substituted pyrimidinyl-pyrroles as kinase inhibitors

专利摘要:
PYRIMIDINYL-PYRROILS SUBSTITUTED ACTIVE AS KINASE INHIBITORS The present invention relates to the substituted pyrimidinyl-pyrroles of formula (I) that modulate protein kinase activity and are therefore useful in the treatment of diseases caused by unregulated protein kinase activity, in particular, the Janus kinases. The present invention also relates to methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases using these compounds or the pharmaceutical compositions containing them.
公开号:BR112013026137B1
申请号:R112013026137-4
申请日:2012-04-05
公开日:2020-12-01
发明作者:Maria Gabriella Brasca；Tiziano Bandiera；Jay Aaron Bertrand；Paola Gnocchi；Danilo Mirizzi；Marcella Nesi；Achille Panzeri
申请人:Nerviano Medical Sciences S.R.L；
IPC主号:

专利说明:

The present invention relates to some substituted pyrimidinyl-pyrrdis derivatives that modulate protein kinase activity. The compounds of the present invention are therefore useful in the treatment of diseases related to unregulated kinase activity, for example cancer, cell proliferation disorders, viral infections, immunological disorders, neurodegenerative diseases and 10 cardiovascular diseases.
The present invention also provides methods for the preparation of these compounds, pharmaceutical compositions comprising those compounds and methods for the treatment of diseases using pharmaceutical compositions comprising those compounds.
Protein kinases mediate intracellular signaling, affecting a transfer of phosphoryl from a nucleoside triphosphate to a host protein that is involved in a signaling pathway. These phosphorylation devices 20 act as a molecular on / off switch that can modulate or regulate the biological function of the target protein and ultimately trigger in response to a variety of extracellular stimuli and other stimuli. Examples of such stimuli include signs of environmental and chemical stress (for example, osmotic check, thermal check, ultraviolet radiation, bacterial endotoxin and H2O2), cytokines (for example, interleukin-3 (IL-3), IL-2) and growth factors (e.g., stimulating factors for macrophage granulocyte colonies (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 the synthesis and regulation of the protein cell cycle. The malfunction of protein kinases (PKs) is the main feature of numerous diseases. A large part of oncogenesis and proto-oncogenes are involved in the human cancer code for PKs. The improved activities of PKs also imply 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, disease Alzheimer's disease and hormone-related diseases. Accordingly, there has been a substantial effort in medical chemistry to find protein kinase inhibitors that are effective as therapeutic agents. For a general reference for the defect or deregulation PKs see current opinions in Chemical Biology 1999, 3: 459-465, Nature Rev. Drogas Discov. 2002; 1: 30925 315 and 2008 carcinogenesis, 29: 1087-191. receivers consisting of JAK1, JAK2, JAK3 and TYK2.
Whereas JAK1, JAK2 and TYK2 are ubiquitously expressed. in mammals, JAK3 is expressed mainly in hematopoietic cells. JAKs play a crucial role in ■ hematopoietic cytocytes and signaling of growth factors (Nature 1995; 377: 591-594, Annu Rev. Immunol. 1998; 16: 293-322) and are critically involved in cell growth, survival, development and differentiation of myeloid cells and immunological. Effective adaptive and innate immune responses require functional JAK signaling to protect the organism against infections or tumors and mutations that lead to loss of function to replenish some of the most common inherited severe immunodeficiencies. As a consequence, JAK / STAT signaling has been implicated in mediating 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 hematologic tumors. , such as leukemias and lymphomas (Immunol Rev. 2009; - 20 228: 273-287).
In particular, the JAK2 kinase is exclusively involved in signal transduction mediated by erythropoietin (EPO), thrombopoietin (TPO), growth hormone (GH), prolactin (PR) and by cytokines that signal through the IL-3 receptor chain. common beta, stimulating factor for macrophage granulocyte colonies (GM-CSF) and IL-5. In addition, JAK2 together with JAK1 and / or TYK2 are important for cytokines that signal via gpl30 receptors (eg IL-6, IL-11), type II cytokine receptors, such as IL-10, IL-19, IL-20 and IL-22, p40 containing cytokine receptors containing IL-12 and IL-23 and for type I and II signal, IFN receptors (Immunol Rev. 2009, 228: 273-287). JAK3 kinase is mainly expressed in hematopoietic cells that are selectively related to 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 function and development, and in homeostasis of the immune system. TYK2 is mainly associated with interferons, IL-12 and IL-23, but also with IL-10 and IL-6 signaling. All of these growth factors and cytokines are mainly involved in the proliferation and differentiation of myeloid cells, the 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).
The binding of the ligand to the specific receptor appears to induce a conformational change in the receptor that allows for the trans and / or autophosphorylation of the two molecules bound to JAK2. Activated JAK2, then the phosphorylated specific tyrosine residues in the cytoplasmic tails of the receptors, create binding sites for the SH2 domain of signal transducers and activators of transcriptional proteins (STAT). Once bound to the receptors, STATs are themselves phosphorylated by JAK2 in tyrosine residues. Phosphorylated STATs dimerize and translocate to the nucleus, where they regulate gene transcription. Thus, JAK2 is 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). JAK2, like the other JAKs, is characterized by a kinase domain (JH1), immediately adjacent to a pseudo kinase domain (JH2) 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). A JAK2 activation point mutation (phenylalanine replacement valine, JAK2-V617F), in the pseudo-kinase domain, together with other activation mutations, in JAK2 exonl2 and the TPO receptor (MPLW515L / K), have been identified in cells hematopoietic diseases of patients with rheumatic diseases or MPD (Nature 2005; 434: 1144-8, N Engl J * 20 Med 2005; 352: 1779-1790, Lancet 2005; 365: 1054-1061, cancer Cell 2005; 7: 387-97 , Blood 2006 108: 1427-1428 and Leukemia 2008, 22: 87-95). All of these studies suggest that JAK2 is a suitable target for the development of a spherical MPD therapy (Curr. One. Reports, 11: 2009, 117-124). In addition, JAK2 in general the JAKs / STAT pathway has been shown to be activated (eg, mutation, amplification, translocation) in hematological malignancies, such as, but not limited to, AML, ALL, Hodgkin's lymphoma, and diffuse lymphoma. large B cells. (Science 1997, 278: 1309-1312, Trends in Biochemical Sciences 2007, 33: 122-131) and in a variety of solid tumors (for example, mutation, STATs phosphorylation, silencing of JAKs / STAT pathway inhibiting SOCS proteins, amplification). Pharmaceutical intervention in the JAKs / STAT pathway was reviewed in AJP 2004, 165: 1449-1460, Cancer Res. 2006, 66: 3162-3168, Clin Cancer Res. 2008; 14: 3716-3721 and Immunol Rev. 2009; 228: 273-10287.
Pyrimidinyl-pyrrdis derivatives for the treatment of diseases associated with unregulated protein activity, such as cancers are described in W02007 / 110344, on behalf of the applicant. Some compounds specific to the aforementioned international patent application 15 are excluded from the present general formula.
The present inventors have now discovered that the compounds of formula (I), described below, are potent and selective JAK inhibitors and, therefore, are useful in cancer therapy, cell proliferation disorders, viral infections, immunological disorders, diseases neurodegenerative diseases and cardiovascular diseases.
Therefore, a first object of the present invention is to provide a substituted pyrimidinyl-pyrrole compound represented by formula (I)
where: R1 and R2 are independently halogen, nitro, cyano, 0R5, NR6R7 or an optionally substituted group selected from linear or branched C-C6 alkyl, linear or branched C2 ~ C6 alkenyl, linear or branched C2-C6 alkynyl, C3C7 cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, and heterocyclic and heterocyclic-alkyl, wherein: R5 is hydrogen or an optionally substituted group selected from linear or branched C1-C6 alkyl, linear or branched C2 ~ Cg alkenyl, C2 alkynyl -Cg linear or branched, C3-C7 cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, and heterocyclic and heterocyclic-alkyl; R6 and R7 are, independently, hydrogen or a group. 15 optionally substituted selected from straight or branched C-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, and heterocyclic and heterocyclic-alkyl or R6 and R7, made together with the nitrogen atom to which 20 are attached, can form a 5- to 6-membered heteroaryl or heterocyclic group optionally containing an additional heteroatom selected from N, 0 and S; R3 and NR8R9 where: R8 and R9 are independently hydrogen or an optionally substituted group selected from linear or branched C1-Cg alkyl, linear or branched C2-Cg alkenyl, linear or branched C2-Cg alkynyl, C3-C7 cycloalkyl, cycloalkyl- alkyl, 5 aryl, arylalkyl, and heterocyclic and heterocyclic-alkyl, or R8 and R9, made together with the nitrogen atom to which they are attached, can form an optionally substituted heteroaryl or heterocyclic group of 5 to 6 elements, optionally containing one additional heteroatom selected from 10 N, 0 and S; R4 is hydrogen, an optionally substituted straight or branched Cj-Cg alkyl or NR10R11, wherein: RIO and R11 are independently a hydrogen atom or an optionally substituted group selected from straight or branched C1-15 Cg alkyl, C2 alkenyl -Cg linear or branched, C2-Cg linear or branched alkynyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, and heterocyclic and heterocyclic-alkyl, or RIO and R11 made together with the nitrogen atom to which they are attached , can form an optionally substituted heteroaryl or heterocyclic group of 5 to 6 elements, optionally containing an additional heteroatom selected from N, 0 and S; R12 is hydrogen or an optionally substituted linear or branched C1-6 alkyl; or pharmaceutically acceptable salt thereof, with the proviso that the following compounds are excluded: 5- (2-amino-pyrimidin-4-yl) -2- (5-fluor-2-methyl-phenyl) -1H-pyrrole-3 -carboxamide, 5- (2-amino-pyrimidin-4-yl) -2- (2,5-difluor-phenyl) -1H-pyrrole-3-carboxamide, 5 5- (2-amino-pyrimidin-4- yl) -2- (2,5-dimethyl-phenyl) -1H-pyrrole-3-carboxamide, 5- (2-amino-pyrimidin-4-yl) -2- (5-chloro-2-methyl-phen. yl) -1H - pyrrole-3-carboxamide; 5- (2-amino-pyrimidin-4-yl) -2- (5-chloro-2-fluorophenyl) -1H-pyrrole-3-carboxamide; 5- (2-amino-pyrimidin-4-yl) -2- (2-fluor-5-methyl-phenyl) -1H-pyrrole-3-carboxamide; and 5- (2-amino-pyrimidin-4-yl) -2- (2-chloro-5-fluorophenyl) -1H-pyrrole-3-carboxamide.
The present invention also provides methods of preparing substituted pyrimidinyl-pyrrole compounds, represented by formula (I), prepared using a process consisting of normal synthetic transformations.
The present invention also provides a method for treating a disease caused by and / or associated with unregulated protein kinase activity, in particular ABL, ACK1, AKT1, ALK, AUR1, AUR2, BRK, BUB1, CDC7 / DBF4, CDK2 / CYCA, CHK1, CK2, EEF2K, EGFR1, EphA2, EphB4, ERK2, FAK, FGFR1, FLT3, GSK3beta, Haspin, IGFR1, IKK2, IR, JAK1, JAK2, JAK3, KIT, LCK, LYN, MAPKAPK2, MELK, METK, MNK, METK MPS1, MST4, NEK6NIM1, P38alfa, PAK4, PDGFR, PDK1, PERK, PIM1, PIM2, PIM3, PKAalfa, PKCbeta, PLK1, RET, ROS1, SULU1, Syk, TLK2, TRKA, TYK, VEGFR3, VEGFR2, ZEG the JAK family, who understand. administering to a mammal, in need thereof, an effective amount of a substituted pyrimidinyl-pyrrole compound, represented by formula (I) as defined above. The mammal in need of it can be, for example, a human being.
A preferred method of the present invention is to treat a disease caused by and / or associated with unregulated activity of the protein kinase selected from the group consisting of cancer, cell proliferation disorders, viral infections, autoimmune diseases, cardiovascular diseases and neurodegenerative diseases.
Another preferred method of the present invention is to treat certain types of cancer, including, but not limited to: carcinoma such as bladder, breast, brain, colon, kidney, liver, lung, small cell lung cancer, esophagus, gallbladder, ovary, pancreas, stomach, neck, thyroid, prostate and skin, including squamous cell carcinoma, hematopoietic tumors of lymphoid lineage, including leukemia, acute B and T (ALL) lymphocytic leukemia, including DS-ALL, B cell lymphoma, lymphoma of T cells, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, hair cell lymphoma, Burkette's lymphoma and mantle cell lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myeloid leukemia, acute megacarioblastic leukemia, myelodysplasic syndrome and promyelocytic leukemia, myeloprofilative diseases such as polycythemia vera (PV), essential thrombocythemia (ET), myelofibria and primary myocardial fibromyalgia and chondrial myelomycosis and chondrial myelomycosis , 5 tumors of mesenchymal origin, including sarcoma, fibrosarcoma and rhabdomyosarcoma, tumor of the central and peripheral nervous system, including neuroblastoma astrocytoma, glioma and schwannomas; other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, 10 keratoacanthoma, follicular thyroid cancer, Kaposi's sarcoma, mesothelioma.
Another preferred method of the present invention is to treat certain cell proliferation disorders, such as, for example, benign prostatic hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, glomerulonephritis arthritis and post-surgical stenosis and restenosis.
Another preferred aspect of the present invention is a method 20 for treating viral infections, in particular the prevention of AIDS developed in HIV-infected individuals.
A preferred method of the present invention is in 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), systemic lupus erythematosus (SLE) Crohn's disease and amyotrophic lateral sclerosis.
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 Lou's disease) Gehrig), Huntington's disease and Pick's disease.
Another preferred method of the present invention is in the treatment of cardiovascular diseases, including, but not limited to: primary or secondary arteriosclerosis, diabetes, heart attack and stroke.
In addition, the methods of the present invention also provide tumor angiogenesis and metastasis inhibition, as well as the treatment and rejection of transplanted organs, diseases due to graft versus host.
In a preferred embodiment, the methods of the present invention additionally comprise subjecting the mammal in need thereof to a regimen of radiation therapy or chemotherapy in combination with at least one cytostatic or cytotoxic agent.
The present invention also provides a pharmaceutical composition, comprising one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof and at least one excipient, carrier and / or pharmaceutically acceptable diluent. a pharmaceutical composition of a compound of formula (I), which further comprises one or more chemotherapeutics, for example,. cytotoxic or cytostatic agents, antibiotic-type agents, alkylating agents, antimetabolite agents, 5 hormonal agents, immunological agents, interferon-type agents, cyclooxygenase inhibitors (for example, COX-2 inhibitors), matrix metalloproteinase inhibitors, telomerase inhibitors , tyrosine kinase inhibitors, agents against growth factor receptors, such as anti-HER agents, anti-EGFR agents, anti-Abl, anti-angiogenic agents (eg, angiogenesis inhibitors), farnesyl transferase inhibitors, ras-raf signal transduction pathway, Akt pathway inhibitors, cell cycle inhibitors, other cdk inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors and the like.
The present invention further provides an in vitro method for inhibiting the activity of protein kinase JAK1, JAK2, JAK3 which comprises contacting the kinase with an effective amount of * 20 a compound of formula (I) as defined above. The present invention further provides a test of the JAK2-dependent human megakaryoblastic leukemia SET-2 cell line, which comprises contacting the cells with an effective amount of a compound of formula (I) as defined above.
Furthermore, the present invention provides an in vivo model where the SET-2 cell line of acute megakaryoblastic leukemia was inoculated into a female mouse from 5 to 6 weeks of age with severe combined immunodeficiency (SCID). Mice with a palpable tumor were treated with a compound of formula (I) for 10 days. The dimensions of the 5 tumors were measured regularly using Vernier gauge and the tumor growth inhibition (TGI) was calculated.
In addition, the invention provides a product 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 use in anticancer therapy .
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.
In addition, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, as defined above, when used in a cancer treatment method.
Finally, the invention provides for 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.
Unless otherwise specified, when referring to the compounds of formula (I) itself, as well as any pharmaceutical composition thereof, or any therapeutic treatment comprising them, the present invention includes all hydrates, solvates, complexes, metabolites , pro-drugs. pharmaceutically acceptable, pharmaceutically acceptable biopercusors, carriers, N-6xoxides and pharmaceutically acceptable salts of the compounds of this invention.
A "metabolite" of a compound of formula (I) and any compound in which this same compound of formula (I) is converted in vivo, for example, with administration to a mammal in need thereof. Normally, however, without representing a limiting example, under the administration of the compound of formula (I), even the derivative can be converted into a variety of compounds, for example, including more soluble derivatives such as hydroxylated derivatives, which are easily excreted. Thus, depending on the metabolic pathway, if so, any of these hydroxylated derivatives can be considered as a metabolite of the compounds of formula (I) - "Pharmaceutically acceptable pro-drugs" and "pharmaceutically acceptable bioprecursors" are any - 20 covalently linked compounds, which release in vivo the original active drug according to formula (I). The term "pharmaceutically acceptable prodrugs" and "pharmaceutically acceptable bioprecursors" as used herein refer to those prodrugs of the compounds of the present invention that are, within the framework of a solid medical evaluation, suitable for use in contact with tissues of humans and inferior animals without undue toxicities, irritations, allergic responses and the like, compatible 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 "pre-drug" refers to compounds that are rapidly transformed in vivo to produce the original active medication, according to formula (I), 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 Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987. "N-6xidos" are compounds of formula (I) where nitrogen and oxygen are trapped through a dative bond.
Pharmaceutically acceptable salts of the compounds of formula (I) include acidic salts with organic or inorganic acids, for example, nitrile, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric, acetyl, trifluoroacetic, propionic, glycolic, latic, oxalic, malonic, malonic, maleic, tartaric, citrusic, benzoic, cinnamic, mandelic, methanesulfonic, isethionic and salicylic.
The pharmaceutically acceptable salts of the compounds of formula (I) also include salts with organic or inorganic bases, for example, alkali or alkaline earth metals, especially sodium, potassium, calcium, ammonium or magnesium hydroxide, carbonates and bicarbonates, cyclic amines or acyclic.
If an estrogenic center or other form of an isomeric center is present in a compound of the present invention, all forms of such an isomer or isomers, including enantiomers and diastereomers, are intended to be encompassed herein. Compounds containing an estrogenic 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 the compounds have double bonds of unsaturated carbon-carbon, both cis (Z) and trans (E) isomers are within the scope of the present invention.
In cases where the compounds may exist in tautomeric forms, for example, in keto-enol tautomers, each tautomeric form is contemplated to be included within this invention if it exists in equilibrium or in a predominant form.
In the present description, unless otherwise specified, the following terms have the following meanings. The term "aryl" includes carbocyclic or heterocyclic hydrocarbons having 1 to 2 portions are fused or linked to each other by a simple bond, where at least one of the 25 and aromatic rings, when present, the aromatic rings comprising a 5 to 6 ring elements with 1 to 3 heteroatoms selected from N, 0 and S.
Examples of aryl groups according to the invention are, for example, phenyl, biphenyl, a- or p-naphthyl, dihydronaphthyl, thienyl, benzothiophenyl, furyl, benzofuranyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolil, oxazolyl, isoxazolyl, isoxazolyl, isoxazolyl, isoxazolyl, isoxazolyl, pyrololyl, isoxazolyl, pyrololyl, isoxazolyl, pyrolol, , pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, purinyl, quinolyl, isoquinolyl, dihydroquinolinyl, quinoxalinyl, benzodioxolyl, indanyl, indenyl, triazolyl, and the like.
With the term "heterocyclic" (also known as "heterocycloalkyl") we mean a carbocyclic ring of 3 to 7 elements, partially saturated or unsaturated when one or more carbon atoms are replaced by hetero atoms, such as nitrogen, oxygen and sulfur. Non-limiting examples of the heterocyclic group are, for example, pyran, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazolidine, pyrazoline, thiazoline, thiazolidine, dihydrofuran, tetrahydrofuran, 1,3-dioxolane, piperidine, piperazine, morpholine and the like.
With the term "straight or branched C1-Cg alkyl", hence comprised of C1-C4 alkyl or C2-C6 alkyl, we mean 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.
With the term "C3-C7 cycloalkyl" and our intention is to refer to, unless otherwise specified, monocyclic carbon rings of 3 to 7 all carbon elements of the monocyclic ring which may contain one or more double ligands, but does not have a n system - fully conjugated electron. Examples of cycloalkyl groups, without limitation, are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene and cyclohexadiene, cycloeptane, cycloeptene and cycloeptadiene.
With the term "linear or branched C2-C6 alkenyl" we mean any of the groups, such as, for example, vinyl, alii, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 1 -hexenil, and the like
With the term "linear or branched C2-C6 alkynyl" we mean any of the groups, such as, for example, ethynyl, 2-propynylbutyl, 4-pentynyl, and the like.
According to the present invention, and unless otherwise specified, any of the groups R1, R2, R3, R4 and R12 can be optionally substituted, in any of their free positions, by one or more groups, for example, groups from 1 to 6, independently selected from: halogen atom, nitro, oxo groups (= 0), cyano, C1-6 alkyl, polyfluorinated alkyl, polyfluorinated alkoxy, alkenyl, alkynyl, hydroxyalkyl, aryl, arylalkyl, heterocyclic, C3-C7 cycloalkyl, hydroxy alkoxy, aryloxy, heterociclicoxi, methylenedioxy, alkylcarbonyloxy, arylcarbonyloxy, cycloalkenyloxy, heterociclicocarboniloxi, alquilidenoaminoxi, carboxy, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, heterociclicoxi-carbonyl, amino, ureldo, alkylamino, dialkylamino, arylamino, diarylamino, heterociclicoamino, formylamino, alkylcarbonylamino, arylcarbonylamino , heterocyclic-carbonylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, heterocyclic-aminocarbonyl, alkoxycarbonylamino, hydroxyaminocarbonyl, alkoxyimino, alkylsulfonylamino, arylsulfonylamino, heterociclicosulfonilamino, formyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, heterociclicocarbonil, alkylsulfonyl, arylsulfonyl, aminosulfonyl, alkylamino-sulfonyl, dialkylaminosulfonyl, arilaminosulfonil, heterociclicoaminosulfonil, arylthio, alkylthio, phosphonate and alkylphosphonate.
In turn, when appropriate, each of the aforementioned substituents may still be replaced by one or more of the groups referred to above.
In this regard, with the term halogen we mean an atom of fluorine, chlorine, bromine or iodine.
With the term cyan we mean a residue -CN.
With the term nitro we mean a -NO2 group.
With the term alkenyl or alkynyl we mean any aforementioned straight or branched C2-C6 alkyl groups plus having a double or triple bond. Not limited to these examples, the alkenyl or alkynyl groups of the invention are, for example, vinyl, allyl, 1-propenyl, butenyl, 3-butenyl, 2-pentenyl, 1-hexenyl, ethynyl, 2-propynylbutyl, 4-pentynyl , and the like.
With the term alkyl or polyfluorinated alkoxy we mean any of the above-branched or branched C 1-6 alkoxy or alkyl groups that are replaced by more fluorine, such as, for example, trifluoromethyl, trifluorethyl, 1> 1,1r3,3,3-hexafluoropropyl , trifluoromethoxy and the like.
With the term alkoxy, aryloxy, heterocyclicoxy and derivatives we mean any of the heterocyclic, aryl, 10 Ci-Cg alkyl groups above, or groups linked to the rest of the molecule through an oxygen atom (-O-).
In view of the above, it is evident to a person skilled in the art that any group whose name and a composite name, such as, for example, arylamino, must be intended as conventionally interpreted by the parties from which it comes, for example, by an amino group which is also replaced by aryl, where aryl is as defined above.
Likewise, any of the terms, such as, for example, alkylthio, alkylamino, dialkylamino, alkoxycarbonyl, alkoxycarbonylamino, heterocycliccarbonyl, heterocycliccarbonylamino, cycloalkyloxycarbonyl and the like, including groups where alkyl, aryl, alkoxy, C1-3 heterocyclic and cycloalkyl and cycloalkyl moieties , are as defined above.
Preferably, a compound of formula (I) is characterized by the fact that R4 and NR10R11, where RIO and R11 are, independently, hydrogen or an optionally substituted linear or branched C1 -C6 alkyl, and R1, R2, R3 and R12 are . as defined above.
More preferably, a compound of formula (I) is characterized by the fact that R3 and NR8R9, wherein R8 and R9 are, independently, hydrogen or an optionally substituted linear or branched C1 -C6 alkyl, and R1, R2, R4 and R12 are as defined above.
Even more preferably, a compound of formula (I) 10 is characterized by the fact that R12 is hydrogen, and R1, R2, R3 and R4 are as defined above.
Preferred, non-limiting spherical compounds (cmpds.) Of the invention, where appropriate in the form of pharmaceutically acceptable salts, are as follows: 1. 5- (2-Aminopyrimidin-4-yl) -2- [2-chloro-5- trifluormethyl) phenyl] -1H-pyrrole-3-carboxamide, 2. 5- (2-Aminopyrimidin-4-yl) -2- (2,5-dichlorophenyl) -1H-pyrrole-3-carboxamide, 3. 5- ( 2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methoxyphenyl) - * 1H-pyrrole-3-carboxamide, 4. 5- (2-Aminopyrimidin-4-yl) -2- (2-chlorine -5-ethylphenyl) -1H-pyrrole-3-carboxamide, 5. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -1H-pyrrole-3-carboxamide, 6. 5- (2-Aminopyrimidin-4-yl) -2- (2-chloro-5-methylphenyl) -1H-pyrrole-3-carboxamide, 7. 5- (2-Aminopyrimidin-4-yl) -2- (2 -chloro-5-cyanophenyl) -1H-pyrrole-3-carboxamide, 8. 5- (2-Aminopyrimidin-4-yl) -2- (5-bromo-2-methoxyphenyl) - 1H-pyrrole-3-carboxamide , 9. 5- (2-Aminopyrimidin-4-yl) -2- (5-bromo-2-fluorophenyl) -1H-pyrrol-3-carboxamide, 10. 5- (2-Aminopyrimidin-4-yl) - 2- [2-chloro-5- (hydroxy-methyl) phenyl] -1H-pyrrole-3-carboxamide, 11. 5- (2-Aminopyrimidi n-4-yl) -2- (2-chloro-5-methoxyphenyl) -1H-pyrrole-3-carboxamide, 12. 5- (2-Aminopyrimidin-4-yl) -2- [2-chloro-5- (trifluoromethoxy) phenyl] -1H-pyrrole-3-carboxamide, 13.. 5- (2-Aminopyrimidin-4-yl) -2- [2-methyl-5- (trifluoromethyl) phenyl] -1H-pyrrol-3-carboxamide, 14. 5- (2-Aminopyrimidin-4-yl) -2- [5-chloro- 2- (propane-2-yl) phenyl] -1H-pyrrol-3-carboxamide, 15. 5- (2-Aminopyrimidin-4-yl) -2- [2,5-bis (trifluormethyl) phenyl] -1H-pyrrol-3-carboxamide, 16. 5- (2-Aminopyrimidin-4-yl) -2- [2-ethyl-5- (trifluor methyl) phenyl] -1H-pyrrole-3- carboxamide, 17. 5- (2-Aminopyrimidin-4-yl) -2- [5-chloro-2- (trifluor methyl) phenyl] -1H-pyrrole-3-carboxamide, 18. 5- (2-Aminopyrimidin-4 -yl) -2- (5-cyano-2-methylphenyl) - 1H-pyrrol-3-carboxamide, 19. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) - N-methyl-1H-pyrrole-3-carboxamide, 20. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N-ethyl-1H-pyrrole-3-carboxamide, 21. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N- (2-hydroxyethyl) -IH-pyrrol-3-carboxamide, 22. 5- (2-Aminopyrimidin -4-yl) -2- (5-chloro-2-methylphenyl) -N- [2- (piperidin-1-yl) ethyl] -1H-pyrrol-3-carboxamide, 23. 5- (2-Aminopyrimidin- 4-yl) -2- (5-chloro-2-methylphenyl) -N- (1-methylpiperidin-4- yl) -1H-pyrrole-3-carboxamide; 24. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N-phenyl-1H-pyrrole-3-carboxamide, 25. 5- (2-Aminopyrimidin-4-i1 ) -2- (5-chloro-2-methylphenyl) -N- (furan-2-ylmethyl) -1H-pyrrole-3-carboxamide, 26. 5- (2-Aminopyrimidin-yl) -2- (5-chlorine -2-methylphenyl) -N- (3-hydroxypropyl) -1H-pyrrol-3-carboxamide, 27. 5- (2-Aminopyrimidin — 4 — yl) -2- (5-chloro-2-methylphenyl) -N- (2-methoxyethyl) -1H-pyrrole-3-carboxamide, 28. 5- (2-Aminopyrimidin — 4 —yl) -2- (5-chloro-2-methylphenyl) -N- (2-fluoroethyl) -lH- pyrrole-3-carboxamide, 29. 5- (2-Aminopyrimidin — 4 — yl) -2- (5-chloro-2-methylphenyl) - N, N-dimethyl-1H-pyrrole-3-carboxamide, 30. N- (2-Aminoethyl) -5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1H-pyrrol-3-carboxamide, 31. 5- (2-Aminopyrimidin-4-yl ) -2- (5-chloro-2-methylphenyl) -N- [2- (methylamino) ethyl] -1H-pyrrol-3-carboxamide, 32. 5- (2-Aminopyrimidin-4-yl) -N-benzyl -2- (5-chloro-2-methylphenyl) -IH-pyrrol-3-carboxamide, 33. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N- ( 2-methylpropyl) -1H-pyrrole-3-carboxamide, 34. 5- (2-Aminopyrimidin-4- yl) -2- (5-chloro-2-methylphenyl) -N- (2,2-dimethylpropyl-1H-pyrrole) -1H-pyrrol-3-carborxamide, 35. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -N- methyl-1H-pyrrol-3-carboxamide, 36. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -N- ethyl-1H-pyrrole-3-carboxamide, 37. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -N- (2-hydroxyethyl) -1H-pyrrole -3-carboxamide, 38. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) - N, N-dimethyl-1H-pyrrole-3-carboxamide, 39. 5- ( 2-Aminopyrimidin-4-yl) -2- [2-chloro-5- (trifluoromethyl) phenyl] -N-methyl-1H-pyrrol-3-carboxamide, 40. 5- (2-Aminopyrimidin-4-yl ) -2- (5-chloro-2-hydroxy-phenyl) -1H-pyrrol-3-carboxamide, 41. 5- (2-Aminopyrimidin-4-yl) -2- (2-chloro-5-hydroxy-phenyl) ) -1H-pyrrol-3-carboxamide, 42. 2- (5-chloro-2-methylphenyl) -5- [2- (methylamino) pyrimidin-4-yl] -1H-pyrrol-3-carboxamide, 43. 5 - (Pyrimidin-4-yl) -2- (5-chloro-2-methyl-phenyl) -1H-pyrrole-3-carboxamide, 44. 2- (5-Chloro-2-methylphenyl) -5- (2- methylpyrimidin-yl) -1H-pyrrole-3-carboxamide, 45. 5- (2-Aminopyrimidin-4-yl) -2- (5-cl oro-2-ethylphenyl) -1- methyl-1H-pyrrol-3-carboxamide, 46. 5- (2-Aminopyrimidin-yl) -2- (5-chloro-2-methylphenyl) -l-methyl-1H-pyrrole -3-carboxamide, 47. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1- ethyl-1H-pyrrole-3-carboxamide, 48. 5- (2- Aminopyrimidin-yl) -2- (5-chloro-2-methylphenyl) -1- (2,2,2-trifluorethyl) -1H-pyrrol-3-carboxamide, 49. 5- (2-Aminopyrimidin-yl) -2 - (5-chloro-2-methylphenyl) -1- (2-hydroxyethyl) -1H-pyrrol-3-carboxamide, 50. 5- (2-Aminopyrimidin-4-yl) -N-methyl-2- [2- meti1-5- (trifluormethyl) phenyl] -1H-pyrrol-3-carboxamide, and 51. 5- (2-Aminopyrimidin-4-yl) -2- [2-ethyl-5- (trifluor methyl) phenyl] - N-methyl-1H-pyrrole-3-carboxamide.
The present invention also provides a process for preparing the compounds of formula (I), as defined above, using the reaction routes and synthetic schemes described below, using the techniques available in the art and the available raw 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 preparations described can be easily adapted to prepare other embodiments of the present invention. For example, the synthesis of unexamplified compounds according to the Invention can be accomplished by changes apparent to those skilled in the art, for example, by adequately protecting interfering groups, by switching to other appropriate reagents known in the art, or by making changes to the routine of the conditions of use. reaction. Alternatively, other reactions referred to herein or known in the art will be recognized as having the adaptability for the preparation of other compounds of the invention.
The compounds of this invention can be prepared from the 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 known procedures.
It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole rate 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 solvent used, but such conditions can be determined by a person skilled in the art by routine optimization procedures. In addition, as is apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Protective groups suitable for various functional groups as well as conditions suitable for protecting and unprotecting particular functional groups are known in the art. For example, several protection groups are described in T.W.Greene and P.G.M.Wuts, Protecting Groups in
Organics Synthesis, Second Edition Wiley, New York, 1991, and references mentioned here.
A compound of formula (I) can be prepared according to the general synthetic processes described hereinafter in methods A, B, C and D. Scheme A shows the preparation of a compound of formula (I) in which R1, R2 and R3 are as defined above, R4 and NN2 and R12 and hydrogen. Scheme A

