 (s, 4h), 3.54-3.60 (m, 4h) H), 1.70-1.48 (m, 4H) HRMS (ESI) calculated for C27H23F3N4O4S2 [M+H]+ 589.1186, found 589.1193.
N-{3-[2-(diethylamino)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide, empd. of the formula (I)U (empd. 16) [m, n=1; R2, R3, R5, Rx=H; R4=F; R6=2,5-difluorophenyl; R7, R8 = ethyl]
HPLC: Rt: 6.17 min
NMR (401 MHz, DMSO-d6) δppm 10.66 (br.s., 1H), 8.31 (d, J = 6.1Hz, 2H), 7.51-7.59 (m , 1H), 7.40-7.48(m, 1H), 7.32-7.39 (m, J = 1.8Hz, 1H), 7.26-7.31 (m, 1H), 7.27 (d, J=5.6Hz, 1H), 7.16-7.25 (m, 1H), 6.82-6.87 (m, 2H), 3 .47 (qj = 7.0 Hz, 4h), 1.14-1.23 (m, 6H) HRMS (ESI) calculated for C24H21F3N4O2S2 [M+H]+ 519.1131, found 519.1134. Example 6
Synthesis of N-{3-[2-(cyclohexylamino)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide, empd. of the formula (I)V [m, n=1; R2, difluorophenyl}-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide (prepared as described in example 3.50 mg, 0.09 mmol) was dissolved in 3 mL of dimethylacetamide and 74 µL (0.85 mmol) ) of cyclohexylamine were added. The mixture was stirred at 110°C for 16 h. The solvent was evaporated under reduced pressure and the residue was taken up with DCM and washed with brine. The organic layer was dried over Na 2 SO 4 and evaporated, giving N-{3-[2-(cyclohexylamino)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2,4-difluorophenyl} -2,5-difluoro-N-(methoxymethyl)benzenesulfonamide. The latter, without any further purification, was treated with 4 ml of TEA and 1 ml of water and stirred at 75°C for 8 h. The solvent was then removed, and the residue taken up with DCM and washed with aqueous NaHCO 3 . The organic layer was dried over Na2SO4 and evaporated. The crude was purified by flash chromatography eluting with cyclohexane-ethanol 9/1, affording 20 mg (42%) of the title compound.
HPLC: Rt: 7.08 min
NMR (401 MHz, DMSO-de) δ ppm 10.67 (br.s., 1H), 8.33 (d, J=5.6Hz, 2H), 8.12 (d,J=7 0.6Hz, 1H), 7.54 (td, J = 4.1, 8.1Hz, 1H), 7.37-7.48 (m, 3H), 7.17 (t,J = 9.1 Hz, 1 H), 6.77-6.83 (m, 2 H), 3.40-3.52 (m, J = 7.8 Hz, 1 H), 1.8 4- 1.97 (m, J = 3.1, 9.6 Hz, 2H), 1.65-1.78 (m, J = 4.6Hz, 2H), 1.48-1.60 (m, J = 3.3 Hz, 1 H), 1.09-1.37 (m, J = 11.8 Hz, 6 H) HRMS (ESI) calculated for C26H22F4N4O2S2 [M+H]+ 563.1193 , found 563.1194.
Analogously, the following compounds were obtained: N-(2,4-difluoro-3-{2-[(2-methoxyethyl)amino]-5-(pyridin-4-yl)-1,3-thiazol-4-yl }phenyl)-2,5-difluorobenzenesulfonamide, cmpd. of the formula (I)V (cmpd. 5) [m, n=1; R2, R3, R7=H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R8=2-methoxyethyl]
HPLC: Rt: 6.01 min
NMR (401 MHz, DMSO-d6) δppm 10.67 (br.s., 1H), 8.34 (d, J = 5.9Hz, 2H), 8.18-8.28 (m , 1H), 7.51-7.61 (m, 1H), 7.36-7.51 (m, 3H), 7.17 (t, J = 8.7Hz, 1H), 6.82 (d, J = 6.1 Hz, 2H), 3.45-3.51 (m, 2H), 3.39-3.44 (m, 2H), 3.27 (s , 3H) HRMS (ESI) calcd for C23H18F4N4θ3S2 [M+H]+ 539.0829, found 539.0845.
N-(2,4-difluoro-3-{5-(pyridin-4-yl)-2-[(pyridin-3-ylmethyl)amino]-1,3-thiazol-4-yl}phenyl)-2, 5-difluorobenzenesulfonamide, cmpd. of the formula (I)V [m, n = 1; R2, R3, R7 = H; R4 = F; R5 = 4-F; R6 = 2,5-difluorophenyl; R8= 3-pyridylmethyl]
HPLC: Rt: 6.11 min
XH NMR (401 MHz, DMSO-d6) δ ppm 8.66 (t, J = 5.7 Hz, 1H), 8.57 (d, J = 1.6Hz, 1H), 8.50 ( d, J = 1.3Hz, 1H), 8.35 (d, J =6.1Hz, 2H), 7.70-7.85 (m, 1H), 7.50-7, 57 (m, J = 6.5 Hz, 1H), 7.32-7.48 (m, 4H), 7.16 (t, J = 9.9Hz, 1H), 6.79- 6.86 (m, 2H), 4.48-4.54 (m, 2H) HRMS (ESI) calcd for C26H17F4N5O2S2 [M+H]+ 572.0833, found 572.0829.
N-(2,4-difluoro-3-{2-[(2-methylpropyl)amino]-5-(pyridin-4-yl)-1,3-thiazol-4-yl)phenyl)-2,5- difluorobenzenesulfonamide cmpd. from the formula (I)V (cmpd. 4) [m, n — 1; R2 , R3 , R7 = H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R8 = isobutyl]

XH NMR (401 MHz, DMSO-d6) δppm 10.67 (br.s., 1H), 8.33 (d, J = 6.1Hz, 2H), 8.20 (t, J = 5.6Hz, 1H), 7.33-7.60 (m, 5H), 7.15 (br.s., 1H), 6.78-6.85 (m, 2H), 3.05 (dd, J = 5.9, 6.7Hz, 2H), 1.80-1.94 (m, 1H), 0.87 - 0.94 (m, 6H) HRMS ( ESI) calculated for C24H20F4N4O2S2 [M+H]+ 537.1037, found 537.1043.
N-3-{2-[cyclohexyl(methyl)amino]-5-(pyridin-4-yl)-1,3-thiazol-4-yl)-2,4-difluorophenyl)-2,5-difluorobenzenesulfonamide , cmpd. of the formula (I)V (cmpd. 7) [m, n=1; R2, R3 = H; R4=F; R5=4-F, R6=2,5-difluorophenyl; R7 = methyl; R8 = cyclohexyl]
HPLC: Rt: 7.64 min
XH NMR (401 MHz, DMSO-d6) δ ppm 10.68 (br.s., 1H), 8.34 (d, J=6.0Hz, 2H), 7.35-7.61 (m , 4H), 7.11-7.20 (m, 1H), 6.79-6.87 (m, 2H), 3.70-3.84 (m, 1H), 2.95 ( s, 3H), 1.77 (br.s., 4H), 1.57 (br.s., 3H), 1.35 (br.s., 2H), 1.06-1.23 (m , 1H) HRMS (ESI) calcd for C27H24F4N4O2S2 [M+H]+ 577.135, found 577.1358.
N-{2,4-difluoro-3-[2-(4-oxopiperidin-1-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]phenyl}-2.5 -difluorobenzenesulfonamide empd. of the formula (I)V (empd. 12) [m, n=1; R2, R3, R4=F; R5=4-F; R6=2,5-difluorophenyl; R7-R8 = - (CH2CH2)2CO]
HPLC: Rt: 6.14 min
XH NMR (401 MHz, DMSO-d6) δ ppm 8.25-8.44 (m, 2H), 7.49 (s, 4h), 7.05 (t, J = 7.6Hz, 1H) ), 6.91 (d, J = 6.2 Hz, 2 H), 3.84 (t, J = 6.3 Hz, 4h), 2.56 (t, J = 6.3 Hz, 4H) ) HRMS (ESI) calcd for C25H18F4N4O3S2 [M+H]+ 563.0829, found 563.083. N-{3-[2-(diethylamino)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide cmpd. of the formula (I)V (cmpd. 3) [m, n=1; R2, R3 = H; R4=F; R5=4-F; 5 R6 = 2,5-difluorophenyl; R7, R8 = ethyl]

HPLC: Rt: 6.99 min XH NMR (401 MHz, DMSO-d6) δ ppm 10.67 (br.s., 1H), 8.35 (d, J=5.6Hz, 2H), 7.36-7.61 (m, 4H), 7.18 (s, 1H), 10. 6.80-6.87 (m, 2H), 3.47 (q, J = 7.2 Hz , 4H), 1.18 (t, J = 7.0Hz, 6H)
HRMS (ESI) calculated for C24H20F4N4O2S2 [M+H]+ 537.1037, found 537.1025. N-(3-{2-[4-(dimethylamino)piperidin-1-yl]-5-(pyridin-4-15yl)-1,3-thiazol-4-yl}-2,4-difluorophenyl)- 2,5-difluorobenzenesulfonamide trifluoroacetate, cmpd. of the formula (I)V (cmpd. 10) [m, n=1; R2, R3 = H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R7-R8 = - (CH2CH2) 2CHN (Me2)]
20 HPLC: Rt: 4.88 min XH NMR (401 MHz, DMSO-dβ) δ ppm 10.67 (br.s., 1H), 9.60 (br.s., 1H), 8. 35-8.44 (m, 2H), 7.53-7.62 (m, 1H), 7.37-7.50 (m, 3H), 7.16-7.23 (m, 1H), 6.85-6.89 (m, 2H), 4.04 (d, J = 13.7Hz, 2H), 3.38-3.47 (m, 1H), 3 .15 (t, J = 11.7 Hz, 3H), 2.78 (s, 6H), 2.07-2.14 (m, 2H), 1.62-1.78 (m, 2 H)
HRMS (ESI) calculated for C27H25F4N5O2S2.C2HF3O2 [M+H] + 592.1459, found 592.1483. N-{2,4-difluoro-3-[2-(piperidin-1-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide , cmpd. of the formula (I)V (cmpd. 9) [m, n=1; R2, R3 = H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R7-R8 = - (CH2CH2) 2CH2]

HPLC: Rt: 6.84 min ∑H NMR (401 MHz, DMSO-d6) δ ppm 10.67 (br.s., 1H), (m, 2H), 8.33-8.45 7. 52-7.61 (m, 1H), 7.38-7.50 (m, 3H), 7.18 (t, J = 8.4Hz, 1H), 6.81-6.91 (m, 2H), 3.46 (br.s., 4H), 1.61 (br.s., 6H) HRMS (ESI) calcd for C25H20F4N4O2S2 [M+H]+ 549.1037, found 549,1046.
N-{2,4-difluoro-3-[2-(morpholin-4-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide , cmpd. of the formula (I)V (cmpd. 15) [m, n=1; R2, R3 = H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R7-R8 = ~(CH2CH2)2O]
HPLC: Rt: 5.95 min
XH NMR (401 MHz, DMSO-d6) δppm 10.67 (br.s., 1H), 8.34-8.47 (m, 2H), 7.51-7.63 (m, 1 H), 7.33-7.51 (m, 3H), 7.18 (t, J = 8.2Hz, 1H), 6.78-7.00 (m, 2H), 3. 66-3.79 (m, 4H), 3.39-3.49 (m, 4H)
HRMS (ESI) calculated for C24HI8F4N4O3S2 [M+H]+ 551.0829, found 551.0855. 1-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2,6-difluorophenyl)-5-(pyridin-4-yl)-1,3-thiazol-2-yl]- piperidine-4-carboxamide, empd. of the formula (I)V [m, n=1; R2, R3 = H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R7-R8 = - (CH2CH2) 2CHCONH2]
HPLC: Rt: min 5.2 5
XH NMR (401 MHz, DMSO-d6) δ ppm 10.67 (br.s., 1H), 8.32-8.41 (m, 1H), 7.52-7.63 (m, J = 7.8 Hz, 1H), 7.37 7.51 (m, 3H), 7.32 (s, 1H), 7.18 (t, J = 8.2 Hz, 1H), 6 .84-6.87 (m, J = 1.5 Hz, 2 H), 6.82 (br.s., 1 H), 3.89 [d, J = 12.6 Hz, 2 H) 3 .03 - 3.19 (m, 2H), 1.82 (d, J = 10.1 Hz, 2H), HRMS (ESI) calculated for C26H2iF4N5O3S2 [M+H]+ 592.1095, found 592. 11.
N-{2,4-difluoro-3-[2-(4-hydroxypiperidin-1-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]phenyl}-2.5 -difluorobenzenesulfonamide, cmpd. of formula (I) V (cmpd. 13) [m, n=1; R2, R3 = H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R7-R8 = - (CH2CH2)2CHOH]

HPLC: Rt: 5.5 min ∑H NMR (401 MHz, DMSO-d6) δ ppm 10.67 (br.s., 1H), 8.36 (d, J = 6.1Hz, 2H) , 7.50-7.59 (m, 1H), 7.36-7.50 (m, 5H), 7.17 (t, J = 8.5 Hz, H 1), 6.78- 6.88 (m, 2H), 4.82 (d, J = 4.2Hz, 1H), 3.66-3.85 (m, 3H), 1.77-1.91 (m , J = 4.3, 8.5 Hz, 1H), 1.39-1.56 (m, 2H)
HRMS (ESI) calculated for C25H2oF4N4θ3S2 [M+H]+ 565.0986, found 565.0993. N-{3-[2-(4,4-difluoropiperidin-1-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2, 5-difluorobenzenesulfonamide, cmpd. of the formula (I)V (cmpd. 14) [m, n=1; R2, R3=H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R7-R8 = - (CH2CH2) 2CF2]
HPLC: Rt: 6.64 min
XH NMR (401 MHz, DMSO-d6) δppm 10.67 (br.s., 1H), 8.39 (d, J = 6.1Hz, 2H), 7.50-7.61 ( m, 1H), 7.34-7.50 (m, 3H), 7.18 (t, J = 8.5Hz, 1H), 6.84-6.95 (m, 2H) , 3.54-3.69 (m, 4H), 2.00-2.22 (m, 4H) HRMS (ESI) calculated for C25H18F6N4O2S2 [M+H]+ 585.0848, found 585.0858. N-{2,4-difluoro-3-[2 — {[2-(morpholin-4-yl)ethyl]amino}-5-(pyridin-4-yl)-1,3-thiazol-4-yl] phenyl}-2,5-difluorobenzenesulfonamide, empd. of the formula (I)V [m, n=1; R2, R3, R7 = H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R8 = 2-(morpholin-4-yl)ethyl]

HPLC: Rt: 5.2 min XH NMR (401 MHz, DMSO-d6) δ ppm 10.70 (s, 1H), 8.28-8.38 (m, 2H), 8.10 (t, J = 5.4 Hz, 1H), 7.50-7.59 (m, 1H), 7.35-7.50 (m, 3H), 7.10-7.20 (m, 1H) ), 6.76-6.86 (m, 2H), 3.50-3.60 (m, 4H), 3.37 (br.s., 2H)
HRMS (ESI) calculated for C26H23F4N5O3S2 [M+H]+ 594.1251, found 594.127. N-(2,4-difluoro-3-{2-[(1-methylpiperidin-4-yl)amino]-5-(pyridin-4-yl)-1,3-thiazol-4-yl)-1, 3-thiazol-4-yl]phenyl]-2,5-difluorobenzenesulfonamide, cmpd. of the formula (I)V [m, n=1; R2, R3, R7 = H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R8 = 1-methylpiperidin-4-yl]

