Classifications

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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Definitions

• the present invention relates to anticancer compounds, their pharmaceutically acceptable salts, combinations with suitable medicament and pharmaceutical compositions thereof containing one or more such compounds, and methods of 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 (Hanahan and Weinberg, Cell, 2000, Vol. 100, 57-70). 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 has 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 (Sebolt-Leopold and Herrera, Nat. Rev.
• 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 (Kyriakis and Avruch, 1996, Vol. 271 , No. 40, pp. 24313-24316; Hammaker et al., J. Immunol. 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.
• International patent applications WO/2003/053960, WO/2005/023251, WO/2005/ 121 142, WO/2005/051906, WO/2010/ 121646 describe MEK inhibitors.
• the present invention provides anticancer compounds of the general formula (I), their pharmaceutically acceptable salts, combinations with suitable medicament and pharmaceutical compositions thereof and use thereof in treating various cancers.
• the compounds of the present inventions are potent inhibitors of MEK and show tumor regression effect with promisingly less side effects.
• the present invention relates to heteroaryl compounds of formula I, their pharmaceutically acceptable salts, their combinations with suitable medicament and pharmaceutical compositions thereof.
• the present invention also includes processes of preparation of the compounds and their use in methods of treatment.
• the compounds are of formula (I) below:
• R 1 is selected from the group consisting of hydrogen, substituted- or unsubstituted-alkyl, substituted- or unsubstituted- alkenyl, substituted- or unsubstituted- alkynyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- cycloalkenyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, and substituted- or unsubstituted- heterocyclyl;
• - 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 5 is substituted- or unsubstituted-aryl, wherein the substituents are selected from the group consisting of R a and R b ;
• R 6 and R 7 are each independently selected from the group consisting of hydrogen, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstituted- heterocyclyl; or R 6 and R 7 taken together with the nitrogen to which they are attached form a substituted- or unsubstituted- heterocyclyl; R 8 and R 9 are each independently selected from the group consisting of hydrogen, substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstituted- heterocyclyl, or R 8 and R 9 taken together with the nitrogen to which they are attached form a substituted- or unsubstituted- heterocyclyl; with the provisos that both R 8 and R 9 cannot be hydrogen at the same time; and when R 8 and R 9 are not a part of a heterocycle formed together with the nitrogen to which they are attached, at least one of the R 8 and R 9 is substituted- or un
• R a and R b are each independently selected from the group consisting of hydrogen, halogen and haloalkyl
• R c and R d are independently selected from the group consisting of hydrogen, halogen, hydroxyl, and substituted- or unsubstituted- alkyl; or R c and R d taken together with the carbon to which they are attached form a substituted- or unsubstituted- cycloalkyl; m is an integer selected from the group consisting of 1 , 2, 3, and 4;
• the heterocyclyl group is substituted with 1 to 3 substituents.
• the substituents are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, -SO 2 R 10a , - -NH-S0 2 -alkyl and -NH- S0 2 -cycloalkyl.
• the heterocyclic group is substituted on a ring sulphur of the 'heterocycle', is the sulphur is substituted with 1 or 2 oxo groups.
• R 10 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl; Rio a i S selected from the group consisting of alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl; and
• Rio b is selected from the group consisting of hydrogen, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl.
• R 1 is selected from the group consisting of hydrogen, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- alkenyl, substituted- or unsubstituted- heterocyclyl, and substituted- or unsubstituted- cycloalkyl.
• R 1 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, allyl, difluoromethyl, cyclopropyl, 3-oxetanyl, -CH2COOH, -CH2COOC2H5, -CH 2 CH(OH)CH 2 (OH), and -C2H4OH.
• R 3 and R 4 are substituted- or unsubstituted- alkyl. In other embodiments, R 3 and R 4 are methyl.
• R 5 is substituted- or unsubstituted- phenyl, wherein the substituents are independently selected from R a and R b .
• R a and R b are independently selected from the group consisting of hydrogen and halogen.
• R a and R b are independently fluorine or iodine.
• R c and R d are independently selected from the group consisting of hydrogen, substituted- or unsubstituted- alkyl, halogen, and hydroxyl, or R c and R d taken together with the carbon to which they are attached form a substituted- or unsubstituted- cycloalkyl ring.
• R c and R d are independently selected from the group consisting of hydrogen, methyl, fluoro and hydroxyl; or R c and R d taken together with the carbon to which they are attached form a cyclopropyl ring.
• m is 1 or 2.
• R 6 and R 7 are independently selected from the group consisting of hydrogen, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstituted- heterocyclyl; or R 6 and R 7 taken together with the nitrogen atom to which they are attached form a substituted- or unsubstituted- heterocycle.
• R 6 and R 7 are independently selected from the group consisiting of hydrogen, methyl, cyclopropyl, and 3-oxetane; or R 6 and R 7 taken together with the nitrogen atom to which they are attached form azetidinyl or 3- hydroxy azetidinyl.
