OA17318A - Heterocyclyl Compounds. - Google Patents

Abstract

The present invention is related to heteroaryl comounds as MEK inhibitors. The invention includes heteroaryl compounds of formula I, their tautomers and pharmaceutically acceptable salts, combinations with suitable medicament and pharmaceutical compositions thereof. The present invention also includes process of preparation of the said compounds and intended use in therapy of them.

Description

HETEROCYCLYL COMPOUNDS

FIELD OF THE INVENTION

The présent invention relates to anticancer compounds, their pharmaceutically acceptable salts, combinations with suitable médicament and pharmaceutical compositions thereof containing one or more such compounds, and methods of treating various cancers.

CROSS-REFERENCE TO A RELATED APPLICATION

The présent application claims the benefit of Indian Provisional Patent Application No. 0288/KOL/2012, fïled 14* March 2012, the disclosure of which Is incorporated herein by reference în its entirety.

BACKGROUND OFTHE INVENTION

Cancer cells possess certain characteristics that allow them a growth advantage. These include six main alterations in cell physiology such as self-suffidency In growth signais, insensitivity to growthinhibitory signais, évasion of apoptosis, indefinite proliférative potentiai, 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 microenvironment conducive for tumor growth. In addition to the above mentioned traits, reprogramming of cellular energy metabolism and évasion of immune destruction has also been observed în 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 hâve 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, Hépatocyte growth factor receptor - HGF, etc. Furthermore, activating mutations hâve 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-assodated signalling leads to activation of immédiate downstream components such as Src, Ras, PI3-kinase, etc. These kinases further activate effectors such as MEK, ERK, AKT, eventually leading to activation of transcription factors that endow the cells with a high proliférative potential, improved survival, subversion of metabolic pathways and inhibition of apoptosis (Hanahan and Weinberg, Cell, 2000, Vol. 100, 57-70; Hanahan and Weinberg Cell 2011, Vol. 144,646-674)

MEK kinase (Mitogen Activated Protein Kinase Kinase (MAPKK)) is an important component of the Ras-RAF-MEK-ERK cell survival pathway. The Ras pathway is activated by binding of growth factors, cytokines, and hormones to their cognate receptors. In cancer celts, this pathway is, however, constitutively activated and leads to increased cancer cell survival, cell prolifération, 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, pancréas, breast, brain, ovary, lungs and skin (Sebolt-Leopold and Herrera, Nat Rev. Cancer 2004,4 937-947; Fukazawa et al., Mol. Cancer Ther. 2002, Vol. 1, 303-309). Activation of Ras (due to upstream signalling or as a resuit of activating point mutations in the Ras oncogene) lead to the phosphorylation and activation of Raf kinase that in tum phosphorylate and activate MEK kinase. MEK1/2 kinase phosphorylâtes and activâtes the ERK1/2 kinase (also referred to as MAP Kinase) that further phosphorylâtes and régulâtes the function of proteins such as Md-1, Bim and Bad that are involved In cell survival and apoptosis. Thus, activation of this phosphorylation mediated cascade leads to enhanced cell prolifération, cell survival, decreased cell death that are necessary for initiation and maintenance of the tumorigenic phenotype (Curr. Opin. Invest. Drugs, 2008,9,614).

The Ras-Raf-MEK-ERK cascade plays a pivotai rôle in survival and prolifération of cancer cells. As such, inhibition of this pathway at any of these levels would lead to the inhibition of cancer cell growth, prolifération 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 rénal cell cardnoma). Henœ, inhibiting MEK is a novel approach towards controlling this pathway in cancer cells. Moreover, 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 a!., J. Immunol. 2004, 172, 1612-1618), including rheumatoid arthritis, inflammatory bowe! disease and COPD. MEk régulâtes the biosynthesis of the inflammatory cytokines TNF, IL-6 and IL-1. It has been shown that MEK inhibitors interfère with the production/secretion of these cytokines. Array BioPharma has developed a first-in-dass MEK inhibitor (ARRY 438162) and initiated ciinical trials in rheumatoid arthritis (RA) patients.

International patent applications WO/2003/053960, WO/2005/023251, WO/2005/121142, WO/2005/051906, WO/2010/121646 describe MEK inhibitors.

BRIEF SUMMARY OF THE INVENTION

The présent invention provides anticancer compounds of the general formula (I), their pharmaceutically acceptable salts, combinations with suitable médicament and pharmaceutical compositions thereof and use thereof in treating various cancers.

^rs

O HN

Wherein, R’-R⁵ are described In detail below.

The compounds of the présent inventions are potent inhibitors of MEK and show tumor régression effect with promisingly less side effects.

DETAILED DESCRIPTION OF THE INVENTION

The présent invention relates to heteroaryl compounds of the general formula I, their pharmaceutically acceptable salts, their combinations with suitable médicament and pharmaceutical compositions thereof. The présent invention also indudes processes of préparation of the compounds and their use in methods of treatment. The compounds are of formula (I) below:

L·

wherein,

R¹ is selected from the group consisting of hydrogen, substituted- or unsubstituted-alkyl, substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstituted- heterocyclyl:

R² is selected from the group consisting of -R^e-E, -SO₂R⁷, and -C(=O)R^e;

R³ is selected from the group consisting of hydrogen, substituted- or unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;

R⁴ is selected from the group consisting of hydrogen, halogen, substituted- or unsubstituted-alkyl, and substituted- or unsubstituted- cycloalkyl;

R⁵ is substituted- or unsubstituted- aryl, wherein the substituents are selected from the group consisting of R* and R”;

R⁸ and R^b are each independently selected from the group consisting of hydrogen, halogen and haloalkyl;

R^e is selected from the group consisting of direct bond, -[C(R^c)R^t5]nNR⁹-, -[C(R^c)R^d]nO-, NHC(=O)[C(R^e)R^d]p-, -S(O)2NH-, -NHC(=O)[CR^c(R^d)]NR⁹-, -NHC(=O)[CR^e(R^d)]O-, and -NHS(O)r;

R^c and R^d are each independently selected from the group consisting of hydrogen and substitutedor unsubstituted alkyl;

E is four membered heterocydic ring substituted- or unsubstituted- with alkyl, halogen, -C(-O)OR and -OR*;

R* is selected from the group consisting of hydrogen, substituted- or unsubstituted-alkyl and substituted or unsubstituted cycloalkyl;

R⁷ is selected from the group consisting of substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstituted- cydoalkenyf;

R⁸ is selected from the group consisting of substituted- or unsubstituted- alkyl,substituted- or unsubstituted- alkenyl, substituted- or unsubstituted- alkynyl, substituted- or unsubstitutedcydoalkyl, and substituted- or unsubstituted- cycloalkenyl;

R⁹ is selected from the group consisting of hydrogen, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- alkenyl, substituted- or unsubstituted- alkynyl, substituted- or unsubstituted- cycloalkyl and substituted or unsubstituted- cycloalkenyl;

n is an integer selected from the group consisting of 0,1 and 2;

p is an integer selected from 0 and 1;

when the alkyl group and alkenyl group is substituted, the alkyl group and alkenyl group is substituted with 1 to 4 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR¹⁰”, -SO2R^10a, C(=O)OR^10a, -OC(=O)R^10a, -C(=O)N(H)R¹⁰,-OR¹⁰’, -C(=O)N(alkyl)R¹⁰, -N(H)C(=O)R^10a, -N(H)R¹⁰, N(alkyl)R¹⁰ -N(H)C(=O)N(H)R¹⁰, -N(H)C(=O)N(alkyl)R¹⁰, -NH-SOralkyl, and -NH-SOz-cycloalkyl;

when the cycloalkyl group and cycloalkenyl group Is substituted, the cycloalkyl group and cycloalkenyl group is substituted with 1 to 3 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, alkyl, alkenyl, perhaloalkyl, aryl, heteroaryl, heterocyclyl, OR¹⁰⁶, -SO2R^10a, -C(=O)R^10a, -C(=O)OR^10a, -OC(=O)R^10a, -C(=O)N(H)R¹⁰, -C(=O)N(alkyl)R¹⁰, N(H)CÎ=O)R^10a, -N(H)R^W, -N(alkyl)R¹⁰t -N(H)C(=O)N(H)R¹°, and -N(H)C(=O)N(alky!)R¹⁰, -NH-SO_r alkyl, and -NH-SO₂-cyc!oalkyl;

when the aryl group is substituted, the aryl group is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, heterocycle, -O-alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, N(H)alkyl, -NH₂, -SOz-alkyl, -SOj-perhaloalkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, C(=O)N(aîkyl)alkyl, -C(=O)N(H)alkyl_f -C(=O)NH_2l -SO₂N(alkyl)alkyl, -SO₂N(H)alky1, -SO₂NH₂, -NHSO₂-alkyi, and -NH-SOrcycloalkyl;

when the heteroaryl group is substituted, the heteroaryl group Is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, heterocycle, -O-alkyl, O-perhaloalkyl, -N(alkyi)aîkyl, N(H)aîkyl, -NH₂, -SOa-alkyl, -SOrperhaloalkyi, -N(aîkyl)C(=O)alkyl, -N(H)C(=O)alkyl, C(=O)N (alkyl Jalkyl, -C(=O)N(H)alkyl, -C(=O)NH₂, -SO₂N(alkyl)alky1, -SO₂N(H)alkyl, -SO₂NH₂, -NHSOralkyl, and -NH-SO₂-cycloalkyl;

when the heterocyclyl group is substituted, the heterocyclyl group is substituted with 1 to 3 substituents. When the substituents are on a ring carbon of the ’heterocyde’, the substituents are Independently selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cydoalkenyl, aryl, heteroaryl, heterocyclyl, -OR^10b, -C(=O)OR¹⁰·, OC(=O)R^10a, -C(=O)N(H)R¹⁰, -C(=O)N(alky1)R¹⁰, -N(H)C(=O)R^10a, -N(H)R¹⁰, -N(alkyl)R¹⁰, N(H)C(=O)N(H)R¹⁰, -N(H)C(=O)N(alkyl)R¹⁰. When the heterocydic group is substituted on a ring nitrogen of the ‘heterocycle’, the substituents are selected from the group consisting of alkyl, alkenyl, cycloalkyl, cydoalkenyl, aryl, heteroaryl, -SO₂R^10a, -C(=O)R^10a, C(=O)OR¹⁰*· C(=O)N(H)R^W, -C(=O)N(alkyl)R¹°, -NH-SCValkyl, and -NH-SOrcydoalkyl;

R¹⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cydoalkenyl, aryl, heteroaryl, and heterocydyl;

R¹⁰’ Is selected from the group consisting of alkyl, alkenyl, perhaloalkyl, cycloalkyl, cydoalkenyl, aryl, heteroaryl, and heterocydyl;

R^10b îs selected from the group consisting of hydrogen, alkyl, alkenyl, perhaloalkyl, cydoalkyl, cydoalkenyl, aryl, heteroaryl, and heterocydyl;

In certain embodiments, R¹ is seleded from the group consisting of hydrogen, substituted- or unsubstituted- alkyl, and substituted- or unsubstituted- cydoalkyl.

In other embodiments, R¹ Is selected from the group consisting of hydrogen, methyl and cydopropyl.

In certain embodiments, R³ is substituted- or unsubstituted- alkyl.

In other embodiments, R³ is methyl.

In certain embodiments, R⁴ îs substituted- or unsubstituted- alkyl.

In other embodiments, R⁴ is methyl.

In certain embodiments, R^s Is substituted- or unsubstituted- phenyl, wherein the substituents are independently seleded from R* and R”.

In certain embodiments, R*and R^b are particularly selected from hydrogen, halogen and haloalkyl.

In other embodiments, R and R^b are independently fluorine oriodine.

In certain embodiments, R® is selected from the group consisting of direct bond, -[CtR^R^nNR⁹-, [CiR^R^O-, and -NHC(=O)[C(R^e)R^e]_pIn other embodiments, R® is selected from the group consisting of direct bond, -NH-, -O-, -CH₂O-, and-NHC(=O)-.

In certain embodiments, E is selected from the group consisting of substituted- or unsubstituted- 3oxetane, 1-azetidine, 1-azetidine-2-one and 3-azetidine; wherein substituents are independently selected from methyl, fluoro, -C(=O)OR*, and -OR*.

In certain embodiments, R* is selected from hydrogen and substituted- or unsubstitued-alkyl.

In other embodiments, R* is selected from hydrogen, tert-butyl, and -CH₂C(=O)NH₂.

In certain embodiments, R⁷ is substituted- or unsubstituted- cycloalkyl.

In other embodiments, R⁷ is cyclopropyl.

In certain embodiments, R^B Is substituted- or unsubtituted- cycloalkyl.

In other embodiments, R^e is cyclopropyl.

In certain embodiments, R® is hydrogen.

In one embodiment, the présent invention is a compound of formula la:

(la)

wherein,

R¹, R³, R⁴, R®, E, R* and R^b are as defined in formula (I).

In another embodiment, the présent Invention is a compound of formula (Ib):

Wherein;

R¹, R³, R⁴, R⁷, R* and R^b are as defined in formula (I);

In another embodiment, the présent invention is a compound of formula (le):

Wherein:

R¹, R³, R⁴, R⁸, R'and R^bare as defined in formula (I).

General terms used In any of the formulae herein can be defined as follows; however, the meaning stated should not be interpreted as limiting the scope ofthe term perse.

The term alkyl, as used herein, means a straight chain or branched hydrocarbon containing from 1 to 20 carbon atoms. Preferably the alkyl chain may contain 1 to 10 carbon atoms. More preferably

alkyl chain may contain up to 6 carbon atoms. Représentative examples of alkyl include, but are not limited to, methyi, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

The term 'alkenyl' as used herein, means an ‘alkyl' group as defined hereinabove containing 2 to 20 carbon atoms and containing at least one double bond. Représentative examples of alkenyl include, but are not limited to, pent-2-enyl, hex-3-enyl, allyl, vinyl, and the like.

‘Alkyl’, 'alkenyl' as defined hereinabove may be substituted with one or more substituents selected independently from the group comprising of oxo, halogen, nitro, cyano, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR^10b, -SO2R^10a, -C(=O)R^10a, -C(=O)OR^10a, -OC(=O)R^10a, -C(=O)N(H)R¹°, -C(=O)N (alkyl )R¹⁰, -N(H)C(=O)R^10al -N(H)R¹⁰, -N(alkyl)R¹⁰, -N(H)C(=O)N(H)R¹⁰, N(H)C(=O)N(alkyl)R¹⁰, -NH-SCh-alkyl and -NH-SOrcydoalkyl; wherein, R¹⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cydoalkenyl, aryl, heteroaryl, and heterocyclyl; R^10a is selected from the group consisting of alkyl, alkenyl, haloalkyl, perhaloalkyl, cycloalkyl, cydoalkenyl, aryl, heteroaryl, heterocydyl; R^10b is selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, perhaloalkyl, cydoalkyl, cydoalkenyl, aryl, heteroaryl, and heterocydyl.

The term haloalkyl means alkyl, as the case may be, substituted with one or more halogen atoms, where alkyl groups are as defined above. The term 'halo is used herein interchangeably with the term halogen and means F, Cl, Br or I. Examples of haloalkyl indude but are not limited to trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl, 4,4, 4trifluorobutyl, 4,4-difluorocyclohexyf, chloromethyl, dichloromethyf, trichloromethyl, 1-bromoethyl and the like. The term ‘perhaloalkyl’ group is defined hereinabove wherein al! the hydrogen atoms of the said alkyl group are substituted with halogen, exemplified by trifluoromethyl, pentafluoroethyl and the like.

The term cycloalkyl as used herein, means a monocydic, bicydic, or tricydic non-aromatic ring system containing from 3 to 14 carbon atoms, preferably monocydic cydoalkyl ring containing 3 to 6 carbon atoms. Examples of monocydic ring Systems indude cydopropyl, cyclobutyl, cydopentyl, cydohexyl, cydoheptyl, and cydooctyl. Bicydic ring Systems are also exemplified by a bridged monocydic ring system in which two non-adjacent carbon atoms of the monocydic ring are linked by an alkylene bridge. Représentative examples of bicyclic ring Systems include, but are not limited to, bicydo[3.1.1]heptane, bicydo[2.2.1]heptane, bicydo[2.2.2]octane, bicydo[3.2.2]nonane, bicydo[3.3.1]nonane, and bicydo[4.2.1]nonane, bicydo[3.3.2jdecane, bicydo[3.1.0] hexane, bicydo[410]heptane, bicydo[3.2.0]heptanes, octahydro-1 H-indene. 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. Représentative examples of tricyclic-ring Systems include, but are not limited to, tricydo[3.3.1.0³⁷]nonane and tricydo[3.3.1.1³⁷]decane (adamantane). The term cycloalkyl also include spiro Systems wherein one of the ring is annulated on a single carbon atom such ring Systems are exemplified by spiro[2.5]octane, spiro[4.5]decane, sptro[bicydo[4.1,0]heptane-2,r-cyclopentane], hexahydro-2'H-spiro[cydopropane-1,1 '-pentaienej.