HPLC: Rt: 4.65 min ∑H NMR (401 MHz, DMSO-d6) δ ppm 8.28-8.41 (m, 2H), 8.18 (d, J = 7.1Hz, 1H ), 7.22-7.49 (m, 4H), 6.91-7.00 (m, 1H), 6.85-6.91 (m, 2H), 3.70 (br. s., 1H), (m, 2H) 2.01-2.13, 1.54-1.66 (m, 2H) HRMS (ESI) calculated for C26H23F4N5O2S2 [M+H]+ 578.1302 , found 578,1301. Example 7 Synthesis of N-(3-{2-[(ethylcarbamoyl)amino]-5-(pyridin-4-yl)-1,3-thiazol-4-yl}-2,4-difluorophenyl)-2,5 - difluorobenzenesulfonamide, cmpd. of the formula (I)K [m, n=1; R2, R3=H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R12=ethyl]
N-{3-[2-amino-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide (prepared as described in example 3.50 mg, 0.1 mmol) was dissolved in 2 mL of dry 1,4-dioxane and a total amount of 320 µL (4 mmol) of the ethylisocyanate was added in portions until the reaction was complete. The solution was heated to 80°C with stirring for 18 h. The solvent was then removed and the residue made up with DCM and washed with water. The organic phase was dried over Na2SO4 and evaporated to dryness, giving N—(3—{2—[(ethylcarbamoyl)amino]-5-(pyridin-4-yl)-1,3-thiazol-4-yl}-2 ,4-difluorophenyl)-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide. The latter, without further purification, was dissolved in 9 ml of TEA and 1 ml of water and the resulting mixture was kept at 60°C under stirring for 8 h. The solvent was evaporated and the residue taken up with DCM and washed with aqueous NaHCO 3 . The organic layer was then dried over Na2SO4 and evaporated again. The product was purified by flash chromatography on a pre-coated silica gel column eluting with DCM-MeOH 95/5, giving, after trituration with diisopropyl ether-diethyl ether, 17 mg (31%) of the title compound. HPLC: Rt: 5.59 min NMR (401 MHz, DMSO-d6) δ ppm 10.82 (s, 1H), 10.68 (br.s., 1H), 8.42 (d, J = 5.4 Hz, 2 H), 7.56 (d, J = 11.4 Hz, 1 H), 7.36-7.51 (m, 4 H), 7.17 (t, J = 8. 6Hz, 1H), 6.937.02 (m, 2H), 6.59 (br.s., 1H), 3.11-3.23 (m, 2H), 1.051.11 (m, 3 H) HRMS (ESI) calcd for C23H17F4N5O3S2 [M+H]+ 552.0782, found 552.078. Example 8 Synthesis of N-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2,6-difluorophenyl)-5-(pyridin-4-yl)-1,3-thiazol-2 -yl]cyclohexanecarboxamide, cmpd. of the formula (I)M [m, n=1; R2, R3 = H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R10 = cyclohexyl]
Method B, steps g, h and b5
50 mg (0.39 mmol) of cyclohexanecarboxylic acid was dissolved in 3 mL of dry DCM and 56 µL (0.39 mmol) of TEA was added to the mixture. A solution of 33 µL of oxalyl chloride was then added dropwise in 2 mL of DCM at room temperature. After 3 hours the solvent was removed under reduced pressure, toluene was added several times and again evaporated. The residue was dissolved in 2 ml of dry DCM and placed in a solution of 50 mg (0.095 mmol) of N-{3-[2-amino-5-(pyridin-4-yl)-1,3-thiazole -4-yl]-2,4-difluorophenyl}-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide in 3 mL of the same solvent containing 56 µL of TEA. The reaction was kept at room temperature overnight, with stirring. The solution was then diluted with DCM and washed with aqueous NaHCO3. The organic layer was dried over Na2SO4 and evaporated to yield N-(cyclohexylcarbonyl)-N-[4-(3-{[(2,5-difluorophenyl)sulfonyl]-(methoxymethyl)amino}-2,6-difluorophenyl) - 5-(pyridin-4-yl)-1,3-thiazol-2-yl]cyclohexanecarboxamide as an oil. The latter was taken up with 5 ml of MeOH and 1 ml of TEA was added to the resulting solution. The reaction was kept at rt overnight. The solvent was then evaporated, and the residue re-dissolved with DCM and washed with brine. The organic phase was dried over Na2SO4 and again evaporated to yield N-[4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)-amino}-2,6-difluorophenyl)-5-(pyridine -4-yl)-1,3-thiazol-2-yl]cyclohexanecarboxamide. The latter was finally dissolved with 9 ml of TEA and 1 ml of water and heated to 75°C for 6 h. The solvent was removed under reduced pressure, the residue was re-dissolved with DCM and washed with aqueous NaHCO3 . The organic layer was dried over Na2SO4 and evaporated. The crude was finally purified by flash chromatography on a silica gel precoated column, eluting with DCM-MeOH 98/2, yielding 35 mg (63% of total) of the title compound. HPLC: Rt: 6.75 min XH NMR (401 MHz, DMSO-d6) δ ppm 12.43 (s, 1H), 10.69 (br.s., 1H), 8.45 (d, J = 6.0 Hz, 2H), 7.55 (br.s., 2H) 7.34-7.49 (m, 4H), 7.17 (br.s., 1H), 7. 00-7.05 (m, 2H)
HRMS (ESI) calculated for C27H22F4N4O3S2 [M+H]+ 591.1142, found 591.1124. Analogously, the following compounds were obtained: N-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2,6-difluorophenyl)-5-(pyridin-4-yl)-1,3 -thiazol-2-yl]-2-methylpropanamide, cmpd. of the formula (I)M [m, n=1; R2, R3 = H; R4=F; R5=4-F; R6=2,5-difluorophenyl; R10 = isopropyl]
HPLC: Rt: 6.11 min
XH NMR (401 MHz, DMSO-d6) δppm 12.48 (s, 1H), 10.69 (d, J = 0.5Hz, 1H), 8.43-8.47 (m, 2H) ), 7.51-7.60 (m, 1H), 7.36-7.52 (m, 4H), 7.18 (br.s., 1H), 7.00-7.06 (m, 2H), 2.76 (quin, J = 6.8Hz, 1H), 1.15 (d, J =6.8Hz, 6H) HRMS (ESI) calculated for C24HiOF4N4θ3S2 [M+ H]+ 551.0829, found 551.0809. N-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2,6-difluorophenyl)-5-(pyridin-4-yl)-1,3-thiazol-2-yl]benzamide cmpd. of the formula (I)M [m, n=1; R2, R3 = H; R4=F; R5=4-F; R6=2,5-difluorophenyl; RIO = phenyl] Method B, steps g and b5

HPLC: Rt: 6.46 min XH NMR (401 MHz, DMSO-d6) δ ppm 13.07 (s, 1H), 10.72 (s, 1H), 8.44-8.50 (m, 2 H), 8.07-8.19 (m, 2H), 7.63-7.73 (m, 1H), 7.54-7.62 (m, 3H), 7.40-7 .50 (m, 4H), 7.18-7.26 (m, 1H), 7.01-7.12 (m, 2H)
HRMS (ESI) calcd for C27Hi6F4N403S2 [M+H]+ 585.0673, found 585.0679. Example 9 Synthesis of N-{3-[5-(2-chloropyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl }-2,5-difluorobenzenesulfonamide, empd. of the formula (I)T [m, n=1; R1 = tetrahydropyran-4-yl; R2=Cl; R3, R5=H; R4=F; R6=2,5-difluorophenyl]
2,5-difluoro-N-{2-fluoro-3-[(2-chloropyridin-4-yl)acetyl]phenyl}-N-(methoxymethyl)benzenesulfonamide, empd. of formula 28 [m, n=1; R2=Cl; R3, R5=H; R4=F; Rx=methoxymethyl; R6= 2,5-difluorophenyl] Method D, step f
Dry diisopropylamine (1.2 mL, 8.604 mmol, 1.2 eq) was dissolved in dry THF (16 mL) under argon atmosphere and cooled to -78°C. 2.5M butyllithium in hexanes (3.44ml, 8.604mmol, 1.2eq) was then added after 5min a solution of 2-Cl-4-methylpyridine (0.628ml, 7.17mmol) 1 eq) in THF (10 ml). The mixture was stirred at -78°C for it, then a solution of 3-{[(2,5-difluorophenyl}-sulfonyl](methoxymethyl)amino}-2-fluoro-N-methoxy-N-methylbenzamide ( prepared as described in Preparation 2, 3.0 g, 7.17 mmol, 1 eq) in THF (20 mL) was added dropwise After 10 min at -78°C the mixture on the yellow background was warmed to 0° C and stirred for 1h. Then it was fused with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (ethyl acetate/Hex 1:1) to yield 2.37 g (68%) of the title compound as a yellow oil. HPLC: Rt: 6.04 min ∑H NMR (600 MHz, DMSO-d6) δ ppm 8.35 (d, J = 5.1Hz, 1H), 7.97-7.93 (m, 1H), 7.73-7.66 (m, 1H), 7.65 -7.56 (m, 2H), 7.52 (ddd, J = 3.3, 5.0, 7.8 Hz, 1H), 7.42 (s, 1H), 7.40 (t , J = 7.9 Hz, 1H), 7.29 (dd, J = 5.1, 1.1, 1H), 5.09 (s, 2H), 4.39 (s2H), 3.37 (s , 3H).
HRMS (ESI) calcd for C21H17N2O4F3SCI [M+H]+ 485, 0544, found 485.0539. Working in a similar way but using the appropriate pyridine derivative the following intermediates were also obtained: 2,5-difluoro-N-{2-fluoro-3-[(2-fluoropyridin-4-yl)acetyl]phenyl}-N -(methoxymethyl)benzenesulfonamide cmpd. from formula 28 [m, n=1; R2 = F; R3, R5=H; R4=F; Rx=methoxymethyl; R6=2,5-difluorophenyl] HPLC: Rt: 5.97 min
XH NMR (600 MHz, DMSO-d6) δ ppm 8.18 (d, J = 5.1 Hz, 1H), 7.95 (t, J = 6.5Hz, 1H), 7.71- 7.65 (m, 1H), 7.64-7.55 10 (m, 2H), 7.54-7.49 (m, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 5.1Hz, 1H), 7.07 (s, 1H), 5.09 (s, 2H), 4.42 (s, 2H ), 3.37 (s, 3H). HRMS (ESI) calcd for C21H17N2O4F4S [M+H]+ 469.0840, found 469.0828. 15 2,5-difluoro-N-{2-fluoro-3-[(pyridin-4-yl)acetyl]phenyl}-
N-(methoxymethyl)benzenesulfonamide cmpd. of formula 28 [m, n=1; R2, R3, R5=H; R4=F; Rx=methoxymethyl; R6= 2,5-difluorophenyl] HPLC: Rt: 5.31 min 20 HRMS (ESI) calculated for C2iHi8N2O4F3S [M+H]+ 451.0934, found 451.0922. tert-butyl-(4-[2-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-2-oxoethyl]pyridin-2-yl}carbamate, cmpd. formula 28 [m, n= 1; R2 = tert-25-butoxycarbonylamino; R3, R5=H; R4=F; Rx=methoxymethyl; R6=2,5-difluorophenyl] HPLC: Rt: 6.49 min XH NMR (600 MHz, DMSO-d6) δ ppm 9.67 (s, 1H), 8.15 (d, J=4.9Hz, 1H), 7.93 (t, J=6.9Hz, 1H) 7.70-7.65 (m, 2H), 7.61-7.54 (m, 2H), 7.53-7.46 (m, 1H), 7.38 (t, J =7.8Hz, 15H), 6.84 (d, J = 4.8Hz, 1H), 5.08 (s, 2H), 4.27 (s, 2H), 3, 31 (s, 3 H), 1.46 (s, 9 H)
HRMS (ESI) calcd for C26H27N3O6F3S [M+H]+ 566, 1567, found 566.1579. N-{3-[5-(2-chloropyridin-4-yl)-2-(tetrahydro-2H-pyran-4-10yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2 ,5-difluoro-N-(methoxymethyl)benzenesulfonamide, cmpd. of the formula (I)S [m, n=1; R1 = tetrahydropyran-4-yl; R2 = Cl; R3, R5=H; R4=F; Rx=methoxymethyl; R6=2,5-difluorophenyl]
Method D, steps I in
2,5-difluoro-N-{2-fluoro-3-[(2-chloropyridin-4-yl)acetyl]phenyl}-N-(methoxymethyl)benzenesulfonamide (937 mg, 1.932 mmol) was dissolved in dry DMF (17 mL) under argon atmosphere. Pyridinium bromide-perbromide (556 mg, 1.739 mmol, 0.9 eq) was added and the mixture was stirred at rt after 50 min tetrahydro-2H-pyran-4-carbothioamide (prepared as described in Preparation 5, 305 mg, 2.1 mmol, 1.09 eq) was added and the reaction mixture was heated to 60 °C and stirred for 2 h. The mixture was concentrated under reduced pressure and taken up in ethyl acetate and washed with saturated aqueous NaHCCb. The aqueous phase was again extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (98:2 DCM/MeOH) to yield 996 mg (72%) of the title product as an oil. HPLC: Rt: 7.14 min XH NMR (600 MHz, DMSO-d6) δ ppm 8.33 (dd, J = 0.5, 5.1 Hz, 1H), 7.68-7.60 (m , 2H), 7.55 (dt, J = 3.9, 9.4 Hz, 1H), 7.47-7.44 (m, 1H), 7.35-7.32 (m, 2H), 7.24 (dd, J=0.6, 1.6Hz, 1H), 7.16 (dd, J=1.6, 5.1Hz, 1H), 4.98( s, 2H), 3.98-3.93 (m, 2H), 3.52-3.46 (m, 2H), 3.39-3.31 (m, 1H), 3. 24 (s, 3H), 2.06 - 2.01 (m, J = 2.9, 13.7Hz, 2H), 1.821.74 (m, 2H)
HRMS (ESI) calculated for C27H24N3O4F3S2Cl [M+H]+ 610.0844, found 610.0860. Operating in a similar manner, but using the appropriate thioamide, the following intermediates were also obtained: N-{3-[5-(2-chloropyridin-4-yl)-2-{1-cyclopropylpiperidin-4-yl]-2- fluorophenyl}-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide, empd. of the formula (I)S [m, n=1; R1 = 1-cyclopropyl-piperidin-4-yl; R2=Cl; R3, R5=H; R4=F; Rx=methoxymethyl; R6= 2,5-difluorophenyl] Method D, steps I in

HPLC: Rt: 7.74 min NMR (600 MHz, DMSO-d6) δ ppm 8.32 (d, J = 5.2 Hz, 1H), 7.70-7.60 (m, 2H), 7.56 (dt, J = 4.0, 9.3 Hz, 1H), 7.46 5 (ddd, J = 3.2, 5.1, 7.8 Hz, 1H), 7.37 -7.27 (m, 2H), 7.26-7.20 (m, 1H), 7.15 (dd, J = 1.4, 5.3Hz, 1H), 4.98 ( s, 2H), 3.24 (s, 3H), 3.14-2.94 (m, 3H), 2.32 (t, J = 11.1Hz, 2H), 2.06 (d, J = 11.9 Hz, 2H), 1.73-1.56 (m, 3H), 0.50 - 0.35 (m, J = 5.0Hz, 2H), 0 .31 (br.s., 2H). 10 HRMS (ESI) calcd for C30H29N4θ3F3S2Cl [M+H]+ 649, 1316, found 649.1313.
N-{3-[2-tert-butyl-5-(2-chloropyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluoro-N-(methoxymethyl) ) benzenesulfonamide, cmpd. of the formula (I)S [m, n=1; R1 = tert-15 butyl; R2=Cl; R3, R5=H; R4=F; Rx=methoxymethyl; R6= 2,5-difluorophenyl ] Method D, steps I in
HPLC: Rt: 7.29 min 20 XH NMR (600 MHz, DMSO-d6) δ ppm 8.32 (d, J = 5.1 Hz, 1H), 7.67-7.61 (m, 2H) ), 7.55 (dt, J = 4.0, 9.4 Hz, 1H), 7.48-7.43 (m, 1H), 7.36-7.30 (m, 2H) , 7.25 (d, J = 0.9 Hz, 1 H), 7.16 (dd, J = 1.6, 5.2 Hz, 1 H), 4.98 (s, 2 H), 3 .24 (s, 3H), 1.47-1.43 (m, 9H)
HRMS (ESI) calculated for C26H24N3θ3F3S2Cl [M+H]+ 582.0894, found 582.0913. Benzyl-4-[5-(2-chloropyridin-4-yl)-4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino)-2-fluorophenyl)-1,3-thiazol- 2-yl]piperidine-1-carboxylate, empd. of the formula (I)S [m, n=1; R1 = 1-benzyloxycarbonyl-piperidin-4-yl; R2=Cl; R3, R5=H; R4=F; Rx=methoxymethyl; R6= 2,5-difluorophenyl] Method D, steps I in

