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WO2016035008A1 - Dérivés de pyridopyrimidine utilisés comme inhibiteurs de mek - Google Patents

Dérivés de pyridopyrimidine utilisés comme inhibiteurs de mek Download PDF

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Publication number
WO2016035008A1
WO2016035008A1 PCT/IB2015/056631 IB2015056631W WO2016035008A1 WO 2016035008 A1 WO2016035008 A1 WO 2016035008A1 IB 2015056631 W IB2015056631 W IB 2015056631W WO 2016035008 A1 WO2016035008 A1 WO 2016035008A1
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Prior art keywords
alkyl
compound
amino
substituted
iodophenyl
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PCT/IB2015/056631
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English (en)
Inventor
Rakesh Kumar Banerjee
Bhavesh Dave
Milind Dattatraya Sindkhedkar
Venkata P. Palle
Rajender Kumar Kamboj
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Lupin Limited
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Publication of WO2016035008A1 publication Critical patent/WO2016035008A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to anticancer compounds, their pharmaceutically acceptable salts, their combinations with suitable medicaments, their pharmaceutical compositions, and uses thereof in treating various cancers.
  • Cancer cells possess certain characteristics that allow them a growth advantage. These include six main alterations in cell physiology such as self-sufficiency in growth signals, insensitivlty to growth-inhibitory signals, evasion of apoptosis, indefinite proliferative potential, sustained angiogenesis, tissue invasion, and metastasis (Douglas Hanahan and Robert A. Weinberg, Cell, Vol. 100, 57-70, 2000). These changes are triggered by genomic instability and inflammation which generates a microenvlronment conducive for tumor growth. In addition to the above mentioned traits, reprogramming of cellular energy metabolism and evasion of immune destruction has also been observed in a majority of cancers.
  • the enhanced survival in cancer cells is further potentiated by the presence of aberrantly activated signalling pathways.
  • a large majority of cancers are known to have mutations in growth factor signalling cascades that lead to constitutive activation of these pathways.
  • Such constitutive activations have been observed in growth factor receptors which include but are not limited to, epidermal growth factor receptor - EGFR, fibroblast growth factor receptor - FGFR, hepatocyte growth factor receptor - HGFR, etc.
  • activating mutations have been reported in certain receptor as well as non receptor tyrosine kinases which include, but are not limited to, MET receptor tyrosine kinase, EGFR- tyrosine kinase, Bcr- Abl tyrosine kinase, Src tyrosine kinase etc.
  • Activation of Ser-Thr kinases such as Ras and lipid kinases such as PI3-kinases also leads to oncogenesis.
  • Chronic activation of the growth factor/ cytokine/hormone-associated signalling leads to activation of immediate downstream components such as Src, Ras, PI3-kinase, etc.
  • kinases further activate effectors such as MEK, ERK, AKT, eventually leading to activation of transcription factors that endow the cells with a high proliferative potential, improved survival, subversion of metabolic pathways and inhibition of apoptosis.
  • effectors such as MEK, ERK, AKT
  • MEK kinase Mitogen Activated Protein Kinase Kinase (MAPKK)
  • MAPKK Mitogen Activated Protein Kinase Kinase
  • the Ras pathway is activated by binding of growth factors, cytokines, and hormones to their cognate receptors. In cancer cells, this pathway is, however, constitutively activated and leads to increased cancer cell survival, cell proliferation, angiogenesis, and metastasis.
  • the tumors that show constitutive activation of the Ras or the MEK kinase include, but are not limited to, those of the colon, pancreas, breast, brain, ovary, lungs, and skin (Judith S. Sebolt-Leopold and Roman Herrera, Nature Reviews Cancer, Vol.
  • Ras due to upstream signalling or as a result of activating point mutations in the Ras oncogene
  • Raf kinase leads to the phosphorylation and activation of Raf kinase that in turn phosphorylate and activate MEK kinase.
  • MEK1/2 kinase phosphorylates and activates the ERK1/2 kinase (also referred to as MAP Kinase) that further phosphorylates and regulates the function of proteins such as Mcl- 1 , Bim and Bad that are involved in cell survival and apoptosis.
  • Ras-Raf-MEK-ERK cascade plays a pivotal role in survival and proliferation of cancer cells. As such, inhibition of this pathway at any of these levels would lead to the inhibition of cancer cell growth, proliferation, and survival. Indeed, it has already been reported that inhibition of Ras or Raf leads to inhibition of tumor growth in animal models as well as in cancer patients. However, the success with these inhibitors has been limited to only certain types of cancers (e.g.
  • Sorafenib which inhibits Raf kinase has been approved for renal cell carcinoma.
  • inhibiting MEK is a novel approach towards controlling this pathway in cancer cells.
  • the possibility of designing allosteric inhibitors also allows enhanced selectivity that is crucial for decreasing the toxic effects associated with kinase inhibitors.
  • the MEK-ERK pathway is activated in numerous inflammatory conditions (John M. Kyriakis and Joseph Avruch, The Journal of Biological Chemistry, Vol. 271 , No. 40, pp. 24313-24316, 1995; Deepa R. Hammaker et al. , The Journal of Immunology, 2004, 172, 1612- 1618) including rheumatoid arthritis, inflammatory bowel disease, and COPD.
  • MEK regulates the biosynthesis of the inflammatory cytokines TNF, IL-6, and IL- 1. It has been shown that MEK inhibitors interfere with the production/secretion of these cytokines.
  • Array BioPharma has developed a first-in- class MEK inhibitor (ARRY 438162) and initiated clinical trials in rheumatoid arthritis (RA) patients.
  • the present invention provides anticancer compound of the general formula (I) , its pharmaceutically acceptable salt, its combinations with suitable medicaments, pharmaceutical compositions containing one or more such compounds, and uses thereof in treating various cancers,
  • the compounds of the present inventions are potent inhibitors of MEK and show tumor regression effect with less side effects. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention relates to heterocyclyl compound of formula (I), its pharmaceutically acceptable salt, its combinations with suitable medicaments, and pharmaceutical compositions thereof.
  • the present invention also includes processes of preparation of the compounds and their use in methods of treatment.
  • a compound of formula (I) is
  • R 1 is selected from the group consisting of hydrogen, substituted- or unsubstituted-alkyl, substituted- or unsubstituted- alkenyl, substituted- or unsubstituted- cycloalkyl;
  • R 2 is selected from the group consisting of wherein, R 2a is selected from -(CR a R b ) P S0 2 R c , -(CR a R b ) P N(R d )S0 2 R e , and -
  • R 2b is selected from the group consisting of
  • R a , R b , R d , and R f are independently selected from hydrogen, substituted- or unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;
  • R c is selected from substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, and NR d R f ;
  • R e is selected from substituted- or unsubstituted- alkyl and substituted- or unsubstituted- cycloalkyl;
  • n, m and p are selected independently as 1 or 2;
  • R 3 is selected from the group consisting of hydrogen, substituted- or unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;
  • R 4 is selected from the group consisting of hydrogen, halogen, substituted- or unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;
  • R 6 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
  • R 6a is selected from the group consisting of alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
  • R 6b is selected from the group consisting of hydrogen, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl.