The term ‘cycloalkenyl as used herein, means a cycloalkyl group as defined above containing at least one double bond.

‘cycloalkyl’ and ‘cycloalkenyl’ as defined hereinabove may be substituted- or unsubstituted- with one or more substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, hydroxyl, hydroxyalkyl, alkyl, alkenyl, perhaloalkyl, aryl, heteroaryl, heterocydyl, -OR^10b, SO2R¹⁰·, -C(=O)R^10a, -C(=O)OR^10a, -OC(=O)R^10a, -C(=O)N(H)R¹⁰, -C(=O)N(alkyi)R¹⁰, N(H)C{=O)R^10a, -N(H)R¹⁰, -N(alkyl)R¹⁰, -N(H)C(=O)N(H)R¹⁰, -N(H)C(=O)N(alkyi)R¹⁰, -NH-SO^alkyl and -NH-SO2-cydoalkyl; wherein, R¹⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, cydoalkyl, cycloalkenyl, aryl, heteroaryl, and heterocydyl; R^10a is seleded from the group consisting of alkyl, alkenyl, perhaloalkyl, cydoalkyl, cydoalkenyl, aryl, heteroaryl, heterocydyl; R^10b is selected from the group consisting of hydrogen, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cydoalkenyl, aryl, heteroaryl, and heterocydyl.

The term aryl refers to a monovalent monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring System. Examples of aryl groups indude phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. Aryl group also indude partially saturated bicyclic and tricydic aromatic hydrocarbons such as tetrahydro-naphthalene. The said aryl group also indudes aryl rings fused with heteroaryl or heterocydic rings such as 2,3-dihydro-benzo[1,4]dioxin-6-yl; 2,3-dihydro-benzo[1,4]dioxin-5-yl; 2,3-dihydro-benzofuran-5-y1; 2,3-dihydro-benzofuran-4-y1; 2,3-dihydro-benzofuran-6-yl; 2,3-dihydrobenzofuran-6-yl; 2,3-dihydro-1H-indol-5-y1; 2,3-dihydro-1H-indol-4-yl; 2,3-dihydro-1H-indol-6-yl; 2,3dihydro-1H-lndol-7-yl; benzo[1,3]dioxol-4-yl; benzo[1,3]dioxol-5-y1; 1,2,3,4-tetrahydroquinolinyl; 1,2,3,4-tetrahydroisoquinolinyi; 2,3-dihydrobenzothien-4-yl, 2-oxoîndolin-5-yl.

Ary! as defined hereinabove may be substituted- or unsubstituted- with one or more substituents seleded independently from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl, cydoalkyl, cydoalkenyl, heterocyde, -O-alkyl, -O-perhaloalkyl, -N(alkyl)alky!, N(H)alkyl, -NH₂, -SO_ralky1, -SOî-perhaloalkyl, -N(alkyf)C(=O)alkyl. -N(H)C(=O)alkyl, 17318

C(=O)N(alky1)alkyl₁ -C(=O)N(H)alkyl, -C(=O)NH₂₁ -SO₂N(alkyl)alkyl, -SO₂N{H)alkyl, -SO₂NH₂, -NHSOralkyl and -NH-SOrcydoalkyl;

The term ’heteroaryT refera to a 5-14 membered monocydic, bicydic, or tricydic 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 substituted-or unsubstituted- 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. Examples of heteroaryl groups indude pyridyl, 1-oxo-pyridyl, furanyl, thienyl, pyrrolyf, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimîdinyl, pyrazinyl, triazinyi. triazolyl, thiadiazolyl, isoquinolinyl, benzoxazolyi, benzofuranyl, indolizinyl, imidazopyridyi, tetrazolyl, benzimtdazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, azaindolyl, imidazopyridyi, quinazolinyl, purinyl, pyrrolop.Slpyrimidinyl, pyrazolop^Jpyrimidinyl, and benzo(b)thieny1, 2,3-thiadiazolyl, 1Hpyrazolo[5,1-c]-1,2,4-triazolyl, pyrrolo[3,4-d]-1,2,3-triazolyl, cyclopentatriazolyl, 3H-pyrrolo[3,4-cI isoxazolyl and the like.

Heteroaryl as defined hereinabove may be substituted- or unsubstituted- with one or more substituents selected independentiy from the group consisting of haiogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, heterocyde, -O-alkyl, O-perhaloalkyl, N(alkyt)alky!, -N(H)alkyl, -NH₂, -SOz-alkyi, -SOz-perhaloalkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyi, -q=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH₂, -SO₂N(alkyl)alkyl, -SO₂N(H)alkyl, -SO₂NH₂, -NHSOralkyl and -NH-SO2-cydoalkyl.

The term heterocycle or heterocydic as used herein, means a ‘cydoalkyi’ group wherein one or more of the carbon atoms replaced by -O-, -S-, -S(O₂)-, -S(O)-, *N(R^m)-, -Si(R^m)R^,'-_> wherein, R^m and Rⁿ are independentiy selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cydoalkyi, and heterocydyl. The heterocyde may be connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocycle. Représentative examples of monocydic heterocyde indude, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothîazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl. oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl. pyrrolinyl, pyrrolidinyl, tetrahydrofùranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1.1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithîanyl. Représentative examples of bicydic heterocyde indude, but are not limited to 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-

1-benzofuranyl, 2,3-dihydro-l-benzothienyl, 2,3-dihydro-1 H-indolyl and 1,2,3,4tetrahydroquinolinyl. The term heterocycle also indude bridged heterocydic Systems such as azabicydo[3.2.1]odane, azabicyc!o[3.3.1]nonane and the like.

Heterocydyl group may be substituted- or unsubstituted- on ring carbons with one or more substituents selected independently from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, perhaloalkyl, cydoalkyl, cydoalkenyl, aryl, heteroaryl, heterocydyl, -OR^10t, -C(=O)OR^10a, OC(=O)R¹⁰’l -C(=O)N(H}R¹⁰, -C(=O)N(alkyl)R¹⁰, -N(H)C(=O)R^10a, -N(H)R¹⁰, -N(alkyl)R¹⁰, N(H)C(=O)N(H)R¹⁰, -N(H)C(=O)N(alkyl)R¹⁰; the substituents on ring nitrogen of ‘heterocyde’ is selected from alkyl, alkenyl, cydoalkyl, cydoalkenyl, aryl, heteroaryl, -SO2R^10a, -C(=O)R^10a, C(=O)OR^10a' -C(=O)N(H)R¹⁰, -C(=O)N(alkyl)R¹⁰, -NH-SO_ralkyl and -NH-SOî-cycloalkyl; R^10a is selected from alkyl, alkenyl, perhaloalkyl, cydoalkyl, cydoalkenyl, aryl, heteroaryl, heterocydyl: R^10b is selected from hydrogen, alkyl, alkenyl, perhaloalkyl, cydoalkyl, cydoalkenyl, aryl, heteroaryl, and heterocydyl.

The term ‘oxo’ means a divalent oxygen (=0) attached to the parent group. For example oxo attached to carbon forms a carbonyi, oxo substituted on cydohexane forms a cyclohexanone, and the like.

The term ‘annulated’ means the ring system under considération is either annulated with another ring at a carbon atom of the cydic System or across a bond of the cyclic system as in the case of fused or spiro ring Systems.

The term 'bridged* means the ring system under considération contain an alkylene bridge having 1 to 4 methylene units joining two non adjuscent ring atoms.

It should be understood that the formulas (I), (la), (lb) and (le) strudurally encompasses ail tautomers and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the généra described herein.

A compound its racemates, tautomers and pharmaceutically acceptable sait thereof as described hereinabove wherein the compound of general formula I, (la), (lb) and (le) is selected from the group consisting of:

1-(3-(cyc!opropylsulfonyl)phenyl}-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl pyrido [4,3-

d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 1)

3-cydopropyl-1-(2-fluoro-4-iodophenyl)-5-((3-(3-hydroxyazetidin-1-yl)phenyl)amino) -6,8dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H_l8H)-trione (Compound 2)

3-cydopropyl-1-(3-(cydopropylsulfonyl)pheny1)-5-((2-fluoro-44odophenyl)amino)-6,8dimethylpyrido[4,3-dJpyrimidine-2,4,7(1H,3H,6H)-trione (Compound 3) 3-cydopropyl-5-((2-fluoro-4-îodophenyl)amÎno)-6,8-dimethyM-(3-(2-oxoazetidin-1yl)pheny1)pyrido[4,3-d]pyrimidine-2,4_l7(1H,3H,6H)-trione (Compound 4) 3-cydopropyl-5-((2-fluoro-4-iodopheny1)amino)-6,8-dimethy!-1-(3-(oxetan-3-y!amino) phenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 5) tert-butyl 3-((3-(3-cydopropy!-5-((2-fluoro-4-iodophenyl)amino)-6₁8-dimethyl-2_t4,7-trioxo3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)pheny!)carbamoyl) azetidine-1-carboxylate (Compound 6) 3-cydopropyl-5-((2-fluoro-4-lodophenyl)amïno)-6,8-dimethyl-1-(3-(oxetan-3-yloxy) phenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 7) 1-(3-(azetidin-1-yl)pheny1)-3-cydopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl pyrido[4,3>d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 8) 3-cydopropy1-5-((2-fluoro-4-iodopheny!)amino)-1-(3-{3-hydroxyoxetan-3-yl)phenyl)-6,8dîmethy!pyrido[4,3-d]pyrimidine-2,4,7(1 H,3H,6H)-trione (Compound 9) N-(3-(3-cydopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7tetrahydropyrido[4,3-d]pyrimidin-1(2H)-y!)pheny!)-3-methy!oxetane-3-carboxamide (Compound 10)

1-(3-(cydopropaneca rbonyl) phe nyl)-3-cydopropyl-5-((2-fl uoro-4-iodophe nyl )amî no)-6,8dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 11) 1-(3-(cydopropylsulfonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amîno)-3_l6,8-trimethyl pyrido[4,3d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 12)

5-((2-fluoFO-4-iodophenyl)amino)-3,6,8-trimethyM-{3-((oxetan-3-ytoxy)methyl) phenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 13) 5-((2-fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxyoxetan-3-y!)pheny!)-3,6,8-trimethylpyrido[4_l3d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 14) 5-((2-fluoro-4-îodophenyl)amino)-3,6,8-trimethyl-1-{3-(oxetan-3-y!oxy)phenyl) pyrido[4,3d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 15)

1-(3-(azetidin-1-yl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethylpyrido[4,3d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 16)

5-((2-fluoro-4-iodophenyl)amtno)-3_l6,8-trimethyl-1-(3-(oxetan-3-ylamino)phenyl) pyrido[4,3dlpyrimidine-2,4,7(1H,3H,6H)-trione (Compound 17)

N-(3-(5-((2-fluoro-44odophenyi)amino)-3,6,8-trimethyl-2,4₁7-trioxo-3₁4,6,7-tetrahydropyrido[4,3d]pyrimidin-1(2H)-yl)pheny1)-3-methyloxetane-3-carboxamtde (Compound 18)

2-{(1-(3-(5-((2-fluoro-44odophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetra hydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)azetidin-3-yl)oxy)acetamide (Compound 19)

5-((2-fluoro-4-iodopheny1)amino}-1-(3-{3-fluorooxetan-3-yl)pheny1)-3_l6_l8-trimethyi pyrido[4,3d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 20)

N-(3-{3-cydopropyl-5-((2-fluoro-44odophenyl)amino)-6,8-dimethyl-2,4₁7-trioxo-3,4,6,7tetrahydropyrido[4,3-d]pyrimidin-1 (2H)-yl)phenyl)azetidine-3-carboxamide (Compound 21 )

The présent disclosure provides a method for inhibiting MEK enzymes comprising contacting said MEK enzyme with a composition comprising a compound of I, la, Ib, le, their tautomeric forms 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, Ib, le, their tautomeric forms or their pharmaceutically acceptable salts. The said method of treatment may also be combined with an additional therapy such as radiation therapy, chemotherapy, or combination thereof.

MEK mediated disorders as stated above include Inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorder, neurological disorders, fibrogenetic disorders, proliférative disorders, hyperproliferative disorders, tumors, leukemias, neoplasms, cancers, cardnomas, metabolic diseases and malîgnant diseases.

The invention further provides a method for the treatment or prophylaxis of a proliférative disease în an individual comprising administering to said individual an effective amount of a composition comprising a compound of formula I, la, Ib, le, their tautomeric forms or their pharmaceutically acceptable salts. The proliférative disease includes cancer, psoriasis, restenosis, autoimmune disease, or atherosderosis.

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, Ib, le, their tautomeric forms 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 dégradé, inhibit the growth of or kill cancer cells, the composition comprising a compound of formula I, la, Ib, le, their tautomeric forms or their pharmaceutically acceptable salts.

The invention also provide a method of inhibiting tumor size Increase, reducing the size of a tumor, reducing tumor prolifération or preventing tumor prolifération 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 prolifération or prevent tumor prolifération, the composition comprising a compound of formula I, la, Ib, le, their tautomeric forms 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. MEK régulâtes the biosynthesis of the inflammatory cytokines TNF, IL-6 and IL-1. It has been shown that MEK inhibitors interfère with the production/secretion of these cytokines.

The présent 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 Iimited to ERK. Such disorders encompass hyperproliferative disorders that include but are not Iimited to psoriasis, keloids, hyperplasia of the skin, benign prostatic hyperplasia (BPH), solid tumors such as cancers of the respiratory tract (induding but not Iimited to small cell and non-small cell lung cardnomas), brain (induding but not Iimited to glioma, medulloblastoma, ependymoma, neuroedodermal and pineal tumors), breast (induding but not Iimited to invasive dudal cardnoma, invasive lobular carcinome, ductal- and lobular cardnoma in situ), reprodudive organs (induding but not Iimited to prostate cancer, testicular cancer, ovarian cancer, endométrial cancer, cervical cancer, vaginal cancer, vulvar cancer, and sarcoma of the utérus), digestive trad (induding but not Iimited to esophageal, colon, colorectal, gastric, gall blabber, pancreatic, rectal, anal, small intestine and salivary gland cancers), urinary tract (induding but not Iimited to bladder, ureter, kidney, rénal, uréthral and papillary rénal cancers), eye (induding but not Iimited to întraocular melanoma, and retinoblastoma), liver (induding but not Iimited to hepatocellular cardnoma, and cholangiocardnoma), skin (induding but not limited to melanoma, squamous cell cardnoma, Kaposi's sarcoma, Merkel cell skin cancer, non-melanoma skin cancer), head and neck (induding but not limited to laryngeal, nasopharyngeal, hypopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell cancer), thyroid, parathyroîd, and their métastasés. The hyperrproliferative disorders also indude, leukemias (induding but not limited to acute lymphoblastic leukemia, acute myeloid leukemia, chronic melogenous leukemia, chronic lymphocytic leukemia, and haîry cell leukemia), sarcomas (induding but not limited to soft tissue sarcoma, osteosarcoma, lymphosarcoma, rhabdomyosarcome), and lymphomas (induding 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 centra! nervous system).

The présent invention describes the inhibitors of MEK kinase for treatment of certain disorders involving aberrant régulation of the mitogen extracellular kinase activity induding but not limited to hepatomegaly, heart failure, cardiomegaly, diabètes, stroke, Alzheimer’s disease, cystic fibrosis, septic shock or asthma.

The présent invention describes the inhibitors of MEK kinase for treatment of diseases and disorders assodated with aberrant abnormal and/or excessive angiogenesis. Such disorders assodated with angiogenesis indude but are not limited to, tumor growth and métastasés, ischémie 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, induding chemotherapeutic agents and anti-inflammatory agents. Such combinations indude 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 cyde inhibitors, kinase inhibitors, growth factor inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiera or antihormones.

The term 'room température* dénotés any température ranging between about 20Ό to about 40^eC, except and otherwise it is spedfically mentioned In the spedfication.