HPLC: Rt: 7.93 min ∑H NMR (600 MHz, DMSO-d6) δ ppm 8.32 (d, J = 5.1 Hz, 1H), 7.68-7.59 (m, 2H) ), 7.55 (dt, J = 4.1, 9.4 Hz, 1H), 7.48-7.42 (m, 1H), 7.40-7.35 (m, 4H) 7.30-7.35 (m, 3H), 7.24 (d, J = 0.9 Hz, 1H), 7.15 (dd, J = 1.6, 5.2 Hz, 1 H), 5.10 (s, 2H), 4.98 (s, 2H), 4.15-3.98 (m, 2H), 3.38-3.33 (m, 1H) , 3.24 (s, 3H), 3.09-2.93 (br.s., 2H), 2.15-2.09 (m, 2H), 1.65 (dq, J = 4.2, 12.2 Hz, 2H). HRMS (ESI) calcd for C35H3iN4O5F3S2Cl [M+H] + 743, 1371, found 743.1379.
N-{3-[5-(2-chloropyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2, 5-difluorobenzenesulfonamide, cmpd. of the formula (I)T [m, n=1; R1 = tetrahydropyran-4-yl; R2=Cl; R3, R5=H; R4=F; R6= 2,5-difluorophenyl] Method D, step n
N-{3-[5-(2-chloropyridin-4-yl)-2-(tetrahydro-2h-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2, 5-difluoro-M-(methoxymethyl)benzenesulfonamide (50 mg, 0.082 mmol) was dissolved in 9:1 water/TFA (1 mL) and stirred at 60 °C for 5 h. The mixture was evaporated to dryness, taken up in DCM and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (toluene/ethyl acetate 6:4) to yield 38 mg (82%) of the product, which was triturated with ethyl acetate/diethyl ether, filtered and dried under high vacuum. 34 mg of the title compound were obtained as white solid. HPLC: Rt: 6.94 min XH NMR (600 MHz, DMSO-d6) δ ppm 10.69 (s, 1H), 8.29 (d, J = 5.1 Hz, 1H), 7.63- 7.52 (m, 1H), 7.50-7.44 (m, 1H), 7.44-7.39 (m, 1H), 7.39-7.32 (m, 2H) ), 7.29-7.23 (m, 1 H), 7.22 (d, J = 0.9 Hz, 1 H), 7.08 (dd, J = 1.6, 5.2 Hz, 1H), 3.97-3.91 (m, 2H), 3.48 (dt, J = 1.9, 11.6Hz, 2H), 3.39-3.34 (m, 1 H), 2.05-1.94 (m, 2H), 1.84-1.57 (m, 2H) HRMS (ESI) calculated for C25H20N3O3F3S2Cl [M+H]+ 566, 0581, found 566, 0588.
Working in a similar way, but using the appropriate starting material and thioamide, the following compounds were also obtained: 2,5-Difluoro-N-{2-fluoro-3-[5-(2-fluoropyridin-4-yl)- 1,3-thiazol-4-yl]phenyl}benzenesulfonamide, cmpd. of the formula (I)T (cmpd. 27) [m, n=1; R1 = 1-methyl-piperidin-4-yl; R2 = F; R3, R5=H; R4=F; R6= 2,5-difluorophenyl] Method D, step n
HPLC: Rt: 4.19 min
NMR (600 MHz, DMSO-d6) δ ppm 8.14 (d, d = 5.3 Hz, 1H), 7.35-7.45 (m, 2H), 7.35-7.24 ( m, 2H), 7.15-6.96 (m, 3H), 6.89 (s, 1H), 3.41-3.36 (m, 1H), 3.23-3.09 (m, 2H), 2.40-2.60 (m, 3H), 2.18 (d, J = 12.6Hz, 2H), 1.93-1.77 (m, 2H) .
HRMS (ESI) calculated for C26H23N4O2F4S2 [M+H]+ 563.1193, found 563.1202. N-{3-[2-tert-butyl-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfon cmpd. of the formula (I)T (cmpd. 43) [m, n=1; R1 = tert-butyl; R2, R3, R5=H; R4=F; R6= 2,5-difluorophenyl] Method D, step n
HPLC: Rt: 7.16 min 1H NMR (600 MHz, DMSO-d6) 5ppm 10.65 (br.s., 1H), 8.49-8.40 (m, 2H), 7.63 -7.52 (m, 1H), 7.51-7.43 (m, 1H), 5 7.44-7.37 (m, 1H), 7.37-7.30 (m, 1H), 2H), 7.27-7.18 (m, 1H), 7.12-6.90 (m, 2H), 1.43 (s, 9H) HRMS (ESI) calculated for C24H21N3O2F3S2 [M +H]+ 504.1022, found 504.1031.
N- {3-[2-(1-cyclopropylpiperidin-4-yl)-5-(pyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesul- phonamide, empd. of the formula (I)T (empd. 21) [m, n=1; R1 = 1-cyclopropyl-pipβridin-4-yl; R2, R3, R5=H; R4=F; R6= 2,5-difluorophenyl] Method D, step n
HPLC: Rt: 4.70 min ∑H NMR (600 MHz, DMSO-d6) δ ppm 10.53 (br.s., 1H), (m, 2H), 8.47-8.44 ( m, 1H), 7.57-7.51 (m, 1H), 7.46-7.43 7.40 (ddd, J = 3.2, 5.1, 7.8 Hz, 1H ), 7.36-7.32 (m, 1H), 7.28 (m, 1H), 7.22-7.18 (m, 1H), 7.08-7.05 (m, 1H), 2H), 3.12-2.98 (m, 3H), 2.35-2.42 (m, 2H), 2.06 (d, J=9.9 Hz, 2H), 1 .73 (m, 1H), 1.71-1.64 (m, 2H), 0.45 (d, J = 4.8Hz, 2H), 0.35 (br.s., 2H) H) HRMS (ESI) calcd for C28H26N4O2F3S2 [M+H]+ 571.1444, found 571.1463. Example 10 N-{3-[5-(2-aminopyridin-4-yl)-2-(1-cyclopropylpiperidin-4-yl)-1,3-thiazol-4'yl]-2-fluorophenyl}- 2,5-dxfluorobenzenesulfonamide, cmpd. of the formula (I)T (cmpd. 22) [m, n=1; R1 = 1-cyclopropyl-piperidin-4-yl; R2=NH2; R3, R5=H; R4=F; R6= 2,5-difluorophenyl] Method D, steps i, m, n
Tert-butyl-{4—[2—(3—{[(2,5-difluorophenyl)sulfonyl] (methoxymethyl)amino}-2-fluorophenyl)-2-oxoethyl]pyridin-2-yl} carbamate (prepared as described in example 9, 374 mg, 0.662 mmol) was dissolved in dry DMF (5 mL) under argon atmosphere. Pyridinium bromide-perbromide (190 mg, 0.596 mmol, 0.9 eq) was added and the reaction mixture was stirred at rt. for 50 min. 1-Cyclopropylpiperidine-4-carbothioamide (146 mg, 0.794 mmol, 1.2 eq) was then added and the mixture was heated to 70°C. After 1 h, the reaction was allowed to cool to room temperature overnight. The solvent was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with saturated aqueous NaHCOa and brine. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (DCM/MeOH 98:2) yielding 290 mg (60%) of tert-butyl {4-[2-(1-cyclopropylpiperidin-4-yl)-4-(3 -{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-1,3-thiazol-5-yl]pyridin-2-yl}carbamate as an amorphous solid. HPLC/MS (ESI): 730 [M+H]+, 728 [M-H]'
This intermediate was dissolved in a 9:1 TFA/H2O mixture (4 mL) and stirred at 70°C for 2 h. The mixture was then concentrated under reduced pressure, taken up with DCM and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (DCM/EtOH 95:5) and treated with a mixture of ethyl acetate/i-propyl ether, filtered and dried under high vacuum to yield 70 mg (30%) of the compound. title, as a light orange solid. HPLC: Rt: 5.49 min NMR (600 MHz, DMSO-de) δ ppm 10.99-10.01 (br.s, 1H), 7.70 (d, J = 5.3Hz, 1 H), 7.57-7.51 (m, 1H), 7.48-7.40 (m, 2H), 7.31 (m, 1H), 7.21 (br.s., 1H), 7.18-7.11 (m, 1H), 6.33, (s, 1H), 6.01 (s, 2H), 5.98 (d, J = 5.3 Hz , 1H), 3.09-2.95 (m, 3H), 2.40-2.28 (m, 2H), 2.10-1.98 (m, 2H), 1.75 -1.54 (m, 3H), 0.50 - 0.41 (m, 2H), -0.29 0.37 (m, 2H) HRMS (ESI) calculated for C28H27N5O2F3S2 [M+H] + 586.1553, found 586.1556. Example 11
Synthesis of N-{ 4-[2-(1-cyclopropylpiperidin-4-yl)-4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol- 5-yl]pyridin-2-yl}acetamide, cmpd. of the formula (I)T (cmpd. 30) [m, n=1; R1 = 1-cyclopropyl-piperidin-4-yl; R2 = acetylamino; R3, R5=H; R4=F; R6=2,5-difluorophenyl]

For a solution of N-{3-[5-(2-aminopyridin-4-yl)-2-(1-cyclopropylpiperidin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}- 2,5-difluorobenzenesulfonamide (prepared as described in example 10, 66 mg, 0.113 mmol) in dry DCM (1 mL), TEA (0.063 mL, 0.452 mmol, 4 eq) and acetyl chloride (0.024 mL, 0.338 mmol, 3 eq) were added and the mixture was stirred at rt. for 16 h. It was then diluted with DCM and washed with saturated aqueous NaHCOa and brine. The organic phase was dried over Na2SO4 and evaporated to dryness to yield a 1:1 mixture of diacetylated and triacetylated products.
To a solution of this mixture in MeOH (2ml) was added 1N sodium hydroxide (1ml) and the solution was stirred at rt. per 1h. The solvent was evaporated under reduced pressure and the residue was taken up in ethyl acetate and washed with saturated aqueous NaHCOs and brine. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (DCM/EtOH 95:5) to give 47 mg (66%) of the title compound as white solid. HPLC: Rt: 5.57 min
ÃH NMR (600 MHz, DMSO-d6) δ ppm 10.54 (s, 1H), 8.12 (d, J = 5.3 Hz, 1H), 8.04 (s, 1H), 7.53 (t, J = 8.3 Hz, 1H), 7.47-7.37 (m, 2H), 7.33-7.23 (m, 2H), 7.21-7.12 ( m, 1H), 6.62 (dd, J=1.6, 5.3Hz, 1H), 3.14-2.96 (m, 3H), 2.38 (dd, J=1 0.83.7Hz, 2H), 2.12-2.01 (m, 2H), 2.06 (s, 3H), 1.791.56 (m, 3H), 0.45 (d, J = 4.8 Hz, 2H), 0.35 (br.s., 2H) HRMS (ESI) calculated for C30H29N5O3F3S2 [M+H]+ 628.1659, found 628.1659. Example 12 Synthesis of N-{3-[5-(2-aminopyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl }-2,5-difluorobenzenesulfonamide, cmpd. of the formula (I)Z2 (cmpd. 24) [m, n=1; R1 = tetrahydropyran-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl]
Tert-butyl-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino)-2-fluorophenyl-2-(tetrahydro-2H-pyran-4-yl)-1, 3-thiazol-5-yl]pyridin-2-yl)carbamate, cmpd. of the formula (I)X [m, n=1; R1 = tetrahydropyran-4-yl; R3, R5=H; R4-F; R6=2,5-difluorophenyl; R18 = tert-butoxycarbonyl]

In a microwave tube N-{3-[5-(2-chloropyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]- 2-fluorophenyl} - 2,5-difluoro-N-(methoxymethyl)benzenesulfonamide (prepared as described in example 9, 200mg, 0.328mmol, 1eq) was dissolved in anhydrous THF (3ml) and the solution was degassed by means of bubbling argon for 5 min. Tert-butyl carbamate (152 mg, 1.311 mmol, 4 eq) was then added, followed by cesium carbonate (212 mg 0.656 mmol, eq 2), palladium acetate (8 mg, 0.033 mmol, 0.1 eq) and Xantphos (40 mg, 0.66 mmol, eq 0.2) and the mixture was irradiated by microwave in an oven at 120°C for 30 min. The mixture was filtered through a pad of celite and the celite was washed with ethyl acetate. The filtrate was washed with saturated aqueous NaHCO3 and brine, dried over Na2SOs and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (ethyl acetate/Hex 6:4) to give 160 mg of the title compound as a pale yellow solid. HPLC: Rt: 7.57 min
XH NMR (600 MHz, DMSO-d6) δ ppm 9.83 (s, 1H), 8.08 (d, J = 5.1 Hz, 1H), 7.76 (s, 1H), 7.65 -7.56 (m, 2 H), 7.56-7.50 (m, 1 H), 7.48-7.42 (m, 1 H), 7.36-7.25 (m = 1 .6, 5.2 Hz, 1H), 3.95 (td, J = 1.9, 9.6 Hz, 2H), 3.48 (dt, J = 1.81 1.6 Hz, 2 H), 3.36-3.32 (m, 1H), 3.23 (S, 3H) 2.11-1.99 (m, 2H), 1.82-1.73 (m, 2H), 1.44 (s, 9H) HRMS (ESI) calcd for C32H34N4O6F3S2 [M+H]+ 691, 1867, 5 found 691.1866.
Operating in a similar manner, but using suitable starting material, the following intermediate was also obtained: Benzyl-4-[5-{2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}-4-(3-{ [(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-10 fluorophenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate, empd. of the formula (I)X [m, n=1; R1 = 1-benzyloxycarbonyl-piperidin-4-yl; R3, R5=H; R4=: F; R6=2,5-difluorophenyl; R18 = tert-butoxycarbonyl] Method F, step cl

