WO2016009306A1 - Heterocyclyl compounds as mek inhibitors - Google Patents

Abstract

The present disclosure is related to heterocyclyl compounds as MEK inhibitors. These compounds include heterocyclyl compounds of formula (I) and (Ia), their pharmaceutically acceptable salts, their combinations with suitable medicaments, and pharmaceutical compositions thereof. The present disclosure also includes processes of preparation of the compounds and their use in methods of treatment. The compounds as disclosed herein are of Formula (I) below:

Description

HETEROCYCLYL COMPOUNDS AS MEK INHIBITORS

FIELD OF THE INVENTION

[ 1] The present invention relates to anticancer compounds, their pharmaceutically acceptable salts, their combinations with suitable medicaments, their pharmaceutical compositions, and uses thereof in treating various cancers.

CROSS-REFERENCE TO A RELATED APPLICATION

[2] The present application claims the benefit of Indian Provisional Patent Application No. 2310/ MUM/ 2014 filed on 15 July 2014, the disclosure of which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

[3] Cancer cells possess certain characteristics that allow them a growth advantage. These include six main alterations in cell physiology such as self- sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis, indefinite proliferative potential, sustained angiogenesis, tissue invasion, and metastasis (Douglas Hanahan and Robert A. Weinberg, Cell, Vol. 100, 57-70, 2000) . These changes are triggered by genomic instability and inflammation which generates a microenvironment conducive for tumor growth. In addition to the above mentioned traits, reprogramming of cellular energy metabolism and evasion of immune destruction has also been observed in a majority of cancers.

[4] The enhanced survival in cancer cells is further potentiated by the presence of aberrantly activated signalling pathways. A large majority of cancers are known to have mutations in growth factor signalling cascades that lead to constitutive activation of these pathways. Such constitutive activations have been observed in growth factor receptors which include but are not limited to, epidermal growth factor receptor - EGFR, fibroblast growth factor receptor - FGFR, hepatocyte growth factor receptor - HGFR, etc. Furthermore, activating mutations have been reported in certain receptor as well as non receptor tyrosine kinases which include, but are not limited to, MET receptor tyrosine kinase, EGFR-tyrosine kinase, Bcr-Abl tyrosine kinase, Src tyrosine kinase etc. Activation of Ser-Thr kinases such as Ras and lipid kinases such as PI3-kinases also leads to oncogenesis. Chronic activation of the growth factor/ cytokine /hormone- associated signalling leads to activation of immediate downstream components such as Src, Ras, PI3-kinase, etc. These kinases further activate effectors such as MEK, ERK, AKT, eventually leading to activation of transcription factors that endow the cells with a high proliferative potential, improved survival, subversion of metabolic pathways and inhibition of apoptosis. (Douglas Hanahan and Robert A. Weinberg, Cell, Vol. 100, 57-70, 2000; Douglas Hanahan and Robert A. Weinberg, Cell, Vol. 144, 646-674, 201 1) .

[5] 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 cells, this pathway is, however, constitutively activated and leads to increased cancer cell survival, cell proliferation, angiogenesis, and metastasis. The tumors that show constitutive activation of the Ras or the MEK kinase include, but are not limited to, those of the colon, pancreas, breast, brain, ovary, lungs, and skin (Judith S. Sebolt-Leopold and Roman Herrera, Nature Reviews Cancer, Vol. 4, 2004, 937-947; Hidesuke Fukazawa et al., Molecular Cancer Therapeutics, Vol. 1 , 303-309, March 2002) . Activation of Ras (due to upstream signalling or as a result of activating point mutations in the Ras oncogene) lead to the phosphorylation and activation of Raf kinase that in turn phosphorylate and activate MEK kinase. MEK1 /2 kinase phosphorylates and activates the ERK1 /2 kinase (also referred to as MAP Kinase) that further phosphorylates and regulates the function of proteins such as Mcl- l , Bim and Bad that are involved in cell survival and apoptosis. Thus, activation of this phosphorylation mediated cascade leads to enhanced cell proliferation, cell survival, and decreased cell death that are necessary for initiation and maintenance of the tumorigenic phenotype (James A McCubrey et al., Current Opinion in Investigational Drugs, 2008, 9(6) , 614-630).