  • R 1 is selected from hydrogen and substituted- or unsubstituted- alkyl. In other embodiments, R 1 is selected from hydrogen and methyl.
  • R 3 and R 4 are substituted- or unsubstituted- alkyl.
  • R 3 and R 4 are methyl.
  • R 5 is substituted aryl; the aryl group is substituted with halogen. In other embodiments, R 5 is substituted phenyl; the phenyl is substituted with fluorine or iodine.
  • n, m and p are selected independently as 1.
  • R 1 is selected from hydrogen, substituted- or unsubstituted-alkyl, and substituted- or unsubstituted- cycloalkyl. In other embodiments, R 1 is selected from hydrogen, methyl, and cyclopropyl.
  • R 2 is selected from,
  • R 3 and R 4 are independently substituted- or unsubstituted- alkyl. In other embodiments, R 3 and R 4 are methyl.
  • R 5 is substituted- or unsubstituted- phenyl.
  • R 5 is 2-fluoro-4-iodobenzene.
  • ⁇ 1 is selected from hydrogen, substituted- or unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;
  • R 2 is selected from,
  • R 3 and R 4 are independently substituted- or unsubstituted- alkyl
  • R 5 is substituted- or unsubstituted- phenyl.
  • R 1 is selected from hydrogen, methyl, and cyclopropyl
  • R 3 and R 4 are methyl
  • R 5 is 2-fluoro-4-iodobenzene.
  • a range of the number of atoms in a structure is indicated (e.g., a Ci-12, Ci-8, Ci-6, or Ci-4 alkyl, alkylamino, etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used.
  • any chemical group e.g., alkyl, alkylamino, etc.
  • any chemical group e.g., alkyl, alkylamino, etc.
  • any sub-range thereof e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1- 10 carbon atoms, 1- 1 1 carbon atoms, 1-12 carbon atoms
  • alkyl means a straight or branched hydrocarbyl chain containing from 1 to 20 carbon atoms. Preferably, the alkyl group contains 1 to 10 carbon atoms. More preferably, alkyl group contains up to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.
  • R 6 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
  • R 6a is selected from the group consisting of alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;
  • R 6b is selected from the group consisting of hydrogen, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl.
  • haloalkyl as used herein, means both branched and straight chain alkyl substituted with one or more halogen, wherein the alkyl group is as herein described.
  • halogen means fluorine, chlorine, bromine, or iodine.
  • hydroxyalkyl as used herein, means an alkyl group in which one or more hydrogens has been replaced with a hydroxyl group, wherein the alkyl group is as herein described.
  • perhaloalkyl means an alkyl group, as defined herein, in which all the hydrogen atoms are replaced with a halogen atom.
  • cycloalkyl as used herein, means a monocyclic, bicyclic, or tricyclic non- aromatic ring system containing from 3 to 14 carbon atoms.
  • the cycloalkyl group is a monocyclic, non-aromatic ring containing 3 to 6 carbon atoms. Examples of monocyclic, non-aromatic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Bicyclic, non- aromatic ring systems include a monocyclic, non-aromatic ring fused across a bond with another cyclic system which may be an alicyclic ring or an aromatic ring.
  • Bicyclic, non-aromatic rings systems also include spirocyclic systems wherein the second ring gets annulated on a single carbon atom.
  • Bicyclic, non-aromatic ring systems are also exemplified by a bridged monocyclic, non-aromatic ring system in which two non-adjacent carbon atoms of the monocyclic, non-aromatic ring are linked by a bond or an alkylene bridge having 1 to 4 methylene units joining the two non-adjacent carbon atoms.
  • bicyclic, non-aromatic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo [2.2.1] heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3. l]nonane, bicyclo[4.2. l]nonane, bicyclo[3.3.2]decane, bicyclo[3.1.0]hexane, bicyclo[4.1.0]heptane, bicyclo [3.2.0] heptane, octahydro- lH- indene, spiro[2.5]octane, and spiro[4.5]decane.
  • Tricyclic, non-aromatic ring systems include bicyclic, non-aromatic systems as described herein further annulated with an alicyclic third ring, which may be alicyclic ring or aromatic ring. Tricyclic, non-aromatic ring systems are also exemplified by a bicyclic, non- aromatic ring system in which two non-adjacent carbon atoms of the bicyclic, non- aromatic ring system are linked by a bond or an alkylene bridge having 1 to 4 methylene units joining the two non-adjacent carbon atoms.
  • tricyclic, non-aromatic ring systems include, but are not limited to, tricyclo[3.3.1.0 3 7 ]nonane, tricyclo[3.3.1.1 3 7 ]decane (adamantane) , spiro [bicyclo [4.1.0]heptane-2, l'-cyclopentane], and hexahydro-2'H- spiro [cyclopropane- 1 , 1 '-pentalene] .
  • aryl refers to a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon ring system having 6 to 20 carbon atoms.
  • aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.
  • Aryl group also includes partially saturated bicyclic and tricyclic aromatic hydrocarbons such as tetrahydro-naphthalene.
  • heteroaryl refers to a 5- 14 membered monocyclic, bicyclic, or tricyclic ring system having 1-4 ring heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon (with appropriate hydrogen atoms unless otherwise indicated), wherein at least one ring in the ring system is aromatic. Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1 , 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent.
  • heteroaryl groups include, but not limited to pyridyl, 1-oxo-pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl.
  • heterocyclic or “heterocyclyl” as used herein, means a "cycloalkyl” group wherein one or more of the carbon atoms is independently replaced by -0-, -S-, - S(0 2 )-, -S(O)-, -N(R m )-, or -Si(R m )R n -, wherein R m and R n are independently selected from hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl.
  • the heterocycle may be connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocycle.
  • the heterocyclyl group when the heterocyclyl group is substituted, the heterocyclyl group is substituted with 1 to 3 substituents.
  • cyano means the group -CN.
  • hydroxy means the group -OH.
  • nitro means the group -N0 2 .
  • oxo attached to carbon forms a carbonyl
  • oxo substituted on cyclohexane forms a cyclohexanone, and the like.
  • annulated means the ring system under consideration is either annulated with another ring at a carbon atom of the cyclic system or across a bond of the cyclic system as in the case of fused or spiro ring systems.
  • bridged means the ring system under consideration contain an alkylene bridge having 1 to 4 methylene units joining two non adjacent ring atoms.
  • a compound, its stereoisomer, racemate, tautomer, and pharmaceutically acceptable salt thereof as described hereinabove wherein the compounds of general formula (I) can be selected from the group consisting of: 2-(6-((l-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo- l ,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)indolin- l-yl)acetamide (Compound 1)
  • the present invention describes the inhibitors of MEK kinase for treatment of disorders that are driven by hyperactivation, abnormal activation, constitutive activation, or gain-of-function mutation of the MEK kinase and/or its substrate kinases that include, but are not limited to, ERK.