HPLC: Rt: 8.22 min XH NMR (600 MHz, DMSO-d6) δ ppm 9.83 (s, 1H), 8.08 (d, J = 5.5 Hz, 1H), 7.76 ( s, 1H), 6.60 (dd, J = 1.6, 5.2 Hz, 1H), 5.10 (s, 2H), 4.96 (s, 2H), 4.16- 4.07 (m, J = 13.4 Hz, 2H), 20 3.25-3.22 (m, 3H), 3.02 (br.s., 2H), 2.11 (d , J = 11.0 Hz2 H), 1.71-1.61 (m, 2H), 1.44 (s, 9H) HRMS (ESI) [M+H]+ calculated for C40H40O7N5S2F3 824.2394, found 824.2386,
N-{3-[5-(2-aminopyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2, 5-difluorobenzenesulfonamide, cmpd. of the formula (I)Z2 (cmpd. 24) [m, n=1; R1 = tetrahydropyran-4-yl; R3, R5=H; R4=F; R6= 2,5-difluorophenyl] Method F, step el
Tert-butyl-{4—[4—(3—{[(2,5-difluorophenyl)sulfonyl] (methoxymethyl)amino}-2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-5-yl]pyridin-2-yl}carbamate (58 mg, 0.084 mmol) was dissolved in a 9:1 mixture of TFA/water and stirred at 70°C for 1 h. The mixture was evaporated to dryness, taken up in DCM and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (pure ethyl acetate) to yield 32 mg (70%) of the product which was triturated with diethyl ether, filtered and dried under high vacuum. 30 mg of the title compound were obtained as white solid. HPLC: Rt: 5.86 min NMR (600 MHz, DMSO-d6) δ ppm 10.69 (br.s., 1H), 7.70 (d, J = 5.3Hz, 1H), 7.61-7.52 (m, J = 4.8, 7.7 Hz, 1H), 7.51-7.42 (m, 2H), 7.33 (t, J = 1.0 Hz, 1H), 7.30-7.23 (m, 1H), 7.22-7.15(m, 1H), 6.34 (s, 1H), 6.04 (br.s. ., 2H), 5.98 (dJ = 5.1Hz, 1H), 3.99-3.78 (m, 2H), 3.46 (dt, J = 1.8, 11.6 Hz, 2H), 3.34-3.26 (m, 1H), 2.05-1.86 (m, 2H), 1.80-1.65 (m, 2H) HRMS (ESI ) calculated for C25H22N4O3F3S2 [M+H]+ 547.1080, found 547.1092.
Operating in a similar manner, but using the appropriate starting material, the following compounds were obtained: N-{3-[5-(2-aminopyridin-4-yl)-2-(piperidin-4-yl)-1,3 - thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide cmpd. of the formula (I)Z2 [m, n=1; R1 = piperidin-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl] Method F, step el

HPLC: Rt: 4.4 6 min 1H NMR (600 MHz, DMSO-dg) (selected signals) δ ppm 8.47 (s, 1H), 7.73 (d, J = 5.3 Hz, 1H) 7.43 (br.s., 1H), 7.40-7.24 (m, 2H), 7.21 (br.s., 1H), 6.36 (s, 1H), 6.13 (br.s., 1H), 5.99 (s, 2H), 2.27-2.19 (m, 2H), 1.98-1.86 (m, 2H) HRMS (ESI) [M+H]+ calculated for C25H22O2N5S2F3 546, 1240, found 546.1251. Example 13
Synthesis of N-{3-[5-(2-aminopyridin-4-yl)-2-(1-methylpiperidin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2, 5-difluorobenzenesulfonamide, cmpd. of the formula (I)R2 (cmpd. 39) [m, n=1; R2 = NH2; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R"= methyl] Method C, steps d, e, and c2

Benzyl-[5-{2-amino [(tert-butoxycarbonyl)]pyridin-4-yl}-4-(3-{[(2,5-difluorophenyl)sulfonyl]-(methoxymethyl)amino}-2-fluorophenyl) -1,3-thiazol-2-yl]piperidine-1-carboxylate (prepared as described in example 10, 110 mg, 0.13 mmol) was dissolved in absolute ethanol (10 mL) under nitrogen atmosphere. Ammonium formate (440 mg, 7 mmol) and 5% palladium on charcoal (150 mg portion) was then added. The mixture was refluxed for 2 days, then filtered through a pad of celite and evaporated to dryness. The residue was taken up with DCM and washed with water. The organic layer was dried over Na2SO4 and evaporated, yielding 75 mg (84%) of tert-butyl-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]-(methoxymethyl)amino}- 2-fluorophenyl)-2-(piperidin-4-yl)-1,3-thiazol-5-yl]pyridin-2-yl]carbamate, HPLC/MS (ESI): 690 [M+H]+, 688 [ MH]'
This intermediate (75 mg of 0.11 mmol) was dissolved in a mixture of MeOH (9 mL) and glacial acetic acid (28 µL, 0.48 mmol). 37% aqueous formaldehyde (12 µL, 0.24 mmol) and sodium cyanoborohydride (16 mg, 0.32 mmol) were added. The solution was stirred at rt. for 1h and then the solvent removed under reduced pressure. The residue was taken up with DCM and washed with dilute aqueous ammonia. The organic layer was finally dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography on silica gel (cyclohexane-ethylacetate-ethanol 4/2/1 to elute impurities, then DCM-MeOH-NH4OH 20/5/0.5 to elute product) giving 55 mg (71 %) of tert-butyl-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl] (methoxymethyl)amino}-2-fluorophenyl)-2 - (1-methylpiperidin-4-yl) - 1,3-thiazol-5-yl]pyridin-2-yl}carbamate. HPLC/MS (ESI): 704 [M+H]+, 702 [M-H]"
The last intermediate (55 mg, 0.08 mmol) was dissolved in a mixture of TFA-H2O 9/1 (10 mL) and stirred at 70°C for 2 h. The solvent was removed and the residue taken up in DCM and washed with a saturated aqueous solution of NaHCOβ. The organic layer was dried over Na 2 SO 4 and evaporated. The product was then purified by flash chromatography on silica gel (DCM- 7N NH3 in MeOH to elute impurities and then DCM-MeOH-NH4OH 30% 20-5-0.5 to elute product) and triturated with diethyl ether to yield 30 mg (67%) of the title compound. HPLC: Rt: 3.65 min
XH NMR (401 MHz, DMSO-d6) δ ppm 7.72 (d, J = 5.2 Hz, 1H), 7.47-7.37 (m, 2H), 7.38-7.29 (m, 1H), 7.25 (dt, J=1.8, 7.9Hz, 1H), 7.04-6.96 (m, 1H), 6.92 (br.s. , 1 H), 6.35 (d, J = 0.9 Hz, 1 H), 6.07 (dd, J = 1.3, 5.2 Hz, 1 H), 5.98 (s, 2 H) 3.18-2.91 (m, 4H), 2.43 (br.s., 5h), 2.18-2.10 (m, J = 12.5Hz, 2H), 1 .89-1.76 (m, 2H) HRMS (ESI) [M+H]+ calculated for C26H24O2N5S2F3 560, 1396, found 560.1403. Example 14 Synthesis of 2,5-difluoro-N-(2-fluoro-3-{5-[2-(methylamino)pyridin-4-yl]-2-(tetrahydro-2H-pyran-4-yl)-1 ,3-thiazol-4-yl)phenyl)benzenesulfonamide, cmpd. of the formula (I)Z (cmpd. 25) [m, n=1; R1 = tetrahydropyran-4-yl; R3, R5, R18 = H; R4=F; R6=2,5-difluorophenyl; R17 = methyl] Method F, fed steps
Tert-butyl-{4—[4—(3—{[(2,5-difluorophenyl)sulfonyl] (methoxymethyl)amino)-2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl) 1, 3-thiazol-5-yl]pyridin-2-yl}carbamate (prepared as described in example 12, 97 mg, 0.140 mmol) was dissolved in dry THF (1.5 mL) under Ar atmosphere. The solution was cooled to 0°C and methyl iodide (0.02 mL, 0.321 mmol 2.3 eq) was added, followed by sodium hydride (60% in mineral oil) (20 mg, 0.353 mmol, 2.5 eq) and the mixture was shaken in ta during the night. The mixture was then diluted with water and ethyl acetate. The two phases were separated and the aqueous phase was extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was treated with a 9:1 mixture of TFA/water (2 ml) and stirred at 70°C for 1 h. The mixture was evaporated to dryness, taken up in DCM and washed with saturated aqueous NaHCCq and brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (ethyl acetate/Hex 3:1) to give 59 mg of the product which was triturated with diethyl ether, filtered and dried under high vacuum. 36 mg (46%) of the title compound was obtained as a white solid. HPLC: Rt: 6.24 min XH NMR (600 MHz, DMSO-d6) δ ppm 10.68 (br.s., 1H), 7.80 (d, J = 5.3Hz, 1H) , 7.56 (t, J = 8.6 Hz, 1H), 7.527.40 (m, 2H), 7.36-7.31 (m, 1H), 7.30-7.23 ( m, J = 6.0Hz, 1H), 7.22-7.16 (m, 1H), 6.54 (br.s., 1H), 6.24 (s, 1H), 6 .03 (d, J = 4.4 Hzl H), 3.96-3.89 (m, 2H), 3.46 (dt, J = 1.9, 11.6 Hz, 2H), 3 , 32-3.26 (m, 1H), 2.66 (d, J = 4.8Hz, 3H), 2.04-1.94 (m, 2H), 1.79-1, 68 (m, 2H) HRMS (ESI) calculated for C2eH24N4O3F3S2 [M+H]+ 561, 1237, found 561.1223.
By operating in a similar manner, but using the appropriate starting material, the following compound was also obtained: N-(3-{2-(1-cyclopropylpiperidin-4-yl)-5-[2-(methylamino)pyridin-4- yl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide, empd. of the formula (I)Z (empd. 37) [m, n = 1; R1 = 1-cyclopropyl-piperidin-4-yl; R3, R5, R18=H; R4=F; R6=2,5-difluorophenyl; R17 = methyl] Method F, fed steps

HPLC: Rt: 5.94 min 5 NMR (600 MHz, DMSO-d6) δ ppm 10.56 (br.s., 1H), 7.80 (d, 5.5Hz, 1H), 7. 58-7.51 (m, 1H), 7.47-7.39 (m, 2H), 7.35-7.29 (m, 1H), 7.26-7.18 (m, 2H), 1H), 7.18-7.09 (m, 1H), 6.52 (q, J = 4.6Hz, 1H), 6.23 (s, 1H), 6.04 (d, J = 5.3 Hz, 1H) 3.03 (m, 3H), 2.66 (d, J = 4.6Hz, 3H), 2.38-2.30 10 (m, 2H) ), 2.09-2.01 (m, 2H), 1.76-1.60 (m, 3H), 0.49-0.42 (br.d, J = 4.8 Hz, 2 H), 0.34 (br.s., 2H) HRMS (ESI) calcd for C29H29N5O2F3S2 [M+H]+ 600.1709, found 600.1710. Example 15 N-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl) -1,3- thiazol-5-yl]pyridin-2-yl}acetamide, cmpd. of the formula (I)Z1 (cmpd. 35) [m, n=1; R1 = tetrahydropyran-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R18=acetyl]
N- {4-[4-(3-{[(2,5-difluorophenyl)sulfonyl] (methoxymethyl)amino}-2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3 -thiazol-5-yl]pyridin-2-yl}acetamide cmpd. of formula 5 (I)X [m, n=1; R1 = tetrahydropyran-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R18 = acetyl; Rx=methoxymethyl] Method F, step cl