The intermediates and the compounds of the présent 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, dichlorométhane, 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 dichlorométhane, ethyl acetate, hexane, methanol, acetone and their combinations. Préparative LC-MS method is also used for the purification of molécules described herein.

Salts of compound of formula I can be obtained by dîssolving 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, éthanol or isopropanol, which was then treated with the desired add or base as described In Berge S.M. et al. Pharmaceutical Salts, a review artide in Journal of Pharmaceutical sdences volume 66, page 1-19 (1977) and in handbook of pharmaceutical salts properties, sélection, and use by P.H.Einrich Stahland Camille G.wermuth, Wiley- VCH (2002). Usts of suitable salts can also be found in Remlngton’s Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977). For example, the sait can be of an alkali meta! (e.g., sodium or potassium), alkaline earth métal (e.g., caldum), or ammonium.

The compound of the invention or a composition thereof can potentially be administered as a pharmaceutically acceptable add-addition, base neutralized or addition sait, formed by reaction with inorganic adds, such as hydrochloric add, hydrobromic add, perchloric add, nitric add, thiocyanic add, sulfuric add, and phosphoric add, and organic adds such as formic add, acetic add, propîonic add, glycolic add, lactic add, pyruvic add, oxalic add, malonic add, sucdnic acid, maleic add, and fumaric acid, or by reaction with an inorganic base, such as sodium hydroxide, potassium hydroxide. The conversion to a sait is accomplished by treatment of the base compound with at least a stoichiometric amount of an appropriate add. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, éthanol, methanol, and the like, and the add is added in a similar solvent The mixture is maintained at a suitable température (e.g., between 0 °C and 50 °C). The resultîng sait predpitates spontaneously or can be brought out of solution with a less polar solvent.

The compounds of formula I of the présent invention can exist in tautomeric forms, such as ketoenol tautomers. Such tautomeric forms are contemplated as an objective of this invention and such tautomers may be in equilibrium or prédominant in one ofthe 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. For example, hydroxy groups can be converted Into esters via treatment with a carboxylic acid in the presence of a catalyst. Examples of deavable alcohol prodrug moieties indude substituted or unsubstituted, branched or unbranched lower alkyl ester moieties, e.g., ethyl esters, lower alkenyl esters, dMower 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 amides.

The term prodrug dénotés a dérivative of a compound, which dérivative, when administered to warm-blooded animais, e.g. humans, is converted into the compound (drug). The enzymatic and/or chemical hydrolytic cleavage of the compounds of the présent invention occurs in such a manner that the proven drug form (parent carboxylic acid drug) is released, and the moiety or moieties splît off remain nontoxic or are metabolized so that nontoxic metabolic products are produced. For example, a carboxylic add group can be esterified, e.g., with a methyl group or ethyl group to yield an ester. When an ester is administered to a subject, the ester is deaved, enzymatically or nonenzymatically, reductively, oxidatively, or hydrolytically, to reveal the anionic group. An anionic group can be esterified with moieties (e.g., acyloxymethy! esters) which are deaved to reveal an intermediate compound which subsequently décomposés to yield the active compound.

The inhibitors mentioned in the présent invention can be combined with antiinflammatory agents or agents that show therapeutic benefit for conditions induding but not limited to hepatomegaly, heart failure, cardiomegaly, diabètes, stroke, alzheimer’s disease, cystic flbrosis, septic shock or asthma, diabetic retinopathy, ischémie retina! vein oedusion, 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. Examples of such aberrant kinase activity indude 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, délétions, substitutions, additions, and the like.

Thus the présent invention further provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, its tautomeric forms, its pharmaceutically acceptable salts in combination with the usua! pharmaceutically acceptable carriers, diluents, excipients and the like.

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 toxidty under the conditions of use. Such pharmaceutically acceptable carriers or exdpients indude saline (e.g., 0.9% saline), Cremophor EL (which is a dérivative 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% éthanol), propylene glycol (e.g., 40% propylene glycol/10% ethanol/50% water), polyethylene glycol (e.g., 40% PEG 400/60% saline), and alcohol (e.g., 40% ethanol/60% water). A preferred pharmaceutical carrier is polyethylene glycol, such as PEG 400, and particulariy a composition comprising 40% PEG 400 and 60% water or satine. 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 varietyof suitable formulations ofthe pharmaceutical composition ofthe présent invention.

The following formulations for oral, aérosol, parentéral, subcutaneous, intravenous, Intraarterial, intramuscuiar, interperitoneal, rectal, and vaginal administration are merely exemplary and are in no way limiting.

The pharmaceutical compositions can be administered parenterally, e.g., intravenously, intraarterially, subcutaneously, intradermally, întrathecally, or intramuscularly. Thus, the invention provides compositions for parentéral administration that comprise a solution of the compound of the Invention dîssolved or suspended in an acceptable carrier suitable for parentéral administration, including aqueous and non-aqueous, isotonie stérile injection solutions.

Overall, the requirements for effective pharmaceutical carriers for parentéral compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986). Such compositions include solutions containing anti-oxidants, buffers, bacteriostats, and solutés that render the formulation isotonie with the blood of the intended récipient, and aqueous and non-aqueous stérile 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 stérile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as éthanol, isopropanol (for example in topical applications), or hexadecyl alcohol, glycols, such as propylene glycol or polyethytene glycol, dimethylsulfoxide, glycerol ketals, such as 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, such as polyfethyleneglycol) 400, an oil, a fatty acid, a fatty add ester or glyceride, or an acetylated fatty add 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, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.

Oils useful in parentéral formulations indude petroleum, animal, vegetable, and synthetic oils. Spedfic examples of oils useful in such formulations indude peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and minerai oil. Suitable fatty adds for use in parentéral formulations indude oleic add, stearic add, and isostearic add. Ethyl oleate and isopropyl myristate are examples of suitable fatty add esters.

Suitable soaps for use in parentéral formulations indude fatty alkali métal, ammonium, and triethanolamine salts, and suitable détergents indude (a) cationic détergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic détergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, ofefin, ether, and monoglyceride sulfates, and sulfosucdnates, (c) nonionic détergents such as, for example, fatty amine oxides, fatty add alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric détergents such as, for example, alkyl-p-aminopropionates, and 2-alkyl-lmidazoline quatemary ammonium salts, and (e) mixtures thereof.

The parentéral 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 indude polyethylene sorbitan fatty add esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobie base, formed by the condensation of propylene oxide with propylene glycol. The parentéral 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 stérile liquid excipient, for example, water, for Injections, immediately prior to use. Extemporaneous Injection solutions and suspensions can be prepared from stérile 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 présent 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 diiuents, 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 émulsions. Liquid formulations can include diiuents, such as water and alcohols, for example, éthanol, 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-shelied gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and comstarch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloïdal silicon dioxide, croscarmellose sodium, talc, magnésium stéarate, calcium stéarate, zinc stéarate, stearic add, and other exdpients, colorants, diiuents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible exdpients. Lozenge forms can comprise the compound ingrédient in a flavor, usually sucrose and acada or tragacanth, as well as pastilles comprising a compound of the invention in an inert base, such as gelatin and glycerin, or sucrose and acada, émulsions, gels, and the like containing, in addition to the compound of the invention, such exdpients as are known in the art.

A compound of the présent invention, alone or in combination with other suitable components, can be made into aérosol 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 Représentative of such surfactants are the esters or partial esters of fatty adds containing from 6 to 22 carbon atoms, such as caproic, odanoic, lauric, palmitic, stearic, linoleic, Ii noie nie, olesteric and oleic adds with an aliphatic polyhydric alcohol or its cydic anhydride. Mixed esters, such as mixed or naturel 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 induded as desired, e.g., ledthin, for intranasal delivery. These aérosol formulations can be placed into acceptable pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticafs for non-pressured préparations, such as in a nebulizer or an atomizer. Such spray formulations can be used to spray mucosa.

Additionally, the compound of the invention can be made into suppositories by mixing with a variety S 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 ingrédient, 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 10 than about 1% to about 10%, to as much as 20% to 50% or more by weight, and can be selected primarily by fluid volumes, and viscosities, in accordance with the particular mode of administration selected.

For example, a typical pharmaceutical composition for intravenous infusion could be made up to contain 250 ml of stérile Ringerfs 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^ ed., Mack Publishing Company, Easton, PA, 1985).

It will be appredated by one of ordinary skill in the art that, in addition to the aforedescribed pharmaceutical compositions, the compound of the invention can be formulated as indusion 20 complexes, such as cydodextrin indusion 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 25 5,019,369.

The compounds of the invention can be administered in a dose suffident to treat the disease, condition or disorder. Such 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' 30 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 présent invention. Thereafter, the dosage is increased by small incréments until the optimum effect under the drcumstances is reached. The présent method can involve the administration of about 0.1 pg 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 pg to about 200 mg of the compound of the invention would be more commonly used, depending on a patient’s physiologîcal response.

By way of example and not intending to limit the invention, 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.

The terms treat, “prevent, ’ameliorate, and inhibit, as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complété treatment, prévention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prévention, amelioration, and inhibition of which one of ordinary skill in the art recognîzes as having a potential benefit or therapeutic effect. In this respect, the disdosed methods can provide any amount of any level of treatment, prévention, amelioration, or inhibition of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%. Furthermore, the treatment, prévention, amelioration, or inhibition provided by the inventive method can include treatment, prévention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer. Also, for purposes herein, “treatment, prévention, “amelioration, or inhibition can encompass delaying the onset of the disorder, or a symptom or condition thereof.

In accordance with the invention, the term subject includes an animal which in tum includes a mammal such as, without limitation, the order Rodentia, such as mice, and the order Lagomorpha, such as rabbits. In one aspectthat the mammals are from the order Camivora, induding Felines (cats) and Canines (dogs). In another aspect the mammals are from the order Artiodactyla, induding Bovines (cows) and Swine (pigs) or of the order Perssodactyla, induding Equines (horses). In a further aspect, the mammals are of the order Primates, Ceboids, or Simoids (monkeys) or of the order Anthropoids (humans and apes). ln yet another aspect, the mammal is the human.

General Method of préparation

The compounds of general formula (I) where ail the symbols are as defined earlier can be prepared by methods given in below schemes or examples illustrated herein below.

However, the disdosure should not be construed to limit the scope of the invention arriving at compound of formula (I) disdosed hereinabove.

Scheme 1 (R¹ Is H)

Compound of formula (I) where R¹ is H, can be prepared as depided in Scheme 1, details of which are given below.

Scheme 1

Step-1

Compound of formula (II) where R¹ is N-protecting group, can be converted to compound of formula (III) by reacting compound of II (Z is any suitable leaving group like Cl, Br, I, -O(SO)2(4MePh), -O(SO)2CH3, -O(SO)2CF3 etc.) with R²NH2 in presence of a suitable base like 2,6-Lutidine,

1,8-Diazablcydo[5.4.0]undec-7-ene (DBU), K₂CO₃, Cs₂CO₃₁ NaH, KH, n-BuU, lithium bis(trimethylsilyl)amide (LIHMDS) etc., in a solvent like THF, DMF, DMSO etc., at température ranging from about -78°C to about 150°C.

Step-2

Compound of formula-(lll) where R¹ is N-protecting group, can be converted to compound of formula-(IV) by reacting compound of formula (111) with suitable base such as NaOMe, K₂CO₃ etc. ln a solvent like Methanol, Ethanol, THF, DMF etc. at température ranging from about -78 °C to about 150°C.

Step-3

Compound of formula-(IV) where R¹ is N-protecting group, can be converted to compound of fomnula-(l) 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 température ranging from about -78 °C to about 150 °C.

Scheme-2:

Compound of formula (I) where R¹ 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 unsubstitutedheterocyclyl, can be prepared as depicted in Scheme 2, details of which are given below

(II) (III)

Scheme 2

Step-1

Compound of formula (II) where where R¹ is selected from substituted- or unsubstituted- alkyl, substituted- or unsubstituted- alkenyl, substituted- or unsubstituted- alkynyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- cycloalkenyl, substituted- or unsubstitutedaryl, 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 Cl, Br, I, -O(SO)2(4-MePh), -O(SO)2CH3> -O(SO)2CF3 etc.) with R²NH2 in presence of a suitable base like 2,6-Lutidine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), K₂CO₃, Cs₂CO₃, NaH, KH, n-BuU, lithium bîs(trimethylsi1yl)amide (LiHMDS) etc., in a solvent like THF, DMF, DMSO etc., at température ranging from about -78°C to about 150°C.

Step-2

Compound of formula-(lll) where R¹ is selected from substituted- or unsubstituted- alkyl, substituted- or unsubstituted- alkenyl, substituted- or unsubstituted- alkynyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- cycloalkenyl, substituted- or unsubstitutedL· aryî, substituted- or unsubstituted- heteroaryl, and substituted- or unsubstituted- heterocyclyl,, can be converted to compound of formula-(l) by reacting compound of formula (III) with suitabie base such as NaOMe, K₂CO₃ etc. in a solvent like Methanol, Ethanol, THF, DMF etc. at température ranging from about -78 ^eC to about 150 °C.

The intermediates and the compounds of the présent 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 suitabie solvent, such as pentane, diethyl ether, isopropyl ether, chloroform, dichioromethane, 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 suitabie support material such as alumina or silica gel using eluent such as dichioromethane, ethyl acetate, hexane, methanol, acetone and their combinations. Préparative LC-MS method is also used for the purification of molécules described herein.

Salts of compound of formula I are obtained by dissolving the compound in a suitabie solvent, for example in a chlorinated hydrocarbon, such as methyl chloride or chloroform or a low molecular weight aliphatic alcohol, for example, éthanol or isopropanol, which was then treated with the desired add or base as described in Berge S. M. et al. ‘Pharmaceutical Salts, a review artide in Journal of Pharmaceutical sdences volume 66, page 1-19 (1977) and in handbook of pharmaceutical salts properties, sélection, and use by P.H.Einrich Stahland Camille G.wermuth , Wiley-VCH (2002).

Examples

The following examples are provided to further illustrate the présent invention and therefore should not be construed in any way to limit the scope of the présent invention. Ail ’HNMR spectra were determined in the solvents indicated and chemical shifts are reported in δ units downfield from the internai standard tetramethylsilane (TMS) and interproton coupling constants are reported in Hertz (Hz).

Unless otherwise stated, work-up indudes distribution of the reaction mixture between the organic and aqueous phase indicated within parenthèses, séparation of layers and drying the organic layer over sodium sulphate, filtration and évaporation of the solvent. Purification, unless otherwise mentioned, Indudes purification by silica gel chromatographie techniques, generally using a mobile phase with suitabie polarity. The following abbreviations are used in the text: DMSO-d6: Hexadeuterodimethy! sulfoxide; DMSO: Dimethylsulfoxide, DMF: Ν,Ν-dimethyl formamîde, DMA: Dîmethylacetamide, THF: Tetrahydrofuran, TFA: Trifluoroacetic add, DAST: Diethylaminosulfur trifluoride; DCM: Dichloromethane, m-CPBA: mefa-Chloroperoxybenzoic add, EDC: 1-Ethyl-3-(3dimethylaminopropyl)carbodiimide, J: Coupling constant in units of Hz, RT or rt room température (22-26’C), Aq.: aqueous, AcOEt: ethyl acetate, equiv. or eq.: équivalents and hr. or h: hourfs) Intermediates:

lntermediate-i: Synthesis of 3-(cyclopropy1sulfonyl)anlline

SH

Step 1: Synthesis of 3-chloropropy!)(3-nltrophenyl)sulfane

To a suspension of 3-nitrobenzenethiol (2.3 g, 14.82 mmol) and NaOH (1.186 g, 29.6 mmol) in Ethanol (40.0 ml) was added 1-bromo-3-chloropropane (1.75 ml, 17.79 mmol). The resulting mixture was stirred at RT under inert atmosphère for 18 h. Solvent was evaporated under vacuum and the residue was partitioned between DCM (200 ml) and water (100 ml). The organic layer was separated and washed with brine (100 ml), dried over anhydrous sodium sulphate and evaporated under vacuum. The residual oil was purified by coiumn chromatography over silicagel, using 15 % EtOAc in Hexane as eluent to afford (3-chloropropyl)(3-nitrophenyl)sulfane (2.92 g, 12.60 mmol, 85 % yield).