  • disorders encompass hyperproliferative disorders that include but are not limited to psoriasis, keloids, hyperplasia of the skin, benign prostatic hyperplasia (BPH), and solid tumors such as cancers of the respiratory tract (including, but not limited to, small cell and non-small cell lung carcinomas), brain (including, but not limited to, glioma, medulloblastoma, ependymoma, neuroectodermal, and pineal tumors), breast (including, but not limited to, invasive ductal carcinoma, invasive lobular carcinoma, and ductal- and lobular carcinoma in situ), reproductive organs (including, but not limited to, prostate cancer, testicular cancer, ovarian cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, and sarcoma of the uterus), digestive tract (including, but not limited to, esophageal, colon, colorectal, gastric, gall blabber, pancreatic, rectal
  • the hyperproliferative disorders also include leukemias (including, but not limited to, acute lymphoblastic leukemia, acute myeloid leukemia, chronic melogenous leukemia, chronic lymphocytic leukemia, and hairy cell leukemia), sarcomas (including, but not limited to, soft tissue sarcoma, osteosarcoma, lymphosarcoma, and rhabdomyosarcoma), and lymphomas (including, but not limited to, non-Hodgkin's lymphoma, AIDS-related lymphoma, cutaneous T cell lymphoma, Burkitt's lymphoma, Hodgkin's disease, and lymphoma of the central nervous system).
  • leukemias including, but not limited to, acute lymphoblastic leukemia, acute myeloid leukemia, chronic melogenous leukemia, chronic lymphocytic leukemia, and hairy cell leukemia
  • sarcomas including, but not limited to
  • the present invention describes the inhibitors of MEK kinase for treatment of certain disorders involving aberrant regulation of the mitogen extracellular kinase activity including, but not limited to, hepatomegaly, heart failure, cardiomegaly, diabetes, stroke, Alzheimer's disease, cystic fibrosis, septic shock, and asthma.
  • the present invention describes the inhibitors of MEK kinase for treatment of diseases and disorders associated with aberrant, abnormal and/or excessive angiogenesis.
  • disorders associated with angiogenesis include but are not limited to, tumor growth and metastases, ischemic retinal vein occlusion, diabetic retinopathy, macular degeneration, neovascular glaucoma, psoriasis, inflammation, rheumatoid arthritis, vascular graft restenosis, restenosis, and in- stent restenosis.
  • the compounds mentioned in this invention can be used as a single (sole) therapeutic agent or in combination with other active agents, including, but not limited to, chemotherapeutic agents and anti-inflammatory agents.
  • active agents including, but not limited to, chemotherapeutic agents and anti-inflammatory agents.
  • Such combinations include, but are not limited to, combining the MEK kinase inhibitors with anti-mitotic agents, anti-antiangiogenic agents, alkylating agents, anti- hyperproliferative agents, antimetabolites, DNA-intercalating agents, cell cycle inhibitors, kinase inhibitors, growth factor inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, and anti-hormones.
  • the inhibitors mentioned in the present invention can be combined with anti- inflammatory agents or agents that show therapeutic benefit for conditions including, but not limited to, hepatomegaly, heart failure, cardiomegaly, diabetes, stroke, Alzheimer's disease, cystic fibrosis, septic shock or asthma, diabetic retinopathy, ischemic retinal vein occlusion, macular degeneration, neovascular glaucoma, psoriasis, inflammation, rheumatoid arthritis, restenosis, in-stent restenosis, and vascular graft restenosis.
  • anti- inflammatory agents or agents that show therapeutic benefit for conditions including, but not limited to, hepatomegaly, heart failure, cardiomegaly, diabetes, stroke, Alzheimer's disease, cystic fibrosis, septic shock or asthma, diabetic retinopathy, ischemic retinal vein occlusion, macular degeneration, neovascular glaucoma, psoriasis, inflammation, rheum
  • the present disclosure provides a method for inhibiting MEK enzyme comprising, contacting said MEK enzyme with a composition comprising a compound of general formula (I) its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit said enzyme, wherein said enzyme inhibits MEK kinase and said contacting occurs within a cell.
  • a composition comprising a compound of general formula (I) its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit said enzyme, wherein said enzyme inhibits MEK kinase and said contacting occurs within a cell.
  • the invention also provides a method of treatment or prevention of a MEK mediated disorder in a subject suffering from said disorder, comprising administering to said subject an effective amount of a composition comprising a compound of general formula (I), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof.
  • the method of treatment may also be combined with an additional therapy such as radiation therapy, chemotherapy, or combination thereof.
  • MEK mediated disorders include inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorder, neurological disorders, fibrogenetic disorders, proliferative disorders, hyperproliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases, and malignant diseases.
  • the invention further provides a method for the treatment or prophylaxis of a proliferative disease in a subject suffering from said disease, comprising administering to said subject an effective amount of a composition comprising a compound of formula (I), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof.
  • the proliferative disease includes cancer, psoriasis, restenosis, autoimmune disease, or atherosclerosis.
  • the invention also provides a method for the treatment or prophylaxis of an inflammatory disease in a subject suffering from said disease, comprising administering to said subject an effective amount of a composition comprising a compound of formula (I), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof.
  • the inflammatory disease includes rheumatoid arthritis or multiple sclerosis.
  • the invention also provides a method for degrading, inhibiting the growth of, or killing cancer cells, comprising contacting the cells with an amount of a composition effective to degrade, inhibit the growth of, or kill the cancer cells, the composition comprising a compound of formula (I), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt.
  • the invention also provides a method of inhibiting tumor size increase, reducing the size of a tumor, reducing tumor proliferation or preventing tumor proliferation in a subject in need thereof, comprising administering to said subject an effective amount of a composition to inhibit tumor size increase, reduce the size of a tumor, reduce tumor proliferation, or prevent tumor proliferation, the composition comprising a compound of formula (I) , its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt.
  • the MEK-ERK pathway is activated in numerous inflammatory conditions (John M. Kyriakis and Joseph Avruch, The Journal of Biological Chemistry, Vol. 271 , No. 40, pp. 24313-24316, 1996; Deepa R. Hammaker et al. , The Journal of Immunology, 2004, 172: 1612- 1618) , including rheumatoid arthritis, inflammatory bowel disease and COPD.
  • the present invention further provides a pharmaceutical composition, comprising a compound of the formula (I) , its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier, diluent, or excipient.
  • the pharmaceutically acceptable carrier or excipient is preferably one that is chemically inert to the compound of the invention and one that has no detrimental side effects or toxicity under the conditions of use.
  • Such pharmaceutically acceptable carriers or excipients include saline (e.g. , 0.9% saline), Cremophor EL (which is a derivative of castor oil and ethylene oxide available from Sigma Chemical Co. , St. Louis, MO) (e.g. , 5% Cremophor EL/5% ethanol/90% saline, 10% Cremophor EL/90% saline, or 50% Cremophor EL/50% ethanol) , propylene glycol (e.g.
  • a preferred pharmaceutical carrier is polyethylene glycol, such as PEG 400, and particularly a composition comprising 40% PEG 400 and 60% water or saline.
