WO2013175415A1 - Composés de pyrimidine substituée et leurs utilisations - Google Patents

Composés de pyrimidine substituée et leurs utilisations Download PDF

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WO2013175415A1
WO2013175415A1 PCT/IB2013/054236 IB2013054236W WO2013175415A1 WO 2013175415 A1 WO2013175415 A1 WO 2013175415A1 IB 2013054236 W IB2013054236 W IB 2013054236W WO 2013175415 A1 WO2013175415 A1 WO 2013175415A1
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alkyl
pyrimidin
trifluoromethyl
pyridin
cancer
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PCT/IB2013/054236
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Meenakshi Sivakumar
Kalpana Sanjay Joshi
Sivaramakrishnan Hariharan
Ravishankar BOKKA
Valmik Sopan Aware
Sonal MANOHAR
Vinay SONAWANE
Suneelmanoharbabu CHENNAMSETTY
Ganesh KALE
Becky Mary Thomas
Jacqueline Vinodkumar TRIVEDI
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Piramal Enterprises Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • A61P37/00—Drugs for immunological or allergic disorders
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    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to substituted pyrimidine compounds (referred to herein as the compounds of formula 1 ), processes for their preparation, pharmaceutical compositions comprising the compounds of formula 1 , and their use in the treatment of diseases or disorders mediated by one or more kinases, particularly proliferative diseases or disorders such as cancer. These compounds can also be used in the treatment of inflammatory disorders.
  • Cancer is an uncontrolled growth and spread of cells that may affect almost any tissue of the body. Cancer can be defined as abnormal growth of tissues characterized by a loss of cellular differentiation. It is caused due to a deregulation of the signaling pathways involved in cell survival, cell proliferation and cell death. It is now well understood that deregulation of oncogenes and tumour-suppressor genes contributes to the formation of malignant tumours, for example, by way of increased cell proliferation or increased cell survival. It is also known that signalling pathways mediated by certain protein kinases have a central role in a number of cell processes including proliferation and survival, and deregulation of these pathways is a causative factor in a wide spectrum of human cancers and other diseases.
  • Cancer therapy currently falls under the following categories that include surgery, radiation therapy, chemotherapy, bone marrow transplantation, stem cell transplantation, hormonal therapy, immunotherapy, antiangiogenic therapy, targeted therapy, gene therapy and others. In the recent times, significant improvements have been observed in the treatment of cancers with identification of small molecules as therapeutic agents acting through different mechanisms.
  • Protein kinases are enzymes that catalyze the phosphorylation of proteins at the hydroxy groups of tyrosine, serine and threonine residues of proteins.
  • the kinase complement of the human genome contains 518 putative protein kinase genes.
  • the consequences of this activity include effects on cell differentiation, proliferation, transcription, translation, metabolism, cell cycle progression, apoptosis, metabolism, cytoskeletal rearrangement and movement; i.e., protein kinases mediate the majority of signal transduction in eukaryotic cells.
  • abnormal protein kinase activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to cancer. Chromosomal mapping has revealed that over two hundred kinases map to disease loci, including cancer, inflammatory and metabolic disease.
  • Chronic myeloid leukemia is a myeloproliferative disorder characterized by uncontrolled growth of progenitor cells expressing the tyrosine kinase fusion gene product, Bcr-Abl.
  • CML chronic myeloid leukemia
  • Bcr-Abl tyrosine kinase fusion gene product
  • Recent reports have shown that ectopic Bcr-Abl expression dramatically increases TGF /Smad-dependent transcriptional activity in Cos1 cells, and that this may be due to enhancement of Smad promoter activity (FEBS Letters, 2007, 581 , 7, 1 329-1 334; Leukemia, 2007, 21 , 494-504).
  • Bcr-Abl expressing TF-1 myeloid cells are more potently growth arrested by TGF compared to the parental TF- 1 cell line.
  • Bcr-Abl leads to hyper-responsiveness of myeloid cells to TGF , and that this novel cross-regulatory mechanism might play an important role in maintaining the transformed progenitor cell population in CML.
  • TGF TGF signaling activity
  • Bcr-Abl A upregulation or prolongation of TGF signaling by Bcr-Abl, suggests that one of the mechanisms by which Bcr-Abl promotes the transformation of haemopoietic progenitor cells, is by influencing the level of TGF signaling activity (FEBS Letters, 2007, 581 , 7, 1 329-1 334).
  • TGF plays a vital role in the preservation of the malignant progenitor population, and is partially responsible for the resistance to treatments targeting Bcr- Abl that is observed in a proportion of CML patients.
  • the phosphatidylinositol-3 kinase (PI3K) mediated signaling pathway plays a very important role in cancer cell survival, cell proliferation, angiogenesis and metastasis.
  • the PI3K pathway is activated by stimuli such as growth factors, hormones, cytokines, chemokines and hypoxic stress.
  • Activation of PI3K results in the recruitment and activation of protein kinase B / Akt to the membrane, which gets phosphorylated at Serine 473.
  • phosphorylation of Ser-473 of Akt is a universally approved read-out/detector for the activation of the PI3K-mediated pathway.
  • a cell- based ELISA technique can be used to study such activation.
  • T315I mutant is one of the more predominant mutations seen in imatinib mesylate-resistant patients. This T315I mutation was shown to preserve kinase activity resulting in ineffective binding of imatinib mesylate to Bcr- Abl.
  • this agent may have activity in resistant CML disease, other myeloid malignancies and solid tumors (Mol. Cancer Ther., 2008, 7 (5), 1 185-94).
  • this agent may have activity in resistant CML disease, other myeloid malignancies and solid tumors (Mol. Cancer Ther., 2008, 7 (5), 1 185-94).
  • US Patent Application publication 20050014753 describes compounds that are substituted pyridinamines and triazinamides to prevent diseases and disorders associated with abnormal or deregulated tyrosine kinase activity, particularly diseases associated with the activity of PDGF-R, c-kit and Bcr-abl.
  • the pyrimidine compounds of this invention inhibit the activity of one or more protein kinases and are, therefore, found to be useful in the treatment of kinase-associated proliferative diseases or disorders, particularly cancers.
  • Tumor Necrosis Factor-alpha a pleiotropic cytokine
  • TNF-a Tumor Necrosis Factor-alpha
  • TNF-a has been shown to play a crucial role in the pathogenesis of many chronic inflammatory disease such as rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic non- rheumatoid arthritis, osteoporosis/bone resorption, coronary heart disease, vasculitis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, adult respiratory distress syndrome, diabetes, psoriasis, skin delayed type hypersensitivity disorders and Alzheimer's disease.
  • chronic inflammatory disease such as rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic non- rheumatoid arthritis, osteoporosis/bone resorption, coronary heart disease, vasculitis, inflammatory bowel disease, ulcerative colitis, Crohn'
  • IL-6 lnterleukin-6
  • IL-6 is a pleiotropic cytokine that regulates immunological reactions involved in host defence, inflammation, haematopoiesis, and oncogenesis.
  • IL-6 is known to be a B-cell differentiation factor, induces T cell growth and cytotoxic T- cell differentiation through effecting IL-2 receptor expression and IL-2 production.
  • This cytokine also acts synergistically with other proteins to affect haematopoiesis, macrophage and osteoclast differentiation and platelet production. It can also work as a cell growth factor inducing proliferation of mesangial cells, epidermal keratinocytes as well as various tumour cells.
  • IL-6 has been implicated as a mediator in inflammatory disorders, multiple myelomas, plasmacytomas, Castleman's disease, polyclonal B-cell activation, T cell proliferation, autoimmune disease, AIDS, adult respiratory distress syndrome, cancer, diabetes, ischemia-reperfusion injury, multiple sclerosis and rheumatoid arthritis.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • ibuprofen e.g. ibuprofen
  • naproxen e.g. ibuprofen
  • many individuals cannot tolerate the doses necessary to treat the disorder over a prolonged period of time as NSAIDs are known to cause gastric erosions.
  • NSAIDs merely treat the symptoms of disorder and not the cause.
  • other drugs such as methotrexate, gold salts, D-penicillamine and corticosteroids are used. These drugs also have significant toxic effects.
  • Monoclonal antibody drugs such as infliximab, etanercept and adalimumab are useful as anti-inflammatory agents, but have drawbacks such as route of administration (only parenteral), high cost, allergy induction, activation of latent tuberculosis, increased risk of cancer and congestive heart disease.
  • TNF-a or interleukins I L- 1 ⁇ , IL-2, IL-6 or IL-8
  • IL-1 ⁇ , IL-2, IL-6 and/or IL-8 small molecule inhibitors of pro-inflammatory cytokines such as TNF-a or interleukins
  • compounds of formula 1 in all their stereoisomeric, and tautomeric forms and mixtures thereof in all ratios, or pharmaceutically acceptable salts, solvates, prodrugs, polymorphs and N-oxides, thereof.
  • compositions comprising one or more compounds of formula 1 , or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof and at least one pharmaceutically acceptable carrier or excipient.
  • a compound of formula 1 a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof, which inhibit one or more kinases as described herein.
  • a compound of formula 1 or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof, for use in the treatment of diseases or disorders mediated by one or more kinases.
  • a method for the treatment of diseases or disorders mediated by one or more kinases comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.
  • a method for the treatment of a disorder mediated by one or more pro-inflammatory cytokines selected from Tumor Necrosis Factor-alpha (TNF-cc) or interleukins (IL- ⁇ ⁇ , IL-2, IL-6, and/or IL-8), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1 .
  • TNF-cc Tumor Necrosis Factor-alpha
  • IL- ⁇ ⁇ , IL-2, IL-6, and/or IL-8 interleukins
  • the compounds of formula 1 for use in the treatment of a disorder mediated by one or more pro-inflammatory cytokines selected from Tumor Necrosis Factor-alpha (TNF-cc) or interleukins (IL- ⁇ ⁇ , IL-2, IL-6, and/or IL-8).
  • cytokines selected from Tumor Necrosis Factor-alpha (TNF-cc) or interleukins (IL- ⁇ ⁇ , IL-2, IL-6, and/or IL-8).
  • TNF-cc Tumor Necrosis Factor-alpha
  • interleukins IL- ⁇ ⁇ , IL-2, IL-6, and/or IL-8.