In the above scheme Ri, R2, R3, R8 and R9 are as defined above, R4 and NH2 and R12 and hydrogen.
Those skilled in the art will appreciate that any transformation carried out in accordance with said methods 15 may require standard modifications such as, for example, protecting interference groups, changing to other appropriate reagents known in the art, or making routine changes to the reaction conditions.
Thus, a process of the present invention comprises the following steps: Step 1: metal-catalyzed coupling reaction a halogenated derivative of formula (II)
with a substituted aryl boronic acid of formula (IIIa) or an aryl boronic ester of formula (IIIB):
wherein R1 and R2 are as defined above; Step 2: hydrolysis of the resulting carboxylic ester (IV)
wherein R1 and R2 are defined as before, by means of basic hydrolysis; Step 3: amidation of the carboxylic acid resulting from formula (V)
wherein R1 and R2 are as defined above, by reaction with a derivative of formula (VI) NHR8R9 (VI) where R8 and R9 are as defined above, to give a compound of formula (I)
wherein R1, R2 and R3 are as defined above, R4 and NH2 and R12 is hydrogen; or Step 3a: direct amidation of the carboxylic ester of formula (IV) as defined above by reaction with a derivative of formula (VI), as defined above, to give a compound of formula (I)
where R1, R2 and R3 are as defined above, R4 is NH2 and R12 is hydrogen; optionally converting a compound of formula (I) to another compound other than formula (I) and, if desired, converting a compound of formula (I) to a pharmaceutically acceptable salt thereof or converting a salt to the free compound (I).
According to step 1 of Scheme A, the conversion of a halogenated derivative of general formula (II) to a compound of formula (IV) can be carried out in several ways. For example, a compound of formula (II) can be reacted by metal-catalyzed coupling reagents with an aryl bordonic acid of formula (Illa) or aryl bordonic ester of formula (Illb). Preferably, a compound of formula (IV) can be prepared from Pd Catalyzed Suzuki-Miyaura coupling intermediates with a substituted aryl bordonic acid of general formula (Illa) or aryl bordonic ester of general formula (Illb). Cross couplings catalyzed by transition metals of aryl halides (hetero) with bordyl aryl acids or boronic esters are well known to those skilled in the art, see references: a) Miyaura, Norio; Suzuki, Akira (1979). "Palladium-Catalyzed CrossCoupling Reaction of Organoboron Compound", Chemical reviews 95 (7): 2457-2483, b) Suzuki, A. in Metal-Catalyzed Cross Coupling Reaction, Diederich F. and Stang PJ, Eds. Wiley-VCH: New York, 1998, pp 49-97. In the so-called Suzuki- Miyaura reaction, the coupling reaction of aryl bordonic or esteric acid with (hetero) aryl halides is typically triggered by palladium complexes. Palladium phosphine complexes, such as tetrakis (triphenylphosphine)-palladium (0), but also used for this reaction, bis (triphenylphosphine) palladium (II) chloride, palladium (II) chloride (II) [1,1— bis ( diphenylphosphine) ferrocene] can be used. A base, such as potassium phosphate, sodium carbonate, cesium carbonate, potassium carbonate, potassium t-butoxide, tetraethyl ammonium hydroxide, triethylamine and added and tetrahydrofuran, dioxane, N, N-dimethylformamide, ethanol and toluene can be used as a reaction medium. Typically, temperatures range from room temperature to 150 ° C. Conventional heaters, together with microwave irradiation can be used. The duration of the reaction varies from about 30 min to about 96 hours. Various combinations of Pd / base / solvent catalyst have been described in the literature, which allows fine-tuning of reaction conditions in order to allow a wide range of additional functional groups on both coupling partners.
According to step 2 of Scheme A, the hydrolysis of a derivative of formula (IV) in a carboxylic acid of formula (V) can be carried out in several ways. Typically, NaOH or KOH, in an alkaline solution and used at a temperature ranging from room temperature to 150 ° C, for a time ranging from about 30 min to about 96 hours.
According to step 3 of Scheme A, the conversion of a carboxylic acid of formula (V) to an amide of formula (I) can be carried out in various forms and experimental conditions, which are widely known in the art of preparing carboxamides . As an example, a compound of formula (V) 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 ranging from about -10 ° C to reflux and for a period of time ranging from about 1 hour to about 96 hours. The acyl chloride can be isolated by evaporation 10 of the solvent, and additionally set to react with a 33% solution of ammonium hydroxide or with an NHR8R9 (VI) amine, 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 (V) can be reacted with the ammonium salt of 1-hydroxybenzotriazole or with an NHR8R9 (VI) amine in the presence of a carbodiimide, such as dicyclohexyl-carbodiimide, '20 diisopropyl-carbodiimide, salt of l-ethyl-3- (3'-dimethylamino) carbodiimide hydrochloric acid. Preferably, this reaction is carried out in a suitable solvent such as, for example, tetrahydrofuran, dichloromethane, toluene, dioxane, N, N-dimethylformamide and in the presence of a protection eliminator such as, for example, triethylamine, N, N -diisopropylethylamine, at a temperature ranging between room temperature and reflux, for a time ranging from about 30 min to about 96 hours.
According to Step 3a of Scheme A, the direct transformation of the ester (IV) into a compound of formula (I) is also synthetically viable and is intended to be included within the scope of the Invention. Recent data from the literature suggest that, for example, such a transformation can be easily accomplished through the use of magnesium nitride (Mg3N2) in a suitable solvent, such as an alcohol under microwave irradiation (Gemma, E.; Veitch, GE; Bridgwood, KL; Ley, SV Org. Lett. 2008, 10, 3623).
The present invention further provides an alternative process for the preparation of a compound of formula (I), which is shown in Scheme B below, where R1, R2 and R3 are as defined above, R4 and NH2 and R12 and hydrogen. Scheme B

In the above scheme R1, R2 and R3 are as defined above, R4 and NH2 and R12 are hydrogen. Accordingly, another process of the present invention comprises the following step: Step 4: The metal-catalyzed coupling reaction of a halogen derivative of formula (VII)
wherein R3 is as defined above, with an aryl 5 boronic acid of formula (IIIa) or an aryl boronic ester of formula (IIIb)
where Ri and R2 are as defined above, to give a compound of formula (I)
where RI, R2 and R3 are as defined above, R4 is NH2 and R12 is hydrogen; optionally converting a compound of formula (I) to another compound other than formula (I) and, if desired, converting a compound of formula (I) to a pharmaceutically acceptable salt thereof or converting a salt to the free compound (I).
According to step 4 of scheme B, the conversion of a halo derivative of general formula (VII) into a compound of general formula (I) can be carried out under the variety of conditions already described in step 1 of Scheme A. The present The invention also provides an alternative process for the preparation of a compound of formula (I), which is shown in Scheme C below, where R1 and R2 are as defined above, R3 and NH2, R4 and NR10R11, where RIO and Rll are as defined above, and R12 is hydrogen. Scheme C

In the above scheme R1 and R2 are as defined above, R3 and NH2, R4 and NR10R11, where RIO and R11 are as defined above, and R12 is hydrogen. Therefore, another process of the present invention 15 comprises the following steps: Step 5: reacting a pyrrole of formula (VIII)
wherein R1 and R2 are as defined above, with acetyl chloride in the presence of a Lewis acid, or in the presence of metallic zinc; Step 6: react the resulting compound of formula (IX)
wherein R1 and R2 are as defined above, with a dialkyl acetal of N, N-dimethylformamide; Step 7: react to the enaminone resulting from formula (X)
wherein R1 and R2 are as defined above, with an optionally substituted guanidine of formula (XI) or a salt thereof
wherein R4 and NR10R11 and RIO and R11 are as defined above; Step 8: hydrolyze the cyano group of the compound resulting from formula (XII) under acidic conditions
wherein R4 and NR10R11, where RIO and R11 are as defined above, and R1 and R2 are as defined above, in order to obtain the compound of formula (I)
where R1 and R2 are as defined above, R3 and NH2, R4 and NR10R11, where RIO and R11 are as defined above, and R12 is hydrogen, optionally, converting a compound of formula (I) into another different compound of formula (I) and, if desired, converting a compound of formula (I) to a pharmaceutically acceptable salt thereof or converting a salt to the free compound (I).
According to step 5 of Scheme C, the acylation of one. compound of formula (VIII) to give a compound of formula (IX) and is preferably carried out with acetyl chloride in the presence of a Lewis acid, for example aluminum trichloride or titanium tetrachloride, operating under cooling, for example, at a temperature of -5 ° C to 0 ° C, or at room temperature, in an anhydrous organic solvent, for example, dichloromethane. A similar reaction is described in J.Het.Chem. 1983, 20, 61. Otherwise, the acylation of a compound of the formula (VIII) to give a compound of the formula (IX) is carried out with acetyl chloride in the presence of metallic zinc, operating at a temperature ranging from room temperature to reflux, in an anhydrous organic solvent, for example, toluene. A similar reaction is described in Te. Le. 2002, 43, 8133.
According to step 6 of Scheme C, the conversion of a compound of formula (IX) to the enaminone of general formula (X) can be carried out using a dialkylacetal, for example, N, N-dimethylformamide - dimethylacetal or diisopropylacetal. Preferably, the reaction is carried out at a temperature between room temperature and reflux, preferably at a temperature between 60 ° C and 90 ° C, in an organic solvent, such as, for example, toluene, benzene, dichloroethane or N, N-dimethylformamide. An analogous transformation has been described, for example, in Heterocycles 1998, 47 689.
According to step 7 of Scheme C, the conversion of a compound of formula (X) to a compound of formula (XII) is conducted by reaction with guanidine or substituted guanidine of formula (XI) or a salt thereof. Preferably, the reaction is carried out at a temperature between 80 ° C to 130 ° C in an organic solvent such as, for example, acetamide, N-methyl-2-pyrrolidone, N, N-dimethylformamide, in the presence of a base, such as potassium carbonate. This type of conversion is described in the scientific literature, for example, in J.Het.Chem. 1989, 26, 1147.
According to step 8 of Scheme C, hydrolysis under acidic conditions of the nitrile derivative of general formula (XII) to obtain the carboxamide of formula (I) and preferably carried out with glacial acetate or trifluoroacetic acid and concentrated sulfuric acid , more preferably, in proportions between 1 by 1 and 5 by 1, optionally in the presence of water, at a temperature between room temperature and 120 ° C, in particular at a temperature of 60 ° C to 90 ° C. An analogous hydrolysis is, for example, described in J. Org. Chem. 2005, 70, 1926. After alkalinization with aqueous concentrated ammonia solution, sodium hydroxide or potassium hydroxide, the free base is separated by filtration as a precipitate.
The present invention further provides an alternative process for the preparation of a compound of formula (I) which is shown in Scheme D below, where R1 and R2 are as defined above, R3 and NH2, R4 and hydrogen or (C1-C6) alkyl linear or optionally substituted branched, and R12 is hydrogen. Scheme D