  • the choice of carrier will be determined in part by the particular compound chosen, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention.
  • the following formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, rectal, and vaginal administration are merely exemplary and are in no way limiting.
  • compositions for parenteral administration that comprises a solution of the compound of the invention dissolved or suspended in an acceptable carrier suitable for parenteral administration, including aqueous and non-aqueous, isotonic sterile injection solutions.
  • compositions include solutions containing anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol (for example in topical applications), or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, dime thylsulf oxide, glycerol ketals, such as 2,2- dimethyl- l ,3-dioxolane-4-methanol, ethers, such as poly(ethyleneglycol)400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropy
  • Oils useful in parenteral formulations include petroleum, animal, vegetable, and synthetic oils. Specific examples of oils useful in such formulations include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral oil. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl- -aminopropionates, 2-alkyl- imidazoline quaternary ammonium salts, and (e) mixtures thereof.
  • the parenteral formulations typically will contain from about 0.5% or less to about 25% or more by weight of a compound of the invention in solution. Preservatives and buffers can be used. In order to minimize or eliminate irritation at the site of injection, such compositions can contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • HLB hydrophile-lipophile balance
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules or vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.
  • Topical formulations, including those that are useful for transdermal drug release, are well known to those of skill in the art and are suitable in the context of the present invention for application to skin.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of a compound of the invention dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a pre-determined amount of a compound of the invention, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations can include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients.
  • Lozenge forms can comprise the compound ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising a compound of the invention in an inert base, such as gelatin and glycerin, or sucrose and acacia.
  • Lozenge forms can also comprise emulsions, gels, and the like containing, in addition to a compound of the invention, such excipients as are known in the art.
  • a compound of the present invention can be made into aerosol formulations to be administered via inhalation.
  • a compound or epimer of the invention is preferably supplied in finely divided form along with a surfactant and propellant. Typical percentages of the compound of the invention can be about 0.01% to about 20% by weight, preferably about 1% to about 10% by weight.
  • the surfactant must, of course, be nontoxic, and preferably soluble in the propellant.
  • Such surfactants are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric, and oleic acids, with an aliphatic polyhydric alcohol or its cyclic anhydride.
  • Mixed esters such as mixed or natural glycerides can be employed.
  • the surfactant can constitute from about 0.1% to about 20% by weight of the composition, preferably from about 0.25% to about 5%.
  • the balance of the composition is ordinarily propellant.
  • a carrier can also be included as desired, e.g., lecithin, for intranasal delivery.
  • aerosol formulations can be placed into acceptable pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer. Such spray formulations can be used to spray mucosa. Additionally, a compound of the invention can be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the compound ingredient, such carriers as are known in the art to be appropriate.
  • the concentration of a compound in the pharmaceutical formulations can vary, e.g., from less than about 1% to about 10%, to as much as about 20% to about 50% or more by weight, and can be selected primarily by fluid volumes, and viscosities, in accordance with the particular mode of administration selected.
  • a typical pharmaceutical composition for intravenous infusion could be made up to contain 250 ml of sterile Ringer's solution, and 100 mg of at least one compound of the invention.
  • Actual methods for preparing parenterally administrable compounds of the invention will be known or apparent to those skilled in the art and are described in more detail in, for example, Remington's Pharmaceutical Science (17 th ed., Mack Publishing Company, Easton, PA, 1985).
  • the compound of the invention can be formulated as an inclusion complexe, such as a cyclodextrin inclusion complexe, or a liposome.
  • Liposomes can serve to target a compound of the invention to a particular tissue, such as lymphoid tissue or cancerous hepatic cells. Liposomes can also be used to increase the half-life of a compound of the invention. Many methods are available for preparing liposomes, as described in, for example, Francis Szoka et al., Ann. Rev. Biophys. Bioeng., 1980, 9, 467-508 and U.S. Patents 4,235,871 ; 4,501 ,728; 4,837,028; and 5,019,369. The compounds of the invention can be administered in a dose sufficient to treat the disease, condition, or disorder.
  • Such doses are known in the art (see, for example, the Physicians' Desk Reference, 58 th Edition, 2004).
  • the compounds can be administered using techniques such as those described in, for example, Todd H. Wasserman et al., Cancer, 36: 1258- 1268, 1975 and Physicians' Desk Reference, 58 th ed., Thomson PDR (2004).
  • Suitable doses and dosage regimens can be determined by conventional range- finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of a compound of the present invention. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the methods disclosed herein can involve the administration of about 0.1 ⁇ g to about 50 mg of at least one compound of the invention per kg body weight of the subject. For a 70 kg patient, dosages of from about 10 ⁇ g to about 200 mg of the compound of the invention would be more commonly used, depending on a patient's physiological response.
  • the dose of the pharmaceutically active agent(s) described herein for methods of treating or preventing a disease or condition as described above can be about 0.001 to about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, about 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg/kg body weight per day.
  • the dose of the pharmaceutically active agent(s) described herein can be about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 0.020 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg/kg body weight per day.
  • the terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disease or disorder in a subject (e.g. a mammal).
  • a disease or disorder, including symptoms or conditions thereof may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.
  • the treatment, prevention, amelioration, or inhibition provided by the inventive method can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disease or disorder, e.g., cancer.
  • "treatment,” “prevention,” “amelioration,” or “inhibition” can encompass delaying the onset of the disease or disorder, or a symptom or condition thereof.
  • aberrant regulation of the mitogen extracellular kinase activity refers to any abnormal expression or activity of the gene encoding the kinase or of the polypeptide it encodes. Examples of such aberrant regulation of the mitogen extracellular kinase activity include, but are not limited to, over-expression of the gene or polypeptide, gene amplification, mutations that produce constitutively active or hyperactive kinase activity, gene mutations, deletions, substitutions, additions, and the like.
  • the term "subject” includes an animal which in turn includes a mammal such as, without limitation, the order Rodentia, such as mice, and the order Lagomorpha, such as rabbits.
  • the mammal is from the order Carnivora, including Felines (cats) and Canines (dogs).
  • the mammal is from the order Artiodactyla, including Bovlnes (cows) and Swine (pigs) or of the order Perssodactyla, including Equines (horses) .
  • mammal is of the order Primates, Ceboids, or Simoids (monkeys) or of the order Anthropoids (humans and apes).
  • the mammal is human.
  • Scheme 1 A Compound of formula (II) where R 1 ' is N-protecting group, can be converted to compound of formula (III) by reacting compound of (II) with R 2 N3 ⁇ 4 in presence of a suitable base like 2,6-Lutidine, l ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), K 2 C0 3 , Cs 2 C0 3 , NaH, KH, n-BuLi, lithium bis(trimethylsilyl) amide (LiHMDS) etc., in a solvent like THF, DMF, DMSO etc., at temperature ranging from about -78 a C to about 150 a C.