’H NMR(400 MHz,CDCI₃) δ 8.14-8.16 (m, 1H), 8.05-8.00 (m, 1H), 7.65-7.60 (m, 1H), 7.49-7.43 (m, 1H), 3.70 (t, J= 6.2 Hz, 2H), 3.2 (t, J= 7.2 Hz, 2H), 2.18-2.12 (m, 2H). GCMS: 231.04 [M+]

Step 2: Synthesis of 1-((3-chloropropy1)sulfonyl)-3-nltrobenzene m-CPBA (7.45 g, 32.4 mmol) was added to a solution of (3-chloropropyl)(3-nitrophenyl)sulfane (3 g, 12.95 mmol) in CHCI₃ (50 mL). Resulting mixture was stirred at RT for 18 hrs and filtered to remove most of the benzoic add. The filtrate was diluted with CHCI₃ (100 ml) and washed with 10 % aq. NaOH (100 ml). Organic phase was dried over anhydrous sodium sulphate and evaporated under vacuum. Residue was purified by silicagel coiumn chromatography eluting with 30% EtOAc:Hexane to afford 1-((3-chloropropyl)sulfonyl)-3-nitrobenzene (2.75 g).

’H NMR(400 MHz,CDCI₃) δ 8.79 (brs, 1H), 8.55 (d, J =8.0 Hz, 1H), 8.28 (d, J =7.6 Hz. 1H), 7.887.84(m, 1H), 3.68 (t, J = 6.0 Hz, 2H), 3.37 (t, J = 7.6 Hz, 2H), 2.32-2.25 (m, 2H). GCMS: 262.96 [M+]

Step 3: Synthesis of 1-(cyclopropylsulfonyl)-3-nitrobenzene

Potassium tert-butoxide (2.13 g, 18.96 mmol) was added to a solution of 1-((3chloropropy1)sulfonyl}-3-nitrobenzene (2 g, 7.58 mmol) in t-BuOH (10 ml) at RT. Resulting solution was stirred at RT for 5 h. Solvent was evaporated under vacuum. Residue was partitioned between EtOAc (150 ml) and water (150 ml). Organic phase was removed and dried over sodium sulphate. Solvent was evaporated under vacuum to obtain 1-(cyclopropylsulfonyl)-3-nitrobenzene (1.206 g, 5.31 mmol, 70 % yield), which was carried forward to the next step without further purification.

Ή NMR(400 MHz,CDClj) δ 8.78 (brs, 1H), 8.52 (d, J = 8.0 Hz, 1H), 8.26 (d, J -7.6 Hz, 1H), 7.84-

7.80 (m, 1H), 2.55-2.52 (m, 1H), 1.45-1.38 (m, 2H), 1.15-1.13 (m, 2H). GCMS: 227.01 [M+] Step 4: Synthesis of 3-(cyclopropylsulfonyl)anIline

Triethylsilane (14 ml, 88 mmol) was added dropwise to a suspension of 1-(cyclopropylsulfonyl)-3nitrobenzene (2 g, 8.80 mmol) and Pd/C (10%, 250 mg) in MeOH (25 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 3(cyclopropylsulfonyl)aniline (1.44 gm).

’H NMR(400 MHz,DMSO-d₆) δ 7.24 (t, J- 8.0 Hz, 1H), 7.03-7.02 (m, 1H), 6.95-6.92 (m, 1H), 6.84-

6.81 (m, 1H), 5.66 (s, 2H), 2.74-2.70 (m, 1H), 1.05-0.95 (m, 4H). GCMS: 197.03 [M+].

Intermediate-li: Synthesis of N-(3-aminopheny1)-3-methy1oxetane-3-carboxamlde

Step-1: Synthesis of 3-methy!-N-(3-nitrophenyl) oxetane-3-carboxamlde

To a stirred solution of 3-nitroaniiine (0.297 g, 2.153 mmol) in pyridine (1 ml), was added 3methyloxetane-3-carboxylic acid (0.250 g, 2.153 mmol) and EDC.HCI (0.619 g, 3.23 mmol). The reaction mixture was stirred at room température for 2 hrs. and then concentrated under vacuum, the residue was diluted with water (10 ml) and extracted with ethyl acetate (3 x 7ml). The combined organic layer was washed with brine and water, dried over sodium sulfate and concentrated under vacuum to afford the title compound (400 mg).

’HNMR (400 MHz, CDClj): □ 8.45 (t, 1H, J=2Hz), 8.06 (bs, 1H), 8.02-7.99 (m, 2H), 7.54 (t, 1H, J=4 Hz). 4.95 (d, 2H, J=6.4Hz), 4.65 (d, 2H, J=6.4Hz), 1.68 (s, 3H). GCMS: 236 (M+)

Step-2: Synthesis of N-(3-am1nophenyl)-3-methy1oxetane-3-carboxamlde

To a stirred solution of 3-methyl-N-(3-nitrophenyl) oxetane-3-carboxamîde (0.5 g, 2.117 mmol) in Ethyl acetate (5 ml). 10% Pd/C (0.225 g) was added and the reaction mixture was stirred room température for 10 hrs under hydrogen atmosphère. The reaction mixture was filtered through celite and concentrated under vacuum to afford the title product (0.400 g).

GCMS: 206 (M+).

Intermedlate-ïii: Synthesls of 3*(3-amlnophenyl) oxetan-3-ol

Br Br NH₂

Step-1 : Synthesis of 3-(3-bromophenyl) oxetan-3-ol

To a stirred solution of 1-bromo-34odobenzene (0.500 g, 1.767 mmol) in THF (5 ml), at 78 ’C was added n-butyllithium (1.1 ml, 1.767 mmol). The reaction mixture was stirred at same température for 1 hr, then oxetan-3-one (0.127 g, 1.767 mmol) was added. The reaction mixture was stirred at 40 °C for one hour and saturated ammonium chloride solution was added. The reaction mixture was extracted with ethyl acetate (3x5 ml). Combined organic layer was dried over sodium sulfate and concentrated under vacuum to afford the crude product which was purified by column chromatography over silica gel using 30% ethyl acetate in hexane as eluent to give the title product (80 mg).

’HNMR (400 MHz, CDCI₃): □ 7.80 (t. 1H, J= 2 Hz), 7.51-7.48 (m, 1H), 7.32 (t. 1H, J=7.6Hz), 5.60-

5.57 (m, 1H), 4.93-4.87 (m, 4H), 2.52 (s, 1H).

Step-2: Synthesls of 3-(3-amlnophenyl) oxetan-3-ol

To a stirred mixture of 3-(3-bromophenyl)oxetan-3-ol (0.2 g, 0.873 mmol) in aq. ammonia (1 ml), copper(ll) oxide (0.069 g, 0.873 mmol) was added and the mixture was heated at 90 ’C for 24 hrs in a sealed tube. The reaction mixture was cooled to room température and ethyl acetate (10 ml) was added, the reaction mixture was filtered through celite and the filtrate was concentrated under vacuum to afford title product (0.1 g).

’HNMR (400 MHz, CDCI₃): □ 7.21 (t, 1H, J=7.6Hz), 7.0-6.97 (m, 1H), 6.93-6.92 (m, 1H), 6.67-6.65 (m, 1H), 4.90 (s, 4H), 3.79 (bs, 2H), 3.02 (bs, 1H). GCMS: 165 (M+).

Intermediate-lv: Synthesis of 3-(azetldin-1-yl) aniline

Step-1: Synthesis of 1-(3-nitropheny!) azetidine

A stirred mixture of 1-fluoro-3-nitrobenzene (0.305 g, 2.161 mmol), Azetidine .HCl (0.2 g, 2.161 mmol) and K₂CO₃ (0.747 g, 5.40 mmol) in DMSO (5 ml) was heated at 86 ’C for 24 hrs. The reaction mixture was cooled to room température and water was added (25 ml), the mixture was extracted with ethyl acetate (3X10 ml). Combined organic layer was dried over sodium sulfate and concentrated under vacuum to afford the crude compound, which was then purified by coiumn chromatography (40 mg).

’HNMR (400 MHz, CDCIj): 7.55-7.52 (m, 1H), 7.31 (t, 1H, J= 8 Hz), 7.20 (t, 1H, J= 2.4 Hz), 6.70-

6.67 (m, 1H), 3.97 (t, 4H, J= 7.6 Hz), 2.48-2.41 (m, 2H). GCMS: 178 (M+).

Step-2: Synthesis of 3-(azetidln-1-y1) aniline

To a stirred solution of 1-(3-nitrophenyl)azetidine (0.040 g, 0.224 mmol) in Ethyl acetate (2 ml) was added Pd/C (10%, 0.01 mg) and the reaction mixture was heated at 55 ’C for 12 hrs under hydrogen atmosphère. The reaction mixture was cooled to room température and diluted with ethyl acetate (10 ml) and the mixture was filtered through celite, and the filtrate was concentrated under vacuum to afford the title compound (30 mg, 90 %).

’HNMR (400 MHz, CDCIj): 7.02 (t, 1H, J= 8 Hz), 6.12-6.10 (m, 1H), 5.93-5.90 (m, 1H), 5.80-5.79 (m, 1H), 3.85 (t, 4H, J= 7.2 Hz), 3.59 (bs, 2H), 2.37-2.30 (m, 2H). GCMS: 148 (M+)

Intermediate-v: Synthesis of tert-butyl 3-((3-aminophenyl)carbamoyl)azetidine-1-carboxylate

Step-1: Synthesis of tert-butyl 3-((3-nitrophenyl)carbamoy1)azetidine-1 -carboxylate

To 3-nitroaniline (0.137 g, 0.994 mmol) in pyridine (6 ml) were added 1-{tertbutoxycarbonyl)azetidine-3-carboxylic acid (0.5 g, 2.485 mmol) and EDC. HCl (0.715 g, 3.73 mmol). After being stirred at room température for 2 hrs reaction mixture was concentrated under vacuum. Diluted above reaction mixture with water (10ml) extracted with 3X7ml chloroform: IPA

(3:1). Washed organic layer with brine and water, dried over sodium sulfate and concentrated to afford titled compound (300 mg, 38 %).

ESI-MS m/z: 322 (M+1).

Step-2: Synthesis of tert-butyl 3-((3-aminophenyl)carbamoyl)azetidine-1-carboxylate

To a stirred solution of tert-butyl 3-((3-nitrophenyl)carbamoyl)azetidine-1-carboxylate (0.3 g, 0.934 mmol) in methanol (10 ml) was added ammonium formate (0.3 g, 4.76 mmol) and Pd/C (10%, 0.05 g) and the mixture was stirred at room température for 10 hrs., since reaction was not complété so, Pd/C (0.05 g) and ammonium formate (0.3 g, 4.76 mmol) were added again and the stirring was continued for further 6 hrs. The reaction ixture was filtered through celite and the filtrate was concentrated. The residue was purified by column chromatography over silica gel using ethyl acetate in hexane as eluent to afford the title compound (200 mg).

ESI-MS m/z: 292 (M+1)

Intermedlate-vi: Synthesis of 1-(3-amlnophenyt) azetidin-3-ol

Step-1: Synthesis of 1-(3-nttrophenyI)azetidin-3-ot

Azetidin-3-ol hydrochloride (1.0 g, 9.13 mmol) was taken in DMSO and 1-fluoro-3-nitrobenzene (1.0 g, 7.09 mmol) was added followed by K₂CO₃ (2.449 g, 17.72 mmol). The reaction mixture was heated to 100 ’C for 16 hrs. After completion of the reaction, the reaction mixture was cooled and poured into water which was then extracted with ethyl acetate (3 x 8ml). The organic layers were combined, washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The resulting crude product was purified by column chromatography to yield the titled compound 1-(3-nitrophenyl)azetidin-3-ol (0.73 g).

’H NMR(400 MHz,CDCI₃) δ 7.58 (dd, 1H, J= 1.6 and 8 Hz), 7.33 (t, 1H, 8 Hz), 7.24 (t, 1H, J= 2 Hz), 6.73-6.71 (m,1H), 4.86-4.84 (m, 1H), 4.28-4.26 (m, 2H), 3.80-3.77 (m, 2H), 2.18 (d, 1H, J=6.4 Hz). ESI-MS [m/z = 194 [M+1 J].

Step-2: Synthesis of 1-(3-amlnophenyl) azetidin-3-ol

In ethyl acetate (10 ml), 1-(3-nitrophenyl)azetidin-3-ol (0.43 g, 2.214 mmol) was taken and Pd/C (10%, 0.04 g) was added and the reaction mixture was stirred under hydrogen atmosphère at room

température for 10 hrs. After completîon of the reaction, the reaction mixture was fîltered through celite, residue was washed with ethyl acetate (3X5 ml). Combined filtrate was concentrated under vacuum to yield the title compound (0.35 g).

’H NMR(400 MHz, CDCI₃) δ 7.01 (t, 1H, J= 8 Hz), 6.15-6.12 (m, 1H). 5.95-5.92 (m, IH), 5.81 (t, 1H,

2.4 Hz), 4.73-4.69 (m, 1H), 4.16-4.12 (m, 2H), 3.66-3.62 (m, 4H), 1.73 (brs, 1H). ESI-MS [m/z = 164 [M+1]].

Intermediate-vil: Synthesis of 1-(3-amlnopheny!)azetidin-2-one

To a mixture of 1-(3-nitrophenyl)azetidin-2-one (600 mg, 3.12 mmol), ammonium formate (591 mg, 10 9.37 mmol) and méthanol (40 ml) at 0“C, was added Pd/C (10%, 0.17 g) and the reaction mixture was stirred at 50^eC for 3 hrs. The reaction mixture was cooled to room température and fîltered through celite, the filtrate was concentrated under vacuum. The residue was taken in ethyl acetate and fîltered through celite and concentrated under vacuum to afford the yellow solid product (230 mg).

’HNMR (400 MHz, CDCI₃): Π 7.11 (t, 1H, J=8 Hz), 6.92-6.91 (m, 1H). 6.59-6.57 (m, 1H), 6.44-6.41 (m, 1H), 3.75 (bs, 2H), 3.60 (t, 2H, J = 4.4 Hz), 3.09 (t, 2H, J=4.4 Hz).

Intermedlate-vili: Synthesis of 3-(oxetan*3-yloxy)anillne

Step-1: Synthesis of 3-(3-nltrophenoxy)oxetane

Oxetan-3-ol (578 mg, 7.80 mmol) was taken in THF (8 ml) under nitrogen atmosphère, cooled to 0’C, KOtBu (962 mg, 8.58 mmol) was added and the mixture was stirred at same température for 30 mîn., 1-fluoro-3-nitrobenzene (0.41 ml, 3.90 mmol) was added and the reaction mixture was stirred at room température for 18 hrs. The reaction mixture was concentrated under vacuum and water (50 ml) was added, the mixture was extracted with ethyl acetate (3X 20 ml). Combined organic layer was dried over sodium sulfate and the mixture was concentrated under vacuum to

afford the crude product, which was purified by column chromatography to afford yellow solid product (350 mg).

GCMS: 195 (M+)

Step-2: Synthesis of 3-(oxetan-3-y1oxy)aniline

To a mixture of 3-(3-Nîtrophenoxy)oxetane (0.350 g, 1.793 mmol), ammonium formate (339 mg,

5.38 mmol) and methanol (40 ml) at 0*C, was added Pd/C (10%, 0.17 g) and the reaction mixture was stirred at 50*C for 3 hrs. The reaction mixture was cooled to room température and filtered through celite, the filtrate was concentrated under vacuum. The residue was taken in ethyl acetate and filtered through celite and concentrated under vacuum to afford the yellow solid product (260 mg).

Intermedlate-lx: Synthesis of 2-((1-(3-aminophenyl)azetldin-3-yl)oxy)acetamlde

Step-1: Synthesis of 1-(3-nitrophenyl)azetidin-3-ol

Azetidin-3-ol hydrochloride (1.863 g, 17.01 mmol), 1-fluoro-3-nîtrobenzene (2. g, 14.17 mmol) were taken in DMSO (20 ml) and K₂CO₃ (4.90 g, 35.4 mmol) was added to the mixture and the reaction mixture was heated at 110’C for 24 hrs. The reaction mixture was cooled to room température, water was added and the mixture was extracted with ethyl acetate (3X 75ml). Combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product which was purified by column chromatography eluting with 0- 20% ethyl acetate in hexane to afford the title product (1.1 g).

Step-2: Synthesis of 2-{(1-(3-nltropheny1)azetldin-3-yl)oxy)acetamlde

1-(3-Nitrophenyl)azetidin-3-ol (1.2 g, 6.18 mmol), 2-bromoacetamide (1.023 g, 7.42 mmol) were taken in DMF (20 ml) and 60% NaH (0.741 g, 18.5 mmol) was added the to the mixture and the mixture was heated at 40 ®C for 16 hrs. The reaction mixture was cooled to room température, water was added and the mixture was extracted with ethyl acetate (3X 75ml). Combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product which was purified by column chromatography eluting with 0- 20% ethyl acetate in hexane to afford the title product (0.8 g).