[6] The Ras-Raf-MEK-ERK cascade plays a pivotal role in survival and proliferation of cancer cells. As such, inhibition of this pathway at any of these levels would lead to the inhibition of cancer cell growth, proliferation, and survival. Indeed, it has already been reported that inhibition of Ras or Raf leads to inhibition of tumor growth in animal models as well as in cancer patients. However, the success with these inhibitors has been limited to only certain types of cancers (e.g. Sorafenib which inhibits Raf kinase has been approved for renal cell carcinoma). Hence, 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.

[7] The MEK-ERK pathway is activated in numerous inflammatory conditions (John M. Kyriakis and Joseph Avruch, The Journal of Biological Chemistry, Vol. 271 , No. 40, pp. 24313-24316, 1995; Deepa R. Hammaker et al., The Journal of Immunology, 2004, 172, 1612- 1618) including rheumatoid arthritis, inflammatory bowel disease, and COPD. MEK regulates the biosynthesis of the inflammatory cytokines TNF, IL-6, and IL- 1. It has been shown that MEK inhibitors interfere with the production/ secretion of these cytokines. Array BioPharma has developed a frrst-in-class MEK inhibitor (ARRY 438162) and initiated clinical trials in rheumatoid arthritis (RA) patients.

[8] International patent applications WO 2003/053960, WO 2005/023251 , WO 2005/ 121 142, WO 2005/051906, and WO 2010/ 121646 describe MEK inhibitors. BRIEF SUMMARY OF THE INVENTION

[9] The present invention provides anticancer compound of the general formula (I) , its pharmaceutically acceptable salt, its combinations with suitable medicaments, pharmaceutical compositions containing one or more such compounds, and uses thereof in treating various cancers,

wherein R¹ to R⁵ are described in detail below.

[ 10] The compounds of the present inventions are potent inhibitors of MEK and show tumor regression effect with less side effects.

DETAILED DESCRIPTION OF THE INVENTION

[ 1 1] The present invention relates to heterocyclyl compound of formula (I) , its pharmaceutically acceptable salt, its combinations with suitable medicaments, and pharmaceutical compositions thereof. The present invention also includes processes of preparation of the compounds and their use in methods of treatment. A compound of formula (I) is

wherein:

R¹ is selected from hydrogen and substituted- or unsubstituted- alkyl;

R² is selected from -S0₂R⁶ and -NHSO2R⁷; R³ and R⁴ are independently selected from hydrogen and substituted- or unsubstituted- alkyl;

R⁵ is substituted- or unsubstituted- aryl; R⁶ is selected from: a) substituted- or unsubstituted- four membered heterocyclic group; b) cycloalkyl substituted with haloalkyl, hydroxyalkyl, and alkoxyalkyl; and c) -(CR^aR^b)C(=0)NR^cR^d, wherein R^a, R^b, R^c, and R^d are each independently selected from the group consisting of hydrogen and substituted- or unsubstituted- alkyl, or R^a and R^b together with the carbon atom to which they are attached form a cyclopropyl ring; R⁷ is cycloalkyl substituted with haloalkyl, hydroxyalkyl, and alkoxyalkyl; when the alkyl group is substituted, it is substituted with 1 to 3 substituents independently selected from oxo, halogen, nitro, cyano, perhaloalkyl, -S02R^8a, - C(=0)OR^8a, -OC(=0)R^8a, -C(=0)N(H)R⁸, -OR^8b, -C(=0)N(alkyl)R⁸, -N(H)C(=0)R^8a, - N(H)R⁸, -N(alkyl)R8, and -NH-S0₂-alkyl; when the aryl group is substituted, it is substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, hydroxy, alkyl, perhaloalkyl, - O-alkyl, -O-perhaloalkyl, -N (alkyl) alkyl, -N(H)alkyl, -NH₂, -S0₂-alkyl, -S0₂- perhaloalkyl, -S0₂N (alkyl) alkyl, -S0₂N(H) alkyl, and -S0₂NH₂; when the heterocyclic group is substituted, it is substituted either on a ring carbon atom(s) or on a ring nitrogen atom; when heterocyclic group substituted on a ring carbon atom(s), it is substituted with 1 or 2 substituents independently selected from halogen, nitro, cyano, oxo, alkyl, perhaloalkyl, -OR^8b, -C(=0)OR^8a, - C(=0)N(H)R⁸, and N(H)R⁸; and when heterocylic group substituted on a ring nitrogen, it is substituted with a substituent selected from alkyl, cycloalkyl, aryl, -S0₂R⁸S

and -C(=0)N(H)R⁸;

