COMPOUNDS OF REPLACED PYRROILS ACTIVE AS KINASE INHIBITORS, PROCESS FOR THE PREPARATION OF SUCH COMP

专利摘要:
substituted pyrroles active as kinase inhibitors. the present invention relates to substituted pyrrolic compounds that modulate the activity of protein kinases and are therefore useful in the treatment of diseases caused by the unregulated activity of protein kinase, in particular, kinases of the jak family. the present invention also provides methods for the preparation of these compounds, pharmaceutical compositions comprising these compounds, and methods of treating disease using these compounds or the pharmaceutical compositions containing them.
公开号:BR112015002152B1
申请号:R112015002152-2
申请日:2013-07-24
公开日:2021-04-27
发明作者:Maria Gabriella Brasca；Simona Bindi；Marina Caldarelli；Marcella Nesi；Sten Christian Orrenius；Achille Panzeri
申请人:Nerviano Medical Sciences S.R.L.；
IPC主号:

专利说明:

[001] The present invention relates to certain substituted pyrrole compounds, which modulate the activity of protein kinases. The compounds of this invention are therefore useful in the treatment of diseases related to the activity of unregulated kinases, for example cancer, proliferative diseases of cells, viral infections, immune disorders, neurodegenerative diseases, cardiovascular diseases and diseases related to bones.
[002] The present invention also provides methods for the preparation of these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases using pharmaceutical compositions comprising these compounds.
[003] Protein kinases mediate intracellular signaling affecting a transfer of phosphoryl from a nucleoside-triphosphate to a protein acceptor that is involved in a signaling pathway. These molecular phosphorylation events act as on / off switches that can modulate or regulate the biological function of the target protein and are ultimately triggered in response to a variety of extracellular and other stimuli. Examples of such stimuli include signs of environmental and chemical stress (eg, osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, and H2O2), cytokines (eg, interleukin-3 (IL-3), IL-2) and growth factors (for example, granulocytes and macrophages, macrophage colony stimulating factor (GM-CSF), fibroblast growth factor (FGF) and erythropoietin (EPO)). An extracellular stimulus can affect one or more cellular responses related to cell growth, migration, differentiation, hormone secretion, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis and regulation of the cell cycle.
[004] The malfunction of protein kinases (PKs) is the hallmark of numerous diseases. A large part of the oncogenes and proto-oncogenes involved in human cancers code for PKs. The improved activities of PKs are also implicated in many non-malignant diseases, which include, but are not limited to, autoimmune diseases, inflammatory diseases, psoriasis, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, allergies and asthma, illness Alzheimer's disease, and hormone-related illnesses. Therefore, there has been a substantial effort in medical chemistry to find protein kinase inhibitors that are effective as therapeutic agents. For a general reference of malfunctioning or deregulation of PKs see Current Opinions in Chemical Biology 1999, 3: 459 -465; Nature Rev. Drug Discov. 2002, 1: 309-315 and Carcinogenesis 2008, 29: 1087-191.
[005] JAKs are a family of non-receptor tyrosine kinases consisting of JAK1, JAK2, JAK3 and TYK2. While JAK1, JAK2 and TYK2 are expressed ubiquitously in mammals, JAK3 is expressed mainly in hematopoietic cells. JAKs play a crucial role in the hematopoietic cytokine and signaling of growth factors (Nature 1995, 377: 591-594, Annu. Rev. Immunol. 1998, 16: 293-322) and are critically involved in growth, survival, development and cell differentiation of myeloid cells and the immune system. Effective innate and adaptive immune responses require functional JAK signaling to protect the body against infections or tumors; and mutations that lead to loss of function make up some of the most common severe inherited immunodeficiencies. As a consequence, JAK / STAT signaling has been implicated in the mediation of many abnormal immune responses such as allergies, asthma, autoimmune diseases, transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as in solid and hematological tumors such as leukemias and lymphomas (Immunol. Rev. 2009, 228: 273-287).
[006] In particular JAK2 kinase is exclusively involved in signal transduction mediated by erythropoietin (EPO), thrombopoietin (TPO), Growth Hormone (GH), prolactin (PR) and by cytokines that signal via common beta chain receptor IL -3, granulocyte and macrophage colony stimulating factor (GM-CSF) and IL-5. In addition, JAK2 together with JAK1 and / or TYK2 are important for cytokines that signal via gp130 receptors (eg IL-6, IL-11), type II as cytokine receptors IL-10, IL-19 , IL-20 and IL-22, receptors containing cytokines containing p40 IL-12 and IL-23 and for the signal of type I and II IFN receptors (Rev. Immunol. 2009; 228: 273-287). JAK3 kinase is mainly expressed in hematopoietic cells and is selectively associated with the common y (yc) chain, which is a common component of receptors for IL-2, IL-4, IL-7, IL-9, IL-15 , and IL-21 which are cytokines involved in lymphoid development and function, and homeostasis of the immune system. TYK2 is mainly associated with interferons, IL-12 and IL-23, involved in the regulation of Th1 and Th17 cells, which play a key role in autoimmune disease. All of these growth factors and cytokines are mainly involved in the proliferation and differentiation of myeloid cells, inflammatory response and cancer (Blood. 2009, 114: 1289-1298, Clin. Cancer Res. 2006, 12: 6270s-6273s, J. Leukoc. Biol. 2010, 88: 1145-1156, Eur. J. Cancer 2010, 46: 1223-1231, J. Immunol. 2010, 184: 141-147, J. Immunol. 2011, 187: 181-189, Brain 2011, 134: 693-703).
[007] The binding of the ligand to the specific receptor appears to induce a conformational change in the receptor that allows trans- and / or autophosphorylation of the two linked JAK molecules. Activated JAK then phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptors, creating anchoring sites for the SH2 domain of transducers and activators of transcriptional protein signals (STAT). Once bound to receptors, STATs are themselves phosphorylated by JAK into tyrosine residues. Phosphorylated STATs dimerize and translocate to the nucleus, where they regulate the transcription of the gene. Thus, JAK are responsible for transducing a signal from the cell surface to the nucleus through a tyrosine phosphorylation signaling mechanism (J. Immun. 2007, 178: 2623-2629, 2007, Oncogene, 26: 6724- 6737 and Cell Biochem. Biophys. 2006, 44: 213-222).
[008] JAKs are characterized by seven distinct regions of JAK homology (JH1 to JH7), between these regions JH1 forms the quinse domain and is immediately adjacent to the pseudo-kinase (JH2) domain within the C-terminal half of the protein. The function of the pseudo-kinase domain is to negatively regulate the activity of the kinase domain (N. Engl. J. Med. 2006, 355: 2452-2466). It should be noted that the majority of JAK activation mutations identified in tumors are in the pseudo-kinase domain. For example, a JAK2 hotspot mutation (replacement of valine by phenylalanine, JAK2-V617F) in the pseudo-kinase domain, along with other activation mutations, in JAK2 exon12 and the TPO receptor (MPLW515L / K), were identified in hematopoietic cells of patients with rheumatic diseases or MPD (Nature 2005, 434: 1144-8, N. Engl. J. Med. 2005,352: 1779-1790, Lancet 2005, 365: 10541061, Cancer Cell 2005, 7: 387-97, Blood 2006, 108: 14271428 and Leukemia 2008, 22: 87-95). All of these data suggest that JAK2 is an appropriate target for the development of a specific MPD therapy (Curr. Onc. Reports 2009, 11: 117124). In addition, the JAK / STAT pathway has been shown to be triggered, not only by mutation but also by amplification, translocation, silencing of JAK / STAT-inhibiting SOCS proteins and over-expression of cytokines in solid and hematological tumors such as, but not limited to, AML, ALL, Hodgkin's lymphoma, diffuse large B cell lymphoma and large B cell mediastinal lymphoma, lung, prostate, colon and breast cancer. General observations on the role of JAK in cancer refer to Science 1997, 278: 1309-1312; 2007 Oncogene, 26: 67246737; Trends in Biochemical Sciences 2007, 33: 122-131, PNAS 2009, 106: 9414-9418, Anti-Cancer Agents Med. Chem. 2007, 7, 643-650.
[009] Data from experimental mice and clinical observations revealed several signaling events, mediated by JAKs, in innate and adaptive immunity. Deficiency of JAK3 or TYK2 results in defined clinical disorders, which are also evident in rat models. An impressive phenotype associated with JAK3 inactivation mutations is the severe combined immunodeficiency syndrome (Science 1995, 270: 797800, Hum. Mutat. 2001, 18: 255-63), while TYK2 mutations result in another primary immunodeficiency called autosomal recessive hyperimmunoglobulin E syndrome (Immunity 2006, 25: 745-755). Combined, these data support the use of JAK inhibitors in several different diseases such as abnormal immune responses such as allergies, asthma, autoimmune diseases, transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as in solid and hematological tumors such as MPD, leukemias and lymphomas. General observations on pharmaceutical intervention on the JAK / STAT pathway were reviewed in J. Leukoc Biol. 2010, 88: 11451156, Eur J. Cancer. 2010, 46: 1223-1231, Immunol. Rev. 2009, 228: 273-287, Trends Blood. 2009, 114: 1289-1298, Clin. Cancer Res. 2008, 14: 3716-3721, Biochem. Sciences, 2007, 33: 122-131, Clin. Cancer Res. 2006, 12: 6270s-6273s, Cancer Res. 2006, 66: 3162-3168, AJP 2004, 165: 1449-146, Eur. J. Hum. Genet. 2009, 17: 1309-1313.
[010] Substituted pyridyl- and pyrimidinyl-pyrrole derivatives and their preparation have been described in WO2007 / 110344, and their use for the treatment of diseases associated with unregulated protein activity, in particular altered Cdc7-kinase activity, was indicated.
[011] Pyrrole [2,3-b] pyridines and pyrimidines substituted with heteroaryl and their preparation have been described in WO2007 / 070514. In particular, this document describes several substituted pyrazoles useful in the treatment of diseases related to Janus kinase activity.
[012] The present inventors have discovered that the substituted pyrroles of formula (I), described below, are potent JAK inhibitors and are thus useful in cancer therapy, cell proliferative disorders, viral infections, immune disorders, neurodegenerative diseases, diseases cardiovascular diseases and bone-related diseases.
[013] Therefore, a first object of the present invention is to provide a substituted pyrrole compound represented by formula (I)
(I) where: ring W is a pyrrole; R1 is an aryl or substituted group; R2 is CN or CONR6R7, where R6 and R7 are independently hydrogen or an optionally substituted group selected from linear or branched C1-C6 alkyl, linear or branched C2-C6 alkenyl, linear or branched C2C6 alkynyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl and heterocyclyl-alkyl, or R6 and R7, taken together with the nitrogen atom to which they are attached, can form a 5- to 7-membered heterocyclyl group optionally substituted optionally containing an additional hetero atom selected from N, O and S; R3 is hydrogen, halo or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl; R4 is an optionally substituted heteroaryl group selected from:
where: R8 is hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl and heterocyclyl-alkyl, COR9, CONR10R11 and SO2R12, where: R9 is an optionally substituted group selected from linear or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl , linear or branched C2-C6 alkynyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl and heterocyclyl-alkyl; R10 and R11 are independently hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl and heterocyclyl-alkyl, or R10 and R11, taken together with the nitrogen atom to which they are attached, can form an optionally substituted 5- to 7-membered heterocyclyl group containing optionally an additional heteroatom selected from N, O and S; R12 is an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl , heteroaryl-alkyl, heterocyclyl and heterocyclyl-alkyl; R5 is hydrogen, halo or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl; or a pharmaceutically acceptable salt thereof.
[014] The present invention also provides methods of preparing pyrrole compounds, represented by formula (I), prepared through a process consisting of standard synthetic transformations.
[015] The present invention also provides a method for treating diseases caused by and / or associated with unregulated protein kinase activity, particularly 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 MET, MNK2, MPS1, MST4, NEK6, NIM1, P38alpha, PAK4, PDGFR, PDK1, PERK, PIM1, PIM2, PKAalpha, PKCbeta, PLK1, RET, ROS1, SULU1, Syk, TLK2, TRKA, TYK2, VEGFR2, VEGFR2, VEGFR2, VEGFR2, VEGFR2, VEGFR2, VEGFR2 ZAP70, more particularly kinases of the JAK family, which comprises administering to a mammal in need thereof, more particularly a human, an effective amount of a substituted pyrrole compound represented by formula (I) as defined above.
[016] A preferred method of the present invention is the treatment of a disease caused by and / or associated with an unregulated activity of the protein kinase selected from the group consisting of cancer, cell proliferation disorders, viral infections, autoimmune disorders, neurodegenerative diseases , cardiovascular diseases and bone-related diseases.
[017] Another preferred method of the present invention is the treatment of certain types of cancer, including but not limited to: carcinoma such as bladder, breast, brain, colon, kidney, liver, lung, including small cell lung cancer, head and neck, esophagus, gallbladder, ovary, uterus, pancreas, stomach, cervix, thyroid, prostate and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphoblastic leukemia (ALL) of type T and B, including ALL-SD, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, lymphoma hairy cells, Burkett's lymphoma and mantle cell lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myeloid leukemias, acute megakarioblastic leukemia, myelodysplastic syndrome and promyelocytic leukemia, myoloproliferative disorders, such as Polycythemia Vera (PV), essential thrombocythemia (TE), myelofibrosis and primary myelofibrosis and secondary to myelofibrosis chronic myelomonocytic; tumors of mesenchymal origin, including sarcoma, fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including neuroblastoma astrocytoma, glioma and schwannomas; other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, follicular thyroid cancer, Kaposi's sarcoma, mesothelioma.
[018] Another preferred method of the present invention is the treatment of specific types of proliferative cell disorders, including, but not limited to: benign prostatic hyperplasia, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-surgical stenosis and restenosis.
[019] Another preferred method of the present invention is to treat viral infections comprising preventing the development of AIDS in HIV-infected individuals.
[020] A preferred method of the present invention is the treatment of autoimmune disorders, including, but not limited to: transplant rejection, skin diseases such as psoriasis, allergies, asthma and autoimmune-mediated diseases, such as rheumatoid arthritis (RA), multiple sclerosis, systemic lupus erythematosus (SLE), Crohn's disease and amyotrophic lateral sclerosis.
[021] Another preferred method of the present invention is the treatment of neurodegenerative disorders including, but not limited to: Alzheimer's disease, degenerative nerve diseases, encephalitis, stroke, Parkinson's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis (ALS or Amyotrophic Lateral Sclerosis) Lou Gehrig), Huntington's disease and Pick's disease.
[022] Another preferred method of the present invention is the treatment of cardiovascular diseases, including, but not limited to: primary or secondary arteriosclerosis for diabetes, heart attack and stroke.
[023] Another preferred method of the present invention is the treatment of bone loss diseases, including, but not limited to osteoporosis and bone metastases.
[024] In addition, the method of the present invention also provides tumor angiogenesis and metastasis inhibition, as well as the treatment of organ transplant rejection and graft versus host disease.
[025] Furthermore, the method of the present invention further comprises subjecting the mammal, which needs it, to radiation therapy or chemotherapy regimen in combination with at least one cytostatic or cytotoxic agent.
[026] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, and at least one excipient, carrier and / or pharmaceutically diluent acceptable.
[027] In addition, the present invention provides a pharmaceutical composition of a compound of formula (I), which further comprises one or more chemotherapeutic agents - for example, cytostatics or cytotoxic agents - antibiotic type agents, alkylating agents, antimetabolite agents , hormonal agents, immunological agents, interferon-like agents, cyclooxygenase inhibitors (for example, COX-2 inhibitors), matrixmetalloprotease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, such as anti-growth agents -HER, anti-EGFR agents, anti-Abl, anti-angiogenesis agents (eg, angiogenesis inhibitors), farnesyl transferase inhibitors, histone deacetylase inhibitors, ras-raf signal transduction pathway inhibitors, Akt pathway, cell cycle inhibitors, other CDK inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, and the like tees.
[028] The present invention further provides an in vitro method for inhibiting the protein kinase activity of the JAK family which comprises contacting said protein with an effective amount of a compound of formula (I) as defined above.
[029] In addition, the invention provides a product or kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential in anticancer therapy.
[030] In yet another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use as a medicament.
[031] In addition, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use in a cancer treatment method.
[032] Finally, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament with anti-cancer activity.
[033] Unless otherwise stated, when referring to the compounds of formula (I) per se, as well as any pharmaceutical composition or for any therapeutic treatment comprising them, the present invention includes all hydrates, solvates, complexes, metabolites, pharmaceutically acceptable prodrugs, pharmaceutically acceptable bio-precursors, vehicles, N-oxides and pharmaceutically acceptable salts of the compounds of this invention.
[034] A metabolite of a compound of formula (I) is a compound in which this same compound of formula (I) is converted in vivo, for example, by administration to a mammal in need of such treatment. Typically, without representing a limiting example, however, with the administration of a compound of formula (I), this same derivative can be converted into a variety of compounds, including, for example, the most soluble derivatives such as hydroxylated derivatives. , which are easily excreted. Thus, depending on the metabolic pathway that occurs, any of these hydroxylated derivatives can be considered as a metabolite of the compounds of formula (I).
[035] "Pharmaceutically acceptable prodrug" and "pharmaceutically acceptable bio-precursors" are any covalently linked compounds that release in vivo the active drug according to formula (I).
[036] The terms "pharmaceutically acceptable prodrug" and "pharmaceutically acceptable bio-precursors", as used herein, refer to those prodrugs of the compounds of the present invention that are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as zwitterionic forms, where possible, of the compounds of the invention. The term "prodrug" refers to compounds that are rapidly transformed in vivo to produce the original active drug, according to formula (I), in vivo, for example, by hydrolysis in the blood. The discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of A.C.S. Symposium Series, and in Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.
[037] N-oxides are the compounds of formula (I) in which nitrogen and oxygen are tied together by means of a dative bond.
[038] Pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts with inorganic or organic acids, for example, nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric, acetic, trifluoroacetic, propionic, glycolic, lactic, fumaric, oxalic, tartaric, citric, benzoic, cinnamic, malic, maleic, malonic, mandelic, methanesulfonic, isethionic and salicylic acid.
[039] Pharmaceutically acceptable salts of the compounds of formula (I) include salts with inorganic or organic bases, for example, alkali or alkaline earth metals, especially sodium, potassium, calcium, ammonium or magnesium hydroxides, carbonates or bicarbonates, acyclic or cyclic amines.
[040] If a stereogenic center or other form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereoisomers, are intended to be encompassed herein. Compounds that contain 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 an individual enantiomer can be used alone. In cases where compounds have unsaturated carbon-carbon double bonds, both cis (Z) and (E) trans isomers are within the scope of the present invention.
[041] In cases where compounds can exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated to be included within this invention, whether it exists in equilibrium or predominantly in one form. In the present description, unless otherwise specified, the following terms have the following meanings.
[042] Ring W is pyrrole of formula (Ia), (Ib), (Ic), (Id) or (Ie):
wherein R1, R2, R3, R4 and R5 are as defined above.
[043] The term "aryl" refers to a mono-, bi- or poly-carbocyclic hydrocarbon group with from 1 to 4 ring systems, optionally still fused or linked to each other by simple bonds, in which at least , one of the carbocyclic rings is "aromatic", where the term "aromatic" refers to a completely conjugated π electron bonding system. The aryl ring can be optionally fused or bonded to aromatic and non-aromatic carbocyclics and heterocyclics. Non-limiting examples of such aryl groups are phenyl, a- or β-naphthyl or biphenyl groups.
[044] The term "heteroaryl" refers to aromatic heterocyclic rings, typically 5 to 8 membered heterocycles with 1 to 3 heteroatoms selected from N, O or S; the heteroaryl ring can optionally be further fused or bonded to aromatic and non-aromatic carbocyclics and heterocyclics. Non-limiting examples of such heteroaryl groups are, for example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolyl, phenyl-pyrrolyl, furyl, phenyl-furyl, oxazolyl, isoxazolyl, benzyl, pyrazyl, benzyl isoindolinyl, benzoimidazolyl, indazolyl, quinolinyl, isoquinolinyl, 1, 2,3-triazolyl, 1-phenyl-1, 2,3-triazolyl, 2,3-dihydroindolyl, 2,3-dihydrobenzofuranyl, 2,3- dihydro-benzothiophenyl, benzopyranyl, 2,3-dihydrobenzoxazinyl, 2,3-dihydroquinoxalinyl and the like.
[045] By the term "heterocyclyl" (also known as "heterocycloalkyl") we mean a carbocyclic ring with 3 to 7 members, saturated or partially unsaturated, where one or more carbon atoms are replaced by hetero atoms such as nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclic groups are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine, morpholine and the like.
[046] With the term "straight or branched C1-C6 alkyl", we intend any of the groups such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , n-pentyl, n-hexyl and the like.
[047] With the term "Cycloalkyl C3-C7", it is intended, unless otherwise indicated, a monocyclic all-carbon ring of 3 to 7 members, which may contain one or more double bonds, but does not have an electron system π completely conjugated. Examples of cycloalkyl groups, without limitation, are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloeptane, cycloptene, cycloheptadiene.
[048] With the term "straight or branched chain C2-C6 alkenyl" we mean any of the groups such as, for example, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1-hexenyl and the like.
[049] With the term "straight or branched C2-C6 alkynyl" we mean any of the groups such as, for example, ethynyl, 2-propynyl, 4-pentynyl and the like.
[050] According to the present invention and, unless otherwise indicated, any of the groups R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 above can be optionally substituted, in any of its free positions, by one or more groups, for example, 1-6 groups, selected independently from: a halogen atom, nitro, oxo (= O), cyano, C1-C6 alkyl, polyfluoro alkyl, alkoxy polyfluorinated, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkylamino, hydroxyheterocyclyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl, heterocyclyl-alkyl, C3-C7-cycloalkyl-alkyl, alkyl-aryl, alkyl-heteroaryl , alkyl-cycloalkyl, alkyl-aryl-alkyl, alkyl-heteroaryl-alkyl, alkyl-heterocyclyl-alkyl, alkyl-cycloalkyl-alkyl, alkyl-heterocyclyl-heterocyclyl, heterocyclyl-heterocyclyl, heterocyclyl-alkyl-heterocyclyl, heterocyclyl-amino, alkyl - heterocyclyl-alkyl-amino, hydroxy, alkoxy, aryloxy, heterocyclyloxy, alkyl-h eterocililoxi, methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, heterociclilcarboniloxi, alkylideneaminooxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, cicloalquilxicarbonil, heterocicliloxicarbonil, amino, ureido, alkylamino, amino alkylamino, dialkylamino, heterocyclyl-dialkylamino, alkylamino, dialkylamino, arylamino, arylalkylamino, diarylamino, heterocyclylamino, alkyl-heterocyclylamino, heterocyclyl-alkylcarbonyl, formylamino, alkyl-carbonylamino, arylcarbonylamino, heterocyclyl-carbonylamino, alkyl-heterocyclylcarbonylamino, alkylamino-carbonyl-alkylamino-carbonyl, alkyl-aminocarbonyl, alkyl-hetero-carbonyl, alkyl-hetero-alkyl -alkylamino, alkoxy-aryl-alkyl, hydroxyl-amino-carbonyl, alkoxy, alkylsulfonylamino, aryl-sulfonylamino, heterocyclylsulfonylamino, formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonyl, aryl sulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, heterocyclylaminosulfonyl, arylthio, alkylthio, phosphonate and alkylphosphonate.
[051] In turn, where appropriate, each of the above substituents may be further substituted by one or more of the groups referred to above.
[052] In this regard, with the term "halogen atom" we mean a fluorine, chlorine, bromine or iodine atom.
[053] With the term "cyan" we mean a CN residue.
[054] With the term "nitro" we mean a -NO2 group.
[055] With the term "alkyl or polyfluoro alkoxy" we mean any of the above straight or branched C1-C6 alkyl or alkoxy groups which are replaced by more than one fluorine atom such as, for example, trifluoromethyl, trifluoroethyl, 1, 1,1,3,3,3-hexafluoropropyl, trifluoro-methoxy and the like.
[056] With the term "alkoxy", "cyclyloxy", "aryloxy", "heterocyclyloxy" and its derivatives we intend any of the C1-C6 alkyl, C3-C7 cycloalkyl, aryl or heterocyclyl groups linked above to the rest of the molecule through of an oxygen atom (-O-). From all of the above, it is evident to the person skilled in the art that any group whose name is a composite name, such as, for example, arylamino, should be understood as conventionally interpreted from the parts where it derives, for example, by an amino group, which can also be replaced by aryl, where aryl is as defined above.
[057] Likewise, any of the terms such as, for example, alkylthio, alkylamino, dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocyclylcarbonyl, heterocyclylcarbonylamino, cycloalkyloxycarbonyl and the like, include groups in which the C3-C7 alkyl, alkoxy, aryl, cycloalkyl and heterocyclyl are as portions defined above.
[058] Preferably, a compound of formula (I) is characterized by the fact that ring W is a substituted pyrrole of formula (Ia), (Ib) or (Id):
wherein R1, R2, R3, R4 and R5 are as defined above.
[059] More preferably, a compound of formula (I) is characterized in that R1 is optionally substituted aryl and W, R2, R3, R4 and R5 are as defined above.
[060] Another most preferred compound of the formula (I) is characterized by the fact that R1 is optionally substituted heteroaryl and W, R2, R3, R4 and R5 are as defined above.
[061] Even more preferably, a compound of formula (I) is characterized by the fact that R2 is CN, and W, R1, R3, R4 and R5 are as defined above.
[062] Another compound even more preferably of formula (I) is characterized by the fact that R2 is CONR6R7 and W, R1, R3, R4, R5, R6 and R7 are as defined above.
[063] More preferably, a compound of formula (I) is characterized by the fact that R3 is hydrogen and W, R1, R2, R4 and R5 are as defined above.
[064] Another most preferred compound of the formula (I) is characterized in that R5 is hydrogen and W, R1, R2, R3 and R4 are as defined above.
[065] The specific, non-limiting, preferred compounds (cmpds.) Of the invention, where appropriate in the form of pharmaceutically acceptable salts, are as follows: 5- (6-aminopyrimidin-4-yl) -2- (5-chlorine -2-ethylphenyl) -1H-pyrrole-3-carbonitrile (compound No 9); 1- (5-chloro-2-methylphenyl) - (7H-pyrrol [2,3-d] pyrimidinyl) -1H-pyrrol-2-carbonitrile (compound No 63); 1- (5-chloro-2-ethylphenyl) -4- (7H-pyrrol [2,3-c] pyrimidin-4-yl) -1H-pyrrol-2-carbonitrile (compound No 68); 1- [2-chloro-5- (trifluormethyl) phenyl] -4- (7H-pyrrol [2,3-d] -pyrimidin-4-yl) -1H-pyrrol-2-carbonitrile (compound No 72); 3- (5-chloro-2-methylphenyl) -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 123); 3- (5-chloro-2-ethylphenyl) -5- (7H-pyrrol [2,3 — d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 124); 3- [2-ethyl-5- (trifluormethyl) phenyl] -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1-pyrrol-2-carboxamide (compound 125); 3- (5-chloro-2-methylphenyl) -N-methyl-5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 129); 3- (5-chloro-2-ethylphenyl) -N-methyl-5- (7H-pyrrol [2,3-d] -pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 130); 3- [2-ethyl-5- (trifluormethyl) phenyl] -methyl-5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 131); 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1H-pyrrole-3-carboxamide (compound No 189); 2- (5-chloro-2-methylphenyl) -5- [6- (methylamino) pyrimidin-4-yl] -1H-pyrrole-3-carboxamide (compound No 190); 2- (5-chloro-2-methylphenyl) -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 191); 2- (5-chloro-2-methylphenyl) -5- (1H-pyrrol [2,3-d] pyridin-4-yl) -1H-pyrrol-3-carboxamide (compound No 192); 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -1H-pyrrole-3-carboxamide (compound No 197); 2- (5-chloro-2-ethylphenyl) -5- [6- (methylamino) pyrimidin-4-yl] -1H-pyrrole-3-carboxamide (compound No 198); 2- (5-chloro-2-ethylphenyl) -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 199); 5- (6-aminopyrimidin-4-yl) -2- [2-chloro-5- (trifluormethyl) -phenyl] -1H-pyrrole-3-carboxamide (compound No 204); 2- [2-chloro-5- (trifluormethyl) phenyl] -5- [6- (methylamino) -pyrimidin-4-yl] -1H-pyrrole-3-carboxamide (compound No 205); 2- [2-chloro-5- (trifluormethyl) phenyl] -5- (7H-pyrrol [2,3-d] -pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 206); 5- (6-aminopyrimidin-yl) -2- [2-methyl-5- (trifluoromethyl) -phenyl] -1H-pyrrole-3-carboxamide (compound No 211); 5- [6- (methylamino) pyrimidin-4-yl] -2- [2-methyl-5- (trifluoromethyl) -phenyl] -1H-pyrrole-3-carboxamide (compound No 212); 2- [2-methyl-5- (trifluormethyl) phenyl] -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 213); 5- (6-aminopyrimidin-4-yl) -2- [2-ethyl-5- (trifluormethyl) -phenyl] -1H-pyrrole-3-carboxamide (compound No 218); 2- [2-ethyl-5- (trifluormethyl) phenyl] -5- [6- (methylamino) -pyrimidin-4-yl] -1H-pyrrole-3-carboxamide (compound No 219); 2- [2-ethyl-5- (trifluormethyl) phenyl] -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 220); 1- (5-chloro-2-methylphenyl) -4- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 229); 1- (5-chloro-2-methylphenyl) -4- (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 234); 4- (6-aminopyrimidin-4-yl) -1- (5-chloro-2-ethylphenyl) -1H-pyrrole-2-carboxamide (compound No 235); 1- (5-chloro-2-ethylphenyl) -4- [6- (methylamino) pyrimidin-4-yl] -1H-pyrrole-2-carboxamide (compound No 236); 1- (5-chloro-2-ethylphenyl) - (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 237); 1- (5-chloro-2-ethylphenyl) -4- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-2-carboxamide (compound No 240); 1- (5-chloro-2-ethylphenyl) -4- (6,7-dihydro-5H-pyrrol [2,3-d] - pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No. 241); 1- [2-chloro-5- (trifluormethyl) phenyl] -4- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound 244); 1- [2-chloro-5- (trifluormethyl) phenyl] -4- (9H-purin-6-yl) - 1H-pyrrole-2-carboxamide (compound No 245); 1- [2-chloro-5- (trifluormethyl) phenyl] -4- (1H-pyrazol [3,4-d] pyrimidin-4-yl) -1H-pyrrole-2-carboxamide (compound No 246); 4- (6-aminopyrimidin-4-yl) -1- [2-ethyl-5- (trifluormethyl) -phenyl] -1H-pyrrole-2-carboxamide (compound No 256); 4- (5-chloro-2-methylphenyl) -1- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 270); 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -N-methyl-1H-pyrrole-3-carboxamide (compound No 301); 2- (5-chloro-2-ethylphenyl) -N-methyl-5- [6- (methylamino) pyrimidin-4-yl] -1H-pyrrole-3-carboxamide (compound No 302); 2- (5-chloro-2-ethylphenyl) -N-methyl-5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 303); 2- [2-methyl-5- (trifluormethyl) phenyl] -N-methyl-5- (7H-pyrrol- [2,3-d] pyrimidin-4-yl) 1H-pyrrol-3-carboxamide (compound 318) ; 5- (6-aminopyrimidin-yl) -2- [2-ethyl-5- (trifluoromethyl) phenyl] -N-methyl-1H-pyrrole-3-carboxamide (compound 321); 2- [2-ethyl-5- (trifluormethyl) phenyl] -N-methyl-5- [6- (methyl-amino) pyrimidin-4-yl] -1H-pyrrol-3-carboxamide (compound No 322); 2- [2-ethyl-5- (trifluormethyl) phenyl] -N-methyl-5- (7H-pyrrol- [2,3-d] -pyrimidin-4-yl) -1H-pyrrol-3-carnoxamide (compound 323); 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1- (2-hydroxyethyl) -1H-pyrrole-3-carboxamide (compound No 331); and 5- (6-Aaminopyrimidin-4-yl) -3- (5-chloro-2-methylphenyl) -1- (2-hydroxyethyl) -1H-pyrrole-2-carboxamide (compound No 335).
[066] The present invention also provides a process for the preparation of a compound of formula (I), as defined above, using the reaction pathways and synthesis schemes described below, employing the techniques available in the art and readily available starting materials . The preparation of certain embodiments of the present invention is described in the examples that follow, but those skilled in the art will recognize that the described preparations can be easily adapted to prepare other embodiments of the present invention. For example, the synthesis of non-exemplified compounds according to the invention can be carried out by modifications evident to those skilled in the art, for example, by adequately protecting interfering groups, by switching to other suitable reagents known in the art, or by taking change in reaction conditions. Alternatively, other reactions referred to herein or known in the art will be recognized as having adaptability for the preparation of other compounds of the invention.
[067] The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. Unless otherwise indicated, the starting materials are known compounds or can be prepared from known compounds according to well-known processes. It will be appreciated that, where typical or preferred process conditions (i.e., reaction temperatures, times, molar ratios of reagents, solvents, pressures) are given, other process conditions can also be used, unless otherwise indicated. Optimal reaction conditions may vary with the particular reagents or solvents used, but those conditions can be determined by a person skilled in the art through routine optimization procedures. In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Protective groups suitable for various functional groups, as well as conditions suitable for protection and deprotection of particular functional groups, are well known in the art. For example, numerous protecting groups are described in a T.W. Greene and P.G.M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited there.
[068] A compound of formula (I) can be prepared according to the general synthetic procedures described below in Schemes A, B, C, D, E and F.
[069] Reported Scheme A shows the preparation of a compound of formula (Ia) in which R1, R3, R4 are as defined above, R2 is CN and R5 is hydrogen. SCHEME A

[070] In the above Scheme R1, R3, R4 are as defined above, R2 is CN, R5 is hydrogen, X is halogen, and PG is a protecting group, such as SEM, Boc or benzenesulfonyl.
[071] Those of ordinary skill in the art will appreciate that any transformation carried out in accordance with said methods may require conventional modifications, such as, for example, protecting interfering groups, switching to other suitable reagents known in the art or making routine changes in reaction conditions.
[072] Thus, a process of the present invention comprises the following steps: Step 1: reaction of a derivative of formula (II)
wherein R1 and R3 are as defined above and PG is a protecting group such as benzenesulfonyl with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxiborolane;
[073] Alternatively: Step 1a: reaction of a halogenated derivative of formula (III)
(III) where R1, R3 are as defined above, X is halogen, and PG is a protecting group, such as SEM, Boc, with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2 -dioxiborolane; Step 2: metal-catalyzed coupling reaction of the compound resulting from formula (IV)
(IV) where R1, R3 are as defined above and PG is a protecting group, such as SEM, Boc, benzenesulfonyl with a halogenated derivative of formula (V): R4
(V) where R4 is as defined above and X is halogen; Step 3: deprotection of the compound resulting from formula (VI)
(VI) where R1, R3, R4 are as defined above and PG is a protecting group, such as SEM, Boc, benzenesulfonyl to give a compound of formula (Ia):
(Ia) where R1, R3, R4 are as defined above, R2 is CN and R5 is hydrogen; optionally, converting a compound of formula (Ia) to a different compound other than formula (Ia), and, if desired, converting a compound of formula (Ia) to a pharmaceutically acceptable salt or converting a salt to the compound free (Ia).
[074] According to Step 1 of Scheme A, the conversion of a compound of general formula (II) to a compound of formula (IV) can be carried out by reaction with 2-isopropoxy-4,4,5,5- tetramethyl-1,3,2-dioxiborolane in the presence of lithium diisopropylamide in THF at -78 ° C.
[075] According to Step 1a of Scheme A, the conversion of a halogenated derivative of general formula (III) to a compound of formula (IV) can be carried out by a subsequent halogen-lithium exchange and reaction with 2-isopropoxy -4,4,5,5-tetramethyl-1,3,2-dioxiborolane in THF at -78 ° C (Q. Jiang, M. Ryan, P. Zhichkin, J. Org. Chem., 2007, 72, 6618 -6620).
[076] According to Step 2 of Scheme A, the metal-catalyzed coupling reaction of a compound of formula (IV) with a halogenated derivative of general formula (V) to give a compound of formula (VI) can be performed in a variety of ways. Preferably, a compound of formula (VI) can be prepared from an intermediate of formula (IV) by coupling Suzuki-Miyaura catalyzed by Pd. Couplings catalyzed by transition metals of (hetero) aryl halides with (hetero) aryl boronic acids or boronic esters are well known to the person skilled in the art, see references: a) Miyaura, Norio; Suzuki, Akira (1979). "Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chemical Reviews 95 (7): 2457-2483; b) Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions ( Metal-catalyzed cross-coupling reactions), Diederich F., and Stang, PJ, Eds .; Wiley-VCH: New York, 1998, pages 49-97. In the so-called Suzuki-Miyaura reaction, coupling reaction of (hetero) aryl boronic acids or boronic esters with (hetero) aryl halides is typically triggered by palladium complexes. Phosphine-palladium complexes, such as tetrakis (triphenylphosphine) palladium (0) are used for this reaction, but also bis (triphenylphosphine) palladium (II), [1,1-bis (diphenylphosphino) ferrocene] dichloro palladium (II) chloride ) can be used. A base such as potassium phosphate, sodium carbonate, cesium carbonate, potassium carbonate, potassium t-butoxide, tetraethylammonium hydroxide, triethylamine is added and tetrahydrofuran, dioxane, N, N-dimethylformamide, ethanol and toluene can be used as a means of reaction. Typically, temperatures range from room temperature to 150 ° C. Conventional heating, along with microwave irradiation can be employed. The duration of the reaction varies from about 30 min to about 96 hours. Various combinations of Pd / base / solvent catalysts have been described in the literature, which allows fine adjustment of reaction conditions in order to allow for a wide range of additional functional groups in both coupling partners.
[077] According to Step 3 of Scheme A, the removal of the protecting group PG from the pyrrole ring of a compound of formula (VI) can be carried out following procedures that are well known in the art (Jolicoeur, B .; Chapman , EE; Thommpson, A .; Lubell, WD Tetrahedron 2006, 62, 11531). Depending on the choice of protection group, the following conditions can be employed: tert-butoxycarbonyl (Boc) can be removed in the presence of TFA in DCM or by Na2CO3 in DME, DMF, at a temperature ranging from room temperature to 130 ° Ç; 2- (trimethylsilyl) ethoxymethyl (SEM) and triisopropylsilyl (TIPS) can be removed with TBAF, HF.Py or TFA in solvents such as THF, DCM, at room temperature or below; benzenesulfonyl (Bs) and toluenesulfonyl (Ts) groups can be removed with KOH, NaOH, K2CO3, LiOH, Triton B, magnesium, also in the presence of ammonium chloride in solvents such as methanol, tetrahydrofuran, dioxane, at temperatures ranging from temperature environment to reflux; the trimethylsilylethylsulfonyl group (SES) can be removed using TBAF in THF at room temperature; the 4-methoxy-benzyl (MB) and 2,4-dimethoxybenzyl (DMB) groups can be removed by exposure to acid in the presence of anisole to intercept the benzyl carbonium ion (for example, 5% H2SO4, TFA, anisol).
[078] The present invention further provides an alternative process for the preparation of a compound of formula (Ia) in which R2 is CONR6R7, R5 is hydrogen and R1, R3, R4, R6 and R7 are as defined above. SCHEME B