  • Figure 1 (A) shows effect of the compound of example 4 on Bcr-abl, Phospho- Smad3, Phospho-crkl (Tyr 207), Bcl-2 and ⁇ -Actin by western blotting comparative study with imatinib mesylate (standard) and dasatinib (standard) at 48 h, at a concentration: 3 ⁇ IC 5 o-
  • Figure 1 (B) shows effect of the compound of example 4 on Bcr-abl, Phospho- Smad3 and ⁇ -Actin by western blotting comparative study with imatinib mesylate (standard) and dasatinib (standard) at 96 h, at a concentration: 3 ⁇ IC 5 o-
  • Figure 2(A) shows effect of the compound of example 4 and the compound of example 10 on protein expression by western blotting, comparative study with imatinib mesylate (standard) in K562 cell line and BAF3 cell line at 48 h, at concentrations: IC 5 o and 3 ⁇ IC 5 o-
  • Figure 2(B) shows effect of the compound of example 4 and the compound of example 10 on protein expression by western blotting comparative study with imatinib mesylate (standard) in T315I cell line and M351 T cell line at 48 h, at concentrations:
  • Figure 3 shows effect of the compound of example 10 on PI3K/Akt pathway in PC3 cells (which show constitutive activation of this path way).
  • the present invention relates to a compound of formula 1 ,
  • Ri at each occurrence is independently selected from (Ci-C 6 )alkyl, -0-(Ci-C 6 )alkyl, hydroxy, CN, halogen, halo(d-C 6 )alkyl, NR a R b , -0-(Ci-C 4 )alkyl-0-(C C 4 )alkyl-0-(Ci- C 4 )alkyl and -C(0)-R; or two Ri groups present on adjacent carbon atoms of the phenyl ring may optionally form a 5 or 6 membered saturated or unsaturated ring containing 0 to 2 heteroatoms independently selected from O, N and S;
  • R is hydroxy or -0-(CrC 6 )alkyl
  • n is an integer from 0 to 3;
  • R 2 is selected from hydrogen, (C-
  • Yi and Y 2 are independently selected from hydrogen and -Z-(R 3 )-W-[R 4 ] P ; and atleast one of Yi and Y 2 is -Z-(R 3 )-W-[R 4 ] P ;
  • Z is selected from O, N or S
  • R 3 is hydrogen or (C-
  • W is a pyridyl or a phenyl ring
  • R 4 at each occurrence is independently selected from (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(Ci-C 6 )alkyl, ar(C-i-C 6 )alkyl, halogen, cyano, amino, nitro, hydroxy, -0-(C-i-C 6 )alkyl, halo(Ci-C 6 )alkoxy, aryl and heterocyclyl; and
  • p is an integer from 0 to 5;
  • R a and R b are independently selected from hydrogen, (C-
  • each of (Ci-C 6 )alkyl, -0-(C-i-C 6 )alkyl, aryl and heterocyclyl may be unsubstituted or substituted with one or more groups independently selected from (d- C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy, -0-(C C 6 )alkyl, halo(CrC 6 )alkyl, halo(C C 6 )alkoxy, halogen, cyano, amino, nitro, -ON0 2 , aryl, heterocyclyl, -C(0)OR a , -C(0)R a , -SR a , -NR a R b and -C(0)NR a R b , wherein R a and R are as defined above;
  • substitution means that one or more hydrogens of the specified moiety are replaced with a suitable substituent and includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and results in a stable compound.
  • alkyi refers to saturated aliphatic groups, including straight or branched-chain alkyi groups. If the number of carbon atoms is not specified, “alkyi” refers to (C.,-C 6 )alkyl. Accordingly, a straight-chain or branched chain alkyi has six or fewer carbon atoms in its backbone, for instance, Ci-C 6 for straight- chain and C 3 -C 6 for branched chain.
  • alkyi groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, isopentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, isohexyl, 2-hexyl, 3-hexyl and the like.
  • alkyi groups may be unsubstituted or substituted.
  • a substituted alkyi refers to a alkyi substituted with one or more groups independently selected from (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy, -0-(C-i-C 6 )alkyl, halo(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, halogen, cyano, amino, nitro, -ON0 2 , aryl, heterocyclyl, -C(0)OR a , -C(0)R a , -SR a , -NR a R b and -C(0)NR a R b ; wherein R a and R b are independently selected from hydrogen, (CrC 6 )alkyl, -C(0)OH, -C(0)0(C 1 -C 6 )alkyl, -C(0)(C
  • substituted alkyls include, but are not limited to, trifluoromethyl, hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 -aminoethyl, benzyl, N-morpholino methyl, N-indolomethyl, and N-piperidinylmethyl.
  • (C 3 -C 6 )cycloalkyl refers to a monocyclic saturated ring system containing 3 to 6 carbon atoms in a ring structure.
  • the cycloalkyl is optionally bridged (i.e., forming a bicyclic moiety), for example a methylene, ethylene or propylene bridge.
  • Examples of cycloalkyl residues are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • 'cycloalkyl' includes unsubstituted cycloalkyl and cycloalkyl which is substituted with one or more groups independently selected from (Ci-C 6 )alkyl, halo(Ci-C 6 )alkyl, 1 -aminoalkyl, (d- C 6 )alkoxy, amino, halogen, aryl and heterocyclyl.
  • alkoxy refers to (C-
  • Representative alkoxy groups include, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
  • a substituted "-0-(Ci-C 6 )alkyl" or “alkoxy” refers to an alkoxy group in which the (C-
  • aryl refers to monocyclic or polycyclic hydrocarbon groups having 6 to 14 ring carbon atoms in which the carbocyclic ring(s) present have a conjugated pi electron system.
  • Examples of (C 6 -C-i 4 )aryl residues are phenyl, naphthyl, fluorenyl or anthracenyl.
  • Aryl groups can be unsubstituted or substituted with one or more groups independently selected from (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy, -0-(C-i-C 6 )alkyl, halo(C-i-C 6 )alkyl, halo(C-i-C 6 )alkoxy, halogen, cyano, amino, nitro, -ON0 2 , aryl, heterocyclyl, -C(0)OR a, -C(0)R a , -SR a , -NR a R b and -C(0)NR a R b ; wherein R a and R b are independently selected from hydrogen, (Ci-C 6 )alkyl, -C(0)OH, - C(0)0(Ci-C 6 )alkyl, -C(0)(C C 6 )alkyl, -S0 2 -(C C 6 )alkyl
  • substituted phenyl groups include, but not limited to, 4-methoxyphenyl, 4- hydroxyphenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 4-aminophenyl, 4- cyanophenyl, 3,4-dimethoxyphenyl, 3,4-dihydroxyphenyl, 2,4-dimethoxyphenyl, 2,4- dihydroxyphenyl, 3,5-dimethoxyphenyl, 3,5-dihydroxyphenyl, 2,4-difluorophenyl, 3,5- difluorophenyl, 2,4-dichlorophenyl, 4-methoxy-3-trifluoromethylphenyl, or 4-methyl-3- trifluoromethylphenyl.
  • aralkyi or "ar(Ci-C 6 )alkyl” refers to an aryl group bonded directly through an (CrC 6 )alkyl group, such as benzyl (-CH 2 Ph).
  • the aryl of the aralkyi group may be unsubstituted or substituted as indicated herein above.
  • heteroatom as used herein includes nitrogen (N), oxygen (O), and sulfur (S). Any heteroatom with unsatisfied valency is assumed to have a hydrogen atom to satisfy the valency.
  • heterocyclyl includes saturated heterocyclic ring systems, which do not contain any double bonds within the rings, as well as unsaturated heterocyclic ring systems, which contain one or more, for example, 3 double bonds within a ring provided that the resulting mono, bi or tricyclic ring system is stable.
  • the heterocyclyl group may, for example, have 1 or 2 oxygen atoms and/or 1 or 2 sulfur atoms and/or 1 to 3 nitrogen atoms in the ring.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S-dioxide.
  • Aromatic heterocyclyl groups may also be referred to by the customary term "heteroaryl" for which all the definitions and explanations relating to heterocyclyl apply.
  • heterocyclyl Preferably, heterocyclyl contain 4 to 6 ring atoms forming the ring system.
  • the heterocycle may be fused with an aromatic aryl group such as phenyl.
  • heterocyclyls include, but are not limited to, oxetane, azetidine, thiophene, thietane, tetrahydrofuran, tetrahydrothiophene, dihydropyran, tetrahydropyran, thio-dihydropyran, thiotetrahydropyran, piperidine, piperazine, morpholine, 1 ,3-oxazinane, 1 ,3-thiazinane, 4,5,6-tetrahydropyrimidine, 2,3-dihydrofuran, dihydrothiene, dihydropyridine, tetrahydropyridine, isoxazolidine, pyrazolidine, pyrrole, pyrrolidine, pyrazole, imidazole, pyrazine, pyridazine, oxazole, triazole, tetrazole, isoxazole, thiazole,
  • heterocyclyl may be unsubstituted or substituted with one or more groups independently selected from (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, hydroxy, -0-(Ci-C 6 )alkyl, halo(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, halogen, cyano, amino, nitro, -ON0 2 , aryl, heterocyclyl, -C(0)OR a, -C(0)R a , -SR a , -NR a R b or -C(0)NR a R b ; wherein R a and R b are independently selected from hydrogen, (Ci-C 6 )alkyl, -C(0)OH, -C(0)0(C 1 -C 6 )alkyl, - C(0)(Ci-C 6 )alkyl, -S0 2 -(Ci-
  • the substituents may be present on either the ring carbon or the ring nitrogen atom.
  • the substituents can be present at one or more positions provided that a stable molecule results.
  • the term "halogen” or “halo” refers to a fluorine, chlorine, bromine, or iodine atom.
  • halo(Ci-C 6 )alkyl or “haloalkyl” refers to radicals wherein one or more of the hydrogen atoms of the alkyl group are substituted with one or more halogens.
  • halo(Ci-C 6 )alkyl or haloalkyl include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoro methyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl and difluoropropyl.
  • halo(CrC 6 )alkoxy or “haloalkoxy” refers to radicals wherein one or more of the hydrogen atoms of the alkoxy group are substituted with one or more halogens.
  • Representative examples of haloalkoxy groups include but not limited to difluoromethoxy (OCHF 2 ), trifluoromethoxy (OCF 3 ) or trifluorethoxy (OCH 2 CF 3 ).