R⁸ is selected from hydrogen, alkyl, and cycloalkyl;

R^8a is selected from alkyl, perhaloalkyl, and cycloalkyl; and

R^8b is selected from the group consisting of hydrogen, alkyl, perhaloalkyl, and cycloalkyl.

[ 12] In certain embodiments, R³ and R⁴ are independently substituted- or unsubstituted- alkyl.

[ 13] In preferred embodiments, R³ and R⁴ are methyl.

[ 14] In certain embodiments, R⁵ is substituted- or unsubstituted- phenyl. [ 15] In one embodiment, the present invention is a compound of formula (la) : j^5a

O HIsT wherein:

R^la is selected from hydrogen and methyl; R^2a is selected from

R^3a and R^4a are methyl; and

R^5a is 2-fluoro-4-iodobenzene.

[ 16] Whenever a range of the number of atoms in a structure is indicated (e.g., a Ci-12, Ci-8, Ci-6, or Ci-4 alkyl, alkylamino, etc.) , it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used. Thus, for instance, the recitation of a range of 1-8 carbon atoms (e.g., Ci-Cs) , 1-6 carbon atoms (e.g., C1-C6) , 1-4 carbon atoms (e.g. , C1-C4) , 1-3 carbon atoms (e.g., C1-C3) , or 2-8 carbon atoms (e.g., C2-C8) as used with respect to any chemical group (e.g., alkyl, alkylamino, etc.) referenced herein encompasses and specifically describes 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , and/or 12 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1- 10 carbon atoms, 1- 1 1 carbon atoms, 1- 12 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 2-9 carbon atoms, 2- 10 carbon atoms, 2- 1 1 carbon atoms, 2- 12 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 3-9 carbon atoms, 3- 10 carbon atoms, 3- 1 1 carbon atoms, 3- 12 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, 4-9 carbon atoms, 4- 10 carbon atoms, 4- 1 1 carbon atoms, and/or 4- 12 carbon atoms, etc., as appropriate). [ 17] 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 of the term per se.

[ 18] The term "alkyl", as used herein, means a straight or branched hydrocarbyl chain containing from 1 to 20 carbon atoms. Preferably, the alkyl group contains 1 to 10 carbon atoms. More preferably, alkyl group contains up to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl. [ 19] When the alkyl group is substituted, it is substituted with 1 to 3 substituents independently selected from oxo, halogen, nitro, cyano, perhaloalkyl, -S0₂R^8a, -C(=0)OR^8a, -OC(=0)R^8a, -C(=0)N(H)R⁸, -OR^Sb, - C(=0)N(alkyl)R⁸, -N(H)C(=0)R^8a, -N(H)R⁸, -N(alkyl)R⁸, and -NH-S0₂-alkyl.

[20] The term "haloalkyl" as used herein, means both branched and straight chain alkyl substituted with one or more halogen, wherein the alkyl group is as herein described.

[21] The term "halogen" means fluorine, chlorine, bromine, or iodine.

[22] The term "hydroxyalkyl" as used herein, means an alkyl group in which one or more hydrogens has been replaced with a hydroxyl group, wherein the alkyl group is as herein described.

[23] The term "alkoxy" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. [24] The term "alkoxyalkyl" as used herein, means an alkoxy group, as defined herein, appendd to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.