• R 8 and R 9 are independently selected from the group consisting of hydrogen, substituted- or unsubstituted- cycloalkyl and substituted- or unsubstituted- heterocyclyl, or R 8 and R 9 taken together with the nitrogen to which they are attached form a substituted- or unsubstituted- heterocycle; with the provisos that both R 8 and R 9 are not hydrogen at the same time, and when R 8 and R 9 are not a part of a heterocycle formed together with the nitrogen to which they are attached, at least one of the R 8 and R 9 is substituted- or unsubstitued- cycloalkyl or substituted- or unsubstituted- heterocyclyl.
• the present invention is a compound of formula la:
• R 1 , R 3 , R 4 , R 6 , R 7 , R a , R b , R c , R d and 'm' are as defined in formula (I).
• the present invention is a compound of formula (lb):
• R 1 , R 3 , R 4 , R 8 , R 9 , R a and R b are as defined in formula (I); with the provisos that both R 8 and R 9 cannot be hydrogen at the same time, and at least one of the R 8 and R 9 is selected from the group consisting of substituted- or unsubstituted- aryl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- cycloalkenyl, substituted- or unsubstituted-heterocyclyl; or R 8 and R 9 taken together with the nitrogen to which they are attached form a substituted- or unsubstituted- heterocycle.
• the present invention is a compound of formula (Ic):
• alkyl means a straight or branched hydrocarbyl chain containing from 1 to 20 carbon atoms.
• 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.
• alkenyl as used herein, means an 'alkyl' group as defined hereinabove containing 2 to 20 carbon atoms and containing at least one double bond.
• alkenyl include, but are not limited to, pent-2-enyl, hex-3-enyl, allyl, vinyl, and the like.
• alkyl or alkenyl groups are substituted alkyl or substituted alkenyl groups
• haloalkyl means alkyl, as the case may be, substituted with one or more halogen atoms, where alkyl groups are as defined above.
• halo is used herein interchangeably with the term “halogen” and means F, CI, Br or I.
• haloalkyl include but are not limited to triiluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentailuoroethyl, pentachloroethyl, 4,4,4- trifluorobutyl, 4,4-difluorocyclohexyl, chloromethyl, dichloromethyl, trichloromethyl, 1-bromoethyl and the like.
• perhaloalkyl group is defined hereinabove wherein all the hydrogen atoms of the said alkyl group are substituted with halogen, exemplified by triiluoromethyl, pentailuoroethyl and the like.
• hydroxy alkyl means alkyl, as the case may be, substituted with one or more hydroxyl group (s), where alkyl groups are as defined above.
• hydroxy as used herein means "-OH”.
• examples of “hydroxyalkyl” include but are not limited to -CH 2 OH, -CH 2 CH 2 OH, -CH(OH)CH 2 OH and the like.
• cycloalkyl as used herein, means a monocyclic, bicyclic, or tricyclic non-aromatic ring system containing from 3 to 14 carbon atoms, preferably monocyclic cycloalkyl ring containing 3 to 6 carbon atoms.
• monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
• Bicyclic ring systems include monocyclic ring system fused across a bond with another cyclic system which may be an alicyclic ring or an aromatic ring.
• Bicyclic rings also include spirocyclic systems wherein the second ring gets annulated on a single carbon atom.
• Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge.
• bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2. l]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.
• Tricyclic ring systems are the systems wherein the bicyclic systems as described about are further annulated with third ring, which may be alicyclic ring or aromatic ring. Tricyclic ring systems are also exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge. Examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.0 3 7 ]nonane and tricyclo[3.3.1.1 3 7 ]decane (adamantane) .
• cycloalkenyl means a cycloalkyl group as defined above containing at least one double bond.
• aryl refers to a monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system.
• 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.
• the aryl group is a substituted aryl group
• 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.
• the heteroaryl group is a substituted heteroaryl group
• heterocycle or “heterocyclic” as used herein, means a 'cycloalkyl' group wherein one or more of the carbon atoms replaced by -0-, -S-, -S(0 2 )-, -S(O)-, - N(R m )-, -Si(R m )R n -, wherein, R m and R n are independently selected from the group consisting of 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.
• Examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1 ,3-dioxanyl, 1 ,3-dioxolanyl, 1,3-dithiolanyl, 1 ,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl.
• pyrrolinyl pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thio morpholinyl, 1.1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl.
• bicyclic heterocycle examples include, but are not limited to 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro- l,4-benzodioxinyl, 2,3- dihydro- l-benzofuranyl, 2,3-dihydro- l-benzothienyl, 2,3-dihydro-l H-indolyl and 1 ,2,3,4-tetrahydroquinolinyl.
• the term heterocycle also include bridged heterocyclic systems such as azabicyclo [3.2.1] octane, azabicyclo[3.3.1]nonane and the like.