In the above scheme R1 and R2 are as defined above, R3 and NH2, R4 is hydrogen or optionally substituted linear or branched C1 -C6 alkyl and R12 is hydrogen. Therefore, another process of the present invention comprises the following steps: Step 9: reacting the enaminone of general formula (X), as defined above, with an optionally substituted amidine of formula (XIII) or a salt thereof
wherein R4 is optionally substituted linear or branched hydrogen or (C1 -C6) alkyl; Step 10: hydrolyze the cyan group of the compound resulting from formula (XIV)
wherein R1 and R2 are as defined above and R4 is optionally substituted linear or branched hydrogen or C1 -C3 alkyl, under acidic conditions, in order to obtain the compound of formula (I)
wherein R1 and R2 are as defined above, R3 and NH2, R4 is hydrogen or alkyl (optionally substituted linear or branched C1-CJ and R12 and hydrogen, optionally, converting a compound of formula (I) into another different compound of formula (I) and, if desired, converting a compound of formula (I) to a pharmaceutically acceptable salt or converting a salt to the free compound (I).
According to step 9 of Scheme D, the conversion of a compound of formula (X) to a compound of formula (XIV) 6 is carried out by reaction with formamidine or substituted amidine of formula (XIII) or a salt thereof. Preferably, the reaction is carried out at a temperature between 80 ° C to 150 ° C in an organic solvent such as, for example, acetamide, N-methyl-2-pyrrolidone, N, N-dimethylformamide.
According to step 10 of Scheme D, hydrolysis under acidic conditions of the nitrile derivative of the formula (XIV) to produce the compound of formula (I) can be carried out under the variety of conditions already described in step 8 of Scheme C. As indicated above, a compound of formula (I), which is prepared according to the processes object of the Invention, can be conveniently converted into another compound of formula (I) operating according to well-known synthetic conditions, following examples of possible conversions: conv.l) conversion of a compound of formula (I), in which one of R1 or R2 and OCH3, to the corresponding compound of formula (I), in which one of R1 or R2 and OH, by treatment with BCL3or BBr3 in a solvents, such as dichloromethane, chloroform, dichloroethane, acetonitrile, at a temperature ranging from -20 ° C to reflux for about 30 min to about 96 hours:
conv.2) conversion of a compound of formula (I), where R12 is hydrogen, to the corresponding compound of formula (I), where R12 is an optionally substituted linear or branched (C1-C6) alkyl,
by treatment with an optionally substituted alkyl halide of the general formula R12'-X (XV), where R12 'is an optionally substituted linear or branched (C1-6) alkyl and X and halogen, in a solvent, such as N, N-dimethylformamide and in the presence of a base at a temperature ranging from room temperature to reflux for about 30 min to about 96 hours.
From all of the above, it is evident to a person skilled in the art that any compound of formula (I) having a functional group that can be further derivatized to another functional group, working and according to methods well known in the art to arrive at other compounds of formula (I), is intended to be understood within the scope of the present invention.
Needless to say, any of the intermediaries of the processes described above can be converted into a different intermediary, if desired and necessary, by means of an analogs operation on any of the conversion reactions described here.
From all of the above, it is evident to a person skilled in the art that when preparing the compounds of formula (I) according to any of the variants of the processes mentioned above, the optional functional groups within the starting materials, reagents or from their intermediaries, ■ that may give rise to undesirable side reactions, need to be adequately protected according to conventional techniques. Likewise, the conversion of these to free unprotected compounds can be carried out according to known procedures.
As will be readily appreciated, if the compounds of formula (I) prepared according to the process described above 10 are obtained as a mixture of isomers, their separation by conventional techniques into individual isomers of formula (I) is within the scope of the present invention.
The final compounds can be isolated and purified by conventional procedures, for example, chromatography and / or crystallization and salt formation.
The carboxamides of formula (I) as defined above can be converted to pharmaceutically acceptable salts. The carboxamides 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.
The synthesis of a compound of formula (I), according to the synthetic process described above, can be carried out step by step, where each intermediate is isolated and purified by conventional purification techniques, such as, for example, column chromatography, before performing the next reaction.
Alternatively, two or more steps of the synthetic sequence can be performed 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.
In cases where a compound of formula (I) contains one or more asymmetric centers, said compound can be separated into individual isomers by the procedures known to those skilled in the art. Such procedures comprise standard chromatographic techniques, including chromatography using a chiral stationary or crystallization phase. General methods for separating compounds containing one or more asymmetric centers are reported, for example, in Jacques, Jean; Collet, Andre; Wilen, Samuel H., - Eenantiomers, Racemates, and Resolutions, John Wiley & Sons, Inc., New York (NY), 1981.
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.
The starting materials of formula (II) and (VII) can be prepared as described in W02007 / 110344.
The starting material of the formula (VIII) can be prepared by known methods, or as described in the experimental part below (Preparations D and E).
The compounds of the formula (Illa), (Illb), (VI), (XI), (XIII) and (XV) are commercially available or can be prepared by known methods, the compounds of the formula (Illa) can also be prepared as described in the experimental part below (Preparaqbes A, B and C).
The present invention also provides an intermediate of formula (Illa):
wherein R1 is ethyl and R2 is chlorine or CF3 or R1 and isopropyl and R2 is chlorine.
The present invention further provides for a pharmaceutical composition comprising a compound of formula (I), in combination with anti-cancer treatments known as, radiation therapy or chemotherapy regimen in combination with cytostatic or cytotoxic agents, antibiotic type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-like agents, cyclooxygenase inhibitors (for example, COX-2 inhibitors), metallomatrix protease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-agents -EGFR, anti-angiogenesis agents (eg, angiogenesis inhibiting agents), farnesyl transferase inhibitors, rasa signal transduption pathway inhibitors, cell cycle inhibitors, other cdks inhibitors, tubulin binding agents, topoisomerase I inhibitors, topoisomerase II inhibitors, and the like.
If formulated as a fixed dose, these product combinations employ compounds of this invention within the dose range described below and another pharmaceutically active agent within the approved dosage range.
Compounds of formula (I) can be used sequentially with known anti-cancer agents when a combination formulation is inadequate.
The compounds of formula (I) of the present invention, suitable for administration to a mammal, for example, humans, can be administered by normal routes, the dosage level depending on the age, weight, conditions of the patient and the route of administration .
For example, a suitable dosage adopted for oral administration of a compound of formula (1) can vary from about 10 to about 1 g per dose, from 1 to 5 times a day. The compounds of the invention can be administered in several - 20 dosage forms, for example, orally, in the form of tablets, capsules, tablets coated with films or sugar, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, for example, intramuscularly, or by intravenous and / or intrathecal injection 25 and / or intraspinal or infusion.
The present invention also includes pharmaceutical compositions comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient, which can be a carrier or a diluent.
Pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form. For example, solid oral forms can confer, together with the active compound, 10 diluents, for example, lactose, dextrose, sucrose, sucrose, cellulose, corn starch or potato starch; lubricants, for example, silica, talc, stearic, calcium or magnesium stearate, and / or polyethylene glycols; binding agents, for example, starches, arabic gum, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disintegrating agents, for example, a starch, alginics, alginates or sodium starch glycolate; effervescent mixtures; dyes; adopters, 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 mixing, granulating, tabletting, sugar coating or 25 film coating processes.
Liquid dispersions for oral administration can be, for example, syrups, emulsions and suspensions.
As an example, syrups can center a vehicle, such as sucrose or sucrose with glycerin and / or mannitol and / or sorbitol.
Suspensions or emulsions may contain, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.
Suspensions or solutions for intramuscular injections may contain, together with the active compound, a vehicle that is pharmaceutically acceptable, for example, sterile water, olive oil, ethyl oleate, glycols, for example, propylene glycol, and, if desired, a adequate amount of lidocaine hydrochloride.
Solutions for intravenous injections or infusions may contain as a vehicle, for example, sterile water or preferably they may be in the form of sterile aqueous isotonic saline solutions, or they may contain a propylene glycol as the vehicle.
Suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, for example, cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty ester surfactant or lecithin.
In order to better illustrate the present invention, without limiting it, the following examples are now given. EXPERIMENTAL SECTION
For reference any specific compound of formula (I) of the invention, optionally in the form of a pharmaceutically acceptable salt, see the experimental section and the claims. Referring to the following examples, the 5 compounds of the present invention were synthesized using the methods described herein, or other methods already known in the art.
General purification and analytical methods
The synthetic preparation and some compounds of formula (I) 10 of the invention are described in the following examples.
The compounds of the present invention, as prepared according to the following examples, were also defined by 1H NMR or and / or ESI (+) exact mass data.
The 1H-NMR spectrometry was performed on a Mercury VX 400 operating at 400.45 MHz equipped with a 5 mm double resonance probe [1H (15N-31P) ID_PFG Varian]. High resolution mass spectra (HRMS) ESI (+) were obtained on an Ultima Q-Tof mass spectrometer directly connected with an Agilent HPLC 1100 micro as previously described in (M. Colombo, FR Sirtori, V. Rizzo, Rapid Commun Mass Spectrom 2004, 18 (4), 511-517). Column chromatography was performed under medium pressure on silica (Merck silica gel 40-63 pm) or on pre-packaged silica gel cartridges (Biotage). The components were visualized by UV light (A: 254 nm) and by iodine vapor. HPLC / MS was performed under a Waters X Terra RP 18 column (4.6 x 50 mm, 3.5 pm) using a 2790 Waters HPLC system equipped with a 996 Waters PDA detector and a mod single quadrupole mass spectrometer. in . Model 2Q Micromass, equipped with an electrospray ionization source (ESI). The Phase moves! A was 5mM buffered ammonium acetate (pH 5.2 with acetate / acetonitrile 95/5), and the Mobile B phase was water / acetonitrile (5/95), the gradient was 10 to 90% B in 8 minutes , retaining 90% B in 2 min. The UV detection was 220 nm and 254 nm. The flow rate was 1 ml / min. The injection volume was 10 pl. Full scan, mass range was between 100 to 800 amu. The capillary voltage was 2.5 KV; the temperature source was 120 ° C; the cone was 10 V. The retention time (HPLC T.A.) was determined in minutes at 220 nm or 254 nm. The mass was determined by the ratio of m / z.
When necessary, the compounds were purified by HPLC preparations on a Waters C18 Symmetry column (19 x 50 mm, 5um) or on a Waters X Terra RP 18 column (30 x 150 mm, 5 pm) using a Waters HPLC 600 preparation equipped with a Waters PDA 996 detector and a single quadrupole mass spectrometer mod. Model ZQ Micromass, an electrospray. 20 ionisation, in positive mode. Mobile phase A was water 0.01% TFA, and mobile phase B was acetonitrile. The gradient was 10 to 90% B in 8 min, retained in 90% B in 2 min. The flow rate is 20 ml / me. Alternatively, mobile phase A was 0.01% NH3 water and mobile phase B was acetonitrile. The gradient was 10 to 100% B in 8 min, retained in 100% B for 2 min. The flow rate was 20 ml / min.
In the following examples, as well as throughout the application, the following abbreviations have the following meanings. If not defined, the terms have commonly accepted meanings. SIGLAS AcOH Acetic acid CH3CN acetonitrile DCM dichloromethane DIPEA N, N-diisopropyetilamine DMF N, N-dimethylformamide DMSO dimethyl sulfoxide eq equivalents ESI ionization eletrospray EtOAc ethyl acetate EDCI N-ethyl-ethanol-ethanol-ethanol-ethanol-ethanol g (grams) h (hours) -HC1 hydrochloric acid HOBt lH-benzotriazol-l-ol HOBt.NH3 ammonium salt 1 / H-benzotriazol-l-ol HPCL high performance liquid chromatography K2CO3 potassium carbonate K3PO4 potassium phosphate KOH potassium hydroxide tBuOK potassium tert-butoxide LiCl lithium chloride. Mole moles MeOH methanol MeNH2 methylamine mg milligram (s) min minute (s) mL milliliter (s) mmol millimole (s) mol mole (s) N normal Na2C03 sodium carbonate Na2S205 sodium metabisulfite Na2S04 sodium sulfate NaHC03 hydrogen carbonate and sodium Pd (PPh3) 2c: l2 bis (triphenylphosphine PdCl2 (dppf) chloride [1,1'-bis (diphenylphosph palladium (II) chloride at room temperature TEA triethylamine TEA trifluoroacetic acid THE tetrahydrofuran uL microliter (s) Preparation) 5-Chloro-2-ethylphenyl) baronic (Illa)
Step 1: 4-ethyl-3-nitroaniline
4-ethylaniline (10.3 ml, 82.5 mmol) was added dropwise to the 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 nitrile acid (100%, 4 ml) and sulfuric acid (96%, 10 ml), maintaining the temperature below 0 ° Ç. The reaction mixture was then stirred at the same temperature for 1 h. The reaction mixture was poured onto ice (200 ml) and the precipitate was filtered and washed with water. The solid was suspended with water (100 ml) and neutralized with ammonium hydroxide (35%). The precipitate was filtered and dried in the oven to obtain a light brown solid (10 g, 73%). 1H NMR (400 MHz, DMSO-d6) 6 ppm 1.11 (t, J = 7.45 Hz, 3H), 2.63 (q, J = 7.45 Hz, 2 H), 5.53 (s , 2H), 6.81 (dd, J = 8.30, 2.44 Hz, 1H), 7.04 (d, J = 2.44 Hz, 1H), 7.11 (d, J = 8, 30 Hz, 1H). Step 2: 4-chloro-1-ethyl-2-nitrobenzene
A solution of sodium nitrite in water (4.2 g, 60 mmol, 5 M, 12 ml) was added dropwise to a cooled (0 ° C) solution of 4-ethyl-3-nitroaniline (10 g, 60 mmol) in cone. HCl (200 ml) and the reaction mixture was stirred at the same temperature for 1.5 h. Copper (I) chloride (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 sodium sulfate. 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) 5 ppm 1.19 (t, J = 7.45 Hz, 3H), 2.78 (q, J = 7.45 Hz, 2 H), 7.57 (d , J = 8.42 Hz, 1 H) 7.74 (dd, J = 8.36, 2.26 Hz, 1H), 8.03 (d, J = 2.32 Hz, 1H). Step 3: 5-Chlorine-2-ethylaniline
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 13 h . The solids were filtered through celite, the filtrate was concentrated and purified by flash chromatography (hexane / EtOAc 9/1) to obtain the title compound as a light pink oil (5.09 g, 97%). 1H NMR (400 MHz, DMSO-d6) 5 ppm 1.09 (t, J = 7.51 Hz, 25 3H), 2.39 (q, J = 7.49 Hz, 2 H), 5.13 ( s, 2H), 6.47 (dd, J = 8.06, 2.20 Hz, 1H), 6.62 (d, J 8.06 Hz, 1H). Step 4: 4-chloro-1-ethyl-2-iodobenzene
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 5 ml) were ground in a mortar for a few minutes to obtain a homogeneous paste in which a solid sodium nitrite (3.71 g, 53.8 mmol) was added and the paste crushed for 10 min. solid potassium lodide (8.94 G, 53.8 mmol) was added and the slurry ground for 20 min. The paste was then dissolved in water (50 ml) and treated with sodium sulfite (10% aq. Sol), before extracting with EtOAc (3 x 100 ml). The combined organic layers were dried over sodium sulfate and the crude product was purified by flash chromatography (hexane) to obtain the title compound 15 as a light yellow oil (4.35 g, 76%). XH NMR (400 MHz, DMSO-d6) 5 ppm 1.12 (t, J = 7.51 Hz, 3H), 2.66 (q, J = 7.53 Hz, 2 H), 7.29-7 , 35 (m, 1H), 7.42 (dd, J = 8.30, 2.20 Hz, 1H), 7.87 (d, J = 2.20 Hz, 1H). Step 5: (5-chloro-2-ethylphenyl) boronic acid
-I-propylmagnesium chloride (2M sol. In THE, 8.98 mL, 17.95 mmol) was added dropwise in a solution of 4-chloro-1-ethyl-2-iodobenzene (4.35 g, 16 , 3 mmol) in dry THE (40 mL) at -30 ° C and the reaction mixture was stirred at the same temperature for 30 min, under an argon atmosphere. After this time, trimethyl borate (3.63 ml, 32.6 mmol) was added dropwise and the reaction mixture was stirred at the same temperature for 1.5 h. HCl (IM, 16 ml) was added and the reaction mixture was extracted with EtOAc (3 x 50 ml). The combined organic layers were dried over sodium sulfate and, after removing the solvent, a solid was obtained, which was triturated with hexane to obtain the title compound as a white solid (2.15 g, 72%). XH NMR (400 MHz, DMSO-d6) 6 1.12 ppm (t, J = 7.51 Hz, 3H), 2.72 (q, J = 7.69 Hz, 2 H), 7.17 (d , J = 8.18 Hz, 1 H), 7.25-7.32 (m, 1H), 7.36 (d, J = 2.32 Hz, 1H), 8.19 (s, 2 H) . Preparation B [5-chloro-2- (propane-2-yl) phenyl] bordenic acid (Illa)
Step 1: 3-Nitro-4- (propane-2-yl) aniline
4- (propane-2-yl) aniline (10.12 ml, 74 mmol) was added dropwise in sulfuric acid (96%, 57 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 nitrile acid (100%, 3.7 ml) and sulfuric acid (96%, 9 ml), keeping the temperature below 0 ° C. The reaction mixture was then stirred at the same temperature for 1 h. The reaction mixture was poured onto ice (200 ml) and the precipitate was filtered and washed with water. The solid was suspended with water (100 ml) and neutralized with ammonium hydroxide (35%). The precipitate was filtered and dried in the oven to obtain a light brown solid (9.49 g, 71%). Step 2: 4-chloro-2-nitro-1- (propane-2-1) benzene
A solution of sodium nitrite in water (3.6 g, 52.2 mmol, 5 M, 10.4 mL) was added dropwise in a solution of 3-nitro-4- (propane-2-yl) aniline (9.4 g, 52.2 mmol) in cone. HCl (175 mL) at 0 ° C and the reaction mixture was stirred at the same temperature for 1.5 h. Copper (i) chloride (8.3 g, 83.5 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 sodium sulfate. The crude product was then purified by flash chromatography (hexane / EtOAc 95/5) to obtain the title compound as a yellow oil (1.8 g, 17%). XH NMR (400 MHz, DMSO-d6) 5 ppm 1.23 (d, J = 6.84 Hz, 6 H), 3.14 (spt, J = 6.94 Hz, 1H), 7.67 (d , J = 8.54 Hz, 1 H), 7.74 (dd, J = 8.54, 2.30 Hz, 1H), 7.95 (d, J = 2.20 Hz, 1H). Step 3: 5-chloro-2- (propane-2-yl) aniline
A solution of hydrazine hydrate (1.7 ml, 35.1 mmol) in methanol (12 ml) was added dropwise to a solution of 25 4-chloro-2-nitro-l- (propane-2-yl) benzene (1.75 g, 8.8 mmol) in methanol (40 ml), in the presence of iron (III) chloride (146 mg, 0.9 mmol) and activated carbon (146 mg) and the reaction mixture was stirred at reflux for 7 h. The solid was removed by filtration over celite, the filtrate was concentrated and purified by flash chromatography (hexane / EtOAc 9/1) to obtain the title compound as a light pink oil (1.4 g, 94%). NMR (400 MHz, DMSO-de) 6 ppm 1.11 (d, J = 6.84 Hz, 6 H), 2.90 (spt, J = 6.75 Hz, 1H), 5.15 (s, 2H), 6.50 (dd, J = 8.18, 2.32 Hz, 1H), 6.62 (d, J = 2.32 Hz, 1H), 6.96 (d, J = 8.18 Hz, 1H). Step 4: 4-chloro-2-iodo-1- (propane-2-yl) benzene
A mixture of 5-chloro-2- (propane-2-yl) aniline (1.4 g, 8.3 mmol), p-toluenesulfonic acid (4.7 g, 24.8 mmol) and water (0.83 mmol) were ground in a mortar for a few minutes to obtain a homogeneous paste to which solid sodium nitrite (1.42 g, 20.6 mmol) was added and the paste was ground for 10 min. solid potassium lodide (3.42 g, 20.6 mmol) was added and the slurry ground for 20 min. The paste was then dissolved in water (20 ml) and treated with sodium sulfite (10% aq. Sol.), Before extracting with EtOAc (3 x 50 ml). The combined organic layers were dried over sodium sulfate and the crude product was purified by flash chromatography (hexane) to obtain the title compound as a light yellow oil (1.79 g, 77%). rH NMR (400 MHz, DMSO-dg) 5 ppm 1.17 (d, J = 6.84 Hz, 6 25 H), 3.08 (spt, J = 6.88 Hz, 1H), 7.33 ( d, J = 8.42 Hz, 1 H), 7.45 (ddd, J = 8.42, 2.20, 0.37 Hz, 1H), 7.87 (d, J = 2.20 Hz, Step 5: [5-Chloro-2- (propane-2-yl) phenyl] boronic acid