  • a suitable base like 2,6-Lutidine, l ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), K 2 C0 3 , Cs 2 C0 3 , NaH, KH, n-BuLi, lithium bis(trimethylsilyl)
  • Compound of formula (III) where R 1' is N-protecting group can be converted to compound of formula (IV) by reacting compound of formula (III) with suitable base such as NaOMe, K2CO3 etc., in a solvent like Methanol, Ethanol, THF, DMF etc., at temperature ranging from about -78 a C to about 150 a C.
  • a Compound of formula (IV) where R 1 ' is N-protecting group can be converted to compound of formula (I) by reacting compound of formula (IV) with suitable N- deprotection agents such as AICI3, Pd-C/]3 ⁇ 4 etc., in a solvent like Anisole, Toluene, Xylene, THF, DMF, DMSO etc., at temperature ranging from about -78 a C to about 150 a C.
  • suitable N- deprotection agents such as AICI3, Pd-C/]3 ⁇ 4 etc.
  • Scheme 2 A Compound of formula (I), where R 1 is selected from the group consisting of substituted- or unsubstituted- alkyl, substituted- or unsubstituted- alkenyl, substituted- or unsubstituted- cycloalkyl, can be prepared by following the process depicted in Scheme 2.
  • a Compound of formula (I) where R 1 is hydrogen can be converted to compound of formula (I) with R 1 as non-hydrogen substituent by reacting it with R Z, wherein Z is any suitable leaving group like CI, Br, I, -0(SO) 2 (4-MePh), -0(SO) 2 CH 3 , - 0(SO)2CF3 etc., in presence of a suitable base like 2,6-Lutidine, 1 ,8- Diazabicyclo[5.4.0]undec-7-ene (DBU), K 2 C0 3 , Cs 2 C0 3 , NaH, KH, n-BuLi, lithium bis(trimethylsilyl)amide (LiHMDS) etc., in a solvent like THF, DMF, DMSO etc., at temperature ranging from about -78 a C to about 150 a C.
  • Z any suitable leaving group like CI, Br, I, -0(SO) 2 (4-MePh), -0(SO)
  • a Compound of formula (I) where R 1 is selected from the group consisting of substituted- or unsubstituted- alkyl, substituted- or unsubstituted- alkenyl, and substituted- or unsubstituted- cycloalkyl can be prepared by following the process depicted in Scheme 3.
  • a Compound of formula (II) where R 1 is selected from the group consisting of substituted- or unsubstituted- alkyl, substituted- or unsubstituted- alkenyl, and substituted- or unsubstituted- cycloalkyl can be converted to compound of formula (III) by reacting compound of formula (II), wherein Z is any suitable leaving group like CI, Br, I, -0(SO) 2 (4-MePh), -0(SO) 2 CH 3 , -0(SO) 2 CF 3 etc., with R 2 NH 2 in presence of a suitable base like 2,6-Lutidine, l ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), K 2 C0 3 , Cs 2 C0 3 , NaH, KH, n-BuLi, lithium bis (trimethylsilyl) amide (LiHMDS) etc., in a solvent like THF, DMF, DMSO and
  • a Compound of formula (III) where R 1 is selected from the group consisting of substituted- or unsubstituted- alkyl, substituted- or unsubstituted- alkenyl, and substituted- or unsubstituted- cycloalkyl can be converted to compound of formula (I) by reacting compound of formula (III) with suitable base such as NaOMe, K 2 C0 3 etc., in a solvent like Methanol, Ethanol, THF, DMF etc., at temperature ranging from about -78 a C to about 150 a C.
  • the intermediates and the compounds of the present invention are obtained in pure form in a manner known per se, for example by distilling off the solvent in vacuum and re- crystallizing the residue obtained from a suitable solvent, such as pentane, diethyl ether, isopropyl ether, chloroform, dichlorome thane, ethyl acetate, acetone, or their combinations or subjecting it to one of the purification methods, such as column chromatography (e.g. flash chromatography) on a suitable support material such as alumina or silica gel using eluent such as dichloromethane, ethyl acetate, hexane, methanol, acetone, and their combinations.
  • a suitable solvent such as pentane, diethyl ether, isopropyl ether, chloroform, dichlorome thane, ethyl acetate, acetone, or their combinations or subjecting it to one of the purification methods, such as column chromatography
  • Salts of a compound of formula (I) can be obtained by dissolving the compound in a suitable solvent, for example, in a chlorinated hydrocarbon, such as methyl chloride or chloroform, or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol, which is then treated with the desired acid or base as described in Stephen M. Berge et al., "Pharmaceutical Salts, a review article in Journal of Pharmaceutical Sciences, vol. 66, No. 1 , page 1- 19, 1977” and in Handbook of Pharmaceutical Salts, Properties, Selection, and Use by P. Heinrich Stahl and Camille G. Wermuth, Wiley- VCH (2002).
  • a suitable solvent for example, in a chlorinated hydrocarbon, such as methyl chloride or chloroform, or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol
  • the salt can be of an alkali metal (e.g., sodium or potassium), an alkaline earth metal (e.g., calcium), or ammonium.
  • alkali metal e.g., sodium or potassium
  • alkaline earth metal e.g., calcium
  • a compound of the invention or a composition thereof can potentially be administered as a pharmaceutically acceptable acid-addition, base neutralized or addition salt, formed by reaction with inorganic acids, such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base, such as sodium hydroxide or potassium hydroxide.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, mal
  • the conversion to a salt is accomplished by treatment of the base compound with at least a stoichiometric amount of an appropriate acid.
  • the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol, methanol, and the like, and the acid is added in a similar solvent.
  • the mixture is maintained at a suitable temperature (e.g., between 0°C and 50°C).
  • the resulting salt precipitates spontaneously or can be brought out of solution with a less polar solvent.
  • stereoisomers of a compound of formula (I) of the present invention may be prepared by stereospecific syntheses or resolution of the achiral compound using an optically active amine, acid or complex forming agent, and separating the diastereomeric salt/complex by fractional crystallization or by column chromatography.
  • a compound of formula (I) of the present invention can exist in tautomeric forms, such as keto-enol tautomers. Such tautomeric forms are contemplated as an objective of this invention and such tautomers may be in equilibrium or predominant in one of the forms.
  • Prodrugs can be prepared in situ during the isolation and purification of a compound, or by separately reacting a purified compound with a suitable derivatizing agent.
  • hydroxy groups can be converted into esters via treatment with a carboxylic acid in the presence of a catalyst.
  • cleavable alcohol prodrug moieties include substituted or unsubstituted, branched or unbranched lower alkyl ester moieties, e.g., ethyl esters, lower alkenyl esters, di- lower alkylamino lower- alkyl esters, e.g., dimethylaminoethyl ester, acylamino lower alkyl esters, acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters, e.g., phenyl ester, aryl-lower alkyl esters, e.g., benzyl ester, substituted- or unsubstituted-, e.g., with methyl, halo, or methoxy substituents aryl and aryl- lower alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy
  • prodrug denotes a derivative of a compound, which derivative, when administered to warm-blooded animals, e.g. humans, is converted into the compound (drug).