• 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.
• phenyl) cyclopropanecarboxamide (Compound 78) and l-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7- tetrahydro pyrido[4,3-d]pyrimidin- 1 (2H)-yl)phenyl)cyclopropanecarboxamide (Compound 79)
• the present disclosure provides a method for inhibiting MEK enzymes comprising contacting said MEK enzyme with a composition comprising a compound of I, la, lb, Ic, their tautomeric forms, their stereoisomers or their pharmaceutically acceptable salts, sufficient to inhibit said enzyme, wherein said enzyme inhibited MEK kinase, which occurs within cell.
• the invention also provides a method of treatment of a MEK mediated disorder in an individual suffering from said disorder, comprising administering to said individual an effective amount of a composition comprising a compound of formula I, la, lb, Ic, their tautomeric forms, their stereoisomers or their pharmaceutically acceptable salts.
• 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 an individual comprising administering to said individual an effective amount of a composition comprising a compound of formula I, la, lb, Ic, their tautomeric forms, their stereoisomers or their pharmaceutically acceptable salts.
• 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 an individual comprising administering to said individual an effective amount of a composition comprising a compound of formula I, la, lb, Ic, their tautomeric forms, their stereoisomers or their pharmaceutically acceptable salts.
• the inflammatory disease includes rheumatoid arthritis or multiple sclerosis.
• the invention also provide 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 cancer cells, the composition comprising a compound of formula I, la, lb, Ic, their tautomeric forms, their stereoisomers or their pharmaceutically acceptable salts.
• the invention also provide a method of inhibiting tumor size increase, reducing the size of a tumor, reducing tumor proliferation or preventing tumor proliferation in an individual in need thereof comprising administering to said individual 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, la, lb, Ic, their tautomeric forms, their stereoisomers or their pharmaceutically acceptable salts.
• the MEK-ERK pathway is activated in numerous inflammatory conditions (Kyriakis and Avruch 1996, Vol. 271, No. 40, pp. 24313-24316; Hammaker et al., J Immunol 2004; 172; 1612- 1618), including rheumatoid arthritis, inflammatory bowel disease and COPD.
• the present invention describes the inhibitors of MEK kinase for treatment of disorders that are driven by hyperactivation, abnormal activation, constitutive activation, 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), 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, meduUoblastoma, ependymoma, neuroectodermal and pineal tumors), breast (including but not limited to invasive ductal carcinoma, invasive lobular carcinoma, 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, anal, small intestine and salivary
• the hyperrproliferative 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, 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 soft tissue sarcoma,
• 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 or asthma.
• the present invention describes the inhibitors of MEK kinase for treatment of diseases and disorders associated with aberrant, abnormal and/or excessive angiogenesis.
• Such 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 chemotherapeutic agents and anti-inflammatory agents.
• Such combinations include but are not limited to combining the MEK kinase inhibitors with antimitotic 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 or anti- hormones.
• room temperature denotes any temperature ranging between about 20°C to about 40°C, except and otherwise it is specifically mentioned in the specification.
• the intermediates and the compounds of the present invention may be 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, dichloro me 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 dichlorome thane, ethyl acetate, hexane, methanol, acetone and their combinations.
• a suitable solvent such as pentane, diethyl ether, isopropyl ether, chloroform, dichloro me thane, ethyl acetate, acetone or their combinations
• the purification methods such as column chromatography (e.g
• Salts of 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 was then treated with the desired acid or base as described in Berge S.M. et al. "Pharmaceutical Salts, a review article in Journal of Pharmaceutical sciences volume 66, page 1- 19 (1977)" and in handbook of pharmaceutical salts properties, selection, and use by P.H.Einrich Stahland 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), alkaline earth metal (e.g., calcium), or ammonium.
• the 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, 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 the compounds of formula I of the present invention may be prepared by stereo specific syntheses or resolution of racemic compound using an optically active amine, acid or complex forming agent, and separating the diastereomeric salt/complex by fractional crystallization or by column chromatography.
• the compounds 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.
• the prodrugs can be prepared in situ during the isolation and purification of the compounds, or by separately reacting the 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 (parent carboxylic acid drug) is released, and the moiety or moieties split off remain nontoxic or are metabolized so that nontoxic metabolic products are produced.
• a carboxylic acid group can be esterified, e.g., with a methyl group or ethyl group to yield an ester.
• an ester When an ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively, oxidatively, or hydrolytically, to reveal the anionic group.
• An anionic group can be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate compound which subsequently decomposes to yield the active compound.
• 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.
• the term "aberrant kinase activity” refers to any abnormal expression or activity of the gene encoding the kinase or of the polypeptide It encodes.
• aberrant kinase activity include but are not limited to over-expression of the gene or polypeptide, gene amplification, mutations that produce constltutlvely active or hyperactive kinase activity, gene mutations, deletions, substitutions, additions, and the like.