I-Propylmagnesium chloride (2 M in THF, 3.34 mL, 6.7 mmol) was added dropwise to a solution of 4-chloro-2-iodo-1- (propane-2-yl) benzene (1 / 7 g, 6.7 mmol) in dry THF (15 mL) at -30 ° C and the reaction mixture was stirred at the same temperature for 30 min, under an argon atmosphere. After this time, trimethyl borate (1.35 ml, 12.1 mmol) was added dropwise and the reaction mixture was stirred at the same temperature for 1.5 h. HCl (1 M, 6 ml) was added and the reaction mixture was extracted with EtOAc (3 x 20 ml). The combined organic layers were dried over sodium sulfate and, after removing the solvent, a solid was obtained, which was triturated with hexane to obtain the title compound as a white solid (1.05 g, 87%). NMR (400 MHz, DMSO-de) 5 ppm 1.16 (d, J = 6.84 Hz, 6 H), 3.17-3.25 (m, 1H), 7.24-7.29 (m , 2 H), 7.29-7.33 (m, 1 H), 8.22 (s, 2 H). Preparation C [2-ethyl-5-trifluormethyl) phenyl] boronic acid (Illa)
Step 1: l-ethyl-4- (trifluormethyl) benzene
A solution of l-ethylenyl-4- (trifluormethyl) benzene (1.72 mL, 11.6 mmol) in THF (60 mL) was stirred, under the presence of Pd / C (10%, 400 mg), under an atmosphere hydrogen (45 psi) 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 5, thus obtained, was used in the next step without further manipulation. NMR (400 MHz, DMSO-df) 5 ppm 1.20 (t, J = 7.63 Hz, 3H), 2.70 (q, J = 7.16 Hz, 2 H), 7.44 (d, J = 7.93 Hz, 2 H), 7.63 (d, J = 7.93 Hz, 2 H). Step 2: 2-iodo-1-ethyl-4- (trifluormethyl) benzene
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 acetate (8.45 ml), acetate anhydride (4.23 ml) at 0 ° C, then l-ethyl-4-15 (trifluoromethyl) benzene (2.0 g, 11.6 mmol) was added dropwise the drop. 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, sodium hydroxide (35%) was added to reach pH = 7. The aqueous layer was extracted with DCM (3 x 50 ml) and the The combined organic layers were dried over sodium sulfate. Once the solvent was removed, the crude product was used without further purification in the next step. XH NMR (400 MHz, DMSO-d6) 6 ppm 1.16 (t, J = 7.51 Hz, 3H), 2.75 (q, J = 7.49 Hz, 2 H), 7.53 (d , J = 8.06 Hz, 1 H), 7.69-7.75 (m, 1H), 8.11 (dq, J = 1.95, 0.73 Hz, 1H). Step 3: [2-ethyl-5 ~ (trifluormethyl) phenyl] boronic acid
- i-Propylmagnesium chloride (2M sol. In THF, 5.81 ml, 11.6 mmol) was added dropwise to a cooled (-30 ° C) solution of 2-iodo-1-ethyl-4- ( trifluormethyl) benzene (3.48 g, 11.6 mmol) in dry THF (30 ml) and the reaction mixture was stirred at the same temperature for 30 min, under an argon atmosphere. After this time, trimethyl borate (2.6 ml, 23.2 mmol) was added dropwise and the reaction mixture was stirred at the same temperature for 1.5 h. HCl (1M, 10 ml) was added and the reaction mixture was extracted with EtOAc (3 x 40 ml). The combined organic layers were dried over sodium sulfate and the solvent was evaporated to obtain the title compound as a white crystallized solid from hexane 15 (2.46 g, 97%). XH NMR (400 MHz, DMSO-d6) 5 ppm 1.16 (t, J = 7.51 Hz, 3H), 2.82 (q, J = 7.45 Hz, 2 H), 7.37 ( d, J = 8.06 Hz, 1 H), 7.56-7.62 (m, 1H), 7.69 (dq, J = 1.80, 0.40 Hz, 1H), 8.27 ( s, 2 H). Preparation D Methyl 5-chloro-2-ethylbenzoate
Methyl 2-bromo-5-chlorobenzoate (1.0 g, 4 mmol), lithium chloride (490 mg, 11.58 mmol), tetraethylthine (0.81 mL, 4.1 mmol) and bis (triphenylphosphine) chloride - palladium (II), (100 mg, 0.13 mmol) were combined in DMF (20 mL) and heated to 100 ° C for 5 h. The solvent was removed under reduced pressure and the residue was diluted with water and EtOAc. The organic layer was separated, washed with water, dried over sodium sulfate and concentrated. Column chromatography on silica gel (0 to 10% EtOAc / hexane) gave the title compound (435 mg, 55%). NMR (400 MHz, DMSO-d6) 5 ppm 1.15 (t, J = 7.43 Hz, 3H) 2.86 (q, J = 7.45 Hz, 2 H) 3.84 (s, 3 H ) 7.40 (d, J = 8.30 Hz, 1H), 7.53-7.61 (m, 1H), 7.75 (d, J = 2.32 Hz, 1H). The procedure described above was used to synthesize the following compound: Methyl 2-ethyl-5- (trifluormethyl) benzoate
TH NMR (600 MHz, DMSO-d6) 6 1.18 (t, J = 7.6 Hz, 3H) 2.97 (q, J = 7.6 Hz, 2 H) 3.87 (s, 3 H ) 7.62 (d, J = 8.1 Hz, 1H) 7.88 (dd, J = 1.5, 8.2 Hz, 1H) 8.04 (d, J = 1.10 Hz, 1H) , Preparation E 2- [2-Chloro-5-trifluormethyl) phenyl] -1H-pyrrole-3-carbonitrile [(VIII), R1 = Cl, R2 = CF3]
Step 1: 3- [2-Chloro-5- (trifluormethyl) phenyl] -3- oxopropanenitrile
1.7 M potassium tert-pentoxide in toluene (7.35 mL, 12.5 mmol) was added dropwise to a solution of methyl 2-chloro-5- (trifluoromethyl) benzoate (2.0 g, 8, 38 mmol) and ACN (1.32 mL, 25.15 mmol) in anhydrous toluene (30 mL). The mixture was stirred at room temperature for 20 min, then diluted with 1 N HCl (20 ml), water (75 ml) and EtOAc (100 ml). The organic layer 5 was separated, washed with water (50 ml x 2) and brine (50 ml x 2), dried over sodium sulfate and concentrated. Column chromatography on silica gel (0 to 20% EtOAc / hexane) gave the title compound (1.73 g, 83%). NMR (400 MHz, DMSO-d6) 6 ppm 4.76 (s, 2 H) 7.81 -7.98 10 (m, 3 H). Step 2: 3- [2-Chloro-5- (trifluoromethyl) phenyl] -3 - [(2,2-diethoxyethyl) amino] -prop-2-enonitrile
A mixture of 3- [2-chloro-5- (trifluormethyl) phenyl] -3-oxopropanenitrile (1.2 g, 4.8 mmol), 2-aminoacetaldehyde-diethyl-acetal (0.77 ml, 5.3 mmol ) and toluene (30 mL) was stirred under reflux for 5 h under nitrogen atmosphere in the Dean-Stark apparatus. The mixture was evaporated in vacuo and used in the next step without further purification. Step 3: 2- (2-Chloro-5-trifluormethyl-phenyl) -1H-pyrrole-3-carbonitrile
For TEA (4 ml), at 5 ° C, the crude 3- [2-chloro-5- (trifluoromethyl) phenyl] -3 - [(2,2-detoxietyl) amino] -prop-2-enonitrile . After stirring at room temperature for 30 min, the reaction mixture was concentrated and then diluted with EtOAc and saturated sodium carbonate solution. The organic layer was separated, washed with water and brine, dried over sodium sulfate and concentrated. Column chromatography on silica gel - (0 to 20% EtOAc / hexane) provided the title compound (584 mg, 45% two steps ). XH NMR (400 MHz, DMS0-d6) 6 ppm 6.65 (t, J = 2.62 Hz, 1H) 7.12 (t, J = 2.81 Hz, 1H) 7.81-7.95 ( m, 3 H) 12.23 (bs, 1H). The procedure described above was used to synthesize the following compounds: 2- (5-Chloro-2-methyl-phenyl) -1H-pyrrole-3-carbonitrile [(VIII), R1 = CH3, R2 = Cl] XH NMR (4 00 MHz, DMSO-de) 6 ppm 2.26 (s, 3 H) 6.59 (t, J = 2.69 Hz, 1H) 7.04 (t, J = 2.81 Hz, 1H) 7, 38 (d, J = 2.20 Hz, 1H), 7.39-7.42 (m, 1H), 7.42-7.47 (m, 1H), 11.99 (bs, 1H). 2- (2-Bromo-5-chloro-phenyl) -1H-pyrrole-3-carbonitrile [(VIII), R1 = Br, R2 = Cl] XH NMR (400 MHz, DMSO-d6) 5 ppm 6.60 ( t, J = 2.62 Hz, 1H), 7.06 (t, J = 2.81 Hz, 1H) 7.51 (dd, J = 8.61, 2.62 Hz, 1 H) 7.59 (d, J = 2.56 Hz, 1H) 7.82 (d, J = 8.54 Hz, 1H) 12.13 (bs, 1H). 2- (2,5-Dichloro-phenyl) -1H = pyrrole-3-carbonitrile [(VIII), R1 = Cl, R2 = Cl] XH NMR (400 MHz, DMSO-dg) 5 ppm 6.62 (t, J = 2.62 Hz, 1H), 7.08 (t, J = 2.81 Hz, 1H), 7.55-7.61 (m, 1H), 7.61-7.63 (m, 1H ) 7.65-7.69 (m, 1H), 12.16 (bs, 1H). 2- (5-chloro-2-ethylphenyl) “1H-pyrrole-3-carbonitrile [(VIII), R1 = CH2CH3, R2 = Cl] XH NMR (400 MHz, DMSO-d6) 5 ppm 0.99 (t, J = 7.51 Hz, 3 H) 2.58 (q, J = 7.53 Hz, 2 H) 6.58 (t, J = 2.65 Hz, 1H) 7.02 (t, J = 2 , 81 Hz, 1H), 7.31-7.37 (m, 1H), 7.41-7.46 (m, 1H), 7.47-7.52 (m, 1H), 11.99 ( bs, 1H). 2- [2-methyl-5- (trifluormethyl) phenyl] -1H-pyrrole-3-carbonitrile [(VIII), R1 = CH3, R2 = CF3] XH NMR (400 MHz, DMSO-d6) 5 2,36- 2.39 (m, 3H), 6.62 (t, J = 2.61 Hz, 1H) 7.08 (t, J = 2.75 Hz, 1H) 7.62 (d, J = 8.24 Hz, 1H), 7.65 (s, 1H), 7.74 (d, J = 7.96 Hz, 1H) 12.08 (br., 10 1H). 2- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrol-3-carbonitrile [(VIII), R1 = CH2CH3, R2 = CF3] XH NMR (400 MHz, DMSO-d6) 5 ppm 1.04 (t, J = 7.51 Hz, 3H) 1.11-1.52 (m, 1 H) 2.07 (s, 1H) 2.69 (q, J = 7.51 Hz, 2 H) 6 , 61 (t, J = 2.75 Hz, 1H), 7.06 (t, J = 2.75 Hz, 1H), 7.61 (s, 1H), 7.66 (d, J = 8, 24 Hz, 1H) 7.79 (dd, J = 1.46, 8.06 Hz, 1H) 12.05 (bs, 1H). Example 1
5- (2-Aminopyrimidin-4-yl) -2- [2-chloro-5- (trifluormethyl) - 20 phenyl] -1H-pyrrole-3-carboxamide (I), R1 = Cl, R2 = CF3, R3 = R4 = NH2, R12 = H] (component 1) Scheme A, steps 1, 2 and 3
Step 1: 5- (2-aminopyrimidin-4-yl) -2- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrol-3-carboxylate For a solution of 5- (2-aminopyrimidin-4- il) -2-bromo-1H-pyrrole-3-carboxylate (prepared according to W02007 / I10344, 2.0 g, 6.43 mmol) dissolved in EtOH (20 ml) and toluene (20 ml), LiCl (408 mg, 9.64 mmol), 1 M aqueous Na2CO3 solution (17 mmol), 2-chloro-5-trifluoromethylphenylboronic acid (1.875 g, 8.35 mmol) and PdC (Ph3P) 2PdCl2 (470 mg; 0 , 67 mmol) were added and the reaction mixture was heated to 100 ° C for 5 h. After cooling to room temperature, the precipitate was filtered and the filtrate was evaporated under reduced pressure, dissolved in DCM and washed with water. The organic layer was then dried over sodium sulfate and concentrated. The crude material was chromatographed on silica gel (DCM / EtOAc 50/50) to obtain the title compound (2.16 g, 82%). XH NMR (400 MHz, DMSO-d6) 6 ppm 1.01 (t, J = 7.08 Hz, 3 H) 4.00 (q, J = 7.08 Hz, 2 H) 6.39 (bs, 2 H) 6.99 (d, J = 5.25 Hz, 1H) 7.29 (d, J = 2.32 Hz, 3H), 7.82 (s, 4H), 8.20 (d, J 5.13 Hz, 3H), 12.36 (bs, 1H) HRMS (ESI) calculated for C18H14CIF3N4O2 + H + 411.0830, found 411.0827. The procedure described above was used to synthesize the following compounds: Ethyl 5- (2-aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1H-pyrrole-3-carboxylate XH NMR (400 MHz, DMSO-d5) 5 ppm 1.09 (t, J = 7.14 Hz, 3 H) 2.11 (s, 3 H) 4.04 (q, J = 7.12 Hz, 2 H) 6.41 (s, 2 H) 7.01 (D, J = 5.25 Hz, 1H), 7.25-7.36 (m, 3 H) 7.37-7.43 (m, 1H), 8, 21 (d, J = 5.13 Hz, 1H) 12.17 (bs, 1H). Ethyl 5- (2-aminopyrimidin-4-yl) -2- (2,5-dichlorophenyl) -1H-pyrrole-3-carboxylate NMR (400 MHz, DMSO-df) 5 ppm 1.07 (t, J = 7 , 08 Hz, 3 H) 4.05 (q, J = 7.16 Hz, 2 H) 6.42 (bs, 2 H) 7.01 (d, J = 5.25 Hz, 1H), 7, 29 (s, 1H), 7.52-7.60 (m, 3 H) 8.22 (d, J = 5.25 Hz, 1H) 12.32 (bs, 1H). Ethyl 5- (2-aminopyrimidin-4-yl) -2- (5-chloro-2-methoxyphenyl) -1H-pyrrole-3-carboxylate: H NMR (400 MHz, DMSO-dg) 5 ppm 1.11 (t , J = 7.08 Hz, 3 H) 3.73 (s, 3 H) 4.05 (q, J = 7.16 Hz, 2 H) 6.43 (bs, 2 H) 7.01 (d , J = 5.25 Hz, 1H) 7.11 (d, J = 8.91 Hz, 1H) 7.26 (d, J = 2.69 Hz, 1H) 7.38 (d, J = 2, 69 Hz, 1H) 7.45 (dd, J = 8.85, 2.75 Hz, 1H) 8.20 (d, J = 5.25 Hz, 1H) 12.01 (bs, 1H). Ethyl 5- (2-aitiinopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -1H-pyrrole-3-carboxylate XH NMR (400 MHz, DMSO-d6) 5 ppm 0.97 (t, J = 7.57 Hz, 3 H) 1.06 (t, J = 7.08 Hz, 3 H) 2.44 (q, J = 7.57 Hz, 2 H) 4.03 - (q, J = 7.08 Hz, 2 H) 7.21 (d, J = 6.10 Hz, 1H) 7.32 (d, J = 2.32 Hz, 1H) 7.38 (d, J = 8.42 Hz, 1H) 7.47 (dd, J = 8.30, 5 2.32 Hz, 1H) 7.50 (d, J = 2.56 Hz, 1H) 8.25 (d, J = 5.98 Hz, 1H) 12.52 (bs, 1H). Ethyl 5- (2-aminopyrimidin-4-yl) -2- (2-chloro-5-methylphenyl) -1H-pyrrole-3-carboxylate TH NMR (400 MHz, DMSO-de) 6 ppm 1.06 (t, J = 7.14 Hz, 3H), 2.34 (s, 3 H) 4.03 (q, J = 7.16 Hz, 2 H) 6.41 (s, 1 H) 7.01 (d, J = 5.25 Hz, 1H), 7.27-7.30 (m, 3 H) 7.42 (d, J = 8.06 Hz, 1H) 8.21 (d, J = 5.25 Hz , 1H) 12.20 (bs, 1H). Ethyl 5- (2-aminopyrimidin-4-yl) -2- (5-bromo-2-methoxyphenyl) -1H-pyrrole-3-carboxylate rH NMR (400 MHz, DMSO-d6) 5 ppm 1.11 (t, J = 7.08 Hz, 3 H) 3.72 (s, 3 H) 4.05 (q, J = 7.16 Hz, 2 H) 6.41 (s, 2 H) 7.01 (d, J = 5.25 Hz, 1H) 7.06 (d, J = 8.91 Hz, 1H) 7.25 (d, J = 2.69 Hz, 1H) 7.49 (d, J = 2.56 Hz, 1H) 7.57 (dd, J = 8.85, 2.62 Hz, 1H) 8.20 (d, J = 5.25 Hz, 1H) 12.01 (bs, 1H). Ethyl 5- (2-aminopyrimidin-4-yl) -2- (5-bromo-2-fluorophenyl) -1H-pyrrole-3-carboxylate XH NMR (400 MHz, DMSO-d6) 5 ppm 1.13 (t, J = 7.08 Hz, 3 H) 4.09 (q, J = 7.16 Hz, 2 H) 6.44 (bs, 2 H) 7.03 (d, J = 5.13 Hz, 1H) 7.29 (dd, J = 9.28, 8.91 Hz, 1H) 7.31 (d, J = 2.32 Hz, 25 1H), 7.63-7.69 (m, 2 H) 7 , 72 (dd, J = 6.47, 2.56 Hz, 1H) 8.23 (d, J = 5.25 Hz, 1H) 12.33 (bs, 1H). Ethyl 5- (2-aminopyrimidin-4-.il) -2- ([2-chloro-5- (hydroxymethyl) phenyl] -1H-pyrrole-3-carboxylate XH NMR (400 MHz, DMSO-dg) 5 ppm 1 .07 (t, J = 7.08 Hz, 3 H) 4.04 (q, J = 7.08 Hz, 2 H) 4.55 (s, 2 H) 7.22 (d, J = 5, 98 5 Hz, 1H)), 7.38-7.55 (m, 4 H) 8.26 (d, J = 5.98 Hz, 1H) 12.55 (bs, 1H). Ethyl 5- (2-aminopyrimidin-4-yl) -2- (2-chloro-5-methoxyphenyl) -1H-pyrrole-3-carboxylate XH NMR (400 MHz, DMSO-d6) 5 ppm 1.07 (t, J = 7.14 Hz, 3 10 H) 3.79 (s, 3 H) 4.04 (q, J = 7.08 Hz, 2 H) 6.41 (s, 2 H) 7.02 (d , J = 5.25 Hz, 1H), 7.03-7.06 (m, 2 H) 7.28 (d, J = 2.56 Hz, 1H), 7.41-7.46 (m, 1H), 8.21 (d, J = 5.25 Hz, 1H) 12.22 (bs, 1H). Ethyl 5- (2-aminopyrimidin-4-yl) -2- [2-chloro-5- (trifluoromethoxy) phenyl] -1H-pyrrole-3-carboxylate XH NMR (400 MHz, DMSO-d6) 5 ppm 1 , 04 (t, J = 7.08 Hz, 3 H) 4.03 (q, J = 7.08 Hz, 2 H) 6.42 (bs, 2 H) 7.01 (d, J = 5, 13 Hz, 1H) 7.30 (d, J = 2.32 Hz, 1H), 7.46-7.54 (m, 2 H) 7.68-7.72 (m, 1H), 8.22 (d, J = 5.25 Hz, 1H) 12.37 (bs, 1H). Ethyl 5- (2-aminopyrimidin-4-yl) -2- [2-methyl-5- (trifluor methyl) phenyl] -1H-pyrrole-3-carboxylate XH NMR (400 MHz, DMSO-d ^) 5 ppm 1.04 (t, J = 7.14 Hz, 3 H) 2.21 (s, 3 H) 4.02 (q, J = 7.04 Hz, 2 H) 6.41 (s, 2 H) 7.01 (d, J = 5.25 Hz, 1H) 7.32 (d, J = 2.44 Hz, 1H) 7.54 (d, J = 25 8.06 Hz, 1H) 7.59 ( d, J = 1.46 Hz, 1H) 7.70 (dd, J = 8.06, 1.46 Hz, 1H) 8.21 (d, J = 5.25 Hz, 1H) 12.24 (bs , 1H). Ethyl 5- (2-aminopyrimidin-4-yl) -2- [5-chloro-2- (propane-2-yl) phenyl] -1H-pyrrole-3-carboxylate. NMR (400 MHz, DMSO-df) 5 ppm 1.02 (t, J = 7.08 Hz, 3 H) 1.07 (d, J = 6.96 Hz, 6 H) 2.71 (spt, J = 6.84 Hz, 1H) 4.00 5 (q, J = 7.08 Hz, 2 H), 6.40 (bs, 2 H) 7.00 (d, J = 5.13 Hz, 1H) 7.25 (d, J = 2.32 Hz, 1H) 7.28 (d, J = 2.56 Hz, 1 H) 7.42 (d, J = 8.30 Hz, 1H) 7.48 ( dd, J = 8.30, 2.32 Hz, 1H) 8.20 (d, J = 5.25 Hz, 1H) 12.23 (bs, 1H). Ethyl 5- (2-aminopyrimidin-4-yl) -2- [2-ethyl-5- (trifluoromethyl) phenyl] -1H-pyrrole-3-carboxylate XH NMR (400 MHz, DMSO-d6) 6 ppm 1 , 01 (t, J = 7.15 Hz, 6 H) 2.54 (q, J = 7.60 Hz, 2 H) 4.00 (q, J = 7.08 Hz, 2 H) 6.41 (bs, 2 H) 7.01 (d, J = 5.25 Hz, 1H) 7.31 (d, J = 2.56 Hz, 1H) 7.56 (d, J = 1.60 Hz, 1H ) 7.58 (d, J = 8.20 Hz, 1 H) 7.74 (dd, 15 J = 8.12, 1.53 Hz, 1H) 8.21 (d, J = 5.13 Hz, 1H) 12.27 (bs, 1H). Ethyl 5- (2-aminopyrimidin-4-yl) -2- [5-chloro-2- (trifluoromethyl) phenyl] -1 H-pyrrole-3-carboxylate XH NMR (400 MHz, DMSO-d6) 5 ppm 0.97 (t, J = 7.08 Hz, 3 - 20 H) 3.97 (q, J = 7.08 Hz, 2 H) 6.41 (bs, 2 H) 6.99 (d, J = 5.25 Hz, 1H) 7.27 (d, J = 2.44 Hz, 1H) 7.66 (d, J = 2.07 Hz, 1H), 7.74-7.79 (m, 1H ), 7.86 (d, J = 8.54 Hz, 1 H) 8.21 (d, J = 5.13 Hz, 1H) 12.37 (bs, 1H). Ethyl 5- (2-aminopyrimidin-4-yl) -2- (5-cyano-2-methylphenyl) -1H-pyrrole-3-carboxylate TH NMR (400 MHz, DMSO-d &) 5 ppm 1.07 (t, J = 7.14 Hz, 3 H) 2.21 (s, 3 H) 4.04 (q, J = 7.08 Hz, 2 H) 6.41 (bs, 2 H) 7.01 (d, J = 5.25 Hz, 1H) 7.32 (d, J = 2.32 Hz, 1H) 7.52 (d, J - = 8.06 Hz, 1H) 7.76 (d, J = 1, 83 Hz, 1H) 7.80 (dd, J = 7.87, 1.77 Hz, 1H) 8.22 (d, J = 5.25 Hz, 1H) 12.24 (bs, 1H). Step 2: 5- (2-Aminopyrimidin-4-yl) -2- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrol-3-carboxylic acid Eth 5- (2-aminopyrimidin-4-yl) -2- [2-chloro-5- (trifluoromethyl) phenyl] -1H-pyrrole-3-carboxylate (1.0 g, 2.43 mmol) was treated with a 1.5 M potassium hydroxide solution in 10 95% EtOH (32.4 mL, 20 eq) under reflux for 20 h. After cooling, the residue was concentrated, dissolved in water and washed with DCM. For the aqueous phase cooled to 5 ° C, a 2 N HCl solution was added, with stirring. The resulting precipitate was collected by filtration to give the title compound 15 (0.88 g, 95%). XH NMR (400 MHz, DMSO-d6) 5 ppm 7.29 (d, J = 6.35 Hz, 1H) 7.62 (bs, 2 H) 7.58 (d, J = 2.20 Hz, 1H ), 7.79-7.92 (m, 3 H), 8.29 (d, J = 6.23 Hz, 1H) 12.67 (bs, 1H) 12.76 (bs, 1H). HRMS (ESI) calculated for CI6HIOCLF3N402 + H + 383.0517, - 20 found 383.0513. The procedure described above was used to synthesize the following compounds: 5- (2-Aminopyrimidin-4-yl) -2 (5-chloro-2-methylphenyl) -1H-pyrrole-3-carboxylic acid LH NMR (400 MHz, DMSO -ds) 5 ppm 2.12 (s, 3H), 7.28-7.37 (m, 3 H) 7.40-7.45 (m, 1H), 7.59 (d, J (bs, 1H), 8.28 (d, J = 6.44 Hz, 1H) 12.06 (s, 1H) 12.54 (bs, 1H) .- 5- (2-Aminopyrimidin-4-yl) -2 acid - (5-chloro-2-ethylphenyl) - 1H-pyrrole-3-carboxylic NMR (400 MHz, DMSO-d ^) 5 ppm 0.98 (t, J = 7.57 Hz, 3 H) 2.46 ( q, J = 7.57 Hz, 2 H) 6.79 (bs, 2 H) 7.08 (d, J = 5.49 Hz, 1H) 7.29 (d, J = 2.32 Hz, 1H ) 7.35 (d, J = 8.30 Hz, 1H) 7.36 (d, J = 2.81 Hz, 1H) 7.43 (dd, J = 8.30, 2.32 Hz, 1H) 8.22 (d, J = 5.62 Hz, 1H) 11.86 (bs, 1H), 12.23 (bs, 1H). 5- (2-Aminopyrimidin-4-yl) -2- (2 -chloro-5-methylphenyl) -1H-pyrrole-3-carboxylic M NMR (400 MHz, DMSO-dff) 5 ppm 2.33 (s, 3 H) 6.88 (bs, 1H) 7.11 (d, J = 5.61 Hz, 1H) 7.24-7.30 (m, 2 H) 7.29 (dq, J = 2.20, 0.60 Hz, 1H) 7.37 (d, J = 2 , 20 Hz, 1H) 7.41 (d, J = 8.06 15 Hz, 1H) 8.22 (d, J = 5.62 Hz, 1H) 11.84 (bs, 1H), 12.26 (bs, 1H). 5- (2-Aminopyrimidin-4-yl) -2 (5-bromo-2-methoxyphenyl) -1H-pyrrole-3-carboxylic acid XH NMR (400 MHz, DMSO-dff) 5 ppm 3.73 (s, 3 H) 7.09 (d, J - 20 = 8.91 Hz, 1H) 7.31 (d, J = 6.59 Hz, 1H) 7.51 (d, J = 2.56 Hz, 1H) 7 , 56 (d, J = 2.32 Hz, 1H) 7.59 (dd, J = 8.85, 2.62 Hz, 1H) 7.81 (bs, 2 H) 8.27 (d, J = 6.47 Hz, 1H) 12.41 (bs, 1H). 5- (2-Aminopyrimidin-4-yl) -2- (5-broino-2-fluorophenyl) -1H-pyrrole-3-carboxylic acid: H NMR (400 MHz, DMSO = dg) 5 ppm 7.27 (d , J = 6.10 Hz, 1H), 7.30 (t, J = 9.10 Hz, 1H) 7.53 (bs, 1H), 7.68 (ddd, J 8.88, 4.49, 2.62 Hz, 1H) 7.73 (dd, J = 6.35, 2.56 Hz, 1H) 8.29 (d, J = 6.10 Hz, 1H) 12.59 (bs, 1H). 5- (2-Aminopyrimidin-4-yl) -2- [2-chloro-5- (trifluoromethoxy) phenyl] -1 H-pyrrole-3-carboxylic acid XH NMR (400 MHz, DMSO-d6) 5 ppm 7.27 (d, J = 6.47 Hz, 1H) 7.47-7.57 (m, 3 H) 7.71 (d, J = 9.03 Hz, 1H) 8.29 (d, J = 6.23 Hz, 1H) 12.06 (s, 1H) 12.65 (bs, 1H). 5- (2-Aminopyrimidin-4-yl) -2- [2-methyl-5- (trifluoromethyl) phenyl] -1H-pyrrole-3-carboxylic acid XH NMR (400 MHz, DMS0-d6) 5 ppm 2 , 23 (s, 3 H) 7.28 (d, J = 6.10 Hz, 1H) 7.55 (d, J = 8.30 Hz, 1H) 7.58 (d, J = 1.80 Hz , 1H) 7.61 (d, J = 1.34 Hz, 1H) 7.71 (dd, J = 8.18, 1.60 Hz, 1H) 8.27 (d, J = 6.22 Hz, 1H) 12.54 (bs, 1 H). 5- (2-Aminopyrimidin-4-yl) -2- [2-ethyl-5- (trifluor-15 methyl) phenyl] -1H-pyrrole-3-carboxylic acid XH NMR (400 MHz, DMSO-d6) 5 ppm 1.02 (t, J = 7.57 Hz, 3 H) 2.56 (q, J = 7.65 Hz, 2 H) 7.18 (d, J = 5.86 Hz, 1H) 7.20 (bs, 2 H) 7.48 (d, J = 2.44 Hz, 1H) 7.57 (bs, 1H), 7.58 (d, J = 8.00 Hz, 1H) 7.74 (dd , J = 7.99, 1.65 Hz, 1 H) 8.25 (d, J = - 20 5.98 Hz, 1H) 11.95 (bs, 1H), 12.43 (bs, 1H). Step 3: 5- (2-Aminopyrimidin-4-yl) -2- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrole-3-carboxamide [(I), R1 = Cl, R2 = CF3, R3 = R4 = NH2, R12 = H] (component 1) A solution of 5- (2-amino-pyrimidin-4-yl) -2- (2-25 chloro-5 trifluoromethyl-phenyl) -1H-pyrrole acid -3-carboxylic acid (581 mg, 1.52 mmol) in DMF (5 mL) and DIPEA (1.06 mL, 6.08 mmol) was stirred at 0 ° C. EDCI (582 mg, 3.04 mmol) and HOBT. NH3 (469 mg, 3.04 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. The mixture was diluted with water and the resulting precipitate was collected by filtration 5 to give the title compound (475 mg, 82%). XH NMR (400 MHz, DMSO-de) 5 ppm 6.36 (bs, 2 H), 6.77 (bs, 1H), 6.90 (d, J = 5.25 Hz, 1H) 7.37 ( d, J = 2.56 Hz, 1 H) 7.42 (bs, 1H), 7.69-7.84 (m, 3 H) 8.22 (d, J = 5.25 Hz, 1H) 12 , 07 (bs, 1H). HRMS (ESI) calculated for CieHuClF3N50 + H + 382.0677, found 382.0675. The procedure described above was used to synthesize the following compounds: 5- (2-Aminopyrimidin-4-yl) -2- (2,5-dichlorophenyl) -IH-pyrrole-15 3-carboxamide [(I), R1 = Cl , R2 = Cl, R3 = R4 = NH2, R12 = H] (comp. 2) XH NMR (400 MHz, DMSO-d6) 5 ppm 6.87 (bs, 1H), 7.09 (d, J = 6 , 10 Hz, 1H) 7.46 (bs, 1H), 7.48-7.56 (m, 3 H) 8.26 (d, J = 6.10 Hz, 1H) 12.35 (bs, 1H ). HRMS (ESI) calculated for C15H11CI2N5O + H + 348.0414, found 348.0419. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methoxyphenyl) -1H-pyrrole-3-carboxamide [(I), R1 = OCH3, R2 = Cl, R3 = R4 = NH2, R12 = H] (comp. 3) XH NMR (400 MHz, DMSO-d6) 5 ppm 3.75 (s, 3H), 6.35 (bs, 2 H), 6.74 (bs, 1H), 6 , 92 (d, J = 5.25 Hz, 1H), 7.08-7.12 (m, 1 H), 7.20 (bs, 1H), 7.25 (d, J = 2.56 Hz , 1H), 7.36-7.41 (m, 2 H) 8.19 (d, J = 5.25 Hz, 1H> 11.63 (bs, 1 H). HRMS (ESI) calculated for C16H14CIN5O2 + H + 344.0909, found 344.0912. 5- (2-Aminopyrimidin-4-yl) -2- (2- chloro-5-ethylphenyl.il) -1H-pyrrole-3-carboxamide [(I), Rl = Cl, R2 = CH2CH3, R3 = R4 = NH2, R12 = H] (compd. 4) NMR (400 MHz, DMS0-dg) 6 ppm 1.20 (t, J = 7.57 Hz, 3 H) 2 , 63 (q, J = 7.57 Hz, 2 H), 6.33 (bs, 2 H), 6.69 (bs, 1 H) 10 6, 93 (d, J = 5.25 Hz, 1H ) 7.14 (bs, 1H), 7.27 (d, J = 2.20 Hz, 1H) 7.26 (dd, J = 7.90, 2.20 Hz, 1H) 7.32 (d, J = 2.56 Hz, 2 H) 7.40 (dd, J = 7.81, 0.49 Hz, 1H) 8.19 (d, J = 5.25 Hz, 1H) 11.87 (bs, HRMS (ESI) calculated for Ci7Hi6ClN5O + H + 342, 1116, 15 found 342.1120. 