[25] The term "perhaloalkyl" as used herein, means an alkyl group, as defined herein, in which all the hydrogen atoms are replaced with a halogen atom. [26] The term "cycloalkyl" as used herein, means a monocyclic, bicyclic, or tricyclic non-aromatic ring system containing from 3 to 14 carbon atoms. Preferably, the cycloalkyl group is a monocyclic, non-aromatic ring containing 3 to 6 carbon atoms. Examples of monocyclic, non-aromatic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic, non-aromatic ring systems include a monocyclic, non-aromatic ring fused across a bond with another cyclic system which may be an alicyclic ring or an aromatic ring. Bicyclic, non-aromatic rings systems also include spirocyclic systems wherein the second ring gets annulated on a single carbon atom. Bicyclic, non-aromatic ring systems are also exemplified by a bridged monocyclic, non-aromatic ring system in which two non-adjacent carbon atoms of the monocyclic, non-aromatic ring are linked by a bond or an alkylene bridge having 1 to 4 methylene units joining the two non-adjacent carbon atoms. Examples of bicyclic, non-aromatic ring systems include, but are not limited to, bicyclo[3. 1. l]heptane, bicyclo[2.2. ljheptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3. ljnonane, bicyclo[4.2. ljnonane, bicyclo[3.3.2]decane, bicyclo[3. 1.OJhexane, bicyclo[4. 1.OJheptane, bicyclo[3.2.0]heptane, octahydro- lH-indene, spiro[2.5]octane, and spiro[4.5]decane. Tricyclic, non-aromatic ring systems include bicyclic, non- aromatic systems as described herein further annulated with an alicyclic third ring, which may be alicyclic ring or aromatic ring. Tricyclic, non-aromatic ring systems are also exemplified by a bicyclic, non-aromatic ring system in which two non-adjacent carbon atoms of the bicyclic, non-aromatic ring system are linked by a bond or an alkylene bridge having 1 to 4 methylene units joining the two non-adjacent carbon atoms. Examples of tricyclic, non-aromatic ring systems include, but are not limited to, tricyclo[3.3. 1.0^{3 7}]nonane, tricyclo[3.3. 1. I^{3 7}]decane (adamantane) , spiro[bicyclo[4. 1.0]heptane-2, Γ- cyclopentane] , and hexahydro-2'H-spiro[cyclopropane- 1 , 1 '-pentalene] .

[27] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon ring system having 6 to 20 carbon atoms. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. Aryl group also includes partially saturated bicyclic and tricyclic aromatic hydrocarbons such as tetrahydro-naphthalene.

[28] When the aryl group is a substituted aryl group, it is substituted with 1 to 3 substituents selected independently from halogen, nitro, cyano, hydroxy, alkyl, perhaloalkyl, -O-alkyl, -O-perhaloalkyl, -N (alkyl) alkyl, -N(H)alkyl, -NH₂, -S0₂- alkyl, -S0₂-perhaloalkyl, -S0₂N (alkyl) alkyl, -S0₂N(H)alkyl, and -S0₂NH₂.

[29] The term "heteroaryl" refers to a 5- 14 membered monocyclic, bicyclic, or tricyclic ring system having 1-4 ring heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon (with appropriate hydrogen atoms unless otherwise indicated), wherein at least one ring in the ring system is aromatic. Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1 , 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent. Examples of heteroaryl groups include, but not limited to pyridyl, 1-oxo-pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl. triazolyl, thiadiazolyl, isoquinolinyl, benzoxazolyl, benzofuranyl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, and benzo(b)thienyl, 2,3-thiadiazolyl, lH-pyrazolo[5, 1- c]- l ,2,4-triazolyl, pyrrolo[3,4-d]- l ,2,3-triazolyl, cyclopentatriazolyl, 3H- pyrrolo[3,4-c] isoxazolyl, 2,3-dihydro-benzo[ l ,4]dioxin-6-yl, 2,3-dihydro- benzo[ 1 ,4]dioxin-5-yl, 2,3-dihydro-benzofuran-5-yl, 2,3-dihydro-benzofuran-4-yl, 2,3-dihydro-benzofuran-6-yl, 2,3-dihydro-benzofuran-6-yl, 2,3-dihydro- lH-indol- 5-yl, 2,3-dihydro- lH-indol-4-yl, 2,3-dihydro- lH-indol-6-yl, 2,3-dihydro- lH-indol- 7-yl, benzo[ l ,3]dioxol-4-yl, benzo[ l ,3]dioxol-5-yl, 1 ,2,3,4-tetrahydroquinolinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, 2,3-dihydrobenzothien-4-yl, 2-oxoindolin-5-yl, and the like.