• the present Invention further provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, Its tautomeric forms, Its stereoisomers, Its pharmaceutically acceptable salts In combination with the usual pharmaceutically acceptable carriers, diluents, exclplents, and the like.
• the pharmaceutically acceptable carrier or exclplent 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 exclplents 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.
• 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.
• compositions for parenteral administration that comprise 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, and 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 and 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 the compound of the invention, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
• liquid solutions such as an effective amount of a compound of the invention dissolved in diluents, such as water, saline, or orange juice
• capsules, sachets, tablets, lozenges, and troches each containing a pre-determined amount of the compound of the invention, as solids or granules
• 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, micro crystalline 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, emulsions, gels, and the like containing, in addition to the compound of the invention, such excipients as are known in the art.
• a flavor usually sucrose and acacia or tragacanth
• pastilles comprising a compound of the invention in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the 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 compounds 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 dichlorodiiluoromethane, 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.
• acceptable pressurized propellants such as dichlorodiiluoromethane, propane, nitrogen, and the like.
• non-pressured preparations such as in a nebulizer or an atomizer.
• Such spray formulations can be used to spray mucosa.
• the compound of the invention can be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases.
• 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 the 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 inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes.
• 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, Szoka et al., Ann. Rev. Biophys. Bioeng., 9, 467 ( 1980) 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.
• doses are known in the art (see, for example, the Physicians' Desk Reference (2004)).
• the compounds can be administered using techniques such as those described in, for example, Wasserman et al., Cancer, 36, pp. 1258- 1268 ( 1975) and Physicians' Desk Reference, 58th 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 the compound of the present invention. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
• the present method 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 individual. 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, 0.002 mg, 0.005 mg, 0.010 mg, 0.015 mg, 0.020 mg, 0.025 mg, 0.050 mg, 0.075 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg/kg body weight per day.
• the dose of the pharmaceutically active agent(s) described herein for the described methods can be about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 0.020 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 750 mg, or 1000 mg/kg body weight per day.
• treat 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.
• the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal.
• a disorder, including symptoms or conditions thereof may be reduced by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 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 disorder, e.g., cancer.
• treatment,” “prevention,” “amelioration,” or “inhibition” can encompass delaying the onset of the disorder, or a symptom or condition thereof.
• 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 mammals are from the order Carnivora, including Felines (cats) and Canines (dogs).
• the mammals are from the order Artiodactyla, including Bovines (cows) and Swine (pigs) or of the order Perssodactyla, including Equines (horses).
• the mammals are of the order Primates, Ceboids, or Simoids (monkeys) or of the order Anthropoids (humans and apes) .
• the mammal is human.
• Step-1 Compound of formula (II) where R 1 is N-protecting group, can be converted to compound of formula (III) by reacting compound of (II) (Prepared as per reference WO2005121142) (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 etc., at temperature ranging from about -78 S C to about 150 S C.
• Z is any suitable leaving group like CI, Br, I, -0
• 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, K 2 C0 3 etc. in a solvent like Methanol, Ethanol, THF, DMF etc. at temperature ranging from about -78 S C to about 150 S C.
• 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/H2 etc. in a solvent like Anisole, Toluene, Xylene, THF, DMF, DMSO etc. at temperature ranging from about -78 S C to about 150 S C.
• R 1 is selected from the group consisting of substituted- or unsubstituted- alkyl, substituted- or unsubstituted- alkenyl, substituted- or unsubstituted- alkynyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- cycloalkenyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, and substituted- or unsubstituted- heterocyclyl, can be prepared as depicted in Scheme 2, details of which are given below
• Compound of formula (la) where R 1 is H can be converted to compound of formula (I) by reacting compound of I with R ! Z (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.) in presence of a suitable base like 2,6-Lutidine, l ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), K2CO3, 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 S C to about 150 S C.
• Scheme-3 is any suitable leaving group like CI, Br, I, -0(SO) 2 (4-MePh), -0(SO) 2 CH 3 , -0(SO
• R 1 is selected from the group consisting of substituted- or unsubstituted- alkyl, substituted- or unsubstituted- alkenyl, substituted- or unsubstituted- alkynyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- cycloalkenyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, and substituted- or unsubstituted- heterocyclyl, can be prepared as depicted in Scheme 3, details of which are given below
• R 1 is selected from the group consisting of substituted- or unsubstituted- alkyl, substituted- or unsubstituted- alkenyl, substituted- or unsubstituted- alkynyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- cycloalkenyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, and substituted- or unsubstituted- heterocyclyl, can be converted to compound of formula (III) by reacting compound of II (Z is any suitable leaving group like CI, Br, I, -0(SO) 2 (4-MePh), -0(SO) 2 CH 3 , - 0(SO)2CF3 etc.) with R 2 N3 ⁇ 4 in presence of a suitable base like 2,6-Lutidine, 1 ,8- Diazabicyclo[5.