[079] In the above Scheme R2 is CONR6R7, R5 is hydrogen, R1, R3, R4, R6 and R7 are as defined above, X is halogen and PG is a protecting group, such as benzenesulfonyl.
[080] Those of ordinary skill in the art will appreciate that any transformation carried out in accordance with said methods may require conventional modifications, such as, for example, protecting interfering groups, switching to other suitable reagents known in the art or making routine changes in reaction conditions.
[081] Thus, a process of the present invention comprises the following steps: Step 4: reaction of a derivative of formula (VII) o (C.-CJ Alkyl rj H- F'G
(VII) where R1 and R3 are as defined above and PG is a protecting group such as benzenesulfonyl with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxiborolane; Step 5: metal-catalyzed coupling reaction of the compound resulting from formula (VIII)
wherein R1 and R3 are as defined above and PG is a protecting group, such as benzenesulfonyl, with a derivative of formula (V), as defined above; Step 6: hydrolysis under basic conditions of the carboxylic ester resulting from formula (IX)
(IX) where R1, R3, R4 and PG are as defined above; Step 7: amidation of the carboxylic acid resulting from formula (X)
(X) where R1, R3 and R4 are as defined above, by reaction with an amine derivative of formula (XI) NHR6R7 (XI) where R6 and R7 are as defined above, to give a compound of formula (Ia )
(Ia) where R2 is CONR6R7, R5 is hydrogen, R1, R3, R4, R6 and R7 are as defined above; optionally, converting a compound of formula (Ia) to a different compound other than formula (Ia), and, if desired, converting a compound of formula (Ia) to a pharmaceutically acceptable salt or converting a salt in the free compound (Ia).
[082] According to Step 4 of Scheme B, the conversion of a compound of general formula (VII) to a compound of formula (VIII) can be carried out by the reaction already described in Step 1 of Scheme A.
[083] According to Step 5 of Scheme B, the metal-catalyzed coupling reaction of a compound of formula (VIII) with a halogenated derivative of general formula (V) to give a compound of formula (IX) can be performed in a variety of ways already described in Step 2 of Scheme A.
[084] According to Step 6 of Scheme B, the hydrolysis of the carboxylic ester resulting from formula (IX) to the carboxylic acid of formula (X) can be carried out in a variety of ways. Typically LiOH.H2O in THF or NaOH or KOH, in alcoholic solution is used, at a temperature ranging from room temperature to 150 ° C, for a time ranging from about 30 min to about 96 hours. Conventional heating, along with microwave irradiation, can be employed. In the meantime, removal of the benzenesulfonyl protecting group occurs.
[085] According to Step 7 of Scheme B, the conversion of a carboxylic acid of formula (X) to a carboxamide of formula (Ia) can be carried out in a variety of forms and experimental conditions, which are widely known in the art. art for the preparation of carboxamides. As an example, a compound of formula (X) can be converted to its corresponding acyl chloride in the presence of thionyl chloride or oxalyl chloride, in a suitable solvent, such as toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, dioxane , at a temperature between about -10 ° C until reflux and for a period of time ranging from about 1 hour to about 96 hours. Acyl chloride can be isolated by evaporation of the solvent and further reacted with a 33% ammonium hydroxide solution or with an NHR6R7 amine (XI) in a suitable solvent, such as toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran , dioxane, at a temperature ranging from about -10 ° C to reflux and for a period of time ranging from about 1 hour to about 96 hours. Alternatively, a compound of formula (X) can be reacted with the ammonium salt of 1-hydroxybenzotriazole or with an amine NHR6R7 (XI) in the presence of a carbodiimide such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, hydrochloric acid salt of 1- ethyl-3- (3'-dimethylamino) - carbodiimide and hydroxybenzotriazole. This reaction is preferably carried out in a suitable solvent, such as, for example, tetrahydrofuran, dichloromethane, toluene, dioxane, N, N-dimethylformamide and in the presence of a proton scavenger such as, for example, triethylamine, N, N - diisopropylethylamine, at a temperature ranging from room temperature to reflux, for a time ranging from about 30 min to about 96 hours.
[086] The reported Scheme C illustrates the preparation of a compound of formula (Ib) in which R1, R3, R4 and R5 are as defined above and R2 is CN. SCHEME C

[087] In the above Scheme R1, R3, R4 and R5 are as defined above, X is halogen and R2 is CN.
[088] Those of ordinary skill in the art will appreciate that any transformation carried out in accordance with said methods may require conventional modifications, such as, for example, protecting interfering groups, switching to other suitable reagents known in the art or making routine changes in reaction conditions.
[089] Thus, a process of the present invention comprises the following steps: Step 8: reaction of a halogenated derivative of formula (XII) (XII)
wherein R1, R3 and R5 are as defined above and X is halogen with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxiborolane; Step 9: metal-catalyzed coupling reaction of the compound resulting from formula (XIII)
wherein R1, R3 and R5 are as defined above, with a halogenated derivative of formula (V), as defined above, to give a compound of formula (Ib)
(Ib) where R1, R3, R4 and R5 are as defined above and R2 is CN; optionally, converting a compound of formula (Ib) to a different compound of formula (Ib), and, if desired, converting a compound of formula (Ib) to a pharmaceutically acceptable salt or converting a salt to the compound free (Ib).
[090] According to Step 8 of Scheme C, the conversion of a halogenated derivative of general formula (XII) to a compound of formula (XIII) can be carried out under the condition already described in Step 1a of Scheme A.
[091] According to Step 9 of Scheme C, the metal-catalyzed coupling reaction of a compound of formula (XIII) with a halogenated derivative of general formula (V) to give a compound of formula (Ib) can be performed in a variety of ways already described in Step 2 of Scheme A.
[092] The reported Scheme D shows the preparation of a compound of formula (Ic) in which R1, R3, R4 and R5 are as defined above and R2 is CN. DI Scheme

[093] In the above Scheme R1, R3, R4 and R5 are as defined above, X is halogen and R2 is CN.
[094] Those of ordinary skill in the art will appreciate that any transformation carried out in accordance with said methods may require conventional modifications, such as, for example, protecting interfering groups, switching to other suitable reagents known in the art or making routine changes in reaction conditions.
[095] Thus, a process of the present invention comprises the following step: Step 10: reaction of a derivative of formula (XIV)
(XIV) wherein R1, R3 and R5 are as defined above, with a halogenated derivative of formula (V), as defined above, in the presence of a base or catalyzed by metal to obtain a compound of formula (Ic)
(Ic) where R1, R3, R4 and R5 are as defined above and R2 is CN; optionally, converting a compound of formula (Ic) to a different compound of formula (Ic), and, if desired, converting a compound of formula (Ic) to a pharmaceutically acceptable salt or converting a salt to the compound free (Ic).
[096] According to Step 10 of Scheme D, the reaction of a compound of formula (XIV) with a halogenated derivative of general formula (V) to give a compound of formula (Ic) can be carried out in the presence of a base , such as sodium hydride and tetrahydrofuran or dioxane can be used as a reaction medium. Typically, temperatures vary between 5 ° C until reflux. The duration of the reaction varies from about 30 min to about 24 hours. Alternatively, the metal catalyzed coupling reaction of a compound of formula (XIV) with a halogenated derivative of general formula (V) to give a compound of formula (Ic) can be carried out in the presence of dipaladium tris (dibenzylidenoacetone) and tri-palladium tert butylphosphine. A base, such as sodium carbonate, cesium carbonate, potassium carbonate is added and tetrahydrofuran, dioxane, N, N-dimethylformamide and toluene can be used as the reaction medium. Typically, temperatures range from room temperature to 150 ° C. Conventional heating, along with microwave irradiation, can be employed. The duration of the reaction varies from about 30 min to about 24 hours.
[097] The reported Scheme E shows the preparation of a compound of formula (Id) in which R2 is CONR6R7, R3 is hydrogen and R1, R4, R5, R6 and R7 are as defined above. Scheme E

[098] In the above Scheme R2 is CONR6R7, R3 is hydrogen, R1, R4, R5, R6 and R7 are as defined above, X is halogen and PG is a protecting group, such as benzenesulfonyl.
[099] All those of ordinary skill in the art will appreciate that any transformation carried out in accordance with said methods may require conventional modifications, such as, for example, protecting interfering groups, switching to other suitable reagents known in the art or making routine changes in reaction conditions.
[100] Thus, a process of the present invention comprises the following steps: Step 11: reaction of a derivative of formula (XV)
wherein R1 and R5 are as defined above and PG is a protecting group such as benzenesulfonyl with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxiborolane; Step 12: Metal-catalyzed coupling reaction of the compound resulting from formula (XVI)
wherein R1 and R5 are as defined above and PG is a protecting group, such as benzenesulfonyl, with a derivative of formula (V), as defined above; Step 13: hydrolysis under basic conditions of the carboxylic ester resulting from formula (XVII)
where R1, R4 and R5 are as defined above and PG is a protecting group; Step 14: amidation of the carboxylic acid resulting from formula (XVIII)
wherein R1, R4 and R5 are as defined above, by reaction with an amine derivative of formula (XI), as defined above, to give a compound of formula (Id)
(Id) where R1, R4, R5, R6 and R7 are as defined above and R3 is hydrogen; optionally, converting a compound of the formula (Id) to another compound other than the formula (Id), and, if desired, converting a compound of the formula (Id) to a pharmaceutically acceptable salt thereof or converting a salt in the free compound (Id).
[101] According to Step 1 of Scheme 1 E, the conversion of a compound of general formula (XV) to a compound of formula (XVI) can be carried out by the reaction already described in Step 1 of Scheme A.
[102] According to Step 12 of Scheme E, the metal-catalyzed coupling reaction of a compound of formula (XVI) with a halogenated derivative of general formula (V) to give a compound of formula (XVII) can be performed in a variety of ways already described in Step 2 of Scheme A.
[103] According to Step 13 of Scheme E, the hydrolysis of the resulting carboxylic ester of formula (XVII) to the carboxylic acid of formula (XVIII) can be carried out by the reaction already described in Step 6 of Scheme B.
[104] According to Step 14 of Scheme E, the conversion of a carboxylic acid of formula (XVIII) to a carboxamide of formula (Id) can be carried out in a variety of experimental forms and conditions already described in Step 7 of Scheme B.
[105] The reported Scheme F shows the preparation of a compound of formula (Ie) in which R2 is CONR6R7 and R1, R3, R4, R5, R6 and R7 are as defined above. SCHEME F

[106] In the Scheme above, R1, R3, R4 and R5 are as defined above, R2 is CONR6R7, where R6 and R7 are as defined above, X is halogen and PG is a protecting group such as Boc.
[107] Those of ordinary skill in the art will appreciate that any transformation carried out in accordance with said methods may require conventional modifications, such as, for example, protecting interfering groups, switching to other suitable reagents known in the art, or making routine changes in reaction conditions.
[108] Thus, a process of the present invention comprises the following steps: Step 15: reaction of a halogenated derivative of formula (XIX)
(XIX) where R1, R3 and R5 are as defined above, PG is a protecting group such as Boc and X is halogen, with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxiborolane ; Step 16: Metal-catalyzed coupling reaction of the compound resulting from formula (XX)
(XX) where R1, R3 and R5 are as defined above and PG is a protecting group such as Boc, with a halogenated derivative of formula (V), as defined above; Step 17: deprotection of the compound resulting from formula (XXI)
(XXI) where R1, R3, R4 and R5 are as defined above and PG is a protecting group such as Boc; Step 18: reaction of the compound resulting from formula (XXII)
(XXII) where R1, R3, R4 and R5 are as defined above, with an amine derivative of formula (XI), as defined above, in the presence of triphosgene, to give a compound of formula (Ie)
(Ie) where R2 is CONR6R7 and R1, R3, R4, R5, R6 and R7 are as defined above; optionally, converting a compound of formula (Ie) to a different compound of formula (Ie), and, if desired, converting a compound of formula (Ie) to a pharmaceutically acceptable salt or converting a salt in the free compound (Ie).
[109] According to Step 15 of Scheme F, the conversion of a halogenated derivative of general formula (XIX) to a compound of formula (XX) can be carried out under conditions already described in Step 1a of Scheme A.
[110] According to Scheme F Step 16, the metal-catalyzed coupling reaction of a compound of formula (XX) with a halogenated derivative of general formula (V) to give a compound of formula (XXI) can be performed in a variety of ways already described in Step 2 of Scheme A.
[111] According to Step 17 of Scheme F, deprotection of the compound of formula (XXI) to give a compound of formula (XXII) can be carried out under the condition already described in Step 3 of Scheme A.
[112] According to Step 18 of Scheme F, the compound of formula (XXII) is reacted with an amine of formula (XI) in the presence of triphosgene to give a compound of formula (Ie). The reaction is carried out in an appropriate halogenated hydrocarbon, preferably dichloromethane, and in the presence of a suitable amine, such as diisopropylethylamine or triethylamine, at room temperature.
[113] As indicated above, a compound of the formula (I), which is prepared according to the process object of the invention, can be conveniently converted into another compound of the formula (I) operating according to the conditions of synthesis as well known, the following being examples of possible conversions: conv.1) conversion of a compound of formula (I), where R2 is CN, to the corresponding compound of formula (I), where R2 is CONH2, by hydrolysis under acidic conditions ,
preferably carried out in glacial acetic acid or trifluoroacetic acid and concentrated sulfuric acid, more preferably in proportions between 1 to 1 and 5 to 1, optionally, in the presence of water, at a temperature between room temperature and 120 ° C, in particular at a temperature from 60 ° C to 90 ° C; conv.2) conversion of a compound of formula (I), where R2 is CONH2, to the corresponding compound of formula (I), where R2 is CONR6R7, where R6 and R7 are as defined above, but both are not hydrogen ,
by exhaustive tert-butoxycarbonylation of a compound of formula (I), treatment with an amine derivative of formula (XXIII) NHR6R7 (XXIII) in which R6 and R7 are as defined above, but both are not hydrogen and deprotection of the protecting groups tert-butoxycarbonyl (light conversion of primary carboxamides to substituted amides (SK Davidsen et al., J. Org. Chem. 1991, 56, 5482-5485); conv.3) conversion of a compound of formula (Ia), wherein R5 is hydrogen or (Id) where R3 is hydrogen, in the corresponding compound of formula (Ia) or (Id), where R5 or R3 are, respectively, an optionally substituted group selected from straight or branched C1-C6 alkyl , C3-C7 cycloalkyl, heterocyclyl and heterocyclyl-alkyl,
by treatment with optionally substituted alkyl halide of the formula R5-X (XXIV) or R3-X (XXV), where R5 or R3 is as defined above and X is halogen, in a solvent such as N, N-dimethylformamide and na presence of a base at a temperature ranging from room temperature to reflux from about 30 min to about 96 hours.
[114] From all of the above, it is evident to the person skilled in the art that all compounds with formula (I) having a functional group, which can be further derivatized to another functional group, by working according to methods well known in the art, thus leading to other compounds of formula (I), are intended to be understood within the scope of the present invention.
[115] Needless to say, also any of the intermediates in the processes described above can be converted to a different intermediate, if desired and necessary, by operating in a similar way as in any of the conversion reactions described above.
[116] From all of the above, it is evident to the person skilled in the art that when preparing the compounds of formula (I), according to any of the process variants mentioned above, the optional functional groups within the materials of starter or its intermediates, which could give rise to unwanted side reactions, need to be adequately protected according to conventional techniques. Likewise, the conversion of the latter to the free unprotected compounds can be carried out according to known procedures.
[117] As will be readily appreciated, if the compounds of formula (I), prepared according to the process described above, are obtained as a mixture of isomers, their separation by conventional techniques in the individual isomers of formula (I) is within the scope of the present invention.
[118] The final compounds can be isolated and purified using conventional procedures, for example, chromatography and / or crystallization and salt formation.
[119] The compounds of formula (I), as defined above, can be converted to pharmaceutically acceptable salts. The compounds of formula (I), as defined above, or their pharmaceutically acceptable salts, can subsequently be formulated with a pharmaceutically acceptable carrier or diluent, to provide a pharmaceutical composition.
[120] The synthesis of a compound of formula (I), according to the synthesis process described above, can be carried out gradually, so that each intermediary is isolated and purified by conventional purification techniques, such as, for example, example, column chromatography, before carrying out the subsequent reaction. Alternatively, two or more steps of the synthetic sequence can be carried out in a process called "one-pot", as is known in the art, in which only the compound resulting from two or more steps is isolated and purified.
[121] In cases where a compound of formula (I) contains one or more asymmetric centers, said compound can be separated into the individual isomers by processes known to those skilled in the art. Such procedures include standard chromatographic techniques, including chromatography using a chiral stationary phase, or by crystallization. General methods for separating compounds that contain one or more asymmetric centers are reported, for example, in Jacques, Jean; Collet, André; Wilen, Samuel H., - Enantiomers, Racemates, and Resolutions, John Wiley & Sons Inc., New York (New York), 1981.
[122] According to any variant of the process for the preparation of the compounds of the formula (I), the starting materials and any other reagents are known or easily prepared according to known methods, or as described in the experimental part below.
[123] For example, the compounds of formula (II) can be prepared as described in the experimental part, Preparation D; the compounds of the formula (III) can be prepared as described in the experimental part, Preparation C; the compounds of formula (VII) can be prepared as described in the experimental part, Preparation E and O; the compounds of the formula (XII) can be prepared as described in the experimental part, Preparation H; the compounds of the formula (XIV) can be prepared as described in the experimental part, Preparation K; the compounds of the formula (XV) can be prepared as described in the experimental part, Preparation L; the compounds of the formula (XIX) can be prepared as described in the experimental part, Preparation H; the compounds of the formula (V) are either commercially available or can be prepared by known methods or can be prepared as described in the experimental part, Preparation N; the compounds of the formula (XI) are commercially available.
[124] The compounds of the present invention can be administered either as isolated agents or, alternatively in combination with known anti-cancer treatments such as radiation therapy or chemotherapy regimen in combination with cytostatic or cytotoxic agents, antibiotic-type agents, alkylating agents, agents antimetabolites, hormones, immunological agents, interferon-like agents, cyclooxygenase inhibitors (eg COX-2 inhibitors), matrixmetaloprotease, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents , anti-EGFR agents, anti-angiogenesis agents (eg, angiogenesis inhibitors), farnesyl transferase inhibitors, ras-raf signal transduction pathway inhibitors, cell cycle inhibitors, other cdk inhibitors, tubulin binding agents , topoisomerase I inhibitors, topoisomerase II inhibitors, and the like.
[125] If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent within the approved dosage range.
[126] The compounds of formula (I) can be used sequentially with known anti-cancer agents when a combination formulation is inappropriate.
[127] The compounds of the formula (I) of the present invention, suitable for administration to a mammal, for example, to humans, can be administered by the usual routes and the dosage level depends on the age, weight, conditions of the patient and route of administration. management.
[128] For example, a suitable dosage adopted for oral administration of a compound of formula (I) can vary from about 10 to about 500 mg per dose, from 1 to 5 times a day. The compounds of the invention can be administered in a variety of 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 through intravenous and / or intrathecal and / or intraspinal injection or infusion.
[129] 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 can be a carrier or a diluent.
[130] Pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a suitable pharmaceutical form. For example, solid oral forms may contain, together with the active compound, diluents, for example, lactose, dextrose, sucrose, cellulose, corn starch or potato starch; lubricants, for example, silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols; binding agents, for example, starches, gum arabic, gelatin methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disintegrating agents, for example, starch, alginic acid, alginates or sodium starch glycolate; effervescent mixtures; coloring matters; 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, compressing, sugar coating or film coating processes.
[131] Liquid dispersions for oral administration can be, for example, syrups, emulsions and suspensions. As an example, syrups may contain, as a vehicle, sucrose or sucrose with glycerin and / or mannitol and sorbitol.
[132] Suspensions and emulsions may contain, as examples of vehicles, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, for example, sterile water, olive oil, ethyl oleate, glycols, for example, propylene glycol and, if desired, an adequate amount of hydrochloride lidocaine.
[133] Solutions for intravenous injections or infusions may contain, as a vehicle, sterile water or, preferably, may be in the form of solutions, aqueous, isotonic, sterile saline, or may contain propylene glycol as a vehicle.
[134] Suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, for example, cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
[135] In order to better illustrate the present invention, without limiting it, the following examples are now given. EXPERIMENTAL SECTION
[136] For a reference to 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 following examples, the compounds of the present invention were synthesized using the methods described herein, or other methods, which are well known in the art. General purification and analytical methods
[137] Thin layer chromatography was performed on pre-coated Merck silica gel 60 F254 plates. Column chromatography was carried out either under medium pressure on silica (Merck silica gel 40-63 μm) or by means of a Biotage SP1 flash purification system with pre-packaged silica gel cartridges (Biotage or Varian). The components were visualized by UV light (À: 254 nm) and by iodine vapor. When necessary, the compounds were purified by preparative HPLC on a Waters Symmetry C18 column (19 x 50 mm, 5 μm) or on a Waters X Terra RP 18 column (30 x 150 mm, 5 μm) using Waters preparative HPLC equipment 600 equipped with a 996 Waters PDA detector and a single ZMD quadrupole mass spectrometer in Micromass mode, electron spray ionization, in positive mode. Method 1: Phase A: 0.1% TFA / ACN 95/5; phase B: ACN / H2O 95/5. Gradient of 10 to 90% B in 8 minutes, keep 90% B for 2 min; flow rate of 20 mL / min. Method 2: Phase A: 0.05% NH4OH / ACN 95/5; Phase B: ACN / H2O 95/5. Gradient from 10 to 100% B in 8 minutes, keep 100% B for 2 min. Flow rate of 20 mL / min.
[138] 1H-NMR spectra were recorded on DMSO-d6 or CDCl3 on a Varian Inova 400 spectrometer operating at 400.50 MHz for 1 H and on a Varian Inova 500 spectrometer operating at 499.75 MHz. The solvent signal residual was used as a reference (δ = 2.50 or 7.27 ppm). Chemical shifts (δ) are reported in parts per million (ppm) and coupling constants (J) in Hz. The following abbreviations are used for multiplicities: s = singlet; br. s. = Broad signal; d = doublet; t = triplet; m = multiplet; dd = doublet of doublets.
[139] Electrospray mass spectra (ESI) were obtained on an Ion Trap Finnigan LCQ.
[140] Unless otherwise indicated, all final compounds were homogeneous (purity of not less than 95%), as determined by high performance liquid chromatography (HPLC). The HPLC-UV-MS analyzes used to evaluate the purity of the compound were performed by combining the MS Ion Trap instrument with the HPLC system SSP4000 (Thermo Separation Products) equipped with an LC Pal automatic sampler (CTC Analytics) and UV6000LP diode array detector (UV detection 215 -400 nm). Instrument control, acquisition and data processing were performed with the Xcalibur 1.2 software (Finnigan). HPLC chromatography was performed at room temperature, with a flow rate of 1 mL / min, using a Waters X Terra RP 18 column (4.6 x 50 mm; 3.5 μm). Mobile phase A was 5 mM ammonium acetate buffer (pH 5.5 with acetic acid): 90:10 acetonitrile, and mobile phase B was 5 mM ammonium acetate buffer (pH 5.5 with acetic acid) : acetonitrile 10:90; the gradient was 0 to 100% B in 7 minutes, then keep 100% B for 2 minutes before rebalancing.
[141] ESI (+) (EMAR) high resolution mass spectra were obtained in a Q-Tof Waters Ultima directly linked with micro HPLC 1100 Agilent, as previously described (Colombo, M .; Riccardi-Sirtori, F .; Rizzo , V .; Rapid Commun. Mass Spectrom., 2004, 18, 511-517).
[142] In the following examples, as well as throughout the application, the following abbreviations have the following meanings. If not defined, the terms have their generally accepted meanings. ABBREVIATIONS

Preparation A 2-chloro-5- (trifluormethyl) methyl benzoate

[143] To a solution of 5-chloro-2 (trifluoromethyl) benzoic acid (8.96 g, 40 mmol) in MeOH (40 mL) sulfuric acid (96%, 4 mL) was added dropwise. The reaction mixture was refluxed for 4 h. The reaction mixture was cooled to room temperature, poured into saturated Na2CO3 solution at 5 ° C, with stirring, and then extracted with EtOAc. The organic phase was washed with water, with aqueous saline, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound as an oil (8.79 g, 92%). 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 2.2 Hz, 1H), 7.97 (dd, J = 2.2, 8.2 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 3.90 (s, 3H).
[144] According to this procedure, but starting from 2-methyl-5- (trifluormethyl) benzoic acid, the following compound was prepared: 2-methyl-5- (trifluormethyl) methyl benzoate 1H NMR (500 MHz, DMSO- d6) δ 8.08 (s, 1H), 7.86 (dd, J = 1.6, 7.9 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 3, 87 (s, 3H), 2.60 (s, 3H).
[145] According to this procedure, but starting from 2-bromo-5- (trifluormethyl) benzoic acid, the following compound was prepared: 2-Bromo-5- (trifluormethyl) methyl benzoate 1H NMR (400 MHz, DMSO- d6) δ 8.10 (d, J = 1.6 Hz, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.85 (dd, J = 2.1, 8.4 Hz, 1H), 3.89 (s, 3H). Preparation B Methyl 5-chloro-2-ethylbenzoate

[146] In a 500 mL round-bottom flask equipped with a stir bar, condenser and three-way valve connected to argon and vacuum, methyl 2-bromo-5-chlorobenzoate (15.0 g, 60 mmol), ethylboronic acid (5.3 g, 72 mmol), K3PO4.3H2O (48.0 g, 180 mmol), tricyclohexylphosphine (1.7 g, 6 mmol) and toluene (250 mL) and water (12 mL) were loaded at room temperature. The resulting reaction mixture was degassed three times, refilled with argon each time before loading Pd (OAc) 2 (0.673 g, 3 mmol). The resulting reaction mixture was degassed four times, filled with argon each time and then heated to 110 ° C for 5 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, washed with EtOAc and the filtrate was concentrated and then diluted with EtOAc (400 ml) and water (300 ml). The two layers were separated, and the aqueous layer was extracted with EtOAc (100 ml). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc 97/3) to obtain the title compound (9.3 g, 78%). 1H NMR (600 MHz, DMSO-d6) δ 7.74 (d, J = 2.4 Hz, 1H), 7.57 (dd, J = 2.4, 8.4 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 3.84 (s, 3H), 2.85 (q, J = 7.4 Hz, 2 H), 1.15 (t, J = 7.4 Hz, 3 H).
[147] In accordance with this procedure, but starting from methyl 2-bromo-5- (trifluormethyl) benzoate, the following compound was prepared: 2-ethyl-5- (trifluormethyl) methyl benzoate 1H NMR (600 MHz , DMSO-d6) δ 8.04 (d, J = 1.10 Hz, 1H), 7.88 (dd, J = 1.5, 8.2 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 3.87 (s, 3H), 2.97 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H). Preparation C: Preparation of compounds of formula (III) 5-Bromo-2- (5-chloro-2-methylphenyl) -1- {[2- (trimethylsilyl) - ethoxy] -methyl} -1H-pyrrole-3-carbonitrile (III)
Step 1: 3- (5-chloro-2-methylphenyl) -3-oxopropanenitrile
[148] To a solution of LiHMDS (76 ml, 1 M solution) in THF (70 ml) cooled to -78 ° C was added ACN (4.1 ml, 79 mmol) dropwise. The solution was stirred at -78 ° C for 1 h, and a solution of methyl 5-chloro-2-methylbenzoate (7.38 g, 40 mmol) in THF (20 ml) was added. The reaction mixture was allowed to warm to room temperature over 16 h. Then NH4Cl (110 ml, 10% aqueous solution) was added, and the mixture was extracted with EtOAc (120 ml). The aqueous layer was further extracted with EtOAc (80 ml), dried over Na2SO4 and evaporated to dryness. The crude residue was purified by flash chromatography (hexane / EtOAc 85/15) to give the title compound (6.2 g, 80%). 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 2.1 Hz, 1H), 7.57 (dd, J = 2.1, 8.4 Hz, 1H), 7.29 -7.47 (m, 1H), 4.69 (s, 2H), 2.41 (s, 3H). Step 2: 3- (5-chloro-2-methylphenyl) -3- [(2,2-diethoxyethyl) amino] prop-2-enonitrile
[149] A mixture of 3- (5-chloro-2-methylphenyl) -3-oxopropanonitrile (4.65 g, 24 mmol), 2-aminoacetaldehyde-diethyl-acetal (3.85 mL, 26.5 mmol) and Toluene (150 mL) was stirred at reflux overnight under nitrogen in the Dean-Stark apparatus. The mixture was evaporated in vacuo and used in the next step without further purification. Step 3: 2- (5-chloro-2-methylphenyl) -1H-pyrrole-3-carbonitrile
[150] For TFA (20 mL) at 5 ° C, the crude product 3- (5-chloro-2-methylphenyl) -3- [(2,2-diethoxyethyl) amino] prop-2-enonitrile dissolved in DCM ( 10 mL) was added. After stirring at room temperature for 30 min, the reaction mixture was concentrated and then diluted with EtOAc and a saturated solution of NaHCO3. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated. Column chromatography on silica gel (EtOAc / hexane, elution gradient between 0% and 20%) provided the title compound (2.31 g, 45%, 2 steps). 1H NMR (400 MHz, DMSO-d6) δ 11.99 (br. S, 1H), 7.42-7.47 (m, 1H), 7.39-7.42 (m, 1H), 7, 38 (d, J = 2.2 Hz, 1H), 7.04 (t, J = 2.8 Hz, 1H), 6.59 (t, J = 2.8 Hz, 1H), 2.26 ( s, 3H).
[151] According to this procedure, but starting from the appropriate benzoate derivative, the following compounds were prepared: 2- (5-chloro-2-ethyl-phenyl) -1H-pyrrole-3-carbonitrile 1H NMR (400 MHz, DMSO -d6) δ 11.99 (br. s., 1H), 7.47-7.52 (m, 1H), 7.41-7.46 (m, 1H), 7.31-7.37 ( m, 1H), 7.02 (t, J = 2.81 Hz, 1H), 6.53-6.61 (m, 1H), 2.58 (q, J = 7.53 Hz, 2H), 0.99 (t, J = 7.51 Hz, 3H). 2- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrole-3-carbonitrile 1H NMR (400 MHz, DMSO-d6) δ 12.23 (br., 1H), 7.80-7 , 96 (m, 3H), 7.12 (t, J = 2.81 Hz, 1H), 6.65 (t, J = 2.69 Hz, 1 H). 2- [2-methyl-5- (trifluormethyl) phenyl] -1H-pyrrole-3-carbonitrile 1H NMR (500 MHz, DMSO-d6) δ 12.08 (br., 1H), 7.74 (d , J = 7.96 Hz, 1H), 7.65 (s, 1H), 7.62 (d, J = 8.24 Hz, 1H), 7.08 (t, J = 2.75 Hz, 1H ), 6.62 (t, J = 2.61 Hz, 1H), 2,362.39 (m, 3H). 2- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrol-3-carbonitrile 1H NMR (600 MHz, DMSO-d6) δ 12.05 (br., 1H), 7.79 (dd , J = 1.46, 8.06 Hz, 1H), 7.66 (d, J = 8.24 Hz, 1H), 7.61 (s, 1H), 7.06 (t, J = 2, 75 Hz, 1H), 6.61 (t, J = 2.75 Hz, 1H), 2.69 (q, J = 7.51 Hz, 1H), 2.07 (s, 1H), 1.11 -1.52 (m, 1H), 1.04 (t, J = 7.51 Hz, 1 H). 2-Phenyl-1H-pyrrole-3-carbonitrile 1H NMR (600 MHz, DMSO-d6) δ 12.15 (br. S., 1H), 7.94 (dd, J = 1.28, 8.42 Hz , 2H), 7.76 (dd, J = 1.28, 8.42 Hz, 2H), 7.49-7.54 (m, 2H), 7.36-7.42 (m, 1H), 7.02 (t, J = 2.84 Hz, 1H), 6.58 (dd, J = 2.38, 2.93 Hz, 1 H). Step 4: 2- (5-chloro-2-methylphenyl) -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole-3-carbonitrile (II)
[152] NaH (60% dispersion in mineral oil, 0.452 g, 11.3 mmol) was added to a suspension of 2- (5-chloro-2-methylphenyl) -1H-pyrrole-3-carbonitrile (1.733 g, 8.0 mmol) in dry THF (25 mL) at 0 ° C. The reaction was maintained at the same temperature for 20 min, then 2- [(chloromethoxy) ethyl] (trimethyl) silane (2.0 ml, 11.3 mmol) was added and the mixture was stirred at room temperature for 2 h . Saturated NaCl solution (30 ml) was added at 0 ° C and the mixture was extracted with EtOAc (2 x 35 ml). The separated organic phase was dried over Na2SO4 and the solvent evaporated to give the title compound (2.637 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ 7.50 (dd, J = 2.3, 8.3 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.21 (d, J = 3.0 Hz, 1H), 6.64 (d, J = 3.0 Hz, 1H), 5.16 (d , J = 10.8 Hz, 1H), 4.95 (d, J = 10.8 Hz, 1H), 3.27-3.30 (m, 2H), 2.10 (s, 3H), 0 , 69-0.76 (m, 2H), -0.08 (s, 9H). EMAR M / z (ESI) calculated for C18H23CIN2OSi + H + 347.1341, found 347.1345. Step 5: 5-Bromo-2- (5-chloro-2-methylphenyl) -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole-3-carbonitrile
[153] To a solution of 2- (5-chloro-2-methylphenyl) -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole-3-carbonitrile (2.5 g, 7.2 mmol ) in MeOH / THF 2/1 (450 mL) NBS (1.281 g, 7.2 mmol) was added in three portions over 3 h at 5 ° C. The mixture was allowed to stir at room temperature after each addition. The mixture was evaporated in vacuo. Saturated NaCl solution was added and the mixture was extracted with EtOAc. The separated organic phase was dried over Na2SO4, the solvent was evaporated and the crude product was purified by flash chromatography (hexane / EtOAc 9/1) to provide the title compound (2.14 g, 70%). 1H NMR (400 MHz, DMSO-d6) δ 7.52-7.57 (m, 1H), 7.40-7.48 (m, 2H), 6.92 (s, 1H), 5.17 ( d, J = 11.2 Hz, 1H), 4.94 (d, J = 11.2 Hz, 1H), 3.27-3.30 (m, 2H), 2.12 (s, 3H), 0.62-0.82 (m, 2H), -0.08 (s, 9H). M / z of EMAR (ESI) calculated for C18H22BrCIN2OSi + H + 425.0446, found 425.0441.
[154] According to this procedure, but starting from the appropriate substituted carbonitrile, the following compounds were prepared: 5-Bromo-2- (5-chloro-2-ethylphenyl) -1- {[2- (trimethylsilyl) ethoxy] methyl } -1H-pyrrole-3-carbonitrile (III) 1H NMR (600 MHz, DMSO-d6) δ 7.59 (dd, J = 2.4, 8.4 Hz, 1H), 7.47-7.51 (m, 1H), 7.40 (d, J = 2.4 Hz, 1H), 6.91 (s, 1H), 5.15 (d, J = 11.2 Hz, 1H), 4.89 (d, J = 11.2 Hz, 1H), 2.40-2.47 (m, 1H), 2.29-2.36 (m, 1H), 1.05 (t, J = 7.5 Hz, 3H), 0.65-0.78 (m, 2H), -0.07 (s, 9H). M / z of EMAR (ESI) calculated for C19H24BrCIN2OSi + Na + 439.0603, found 439.0600. 5-Bromo-2- [2-chloro-5- (trifluormethyl) phenyl] -1- {[2- (trimethylsilyl) ethoxy) methyl} -1H-pyrrole-3-carbonitrile (III) 1H NMR (400 MHz, DMSO -d6) δ 8.03 (s, 1H), 7.93-8.01 (m, 2H), 6.98 (s, 1H), 5.23 (d, J = 11.4 Hz, 1H) , 5.06 (d, J = 11.4 Hz, 1H), 3.27-3.30 (m, 2H), 0.61-0.77 (m, 2H), -0.11 (m, 9H).
[155] M / z of EMAR (ESI) calculated for C18H19BrCIF3N2OSi + Na + 500.9983, found 500.9982. 5-bromo-2- [2-methyl-5- (trifluormethyl) phenyl] -1- {[2- (tri-methylsilyl) ethoxy] methyl} -1H-pyrrole-3-carbonitrile (III) 1H NMR (600 MHz , DMSO-d6) δ 7.80-7.90 (m, 1H), 7.73 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 6.94 (s, 1H), 5.15 (d, J = 11.2 Hz, 1H), 4.93 (d, J = 11.2 Hz, 1H), 3.28-3.30 (m, 2H), 2, 22 (s, 3H), 0.62-0.75 (m, 2H), -0.10 (s, 9H). M / z of EMAR (ESI) calculated for C19H22BrF3N2OSi + Na + 481.0529, found 481.0531. 5-bromo-2- [2-ethyl-5- (trifluormethyl) phenyl] -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole-3-carbonitrile (III) 1H NMR (600 MHz, DMSO -d6) δ 7.89 (dd, J = 1.5, 8.2 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.69 (s, 1H), 6 , 94 (s, 1H), 5.14 (d, J = 11.2 Hz, 1H), 4.88 (d, J = 11.2 Hz, 1H), 3.28-3.30 (m, 2H), 2.55-2.59 (m, 1H), 2.44 (qd, J = 7.4, 14.7 Hz, 1H), 1.08-1.12 (m, 3H), 0 , 65-0.76 (m, 2H), -0.09 (s, 9H). M / z of EMAR (ESI) calculated for C20H24BrF3N2OSi + Na + 495.0685, found 495.0689. 5-Bromo-2-phenyl-1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole-3-carbonitrile (III) 1H NMR (600 MHz, DMSO-d6) δ 7.51-7.63 (m, 5H), 6.91 (s, 1H), 5.23 (s, 2H), 3.34-3.38 (m, 2H), from 0.71-0.78 (m, 2H) , -0.08 (s, 9H). M / z EMAR (ESI) calculated for C17H21BrN2OSi + H + 377.0680, found 377.0685. Step 5a: 5-Bromo-2- (5-chloro-2-methylphenyl) -1H-pyrrole-3-carbonitrile
[156] To a solution of 2- (5-chloro-2-methylphenyl) -1H-pyrrole-3-carbonitrile (400 mg, 1.85 mmol) in ACN (20 mL) was added NBS (329 mg, 1, 85 mmol) in two portions for 2 h at 5 ° C. The mixture was allowed to stir at room temperature after each addition. The mixture was evaporated in vacuo and the crude product was purified by flash chromatography (hexane / EtOAc 9/1) to provide the title compound (379 mg, 69%). 1H NMR (400 MHz, DMSO-d6) δ 12.72 (br. S., 1H), 7.44-7.48 (m, 1H), 7.38-7.44 (m, 2H), 6 , 73 (s, 1H), 2.26 (s, 3H).
[157] According to this procedure, but starting from 2- (5-chloro-2-ethylphenyl) -1H-pyrrole-3-carbonitrile, the following compound was prepared: 5-Bromo-2- (5-chloro-2 -ethylphenyl) -1H-pyrrole-3-carbonitrile 1H NMR (400 MHz, DMSO-d 6) δ 12.73 (br. s., 1H), 7.51 (dd, J = 2.20, 8.43 Hz, 1H), 7.44 (d, J = 8.42 Hz, 1H), 7.39 (d, J = 2.38 Hz, 1H), 6.72 (s, 1H), 2.58 ( q, J = 7.57 Hz, 2H), 1.02 (t, J = 7.60 Hz, 3H). Preparation D: Preparation of compounds of formula (II) 2- (5-chloro-2-ethylphenyl) -1- (phenylsulfonyl) -1H-pyrrole-3-carbonitrile (II)