N-{3-[5-(2-chloropyridin-4-yl)-2-(tetrahydro-2H-pyran-4-10yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2 ,5-difluoro-N-(methoxymethyl)benzenesulfonamide (prepared as described in example 9, 100 mg, 0.164 mmol) was dissolved in dry THF (2 mL) and the solution was degassed by bubbling Ar for 5 min. Acetamide (20 mg, 2.1 eq 0.339 mmol) was then added, followed by cesium carbonate (107 mg, 0.328 mmol, eq 2), palladium acetate (2 mg, 0.008 mmol, 0.05 eq) and Xantphos (10 mg0.016 mmol, 0.1 eq) and the mixture was microwaved in an oven at 100°C for 30 min. The mixture was filtered through a pad of celite and the celite was washed with ethyl acetate. The filtrate was washed with saturated aqueous NaHCO3 , water and brine, dried over Na2 SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (DCM/EtOH 98:2) to obtain 50 mg of the title compound. MS (ESI) [M+H]+ 633, [M-H]" 631
Operating in a similar manner, but using the appropriate starting material, the following intermediates were also obtained: N-{4-[2-(1-cyclopropylpiperidin-4-yl)— 4 —(3 — <[(2,5- difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-1,3-thiazol-5-yl]pyridin-2-yl}acetamide cmpd. of the formula (I) X [m, n=1; R1 = 1-cyclopropyl-piperidin-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R18 = acetyl; Rx=methoxymethyl] Method F, step cl
HPLC: Rt: 5.01 min
XH NMR (600 MHz, DMSO-d6) δ ppm 10.52 (s, 1H), 8.16 (d, J = 5.4 Hz, 1H), 8.01 (s, 1H), 7.67 -7.50 (m, 3H), 7.46-7.40 (m, 1H), 7.33-7.22 (m, 2H), 6.73 (dd, J = 1.3 , 5.1Hz, 1H), 4.95 (s, 2H), 3.23 (s, 3H), 3.11-2.95 (m, 3H), 2.40-2, 26 (m 2 H), 2.12-2.06 (m, J = 1.7, 4.3 Hz, 2H), 2.04 (s, 3H) 1.761.55 (m, 3H) , 0.49 - 0.38 (m, J = 4.8Hz, 2H), 0.31 (br.s., 2H)
HRMS (ESI) calculated for C32H33N5O4F3S2 [M+H]+ 672, 1921, found 672.1926. N-{4-[2-Tert-butyl-4-(3—{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-1,3-thiazol-5-yl]pyridin -2-yljacetamide, empd. of the formula (I)X [m, n=1; R1 = tert-butyl; R3, R5=H; R4=F; Rβ=2,5-difluorophenyl; R18=acetyl; Rx= me tox ime til] Method F, step cl
HPLC: Rt:7.23 min MS (ESI) [M+H]+ 605, [MH]" 603
Benzyl-4-{5-[2-(acetylamino)pyridin-4-yl]— 4 —(3 — { [(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino)-2-fluorophenyl)-1,3 - thiazol-5-yl]pyridine-1-Carboxylate, empd. of the formula (I)X [m, n=1; R1 = 1-benzyloxycarbonyl-piperidin-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R18 = acetyl; Rx=methoxymethyl]
HPLC: Rt: 7.23 min
XH NMR (401 MHz, DMSO-d6) δ ppm 10.52 (s, 1H), 8.17 (dd, J=0.7, 5.2 Hz, 1H), 8.02 (s, 1H) 7.66-7.48 (m, 3H), 7.467.41 (m, 1H), 7.39-7.35 (m, 3H), 7.34-7.26 (m, 3H) H), 6.73 (dd, J = 1.6, 5.2 Hz, 1H), 5.10 (s, 2H), 4.96 (s, 2H), 4.10 (td, J = 3.9, 13.7 Hz, 1 H), 3.23 (s, 3 H), 3.05 (br.s., 2 H), 2.11 (d, J = 10.5 Hz) , 2H), 2.04 (s, 3H), 1.76-1.56 (m, 2H) HRMS (ESI) [M+H]+ calculated for C37H34θ6N5S2F3 766, 1976, found 766.1995.
N-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(tetrahidor-2H-pyran-4-yl)-1,3-thiazol- 5-yl]pyridin-2-yl}acetamide, cmpd. of the formula (I)Z1 (cmpd. 35) [m, n=1; R1 = tetrahydropyran-4-yl; R3, R5=H; R4=F; R6—2,5-difluorophenyl; R18 = acetyl] Method F, step dl N-{4-[2-(tetrahydropyran-4-yl)-4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl Crude )-1,3-thiazol-5-yl]pyridin-2-yl}acetamide (50mg) was treated with a 9:1 mixture of TFA/water (1ml) and stirred at 70°C for 1.5 H. The mixture was evaporated to dryness, taken up in DCM and washed with saturated aqueous NaHCOs and brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (95:5 DCM/MeOH) to yield 35 mg of product, which was triturated with ethyl ether, filtered and dried under high vacuum. 28 mg (60%) of the title compound were obtained as an off-white solid. HPLC: Rt: 5.84 min
NMR (600 MHz, DMSO-d6) δppm 10.63 (s, 1H), 10.54 (s, 1H), 8.12 (d, J = 5.3 Hz, 1H), 8.04 ( s, 1H), 7.59-7.51 (m, 1H), 7.47-7.42 (m, 1H), 7.42-7.38 (m, 1H), 7.37 -7.28 (m, 2H), 7.25-7.17 (m, 1H), 6.62 (dd, J = 1.6, 5.3Hz, 1H), 3.93 ( tdJ = 2.2, 9.4 Hz, 2H), 3.47 (dt, J = 2.2, 11.6Hz, 2H), 3.39-3.31 (m, 1H), 2.07 (s, 3H), 2.03-1.97 (m, 2H), 1.81-1.69 (m, 2H) HRMS (ESI) calculated for C27H24N4O4F3S2 [M+H]+ 589, 1186, found 589.1187,
Operating in a similar manner, but using the appropriate starting material, the following compounds were also obtained: N-{4-(2-(1-cyclopropylpiperidin-4-yl)-4-(3-{[(2,5-difluorophenyl) )sulfonyl]amino]-2-fluorophenyl)-1,3-thiazol-5-yl]pyridin-2-yl}acetamide, cmpd. of formula (I)Z1 (cmpd. 30) [m, n=1; R1 = 1-cyclopropyl-piperidin-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R18 = acetyl] Method F, step dl
HPLC: Rt: 5.57 min NMR (600 MHz, DMSO-d6) δ ppm 10.54 (s, 1H), 8.12 (d, J = 5.3 Hz, 1H), 8.04 (s , 1H), 7.53 (t, J = 8.3 Hz, 1H), 5. 7.47-7.37 (m, 2H), 7.33-7.23 (m, 2H), 7.21-7.12 (m, 1H), 6.62 (dd, <J=1.6, 5.3Hz, 1H), 3.14-2.96 (m, 3H), 2.38 (dd, J = 1.83.7 Hz, 2H), 2.12-2.01 (m, 2H), 2.06 (s, 3H), 1.79-1.56 (m, 3H), 0.45 (d, J = 4.8Hz, 2H), 0.35 (br.s., 2H) HRMS (ESI) calculated for C3oH29N503F3S2 [M+H]+ 628 ,1659, 10 found 628,1659.
N-{4-[2-tert-butyl-4-(3-{[(2,5-difluorophenyl)sulfonyl]amino)-2-fluorophenyl)-1,3-thiazol-5-yl]pyridine-2- il} acetamide, empd. of the formula (I) Z1 (empd. 42) [m, n=1; R1 = tert-butyl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R18 = acetyl]
HPLC: Rt: 6.11 min ∑H NMR (600 MHz, DMSO-d6) δ ppm 10.63 (s, 1H), 10.54 (s, 1H), 8.12 (d, J = 5.3 Hz, 1H), 8.05 (s, 1H), 7.59-7.51 (ddd, J = 4.2, 4.2, 8.4 Hz, 1H), 7.45 (dt, J = 3.9, 9.1 Hz, 1H), 7.43-7.38 (m, 1H), 7.37-7.29 (m, 2H), 7.25-7.16 (m, 1H), 6.61 (dd, J = 1.6, 5.3Hz, 1H), 2.07 (s, 3H), 1.43 (s, 9H) HRMS (ESI ) calculated for C26H24N4O3F3S2 [M+H]+ 561, 1237, found 561.1257. N-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino)-2-fluorophenyl)-2-(piperidin-4-yl)-1,3-thiazol-5-yl] pyridin-2-yl}acetamide; cmpd. of the formula (I)Z1 (cmpd. 44) [m, n=1; R1 = piperidin-4yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R18 = acetyl] Method F, step dl
HPLC: Rt: 4.70 min XH NMR (401 MHz, DMSO-d6) (selected signals) δ ppm 10.56 (s, 1H), 8.12 (d, J = 4.8 Hz, 1H), 7.43-7.17 (m, 4H), 6.92 (br.s., 1H), 6.72-6.67 (m, 1H), 3.04 (dt, J = 2 0.9, 12.5Hz, 1H), 2.30-2.19 (m, J = 2.8, 14.2Hz, 2H), 2.07 (s, 3H), 1.85 -1.99 (m, 2H) HRMS (ESI) [M+H]+ calculated for C27H24O3N5S2F3 588, 1346, found 588.1349. Example 16 Synthesis of N-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1-methylpiperidin-4-yl)-1,3- thiazol-5-yl]pyridin-2-yl}acetamide, cmpd. of the formula (I)Z1 (cmpd. 23) [m, n=1; R1 = 1-methyl-piperidin-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R18=acetyl]
Method F (analogous to method C, step e)
W-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl] (methoxymethyl)amino}-2-fluorophenyl)-2-(piperidin-4-yl)-1,3-thiazol-5 -yl]pyridin-2-yl}acetamide (prepared as described in example 15, 50 mg, 0.085 mmol) was dissolved in MeOH (5 mL) and glacial acetic acid (15 µL, 0.26 mmol). 37% aqueous formaldehyde (6.5 µL, 0.13 mmol) and sodium cyanoborohydride (8.5 mg, 0.17 mmol) were then added to the mixture, which was stirred at rt for 1h. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and aqueous NaHCO3 . The organic phase was dried over Na2SO4 and evaporated to dryness. The product was purified by flash chromatography on silica gel (DCM-MeOH 4/1) giving 30 mg (59%) of the title compound, after trituration with petroleum ether. HPLC: Rt: 3.7 2 min *H NMR (600 MHz, DMSO-dg) (selected signals) δ ppm 10.55 (s, 1H), 8.11 (d, J = 5.3 Hz, 1H ), 8.09 (s, 1H), 7.447.36 (m, J = 5.3 Hz, 2H), 7.35-7.28 (m, 1H), 7.26 (t, J = 7.5Hz, 1H), 7.02 (br.s., 2H), 6.66 (dd, J = 1.4, 5.2Hz, 1H), 3.18-2.97 (m, 3H), 2.44 (br.s., 3H), 2.20-2.12 (m, J = 14.1Hz, 2H), 2.07 (s, 3H) , 1.91-1.78 (m, 2H) HRMS (ESI) [M+H]+ calculated for C28H26O3N5S2E3 602.1502, found 602.1503. Example 17
Synthesis of 2,5-difluoro-N-(2-fluoro-3-{5-[2-(methylamino)pyridin-4-yl]-2-(1-methylpiperidin-4-yl)-1,3-thiazole -4-yl}phenyl)benzenesulfonamide, empd. of the formula (I) Z (empd. 38) [m, n=1; R1 = 1-methyl-piperidin-4-yl; R3, R5, R17 = H; R4=F; R6=2,5-difluorophenyl; R18 = methyl]

Benzyl-4-[5-{2-[(Tert-butoxycarbonyl)(methyl)amino]pyridin-4-yl}-4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino]- 2-fluorophenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate, empd. of the formula 49 [m, n=1; R1 = 1-benzyloxycarbonyl-piperidin-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R17' = tert-butoxycarbonyl; R18 = methyl; Rx=methoxymethyl] Method F, step c
Benzyl-4-[5-(2-chloropyridin-4-yl)— 4 —(3 —{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino]-2-fluorophenyl)-1,3-thiazol- 2-yl]piperidine-1-carboxylate (prepared as described in example 9, 100mg, 0.14mmol) was dissolved in dry THF (6ml) and CS 2 CO 3 (90mg, 0.28mmol), Xantphos (17mg , 0.03 mmol) tert-butyl methylcarbamate (prepared as described in preparation 8.74 mg, 0.56 mmol) and Pd(AcO)2 (12 mg, 0.03 mmol) were added consecutively. The mixture was subjected to microwave irradiation in a closed flask at 120°C for 2 h and 3 times. The suspension was then filtered through a pad of celite and the solvent evaporated under reduced pressure. The suspension was then filtered through a pad of celite and the solvent evaporated under reduced pressure. The crude was then purified by flash chromatography (cyclohexane-ethylacetate-ethanol 4/0.5/0.5) giving 73 mg (62%) of benzyl-4-[5-{2-[(tert-butoxycarbonyl)(methyl) ) amino]pyridin-4-yl}-4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-1,3-thiazol-2-yl]piperidine-1 -carboxylate. HPLC: Rt: 7.66 min
XH NMR (600 MHz, DMSO-d6) δ ppm 8.24 (d, J = 5.3 Hz, 1H), 7.65-7.57 (m, 2H), 7.53 (dt, J = 3.9, 9.4 Hz, 1H), 7.43 (ddd, J = 3.1, 5.0, 7.6Hz, 1H), 7.39-7.35 (m, 3 H), 7.34-7.29 (m, 2H), 6.75 (dd, J = 1.6, 5.2 Hz, 1H), 5.10 (s, 2H), 4. 96 (s, 2H), 4.17-4.06 (m, J = 1.9Hz, 2H), 3.28-3.27 (m, 3H), 3.24-3.19 (m, 3H), 3.02 (br.s., 2H), 2.12 (d, J = 4.6Hz, 1H), 1.71-1.62 (m, 2H) , 1.41 (s, 9H) HRMS (ESI) [M+H] calcd for C41H42O7N5S2F3 838.2551, found 838.2573. Tez-t-butyl{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino)-2-fluorophenyl)-2-(piperidin-4-yl)-1,3- thiazol-5yl]pyridin-2-yl)methylcarbamate, cmpd. of formula 47 [m, n=1; R2" = N-methyl-N-tert-butoxycarbonyl amine; R3, R5=H; R4=F; R6=2,5-difluorophenyl; Rx=methoxymethyl] Method C, step d
Benzyl-4-[5-{2-[(tert-butoxycarbonyl)(methyl)amino]pyridin-4-yl}-4-(3—{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}- 2-fluorophenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (177 mg, 0.21 mmol) was dissolved in absolute ethanol (7 mL) under nitrogen atmosphere. Ammonium formate (53 mg, 0.84 mmol) and 5% palladium on charcoal (150 mg portions) were then added. The mixture was refluxed for 2 days, then filtered through a pad of celite and evaporated to dryness. The residue was taken up with DCM and washed with water. The organic layer was dried over Na2SO4 and evaporated. The crude was then purified by flash chromatography on silica gel (DCM-MeOH to elute impurities and then DCM-MeOH-NH4OH 30% 20-5-0.5 to elute product) yielding 65 mg (44%) of the title compound. HPLC: Rt: 5.60 min ∑H NMR (500 MHz, DMSO-d6) δ ppm 8.24 (d, J = 5.2 Hz, 1H), 7.70-7.52 (m, 5H) ), 7.44 (br.s., 1H), 6.76 (d, J = 5.2Hz, 1H), 4.96 (s, 2H) HRMS (ESI) [M+H] + calculated for C33H3SO5N5S2F3 704.2183, found 704.2191.
Tert-butyl{4-[4 — (3—{[(2,5-difluorophenyl)sulfonyl] (methoxymethyl)amino}-2-fluorophenyl)-2-(1-methylpiperidin-4-yl) - 1,3- thiazol-5-yl]pyridin-2-yl}methylcarbamate, empd. of formula 48 [m, n=1; R" = methyl; R2" = N-methyl-N-tert-butoxycarbonyl amine; R3, R5=H; R4=F; R6=2,5-difluorophenyl; Rx = methoxymethyl] Method C, step e
Tert-butyl-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl] (methoxymethyl)amino}-2-fluorophenyl)-2-(piperidin-4-yl)-1,3-thiazole -5-yl]pyridin-2-yl}methylcarbamate (65 mg, 0.09 mmol) was dissolved in MeOH (5 mL) and glacial acetic acid (15 µL, 0.26 mmol). 37% aqueous formaldehyde (6.5 µL, 0.13 mmol) and sodium cyanoborohydride (8.5 mg, 0.17 mmol) were then added to the mixture, which was stirred at rt. per 1h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 15% aqueous ammonia. The organic phase was dried over NaSO4 and evaporated to dryness, to yield 34 mg of tert-butyl-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2- fluorophenyl)-2-(1-methylpiperidin-4-yl)-1,3-thiazol-5-yl]-2-yl]methylcarbamate which were used in the next step without further purification. HPLC/MS (ESI): 718 [M+H]+, 716 [MH]" 2,5-difluoro-N-(2-fluoro-3-{5-[2-(methylamino)pyridin-4-yl] -2-(1-methylpiperidin-4-yl)-1,3-thiazol-4-yl}phenyl)benzenesulfonamide, cmpd. of formula (I)Z (cmpd. 38) [m, n=1; R1=1 -methyl-piperidin-4-yl; R3, R5, R17 = H; R4=F; R6=2,5-difluorophenyl; R18 - methyl] Method F, step d
Tert-butyl-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-2-(1-methylpiperidin-4-yl)-1,3 -thiazol-5-yl]pyridin-2-yl}methylcarbamate (34 mg, 0.05 mmol) was dissolved in a mixture of TFA-H 2 O 9/1 (mL 5) and stirred at 70 °C for 2 h. The solvent was removed under reduced pressure and the residue was partitioned between DCM and 15% aqueous NH4OH. The aqueous phase was extracted twice more with ethyl acetate and the solvent evaporated to dryness. The crude was purified by RP-HPLC (mobile phase A: 0.05% NH3 in water and acetonitrile (95:5), mobile phase b: acetonitrile/H2O (95:5); gradient from 0 to 60% B in 15 min, rising to 100% B in 0.1 min) providing 15mg (37%) of the title compound as the trifluoroacetate salt. HPLC: Rt: 3.85 min XH NMR (600 MHz, DMSO-d6) δ ppm 10.70 (br.s., 1H), 9.46 (br.s., 1H), 7.83 ( d, J = 6.0Hz, 1H), 7.64-7.54 (m, 1H), 7.52-7.41 (m, 2H), 7.39-7.30 (m) , 1H), 7.27-7.21 (m, 1H), 6.65-6.39 (m, 1H), 6.27 (br.s., 1H), 3.56 ( br.s., 2H), 3.14-3.04 (m, 2H), 2.82 (d, J = 3.5Hz, 2H), 2.78 (br.s., 2H) H), 2.35-2.28 (m, J = 14.3 Hz, 2H), 1.99-1.86 (m, 2H) HRMS (ESI) [M+H]+ calculated for C27H26O2N5S2F3 574.1553, found 574.1564.
Operating in a similar manner, but using the appropriate aldehyde in the reductive amination step, the following compound was also obtained: N-(3—{2 —(1-ethylpiperidin-4-yl)-5-[2-(methylamino) 5 pyridin-4-yl]-1,3-thiazol-4-yl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide, cmpd. of the formula (I)Z [m, n=1; R1 = 1-ethyl-piperidin-4-yl; R3, R5, R17 = H; R4=F; R6=2,5-difluorophenyl; R18 = methyl] Method F, step d
HPLC: Rt: 4.90 min
XH NMR (600 MHz, DMSO-d6) δppm 10.70 (br.s., 1H), 9.19 (br.s., 1H), 7.82 (d, J = 5.9 Hz , 1H), 7.58 (t, J = 8.4Hz, 1H), 7.52-7.41 (m, 3H), 7.37-7.29 (m, 2H), 7.27-15 7.20 (m, 1H), 6.48 (br.s., 1H), 6.24 (br.s., 1H), 3.64-3.56 (m , J = 12.3 Hz2 H), 3.19-3.12 (m, 2H), 3.09-3.00 (m, 2H), 2.76 (br.s., 3H) , 2.33 (d, J = 13.6Hz, 2H), 2.00-1.86 (m, 2H), 1.27-1.22 (m, 3H) HRMS (ESI) [ M+H] + calcd for C28H28O2N5S2F3 588.1709, 20 found 588.1729, Example 18 Synthesis of N-{3-[2-(1-cyclopropylpiperidin-4-yl)-5-(2-methylpyridin-4-yl) )-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide, empd. of the formula (I)AC (empd. 31) [m, n=1; R1 = 1-cyclopropyl-piperidin-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R2' = methyl] Method F, steps g and d2