5- (2- Aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -1H-pyrrole-3-carboxamide [(I), Rl = CH2CH3, R2 = Cl, R3 = R4 = NH2, R12 = H] ( compd. 5) XH NMR (400 MHz, DMSO-df) 5 ppm 0.97 (t, J = 7.57 Hz, - 20 3H), 2.41-2.49 (m, 2 H), 6.32 ( bs, 2 H), 6.71 (bs, 1H), 6.92 (D, J = 5.25 Hz, 1H) 7.16 (bs, 1H), 7.25 (d, J = 2.20 Hz, 1H), 7.30-7.33 (m, 1H), 7.34 (d, J = 2.69 Hz, 1 H) 7.37-7.46 (M, 1H), 8.19 (d, J = 5.25 Hz, 1H) 11.87 (bs, 1H). HRMS (ESI) calculated for C17H16CIN5O + H + 342.1111, 25 found 342.1111. 5- (2-Aminopyrimidin-4-yl) -2- (2-chloro-5-methylphenyl) -1H-pyrrole-3-carboxamide [(I), R1 = Cl, R2 = CH3, R3 = R4 = NH2, R12 = H] (compd. 6). NMR (400 MHz, DMS0-d5) 5 ppm 2.32 (s, 3H), 6.33 (bs, 2 H), 6.68 (bs, 1H), 6.93 (d, J = 5.25 Hz, 1H) 7.14 (bs, 1H) 5 7.20-7.24 (m, 1 H) 7.25 (dq, J = 2.20, 0.60 Hz, 1H) 7.31 (d , J = 2.56 Hz, 1H) 7.38 (d, J = 8.18 Hz, 1H) 8.19 (d, J = 5.25 Hz, 1H) 11.85 (bs, 1H). HRMS (ESI) calculated for CI6HI4C1N5O + H + 328.0960, found 328.0965. 5- (2-Aminopyrimidin-4-yl) -2- (2-chloro-5-cyanophenyl) -1H-pyrrole-3-carboxamide [(I), R1 = Cl, R2 = CN, R3 = R4 = NH2, R12 = H] (comp. 7) NMR (400 MHz, DMSO-dg) 6 ppm 6.42 (bs, 2 H), 6.79 (bs, 1H), 6.90 (d, J = 5.25 Hz, 1H) 7.38 (d, J = 2.56 Hz, 1 H) 7.44 (bs, 1H), 7.73 (d, J = 8.42 Hz, 1H) 7.88 (dd, J = 8.42, 2.07 Hz, 1H) 7.94 (d, J = 2.07 Hz, 1H) 8.23 (d, J = 5.37 Hz, 1H) 12.07 (bs, 1H ). HRMS (ESI) calculated for CigHuClNgO + H + 339.0756, found 339.0761. . 5- (2-Aminopyrimidin-4- ± l) -2- (5-bromo-2-methoxyphenyl) -1H-pyrrole-3-carboxamide [(I), R1 = OCH3, R2 = Br, R3 = R4 = NH2 , R12 = H] (compd. 8) rH NMR (400 MHz, DMSO-d6) 6 ppm 3.74 (s, 3H), 6.36 (bs, 2 H), 6.86 (bs, 1H), 7.07 (d, J = 8.91 Hz, 1H) 7.14 (d, J = 6.23 25 Hz, 1H) 7.29 (bs, 1H), 7.47 (d, J = 2, 44 Hz, 1H) 7.51 (d, J = 2.56 Hz, 1H) 7.55 (dd, J = 8.79, 2.56 Hz, 1 H) 8.23 (d, J 6.23 Hz, 1H) 12.05 (bs, 1H). HRMS (ESI) calculated for Ci6H14BrN5O2 + H + 388.0404,. found 388.0410. 5- (2-Aminopyrimidin-4-yl) -2- (5-bromo-2-fluorophenyl) -1H- 5 pyrrole-3-carboxamide [(I), R1 = F, R2 = Br, R3 = R4 = NH2 , R12 = H] (comp. 9) NMR (400 MHz, DMSO-d6) 6 ppm 6.46 (bs, 2 H), 6.91 (bs, 1H), 7.11 (d, J = 6, 10 Hz, 1H) 7.25 (dd, J = 9.46, 8.97 Hz, 1H) 7.33 (bs, 1H), 7.51 (d, J = 2.32 Hz, 2 H) 7 , 63 (ddd, J 10 = 8.76, 4.49, 2.62 Hz, 1H) 7.69 (dd, J = 6.47, 2.56 Hz, 1 H) 8.27 (d, J = 5.98 Hz, 1H) 12.31 (bs, 1H). HRMS (ESI) calculated for C15HuBrFN5O + H + 376, 0204, found 376.0209. 5- (2-Aminopyrimidin-4-yl) -2- [2-chloro-5- (hydroxymethyl) phenyl] -1H-pyrrole-3-carboxamide [(I), R1 = Cl, R2 = CH2OH, R3 = R4 = NH2, R12 = H] (comp. 10); H NMR (400 MHz, DMSO-dff) 5 ppm 4.53 (d, J = 5.74 Hz, 2 H) 5.33 (t, J = 5 , 68 Hz, 1H) 6.33 (bs, 2 H), 6.68 (bs, 1 H) 6.93 (d, J = 5.25 Hz, 1H) 7.15 (bs, 1H), 7 , 32 (d, J = 2.56 Hz, .20 1H), 7.33-7.37 (m, 2 H) 7.45 (d, J = 8.80 Hz, 1 H) 8.19 ( d, J = 5.25 Hz, 1H) 11.88 (bs, 1H). ^ RMS (ESI) calculated for Ci6Hi4ClN5O2 + H + 344.0909, found 344.0902. 5- (2-Aminopyrimidin-4-yl) -2- (2-chloro-5-methoxyphenyl) -1H-25 pyrrole-3-carboxamide [(I), R1 = Cl, R2 = OCH3, R3 = R4 = NH2 , R12 = H] (compd. 11) XH NMR (400 MHz, DMSO-d &) 6 ppm 3.78 (s, 3H), 6.33 (s, 2H), 6.70 (bs, 1H), 6 , 93 (d, J = 5.25 Hz, 1H), 6.97-7.02 (m, 2. H), 7.15 (bs, 1H), 7.31 (d, J = 2.56 Hz, 1H), 7.36-7.42 (m, 1H), 8.19 (d, J = 5.25 Hz, 1H) 11.88 (bs, 1 H). HRMS (ESI) calculated for Ci6Hi4ClN5O2 + H + 344.0909, found 344.0907. 5- (2-Aminopyrimidin-4-yl) -2- [2-chloro-5- (trifluormethoxy) phenyl] -1H-pyrrole-3-carboxamide [(I), R1 = Cl, R2 = OCF3, R3 = R4 = NH2, R12 = H] (comp. 12) TH NMR (400 MHz, DMSO-d6) 5 ppm 6.35 (bs, 2 H), 6.76 (bs, 1H), 6.90 (d, J = 5.13 Hz, 1H) 7.35 (d, J = 2.56 Hz, 1 H) 7.39 (bs, 1H), 7.41-7.46 (m, 1H), 7.42 ( dq, J = 1.74, 0.90 Hz, 1H) 7.64 (ddd, J = 8.79, 1.46, 1.10 Hz, 1H) 8.21 (d, J = 5.25 Hz , 1H) 12.04 (bs, 1H). HRMS (ESI) calculated for CieHuClF3N5O2 + H + 398.0626, found 398.0624. 5- (2-Aminopyrimidin-4-yl) -2- [2-methyl-5- (trifluormethyl) phenyl] -1H-pyrrole-3-carboxamide [(I), R1 = CH3, R2 = CF3, R3 = R4 = NH2, R12 = H] (13 compd.) XH NMR (400 MHz, DMSO-ds) 5 ppm 2.23 (s, 3H), 6.32 (bs, 2 H), 6.74 (bs, 1H ), 6.92 (d, J = 5.25 Hz, 1H) 7.32 (bs, 1 H) 7.37 (d, J = 2.44 Hz, 1H) 7.49 (d, J = 8 , 06 Hz, 1H) 7.53 (d, J = 1.46 Hz, 1H) 7.64 (dd, J = 8.06, 1.46 Hz, 1 H) 8.20 (d, J = 5.25 Hz, 1H) 11.91 (bs, 1H). HRMS (ESI) calculated for C17H14F3N5O + H + 362, 1223, found 362.1225. 5- (2-Aminopyrimidin-4-yl) -2- [5-chloro-2- (propane-2-yl) phenyl] -1H-pyrrole-3-carboxamide [(I), R1 = CH (CH3) 2 , R2 = Cl,. R3 = R4 = NH2, R12 = H] (comp. 14) XH NMR (400 MHz, DMSO-dg) 5 ppm 1.06 (d, J = 6.84 Hz, 6 H) 2.79 (spt, J = 6.90 Hz, 1H) 6.32 (bs, 2 H), 6.71 (bs, 1 H) 6.91 (d, J = 5.25 Hz, 1H) 7.11 (bs, 1H) , 7.21 (d, J = 2.32 Hz, 1H) 7.34 (d, J = 2.69 Hz, 1H) 7.38 (d, J = 8.30 Hz, 1H) 7.44 ( dd, J = 8.30, 2.32 Hz, 1H) 8.18 (d, J = 5.25 Hz, 1H) 11.89 (bs, 1H). HRMS (ESI) calculated for C13H18C1N5O + H + 356, 1273, found 356.1271. 5- (2-Aminopyrimidin-4-yl) -2- [2,5-bis (trifluormethyl) phenyl] -1H-pyrrole-3-carboxamide [(I), R1 = CF3, R2 = CF3, R3 = R4 = NH2, R12 = H] (comp. 15) XH NMR (400 MHz, DMSO-d6) 6 ppm 6.34 (bs, 2 H), 6.69 (bs, 1H), 6.85 (d, J = 5.25 Hz, 1H) 7.37 (d, J = 2.44 Hz, 1 H) 7.40 (bs, 1H), 7.79 (bs, 1H), 8.0-8.06 (m , 2 H) 8.21 (d, J = 5.25 Hz, 1H) 12.08 (bs, 1H). HRMS (ESI) calculated for Ci7HnF6ClN5O + H + 416, 0941,. 20 found 416.0945. 5- (2-Aminopyrimidin-4-yl) -2- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrol-3-carboxamide [(I), R1 = CH2CH3, R2 = CF3, R3 = R4 = NH2, R12 = H] (comp. 16) XH NMR (400 MHz, DMSO-d6) 5 ppm 1.02 (t, J = 7.55 Hz, 3 H) 2.57 (q, J = 7, 60 Hz, 4 H), 6.37 (bs, 2 H), 6.76 (bs, 1 H) 6.92 (d, J = 5.49 Hz, 1H) 7.33 (bs, 1H), 7.38 (d, J = 2.47 Hz, 1H), 7.47-7.57 (m, 2 H) 7.70 (d, J = 7.14 Hz, 1 H) 8.21 (d , J = 5.22 Hz, 1H) 11.97 (bs, 1H). HRMS (ESI) calculated for C18H16F3N5O + H + 376, 138, found 376.1384. 5- (2-Aminopyrimidin-4-yl) -2- [5-chloro-2-trifluormethyl) phenyl] -1H-pyrrole-3-carboxamide [(I), R1 = CF3, R2 = Cl, R3 = R4 = NH2, R12 = H] (compd. 17) 1H NMR (400 MHz, DMSO-cU) 5 ppm 6.36 (bs, 2 H), 6.68 (bs, 1H), 6.86 (d, J = 5.25 Hz, 1H) 7.34 (bs, 1H), 7.35 (d, J = 10 2.56 Hz, 1H) 7.54 (d, J = 1.95 Hz, 1H) 7.70 (dd, J = 8.48, 1.40 Hz, 1H) 7.80 (d, J = 8.54 Hz, 1H) 7.95 (s, 1 H) 8.21 (d, J = 5, 37 Hz, 1H) 12.03 (bs, 1H). HRMS (ESI) calculated for Ci6HnClF3N5O + H + 382.0677, found 382.0679. 5- (2-Aminopyrimidin-4-yl) -2- (5-cyano-2-methylphenyl) -1H-pyrrole-3-carboxamide [(I), R1 = CH3, R2 = CN, R3 = R4 = NH2, R12 = H] (comp. 18) XH NMR (400 MHz, DMSO-d6) 5 ppm 2.22 (s, 3H), 6.33 (bs, 2 H), 6.76 (bs, 1H), 6 , 91 (d, J = 5.25 Hz, 2 H), 7.35 (bs, 1 H). 20 7.37 (d, J = 2.56 Hz, 1H) 7.47 (d, J = 7.93 Hz, 2 H) 7.69 (d, J = 1.83 Hz, 2 H) 7, 74 (dd, J = 7.93, 1.83 Hz, 2 H) 8.21 (d, J = 5.25 Hz, 2 H), 11.90 (bs, 1H). HRMS (ESI) calculated for CI7HI4N60 + H + 319, 1302, found 319.1314. Example 2
5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N-methyl-1H-pyrrol-3-carboxamide [(I), Rl = CH3, R2 - Cl, R3 - NHCH3, R4 = NH2, R12 = H] (compd. 19) Scheme A, step 3
For a solution of 5- (2-aminopyrimidin-yl) -2- (5-chloro-2-methylphenyl) -1H-pyrrol-3-carboxylic acid (142 mg, 0.43 mmol) in DMF / THF 1/1 (4 ml) of DIPEA (0.301 ml, 1.72 mmol) and MeNH22 M in THF (0.432 ml, 0.86 mmol) were added and the solution was stirred at 0 ° C. EDCI (157 mg, 0.86 mmol) and HOBT (117 mg, 0.86 mmol) were added and the reaction mixture was stirred for 4 h at room temperature. The mixture was diluted with water and extracted with DCM (4 x 10 ml). The organic phase was washed with brine, water and then dried over sodium sulfate and concentrated. The crude material was chromatographed on silica gel (DCM / MeOH 90/10) to give the title compound (124 mg, 84%). XH NMR (400 MHz, DMSO-de) 5 ppm 2.10 (s, 3 H) 2.62 (d, J = 4.52 Hz, 3H), 6.32 (bs, 1H), 6.93 ( d, J = 5.25 Hz, 1 H) 7.27 (d, J = 8.00 Hz, 1H) 7.29 (d, J = 2.32 Hz, 1H) 7.31 (d, J = 2.56 Hz, 1H) 7.35 (dd, J = 8.30, 2.32 Hz, 1H) 7.80 (q, J = 4.76 Hz, 1H) 8.19 (d, J = 5 , 37 Hz, 1H) 11.84 (bs, 1H). HRMS (ESI) calculated for CI7H16C1N5O + H + 342.1111, found 342.1111. The procedure described above was used to synthesize the following compounds: 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N-ethyl-1H-pyrrole-3-carboxamide [(I ), R1 = CH3, R2 = Cl, R3 = NHCH2CH3, R4 = NH2, R12 = H] (comp. 20) XH NMR (400 MHz, DMSO-d6) 5 ppm 1.02 (t, J = 7.20 Hz, 3H), 2.11 (s, 3H), 3.12 (dq, J = 7.10, 5.92 Hz, 2 H), 6.32 (bs, 2 H) 6.94 (d, J = 5.25 Hz, 1H) 7.28 (d, J = 2.32 Hz, 1H) 7.28 (d, J = 8.30 Hz, 1H) 7.33 (d, J = 2.56 Hz, 1 H) 7.35 (dd, J = 8.30, 2.32 Hz, 1H), 7.80 (t, J = 5.68 Hz, 1H) 8.19 (d, J = 5, 25 Hz, 1H) 11.83 (bs, 1H). HRMS (ESI) calculated for C18H18C1N5O + H + 356.1273, found 356.1277. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N- (2-hydroxyethyl) -1H-pyrrole-3-carboxamide [(I), R1 = CH3, R2 = Cl, R3 = NHCH2CH2OH, R4 = NH2, R12 = H] (compd. 21) XH NMR (400 MHz, DMSO-d6) 6 ppm 2.10 (s, 3 H) 3.17 (q, J = 6, 06 Hz, 2 H) 3.38-3.44 (m, 2 H) 4.61 (t, J = 5.37 Hz, 1H) 6.34 (bs, 2 H) 6.94 (d, J = 5.25 Hz, 1H) 7.23-7.30 (m, 2 H) 7.32-7.38 (m, 2 H) 7.71 (t, J = 5.80 Hz, 1 H) 8.20 (d, J = 5.37 Hz, 1H) 11.86 (bs, 1H). HRMS (ESI) calculated for Ci8H18ClN5O2 + H + 372.1222, found 372.1230. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N- [2- (piperidin-1-yl) ethyl] -1H-pyrrol-3-carboxamide [[(I ), R1 R2 = Cl, R3 = NH- [2- (piperidine-1-yl) -ethyl R4 = NH2, R12 = H] (compd. 22). XH NMR (400 MHz, DMSO-d6) 5 ppm 1.28-1, 39 (m, 2 H) 1.39 1.48 (m, 4 H) 2.11 (s, 3H), 2.20- 2.35 (m, 6 H) 3.19 (dq, J = 5 6.80, 5.50 Hz, 2 H), 6.33 (bs, 2 H) 6.94 (d, J = 5, 25 Hz, 1H) 7.30 (d, J = 7.95 Hz, 1H) 7.29 (d, J = 2.20 Hz, 1 H) 7.30 (d, J = 2.00 Hz, 1H ) 7.37 (dd, J = 8.18, 2.20 Hz, 1H), 7.41 (t, J = 5.37 Hz, 1H) 8.19 (d, J = 5.25 Hz, 1H ), 11.86 (bs, 1H). HRMS (ESI) calculated for C23H27C1N6O + H + 439.2008, found 439, 2012. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N- (1-methylpiperidin-4 -yl) -1H-pyrrole-3-carboxamide [(I), R1 = CH3, R2 = Cl, R3 = NH- (1-methylpiperidin-4-yl), R4 = NH2, R12 = H] (compd. 23 ) XH NMR (400 MHz, DMSO-d6) 6 1.45 ppm (dq, J = 11.64, 3.91 Hz, 2 H) 1.65 (dq, J = 12.66, 3.14 Hz, 2 H) 1.88 (td, J = 11.41, 2.07 Hz, 2 H) 2.10 (s, 3H), 2.12 (s, 3 H) 2.63 (d, J = 11 , 23 Hz, 2 H) 3.49-3, 62 (m, 1H), 6.32 (bs, 2 H) 6.94 (d, J = 5.25 Hz, 1H) 7.28 (d, J = 8.67 Hz, 1H) 7.29 (d, J = 2.00 Hz, .20 1H), 7.33-7.38 (m, 2 H) 7.48 (d, J = 8, 18 Hz, 1 H) 8.19 (d, J = 5.25 Hz, 1H) 11.85 (bs, 1H). HRMS (ESI) calculated for C22H25C1N6O + H + 425, 1851, found 425.1846. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N-phenyl-1H-pyrrol-3-carboxamide [(I), R1 = CH3, R2 = Cl, R3 = NHPh, R4 = NH2, R12 = H] (comp. 24) XH NMR (400 MHz, DMSO-d6) 6 ppm 2.14 (s, 3 H) 6.37 (bs, 2 H) 6.99 (d , J = 5.25 Hz, 1H) 7.00 (tt, J = 7.40, 1.15 Hz, 1 H) 7.26 (dd, J = 8.36, 7.63 Hz, 2 H) 7.30 (d, J = 7.93 Hz, 1H) 7.34 (d, J = 2.32 Hz, 1H) 7.37 (dd, J = 7.93, 2.32 Hz, 1H) 7 , 57 (d, J = 1.34 Hz, 1H) 7.65 (dd, J = 8.61, 1.04 Hz, 2 H) 8.23 (d, J = 5.25 Hz, 1H), 9.74 (s, 1H) 12.05 (bs, 1H). HRMS (ESI) calculated for C22HI8C1N5O + H + 404.1273, found 404.1274. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N- (furan-2-ylmethyl) -1H-pyrrole-3-carboxamide [(I), Rl = CH3, R2 = Cl, R3 = NH- (furan-2-ylmethyl), R4 = NH2, R12 = H] (compd. 25) rH NMR (400 MHz, DMSO-dg) 5 2.08 ppm (s, 3 H) 4.30 (d, J = 5.86 Hz, 2 H) 6.16 (dq, J = 3.22, 0.80 Hz, 1H) 6.32 (bs, 2 H) 6.36 (dd, J = 3.17, 1.83 Hz, 1H) 6.93 (d, J = 5.25 Hz, 1H) 7.27 (d, J = 7.93 Hz, 1H) 7.28 (d, J = 2.20 Hz, 1 H) 7.35 (dd, J = 7.93, 2.20 Hz, 1H) 7.39 (d, J = 2.56 Hz, 1H) 7.53 (dd, J = 1.83, 0.85 Hz, 1H) 8.19 (d, J = 5.37 Hz, 1H), 8.28 (t, J = 5.86 Hz, 1H) 11.90 (bs, 1H ). HRMS (ESI) calculated for C2IHI8C1N5O2 + H + 408.1222, found 408.1229. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N- (3-hydroxypropyl) -1H-pyrrole-3-carboxamide [(I), Rl = CH3, R2 = Cl, R3 = NHCH2CH2CH2OH, R4 = NH2, R12 = H] (comp. 26) THNMR (400 MHz, DMSO-d6) 6 ppm 1.57 (quin, J = 6, 65 Hz, 2 H) 2.10 ( s, 3 H) 3.15 (q, J = 6.50 Hz, 2 H) 4.40 (t, J = 5.13 Hz, 1H) 6.33 (bs, 1H), 6.94 (d , J = 5.13 Hz, 1H) 7.28 (d, J = 8.18 Hz, 1H) 7.28 (d, J = 2.32 Hz, 1H) 7.32 (s, 1H), 7 , 35 (dd, J = 8.18, 2.20 Hz, 1H), 7.77 (t, J = 5.55 Hz, 1H) 8.19. (d, J = 5.25 Hz, 1H) 11.85 (bs, 1 H). HRMS (ESI) calculated for C19H20CIN5O2 + H + 386, 1379, 5 found 386.1381. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N- (2-methoxyethyl) -1H-pyrrole-3-carboxamide [(I), R1 = CH3, R2 - Cl, R3 = NHCH2CH2OCH3, R4 = NH2, R12 = H] (compd. 27) 1H NMR (400 MHz, DMSO-dg) 5 ppm 2.10 (s, 3H), 3.22 (s, 3 10 H) , 6.33 (bs, 2 H) 6.94 (d, J - 5.25 Hz, 1H) 7.28 (d, J = 2.32 Hz, 1H) 7.29 (d, J = 7, 93 Hz, 1H) 7.34 (d, J = 2.56 Hz, 1H) 7.36 (dd, J = 8.18, 2.20 Hz, 1H), 7.69 (t, J = 5, 49 Hz, 1H) 8.19 (d, J = 5.25 Hz, 1H) 11.87 (bs, 1H). HRMS (ESI) calculated for Ci9H2oClNsO2 + H + 386, 1379, 15 found 386.1385. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N- (2-fluorethyl) -1H-pyrrol-3-carboxamide [(I), R1 = CH3, R2 = Cl, R3 = NHCH2CH2F, R4 = NH2, R12 = H] (comp. 28) XH NMR (400 MHz, DMSO-ci6) 5 ppm 2.10 (s, 3 H) 3.44 (q, J. 20 = 5.25 Hz, 2 H) 4.43 (dt, J = 47.48, 5.25 Hz, 2 H), 6.33 (bs, 1 H) 6.94 (d, J = 5.25 Hz, 1H) 7.28 (d, J = 8.30 Hz, 1H) 7.28 (d, J = 2.32 Hz, 1H) 7.35 (dd, J = 8.30, 2.32 Hz , 1 H) 7.38 (d, J = 1.95 Hz, 1H) 8.03 (t, J = 5.55 Hz, 1H) 8.20 (d, J = 5.25 Hz, 1H) 11 , 90 (bs, 1H). HRMS (ESI) calculated for CI0HI7C1FN5O + H + 374.1179, found 374.1185. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N, N-dimethyl-1H-pyrrole-3-carboxamide [(I), R1 = CH3, R2 = Cl, R3 =. N (CH3) 2, R4 = NH2, R12 = H] (compd. 29) NMR (400 MHz, DMSO-d6) 5 2.17 ppm (s, 3 H) 2.84 (s, 6 5 H) 6 , 36 (s, 1H), 6.99 (d, J = 5.25 Hz, 1H), 7.00 (s, 1 H) 7.30 (d, J = 8.06 Hz, 1H) 7, 29 (d, J = 2.20 Hz, 1H) 7.35 (dd, J = 8.30, 2.32 Hz, 1H) 8.19 (d, J = 5.25 Hz, 1H) 11.84 (bs, 1H). HRMS (ESI) calculated for Ci8HieClN5O + H + 356.1273, found 356.1277. N- (2-Aminoethyl) -5- (2-aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1H-pyrrole-3-carboxamide [(I), R1 = CH3, R2 = Cl, R3 = NHCH2CH2NH2, R4 = NH2, R12 = H] (compd. 30) Obtained from tert-butyl- [3 - ({[5- (2-aminopyrimidin-4-yl) -2- (5- chloro-2-methylphenyl) -1H-pyrrol-3-yl] carbonyl} amino) 15 ethyl] carbamate, after treatment with TEA in DCM. : H NMR (400 MHz, DMSO-d6) 5 ppm 2.11 (s, 3H), 2.90 (sxt, 4 H) 3.18 (q, J = 6.35 Hz, 2 H), 7, 09 (bs, 2 H) 7.07 (d, J = 5.86 Hz, 1H) 7.30 (d, J = 8.30 Hz, 1H) 7.30 (d, J = 2.32 Hz, 1H) 7.38 (dd, J = 8.30, 2.32 Hz, 1H) 7.51 (d, J = 2.20 Hz, 1H) 7.71 (bs, 3 H) 8.15 (t , J = 5.55 Hz, 1H) 8.25 (d, J = 5.86 Hz, 1H) 12.23 (bs, 1H). HRMS (ESI) calculated for CieHi9ClN6O + H + 371.1382, found 371.1381. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N- [2- 25 (methylamino) -ethyl] -1H-pyrrole-3-carboxamide [(I), R1 = CH3, R2 = Cl, R3 = NHCH2CH2NHCH3, R4 = NH2, R12 = H] (compd. 31) NMR (400 MHz, DMSO-d6) 5 ppm 2.11 (s, 3 H) 2.26 (s, 3 H) 2.54 (t, J = 6.47 Hz, 2 H) 3.18 (q, J = 6.35 Hz, 2 H) 6.33, (bs, 2 H) 6.94 (d , J = 5.25 Hz, 1H) 7.29 (d, J = 8.18 Hz, 1H) 7.29 (d, J = 2.32 Hz, 1H), 7.33 (s, 1 H) 7.36 (dd, J = 8.18, 5 2.20 Hz, 1H), 7.66 (t, J = 5.74 Hz, 1H) 8.19 (d, J = 5.25 Hz, 1H ) 11.86 (bs, 1H). HRMS (ESI) calculated for CigHaiCINgO + H + 385.1538, found 385.1541. 5- (2-Aminopyrimidin-4-yl) -N-benzyl-2- (5-chloro-2-methylphenyl) -1H-pyrrole-3-carboxamide [(I), R1 = CH3, R2 = Cl, R3 = NHCH2Ph, R4 = NH2, R12 = H] (comp. 32) XH NMR (400 MHz, DMSO-d6) 5 ppm 2.09 (s, 3 H) 4.32 (d, J = 6.10 Hz, 2 H), 6.33 (bs, 2 H) 6.94 (d, J = 5.25 Hz, 1 H) 7.17-7.32 (m, 7 H), 7.32-7.37 ( m, 1H), 7.40 (d, J = 2.56 Hz, 1H) 8.20 (d, J = 5.25 Hz, 1H), 8.38 (t, J = 6.04 Hz, 1H ) 11.89 (bs, 1H). HRMS (ESI) calculated for Ci9H20ClN5O + H + 370, 1429, found 370.1431. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N- (2 methylpropyl) -1H-pyrrole-3-carboxamide [(I), Rl = CH3, R2 = Cl , R3 = NHCH2CH (CH3) 2, R4 = NH2, R12 = H] (comp. 33) 1H NMR (400 MHz, DMSO-dg) 5 ppm 0.81 (d, J = 6.71 Hz, 6 H) 1.71 (spt, J = 6.80 Hz, 1H) 2.11 (s, 3 H) 2.92 (t, J = 6.41 Hz, 2 H), 6.33 (bs, 2 H) 6.95 (d, J = 5.25 Hz, 1H) 7.28 (d, J = 8.30 Hz, 1H) 7.29 (d, J = 2.20 Hz, 1H) 7.35 (d , J = 2.50 Hz, 1H) 7.35 (dd, J = 8.30, 2.30 Hz, 1H), 7.72 (t, J = 5.92 Hz, 1H) 8.19 (d , J = 5.25 Hz, 1H) 11.84 (bs, 1H). HRMS (ESI) calculated for CI8H18C1N5O + H + 356.1273,. found 356.1276. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -N- 5 (2,2-dimethylpropyl) -1H-pyrrole-3-carboxamide [(I), R1 = CH3 , R2 = Cl, R3 = NHCH2C (CH3) 3, R4 = NH2, R12 = H] (comp. 34) 1H NMR (400 MHz, DMS0-d6) 6 ppm 0.78 (s, 9 H) 2.11 (s, 3 H) 2.94 (d, J = 6.35 Hz, 2 H) 6.33 (s, 2 H) 6.96 (d, J = 5.37 Hz, 1H) 7.30 ( d, J = 8.20 Hz, 1H) 7.32 (d, J = 2.32 Hz, 1H), 7.33-7, 40 (m, 3 H) 8.19 (d, J = 5, 37 Hz, 1H) 11.86 (bs, 1H). HRMS (ESI) calculated for C19H20CIN5O + H + 370, 1429, found 370.1433. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -N-methyl-1H-pyrrol-3-carboxamide [(I), R1 = CH2CH3, R2 = Cl, R3 - 15 NHCH3, R4 = NH2, R12 = H] (comp. 35) NMR (400 MHz, DMSO-dg) 0.95 5 ppm (t, J = 7.57 Hz, 3 H) 2.44 (q, J = 7.61 Hz, 2 H) 2.61 (d, J = 4.64 Hz, 3 H) 6.49 (bs, 2H), 6, 94-6, 96 (m, 1H), 7.24 (d, J = 2.32 Hz, 1H), 7.307.33 (m, 1H), 7.34 (d, J = 2M HZ, 1H), 7.39 (dd, J = 8.30, - 20 2.32 Hz, 1H), 7.75-7.83 (m, 1H), 8.19 (d, J = 5.37 Hz, 1H) 11.94 (bs, 1H). HRMS (ESI) calculated for CI8H18C1N5O + H + 356, 1273, found 356.1281. 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -N-ethyl-25 1H-pyrrole-3-carboxamide [(I), R1 = CH2CH3, R2 = Cl, R3 = NHCH2CH3, R4 = NH2, R12 = H] (comp. 36) NMR (400 MHz, DMSO-de) 0.95 5 ppm (t, J = 7.57 Hz, 3 H) 1.01 (t, J = 7.20 Hz, 3 H) 2.44 (q, J = 7.65 Hz, 2 H) 3.03. - 3.16 (m, 2 H), 6.32 (bs, 2 H) 6.93 (d, J = 5.25 Hz, 1H) 7.24 (d, J = 2.32 Hz, 1H) 7.32 (d, J = 12.08 Hz, 1 H) 7.32 (s, 1H), 5 7.39 (dd, J = 8.31, 2.30 Hz, 1H), 7.75 ( t, J = 5.68 Hz, 1H) 8.19 (d, J = 5.25 Hz, 1H) 11.87 (bs, 1H). HRMS (ESI) calculated for C19H20CIN5O + H + 370, 1429, found 370.1434. 5- (2-aminopyrimxdin-4-yl) -2- (5-chloro-2-ethylphenyl) -N- (2- 10 hydroxyethyl) -1H-pyrrole-3-carboxamide [(I), R1 = CH2CH3, R2 = Cl, R3 = NHCH2CH2OH, R4 = NH2, R12 = H] (comp. 37) rH NMR (400 MHz, DMSO-d6) 5 ppm 0.96 (t, J = 7.57 Hz, 3 H) 2, 44 (q, J = 7.61 Hz, 2 H) 3.11 - 3.18 (m, 2 H) 3.36 - 3.41 (m, 2 H), 4.60 (bs, 1H), 6.35 (bs, 2 H) 6.93 (d, J = 5.37 Hz, 15 1H) 7.24 (d, J = 2.32 Hz, 1H) 7.32 (d, J = 12, 08 Hz, 1H) 7.36 (d, J = 2.56 Hz, 1H) 7.40 (dd, J = 8.30, 2.30 Hz, 1H), 7.67 (t, J = 5, 55 Hz, 1H) 8.19 (d, J = 5.25 Hz, 1H) 11.90 (bs, 1H). HRMS (ESI) calculated for C19H20CIN5O2 + H + 386, 1379, * found 386.1380. r 20 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -N, N-dimethyl-1H-pyrrol-3-carboxamide [(I), R1 = CH2CH3, R2 = Cl, R3 = N (CH3) 3, R4 = NH2, R12 = H] (comp. 38) XH NMR (400 MHz, DMSO-d6) 5 ppm 0.99 (t, J = 7.57 Hz, 3H) , 2.86 (bs, 6 H) 6.36 (s, 2 H) 6.98 (d, J = 5.25 Hz, 1 H) 25 7.29 (d, J = 2.32 Hz, 1H ) 7.34 (d, J = 8.30 Hz, 1H) 7.40 (dd, J = 8.30, 2.32 Hz, 1H) 8.18 (d, J = 5.37 Hz, 1 H ) 11.85 (bs, HRMS (ESI) calculated for C21H24CIN5O + H + 398.1742, „found 398.1740. 5- (2-Aminopyrimidin-4-yl) -2- [2-chloro-5- (trifluormethyl) A phenyl] -N-methyl-1H-pyrrole-3-carboxamide [(I), R1 = Cl, R2 = CF3, R3 = NHCH3, R4 = NH2, R12 = H] (compd. 39) NMR (400 MHz, DMSO-d6) 6 ppm 2.63 (d, J = 4.64 Hz, 3H), 6.35 (bs, 2 H) 6.90 (d, J = 5.25 Hz, 1H) 7.33 ( d, J = 2.56 Hz, 1H), 7.72-7.80 (m, 3 H) 7, 90-7.94 (m, 1H), 8.22 (d, J 10 = 5.25 Hz, 1H) 12.07 (bs, 1H) HRMS (ESI) calculated for CI7H13CI F3N5O + H + 396.0834, found 396.0828. 5- (2-Aminopyrimidin-4-yl) -N-methyl-2 - [2-methyl-5- (trifluoromethyl) phenyl] -1H-pyrrole-3-carboxamide [(I), R1 = CH3, R2 = CF3, R3 = NHCH3, R4 = NH2, R12 = H] (compd. 50) TH NMR (400 MHz, DMSO-d6) 5 ppm 2.20 (s, 3H), 2.62 (d, J = 4.64 Hz, 3H), 6.32 (bs, 2H), 6, 92 (d, J = 5.25 Hz, 1 H) 7.34 (d, J = 2.44 Hz, 1H), 7.53 (s, 1H), 7.47-7.51 (m, 1H ), I 7.53 (s, 1H), 7.64 (d, J = 7.93 Hz, 1 H), 7.86 (d, J = 4.64 Hz, 1H), 8.20 (d , J = 5.25 Hz, 1H), 11.92 (bs, 1H). HRMS (ESI) calculated for CigHigFgNsO + H * 376, 1380, found 376.1380. 5- (2-Aminopyrimidin-4-yl) -2- [2-ethyl-5- (trifluoromethyl) phenyl] -N-methyl-1H-pyrrol-3-carboxamide [(I), Rl = CH2CH3, R2 = 25 CF3, R3 = NHCH3, R4 = NH2, R12 = H] (comp. 51) XH NMR (400 MHz, DMSO-dg) 5 ppm 1.00 (t, J = 7.57 Hz, 3H), 2.52 -2.57 (m, 2H), 2.61 (d, J = 4.52 Hz, 3H), 6.32 (bs, 2H), 6.91 (d, J = 5.25 Hz, 1H) , 7.34 (d, J = 2.32 Hz, 1H),. 7.49 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 8.18 Hz, 1H), 7.84 (q, J - 4 , 27 Hz, 1H), 8.19 (d, J = 5.25 Hz, 1H), 5 11.94 (bs, 1H). HRMS (ESI) calculated for CigHigFgNsO + H + 390.1536, found 390.1535. Example 3
5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-hydroxyphenyl) -1H-pyrrole-3-carboxamide [(I), R1 = OH, R2 = Cl, R3 = R4 = NH2, R12 = H] (comp. 40) Conv. 1