• 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, dichloro me 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 dichlorome thane, ethyl acetate, hexane, methanol, acetone and their combinations.
• a suitable solvent such as pentane, diethyl ether, isopropyl ether, chloroform, dichloro me thane, ethyl acetate, acetone or their combinations
• purification methods such as column chromatography (e.g. flash chromat
• Salts of compound of formula I are 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 was then treated with the desired acid or base as described in Berge S. M. et al. "Pharmaceutical Salts, a review article in Journal of Pharmaceutical sciences volume 66, page 1- 19 (1977)" and in handbook of pharmaceutical salts properties, selection, and use by P.H.Einrich Stahland 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
• stereoisomers of the compounds 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.
• work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and 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 Dimethylsulfoxide
• CDI 1, 1'- Carbonyldiimidazole
• DMF ⁇ , ⁇ -dimethyl formamide
• DMA Dimethylacetamide
• HBTU 2-(lH-Benzotriazole- l-yl)- l, l ,3,3-tetra methyluronium hexafluorophosphate
• THF Tetrahydrofuran
• DCM Dichloro methane
• EDC 1- Ethyl-3-(3-dimethylaminopropyl)carbodiimide
• HATU 0-(7-Azabenzotriazol- 1-yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium hexafluorophosphate
• DIPEA ⁇ , ⁇ -Diisopropyl ethyl
• Step a Synthesis of 3-((tert-butoxycarbonyl) amino) benzoic acid: To a stirred solution of 3-aminobenzoic acid (5 g, 36.5 mmol) in water (40.0 ml) was added aq. solution of sodium hydroxide (2.187 g, 54.7 mmol) followed by (BOC)20 (10.16 ml, 43.8 mmol) in dioxane (20.0 ml) under ice cooling. The mixture was stirred under ice cooling for 30 min and further at room temperature for 12 hrs. To the reaction mixture ethyl acetate (50.0 ml) was added and the aq. layer was separated. The aq.
• Step b Synthesis of tert-butyl (3-(azetidine-l-carbonyl) phenyl) carbamate
• 3-((tert-butoxycarbonyl)amino)benzoic acid 1.5 g, 6.32 mmol
• DMF DMF
• ⁇ , ⁇ -diisopropyl ethylamine 2.208 ml, 12.64 mmol
• o-Benzotriazol- l-yl-tetramethyluronium hexafluorophosphate 2.398 g, 6.32 mmol
• azetidine hydrochloride (1.183 g, 12.64 mmol
• Step c Synthesis of (3-aminophenyl)(azetidin-l-yl)methanone
• tert-butyl (3-(azetidine- l-carbonyl) phenyl) carbamate 600 mg, 2. 171 mmol
• trifluoroacetic acid 0.167 ml, 2.171 mmol
• Reaction was stirred at room temperature for lhr.
• Solvent evaporated up to dryness and the residual solid was dissolved in DCM (20 ml) and washed with saturated solution of NaHCOa.
• DCM layer was dried over sodium sulphate and evaporated under vacuum.
• Step b Synthesis of 2-(3-aminophenyl)-N-cyclopropylacetamide
• Triethylsilane (27.0 ml, 169 mmol) was added dropwlse to a suspension of N- cyclopropyl-2-(3-nitrophenoxy)acetamide (4 g, 16.93 mmol) and Pd/C ( 10%, 400 mg) in MeOH (50 ml) . Resulting suspension was stirred at RT for 20 min. and filtered through celite. The filtrate was evaporated under vacuum and triturated in hexane to obtain the crystals which were collected by filtration to afford 2- (3- aminophenoxy)-N-cyclopropylacetamide (2.86 gm).
• Step c Synthesis of (3-aminophenyl)(l, l-dioxidothiazolidin-3-yl)methanone
• a solution of (l , l-dioxidothiazolidin-3-yl)(3-nitrophenyl)methanone (3 g, 1 1.10 mmol) in MeOH (30 ml) and 10% Pd-C (300 mg) was stirred under H 2 (1 atm) for overnight. Reaction mixture was filtered through celite pad and the filtrate was evaporated under vacuum to afford the titled compound (2.3 gm).
• Step b Synthesis of (1 , 1-dioxidothiomorpholino) (3-nitrophenyl) methanone
• acetic acid 80 ml
• H2O2 45 ml, 30 % solution
• reaction mixture was heated at 90 °C for 3 hr.
• Solvents were evaporated under vacuum, the residue was dissolved in DCM:MeOH (20:20 mL) and passed through a celite bed. The filtrate was concentrated under vacuum to obtain the crude product (7.3 gm).
• Step c Synthesis of (3-aminophenyl) (l, l-dioxidothiomorpholino)methanone
• MeOH MeOH
• Pd-C 50%, 350 mg
• triethylsilane 8.5 ml
• Reaction was stirred at RT for lh.