  • amino refers to the group “NH 2 " which may be unsubstituted or substituted with one or more substituents.
  • substituents include, but not limited to, (CrC 4 )alkyl, aryl or the like groups.
  • the terms “compound of formula 1 ", “compounds of formula 1 ", and “compounds of the present invention” include all the stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and the pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable polymorphs and N-oxides thereof.
  • subject refers to an animal, preferably a mammal, and most preferably a human.
  • mammal refers to warm-blooded vertebrate animals of the class Mammalia, including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young.
  • mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig as well as human.
  • therapeutically effective amount means an amount of the compound of formula 1 or a composition comprising a compound of formula 1 , sufficient to significantly induce a positive modification in the condition (a disease or a disorder) to be treated, but low enough to avoid undue or severe side effects within the scope of sound medical judgment.
  • the therapeutically effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the patient (subject in need of the treatment), the severity of the condition being treated/prevented, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically acceptable carrier utilized.
  • treatment refers to alleviate, slow the progression, attenuation or cure of existing disease or condition (e.g., cancer). Treatment also includes treating the symptoms of the disease or condition.
  • Prevent or “Prevention” refers to delaying, slowing, inhibiting, reducing or ameliorating the onset of cancer.
  • stereoisomer is a general term used for all isomers of individual compounds that differ only in the orientation of their atoms in space.
  • stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
  • tautomer refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers.
  • the term "pharmaceutically acceptable” means that the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation or composition, and not deleterious to the recipient thereof.
  • pharmaceutically acceptable salt refers to a product obtained by reaction of the compound of the present invention with a suitable acid or a base.
  • solvate or “pharmaceutically acceptable solvate” describes a complex wherein the compound is coordinated with a proportional amount of a solvent molecule.
  • prodrugs or “pharmaceutically acceptable prodrugs” includes simple prodrugs of the compounds of formula 1 , for example esters, amides and other simple derivatives.
  • prodrug refers to compounds that are drug precursors, which following administration, release the drug in vivo via a chemical or physiological process e.g., a prodrug on being brought to the physiological pH or through an enzyme action is converted to the desired drug form.
  • the compounds can be crystallized in different forms.
  • polymorph or “pharmaceutically acceptable polymorph” refers to a specific crystalline form of a compound which differs only in the arrangement and/or conformation of the molecule in the crystal lattice. Polymorphs of a compound have different physical and chemical properties.
  • N-oxide refers to the oxide of the nitrogen atom of a nitrogen-containing heteroaryl or heterocycle. N-oxide can be formed in presence of an oxidizing agent for example peroxide such as m-chloro-perbenzoic acid or hydrogen peroxide. N-oxide refers to an amine oxide, also known as amine-N-oxide, and is a chemical compound that contains N->0 bond.
  • the present invention provides a compound of formula 1 ,
  • Ri at each occurrence is independently selected from (CrC 6 )alkyl, -0-(Ci-C 6 )alkyl, hydroxy, CN, halogen, halo(C C 6 )alkyl, NR a R b , -0-(Ci-C 4 )alkyl-0-(C C 4 )alkyl-0-(Ci- C 4 )alkyl and -C(0)-R; or two Ri groups present on adjacent carbon atoms of the phenyl ring may optionally form a 5 or 6 membered saturated or unsaturated ring containing 0 to 2 heteroatoms independently selected from O, N and S;
  • R is hydroxy or -0-(CrC 6 )alkyl
  • n is an integer from 0 to 3;
  • R 2 is selected from hydrogen, (C-
  • Z is selected from O, N or S
  • R 3 is hydrogen or (C-
  • W is a pyridyl ring selected from the groups of formula (i), (ii) or (iii),
  • R 4 at each occurrence is independently selected from (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(Ci-C 6 )alkyl, ar(Ci-C 6 )alkyl, halogen, cyano, amino, nitro, hydroxy, -0-(Ci-C 6 )alkyl, halo(Ci-C 6 )alkoxy, aryl and heterocyclyl; and
  • p is an integer from 0 to 5;
  • R a and R b are independently selected from hydrogen, (C-
  • each of (Ci-C 6 )alkyl, -0-(Ci-C 6 )alkyl, aryl and heterocyclyl may be unsubstituted or substituted with one or more groups independently selected from (d- C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C-i-C 6 )alkyl, halogen, cyano, amino, nitro, -ON0 2 , hydroxy, -0-(CrC 6 )alkyl, halo(CrC 6 )alkoxy, aryl, heterocyclyl, -C(0)OR a , -C(0)R a , - SR a , -NR a R b and -C(0)NR a R b , wherein R a and R b are as defined above;
  • the present invention provides a compound of formula
  • Ri at each occurrence is independently selected from (Ci-C 6 )alkyl, -0-(C-i-C 6 )alkyl, hydroxy, CN, halogen, halo(C 1 -C 6 )alkyl, NR a R b , -O-td-C ⁇ alkyl-O-td-C ⁇ alkyl-O-td- C 4 )alkyl and -C(0)-R; or two Ri groups present on adjacent carbon atoms of the phenyl ring may optionally form a 5 or 6 membered saturated or unsaturated ring containing 0 to 2 heteroatoms independently selected from O, N and S;
  • R is hydroxy or -0-(CrC 6 )alkyl
  • n is an integer from 0 to 3;
  • R 2 is selected from hydrogen, halogen or (C-
  • Yi is hydrogen and Y 2 is -Z-(R 3 )-W-[R 4 ] P ;
  • Z is selected from O, N or S
  • R 3 is hydrogen or (C-
  • W is a pyridyl ring selected from the groups of formula (i), (ii) or (iii),
  • R 4 at each occurrence is independently selected from (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(Ci-C 6 )alkyl, ar(C-i-C 6 )alkyl, halogen, cyano, amino, nitro, hydroxy, -0-(C-i- C 6 )alkyl, halo(C-i-C 6 )alkoxy, aryl and heterocyclyl; and
  • p is an integer from 0 to 5;
  • R a and Rb are independently selected from hydrogen, (CrC 6 )alkyl, -C(0)OH, - C(0)0(C 1 -C 6 )alkyl, -C(0)(CrC 6 )alkyl, -S0 2 -(C 1 -C 6 )alkyl, -S0 2 -aryl, -S0 2 -heterocyclyl, ar(CrC 6 )alkyl, aryl and heterocyclyl;
  • each of (Ci-C 6 )alkyl, -0-(Ci-C 6 )alkyl, aryl and heterocyclyl may be unsubstituted or substituted with one or more groups independently selected from (d- C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, halo(C-i-C 6 )alkyl, halogen, cyano, amino, nitro, -ON0 2 , hydroxy, -0-(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, aryl, heterocyclyl, -C(0)OR a, -C(0)R a , - SR a , -NR a R b and -C(0)NR a R b , wherein R a and R b are as defined above;
  • the present invention provides a compound of formula
  • Ri is hydroxy or -0-(CrC 6 )alkyl; n is an integer from 0 to 3;
  • R 2 is hydrogen or halogen
  • Yi is hydrogen and Y 2 is -Z-(R 3 )-W-[R 4 ] P ;
  • R 3 is hydrogen or (Ci-C 6 )alkyl
  • W is a pyridyl ring selected from the groups of formula (i), (ii) or (iii), or a phenyl ring of formula (iv),
  • R 4 at each occurrence is independently selected from halogen, halo(CrC 6 )alkyl, (d- C 6 )alkyl, and -0-(CrC 6 )alkyl;
  • p is an integer from 0 to 5;
  • (CrC 6 )alkyl and -0-(CrC 6 )alkyl may be unsubstituted or substituted with one or more groups independently selected from halogen, hydroxy, cyano, nitro and -O- (d-C 6 )alkyl;
  • the present invention provides a compound of formula
  • Ri is hydroxy or -OCH 3 ;
  • n 2;
  • Ri groups are present on adjacent carbon atoms C-3 and C-4 of the phenyl ring;
  • R 2 is hydrogen
  • Yi is hydrogen and Y 2 is -Z-(R 3 )-W-[R 4 ] P ;
  • R 3 is hydrogen
  • W is a pyridyl ring selected from the groups of formula (i), (ii) or (iii),
  • R 4 at each occurrence is independently selected from bromine, fluorine and trifluoromethyl
  • p is an integer from 0 to 5;
  • the present invention provides a compound of formula 1 ,
  • Ri is hydroxy
  • n 2;
  • Ri groups are present on adjacent carbon atoms C-3 and C-4 of the phenyl ring;
  • R 2 is hydrogen
  • Yi is hydrogen and Y 2 is -Z-(R 3 )-W-[R 4 ] P ;
  • R 3 is hydrogen
  • W is a pyridyl rin selected from the roups of formula (i), (ii) or (iii),
  • R 4 at each occurrence is independently selected from bromine, fluorine and trifluoromethyl
  • p is an integer from 0 to 5; or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.