L·

Step-3: Synthesis of 2-((1 -(3-aminopheny!)azetidin-3-yl)oxy)acetamide

2-((1-(3-Nitrophenyl)azetidin-3-yl)oxy)acetamide (0.8 g, 3.18mmol) was taken in methanol (20 ml) and at 0*C, Pd-C (10%, 0.07 g) was added. The reaction mixture was stirred under hydrogen atmosphère at room température 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).

Intermedlate-x: Synthesis of Nl-ioxetan-S-ylJbenzene-l^-dlamlne

NO₂ nh₂

Step-1: Synthesis of N-(3-nltrophenyl)oxetan-3-amlne

To a solution of 3-nitroaniline (2 g, 14.48 mmol) in methanol (30 ml), were added oxetan-3-one (1.565 g, 21.72 mmol) and zinc chloride (7.89 g, 57.9 mmol)and the reaction mixture was cooled with an ice bath. Sodium cyanoborohydride (2.73 g, 43.4 mmol) was added to the reaction mixture and the mixture was stirred at room température for 5 hrs. The reaction mixture was poured over cold aq. satd. ammonium chloride solution and extracted with ethyl acetate (3X75ml). Combined organic layer was dried over sodium sulfate and concentrated under vacuum. The crude residue was adsorbed purified by column chromatography using 0- 50% ethyl acetate in hexanes as eluent to afford the title product (1.2 g).

Step-2: Synthesis of N1-(oxetan-3-yi)benzene-1,3-diamine

N-(3-Nitropheny1)oxetan-3-amine (0.55g, 2.83 mmol) was taken in methanol (10 ml) and at 0’C, PdC (10%, 0.1 g) was added. The reaction mixture was stirred under hydrogen atmosphère at room température for 5 hrs. The reaction mixture was filtered through celite and the filtrate was concentrated under vacuum to afford the title product (0.4 gm).

’HNMR (400 MHz. CDCI₃): □ 6.98 (t. 1H, J=8Hz), 6.16-6.13 (m. 1H), 5.98-5.95 (m, 1H), 5.84 (t, 1H, J= 2.4 Hz), 4.99 (t, 2H, J= 6.4 Hz), 4.65-4.57 (m, 1H), 5.27 (t, 2H, J= 6 Hz), 4.05 (d, 1H, J= 6.4 Hz), 3.50 (bs, 2H).

Intermediate-xi: Synthesis of 3-((oxetan-3-yloxy)methyl)anlllne

p-1: Synthesis of 1-(chloromethy1)-3-nItrobenzene (3-Nitrophenyl)methanol (1 g, 6.53 mmol) was dissolved in DCM (8 ml) and cooled to 0’C followed by addition of thionyl chloride (2.15 ml, 19.59 mmol). The Reaction mixture was stirred for 4 hrs at room température and concentrated under vacuum, saturated solution of sodium bicarbonate was added to the residue. The mixture was extracted with ethyl acetate (3X 75ml), combined organic layer was dried over sodium sulfate and concentrated under vacuum to afford the title compound (0.9 gm).

Step-2: Synthesis of 3-((3-nltrobenzy1)oxy)oxetane

A mixture of oxetan-3-ol (0.432 g, 5.83 mmol), K₂CO₃ (1.611 g, 11.66 mmol) and 1-(chloromethyl)-

3-nitrobenzene (1 g, 5.83 mmol) in DMF (10 ml) was heated at 80’C for 18 hrs. The reaction mixture was cooled to room température, water was added and the mixture was extracted with ethyl acetate (3X 75ml). Combined organic layer was dried over sodium sulphate and concentrated under vacuum to afford the crude product which was purified by column chromatography to afford the title product (0.8 g).

Step-3: Synthesis of 3-((oxetan-3-ytoxy)methyl)anlline

3-((3-Nitrobenzyl)oxy)oxetane (0.3g, 1.434 mmol) was taken in methanol (10 ml) and at 0*C, Pd-C (10%, 0.07 g) was added. The reaction mixture was stirred under hydrogen atmosphère at room température for 5 hrs. The reaction mixture was filtered through celite and the filtrate was concentrated under vacuum to afford the title product (0.2 gm).

’HNMR (400 MHz, CDCI₃): □ 7.12 (t, 1H, J= 8 Hz) 6.70-6.52 (m, 3H), 4.60 (bs. 2H), 4.37-4.12 (m, 5H), 3.73 (brs, 2H).

Intermediate xli: (3-aminophenyl)(cyclopropyl)methanone

o

Intermediate xiv was prepared using procedure depicted in the reference ‘Journal of Médicinal

Chemistry, 1995, Vol. 38, #18, page 3624-3637.

L·

Examples

The following examples demonstrate préparation of few représentative compounds embodied in formula (I), however, the same should not be construed as limiting the scope of the invention.

Example-1: Synthesis of 1-{3-(cyclopropylsulfonyl)phenyl)-5-((2-fluoro-4-lodo pheny1)amino)-

6,8-dimethy!pyrldo[4,3-d]pyrimldine-2,4,7(1H,3H,6H)-trione (Compound 1)

Step-1: Synthesis of 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-

1_l2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-y! 4-methylbenzenesulfonate (1b)

Under nitrogen atmosphère, to a solution of 1-(2-fluoro-4-lodophenyl)-5-hydroxy-3-(4methoxybenzyQ-e.e-dimethylpyridop.S-dJpyrimidine^^JtlH.SH.eHJ-trione (1a) (41g, 72.8mmol) (Prepared as per reference W02005121142) in acetonitrile (300 ml), triethylamine (30.4 ml, 218 mmol) and trimethylamine hydrochloride (3.48 g, 36.4 mmol) was added dropwise ptoluensulfonylchloride (27.8 g, 146 mmol) ln acetonitrile (300 ml) at 0 ’C, and the mixture was stirred under ice cooling for 1hr, and at room température for 24 h. To the reaction mixture was added methanol (220 ml), and the mixture was stirred at room température for 1h. The precipitated crystals were collected by filtration, dried under vacuum to afford the titled compound (40.5 g, 78%) ¹H NMR(400 MHz,DMSO-de) δ: 7.95 (dd, J= 1.6and 9.6 Hz, 1H), 7.84 (d, J= 8.4 Hz, 2H), 7.72 (dd, J= 1.2 and 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.35 (t, J = 8.4 Hz, 1H), 7.23 (d, J= 8.8 Hz, 2H), 6.86 (d, J= 8.8 Hz, 2H), 4.92 (d, J = 16 Hz, 1H), 4.77 (d, J= 16 Hz, 1H), 3.71 (s, 3H), 2.76 (s, 3H), 2.42 (s, 3H), 1.53 (s, 3H).

MS: m/z :717.9

Step-2: Synthesis of 5-((3-(cyclopropy!sulfonyl)phenyl)amino)-1-(2-fluoro-4-iodophenyl)-3-(4methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (1 c)

A mixture of 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethy!-2_l4,7-trioxo-1,2,3,4,7,8hexahydropyrido[2,3-d]pyrimÎdin-5-y! 4-methylbenzenesulfonate (1b) (1.0 g, 1.394 mmol), 3-

(cyclopropylsulfonyl)aniline (intermediate-î) (1.237 g, 6.27 mmol) and 2,6-LUTIDINE (0.487 ml,

4.18 mmol) in Ν,Ν-Dimethylacetamide ( 0.5 ml) was heated at 140^e C for 18h in sealed vial. After cooling to rt, the reaction mixture was poured over water (100 ml) and resulting solid was filtered. Residue was purified by flash chromatogrhaphy on a combiflash instrument to obtain the product. ’HNMR (400 MHz, DMSO-d_e) δ (ppm): 10.22 (s, 1H), 7.97 (dd, J=9.2 and 1.6 Hz, 1H), 7.74 (dd, J=8 and 1.2Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.47 (d, J= 8.0Hz, 1H), 7.38 (t, J=8 Hz, 1H), 7.27-7.33 (m, 4H), 6.83-6.87 (m, 2H), 4.94-5.04 (m, 2H). 3.69 (s, 3H), 2.84 - 2.87 (m, 1H), 2.78 (s, 3H), 1.55 (s, 3H), 1.02-1.04 (m, 2H), 1.05-1.09 (m, 2H)

MS: m/z :743.1 [M+1]

Step-3: Synthesis of synthesis of 1-(3-(cyclopropylsulfony1)phenyl)-5-((2-fluoro-4iodopheny!)amino)-3-(4-methoxybenzy1)-6_l8-dimethylpyrido[4_l3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (1d)

Sodium methoxide (25% solution in MeOH) (0.2 ml) was added to a solution of 5-((3(cyclopropylsulfonyl)phenyl)amino)-1-{2-fluoro-4-iodophenyt)-3-(4-methoxybenzyl)-6,8dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (1c) (0.4 g, 0.539 mmol) in THF (3.5 ml). Resulting solution was stirred unde N₂ atm for 1 h, and quenched by addition of dil. HCl. Solvents were evaporated in vacuo. and residue was triturated in water. Solid product was filtered and dried under vacuum and used as such for the next step.

’H NMR (400 MHz, DMSO-cf_e) δ (ppm): 11.09 (s, 1H). 7.88 (brs, 2H), 7.71 (brs, 3H), 7.15 (brs, 3H),

6.81 to 6.83 (d, J=7.2Hz, 3H ), 4.87 (brs, 2H), 3.70 (s, 3H). 3.32 (brs, 3H), 2.88-2.89 (m, 1H), 1.14 (s, 3H), 1.10-1.11 (m, 2H), 1.03-1.05 (d, J= 7.4Hz, 2H)

MS: m/z: 743.1 [M+1].

Step-4: Synthesis of synthesis of 1-(3-(cyclopropylsulfonyl)phenyl)-5-{(2-fluoro-4iodophenyi)amino)-6_l8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (1)

Aluminium chloride (0.628 g, 4.71 mmol) was added to a solution of 1-(3(cyclopropylsulfonyl)phenyl)-5-((2-fluoro-44odopheny1)amino)-3-(4-methoxybenzyl )-6,8dimethylpyrido[4,3-d]pyrimÎdine-2,4,7(1H,3H,6H)-trione (1 d) (0.350 g, 0.471 mmol) in Anisole (2 ml). Resulting mixture was stirred under N₂ atm for 18 h at RT. Reaction was quenched by addition of MeOH. Solvents were evaporated in vacuo. Residue was actdified using dil. HCl. Resulting solid was filtered and heated to reflux in 2-propanol (20 ml) for 1 hr. Reaction mixture was brought to RT and filtered. Residue was purified by flash chromatography to give the pure product

L ’HNMR (400 MHz, DMSO-d6), δ 11.66 (s. 1H), 11.20 (s, 1H), 7.93-7.83 (m, 2H), 7.83-7.73 (m, 3H),

7.56 (dd, J ~ 1.2 and 8.4 Hz, 1H), 6.97 (t, J - 8.8 Hz, 1H), 3.07 (s, 3H). 2.91-2.87 (m, 1H), 1.16 (s,

3H), 1.15-1.11 (m,2H), 1.06-1.04 (m,2H).

Example-2: Synthesis of 3-cyc!opropyl-1-(2-fluoro-4-lodophenyl)-5-((3-(3-hydroxyazetidin-1· yl)phenyl)amlno)-6,8-dimethylpyrldo[2,3-d]pyrimldine-2,4,7(1 H,3H,8H)-trione. (Compound 2)

Step-1: Synthesis of 3-cydopropy!-1 -(2-fluoro-4-iodophenyl)-5-((3-{3-hydroxyazetidjn-1 yl)phenyl)amino)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1 H,3H,8H)-trione (2b)

3-cyc!opropy!-1-(2-fluoro-4-iodophenyl)-6_l8-dimethyl-2,4_t7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3d]pyrimidin-5-yl 4-methylbenzenesulfonate (2a) (0.5 g, 0.78 mmol), 1-(3-aminophenyl)azetidin-3-ol (vi) (0.13 g, 0.784 mmol) in DMA (1.5 ml), and 2,6-lutîdine (0.33 ml, 2.86 mmol) was added in the sealed tube and heated at 130*C for 10 hr under nitrogen atmosphère. After completion of the reaction, the réaction mixture was poured into ice cold water and extracted with ethyl acetate (2 x 10 ml). The organic layers were combined, washed with saturated ammonium chloride, water and dried over sodium sulfate. The organic layer was then concentrated under reduced pressure to obtain a crude product which was purified by column chromatography to yield the titled compound (2b) as a white solid (0.09 g, 18 %) [MS: m/z = 630 (M+1)].

Step-2: Synthesis of 3-cyclopropyi-5-((2-fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxyazetidin-1yl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H, 6H)-trione (2) 3-cyclopropyM-(2-fïuoro-4-iodophenyl)-5-((3-(3-hydroxyazetidÎn-1-yl)phenyl)amino)-6,8dimethylpyrido[2,3-d]pyriniidine-2,4,7(1H,3H,8H)-trione (2b) (0.03 g, 0.048 mmol) was taken in tetrahydrofuran (1 ml) at room température, sodium methoxide (30% in MeOH, 23 pL) was added

and the reaction mixture was stirred at the same température for 2 hr under nitrogen atmosphère. The progress of the reaction was monitored on HPLC. After complété consumption of the substrate, the reaction mixture was concentrated and submitted as such for LCMS and préparative HPLC to yield the titled compound (2) as white solid (0.013 g)

S ’HNMR (400 MHz, DMSO-dB), δ 11.09 (s. 1 H), 7.75 (bs, 1 H), 7.53-7.51 (m. 1 H), 7.20 (t, 1 H), 6.90 (L 1H), 6.64 (d, 1H, J=8Hz), 6.43 (d, 2H, J=2Hz), 5.63 (d, 1H,J=6.4Hz), 4.56 (bs, 1H), 4.07-4.04 (m, 2H), 3.50-3.47 (m. 2H), 3.07 (s, 3H). 1.29 (s, 3H), 1.09 (t, 1H,J=6.8Hz), 1.0-0.9 (m, 2H), 0.64-0.62 (m, 2H). MS: m/z = 630 (M+1)].

The compounds given below in Table 1: were prepared by procedure similar to the one described 10 above in Example 2 with the above stated intermediates with appropriate variations in reactants, reaction conditions and quantifies of reagents.

Table-1:

Compound No.	Intermediate No.	IUP AC name	Analytical data
3	i	3-cyclopropyl-1 -(3(cyclopropylsulfonyl)ph enyl)-5-((2-fluoro-4iodophenyl)amino)-6,8dimethylpyrido[4,3d]pyrimidine2,4,7(1 H, 3H,6H)-trione	’HNMR (400 MHz, DMSO-d6), δ 11.06 (s, 1H), 7.91-7.90 (m, 2H), 7.817.73 (m, 3H). 7.57-7.54 (m, 1H). 6.96 (t, J = 8.4 Hz, 1H), 3.09 (s, 3H), 2.912.87 (m, 1H), 2.64-2.60 (m, 1H). 1.16 (s, 3H), 1.13-0.86 (m, 6H), 0.69-0.67 (m, 2H). MS: m/z 662.9 (M+1).
4	vii	3-cydopropyl-5-((2fluoro-4iodophenyl)amino)-6,8dim ethyl-1-(3-(2oxoazetidin-1yl)phenyl)pyrido[4,3d]pyrimidine2,4,7(1 H,3H,6H)-trione	’HNMR (400 MHz, DMSO-d6), δ 11.10(s, 1H), 7.9 (dd, 1H ,J= 2 and 8.4 Hz ), 7.50 (dd, 1H, J= 2 and 8.4 Hz), 7.43-7.41 (m, 2H), 7.33 (d, 1H, 6.0 Hz), 7.07 (d, 1H, */=6.0 Hz), 6.92 (t, 1H, J=8.6 Hz), 3.65 (t. 2H, J= 4.4 Hz), 3.10-3.07 (m, 5H), 2.63-2.59 (m, 1H), 1.25 (s, 3H). 0.96-0.94 (m, 2H), 0.68-0.66 (m, 2H).