• Reaction mixture was filtered through celite and washed with methanol (50ml). Filtrate was concentrated under vacuum and triturated in hexane to get crude product (2.8 gm).
• Step b Synthesis of 2,2-difluoro-2-(3-nitrophenyl) acetamide
• Step b Synthesis of 3-(3-aminophenyl)- methyl propanamide
• N-methyl-3-(3-nitrophenyl)acrylamide (4 g, 19.40 mmol) and Pd-C ( 10%, 200 mg) in MeOH (30.0 ml)
• triethylsilane 31 ml, 194 mmol
• reaction mixture was filtered through celite bed. The filtrate was concentrated under vacuum to give the title compound (2.5 gm).
• Step a Synthesis of (4-hydroxypiperidin-l-yl)(3-nitrophenyl) methanone
• Step-c Synthesis of (3-aminophenyl)(4-hydroxypiperidin-l-yl) methanone
• Step-a Synthesis of 3-Nitro-N-(tetrahydrofuran-3-yl) benzamide Tetrahydrofuran-3-amine (0.1 g, 1.148 mmol) and 3-nitrobenzoic acid (0.192 g, 1.148 mmol) were taken in pyridine (2 ml), to the mixture EDC.HC1 (0.220 g, 1.148 mmol) was added, the reaction mixture was stirred under nitrogen for 10 hrs at room temperature. The reaction mixture was diluted with cold water (15 ml), extracted with ethyl acetate (2X10 ml). Combined organic layer was washed with satd. aq.
• Step-b Synthesis of 2-(3-nitrophenyl)-2-oxoacetamide Under nitrogen amosphere, (tert-butyl)-2-(3-nitrophenyl)-2-oxoacetamide (1.50 g, 5.99 mmol) was taken in toluene (10 ml) at room temperature, tert- butyldimethylsilyl trifluoromethane sulfonate (1.378 ml, 5.99 mmol) was added and the reaction mixture was heated at 100°C for 8 hrs. The reaction mixture was concentrated under vacuum and satd. sodium bicarbonate solution was added, the mixture was extracted with ethyl acetate (3X 20 ml).
• Step-a Synthesis of l-(Azetidin-l-yl)-2-(3-nitrophenyl)ethanone
• THF (30 niL) was added to a mixture of 2- (3-Nitrophenyl) acetic acid (1 g, 5.52 mmol) and CDI (1.34 g, 8.28 mmol), the mixture was stirred for 2 hrs at 0 °C followed by addition of triethylamine (2.308 ml, 16.56 mmol) and azetidine hydrochloride (1.033 g, 1 1.04 mmol). The reaction mixture was stirred for 12 hrs at room temperature and then concentrated under vacuum. The crude residue was purified by column chromatography using 0- 50% ethyl acetate in hexanes as eluent to afford the title product (0.53 g).
• Step-b Synthesis of 2-(3-Aminophenyl)-l-(azetidin-l-yl)ethanone l-(Azetidin- l-yl)-2-(3-nitrophenyl)ethanone (0.5 g, 2.27mmol) was taken in methanol (20 ml) and at 0°C, Pd-C (10%, 0.05g) was added. The reaction mixture was stirred under hydrogen atmosphere at room temperature for 5 hrs. The reaction mixture was filtered through celite and the filtrate was concentrated under vacuum to afford the title product (0.34 gm).
• Step-b Synthesis of 2-(3-Aminophenyl)-N-(oxetan-3-yl)acetamide
• 2-(3-Nitrophenyl)-N-(oxetan-3-yl)acetamide (0.5 g, 2.1 1mmol) was taken in methanol (20 ml) and at 0°C, 10% Pd-C (0.5g) was added.
• the reaction mixture was stirred under hydrogen atmosphere at room temperature for 5 hrs.
• the reaction mixture was filtered through celite and the filtrate was concentrated under vacuum to afford the title product (0.42 gm).
• Step-a Synthesis of l-(3-Hydroxyazetidin-l-yl)-2-(3-nitrophenyl)ethanone
• THF (30 mL) was added to a mixture of 2-(3-Nitrophenyl)acetic acid (0.5 g, 2.76 mmol), CDI (0.671 g, 4.14 mmol), the mixture was stirred for 2 hrs at 0 °C followed by addition of triethylamine (1.2154 ml, 8.28mmol) and azetidin-3-ol hydrochloride (0.756 g, 6.90 mmol). The reaction mixture was stirred for 12 hrs at room temperature and then concentrated under vacuum. The crude residue was purified by column chromatography using 0- 50% ethyl acetate in hexanes as eluent to afford the title product (0.51 g).