[158] To a solution of 2- (5-chloro-2-ethylphenyl) -pyrrole-3-carbonitrile (1.26 g, 5.46 mmol) in DMF (13 mL) was added NaH (60% dispersion in oil, 262 mg, 6.55 mmol) at 5 ° C, under an argon atmosphere. The reaction mixture was stirred for 1 h, then, dropwise, benzenesulfonyl chloride (0.766 ml, 6.01 mmol) was added. After 24 h, the reaction mixture was added to water (50 ml) with stirring. EtOAc (75 mL) was added, the organic layer was separated and washed with water, brine, dried over Na2SO4, filtered, the solvent was evaporated under reduced pressure to give an oil, which was purified by flash chromatography SP1 (Biotage) (hexane / EtOAc 9/1) to provide the title compound (1.44 g, 71%). 1H NMR (600 MHz, DMSO-d6) δ 7.79-7.87 (m, 1H), 7.61 (dd, J = 7.7, 8.4 Hz, 1H), 7.56 (dd, J = 2.2, 8.4 Hz, 1H), 7.51 (dd, J = 0.9, 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 3.6 Hz, 1H), 6.80 (d, J = 2.2 Hz, 1H), 2.01 (q, J = 7.6 Hz, 1H), 0, 96 (t, J = 7.6 Hz, 1 H). Preparation E: Preparation of compounds of formula (VII) 2-phenyl-1- (phenylsulfonyl) -1H-pyrrole-3-carboxylate (VII)
Step 1: Ethyl 3-oxo-3-phenylpropanoate-1H-imidazole
[159] Carbonyldiimidazole (7.31 g, 45 mmol) was added to a solution of benzoic acid (5.0 g, 41 mmol) in DMF (50 mL). The mixture was stirred at room temperature. After 2 h of magnesium chloride (4.68 g, 49 mmol) and potassium monoethyl malonate (14 g, 82 mmol) were added. The mixture was heated to 100 ° C with stirring until the reaction was complete, then cooled to room temperature and added slowly to 750 ml of ice water to precipitate a solid. The solid was recovered by filtration, yielding the title compound (8.66 g, 81.1%), which was used in the next step without further purification. 1H NMR (600 MHz, DMSO-d 6) δ 11.99 (br. S., 1H), 7.71-7.81 (m, 2H), 7.28-7.39 (m, 3H), 5.24 (s, 2H), 4.00 (q, J = 6.9 Hz, 2H), 1.16 (t, J = 7.0 Hz, 3H). Step 2: Ethyl 2-phenyl-1H-pyrrole-3-carboxylate
[160] Acetyl chloride (4.17 g, 53.14 mmol) was added to a solution of 2,2-diethoxyethanamine (6.43 g, 48.3 mmol) and TEA (6.84 g, 67.62 mmol) in EtOAc (70 mL), at room temperature. After 1 h, EtOH (0.7 ml) was added. The resulting suspension was stirred for 1 h, and then filtered. EtOAc was removed by evaporation from the filtration waters giving N- (2,2-diethoxyethyl) acetamide as an oil, which was used without further purification in the next step. ethyl 3-oxo-3-phenylpropanoate-1H-imidazole (8.66 g, 33.26 mmol) in TFA (10.6 mL) was treated with N- (2,2-diethoxyethyl) acetamide (48.3 mmol) . The reaction mixture was heated for 60 min at 60 ° C, then the TFA was removed by evaporation and the oily residue was dissolved in EtOAc, washed twice with water and a saturated solution of NaHCO3. The organic layer was recovered and the solvent was evaporated to obtain a dark oil. The oil was treated with EtOH (28 ml) and 2N NaOH (14 ml), the resulting reaction mixture was stirred at room temperature overnight. The solution was added slowly to ice water, obtaining, after filtration, the title compound (6.2 g, 55.8%). 1H NMR (600 MHz, DMSO-d 6) δ 11.60 (br. S., 1H), 7.53-7.61 (m, 2H), 7.38-7.43 (m, 2H), 7.31-7.36 (m, 1H), 6.84 (t, J = 2.75 Hz, 1H), 6.53 (t, J = 2.75 Hz, 1H), 4.10 (q , J = 7.02 Hz, 2H), 1.17 (t, J = 7.14 Hz, 3H). Step 3: Ethyl 2-phenyl-1- (phenylsulfonyl) -1H-pyrrole-3-carboxylate
[161] To a solution of ethyl 2-phenyl-1H-pyrrole-3-carboxylate (1.0 g, 4.65 mmol) in DMF (12 mL), NaH (60% oil dispersion, 223 mg, 5 , 58 mmol) was added at 5 ° C, under an argon atmosphere. The reaction mixture was stirred for 1 h, then, dropwise, benzenesulfonyl chloride (0.653 ml, 5.11 mmol) was added. After 2 h, the reaction mixture was added to water and ice with stirring. EtOAc (150 ml) was added, the organic layer was separated and washed with water, brine, dried over Na2SO4, filtered, the solvent was evaporated under reduced pressure to give an oil, which was purified by flash chromatography SP1 (Biotage) (cycle -hexane / EtOAc 9/1) to provide the title compound (1.24 g, 75%). 1H NMR (600 MHz, DMSO-d 6) δ 7.70-7.75 (m, 1H), 7.62-7.65 (m, 1H), 7.50-7.55 (m, 2H) , 7.40-7.43 (m, 1H), 7.37-7.39 (m, 2H), 7.24-7.30 (m, 2H), 6.90-6.98 (m, 2H), 6.72 - 6.76 (m, 1H), 3.88-3.94 (m, 2H), 0.82-0.96 (m, 3H). Preparation F 5-chloro-2-ethylaniline
Step 1: 4-ethyl-3-nitroaniline
[162] 4-ethylaniline (10.3 ml, 82.5 mmol) was added dropwise to sulfuric acid (96%, 63 ml), cooled to 8 ° C, maintaining the temperature below 10 ° C. After the addition, the reaction mixture was cooled to -5 ° C, before adding a mixture of nitric acid (100%, 4 ml) and sulfuric acid (96%, 10 ml), keeping the temperature below 0 ° Ç. The reaction mixture was then stirred at the same temperature for 1 h. The reaction mixture was poured into ice (200 ml) and the precipitate was filtered and washed with water. The solid was suspended with water (100 ml) and neutralized with NH4 OH (35%). The precipitate was filtered and dried in the oven to obtain a light brown solid (10.0 g, 73%). 1H NMR (400 MHz, DMSO-d 6) δ 7.11 (d, J = 8.3 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 2.4, 8.3 Hz, 1H), 5.53 (s, 2H), 2.63 (q, J = 7.4 Hz, 2H), 1.11 (t, J = 7.4 Hz, 3H). Step 2: 4-chloro-1-ethyl-2-nitrobenzene
[163] A solution of sodium nitrite in water (4.2 g, 60 mmol, 5 M, 12 mL) was added dropwise to a cooled (5 ° C) solution of 4-ethyl-3-nitroaniline (10 g, 60 mmol) in conc. (200 ml) and the reaction mixture was stirred at the same temperature for 1.5 h. CuCl (9.5 g, 96 mmol) was then added and the solution was stirred at room temperature for 1 h and then at 80 ° C for an additional hour. After cooling, the reaction mixture was extracted with DCM (3 x 100 ml) and the combined organic layers were dried over Na2SO4. The crude product was then purified by flash chromatography (hexane / EtOAc 9/1) to obtain the title compound as a yellow oil (6.28 g, 56%). 1H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 2.3 Hz, 1H), 7.74 (dd, J = 2.2, 8.3 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 2.78 (q, J = 7.4 Hz, 2H), 1.19 (t, J = 7.4 Hz, 3H) Step 3: 5-chlorine -2-ethylaniline
[164] A solution of hydrazine hydrate (6.95 ml, 134.7 mmol) in methanol (50 ml) was added dropwise to a solution of 4-chloro-1-ethyl-2-nitrobenzene (6.25 g, 33.7 mmol) in methanol (120 mL), in the presence of iron (III) chloride (547 mg, 3.4 mmol) and activated carbon (547 mg) and the reaction mixture was stirred under reflux for 14 H. The solids were removed by filtration through Celite, the filtrate was concentrated and purified by flash chromatography (hexane / EtOAc 9/1) to obtain the title compound as a light light oil (5.09 g, 97%). 1H NMR (400 MHz, DMSO-d6) δ 6.89 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 2.2 Hz, 1H), 6.47 (dd, J = 2.2, 8.0 Hz, 1H), 5.12 (s, 2H), 2.39 (q, J = 7.5 Hz, 2H), 1.09 (t, J = 7.4 Hz , 3H). Preparation G 2-ethyl-5- (trifluoromethyl) aniline
Step 1: 1-Ethenyl-2-nitro-4- (trifluormethyl) benzene
[165] 1-Bromo-2-nitro-4- (trifluoromethyl) benzene (6.14 ml, 40.1 mmol) was dissolved in 2-propanol (200 ml). To this mixture of TEA (19.8 ml, 140.3 mmol) and vinyl potassium trifluoroborate (6.44 g, 48.1 mmol) were added. The resulting reaction mixture was degassed three times and refilled with argon each time, before PDCl2 (dppf) was loaded (1.5 g, 2.0 mmol). The resulting reaction mixture was degassed four times, filled with argon each time and then heated to reflux for 3 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, washed with EtOAc, and the filtrate was concentrated and then diluted with EtOAc and water. The two layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic fractions were washed with aqueous saline, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc 9/1) to provide the title compound (5.6 g, 64%). 1H NMR (600 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H ), 7.03 (dd, J = 11.1, 17.3 Hz, 1H), 6.07 (d, J = 17.3 Hz, 1H), 5.68 (d, J = 11.1 Hz , 1 H). Step 2: 2-ethyl-5- (trifluormethyl) aniline
[166] 1-Etenyl-2-nitro-4- (trifluormethyl) benzene (2.2 g, 10.13 mmol) dissolved in THF (150 mL) was stirred at room temperature under H2 (40 psi) in the presence of 10 % Pd / C (200 mg) for 8 h. The reaction mixture was filtered through a pad of Celite, washed with EtOAc, and the filtrate was concentrated. The residue was purified by flash chromatography (hexane / EtOAc 9/1) to provide the title compound (1.76 g, 92%). 1H NMR (600 MHz, DMSO-d6) δ 7.10 (d, J = 7.7 Hz, 1H), 6.89 (d, J = 1.5 Hz, 1H), 6.61-6.81 (d, J = 7.7 Hz, 1H), 5.30 (s, 2H), 2.48 (q, J = 7.5 Hz, 2 H), 1.13 (t, J = 7.5 Hz, 3H).
Bromo-1- (5-chloro-2-ethylphenyl) -1H-pyrrol-2-carbonitrile (XII) Step 1: 1- (5-chloro-2-ethyl-phenyl) -1H-pyrrole
[167] 5-chloro-2-ethylaniline (10.8 g, 69.44 mmol) and 2,5-dimethoxy-tetrahydrofuran (9.87 mL, 76.38 mmol) were refluxed for 3 h in AcOH ( 20 mL). The reaction mixture was evaporated and the residue was diluted in EtOAc, washed with water, saturated NaHCO3 solution, brine, and then dried over Na2SO4. The solvent was evaporated and the crude product was purified by means of SP1 flash chromatography (Biotage) (gradient elution from 0% to 15% EtOAc in hexane) to obtain the title compound (12.52 g, 88%). 1H NMR (600 MHz, DMSO-d6) δ 7.36-7.47 (m, 2H), 7.31 (d, J = 1.3 Hz, 1H), 6.93 (t, J = 2, 1 Hz, 2H), 6.23 (t, J = 2.1 Hz, 2H), 2.46 (q, J = 7.5 Hz, 2H), 0.99 (t, J = 7.5 Hz , 3H). Step 2: 1- (5-chloro-2-ethylphenyl) -1H-pyrrole-2-carbonitrile
[168] To a solution of 1- (5-chloro-2-ethylphenyl) -1H-pyrrole (11.8 g, 57.56 mmol) in anhydrous ACN (150 mL) was added chlorosulfonyl isocyanate (5.32 mL , 61.11 mmol) dropwise at 0 ° C. The mixture was stirred at the same temperature for 30 min and then DMF (12 ml) was added to this mixture dropwise. After stirring at the same temperature for 1 h, the reaction mixture was poured into ice water, stirred for 10 min and then diluted with EtOAc. The organic layer was isolated and the aqueous layer was extracted twice with EtOAc. The combined organic phases were dried over Na2SO4 and evaporated in vacuo. The crude product was purified by means of SP1 flash chromatography (Biotage) (elution gradient from 0% to 15% EtOAc in hexane) to give the title compound (10.62 g, 80%). 1H NMR (600 MHz, DMSO-d6) δ 7.57-7.62 (m, 1H), 7.51-7.55 (m, 2H), 7.39 (dd, J = 1.5, 2 , 6 Hz, 1H), 7.19 (dd, J = 1.5, 3.9 Hz, 1H), 6.44 (dd, J = 2.7, 4.0 Hz, 1H), 2.33 (q, J = 7.5 Hz, 2H), 1.00 (t, J = 7.5 Hz, 3H). Step 3: 4-Bromo-1- (5-chloro-2-ethylphenyl) -1H-pyrrole-2-carbonitrile
[169] To a solution of 1- (5-chloro-2-ethylphenyl) -1H-pyrrole-2-carbonitrile (2.307 g, 10 mmol) in THF (50 mL) was added a solution of NBS (1.87 g , 10.5 mmol) in THF (50 mL). The mixture was allowed to stir at room temperature for 90 min and then a solution of NBS (356 mg, 2 mmol) in THF (10 ml) was added. The mixture was allowed to stir at room temperature for 90 min and then it was evaporated in vacuo. Saturated NaCl solution was added and the mixture was extracted with EtOAc. The separated organic phase was dried over Na2SO4, the solvent evaporated and the crude product was purified by means of SP1 flash chromatography (Biotage) (elution gradient between 0% and 15% EtOAc in hexane) to obtain the title compound ( 2.38 g, 77%). 1H NMR (600 MHz, DMSO-d6) δ 7.68 (d, J = 1.8 Hz, 1H), 7.607.64 (m, 2H), 7.53 (d, J = 8.8 Hz, 1H ), 7.38 (d, J = 1.6 Hz, 1H), 2.34 (q, J = 7.3 Hz, 2H), 1.03 (t, J = 7.3 Hz, 3H).
[170] According to this procedure, but starting from the appropriate aniline, the following compounds were prepared: 4-Bromo-1- (5-chloro-2-methylphenyl) -1H-pyrrole-2-carbonitrile (XII) 1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 1.7 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.55-7.59 ( m, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 1.7 Hz, 1H), 2.06 (s, 1 H). 4-Bromo-1- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrole-2-carbonitrile (XII) 1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 8 , 03 (d, J = 0.7 Hz, 2H), 7.77 (d, J = 1.8 Hz, 1H), 7.45 (d, J = 1.7 Hz, 1 H). 4-Bromo-1- [2-methyl-5- (trifluormethyl) phenyl] -1H-pyrrole-2-carbonitrile (XII) ESI (+) MS: m / z 330 (MH +). 4-Bromo-1- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrole-2-carbonitrile (XII) 1H NMR (600 MHz, DMSO-d6) δ 7.89-7.95 (m, 2H), 7.76 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 1.6 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H) , 2.44 (q, J = 7.3 Hz, 2H), 1.08 (t, J = 7.3 Hz, 3H). 4-Bromo-1-phenyl-1H-pyrrole-2-carbonitrile (XII) ESI (+) MS: m / z 248 (MH +). Preparation I 4-chloro-2-iodo-1-ethylbenzene

[171] A mixture of 5-chloro-2-ethylaniline (3.35 g, 21.5 mmol), p-toluenesulfonic acid (12.29 g, 64.6 mmol) and water (2.15 mL) were ground in a mortar for a few minutes, to obtain a homogeneous suspension to which solid sodium nitrite (3.71 g, 53.8 mmol) was added and the suspension ground for 10 min. Solid potassium iodide (8.94 g, 53.8 mmol) was added and the suspension ground for 20 min. The suspension was then dissolved in water (50 ml) and treated with sodium sulfite (10% aq. Aq.), Before extracting with EtOAc (3 x 100 ml). The combined organic layers were dried over Na2SO4 and the crude product was purified by flash chromatography (hexane) to obtain the title compound as a light yellow oil (4.35 g, 76%). 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 2.2 Hz, 1H), 7.42 (dd, J = 2.2, 8.30 Hz, 1H), 7.29 -7.35 (m, 1H), 2.66 (q, J = 7.5 Hz, 2H), 1.12 (t, J = 7.5 Hz, 3H). Preparation J 1-ethyl-2-iodo-4- (trifluormethyl) benzene
Step 1: 1-ethyl-4- (trifluormethyl) benzene
[172] A solution of 1-ethylenyl-4- (trifluormethyl) benzene (1.72 mL, 11.6 mmol) in THF (60 mL) was stirred in the presence of Pd / C (10%, 400 mg), under a hydrogen atmosphere (45 psi / 0.31 MPa) for 7 h. The solid was filtered through celite (washed with DCM) and the filtrate was carefully concentrated, keeping the bath temperature below 20 ° C to 200 mmHg. The concentrated solution, thus obtained, was used in the next step without further manipulation. 1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 7.9 Hz, 2H). 7.44 (d, J = 7.9 Hz, 2H), 2.70 (q, J = 7.1 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H). Step 2: 1-ethyl-2-iodo-4- (trifluormethyl) benzene
[173] Sulfuric acid (96%, 1.9 mL) was added dropwise to a solution of sodium periodate (3.73 g, 17.4 mmol) and iodine (2.95 g, 11.6 mmol) in a mixture of acetic acid (8.45 ml) and acetic anhydride (4.23 ml), at 0 ° C, followed by the dropwise addition of 1-ethyl-4- (trifluoromethyl) benzene (2.0 g, 11.6 mmol). The reaction mixture was allowed to warm to room temperature while stirring for a period of 24 h. A solution of sodium metabisulfite (10%) was added to extinguish the remaining iodine and, successively, NaOH (35%) was added to reach pH = 7. The aqueous layer was extracted with DCM (3 x 50 mL) and the layers Combined organics were dried over Na2SO4. Once the solvent was removed, the crude product was used without further purification in the next step. 1H NMR (400 MHz, DMSO-cf 6) δ 8.11 (dq, J = 1.9, 0.7 Hz, 1H), 7.69-7.75 (m, 1H), 7.53 (d , J = 8.0 Hz, 1H), 2.75 (q, J = 7.5 Hz, 2H), 1.16 (t, J = 7.51 Hz, 3H). Preparation K: Preparation of compounds of formula (XIV) 4- (5-chloro-2-methylphenyl) -1H-pyrrole-3-carbonitrile (XIV)
Step 1: 5-chloro-2-methylbenzaldehyde
[174] To a solution of 4-chloro-2-iodo-1-methylbenzene (5.0 g, 19.8 mmol) in THF (40 mL) n-BuLi (2.5 M in hexane, 8.72 mL , 21.8 mmol) was added slowly dropwise at -78 ° C under an argon atmosphere. The mixture was stirred at - 78 ° C for 1 h, then DMF (7.7 ml, 99 mmol) was added, followed by heating to room temperature in 4 hours and quenched with 1N HCl (5 ml) . The reaction mixture was stirred overnight, diluted with 1N HCl (50 ml) and Et2O, the organic phase was separated, washed with aqueous saline, dried over Na2SO4 and evaporated to give the title compound (3.14 g, 94%) as a yellow oil. 1H NMR (600 MHz, DMSO-d 6) δ 10.17 (s, 1H), 7.80 (d, J = 2.2 Hz, 1H), 7.60 (dd, J = 2.4, 8 , 1 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 2.57 (s, 3H). Step 2: 3- (5-chloro-2-methylphenyl) -acrylonitrile
[175] To a suspension of NaH (60% dispersion in oil, 950 mg, 23.28 mmol) in dry THF (43 mL) a solution of diethyl cyanomethylphosphonate (3.67 mL, 23.28 mmol) in THF (17 mL) was added dropwise at 5 ° C over 20 min, keeping the reaction temperature below 10 ° C. The suspension was stirred at 5 ° C for 60 min. A solution of 5-chloro-2-methyl-benzaldehyde (2.99 g, 19.4 mmol) in THF (30 mL) was added dropwise over 20 min, keeping the reaction temperature below 10 ° C . The reaction mixture was allowed to warm to room temperature and stirred overnight. Water was added, the solvent was evaporated, the residue was partitioned between EtOAc and water. The aqueous layer was separated and extracted with EtOAc, the combined organic layers were washed with water, brine, dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the title compound (3.26 g, 95%) as a pale yellow oil. Step 3: 4- (5-chloro-2-methylphenyl) -1H-pyrrole-3-carbonitrile
[176] To a suspension of NaH (60% dispersion in oil, 263 mg, 6.58 mmol) in dry THF (40 mL) a solution of 3- (5-chloro-2-methylphenyl) acrylonitrile (970 mg, 15.48 mmol) and (p-toluenesulfonyl) methylisocyanate (1.28 g, 6.58 mmol) in THF (20 mL) was added dropwise at 5 ° C over 10 min, maintaining the temperature of the reaction below 5 ° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. Water was added, the solvent was evaporated, the residue was partitioned between DCM and water. The aqueous layer was separated and extracted with DCM, the combined organic layers were washed with water, brine, dried over Na2SO4, filtered, the solvent was evaporated under reduced pressure and the crude product was purified by means of SP1 flash chromatography (Biotage) ( hexane / EtOAc 7/3) to produce the title compound (497 mg, 42%). 1H NMR (600 MHz, DMSO-d6) δ 11.95 (br. S., 1H), 7.71 (s, 1H), 7.29-7.35 (m, 2H), 7.27 (d , J = 2.2 Hz, 1H), 7.08 (d, J = 1.5 Hz, 1H), 2.27 (s, 3H).
[177] According to this procedure, but starting from suitable substituted iodo-benzene, the following compounds were prepared: 4- (5 chloro-2-ethylphenyl) -1H-pyrrole-3-carbonitrile (XIV) ESI (+) MS : m / z 231 (MH +); 4- [2-chloro-5- (trifluoromethyl) phenyl] -1H-pyrrole-3-carbonitrile (XIV) ESI (+) MS: m / z 271 (MH +); 4- [2-methyl-5- (trifluoromethyl) phenyl] -1H-pyrrole-3-carbonitrile (XIV) ESI (+) MS: m / z 251 (MH +); 4- [2-ethyl-5- (trifluoromethyl) phenyl] -1H-pyrrole-3-carbonitrile (XIV) ESI (+) MS: m / z 265 (MH +); 4-Phenyl-1H-pyrrole-3-carbonitrile (XIV) ESI (+) MS: m / z 169 (MH +). Preparation L: Preparation of compounds of formula (XV) 3- (5-chloro-2-methylphenyl) -1- (phenylsulfonyl) -1H-pyrrole-2-ethyl (XV) carboxylate
Step 1: (E) -2- (5-chloro-2-methylphenyl) ethenyl 4-methylphenyl sulfone
[178] To a solution of methyl- (4-methyl-phenyl) sulfone (6.74 g, 39.6 mmol) in THF (200 mL) n-BuLi (2.5 M in hexane, 34.8 mL, 87.12 mmol) was added dropwise at 0 ° C under an argon atmosphere. After stirring for 30 min at 0 ° C, diethyl chlorophosphate (5.70 ml, 39.6 mmol) in THF (30 ml) was added slowly dropwise. The reaction mixture was stirred at 0 ° C for 30 min, then cooled to -78 ° C, followed by the addition of a solution of 5-chloro-2-methyl-benzaldehyde (6.1 g, 39.6 mmol) in THF (10 mL). After stirring at -78 ° C for 1 h, the temperature of the reaction mixture was allowed to rise to room temperature. Water (50 ml) was added and the reaction mixture was concentrated under reduced pressure to give a precipitate which was filtered, washed with water and dried in an oven under reduced pressure to give the title compound as a beige solid (8.24 g, 68%). 1H NMR (600 MHz, DMSO-d6) δ 7.79-7.85 (m, 2H), 7.76 (d, J = 8.2 Hz, 1H), 7.68-7.72 (m, 1H), 7.62-7.67 (m, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.37-7.43 (m, 1H), 7.30-7 , 34 (m, 1H), 2.41 (s, 3H), 2.39 (s, 3H). Step 2: Ethyl 3- (5-chloro-2-methylphenyl) -1H-pyrrole-2-carboxylate
[179] To a suspension of NaH (60% dispersion in oil, 2.25 g, 56.19 mmol) in dry THF (140 mL) a solution of (E) -2- (5-chloro-2-methylphenyl) ) Ethenyl 4-methylphenyl sulfone (8.18 g, 26.76 mmol) and ethyl isocyanacetate (5.85 mL, 53.52 mmol) in THF (200 mL) was added dropwise at room temperature over 1 h, under an argon atmosphere. The reaction mixture was stirred for 2 h, then water and EtOAc were added. The organic layer was separated and washed with water, brine, dried over Na2SO4, filtered, the solvent was evaporated under reduced pressure to give a brown oil, which was purified by flash chromatography SP1 (Biotage) (hexane / EtOAc 9/1) to obtain the title compound (3.44 g, 49%). 1H NMR (600 MHz, DMSO-d6) δ 11.90 (br. S., 1H), 7.19-7.28 (m, 2H), 7.13 (d, J = 1.6 Hz, 1H ), 7.02-7.08 (m, 1H), 6.14 (t, J = 2.5 Hz, 1H), 4.06 (q, J = 7.1 Hz, 2H), 2.08 (s, 3H), 1.05 (t, J = 7.1 Hz, 1H). Step 3: Ethyl 3- (5-chloro-2-methylphenyl) -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate
[180] To a solution of ethyl 3- (5-chloro-2-methylphenyl) -1H-pyrrole-2-carboxylate (526 mg, 2 mmol) in DMF (5 mL) NaH (60% dispersion in oil, 96 mg, 2.4 mmol) was added at 5 ° C, under an argon atmosphere. The reaction mixture was stirred for 1 h, then, dropwise, benzenesulfonyl chloride (0.306 ml, 2.4 mmol) was added. After 2.5 h at room temperature, the reaction mixture was added to water and ice with stirring. EtOAc was added, the organic layer was separated and washed with water, brine, dried over Na2SO4, filtered, the solvent was evaporated under reduced pressure to give an oil, which was purified by flash chromatography SP1 (Biotage) (hexane / EtOAc 9 / 1) to provide the title compound (783 mg, 97%). 1H NMR (600 MHz, DMSO-d6) δ 8.03 (dd, J = 1.0, 8.3 Hz, 2H), 7.85 (d, J = 3.3 Hz, 1H), 7.78 -7.83 (m, 1H), 7.62 -7.75 (m, 2H), 7.29-7.35 (m, 1H), 7.23-7.28 (m, 1H), 7 , 11 (d, J = 2.2 Hz, 1H), 6.52 (d, J = 3.3 Hz, 1H), 3.96 (q, J = 7.1 Hz, 2H), 2.04 (s, 3H), 0.82 (t, J = 7.0 Hz, 3H).
[181] According to this procedure, but starting from the appropriate substituted benzaldehyde, the following compounds were prepared: ethyl 3- (5-chloro-2-ethylphenyl) -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate ( XV) 1H NMR (600 MHz, DMSO-d6) δ 7.94-8.06 (m, 2H), 7.85 (d, J = 3.30 Hz, 1H), 7.77-7.82 ( m, 1H), 7.68-7.73 (m, 2H), 7.347.37 (m, 1H), 7.28-7.31 (m, 1H), 7.08 (d, J = 2, 38 Hz, 1H), 6.51 (d, J = 3.30 Hz, 1H), 3.93 (q, J = 7.08 Hz, 2H), 2.28-2.40 (m, 2H) , 0.94 (t, J = 7.60 Hz, 3H), 0.78 (t, J = 7.05 Hz, 3H) 3- [2-chloro-5- (trifluormethyl) phenyl] -1- ( ethyl (XV) phenylsulfonyl) -1H-pyrrole-2-carboxylate ESI (+) MS: m / z 458 (MH +). Ethyl 3- [2-methyl-5- (trifluoromethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate (XV) ESI (+) MS: m / z 438 (MH +). Ethyl 3- [2-ethyl-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate (XV) 1H NMR (600 MHz, DMSO-d6) δ 8.04 (dd, J = 1.19, 8.52 Hz, 2H), 7.89 (d, J = 3.11 Hz, 1H), 7.79-7.82 (m, 1H), 7.69-7.73 (m, 2H), 7.66 (d, J = 8.06 Hz, 1H), 7.52 (d, J = 8.06 Hz, 1H), 7.35 (s, 1H), 6.57 (d, J = 3.30 Hz, 1H), 3.88 (q, J = 7.02 Hz, 2H), 2.43-2.49 (m, 2H), 0.98 (t, J = 7.51 Hz, 3H), 0.71 (t, J = 7.14 Hz, 3H). Ethyl (XV) ESI (+) MS 3-phenyl-1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate: m / z 356 (MH +). Preparation M: Preparation of compounds of formula (XIX) 2- (5) chloro-2-methylphenyl) -4-iodo-1H-pyrrole-1-carboxylate (XIX)