  • the enzymatic and/or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a manner that the proven drug form is released, and the moiety or moieties split off remain nontoxic or are metabolized so that nontoxic metabolic products are produced.
  • work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers, drying the organic layer over sodium sulphate, filtration, and evaporation of the solvent.
  • Purification includes purification by silica gel chromatographic techniques, generally using a mobile phase with suitable polarity.
  • DMSO-d6 Hexadeuterodimethyl sulfoxide
  • DMSO Dimethylsulf oxide
  • DMF N,N-dimethyl formamide
  • DMA Dimethylacetamide
  • TEA Trifluoroacetic acid
  • THF Tetrahydrofuran
  • DCM Dichloromethane
  • EDC l-Ethyl-3-(3- dimethylaminopropyl)carbodiimide
  • Boc tert-butoxycarbonyl
  • Bn benzyl
  • Ts tosyl
  • Tf trifluoromethanesulfonyl
  • DIPEA ⁇ , ⁇ -Diisopropyl ethyl amine
  • HOBT 1- Hydroxy- lH-benzotriazole
  • PMB p-methoxybenzyl
  • DAST Diethylaminosulfur trifluoride
  • PyBOP (benzotriazol- l
  • room temperature denotes any temperature ranging between about 20°C to about 40°C, unless it is specifically mentioned as otherwise.
  • Step 1 Synthesis of 2-(6-nitroindolin-l-yl)acet amide.
  • Step 2 Synthesis of 2-(6-aminoindolin-l-yl)acetamide.
  • 2-(6-nitroindolin- l-yl)acetamide 900 mg, 4.07 mmol
  • 10% Pd-C 361 mg
  • Methanol 5 ml
  • triethylsilane 0.650 ml, 4.07 mmol
  • the reaction mixture was stirred for 1 hr. After completion of reaction, the reaction mixture was filtered through celite bed. The filtrate was concentrated under vacuum. The residue was recrystallized in diethylether to give titled compound.
  • Step-1 Synthesis of methyl 2-((3-nitrophenyl)amino)acetate
  • Step 1 Synthesis of l-((methylsulfonyl)methyl)-3-nitrobenzene
  • l-(chloromethyl)-3-nitrobenzene 2.8 g, 16.32 mmol
  • sodium methyl sulfinate 2.3 g, 22.85 mmol
  • the reaction mixture was heated at 90 °C for 5 hrs.
  • the solvent was evaporated under vacuum; water (20 ml) was added to the residue and stirred the mixture for 20 minutes.
  • the mixture was filtered to obtain the crude product (3. 1 g) which was used for the next step without further purification.
  • Step 2 Synthesis of 3-((methylsulfonyl)methyl)aniline To a solution of l -((methylsulfonyl)methyl)-3-nitrobenzene ( 1.5 g, 6.97 mmol) in methanol (20 ml) was added 50 % wet 10 % Pd-C (0. 15 g) . The reaction mixture was stirred under hydrogen atmosphere at room temperature for 5 hrs. The reaction mixture was filtered through celite bed and filtrate was concentrated under vacuum to obtain titled compound ( 1.05 g, 81 %).
  • Step 1 Synthesis of N-cyclopropyl-l-(3-nitrophenyl)methanesulfonamide
  • Step 2 Synthesis of l-(3-aminophenyl)-N-cyclopropylmethanesulfonamide
  • Step 1 Synthesis of l-(2-(methylsulfonyl)propan-2-yl)-3-nitrobenzene
  • Step 1 Synthesis of l-(2-(ethylsulfonyl)propan-2-yl)-3-nitrobenzene
  • Step 1 Synthesis of ethyl(3-nitrobenzyl)sulfane
  • ethyl(3-nitrobenzyl)sulfane To a stirred suspension of (3-nitrophenyl)methanethiol (0.2 g, 1. 18 mmol) and potassium carbonate (0.24 g, 1.77 mmol) in DMF (4 ml) , ethyl iodide (0. 1 ml, 1.2 mmol) was added at room temperature. The reaction mixture was heated at 45 °C for 1 hr. The reaction mixture was cooled to room temperature and diluted with water (20 ml) . The mixture was extracted with ethyl acetate (3 X 25 ml) .
  • Step 2 Synthesis of l-(3-aminophenyl)-N-methylmethanesulfonamide
  • Step 1 -Synthesis of N,N-dimethyl-l-(3-nitrophenyl)methanesulfonamide.
  • Step 2 -Synthesis of l-(3-aminophenyl)-N,N-dimethylmethanesulfonamide
  • N,N-dimethyl- l-(3-nitrophenyl)methanesulfonamide (0.66 g, 2.70 mmol)
  • 50 % wet 10 % Pd-C 115 mg was added.
  • the reaction mixture was stirred under hydrogen atmosphere for 5 hrs at room temperature.
  • the reaction mixture was filtered through celite bed and residue was washed with methanol (20 ml).
  • the combined filtrate was concentrated to afford the title product (0.52 g, 90 %).
  • Step-1 Synthesis of N-(2-(3-nitrophenyl)propan-2-yl)methanesulfonamide
  • 2-(3-nitrophenyl)propan-2-amine (0.54 g, 3 mmol) and triethylamine (0.6 ml, 4.49 mmol) in dichloromethane ( 25 ml)
  • methansulfonyl chloride (0.28 ml, 3.60 mmol) was added under nitrogen atmosphere.
  • the reaction mixture was then stirred at room temperature for 16 hrs.
  • the reaction mixture was cooled to 0 °C, water (20 ml) was added and the mixture was further stirred for 15 min.
  • Step 2 N-(3-aminobenzyl)cyclopropanesulfonamide
  • N-(3-nitrobenzyl)cyclopropanesulfonamide 0.5 g, 1.951 mmol
  • methanol 10 ml
  • 50% wet 10% Pd-C 0. 1 g
  • Reaction mixture was filtered through celite bed. Filtrate was collected and solvent was evaporated under vacuum to afford N-(3-aminobenzyl)cyclopropanesulfonamide (0.4 g, 91 %) as an yellow liquid.
  • Step 1 Preparation of l-((cyclopropylsulfonyl)methyl)-3-nitrobenzene
  • Step 2 Preparation of 3-((cyclopropylsulfonyl)methyl)aniline
  • a solution of l-((cyclopropylsulfonyl)methyl)-3-nitrobenzene (0.2 g, 0.829 mmol) in methanol (5 ml) was added 50 % wet 10 % Pd-C (0. 1 g) at room temperature, and continued stirring for 2 hrs under hydrogen atmosphere. Reaction mixture was filtered through celite bed. Filtrate was collected and solvent was evaporated under vacuum to afford 3-((cyclopropylsulfonyl)methyl)aniline (0. 15 g, 86 %).
  • GCMS m/z: 21 1 (M+) .
  • Intermediate- 15 Preparation of N-(3-aminobenzyl)ethanesulfonamide
  • Step 1 Preparation of N-(3-nitrobenzyl)ethanesulfonamide
  • a suspension of (3-nitrophenyl)methanamine hydrochloride (1.1 g, 5.83 mmol) in pyridine (8 ml) was added ethanesulfonyl chloride (0.75 g, 5.83 mmol) drop-wise at 0 - 5 °C and continued stirring for 1 hr.