[30] The term "heterocyclic" or "heterocyclyl" as used herein, means a "cycloalkyl" group wherein one or more of the carbon atoms is independently replaced by -0-, -S-, -S(0₂)-, -S(O)-, -N(R^m)-, or -Si(R^m)Rⁿ-, wherein R^m and Rⁿ are independently selected from hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl. The heterocycle may be connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocycle. [31] When the heterocyclic group is substituted, it is substituted either on a ring carbon atom(s) or on a ring nitrogen atom; when heterocyclic group substituted on a ring carbon atom(s), it is substituted with 1 or 2 substituents independently selected from halogen, nitro, cyano, oxo, alkyl, perhaloalkyl, -OR^8b, -C(=0)OR^8a, - C(=0)N(H)R⁸, and N(H)R⁸; and when heterocylic group substituted on a ring nitrogen, it is substituted with a substituent selected from alkyl, cycloalkyl, aryl, -S0₂R^8a, -C(=0)R⁸*, -C(=0)OR^8a, and -C(=0)N(H)R⁸.

[32] The term "cyano", as used herein, means the group -CN.

[33] The term "hydroxy", as used herein, means the group -OH.

[34] The term "nitro", as used herein, means the group -NO₂. [35] The term "oxo" means a divalent oxygen (=0) attached to the parent group. For example oxo attached to carbon forms a carbonyl, oxo substituted on cyclohexane forms a cyclohexanone, and the like.

[36] The term "annulated" means the ring system under consideration is either annulated with another ring at a carbon atom of the cyclic system or across a bond of the cyclic system as in the case of fused or spiro ring systems. [37] The term "bridged" means the ring system under consideration contain an alkylene bridge having 1 to 4 methylene units joining two non adjacent ring atoms.

[38] It should be understood that the compounds of formula (I) and (la) structurally encompass all stereoisomers, tautomers, and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.

[39] A compound, its stereoisomer, racemate, tautomer, and pharmaceutically acceptable salt thereof as described hereinabove wherein the compounds of general formula (I) and (la) can be selected from the group consisting of:

[40] 5-((2-fluoro-4-iodophenyl)amino)- l-(3-(( l-

(fluoromethyl)cyclopropyl)sulfonyl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidine- 2,4,7( lH,3H,6H)-trione (Compound 1),

[41] 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- 1 (2H)-yl)phenyl)sulfonyl)acetamide (Compound 2) ,

[42] 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido [4 , 3- d] pyrimidin- 1 (2 H) -yl) phenyl) sulfonyl) - N , N , 2 - trimethylpropanamide (Compound 3) ,

[43] 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- 1 (2H)-yl)phenyl)sulfonyl)acetamide (Compound 4) ,

[44] 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- l (2H)-yl)phenyl)sulfonyl)propanamide

(Compound 5), [45] l-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- 1 (2H)- yl) phenyl) sulfonyl) cyclopropanecarboxamide (Compound 6) ,

[46] 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido [4 , 3-d] pyrimidin- 1 (2H) -yl) phenyl) sulfonyl) -N-methylpropanamide (Compound 7),

[47] 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido [4 , 3- d] pyrimidin- 1 (2 H) -yl) phenyl) sulfonyl) - N , 2 - dimethylpropanamide (Compound 8),

[48] 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido [4 , 3-d] pyrimidin- 1 (2H) -yl) phenyl) sulfonyl) -2-methylpropan amide (Compound 9),

[49] 5-((2-fluoro-4-iodophenyl)amino)- l-(3-(( l-

(hydr oxymethyl) cyclopr opyl) sulfonyl) phenyl) -6,8- dimethylpyrido [4 , 3- d] pyrimidine- 2,4,7( lH,3H,6H)-trione (Compound 10) ,

[50] l-(3-(azetidin-3-ylsulfonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8- dimethylpyrido[4,3-d]pyrimidine-2,4,7( lH,3H,6H)-trione (Compound 1 1) ,