			MS: m/z 628 (M+1).
5	x	3-cydopropy!-5-((2fluoro-4iodophenyl)amino)-6,8dimethyl-1 -(3-(oxetan3y!amino)phenyl)pyrido[4 ,3-dJpyrimîdine2,4,7(1 H,3H,6H)-trione	’HNMR (400 MHz, DMSO-d6), δ 11.09 (s, 1H), 7.79 (d, 1H, J= 10.4 Hz), 7.55 (d, 1H, J=8.8 Hz), 7.24 (m, 1H), 6.90 (t, 1H, J= 8.8 Hz), 6.58-6.56 (m, 2H), 6.51-6.50 (m, 1H), 6.47-6.45 (m, 1H), 4.82 (t, 2H, J= 6.4 Hz), 4.55-4.50 (m, 1H), 4.38 (bs, 2H), 3.07 ( s, 3H), 2.63-2.55 (m, 1H), 1.3 (s, 3H), 0.95-0.94 (m, 2H), 0.66-0.64 (bs, 2H). MS: m/z 630 (M+1).
6	V	tert-butyl 3-((3-(3- cyclopropyl-5-((2-fluoro4-iodophenyl)amino)6,8-dimethyl-2,4,7trioxo-3,4,6,7tetrahydropyrido[4,3d]pyrimidin-1(2H)yl)phenyl)carbamoyl)az etidine-1 -carboxylate	MS: m/z 757 (M+1).
7	viîi	3-cyd opro pyl -5-({ 2fluoro-4iodophenyl)amino)-6,8dimethyl-1-(3-(oxetan3yloxy)phenyl)pyrido[4,3djpyrimidine2,4,7(1 H,3H,6H)-trione	’HNMR (400 MHz, DMSO-d6), δ 11.06 (s, 1H), 7.78 (d, 1H, J= 10.8 Hz), 7.54 (d, 1H, J=8.0 Hz), 7.36 (t, 1H, J=8.0 Hz), 7.99 (d, 1H, J=8.0 Hz), 6.95-6.87 (m, 2H), 6.80 (dd, 1H, 2.4 and 6.0 Hz), 5.30-5.27 (m, 1H), 4.91 (t, 2H, J= 6.6 Hz), 4.52 (t, 2H. J=5.8 Hz), 3.08 (s, 3H), 2.61 (bs, 1H), 1.23 (s, 3H), 0.96-0.94 (m, 2H), 0.670.65 (m, 2H).

			MS:m&631 (M+1).
8	iv	1-(3-(azetidin-1y!)phenyl)-3cydopropyl-5-((2-fluorD4-iodophenyl)amino)6,8-dimethylpyrido[4,3djpyrimidine2.4,7(1 H,3H,6H)-trione	MS: 614 (M+1).
9	iii	3-cydopropy1-5-((2fluoro-4iodophenyl)amîno)-1 (3-(3-hydroxyoxetan-3yl)phenyl)-6,8dimethylpyrido[4,3djpyrimidine2,4,7(1 H, 3H,6H)-trione	’HNMR (400 MHz, DMSO-d5), δ 11.33 (s, 1H), 7.70 (d, 1H, J= 8 Hz), 7.55-7.46 (m, 3H), 7.31-7.30 (m, 1H), 6.74-6.60 (m, 2H), 4.94-4.86 (m. 4H), 3.21 (s, 3H), 2.78-2.72 (m, 2H). 1.36 (s, 3H). 1.15-1.13 (m, 2H), 0.83-0.81 (m, 2H). MS: mL· 631 (M+1).
10	ii	N-(3-(3-cydopropyl-5((2-fluoro-4iodophenyl)amino)-6,8dimethyl-2,4,7-trioxo3,4,6,7tetrahydropyrido[4,3d]pyrimidin-1(2H)yf)pheny!)-3methyloxetane-3carboxamide	1HNMR (400 MHz, DMSO-d6), δ 11.05 (s, 1H), 9.94 (s, 1H), 7.78 (d, 1H, J=9.6Hz), 7.67 (d, 1H, J=8Hz), 7.61 (s, 1H). 7.54 (d, 1H, J=8.4Hz), 7.38 (t, 1H, J=7.2Hz), 7.07 (d, 1H, J=7.2Hz), 6.91 (t, IH, J=8.4Hz), 4.82 (d, 2H. J=6Hz), 4.33 (d, 2H, J=6Hz), 3.07 (s, 3H), 2.60 (m, 1H), 1.60 (s, 3H). 1.27 (s, 3H), 0.97-0.94 (m, 2H), 0.66-0.64 (s, 2H). MS: HVÏ672 (M+1).
11	xïi	1-(3(cydopropanecarbonyl) pheny!)-3-cydopropyl-	1HNMR (400 MHz, DMSO-d6), δ 11.08 (s,1H), 8.12-8.09 (m, 1H), 8.01 (bs, 1H), 7.79 (dd, 1H. J=2 Hz

L·

		5-((2-fluoro-4iodophenyl)amÎno)-6,8dimethy!pyrido[4,3djpyrimidine2,4,7(1 H,3H,6H)-trione	J=10.4Hz), 7.69-7.62 (m, 2H). 7.567.54 (m,1H), 6.94 (t, 1H J=8.4Hz), 0.68 (bs, 2H), 3.07 (s, 3H), 2.90 (m, 1H), 2.61-2.60 (m, 1H), 1.18 (s, 3H), 1.06-1.08 (m, 4H), 0.96-0.95 (m, 2H). MS: m/z 627.1 (M+1).
12	i	H3(cyclopropylsulfo nyl ) ph enyl)-5-((2-fluoro-4iodophenyl)amino)3,6,8trimethylpyrido[4,3djpyrimidine2,4,7(1 H,3H,6H)-trione	’HNMR (400 MHz, DMSO-d6), δ 11.18 (s, 1H), 7.94-7.92 (m, 2H), 7.847.45 (m, 3H), 6.96 (t, J = 8.8 Hz, 1H), 3.22 (s, 3H), 3.09 (s, 3H), 1.78-1.74 (m, 1H). 1.18 (s, 3H), 1.13-1.12 (m, 2H), 1.07-1.05 (m, 2H). MS: m/z 637 (M+1).
13	xi	5-((2-fluoro-4iodophenyl)amino)3,6,8-trimethyl-1-(3((oxetan-3yloxy)methyl)phenyl)pyr ldo[4,3-d]pyrimidine2,4,7(1 H, 3H,6H)-trione	’HNMR (400 MHz, DMSO-d6), δ 11.20 (s, 1H), 7.79 (dd, 1H, 2 and 8 Hz), 7.55 (d, 1H, J= 8.4 Hz), 7.477.43 (m. 1H), 7.39-7.33 (m, 3H), 6.93 (t, 1H, J=8.4 Hz), 4.63-4.60 (m, 3H), 4.69 (s, 2H), 4.42-4.41 (m, 2H), 3.21 (s, 3H), 3.08 (s, 3H), 1.19 (s, 3H). MS: m/z 619 (M+1).
14	iii	5-((2-fluoro-4iodophenyl)amtno)-1 (3-(3-hydroxyoxetan-3y1)pheny1)-3,6,8trimethyîpyrido(4,3djpyrimidine2,4,7(1 H,3H,6H)-trione	’HNMR (400 MHz, DMSO-c/6), δ 11.22 (s, 1H), 7.79 (dd, 1H. J= 10 and 1.6 Hz), 7.66 (d, 1H, J= 8 Hz), 7.587.43 (m, 3H), 7.36 (dd, 1H, J= 8.8 and 1.2 Hz), 6.93 (t, 1H, J= 8.8 Hz), 4.78 (d, 2H, J= 6.4 Hz), 4.65 (bs, 2H), 3.20 (s, 3H). 2.60 (bs, 1H), 3.08 (s, 3H), 1.19 (S, 3H).

L

			MS: m/z 605 (M+1).
15	viii	5-((2-fluoro-4iodophenyljamino)3,6,8-trimethyl-l-<3(oxetan-3yloxy)phenyl)pyrido[4,3djpyrimidine2,4,7(1 H,3H,6H)-trione	’HNMR (400 MHz, DMSO-d6), δ 11.19 (s, 1H), 7.79 (dd, 1H, J= 2 and 8.4 Hz), 7.55 (d, 1H, 8.4 Hz), 7.37 (t, 1H, J= 8.0 Hz), 7.02 (dd, 1H, J= 1.2 and 6.8 Hz), 6.96-6.91 (m, 2H), 6.86 (dd, 1H. 2 and 8.4 Hz), 5.32-5.27 (m, 1H), 4.91 (t, 2H, J= 6.8 Hz), 4.52 (t, 2H, J=6.0 Hz), 3.21 (s, 3H), 3.08 (s, 3H), 1.24 (s, 3H). MS: m/z 604 (M+1).
16	iv	1-(3-(azetidin-1y1)phenyl)-5-((2-fl uoro4-iodophenyt)amino)3,6,8trimethy!pyrido[4,3djpyrimidine2,4,7(1 H, 3H,6H)-trione	’HNMR (400 MHz, CDCI3), δ 11.45 (s, 1H), 7.53 (dd, 1H, J=2 and 10 Hz), 7.45( d, 1H, J= 8.4), 7.22 (t, 1H, J=8 Hz), 6.70-6.63 (m, 3H), 6.56-6.55 (m, 1H), 3.66 (t, 2H, J= 6.4 Hz), 3.39 (s, 3H), 3.34 (t, 2H,J=6.8Hz), 3.23(s, 3H), 2.10-2.04 (m, 2H), 1.5 (s, 3H). MS: m/z 588 (M+1).
17	X	5-((2-fluoro-4iodophenyfjamino}3,6,8-trimethyl-1-(3(oxetan-3ylamino)phenyl)pyrido[4 ,3-d]pyrimidine2,4,7(1 H,3H,6H)-trione	’HNMR (400 MHz, DMSO-d6), δ 11.22 (s, 1H), 7.79 (dd, 1H, J= 2 and 12 Hz), 7.55 (d, 1H, J=8.4), 7.15 (t, 1H, J=8 Hz), 6.91 (t, 1H, J= 8.8 Hz). 6.59 (d, 2H, J= 6.8), 6.49 (d, 2H, J= 8Hz), 4.82 (t, 2H, J=6.4), 4.54-4.50 (m, 1H), 4.40-4.37 (m, 2H), 3.2 (s, 3H), 3.07(s, 3H), 1.32 (s, 3H). MS: m/z 604 (M+1).
18	iî	N-(3-(5-((2-fluoro-4iodophenyl)amino)3,6,8-trimethy1-2,4,7-	’HNMR (400 MHz, DMSO-d6), δ 11.18 (s. 1H), 9.93 (s, 1H), 7.78 (d, 1H, J=8.8Hz) 7.67 (s, 1H), 7.64 (d,

		trioxo-3,4,6,7tetrahydropyrido[4,3d]pyrimidin-1(2H}y!)phenyl)-3methyloxetane-3carboxamide	1H, J=8 Hz), 7.54 (d, 1H, J=8.8Hz), 7.40 (t, 1H, J=8Hz), 7.11 (dd, 1H, J=1.2 and 8Hz), 6.93 (t, 1H, J=8.8Hz), 4.82 (d, 2H, J=6Hz), 4.33 (d, 2H, J=6Hz), 3.2 (s, 3H), 3.08 (s, 3H), 1.60 (s, 3H), 1.28 (s, 3H). MS: m/z 646 (M+1).
19	ix	2-((1-(3-(5-((2-fluoro-4iodophenyljamino)3,6,8-trimethyl-2,4,7trioxo-3,4,6,7tetrahydropyrido[4,3d]pyrimidin-1(2H)yl)phenyl)azetidin-3yl)oxy)acetamide	’HNMR (400 MHz, DMSO-d6), δ 11.24 (s, 1H), 7.77 (d, 1H, J= 9.6 Hz), 7.53 (d, 1H. J=8 Hz), 7.33 (s, 1H), 7.26-7.21 (m, 2H), 6.91 (t, 1H, J= 8.4 Hz), 6.68 (d, 1H, J=8.4 ), 6.48- 6.46 (m, 2H), 4.47 (m, 1H), 4.06-4.02 (m, 2H), 3.82 (s, 2H), 3.68-3.65 (m, 2H), 3.19 ( s, 3H), 3.08 (s, 3H), 1.31 (s, 3H). MS:mZz661 (M+1).

Example 3: Synthesis of 5-((2-fluoro-4-lodophenyl)amlno)-1-(3-(3-fluorooxetan-3-yl)phenyl)-

3,6,8-trlmethylpyrfdo[4_t3-d]pyrimldine-2_l4_l7(1H,3H,6H)-trione (Compound 20).

(14) (20)

To a solution of 5-((2-Fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxyoxetan-3-yl)pheny1)-3,6,8trimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (compound 14) (0.02 g, 0.033 mmol) In DCM (7 ml), DAST (0.017ml, 0.132 mmol) was added at-78 ’C, the reaction mixture was stirred at

room température for 1hr. Reaction mixture was concentrated and crude compound was purified by column chromatography over silica gel using ethyl acetate (40%) in hexane as eluent. Obtained solid was triturated in diethyl ether to afford the titled compound (0.012 g).

’HNMR (400 MHz, DMSO-d6), δ 11.21 (s. 1H), 7.79 (dd, 1H, J= 2.0 and 8.4 Hz), 7.63-7.59 (m, 3H), 7.55 (d, 1H, J=10) 7.49 (d, 1H, J= 7.6 Hz), 6.94 (t, 1H, J= 8.8Hz), 5.02-4.87 (m, 4H), 3.21 (s, 3H), 3.08 (s, 3H). 1.19 (s, 3H). ESI-MS: [m/z = 607 (M+1)].

Example 4: Synthesis of N-(3-(3-cyc1opropyl-5-((2-fluoro-4-lodophenyl)amlno)-6,8-dimethyl2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyr1mldin-1(2H)-yi)phenyl)azetidine-3carboxamide (21).

To a solution of tert-butyl 3-((3-(3-cyclopropyl-5-((2-fluoro-4-Îodophenyl)amÎno)-6,8-dÎmethyl-2,4,7trioxo-3_l4,6_l7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl) carbamoyl)azetidÎne-1 -carboxylate (compound 6) (0.075 g, 0.099 mmol) in DCM (5.0 ml), TFA (0.038 ml, 0.496 mmol) was added at 0 °C. Reaction mixture was stined at room température for 15 hrs, treated with satd. aq. NaHCOj and the resulting mixture was extracted with DCM (3 x 10 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated under vacuum to obtain a crude product wchich was triturated in diethyl ether to afford titled compound (0.03 g).

’HNMR (400 MHz, DMS0-c6), δ 11.07 (s, 1H), 10.32 (s, 1H), 8.67 (bs. 1H), 7.81-7.80 (dd, 1H, J=

10.4 and 1.6 Hz), 7.65-7.63 (m, 1H), 7.57-7.55 (d, 1H), 7.44-7.39 (m, 1H), 7.09-7.07 (d, 1H, J= 6.4 Hz), 6.94-6.90 (t, 1H, J= 8.8 Hz), 4.81-4.79 (d, 1H. J= 8.8 Hz), 4.10-4.09 (m, 1H), 3.76-3.72 (m,

1H), 3.07 (s, 3H), 2.67-2.60 (m, 2H), 2.33-2.27 (m, 2H), 1.25 (s, 3H), 0.66 (bs, 2H), 0.96-0.94 (m,

2H). ESI-MS: [m/z - 657 (M+1)]

PHARMACOLOGICAL ACTIVITY:

Protocol for ln-Vitro Experiments:

Example-A: Identification of compounds Inhlbltlng MEK kinase activity

In a 25 μ!_ reaction, MEK enzyme (final concentration 2-4 pg/ml), and ERK substrate (final concentration 50-100 pg/ml), were incubated with various concentration of test compounds (diluted such that the reaction had 1% DMSO), at 25-30°C for 20 to 120 min on a shaker incubator. The 10 reactions were initiated by the addition of ATP. The reactions were terminated by adding an equal volume of KinaseGIo reagent (Promega), following the manufacturées instructions. The plates were read on a luminometer. IC_M calculations were done using GraphPad Prism 5.

The Compounds of the invention exhibited ICgo values ranging between 1 nM to 600nM in MEK inhibition assay.

Compound No's 1, 5,7,10,11,12,13,14,15,16,18 and 19 exhibited ICso values in the range 1 to 600 nM.

Example-B: Analysis of ERK phosphorylation

This assay was carried out with human melanoma cells, human and mouse colon cancer cells. Cells were treated for 1h with various concentrations of test compounds. ERK phosphorylation 20 analysis was performed using the Alphascreen SureFire Phospho-ERK 1/2 Kit (Perkin Elmer), by following the manufacturées instructions. % inhibition of ERK phosphorylation was determined as:

100 - {(RFU test - RFU lysis buffer control) / (RFU vehide treated control - RFU lysis buffer control)} x 100.