• Step-b Synthesis of 2-(3-aminophenyl)-l-(3-hydroxyazetidin-l-yl)ethanone l-(3-hydroxyazetidin-l-yl)-2-(3-nitrophenyl)ethanone (0.5 g, 2.117mmol) was taken in methanol (20 ml) and at 0°C, Pd-C (10%, 0.5 g) was added. The reaction mixture was stirred under hydrogen atmosphere at room temperature for 5 hrs. The reaction mixture was filtered through celite and the filtrate was concentrated under vacuum to afford the title product (0.42 gm).
• Step-a Synthesis of Ethyl l-(3-nitrobenzamido)cyclopropanecarboxylate
• 3-nitrobenzoic acid 1 g, 5.98 mmol
• pyridine 10ml
• ethyl 1-aminocyclopropanecarboxylate hydrochloride 1.090 g, 6.58 mmol
• EDC.HC1 1.721 g, 8.98 mmol
• Reaction mixture was stirred at room temperature for 3hrs.
• Reaction mixture was diluted with cold water ( 100ml) and extracted with ethyl acetate (2X25ml). Separated organic layer was washed with brine and water, dried over sodium sulfate and concentrated under vacuum till dryness to obtain product ( 1.26g, 76%).
• Step-b Synthesis of l-(3-Nitrobenzamido)cyclopropanecarboxylic acid
• Step-b Synthesis of 3-Amino-N-(l -(hydroxy methyl)cyclopropyl)benzamide
• Step a Synthesis of l-(3-nitrophenyl)cyclopropanecarbonitrile
• Step b Synthesis of l-(3-nitrophenyl)cyclopropanecarboxamide:
• Step c Synthesis of l-(3-aminophenyl)cyclopropanecarboxamide
• Triethylsilane (7.75 ml, 48.5 mmol) was added dropwise to a suspension of l-(3- nitrophenyl)cyclopropanecarboxamide (1 g, 4.85 mmol) and Pd/C (10%, 250 mg) in MeOH (20 ml). Resulting suspension was stirred at RT for 20 min. and filtered through celite. The filtrate was evaporated and triturated in hexane to obtain the crystals which were collected by filtration to afford the title compound (0.68 g).
• Step-1 Synthesis of 3-(3-((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)phenyl) propanamide (lb)
• Step-2 Synthesis of 3-(3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)- 6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyr 1 do[4,3-d]pyT 1 midin- l (2H)-yl)phenyl) propanamide ( lc)
• Aluminium chloride (2.82 g, 21.14 mmol) was added in small portions to a solution of 3-(3-(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- 1 (2H)-yl)phenyl)propanamide ( lc) ( 1.500 g, 2.1 14 mmol) in anisole (15 ml). The resulting reaction mixture was stirred at room temperature for 24 h, then quenched by addition of MeOH ( 15 ml) and 2N HC1 (0.5 ml).
• Example-2 Synthesis of 5-((2-fluoro-4-iodophenyl)amino)-l-(3-(3- hydroxypyirolidine-l-carbonyl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidine- 2,4,7(lH,3H,6H)-trione (22).
• Step-1 Synthesis of 3-((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)benzoic acid (2b) To a stirred solution of 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 4- methylbenzene sulfonate (2a) (2.0 gm, 2.79 mmol) in DMA (5 ml) was added 2,6- lutidine (0.98 ml, 8.36 mmol) and 3-aminobenzoic acid ( 1.147 g
• Step-2 Synthesis of l-(2-fluoro-4-iodophenyl)-5-((3-(3-hydroxypyrrolidine-l- carbonyl)phenyl)amino)-3-(4-methoxybenzyl)-6 , 8-dimethylpy rido [2 , 3- d]pyrimidine-2,4,7(lH,3H,8H)-trione (2c)
• Step-3 Synthesis of 5-((2-fluoro-4-iodophenyl)amino)-l-(3-(3- hydroxypyrrolidine-l-carbonyl)phenyl)-3-(4-methoxybenzyl)-6,8- dimethylpyrido[4, 3-d]pyrimidine-2,4, 7( 1 H, 3H, 6H)-trione (2d)
• reaction mixture was stirred at room temperature for 3 h under N2 atm.
• the solvents were evaporated in vacuo and the residue was suspended in dilute HC1 (10 ml).
• the suspension was extracted several times with ethyl acetate.
• the combined organic phase was washed with brine and dried over sodium sulphate.
• Step-4 Synthesis of 5-((2-fluoro-4-iodophenyl)amino)-l-(3-(3- hydroxypyrrolidine-l-carbonyl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-
• Example-3 Synthesis of 5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-l-(3- (piperazine-l-carbonyl)phenyl)pyrido[4,3-d]pyrimidine-2,4,7(lH,3H,6H)-trione (Compound 23).