  • the present invention provides a compound of formula 1 ,
  • n 2;
  • Ri groups are present on adjacent carbon atoms C-3 and C-4 of the phenyl ring;
  • R 2 is hydrogen
  • Yi is hydrogen and Y 2 is -Z-(R 3 )-W-[R 4 ] P ;
  • R 3 is hydrogen
  • W is a pyridyl rin selected from the groups of formula (i), (ii) or (iii),
  • R at each occurrence is independently selected from bromine, fluorine or trifluoromethyl
  • p is an integer from 0 to 5;
  • the present invention provides a compound of formula 1 ,
  • Ri is hydroxy or -OCH 3 ;
  • n 2;
  • Ri groups are present on carbon atoms C-2 and C-4 of the phenyl ring;
  • R 2 is hydrogen
  • Yi is hydrogen and Y 2 is -Z-(R 3 )-W-[R 4 ] P ;
  • Z is N;
  • R 3 is hydrogen or (C-
  • W is a pyridyl rin selected from the roups of formula (i), (ii) or (iii), or a phenyl ring of formula (iv) ,
  • R at each occurrence is independently selected from bromine, fluorine or trifluoromethyl
  • p is an integer from 0 to 5;
  • the present invention provides a compound of formula 1 ,
  • Ri is hydroxy or -OCH 3 ;
  • n 2;
  • Ri groups are present on carbon atoms C-3 and C-5 of the phenyl ring;
  • R 2 is hydrogen
  • Yi is hydrogen and Y 2 is -Z-(R 3 )-W-[R 4 ] P ;
  • R 3 is hydrogen or (CrC 6 )alkyl
  • W is a pyridyl ring selected from the roups of formula (i (ii) or (iii),
  • R at each occurrence is independently selected from bromine, fluorine or trifluoromethyl; and p is an integer from 0 to 5;
  • the present invention provides a compound of formula 1 ,
  • Ri at each occurrence is independently selected from NR a R b , halogen, halo(d- C 6 )alkyl, CN, -C(0)R and (C 1 -C 6 )alkyl;
  • R is hydroxy or -0-(C-i-C 6 )alkyl
  • n is an integer from 0 to 3;
  • R 2 is hydrogen or halogen
  • Y is hydrogen and Y 2 is -Z-(R 3 )-W-[R 4 ] P ;
  • R 3 is hydrogen or (Ci-C 6 )alkyl
  • W is a pyrid or (iii),
  • R 4 at each occurrence is independently selected from halogen, halo(CrC 6 )alkyl, (d- C 6 )alkyl and -0-(CrC 6 )alkyl;
  • p is an integer from 0 to 5;
  • R a and R b are independently selected from hydrogen, (C-
  • each of (Ci-C 6 )alkyl, -0-(Ci-C 6 )alkyl, aryl and heterocyclyl may be unsubstituted or substituted with one or more groups independently selected from halogen, halo(Ci-C 6 )alkyl, hydroxy, cyano, nitro, aryl, -ON0 2 and -0-(C-i-C 6 )alkyl; or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.
  • the present invention provides a compound of formula 1 , wherein,
  • Ri groups present on carbon atoms C-3 and C-4 of the phenyl ring form a 5 or 6 membered saturated or unsaturated ring containing 1 to 2 heteroatoms independently selected from O and N ;
  • R 2 is selected from hydrogen, (C-
  • Yi is hydrogen and Y 2 is -Z-(R 3 )-W-[R 4 ] P ;
  • Z is selected from O, N or S
  • R 3 is hydrogen or (C-
  • W is a pyridyl ring selected from the groups of formula (i), (ii) or (iii),
  • R 4 at each occurrence is independently selected from (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(Ci-C 6 )alkyl, ar(C-i-C 6 )alkyl, halogen, cyano, amino, nitro, hydroxy, -0-(C-i- C 6 )alkyl, halo(C-i-C 6 )alkoxy, aryl and heterocyclyl; and
  • p is an integer from 0 to 5;
  • R a and Rb are independently selected from hydrogen, (CrC 6 )alkyl, -C(0)OH, - C(0)0(C 1 -C 6 )alkyl, -C(0)(CrC 6 )alkyl, -S0 2 -(C 1 -C 6 )alkyl, -S0 2 -aryl, -S0 2 -heterocyclyl, ar(CrC 6 )alkyl, aryl and heterocyclyl;
  • each of (Ci-C 6 )alkyl, -0-(Ci-C 6 )alkyl, aryl and heterocyclyl may be unsubstituted or substituted with one or more groups independently selected from (d- C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C-i-C 6 )alkyl, halogen, cyano, amino, nitro, -ON0 2 , hydroxy, -0-(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, aryl, heterocyclyl, -C(0)OR a, -C(0)R a , - SR a , -NR a R b and -C(0)NR a R b , wherein R a and R b are as defined above;
  • the present invention provides a compound of formula 1 , wherein,
  • Ri at each occurrence is independently selected from (Ci-C 6 )alkyl, -0-(Ci-C 6 )alkyl, hydroxy, CN, halogen, halo(CrC 6 )alkyl, NR a R b , -0-(Ci-C 4 )alkyl-0-(C C 4 )alkyl-0-(Ci- C 4 )alkyl and -C(0)-R; or when two Ri groups are present on adjacent carbon atoms of the phenyl ring, they may optionally form a 5 or 6 membered saturated or unsaturated ring containing 0 to 2 heteroatoms selected from O, N and S;
  • R is hydroxy or -0-(C-i-C 6 )alkyl
  • n is an integer from 0 to 3;
  • R 2 is selected from hydrogen, (CrC 6 )alkyl or halogen
  • Yi is -Z-(R 3 )-W-[R 4 ] P and Y 2 is hydrogen;
  • Z is selected from O, N or S
  • R 3 is hydrogen or (C-
  • W is a pyridyl ring selected from the groups of formula (i), (ii) or (iii),
  • R 4 at each occurrence is independently selected from (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(Ci-C 6 )alkyl, ar(C-i-C 6 )alkyl, halogen, cyano, amino, nitro, hydroxy, -0-(C-i- C 6 )alkyl, halo(Ci-C 6 )alkoxy, aryl and heterocyclyl; and
  • p is an integer from 0 to 5;
  • R a and R b are independently selected from hydrogen, (C-
  • each of (Ci-C 6 )alkyl, -0-(Ci-C 6 )alkyl, aryl and heterocyclyl may be unsubstituted or substituted with one or more groups independently selected from (C C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, halo(C-i-C 6 )alkyl, halogen, cyano, amino, nitro, -ON0 2 , hydroxy, -0-(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, aryl, heterocyclyl, -C(0)OR a, -C(0)R a , - SR a , -NR a R b and -C(0)NR a R b , wherein R a and R b are as defined above;
  • the present invention provides a compound of formula
  • Ri at each occurrence is independently selected from (Ci-C 6 )alkyl, -C(0)R, -0-(C r C 6 )alkyl and hydroxy;
  • n 2;
  • R is hydroxy or -0-(C-i-C 6 )alkyl
  • R 2 is hydrogen or halogen
  • Yi is -Z-(R 3 )-W-[R 4 ] P and Y 2 is hydrogen;
  • R 3 is hydrogen or (Ci-C 6 )-alkyl
  • R 4 at each occurrence is independently selected from halogen, halo(Ci-C 6 )alkyl, (d- C 6 )alkyl and -0-(C 1 -C 6 )alkyl;
  • p is an integer from 0 to 5 ;
  • (CrC 6 )alkyl and -0-(CrC 6 )alkyl is unsubstituted or substituted with one or more groups independently selected from halogen, hydroxy, cyano, nitro and 0-(Ci- C 6 )alkyl;
  • the present invention provides a compound of formula
  • Ri at each occurrence is independently selected from hydroxy, -OCH 3 and -C(0)R; n is 2;
  • R is hydroxy or -0-(C C 6 )alkyl
  • Ri groups are present on adjacent carbon atoms C-3 and C-4 of the phenyl ring;
  • R 2 is hydrogen
  • Yi is -Z-(R 3 )-W-[R 4 ] P and Y 2 is hydrogen;
  • Z is N; R 3 is hydrogen;
  • W is a pyridyl ring selected from the groups of formula (i), (ii) or (iii),
  • R at each occurrence is independently selected from bromine, fluorine or trifluoromethyl
  • p is an integer from 0 to 5;
  • the present invention provides a compound of formula 1 ,
  • Ri at each occurrence is independently selected from hydroxy and -OCH 3 ;
  • n 2;
  • Ri groups are present on carbon atoms C-2 and C-4 of the phenyl ring;
  • R 2 is hydrogen
  • Yi is -Z-(R 3 )-W-[R 4 ] P and Y 2 is hydrogen;
  • R 3 is hydrogen
  • W is a pyridyl rin selected from the groups of formula (i), (ii) or (iii),
  • R 4 is bromine or trifluoromethyl
  • p is an integer from 0 or 1 ; or a stereoisomer or a tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.
  • the present invention provides a compound of formula 1 ,
  • R 2 is hydrogen
  • Yi is -Z-(R 3 )-W-[R 4 ] P and Y 2 is hydrogen;
  • R 3 is hydrogen
  • W is a pyridyl rin selected from the roups of formula (i), (ii) or (iii),
  • R is bromine or trifluoromethyl
  • p is an integer 0 or 1 ;
  • the present invention provides a compound of formula 1 ,
  • Ri at each occurrence is independently selected from (Ci-C 6 )alkyl, -0-(C-i-C 6 )alkyl and hydroxy;
  • n 2;
  • R 2 is halogen
  • Yi is -Z-(R 3 )-W-[R 4 ] P and Y 2 is hydrogen;
  • R 3 is hydrogen or (CrC 6 )-alkyl
  • W is a pyridyl ring selected from the groups of formula (i), (ii) or (iii),
  • R 4 at each occurrence is independently selected selected from halogen, halo(C-i- C 6 )alkyl, (C 1 -C 6 )-alkyl, and -0-(CrC 6 )-alkyl;
  • p is an integer from 0 to 5 ;
  • (Ci-C 6 )alkyl and -0-(CrC 6 )alkyl is unsubstituted or substituted with one or more groups independently selected from halogen, hydroxy, cyano, nitro and 0-(C C 6 )alkyl;
  • representative compounds of the present invention are:
  • the compounds of the present invention also include all stereoisomeric and tautomeric forms and mixtures thereof in all ratios and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable polymorphs and N-oxides.
  • One or more of the reagents, reactants and intermediates used in the following processes are either commercially available or can be prepared according to standard procedures known in the art.
  • the starting compounds and the intermediates used for the synthesis of compounds of the present invention are referred to by the symbols A, B, C, D, E, F and G.
  • Scheme 1 Preparation of the compound of formula 1 [referred to in Scheme 1 as compound of formula D (wherein R-i, n, R 2 , Yi and Y 2 are as defined in any one of the embodiments of the compound of formula 1 described herein) and compound of formula E (wherein R is a hydroxy, and n, R 2 , Yi and Y 2 are as defined in any one of the embodiments of the compound of formula 1 described herein)].
  • reaction step 1a The resulting reaction mixture is warmed to 70 °C to 95 °C, for 12 - 20 h, which results in the formation of a boron complex represented by the compound of formula B (wherein R and n are as defined in any one of the embodiments of the compound of formula 1 described herein) (Reaction step 1a).