[182] PdCl2 (PPh3) 2 (70 mg, 0.10 mmol) and CuI (39 mg, 0.20 mmol) were placed under an argon atmosphere in a screw-cap, flame-dried container. Dry THF (25 mL) was added, and the mixture was degassed with argon. TEA (0.69 mL, 5.00 mmol), 5-chloro-2-methylbenzoyl chloride (945 mg, 5.00 mmol), and tert-butyl prop-2-ynylcarbamate (776 mg, 5.00 mmol ) were added successively to the mixture which was then stirred at room temperature for 1 h. Sodium iodide (3.79 g, 25.0 mmol), toluene-4-sulfonic acid monohydrate (1.94 g, 10.0 mmol), and tert-butyl alcohol (5 mL) were added successively to the mixture, which was stirred at room temperature for 1 h. The reaction mixture was diluted with brine (50 ml), the phases were separated and the aqueous phase was extracted with DCM (3 x 25 ml). The combined organic layers were dried over Na2SO4. After removing the solvents in vacuo, the residue was taken up in celite and chromatographed on silica gel (hexane / EtOAc 95/5) to give the title compound (1.04 g, 50%) as a colorless solid. 1H NMR (600 MHz, DMSO-d6) δ 7.53 (d, J = 1.71 Hz, 1 H,), 7.42 (dd, J = 8.09 Hz, 1H), 7.23 (dd , 1H), 7.20 (dd, 1H), 6.30 (d, J = 1.71 Hz, 1 H) 2.38 (s, 3H), 1.44 (s, 9H).
[183] According to this procedure and using the appropriate acyl chloride, the following compounds were prepared: tert-butyl 2- (5-chloro-2-ethylphenyl) -4-iodo-1H-pyrrol-1-carboxylate ( XIX) ESI (+) MS: m / z 432 (MH +); Tert-butyl 2- [2-chloro-5- (trifluoromethyl) phenyl] -4-iodo-1H-pyrrole-1-carboxylate (XIX) ESI (+) MS: m / z 472 (MH +); Tert-butyl 2- [2-methyl-5- (trifluoromethyl) phenyl] -4-iodo-1H-pyrrole-1-carboxylate (XIX) ESI (+) MS: m / z 452 (MH +); Tert-butyl 2- [2-ethyl-5- (trifluoromethyl) phenyl] -4-iodo-1H-pyrrole-1-carboxylate (XIX) ESI (+) MS: m / z 466 (MH +); 2- (Phenyl) -4-iodine-1H-pyrrole-1-carboxylate (XIX) ESI (+) MS: m / z 370 (MH +). Preparation N: Preparation of compounds of formula (V) 4-chloro-7- (4-methoxy-benzyl) -6,7-dihydro-5H-pyrrol [2,3-d] pyrimidine (V)
Step 1: 2- {4-chloro-6- [(4-methoxybenzyl) amino] pyrimidin-5-yl} ethanol
[184] To a solution of 2- (4,6-dichloropyrimidin-5-yl) ethanol (470 mg, 2.43 mmol) in EtOH (10 mL) were added DIPEA (592 μL, 2.9 mmol) and 4 -methoxybenzylamine (380 μl, 3.40 mmol) was added. The solution was refluxed for 5 h. The solvent was removed in vacuo and the residue was diluted with EtOAc, washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound as an oil (520 mg, 73%). 1H NMR (600 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.76 (t, J = 5.7 Hz, 1H), 7.22 (d, J = 8.6 Hz, 2H ), 6.86 (d, J = 8.6 Hz, 2H), 4.82 (t, J = 5.2 Hz, 1H), 4.52 (d, J = 5.8 Hz, 2H), 3.71 (s, 3H), 3.51-3.61 (m, 2H), 2.81 (t, J = 6.8 Hz, 2H). Step 2: 6-chloro-5- (2-chloroethyl) -N- (4-methoxybenzyl) pyrimidin-4-amine
[185] 2- {4-chloro-6- [(4-methoxybenzyl) amino] pyrimidin-5-yl} ethanol (293 mg, 1 mmol) in toluene (5 mL) was treated with SOCl2 (145 μL, 2 mmol ). The reaction mixture was refluxed for 1 h and then concentrated to give the title compound as an oil. The crude product was used for the next reaction without purification. 1H NMR (600 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.03 (t, J = 5.59 Hz, 1H), 7.22 (d, J = 8.6 Hz, 2H ), 6.86 (d, J = 8.6 Hz, 2H), 4.53 (d, J = 5.8 Hz, 2H), 3.72 (t, J = 7.3 Hz, 2H), 3.71 (s, 3H), 3.13 (t, J = 7.3 Hz, 2H). Step 3: 4-chloro-7- (4-methoxybenzyl) -6,7-dihydro-5H-pyrrol- [2,3-d] pyrimidine
[186] To a solution of 6-chloro-5- (2-chloroethyl) -N- (4-methoxybenzyl) pyrimidin-4-amine in DMF (5 ml) K2CO3 (414 mg, 3 mmol) was added and, in then, it was heated to 110 ° C for 2 h. The reaction mixture was diluted with water and extracted with EtOAc, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the title compound as an oil (261 mg, 95%). 1H NMR (600 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.21 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H ), 4.50 (s, 2H), 3.73 (s, 3H), 3.53 (t, J = 8.7 Hz, 2H), 3.00 (t, J = 8.7 Hz, 2H ). Preparation O: Preparation of compounds of formula (VII) 2- (5-chloro-2-ethylphenyl) -1- (phenylsulfonyl) -1H-pyrrole-3-methyl carboxylate (VII)
Step 1: Methyl 3- (5-chloro-2-ethylphenyl) prop-2-inoate
[187] To a solution of 4-chloro-1-ethyl-2-iodo-benzene (2.66 g, 10 mmol) and methyl propiolate (1.79 mL, 20 mmol) in DMF (20 mL), Cu2O (1.43 g, 10 mmol) was added. The reaction was heated to 110 ° C (oil bath temperature) for 20 hours with mechanical stirring. The reaction was filtered through a plug of celite, the plug was washed with EtOAc (100 ml) and the filtrate was washed first with water, then with brine. Drying over sodium sulfate from the organic phase, evaporating and purifying the crude product by chromatography on silica gel (heptane / Et2O 95/5) provided the title compound as an oil (1.29 g, 58%). 1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 2.3 Hz, 1H), 7.56 (dd, J = 2.3, 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 3.80 (s, 3H), 2.75 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.57 Hz , 3H). Step 2: Methyl 3- [acetyl- (2,2-diethoxyethyl) amino] -3- (2-ethylphenyl-5-chloro) prop-2-enoate
[188] Methyl 3- (5-chloro-2-ethylphenyl) prop-2-inoate (500 mg, 2.25 mmol) in DMF (4.5 mL) was treated with 2,2-diethoxyethanamine (0.368 mL, 2.48 mmol) and heated to 110 ° C (oil bath temperature) for 18 h. The volatiles were evaporated under reduced pressure and the crude product was heated to reflux in acetic anhydride (9 ml). After 10 h the reaction was stopped and removal of the volatiles under reduced pressure provided the title compound which was used in the next step without further purification. Step 3: 2- (5-chloro-2-ethylphenyl) -1H-pyrrole-3-carboxylate
[189] Methyl 3- [acetyl (2,2-diethoxyethyl) amino] -3- (5-chloro-2-ethylphenyl prop-2-enoate (2.25 mmol) in DCM (0.350 mL) was added to chloride magnesium (43 mg, 0.45 mmol) in TFA (0.6 mL), heated to 65 ° C (oil bath temperature). After 0.5 h, the reaction was evaporated and the crude product isolated by chromatography over silica gel (hexane: EtOAc 8: 2) to obtain the title compound as a yellow crystalline solid (142 mg, 24%). ESI (+) MS: m / z 264 (MH +). Step 4: 2- Methyl (5-chloro-2-ethylphenyl) -1- (phenylsulfonyl) -1H-pyrrole-3-carboxylate
[190] To a solution of methyl 2- (5-chloro-2-ethylphenyl) -1H-pyrrole-3-carboxylate (0.2 g, 0.76 mmol) in DMF (3 mL) NaH (60 ° dispersion) % in oil, 36 mg, 0.91 mmol) was added at 5 ° C, under an argon atmosphere. The reaction mixture was stirred for 1 h, then, dropwise, benzenesulfonyl chloride (0.106 ml, 0.83 mmol) was added. After 2 h, the reaction mixture was added to water and ice, with stirring. EtOAc (30 mL) was added, the organic layer was separated and washed with water, brine, dried over Na2SO4, filtered, the solvent was evaporated under reduced pressure to give an oil, which was purified by flash chromatography SP1 (Biotage) (cycle -hexane / EtOAc 9/1) to obtain the title compound (248 mg, 81%). ESI (+) MS: m / z 404 (MH +). EXAMPLE 1 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1H-pyrrole-3-carbonitrile (compound No 1)
Scheme A: Steps 1a, 2, 3 Step 1a: 2- (5-chloro-2-methylphenyl) -5- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) - 1- {[2- (trimethylsilyl) -ethoxy] - methyl} -1H-pyrrole-3-carbonitrile (IV)
[191] To a solution of 5-bromo-2- (5-chloro-2-methylphenyl) -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole-3-carbonitrile (948 mg, 2, 23 mmol) in THF (10 mL) 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxiborolane (0.683 mL, 3.35 mmol) was added to the mixture at -78 ° C under atmosphere argon. n-BuLi (2.5 M in hexane, 1.95 mL, 5.025 mmol) was added slowly dropwise at -78 ° C. The mixture was stirred at - 78 ° C for 1 h. MeOH (1.5 ml) was added and the resulting mixture was stirred at room temperature after slowly raising the temperature. NH4Cl solution (10 ml) was added and the mixture was extracted with EtOAc (30 ml), washed with aqueous saline, dried over Na2SO4, filtered, concentrated under reduced pressure and used in the next step without further purification. Step 2: 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-methyl-phenyl) -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole-3-carbonitrile (SAW)
[192] In a 50 mL round-bottom flask equipped with a stirring bar, condenser and 3-way valve connected to a vacuum and argon atmosphere 2- (5-chloro-2-methylphenyl) -5- (4.4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) - 1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrol-3-carbonitrile from the previous step, 6-iodopyrimidine- 4-amine (740 mg, 3.35 mmol), 2M Na2CO3 (3.35 mL, 6.70 mmol) and dioxane (22 mL) were charged at room temperature. The resulting reaction mixture was degassed three times, filled with argon again each time, before PdCl2 (dppf) (182 mg, 0.223 mmol) was loaded. The resulting reaction mixture was degassed four times, filled with argon each time and then heated to 110 ° C for 1 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, washed with EtOAc, and the filtrate was concentrated and then diluted with EtOAc (30 ml) and water (10 ml). The two layers were separated, and the aqueous layer was extracted with EtOAc (25 ml). The combined organic fractions were washed with aqueous saline solution (2 x 20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by means of SP1 flash chromatography (Biotage) (DCM / MeOH / 7N NH3 in MeOH 97/2/1) to yield the title compound (343 mg, 35%, 2 steps). 1H NMR (400 MHz, DMSO-d 6) δ 8.40 (s, 1H), 7.52-7.58 (m, 1H), 7.39-7.51 (m, 2H), 7.15 (s, 1H), 7.01 (d, J = 3.6 Hz, 3H), 6.69 (s, 1H), 5.78 (d, J = 10.3 Hz, 1H), 5.40 (d, J = 10.3 Hz, 1H), 3.02-3.17 (m, 2H), 2.14 (s, 3H), 0.53 -0.63 (m, 1H), -0 , 18 (s, 9H). M / z of EMAR (ESI) calculated for C22H26CIN5OSi + H + 440.1668, found 440.1671. Step 3: 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1H-pyrrole-3-carbonitrile
[193] TFA (1.4 mL) was added to a solution of 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1- {[2- (trimethylsilyl) ethoxy ] methyl} -1H-pyrrole-3-carbonitrile (61 mg, 0.14 mmol) in dry DCM (2.8 mL) and stirred for 4 h at room temperature. After removing the solvent, the residue was treated with EtOH (3 ml), 33% NH4OH (0.4 ml) and stirred for 0.5 h. The solvent was evaporated to dryness and the residue was purified by flash chromatography (DCM / MeOH / 7N NH3 in MeOH 93/7 / 0.7) to produce the title compound as a solid (28 mg, 65%). 1H NMR (600 MHz, DMSO-d 6) δ 12.71 (s, 1 H ..), 8.36 (d, J = 0.9 Hz, 1H), 7.48-7.53 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.22 (s, 1H), 6.89 (s, 2H), 6.73 (d, J = 1.1 Hz, 1H), 2.14 (s, 3H).
[194] According to this procedure, but using 6-chloro-N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2- (5-chloro-2 -methylphenyl) -5- [6- (methylamino) pyrimidin-4-yl] - 1H-pyrrole-3-carbonitrile (compound No 2) ESI (+) MS: m / z 324 (MH +).
[195] According to this procedure, but using 4-chloro-7- {[2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrole [2,3-d] - pyrimidine instead of 6-iodopyrimidine-4- amine in step 2, the following compound was prepared: 2- (5-chloro-2-methylphenyl) -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carbonitrile (compound No 3) ESI (+) MS: m / z 334 (MH +).
[196] According to this procedure, but using 4-chloro-1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole [2,3-d] pyridine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2- (5-chloro-2-methylphenyl) -5- (1H-pyrrol [2,3-d)] pyridin-4-yl) - 1H-pyrrol-3-carbonitrile (compound No 4) 1H NMR (400 MHz, DMSO-d6) δ 12.94 (br. s., 1H), 12.21 (br. s., 1H), 8.75 (s, 1H), 7 , 70 (br. S., 1H), 7.64 (dd, J = 2.5, 3.4 Hz, 1H), 7.45-7.52 (m, 2H), 7.39-7, 43 (m, 1H), 7.09 (dd, J = 1.7, 3.5 Hz, 1H), 2.32 (s, 3H). M / z of EMAR (ESI) calculated for C18H12CIN5 + H + 334.0854, found 334.0860.
[197] According to this procedure, but using 6-chloro-9- (4-methoxybenzyl) -9H-purine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2- (5 -chloro-2-methylphenyl) -5- (9H-purin-6-yl) -1H-pyrrole-3-carbonitrile (compound No 5) ESI (+) MS: m / z 335 (MH +).
[198] According to this procedure, but using 4-chloro-1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol [3,4-d] pyrimidine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2- (5-chloro-2-methylphenyl) -5- (1H-pyrazol [3,4-d] pyrimidin-4-yl) -1H-pyrrol-3-carbonitrile ( compound No 6) ESI (+) MS: m / z 335 (MH +).
[199] According to this procedure, but using 4-chloropyrrole [2,1-f] [1,2,4] triazine instead of 6-iodopyrimidin-4-amine in step 2, the following compound was prepared: 2 - (5-chloro-2-methylphenyl) -5- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-3-carbonitrile (compound No 7) ESI ( +) MS: m / z 334 (MH +).
[200] According to this procedure, but using 4-chloro-7- (4-methoxy-benzyl) -6,7-dihydro-5H-pyrrol [2,3-c] pyrimidine instead of 6-iodopyrimidine -4-amine in step 2, the following compound was prepared: 2- (5-chloro-2-methylphenyl) -5- (6,7-dihydro-5H-pyrrole [2,3-d] pyrimidin-4 -yl) -1H-pyrrole-3-carbonitrile (compound No 8) ESI (+) MS: m / z 336 (MH +).
[201] According to this procedure, but starting from 5-bromo-2- (5-chloro-2-ethylphenyl) -1- {[2- (trimethylsilyl) - ethoxy] -methyl} -1H-pyrrole-3- carbonitrile in step 1a, the following compound was prepared: 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -1H-pyrrole-3-carbonitrile (compound No 9) 1H NMR ( 600 MHz, DMSO-d 6) δ 12.71 (br. S., 1H), 8.36 (d, J = 0.9 Hz, 1H), 7.48-7.53 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.22 (s, 1H), 6.89 (s, 2H), 6.73 (d, J = 1.1 Hz, 1H), 2.61 (q, J = 7.6 Hz, 2H), 1.01 (t, J = 7.6 Hz, 3H). EMAR (ESI) calculated for C17H14CIN5 + H + 324,1011, found 324,1007.
[202] According to this procedure, but starting from 5-bromo-2- (5-chloro-2-ethylphenyl) -1- {[2- (trimethylsilyl) - ethoxy] methyl} -1H-pyrrole-3-carbonitrile in step 1a and using 6-chloro-N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2- (5-chloro-2-ethylphenyl) -5- [6- (methylamino) pyrimidin-4-yl] - 1H-pyrrol-3-carbonitrile (compound No 10) 1H NMR (600 MHz, DMSO-d 6) δ 12.78 (br. S., 1H), 8 , 54 (br. S, 1H), 8.19 (br. S, 1H), 7.52-7.61 (m, 1H), 7.42-7.52 (M, 3H), 6 , 90 (br. S., 1H), 2.89 (br. S., 3H), 2.61 (q, J = 7.6 Hz, 2H), 1.01 (t, J = 7.6 Hz, 3H). EMAR (ESI) calculated for C18H16CIN5 + H + 338.1167, found 338.1169.
[203] According to this procedure, but starting from 5-bromo-2- (5-chloro-2-ethylphenyl) -1- {[2- (trimethylsilyl) - ethoxy] methyl} -1H-pyrrole-3-carbonitrile in step 1a and using 4-chloro-7- {[2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrole [2,3-d] pyrimidine instead of 6-iodopyrimidine-4-amine in step 2 compound was prepared: 2- (5-chloro-2-ethylphenyl) -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carbonitrile (compound No 11) 1H NMR (600 MHz, DMSO-d6) δ 12.96 (br. S, 1H), 12.21 (br. S., 1H), 8.73 (s, 1H), 7.71 (s, 1H) , 7.60-7.66 (m, 1H), 7.50-7.55 (m, 1H), 7.40-7.47 (m, 2H), 7.09 (d, J = 2, 0 Hz, 1H), 2.65 (q, J = 7.5 Hz, 2H), 1.03 (t, J = 7.5 Hz, 3H). EMAR (ESI) calculated for C19H14CIN5 + H + 348.1011, found 348.1014.
[204] According to this procedure, but starting from 5-bromo-2- (5-chloro-2-ethylphenyl) -1- {[2- (trimethylsilyl) - ethoxy] -methyl} -1H-pyrrole-3- carbonitrile in step 1a and using 6-chloro-9- (4-methoxybenzyl) -9H-purine instead of 6-iodopyrimidin-4-amine in step 2, the following compound was prepared: 2- (5-chloro-2- ethylphenyl) -5- (9H-purin-6-yl) -1H-pyrrole-3-carbonitrile (compound No 12) ESI (+) MS: m / z 349 (MH +).
[205] According to this procedure, but starting from 5-bromo-2- (5-chloro-2-ethylphenyl) -1- {[2- (trimethylsilyl) - ethoxy] methyl} -1H-pyrrole-3-carbonitrile in step 1a and using 4-chloro-1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol [3,4-d] pyrimidine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2- (5-chloro-2-ethylphenyl) -5- (1H-pyrazol [3,4-d] pyrimidin-4-yl) -1H-pyrrole-3-carbonitrile (compound No 13) ESI ( +) MS: m / z 349 (MH +).
[206] According to this procedure, but starting from 5-bromo-2- (5-chloro-2-ethylphenyl) -1- {[2- (trimethylsilyl) - ethoxy] methyl} -1H-pyrrole-3-carbonitrile in step 1a and using 4-chloropyrrole [2,1-f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2- (5-chloro- 2-ethylphenyl) -5- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-3-carbonitrile (compound No 14) ESI (+) MS: m / z 348 (MH +).
[207] According to this procedure, but starting from 5-bromo-2- (5-chloro-2-ethylphenyl) -1- {[2- (trimethylsilyl) - ethoxy] methyl} -1H-pyrrole-3-carbonitrile in step 1a and using -7-chloro-4- (4-methoxy-benzyl) -6,7-dihydro-5H-pyrrol [2,3-d] pyrimidine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2- (5-chloro-2-ethylphenyl) -5- (6,7-dihydro-5H-pyrrol [2,3- d] pyrimidin-4-yl) -1H -pyrrole-3-carbonitrile (compound No 15) ESI (+) MS: m / z 350 (MH +).
[208] According to this procedure, but starting from 5-bromo-2- [(trifluormethyl) phenyl-5-chloro-2] -1- {[2- (tri-methylsilyl) ethoxy] methyl} -1H-pyrrole -3-carbonitrile in step 1a, the following compound was prepared: 5- (6-aminopyrimidin-4-yl) -2- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrole-3-carbonitrile (compound No 16) 1H NMR (600 MHz, DMSO-d 6) δ 12.90 (br. S., 1H), 8.38 (d, J = 1.1 Hz, 1H), 7.96 (s, 1H ), 7.84-7.92 (m, 2H), 7.28 (s, 1H), 6.94 (s, 2H), 6.75 (d, J = 1.28 Hz, 1 H). EMAR (ESI) calculated for C16H9CIF3N5 + H + 364.0572, found 364.0572.
[209] According to this procedure, but starting from 5-bromo-2- [(trifluormethyl) phenyl-5-chloro-2] -1- {[2- (tri-methylsilyl) -ethoxy] methyl} -1H- pyrrole-3-carbonitrile in step 1a and using 6-chloro-N-methyl-pyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2- [2-chloro- 5- (trifluormethyl) phenyl] -5- [6- (methylamino) - pyrimidin-4-yl] -1H-pyrrole-3-carbonitrile (compound No 17) 1H NMR (600 MHz, DMSO-d 6) δ 12, 53-13.20 (m, 1H), 8.44 (br. S., 1H), 7.72-8.05 (m, 3H), 7.23-7.56 (m, 1H), 6 , 82 (br. S., 1H), 2.84 (d, J = 3.5 Hz, 3H). EMAR (ESI) calculated for C17H11CIF3N5 + H + 378.0728, found 378.0732.
[210] According to this procedure, but starting from 5-bromo-2- [(trifluormethyl) phenyl-5-chloro-2] -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole -3-carbonitrile in step 1a and using 4-chloro-7- {[2- (trimethylsilyl) ethoxy] methyl} - 7H-pyrrole [2,3-d] pyrimidine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2- [2-chloro-5- (trifluormethyl) phenyl] -5- (7H-pyrrol'2,3- d] pyrimidin-4-yl) -1H-pyrrol-3-carbonitrile (compound No 18) ESI (+) MS: m / z 388 (MH +).
[211] According to this procedure, but starting from 5-bromo-2- [(trifluormethyl) phenyl-5-chloro-2] -1- {[2- (tri-methylsilyl) -ethoxy] methyl} -1H- pyrrole-3-carbonitrile in step 1a and using 6-chloro-9- (4-methoxybenzyl) -9H-purine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2- [2- chloro-5- (trifluormethyl) phenyl] -5- (9H-purin-6-yl) -1H-pyrrole-3-carbonitrile (compound No 19) ESI (+) MS: m / z 389 (MH +).
[212] According to this procedure, but starting from 5-bromo-2- [(trifluormethyl) phenyl-5-chloro-2] -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole-3 -carbonitrile in step 1a and using 4-chloro-1- {[2- (trimethylsilyl) ethoxy] -methyl} -1H-pyrazol [3,4-d] pyrimidine instead of 6-iodo-pyrimidine-4-amine in step 2, the following compound was prepared: 2- [2-chloro-5- (trifluormethyl) phenyl] -5- (1H-pyrazol [3,4- d] pyrimidin-4-yl) -1H-pyrrol-3- carbonitrile (compound No 20) ESI (+) MS: m / z 389 (MH +).
[213] According to this procedure, but starting from 5-bromo-2- [(trifluormethyl) phenyl-5-chloro-2] -1- {[2- (trimethylsilyl) -ethoxy] methyl} -1H-pyrrole- 3-carbonitrile in step 1a and using 4-chloropyrrole [2,1-f] [1, 2,4] triazine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2- [2 -chloro-5- (trifluormethyl) phenyl] -5- (pyrrole [2,1-f] [1,2,4] -triazin-4-yl) -1H-pyrrole-3-carbonitrile (compound No 21) ESI (+) MS: m / z 388 (MH +).
[214] According to this procedure, but starting from 5-bromo-2- [(trifluormethyl) phenyl-5-chloro-2] -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole-3 -carbonitrile in step 1a and using 4-chloro-7- (4-benzyl-methoxy) -6,7-dihydro-5H-pyrrol [2,3-d] pyrimidine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2- [2-chloro-5- (trifluormethyl) phenyl] -5- (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrole-3-carbonitrile (compound No 22) ESI (+) MS: m / z 390 (MH +).
[215] According to this procedure, but starting from 5-bromo-2- [(trifluormethyl) phenyl-5-2-methyl] -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole-3 -carbonitrile in step 1a, the following compound was prepared: 5- (6-aminopyrimidin-4-yl) -2- [2-methyl-5- (trifluormethyl) -phenyl] -1H-pyrrole-3-carbonitrile (compound No 23) 1H NMR (600 MHz, DMSO-d6) δ 12.77 (br. S., 1H), 8.37 (d, J = 0.9 Hz, 1H), 7.76 (d, J = 8 , 0 Hz, 1H), 7.71 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H), 6.91 (s, 2H), 6.74 (d, J = 1.1 Hz, 1H), 2.41 (s, 3H). EMAR (ESI) calculated for C17H12F3N5 + H + 344.1111, found 344.1111.
[216] According to this procedure, but starting from 5-bromo-2- [(trifluormethyl) phenyl-5-2-methyl] -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole-3 -carbonitrile in step 1a and using 6-chloro-N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 5- [6- (methylamino) pyrimidin-4- yl] -2- [2-methyl-5- (trifluoromethyl) -phenyl] -1H-pyrrole-3-carbonitrile (compound No 24) 1H NMR (600 MHz, DMSO-d6) δ 12.76 (br. s., 1H), 8.42 (br., 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.72 (s, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.35 (br., 2H), 6.81 (br., 1H), 2.83 (d, J = 4.21 Hz, 3H), 2 , 41 (s, 3H). EMAR (ESI) calculated for C18H14F3N5 + H + 358.1274, found 358.1271.
[217] According to this procedure, but starting from 5-bromo-2- [(trifluormethyl) phenyl-5-2-methyl] -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole -3-carbonitrile in step 1a and using 4-chloro-7- {[2- (trimethylsilyl) ethoxy] methyl} - 7H-pyrrole [2,3-d] pyrimidine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2- [2-methyl-5- (trifluormethyl) phenyl] -5- (7H-pyrrol [2,3- d] pyrimidin-4-yl) -1H-pyrrol-3-carbonitrile (compound No 25) ESI (+) MS: m / z 368 (MH +).
[218] According to this procedure, but starting from 5-bromo-2- [(trifluormethyl) phenyl-5-2-methyl] -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole-3 -carbonitrile in step 1a and using 4-chloropyrrole [2,1-f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2- [2- methyl-5- (trifluormethyl) phenyl] -5- (pyrrole [2,1- f] [1,2,4] triazin-4-yl) -1H-pyrrole-3-carbonitrile (compound No 2 6) ESI ( +) MS: m / z 368 (MH +).
[219] According to this procedure, but starting from 5-bromo-2- [(trifluormethyl) phenyl-5-2-methyl] -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole -3-carbonitrile in step 1a and using 4-chloro-7- (4-benzyl-methoxy) -6,7-dihydro-5H-pyrrol [2,3-d] pyrimidine instead of 6-iodopyrimidine-4 - amine in step 2, the following compound was prepared: 2- [2-methyl-5- (trifluormethyl) phenyl] -5- (6,7-dihydro-5H-pyrrole [2,3-d] pyrimidun-4- yl) -1H-pyrrole-3-carbonitrile (compound No 27) ESI (+) MS: m / z 370 (MH +).
[220] According to this procedure, but starting from 5-bromo-2- [(trifluormethyl) phenyl-5-2-ethyl] -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole-3 -carbonitrile in step 1a, the following compound was prepared: 5- (6-aminopyrimidin-4-yl) -2- [2-ethyl-5- (trifluormethyl) -phenyl] -1H-pyrrole-3-carbonitrile (compound No 28) ESI (+) MS: m / z 358 (MH +).
[221] According to this procedure, but starting from 5-bromo-2- [(trifluormethyl) phenyl-5-2-ethyl] -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole -3-carbonitrile in step 1a and using 6-chloro-N-methyl-pyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 5- [6- (methylamino) pyrimidin-4-yl] -2- [2-ethyl-5- (trifluoromethyl) -phenyl] -1H-pyrrole-3-carbonitrile (compound No 29) ESI (+) MS: m / z 372 (MH +) .
[222] According to this procedure, but starting from 5-bromo-2- [(trifluormethyl) phenyl-5-2-ethyl] -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole -3-carbonitrile in step 1a and using 4-chloro-7- {[2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrole [2,3-d] pyrimidine instead of 6-iodopyrimidine-4-amine 2, the following compound was prepared: 2- [2-ethyl-5- (trifluormethyl) phenyl] -5- (7H-pyrrol [2,3-d] pyrimidin-yl) -1H-pyrrol-3-carbonitrile (compound No 30) 1H NMR (600 MHz, DMSO-d6) δ 13.05 (br. S., 1H), 12.22 (br. S., 1H), 8.74 (s, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.74 (s, 1H), 7.72 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.62 -7.66 (m, J = 2.7 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 2.76 (q, J = 7.6 Hz, 2H), 1 08 (t, J = 7.5 Hz, 3H). ESI (+) MS: m / z 382 (MH +).
[223] According to this procedure, but starting from 5-bromo-2- [(trifluormethyl) phenyl-5-2-ethyl] -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole -3-carbonitrile in step 1a and using 4-chloropyrrole [2,1-f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2- [ 2-ethyl-5- (trifluormethyl) phenyl] -5- (pyrrole [2,1-f] [1,2,4] - triazin-4-yl) -1H-pyrrole-3-carbonitrile (compound No 31) ESI (+) MS: m / z 382 (MH +).
[224] According to this procedure, but starting from 5-bromo-2- [(trifluormethyl) phenyl-5-2-ethyl] -1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole -3-carbonitrile in step 1a and using 4-chloro-7- (4-benzyl-methoxy) -6,7-dihydro-5H-pyrrol [2,3-d] pyrimidine instead of 6-iodopyrimidine-4 -amine in step 2, the following compound was prepared: 5- (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -2- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrole-carbonitrile (compound No 32) ESI (+) MS: m / z 384 (MH +).
[225] According to this procedure, but starting from 5-bromo-2-phenyl-1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole-3-carbonitrile in step 1a, the following compound was prepared : 5- (6-aminopyrimidin-4-yl) -2-phenyl-1H-pyrrole-3-carbonitrile (compound No 33) ESI (+) MS: m / z 262 (MH +).
[226] According to this procedure, but starting from 5-bromo-2-phenyl-1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole-3-carbonitrile in step 1a and using 6-chloro- N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 5- [6- (methylamino) pyrimidin-4-yl] -2-phenyl-1H-pyrrole- 3-carbonitrile (compound No 34) 1H NMR (600 MHz, DMSO-d 6) δ 12.64 (br. S., 1H), 8.54 (br. S., 1H), 7.79 -7, 88 (m, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.47-7.51 (m, 1H), 7.35-7.41 (m, 1H), 6 , 93 (br. S., 1H), 2.90 (d, J = 4.40 Hz, 3H). EMAR (ESI) calculated for C16H13N5 + H + 276.1244, found 276.1243.
[227] According to this procedure, but starting from 5-bromo-2-phenyl-1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole-3-carbonitrile in step 1a and using 4-chloro- 7- {[2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrole [2,3-d] pyrimidine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2-phenyl-5 - (7H-pyrrole [2,3-d] pyrimidin-4-yl) -1H-pyrrole-3-carbonitrile (compound No 35) ESI (+) MS: m / z 286 (MH +).
[228] According to this procedure, but starting from 5-bromo-2-phenyl-1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole-3-carbonitrile in step 1a and using 4-chloropyrrole [ 2,1-f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2-Phenyl-5- (pyrrole [2,1-f] [ 1,2,4] triazin-4-yl) -1H-pyrrole-3-carbonitrile (compound No 36) ESI (+) MS: m / z 286 (MH +).
[229] According to this procedure, but starting from 5-bromo-2-phenyl-1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole-3-carbonitrile in step 1a and using 4-chloro- 7- (4-methoxy-benzyl) -6,7-dihydro-5H-pyrrol [2,3-d] pyrimidine instead of 6-iodopyrimidine-4-amine in step 2, the following compound was prepared: 2 -Fenyl-5- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-3-carbonitrile ((broad s, 37) ESI (+) MS: m / z 288 (MH +) EXAMPLE 2 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -1H-pyrrole-3-carbonitrile (compound No 9)
Scheme A: Steps 1, 2, 3 Step 1: 2- (5-chloro-2-ethylphenyl) -1- (phenylsulfonyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl) -1H-pyrrole-3-carbonitrile (IV)
[230] To a solution of 2- (5-chloro-2-ethylphenyl) -1- (phenylsulfonyl) -1H-pyrrole-3-carbonitrile (1.02 g, 2.77 mmol) and 2-isopropoxy-4, 4,5,5-tetramethyl-1,3,2-dioxiborolane (0.791 mL, 3.88 mmol) in THF (8.5 mL) LDA (2M in THF / heptane / ethylbenzene, 4.6 mL, 9.15 mmol) dropwise was added slowly at -78 ° C under argon. After 50 min, MeOH (4 ml) was added, the temperature was allowed to rise and NH4Cl solution (20 ml) was added dropwise at room temperature. The reaction was then diluted with water and extracted with Et2O, dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to obtain the title compound which was used without further purification. Step 2: 5- (6-aminopyrimidin-yl) -2- (5-chloro-2-ethylphenyl) -1- (phenylsulfonyl) -1H-pyrrole-3-carbon (VI)
[231] 2- (5-chloro-2-ethylphenyl) -1- (phenylsulfonyl) -5- (4.4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1-pyrrole -3- carbonitrile (2.77 mmol), 6-iodopyrimidin-4-amine (918 mg, 4.16 mmol), PDCl2 (dppf) (226 mg, 0.277 mmol) and Cs2CO3 (2.71 g, 8.31 mmol) were degassed and filled back with argon and then dissolved in dioxane (20 mL) and water (4 mL) under nitrogen. The reaction mixture was stirred at room temperature overnight, then diluted with EtOAc, washed with aqueous saline, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by means of Flash Chromatography SP1 (Biotage) (DCM / MeOH / NH3 7N in MeOH 95/5 / 0.5) to produce the title compound (540 mg, 39%, 2 steps). 1H NMR (600 MHz, DMSO-d 6) δ 8.45 (d, J = 0.92 Hz, 1H), 7.82 (t, J = 7.42 Hz, 1H), 7.71-7, 78 (m, 1H), 7.59-7.63 (m, 1H), 7.56 (dd, J = 2.29, 8.33 Hz, 1H), 7.39 (d, J = 8, 43 Hz, 1H), 7.11 (br. S., 1H), 7.09 (s, 1H), 6.83 (d, J = 2.20 Hz, 1H), 6.64 (d, J = 1.10 Hz, 1H), 2.03-2.24 (m, 2H), 1.01 (t, J = 7.60 Hz, 3H). EMAR (ESI) m / z calculated for C23H18N5O2SCl + H + 464.0943, found 464.0938. Step 3: 5- (6-aminopyrimidin-4-yl) -2- (2-ethylphenyl-5-chlorine) -1H-pyrrole-3-carbonitrile
[232] 5- (6-aminopyrimidin-yl) -2- (2-ethylphenyl-5-chloro) - 1- (phenylsulfonyl) -1H-pyrrole-3-carbonitrile (299 mg, 0.647 mmol) in THF (6, 5 ml) was treated with LiOH.H2O (109 mg, 2.59 mmol) in water (3 ml) and heated under reflux for two days. After cooling, the residue was diluted with water (20 ml) and washed with Et2O (20 ml). The aqueous phase was slowly added to 1N HCl (7 ml) in ice water (70 ml) with stirring and the white solid was collected by filtration obtaining, after drying at 50 ° C under vacuum, the title compound (157 mg , 70%). 1H NMR (600 MHz, DMSO-d 6) δ 12.71 (br. S., 1H), 8.36 (d, J = 0.9 Hz, 1H), 7.48-7.53 (m, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.22 (s, 1H), 6.89 (s, 2H), 6.73 (d, J = 1.1 Hz, 1H), 2.61 (q, J = 7.6 Hz, 2H), 1.01 (t, J = 7.6 Hz, 3H) . EMAR (ESI) calculated for C17H14CIN5 + H + 324,1011, found 324,1007. EXAMPLE 3 5- (6-aminopyrimidin-4-yl) -2-phenyl-1H-pyrrole-3-carboxamide (compound No 38)
Scheme B: Steps 4, 5, 6, 7 Step 4: 2-phenyl-1- (phenylsulfonyl) -5- (1,3,2-dioxaborolan-2-yl-4,4,5,5 tetramethyl) -1H ethyl pyrrole-3-carboxylate (VIII)
[233] To a solution of ethyl 2-phenyl-1- (phenylsulfonyl) -1H-pyrrole-3-carboxylate (440 mg, 1.24 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl- 1,3,2-dioxiborolane (0.303 ml, 1.2 mmol) in THF (1.9 ml) LDA (2M in THF / heptane / ethylbenzene, 1.61 ml, 3.22 mmol) was added slowly dropwise at -78 ° C under an argon atmosphere. After 50 min, MeOH (1 ml) was added, the temperature was allowed to rise and NH4Cl solution (2 ml) was added dropwise at room temperature. The reaction was diluted with water and extracted with Et2O, dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to obtain the title compound which was used without further purification. Step 5: Ethyl 5- (6-aminopyrimidin-4-yl) -2-phenyl) -1- (phenylsulfonyl) -1H-pyrrole-3-carboxylate (IX)
[234] Ethyl 2-phenyl-1- (phenylsulfonyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-3-carboxylate (1 , 24 mmol), 6-iodopyrimidine-4-amine (411 mg, 1.86 mmol), PDCl2 (dppf) (101 mg, 0.124 mmol) and Na2CO3 (394 mg, 3.72 mmol) were degassed and filled back with argon and then dissolved in dioxane (12 mL) and water (1.9 mL) under nitrogen. The reaction mixture was stirred at room temperature overnight, then diluted with EtOAc, washed with aqueous saline, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by means of SP1 Flash Chromatography (Biotage) (DCM / MeOH / NH 3 7 N in MeOH 95/5 / 0.5) to produce the title compound (240 mg, 43%, 2 steps). 1H NMR (600 MHz, DMSO-d6) δ 8.42 (d, J = 1.1 Hz, 1H), 7.72 (quin, J = 4.3 Hz, 1H), 7.48-7.53 (m, 4H), 7.37-7.44 (m, 1H), 7.26 (t, J = 7.7 Hz, 2H), 7.00 (s, 2H), 6.96 (dd, J = 1.2, 8.1 Hz, 2H), 6.82-6.86 (m, 1H), 6.67-6.70 (m, 1H), 3.95 (q, J = 7, 0 Hz, 2H), 0.87-1.01 (m, 3H). M / z of EMAR (ESI) calculated for C23H20N4O4S + H + 449.1278, found 449.1273. Step 6: 5- (6-Aminopyrimidin-4-yl) -2-phenyl-1H-pyrrole-3-carboxylic acid (X)
[235] Ethyl 5- (6-aminopyrimidin-4-yl) -2-phenyl) -1- (phenylsulfonyl) -1H-pyrrole-3-carboxylate (290 mg, 0.647 mmol) in THF (6.5 ml) was treated with LiOH.H2O (109 mg, 2.59 mmol) in water (3 ml) and heated under reflux for two days. After cooling, the residue was diluted with water (20 ml) and washed with Et2O (20 ml). To the aqueous phase, 1 N HCl (7 ml) in ice water (70 ml) was added slowly with stirring and the white solid was collected by filtration obtaining, after drying at 50 ° C under vacuum, the title compound (153 mg, 85%). 1H NMR (600 MHz, DMSO-d6) δ 12.42 (br. S., 1H), 12.10 (br. S., 1H), 8.53 (br. S., 1H), 7.63 (d, J = 6.8 Hz, 2H), 7.39 -7.48 (m, 4H), 7.25-7.34 (m, 1H), 6.94 (br. s., 1H) . M / z EMAR (ESI) calculated for C15H12N4O2 + H + 281.1033, found 281.1033. Step 7: 5- (6-aminopyrimidin-4-yl) -2-phenyl-1H-pyrrole-3-carboxamide
[236] A solution of 5- (6-aminopyrimidin-4-yl) -2-phenyl-1H-pyrrole-3-carboxylic acid (40 mg, 0.143 mmol) in DMF (0.5 mL) and DIPEA (99 μL , 0.571 mmol) was stirred at 0 ° C. EDCl (55 mg, 0.286 mmol) and HOBT.NH3 (44 mg, 0.286 mmol) were added and the reaction mixture was stirred overnight at room temperature. The mixture was diluted with saturated NaHCO3 solution (20 ml), extracted with EtOAc (50 ml), dried over filtered Na2SO4. The solvent was evaporated under reduced pressure and the crude product was purified by means of Flash Chromatography SP1 (Biotage) (DCM / MeOH / NH 3 7 N in MeOH 9/1 / 0.1) to produce the title compound (35 mg, 89%). 1H NMR (600 MHz, DMSO-d6) δ 11.77 (br. S., 1H), 8.33 (s, 1H), 7.64 (d, J = 7.1 Hz, 2H), 7, 35-7.40 (m, 2H), 7.28 - 7.34 (m, 2H), 7.19 (s, 1H), 6.79 (br. S., 1H), 6.76 (s , 2H), 6.73 (d, J = 1.1 Hz, 1 H). M / z EMAR (ESI) calculated for C15H13IN5O + H + 280,1193, found 280,1196.
[237] According to this procedure, but using 6-chloro-N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 5, the following compound was prepared: 5- [6- (methylamino) pyrimidin-4-yl] -2-phenyl-1H-pyrrole-3-carboxamide (compound No 39) 1H NMR (600 MHz, DMSO-d6) δ 11.77 (br., 1H), 8.36, 7.62 (br. S., 1H) - 7.65 (m, 2H), 7.37-7.42 (m, 2H), 7.32 -7.36 (m, 1H), 7.30 (br. s., 1H), 7.26 (br. s., 1H), 7.18 (br. s., 1H), 6.80 (br. s., 2H), 2.82 (d , J = 4.58 Hz, 3H). EMAR (ESI) calculated for C16H15N5O + H + 294.1350, found 294.1350.
[238] According to this procedure, but using 4-chloropyrrole [2,1-f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 5, the following compound was prepared: 2 -Fenyl-5- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-3-carboxamide (compound No 40) ESI (+) MS: m / z 304 (MH +).
[239] According to this procedure, but using methylamine in step 7, the following compound was prepared: 5- (6-aminopyrimidin-4-yl) -2-phenyl-N-methyl-1H-pyrrol-3-carboxamide ( compound No 41) 1H NMR (600 MHz, DMSO-d6) δ 11.77 (br. s., 1H), 8.33 (d, J = 0.9 Hz, 1H), 7.83 (q, J = 4.2 Hz, 1H), 7.60 - 7.67 (m, 2H), 7.35-7.40 (m, 2H), 7.28-7.34 (m, 1H), 7, 14 (s, 1H), 6.76 (s, 2H), 6.73 (d, J = 1.1 Hz, 1H), 2.67 (d, J = 4.6 Hz, 3H). M / z EMAR (ESI) calculated for C16H15N5O + H + 294.1350, found 294.1348.
[240] According to this procedure, but using 6-chloro-N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 5 and methylamine in step 7, the following compound was prepared: N-methyl -5- [6- (methylamino) pyrimidin-4-yl] -2-phenyl-1H-pyrrole-3-carboxamide (compound No 42) 1H NMR (600 MHz, DMSO-d 6) δ 11.78, 8, 37 (br. S, 1H), 7.83 (d, J = 4.58 Hz, 1H), 7.59 (br. S., 1H) - 7.66 (m, 2H), 7.37 -7.41 (m, 2H), 7.33 (d, J = 7.33 Hz, 1H), 7.21 (br. S., 2H), 6.81 (br. S., 1H), 2.83 (d, J = 4.58 Hz, 3H), 2.67 (d, J = 4.58 Hz, 3H). M / z of EMAR (ESI) calculated for C17H17N5O + H + 308.1506, found 308.1501.
[241] According to this procedure, but using 4-chloropyrrole [2,1-f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 5 and methylamine in step 7, the following compound was prepared: N-methyl-2-phenyl-5- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-3-carboxamide (compound No 43) ESI (+) MS: m / z 318 (MH +). EXAMPLE 4 4- (6-aminopyrimidin-4-yl) -1- (5-chloro-2-methylphenyl) -1H-pyrrole-2-carbonitrile (compound No 44)
(XII) (XI I) (lb) Scheme C: Steps 8, 9 Step 8: 1- (5-chloro-2-methylphenyl) -4- (4,4,5,5-tetramethyl- 1,3,2 -dioxiborolane-2-yl) -1H-pyrrole-2-carbonitrile (XIII)
[242] To a solution of 4-bromo-1- (5-chloro-2-methylphenyl) -1H-pyrrole-2-carbonitrile (591 mg, 2.0 mmol) in THF (10 mL) 2-isopropoxy-4 , 4,5,5-tetramethyl-1,3,2-dioxiborolane (0.446 ml, 2.2 mmol) was added to the mixture at -78 ° C under an argon atmosphere. n-BuLi (2.5 M in hexane, 0.88 mL, 2.2 mmol) was added slowly dropwise at -78 ° C. The mixture was stirred at -78 ° C for 1 h. MeOH (1.0 ml) was added and the resulting mixture was stirred at room temperature after slowly raising the temperature. NH4Cl solution (10 ml) was added and the mixture was extracted with EtOAc (3 x 30 ml), washed with aqueous saline, dried over Na2SO4, distilled under reduced pressure and used in the next step without further purification. 1H NMR (600 MHz, DMSO-d6) δ 7.59 (d, J = 1.5 Hz, 1H), 7,527.57 (m, 2H), 7.44-7.50 (m, 1H), 7 , 32 (d, J = 1.5 Hz, 1H), 2.03 (s, 3H), 1.27 (s, 12H). Step 9: 4- (6-aminopyrimidin-4-yl) -1- (5-chloro-2-methylphenyl) -1H-pyrrole-2-carbonitrile
[243] In a 50 mL round bottom flask equipped with a stir bar, condenser and 3-way valve connected to argon and vacuum, 1- (5-chloro-2-methylphenyl) -4- (4.4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-2-carbo-nitrile from the previous step, 6-iodopyrimidine-4-amine (663 mg, 3.0 mmol), 2M Na2CO3 (3.0 mL, 6.0 mmol) and dioxane (20 mL) were charged at room temperature. The resulting reaction mixture was degassed three times, filled with argon again each time, before PdCl2 (dppf) (163 mg, 0.2 mmol) was loaded. The resulting reaction mixture was degassed four times, filled with argon each time and then heated to 110 ° C for 1 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, washed with EtOAc, and the filtrate was concentrated and then diluted with EtOAc and water. The two layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic fractions were washed with aqueous saline, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by means of Flash Chromatography SP1 (Biotage) (DCM / MeOH / NH 3 7 N in MeOH 95/5 / 0.5) to produce the title compound (291 mg, 47%, 2 steps). 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 0.98 Hz, 1H), 7.96 (d, J = 1.7 Hz, 1H), 7.64-7.69 (m, 2H), 7.55-7.61 (m, 1H), 7.50-7.54 (m, 1H), 6.81 (s, 2H), 6.65 (d, J = 1 , 1 Hz, 1H), 2.10 (s, 3H). M / z of EMAR (ESI) calculated for C16H12CIN5 + H + 310.0854, found 310.0858.
[244] According to this procedure, but using 6-chloro-N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 9, the following compound was prepared: 1- (5-chloro-2 -methylphenyl) - [6- (methylamino-pyrimidin-4-yl] -1H-pyrrole-2-carbonitrile (compound No 45) 1H NMR (600 MHz, DMSO-d6) δ 8.38 (br. s., 1H ), 8.01 (br. S., 1H), 7.71 (br. S., 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.58, (Dd, J = 2.2, 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.25 (br. S., 1H), 6.72 (br. S., 1H), 2.82 (d, J = 4.4 Hz, 3H), 2.10 (s, 3H) .M / z of EMAR (ESI) calculated for C17H14CIN5 + H + 324.1011, found 324.1014.
[245] According to this procedure, but using 4-chloropyrrole [2,1-f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 9, the following compound was prepared: 1 - (5-chloro-2-methylphenyl) -4- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-2-carbonitrile (compound No 46) 1H NMR (600 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.49 (d, J = 1.6 Hz, 1H), 8.11 (dd, J = 1.3, 2.6 Hz , 1H), 8.07 (d, J = 1.8 Hz, 1H), 7.77 (d, J = 2.3, 1H), 7.62 (dd, J = 2.3, 8.3 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.50 (dd, J = 1.3, 4.8 Hz, 1H), 7.03-7.09 (m , 1H), 2.14 (s, 3H). M / z of EMAR (ESI) calculated for C18H12CIN5 + H + 334.0854, found 334.0851.
[246] According to this procedure, but starting from 4-bromo-1- (5-chloro-2-ethylphenyl) -1H-pyrrole-2-carbonitrile in step 8, the following compound was prepared: 4- (6- aminopyrimidin-4-yl) -1- (5-chloro-2-ethylphenyl) -1H-pyrrole-2-carbonitrile (compound No 47) 1H NMR (600 MHz, DMSO-d6) δ 8.33 (s, 1H) , 7.97 (d, J = 1.5 Hz, 1H), 7.65 (s, 1H), 7.61-7.64 (m, 1H), 7.55 (d, J = 8.4 Hz, 1H), 6.81 (s, 2H), 6.65 (s, 1 H) 2.39 (q, J = 7.3 Hz, 2H), 1.04 (t, J = 7.3 Hz, 3H). EMAR (ESI) calculated for C17H14CIN5 + H + 324,1011, found 324,1006.