The compounds prepared were tested using the above assay procedure and the results obtained are given in Table 2. Percentage inhibition at concentrations of pERK at 100nM, 10nM, 1nM for the stated examples is setworth here. The percentage inhibiton at the above depicted concentrations for the compounds stated are given in the following groups.

Group-A: Compounds having 50-100% inhibition at 1 nM.

Group-B: Compounds having 50-100% inhibition at 10nM

Group-C: Compounds having 50-100% inhibition at 100nM.

Table-2:

Group	Compounds
A	1,8,11,12,14,15, and 17
B	2,4, 5,10,13,18,19 and 20
C	3,7,9,16 and 21

Claims (38)

1- (3-(azetidin-1-yl)pheny!)-5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethylpyrido[4_l3d]pyrimidine-2,4,7(1H,3H.6H)-trione (Compound 16)

1-{3-(cyclopropanecarbonyl)phenyl)-3-cydopropy1-5-((2-fluoro-4-iodopheny1)amino)-6,8dimethylpyrido[4,3-d]pyrimidine-2,4_l7(1H,3H,6H)-trione (Compound 11) 1-(3-(cydopropylsulfonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-3,6_l8-trimethyl pyrido[4,3d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 12)

1-(3-(azetidin-1-yl)phenyl)-3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6_l8-dimethyl pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 8) 3-cydopropyl-5-((2-fluorO’4-îodophenyl)amino)-1-(3-{3-hydroxyoxetan-3-yl)phenyl)-6_l8dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H_l3H_l6H)-trione (Compound 9) N-(3-(3-cydopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethy!-2,4,7-trioxo-3,4,6,7tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-3-methyloxetane-3-carboxamide (Compound 10)

1-(3-(cydopropytsulfony1)pheny!)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyt pyrido [4,3d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 1)

1. A compound of the general formula I, its tautomeric forms, its pharmaceutically acceptable salts, their combinations with suitable médicament and pharmaceutical compositions containîng them.

wherein,

R¹ is selected from the group consisting of hydrogen, substituted- or unsubstïtuted-alkyl, substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstituted- heterocyclyl;

R² is selected from the group consisting of -R®-E, -SO₂R⁷, and -C(O)R⁸;

R³ is selected from the group consisting of hydrogen, substituted- or unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;

R* is selected from the group consisting of hydrogen, halogen, substituted- or unsubstituted-alkyl, and substituted- or unsubstituted- cycloalkyl;

R^s is substituted- or unsubstituted- aryl, wherein the substituents are selected from with R^a and R^b; R* and R” are selected from the group consisting of hydrogen, halogen and haloalkyl;

R® is selected from the group consisting of direct bond, -[C(R^c)R^d]nNR⁹-, -[CtR'JR^nO-, NHC(=O)[C(R^c)R^d]_p-, -S(O)₂NH-, -NHC(=O)[CR^c(R^d)]NR⁹-, -NHC(=O)[CR^e(R^d)]O-, and -NHS(O)2-;

R^e and R^d are each independently selected from the group consisting of hydrogen and substitutedor unsubstituted- alkyl;

E is substituted- or unsubstituted-four membered heterocyclic ring, wherein the substituents are selected from the group consisting of alkyl, halogen, -C(=O)OR^a, and -OR^a;

R* is selected from the group consisting of hydrogen, substituted- or unsubstituted-alkyl, and substituted or unsubstituted cycloalkyl;

L

R⁷ is selected from the group consisting of substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstituted- cycloalkenyl;

R® îs selected from the group consisting of substituted- or unsubstituted- alkyl, substituted- or unsubstituted- alkenyl, substituted- or unsubstituted- alkynyl, substituted- or unsubstituted5 cycloalkyl, and substituted- or unsubstituted- cycloalkenyl;

R⁹ is selected from the group consisting of hydrogen, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- alkenyl, substituted- or unsubstituted- alkynyl, substituted- or unsubstituted- cycloalkyl and substitutedor unsubstituted- cycloalkenyl;

n Is an integer selected from the group consisting of 0,1 and 2;

2- {(1-(3-(5-((2-fluoro-4-iodopheny1)amÎno)-3,6,8-trimethyl-2,4,7-trioxo-3,4_l6,7-tetra hydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)azetidin-3-y1)oxy)acetamide (Compound 19) 5-((2-fluoro-4-iodopheny!)amino)-1-{3-(3-fluorooxetan-3-yl}phenyl)-3,6,8-trimethyl pyrido[4,3d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 20)

N-(3-(3-cydopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7tetrahydropyrido[4,3-d]pyrimidin-1 (2H)-yl)phenyl)azetidine-3-carboxamide (Compound 21 )

2. A compound of the general formula la, its tautomeric forms, its pharmaceutically acceptable salts, their combinations with suitable médicament and pharmaceutical compositions containing them, wherein,

L·

SI

R¹ is selected from the group consisting of hydrogen, substituted- or unsubstituted-alkyl, substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstituted- heterocyclyl;

R³ is selected from the group consisting of hydrogen, substituted- or unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;

3-cydopropy!-1 -(2-fluoro-4-iodophenyl)-5-((3-(3-hydroxyazetidin-1 -yl}phenyl)amino) -6,8dimethylpyrido[2_l3-dlpyrimidine-2,4,7(1H,3H,8H)-trione (Compound 2) 3-cydopropyl-1-(3-(cydopropylsulfonyl)phenyl)-5-{(2-fluoro-4-lodopheny!)amino)-6,8dimethylpyrido[4_l3-d]pyrimidine-2_l4,7(1H,3H,6H)-trione (Compound 3) 3-cydopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-(2-oxoazetidin-1yl)pheny!)pyrido[4,3-d]pyrimidine-2,4_t7(1H,3H,6H)-trione (Compound 4) 3-cydopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-(oxetan-3-ylamino) phenyi)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 5) 3-cydopropyl-5-((2-fluoro-4-lodophenyl)amino)-6,8-dimethyl-1-(3-(oxetan-3-y!oxy) phenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 7)

3. A compound of the general formula Ib, its tautomeric forms, its pharmaceutically acceptable salts, their combinations with suitable médicament and pharmaceutical compositions containing 30 them, wherein,

R¹ is selected from the group consisting of hydrogen, substituted- or unsubstituted-alkyl, substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstituted- heterocyclyl;

R³ is selected from the group consisting of hydrogen, substituted- or unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;

R* is selected from the group consisting of hydrogen, halogen, substituted- or unsubstituted-alkyl, and substituted- or unsubstituted- cycloalkyl;

R* and R^b are selected from the group consisting of hydrogen, halogen and haloalkyl;

R^T is selected from the group consisting of substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstituted- cycloalkenyl;

when the alkyl group and alkenyl group is substituted, the alkyl group and alkenyl group ls substituted with 1 to 4 substituents independently selected from the group consisting of oxo, halogen, rirtro, cyano, perhaloalkyf, cycloalkyl, aryl, heteroaryl, heterocyclyf, -OR^10t>, -SO₂R^10a, C(=O)OR^t0a, -OC(=O}R^10a, -C(=O)N(H}R^W, -OR^10a, -C(=O)N(alkyl)R¹⁰, -N(H)C(=O)R^10a, -N(H)R¹⁰, N (alkyl)R¹⁰ -N(H)C(=O)N(H)R¹⁰, -N(H)C(=O)N(alky1)R¹⁰, -NH-SOr-alkyl and -NH-SOrcycloalkyl;

when the cycloalkyl group and cycloalkenyl group is a substituted, the cycloalkyl group and cycloalkenyl group is substituted with 1 to 3 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, alkyl, alkenyl, perhaloalkyl, aryl, heteroaryl, heterocyclyl, OR^10b, -SO2R^10a, -C(=O)R¹⁰*, -C(=O)OR^10a, -OC(=O)R^,0a, -C(=O)N(H)R¹⁰, -C(=O)N(alkyl)R¹⁰, N(H)C(=O)R^10a, -N(H)R¹⁰. -N(alkyl)R¹⁰, -N(H)C(=O)N(H)R¹⁰, and -N(H)C(=O)N(alkyf)R¹⁰1 -NH-SOr alkyl and -NH-SOrcycloalkyl;

L· when the aryl group is a substituted, the aryl group is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cydoalkenyl, heterocycle, -O-alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, N(H)alkyl, -NH₂, -SOj-alkyl, -SOz-perhaloalkyl, -N(aIkyf)C(=O)alkyl_> -N(H)C(=O)aTkyî, C(=O)N(alkyl)alkyL -C(=O)N(H)alkyl, -C(=O)NH₂, -SO₂N(alkyl)alkyl, -SO₂N(H)alkyl, -SO₂NH₂, -NHSO_ralkyl and -NH-SOz-cydoatkyl;

when the heteroaryl group is a substituted, the heteroaryl group is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cydoalkenyl, heterocyde, -O-alkyl, O-perhaloalkyl, N(alkyl)alkyl, -N(H)alkyl, -NH₂, -SO_ralkyl, -SO_rperhaloalkyl, -N(alkyl)C(=O)alkyf, -N(H)C(=O)alkyl, -C(=O)N(alky!)aîkyl, -C(=O)N(H)alkyl, -C(=O)NH₂, -SO₂N(alkyl)alkyl, -SO₂N(H)alkyl, -SO₂NH₂, -NHSO^alkyl and -NH-SOrcydoalkyl;

when the heterocydyl group is a substituted, the heterocydyl group is substituted with 1 to 3 substituents, when the heterocyclic group is substituted on a ring carbon of the ‘heterocyde*, the substituents are independently selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, perhaloalkyl, cydoalkyl, cydoalkenyl, aryl, heteroaryl, heterocydyl, -OR^10b, C(=O)OR^10a, -OC^OJR¹⁰*, -C(=O)N(H)R¹⁰, -C(=O)N(alky1)R¹⁰, -N(H)C(=O)R^10a, -N(H)R¹⁰, N(alky1)R¹⁰, -N(H)C(=O)N(H)R^t0, -N(H)C(=O)N(alkyl)R¹⁰; the substituents on ring nitrogen of the ‘heterocyde*; substituents are Independently selected from the group consisting of alkyl, alkenyl, cydoalkyl, cydoalkenyl, aryl, heteroaryl, -SO2R^10a, -C(=O)R^10a, C(=O)OR^10a· -C(=O)N(H)R¹⁰, C(=O)N(alkyl)R¹⁰t -NH-SO_ralkyl and -NH-SOj-cydoalkyl;

R¹⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cydoalkenyl, aryl, heteroaryl, and heterocydyl;

R¹⁰· is selected from the group consisting of alkyl, alkenyl, perhaloalkyl, cycloalkyl, cydoalkenyl, aryl, heteroaryl, and heterocydyl; and

R¹⁰⁶ is selected from the group consisting of hydrogen, alkyl, alkenyl, perhaloalkyl, cydoalkyl, cydoalkenyl, aryl, heteroaryl, and heterocydyl.

4. A compound of the general formula le, its tautomeric forms, its pharmaceutically acceptable salts, their combinations with suitable médicament and pharmaceutical compositions containing them, wherein,

R¹ is selected from the group consisting of hydrogen, substituted- or unsubstituted-alkyl, substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstituted- heterocyclyl;

R³ is selected from the group consisting of hydrogen, substituted- or unsubstituted- alkyl, and substituted- or unsubstituted- cycloalkyl;

R* is selected from the group consisting of hydrogen, halogen, substituted- or unsubstituted-alkyl, and substituted- or unsubstituted- cycloalkyl;

R* and R^b are selected from the group consisting of hydrogen, halogen and haloalkyl;

R* is selected from the group consisting of substituted- or unsubstituted- alkyl,substituted- or unsubstituted- alkenyl, substituted- or unsubstituted- alkynyl, substituted- or unsubstitutedcydoalkyl, and substituted- or unsubstituted- cycloalkenyl;

when the alkyl group and alkenyl group is substituted, the alkyl group and alkenyl group is substituted with 1 to 4 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR^10b, -SO₂R^10a, C(=O)OR^10a, -OC(=0)R¹⁰’, -C(=O)N(H)R¹⁰, -OR¹⁰’, -C{=O)N(alkyl}R¹⁰, -N(H)C(=O)R^10a, -N(H)R¹⁰, N(alkyl)R^w -N(H)C(=O)N(H)R¹⁰. -N(H)C(=O)N(alkyl)R¹⁰, -NH-SOj-alkyl and -NH-SOrcycloalkyl;

when the cycloalkyl group and cycloalkenyl group is a substituted, the cycloalkyl group and cycloalkenyl group is substituted with 1 to 3 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, alkyl, alkenyl, perhaloalkyl, aryl, heteroaryl, heterocyclyl, OR^10b, -SO₂R¹⁰*, -C(=O)R¹⁰’, -C(=O)OR^10a, -OC(=O)R¹⁰‘, -C(=O)N(H)R¹⁰, -C(=O)N(alkyl)R¹⁰, L

N(H)C(=O)R^10a, -N(H)R’°, -N(alkyi)R^w. -N(H)C(=O)N(H)R¹⁰, and -N(H)C(=O)N(alkyl}R¹⁰, -NH-SO_r alkyl and -NH-SOrCydoalkyl;

when the aryl group Is a substituted, the aryl group is substituted with 1 to 3 substituents independentiy selected from the group consisting of haiogen, nitro, cyano, hydroxy, alkyl, alkenyl, 5 perhaloalkyl, cycloalkyl, cydoalkenyl, heterocyde, -O-alkyl, -O-perhaloalkyl, -N(a1ky1)alky!, N(H)alkyt, -NH₂, -SOj-alkyl, -SOrperhaloalkyl, -N(alkyl)C(=O)alky1, -N(H)C(=O)alkyl, C(=O)N(alkyl)alkyl, -C(=O)N(H)alky1, -C(=O)NH₂, -SO₂N(alkyl)alkyl, -SO₂N(H)alkyt, -SO₂NH₂, -NHSO^alky! and -NH-S0₂-cydoalky1;

when the heteroaryl group is a substituted, the heteroaryl group is substituted with 1 to 3

5-((2-fluoro-4-îodophenyl)amino)-3,6,8-trimethyl-1-(3-(oxetan-3-y!amino)phenyl) pyrido[4,3d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 17)

N-(3-(5-((2-fluoro-4-iodophenyl)amino)-3₁6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro pyrido[4,3-d]pyrimidin-1(2H)-y1)pheny!)-3-methyloxetane-3-carboxamide (Compound 18)

5-{(2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-1 -(3-(oxetan-3-yloxy) phenyl) pyrido[4,3dJpyrirnidine^^JÎIH.SH.eHÏ-trione (Compound 15)

5-((2-fluoro-4-iodophe nyl)a mi no)-3,6,8-trimethyl-1 -{3-((oxetan-3-yloxy)m ethyl) phenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 13) 5-((2-fluoro-4-iod ophenyl )ami no)-1 -(3-(3-hyd roxyoxetan-3-yl) phenyl)-3,6,8-trimethy!pyrido[4,3d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 14)

5 R⁴ is selected from the group consisting of hydrogen, halogen, substituted- or unsubstituted-alkyl, and substituted- or unsubstituted- cycloalkyl;

R and R^b are selected from the group consisting of hydrogen, halogen and haloalkyl;

R* is selected from the group consisting of direct bond, -[C(R^c)R^d]nNR⁹-, -{C(R^<:)R‘^,]nO-, NHC^OHCÎR'JRV. -S(O)₂NH-, -NHC(=O)[CR^c(R^d)]NR⁹-, -NHC(=O)[CR^e(R^d)]O-, and -NHSfO)^;

6. The compound of any one of daims 1-5, wherein R¹ is seleded from the group consisting of hydrogen, methyl and cydopropyl.