  • the boron complex i.e. the compound of formula B (as obtained in step 1 ; wherein R and n are as defined in any one of the embodiments of the compound of formula 1 described herein) is reacted with a compound of formula G, which is a dihalopyrimidine compound (wherein, Xi is halogen, R x and R y are selected from hydrogen or halogen such that at least one of R x and R y is hydrogen and the other is halogen; and R 2 is as defined in any one of the embodiments of the compound of formula 1 described herein), in the presence of reagents such as potassium carbonate, triphenyl phosphine and palladium acetate, in a mixture of solvents; such as dimethoxy ethane-water or dioxane-water, at a temperature ranging from 25 °C to 30 °C.
  • reagents such as potassium carbonate, triphenyl phosphine and palladium acetate
  • reaction step 1 b The reaction mixture is warmed to 70 °C to 90 °C, for 12 - 20 h, which results in the formation of the compound of formula C (wherein, X is halogen, R x and R y are selected from hydrogen or halogen such that at least one of R x and R y is hydrogen and the other is halogen; and R-i, n and R 2 are as defined in any one of the embodiments of the compound of formula 1 described herein) (Reaction step 1 b).
  • the compound of formula C (as obtained in step 2; wherein, Xi is halogen, R x and R y are selected from hydrogen or halogen such that at least one of R x and R y is hydrogen and the other is halogen; and R-i, n and R 2 are as defined in any one of the embodiments of the compound of formula 1 described herein) is reacted with an amine represented by the formula, R 3 -NH-W-[R 4 ] P (wherein R 3 , R 4 , W and p are as defined in any one of the embodiments of the compound of formula 1 described herein) in the presence of a base selected from sodium hydride, potassium carbonate or sodium carbonate and a solvent such as ⁇ , ⁇ -Dimethylformamide (DMF) and dimethylsulfoxide (DMSO), at a temperature ranging from 25 °C to 30 °C, for 12 - 20 h, which results in the formation of a compound of formula D (wherein R-i , n,
  • the compound of formula D (as obtained in step 3; wherein R ; n, R 2 , Y and Y 2 are as defined in any one of the embodiments of the compound of formula 1 described herein) is reacted with boron tribromide in a solvent selected from dichloromethane, chloroform or carbon tetrachloride, at a temperature ranging from -40 °C to -10 °C, for 10 - 55 min.
  • reaction step 1d The reaction mixture is warmed to 20 °C to 30 °C, for 2 - 5 h, which results in the formation of a compound of formula E (wherein R is a hydroxy, and R-i , n, R 2 , Yi and Y 2 are as defined in any one of the embodiments of the compound of formula 1 described herein) (Reaction step 1d).
  • Scheme 2 Preparation of the compound of formula 1 [referred in Scheme 2 as the compound of formula D (wherein R-i , n, R 2 , Y and Y 2 are as defined in any one of the embodiments of the compound of formula 1 described herein) and the compound of formula E (wherein Ri is a hydroxy and R-i , n, R 2 , Yi and Y 2 are as defined in any one of the embodiments of the compound of formula 1 described herein)].
  • a compound of formula F (wherein R and n are as defined in any one of the embodiments of the compound of formula 1 described herein) is reacted with a compound of formula G, which is a dihalopyrimidine compound (wherein, X is halogen, R x and R y are selected from hydrogen or halogen such that at least one of R x and R y is hydrogen and the other is halogen; and R 2 is as defined in any one of the embodiments of the compound of formula 1 described herein), in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium and a base selected from potassium carbonate, sodium carbonate or cesium carbonate, in the presence of a mixture of solvents such as dimethoxy ethane-water or dioxane-water.
  • a catalyst such as tetrakis(triphenylphosphine)palladium
  • a base selected from potassium carbonate, sodium carbonate or cesium carbonate
  • reaction step 2a The reaction mixture is warmed to 70 °C to 95 °C, for 15 - 25 h which results in the formation of a compound of formula C (wherein, X is halogen, R x and R y are selected from hydrogen or halogen such that at least one of R x and R y is hydrogen and the other is halogen; and R-i , n and R 2 are as defined in any one of the embodiments of the compound of formula 1 described herein) (Reaction step 2a).
  • X is halogen
  • R x and R y are selected from hydrogen or halogen such that at least one of R x and R y is hydrogen and the other is halogen
  • R-i , n and R 2 are as defined in any one of the embodiments of the compound of formula 1 described herein
  • the compound of formula C (as obtained in step 1 ; wherein, X is halogen, R x and R y are selected from hydrogen or halogen such that at least one of R x and R y is hydrogen and the other is halogen; and R-i , n, R 2 , are as defined in any one of the embodiments of the compound of formula 1 described herein) is reacted with an amine represented by formula, R 3 -NH-W-[R 4 ] P (wherein R 3 , R 4 , W and p are as defined in any one of the embodiments of the compound of formula 1 described herein) in the presence of a base selected from sodium hydride, potassium carbonate or sodium carbonate and an inert solvent such as DMF and DMSO, at a temperature ranging from 25 °C to 30 °C, for 12 - 20 h which results in the formation of compound of formula D (wherein R ; n, R 2 , Yi and Y 2 are as defined in any one of the embodiments
  • compound of formula C (as obtained in step 1 ; wherein, Xi is halogen, R x and R y are selected from hydrogen or halogen such that at least one of R x and R y is hydrogen and the other is halogen; and R-i , n, R 2 , are as defined in any one of the embodiments of the compound of formula 1 described herein) is reacted with an amine represented by the formula, R 3 -NH-W-[R 4 ] P (wherein R 3 , R 4 , W and p are as defined in any one of the embodiments of the compound of formula 1 described herein) in the presence of an inert solvent such as dioxane, at a temperature ranging from 80 °C to 90 °C, for 12 - 20 h which results in the formation of compound of formula D (wherein R-i, n, R 2 , Y and Y 2 are as defined in any one of the embodiments of the compound of formula 1 described herein) (Reaction step 1)
  • step 2 The compound of formula D (as obtained in step 2; wherein R-i , n, R 2 , Yi and Y 2 are as defined in any one of the embodiments of the compound of formula 1 described herein) is reacted with 40 % hydrobromic acid in water at a temperature ranging from 120 °C to 140 °C, for 12 - 20 h which results in the formation of compound of formula E (wherein R is a hydroxy, n, R 2 , Y and Y 2 are as defined in any one of the embodiments of the compound of formula 1 described herein) (Reaction step 2c).
  • the compound of formula D (as obtained in step 2; wherein R ; n, R 2 , Yi and Y 2 are as defined in any one of the embodiments of the compound of formula 1 described herein) and methane sulphonic acid is reacted with L-methionine at a temperature ranging from 25 °C to 30 °C, for 20 - 50 min.
  • the reaction mixture is warmed to 70 °C to 1 10 °C, for the period of 12 - 20 h which results in the formation of compound of formula E (wherein Ri is a hydroxy, n, R 2 , Yi and Y 2 are as defined in any one of the embodiments of the compound of formula 1 described herein) (Reaction step 2d).
  • the compound of formula D (as obtained in step 2; wherein R-i , n, R 2 , Yi and Y 2 are as defined in any one of the embodiments of the compound of formula 1 described herein) is reacted with boron tribromide in the presence of a solvent selected from dichloromethane, chloroform or carbon tetrachloride at a temperature -78 °C, for 10 - 55 min.
  • a solvent selected from dichloromethane, chloroform or carbon tetrachloride at a temperature -78 °C, for 10 - 55 min.
  • reaction step 2e The reaction mixture is warmed to 20 °C to 30 °C, for 2 - 5 h, and was stirred for 20 - 30 h which results in formation of a compound of formula E (wherein R is a hydroxy, n, R 2 , Y and Y 2 are as defined in any one of the embodiments of the compound of formula 1 described herein) (Reaction step 2e).
  • pharmaceutically acceptable salt(s) means those salts of compounds of the formula 1 that are safe for use in mammals.
  • Pharmaceutically acceptable salts include salts of acidic or basic groups present in the compounds of the invention (the compounds of formula 1 ).
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate or p-toluenesulfonate salts.
  • Certain compounds of the invention can form pharmaceutically acceptable salts with various organic bases such as lysine, arginine, guanidine, diethanolamine or metformin.
  • Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc, salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compound of formula 1 , which contains a basic or an acidic group, by using conventional chemical methods.
  • the salts are prepared by treating the compound of formula 1 which may be a free base or an acid with a suitable salt-forming inorganic or organic acid or a base in a suitable solvent or dispersant or from another salt by cation or anion exchange.
  • suitable solvents are, for example, ethyl acetate, diethyl ether, methanol, ethanol, acetone, tetrahydrofuran, dioxane or mixtures of these solvents.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are suitable for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • polymorphs of compound of formula 1 can be prepared by crystallization of the compound under different conditions.
  • the different conditions are, for example, using different solvents or their mixtures for carrying out crystallization; crystallization at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallization or by heating or melting the compound followed by gradual or fast cooling.
  • the presence of polymorphs can be determined by IR (Infra-red) spectroscopy, solid probe NMR (Nuclear Magnetic Resonance) spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the present invention also encompasses within its scope prodrugs of the compound of formula 1 .
  • the prodrugs of the compounds of the present invention are derivatives of the said compounds which upon administration to a subject in need thereof undergoes conversion by metabolic or chemical processes to release the parent drug in vivo from which the prodrug is derived.
  • the preferred prodrugs are pharmaceutically acceptable ester derivatives e.g., alkyl esters, cycloalkyl esters, alkenyl esters, benzyl esters, mono- or di-substituted alkyl esters that are convertible by solvolysis under physiological conditions to the parent carboxylic acid (e.g. the compound of Formula I containing the carboxylic acid group), and those conventionally used in the art.
  • the present invention furthermore relates to pharmaceutical compositions containing a therapeutically effective amount of at least one compound of formula 1 or a pharmaceutically acceptable salt thereof in addition to a customary pharmaceutically acceptable carrier or excipient, and to a process for the production of a pharmaceutical compositions, which includes bringing at least one compound of formula 1 , into a suitable administration form using a pharmaceutically acceptable excipient and, if appropriate, further suitable additives or auxiliaries.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the present invention relates to a method for the treatment of a disease or a disorder mediated by one or more kinases comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1 , or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.
  • the present invention relates to use of a compound of formula 1 or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N- oxide thereof, for the treatment of a disease or a disorder mediated by one or more kinases.