[247] According to this procedure, but starting from 4-bromo-1- (5-chloro-2-ethylphenyl) -1H-pyrrol-2-carbonitrile in step 8 and using 6-chloro-N-methylpyrimidin-4- amine instead of 6-iodopyrimidine-4-amine in step 9, the following compound was prepared: 1- (5-chloro-2-ethyl-phenyl) - [6- (methylamino) pyrimidin-4-yl] -1H- pyrrole-2-carbonitrile (compound No 48) 1H NMR (600 MHz, DMSO-d6) δ 8.38 (br. s, 1H), 8.02 (br. s., 1H), 7.71 (br . s., 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.63 (dd, J = 2.2, 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.25 (br., 1H), 6.72 (br., 1H), 2.82 (d, J = 4.4 Hz, 3H), 2 , 39 (q, J = 7.33 Hz, 2H), 1.04 (t, J = 7.3 Hz, 3H). EMAR (ESI) calculated for C18H16CIN5 + H + 338.1167, found 338.1164.
[248] According to this procedure, but starting from 4-bromo-1- (5-chloro-2-ethylphenyl) -1H-pyrrol-2-carbonitrile in step 8 and using 4-chloropyrrole [2,1-f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 9, the following compound was prepared: 1- (5-chloro-2-ethylphenyl) -4- (pyrrole [2,1] [ 1,2,4] triazin-4-yl) - 1H-pyrrole-2-carbonitrile (compound No 49) 1H NMR (600 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.51 (d , J = 1.8 Hz, 1H), 8.11 (dd, J = 1.3, 2.6 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.67 (dd, J = 2.2, 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7 , 49 (d, J = 4.8 Hz, 1H), 7.06 (dd, J = 2.6, 4.8 Hz, 1H), 2.39-2.46 (q, J = 7.1 Hz, 2H), 1.06 (t, J = 7.6 Hz, 3H). EMAR (ESI) calculated for C19H14CIN5 + H + 348.1011, found 348.1008.
[249] According to this procedure, but starting from 4-bromo-1- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carbonitrile in step 8, the following compound was prepared: 4- (6-aminopyrimidin-yl) -1- [2-chloro-5- (rifluoromethyl) phenyl] - 1H-pyrrole-2-carbonitrile (compound No 50) 1H NMR (600 MHz, DMSO-d6) δ 8.34 ( d, J = 0.9 Hz, 1H), 8.27 (s, 1H), 8.07 (d, J = 1.8 Hz, 1H), 7.94-8.06 (m, 2H), 7.72 (d, J = 1.6 Hz, 1H), 6.84 (br. S., 2H), 6.67 (d, J = 1.1 Hz, 1 H). EMAR (ESI) calculated for C16H9CIF3N5 + H + 364.0572, found 364.0577.
[250] According to this procedure, but starting from 4-bromo-1- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carbonitrile in step 8 and using 6-chloro-N-methylpyrimidin -4-amine instead of 6-iodopyrimidine-4-amine in step 9, the following compound was prepared: 1- [2-chloro-5- (trifluormethyl) phenyl] -4- [6- (methylamino) - pyrimidin- 4-yl] -1H-pyrrole-2-carbonitrile (compound No 51) 1H NMR (600 MHz, DMSO-d6) δ 8.39 (br. S., 1H), 8.26 (br. S., 1H ), 8.10 (br. S., 1H), 8.03 (br. S., 2H), 7.77 (br. S., 1H), 7.28 (br. S., 1H), 6.73 (br. S., 1H), 2.82 (d, J = 4.4 Hz, 3H). EMAR (ESI) calculated for C17H11CIF3N5 + H + 378.0728, found 378.0733.
[251] According to this procedure, but starting from 4-bromo-1- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carbonitrile in step 8 and using 4-chloropyrrole [2,1 -f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 9, the following compound was prepared: 1- [2-chloro-5- (trifluormethyl) phenyl] -4- (pyrrole [2,1-f] [1,2,4] -triazin-4-yl) -1H-pyrrol-2-carbonitrile (compound No 52) 1H NMR (600 MHz, DMSO-d6) δ 8.62 (d , J = 1.6 Hz, 1H), 8.54 (s, 1H), 8.40 (s, 1H), 8.10-8.14 (m, 2H), 8.08 (br. S. , 2H), 7.45-7.50 (m, 1H), 7.08 (dd, J = 2.56, 4.58 Hz, 1 H). EMAR (ESI) calculated for C18H9CIF3N5 + H + 388.0572, found 388.0566.
[252] According to this procedure, but starting from 4-bromo-1- [2-methyl-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carbonitrile in step 8, the following compound was prepared: 4- (6-aminopyrimidin-4-yl) -1- [2-methyl-5- (trifluormethyl) -phenyl] -1H-pyrrole-2-carbonitrile (compound No 53) ESI (+) MS: m / z 344 (MH + ).
[253] According to this procedure, but starting from 4-bromo-1- [2-methyl-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carbonitrile in step 8 and using 6-chloro-N-methylpyrimidin -4-amine instead of 6-iodopyrimidine-4-amine in step 9, the following compound was prepared: 4- [6- (methylamino) pyrimidin-4-yl] -1- [2-methyl-5- (trifluoro - methyl) phenyl] -1H-pyrrole-2-carbonitrile (compound No 54) ESI (+) MS: m / z 358 (MH +).
[254] According to this procedure, but starting from 4-bromo-1- [2-methyl-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carbonitrile in step 8 and using 4-chloropyrrole [2,1 -f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 9, the following compound was prepared: 1- [2-methyl-5- (trifluormethyl) phenyl] -4- (pyrrole - [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-2-carbonitrile (compound No 55) ESI (+) MS: m / z 368 (MH +).
[255] According to this procedure, but starting from 4-bromo-1- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carbonitrile in step 8, the following compound was prepared: 4- (6-aminopyrimidin-4-yl) -1- [2-ethyl-5- (trifluormethyl) -phenyl] -1H-pyrrol-2-carbonitrile (compound No 56) 1H NMR (600 MHz, DMSO-d6) δ 8 , 31-8.36 (m, 1H), 8.03 (d, J = 1.65 Hz, 1H), 7.87-7.96 (m, 2H), 7.78 (d, J = 8 , 61 Hz, 1H), 7.68 (d, J = 1.65 Hz, 1H), 6.82 (s, 2H), 6.66 (d, J = 1.10 Hz, 1H), 2, 52 (q, J = 7.3 Hz, 2H), 1.08 (t, J = 7.3 Hz, 3H). EMAR (ESI) calculated for C18H14F3N5 + H + 358.1274, found 358.1279.
[256] According to this procedure, but starting from 4-bromo-1- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carbonitrile in step 8 and using 6-chloro-N-methylpyrimidin -4-amine instead of 6-iodopyrimidine-4-amine in step 9, the following compound was prepared: 1- [2-ethyl-5- (trifluormethyl) phenyl] -4- [6- (methylamino) - pyrimidin- 4-yl] -1H-pyrrole-2-carbonitrile (compound No 57) ESI (+) MS: m / z 372 (MH +).
[257] According to this procedure, but starting from 4-bromo-1- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carbonitrile in step 8 and using 4-chloropyrrole [2,1 -f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 9, the following compound was prepared: 1- [2-ethyl-5- (trifluormethyl) phenyl] -4- (pyrrole [2,1-f] [1,2,4] - triazin-4-yl) -1H-pyrrole-2-carbonitrile (compound No 58) ESI (+) MS: m / z 382 (MH +).
[258] According to this procedure, but starting from 4-bromo-1-phenyl-1H-pyrrol-2-carbonitrile in step 8, the following compound was prepared: 4- (6-aminopyrimidin-4-yl) -1 -phenyl-1H-pyrrole-2-carbonitrile (compound No 59) ESI (+) MS: m / z 262 (MH +).
[259] According to this procedure, but starting from 4-bromo-1-phenyl-1H-pyrrol-2-carbonitrile in step 8 and using 6-chloro-N-methylpyrimidin-4-amine instead of 6-iodopyrimidine- 4-amine in step 9, the following compound was prepared: 1-phenyl-4- [6- (methylamino) pyrimidin-4-yl] -1H-pyrrol-2-carbonitrile (compound No 60) ESI (+) MS: m / z 276 (MH +).
[260] According to this procedure, but starting from 4-bromo-1-phenyl-1H-pyrrol-2-carbonitrile in step 8 and using 4-chloropyrrol [2,1-f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 9, the following compound was prepared: 1-Phenyl-4- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H -pyrrole-2-carbonitrile (compound No 61) ESI (+) MS: m / z 286 (MH +). EXAMPLE 5
Scheme C: Steps 8, 9 Step 8: 1- [2-chloro-5- (trifluormethyl) phenyl] -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 1H-pyrrole-2-carbonitrile (XIII)
[261] To a solution of 4-bromo-1- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrole-2-carbonitrile (349 mg, 1.0 mmol) in THF (4 mL) 2- isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxiborolane (0.230 ml, 1.1 mmol) was added to the mixture, at -78 ° C under argon. n-BuLi (2.5 M in hexane, 0.440 mL, 1.1 mmol) was added slowly dropwise at -78 ° C. The mixture was stirred at -78 ° C for 1 h. MeOH (0.5 ml) was added and the resulting mixture was stirred at room temperature after slowly raising the temperature. NH4Cl solution (5 ml) was added and the mixture was diluted with water and extracted with EtOAc (30 ml), washed with aqueous brine, dried over Na2SO4, distilled under reduced pressure and used in the next step without further purification. 1H NMR (600 MHz, DMSO-d6) δ 7.59 (d, J = 1.5 Hz, 1H), 7,527.57 (m, 2H), 7.44-7.50 (m, 1H), 7 , 32 (d, J = 1.5 Hz, 1H), 2.03 (s, 3H), 1.27 (s, 12H). Step 9: 1- [2-chloro-5- (trifluormethyl) phenyl] -4- (9H-purin-6-yl) -1H-pyrrole-2-carbonitrile
[262] In a 50 mL round-bottom flask, equipped with a stir bar, condenser and three-way valve, connected to argon and vacuum, 1- [2-chloro-5- (trifluormethyl) phenyl] -4- (4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl) -1H-pyrrol-2-carbonitrile from the previous step, 6-chloro-9- (4-methoxybenzyl) - 9H-purine (412 mg, 1.5 mmol), 2M Na2CO3 (1.5 mL, 3.0 mmol) and dioxane (8 mL) were charged at room temperature. The resulting reaction mixture was degassed three times, refilled with argon each time, before PdCl2 (dppf) (81.6 mg, 0.1 mmol) was loaded. The resulting reaction mixture was degassed four times, filled with argon each time and then heated to 110 ° C for 2 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, washed with EtOAc, and the filtrate was concentrated and then diluted with EtOAc and water. The two layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic fractions were washed with aqueous brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by means of SP1 flash chromatography (Biotage) (elution gradient from 30% to 50% EtOAc in hexane) to provide 1- [2-chloro-5- (trifluoromethyl) phenyl] -4- [9- (4-methoxybenzyl) -9H-purin-6-yl] -1H-pyrrole-2-carbonitrile (178 mg, 35%, 2 steps). 1H NMR (600 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.72 (s, 1H), 8.54 (d, J = 1.65 Hz, 1H), 8.33 (s , 1H), 8.15 (d, J = 1.5 Hz, 1H), 7.97-8.05 (m, 2H), 7.33 (d, J = 8.8 Hz, 2H), 6 , 88 (d, J = 8.8 Hz, 2H), 5.42 (s, 2H), 3.69 (s, 3H). M / z of EMAR (ESI) calculated for C25H16CIF3N6 + H + 509,1099, found 509,1100.
[263] A solution of 1- [2-chloro-5- (trifluormethyl) -phenyl] -4- [9- (4-methoxybenzyl) -9H-purin-6-yl] -1H-pyrrole-2-carbonitrile ( 60 mg, 0.12 mmol) in TFA (1.0 mL) was stirred for 5 h at 70 ° C. The solution was concentrated and then it was diluted with DCM and washed with saturated NaHCO3 solution. The combined organic fractions were washed with aqueous saline, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was crystallized from Et2O to obtain the title compound (33 mg, 72%). 1H NMR (600 MHz, DMSO-d6) δ 13.50 ((br. S., 1H), 8.85 (s, 1H), 8.59 (br. S., 1H), 8.56 (d , J = 1.5 Hz, 1H), 8.36 (s, 1H), 8.18 (d, J = 1.5 Hz, 1H), 7.98 - 8.11 (m, 2H). / z EMAR (ESI) calculated for C17H8CIF = N6 + H + 389.0524, found 389.0527.
[264] According to this procedure, but starting from 4-bromo-1- (5-chloro-2-methylphenyl) -1H-pyrrol-2-carbonitrile in step 8 and using 4-chloro-7- {[2- (trimethylsilyl) - ethoxy] methyl} -7H-pyrrole [2,3-d] pyrimidine instead of 6-chloro-9- (4-methoxybenzyl) -9H-purine in step 9, the following compound was prepared: 1- (5-chloro-2-methylphenyl) -4- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carbonitrile (compound No 63) 1H NMR (400 MHz, DMSO- d 6) δ 12.13 (br. s., 1H), 8.72 (br. s., 1H), 8.32 (d, J = 1.7 Hz, 1H), 8.01 (d, J = 1.7 Hz, 1 H), 7.72 (d, J = 2.2 Hz, 1H), 7.51-7.65 (m, 3H), 7.09 (dd, J = 1, 6, 3.6 Hz, 1H), 2.14 (s, 3H). M / z of EMAR (ESI) calculated for C18H12CIN5 + H + 334.0854, found 334.0859.
[265] According to this procedure, but starting from 4-bromo-1- (5-chloro-2-methylphenyl) -1H-pyrrol-2-carbonitrile in step 8 and using 4-chloro-1- {[2- (trimethylsilyl) - ethoxy] methyl} -1H-pyrrole [2,3-d] pyridine instead of 6-chloro-9- (4-methoxybenzyl) -9H-purine in step 9, the following compound was prepared: 1- (5-chloro-2-methylphenyl) -4- (1H-pyrrol [2,3-b)] pyridin-4-yl) - 1H-pyrrol-2-carbonitrile (compound No 64) ESI (+) MS: m / z 333 (MH +).
[266] According to this procedure, but starting from 4-bromo-1- (5-chloro-2-methylphenyl) -1H-pyrrole-2-carbonitrile in step 8, the following compound was prepared: 1- (5- chloro-2-methylphenyl) -4- (9H-purin-6-yl) -1H-pyrrole-2-carbonitrile (compound No 65) ESI (+) MS: m / z 335 (MH +).
[267] According to this procedure, but starting from 4-bromo-1- (5-chloro-2-methylphenyl) -1H-pyrrol-2-carbonitrile in step 8, using 4-chloro-1- {[2- (trimethylsilyl) - ethoxy] methyl} -1H-pyrazol [3,4-d] pyrimidine instead of 6-chloro-9- (4-methoxybenzyl) -9H-purine in step 9, the following compound was prepared: 1- (5-chloro-2-methylphenyl) -4- (1H-pyrazol [3,4-d] pyrimidin-4-yl) -1H-pyrrol-2-carbonitrile (compound No 66) ESI (+) MS: m / z 335 (MH +).
[268] According to this procedure, but starting from 4-bromo-1- (5-chloro-2-methylphenyl) -1H-pyrrol-2-carbonitrile in step 8, using 4-chloro-7- (4-methoxybenzyl ) -6,7-dihydro-5H-pyrrole [2,3-d] pyrimidine instead of 6-chloro-9- (4-methoxybenzyl) -9H-purine in step 9, the following compound was prepared: 1 - (5-chloro-2-methylphenyl) -4- (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carbonitrile (compound No 67 ) ESI (+) MS: m / z 336 (MH +).
[269] According to this procedure, but starting from 4-bromo-1- (5-chloro-2-ethylphenyl) -1H-pyrrol-2-carbonitrile in step 8 and using 4-chloro-7- {[2- (trimethylsilyl) - ethoxy] methyl} -7H-pyrrole [2,3-d] pyrimidine in step 9 instead of 6-chloro-9- (4-methoxybenzyl) -9H-purine, the following compound was prepared: 1- (5-chloro-2-ethylphenyl) -4- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carbonitrile (compound No 68) 1H NMR (600 MHz, DMSO- d6) δ 12.13 (br. s., 1H), 8.72 (s, 1H), 8.33 (d, J = 1.8 Hz, 1H), 8.01 (d, J = 1, 65 Hz, 1 H), 7.73 (d, J = 2.2 Hz, 1H), 7.63-7.67 (m, 1H), 7.56-7.61 (m, 3H), 7 .08 (dd, J = 1.6, 3.6 Hz, 1H), 2.43 (q, J = 7.3 Hz, 2H), 1.06 (t, J = 7.5 Hz, 3H) . EMAR (ESI) calculated for C19H14CIN5 + H + 348.1011, found 348.1014.
[270] According to this procedure, but starting from 4-bromo-1- (5-chloro-2-ethylphenyl) -1H-pyrrole-2-carbonitrile in step 8, the following compound was prepared: 1- (5- chloro-2-ethylphenyl) -4- (9H-purin-6-yl) -1H-pyrrole-2-carbonitrile (compound No 69) ESI (+) MS: m / z 349 (MH +).
[271] According to this procedure, but starting from 4-bromo-1- (5-chloro-2-ethylphenyl) -1H-pyrrol-2-carbonitrile in step 8 and using 4-chloro-1- {[2- (trimethylsilyl) - ethoxy] methyl} -1H-pyrazol [3,4-d] pyrimidine instead of 6-chloro-9- (4-methoxybenzyl) -9H-purine in step 9, the following compound was prepared: 1- (5-chloro-2-ethylphenyl) -4- (1H-pyrazol [3,4-d] pyrimidin-4-yl) -1H-pyrrol-2-carbonitrile (compound No 70) ESI (+) MS: m / z 349 (MH +).
[272] According to this procedure, but starting from 4-bromo-1- (5-chloro-2-ethylphenyl) -1H-pyrrol-2-carbonitrile in step 8 and using 4-chloro-7- (4-methoxybenzyl ) -6,7-dihydro-5H-pyrrole [2,3-d] pyrimidine instead of 6-chloro-9- (4-methoxybenzyl) -9H-purine in step 9, the following compound was prepared: 1 - (5-chloro-2-ethylphenyl) -4- (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carbonitrile (compound No 71 ) ESI (+) MS: m / z 350 (MH +).
[273] According to this procedure, but using 4-chloro-7- {[2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrol [2,3-d] - pyrimidine instead of 6-chloro-9- (4-methoxybenzyl) -9H-purine in step 9, the following compound was prepared: 1- [2-chloro-5- (trifluormethyl) phenyl] - (7H-pyrrole [2,3-d] - pyrimidin-4- il) -1H-pyrrole-2-carbonitrile (compound No 72) 1H NMR (400 MHz, DMSO-d6) δ 12.15 (br. s., 1H), 8.73 (s, 1H), 8.45 (d, J = 1.7 Hz, 1H), 8.36 (d, J = 0.8 Hz, 1H), 8.03-8.09 (m, 3H), 7.61 (dd, J = 2.4, 3.5 Hz, 1H), 7.07 (dd, J = 1.7, 3.6 Hz, 1 H). EMAR (ESI) calculated for C18H9CIF3N5 + H + 388.0572, found 388.0575.
[274] According to this procedure, but using 4-chloro-1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol [3,4-d] pyrimidine instead of 6-chloro-9- ( 4-methoxybenzyl) -9H-purine in step 9, the following compound was prepared: 1- [2-chloro-5- (trifluormethyl) phenyl] -4- (1H-pyrazol [3,4-d] pyrimidin-4- yl) -1H-pyrrole-2-carbonitrile (compound No 73) ESI (+) MS: m / z 389 (MH +).
[275] According to this procedure, but using 4-chloro-7- (4-methoxybenzyl) -6,7-dihydro-5H-pyrrol [2,3-d] - pyrimidine instead of 6-chloro- 9- (4-methoxybenzyl) -9H-purine in step 9, the following compound was prepared: 1- [2-chloro-5- (trifluormethyl) phenyl] - (6,7-dihydro-5H-pyrrole- [2, 3-d] -pyrimidin-4-yl) -1H-pyrrole-2-carbonitrile (compound NO 74) ESI (+) MS: m / z 390 (MH +).
[276] According to this procedure, but starting from 4-bromo-1- [2-methyl-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carbonitrile in step 8 and using 4-chloro-7- { [2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrole [2,3-d] pyrimidine instead of 6-chloro-9- (4-methoxybenzyl) -9H-purine in step 9, the following compound was prepared: 1- [2-methyl-5- (trifluormethyl) phenyl] - (7H-pyrrol [2,3-d] - pyrimidin-4-yl) -1H-pyrrol-2-carbonitrile (compound No 75) ESI (+) MS: m / z 368 (MH +).
[277] According to this procedure, but starting from 4-bromo-1- [2-methyl-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carbonitrile in step 8, the following compound was prepared: 1- [2-methyl-5- (trifluormethyl) phenyl] -4- (9H-purin-6-yl) -1H-pyrrole-2-carbonitrile (compound No 76) ESI (+) MS: m / z 369 (MH +) .
[278] According to this procedure, but starting from 4-bromo-1- [2-methyl-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carbonitrile in step 8 and using 4-chloro-1- { [2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol [3,4-d] pyrimidine instead of 6-chloro-9- (4-methoxybenzyl) -9H-purine in step 9, the following compound was prepared: 1- [2-methyl-5- (trifluormethyl) phenyl] -4- (1H-pyrazol [3,4- d] pyrimidin-4-yl) -1H-pyrrol-2-carbonitrile (compound No 77) ESI (+ ) MS: m / z 369 (MH +).
[279] According to this procedure, but starting from 4-bromo-1- [2-methyl-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carbonitrile in step 8 and using 4-chloro-7- ( 4-methoxybenzyl) -6,7-dihydro-5H-pyrrole [2,3-d] pyrimidine instead of 6-chloro-9- (4-methoxybenzyl) -9H-purine in step 9, the following compound was prepared: 1- [2-methyl-5- (trifluormethyl) phenyl] - (6,7-dihydro-5H-pyrrol- [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carbonitrile ( compound NO 78) ESI (+) MS: m / z 370 (MH +).
[280] According to this procedure, but starting from 4-bromo-1- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carbonitrile in step 8 and using 4-chloro-7- { [2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrole [2,3-d] pyrimidine instead of 6-chloro-9- (4-methoxybenzyl) -9H-purine in step 9, the following compound was prepared: 1- [2-ethyl-5- (trifluormethyl) phenyl] - (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carbonitrile (compound No 79) ESI (+) MS : m / z 382 (MH +).
[281] According to this procedure, but starting from 4-bromo-1- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carbonitrile in step 8, the following compound was prepared: 1- [2-ethyl-5- (trifluormethyl) phenyl] -4- (9H-purin-6-yl) -1H-pyrrole-2-carbonitrile (compound No 80) ESI (+) MS: m / z 383 (MH +) .
[282] According to this procedure, but starting from 4-bromo-1- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carbonitrile in step 8 and using 4-chloro-1- { [2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol [3,4-d] pyrimidine instead of 6-chloro-9- (4-methoxybenzyl) -9H-purine in step 9, the following compound was prepared: 1- [2-ethyl-5- (trifluormethyl) phenyl] -4- (1H-pyrazol [3,4- d] pyrimidin-4-yl) -1H-pyrrol-2-carbonitrile (compound No 81) ESI (+ ) MS: m / z 383 (MH +).
[283] According to this procedure, but starting from 4-bromo-1- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carbonitrile in step 8 and using 4-chloro-7- ( 4-methoxybenzyl) -6,7-dihydro-5H-pyrrole [2,3-d] pyrimidine instead of 6-chloro-9- (4-methoxybenzyl) -9H-purine in step 9, the following compound was prepared: 1- [2-ethyl-5- (trifluormethyl) phenyl] - (6,7-dihydro-5H-pyrrol- [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2- carbonitrile (Compound No. 82) ESI (+) MS: m / z 384 (MH +).
[284] According to this procedure, but starting from 4-bromo-1-phenyl-1H-pyrrol-2-carbonitrile in step 8 and using 4-chloro-7- {[2- (trimethylsilyl) ethoxy] methyl} - 7H-pyrrole [2,3-d] pyrimidine instead of 6-chloro-9- (4-methoxybenzyl) -9H-purine in step 9, the following compound was prepared: 1-Phenyl-4- (7H-pyrrole [ 2,3-d] pyrimidin-4-yl) -1H-pyrrole-2-carbonitrile (compound No 83) ESI (+) MS: m / z 286 (MH +).
[285] According to this procedure, but starting from 4-bromo-1-phenyl-1H-pyrrol-2-carbonitrile in step 8, the following compound was prepared: 1-phenyl-4- (9H-purin-6- yl) -1H-pyrrole-2-carbonitrile (compound No 84) ESI (+) MS: m / z 287 (MH +).
[286] According to this procedure, but starting from 4-bromo-1-phenyl-1H-pyrrol-2-carbonitrile in step 8 and using 4-chloro-1- {[2- (trimethylsilyl) ethoxy] methyl} - 1H pyrazolo [3,4-d] pyrimidine instead of 6-chloro-9- (4-methoxybenzyl) -9H-purine in step 9, the following compound was prepared: 1-phenyl-4- (1H-pyrazolo [3 , 4-d] pyrimidin-4-yl) -1H-pyrrole-2-carbonitrile (compound No 85) ESI (+) MS: m / z 287 (MH +).
[287] According to this procedure, but starting from 4-bromo-1-phenyl-1H-pyrrol-2-carbonitrile in step 8 and using 4-chloro-7- (4-methoxybenzyl) -6,7-di- hydro-5H-pyrrole [2,3-d] pyrimidine instead of 6-chloro-9- (4-methoxybenzyl) -9H-purine in step 9, the following compound was prepared: 1-Phenyl-4- (6, 7-dihydro-5H-pyrrole [2,3-d] pyrimidin-4-yl) -1H-pyrrole-2-carbonitrile (compound No 86) ESI (+) MS: m / z 288 (MH +). EXAMPLE 6 1- (6-aminopyrimidin-4-yl) -4- (5-chloro-2-methylphenyl) -1H-pyrrole-2-carbonitrile (compound No 87)
Scheme D: Step 10
[288] To a suspension of NaH (60% dispersion in oil, 60 mg, 1.5 mmol) in dry THF (4 mL) a solution of 4- (5-chloro-2-methylphenyl) -1H-pyrrole- 3-carbonitrile (216 mg, 1 mmol) in THF (4 mL) was added at 5 ° C, dropwise over 20 min, keeping the reaction temperature below 10 ° C. The suspension was stirred at 5 ° C for 60 min. A solution of 4,6-dichloropyrimidine (179 mg, 1.2 mmol) in THF (4 ml) was added dropwise over 10 min, keeping the reaction temperature below 10 ° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into an NH4Cl solution and extracted with EtOAc (2x 30 ml). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by means of SP1 flash chromatography (Biotage) (hexane / EtOAc 8/2) to obtain 4- (5-chloro-2-methylphenyl) -1- (6-chloropyrimidine-4-yl) -1H- pyrrole-3-carbonitrile (203 mg, 62%). 1H NMR (600 MHz, DMSO-d6) δ 9.01 (d, J = 0.9 Hz, 1H), 8.77 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 0.9 Hz, 1H), 8.11 (d, J = 2.2 Hz, 1H), 7.36-7.44 (m, 3H), 2.33 (s, 3H). M / z of EMAR (ESI) calculated for C16H10CI2N = + Na + 351.0175, found 351.0172.
[289] 4- (5-chloro-2-methylphenyl) -1- (6-chloropyrimidine-4-yl) -1H-pyrrole-3-carbonitrile (100 mg, 0.30 mmol) was treated with NH4OH c. (4 mL) in a closed container at 130 ° C for 1 h in a microwave oven. After cooling, the precipitate was collected, washed with water to give the title compound (82 mg, 88%). 1H NMR (600 MHz, DMSO-d6) δ 8.52 (d, J = 2.2 Hz, 1H), 8.35 (s, 1H), 7.85 (d, J = 2.4 Hz, 1H ), 7.33-7.46 (m, 3H), 7.24 (s, 2H), 6.66 (d, J = 0.7 Hz, 1H), 2.32 (s, 3H). M / z of EMAR (ESI) calculated for C16H12CIN5 + H + 310.0854, found 310.0852.
[290] According to this step, but using methylamine instead of NH4OH, the following compound was prepared: 4- (5-chloro-2-methylphenyl) -1- [6- (methylamino) pyrimidin-4-yl] - 1H-pyrrole-3-carbonitrile (compound No 88) 1H NMR (600 MHz, DMSO-d6) δ 8.79 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 2.2 Hz, 1H), 7.45 (s, 1H), 7.41 (s, 2H), 2.32 (s, 3H). EMAR M / z (ESI) calculated for C17H 14 CIN 5 + H + 324,1011, found 324,1013.
[291] According to this procedure, but starting from 4- (5-chloro-2-ethylphenyl) -1H-pyrrole-3-carbonitrile, the following compound was prepared: 1- (6-aminopyrimidin-4-yl ) -4- (2-ethylphenyl-5-chloro) -1H-pyrrole-3-carbonitrile (compound No 89) ESI (+) MS: m / z 324 (MH +).
[292] According to this procedure, but starting from 4- (5-chloro-2-ethylphenyl) -1H-pyrrole-3-carbonitrile and using methylamine instead of NH4OH, the following compound was prepared: 4- ( 5-chloro-2-ethylphenyl) -1- [6- (methylamino) pyrimidin-4-yl] - 1H-pyrrole-3-carbonitrile (compound No 90) EMAR (ESI) calculated for C18H16CIN5 + H + 338.1167, found 338,1169.
[293] According to this procedure, but starting from 4- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrole-3-carbonitrile, the following compound was prepared: 1- (6-aminopyrimidin-4- il) -4- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrole-3-carbonitrile (compound No 91) EMAR (ESI) calculated for C16H9CIF3N5 + H + 364.0572, found 364.0575.
[294] According to this procedure, but starting from 4- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrole-3-carbonitrile and using methylamine instead of NH4OH, the following compound was prepared: 4- [2-chloro-5- (trifluormethyl) phenyl] -1- [6- (methylamino) -pyrimidin-4-yl] -1H-pyrrol-3-carbonitrile (compound No 92) EMAR (ESI) calculated for C17H11CIF3N5 + H + 378.0728, found 378.0731.
[295] According to this procedure, but starting from 4- [2-methyl-5- (trifluormethyl) phenyl] -1H-pyrrol-3-carbonitrile, the following compound was prepared: 1- (6-aminopyrimidin-4- il) -4- [2-methyl-5- (trifluoromethyl) -phenyl] -1H-pyrrole-3-carbonitrile (compound No 93) ESI (+) MS: m / z 344 (MH +).
[296] According to this procedure, but starting from 4- [2-methyl-5- (trifluormethyl) phenyl] -1H-pyrrol-3-carbonitrile and using methylamine instead of NH4OH, the following compound was prepared: 1- [6- (methylamino) pyrimidin-4-yl] -4- [2-methyl-5- (trifluoro-methyl) phenyl] -1H-pyrrol-2-carbonitrile (compound No 94) ESI (+) MS: m / z 358 (MH +).
[297] According to this procedure, but starting from 4- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrole-3-carbonitrile, the following compound was prepared: 1- (6-aminopyrimidin-4- il) -4- [2-ethyl-5- (trifluoromethyl) -phenyl] -1H-pyrrole-3-carbonitrile (compound No 95) EMAR (ESI) calculated for C18H14F3N5 + H + 358.1274, found 358.1270.
[298] According to this procedure, but starting from 4- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrol-3-carbonitrile and using methylamine instead of NH4OH, the following compound was prepared: 4- [2-ethyl-5- (trifluormethyl) phenyl] -1- [6- (methylamino) -pyrimidin-4-yl] -1H-pyrrol-3-carbonitrile (compound No 96) ESI (+) MS: m / z 372 (MH +).
[299] According to this procedure, but starting from 4-phenyl-1H-pyrrol-3-carbonitrile, the following compound was prepared: 1- (6-aminopyrimidin-4-yl) -4-phenyl-1H-pyrrole- 2-carbonitrile (compound No 97) ESI (+) MS: m / z 262 (MH +).
[300] According to this procedure, but starting from 4-phenyl-1H-pyrrol-3-carbonitrile and using methylamine instead of NH4OH, the following compound was prepared: 1- [6- (methylamino) pyrimidin-4-yl ] -4-phenyl-1H-pyrrole-3-carbonitrile (compound No 98) ESI (+) MS: m / z 276 (MH +). EXAMPLE 7 4- (5-chloro-2-methylphenyl) -1- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-3-carbonitrile (compound No 99 )
Scheme D: Step 10
[301] To a suspension of NaH (60% dispersion in oil, 60 mg, 1.5 mmol) in dry THF (4 mL) a solution of 4- (5-chloro-2-methylphenyl) -1H-pyrrole- 3-carbonitrile (216 mg, 1 mmol) in THF (4 mL) was added at 5 ° C, dropwise over 20 min, keeping the reaction temperature below 10 ° C. The suspension was stirred at 5 ° C for 60 min. 4-chloropyrrole [2,1-f] [1,2,4] triazine (183 mg, 1.2 mmol) was added and the reaction was stirred under reflux for 2 h. The reaction mixture was poured into an NH4Cl solution and extracted with EtOAc (2x 30 ml). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by means of flash chromatography SP1 (Biotage) (hexane / EtOAc 85/15) to obtain the title compound (183 mg, 55%). 1H NMR (600 MHz, DMSO-d6) δ 8.81 (d, J = 2.38 Hz, 1H), 8.54 (s, 1H), 8.32 (dd, J = 1.19, 2, 66 Hz, 1H), 8.09 (d, J = 2.38 Hz, 1H), 7.59 (dd, J = 1.28, 4.76 Hz, 1H), 7.44-7.46 ( m, 1H), 7.41 (d, J = 1.28 Hz, 2H), 7.19 (dd, J = 2.56, 4.76 Hz, 1H), 2.35 (s, 3H). EMAR (ESI) calculated for C18H12CIN5 + H + 334.0854, found 334.0858.
[302] According to this procedure the following compounds were prepared: 4- (5-chloro-2-ethylphenyl) -1- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-3-carbonitrile (compound No 100) EMAR (ESI) calculated for C19H14CIN5 + H + 348.1011, found 348.1013. 4- [2-chloro-5- (trifluormethyl) phenyl] -1- (pyrrol [2,1-f] [1,2,4] -triazin-4-yl) -1H-pyrrole-3-carbonitrile (compound No 101) EMAR (ESI) calculated for C18H9CIF3N5 + H + 388.0572, found 388.0568. 4- [2-methyl-5- (trifluormethyl) phenyl] -1- (pyrrole [2,1-f] [1,2,4] - triazin-4-yl) -1H-pyrrole-3-carbonitrile (compound No 102) ESI (+) MS: m / z 368 (MH +). 4- [2-ethyl-5- (trifluormethyl) phenyl] -1- (pyrrol [2,1-f] [1,2,4] - triazin-4-yl) -1H-pyrrol-2-carbonitrile (compound No. 103) ESI (+) MS: m / z 382 (MH +). 4-Phenyl-1- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-2-carbonitrile (compound No 104) ESI (+) MS: m / z 286 (MH +). EXAMPLE 8 4- (5-chloro-2-methylphenyl) -1- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carbonitrile (compound No 105)
Scheme D: Step 10
[303] 4-chloro-7- {[2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrole [2,3-d] pyrimidine (157 mg, 0.55 mmol), Cs2CO3 (223 mg, 0.69 mmol), 4- (5-chloro-2-methylphenyl) -1H-pyrrole-3-carbonitrile (100 mg, 0.46 mmol) and dry toluene (2.5 mL) were charged at room temperature. The resulting reaction mixture was degassed three times, filled with argon again each time, before Pd2 (dba) 3 (10 mg, 0.011 mmol) and tri-tert-butylphosphine (23 μL, 0.023 mmol, 1.0 M in toluene ) to be loaded. The resulting reaction mixture was degassed four times, filled with argon each time, and then heated at 100 ° C for 6 h. The reaction mixture was concentrated and purified by means of SP1 Biotage flash chromatography (elution gradient from 10% to 20% EtOAc in hexane) to obtain 4- (5-chloro-2-methylphenyl) -1- (7- {[2-trimethylsilyl) ethoxy] methyl} -7H-pyrrol [2,3-d] pyrimidin-4-yl) - 1H-pyrrol-3-carbonitrile (110 mg, 51%). 1H NMR (600 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.79 (d, J = 2.2 Hz, 1H), 8.10 (d, J = 2.2 Hz, 1H ), 7.94 (d, J = 3.8 Hz, 1H), 7.45 (s, 1H), 7.41 (s, 2H), 7.26 (d, J = 3.8 Hz, 1H ), 5.69 (s, 2H), 3.56 (t, J = 8.0 Hz, 2H), 2.36 (s, 3H), 0.85 (t, J = 8.0 Hz, 2H ), -0.09 (s, 9H). M / z of EMAR (ESI) calculated for C24H26CIN5OSi + H + 464.1668, found 464.1665.
[304] TFA (2.1 mL) was added to a solution of 4- (5-chloro-2-methylphenyl) 1- (7- {[2-trimethylsilyl) ethoxy] methyl} - 7H-pyrrole [2,3 -d] pyrimidin-4-yl) -1H-pyrrole-3-carbonitrile (100 mg, 0.21 mmol) in dry DCM (4.2 mL) and stirred for 5 h at room temperature. After removing the solvent, the residue was treated with 96% EtOH (6 ml), 33% NH4OH (0.5 ml) and stirred for 1 h at room temperature. The precipitate was filtered and washed with EtOH, to provide the title compound as a white solid (57 mg, 79%). 1H NMR (600 MHz, DMSO-d6) δ 12.57 (br. S., 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.69 (s, 1H), 8, 06 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 3.5 Hz, 1H), 7.31-7.44 (m, 3H), 7.12 (d, J = 3.5 Hz, 1H), 2.33 (s, 3H). M / z of EMAR (ESI) calculated for C18H12CIN5 + H + 334.0854, found 334.0858.
[305] According to this procedure, but using 4-chloro-1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrrole [2,3-d] pyridine instead of 4-chloro-7- { [2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrole [2,3-d] pyrimidine, the following compound was prepared: 4- (5-chloro-2-methylphenyl) -1- (1H-pyrrole [2, 3-b)] pyridin-4-yl) - 1H-pyrrole-3-carbonitrile (compound No. 106) ESI (+) MS: m / z 333 (MH +).
[306] According to this procedure, but using 6-chloro-9- (4-methoxybenzyl) -9H-purine instead of 4-chloro-7- {[2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrole [2,3-d] pyrimidine, the following compound was prepared: 4- (5-chloro-2-methylphenyl) -1- (9H-purin-6-yl) -1H-pyrrol-3-carbonitrile (compound No 107 ) ESI (+) MS: m / z 335 (MH +).
[307] According to this procedure, but using 4-chloro-1- {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazolo [3,4- d] pyrimidine instead of 4-chloro-7- { [2- (trimethylsilyl) - ethoxy] methyl} -7H-pyrrole [2,3-d] pyrimidine, the following compound was prepared: 4- (5-chloro-2-methylphenyl) -1- (1H-pyrazole [3 , 4-d] pyrimidin-4-yl) -1H-pyrrole-3-carbonitrile (compound No 108) ESI (+) MS: m / z 335 (MH +).
[308] According to this procedure, but using 4-chloro-7- (4-methoxy-benzyl) -6,7-dihydro-5H-pyrrol [2,3- d] pyrimidine instead of 4-chloro -7- {[2- (trimethylsilyl) - ethoxy] methyl} -7H-pyrrole [2,3-d] pyrimidine, the following compound was prepared: 4- (5-chloro-2-methylphenyl) -1- (6 , 7-dihydro-5H-pyrrole [2,3-d] - pyrimidin-4-yl) -1H-pyrrole-3-carbonitrile (compound No 109) ESI (+) MS: m / z 336 (MH +) .
[309] According to this procedure, but starting from 4- (5-chloro-2-ethylphenyl) -1H-pyrrole-3-carbonitrile, the following compound was prepared: 4- (5-chloro-2-ethylphenyl) ) -1- (7H-pyrrole [2,3-d] pyrimidin-4-yl) - 1H-pyrrole-3-carbonitrile (compound No 110) EMAR (ESI) calculated for C19H14CIN5 + H + 348,1011, found 348, 1015.
[310] According to this procedure, but starting from 4- (5-chloro-2-ethylphenyl) -1H-pyrrole-3-carbonitrile and using 4-chloro-7- (4-methoxy-benzyl) -6 , 7-dihydro-5H-pyrrol [2,3-c] pyrimidine instead of 4-chloro-7- {[2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrole [2,3-c] pyrimidine , the following compound was prepared: 4- (5-chloro-2-ethylphenyl) -1- (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrole -3-carbonitrile (compound No 111) ESI (+) MS: m / z 350 (MH +).
[311] According to this procedure, but starting from 4- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrole-3-carbonitrile, the following compound was prepared: 4- [2-chloro-5- (trifluormethyl) phenyl] -1- (7H-pyrrol [2,3-d] - pyrimidin-4-yl) -1H-pyrrol-3-carbonitrile (compound No 112) EMAR (ESI) calculated for C18H9CIF3N5 + H + 388, 0572, found 388.0575.
[312] According to this procedure, but starting from 4- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrol-3-carbonitrile and using 4-chloro-7- (4-methoxy-benzyl) - 6,7-dihydro-5H-pyrrole [2,3-d] pyrimidine instead of 4-chloro-7- {[2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrole [2,3-d] pyrimidine, the following compound was prepared: 4- [2-chloro-5- (trifluormethyl) phenyl] -1- (7H-pyrrol [2,3-d] -pyrimidin-4-yl) -1H-pyrrol-3- carbonitrile (compound No 113) ESI (+) MS: m / z 390 (MH +).
[313] According to this procedure, but starting from 4- [2-methyl-5- (trifluormethyl) phenyl] -1H-pyrrole-3-carbonitrile, the following compound was prepared: 4- [2-methyl-5- (trifluormethyl) phenyl] -1- (6,7-dihydro-5H-pyrrol- [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carbonitrile (compound No 114) ESI (+ ) MS: m / z 368 (MH +).
[314] According to this procedure, but starting from 4- [2-methyl-5- (trifluormethyl) phenyl] -1H-pyrrol-3-carbonitrile and using 4-chloro-7- (4-methoxy-benzyl) - 6,7-dihydro-5H-pyrrole [2,3-d] pyrimidine instead of 4-chloro-7- {[2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrole [2,3-d] pyrimidine, the following compound was prepared: 4- [2-methyl-5- (trifluoromethyl) phenyl] -1- (6,7-dihydro-5H-pyrrole [2,3-d] pyrimidin-4-yl) -1H-pyrrole-3-carbonitrile (compound No 115) ESI (+) MS: m / z 370 (MH +).
[315] According to this procedure, but starting from 4- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrole-3-carbonitrile, the following compound was prepared: 4- [2-ethyl-5- (trifluormethyl) phenyl] -1- (7H-pyrrol [2,3-d] - pyrimidin-4-yl) -1H-pyrrol-3-carbonitrile (compound No 116) ESI (+) MS: m / z 382 ( MH +).
[316] According to this procedure, but starting from 4- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrol-3-carbonitrile and using 4-chloro-7- (4-methoxy-benzyl) - 6,7-dihydro-5H-pyrrole [2,3-d] pyrimidine instead of 4-chloro-7- {[2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrole [2,3-d] pyrimidine, the following compound was prepared: 4- [2-ethyl-5- (trifluormethyl) phenyl] -1- (6,7-dihydro-5H-pyrrol- [2,3-d] pyrimidin-4-yl ) -1H-pyrrole-3-carbonitrile (compound No 117) ESI (+) MS: m / z 384 (MH +).
[317] According to this procedure, but starting from 4-phenyl-1H-pyrrol-3-carbonitrile, the following compound was prepared: 4-phenyl-1- (7H-pyrrol [2,3-d] pyrimidin-4 -yl) -1H-pyrrole-2-carbonitrile (compound No 118) ESI (+) MS: m / z 286 (MH +).
[318] According to this procedure, but starting from 4-phenyl-1H-pyrrol-3-carbonitrile and using 4-chloro-7- (4-methoxybenzyl) -6,7-dihydro-5H-pyrrole [2 , 3-d] pyrimidine instead of 4-chloro-7- {[2- (trimethylsilyl) ethoxy] methyl} -7H-pyrrole [2,3-d] pyrimidine, the following compound was prepared: 4-phenyl-1 - (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carbonitrile (compound No 119) ESI (+) MS: m / z 288 ( MH +). EXAMPLE 9 5- (6-aminopyrimidin-4-yl) -3- (5-chloro-2-methylphenyl) -1H-pyrrole-2-carboxamide (compound No 120)
Scheme E: Steps 11, 12, 13, 14 Step 11: 3- (5-chloro-2-methylphenyl) -1- (phenylsulfonyl) -5- (4,4,5,5-tetramethyl-1,3,2 -dioxiborolan — il) -1H-pyrrole-2-ethyl carboxylate (XVI)
[319] To a solution of ethyl 3- (5-chloro-2-methylphenyl) -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate (403 mg, 1.0 mmol) in THF (5 mL) LDA (2M in THF / heptane / ethylbenzene, 0.55 ml, 1.1 mmol) was added slowly dropwise at -78 ° C under an argon atmosphere. After 30 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxiborolane (0.230 ml, 1.1 mmol) was added to the mixture at -78 ° C and stirred for 1 h. MeOH (0.5 ml) was added and the resulting mixture was stirred at room temperature after slowly raising the temperature, diluted with water and extracted with EtOAc (30 ml x 3), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure to give the title compound that was used without further purification. Step 12: Ethyl 5- (6-aminopyrimidin-4-yl) -3- (5-chloro-2-methylphenyl) -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate (XVII)
[320] 3- (5-chloro-2-methylphenyl) -1- (phenylsulfonyl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole -2-ethyl carboxylate, 6-iodopyrimidine-4-amine (221 mg, 1 mmol) and Na2CO3 (318 mg, 3 mmol) were dissolved in dioxane / water (3/1, 10 mL). The resulting reaction mixture was degassed three times, refilled with argon each time, before PdCl2 (dppf) (81 mg, 0.1 mmol) was loaded. The resulting reaction mixture was degassed four times, filled with argon each time, and then heated to 110 ° C for 30 min. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, washed with EtOAc. The filtrate was concentrated and then diluted with EtOAc, washed with aqueous saline, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by means of SP1 flash chromatography (Biotage) (DC / MeOH / 7N NH3 in EOH 98/2 / 0.2) to produce the title compound (198 mg, 40%). 1H NMR (600 MHz, DMSO-d6) δ 8.23-8.30 (m, 3H), 7.77-7.83 (m, 1H), 7.66-7.73 (m, 2H), 7.33-7.37 (m, 1H), 7.29-7.32 (m, 1H), 7.17 (d, J = 2.20 Hz, 1H), 7.04 (s, 2H) , 6.76 (s, 1H), 6.63 (d, J = 0.92 Hz, 1H), 3.99-4.10 (m, 2H), 2.11 (s, 3H), 0, 90 (t, J = 7.11 Hz, 3H). M / z of EMAR (ESI) calculated for C24H21CIN4O4S + H + 497.1045, found 497.1049.
[321] According to this step, but using 2,2-dimethylpropanoate (4-chloro-7H-pyrrol [2,3-d] pyrimidin-7-yl) methyl instead of 6-iodopyrimidine-4-amine, the following compound was prepared: 3- (5-chloro-2-methylphenyl) -5- (7- {[2,2-dimethylpropanoyl) -oxy] - methyl} -7H-pyrrole [2,3-d] pyrimidin- Ethyl 4-yl) -1- (phenylsulfonyl) - 1H-pyrrole-2-carboxylate (XVII) 1H NMR (600 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.35 (dd, J = 1.19, 8.52 Hz, 2H), 7.80-7.85 (m, 2H), 7.70-7.78 (m, 2H), 7.35-7.40 (m, 1H ), 7.32-7.34 (m, 1H), 7.31 (d, J = 2.20 Hz, 1H), 7.09 (s, 1H), 6.88 (d, J = 3, 66 Hz, 1H), 6.27 (s, 2H), 4.09 (q, J = 7.14 Hz, 2H), 2.17 (s, 3H), 1.11 (s, 9H), 0 , 92 (t, J = 7.05 Hz, 3H).
[322] According to this procedure, but starting from 3- (5-chloro-2-ethylphenyl) -1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate, the following compound was prepared: 5- (6-aminopyrimidin -4-yl) -3- (5-chloro-2-ethylphenyl) -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate (XVII) ESI (+) MS: m / z 511 (MH + ).
[323] According to this procedure, but starting from 3- (5-chloro-2-ethylphenyl) -1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate and using 4-chloro-7H 2,2-dimethylpropanoate -pyrrole [2,3-d] pyrimidin-7-yl) methyl instead of 6-iodopyrimidine-4-amine, the following compound was prepared: 3- (5-chloro-2-ethylphenyl) -5- (7- Ethyl {[(2,2-dimethylpropanoyl) oxy] - methyl} -7H-pyrrol [2,3-d] piramidin-4-yl) -1- (phenylsulfonyl) - 1H-pyrrol-2-carboxylate (XVII) 1H NMR (600 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.33 (dd, J = 1.01, 8.52 Hz, 2H), 7.80-7.85 (m, 2H), 7.70-7.78 (m, 2H), 7.39-7.44 (m, 1H), 7.31-7.38 (m, 1H), 7.27 (d, J = 2.20 Hz, 1H), 7.09 (s, 1H), 6.83 (d, J = 3.66 Hz, 1H), 6.27 (s, 2H), 3.99-4.10 ( m, 2H), 1.11 (s, 9H), 1.02-1.07 (m, 3H), 0.88 (t, J = 7.14 Hz, 3H).
[324] In accordance with this procedure, but starting from ethyl 3- [2-ethyl-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate, the following compound was prepared : 5- (6-aminopyrimidin-4-yl) -3- [2-ethyl-5- (trifluormethyl) -phenyl] -1H-pyrrole-2-carboxylate (XVII) ESI (+) MS: m / z 545 (MH +).