[51] 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido [4 , 3- d] pyrimidin- 1 (2 H) -yl) phenyl) sulfonyl) - N , N- dimethylpropanamide (Compound 12) ,

[52] N-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- 1 (2H)-yl)phenyl)- 1- (hydroxymethyl) cyclopropane- 1- sulfonamide (Compound 13) ,

[53] N-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- 1 (2H)-yl)phenyl)- l-(fluoromethyl)cyclopropane- 1-sulfonamide (Compound 14), [54] N-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- 1 (2H)-yl)phenyl)- 1- (methoxymethyl) cyclopropane- 1- sulfonamide (Compound 15) , and

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

(hydroxymethyl) cyclopropane- 1- sulfonamide (Compound 16) .

[56] The present disclosure provides a method for inhibiting MEK enzyme comprising, contacting said MEK enzyme with a composition comprising a compound of general formula (I) or (la) , its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof, in an amount sufficient to inhibit said enzyme, wherein said enzyme inhibits MEK kinase and said contacting occurs within a cell.

[57] The invention also provides a method of treatment or prevention of a MEK mediated disorder in a subject suffering from said disorder, comprising administering to said subject an effective amount of a composition comprising a compound of general formula (I) or (la) , its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof. The method of treatment may also be combined with an additional therapy such as radiation therapy, chemotherapy, or combination thereof. [58] MEK mediated disorders, as stated above, include inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorder, neurological disorders, fibrogenetic disorders, proliferative disorders, hyperproliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases, and malignant diseases. [59] The invention further provides a method for the treatment or prophylaxis of a proliferative disease in a subject suffering from said disease, comprising administering to said subject an effective amount of a composition comprising a compound of formula (I) or (la) , its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof. The proliferative disease includes cancer, psoriasis, restenosis, autoimmune disease, or atherosclerosis.

[60] The invention also provides a method for the treatment or prophylaxis of an inflammatory disease in a subject suffering from said disease, comprising administering to said subject an effective amount of a composition comprising a compound of formula (I) or (la) , its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof. The inflammatory disease includes rheumatoid arthritis or multiple sclerosis.

[61 ] The invention also provides a method for degrading, inhibiting the growth of, or killing cancer cells, comprising contacting the cells with an amount of a composition effective to degrade, inhibit the growth of, or kill the cancer cells, the composition comprising a compound of formula (I) or (la), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof.

[62] The invention also provides a method of inhibiting tumor size increase, reducing the size of a tumor, reducing tumor proliferation or preventing tumor proliferation in a subject in need thereof, comprising administering to said subject an effective amount of a composition to inhibit tumor size increase, reduce the size of a tumor, reduce tumor proliferation, or prevent tumor proliferation, the composition comprising a compound of formula (I) or (la) , its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof.

[63] The MEK-ERK pathway is activated in numerous inflammatory conditions (John M. Kyriakis and Joseph Avruch, The Journal of Biological Chemistry, Vol. 271 , No. 40, pp. 24313-24316, 1996; Deepa R. Hammaker et al., The Journal of Immunology, 2004, 172: 1612- 1618), including rheumatoid arthritis, inflammatory bowel disease and COPD.