For a well-stirred solution of 5- (2-aminopyrimidin-4-yl) -2- (5-chloro-2-methoxyphenyl) -1H-pyrrole-3-carboxamide (50 mg, 0.15 mmol) in DCM (1 , 5 ml) of boron tribromide (1 M in DCM, 3 ml, 3 mmol) was added dropwise at 0 ° C. The mixture was stirred at room temperature overnight. The mixture was poured into water and the organic phase separated. The aqueous phase was extracted with EtOAc. The organic phases were collected, dried over sodium sulfate and concentrated. The crude material was purified by preparative HPLC (Method 2) to provide the title compound (11 mg, 22%). NMR (400 MHz, DMSO-dJ 5 ppm 6.41 (s, 2 H) 6.95 (d, J = 8.67 Hz, 1H) 6.99 (d, J = 5.25 Hz, 1H) 7 , 28 (dd, J = 8.67, 2.69 Hz, 1H) 7.33 (bs, 2 H) 7.42 (d, J = 2.69 Hz, 1H) 7.77 (bs, 1H) , 8.22 (d, J = 5.25 Hz, 1H) 10.90 (bs, 1H) 11.71 (bs, 5 1H) HRMS (ESI) calculated for C15H12CIN5O2 + H + 330.0753, found 330, 0758. The procedure described above was used to synthesize the following compound: 5- (2-Aminopyrimidin-4-yl) -2- (2-chloro-5-hydroxyphenyl) -1H-pyrrole-3-carboxamide [(I), R1 = Cl, R2 = OH, R3 = R4 = NH2, R12 = H] (compd. 41) XH NMR (400 MHz, DMSO-dg) 5 ppm 6.33 (s, 2H), 6.70 (bs, 1H), 6.77-6.85 (m, 2 H) 6.93 (d, J = 5.25 Hz, 1H), 7.08 (bs, 15 1H), 7.24-7.33 ( m, 2 H) 8.19 (d, J = 5.25 Hz, 1H), 9.72 (s, 1H) 11.83 (bs, 1H) HRMS (ESI) calculated for C15HI2C1N5O2 + H + 330.0753 , found 330.0751. Example 4
5- (2-Aminopyrimidin-4-yl) -2- (2-chloro-5-cyanophenyl) -1H-pyrrole-3-carboxamide [(I), R1 = Cl, R2 = CN, R3 = R4 = NH2, R12 = H] (compd. 7) Scheme B, Step 4
5- (2-Aminopyrimidin-4-yl) -2-bromo-1H-pyrrol-3-carboxamide (prepared according to WO2007 / I10344, 0.1 g, 0.35 mmol), 2-chloro-5- acid cyanophenylboronic acid (127 mg, 0.7 mmol), Na2CO3 5 (111 mg, 1.05 mmol) and PdCl2 (dppf) (28 mg, 0.035 mmol) in DME (2.5 ml) and water (1 ml) were heated to 80 ° C for 12 h, under argon. After cooling to room temperature, the precipitate was filtered and the filtrate was evaporated under reduced pressure. The crude material was purified by preparative HPLC 10 (Method 1) to obtain the title compound (15 mg, 13%). 1H NMR (400 MHz, DMSO-de) 5 ppm 6.42 (bs, 2 H) 6.79 (bs, 1H) 6.90 (d, J = 5.25 Hz, 1H) 7.38 (d, J = 2.56 Hz, 1 H) 7.44 (bs, 1H), 7.73 (d, J = 8.42 Hz, 1H) 7.88 (dd, J = 8.42, 2.07. * 15 Hz, 1H) 7.94 (d, J = 2.07 Hz, 1H) 8.23 (d, J = 5.37 Hz, 1H) 12.07 (bs, 1H). * HRMS (ESI) calculated for C16HnClN6O + H + 339, 0756, found 339.0761. Example 5
2- (5-Chloro-2-methylphenyl) -5- [2- (methylamino) pyrimidin-4-yl] -1H-pyrrol-3-carboxamide [(I), Rl = CH3, R2 = Cl, R3 = NH2 , R4 = NHCH3, R12 = H] (compd. 42) Scheme C, step 5, 6, 7 and 8
Step 5: 5-Acetyl-2- (5-chloro-2-methyl-phenyl) -1H-pyrrole-3-carbonitrile
To a mixture of 2- (5-chloro-2-methyl-phenyl) -iH-pyrrole-3-carbonitrile (900 mg, 4.14 mmol) in DCM (20 mL) was added acetyl chloride (0.468 mL, 6 , 57 mmol), at room temperature, under nitrogen. The resulting mixture was cooled to 0 ° C and anhydrous aluminum trichloride (1.31 g, 9.9 mmol) was added in small portions over a period of 10 min, keeping the internal temperature below 5 ° C. After complete addition, the mixture was brought to room temperature and ■ left under stirring for 30 min. Then, the mixture was slowly poured into an ice-cooled solution of 1 M HCl (9 ml). The aqueous layer was separated and extracted twice with DCM (20 ml). The combined organic extracts were washed with a saline solution, dried over Na2S04 and concentrated under reduced pressure. The crude material was chromatographed on silica gel (10 to 20% EtOAc / hexane) to give the title compound (1.0 g, 86%). NMR (400 MHz, DMSO-dff) 5 ppm 2.24 (s, 3H), 2.43 (s, 3H), 7.38-7.42 (m, 1H), 7.43 (d, J = 2.32 Hz, 1H) 7.46 - 7.50 (m, 1H), 7.60 (s, 1H) 12.89 (bs, 1H). HRMS (ESI) calculated for C14HnClN20 + H + 259, 0633, found 2 59.0638. Step 6: 2- (5-Chloro-2-methyl-phenyl) -5- (E) -3-dimethylamino-acryloyl-1H-pyrrole-3-carbonitrile
To a suspension of 5-acetyl-2- (5-chloro-2-methyl-phenyl) -1H-pyrrole-3-carbonitrile (990 mg, 3.83 mmol) in DMF (5 mL) was added N, N- dimethylformamide diisopropyl acetal (2.4 mL, 10 11.5 mmol). The mixture was left under stirring overnight at 90 ° C. The mixture was evaporated in vacuo and used in the next step without further purification. Step 7: 2- (5-Chloro-2-methyl-phenyl) -5- (2-methylamino-pyrimidin-4-yl) -1H-pyrrole-3-carbonitrile.
For a suspension of 2- (5-chloro-2-methyl-phenyl) -5- (E) -3-dimethylamino-acryloyl-1H-pyrrole-3-carbonitrile (618 mg, 1.91 mmol) in DMF (5 ml) methylguanidine hydrochloride (230 mg, 2.1 mmol) and K2CO3 (318 mg, 2.29 mmol) were added. The mixture was heated to 110 ° C overnight under efficient stirring. The resulting mixture was concentrated and chromatographed on silica gel (10 to 30% EtOAc / hexane) to yield the title compound (300 mg, 48%, 2 Steps). XH NMR (400 MHz, DMSO-d6) 6 ppm 2.28 (s, 3 H) 2.88 (d, J = 4.52 Hz, 3H), 6.83-6.95 (m, 1H), 6.95-7.03 (m, 1H) 7.36-7.41 25 (m, 1H), 7.41-7.46 (m, 1H), 7.46-7.53 (m, 3 H) 8.27 (d, J = 4.64 Hz, 1H) 12.53 (bs, 1H). HRMS (ESI) calculated for C17H14CIN5 + H + 324,1011, found 324,1013. Step 8: 2- (5-Chloro-2-methyl-phenyl) -5- (2-methylamino-pyrimidin-4-yl) -1H-pyrrole-3-carboxamide.
For a solution of 2- (5-chloro-2-methyl-phenyl) -5- (2-methylamino-pyrimidin-4-yl) -1H-pyrrole-3-carbonitrile (74 mg, 0.23 mmol) in TEA (1.0 ml) was added sequentially to water (0.15 ml) and 98% sulfuric acid (0.30 ml) added under efficient stirring. The mixture was left under stirring for 8 h at 70 ° C and then diluted by adding dropwise water (3 ml). The reaction mixture was made basic (pH 10 to 12) by adding 30% aqueous ammonia (1 ml), under stirring. The solid precipitate was collected by filtration, washed with water and finally dried in a vacuum oven at 50 ° C, obtaining the title compound as an off-white solid (66 mg, 88%). XH NMR (400 MHz, DMSO-d6) 5 ppm 2.12 (s, 3 H) 2.88 (d, J = 4.15 Hz, 3H), 6.67-6.83 (m, 1H), 6.88 (d, J = 5.13 Hz, 1H) 7.19 (bs, 1H) 7.26-7.32 (m, 2 H) 7.34-7.38 (m, 1 H) 7 , 39 (s, 1H) 8.20 (d, J = 5.37 Hz, 1H) 11.87 (bs, 1 H). HRMS (ESI) calculated for Ci7H16ClN5O + H * 342, 1116, found 342.1111. Example 6
5- (pyrimidin-4-yl) -2- (5-chloro-2-methyl-phenyl) -1H-pyrrole-3-carboxamide [(I), R1 = CH3, R2 = Cl, R3 = NH2, R4 = H, R12 = H] (compd. 43) Scheme D, steps 9 and 10
Step 9: 5- (pyrimidin-4-yl) -2- (5-chloro-2-methyl-phenyl) -1H-pyrrole-3-carbonitrile
For a suspension of 2- (5-chloro-2-methyl-phenyl) -5 - ((E) -3-dimethylamino-acryloyl) -1H-pyrrole-3-carbonitrile (313 mg, 1.0 mmol) in DMF (5 ml) formamidine acetate (208 mg, 2.0 mmol) was added. The mixture was heated at 150 ° C for 5 h, with efficient stirring. The resulting mixture was diluted by adding water dropwise and extracted with EtOAc. The organic phase was washed with brine, water and then dried over Na2S04 and concentrated. The crude material was chromatographed on silica gel (hexane / EtOAc 90/10) to yield the title compound (90 mg, 30%). 1H NMR (400 MHz, DMSO-d6) 5 ppm 2.30 (s, 3H), 7.40-7.45 (m, 1H), 7.46-7.53 (m, 2 H) 7.61 (s, 1H), 7.90 (dd, J = 5.43, 1.28 Hz, 1H) 8.79 (d, J = 5.37 Hz, 1H) 9.13 (d, J = 1, 22 Hz, 1H) 12.98 (bs, 1H). HRMS (ESI) calculated for Ci6HnClN4 + H + 295.0745, found 2 95.0750. Step 10: 5- (pyrimidin-4-yl) -2- (5-chloro-2-methyl-phenyl) -1H-pyrrole-3-carboxamide
For a solution of 5- (pyrimidin-4-yl) -2- (5-chloro-2-methyl-phenyl) -1H-pyrrole-3-carbonitrile (85 mg, 0.28 mmol) in TFA (1.0 ml) water (0.15 ml) and 98% sulfuric acid (0.30 ml) were added sequentially under efficient stirring. The mixture was left under stirring for 5 h at 70 ° C 5 and then diluted with water dropwise (1 ml). The reaction mixture was made basic (pH 10 to 12) by addition of 30% aqueous ammonia (3 ml), under stirring. The solid precipitate was collected by filtration, washed with water and finally dried in a vacuum oven at 50 ° C, obtaining the title compound (72 10 mg, 83%). NMR (400 MHz, DMSO-d6) 5 ppm 2.13 (s, 3H), 6.81 (bs, 1H), 7.19-7.33 (m, 3 H) 7.33-7.40 ( m, 1H), 7.57 (d, J = 2.69 Hz, 1H) 7.74 (dd, J = 5.43, 1.40 Hz, 1H) 8.70 (d, J = 5.49 Hz, 1H) 9.04 (d, J = 1.10 Hz, 1H) 12.22 (bs, 1H). HRMS (ESI) calculated for C16H13C1N4O + H + 313, 0851, found 313.0853. The procedure described above was used to synthesize the following compound: 2- (5-Chloro-2-methylphenyl) -5- (2-methylpyrimidin-4-yl) -1H-pyrrole-3-carboxamide [(I), R1 = CH3, R2 = Cl, R3 = NH2, R4 = CH3, R12 = H] (compd. 44) rH NMR (400 MHz, DMSO-de) 5 ppm 2.12 (s, 3H), 2.59 (s, 3 H), 6.80 (bs, 1H), 7.24-7.31 (m, 2 H), 7.33 (bs, 1H) 7.34-7.38 (m, 1H), 7, 50-7.58 (m, 2H), 8.59 (d, J = 5.34 Hz, 1H) 12.13 25 (bs, 1H). HRMS (ESI) calculated for C17H15CIN4O + H 327,1007, found 327,1011. Example 7
5- (2-Aminopyrimidin-4-yl) -2- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrole-3-carboxamide [(I), R1 = Cl, R2 = CF3, R3 = R4 = NH2, R12 = H] (compd. 1) Scheme C, Steps 5, 6, 7, 8
Step 5: 5- Acetyl-2- [2-chloro-5- (trifluormethyl) phenyl] -1 H-pyrrole-3-carbonitrile
To a mixture of 2- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrole-3-carbonitrile (450 mg, 1.66 mmol) in toluene (3 ml) was added acetyl chloride (0176 ml, 2.49 mmol) at room temperature, under nitrogen, and zinc (217 mg, 3.32 mmol). The mixture was left under stirring for 3 h at 80 ° C. The mixture was cooled to room temperature, diluted with EtOAc and washed with water. The aqueous layer was separated and extracted twice with EtOAc. The combined organic extracts were washed with a saline solution, dried over Na2S04 and concentrated under reduced pressure. The crude material was chromatographed on silica gel (0 to 10% EtOAc / hexane) to yield the title compound (386 mg, 74%). NMR (400 MHz, DMSO-d6) 6 ppm 2.45 (s, 3H), 7.66 (s, 1H), 7.81-7.96 (m, 2 H) 7.98 (s, 1H) , 13.15 (bs, 1H). Step 6: 2- [2-Chloro-5- (trifluoromethyl) phenyl] -5- (E) -3-dimethylamino-acryloyl) -H-pyrrole-3-carbonitrile
To a mixture of 5-acetyl-2- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrole-3-carbonitrile (280 mg, 0.89 mmol) in toluene (3 ml) was added N, N -dimethylformamide diisopropyl acetal (0.74 mL, 3.56 mmol). The mixture was left under stirring for 2 H at 80 ° C. After cooling to room temperature, the solid was collected by suction, washed with toluene and air dried to yield the title compound as a white solid (170 mg, 52%). NMR (400 MHz, DMSO-d6) 5 ppm 2.91 (bs, 3 H), 3.14 (bs, 3 H) 5.74 (d, J = 12.45 Hz, 1 H) 7.40 ( s, 1H), 7.69 (d, J = 12.45 Hz, 1H), 7.81-7.99 (m, 3 H) 12.74 (bs, 1H). Step 7: 5- (2-Amino-pyrimidin-4-yl) -2- [2-chloro-5- (trifluormethyl) phenyl] -1H-pyrrole-3-carbonitrile
For a mixture of 2- [2-chloro-5- (trifluormethyl) phenyl] - 5- (E) -3-dimethylamino-acryloyl) -1H-pyrrole-3-carbonitrile (167 mg, 0.46 mmol) in DMF (2 ml) guanidine carbonate (388 mg, 2.15 mmol) was added. The mixture was heated to 110 ° C 2 H under efficient stirring. The resulting mixture was concentrated and chromatographed on silica gel (20 to 50% EtOAc / hexane) to give the title compound (142 mg, 86%). XH NMR (400 MHz, DMSO-dg) 5 ppm 6.49 (bs, 2 H) 7.02 (d, J = 5.13 Hz, 1H), 7.39 (s, 1H), 7.85- 8.03 (m, 3 H) 8.28 (d, J = 5.13 Hz, 1H) 12.81 (bs, 1H). Step 8: 5- (2-Aminopyrimidin-4-yl) -2- [2-chloro-5- 5 (trifluormethyl) phenyl] -1H-pyrrole-3-carboxamide
To a solution of TFA (2.0 ml), water (0.4480 ml) and 98% sulfuric acid (0.240 ml) was added 5- (2-amino-pyrimidin-4-yl) -2- [2-chlorine -5- (trifluormethyl) phenyl] -1H-pyrrole-3-carbonitrile (137 mg, 0.415 mmol). The mixture was left under stirring for 8 h at 70 ° C and then diluted by adding dropwise water (6 ml). The reaction mixture was made basic (pH 10 to 12) by addition of 30% aqueous ammonia under stirring. The precipitated solid was collected by filtration, washed with water and finally dried in a vacuum oven at 50 ° C, obtaining the title compound as a white solid (133 mg, 92%). XH NMR (400 MHz, DMS0-d6) 5 ppm 6.36 (bs, 2 H), 6.77 (bs, 1H), 6.90 (d, J = 5.25 Hz, 1H) 7.37 ( d, J = 2.56 Hz, 1H), 7.42 (bs, 1H), 7.69-7.84 (m, 3 H) 8.22 (d, J = 5.25 Hz, 1H) 12 , 07 (bs, 1H). HRMS (ESI) was calculated for C16H11CIF3N5O + H + 382.0677, found 382.0675. Example 8
5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -1- methyl-1H-pyrrol-3-carboxamide [(I), R1 = CH2CH3, R2 = Cl, R3 = R4 ~ NH2, R12 = CH3] (comp. 45)] Conv. two