  • the present invention provides use of the compound of formula 1 or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N- oxide thereof, for the manufacture of a medicament, for treating a disease or a disorder mediated by one or more kinases.
  • a method of inhibiting one or more kinases comprising treating a subject in need thereof, an effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof capable of inhibiting said kinases.
  • the kinases which can be inhibited by the compounds of formula 1 are selected from, but not limited to, Abelson murine leukemia viral oncogene homolog 1 T315I (ABL1 T315I), Abelson murine leukemia viral oncogene homolog 1 wt (ABL1 wt), activin receptor-like kinase 1 RL-1 (ACV-RL1 ), v-raf murine sarcoma viral oncogene homolog B1 600E (B-RAF V600E), v-raf murine sarcoma viral oncogene homolog B1 wt (B-RAF wt), Cyclin- dependent kinase 1 / cyclin A (CDK1 /CycA), Cyclin- dependent kinase 1 / cyclin B1 (CDK1 /CycB1 ), Cyclin- dependent kinase 1 / cyclin E1 (CDK1 /CycE1
  • the kinase(s) that mediate the disease or disorder, particularly a proliferative disorder e.g. cancer, that is capable of being treated by the compounds of the present invention include one or more kinases selected from, ABL1 T31 5I, ABL1 wt, ACV-RL1 , B-RAF V600E, B-RAF wt, CDK1 /CycA, CDK1 /CycB1 , CDK1 /CycE1 , CDK2/CycA, CDK2/CycE1 , CDK3/CycE1 , CDK4/CycD1 , CDK4/CycD3, CDK5/p25NCK, CDK5/p35NCK, CDK6/CycD1 , CDK8/CycC, CDK9/CycK, CDK9/CycT, CLK1 , CLK4, FLT3 D835Y, FL
  • the proliferative disorder is cancer.
  • the present invention relates to a method for the treatment of cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1 , or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof.
  • the present invention relates to use of a compound of formula 1 or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof, for the treatment of cancer.
  • the present invention provides use of the compound of formula 1 or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof, for the manufacture of a medicament for treating cancer.
  • the cancer is selected from: leukemia, lung cancer, brain tumors, non-Hodgkin's lymphoma, Hodgkin's disease, liver cancer, kidney cancer, bladder cancer, cancer of urinary tract, breast cancer, head and neck cancer, endometrial cancer, lymphoma, melanoma, cervical cancer, thyroid cancer, gastric cancer, germ cell tumor, cholangiocarcinoma, extracranial cancer, sarcoma, mesothelioma, malignant fibrous histiocytoma of bone, retinoblastoma, esophageal cancer, multiple myeloma, pancreatic cancer, ependymoma, neuroblastoma, skin cancer, ovarian cancer, recurrent ovarian cancer, prostate cancer, testicular cancer, colorectal cancer, lymphoproliferative disease, refractory multiple myeloma, resistant multiple myeloma or myeloproliferative
  • the cancer is selected from: acute lymphocytic leukemia, acute myeloid leukemia, adult acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia resistant to treatment with imatinib mesylate, hairy cell leukemia, non-small-cell lung cancer, small-cell lung cancer, brain stem glioma, glioblastoma, astrocytoma including cerebellar astrocytoma and cerebral astrocytoma, visual pathway glioma, hypothalamic glioma, supratentorial primitive neuroectodermal, pineal tumors, medulloblastoma, primary central nervous system lymphoma, mantle cell lymphoma, Hodgkin's disease, hepatocellular carcinoma, renal cell carcinoma, Wilms' tumor, bladder cancer, cancer of urinary tract, Ewing's sarcom
  • the cancer is selected from: acute lymphocytic leukemia, acute myeloid leukemia, adult acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloid leukemia resistant to treatment with imatinib mesylate, hairy cell leukemia, non-small-cell lung cancer, small-cell lung cancer, brain stem glioma, glioblastoma, astrocytoma including cerebellar astrocytoma and cerebral astrocytoma, medulloblastoma, renal cell carcinoma, bladder cancer, cancer of urinary tract, breast cancer, oral cancer, melanoma, cervical cancer, thyroid cancer, gastric cancer, pancreatic cancer, skin cancer, frovarian cancer, recurrent ovarian cancer, prostate cancer or colorectal cancer.
  • the cancer is selected from acute lymphoblastic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, adult acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, imatinib resistant chronic myeloid leukemia, or hairy cell leukemia.
  • the cancer is chronic myeloid leukemia.
  • the cancer is chronic myeloid leukemia that is resistant to treatment with imatinib mesylate.
  • the compounds of the present invention are used in a method for reducing the population of imatinib mesylate sensitive (e.g., K-562 , KU 812 or Ba/F3 Bcr-AbI/ WT) and imatinib mesylate resistant (Ba/F3 Bcr-AbI/ T315I, Ba/F3 Bcr-AbI/ E255K, Ba/F3 Bcr-AbI/ M351 T, Ba/F3 Bcr-AbI/ F359V, Ba/F3 Bcr-AbI/ E255V, Ba/F3 Bcr-AbI/ F317V, Ba/F3 Bcr-AbI/ H396R, Ba/F3 Bcr-AbI/ H396P, Ba/F3 Bcr-AbI/ M244V, Ba/F3 Bcr-AbI/ Q252H, Ba/F3 Bcr-AbI/ Y253F and Ba/F3 B
  • the compounds of the present invention can be used to reduce proliferation of the human cell lines that comprise: H460 (lung carcinoma), HCT-1 16 (colon carcinoma), A2780 (ovarian carcinoma), Miapaca-2 (pancreatic carcinoma), PC-3 (prostate carcinoma), MCF-7, MDA-MB-231 , MDA-MB-468 and BT- 549 (human breast cell lines), Miapaca-2, Panc-1 , Capan-1 and BxPC-3 (human pancreatic cell lines).
  • the in vivo efficacy of the compounds of the present invention in imatinib mesylate-sensitive and imatinib mesylate-resistant tumor models can be evaluated by using cell lines such as Ba/F3 transfectants expressing full-length wild type Bcr-Abl (Ba/F3 Bcr-Abl/ WT) or mutated Bcr-Abl (Ba/F3 Bcr-Abl/T315l) in xenograft models of SCID (Severely Combined Immune-Deficient) mice.
  • cell lines such as Ba/F3 transfectants expressing full-length wild type Bcr-Abl (Ba/F3 Bcr-Abl/ WT) or mutated Bcr-Abl (Ba/F3 Bcr-Abl/T315l) in xenograft models of SCID (Severely Combined Immune-Deficient) mice.
  • a compound of formula 1 or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof can be used to reduce, inhibit, or diminish the proliferation of tumor cells, and thereby asist in reducing the size of a tumor.
  • the present invention provides use of the compound of formula 1 , or a stereoisomer, tautomer, or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof, for reduction in the proliferation of CML stem cells.
  • the present invention also relates to use of a compound of formula 1 or a pharmaceutically acceptable salt thereof; in combination with at least one further therapeutically active compound or other therapies such as radiation.
  • the compounds of the present invention can be administered alone or in combination with other therapies suitable for the disease or disorder e.g. cancer to be treated. Where separate dosage formulations are used, the compound and the other therapeutic agent can be administered at essentially the same time (concurrently) or at separately staggered times (sequentially).
  • the pharmaceutical combination is understood to include all these regimens.
  • Administration in these various ways are suitable for the present invention as long as the beneficial therapeutic effect of the compound and the other therapeutic agent are realized by the patient at substantially the same time. In an embodiment, such beneficial effect is achieved when the target blood level concentrations of each active drug are maintained at substantially the same time.
  • the compound of formula 1 or a pharmaceutically acceptable salt thereof can be combined with one or more therapeutic agents, particularly anti-cancer agents.
  • the compounds of the present invention can be used in combination with one or more known anti-cancer agents or an investigational drug that could be approved by regulatory agencies for use in the treatment of cancers.
  • a pharmaceutical composition containing a compound of formula 1 or a pharmaceutically acceptable salt can be administered to a subject in need thereof, particularly a mammal e.g. a human, with one or more anti-cancer compound, in combination.
  • the present invention encompasses pharmaceutical compositions comprising a therapeutically effective amount of the compound of the present invention and a pharmaceutically acceptable carrier and a further therapeutic active agent, such as an anti-cancer agent.
  • anti-cancer agents include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, apoptosis inducing agents, agents that interfere with cell cycle checkpoints, agents that interfere with receptor tyrosine kinases (RTKs) and cancer vaccines.
  • RTKs receptor tyrosine kinases
  • anticancer agents are, but not limited to, asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin, epirubicin, etoposide, fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, streptozocin, tamoxifen, thioguanine, vinblastine, vincristine, vindesine, aminoglutethimide, 5-azacytidine, cladribine, busulfan
  • the present invention relates to a compound of formula 1 or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder mediated by one or more pro-inflmmatory cytokines selected from Tumor Necrosis Factor-alpha (TNF-a), and interleukins (IL-1 ⁇ , IL-2, IL-6 and/or IL-8).
  • TNF-a Tumor Necrosis Factor-alpha
  • IL-1 ⁇ , IL-2, IL-6 and/or IL-8 interleukins
  • compositions including a therapeutically effective amount of one compound of formula 1 or a pharmaceutically acceptable salt thereof, as an active ingredient and pharmaceutically acceptable carrier, for use in the treatment of a disorder mediated by one or more pro-inflmmatory cytokines selected from Tumor Necrosis Factor-alpha (TNF-a), and interleukins (IL-1 ⁇ , IL-2, IL-6 and/or IL-8).
  • TNF-a Tumor Necrosis Factor-alpha
  • IL-1 ⁇ , IL-2, IL-6 and/or IL-8 interleukins
  • a method of treatment of a disorder mediated by one or more pro-inflammatory cytokines selected from Tumor Necrosis Factor-alpha (TNF-a), and interleukins (IL-1 ⁇ , IL-2, IL-6 and/or IL-8), comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof.
  • TNF-a Tumor Necrosis Factor-alpha
  • IL-1 ⁇ , IL-2, IL-6 and/or IL-8 interleukins
  • the present invention provides use of the compound of formula 1 or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph or an N-oxide thereof, for the manufacture of a medicament, for treating a disorder mediated by one or more pro-inflammatory cytokines selected from Tumor Necrosis Factor-alpha (TNF-a), and interleukins (IL-1 ⁇ , IL-2, IL-6 and/or IL-8).