7. The compound of any one of daims 1-6, wherein R³ is methyl.

8. The compound of any one of daims 1-7, wherein R⁴ is selected as methyl.

9. The compound of any one of daims 1-8, wherein R* and R^b are halogen.

10. The compound of any one of daims 1 -9, wherein R^a and R^b are independently fluorine and iodine.

10 substituents independentiy selected from the group consisting of haiogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cydoalkenyl, heterocyde, -O-alkyl, O-perhaloalkyl, N(alkyl)alky!, -N(H)alkyl, -NH₂, -SOralkyl, -SOi-perhaloalkyl, -N(alkyl)C(=O)alky1₁ -NiHJCi^OJalkyl, -C(=O)N(alkyi)alkyl, -C(=O)N(H)alkyl, -C{=O)NH₂₁ -SO₂N(alkyl)alkyl_t -SO₂N(H)alkyl, -SO₂NH₂, -NHSOï-alkyl and -NH-SOz-cydoalkyl;

10 R^c and R^d are each independently selected from the group consisting of hydrogen and substitutedor unsubstituted- alkyl;

E is substituted- or unsubstituted-four membered heterocyclic ring, wherein the substituents are selected from the group consisting of alkyl, halogen, -C(=O)OR·, and -OR;

R* is selected from the group consisting of hydrogen, substituted- or unsubstituted-alkyl, and

10 p is an integer selected from the group consisting of 0 and 1.

when the alkyl group and alkenyl group is substituted, the alkyl group and alkenyl group is substituted with 1 to 4 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR¹⁰®, -SO₂R^10a, C(=O)OR^10a, -OC(=O)R^10a, -C(=O)N(H)R¹⁰, -OR^10a, -C(=O)N(a!ky!)R¹⁰, -N(H)C(=O)R^10a, -N(H)R¹⁰, 15 N(a!kyl)R¹⁰ -N(H)C(=O)N(H)R¹⁰. -N(H)C(=O)N(alkyl)R¹°, -NH-SOralkyl and -NH-SOrcydoalkyl;

when the cycloalkyl group and cycloalkenyl group is a substituted, the cycloalkyl group and cycloalkenyl group is substituted with 1 to 3 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, alkyl, alkenyl, perhaloalkyl, aryl, heteroaryl, heterocyclyl, OR^10b, -SO2R^10a, -C(=O)R^10a, -C(=O)OR^10a, -OC(=O)R^10a, -C(=O)N(H)R¹⁰, -C(=O)N(alkyl)R¹⁰t 20 N(H)C(=O)R¹⁰’, -N(H)R^W, -N(alkyl)R¹⁰, -N(H)C(=O)N(H)R¹⁰, and -N(H)C(=O)N(alky1)R¹⁰, -NH-SOr alkyl and -NH-SOrcycloalkyl;

when the aryl group is a substituted, the aryl group is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, heterocycle, -O-alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, 25 N(H)alkyl, -NH₂, -SOr-alkyl, -SOrperhaloalkyl, -N{alkyl)C{=O)alkyl₁ -frJ(H)C(=O)alky1. C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH₂, -SO₂N(alkyl)alkyl, -SO₂N(H)alkyl, -SO₂NH₂, -NHSOralky! and -NH-SOrcydoalkyl;

when the heteroaryl group is a substituted, the heteroaryl group îs substituted with 1 to 3 substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, 30 alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, heterocycle, -O-alkyl, O-perhaloalkyl, N(alky1)alky1, -N(H)alkyl, -NH₂, -SO_ralkyl, -SOrperhaloalkyl, -N(alkyl)C(=O)a!kyf, -N(H)C(=O)alkyl,

-O(=O)N(alky1)aIkyî_I -C(=O)N(H)alkyl, -C(=O)NH₂, -SO₂N(alkyl)alkyl, -SO₂N(H)alkyl, -SO₂NH₂, -NHSO^alkyl and -NH-SOz-cydoalkyl;

when the heterocyclyl group Is a substîtuted, the heterocydyl group is substîtuted with 1 to 3 substituents, when the heterocyclic group is substîtuted on a ring carbon of the ‘heterocycle*, the substituents are independently selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, perhaloalkyl, cycloalkyi, cycloalkenyl, aryl, heteroaryl, heterocyclyl, -OR^10b, C(=O)OR^10a, -OC(=O)R^10a, -C(=O)N(H)R¹⁰, -C(=O)N(alkyl)R’°, -N(H)C(=O)R^10a, -N(H)R¹⁰, N(alkyl)R¹°, -N(H)C(=O)N(H)R^W, -N(H)C(=O)N(alkyl)R¹⁰; the substituents on ring nitrogen of the ‘heterocycle’; substituents are independently selected from the group consisting of alkyl, alkenyl, cycloalkyi, cycloalkenyl, aryl, heteroaryl, -SO2R^Wa, -C(=O)R^10a, C(=O)OR^10a· -C(=O)N(H)R¹⁰, C(=O)N(alkyl)R¹⁰, -NH-SOralkyl and -NH-SOrCydoalkyl;

R¹⁰ îs selected from the group consisting of hydrogen, alkyl, alkenyl, cydoalkyl, cydoalkenyl, aryl, heteroaryl, and heterocydyl;

R^10a is selected from the group consisting of alkyl, alkenyl, perhaloalkyl, cydoalkyl, cydoalkenyl, aryl, heteroaryl, and heterocydyl; and

R^10b is selected from the group consisting of hydrogen, alkyl, alkenyl, perhaloalkyl, cydoalkyl, cydoalkenyl, aryl, heteroaryl, and heterocydyl.

11. The compound of any one of daims 1-10, wherein R⁸ is selected from the group consisting of direct bond, -{CiR'JR^NR⁹- -[CfR^R^O-, and -NHC(=O}[C(R^c)R^d]p-

12. The compound of any one of daims 1-11, wherein R® is selected from the group selected from direct bond, -NH-, -O-, -CH₂O-, and -NHC(=O)-.

13. The compound of any one of daims 1-12, wherein E Is substitutued- or unsubstituted- four membered heterocydic ring.

14. The compound of any one of daims 1-13, wherein E is seleded from the group consisting of 3-oxetane, 1-azetidine, 1-azetidine-2-one and 3-azetidine substituted- or unsubstituted-with methyl, fluoro, -C(=O)OR^e and -OR·; wherein R’is hydrogen, tert-butyl, and -CH₂C(=O)NH₂.

15. The compound of any one of daims 1-14, wherein R⁷ is cyclopropyl.

15 when the heterocydyl group is a substituted, the heterocyclyl group is substituted with 1 to 3 substituents, when the heterocyclic group is substituted on a ring carbon of the ‘heterocyde’, the substituents are independentiy seleded from the group consisting of haiogen, nitro, cyano, oxo, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cydoalkenyl, aryl, heteroaryl, heterocydyl, -OR^Wb, C(=O)OR^10a, -OC(=O)R^10a, -C(=O)N(H)R¹⁰, -C(=O)N(alkyl)R¹⁰. -N(H)C(=O)R^10a, -N(H)R¹⁰, 20 N(alkyt)R¹⁰, -N(H)C(=O)N(H)R¹°, -N(H)C(=O)N(alkyl)R¹⁰; the substituents on ring nitrogen of the ‘heterocyde’; substituents are independentiy seleded from the group consisting of alkyl, alkenyl, cydoalkyi, cydoalkenyl, aryl, heteroaryl, -SO₂R^10a, -C(=O)R^10a, C(=O)OR^10a· -C(=O)N(H)R¹⁰, C(=O)N(alkyl)R¹⁰. -NH-SOralkyl and -NH-SOj-cydoalkyl;

R¹⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, cydoalkyi, cydoalkenyl, aryl, 25 heteroaryl, and heterocydyl;

R^10a is selected from the group consisting of alkyl, alkenyl, perhaloalkyl, cydoalkyi, cydoalkenyl, aryl, heteroaryl, and heterocydyl; and

R^10b is selected from the group consisting of hydrogen, alkyl, alkenyl, perhaloalkyl, cydoalkyi, cydoalkenyl, aryl, heteroaryl, and heterocydyl.

15 substituted or unsubstituted cycloalkyl;

R⁹ is selected from the group consisting of hydrogen, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- alkenyl, substituted- or unsubstituted- alkynyl, substituted- or unsubstituted- cycloalkyl and substitutedor unsubstituted- cycloalkenyl;

n is an integer selected from the group consisting of 0,1 and 2;

16. The compound of any one of daims 1-15, wherein R® is cydopropyl.

17. The compound of any one of daims 1-16, wherein R¹ is selected from the group consisting of hydrogen, alkyl, cydoalkyl; R³ is alkyl; R⁴ is alkyl; R* and R^b are halogen; R® is seleded from the group consisting of direct bond, -[C(R^c)R^<’]riNR⁹-, -[CiR^R^O- and -NHC(=O)[C(R^C)R®]P-; E Is substitutued- or unsubstituted- four membered heterocydic ring; R⁷ is substituted- or unsubstitutedcydoalkyl; R® is substituted- or unsubstituted- cycloalkyl.

18. The compound of any one of daims 1-17, wherein R¹ is selected from the group consisting of hydrogen, methyl, cyclopropyl; R³ is methyl; R⁴ is methyl; R® and R^b are fluoro and iodo; R® is direct bond, -NH-, -O-, -CH₂O- and -NHC(=O)-; E is 3-oxetane, 1-azetidine, 1-azetidine-2-one and 3-azetidine substituted- or unsubstituted- with methyl, fluoro, tert-butoxy carbonyl, -OH and OCH₂C(=O)NH₂; R⁷ is cydopropyl and R® is cydopropyl.

19. The compound of any one of claims 1-18, wherein the compound is selected from the group consisting of-

20. A pharmaceutical composition comprising a compound or apharmaceutically acceptable sait of any one of claims 1-19 and one or more pharmaceutically acceptable carriers, diluents, or excipients.

20 p is an integer selected from the group consisting of 0 and 1.

when the alkyl group and alkenyl group is substituted, the alkyl group and alkenyl group is substituted with 1 to 4 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR^10b, -SO2R^10a, C(=O)OR^10a. -OC(=O)R¹⁰’, -C(=O)N(H)R’°, -OR^Wa, -C(=O)N(alkyl)R¹⁰, -N(H)C(=O)R^10a, -N(H)R¹⁰, 25 NfalkyQR¹⁰ -N(H)C(=O)N(H)R¹⁰, -N(H)C(=O)N(alkyl)R¹°, -NH-SOralkyl and -NH-SOycycloalkyl;

when the cycloalkyl group and cycloalkenyl group is a substituted, the cycloalkyl group and cycloalkenyl group is substituted with 1 to 3 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, alkyl, alkenyl, perhaloalkyl, aryl, heteroaryl, heterocyclyl, · OR^10t>, -SO2R^10a, -C(=O)R¹⁰*t -Ct=O)OR¹⁰·, -OC(=O)R^10a, -C(=O}N(H)R¹⁰, -C(=O)N(alkyl)R¹⁰, 30 N(H)C(=O)R¹⁰*1 -N(H)R¹⁰, -N(alky1)R¹⁰. -N(H)C(=O)N(H)R¹⁰, and -N{H)C(=O)N(alkyl}R¹⁰, -NH-SOr alkyl and -NH-SOrcydoalkyl;

when the aryl group is a substituted, the aryl group is substituted with 1 to 3 substituents Independently selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cydoalkenyl, heterocycle, -O-alkyl, -O-perhaloalkyl, -N(alky!)alkyf, N(H)alkyf. -NH₂, -SOj-alkyl, -SOî-perhaloalkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, 5 C(=O)N{aîkyî)aîkyt. -C(=O)N(H)alky1, -C(=O)NH₂, -SO₂N(alkyl)alkyl, -SO₂N(H)alkyl, -SO₂NH₂, -NHSO^alkyl and -NH-SOrcydoalkyl;

when the heteroaryl group is a substituted, the heteroaryl group is substituted with 1 to 3 substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cydoalkenyl, heterocycle, -O-alkyl, O-perhaloalkyl, 10 N(alkyl)aîkyl, -N(H)alkyl, -NH₂, -SO₂-alkyi, -SOj-perhaloalkyl, -N(alkyl}C(=O)alkyl, -N(H)C(=O)alkyl,

-C(=O)N(alkyl)aîkyl, -C(=O)N(H)alkyl, -C{=O)NH₂, -SO₂N(alkyl)alkyl. -SO₂N(H)alkyl, -SO₂NH₂, -NHSOralkyl and -NH-SO2-cydoalkyl;

when the heterocyclyl group is a substituted, the heterocydyl group is substituted with 1 to 3 substituents, when the heterocydic group is substituted on a ring carbon of the ‘heterocyde’, the 15 substituents are independently selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cydoalkenyl, aryl, heteroaryl, heterocydyl, -OR^10b, C(=O)OR^Wa, -OC^OJR¹⁰⁸, -C(=O)N(H)R¹⁰, -C(=O)N(alky1)R¹°, -N(H)C(=O)R^10a, -N(H)R¹⁰, N(alkyl)R¹⁰, -N(H)C(=O)N(H)R¹⁰, -N(H)C(=O)N(afkyl)R¹⁰; the substituents on ring nitrogen of the ‘heterocyde’; substituents are independently selected from the group consisting of alkyl, alkenyl, 20 cydoalkyl, cydoalkenyl, aryl, heteroaryl, -SO2R^10a. -C(=O)R^10a, C(=O)OR^10a· -C(=O)N(H)R¹⁰, C(=O)N(alkyl)R¹⁰, -NH-SO2-alkyt and -NH-SCh-cydoalkyl;

R¹⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, cydoalkyl, cydoalkenyl, aryl, heteroaryl, and heterocydyl;

R^10a is selected from the group consisting of alkyl, alkenyl, perhaloalkyl, cydoalkyl, cydoalkenyl, 25 aryl, heteroaryl, and heterocydyl; and

R^10b is selected from the group consisting of hydrogen, alkyl, alkenyl, perhaloalkyl, cydoalkyl, cydoalkenyl, aryl, heteroaryl, and heterocydyl.

21. Use of a composition comprising a compound of formula I, la, tb, le, its tautomeric forms, its stereoisomers, or its pharmaceutically acceptable sait as daimed in any one of daims 1-19 in a method of manufaduring a médicament for use in inhibiting MEK enzymes comprising contacting said MEK enzyme with the said composition.

22. The use of daim 21, wherein said MEK enzyme is MEK kinase.

23. The use of daim 21 wherein said contacting MEK enzyme occurs within a cell.

24. Use of a composition comprising a compound of formula I, la, Ib. le, its tautomeric forms, its stereoisomers, or its pharmaceutically acceptable sait as daimed in any one of daims 1-19 in a method of manufaduring a médicament for use in treatment of a MEK mediated disorder in an individual suffering from said disorder.

25. The use of daim 24, further comprising use of an additional therapy.

26. The use of daim 25, wherein said additional therapy is radiation therapy, chemotherapy or a combination of both.

27. The use of daim 24, further comprising using at least one additional therapeutic agent.

28. The use of daim 24, wherein said MEK mediated disorder is selected from the group consisting of inflammatory diseases, infections, autoimmune disorders. Stroke, ischemia, cardiac disorder, neurological disorders, fibrogenetic disorders, proliférative disorders, hyperproliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases and malignant diseases.

29. The use of daim 24, wherein said MEK mediated disorder is a hyperproliferative disease.

30. The use of daim 24, wherein said MEK mediated disorder is cancer, tumors, leukemias, neoplasms, or cardnomas.

30 5. The compound of any one of daims 1-4, wherein R¹ is selected from the group consisting of hydrogen, alkyl, and cydoalkyi.

31. The use of daim 24, wherein said MEK mediated disorder is an inflammatory disease.

32. The use of daim 24, wherein said individual is a mammal.

33. Use of a composition comprising a compound of formula I, la, Ib, le, its tautomeric forms, its stereoisomers, or its pharmaceutically acceptable sait as daimed in any one of daims 1-19 in a method of manufaduring a médicament for use in the treatment or prophylaxis of a proliférative disease in an individual in need.

34. The use of daim 33, wherein said proliférative disease is cancer, psoriasis, restenosis, autoimmune disease, or atherosderosis.

35. Use of a composition comprising a compound of formula I, la, Ib, le, its tautomeric forms, its stereoisomers, or its pharmaceutically acceptable sait as daimed in any one of daims 1-19 in a method of manufaduring a médicament for use in the treatment or prophylaxis of an inflammatory disease in an individual in need thereof.

36. The use of daim 35, wherein said inflammatory disease is rheumatoid arthritis or multiple sderosis.

37. Use of a composition comprising a compound of formula I, la, Ib, le, its tautomeric forms, its stereoisomers, or its pharmaceutically acceptable sait as daimed in any one of daims 1-19 in a method of manufacturing a médicament for use in degrading, inhibiting the growth of, or killing cancer cells comprising contacting the cells with the composition.

38. Use of a composition comprising a compound of formula I, la, Ib, le, its tautomeric forms, its stereoisomers, or its pharmaceutically acceptable sait as daimed in any one of daims 1-19 in a method of manufacturing a médicament for use in inhibiting tumor size increase, redudng the size of a tumor, redudng tumor prolifération, or preventing tumor prolifération in an individual in need.