[325] According to this procedure, but starting from 3- [2-ethyl-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate and using 2,2-dimethylpropanoate (4-chloro-7H-pyrrole [2,3-d] pyrimidin-7-yl) methyl instead of 6-iodopyrimidine-4-amine, the following compound was prepared: 3- [2-ethyl-5- (trifluormethyl ) phenyl] -5- (7- {[2,2-dimethyl-propanoyl) -oxy [methyl} -7H-pyrrol [2,3-d] pyrimidin-4-yl) -1- (phenylsulfonyl) -1H- ethyl pyrrole-2-carboxylate (XVII) 1H NMR (600 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.28-8.45 (m, 2H), 7.81-7.87 (m, 2H), 7.73-7.78 (m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H) , 7.54 (s, 1H), 7.14 (s, 1H), 6.84 (d, J = 3.6 Hz, 1H), 6.27 (s, 2H), 4.02 (q, J = 6.9 Hz, 2H), 2.61 (q, J = 7.6 Hz, 2H), 1.11 (s, 9H), 1.06-1.10 (m, 3H), 0, 81 (t, J = 7.0 Hz, 3H). Step 13: 5- (6-Aminopyrimidin-4-yl) -3- (5-chloro-2-methylphenyl) -1H-pyrrole-2-carboxylic acid (XVIII)
[326] Ethyl 5- (6-aminopyrimidin-4-yl) -3- (5-chloro-2-methyl-phenyl) -1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate (80 mg, 0.161 mmol ) in THF (0.5 mL) was treated with LiOH.H2O (27 mg, 0.644 mmol) at 150 ° C in the microwave device for 15 min. After cooling, the residue was concentrated, treated with 1 N HCl (300 μL), neutralized with saturated sodium hydrogen carbonate solution, the resulting precipitate was collected by filtration to give the title compound (52 mg, 98%). ESI (+) MS: m / z 329 (MH +).
[327] According to this step, the following compounds were prepared: 5- (6-Aminopyrimidin-4-yl) -3- (5-chloro-2-ethylphenyl) -1H-pyrrole2-carboxylic acid (XVIII) ESI ( +) MS: m / z 343 (MH +). 5- (6-aminopyrimidin-4-yl) -3- [2-ethyl-5- (trifluoro-methyl) phenyl] -1H-pyrrole-2-carboxylic acid (XVIII) ESI (+) MS: m / z 377 (MH +). 3- (5-chloro-2-methylphenyl) -5- (7H-pyrrol [2,3-d] -pyrimidin-4-yl) -1H-pyrrol-2-carboxylic acid (XVIII) ESI (+) MS: m / z 353 (MH +). 3- (5-chloro-2-ethylphenyl) -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxylic acid (XVIII) 1H NMR (600 MHz, DMSO -d6) δ 12.42-12.89 (m, 1H), 12.24, 11.39 (br. s., 1H), 8.79 (s, 1 H (br. S., 1H), 7.62 (dd, J = 2.47, 3.39 Hz, 1H), 7.29-7.36 (m, 1H), 7.25 (d, J = 2.01 Hz, 1H), 7 , 19 (s, 1H), 7.01 (dd, J = 1.65, 3.48 Hz, 1H), 2.52-2.56 (m, 2H), 1.00-1.05 (m , 3H) 3- [2-Ethyl-5- (trifluormethyl) phenyl] -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrole-2-carboxylic acid (XVIII) ESI (+) MS: m / z 401 (MH +) Step 14: 5- (6-aminopyrimidin-4-yl) -3- (5-chloro-2-methyl-phenyl) -1H-pyrrole-2-carboxamide
[328] A solution of 5- (6-aminopyrimidin-4-yl) -3- (5-chloro-2-methylphenyl) -1H-pyrrole-2-carboxylic acid (52 mg, 0.158 mmol) in DMF (1, 0 mL) and DIPEA (55 μL, 0.634 mmol) was stirred at 0 ° C. EDCl (60 mg, 0.317 mmol) and HOBT.NH3 (48 mg, 0.317 mmol) were added and the reaction mixture was stirred for 3 h at room temperature. The mixture was diluted with saturated sodium hydrogen carbonate solution at 5 ° C, stirred for 30 min, the resulting precipitate was collected by filtration to give the title compound (42 mg, 80%). 1H NMR (600 MHz, DMSO-d6) δ 11.83 (br. S., 1H), 8.39 (s, 1H), 7.38, 7.21 (br. S., 1H) - 7, 27 (m, 2H), 7.15 (s, 1H), 7.08 (br. S., 1H), 6.85 (s, 2H), 6.74 (s, 1H), 6.67 ( s, 1H), 2.10 (s, 3H). M / z of EMAR (ESI) calculated for C16H14CIN5O + H + 328.0960, found 328.0955.
[329] According to this step, the following compounds were prepared: 5- (6-aminopyrimidin-4-yl) -3- (2-ethylphenyl-5-chloro) -1H-pyrrole-2-carboxamide (compound No 121 ) ESI (+) MS: m / z 342 (MH +). 5- (6-aminopyrimidin-yl) -3- [2-ethyl-5- (trifluormethyl) -phenyl] - 1H-pyrrole-2-carboxamide (compound No 122) ESI (+) MS: m / z 376 (MH + ). 3- (5-chloro-2-methylphenyl) -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 123) 1H NMR (600 MHz, DMSO-d6) δ 12.16 (br. S., 1H), 12.04, 8.78 (s, 1H), 7.63 (br. S., 1H) - 7.76 (m, 1H) , 7.58 (dd, J = 2.38, 3.48 Hz, 1H), 7.24-7.27 (m, 2H), 7.22 (d, J = 1.28 Hz, 1H), 7.14-7.18 (m, 1H), 7.12 (s, 1H), 7.01 (dd, J = 1.74, 3.57 Hz, 1H), 2.14 (s, 3H) . M / z of EMAR (ESI) calculated for C18H14CIN5O + H + 352.0960, found 352.0961. 3- (5-chloro-2-ethylphenyl) -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) - 1H-pyrrol-2-carboxamide (compound No 124) 1H NMR (600 MHz, DMSO-d6) δ 12.17 (br. S., 1H), 12.03 (br. S., 1H), 8.78 (s, 1H), 7.64 (br. S., 1H), 7.58 (dd, J = 2.38, 3.48 Hz, 1H), 7.26 - 7.33 (m, 2H), 7.19 (d, J = 2.02 Hz, 1H), 7 , 14 (br. S., 1H), 7.12 (d, J = 2.20 Hz, 1H), 6.99 (dd, J = 1.83, 3.66 Hz, 1H), 1.01 (t, J = 7.51 Hz, 3H). M / z of EMAR (ESI) calculated for C19H16CIN5S + H + 366.11116, found 366.1111. 3- [2-ethyl-5- (trifluormethyl) phenyl] -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 125) 1H NMR ( 600 MHz, DMSO-d6) δ 12.17 (br. S, 1H), 12.14 (br. S., 1H), 8.79 (s, 1H), 7.79 (br. S., 1H), 7.60 (dd, J = 1.28, 8.06 Hz, 1H), 7.58 (dd, J = 2.56, 3.48 Hz, 1H), 7.49 (d, J = 8.06 Hz, 1H), 7.45 (d, J = 1.28 Hz, 1H), 7.17 (d, J = 1.65 Hz, 1H), 7.13 (br. S., 1H), 7.01 (dd, J = 1.74, 3.57 Hz, 1H), 2.60 (q, J = 7.51 Hz, 2H), 1.05 (t, J = 7.51 Hz, 3H). M / z of EMAR (ESI) calculated for C20H16F3N5O + H + 400.1380, found 400.1380.
[330] According to this step, but using methylamine, the following compounds were prepared: 5- (6-aminopyrimidin-4-yl) -N-methyl-3- (5-chloro-2-methylphenyl) - 1H-pyrrole -2-carboxamide (compound No 126) ESI (+) MS: m / z 342 (MH +). 5- (6-aminopyrimidin-4-yl) -N-methyl-3- (5-chloro-2-ethylphenyl) - 1H-pyrrole-2-carboxamide (compound No 127) ESI (+) MS: m / z 356 (MH +). 5- (6-aminopyrimidin-4-yl) -N-methyl-3- [2-ethyl-5- (trifluoro-methyl) phenyl] -1H-pyrrole-2-carboxamide (compound No 128) ESI (+) MS : m / z 390 (MH +). 3- (5-chloro-2-methylphenyl) -N-methyl-5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 129) 1H NMR (600 MHz, DMSO-d6) δ 12.16 (br. S., 1H), 12.03 (br. S., 1H), 8.77 (s, 1H), 8.29 (q, J = 4.15 Hz, 1H), 7.58 (dd, J = 2.47, 3.39 Hz, 1H), 7.22-7.28 (m, 2H), 7.21 (d, J = 1 , 65 Hz, 1H), 7.13 (d, J = 2.01 Hz, 1H), 7.01 (dd, J = 1.65, 3.48 Hz, 1H), 2.70 (d, J = 4.58 Hz, 3H), 2.13 (s, 3H). M / z of EMAR (ESI) calculated for C19H16CIN5S + H + 366.1111, found 366.1111. 3- (5-chloro-2-ethylphenyl) -N-methyl-5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 130) 1H NMR (600 MHz, DMSO-d6) δ 12.16 (br. S., 1H), 12.03 (br. S., 1H), 8.78 (s, 1H), 8.27 (q, J = 4.33 Hz, 1H), 7.57 (dd, J = 2.38, 3.48 Hz, 1H), 7.29-7.32 (m, 1H), 7.26-7.28 (m , 1H), 7.17 (d, J = 2.20 Hz, 1H), 7.13 (d, J = 2.20 Hz, 1H), 6.99 (dd, J = 1.65, 3, 66 Hz, 1H), 2.69 (d, J = 4.58 Hz, 3H), 2.45-2.48 (m, 1H), 1.00 (t, J = 7.60 Hz, 3H) . EMAR (ESI) calculated for C20H18CIN5O + H + 380.1273, found 380.1272. 3- [2-ethyl-5- (trifluormethyl) phenyl] -N-methyl-5- (7H-pyrrol- [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (Compound No 131) 1H NMR (600 MHz, DMSO-d6) δ 12.16 (br. S., 1H), 12.12 (br. S., 1H), 8.78 (s, 1H), 8.38 ( q, J = 4.03 Hz, 1H), 7.59 (dd, J = 1.37, 8.15 Hz, 1H), 7.57 (dd, J = 2.47, 3.39 Hz, 1H ), 7.49 (d, J = 8.06 Hz, 1H), 7.44 (d, J = 1.10 Hz, 1H), 7.17 (d, J = 1.65 Hz, 1H), 7.01 (dd, J = 1.74, 3.57 Hz, 1H), 2.69 (d, J = 4.40 Hz, 3H), 2.58 (q, J = 7.51 Hz, 2H ), 1.04 (t, J = 7.60 Hz, 3H). EMAR (ESI) calculated for C21H18F3N5O + H + 414.1536, found 414.1534.
[331] According to this procedure, but using 6-chloro-N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 12, the following compound was prepared: 3- (5-chloro-2 -methylphenyl) -5- [6- (methylamino) pyrimidin-4-yl] - 1H-pyrrole-2-carboxamide (compound No 132) ESI (+) MS: m / z 342 (MH +).
[332] According to this procedure, but using 4-chloropyrrole [2,1-f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 12, the following compound was prepared: 3 - (5-chloro-2-methylphenyl) -5- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-2-carboxamide (compound No 133) ESI ( +) MS: m / z 352 (MH +).
[333] According to this procedure, but using 4-chloro-7- (4-methoxy-benzyl) -6,7-dihydro-5H-pyrrol [2,3-c] pyrimidine instead of 6-iodopyrimidine -4-amine in step 12 and by removing the 4-methoxy-benzyl protecting group with TFA in DCM, the following compound was prepared: 3- (5-chloro-2-methylphenyl) -5- (6,7-di- hydro-5H-pyrrole [2,3-d] pyrimidin-4-yl) -1H-pyrrole-2-carboxamide (compound No 134) ESI (+) MS: m / z 354 (MH +).
[334] According to this procedure, but starting from 3- (5-chloro-2-ethylphenyl) -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, and using 6-chlorine -N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 12, the following compound was prepared: 3- (5-chloro-2-ethylphenyl) -5- [6- (methylamino) pyrimidin- 4-yl] - 1H-pyrrole-2-carboxamide (compound No 135) ESI (+) MS: m / z 356 (MH +).
[335] According to this procedure, but starting from 3- (5-chloro-2-ethylphenyl) -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, and using 4-chloropyrrole [2,1-f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 12, the following compound was prepared: 3- (5-chloro-2-ethylphenyl) -5- ( pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-2-carboxamide (compound No 136) ESI (+) MS: m / z 366 (MH +).
[336] According to this procedure, but starting from ethyl 3- (5-chloro-2-ethylphenyl) -1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11, using 4-chloro- 7- (4-methoxy-benzyl) -6,7-dihydro-5H-pyrrol [2,3-c] pyrimidine instead of 6-iodopyrimidine-4-amine in step 12 and removing the 4- methoxy-benzyl with TFA in DCM, the following compound was prepared: 3- (5-chloro-2-ethylphenyl) -5- (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4 -yl) -1H-pyrrole-2-carboxamide (compound No 137) ESI (+) MS: m / z 368 (MH +).
[337] According to this procedure, but starting from ethyl 3- [2-chloro-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, the following compound was prepared: 5- (6-aminopyrimidin-yl) -3- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrole-2-carboxamide (compound No 138) ESI (+) MS: m / z 382 (MH +).
[338] According to this procedure, but starting from ethyl 3- [2-chloro-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, and using 6-chloro-N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 12, the following compound was prepared: 3- [2-chloro-5- (trifluoromethyl) phenyl] -5- [6- (methylamino) -pyrimidin-4-yl] -1H-pyrrol-2-carboxamide (compound No 139) ESI (+) MS: m / z 396 (MH +).
[339] According to this procedure, but starting from methyl 3- [2-chloro-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, and using 4-chloro-7H-pyrrole [2,3-d] pyrimidin-7-yl) methyl 2,2-dimethylpropanoate instead of 6-iodopyrimidine-4-amine in step 12, the following compound was prepared: 3 - [2-chloro-5- (trifluormethyl) phenyl] -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 140) ESI (+) MS: m / z 406 (MH +).
[340] According to this procedure, but starting from ethyl 3- [2-chloro-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, and using 4-chloropyrrole [2,1-f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 12, the following compound was prepared: 3- [2-chloro-5- ( trifluormethyl) phenyl] -5- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-2-carboxamide (compound No 141) ESI (+) MS: m / z 406 (MH +).
[341] According to this procedure, but starting from ethyl 3- [2-chloro-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11, using 4-chloro-7- (4-methoxy-benzyl) -6,7-dihydro-5H-pyrrole [2,3-d] pyrimidine instead of 6-iodopyrimidine-4-amine in step 12 and removing the protecting group 4-methoxybenzyl with TFA in DCM, the following compound was prepared: 3- [2-chloro-5- (trifluormethyl) phenyl] -5- (6,7-dihydro-5H-pyrrole [2,3- d] pyrimidin-4-yl) -1H-pyrrole-2-carboxamide (compound No 142) ESI (+) MS: m / z 408 (MH +).
[342] According to this procedure, but starting from ethyl 3- [2-methyl-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, the following compound was prepared: 5- [6-aminopyrimidin-4-yl] -3- [2-methyl-5- (trifluormethyl) -phenyl] -1H-pyrrole-2-carboxamide (compound No 143) ESI (+) MS: m / z 362 (MH +).
[343] According to this procedure, but starting from ethyl 3- [2-methyl-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11, and using 6-chloro-N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 12, the following compound was prepared: 5- [6- (methylamino) pyrimidin-4-yl] -3- [2-methyl-5- (trifluoromethyl) phenyl] -1H-pyrrole-2-carboxamide (compound No 144) ESI (+) MS: m / z 376 (MH +).
[344] According to this procedure, but starting from ethyl 3- [2-methyl-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, and using 4-chloro-7H-pyrrole [2,3-d] pyrimidin-7-yl) methyl 2,2-dimethylpropanoate instead of 6-iodopyrimidine-4-amine in step 12, the following compound was prepared: 3- [ 2-methyl-5- (trifluormethyl) phenyl] -5- (7H-pyrrol [2,3- d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 145) ESI (+) MS: m / z 386 (MH +).
[345] According to this procedure, but starting from ethyl 3- [2-methyl-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, and using 4-chloropyrrole [2,1-f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 12, the following compound was prepared: 3- [2-methyl-5- (trifluoromethyl) phenyl] -5- (pyrrole [2,1-f] [1,2,4] - triazin-4-yl) -1H-pyrrole-2-carboxamide (compound No 146) ESI (+) MS: m / z 386 (MH +).
[346] According to this procedure, but starting from ethyl 3- [2-methyl-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, using 4 -chloro-7- (4-methoxy-benzyl) -6,7-dihydro-5H-pyrrole [2,3-c] pyrimidine instead of 6-iodopyrimidine-4-amine in step 12 and removing the protecting group 4-methoxybenzyl with TFA in DCM, the following compound was prepared: 3- [2-methyl-5- (trifluormethyl) phenyl] -5- (6,7-dihydro-5H-pyrrole [2,3-d] pyrimidin-4-yl) -1H-pyrrole-2-carboxamide (compound No 147) ESI (+) MS: m / z 388 (MH +).
[347] According to this procedure, but starting from ethyl 3- [2-ethyl-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, using 6-chloro-N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 12, the following compound was prepared: 3- [2-ethyl-5- (trifluoromethyl) phenyl] -5- [ 6- (methylamino) - pyrimidin-4-yl] -1H-pyrrole-2-carboxamide (compound No 148) ESI (+) MS: m / z 390 (MH +).
[348] According to this procedure, but starting from ethyl 3- [2-ethyl-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11, and using 4-chloropyrrole [2,1-f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 12, the following compound was prepared: 3- [2-ethyl-5- ( trifluormethyl) phenyl] -5- (pyrrole [2,1-f] [1,2,4] - triazin-4-yl) -1H-pyrrol-2-carboxamide (compound No 149) ESI (+) MS: m / z 400 (MH +).
[349] According to this procedure, but starting from ethyl 3- [2-ethyl-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, using 4-chloro-7- (4-methoxy-benzyl) -6,7-dihydro-5H-pyrrole [2,3-d] pyrimidine instead of 6-iodopyrimidine-4-amine in step 12 and removing the protection group 4-methoxybenzyl with TFA in DCM, the following compound was prepared: 3- [2-ethyl-5- (trifluormethyl) phenyl] -5- (6,7-dihydro-5H-pyrrole- [2, 3-d] pyrimidin-4-yl) -1H-pyrrole-2-carboxamide (compound No 150) ESI (+) MS: m / z 402 (MH +).
[350] According to this procedure, but from ethyl 3-phenyl-1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11, the following compound was prepared: 5- (6-aminopyrimidin-4 -yl) -3-phenyl-1H-pyrrole-2-carboxamide (compound No 151) ESI (+) MS: m / z 280 (MH +).
[351] According to this procedure, but from ethyl 3-phenyl-1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11, and using 6-chloro-N-methylpyrimidin-4-amine in Instead of 6-iodopyrimidin-4-amine in step 12, the following compound was prepared: 5- [6- (methylamino) pyrimidin-4-yl] -3-phenyl-1H-pyrrol-2-carboxamide (compound No 152) ESI (+) MS: m / z 294 (MH +).
[352] According to this procedure, but from ethyl 3-phenyl-1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11, and using 4-chloro-7H- 2,2-dimethylpropanoate pyrrol [2,3-d] pyrimidin-7-yl) methyl instead of 6-iodopyrimidine-4-amine in step 12, the following compound was prepared: 3-Phenyl-5- (7H-pyrrol [2,3- d] pyrimidin-4-yl) -1H-pyrrole-2-carboxamide (compound No 153) ESI (+) MS: m / z 304 (MH +).
[353] According to this procedure, but from ethyl 3-phenyl-1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11, and using 4-chloropyrrole [2,1-f] [1 , 2,4] triazine instead of 6-iodopyrimidine-4-amine in step 12, the following compound was prepared: 3-Phenyl-5- (pyrrole [2,1-f] [1,2,4] triazin- 4-yl) -1H-pyrrole-2-carboxamide (compound No 154) ESI (+) MS: m / z 304 (MH +).
[354] According to this procedure, but starting from ethyl 3-phenyl-1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11, using 4-chloro-7- (4-methoxy-benzyl ) -6,7-dihydro-5H-pyrrole [2,3-d] pyrimidine instead of 6-iodopyrimidine-4-amine in step 12 and removing the 4-methoxybenzyl protecting group with TFA in DCM, the following compound was prepared: 5- (6,7-Dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -3-phenyl-1H-pyrrol-2-carboxamide (compound No 155) ESI ( +) MS: m / z 306 (MH +).
[355] According to this procedure, but using 6-chloro-N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 12 and methylamine in step 14, the following compound was prepared: 3- ( 5-chloro-2-methylphenyl) -N-methyl-5- [6- (methylamino) - pyrimidin-4-yl] -1H-pyrrol-2-carboxamide (compound No 156) ESI (+) MS: m / z 356 (MH +).
[356] According to this procedure, but using 4-chloropyrrole [2,1-f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 12 and methylamine in step 14, the following compound was prepared: 3- (5-chloro-2-methylphenyl) -N-methyl-5- (pyrrole [2,1-f] [1,2,4] - triazin-4-yl) -1H-pyrrole- 2-carboxamide (compound No 157) ESI (+) MS: m / z 366 (MH +).
[357] According to this procedure, but using 4-chloro-7- (4-methoxy-benzyl) -6,7-dihydro-5H-pyrrol [2,3-d] - pyrimidine instead of 6- iodopyrimidine-4-amine in step 12 and methylamine in step 14 and by removing the 4- methoxybenzyl protecting group with TFA in DCM, the following compound was prepared: 3- (5-chloro-2-methylphenyl) -5- (6, 7-dihydro-5H-pyrrole [2,3-d] -pyrimidin-4-yl) -N-methyl-1H-pyrrol-2-carboxamide (compound No 158) ESI (+) MS: m / z 368 (MH +).
[358] According to this procedure, but starting from 3- (5-chloro-2-ethylphenyl) -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, using 6-chloro- N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 12 and methylamine in step 14, the following compound was prepared: 3- (5-chloro-2-ethylphenyl) -N-methyl-5- [6- (methylamino) pyrimidin-4-yl] -1H-pyrrol-2-carboxamide (compound No 159) ESI (+) MS: m / z 368 (MH +).
[359] According to this procedure, but starting from 3- (5-chloro-2-ethylphenyl) -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, using 4-chloropyrrole [ 2,1-f] [1,2,4] triazine instead of 6-iodo-pyrimidin-4-amine in step 12 and methylamine in step 14, the following compound was prepared: 3- (5-chloro-2- ethylphenyl) -N-methyl-5- (pyrrole [2,1-f] [1,2,4] - triazin-4-yl) -1H-pyrrole-2-carboxamide (compound No 160) ESI (+) MS : m / z 380 (MH +).
[360] According to this procedure, but starting from ethyl 3- (5-chloro-2-ethylphenyl) -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, using 4-chloro- 7- (4-methoxy-benzyl) -6,7-dihydro-5H-pyrrol [2,3-d] -pyrimidine instead of 6-iodopyrimidine-4-amine in step 12 and methylamine in step 14 and by removing the 4-methoxy-benzyl protecting group with TFA in DCM, the following compound was prepared: 3- (5-chloro-2-ethylphenyl) -5- (6,7-dihydro-5H-pyrrole [2, 3-d] pyrimidin-4-yl) -N-methyl-1H-pyrrol-2-carboxamide (compound NO 161) ESI (+) MS: m / z 382 (MH +).
[361] According to this procedure, but starting from ethyl 3- [2-chloro-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11 and using methylamine in step 14, the following compound was prepared: 5- (6-aminopyrimidin-4-yl) -3- [2-chloro-5- (trifluormethyl) -phenyl] -N-methyl-1H-pyrrole-2- carboxamide (compound No 162) ESI (+) MS: m / z 396 (MH +).
[362] According to this procedure, but starting from ethyl 3- [2-chloro-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, using 6-chloro-N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 12 and methylamine in step 14, the following compound was prepared: 3- [2-chloro-5- (trifluormethyl) phenyl ] -N-methyl-5- [6- (methylamino) pyrimidin-4-yl) -N-methyl-1H-pyrrole-2-carboxamide (compound No 163) ESI (+) MS: m / z 410 (MH +) .
[363] According to this procedure, but starting from ethyl 3- [2-chloro-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, using 4-chloro-7H-pyrrole [2,3-d] pyrimidin-7-yl) methyl 2,2-dimethylpropanoate instead of 6-iodopyrimidine-4-amine in step 12 and methylamine in step 14, the following compound was prepared: 3- [2-chloro-5- (trifluormethyl) phenyl] -N-methyl-5- (7H-pyrrol- [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 164) ESI (+) MS: m / z 420 (MH +).
[364] According to this procedure, but starting from ethyl 3- [2-chloro-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11, using 4-chloropyrrole [2,1-f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 12 and methylamine in step 14, the following compound was prepared: 3- [2-chlorine -5- (trifluormethyl) phenyl] -N-methyl-5- (pyrrol [2,1- f] [1,2,4] triazin-4-yl) -1H-pyrrol-2-carboxamide (compound No 165) ESI (+) MS: m / z 420 (MH +).
[365] According to this procedure, but starting from ethyl 3- [2-chloro-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11, using 4-chloro-7- (4-methoxy-benzyl) -6,7-dihydro-5H-pyrrole [2,3-c] pyrimidine instead of 6-iodopyrimidine-4-amine in step 12 and methylamine in step 14 and removing the 4-methoxybenzyl protecting group with TFA in DCM, the following compound was prepared: 3- [2-chloro-5- (trifluormethyl) phenyl] -5- (6,7-dihydro-5H- pyrrole [2,3-d] pyrimidin-4-yl) -N-methyl-1H-pyrrole-2-carboxamide (compound No. 166) ESI (+) MS: m / z 422 (MH +).
[366] According to this procedure, but starting from ethyl 3- [2-methyl-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11 and using methylamine in step 14, the following compound was prepared: 5- (6-aminopyrimidin-4-yl) -N-methyl-3- [2-methyl-5- (trifluoro-methyl) phenyl] -1H-pyrrole-2 -carboxamide (compound No 167) ESI (+) MS: m / z 390 (MH +).
[367] According to this procedure, but starting from ethyl 3- [2-methyl-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, using 6-chloro-N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 12 and methylamine in step 14, the following compound was prepared: N-methyl-5- [6- (methylamino) pyrimidin -4-yl] -3- [2-methyl-5- (trifluoromethyl) phenyl] -1H-pyrrole-carboxamide (Compound No. 168) ESI (+) MS: m / z 404 (MH +).
[368] According to this procedure, but starting from ethyl 3- [2-methyl-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, using 4-chloro-7H-pyrrole [2,3-d] pyrimidin-7-yl) methyl 2,2-dimethylpropanoate instead of 6-iodopyrimidine-4-amine in step 12 and methylamine in step 14, the following compound was prepared: N-methyl-3- [2-methyl-5- (trifluormethyl) phenyl] -5- (7H-pyrrol- [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (Compound No. 169) ESI (+) MS: m / z 400 (MH +).
[369] According to this procedure, but starting from ethyl 3- [2-methyl-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11, using 4-chloropyrrole [2,1-f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 12 and methylamine in step 14, the following compound was prepared: N-methyl-3- [2-methyl-5- (trifluormethyl) phenyl] -5- (pyrrole [2,1- f] [1,2,4] triazin-4-yl) -1H-pyrrole-2-carboxamide (compound No 170) ESI (+) MS: m / z 400 (MH +).
[370] According to this procedure, but starting from ethyl 3- [2-methyl-5- (trifluoromethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, using 4-chloro-7- (4-methoxy-benzyl) -6,7-dihydro-5H-pyrrole [2,3-d] pyrimidine instead of 6-iodopyrimidine-4-amine in step 12 and methylamine in step 14 and removing the protecting group 4-methoxybenzyl with TFA in DCM, the following compound was prepared: 3- [2-methyl-5- (trifluormethyl) phenyl] -5- (6,7-dihydro-5H-pyrrole [2,3-d] pyrimidin-4-yl) -N-methyl-1H-pyrrole-2-carboxamide (compound No 171) ESI (+) MS: m / z 402 (MH +).
[371] According to this procedure, but starting from ethyl 3- [2-ethyl-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11, using 6-chloro-N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 12 and methylamine in step 14, the following compound was prepared: 3- [2-ethyl-5- (trifluormethyl) phenyl ] -N-methyl-5- [6- (methyl-amino) pyrimidin-4-yl] -1H-pyrrol-2-carboxamide (compound No 172) ESI (+) MS: m / z 404 (MH +).
[372] According to this procedure, but starting from ethyl 3- [2-ethyl-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11, using 4-chloropyrrole [2,1-f] [1,2,4] triazine instead of 6-iodopyrimidine-4-amine in step 12 and methylamine in step 14, the following compound was prepared: 3- [2-ethyl -5- (trifluormethyl) phenyl] -N-methyl-5-pyrrol [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrol-2-carboxamide (Compound No. 173) ESI (+) MS: m / z 414 (MH +).
[373] According to this procedure, but starting from ethyl 3- [2-ethyl-5- (trifluormethyl) phenyl] -1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, using 4-chloro-7- (4-methoxy-benzyl) -6,7-dihydro-5H-pyrrole [2,3-c] pyrimidine instead of 6-iodopyrimidine-4-amine in step 12 and methylamine in step 14 and removing the protecting group 4-methoxybenzyl with TFA in DCM, the following compound was prepared: 3- [2-ethyl-5- (trifluormethyl) phenyl] -5- (6,7-dihydro-5H- pyrrole [2,3-d] pyrimidin-4-yl) -N-methyl-1H-pyrrole-2-carboxamide (compound No 174) ESI (+) MS: m / z 416 (MH +).
[374] According to this procedure, but starting from ethyl 3-phenyl-1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11 and methylamine in step 14, the following compound was prepared: 5- (6-aminopyrimidin-4-yl) -N-methyl-3-phenyl-1H-pyrrole-2-carboxamide (compound No 175) ESI (+) MS: m / z 294 (MH +).
[375] According to this procedure, but starting from ethyl 3-phenyl-1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11, using 6-chloro-N-methylpyrimidin-4-amine in Instead of 6-iodopyrimidin-4-amine in step 12 and methylamine in step 14, the following compound was prepared: 5- [6- (methylamino) pyrimidin-4-yl] -N-methyl-3-phenyl-1H-pyrrole - 2-carboxamide (compound No 176) ESI (+) MS: m / z 306 (MH +).
[376] According to this procedure, but starting from ethyl 3-phenyl-1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11, using 4-chloro-7H- 2,2-dimethylpropanoate pyrrole [2,3-d] pyrimidin-7-yl) methyl instead of 6-iodopyrimidine-4-amine in step 12 and methylamine in step 14, the following compound was prepared: N-methyl-3-phenyl-5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 177) ESI (+) MS: m / z 318 (MH +).
[377] According to this procedure, but starting from ethyl 3-phenyl-1- (phenylsulfonyl) -1H-pyrrole-2-carboxylate in step 11, using 4-chloropyrrole [2,1-f] [1 , 2,4] triazine instead of 6-iodopyrimidine-4-amine in step 12 and methylamine in step 14, the following compound was prepared: N-methyl-3-phenyl-5- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-2-carboxamide (compound No 178) ESI (+) MS: m / z 318 (MH +).
[378] According to this procedure, but starting from ethyl 3-phenyl-1- (phenylsulfonyl) -1H-pyrrol-2-carboxylate in step 11, using 4-chloro-7- (4-methoxy-benzyl ) -6,7 dihydro-5H-pyrrole [2,3-d] pyrimidine instead of 6-iodopyrimidine-4-amine in step 12 and methylamine in step 14 and removing the 4-methoxybenzyl protecting group with TFA in DCM, the following compound was prepared: 5- (6,7-Dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -N-methyl-3-phenyl-1H-pyrrol-2- carboxamide (compound No 179) ESI (+) MS: m / z 320 (MH +). EXAMPLE 10 4- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N-methyl-1H-pyrrole-1-carboxamide (compound No 180)
Scheme F: Steps 15, 16, 17, 18 Step 15: 2- (5-chloro-2-methylphenyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Tert-butyl -1H-pyrrole-1-carboxylate (XX)
[379] 2- (5-chloro-2-methylphenyl) -4-iodo-1H-pyrrole-1-tert-butyl carboxylate (442 mg, 1.06 mmol) and 4,4,5,5-tetramethyl- 2- (propan-2-yloxy) -1,3,2-dioxaborolane (217 mg, 1.16 mmol) in dry THF (1.6 mL), under argon at -78 ° C was treated with n-BuLi ( 2 M in hexane, 0.58 mL, 1.6 mmol) and the reaction mixture was stirred at -78 ° C. After 2 h, MeOH (1 ml) was added, the temperature was allowed to rise and NH4Cl solution (2 ml) was added dropwise at room temperature. The solution was diluted with diethyl ether and washed sequentially with water and brine. The organic layer was dried over anhydrous Na2SO4 and evaporated to obtain the title compound, which was used without further purification for the next reaction. Step 16: tert-Butyl 4- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-methyl-phenyl) -1H-pyrrole-1-carboxylate (XXI)
[380] The product 2- (5-chloro-2-methylphenyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrrole-1-carboxylate of crude tert-butyl (392 mg, 0.94 mmol), Na2CO3 (250 mg, 2.36 mmol), PdCl2 (dppf) (77 mg, 0.094 mmol) and 6-iodopyrimidine-4-amine (311 mg, 1.41 mmol) were degassed and purged with argon and suspended in degassed 1,4-dioxane (3 mL) and water (1 mL). The reaction mixture was heated to 110 ° C (oil bath temperature) for 2 h. The solution was diluted with EtOAc and washed with water. After drying over anhydrous Na2SO4, the organic layer was evaporated. The crude product was purified by chromatography on silica gel (8: 2 hexane / EtOAc) providing the title compound (220 mg, 58%). 1H NMR (600 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.79 (s, 1H), 7.41 (d, 1H), 7.29 (d, 1H), 7.16 (m, 1H), 6.98 (s, 1H), 6.66 (s, 1H), 2.30 (s, 3H), 1.44 (s, 9H). Step 17: 6- [5- (5-chloro-2-methylphenyl) -1H-pyrrol-3-yl] pyrimidin-4-amine (XXII)
[381] tert-butyl 4- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-methyl-phenyl) -1H-pyrrole-1-carboxylate (210 mg, 0.55 mmol) DCM (11 ml) was treated with TFA (5.5 ml). The reaction mixture was stirred at room temperature for 3 days. The volatiles were evaporated and the solid obtained was suspended with EtOH and treated with 30% ammonium hydroxide until pH 9-10. The solution was diluted with EtOAc and washed first with 10% ammonium hydroxide, then with saline and, after drying over anhydrous Na2SO4, the organic layer was evaporated leaving the title compound which was used in the next step without further purification. 1H NMR (600 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.41 (m, 1H), 7.40 (m, 1H), 7.23 (m, 1H), 7.16 (m, 1H), 6.83 (s, 1H), 6.29 (s, 1H), 2.23 (s, 3H). Step 18: 4- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N-methyl-1H-pyrrole-1-carboxamide
[382] To a solution of triphosgene (97.5 mg, 0.325 mmol) in DCM (7 mL) was added a solution of 6- [5- (5-chloro-2-methylphenyl) -1H-pyrrol-3-yl ] pyrimidin-4-amine (156 mg, 0.55 mmol) in DCM (10 mL), followed by DIPEA (373 μL, 2.15 mmol). After 3 h, a solution of methylamine (2 M in tetrahydrofuran, 430 μL, 0.86 mmol) and DIPEA (97 μL, 0.56 mmol) in DCM (4 mL) was added. The reaction was stirred overnight at room temperature. The solution was washed with saline, the organic phase was dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (DCM / MeOH 90/10) to obtain the title compound (120 mg, 64%, 2 steps). 1H NMR (600 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.40 (m, 1H), 8.05 (s, 1H), 7.40 (m, 1H), 7.30 (m, 1H), 6.90 (s, 1H), 6.58 (s, 1H), 2.78 (s, 3H), 2.22 (s, 3H).
[383] According to this procedure, but using 6-chloro-N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 16, the following compound was prepared: 2- (5-chloro-2 -methylphenyl) -N-methyl-4- [6- (methylamino) -pyrimidin-4-yl) -1H-pyrrole-1-carboxamide (compound No 181) ESI (+) MS: m / z 356 (MH +).
[384] According to this procedure, but using 4-chloro-7H-pyrrol [2,3-d] pyrimidin-7-yl) methyl 2,2-dimethylpropanoate instead of 6-iodopyrimidine-4-amine in step 16 and removing the 2,2-dimethylpropanoyl protecting group with LiOH.H2O in THF / water at room temperature, the following compound was prepared: 2- (5-chloro-2-methylphenyl) -N-methyl-4- (7H- pyrrole [2,3-d] pyrimidin-4-yl) -1H-pyrrole-1-carboxamide (compound No 182) ESI (+) MS: m / z 366 (MH +).
[385] According to this procedure, but starting from tert-butyl 2- (5-chloro-2-ethylphenyl) -4-iodo-1H-pyrrol-1-carboxylate the following compound was prepared: 4- ( 6-aminopyrimidin-yl) -2- (5-chloro-2-ethylphenyl) -N-methyl-1H-pyrrole-1-carboxamide (compound No 183) ESI (+) MS: m / z 356 (MH +).
[386] According to this procedure, but starting from tert-butyl 2- (5-chloro-2-ethylphenyl) -4-iodo-1H-pyrrol-1-carboxylate and using 6-chloro-N-methylpyrimidin -4-amine instead of 6-iodopyrimidin-4-amine in step 16, the following compound was prepared: 2- (5-chloro-2-ethylphenyl) -N-methyl-4- [6- (methylamino) pyrimidin- 4-yl] -1H-pyrrole-1-carboxamide (compound No 184) ESI (+) MS: m / z 370 (MH +).
[387] According to this procedure, but starting from tert-butyl 2- (5-chloro-2-ethylphenyl) -4-iodo-1H-pyrrol-1-carboxylate, using 2,2-dimethylpropanoate of 4 -chloro-7H-pyrrole [2,3-d] pyrimidin-7-yl) methyl instead of 6-iodopyrimidine-4-amine in step 16 and removing the 2,2-dimethylpropanoyl protecting group with LiOH.H2O in THF / water at room temperature, the following compound was prepared: 2- (5-chloro-2-ethylphenyl) -N-methyl-4- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrole -1-carboxamide (compound No 185) ESI (+) MS: m / z 380 (MH +).
[388] According to this procedure, but starting from tert-butyl 2- [2-ethyl-5- (trifluormethyl) phenyl] -4-iodo-1H-pyrrole-1-carboxylate, the following compound was prepared : 4- (6-aminopyrimidin-4-yl) -2- [2-ethyl-5- (trifluormethyl) -phenyl] -N-methyl-1 H-pyrrol-1-carboxamide (compound No 186) ESI (+) MS: m / z 390 (MH +).
[389] According to this procedure, but starting from 2- [2-ethyl-5- (trifluormethyl) phenyl] -4-iodo-1H-pyrrole-1-carboxylate and using 6-chloro- N-methylpyrimidin-4-amine instead of 6-iodopyrimidine-4-amine in step 16, the following compound was prepared: 2- [2-ethyl-5- (trifluormethyl) phenyl] -N-methyl-4- [6 - (methyl-amino) pyrimidin-4-yl] -1H-pyrrole-1-carboxamide (compound No 187) ESI (+) MS: m / z 404 (MH +).
[390] According to this procedure, but starting from tert-butyl 2- [2-ethyl-5- (trifluormethyl) phenyl] -4-iodo-1H-pyrrol-1-carboxylate, using 2,2-dimethylpropanoate 4-chloro-7H-pyrrole [2,3-d] pyrimidin-7-yl) methyl instead of 6-iodopyrimidine-4-amine in step 16 and removing the 2,2-dimethylpropanoyl protecting group with LiOH.H2O in THF / water at room temperature, the following compound was prepared: 2- [2-ethyl-5- (trifluormethyl) phenyl] -N-methyl-4- (7H-pyrrol- [2,3-d] pyrimidin-4-yl ) -1H-pyrrole-1-carboxamide (compound No 188) ESI (+) MS: m / z 414 (MH +). EXAMPLE 11 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1H-pyrrole-3-carboxamide (compound No 189)
Conv.1
[391] To a solution of 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1H-pyrrole-3-carbonitrile (59 mg, 0.19 mmol) in TFA ( 0.90 ml) water (0.11 ml) and 96% sulfuric acid (0.22 ml) were added sequentially, with efficient stirring. The mixture was allowed to stir for 5 h at 70 ° C and then diluted by adding, dropwise, water (1.5 ml). The reaction mixture was made basic (pH 10-12) by adding 30% aqueous ammonia solution, with stirring. The precipitated solid was collected by filtration, washed with water and finally dried in a vacuum oven at 50 ° C to obtain the title compound as an off-white solid (42 mg, 68%). 1H NMR (400 MHz, DMSO-d6) δ 11.91 (br. S., 1H), 8.31 (d, J = 0.8 Hz, 1H), 7.30-7.36 (m, 1H ), 7.23-7.30 (m, 3H), 7.22 (br. S, 1H), 6.76 (s, 2H), 6.70 (br. S., 1H), 6, 66 (d, J = 1.1 Hz, 1H), 2.12 (s, 3H). M / z EMAR (ESI) calculated for C16H14CIN5O + H + 328.0960, found 328.0964.
[392] The above procedure was employed, starting with the appropriate carbonitrile derivative, to synthesize the following compounds: 2- (5-chloro-2-methylphenyl) -5- [6- (methylamino) pyrimidin-4-yl] - 1H -pyrrole-3-carboxamide (compound No 190) 1H NMR (400 MHz, DMSO-d6) δ 11.91 (br. s., 1H), 8.35 (s, 1H), 7.10 - 7.39 (m, 5H), 6.52-6.78 (m, 2H), 2.81 (d, J = 4.5 Hz, 3H), 2.12 (m, 3H). M / z EMAR (ESI) calculated for C17H16CIN5O + H + 342.1111, found 342.1112. 2- (5-chloro-2-methylphenyl) -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 191) 1H NMR (400 MHz, DMSO-d6) δ 12.16 (br. S., 1H), 12.08 (br. S., 1H), 8.66 (s, 1H), 7.71 (s, 1H), 7.61 (dd, J = 2.5, 3.3 Hz, 1H), 7.47 (br. s., 1H), 7.29 - 7.36 (m, 1H), 7.217.28 (m, 1H) , 7.11 (dd, J = 1.6, 3.5 Hz, 1H), 6.79 (br. S., 1H), 2.14 (s, 3H). M / z of EMAR (ESI) calculated for C18H14CIN5O + H + 352.0960, found 352.0962. 2- (5-chloro-2-methylphenyl) -5- (1H-pyrrol [2,3-b)] pyridin-4-yl) - 1H-pyrrol-3-carboxamide (compound No 192) 1H NMR (400 MHz , DMSO-d6) δ 11.85 (br. S., 1H), 11.65 (br. S., 1H), 8.16 (d, J = 5.0 Hz, 1H), 7.53 ( d, J = 3.3 Hz, 1H), 7.44 (s, 2H), 7.39 (d, J = 5.1 Hz, 1H), 7.27-7.38 (m, 4H), 7.02 (d, J = 3.5 Hz, 1H), 6.74 (br. S., 1H), 2.17 (s, 3H). M / z of EMAR (ESI) calculated for C19H15CIN4O + H + 351,1007, found 351,1011. 2- (5-chloro-2-methylphenyl) -5- (9H-purin-6-yl) -1H-pyrrole-3-carboxamide (compound No 193) 1H NMR (500 MHz, DMSO-d6) δ 12.21 (br. s, 1H), 8.78 (s, 1H), 8.59 (s, 1H), 7.99 (d, J = 2.20 Hz, 1H), 7.33-7.38 (M, 1H), 7.21-7.33 (m, 3H), 6.82 (br. S., 1H), 2.16 (s, 3H). M / z EMAR (ESI) calculated for C17H13CIN6O + H + 353.0912, found 353.0917. 2- (5-chloro-2-methylphenyl) -5- (1H-pyrazol [3,4-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 194) 1H NMR (400 MHz, DMSO-d6) δ 14.00 (s, 1H), 12.47, 8.82 (s, 1H), 8.78 (s, 1H), 7.93 (br. S., 1H) - 7, 98 (m, 1H), 7.49 (br. S, 1H), 7.22-7.39 (m, 3H), 6.90 (br. S., 1H), 2.14 (s, 3H). M / z of EMAR (ESI) calculated for C17H13CIN6O + H + 353.0912, found 353.0914. 2- (5-chloro-2-methylphenyl) -5- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-3-carboxamide (compound No 195) 1H NMR (600 MHz, DMSO-d6) δ 11.67 (s, 1H), 8.41 (s, 1H), 8.02 (dd, J = 1.3, 2.5 Hz, 1H), 7, 91 (s, 1H), 7.54, 7.47 (dd, J = 1.3, 4.7 Hz, 1H), 7.27 (br. S, 1H) - 7.37 (m, 1H ), 7.16-7.27 (m, 2H), 7.05 (dd, J = 2.5, 4.6 Hz, 1H), 6.85 (br. S., 1H), 2.10 (s, 3H). M / z of EMAR (ESI) calculated for C18H14CIN5O + H + 352.0960, found 352.0955. 2- (5-chloro-2-methylphenyl) -5- (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 196) ESI (+) MS: m / z 354 (MH +). 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -1H-pyrrole-3-carboxamide (compound No 197) 1H NMR (600 MHz, DMSO-d6) δ 11.94 (br. s., 1H), 8.31 (d, J = 0.9 Hz, 1H), 7.37 (dd, J = 2.4, 8.2 Hz, 1H), 7.30 (d , J = 8.2 Hz, 1H), 7.28 (s, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.16 (br. S., 1H), 6, 76 (s, 1H), 6.68 (br., 1H), 6.66 (d, J = 1.1 Hz, 1H), 2.46 (q, J = 7.7 Hz, 2H) , 0.96 (t, J = 7.6 Hz, 3H). EMAR (ESI) calculated for C17H16CIN5S + H + 342.1111, found 342.1111. 2- (5-chloro-2-ethylphenyl) -5- [6- (methylamino) pyrimidin-4-yl] - 1H-pyrrol-3-carboxamide (compound No 198) 1H NMR (600 MHz, DMSO-d6) δ 11.94 (br., 1H), 8.35 (br., 1H), 7.39 (dd, J = 2.3, 8.3 Hz, 1H), 7.34 (br. s., 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 7.17 (br. s., 2H), 6.73 (br. S, 1H), 6.68 (br. S, 1H), 2.80 (br. S., 3H), 2.46 (q, J = 7.6 Hz, 2H ), 0.97 (t, J = 7.6 Hz, 3H). EMAR (ESI) calculated for C18H15CIN5O + H + 356.1273, found 356.1273. 2- (5-chloro-2-ethylphenyl) -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) - 1H-pyrrol-3-carboxamide (compound No 199) 1H NMR (600 MHz, DMSO-d6) δ 12.17 (br. S., 1H), 12.08 (br. S., 1H), 8.65 (s, 1H), 7.71 (s, 1H), 7.61 (dd, J = 2.2, 3.3 Hz, 1H), 7.42 (br. s., 1H), 7.37 (dd, J = 2.3, 8.4 Hz, 1H), 7 , 29 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 7.00 - .. 7.14 (m, 1H), 6.76 ( br., 1H), 2.45 (q, J = 7.5 Hz, 2H), 0.98 (t, J = 7.5 Hz, 3H). EMAR (ESI) calculated for C19H16CIN5O + H + 366.1111, found 366.1111. 2- (5-chloro-2-ethylphenyl) -5- (9H-purin-6-yl) -1H-pyrrole-3-carboxamide (compound No 200) ESI (+) MS: m / z 367 (MH +). 2- (5-chloro-2-ethylphenyl) -5- (1H-pyrazol [3,4-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 201) ESI (+) MS: m / z 367 (MH +). 2- (5-chloro-2-ethylphenyl) -5- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-3-carboxamide (compound No 202) ESI (+) MS: m / z 366 (MH +). 2- (5-chloro-2-ethylphenyl) -5- (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 203) ESI (+) MS: m / z 368 (MH +). 5- (6-aminopyrimidin-4-yl) -2- [2-chloro-5- (trifluormethyl) -phenyl] -1H-pyrrole-3-carboxamide (compound No 204) 1H NMR (600 MHz, DMSO-d6) δ 12.17 (br. s., 1H), 8.34 (s, 1H), 7.65-7.81 (m, 3H), 7.43 (.. br s, 1H), 7.31 (s, 1H), 6.89 (br., 2H), 6.76 (br., 1H), 6.66 (s, 1 H). EMAR (ESI) calculated for C16H11CIF3N5O + H + 382.0677, found 382.0674. 2- [2-chloro-5- (trifluormethyl) phenyl] -5- [6- (methylamino) -pyrimidin-4-yl] -1H-pyrrole-3-carboxamide (compound No 205) 1H NMR (400 MHz, DMSO -d6) δ 12.13 (br. s., 1H), 8.38 (s, 1H), 7.62-7.87 (m, 3H), 7.40 (br. s., 1H), 7.34 (br. S, 1H), 7.26 (br. S, 1H), 6.74 (br. S., 1H), 6.70 (s, 1H), 2.82 (d , J = 4.39 Hz, 3H). EMAR (ESI) calculated for C17H13CIF3N5O + H + 396.0834, found 396.0831. 2- [2-chloro-5- (trifluormethyl) phenyl] -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 206) EMAR (ESI ) calculated for C18H11CIF3N5O + H + 406.0677, found 406.0679. 2- [2-chloro-5- (trifluormethyl) phenyl] -5- (9H-purin-6-yl) -1H-pyrrole-3-carboxamide (compound No 207) 1H NMR (500 MHz, DMSO-d6) δ 12.51 (br. S., 1H), 8.80 (s, 1H), 8.60 (s, 1H), 8.03 (d, J = 1.9 Hz, 1H), 7.68- 7.81 (m, 3H), 7.56 (br. S., 1H), 6.83 (br. S., 1H). EMAR (ESI) calculated for C17H10CIF3N6O + H + 407.0630, found 407.0625. 2- [2-chloro-5- (trifluormethyl) phenyl] -5- (1H-pyrazol [3,4-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 208) 1H NMR ( 500 MHz, DMSO-d6) δ 14.08 (br. S., 1H), 12.74 (br. S., 1H), 8.86 (s, 1H), 8.79 (s, 1H), 8.01 (s, 1H), 7,697.82 (m, 3H), 7.62 (br. S., 1H), 6.97 (br. S., 1H). EMAR (ESI) calculated for C17H10CIF3N6O + H + 407.0630, found 407.0627. 2- [2-chloro-5- (trifluormethyl) phenyl] -5- (pyrrol [2,1-f] [1,2,4] -triazin-4-yl) -1H-pyrrole-3-carboxamide (compound No. 209) ESI (+) MS: m / z 406 (MH +). 2- [2-chloro-5- (trifluormethyl) phenyl] -5- (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 210) ESI (+) MS: m / z 408 (MH +). 5- (6-aminopyrimidin-yl) -2- [2-methyl-5- (trifluormethyl) -phenyl] -1H-pyrrole-3-carboxamide (compound No 211) 1H NMR (600 MHz, DMSO-d6) δ 12 .00 (br. S, 1H), 8.32 (d, J = 0.9 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.51 (s, 1H ), 7.47 (d, J = 7.9 Hz, 1H), 7.32 (br. S., 1H), 7.30 (s, 1H), 6.78 (br. S., 1H) , 6.72 (br. S., 1H), 6.66 (d, J = 1.1 Hz, 1H), 2.23 (s, 3H). EMAR (ESI) calculated for C17H14F3N5O + H + 362.1223, found 362.1223. 5- [6- (methylamino) pyrimidin-4-yl] -2- [2-methyl-5- (trifluoromethyl) phenyl] -1H-pyrrole-3-carboxamide (compound No 212) 1H NMR (600 MHz, DMSO-d6) δ 11.96 (br. S., 1H), 8.34 (br. S., 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.50 (s , 1H), 7.44-7.48 (m, 1H), 7.33 (br. S., 1H), 7.29 (br. S., 1H), 7.20 (br. S., 1H), 6.70 (br., 2H), 2.78 (br., 3H), 2.20 (s, 3H). EMAR (ESI) calculated for C18H16F3N5O + H + 376.1380, found 376.1380. 2- [2-methyl-5- (trifluormethyl) phenyl] -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 213) 1H NMR ( 600 MHz, DMSO-d6) δ 12.27 (br. S., 1H), 12.10 (br. S., 1H), 8.67 (s, 1H), 7.75 (s, 1H), 7.58 - 7.64 (m, 2H), 7.55 (br. S., 1H), 7.54 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.12 (d, J = 2.6 Hz, 1H), 6.81 (br. S., 1H), 2.25 (s, 3H). EMAR (ESI) calculated for C19H14F3N5O + H + 386.1223, found 386.1223. 2- [2-methyl-5- (trifluormethyl) phenyl] -5- (9H-purin-6-yl) -1H-pyrrole-3-carboxamide (compound No 214) ESI (+) MS: m / z 387 ( MH +). 2- [2-methyl-5- (trifluormethyl) phenyl] -5- (1H-pyrazol [3,4-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 215) ESI (+ ) MS: m / z 387 (MH +). 2- [2-methyl-5- (trifluormethyl) phenyl] -5- (pyrrole [2,1-f] [1,2,4] -triazin-4-yl) -1H-pyrrole-3-carboxamide (compound No. 216) ESI (+) MS: m / z 386 (MH +). 2- [2-methyl-5- (trifluormethyl) phenyl] -5- (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 217) ESI (+) MS: m / z 388 (MH +). 5- (6-aminopyrimidin-4-yl) -2- [2-ethyl-5- (trifluormethyl) -phenyl] -1H-pyrrole-3-carboxamide (compound No 218) 1H NMR (600 MHz, DMSO-d 6 ) δ 12.00 (br. s., 1H), 8.31 (d, J = 1.10 Hz, 1H), 7.64-7.68 (m, 1H), 7.51 (d, J = 8.06 Hz, 1H), 7.47 (s, 1H), 7.31 (s, 1H), 7.28 (br., 1H), 6.77 (br., 2H) , 6.68 (br. S., 1H), 6.66 (d, J = 1.10 Hz, 1H), 2.56 (q, J = 7.63 Hz, 2H), 1.00 (t , J = 7.63 Hz, 3H). EMAR (ESI) calculated for C18H16F3N5O + H + 376.1380, found 376.1382. 2- [2-ethyl-5- (trifluormethyl) phenyl] -5- [6- (methylamino) -pyrimidin-4-yl] -1H-pyrrole-3-carboxamide (compound No 219) 1H NMR (600 MHz, DMSO -d6) δ 12.00 (br. s., 1H), 8.35 (br. s., 1H), 7.68 (d, J = 7.51 Hz, 1H), 7.52 (d, J = 8.24 Hz, 1H), 7.49 (s, 1H), 7.36 (br. S, 1H), 7.27 (br. S., 1H), 7.20 (br. S ., 1H), 6.70 (br., 1H), 6.68 (br., 1H) "2.81 (br., 3H), 2.56 (q, J = 7.60 Hz, 2H), 1.01 (t, J = 7.60 Hz, 3H) EMAR (ESI) calculated for C19H18F3N5O + H + 390.1536, found 390.1538. 2- [2-ethyl-5 - (trifluormethyl) phenyl] -5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 220) 1H NMR (600 MHz, DMSO-d6) δ 12.27 (br. S, 1H), 12.09 (br. S, 1H), 8.66 (s, 1H), 7.75 (d, J = 0.55 Hz, 1H), 7 , 66 (dd, J = 1.28, 8.24 Hz, 1H), 7.62 (d, J = 3.11 Hz, 1H), 7.44-7.55 (m, 2H), 7, 12 (d, J = 3.48 Hz, 1H), 6.78 (br. S., 1H), 2.59 (q, J = 7.61 Hz, 2H), 1.02 (t, J = 7.61 Hz, 3H) EMAR (ESI) calculated for C20H16F3N5O + H + 400.1380, found 400.1385. 2- [2-ethyl-5- (trifluormethyl) pheni 1] -5- (9H-purin-6-yl) -1H-pyrrole-3-carboxamide (compound No 221) ESI (+) MS: m / z 401 (MH +). 2- [2-ethyl-5- (trifluormethyl) phenyl] -5- (1H-pyrazol [3,4-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 222) ESI (+ ) MS: m / z 401 (MH +). 2- [2-ethyl-5- (trifluormethyl) phenyl] -5- (pyrrole [2,1-f] [1,2,4] - triazin-4-yl) -1H-pyrrole-3-carboxamide (compound No. 223) ESI (+) MS: m / z 400 (MH +). 2- [2-ethyl-5- (trifluormethyl) phenyl] -5- (6,7-dihydro-5H-pyrrol- [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3- carboxamide (compound No 224) ESI (+) MS: m / z 402 (MH +). 2-Phenyl-5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 225) 1H NMR (600 MHz, DMSO-d6) δ 12.09 (br. s, 1H), 11.99, 8.70 (s, 1H), 7.66 (br. s, 1H) - 7.73 (m, 2H), 7.59-7.62 (m, 2H), 7.53 (br. s., 1H), 7.36-7.41 (m, 2H), 7.30-7.35 (m, 1H), 7.09 (dd, J = 1.74, 3.57 Hz, 1H), 6.87 (br. S., 1H). EMAR (ESI) calculated for C17H13N5O + H + 304.1193, found 304.1188. 5- (6,7-Dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -2-phenyl-1H-pyrrol-3-carboxamide (compound No 226) ESI (+) MS: m / z 306 (MH +). EXAMPLE 12 4- (6-aminopyrimidin-4-yl) -1- (5-chloro-2-methylphenyl) -1H-pyrrole-2-carboxamide (compound No 227)