  • TNF-a Tumor Necrosis Factor-alpha
  • IL-1 ⁇ , IL-2, IL-6 and/or IL-8 interleukins
  • a method of inhibiting one or more pro-inflammatory cytokines selected from Tumor Necrosis Factor-alpha (TNF-a), and interleukins (IL-1 ⁇ , IL-2, IL-6 and/or IL-8), comprising treating a subject in need thereof, an effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof capable of inhibiting said pro-inflammatory cytokines.
  • TNF-a Tumor Necrosis Factor-alpha
  • IL-1 ⁇ , IL-2, IL-6 and/or IL-8 interleukins
  • the disorder mediated by the pro-inflammatory cytokine is selected from: inflammatory bowel disease, inflammation, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic non- rheumatoid arthritis, osteoporosis/bone resorption, Crohn's disease, septic shock, endotoxic shock, atherosclerosis, ischemia-reperfusion injury, coronary heart disease, vasculitis, amyloidosis, multiple sclerosis, sepsis, chronic recurrent uveitis, hepatitis C virus infection, malaria, ulcerative colitis, cachexia, psoriasis, plasmocytoma, endometriosis, Behcet's disease, Wegener's granulomatosis, meningitis, AIDS (Acquired immune deficiency syndrome), HIV infection, autoimmune disease, immune deficiency syndrome
  • the disease or disorder mediated by proinflammatory cytokine, interleukins (I L- 1 ⁇ , IL-2, IL-6 and/or IL-8) is selected from: rheumatoid arthritis, osteoarthritis and other autoimmune conditions.
  • the methods of treatment and the uses as described herein as well as the methods of inhibiting one or more kinases or TNF-a or the interleukins (I L- 1 ⁇ , IL-2, IL- 6 and/or IL-8) described herein, involve use of the pharmaceutical compositions described above that can be administered by the following routes or modes of administration.
  • compositions of the present invention can be administered orally, for example in the form of pills, tablets, coated tablets, capsules, granules or elixirs. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of ointments or creams or transdermally, in the form of patches, or in other ways, for example in the form of aerosols or nasal sprays.
  • compositions according to the invention are prepared in a manner known and familiar to one skilled in the art.
  • Pharmaceutically acceptable inert inorganic and/or organic carriers and/or additives can be used in addition to the compound of formula 1 , or a pharmaceutically acceptable salt for the production of pills, tablets, coated tablets and hard gelatin capsules it is possible to use, for example, lactose, corn starch or derivatives thereof, gum arabica, magnesia or glucose, etc.
  • Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, natural or hardened oils, etc.
  • Suitable carriers for the production of solutions for example injection solutions, or of emulsions or syrups are, for example, water, physiological sodium chloride solution or alcohols, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the various solvents which have been mentioned.
  • the pharmaceutical preparations normally contain about 1 to 99 %, for example, about 5 to 70 %, or from about 10 to 30 % by weight of the compound of the formula 1 or a pharmaceutically acceptable salt thereof.
  • the amount of the compound of the formula 1 or its salt in the pharmaceutical compositions can normally range from about 5 to 500 mg.
  • the dose of the compounds of the present invention, which is to be administered can cover a wide range.
  • the dose to be administered daily is to be selected to suit the desired therapeutic effect.
  • a suitable dose can range from about 0.01 to 100 mg/kg/day of the compound of formula 1 or a pharmaceutically acceptable salt, for example, about 0.1 to 50 mg/kg/day of a compound of formula 1 or a pharmaceutically acceptable salt of the compound. If required, higher or lower daily doses can also be administered.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compounds employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and factors well known in the medical arts.
  • the pharmaceutical preparations can contain additives such as, for example, fillers, antioxidants, dispersants, emulsifiers, defoamers, flavors, preservatives, solubilizers or colorants. They can also contain two or more compounds of formula 1 or their salts.
  • reaction mixture was cooled to temperature 25 - 30 °C and ethyl acetate
  • the reaction mixture was cooled to 25 °C and ethyl acetate (25 mL) was added and was stirred for 5 - 10 min.
  • 1 N HCI 60 mL was added to the reaction mixture and stirred for 1 5 - 20 min.
  • the reaction mixture was filtered through celite. The organic layer was dried over anhydrous sodium sulphate and the solvent was evaporated to obtain the crude product (5.6 g).
  • the crude product was suspended in methanol (25 mL) at 50 °C and slowly cooled to 25 - 30 °C. The precipitated product was filtered and washed with chilled methanol (5 mL) and dried to obtain the title compound.
  • the reaction mixture was cooled to 10 °C and to it methanol (2 mL) was added.
  • a chilled solution of 20 % ammonium chloride solution (100 mL) was added drop-wise to the reaction mixture at 10 - 15 °C and was stirred for 25 - 30 min.
  • the precipitated product was filtered and was washed with water followed by petroleum ether. The product was dried at 45 - 50 °C for 20 - 22 h.
  • the reaction mixture was quenched into chilled 5 % sodium bicarbonate (20 mL) solution at 15 - 20 °C (pH 8-9).
  • the product was extracted with ethyl acetate (25 mL).
  • the organic layer was washed with brine and was dried over anhydrous sodium sulphate.
  • the solvent was evaporated to obtain the crude product (0.25 g).
  • the crude product was purified by column chromatography (silica gel, 1 % methanol in chloroform) to obtain the title compound.
  • the reaction mixture was cooled to 10 °C and to it methanol (1 mL) was added.
  • the reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (8 ml_) till pH was 9, at 15 - 20 °C.
  • the product was extracted with ethyl acetate (10 ml_), was washed with brine and was dried over anhydrous sodium sulphate.
  • the solvent was evaporated to obtain the crude product (0.096 g) and was purified by column chromatography (silica gel, 1 % methanol in chloroform) to obtain the title compound.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (7 mL) and the organic layer was dried over anhydrous sodium sulphate.
  • the solvent was evaporated to obtain the crude product (0.1 g) which was further purified by column chromatography (silica gel, 1 % methanol in chloroform) to obtain the title compound.
  • 6-(Trifluoromethyl)-pyridin-2ylamine (0.7 g, 4.27 mmol) was added to a mixture of sodium hydride (1 .2 g, 49.7 mmol) and N,N-dimethylformamide (9.96 mL) under nitrogen gas at 25 - 30 °C and the reaction mixture was stirred for 15 - 20 min.
  • Compound of example 2 (1 .245 g, 4.97 mmol) was added to the reaction mixture and was stirred for 16 -18 h.
  • the reaction mixture was cooled to 10 °C and methanol (2.5 mL) was added slowly.
  • a solution of chilled 20 % ammonium chloride solution (125 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min.
  • the precipitated product was filtered, and was washed with water followed by petroleum ether. The resulting product was dried at 45 - 50 °C for 20 - 22 h.
  • 6-trifluoromethyl-pyridin-3-ylamine (0.25 g, 1 .54 mmol) was added to a mixture of sodium hydride (0.22 g, 9.16 mmol) and N,N-dimethylformamide (2 mL) at 25 - 30 °C under nitrogen gas and the reaction mixture was stirred for 15 - 20 min.
  • Compound of example 2 (0.44 g, 1 .7 mmol) was added to the reaction mixture and was stirred for 6 - 8 h.
  • the reaction mixture was cooled to 10 °C and methanol (1 .2 mL) was added slowly.
  • a solution of chilled 20 % ammonium chloride solution (10 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min.
  • the precipitated product was filtered, and was washed with water followed by petroleum ether.
  • the resulting product was dried at 45 - 50 °C for 20 - 22 h.
  • the reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (8 mL) at 15 - 20 °C (pH was 9).
  • the product was extracted with ethyl acetate (15 mL), the organic layer was washed with brine and dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product (0.085 g).
  • the crude product was purified by column chromatography (silica gel, 1 % methanol in chloroform) to obtain the title compound.
  • the reaction mixture was cooled to 10 °C and methanol (1 .2 mL) was added slowly.
  • a solution of chilled 20 % ammonium chloride solution (10 mL) was added drop-wise to the reaction mixture at 10 °C and was stirred for 25 - 30 min.
  • the precipitated product was filtered, and was washed with water followed by petroleum ether.
  • the resulting product was dried at 45 - 50 °C for 20 - 22 h.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (7 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (16 ml_) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (21 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 ml_) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (7 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (7 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • 3,5,6-Trifluoropyridin-2-amine (0.51 g, 3.44 mmol) was added to a mixture of sodium hydride (0. 495 g, 20.6 mmol) and N,N-dimethylformamide (10 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min.
  • Compound of example 2 (1 .0 g, 3.99 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h.
  • the reaction mixture was cooled to 10 °C and methanol (1 .7 mL) was added slowly.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (7 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • 2,3,4,5,6-Pentafluoroaniline (0.63 g, 3.47 mmol) was added to a mixture of sodium hydride (0. 5 g, 20.8 mmol) and N,N-dimethylformamide (12 ml_) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min.
  • Compound of example 2 (1 .0g, 4.02 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (2.1 ml_) was added slowly.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (22 ml_) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (28 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • 6-(Trifluoromethyl)pyridin-2-amine (0.146 g, 0.90 mmol) was added to a mixture of sodium hydride (0.129 g, 5.4 mmol) and N,N-dimethylformamide (3.0 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min.
  • Compound of example 31 (0.26 g, 1 .04 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.5 mL) was added slowly.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 ml_) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (7 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • 6-(Trifluoromethyl)pyridin-2-amine (0.19 g, 1 .17 mmol) was added to a mixture of sodium hydride (0.168 g, 7.02 mmol) and N,N-dimethylformamide (3.8 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min.
  • Compound of example 34 (0.339 g, 1 .35 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.6 mL) was added slowly.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (7 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • 6-(Trifluoromethyl)pyridin-2-amine (0.31 g, 1 .91 mmol) was added to a mixture of sodium hydride (0.275 g, 1 1 .4 mmol) and N,N-dimethylformamide (6.2 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min.
  • Compound of example 37 (0.48 g, 2.21 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h.
  • the reaction mixture was cooled to 10 °C and methanol (1 .0 mL) was added slowly.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (8.4 ml_) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (10 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • 6-(Trifluoromethyl)pyridin-2-amine (0.15 g, 0.92 mmol) was added to a mixture of sodium hydride (0. 13 g, 5.5 mmol) and N,N-dimethylformamide (3.0 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min.