N-{3-[5-(2-chloropyridin-4-yl)-2-(1-cyclopropylpiperidin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5- difluoro-N-(methoxymethyl)benzenesulfonamide (prepared as described in example 9, 100mg, 0.154mmol) was dissolved in dry dioxane (1ml). Argon was bubbling through the solution for 5 min and a 2M solution of AlMe3 in Hex (0.154 mL, 0.308 mmol, 2 eq) was added, followed by Pd(PPh3)4 (4 mg, 0.004 mmol, 0.02 eq) . The mixture was heated to 105 °C in a sealed tube for 2 h. This was then diluted with ethyl acetate and saturated aqueous NaHCO3 . The two phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. N-{3-[2-(1-Cyclopropylpiperidin-4-yl)-5-(2-methylpyridin-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5- Crude difluoro-N-(methoxymethyl)benzenesulfonamide was treated with a 9:1 mixture of water/TFA at 70°C for 1.5 h. The mixture was evaporated to dryness, taken up in DCM and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (DCM/MeOH 95:5) to give 72 mg (80%) of the title compound as a pale yellow solid. HPLC: Rt: 6.00 min
XH NMR (600 MHz, DMSO-d6) δppm 10.56 (br.s., 1H), 8.29 (d, J = 5.3Hz, 1H), 7.51-7.59 ( m, 1H), 7.44 (dt, J = 4.0, 9.2 Hz, 1H), 7.40-7.36 (m, 1H), 7.33 (dt, J = 1 .5.5, 7.7Hz, 1H), 7.27 (m, 1H), 7.22-7.15 (m, 1H), 7.02 (s, 1H), 6.79 (dd , J = 1.45.3 Hz, 1H), 3.07-3.00 (m, 3H), 2.38 (s, 3H), 2.42-2.33 (m, 2H ), 2.06 (d, J = 12.6 Hz, 2 H), 1.76-1.60 (m, 3 H), 0.45 (br. d, J = 4.6 Hz, 2 H) ), 0.35 (br.s., 2H) HRMS (ESI) calculated for C29H28N4O2F3S2 [M+H]+ 585.1601, found 585.1599, Operating in a similar manner but using appropriate starting materials, the following compounds were obtained: 2,5-difluoro-N-{2-fluoro-3-[5-(2-methylpyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3- thiazol-4-yl]phenyl}benzenesulfonamide, cmpd. of the formula (I)AC (cmpd. 28) [m, n=1; R1 = tetrahydropyran-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R2' - methyl]
Method F, steps g and d2
HPLC: Rt: 6.23 min 1H NMR (600 MHz, DMSO-dg) (selected signals) δ ppm 10.67 (s, 1H), 8.29 (d, J = 5.2 Hz, 1H), 7.63-7.53 (m, 1H), 7.46 (dt, J = 3.9, 9.2Hz, 1H), 7.43-7.38 (m, 1H), 7 .37-7.29 (m, 2H), 7.25-7.17 (m, 1H), 7.03 (s, 1H), 6.79 (dd, J=1.2.5, 2Hz, 1H), 3.93 (tdJ = 2.1, 9.6Hz, 2H), 3.53-3.42 (m, 2H), 2.39 (s, 3H), 2.01 (m, 2H), 1.81-1.63 (m, 2H) HRMS (ESI) calculated for C26H23N3O3F3S2 [M+H]+ 546, 1128, found 546.1127. 2,5-difluoro-N-{2-fluoro-3-[5-(2-methylpyridin-4-yl)-2-(piperidin-4-yl)-1,3-thiazol-4-yl]phenyl} benzenesulfonamide, cmpd. of formula (I) AC [m, n=1; R1 = piperidin-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R2' = methyl] Method F, steps g and d2
HPLC: Rt: 4.79 min XH NMR (600 MHz, DMSO-d6) δ ppm 8.33 (d, J = 5.3 Hz, 1H), 7.35-7.42 (m, 1H) ), 7.30-7.14 (m, 3H), 7.08 (br.s, 1H), 6.91 (d, J = 5.3Hz, 1H), 6.88-6 .78 (m, 1H), 6.60 (br.s., 1H), 3.49-3.27 (m, 3H), 3.02 (dt, J = 2.4, 12, 4Hz, 2H), 2.37 (s, 3H), 2.23 (dd, J = 2.4, 14.0Hz, 2H), 1.96-1.83 (m, 2H) ) HRMS (ESI) calcd for C26H24N4O2F3S2 [M+H]+ 545, 1288, found 545.1304. Example 19 Synthesis of 2,5-difluoro-N-{2-fluoro-3-[2-(1-methylpiperidin-4-yl)-5-(2-methylpyridin-4-xl)-1,3-txazol- 4-yl]phenyl]benzenesulfonamide, cmpd. of the formula (I)AC (cmpd. 26) [m, n=1; R1 = 1-methyl-piperidin-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R2' = methyl]
Method F (analogously to method C, step e)
2,5-difluoro-N-{2-fluoro-3-[5-(2-methylpyridin-4-yl)-2-(piperidin-4-yl)-1,3-thiazol-4-yl]phenyl} benzenesulfonamide (obtained as described in example 18, 100 mg, 0.184 mmol) was dissolved in MeOH (2 mL). Aqueous formaldehyde (37%, 0.021 mL, 0.276 mmol, 1.5 eq) was added, followed by acetic acid (0.032 mL, 0.552 mmol, 3 eq) and sodium cyanoborohydride (22g, 0.294 mmol, 1.6 eq) and the mixture was stirred at rt for 1h. The mixture was then diluted with ethyl acetate, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (DCM/MeOH/7N NH 3 in MeOH 90:9:1), treated with diethyl ether, filtered and dried under high vacuum to give 68 mg (66%) of the title compound, as a pale yellow solid. HPLC: Rt: 4.87 min
NMR (401 MHz, DMSO-d6) δ ppm 8.29 (d, J = 5.1 Hz, 1H), 7.41-7.37 (m, 1H), 7.37-7.33 ( m, 1H), 7.29 (dt, J = 4.0, 8.9Hz, 1H), 7.27-7.21 (m, 1H), 7.06 (br.s, 1H). H), 6.97 (t, J = 7.4 Hz, 1 H), 6.86 (dd, J = 1.1, 5.1 Hz, 1 H), 6.86-6.82 (m , 1H), 3.13-3.06 (m, 1H), 3.06-2.98 (m, 1H), 2.27-2.44 (m, 5H), 2.15 -2.10 (m, 2H), 1.87-1.76 (m, 2H) HRMS (ESI) calculated for C27H26N4O2F3S2 [M+H]+ 559, 1444, found 559.1464.
By operating in a similar manner, but using the appropriate aldehyde, the following compound was also obtained: 2,5-difluoro-N-{2-fluoro-3-[2-(1-ethylpiperidin-4-yl)-5-(2 - methylpyridin-4-yl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide, empd. of the formula (I)AC [m, n=1; R1 = 1-ethyl-piperidin-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R2'=methyl]
Method F (analogously to method C, step e)
HPLC: Rt: 5.00 min ÃH NMR (401 MHz, DMSO-d6) δ ppm 8.30 (d, J = 5.3 Hz, 1H), 7.45-7.36 (m, 2H) 7.36-7.30 (m, 2H), 7.27 (m, 1H), 7.05 (br.s, 1H), 7.04-6.89 (m, 2H) , 6.85 (br.d, J = 5.3Hz, 1H), 2.87-2.54 (m, 3H), 2.42-2.28 (m, 5H), 2. 27- 2.10 (m, 2 H), 2.09-2.09 (m, 2 H), 1.92-1.73 (m, 2 H), 1.13 (t, J = 7 um Hz, 3H) HRMS (ESI) calcd for C28H28N4O2F3S2 [M+H]+ 573.1601, found 573.1600. Example 20
Synthesis of 2,5-difluoro-N-(2-fluoro-3-[5-(3-fluoropyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol- 4-yl]phenyl]benzenesulfonamide, cmpd. of formula (I)B (cmpd. 34) [m, n=1; R2, R5=H; R3=3-F; R4=F; R6=2,5-difluorophenyl; R1'=tetrahydropyran-4-yl]
2,5-difluoro-N-{2-fluoro-3-[2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-N-(methoxymethyl)benzenesulfona- data, cmpd. of formula 9 [n=1; R1 = tetrahydropyran-4-yl; R4=F; R5=H; R6=2,5-difluorophenyl; Rx = methoxymethyl] Method A, steps dl and e
To a solution of N-(3-acetyl-2-fluorophenyl)-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide (prepared as described in Preparation 1, 2.55 g, 6.830 mmol) in dry THF (34 mL) ) pyridinium bromide perbromide (2.18 g, 6.83 mmol, 1 eq) was added and the mixture was refluxed for 1 h. The mixture was then concentrated under reduced pressure, taken up with ethyl acetate and washed with 0.25 M HCl, water and brine.
The organic phase was dried over Na 2 SO 4 and evaporated to dryness, yielding 4.1 g of crude N-[3-(bromoacetyl)-2-fluorophenyl]-2,5-difluoro-N-(methoxymethyl)benzenesulfonamide.
Half of this material (3.40 mmol) was dissolved in absolute ethanol (34 mL). Tetrahydro-2H-pyran-4-carbothioamide (prepared as described in Preparation 6.595 mg, 1.2 eq) was added and the mixture was stirred at 60°C for 1 h. The mixture was then concentrated under reduced pressure, taken up with ethyl acetate and washed with saturated aqueous NaHCO, water and brine. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (ethyl acetate/Hex 6:4) to give 1.5 g (88%) of the title compound as an amorphous solid. HPLC: Rt: 7.07 min NMR (600 MHz, DMSO-d6) δ ppm 8.17-8.05 (m, 1H), 7.78 (d, J = 2.4Hz, 1H), 7.71-7.64 (m, 1H), 7.61 (dt, J = 4.0, 9.3Hz, 1H), 7.54-7.46 (m, 1H), 7 .34-7.29 (m, 1H), 7.297.21 (m, 1H), 5.10 (s, 2H), 3.98-3.90 (m, J = 2.1, a 2.1, 9.6Hz, 2H), 3.48 (dt, J = 1.9, 11.6Hz, 2H), 3.38 (s, 3H), 3.37-3, 31 (m, 1H), 2.04-1.99 (m, J = 1.8, 12.8Hz, 2H), 1.81-1.66 (m, 2H)
HRMS (ESI) calcd for C22H22N2O4F3S2 [M+H]+ 499.0968, found 499.0974. Operating in a similar manner, but using the appropriate thioamide, the following intermediate was also obtained: 4-[4-(3—{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino)-2-fluorophenyl)-1, 3-thiazol-2-yl]piperidine-1-carboxylate, empd. of formula 9 [n=1; R1 = 1-benzyloxycarbonyl-piperidin-4-yl; R4=F; R5=H; R6=2,5-difluorophenyl; Rx=methoxymethyl]
Method A, steps dl and ee HPLC: Rt: 7.90 min NMR (600 MHz, DMSO-d6) δ ppm 8.15-8.07 (m, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.70-7.64 (m, 1H), 7.63-7.57 (m, 1H), 7.53-7.46 (m, 1H), 7. 40-7.34 (m, 4H), 7.34-7.28 (m, 2H), 7.28-7.24 (m, 1H), 5.10 (s, 2H), 5.09 (s, 2H), 4.14-4.05 (m, 2H), 3.12-2.93 (m, 2H), 3.37 (s, 3H), 3. 37-3.31 (m, 1 H), 2.13-2.03 (m, J = 11.5 Hz, 2 H), 1.63 (dq, J = 4.2, 12.2 Hz, 2 H)
HRMS (ESI) calcd for C30H29N3O5F3S2 [M+H]+ 632.1495, found 632.1501. N-{3-[5-bromo-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl)-2,5-difluoro-N-(methoxymethyl) ) benzenesulfonamide, empd. of formula 10 [n=1; R1 = tetrahydropyran-4-yl; R4=F; R5=H; R6=2,5-difluorophenyl; Rx=methoxymethyl; Hal = Br]
Method A, step f 2,5-difluoro-N-{2-fluoro-3-[2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-N- (methoxymethyl)benzenesulfonamide (1.4 g, 2.808 mmol) was dissolved in acetic acid (28 mL), sodium acetate (461 mg, eq 2 5.616 mmol) was added and the mixture was stirred until complete dissolution. Bromine (0.2 mL, 3.9 mmol, 1.4 eq) was then added dropwise over 45 min and stirred at rt. during the night. The reaction mixture was then added dropwise into a 1N cooled sodium hydroxide solution (300ml) and the mixture was extracted with ethyl acetate. The organic phase was washed with 0.5N sodium hydroxide, 5% NaHSO3 and brine, dried over Na2SO4 and evaporated to dryness, yielding 1.26 g (78%) of the title product as colorless oil. HPLC: Rt: 7.24 min XH NMR (600 MHz, DMSO-d6) δ ppm 7.69-7.64 (m, 1H), 7.63-7.56 (m, 2H), 7. 53-7.48 (m, 1H), 7.47-7.42 (m, 1H), 7.35 (t, J = 7.9, 1H), 5.10 (s, 2H) ), 3.95-3.85 (m, 2H), 3.44 (dt, J = 1.9, 11.6Hz, 2H), 3.38 (s, 3H) 3.31- 3.23 (m, 1H), 1.98-1.92 (m, 2H), 1.75-1.65 (m, 2H) HRMS (ESI) calculated for C22H2iN2O4F3S2Br [M+H]+ 577.0073, found 577.0075.
Working analogously, the following intermediate was also obtained: Benzyl 4-[5-bromo-4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino)-2-fluorophenyl)-1,3 -thiazol-2-yl]piperidine-1-carboxylate, cmpd. of the formula 10 [n-1; R1 = 1-benzyloxycarbonyl-piperidin-4-yl; R4=F; R5=H; R6=2,5-difluorophenyl; Rx=methoxymethyl; Hal — Br] Method A, step f HPLC: Rt: 8.03 min ∑H NMR (600 MHz, DMSO-d6) δ ppm 7.67-7.62 (m, 1H), 7.62-7, 55 (m, 2H), 7.53-7.47 (m, 1H), 7.47-7.42 (m, 1H), 7.40-7.33 (m, 5H), 7.33-7.29 (m, 1H), 5.09 (br.s., 2H), 5.08 (br.s., 2H), 4.10-4.04 (m, J = 13.2 Hz, 2 H), 3.38 (s, 3 H), 3.29-3.22 (m 1 H), 3.05-2.93 (m, J = 11.0 Hz , 2H), 5. 2.05-1.99 (m, J = 11.5Hz, 2H), 1.63-1.54 (m, 2H)
HRMS (ESI) calcd for C3oH28N3θ5F3S2Br [M+H]+ 710.0601, found 710.0618. 2,5-difluoro-N-{2-fluoro-3-[5-(3-fluoropyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4- yl]phenyl}benzenesulfonamide, cmpd. of formula (I)B (cmpd. 34) [m, n=1; R2, R5=H; R3 = 3-F; R4=F; R6=2,5-difluorophenyl; R1' = tetrahydropyran-4-yl]
Method A, steps hej N-{3-[5-bromo-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-15yl]-2-fluorophenyl}-2,5- difluoro-N-(methoxymethyl)benzenesulfonamide (105 mg, 0.182 mmol) was dissolved in a microwave tube in a 9:1 DME/H2O mixture (2.2 mL) and argon bubbled through the solution for 5 min. Cesium carbonate (148 mg, 2.5 eq 0.454 mmol) was added, followed by 3-F-4-pyridineboronic acid pinacol ester (82 mg, 0.368 mmol, 2 eq) and Pd (dppf) CI2.DCM (15 mg , 0.018 mmol, 0.1 eq) and the mixture was microwaved in an oven at 100°C for 30 min. Addition of Pd(dppf)Cl2.DCM (15 mg, 0.018 mmol, 0.1 eq) was made and the mixture was subjected to a second microwave cycle. The mixture was filtered through a pad of celite and the celite was washed with ethyl acetate. The filtrate was washed with saturated aqueous NaHCO3 and brine, dried over Na2 SO4 and evaporated to dryness. The crude product was purified by silica gel flash chromatography to give 76 mg of 2,5-difluoro-N-{2-fluoro-3-[5-(3-fluoropyridin-4-yl)-2-(tetrahydro-2H -pyran-4-yl)-1,3-thiazol-4-yl]phenyl}-N-(methoxymethyl)benzenesulfonamide impure from a dimeric by-product. This product was treated with a 9:1 mixture of water/TFA (1 ml) and stirred at 60°C for 1 h. The mixture was evaporated to dryness, taken up in DCM and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (Hex/acetone 65:35) to give 24 mg of the title compound as an off-white solid.
HPLC: Rt: 6.27 min 15 XH NMR (401 MHz, DMSO-dg) (selected signals) δ ppm 10.64 (s, 1H), 8.56 (d, J = 1.6 Hz, 1H) , 8.33 (d, J = 4.9 Hz, 1H), 7.61-7.54 (m, 1H), 7.49-7.43 (m, 1H), 7.39- 7.35 (m, 1H), 7.34-7.28 (m, 2H), 7.22-7.16 (m, 2H), 4.00-3.88 (m, 2H) ), 3.48 (dt, J = 2.011.6 Hz, 2 H), 2.02 (dd, J = 2.0, 12.8 20 Hz, 2 H), 1.82-1.71 (m , 2H) HRMS (ESI) calcd for C25H20N3O3F4S2 [M+H]+ 550.0877, found 550.0894. Example 21
Synthesis of N-[2-({4-[4-(3-{[(2,5-difluorophenyl) 25 sulfonyl]amino}-2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl) - 1,3-thiazol-5-yl]pyridin-2-yl}amino)ethyl]acetamide, cmpd. of the formula (I)Z1 (empd. 36) [m, n=1; R1 = tetrahydropyran-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R18 = 2-acetylaminoethyl]
2,5-difluoro-N-{2-fluoro-3-[5-(pyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl] phenyl)-N-(methoxymethyl)benzenesulfonamide, empd. of formula (I)A [m, n=1; R2, R3, R5=H; R4=F; R6=2,5-difluorophenyl; R1' = tetrahydropyran-4-yl; Rx = methoxymethyl] (corresponding to empd. 10 of formula (I)W of method F, where m, n = 1; R1 = tetrahydropyran-4-yl; R3, R5 = H; R4 = F; R6 = 2.5 - difluorophenyl; Rx = methoxymethyl)
Method A, step h
15 2V-{ 3-[5-bromo-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl}-2-fluorophenyl}-2,5-difluoro-N-( methoxymethyl)benzenesulfonamide (1.26 g, 2.182 mmol) was dissolved in a mixture of 9:1 dioxane/H2O (22 mL) and argon was bubbled through the solution for 5 min. Cesium carbonate (1.78 mg, 20 5.455 mmol, 2.5 eq) was added, followed by 4-pyridineboronic acid pinacol ester (895 mg, 4.364 mmol, 2 eq) and Pd(dppf) C12 DCM (178 mg, 0.218 mmol, 0.1 eq) and the mixture was stirred at 100°C for 1.5 h. The mixture was filtered through a pad of celite and the celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, taken up with ethyl acetate and washed with brine and saturated aqueous NaHCO3 , dried over NaSO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (DCM/MeOH 97:3) to give 1.09 g (87%) of the title compound as an amorphous solid. HPLC: Rt: 5.83 min. NMR (401 MHz, DMSO-dg) δppm 8.46-8.50 (m, J - 4.9Hz, 2H), 7.41-7.67 (m, 4H), 7.28- 7.38 (m, 2H), 7.07-7.17 (m, 3H), 4.97 (s, 2H), 3.91-3.99 (m, 1H), 3. 44-3.52 (m, 1H), 1.98-2.06 (m, 2H), 1.70-1.84(m, 2H) HRMS (ESI) calculated for C27H25F3N3O4S2 [M+H ]+ 576, 1233, found 576,1252. Working in an analogous way, the following compound was also obtained:
Benzyl-4-[4-(3-{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-5-(pyridin-4-yl)-1,3-thiazol-2- yl]piperidine-1-carboxylate, cmpd. of the formula (I)A [m, n-1; R2, R3, R5=H; R4=F; R6 difluorophenyl; R1' = 1-benzyloxycarbonyl-piperidin-4-yl; Rx=methoxymethyl] Method A, step h
HPLC: Rt: 7.37 min.
XH NMR (600 MHz, DMSO-d6) δppm 8.54-8.43 (m, 2H), (m, 2H), 7.65-7.56 7.52 (dt, J=4, 0.9.4 Hz, 1H), 7.47-7.42 (m, 1H), 7.40-7.35 (m, 4H), 7.35-7.28 (m, 3 H), 7.14-7.03 (m, 2H), 5.09 (s, 2H), 4.96 (s, 2H), 4.16-4.01 (m, 2H) , 3.353.29 (m, 1H), 3.23 (s, 3H), 3.03 (dd, J = 7.1, 11.6Hz, 2H), 2.13-2.07 ( m, J = 13.0 Hz, 2 H), 1.65 (dq, J = 4.2, 12.2 Hz, 2 H)
HRMS (ESI) calcd for C35H31N4θ5F3S2 [M+H]+ 709, 1761, found 709.1763. 2,5-difluoro-N-{2-fluoro-3-[5-(1-oxidopyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl yl]phenyl}-N-(methoxymethyl)benzenesulfonamide, cmpd. of formula 44 [m, n=1; R1 = tetrahydropyran-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; Rx=methoxymethyl]
Method F, step a 2,5-Difluoro-N-{2-fluoro-3-[5-(pyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazole -4-yl]phenyl}-N-(methoxymethyl)benzenesulfonamide (500 mg, 0.869 mmol) was dissolved in DCM (mL 9) and 70% m-chloroperbenzoic acid was added acid (215 mg, 0.869 mmol, 1 eq). After stirring for 1h, an addition of m-chloroperbenzoic acid (215mg, 0.869mmol, 1eq) was made, followed by a second addition of 190mg after more than 1h. After a total of 5h the mixture was diluted with DCM and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by silica gel flash chromatography (95:5 DCM/MeOH) to give 420 mg (82%) of the title compound as an amorphous solid. HPLC: Rt: 5.40 min. XH NMR (600 MHz, DMSO-d6) δ ppm 8.20-8.02 (m, 2H), 7.68-7.61 (m, 2H), 7.58-7.53 (m, 1H), 7.53-7.49 (m, 1H), 7.36-7.23 (m, 2H), 7.19-7.09 (m, 2H), 4.99 ( s, 2H), 3.983.87 (m, 2H), 3.48 (dt, J = 2.0, 11.6Hz, 2H), 3.39-3.31 (m, 1H) , 3.26 (s3,H), 2.05-1.94 (m, 2H), 1.81-1.71 (m, 2H)
HRMS (ESI) calculated for C27H25N3O5F3S2 [M+H]+ 592.1182, found 592.1188. Working analogously, the following compound was also obtained: Benzyl 4-[4-(3—{[(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-5-(1-oxidopyridin- 4-yl)-1,3-thiazol-2-yl]piperidine-1-carboxylate, empd. of formula 44 [m, n=1; R1 = 1-benzyloxycarbonyl-piperidin-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; Rx=methoxymethyl] Method F, step a HPLC: Rt: 6.52 min
XH NMR (600 MHz, DMSO-d6) δ ppm 8.16-8.02 (m, 2H), (m, 2H), 7.66-7.61 7.56 (dd, J=3, 9.9.4Hz, 1H), 7.52-7.48 (m, 1H), 7.39-7.36 (m, 4H), 7.34-7.29 (m, 3 H), 7.19-7.11 (m, 2H), 5.10 (s, 2H), 4.99 (s, 2H), 4.15-3.97 (m, J = 13 .6Hz, 2H) 3.34-3.29 (m, 1H), 3.26 (s, 3H), 3.08-2.96 (m, 2H), 2.13-2 .07 (m, 2H), 1.69-1.59 (m, J = 3.6, 12.2Hz, 2H)
HRMS (ESI) calculated for C35H32N4O6F3S2 [M+H]+ 725.1710, found 725.1710. N-[2-({4-[4-(3-{[(2,5-difluorophenyl)sulfonyl] (methoxymethyl)amino]-2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl) -1,3-thiazol-5-yl]pyridin-2-yl]amino)ethyl]acetamide, cmpd. of the formula (I)X [m, n=1; R1 = tetrahydropyran-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; Rx=methoxymethyl; R18 = 2-acetylaminoethyl;]
Method F, step b
2,5-Difluoro-N-{2-fluoro-3-[5-(1-oxidopyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl yl]phenyl}-N-(methoxymethyl)benzenesulfonamide (104 mg, 0.175 mmol) was dissolved in DCM (1.5 mL). DIPEA (0.112 mL, 0.656 mmol, 3.75 eq) was added, followed by PyBroP (106 mg, 0.228 mmol, 1.3 eq) and N-acetylethylenediamine (0.021 mL, 0.219 mmol, 1.25 eq) and the mixture was stirred at t overnight. New additions of PyBroP (20 mg) and acetylethylenediamine (0.01 mL) were made and, after more than 2 h of stirring, the mixture was diluted with DCM and washed with water and brine, dried over
Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (DCM/MeOH 96:4) to give 110 mg (93%) of the title compound. HPLC: Rt: 5.78 min. XH NMR (600 MHz, DMSO-de) δ ppm 7.88 (t, J = 5.4 Hz, 1H), 7.80 (d, J = 5.1Hz, 1H), 7.67- 7.59 (m, 1H), 7.58-7.51 (m, 2H), 7.49-7.43 (m, 1H), 7.36-7.31 (m, 1H) ), 7.29 (t, 7.9Hz, 1H), 6.63 (t, J = 5.6Hz, 1H), 6.33 (s, 1H), 6.06 (ddJ = 1 .4, 5.2 Hz, 1H), 4.98 (s, 2H), 3.94 (ddd, J = 1.9, 1.9, 9.7 Hz, 2H), 3.47 (dt, J = 2.0, 11.6 Hz, 2H), 3.42-3.35 (m, 1H), 3.32-3.28 (m, 1H), 3.26 ( s, 3H), 3.24-3.19 (m, 1H), 3.18-3.09 (m, 2H), 2.01 (dd, J = 2.1, 12.7 Hz , 2H), 1.78 (s3H), 1.30-1.21 (m, 2H)
HRMS (ESI) calculated for C3IH33N5O5F3S2 [M+H]+ 676, 1870, found 676.1880. N-[2—({4—[4—(3—{[(2,5-difluorophenyl)sulfonyl]amino)-2-fluorophenyl)-2-(tetrahydro-2h-pyran-4-yl)-1, 3-thiazol-5-yl]pyridin-2-yl)amino)ethyl]acetamide, empd. of the formula (I) Z1 (empd. 36) [m, n=1; R1 = tetrahydropyran-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R18 ~ 2-acetylaminoethyl]
Method F, step dl N—[2—({4 — [4—(3—{ [(2,5-difluorophenyl)sulfonyl](methoxymethyl)amino}-2-fluorophenyl)-2-(tetrahydro-2H-pyran -4-yl)-1,3-thiazol-5-yl]pyridin-2-yl}amino)ethyl]acetamide (197 mg, 0.158 mmol) was treated with a 9:1 mixture of water/TFA (2 mL) and stirred at 60°C for 2 h. The mixture was evaporated to dryness, taken up in DCM and washed with saturated aqueous NaHCOa and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (95:5 DCM/MeOH) to give 55 mg of the title compound as an off-white solid. HPLC: Rt: 5.47 min.
NMR (600 MHz, DMSO-d6) δppm 10.68 (br.s., 1H), 7.91 (t, J = 5.4 Hz, 1H), 7.77 (d, J = 5 .5Hz, 1H), 7.607.53 (m, 1H), 7.48-7.42 (m, 2H), 7.36-7.26 (m, 2H), 7.247.16 ( m, 1H), 6.83-6.59 (m, 1H), 6.38 (br.s., 1H), 6.02 (br.s., 1H), 3.93( td, J = 2.1, 9.5 Hz, 2H), 3.46 (dt, J = 1.8, 11.6Hz, 2H), 3.32-3, 27 (m, 1H) ), 3.26-3.21 (m, J = 5.3 Hz, 2H), 3.16 (q, J = 5.9 Hz, 2H), 2.03-1.96 (m, J = 1.9, 12.9 Hz, 2H), 1.80 (s, 3H), 1.77-1.68 (m, 2H)
HRMS (ESI) calcd for C29H29N5O4F3S2 [M+H]+ 632, 1608, found 632.1625. The following co-product was also isolated: N-<3-{5-[2-(3-acetylimidazolidin-1-yl)pyridin-4-yl]-2-(tetrahydro-2H-pyran-4-yl)-1, 3-thiazol-4-yl}-2-fluorophenyl) - 2,5-difluorobenzenesulfonamide, cmpd. of the formula (I)Z [m, n=1; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R1 = tetrahydropyran-4-11; R17-R18 = 3-acetyl-imidazolidin-1-yl]
Method F, step dl
HPLC: Rt: 5.74 min. H NMR (600 MHz, DMSO-d6) δ ppm 10.67 (br.s., 1H), 7.99 (t, J = 5.9 Hz, 1H), 7.55 (br.s., 1H). , 1H), 7.45 (br.s., 15H), 7.41-7.37 (m, 1H), 7.33 (t, J = 6.9Hz, 2H), 7.23 (br.s., 1 H), 6.34 (dd, J = 4.9, 19.6 Hz, 1 H), 6.28 (d, J = 7.7 Hz, 1 H) , 4.78 and 4.66 (s, H, 2 rotamers of 2), 3.98-3.87 (m, J = 2.4, 9.0 Hz, 2 H), 3.81-3, 75 (m, 1 H), 3.63 (t, J = 6.8 Hz, 1 H), 3.54-3.50 (m, 1 H), 3.47 (t, J = 11.0 Hz, 2H), 10 3.44-3.40 (m, 3H), 3.32-3.27 (m, 1H), 2.04-1.97 (m, 3H), 1 .79-1.74 (m, 2H)
HRMS (ESI) calculated for C30H29N5O4F3S2 [M+H]+ 644.1608, found 644.1623. Operating in a similar manner, but using the appropriate amine 15, the following compounds were also obtained: N-{3-[5-(2-{[2-(dimethylamino)ethyl]amino}pyridin-4-yl)-2- (tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide, cmpd. of the formula (I)Z1 (cmpd. 40) [m, n=1; R3, R5=H; R4=F; R6 = 2,5-difluorophenyl; R1 = 20 tetrahydropyran-4-yl; R18= 2-dimethylaminoethyl] Method F, step dl