Conv.1
[393] To a solution of 4- (6-aminopyrimidin-4-yl) -1- (5-chloro-2-methylphenyl) -1H-pyrrole-2-carbonitrile (32 mg, 0.103 mmol) in TFA (0.512 mL ) water (64 μL) and 95% sulfuric acid (128 μL) were added sequentially under efficient stirring. The mixture was allowed to stir for 4 h at 70 ° C and then diluted by addition, dropwise with water (1.5 ml). The reaction mixture was made basic (pH 10-12) by adding 30% aqueous ammonia solution, with stirring. The precipitated solid was collected by filtration, washed with water and finally dried in a vacuum oven at 50 ° C to obtain the title compound as an off-white solid (18 mg, 53%). 1H NMR (400 MHz, DMSO-d 6) δ 8.30 (d, J = 1.0 Hz, 1H), 7.69 (br., 1H), 7.45 - 7.51 (m, 2H), 7.36-7.40 (m, 1 H), 7.27-7.35 (m, 2H), 6.92 (br., 1H), 6.71 (s, 2H) , 6.57 (d, J = 1.1 Hz, 1H), 1.94 (s, 3H). EMAR (ESI) calculated for C16H14CIN5O + H + 328.0960, found 328.0958.
[394] The above procedure was employed, starting from the appropriate carbonitrile derivative, to synthesize the following compounds: 1- (5-chloro-2-methylphenyl) -4- [6- (methylamino) pyrimidin-4-yl] - 1H -pyrrole-2-carboxamide (compound No 228) 1H NMR (600 MHz, DMSO-d6) δ 8.35 (br. s., 1H), 7.70 (br. s., 1H), 7.51 ( br. s., 1H), 7.35 - 7.40 (m, 1H), 7.26 - 7.35 (m, 2H), 7.15 (br. s., 1H), 6.92 ( br., 1H), 6.62 (s, 1H), 2.81 (d, J = 3.8 Hz, 3H), 1.94 (s, 3H). M / z of EMAR (ESI) calculated for C17H16CIN5O + H + 342.1111, found 342.1120. 1- (5-chloro-2-methylphenyl) - (7H-pyrrol [2,3-d] pyrimidin-4-yl) - 1H-pyrrol-2-carboxamide (compound No 229) 1H NMR (400 MHz, DMSO- d6) δ 12.16 (br. s., 1H), 12.08 (br. s., 1H), 8.66 (s, 1H), 7.71 (s, 1H), 7.61 (dd , J = 2.5, 3.3 Hz, 1H), 7.47 (br. S, 1H), 7.29 - 7.36 (m, 1H), 7.217.28 (m, 1H), 7 , 11 (dd, J = 1.6, 3.5 Hz, 1H), 6.79 (br. S., 1H), 2.14 (s, 3H). M / z of EMAR (ESI) calculated for C18H14CIN5O + H + 352.0960, found 352.0962. 1- (5-chloro-2-methylphenyl) -4- (1H-pyrrol [2,3-b)] pyridin-4-yl) - 1H-pyrrol-2-carboxamide (compound No 230) ESI (+) MS : m / z 351 (MH +). 1- (5-chloro-2-methylphenyl) -4- (9H-purin-6-yl) -1H-pyrrole-2-carboxamide (compound No 231) ESI (+) MS: m / z 353 (MH +). 1- (5-chloro-2-methylphenyl) -4- (1H-pyrazol [3,4-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 232) 1H NMR (400 MHz, DMSO-d6) δ 13.97 (s, 1H), 8.85 (s, 1H), 8.80 (s, 1H), 8.06 (d, J = 1.8 Hz, 1H), 7, 95 (d, J = 1.8 Hz, 1H), 7.85 (br. S, 1H), 7.41-7.45 (m, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.06 (br. S., 1H), 1.98 (s, 3H). M / z of EMAR (ESI) calculated for C17H13CIN6O + H + 353.0912, found 353.0911. 1- (5-chloro-2-methylphenyl) -4- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-2-carboxamide (compound No 233) 1H NMR (600 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.05 (dd, J = 1.3, 2.5 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.90 (d, J = 1.8 Hz, 1H), 7.88 (br. S., 1H), 7.48 (dd, J = 1.1, 4.6 Hz, 1H), 7.41 - 7.45 (m, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7, 06 (br. S., 1H), 7.02 (dd, J = 2.5, 4.6 Hz, 1H), 1.97 (s, 3H). M / z of EMAR (ESI) calculated for C18H14CIN5O + H + 352.0960, found 352.0956. 1- (5-chloro-2-methylphenyl) -4- (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (Compound No 234) 1H NMR (600 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.75 (br., 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.36-7.42 (m, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.30 (d , J = 2.0 Hz, 2H), 6.92 (br. S, 1H), 3.59 (t, J = 8.6 Hz, 2H), 3.20 (t, J = 8.6 Hz, 2H), 1.94 (s, 3H). M / z of EMAR (ESI) calculated for C18H16CIN5O + H + 354.11116, found 354.11116. 4- (6-aminopyrimidin-4-yl) -1- (5-chloro-2-ethylphenyl) -1H-pyrrole-2-carboxamide (compound No 235) 1H NMR (600 MHz, DMSO-d6) δ 8.30 (d, J = 1.0 Hz, 1H), 7.71 (br. s, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.47 (d, J = 1 , 8 Hz, 1H), 7.40-7.45 (m, 1H), 7.33 - 7.38 (m, 1H), 7.29 (d, J = 2.2 Hz, 1H), 6 , 91 (br. S, 1H), 6.71 (s, 2H), 6.57 (d, J = 1.1 Hz, 1H), 2.25 (dq, J = 0.73, 7, 53 Hz, 1H), 0.97 (t, J = 7.63 Hz, 3H). EMAR (ESI) calculated for C17H16CIN5O + H + 342.1111, found 342.1120. 1- (5-chloro-2-ethylphenyl) -4- [6- (methylamino) pyrimidin-4-yl] - 1H-pyrrol-2-carboxamide (compound No 236) 1H NMR (600 MHz, DMSO-d6) δ 8.35 (br., 1H), 7.69 (br., 1H), 7.57 (br., 1H), 7.51 (br., 1H), 7, 43 (dd, J = 2.3, 8.3 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.15 (br. S, 1H), 6.91 (br. S, 1H), 6.62 (s, 1H), 2.81 (d, J = 4.0 Hz, 3H), 2 , 25 (dq, J = 2.5, 7.5 Hz, 2H), 0.98 (t, J = 7.6 Hz, 3H). EMAR (ESI) calculated for C18H15CIN5O + H + 356.1273, found 356.1269. 1- (5-chloro-2-ethylphenyl) -4- (7H-pyrrol [2,3-d] pyrimidin-4-yl) - 1H-pyrrol-2-carboxamide (compound No 237) 1H NMR (600 MHz, DMSO-d6) δ 12.03 (br. S., 1H), 8.66 (s, 1H), 7.87 (d, J = 1.8 Hz, 1H), 7.83 (d, J = 1.6 Hz, 2H), 7.55 (dd, J = 2.6, 3.5 Hz, 1H), 7.45 (dd, J = 2.2, 8.4 Hz, 1H), 7, 38 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 2.2 Hz, 1H), 7.07 (dd, J = 1.6, 3.5 Hz, 1H), 6.96 (br. S., 1H), 2.29 (dq, J = 2.5, 7.5 Hz, 2H), 1.00 (t, J = 7.5 Hz, 3H). EMAR (ESI) calculated for C19H16CIN5O + H + 366.1111, found 366.1111. 1- (5-chloro-2-ethylphenyl) -4- (9H-purin-6-yl) -1H-pyrrole-2-carboxamide (compound No 238) ESI (+) MS: m / z 367 (MH +). 1- (5-chloro-2-ethylphenyl) -4- (1H-pyrazol [3,4-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 239) ESI (+) MS: m / z 367 (MH +). 1- (5-chloro-2-ethylphenyl) -4- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-2-carboxamide (compound No 240) 1H NMR (600 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.98 - 8.10 (m, 2H), 7.90 (d, J = 1.8 Hz, 1H), 7, 88 (br., 1H), 7.44 - 7.51 (m, 2H), 7.34 - 7.41 (m, 2H), 7.04 (br., 1H), 7, 02 (dd, J = 2.6, 4.6 Hz, 1H), 2.21-2.34 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H). EMAR (ESI) calculated for C19H16CIN5O + H + 366.1111, found 366.1111. 1- (5-chloro-2-ethylphenyl) -4- (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 241) 1H NMR (600 MHz, DMSO-d6) δ 8.41 (br. S., 1H), 7.81 (br. S., 1H), 7.60 (br. S., 1H), 7 , 44 - 7.52 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.09 (s, 1H), 3.79 (br s, 2H), 2.18 - 2.32 (m, 2H), 0.98 (t, J = 7.6 Hz, 3H). EMAR (ESI) calculated for C19H18CIN5O + H + 368.1273, found 368.1276. 4- (6-aminopyrimidin-4-yl) -1- [2-chloro-5- (trifluormethyl) -phenyl] -1H-pyrrole-2-carboxamide (compound No 242) 1H NMR (600 MHz, DMSO-d6) δ 8.31 (d, J = 1.1 Hz, 1H), 7.87 (s, 1H), 7.81 - 7.84 (m, 2H), 7.79 (br. s., 1H) , 7.63 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 6.96 (br., 1H), 6.75 (br . s., 2H), 6.59 (d, J = 1.1 Hz, 1 H). EMAR (ESI) calculated for C16HCIF3N5O + H + 382.0677, found 382.0681. 1- [2-chloro-5- (trifluormethyl) phenyl] -4- [6- (methylamino) -pyrimidin-4-yl] -1H-pyrrol-2-carboxamide (compound No 243) 1H NMR (600 MHz, DMSO -d6) δ 8.36 (br. s, 1H), 7.88 (s, 1H), 7.80 - 7.84 (m, 1H), 7.76 (br. s., 1H.) , 7.60 (br., 1H), 7.57 (br., 1H), 7.19 (br., 1H), 6.96 (br., 1H), 6 , 63 (s, 1H), 2.81 (d, J = 3.5 Hz, 3H). EMAR (ESI) calculated for C17H13CIF3N5O + H + 396.0834, found 396.0836. 1- [2-chloro-5- (trifluormethyl) phenyl] - (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 244) 1H NMR (600 MHz , DMSO-d6) δ 12.07 (s, 1H), 8.68 (s, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.92-7.97 (m, 2H), 7.91 (br. S, 1H), 7.78 - 7.87 (m, 2H), 7.57 (dd, J = 2.5, 3.3 Hz, 1H), 7, 08 (dd, J = 1.6, 3.6 Hz, 1H), 7.04 (br. S., 1 H). EMAR (ESI) calculated for C18H11CIF3N5O + H + 406.0677, found 406.0680. 1- [2-chloro-5- (trifluormethyl) phenyl] -4- (9H-purin-6-yl) -1H-pyrrole-2-carboxamide (compound No 245) 1H NMR (500 MHz, DMSO-d6) δ 12.51 (br. S., 1H), 8.80 (s, 1H), 8.60 (s, 1H), 8.03 (d, J = 1.9 Hz, 1H), 7.68- 7.81 (m, 3H), 7.56 (br. S., 1H), 6.83 (br. S., 1H). EMAR (ESI) calculated for C17H10CIF3N6O + H + 407.0630, found 407.0630. 1- [2-chloro-5- (trifluormethyl) phenyl] - (1H-pyrazol [3,4-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 246) 1H NMR (500 MHz , DMSO-d6) δ 14.02 (s, 1H), 8.87 (s, 1H), 8.80 (s, 1H), 8.23 (d, J = 1.4 Hz, 1H), 8 .00 (s, 2H), 7.92 (br. S., 1H), 7.81 - 7.89 (m, 2H), 7.12 (br s, 1H). EMAR (ESI) calculated for C17H10CIF3N6O + H + 407.0630, found 407.0627. 1- [2-chloro-5- (trifluormethyl) phenyl] -4- (pyrrol [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrol-2-carboxamide (compound No 247) 1H NMR (500 MHz, DMSO-d6) δ 8.48 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 8.06 (d , J = 1.1 Hz, 1H), 7.98 (s, 1H), 7.96 (d, J = 1.6 Hz, 1H), 7.94 (br. S., 1H), 7, 82 - 7.88 (m, 2H), 7.46-7.49 (m, 1H), 7.09 (br. S., 1H), 7.04 (dd, J = 2.4, 4, 4 Hz, 1H). EMAR (ESI) calculated for C17H10CIF3N6O + H + 406.0677, found 406.0674. 1- [2-chloro-5- (trifluormethyl) phenyl] - (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No. 248) ESI (+) MS: m / z 408 (MH +). 4- (6-aminopyrimidin-4-yl) -1- [2-methyl-5- (trifluormethyl) -phenyl] pyrrole-2-carboxamide (compound No 249) ESI (+) MS: m / z 362 (MH +) . 4- [6- (methylamino) pyrimidin-4-yl] -1- [2-methyl-5- (trifluoromethyl) phenyl] -1H-pyrrole-2-carboxamide (compound No 250) ESI (+) MS: m / z 376 (MH +). 1- [2-methyl-5- (trifluormethyl) phenyl] - (7H-pyrrol [2,3-d] - pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 251) ESI (+) MS: m / z 386 (MH +). 1- [2-methyl-5- (trifluormethyl) phenyl] -4- (9H-purin-6-yl) -1H-pyrrole-2-carboxamide (compound No 252) ESI (+) MS: m / z 387 ( MH +). 1- [2-methyl-5- (trifluormethyl) phenyl] - (1H-pyrazol [3,4-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 253) ESI (+) MS : m / z 387 (MH +). 1- [2-methyl-5- (trifluormethyl) phenyl] - (pyrrol [2,1-f] [1,2,4] - triazin-4-yl) -1H-pyrrol-2-carboxamide (compound No 254 ) ESI (+) MS: m / z 386 (MH +). 4- (6,7-Dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1- [2-methyl-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carboxamide (compound No 255) ESI (+) MS: m / z 388 (MH +). 4- (6-aminopyrimidin-4-yl) -1- [2-ethyl-5- (trifluormethyl) -phenyl] -1H-pyrrole-2-carboxamide (compound No 256) 1H NMR (600 MHz, DMSO-d6) δ 8.36 (br. s., 1H), 7.77 (br. s., 1H), 7.74 (dd, J = 1.28, 7.88 Hz, 1H), 7.57-7 , 64 (m, 2H), 7.55 (s, 1H), 7.51 (d, J = 1.83 Hz, 1H), 6.95 (br., 3H), 6.61 (s , 1H), 2.29 - 2.38 (m, 2H), 1.02 (t, J = 7.60 Hz, 3H). EMAR (ESI) calculated for C18H16F3N5O + H + 376.1380, found 376.1383. 1- [2-ethyl-5- (trifluormethyl) phenyl] -4- [6- (matilamino) pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 257) ESI (+) MS: m / z 390 (MH +). 1- [2-ethyl-5- (trifluormethyl) phenyl] -4- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 258) ESI (+ ) MS: m / z 400 (MH +). 1- [2-ethyl-5- (trifluormethyl) phenyl] -4- (9H-purin-6-yl) -1H-pyrrole-2-carboxamide (compound No 259) ESI (+) MS: m / z 401 ( MH +). 1- [2-ethyl-5- (trifluormethyl) phenyl] - (1H-pyrazol [3,4-d] pyrimidin-4-yl) -1H-pyrrol-2-carboxamide (compound No 260) ESI (+) MS : m / z 401 (MH +). 1- [2-ethyl-5- (trifluormethyl) phenyl] - (pyrrol [2,1-f] [1,2,4] - triazin-4-yl) -1H-pyrrol-2-carboxamide (compound No 261 ) ESI (+) MS: m / z 400 (MH +). 4- (6,7-Dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrol-2-carboxamide (compound No 262) ESI (+) MS: m / z 402 (MH +). 4- (6-aminopyrimidin-4-yl) -1-phenyl-1H-pyrrole-2-carboxamide (compound No 263) ESI (+) MS: m / z 280 (MH +). 4- [6- (methylamino) pyrimidin-4-yl] -1-phenyl-1H-pyrrole-2-carboxamide (compound No 264) ESI (+) MS: m / z 294 (MH +). 1-Phenyl-4- (7H-pyrrole [2,3-d] pyrimidin-4-yl) -1H-pyrrole-2-carboxamide (compound No 265) ESI (+) MS: m / z 304 (MH +). 1-Phenyl-4- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-2-carboxamide (compound No 266) ESI (+) MS: m / z 304 (MH +). 4- (6,7-Dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1-phenyl-1H-pyrrol-2-carboxamide (compound No 267) ESI (+) MS: m / z 306 (MH +). EXAMPLE 13 1- (6-aminopyrimidin-4-yl) -4- (5-chloro-2-methylphenyl) -1H-pyrrole-3-carboxamide (compound No 268)
Conv.1
[395] To a solution of 1- (6-aminopyrimidin-4-yl) -4- (5-chloro-2-methylphenyl) -1H-pyrrole-3-carbonitrile (80 mg, 0.258 mmol) in TFA (1, 3 ml) water (0.16 ml) and 95% sulfuric acid (0.32 ml) were added sequentially, with efficient stirring. The mixture was allowed to stir for 8 h at 70 ° C and then diluted by adding, dropwise, water (2.0 ml). The reaction mixture was made basic (pH 10-12) by adding 30% aqueous ammonia solution, under stirring. The precipitated solid was collected by filtration, washed with water and finally dried in a vacuum oven at 50 ° C. Purification by flash chromatography (DCM / MeOH 95/5) provided the title compound (47 mg, 55%). 1H NMR (600 MHz, DMSO-d6) δ 8.32 (d, J = 1.0 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 7.49 ((d, J = 2.4 Hz, 1H), 7.34 (br. S., 1H), 7.19-7.26 (m, 2H), 7.18 (d, J = 2.2 Hz, 1H) , 7.10 (s, 2H), 6.84 (br. S., 1H), 6.56 (d, J = 1.0 Hz, 1H), 2.13 (s, 3H). ) calculated for C16H14CIN5O + H + 328.0960, found 328.0962.
[396] The procedure described above was used to synthesize the following compounds: 4- (5-chloro-2-methylphenyl) -1- [6- (methylamino) pyrimidin-4-yl] - 1H-pyrrol-3-carboxamide ( compound No 269) 1H NMR (600 MHz, DMSO-d6) δ 8.35 (br. s., 2H), 7.73 (br. s., 1H), 7.43 - 7.56 (m, 1H ), 7.32 (br. S., 1H), 7.24-7.26 (m, 2H), 7.21 (s, 1H), 7.19 (d, J = 1.6 Hz, 1H ), 6.84 (br. S., 1H), 6.63 (br. S., 1H), 2.85 (br. S., 3H), 2.11 - 2.15 (s, 3H). EMAR (ESI) calculated for C17H16CIN5O + H + 342.1111, found 342.111. 4- (5-chloro-2-methylphenyl) -1- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 270) 1H NMR (600 MHz, DMSO-d 6) δ 12.47 (br. S., 1H), 8.66 (s, 1H), 8.47 (d, J = 2.2 Hz, 1H), 7.78 (d, J = 2.2 Hz, 1H), 7.71 (br. S., 1H), 7.61 (br. S., 1H), 7.21 - 7.29 (m, 3H), 7.17 ( d, J = 3.3 Hz, 1H), 6.91 (br. s., 1H), 2.17 (s, 3H). EMAR (ESI) calculated for C18H14CIN5O + H + 352.0960, found 352.0960. 4- (5-chloro-2-methylphenyl) -1- (1H-pyrrol [2,3-b] pyridin-4-yl) - 1H-pyrrol-3-carboxamide (compound No 271) ESI (+) MS: m / z 351 (MH +). 4- (5-chloro-2-methylphenyl) -1- (9H-purin-6-yl) -1H-pyrrole-3-carboxamide (compound No 272) ESI (+) MS: m / z 353 (MH +). 4- (5-chloro-2-methylphenyl) -1- (1H-pyrazol [3,4-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 273) M / z of EMAR ( ESI) calculated for C17H13CIN6O + H + 353.0912, found 353.0909. 4- (5-chloro-2-methylphenyl) -1- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-3-carboxamide (compound No 274) 1H NMR (600 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.46 (d, J = 2.2 Hz, 1H), 8.25 (d, J = 1.3 Hz, 1H) , 7.80 (d, J = 2.2 Hz, 1H), 7.68 (br. S., 1H), 7.62 (d, J = 4.2 Hz, 1H), 7.26 - 7 , 29 (m, 1H), 7.21-7.26 (m, 2H), 7.15 (dd, J = 2.7, 4.6 Hz, 1H), 7.00 (br. S., 1H), 2.16 (s, 3H). EMAR (ESI) calculated for C18H14CIN5O + H + 352.0960, found 352.0960. 4- (5-chloro-2-methylphenyl) -1- (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (Compound No 275) M / z of EMAR (ESI) calculated for C18H16CIN5O + H + 354.1111, found 354.1120. 4- (6-aminopyrimidin-4-yl) -1- (2-ethylphenyl-5-chloro) -1H-pyrrole-3-carboxamide (compound No 276) EMAR (ESI) calculated for C17H16CIN5O + H + 342.1111, found 342.1111. 4- (5-chloro-2-ethylphenyl) -1- [6- (methylamino) pyrimidin-4-yl] - 1H-pyrrol-3-carboxamide (compound No 277) EMAR (ESI) calculated for C18H15CIN5O + H + 356, 1273, found 356.1267. 4- (5-chloro-2-ethylphenyl) -1- (7H-pyrrol [2,3-d] pyrimidin-4-yl) - 1H-pyrrol-3-carboxamide (compound No 278) EMAR (ESI) calculated for C19H16CIN5O + H + 366.1111, found 366.1111. 4- (5-chloro-2-ethylphenyl) -1- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-3-carboxamide (compound No 279) EMAR (ESI) calculated for C19H16CIN5O + H + 366.1111, found 366.1111. 4- (5-chloro-2-ethylphenyl) -1- (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 280) EMAR (ESI) calculated for C19H18CIN5O + H + 368.1273, found 368.1277. 1- (6-aminopyrimidin-4-yl) -4- [2-chloro-5- (trifluormethyl) -phenyl] -1H-pyrrol-3-carboxamide (compound No 281) EMAR (ESI) calculated for C16H11CIF3N5O + H + 382 , 0677, found 382.0681. 4- [2-chloro-5- (trifluormethyl) phenyl] -1- [6- (methylamino) -pyrimidin-4-yl] -1H-pyrrol-3-carboxamide (compound No 282) EMAR (ESI) calculated for C17H13CIF3N5O + H + 396.0834, found 396.0838. 4- [2-chloro-5- (trifluormethyl) phenyl] -1- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 283) EMAR (ESI ) calculated for C18H11CIF3N5O + H + 406.0677, found 406.0674. 4- [2-chloro-5- (trifluormethyl) phenyl] -1- (pyrrol [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrol-3-carboxamide (compound No 284) EMAR (ESI) calculated for C17H10CIF3N6O + H + 406.0677, found 406.0676. 4- [2-chloro-5- (trifluormethyl) phenyl] -1- (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 285) ESI (+) MS: m / z 408 (MH +). 1- (6-aminopyrimidin-4-yl) -4- [2-methyl-5- (trifluormethyl) -phenyl] -1H-pyrrole-3-carboxamide (compound No 286) ESI (+) MS: m / z 362 (MH +). 1- [6- (methylamino) pyrimidin-4-yl] -4- [2-methyl-5- (trifluoromethyl) phenyl] -1H-pyrrole-3-carboxamide (compound No 287) ESI (+) MS: m / z 376 (MH +). 4- [2-methyl-5- (trifluormethyl) phenyl] -1- (7H-pyrrol [2,3- (flpyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 288) ESI (+) MS: m / z 386 (MH +). 4- [2-methyl-5- (trifluormethyl) phenyl] -1- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) - 1H-pyrrole-3-carboxamide (compound No 289) ESI (+) MS: m / z 386 (MH +). 1- (6,7-Dihydro-5H-pyrrole [2,3-d] pyrimidin-4 -yl) -4- [2-methyl- 5- (trifluormethyl) phenyl] -1H-pyrrole-3-carboxamide (compound No 290) ESI (+) MS: m / z 388 (MH +). 1- (6- aminopyrimidin-4-yl) -4- [2-ethyl-5- (trifluormethyl) - phenyl] -1H-pyrrole-3-carboxamide (compound No 291) EMAR (ESI) calculated for C18H16F3N5O + H + 376.1380, found 376 , 1385. 4- [2-ethyl-5- (trifluormethyl) phenyl] -1- [6- (methylamino) -pyrimidin-4-yl] -1H-pyrrol-3-carboxamide (compound No 292) ESI (+) MS: m / z 390 (MH +). 4- [2-ethyl-5- (trifluormethyl) phenyl] -1- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrole-3 -carboxamide (compound No 293) ESI (+) MS: m / z 400 (MH +). 4- [2-ethyl-5- (trifluormethyl) phenyl] -1- (pyrrole [2,1-f] [1, 2.4] - triazin-4-yl) -1H-pyrrole-3-carboxamide (compost o No 294) ESI (+) MS: m / z 400 (MH +). 1- (6,7-Dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -4- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrol-3-carboxamide (compound No 295) ESI (+) MS: m / z 402 (MH +). 1- (6-aminopyrimidin-4-yl) -4-phenyl-1H-pyrrole-3-carboxamide (compound No. 296) ESI (+) MS: m / z 280 (MH +). 1- [6- (methylamino) pyrimidin-4-yl] -4-phenyl-1H-pyrrole-3-carboxamide (compound No 297) ESI (+) MS: m / z 294 (MH +). 4-Phenyl-1- (7H-pyrrole [2,3-d] pyrimidin-4-yl) -1H-pyrrole-3-carboxamide (compound No 298) ESI (+) MS: m / z 304 (MH +). 4-Phenyl] -1- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-3-carboxamide (compound No 299) ESI (+) MS: m / z 304 (MH +). 1- (6,7-Dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -4-phenyl-1H-pyrrol-3-carboxamide (compound No 300) ESI (+) MS: m / z 306 (MH +). EXAMPLE 14 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -N-methyl-1H-pyrrole-3-carboxamide (compound No 301)
Conv.2
[397] A solution of 5- (6-aminopyrrinidin-4-yl) -2- (5-chloro-2-ethylphenyl) -1H-pyrrole-3-carboxamide (341 mg, 1.0 mmol) in DMF (0 , 3 ml) and THF (6 ml) was treated with di-tert-butyl dicarbonate (1.309 g, 6 mmol) and DMAP (15.8 mg, 0.13 mmol). After 3 h at room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue dissolved in THF (2 ml) was treated with methylamine (2 in THF, 2 ml, 4 mmol) and stirred overnight at room temperature. The reaction mixture was concentrated, dissolved in DCM (5 ml) and treated with TFA (5 ml). After 3 h at room temperature, the reaction mixture was concentrated, diluted with EtOAc, washed with 10% ammonia. The organic phase was separated, washed with aqueous saline, dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. Purification by flash chromatography (DCM / MeOH / NH 3 7 N in MeOH 98/2 / 0.2) provided the title compound (220 mg, 62%). 1H NMR (600 MHz, DMSO-d6) δ 11.93 (br. S., 1H), 8.30 (d, J = 1.10 Hz, 1H), 7.74 (q, J = 4.21 Hz, 1H), 7.37 (dd, J = 2.29, 8.33 Hz, 1H), 7.29 (d, J = 8.24 Hz, 1H), 7.25 (s, 1H), 7.20 (d, J = 2.38 Hz, 1H), 6.76 (br. S., 2H), 6.66 (d, J = 1.10 Hz, 1H), 2.61 (d, J = 4.58 Hz, 3H), 2.44 (q, J = 7.63 Hz, 2H), 0.95 (t, J = 7.51 Hz, 3H). M / z EMAR (ESI) calculated for C18H18CIN5O + H + 356.1273, found 356.1272.
[398] The procedure described above was used to synthesize the following compounds: 2- (5-chloro-2-ethylphenyl) -N-methyl-5- [6- (methylamino) pyrimidin-4-yl] -1H-pyrrole- 3-carboxamide (compound No 302) 1H NMR (600 MHz, DMSO-d6) δ 11.96 (br. S., 1H), 8.36 (br. S., 1H), 7.75 (d, J = 4.76 Hz, 1H), 7.39 (dd, J = 1.92, 8.15 Hz, 1H), 7.31 (d, J = 8.24 Hz, 2H), 7.23 (d , J = 1.65 Hz, 2H), 6.74 (br. S, 1H), 2.81 (br. S, 3H), 2.61 (d, J = 4.58 Hz, 4H) , 2.44 (q, J = 7.63 Hz, 2H), 0.96 (t, J = 7.60 Hz, 3H). M / z EMAR (ESI) calculated for C19H20CIN5O + H + 370.1429, found 370.1432. 2- (5-chloro-2-ethylphenyl) -N-methyl-5- (7H-pyrrol [2,3-d] - pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 303) 1H NMR (600 MHz, DMSO-d6) δ 12.18 (br. S., 1H), 12.09 (br. S., 1H), 8.66 (s, 1H), 7.93 (q, J = 4.21 Hz, 1H), 7.68 (d, J = 1.10 Hz, 1H), 7.60-7.64 (m, J = 2.93 Hz, 1H), 7.36 (dd , J = 2.29, 8.33 Hz, 1H), 7.29 (d, J = 8.24 Hz, 1H), 7.22 (d, J = 2.20 Hz, 1H), 7.07 (d, J = 3.30 Hz, 1H), 2.67 (d, J = 4.58 Hz, 3H), 2.46 (q, J = 7.57 Hz, 2H), 0.97 (t , J = 7.60 Hz, 3H). EMAR (ESI) calculated for C20H18CIN5O + H + 380.1273, found 380.1275. 2- (5-chloro-2-ethylphenyl) -N-methyl-5- (pyrrole [2,1-f] [1,2,4] triazine-4-yl) -1H-pyrrole-3-carboxamide (compound No. 304) ESI (+) MS: m / z 380 (MH +). 2- (5-chloro-2-ethylphenyl) -5- (6,7-dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -N-methyl-1H-pyrrol-3- carboxamide (compound No 305) ESI (+) MS: m / z 382 (MH +). 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N-methyl-1H-pyrrole-3-carboxamide (compound No 306) ESI (+) MS: m / z 342 (MH +). 2- (5-chloro-2-methylphenyl) -N-methyl-5- [6- (methylamino) -pyrimidin-4-yl] -1H-pyrrole-3-carboxamide (compound No 307) ESI (+) MS: m / z 364 (MH +). 2- (5-chloro-2-methylphenyl) -N-methyl-5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 308) ESI ( +) MS: m / z 366 (MH +). 2- (5-chloro-2-methylphenyl) -N-methyl-5- (pyrrole [2,1-f] [1,2,4] - triazin-4-yl) -1H-pyrrole-3-carboxamide ( compound No 309) ESI (+) MS: m / z 366 (MH +). 2- (5-chloro-2-methylphenyl) -5- (6,7-dihydro-5H-pyrrol [2,3-d] -pyrimidin-4-yl) -N-methyl-1H-pyrrol-3 -carboxamide (compound No 310) ESI (+) MS: m / z 382 (MH +). 5- (6-aminopyrimidin-yl) -N-methyl-2- [2-chloro-5- (trifluoromethyl) -phenyl] -1H-pyrrole-3-carboxamide (compound No 311) ESI (+) MS: m / z 396 (MH +). N-methyl-5- [6- (methylamino) pyrimidin-4-yl] -2- [2-chloro-5- (trifluoromethyl) phenyl] -1H-pyrrole-3-carboxamide (compound No 312) ESI ( +) MS: m / z 410 (MH +). 2- [2-chloro-5- (trifluormethyl) phenyl] -N-methyl-5- (7H-pyrrol- [2,3-d] -pyrimidin-4-yl) -N-methyl-1H-pyrrole-3 -carboxamide (compound No 313) ESI (+) MS: m / z 420 (MH +). 2- [2-chloro-5- (trifluormethyl) phenyl] -N-methyl-5- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-3- carboxamide (Compound No. 314) ESI (+) MS: m / z 420 (MH +). 2- [2-chloro-5- (trifluormethyl) phenyl] -5- (6,7-dihydro-5H-pyrrole- [2,3-d] -pyrimidin-4-yl) -N-methyl-1H -pyrrole-3-carboxamide (compound No 315) ESI (+) MS: m / z 422 (MH +). 5- (6-aminopyrimidin-4-yl) -N-methyl-2- [2-methyl-5- (trifluoromethyl) phenyl] -1H-pyrrole-3-carboxamide (compound No 316) 1H NMR (600 MHz , DMSO-d6) δ 12.00 (br. S., 1H), 8.32 (d, J = 1.10 Hz, 1H), 7.85 (q, J = 4.40 Hz, 1H), 7.58 - 7.63 (m, 1H), 7.51 (s, 1H), 7.47 (d, J = 8.24 Hz, 1H), 7.28 (d, J = 1.10 Hz , 1H), 6.79 (s, 2H), 6.66 (d, J = 1.10 Hz, 1H), 2.61 (d, J = 4.52 Hz, 3H), 2.20 (s , 3H). M / z of EMAR (ESI) calculated for C18H16F3N5O + H + 376.1380, found 376.1384. N-methyl-5- [6- (methylamino) pyrimidin-4-yl] -2- [2-methyl-5- (trifluoromethyl) phenyl] -1H-pyrrole-3-carboxamide (compound No 317) 1H NMR (600 MHz, DMSO-d6) δ 11.99 (br. S, 1H), 8.36 (br. S., 1H), 7.84 (q, J = 4.85 Hz, 1H), 7 , 63 (d, J = 7.88 Hz, 1H), 7.53 (s, 1H), 7.44 - 7.50 (m, 1H), 7.33 (br. S., 1H), 7 , 22 (br., 1H), 6.72 (br., 1H), 2.81 (br., 3H), 2.62 (d, J = 4.71 Hz, 3H) , 2.21 (s, 3H). M / z of EMAR (ESI) calculated for C19H18F3N5O + H + 390.1536, found 390.1531. 2- [2-methyl-5- (trifluormethyl) phenyl] -N-methyl-5- (7H-pyrrol- [2,3-d] -pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 318) 1H NMR (600 MHz, DMSO-d6) δ 12.27 (br. S., 1H), 12.11 (br. S., 1H), 8.67 (s, 1H), 8.01 (q, J = 4.46 Hz, 1H), 7.71 (d, J = 1.28 Hz, 1H), 7.64 (dd, J = 2.56, 3.48 Hz, 1H), 7 , 61 (dd, J = 1.37, 8.15 Hz, 1H), 7.54 (s, 1H), 7.46 (d, J = 7.88 Hz, 1H), 7.09 (dd, J = 1.83, 3.48 Hz, 1H), 2.69 (d, J = 4.40 Hz, 3H), 2.23 (s, 3H). M / z of EMAR (ESI) calculated for C20H16F3N5O + H + 400.1380, found 400.1382. 2- [2-methyl-5- (trifluormethyl) phenyl] -N-methyl-5- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-3- carboxamide (compound No 319) ESI (+) MS: m / z 400 (MH +). 2- [2-methyl-5- (trifluormethyl) phenyl] -5- (6,7-dihydro-5H-pyrrole- [2,3-d] -pyrimidin-4-yl) -N-methyl-1H -pyrrole-3-carboxamide (compound No 320) ESI (+) MS: m / z 402 (MH +). 5- (6-aminopyrimidin-4-yl) -2- [2-ethyl-5- (trifluormethyl) -phenyl] -N-methyl-1H-pyrrol-3-carboxamide (compound No 321) 1H NMR (600 MHz, DMSO-d6) δ 12.01 (br. S., 1H), 8.31 (d, J = 1.10 Hz, 1H), 7.82 (q, J = 4.52 Hz, 1H), 7 , 66 (dd, J = 1.56, 8.15 Hz, 1H), 7.50 (d, J = 8.24 Hz, 1H), 7.47 (s, 1H), 7.28 (s, 1H), 6.78 (s, 2H), 6.66 (d, J = 1.10 Hz, 1H), 2.61 (d, J = 4.58 Hz, 3H), 2.54 (q, J = 7.57 Hz, 2H), 0.99 (t, J = 7.60 Hz, 3H). M / z of EMAR (ESI) calculated for C19H18F3N5O + H + 390.1536, found 390.1541. 2- [2-ethyl-5- (trifluormethyl) phenyl] -N-methyl-5- [6- (methylamino) pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 322) 1H NMR (600 MHz, DMSO-d6) δ 12.00 (br. S., 1H), 8.35 (br. S., 1H), 7.83 (d, J = 4.58 Hz, 1H), 7.68 (d, J = 8.24 Hz, 1H), 7.52 (d, J = 8.24 Hz, 1H), 7.49 (s, 1H), 7.33 (br. s., 1H), 7.20 (br., 1H), 6.72 (br., 1H), 2.81 (br., 3H), 2.61 (d, J = 4.58 Hz, 3H ), 2.55 (q, J = 7.63 Hz, 2H), 1.00 (t, J = 7.60 Hz, 3H). M / z of EMAR (ESI) calculated for C20H20F3N5O + H + 404.1693, found 404.1698. 2- [2-ethyl-5- (trifluormethyl) phenyl] -N-methyl-5- (7H-pyrrol- [2,3-d] -pyrimidin-4-yl) -1H-pyrrol-3-carboxamide (compound No 323) 1H NMR (600 MHz, DMSO-d 6) δ 12.27 (br. S., 1H), 12.11 (br. S., 1H), 8.66 (s, 1H), 7, 99 (q, J = 4.40 Hz, 1H), 7.72 (s, 1H), 7.66 (dd, J = 1.56, 7.97 Hz, 1H), 7.63 - 7.64 (m, 1H), 7.51 (br s, 1H), 7.49 (br. s., 1H), 7.08 (dd, J = 1.83, 3.48 Hz, 1H), 2, 68 (s, 3H), 2.57 (q, J = 7.51 Hz, 2H), 1.01 (t, J = 7.60 Hz, 3H). M / z of EMAR (ESI) calculated for C21H18F3N5O + H + 414.1536, found 414.1534. 2- [2-ethyl-5- (trifluormethyl) phenyl] -N-methyl-5- (pyrrole [2,1-f] [1,2,4] triazin-4-yl) -1H-pyrrole-3- carboxamide (compound No. 324) ESI (+) MS: m / z 414 (MH +). 2- [2-ethyl-5- (trifluormethyl) phenyl] -5- (6,7-dihydro-5H-pyrrole [2,3-d] -pyrimidin-4-yl) -N-methyl-1H- pyrrole-3-carboxamide (compound No 325) ESI (+) MS: m / z 416 (MH +). N-methyl-2-phenyl-5- (7H-pyrrol [2,3-d] pyrimidin-4-yl) -1H-pyrrole-3-carboxamide (compound No. 326) 1H NMR (600 MHz, DMSO-d6) δ 12.10 (br. s., 1H), 11.99 (br. s., 1H), 8.70 (s, 1H), 7.99 (q, J = 4.76 Hz, 1H), 7.66 - 7.73 (m, 2H), 7.61 (dd, J = 2.38, 3.48 Hz, 1H), 7.55 (s, 1H), 7.36-7.40 ( m, 2H), 7.30-7.34 (m, 1H), 7.06 (dd, J = 1.74, 3.57 Hz, 1H), 2.73 (d, J = 4.58 Hz , 3H). M / z of EMAR (ESI) calculated for C 18 H 15 N5O + H + 318.1350, found 318.1350. 5- (6,7-Dihydro-5H-pyrrol [2,3-d] pyrimidin-4-yl) -N-methyl-2-phenyl-1H-pyrrol-3-carboxamide (compound No 327) ESI ( +) MS: m / z 320 (MH +). EXAMPLE 15 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1-methyl-1H-pyrrole-3-carboxamide (compound No 328)
Conv.3
[399] To a solution of 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1H-pyrrole-3-carboxamide (98 mg, 0.3 mmol) in DMF ( 1 mL), Cs2CO3 (107 mg, 0.33 mmol) and MeI (28 μL, 0.43 mmol) were added. The mixture was stirred at room temperature for 3 h, then the solvent was removed. For the residue, EtOAc and water were added, the layers were separated, the aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography (DCM / MeOH / NH3 in MeOH 95/5 / 0.5) to obtain the title compound (43 mg, 42%). ESI (+) MS: m / z 342 (MH +).
[400] According to this procedure, but using ethane iodine, the following compound was prepared: 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1-ethyl- 1H- pyrrole-3-carboxamide (compound No 329) ESI (+) MS: m / z 366 (MH +).
[401] According to this procedure, but using 2,2,2-trifluoroethyl trifluoromethanesulfonate, the following compound was prepared: 5- (6-aminopyrimidin-yl) -2- (5-chloro-2-methylphenyl) -1 - (2,2,2-trifluoroethyl) -1H-pyrrole-3-carboxamide (compound No 330) ESI (+) MS: m / z 410 (MH +).
[402] According to this procedure, but using 2- (2-iodoethoxy) -tetrahydro-2H-pyran and removing the tetrahydro-2H-pyran-2-yl protecting group with conc. in EtOH, the following compound was prepared: 5- (6-aminopyrimidin-yl) -2- (2-methylphenyl-5-chloro) -1- (2-hydroxyethyl) -1H-pyrrole-3-carboxamide (compound No 331 ) ESI (+) MS: m / z 372 (MH +).
[403] According to this procedure, but from 5- (6-aminopyrimidin-4-yl) -3- (5-chloro-2-methylphenyl) -1H-pyrrole-2-carboxamide, the following compound was prepared : 5- (6-aminopyrimidin-4-yl) -3- (5-chloro-2-methylphenyl) -1-methyl-1H-pyrrole-2-carboxamide (compound No 332) ESI (+) MS: m / z 342 (MH +).
[404] According to this procedure, but starting from 5- (6-aminopyrimidin-4-yl) -3- (5-chloro-2-methylphenyl) -1H-pyrrole-2-carboxamide and using ethane iodine following compound was prepared: 5- (6-aminopyrimidin-4-yl) -3- (5-chloro-2-methylphenyl) -1-ethyl-1H-pyrrole-2-carboxamide (compound No 333) ESI (+) MS : m / z 366 (MH +).
[405] According to this procedure, but starting from 5- (6-aminopyrimidin-4-yl) -3- (5-chloro-2-methylphenyl) -1H-pyrrole-2-carboxamide and using 2-trifluoromethanesulfonate 2,2-trifluorethyl, the following compound was prepared: 5- (6-aminopyrimidin-yl) -3- (5-chloro-2-methylphenyl) -1- (2,2,2-trifluoroethyl) -1H-pyrrole- 2-carboxamide (compound No 334) ESI (+) MS: m / z 410 (MH +).
[406] According to this procedure, but starting from 5- (6-aminopyrimidine-4-yl) -3- (5-chloro-2-methylphenyl) -1H-pyrrole-2-carboxamide and using 2- (2 -iodoethoxy) -tetra-2H-pyran and removing the tetrahydro-2H-pyran-2-yl protecting group with conc. in EtOH, the following compound was prepared: 5- (6-aminopyrimidin-4-yl) -3- (5-chloro-2-methylphenyl) -1- (2-hydroxyethyl) -1H-pyrrole-2-carboxamide (compound No 335) ESI (+) MS: m / z 372 (MH +). PHARMACOLOGY Biochemical assay for inhibitors of JAK kinase activity
[407] General principle - specific JAK2, JAK1 or JAK3 peptide substrates are trans-phosphorylated by JAK kinases in the presence of ATP screened with 33P-Y-ATP. At the end of the phosphorylation reaction, cold and radioactive ATP that is unreacted is captured by an excess of Dowex ion exchange resin that eventually settles down by gravity at the bottom of the reaction plate. The supernatant is subsequently removed and transferred to a counting plate, which is then evaluated by β counting.
[408] Dowex resin preparation - 500 g wet resin (SIGMA, DOWEX resin prepared to order 1x8 200-400 mesh, 2.5 kg) are weighed and diluted to 2 to 1 in 150 mM sodium format, pH 3, 00. The resin is allowed to settle overnight and then the supernatant is discarded. After three washes as above over a couple of days, the resin is allowed to settle and two volumes (relative to the volume of resin) of 150 mM sodium formate buffer are added.
[409] Kinase buffer (KB) - kinase buffer was composed of 50 mM HEPES pH 7.5 containing 10 mM MgCl2, 2.5 mM DTT, 10 μM Na3VO4 and 0.2 mg / mL BSA . JAK2 specific test conditions
[410] Enzyme - The assays were performed with the commercially available JAK2 kinase domain (Invitrogen, Eugene, OR) which showed linear kinetics without pre-phosphorylation.
[411] Test conditions - The JAK2 kinase assay was performed with a final enzyme concentration of 1 nM, in the presence of 60 μM ATP, 3 nM 33P-Y-ATP and 64 μM of BioDBn * 306 substrate (sequence of amino acids: LPLDKDYYVVREPGQ - SEQ ID NO: 1). The peptide substrate was purchased by the American Peptide Company (Sunnyvale, CA). JAK1 specific test conditions
[412] Enzyme - The assays were performed with the JAK1 kinase domain (residues 861-1152 of the 1154 full-length amino acid sequence, accession number P23458 from UniProtKB / Swiss-Prot).
[413] The JAK1 kinase domain was pre-activated with ATP for 1 hour at 28 ° C in order to obtain linear kinetics.
[414] Test conditions - The JAK1 kinase assay was performed with a final pre-activated enzyme concentration of 2.5 nM, in the presence of 100 μM ATP, 2 nM 33P-Y-ATP and 154 μM substrate BioDBn * 333 (amino acid sequence: KKHTDDGYMPMSPGVA - SEQ ID NO: 2). The peptide substrate was purchased by the American Peptide Company (Sunnyvale, CA). JAK3 specific test conditions
[415] Enzyme - Assays were performed using the JAK3 kinase domain (residues 781-1124 of the 1124 full-length amino acid sequence, accession number P52333 of UniProtKB / Swiss-Prot databse) which showed linear kinetics without pre-phosphorylation .
[416] Test conditions - The JAK3 kinase assay was performed with a final enzyme concentration of 1 nM, in the presence of 22 μM ATP, 1 nM 33P-Y-ATP and 40 μM of BioDBn * 306 substrate (sequence amino acid: LPLDKDYYVVREPGQ -SEQ ID NO: 1). The peptide substrate was purchased by the American Peptide Company (Sunnyvale, CA). TYK2 specific test conditions
[417] Enzyme - The assays were performed with the TYK2 kinase domain (residues 833-1187 of the long sequence of 1187 amino acids total length, accession number database P29597 of UniProtKB / Swiss-Prot) which showed linear kinetics without pre -phosphorylation.
[418] Test conditions - The TYK2 kinase assay was performed with a final enzyme concentration of 3 nM, in the presence of 31 μM ATP, 0.8 nM 33P-Y-ATP and 71 μM of BioDBn * 333 substrate (amino acid sequence: KKHTDDGYMPMSPGVA - SEQ ID NO: 2). The peptide substrate was purchased by the American Peptide Company (Sunnyvale, CA). Cell proliferation
[419] Cell lines: the JAK2-dependent human megakaryoblastic leukemia SET-2 cell line (DSMZ, Braunschweig GERMANY), and the JAK2 independent human chronic myeloid leukemia cell line K562 (ECACC, Wiltshire, UK) were grown in RPMI-1640 Glutamax (Gibco BRL, Gaithesburg, MD, USA), supplemented with 10% fetal bovine serum (FBS) at 37 ° C and 5% CO2. IL-2 DERL-7 lymphoma-dependent human cell line (DSMZ, Braunschweig GERMANY) was used to test the activity of the compounds in IL-2 activated JAK1 / JAK3 kinase cells. DERL-7 cell lines were grown in Glutamax in RPMI-1640 medium (Gibco BRL, Gaithesburg, MD, USA), supplemented with 20% FBS and 20 ng / mL human IL-2 (Sigma-Aldrich, St. Louis, MO, USA).
[420] Cell proliferation assay. Approximately 5x103 cells were plated in 384 wells of microtiter plates in 50 μL of growth medium with different concentrations of inhibitors. The cells were incubated at 37 ° C and 5% CO2 for 72 hours, then the plates were processed using the CellTiter-Glo assay (Promega, Madison, WI, USA) following the manufacturer's instructions. Briefly 25 μL / well reagent solution is added to each well and after 5 minutes the stirring microplates are read by the Envision luminometer (PerkinElmer, Waltham, MA, USA).
[421] Data adjustment - The data are analyzed by the Symix Assay Explorer software (Symix Technologies Inc.) which provides a sigmoidal adjustment algorithm for the 8-point dilution curves for the determination of IC50. In vivo model
[422] SET-2 acute megacarioblastic leukemia cell line (107 cells) was inoculated sc in 5-6 weeks old severely combined immunodeficient female mice (SCID) (Charles River) previously exposed to gamma radiation (200 Rads gamma radiation). The rats with a palpable tumor (100-200 mm 3) were treated with a vehicle (0.5% Methocel) or a compound of formula (I) for 10 days, bid. The tumor dimensions were measured using Vernier calipers regularly and the tumor growth inhibition (TGI) was calculated.
[423] In biochemical assays, the compounds of formula (I) tested as described above demonstrate remarkable potent JAK inhibitory activity. See, as an example, the following data from Table A, in which the experimental data (IC50) of the compounds of the invention obtained by enzymes representative of kinases of the JAK family (i.e., JAK1 and JAK2) are reported.
[424] In cell assays, the compounds of formula (I), assayed as described above, exhibit superior activity on the JAK2-dependent SET-2 cell line compared to the JAK2-independent K562 cell line (see Table A). TABLE A