For a solution of 5- (2-Aminopyrimidin-yl) -2- (5-chloro-2-ethylphenyl) -1H-pyrrole-3-carboxamide (101 mg, 0.295 mmol) in DMF (1 ml), Cs2CO3 (101 mg, 0.31 mmol) and Mel (28 µL, 0.43 mmol) were added. The mixture was stirred at room temperature for 3 hours, then the solvent was removed. For the EtOAc residue 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 / NHs in MeOH 95/5 / 0.5), yielding the title compound (36 mg, 34% yield). NMR (400 MHz, DMSO-d6) 6 ppm 0.96 (t, J = 7.57 Hz, 3H), 2.18-2.45 (m, 2 H) 3.61 (s, 3 H) 6 , 58 (s, 2H), 6.71 (bs, 1H), 6.82 (d, J = 5.37 Hz, 1H) 7.03 (bs, 1H), 7.21 (d, J = 2 , 32 Hz, 1H), 7.35 (s, 1H), 7.36-7.40 (m, 1H), 7.41-7.48 (m, 1H), 8.21 (d, J = 5.37 Hz, 1H). The procedure described above was used to synthesize the following compounds: 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1- methyl-1H-pyrrole-3-carboxamide [(I ), R1 = CH3, R2 = Cl, R3 = R4 = NH2, R12 = CH3] (comp. 46) NMR (400 MHz, DMS0-d6) 5 ppm 2.00 (s, 3H), 3.61 (s , 3 H) 6.54 (s, 2H), 6.71 (bs, 1H), 6, 81 (d, J = 5.36 Hz, 1H) 7.04 (bs, 1H), 7.23 ( d, J = 2.19 Hz, 1H) 7.35 (d, J = 8.30 Hz, 1H), 7.33 (s, 1H), 7.40 (dd, J = 8.17, 2, 19 Hz, 1H) 8.21 (d, J = 5.36 Hz, 1H). 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1- ethyl-1H-pyrrole 3 -carboxamide [(I), Rl = CH3, R2 = Cl, R3 = R4 = NH2, R12 = CH2CH3] (comp. 47) XH NMR (400 MHz, DMSO-d6) 5 ppm 0.99 (t, J = 7.20 Hz, 3H), 2.01 (s, 3H), 4 .00 (dq, J = 13.66, 6, 96 Hz, 1H), 4.43 (dq, J = 13.55, 6.92 Hz, 1H), 6.52 (s, 2H), 6, 70 (bs, 1H), 6.81 (d, J = 5.37 Hz, 1H) 7.03 (bs, 1H), 7.25 (d, J = 2.32 Hz, 1H) 7.35 ( d, J = 8.18 Hz, 1H), 7.36 (s, 2 H) 7.41 (dd, J = 8.18, 2.20 Hz, 1H) 8.20 (d, J = 5, 25 Hz, 1H). 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1- (2,2,2-trifluorethyl) -1H-pyrrole-3-carboxamide [(I), Rl = CH3, R2 = Cl, R3 = R4 = NH2, R12 = CH2CF3] (compd. 48) JH NMR (400 MHz, DMSO-d6) 5 ppm 2.02 (s, 3H), 5.46 (bs, 2 H ) 6.67 (s, 2 H) 6.84 (d, J = 5, 24 Hz, 1H) 6.90 (bs, 1H), 7.24 (bs, 1H), 7.25 (d, J = 2.07 Hz, 1H) 7.34-7.38 (m, 1H) 7.41-7.45 (m, 1H), 7.45 (s, 1H), 8.26 (d, J = 5.24 Hz, 1H). 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1- (2-hydroxyethyl) -1H-pyrrole-3-carboxamide [(I), Rl = CH3, R2 = Cl, R3 = R4 = NH2, R12 = CH2CH2OH] (compd. 49) Obtained from 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-methylphenyl) -1- [2- (tetrahydro -2H-pyran-2-yloxy) ethyl] -1H-pyrrole -3-carboxamide after treatment with the cone. HCl in EtOH. NMR (400 MHz, DMSO-dg) 6 2.00 ppm (s, 3 H) 3.98 (dt, J = 12.97, 7.00 Hz, 1 H) 4.08 (q, J = 5, 17 Hz, 2 H) 4.46 (ddd, J = 12.97, 7.11, 5, 92 Hz, 1H), 4.67 (t, J = 5.80 Hz, 1H), 6, 54 ( s, 2H), 6.70 (bs, 1H), 6.82 (d, J = 5.37 Hz, 1H) 7.01 (bs, 1H), 7.26 (d, J = 2, 32 Hz , 1H) 7.33 (d, J = 8.30 Hz, 1H), 7.38 (s, 1H), 7.39 (dd, J = 8.30, 2.32 Hz, 1H) 8.20 (d, J = 5.25 Hz, 1H). PHARMACOLOGY Biochemical assay for inhibitors of JAK kinase activity
General principle - specific peptide substrates JAK1, JAK2 or JAK3 are transfosphorylated by JAK kinases in the presence of 33P-y-ATP-labeled ATP. At the end of the phosphorylation reaction, the unreacted ATP, cold and radioactive, is captured by an excess of ion exchange Dowex resins. The resin that eventually settled at the bottom of the gravity reaction wells to the bottom of the reaction plate. The supernatant is subsequently removed and transferred to a counting plate which is then evaluated by post-counting.
Prepare the Dowex resin - 500 g of wet resin (SIGMA, Dowex resin prepared 1x8 200 to 400 mesh, 2.5 kg) were weighed, and diluted to 2L in 150 mM sodium formate, pH 3. The resin rested for the night and then the supernatant was discarded. After three washes as above, over two days, the resin settled, and two 150 mM volumes of the sodium formate plug were added.
Buffer Kinase (KB) - Buffer kinase was composed of 50 mM HEPES, pH 7.5, containing 10 mM MgCl2, 2.5 mM DTT, 10 pM NaVO4, and 0.2 mg / ml BSA. JAK2 specific test conditions
Enzymes - The assays were performed with the commercially available JAK2 kinase domain (Invitrogen, Eugene, OR), which showed linear kinetics without prephosphorylation.
The test conditions - The JAK2 kinase assay was performed with an end enzyme concentration of 1 nM, in the presence of 60 µM ATP, 3 nM 33P-y_ATP and 64 pM of BioDBn * 306 substrate (amino acid sequence: LPLDKDYYWREPGQ- SEQ ID NO: 1). The peptide substrate was purchased from the American Peptide Society (Sunnyvale, CA). Specific test conditions for JAK1
Enzymes - The assays were performed with the JAK1 kinase domain (residues 861-1152 of the full length amino acid sequence 1154, accession number P23458 from UniProtKB / Swiss-Prot database). The JAK1 kinase domain was pre-activated with ATP for 1 hour at 28 ° C, in order to obtain linear kinetics.
The test conditions - The JAK1 kinase assay was performed with a final concentration of 2.5 nM pre-activated enzyme in the presence of 100 pM ATP, 2 nM 33P-y-ATP and 154 pM of BioDBn * 333 substrate (sequence of amino acids: KKHTDDGYMPMSPGVA - SEQ ID NO: 2). The peptide substrate was purchased from the American Peptide Society (Sunnyvale, CA). Specific test conditions for JAK3
Enzymes - The assays were performed with the JAK3 kinase domain (residues 781-1124 of the full length amino acid sequence 1124, accession number P52333 of the UniProtKB / Swiss-Prot database), which showed linear kinetics without pre-phosphorylation.
Assay conditions - The JAK3 kinase assay was performed with a final enzyme concentration of 1 nM, in the presence of 22 qM ATP, 1 nM 33P-y-ATP and 40 pM of BioDBn * 306 substrate (amino acid sequence: LPLDKDYYWREPGQ -SEQ ID NO: 1). The peptide substrate was purchased from the American Peptide Society (Sunnyvale, CA).
Compound Dilution - For the determination of IC50, the test compounds are received as a 1 mM of the solution in 100% DMSO, distributed in 96-well plates: the compounds are then placed on the plates in the first column of a microtiter plate (Al to Gl), 100 pL / well. An automated serial dilution station (Biomek FX, Beckman) is used to produce 1: 3 dilutions in 100% DMSO, from line A1 to A10, and for all compounds in the column. In addition, 4 to 5 copies of the daughter plates are prepared by reformatting 5 μl of this first set of 100% DMSO dilution plates into 384 deep well plates: one of these plates with the serial dilutions of the test compounds will be thawed on the day of the experiment, reconstituted to a 3x concentration with water and used in the IC50 determination tests. In a normal experiment, the highest concentration (3X) of all compounds is 30 pM, while the lowest is 1.5 nM. Each 384 well plate will confer at least one curve of the standard staurosporine inhibitor and reference powders (total enzyme activity versus no enzyme activity) for the Z'e 10 signal and background evaluation.
Test Scheme - 384 wells with V-bottom test plates (test plates) are prepared with 5 pL of the dilution compound (3x) and then placed on a robotic station PlateTrak 12 (Perkin Elmer, the machine has 384 -15 points pipetting to start the test plus 96 tips to dispense the resin), together with a reservoir for the enzyme mixture (3x) and one for the ATP mixture (3X) and another for the ATP mixture (3X). At the start of operation, the machine aspirates 5 pL of the ATP mixture, creates an air gap inside the 20 tips (3 pL) and aspirates 5 pL of the JAK2 mixture. Then, 3 more cycles of the mixture are dispensed on the plates, made by the machine itself, starting the kinase reaction. At this point, the correct concentrations are restored for all reagents. The machine incubates the plates for 60 minutes at room temperature, and then stops the reaction by pipetting 60 µl of the Dowex resin suspension into the reaction mixture. To avoid clogging the tip, tips with wide holes are used to dispense the resin suspension. Three mixing cycles are performed immediately after the resin is added. Another cycle of mixing is performed after all the plates have stopped, this time using normal tips: the plates are then put to rest for about an hour in order to allow the resin to settle. At this point, 27 pL of the supernatant is transferred to Optiplates 384 (Perkin-Elmer), with 50 pL of Microscint 40 (Perkin-Elmer), and 10 after 5 min of orbital shaking the plates were read in a Perkin-Elmer radioactivity counter Top Count.
Adjusting the data - The data is analyzed by an internally customized version of the SW package "Assay Explorer", which provides sigmoidal adjustment of ten dilution curves for the determination of the IC50 for the successful confirmation / secondary test routines. Cell proliferation
Cell line: the SET-2 cell line for JAK2-dependent human megacarioblasic leukemia (DSMZ, 20 Braunschweig GERMANY), K562 cell line for JAK2-independent acute megacarioblastic leukemia (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.
Cell proliferation assay: Approximately 5x10 3 cells were placed in 384 well microtiter plates in 50 µl of the growth medium with different concentrations of inhibitors. The cells were incubated at 37 ° C and 5% CO2 and after 72 hours the plates were processed using CellTiter-Glo test (Promega), following the manufacturer's instructions. Briefly 25 pL / wells of the reagent solution are added to each well and after 5 minutes under agitation the microplates are read by the Envision lumeter (PerkinElmer, Waltham, MA, USA).
Adjustment Data - The data are analyzed by the Symix Assay Explorer programs (Symix Technologies Inc.), which provides a sigmoidal adjustment algorithm for the 8 points of the dilution curves for determining IC50. In the living model
The SET-2 cell line for acute human megakaryoblastic leukemia (107 cells) was inoculated sc in an immunodeficient rat from 5 to 6 weeks of age (Charles River), previously exposed to a radiation range (200 Rads of radiation range in the body whole). Rats with a palpable tumor (100 to 200 mm3) were treated with a vehicle (0.5% Methocel) or a compound of formula (I), for 10 days, at will. The dimensions of the tumors were measured regularly using Vernier gauge and tumor growth inhibition (TGI) was calculated.
Surprisingly, in biochemical assays, the compounds of formula (I) tested as described above, demonstrate an extremely potent inhibitory activity JAK2, typically less than 0.020 pM. See, for example, Table A below, in which said experimental data (IC 50) of the representative compounds of the invention of formula (I) are shown in comparison with the reference compound. The reference compound corresponds to the compound F25 of patent application W02007 / 110344 mentioned above and the fourth compound is waived in the present general formula (I).
In cell assays, the compounds of formula (I) 10 showed greater activity in the JAK2-dependent cell line SET-2 compared to the JAK2-independent cell line K562. In addition, the greater selectivity in the JAK2-dependent cell line, the compounds of formula (I) vs. the reference compound 15 is indicated by the relationship between K-562 (IC50) and SET-2 (IC50), which is greater than 9 for the compounds of formula (I) versus 4.65 for the reference compound (see last column of Table A below). TABLE A