HPLC: Rt: 5.33 min. XH NMR (600 MHz, DMSO-d6) δ ppm 7.85 (d, J = 5.3 Hz, 1H), 7.42 (ddd, J = 3.3, 5.1, 8.1 Hz, 1H), 7.39-7.34 (m, 1H), 7.31 (dt, J = 4.2, 9.0 Hz, 1H), 7.23 (dt, J = 1.4 , 7.9 Hz, 1 H), 6.96 (t, J = 7.9 Hz, 1 H), 6.86 (br.s., 1 H), 6.66 (t, J = 5. 2Hz, 1H), 6.40 (s, 1H), 6.22 (dd, J = 1.2, 5.2 Hz, 1H), 3.93 (td, J = 2.0.9 0.6Hz, 2H), 3.47 (dt, J = 1.8, 11.6Hz, 2H), 3.41-3.25 (m, 3H), 2.86 (br.s. ., 2H), 2.56 (s, 6H), 2.07-1.93 (m, J =2.0, 12.8Hz, 2H), 1.79-1.68 (m , 2 H)
HRMS (ESI) calcd for C29H31N5O3F3S2 [M+H]+ 618.1815, found 618.1822. Methyl [(2S)-1-<{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(tetrahydro-2H-pyran-4-yl) -1,3-thiazol-5-yl]pyridin-2-yl}amino)propan-2-yl]carbamate, empd. of the formula (I)Z1 (empd. 41) [m, n=1; R1 = tetrahydropyran-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R18 = 2-methoxyαarbonyl-2-methyl-aminoethyl] Method F, step dl
HPLC: Rt: 6.11 min. XH NMR (600 MHz, DMSO-d6) δ ppm 10.66 (br.s., 1H), 7.75 (d, J = 5.5H 1 Hz), 7.60-7-54 (m , 1H), 7.51-7.42 (m, 2H), 7.33 (t, J = 6.9Hz, 1H), 7.27 (br.s., 1H), 7 .22-7.16 (m, 1H), 7.01 (d, J = 7.3Hz, 1H), 6.63 (br.s., 1H), 6.40 (s, 1H) H), 5.96 (d, J = 4.9 Hz, 1H), 3.93 (td, J = 2.0, 9.5 Hz, 2H), 3.64 (td, J = 6 .8, 14.0 Hz, 1H), 3.50 (s, 3H), 3.47 (dt, J = 1.9, 11.6Hz, 2H), 3.34-3.26 (m, 1H), 3.21-3.15 (m, 2H), 2.00 (dd, J=1.9, 12.9Hz, 2H), 1.80-1.65 ( m, 2H), 1.03 (d, J = 6.6Hz, 3H)
HRMS (ESI) calculated for CaoHaaNsOsFaSa [M+H]+ 662.1713, found 662.1714. The following co-product was also isolated: 2,5-difluoro-N-{2-fluoro-3-[5-{2-[(4S)-3-(methoxymethyl)-4-methyl-2-ooimidazolidin-1-yl ]pyridin-4-yl}-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}benzenesulfonamide, cmpd. of the formula (I)Z [m, n=1; R1 = tetrahydropyran-4-yl; R3, R5=H; R4=F; R6=2,5-difluorophenyl; R17-R18 = 3-methoxymethyl-4-methyl-2-oxoimidazolidin-1-yl]
Method F, step dl
HPLC: Rt: 6.66 min. NMR (600 MHz, DMSO-d6) δppm 10.67 (s, 1H), 7.98 (d, J = 5.3 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.46 (dt, J = 3.8, 9.0Hz, 1H), 7.42-7.38 (m, 1H), 7.37-7.29 (m, 2 H), 7.26-7.14 (m, 1H), 6.33 (d, J = 4.9Hz, 1H), 6.25 (s, 1H), 4.67 (s2H) ), 4.19 (dquin, J = 2.8, 6.6 Hz, 1H), 3.98-3.87 (m, 2H), 3.65 (s, 3H), 3.51 -3.42 (m, 3H), 3.29-3.14 (m, 2H), 2.05-1.97 (m, J = 1.9, 12.7Hz, 2H), 1.80-1.67 (m, 2H), 1.21 (d, J = 6.4Hz, 3H) 10 HRMS (ESI) calculated for C31H31N5O5F3S2 [M+H]+ 674.1713, found 674 ,1726. Example 22
Synthesis of 2,5-difluoro-W-{3-[5-(pyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl} benzenesulfonamide, cmpd. of the formula (I)T [m, n=1; R1 = tetrahydropyran-4-yl; R2, R3, R4, R5 = H; R6=2,5-difluorophenyl]
4-(3-nitrophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-20 thiazole, cmpd. of formula 40 [n=1; R1 = tetrahydropyran-4-yl; R4, R5= H] Method E, step b
A mixture of 2-bromo-1-(3-nitrophenyl)ethanone (245 mg, 1 mmol) tetrahydro-2H-pyran-4-carbothioamide (144 mg, 1 mmol) is suspended in absolute ethanol (20 mL) and heated to reflux for 2 h. The solution is then cooled and evaporated to dryness. The crude is dissolved in DCM and washed twice with saturated sodium bicarbonate solution and once with water. The organic layer is dried with sodium sulfate, filtered and evaporated to dryness to yield 285 mg of the title compound (98%). HPLC: Rt: 5.66 min NMR (600 MHz, DMSO-d6) δ ppm 8.75 (t, J = 1.4 Hz, 1H), 8.40 (dt, J = 1.4, 8, 0Hz, 1H), 8.33 (s, 1H), 8.19 (dd, J = 1.4, 8.0Hz, 1H), 7.75 (t, J = 8.0Hz, 1H), 3.95 (dt, J=1.8, 11.7Hz, 2H), 3.50 (dt,J=1.8, 11.7Hz, 2H), 3.40- 3.33 (m, 1H), 2.06-1.99 (m, 2H), 1.84-1.71 (m, 2H). HRMS (ESI) calculated for C14H15N2O3S [M+H]+ 291.0798, found 291.0798. 5-bromo-4-(3-nitrophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazole, empd. of formula 41 [n=1; R1 = tetrahydropyran-4-yl; R4, R5=H; Hal = Br]
Method E, step c For a solution of 4-(3-nitrophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazole (113 mg, 0.390 mmol) in acetic acid (10.5 mL), sodium acetate (0.1 mg, 0.866 mmol, 2.2 eq) is added, and the mixture is stirred for 30 min. In the solution thus obtained, bromine was added dropwise and the reaction followed by HPLC until completion (total Br2: 44 µL, 137 mg, 0.86 mmol, 2.2 eq). The solution was poured into 100 ml of 1 M sodium hydroxide and extracted three times with ethyl acetate. The organic layer was washed with brine, and dried over sodium sulfate and evaporated to dryness to yield 5-bromo-4-(3-nitrophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3- thiazole (141 mg, 100%) HPLC: Rt: 7.29 min
XH NMR (600 MHz, DMSO-d6) δ ppm 8.72 (t, J = 2.2 Hz, 1H), 8.39 (ddd, J = 1.2, 2.2, 8.0 Hz, 1H), 8.29 (ddd, J = 1.2, 2.2, 8.0Hz, 1H), 7.82 (t, J = 8.0Hz, 1H), 3.93 ( dt, J = 2.1, to 2.1, 11.6 Hz, 2H), 3.47 (dt, J = 2.1, 11.6 Hz, 2H), 2.03-1.98 (m, 2H) 1.81-1.69 (m, 2H). HRMS (ESI) calcd for C14Hi4N2O3SBr [M+H]+ 368, 9903, found 368.9894. 4-[4-(3-nitrophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-5-yl]pyridine, cmpd. of formula 42 [m, n=1; R1 = tetrahydropyran-4-yl; R2, R3, R4, R5=H]
Method E, step d 5-Bromo-4-(3-nitrophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazole (140 mg, 0.379 mmol) was dissolved in a mixture of dioxane degassed (8 ml) and water (1.6 ml). 2-(4-pyridyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (78 mg, 0.379 mmol, 1 eq.), cesium carbonate (370 mg, 1.137 mmol, 3 eq. ) and PdCl2(dppf)2 CH2C12 (31 mg, 0.0379 mmol, 0.1 eq) were then added to the solution. The mixture thus obtained was stirred and heated to reflux under an argon atmosphere for 5h. After cooling, the suspension was filtered through a pad of celite and evaporated to dryness. The crude was re-dissolved in ethyl acetate and washed twice with brine. The organic layer was dried over sodium sulphate and evaporated to dryness. The solid material obtained was then purified by column chromatography on silica gel eluting with ethyl acetate/Hex (6/4) yielding the title compound (98 mg, 70%). HPLC: Rt: 6.01 min
XH NMR (600 MHz, DMSO-d6) δppm 8.65-8.51 (m, 2H), 8.29 (t, J = 2.1 Hz, 1H), 8.21 (ddd, J = 1.2, 2.1, 8.1 Hz, 1 H), 7.82 (td, J = 1.2, 8.1 Hz, 1 H), 7.65 (t, J = 8.1 Hz, 1H), 7.42-7.29 (m, 2H), 4.02-3.91 (m, 2H), 3.50 (dt, J = 1.8, 11.6 Hz , 2H), 2.10-2.02 (m, J = 2.6, 12.3 Hz, 2H), 1.85-1.73 (m, J = 4.3, 13.1 Hz) , 2H). HRMS (ESI) calcd for C19H18N3O3S [M+H]+ 368.1064, found 368.1062. 3-[5-(pyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]aniline, cmpd. of formula 43 [m, n=1; R1 = tetrahydropyran-4-yl; R2, R3, R4, R5=H] Method E, step e
A solution of 4-[4-(3-nitrophenyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-5-yl]pyridine was added in absolute ethanol (5 mL) and acid acetic (1 ml), zinc (300 mg). The mixture was stirred and heated to reflux for 3h. The mixture was dried and treated with a small amount of 1 N HCl.
After being stirred for 1 h, the solution was brought to pH 14 using sodium hydroxide and extracted with DCM. The organic layer was dried with sodium sulphate and evaporated to dryness. The solid material obtained was purified by column chromatography on silica gel eluting with ethyl acetate/Hex/ammonium hydroxide 8/2/0.1 yielding the title compound (52 mg, 59%). HPLC: Rt: 4.97 min XH NMR (600 MHz, DMSO-d6) δ ppm 8.70-8.30 (m, 2H), (m, 2H), 7.34-7.18 6, 96 (t, J=7.8Hz, 1H), 6.74(t,<7=1.8Hz, 1H), 6.58-6.50 (m, 1H), (m, 1H), 6.48-6.31 5.13 (s, 2H), 3.95 (dt, J = 2.1, 11.6 Hz, 2H), 3.48 (dt, J = 2.1, 11.6 Hz, 3H) 3.33-3.26 (m, 2H), 2.02 (dd, J = 1.8, 13.0Hz, 2H), 1.82 -1.71 (m, 2H).
HRMS (ESI) calcd for C19H20N3OS [M+H]+ 338.1322, found 338.1331. 2,5-difluoro-N-{3-[5-(pyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]phenyl}bezenesulfonamide, empd. of the formula (I) T [m, n=1; R1 = tetrahydropyran-4-yl; R2, R3, R4, R5=H; R6= 2,5-difluorophenyl] Method E, step f 3-[5-(pyridin-4-yl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl] aniline (28 mg, 0.083 mmol) was dissolved in DCM (2 mL) under nitrogen atmosphere. Dry pyridine (10 uL) was added followed by 2,5-difluorobenzenesulfonyl chloride (20 uL). The mixture was stirred at rt. for 2 h, then diluted with DCM and washed with a saturated solution of sodium bicarbonate. The organic layer was dried with sodium sulphate and evaporated to dryness. The crude was purified by column chromatography on silica gel eluting with DCM/MeOH/ammonium hydroxide 100/2/0.2 yielding the title compound (23mg, 53%). HPLC: Rt: 6.11 min
1 H NMR (600 MHz, DMSO-d 6 ) Õ ppm 10.83 (br.s., 1H), 8.75-8.24 (m, 2H), 7.63-7.57 (m, 1 H), 7.54-7.40 (m, 2H), 7.26-7.22 (m, 2H), 7.21-7.18 (m, 2H), 7.14-7 .04 (m, 2H), 3.95 (td, J=2.1, 11.7Hz, 2H), 3.49 (dt,J=2.0, 11.6Hz, 2H) , 2.06-1.96 (m, 2H), 1.82-1.67 (m, 2H) HRMS (ESI) calculated for C25H22N3O3F2S2 [M+H]+ 514.1065, found 514.1075.
Working analogously, but using suitable sulfonyl chloride, the following compound was obtained: 2,6-difluoro-N-{3-[5-(pyridin-4-yl)-2-(tetrahydro-2H-pyran- 4-yl)-1,3-thiazol-4-yl]phenyl]benzenesulfonamide, cmpd. of the formula (I) T [m, n=1; R1 = tetrahydropyran-4-yl; R2, R3, R4, R5=H; R6=2,6-difluorophenyl]
HPLC: Rt: 5.89 min TH NMR (600 MHz, DMSO-d6) δ ppm 10.96 (s, 1H), (m, 2H), 8.60-8.38 7.80-7, 62 (m, 1H), 7.30 (s, 1H), 7.28-7.21 (m, 3H), 7.20-7.17 (m, 2H), 7.13 (dd , J = 1.2, 8.2 Hz, 1 H), 7.06 (d, J = 7.5 Hz, 1 H), 3.99-3.91 (m, J = 2.0, 2 .0, 9.5 Hz, 2H), 3.49 (dt, J = 1.9, 11.6 Hz, 2H), 3.36-3.32 (m, 1H), 2.05 -1.98 (m, J = 2.0, 12.8 Hz, 2H), 1.82-1.70 (m, 2H) HRMS (ESI) calculated for C25H22N3O3F2S2 [M+H]+ 514, 1065, 5 found 514,1074.