  • the reaction mixture was poured on crushed ice, acidified with IN HC1 and extracted with ethyl acetate (2 X 10 ml).
  • Step 1 Preparation of N-(l-(3-nit rophenyl)e thy l)methanesulfonamide
  • N-( l-(3-nitrophenyl)ethyl)methanesulfonamide 0.8 g, 3.28 mmol
  • methanol 10 ml
  • 50 % wet 10 % Pd-C 0.3 g
  • Reaction mixture was filtered through celite bed. Filtrate was collected and solvent was evaporated under vacuum to afford N-( l-(3-aminophenyl)ethyl)methanesulfonamide (0.6 g, 85 %)as an yellowish liquid.
  • Step-1 Synthesis of l-(cyclopropylsulfonyl)-6-nitroindoline.
  • 6-nitroindoline 2.0 g, 12.18 mmol
  • pyridine 15 ml
  • cyclopropanesulfonyl chloride 1.7 g, 12.18 mmol
  • the reaction mixture was stirred at room temperature for 18 h. Most of the pyridine was removed in vacuo. The residue was partitioned between water and EtOAc. The organic phase was separated, dried over sodium sulphate. The solvent was evaporated in vacuo to give the title compound (2.1 g).
  • GCMS m/z: 268.06 (M+)
  • Step-2 Synthesis of l-(cyclopropylsulfonyl)indolin-6-amine.
  • Trie thy lsilane (8.5 ml, 52.2 mmol) was added dropwise to a suspension of 1- (cyclopropylsulfonyl)-6-nitroindoline (2.0 g, 7.45 mmol) and 10% Pd/C (500 mg) in MeOH (20 ml). Resulting suspension was stirred at room temperature for 20 min. The reaction mixture was filtered through celite bed and washed with methanol (50 ml). The combined filtrate was evaporated in vacuo to remove most of the methanol.
  • Step 1 Synthesis of 2-(6-((l-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8- dimethyl-2,4,7-trioxo-l ,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5- yl)amino)indolin- 1 -yl)acetamide
  • Step 2 Synthesis of 2-(6-(5-((2-fluoro-4-iodophenyl)amino)-3-(4- methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3- d]pyrimidin-l(2H)-yl)indolin-l-yl)acetamide
  • Step 3 Synthesis of 2-(6-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7- trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)indolin-l- yl)acetamide
  • Step-1 Synthesis of 2-((3-((3-cyclopropyl-l-(2-fluoro-4-iodophenyl)-6,8- dimethyl-2,4,7-trioxo-l ,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5- yl)amino)phenyl)amino)acetamide
  • Step-2 Synthesis of 2-((3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8- dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)- yl)phenyl)amino)acetamide .
  • Example-3 Synthesis of 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8- trimethyl-2 , 4, 7-trioxo-3 ,4,6, 7-tetrahydropy rido [4, 3-d]pyrimidin- 1 (2H)- yl)phenyl)amino)acet amide. (Compound 17)
  • Example A Identification of compounds inhibiting MEK kinase activity.
  • MEK enzyme final concentration 2-4 ug/ml
  • ERK substrate final concentration 50- 100 ug/ml
  • test compounds diluted such that the reaction had 1% DMSO
  • the reactions were initiated by the addition of ATP.
  • the reactions were terminated by adding an equal volume of KinaseGlo reagent (Promega) following the manufacturer's instructions.
  • the plates were read on a luminometer. IC50 calculations were done using GraphPad Prism 5.
  • IC5 0 values of the test compounds of inventions were below 450 nM.
  • Example B Analysis of ERK phosphorylation. This assay was carried out with human melanoma cells amd human and mouse colon cancer cells. Cells were treated for 1 h with various concentrations of test compounds. ERK phosphorylation analysis was performed using the Alphascreen SureFire Phospho-ERK 1 /2 Kit (Perkin Elmer) by following the manufacturer's instructions. % inhibition of ERK phosphorylation was determined as: 100 - ⁇ (RFU test - RFU lysis buffer control) / (RFU vehicle treated control - RFU lysis buffer control) ⁇ x 100. The compounds prepared were tested using the above assay procedure.
  • the minimum concentration of the compounds of invention required for ⁇ 80% inhibition of pERK was 0.1 nM.

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Abstract

La présente invention concerne des composés hétérocyclyle utilisés comme inhibiteurs de MEK. Ces composés comprennent des composés hétérocyclyle de formule (I), leurs sels pharmaceutiquement acceptables, leurs associations avec des médicaments appropriés et leurs compositions pharmaceutiques. La présente invention concerne également des procédés de préparation des composés et leur utilisation dans des méthodes de traitement. Les composés selon la présente invention sont représentés par la formule (I) ci-dessous : (I)
PCT/IB2015/056631 2014-09-04 2015-09-01 Dérivés de pyridopyrimidine utilisés comme inhibiteurs de mek WO2016035008A1 (fr)

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109320513A (zh) * 2018-11-09 2019-02-12 安庆奇创药业有限公司 一种合成曲美替尼的方法
CN112362781A (zh) * 2020-11-09 2021-02-12 河北诚信集团有限公司 一种甲基亚磺酸钠的含量测定方法
CN114456166A (zh) * 2022-03-30 2022-05-10 沈阳药科大学 5-取代氨基-3-甲基吡啶并[2,3-d]嘧啶类化合物及其制备与应用
WO2022120354A1 (fr) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Inhibiteurs de tead et utilisations associées
WO2022159986A1 (fr) 2021-01-25 2022-07-28 Ikena Oncology, Inc. Combinaison d'un inhibiteur de tead de 3-(imidazol-4-yl)-4-(amino)-benzène sulfonamide avec un inhibiteur de l'egfr et/ou un inhibiteur de mek pour une utilisation dans le traitement du cancer du poumon
WO2023114984A1 (fr) 2021-12-17 2023-06-22 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
US11766436B2 (en) 2018-05-04 2023-09-26 Amgen Inc. KRAS G12C inhibitors and methods of using the same
US11827635B2 (en) 2019-05-21 2023-11-28 Amgen Inc. Solid state forms
US11878958B2 (en) 2022-05-25 2024-01-23 Ikena Oncology, Inc. MEK inhibitors and uses thereof
US11905281B2 (en) 2017-05-22 2024-02-20 Amgen Inc. KRAS G12C inhibitors and methods of using the same