[425] In biochemical assays, the compounds of formula (I) tested as described above, demonstrated a notable potent TYK2 inhibitory activity. See, as an example, table B below in which experimental data (IC50) of the compounds of the invention obtained for TYK2 kinase are reported (see table B):




[426] In cell assays, the compounds of formula (I) tested as described above show high activity on JAK1 / 3-dependent human T-lymphoma DERL-7 cell lines (see Table C).



[427] So far, the new compounds of the invention are endowed with a potent inhibitory activity of JAK and TYK2 and are, therefore, particularly advantageous, in therapy, against cancer and metastases, cell proliferative diseases, viral infections, immune disorders, neurodegenerative diseases, cardiovascular diseases and diseases related to bones.

权利要求:
Claims (10)
[0001]
1. Compound CHARACTERIZED because it is of formula (Ia), (Ib), (Ic), (Id) or (Ie):
[0002]
A compound or a pharmaceutically acceptable salt thereof, according to claim 1, CHARACTERIZED by being selected from the group consisting of: 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2- methylphenyl) -1H-pyrrole-3-carboxamide (compound No 189); 2- (5-chloro-2-methylphenyl) -5- [6- (methylamino) pyrimidin-4-yl] -1H-pyrrole-3-carboxamide (compound No 190); 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -1H-pyrrole-3-carboxamide (compound No 197); 2- (5-chloro-2-ethylphenyl) -5- [6- (methylamino) pyrimidin-4-yl] -1H-pyrrole-3-carboxamide (compound No 198); 5- (6-aminopyrimidin-4-yl) -2- [2-chloro-5- (trifluormethyl) -phenyl] -1H-pyrrole-3-carboxamide (compound No 204); 2- [2-chloro-5- (trifluormethyl) phenyl] -5- [6- (methylamino) -pyrimidin-yl] -1H-pyrrole-3-carboxamide (compound No 205); 5- (6-aminopyrimidin-4-yl) -2- [2-methyl-5- (trifluoromethyl) -phenyl] -1H-pyrrole-3-carboxamide (compound No 211); 5- [6- (methylamino) pyrimidin-4-yl] -2- [2-methyl-5- (trifluoromethyl) -phenyl] -1H-pyrrole-3-carboxamide (compound No 212); 5- (6-aminopyrimidin-4-yl) -2- [2-ethyl-5- (trifluormethyl) -phenyl] -1H-pyrrole-3-carboxamide (compound No 218); 2- [2-ethyl-5- (trifluormethyl) phenyl] -5- [6- (methylamino) -pyrimidin-4-yl] -1H-pyrrole-3-carboxamide (compound No 219); 4- (6-aminopyrimidin-4-yl) -1- (5-chloro-2-ethylphenyl) -1H-pyrrole-2-carboxamide (compound No 235); 1- (5-chloro-2-ethylphenyl) -4- [6- (methylamino) pyrimidin-4-yl] -1H-pyrrole-2-carboxamide (compound No 236); 4- (6-aminopyrimidin-4-yl) -1- [2-ethyl-5- (trifluormethyl) -phenyl] -1H-pyrrole-2-carboxamide (compound No 256); 5- (6-aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -N-methyl-1H-pyrrole-3-carboxamide (compound No 301); 2- (5-chloro-2-ethylphenyl) -N-methyl-5- [6- (methylamino) pyrimidin-4-yl] -1H-pyrrole-3-carboxamide (compound No 302); 5- (6-aminopyrimidin-yl) -2- [2-ethyl-5- (trifluoromethyl) phenyl] -N-methyl-1H-pyrrole-3-carboxamide (compound 321); and 2- [2-ethyl-5- (trifluormethyl) phenyl] -N-methyl-5- [6- (methylamino) pyrimidin-4-yl] -1H-pyrrol-3-carboxamide (compound No 322).
[0003]
3. Process for the preparation of a compound of formula (Ia), (Id) and (Ie), as defined in claim 1, or pharmaceutically acceptable salts thereof, CHARACTERIZED by comprising the following steps: step 4: reaction of a derivative of formula (VII)
[0004]
4. Process for the preparation of a compound of formula (Ia), (Id) and (Ie), as defined in claim 3, CHARACTERIZED by the optional conversion of a compound of formula (Ia), (Id) and (Ie) into another compound of formula (Ia), (Id) and (Ie) be carried out by the following reaction: conv.2) conversion of a compound of formula (Ia), (Id) and (Ie), where R2 is CONH2 , in the corresponding compound of formula (Ia), (Id) and (Ie), where R2 is CONR6R7, where R6 and R7 are as defined in claim 1 but both are not hydrogen by exhaustive tert-butoxycarbonylation of a compound of the formula (Ia), (Id) and (Ie), treatment with an amine derivative of formula (XXIII) NHR6R7 (XXIII) in which R6 and R7 are as defined above, but both are not hydrogen and the deprotection of tertiary protection groups - butoxycarbonyl.
[0005]
5. Pharmaceutical composition CHARACTERIZED in that it comprises a compound of formula (Ia) - (Ie) or a pharmaceutically acceptable salt thereof, as defined in claim 1, and a pharmaceutically acceptable excipient, carrier and / or diluent.
[0006]
Pharmaceutical composition, according to claim 5, CHARACTERIZED by further comprising chemotherapeutic agents.
[0007]
7. In vitro method for inhibiting the activity of protein kinases of the JAK family, CHARACTERIZED by understanding the contact of said protein with a compound of formula (Ia) - (Ie), as defined in claim 1.
[0008]
8. Product CHARACTERIZED for comprising a compound of formula (Ia) - (Ie) or a pharmaceutically acceptable salt thereof, as defined in claim 1, and a chemotherapeutic agent, as a combined preparation for simultaneous use in anticancer therapy.
[0009]
Compound of formula (Ia) - (Ie) or a pharmaceutically acceptable salt thereof, according to claim 1, CHARACTERIZED for being for use as a medicament.
[0010]
A compound of formula (Ia) - (Ie) or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, CHARACTERIZED for being for use as a medicament for the treatment of acute megakarioblastic leukemia; transplant rejection, rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, atopic dermatitis, solid tumors, myelofibrosis, myeloproliferative disorders, polycythemia vera (PV), essential thrombocythemia (ET), acute myeloid leukemia (AML), acute myeloid leukemia (acute myeloid leukemia (acute myeloid leukemia) CML) and acute lymphoblastic leukemia (ALL).

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

EP1611125A1|2003-02-07|2006-01-04|Vertex Pharmaceuticals Incorporated|Heteroaryl substituted pyrolls useful as inhibitors of protein kinases|

---

US20050014753A1|2003-04-04|2005-01-20|Irm Llc|Novel compounds and compositions as protein kinase inhibitors|

---

EP1844020B1|2005-01-10|2017-09-06|Exelixis, Inc.|Heterocyclic carboxamide compounds as steroid nuclear receptor ligands|

---

LT2474545T|2005-12-13|2017-02-27|Incyte Holdings Corporation|Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors|

---

EP1968568A4|2005-12-22|2011-04-13|Glaxosmithkline Llc|INHIBITORS OF Akt ACTIVITY|

---

MX2008012422A|2006-03-27|2008-10-09|Nerviano Medical Sciences Srl|Pyridyl- and pyrimidinyl-substituted pyrrole-, thiophene- and furane-derivatives as kinase inhibitors.|

---

KR20090101281A|2007-01-23|2009-09-24|팔라우 파르마 에스에이|Purine derivatives|

---

LT2288610T|2008-03-11|2016-12-12|Incyte Holdings Corporation|Azetidine and cyclobutane derivatives as jak inhibitors|

---

BR112015002152B1|2012-08-02|2021-04-27|Nerviano Medical Sciences S.R.L.|COMPOUNDS OF REPLACED PYRROILS ACTIVE AS KINASE INHIBITORS, PROCESS FOR THE PREPARATION OF SUCH COMPOUNDS, PHARMACEUTICAL COMPOSITION, IN VITRO METHOD FOR INHIBITION OF THE ACTIVITY OF KINASE PROTEINS OF THE JAK FAMILY|AR077468A1|2009-07-09|2011-08-31|Array Biopharma Inc|PIRAZOLO COMPOUNDSPYRIMIDINE SUBSTITUTED AS TRK-QUINASA INHIBITORS|

---

BR112015002152B1|2012-08-02|2021-04-27|Nerviano Medical Sciences S.R.L.|COMPOUNDS OF REPLACED PYRROILS ACTIVE AS KINASE INHIBITORS, PROCESS FOR THE PREPARATION OF SUCH COMPOUNDS, PHARMACEUTICAL COMPOSITION, IN VITRO METHOD FOR INHIBITION OF THE ACTIVITY OF KINASE PROTEINS OF THE JAK FAMILY|

---

JP6604664B2|2014-08-04|2019-11-13|ヌエヴォリューション・アクティーゼルスカブ|Compounds active against nuclear receptors|

---

KR20180041135A|2015-07-16|2018-04-23|어레이 바이오파마 인크.|A pyrazolo [1,5-a] pyridine compound substituted as a RET kinase inhibitor|

---

RU2744852C2|2015-10-26|2021-03-16|Локсо Онколоджи, Инк.|Point mutations in trk inhibitor-resistant malignant tumors and related methods|

---

US9630968B1|2015-12-23|2017-04-25|Arqule, Inc.|Tetrahydropyranyl amino-pyrrolopyrimidinone and methods of use thereof|

---

US10045991B2|2016-04-04|2018-08-14|Loxo Oncology, Inc.|Methods of treating pediatric cancers|

---

TN2018000335A1|2016-04-04|2020-01-16|Loxo Oncology Inc|Liquid formulations of -n--2--pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide|

---

WO2017176744A1|2016-04-04|2017-10-12|Loxo Oncology, Inc.|Methods of treating pediatric cancers|

---

PL3458456T3|2016-05-18|2021-04-19|Loxo Oncology, Inc.|Preparation of -n--2-pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide|

---

WO2018019681A1|2016-07-25|2018-02-01|Nerviano Medical Sciences S.R.L.|Purine and 3-deazapurine analogues as choline kinase inhibitors|

---

CN109890821A|2016-08-24|2019-06-14|艾科尔公司|Amino-pyrrolopyrimidine ketone compound and its application method|

---

IT201600092469A1|2016-09-14|2018-03-14|Lundbeck Pharmaceuticals Italy S P A|Blonanserine production process|

---

TWI704148B|2016-10-10|2020-09-11|美商亞雷生物製藥股份有限公司|Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors|

---

CR20190224A|2016-10-10|2019-09-30|Array Biopharma Inc|Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors|

---

MA45802A1|2017-06-26|2019-12-31|Loxo Oncology Inc|Process for the preparation of pyrazolo [1,5-a] pyrimidines and salts thereof|

---

WO2018136661A1|2017-01-18|2018-07-26|Andrews Steven W|SUBSTITUTED PYRAZOLO[1,5-a]PYRAZINE COMPOUNDS AS RET KINASE INHIBITORS|

---

WO2018136663A1|2017-01-18|2018-07-26|Array Biopharma, Inc.|Ret inhibitors|

---

TN2019000263A1|2017-03-16|2021-01-07|Array Biopharma Inc|Macrocyclic compounds as ros1 kinase inhibitors|

---

GB201708457D0|2017-05-26|2017-07-12|Univ Oxford Innovation Ltd|Inhibitors of metallo-beta-lactamases|

---

TW201922741A|2017-10-10|2019-06-16|美商亞雷生物製藥股份有限公司|Crystalline forms|

---

TW201922252A|2017-10-10|2019-06-16|美商絡速藥業公司|Formulations of 6--4-methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile|

---

US20200339579A1|2018-01-18|2020-10-29|Array Biopharma Inc.|Substituted pyrazolyl[4,3-c]pyridine compounds as ret kinase inhibitors|

---

CA3087354A1|2018-01-18|2019-07-25|Array Biopharma Inc.|Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors|

---

CA3108065A1|2018-07-31|2020-02-06|Loxo Oncology, Inc.|Spray-dried dispersions and formulations of -5-amino-3-methyl)phenyl)-1--1h-pyrazole-4-carboxamide|

---

JP2022500383A|2018-09-10|2022-01-04|アレイ バイオファーマ インコーポレイテッド|Condensed heterocyclic compound as a RET kinase inhibitor|

---

CN109020860B|2018-09-25|2021-06-22|宝鸡文理学院|2-aryl-3-ester group polysubstituted pyrrole compound and synthesis and refining method thereof|

---

CN113490666A|2018-12-19|2021-10-08|奥瑞生物药品公司|Substituted pyrazolo [1,5-A ] pyridine compounds as inhibitors of FGFR tyrosine kinases|

---

US20220041579A1|2018-12-19|2022-02-10|Array Biopharma Inc.|Substituted quinoxaline compounds as inhibitors of fgfr tyrosine kinases|

---

WO2021134004A1|2019-12-27|2021-07-01|Schrodinger, Inc.|Cyclic compounds and methods of using same|

---

WO2021155004A1|2020-01-30|2021-08-05|The Regents Of The University Of California|Strad-binding agents and uses thereof|

---

CN111825678A|2020-06-05|2020-10-27|连庆泉|Preparation method of carbamatinib|

法律状态:
2018-03-06| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2019-12-17| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

---

2019-12-24| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

---

2020-07-21| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|

---

2020-11-17| B07A| Technical examination (opinion): publication of technical examination (opinion) [chapter 7.1 patent gazette]|

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2021-03-16| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-04-27| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 24/07/2013, 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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EP12178946.5|2012-08-02|

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EP12178946|2012-08-02|

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PCT/EP2013/065598|WO2014019908A2|2012-08-02|2013-07-24|Substituted pyrroles active as kinases inhibitors|

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