  • Compound of example 40 (0.24 g, 1 .06 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.5 mL) was added slowly.
  • the reaction mixture was stirred under nitrogen at 80-90 °C for 20 h.
  • the reaction mixture was cooled to room temperature and was concentrated.
  • the residue was partitioned between ethyl acetate (2 x 100 mL) and water (50 mL). Combined organic layers were dried over anhydrous sodium sulphate.
  • the solvent was evaporated to obtain the title compound, which was further purified by column chromatography to obtain the title compound.
  • 6-(Trifluoromethyl)pyridin-2-amine (0.56 g, 3.45 mmol) was added to a mixture of sodium hydride (0.25 g, 10.4 mmol) and N,N-dimethylformamide (1 1 .2 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min.
  • Compound of example 42 (1 .0 g, 4.0 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h.
  • the reaction mixture was cooled to 10 °C and methanol (1 .9 mL) was added slowly.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (4.5 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (6 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • 6-(Trifluoromethyl)pyridin-3-amine (0.169 g, 1 .043 mmol) was added to a mixture of sodium hydride (0.075 g, 3.125 mmol) and N,N-dimethylformamide (3.38 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min.
  • Compound of example 42 (0.3 g, 1 .209 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (0.5 mL) was added slowly.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (7 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (4.5 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (6 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (6 mL) and the organic layer was dried over anhydrous sodium sulphate.
  • 5-Bromopyridin-2-amine (0.5 g, 2.89 mmol) was added to a mixture of sodium hydride (0. 41 g, 17.3 mmol) and N,N-dimethylformamide (10 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min.
  • Compound of example 42 (0.83 g, 3.35 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h.
  • the reaction mixture was cooled to 10 °C and methanol (1 .7 mL) was added slowly.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (6.1 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (8 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (7 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 ml_) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (7 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution 3.4 ml_) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (5 ml_) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.0 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (6 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • 2,3,4,5,6-Pentafluoroaniline (0.63 g, 3.47 mmol) was added to a mixture of sodium hydride (0.5 g, 20.8 mmol) and N,N-dimethylformamide (12 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min.
  • Compound of example 42 (1 .0 g, 4.02 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (2.0 mL) was added slowly.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (1 1 .2 mL) till pH was 9, at 15 - 20 °C
  • the product was extracted with ethyl acetate (14 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • 3,5,6-Trifluoropyridin-2-amine (0.51 g, 3.47 mmol) was added to a mixture of sodium hydride (0. 5 g, 20.8 mmol) and N,N-dimethylformamide (10 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min.
  • Compound of example 42 (1 .0 g, 4.02 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (1 .7 mL) was added slowly.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (1 1 .2 mL) till pH was 9, at 15 - 20 °C
  • the product was extracted with ethyl acetate (14 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • 6-(Trifluoromethyl)pyridin-2-amine (0.108g, 0.66 mmol) was added to a mixture of sodium hydride (0. 095 g, 3.96 mmol) and N,N-dimethylformamide (2.1 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min.
  • Compound of example 65 (0.238 g, 0.77 mmol) was added to the reaction mixture at 5
  • 3-(trifluoromethyl)pyridin-2-amine (0.15 g, 0.92 mmol) was added to a mixture of sodium hydride (0.14 g, 5.5 mmol) and N,N-dimethylformamide (3.0 ml_) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min.
  • Compound of example 65 (0.248 g, 1 .06 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h.
  • the reaction mixture was cooled to 10 °C and methanol (0.5 ml_) was added slowly.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (3.0 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (4 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (3.0 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (8 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (3.0 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (4 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (4.5 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (6 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • 3,5,6-Trifluoropyridin-2-amine (0.48 g, 3.24 mmol) was added to a mixture of sodium hydride (0.46 g, 19.4 mmol) and N,N-dimethylformamide (10 mL) under nitrogen gas at 15 - 20 °C and the reaction mixture was stirred for 15 - 20 min.
  • Compound of example 72 (1 .0 g, 3.76 mmol) was added to the reaction mixture at 5 - 10 °C and was stirred for 3 - 6 h. The reaction mixture was cooled to 10 °C and methanol (1 .6 mL) was added slowly.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (10 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (13 mL) and the organic layer was dried over anhydrous sodium sulphate.
  • the solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.5 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (7 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (5.6 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (7 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (2.2 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (4 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.
  • 6-(Trifluoromethyl)pyridin-2-amine (10 g, 61 .72 mmol) was added to a mixture of sodium hydride (4.44 g, 185.18 mmol) and N,N-dimethylformamide (100 ml_) under nitrogen gas at 0-5 °C and the reaction mixture was stirred for 15 - 20 min.
  • Compound of 4,6-dichloropyrimidine (10.1 1 g, 67.90 mmol) was added to the reaction mixture at 0-5 °C, then allow the temperature to 25-30 °C and stirred for 14-16 h.
  • the reaction mixture was cooled to 0 -5 °C and methanol (10 ml_) was added slowly.
  • reaction mixture was stirred at 1 10 °C for 16-18 h.
  • the reaction mixture was cooled to room temperature, filter through celite bed, washed with DMF and filtrate was concentrated.
  • the residue was dissolved in ethyl acetate (20 ml_) and washed with water (10 ml_).
  • Organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain crude. It was further purified by column chromatography to obtain the title compound.
  • reaction mixture was quenched into chilled 5 % sodium bicarbonate solution (4.5 mL) till pH was 9, at 15 - 20 °C
  • product was extracted with ethyl acetate (6 mL) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the crude product, which was further purified by column chromatography to obtain the title compound.

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Abstract

La présente invention concerne des composés de pyrimidine, (les composés de formule 1), dans toutes leurs formes stéréo-isomères et tautomères, et leurs mélanges dans tous les rapports ; et leurs sels, solvates, promédicaments et polymorphes pharmaceutiquement acceptables et des N-oxydes correspondants. L'invention concerne également des procédés de préparation de composés de pyrimidine et des compositions pharmaceutiques les contenant. L'invention concerne également l'utilisation des composés de formule 1 dans le traitement de maladies ou de troubles médiés par une ou plusieurs kinases, en particulier des maladies prolifératives ou des troubles prolifératifs tels que le cancer. Ces composés peuvent également être utilisés dans le traitement de troubles médiés par une ou plusieurs cytokines pro-inflammatoires sélectionnées parmi le facteur alpha de nécrose tumorale (TNF-α) ou les interleukines (IL-1β, IL-2, IL-6 et/ou IL-8).
PCT/IB2013/054236 2012-05-23 2013-05-22 Composés de pyrimidine substituée et leurs utilisations WO2013175415A1 (fr)

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US20140057911A1 (en) * 2012-08-23 2014-02-27 Franco Lori Novel 4,6-disubstituted aminopyrimidine derivatives having both aromatic and halogenic substituents
JP2017501200A (ja) * 2014-01-01 2017-01-12 メディベイション テクノロジーズ， インコーポレイテッド 化合物及び使用方法
WO2019079375A1 (fr) * 2017-10-17 2019-04-25 Merck Patent Gmbh Composés inhibiteurs τβκ/ικκε pyrimidine et leurs utilisations
WO2020257261A1 (fr) * 2019-06-17 2020-12-24 Northwestern University Hétérocycles substitués servant d'agents de ciblage de c-myc
CN113264920A (zh) * 2021-05-10 2021-08-17 中国药科大学 一种嘧啶苯并六元环母核的cdk6抑制剂及其制备方法和应用
US11174252B2 (en) 2018-02-15 2021-11-16 Nuvation Bio Inc. Heterocyclic compounds as kinase inhibitors

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Cited By (16)

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Publication number Priority date Publication date Assignee Title
US9617225B2 (en) * 2012-08-23 2017-04-11 Virostatics Srl 4,6-disubstituted aminopyrimidine derivatives have anti-HIV activity
US20140057911A1 (en) * 2012-08-23 2014-02-27 Franco Lori Novel 4,6-disubstituted aminopyrimidine derivatives having both aromatic and halogenic substituents
US11053216B2 (en) 2014-01-01 2021-07-06 Medivation Technologies Llc Compounds and methods of use
JP2017501200A (ja) * 2014-01-01 2017-01-12 メディベイション テクノロジーズ， インコーポレイテッド 化合物及び使用方法
US10501436B2 (en) 2014-01-01 2019-12-10 Medivation Technologies Llc Compounds and methods of use
US11702401B2 (en) 2014-01-01 2023-07-18 Medivation Technologies Llc Compounds and methods of use
US11440899B2 (en) 2017-10-17 2022-09-13 Merck Patent Gmbh Pyrimidine TBK/IKKe inhibitor compounds and uses thereof
JP2020537661A (ja) * 2017-10-17 2020-12-24 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ ピリミジンＴＢＫ／ＩＫＫεインヒビター化合物およびそれらの使用
WO2019079375A1 (fr) * 2017-10-17 2019-04-25 Merck Patent Gmbh Composés inhibiteurs τβκ/ικκε pyrimidine et leurs utilisations
TWI802605B (zh) * 2017-10-17 2023-05-21 德商默克專利有限公司 嘧啶ＴＢＫ/ＩＫＫε抑制劑化合物及其用途
JP7284161B2 (ja) 2017-10-17 2023-05-30 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング ピリミジンＴＢＫ／ＩＫＫεインヒビター化合物およびそれらの使用
CN111247134A (zh) * 2017-10-17 2020-06-05 默克专利股份公司 嘧啶ΤΒΚ/ΙΚΚε抑制剂化合物及其用途
US11174252B2 (en) 2018-02-15 2021-11-16 Nuvation Bio Inc. Heterocyclic compounds as kinase inhibitors
WO2020257261A1 (fr) * 2019-06-17 2020-12-24 Northwestern University Hétérocycles substitués servant d'agents de ciblage de c-myc
US11420957B2 (en) 2019-06-17 2022-08-23 Northwestern University Substituted heterocycles as c-MYC targeting agents
CN113264920A (zh) * 2021-05-10 2021-08-17 中国药科大学 一种嘧啶苯并六元环母核的cdk6抑制剂及其制备方法和应用

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