US11918584B2 (en) 2018-11-19 2024-03-05 Amgen Inc. Combination therapy including a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
US11993597B2 (en) 2017-09-08 2024-05-28 Amgen Inc. Inhibitors of KRAS G12C and methods of using the same
US12083121B2 (en) 2018-06-12 2024-09-10 Amgen Inc. Substituted piperazines as KRAS G12C inhibitors

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
US5019369A (en) 1984-10-22 1991-05-28 Vestar, Inc. Method of targeting tumors in humans
WO2003053960A2 (fr) 2001-12-05 2003-07-03 Astrazeneca Ab Composes chimiques
WO2005023251A1 (fr) 2003-08-29 2005-03-17 Array Biopharma Inc. Derives de benzimidazole n3 alkyles utilises comme inhibiteurs de mek
WO2005051906A2 (fr) 2003-11-19 2005-06-09 Array Biopharma Inc. Inhibiteurs heterocycliques de mek et methodes d'utilisation associees
WO2005121142A1 (fr) 2004-06-11 2005-12-22 Japan Tobacco Inc. Dérivés de 5-amino-2,4,7-trioxo-3,4,7,8-tétrahydro-2h-pyrido’2,3-d! pyrimidine et composés apparentés pour le traitement du cancer
WO2010121646A1 (fr) 2009-04-21 2010-10-28 Novartis Ag Composés hétérocycliques comme inhibiteurs de mek
WO2013136254A1 (fr) * 2012-03-14 2013-09-19 Lupin Limited Composés hétérocyclyle

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4501728A (en) 1983-01-06 1985-02-26 Technology Unlimited, Inc. Masking of liposomes from RES recognition
US5019369A (en) 1984-10-22 1991-05-28 Vestar, Inc. Method of targeting tumors in humans
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
WO2003053960A2 (fr) 2001-12-05 2003-07-03 Astrazeneca Ab Composes chimiques
WO2005023251A1 (fr) 2003-08-29 2005-03-17 Array Biopharma Inc. Derives de benzimidazole n3 alkyles utilises comme inhibiteurs de mek
WO2005051906A2 (fr) 2003-11-19 2005-06-09 Array Biopharma Inc. Inhibiteurs heterocycliques de mek et methodes d'utilisation associees
WO2005121142A1 (fr) 2004-06-11 2005-12-22 Japan Tobacco Inc. Dérivés de 5-amino-2,4,7-trioxo-3,4,7,8-tétrahydro-2h-pyrido’2,3-d! pyrimidine et composés apparentés pour le traitement du cancer
WO2010121646A1 (fr) 2009-04-21 2010-10-28 Novartis Ag Composés hétérocycliques comme inhibiteurs de mek
WO2013136254A1 (fr) * 2012-03-14 2013-09-19 Lupin Limited Composés hétérocyclyle
WO2013136249A1 (fr) * 2012-03-14 2013-09-19 Lupin Limited Composés hétérocyclyle en tant qu'inhibiteurs de mek

Non-Patent Citations (19)

* Cited by examiner, † Cited by third party
Title
"Pharmaceutics and Pharmacy Practice", 1982, J. B. LIPPINCOTT COMPANY, pages: 238 - 250
"Physicians' Desk Reference", 2004
"Physicians' Desk Reference", 2004, THOMSON PDR
"Remington's Pharmaceutical Science", 1985, MACK PUBLISHING COMPANY
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING COMPANY, pages: 1445
DEEPA R. HAMMAKER ET AL., JOURNAL OF IMMUNOLOGY, vol. 172, 2004, pages 1612 - 1618
DEEPA R. HAMMAKER ET AL., THE JOURNAL OF IMMUNOLOGY, vol. 172, 2004, pages 1612 - 1618
DOUGLAS HANAHAN; ROBERT A. WEINBERG, CELL, vol. 100, 2000, pages 57 - 70
DOUGLAS HANAHAN; ROBERT A. WEINBERG, CELL, vol. 144, 2011, pages 646 - 674
HIDESUKE FUKAZAWA ET AL., MOLECULAR CANCER THERAPEUTICS, vol. 1, March 2002 (2002-03-01), pages 303 - 309
JAMES A MCCUBREY ET AL., CURRENT OPINION IN INVESTIGATIONAL DRUGS, vol. 9, no. 6, 2008, pages 614 - 630
JOHN M. KYRIAKIS; JOSEPH AVRUCH, THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 271, no. 40, 1995, pages 24313 - 24316
JOHN M. KYRIAKIS; JOSEPH AVRUCH, THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 271, no. 40, 1996, pages 24313 - 24316
JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 2 - 19
JUDITH S; SEBOLT-LEOPOLD; ROMAN HERRERA, NATURE REVIEWS CANCER, vol. 4, 2004, pages 937 - 947
LAWRENCE A. TRISSEL: "ASHP Handbook on Injectable Drugs", 1986, pages: 622 - 630
P. HEINRICH STAHL; CAMILLE G. WERMUTH: "Handbook of Pharmaceutical Salts, Properties, Selection, and Use", 2002, WILEY- VCH
STEPHEN M. BERGE ET AL., JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 66, no. 1, 1977, pages 1 - 19
TODD H. WASSERMAN ET AL., CANCER, vol. 36, 1975, pages 1258 - 1268

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* Cited by examiner, † Cited by third party
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US11905281B2 (en) 2017-05-22 2024-02-20 Amgen Inc. KRAS G12C inhibitors and methods of using the same
US11993597B2 (en) 2017-09-08 2024-05-28 Amgen Inc. Inhibitors of KRAS G12C and methods of using the same
US11766436B2 (en) 2018-05-04 2023-09-26 Amgen Inc. KRAS G12C inhibitors and methods of using the same
US12083121B2 (en) 2018-06-12 2024-09-10 Amgen Inc. Substituted piperazines as KRAS G12C inhibitors
CN109320513B (zh) * 2018-11-09 2021-03-16 安庆奇创药业有限公司 一种合成曲美替尼的方法
CN109320513A (zh) * 2018-11-09 2019-02-12 安庆奇创药业有限公司 一种合成曲美替尼的方法
US12280056B2 (en) 2018-11-19 2025-04-22 Amgen Inc. Combination therapy including a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
US11918584B2 (en) 2018-11-19 2024-03-05 Amgen Inc. Combination therapy including a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
US11827635B2 (en) 2019-05-21 2023-11-28 Amgen Inc. Solid state forms
CN112362781A (zh) * 2020-11-09 2021-02-12 河北诚信集团有限公司 一种甲基亚磺酸钠的含量测定方法
WO2022120354A1 (fr) 2020-12-02 2022-06-09 Ikena Oncology, Inc. Inhibiteurs de tead et utilisations associées
WO2022159986A1 (fr) 2021-01-25 2022-07-28 Ikena Oncology, Inc. Combinaison d'un inhibiteur de tead de 3-(imidazol-4-yl)-4-(amino)-benzène sulfonamide avec un inhibiteur de l'egfr et/ou un inhibiteur de mek pour une utilisation dans le traitement du cancer du poumon
WO2023114984A1 (fr) 2021-12-17 2023-06-22 Ikena Oncology, Inc. Inhibiteurs de tead et leurs utilisations
CN114456166A (zh) * 2022-03-30 2022-05-10 沈阳药科大学 5-取代氨基-3-甲基吡啶并[2,3-d]嘧啶类化合物及其制备与应用
US11878958B2 (en) 2022-05-25 2024-01-23 Ikena Oncology, Inc. MEK inhibitors and uses thereof

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