权利要求:
Claims (11)
[0001]
1. Compound CHARACTERIZED by having the formula (I):
[0002]
2. A compound of formula (I), according to claim 1, CHARACTERIZED by the fact that: R1 is NR7R8 or an optionally substituted heterocyclyl, where R7 and R8 are as defined in claim 1.
[0003]
3. Compound of formula (I), according to claims 1 or 2, CHARACTERIZED by the fact that: R3 is hydrogen, R4 is halogen and R5 is hydrogen or halogen.
[0004]
4. Compound of formula (I), according to any one of claims 1 to 3, CHARACTERIZED by the fact that: RX is hydrogen.
[0005]
5. Compound of formula (I) or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, CHARACTERIZED by the fact that it is selected from the group consisting of: N-{4-[4-(3- {[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1-methylpiperidin-4-yl)1,3-thiazol-5-yl]pyridin-2-yl}acetamide; N-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1-methylpiperidin-4-yl)-1,3-thiazol-5- yl]pyridin-2-yl}-2-methylpropanamide; N-{4-[2-(1-cyclopropylpiperidin-4-yl)-4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-5- yl]pyridin-2-yl}acetamide; N-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2,6-difluorophenyl)-5-(pyridin-4-yl)-1,3-thiazol-2-yl]acetamide ; N-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(tetrahydro-2h-pyran-4-yl)-1,3-thiazol- 5-yl]pyridin-2-yl}acetamide; N-{4-[2-tert-butyl-4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-1,3-thiazol-5-yl]pyridin-2- yl}acetamide; N-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(piperidin-4-yl)-1,3-thiazol-5-yl] acetamide; and N-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1-ethylpiperidin-4-yl)-1,3-thiazol-5 -yl]pyridin-2-yl}acetamide.
[0006]
6. An in vitro method for inhibiting Raf family activity, CHARACTERIZED in that it comprises contacting said receptor with an effective amount of a compound as defined in claim 1.
[0007]
A pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, and at least one pharmaceutically acceptable excipient, carrier or diluent.
[0008]
A pharmaceutical composition according to claim 7, characterized in that it additionally comprises one or more chemotherapeutic agents.
[0009]
9. Product or kit, CHARACTERIZED by the fact that it comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, or pharmaceutical compositions thereof, as defined in claim 7, and one or more chemotherapeutic agents, such as a combined preparation for simultaneous, or separate use in anticancer therapy.
[0010]
10. Compound of formula (I) or a pharmaceutically acceptable salt thereof, according to claim 1, CHARACTERIZED by the fact that it is used as a medicine.
[0011]
11. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, CHARACTERIZED by the fact that it is applied in the manufacture of a drug with anticancer activity.

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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-07-02| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-09-03| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-05-25| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-08-10| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 21/02/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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EP11155857.3|2011-02-24|

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EP11155857|2011-02-24|

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PCT/EP2012/052906|WO2012113774A1|2011-02-24|2012-02-21|Thiazolylphenyl-benzenesulfonamido derivatives as kinase inhibitors|

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