So far, the new compounds of the invention are unexpectedly endowed with a potent and selective inhibitory activity of JAK2, significantly greater than that of the 5 compounds structurally closest to the prior art, and are therefore particularly advantageous in cancer therapy, cell proliferation disorders, viral infections, immunological disorders, neurodegenerative diseases and cardiovascular diseases.

权利要求:
Claims (6)
[0001]
1. Compound or a pharmaceutically acceptable salt thereof, CHARACTERIZED by the fact that it is selected from the group consisting of: 5- (2-Aminopyrimidin-4-yl) -2- [2-chloro-5-trifluormethyl) phenyl] - 1H-pyrrole-3-carboxamide (compound 1), 5- (2-Aminopyrimidin-4-yl) -2- (2,5-dichlorophenyl) -1H-pyrrole-3-carboxamide (compound 2), 5- (2 -Aminopyrimidin-4-yl) -2- (2-chloro-5-ethylphenyl) -1H-pyrrole-3-carboxamide (compound 4), 5- (2-Aminopyrimidin-4-yl) -2- (5-chlorine -2-ethylphenyl) -1H-pyrrole-3-carboxamide (compound 5), 5- (2-Aminopyrimidin-4-yl) -2- [2-chloro-5- (hydroxymethyl) phenyl] -1H-pyrrole-3 -carboxamide (compound 10), 5- (2-Aminopyrimidin-4-yl) -2- [5-chloro-2- (propane-2-yl) phenyl] -1H-pyrrole-3-carboxamide (compound 14), 5- (2-Aminopyrimidin-4-yl) -2- [2,5-bis (trifluormethyl) phenyl] -1H-pyrrole-3-carboxamide (compound 15), 5- (2-Aminopyrimidin-4-yl) - 2- [2-ethyl-5- (trifluormethyl) phenyl] -1H-pyrrol-3-carboxamide (compound 16), 5- (2-Aminopyrimidin-4-yl) -2- [5-chloro-2- (trifluormethyl ) phenyl] -1H-pyrrole-3-carboxamide (compound 17), 5- (2-Amino pyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -N-methyl-1H-pyrrole-3-carboxamide (compound 35), 5- (2-Aminopyrimidin-4-yl) -2- ( 5-chloro-2-ethylphenyl) -N-ethyl-1H-pyrrol-3-carboxamide (compound 36), 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -N - (2-hydroxyethyl) -1H-pyrrole-3-carboxamide (compound 37), 5- (2-Aminopyrimidin-4-yl) -2- (5-chloro-2-ethylphenyl) -N, N-dimethyl-1H -pyrrol-3-carboxamide (compound 38), 5- (2-Aminopyrimidin-4-yl) -2- [2-chloro-5- (trifluoromethyl) phenyl] -N-methyl-1H-pyrrole-3- carboxamide (compound 39), and 5- (2-Aminopyrimidin-4-yl) -2- [2-ethyl-5- (trifluormethyl) phenyl] -N-methyl-1H-pyrrole-3-carboxamide (compound 51).
[0002]
2. Process for preparing a compound of formula (I), as defined in claim 1 or a pharmaceutically acceptable salt thereof, CHARACTERIZED by the fact that the process comprises the following steps: Step 1: The coupling reaction catalyzed by metal by a derivative halogen formula (II)
[0003]
3. Pharmaceutical composition, CHARACTERIZED in that it comprises a compound or a pharmaceutically acceptable salt thereof, as defined in claim 1, and at least one pharmaceutically acceptable excipient, carrier or diluent.
[0004]
4. A compound or a pharmaceutically acceptable salt thereof, according to claim 1, CHARACTERIZED by the fact that it is used as a medicine.
[0005]
5. Use of a compound or a pharmaceutically acceptable salt thereof, as defined in claim 1, CHARACTERIZED by the fact that it is applied in the manufacture of a medicine with anti-cancer activity.
[0006]
6. Intermediate of formula (Illa) CHARACTERIZED by the fact that R1 is isopropyl and R2 is chlorine.

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法律状态:
2018-03-06| B07D| Technical examination (opinion) related to article 229 of industrial property law|

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2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|

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2019-12-17| B07E| Notice of approval relating to section 229 industrial property law|

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2019-12-31| B06U| Preliminary requirement: requests with searches performed by other patent offices: suspension of the patent application procedure|

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2020-12-01| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 05/04/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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EP11162960.6|2011-04-19|

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EP11162960|2011-04-19|

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PCT/EP2012/056266|WO2012143248A1|2011-04-19|2012-04-05|Substituted pyrimidinyl-pyrroles active as kinase inhibitors|

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