• Step -1 Synthesis of methyl 3-((l-(2-fluoro-4-iodophenyl)-3-(4- methoxybenzyl)-6, 8-dimethyl-2 ,4 , 7-trioxo- 1 , 2, 3,4, 7, 8-hexahydropyrido[2, 3- d]pyrimidin-5-yl)amino)benzoate (3b)
• Step -2 Synthesis of methyl 3-(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)benzoate (3c)
• Step -3 Synthesis of 3-(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)benzoic acid (3d)
• a mixture of methyl 3-(5-((2-fluoro-4-lodophenyl)amlno)-3-(4-methoxybenzyl)-6,8- dlmethyl-2,4,7-trloxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimldln- l (2H)-yl)benzoate (0.500 g, 0.718 mmol) and LIOH.H2O (0.
• Step-4 Synthesis of tert-butyl 4-(3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4- methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3- dlpyrimidin- 1 (2H)-yl)benzoyl)piperazine- 1 -carboxylate (3e)
• Step-5 Synthesis of 5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-l-(3- (piperazine-l-carbonyl)phenyl)pyrido[4,3-d]pyrimidine-2,4,7(lH,3H,6H)-trione (23).
• Aluminium chloride ( 1.57 g, 1 1.76 mmol) was added in small portions to a solution of crude tert-butyl 4-(3-(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)benzoyl)piperazine- l-carboxylate ( 1 g, 1. 176 mmol) in Anisole (5 ml) .
• Step-1 Synthesis of 5-((3-(azetidine- l-carbonyl)phenyl)amino)-3-cyclopropyl- l-(2- fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7( lH,3H,8H)- trione.
• Step-2 Synthesis of l-(3-(azetidine-l-carbonyl)phenyl)-3-cyclopropyl-5-((2- fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine- 2,4,7(lH,3H,6H)-trione (24) 5-((3-(azetidine- l-carbonyl)phenyl)amino)-3-cyclopropyl- l-(2-fluoro-4-iodophenyl)- 6,8-dimethylpyrido[2,3-d]pyrimidine-2,4, 7( lH,3H,8H)-trione (4b) (0.
• Example-5 N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl- 2,4, 7-trioxo-3, 4, 6 , 7-tetrahy dropy rido [4, 3-d]py rimidin- 1 (2H)-yl)benzamide
• reaction mixture was cooled to room temperature followed by the addition of water and the mixture was extracted with ethyl acetate (3 x 10ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to obtain a crude product, which was purified by column chromatography to yield the product (55) (0.06 gm).
• reaction mixture was cooled to room temperature followed by the addition of water and the mixture was extracted with ethyl acetate (3 x 10ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to obtain a crude product, which was purified by column chromatography to yield the product (72) as solid (0.05 mg).
• Example 7 N-cyclopropyl-3-(3-(2,3-dihydroxypropyl)-5-((2-fluoro-4-iodophenyl) amino) -6 , 8-dimethyl-2 , 4, 7-trioxo-3 ,4, 6, 7-tetrahy dropy rido [4, 3-d] py rimidin- l(2H)-yl)benzamide (Compound 73)
• Example 8 2-( l-(3-(cyclopropylcarbamoyl)phenyl)-5-((2-fluoro-4-iodophenyl) amino)-6,8-dimethyl-2,4,7-trioxo-l,2,6,7-tetrahydropyrido[4,3-d]pyrimidin- 3(4H)-yl)acetic acid (Compound 74)
• 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. IC5 0 calculations were done using GraphPad Prism 5.
• IC5 0 values of the compounds of inventions were provided below in table 5. Compounds exhibiting IC5 0 in the range 1 nM to 499 nM were grouped as 'a', compounds exhibiting IC50 value in the range 0.5 uM to 1.5 uM were grouped as 'b', and the compounds exhibiting IC5 0 value in the range 1.6 uM to 3.0 uM were grouped as 'c'.
• 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:
• Example-C Analysis of B-Raf-mediated MEK phosphorylation
• mice were acclimatized in the experimental animal room for 15 days prior to the cell inoculation. Mice were inoculated subcutaneously at 5xl0 6 COLO205/A375 cells (in 0.2 mL PBS) single cell suspension without conglomerates with viability of 98% into the right flank of the mice. Post cell inoculation, tumor dimension were measured with digimatic Vernier caliper (Mitutoyo, Japan) when tumor becomes palpable. Tumor volume was calculated by using the formula:
• Tumor volume in mm 3 (Length xWidth xWidth)/ 2 Mice were randomized on the basis of tumor volume into different groups with approximately equal mean and equal variation on desired day post cell inoculation. All groups were orally administered once /twice daily with some compounds of the invention and vehicle control for 21/22 days. Tumor measurements were done with Vernier caliper twice weekly. Body weights of mice were recorded daily.
• Percent tumor growth inhibition was calculated as:
• Tf and Ti are the final and initial treatment tumor volumes
• Cf and Ci are the final and initial control mean tumor volumes, respectively.
• TR% Percent tumor regression

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