[64] The present invention describes the inhibitors of MEK kinase for treatment of disorders that are driven by hyperactivation, abnormal activation, constitutive activation, or gain-of- function mutation of the MEK kinase and/or its substrate kinases that include, but are not limited to, ERK. Such disorders encompass hyperproliferative disorders that include but are not limited to psoriasis, keloids, hyperplasia of the skin, benign prostatic hyperplasia (BPH) , and solid tumors such as cancers of the respiratory tract (including, but not limited to, small cell and non-small cell lung carcinomas) , brain (including, but not limited to, glioma, meduUoblastoma, ependymoma, neuroectodermal, and pineal tumors) , breast (including, but not limited to, invasive ductal carcinoma, invasive lobular carcinoma, and ductal- and lobular carcinoma in situ) , reproductive organs (including, but not limited to, prostate cancer, testicular cancer, ovarian cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, and sarcoma of the uterus) , digestive tract (including, but not limited to, esophageal, colon, colorectal, gastric, gall blabber, pancreatic, rectal, anal, small intestine, and salivary gland cancers) , urinary tract (including, but not limited to, bladder, ureter, kidney, renal, urethral, and papillary renal cancers), eye (including, but not limited to, intraocular melanoma, and retinoblastoma) , liver (including, but not limited to, hepatocellular carcinoma, and cholangiocarcinoma) , skin (including, but not limited to, melanoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, and non-melanoma skin cancer), head and neck (including, but not limited to, laryngeal, nasopharyngeal, hypopharyngeal, oropharyngeal cancer, lip and oral cavity cancer, and squamous cell cancer) , thyroid, parathyroid, and their metastases. The hyperproliferative disorders also include leukemias (including, but not limited to, acute lymphoblastic leukemia, acute myeloid leukemia, chronic melogenous leukemia, chronic lymphocytic leukemia, and hairy cell leukemia) , sarcomas (including, but not limited to, soft tissue sarcoma, osteosarcoma, lymphosarcoma, and rhabdomyosarcoma) , and lymphomas (including, but not limited to, non-Hodgkin's lymphoma, AIDS- related lymphoma, cutaneous T cell lymphoma, Burkitt's lymphoma, Hodgkin's disease, and lymphoma of the central nervous system) .

[65] The present invention describes the inhibitors of MEK kinase for treatment of certain disorders involving aberrant regulation of the mitogen extracellular kinase activity including, but not limited to, hepatomegaly, heart failure, cardiomegaly, diabetes, stroke, Alzheimer's disease, cystic fibrosis, septic shock, and asthma.

[66] The present invention describes the inhibitors of MEK kinase for treatment of diseases and disorders associated with aberrant, abnormal and/or excessive angiogenesis. Such disorders associated with angiogenesis include but are not limited to, tumor growth and metastases, ischemic retinal vein occlusion, diabetic retinopathy, macular degeneration, neovascular glaucoma, psoriasis, inflammation, rheumatoid arthritis, vascular graft restenosis, restenosis, and in- stent restenosis. [67] The compounds mentioned in this invention can be used as a single (sole) therapeutic agent or in combination with other active agents, including, but not limited to, chemotherapeutic agents and anti-inflammatory agents. Such combinations include, but are not limited to, combining the MEK kinase inhibitors with anti-mitotic agents, anti-antiangiogenic agents, alkylating agents, anti-hyperproliferative agents, antimetabolites, DNA-intercalating agents, cell cycle inhibitors, kinase inhibitors, growth factor inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, and anti-hormones.

[68] The inhibitors mentioned in the present invention can be combined with anti-inflammatory agents or agents that show therapeutic benefit for conditions including, but not limited to, hepatomegaly, heart failure, cardiomegaly, diabetes, stroke, Alzheimer's disease, cystic fibrosis, septic shock or asthma, diabetic retinopathy, ischemic retinal vein occlusion, macular degeneration, neovascular glaucoma, psoriasis, inflammation, rheumatoid arthritis, restenosis, in-stent restenosis, and vascular graft restenosis. [69] The term "aberrant regulation of the mitogen extracellular kinase activity" refers to any abnormal expression or activity of the gene encoding the kinase or of the polypeptide it encodes. Examples of such aberrant regulation of the mitogen extracellular kinase activity include, but are not limited to, over-expression of the gene or polypeptide, gene amplification, mutations that produce constitutively active or hyperactive kinase activity, gene mutations, deletions, substitutions, additions, and the like.

[70] Thus the present invention further provides a pharmaceutical composition, comprising a compound of the formula (I) or (la) , its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier, diluent, or excipient.

[71 ] The pharmaceutically acceptable carrier or excipient is preferably one that is chemically inert to the compound of the invention and one that has no detrimental side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers or excipients include saline (e.g., 0.9% saline), Cremophor EL (which is a derivative of castor oil and ethylene oxide available from Sigma Chemical Co., St. Louis, MO) (e.g., 5% Cremophor EL/ 5% ethanol/90% saline, 10% Cremophor EL/90% saline, or 50% Cremophor EL/50% ethanol), propylene glycol (e.g. , 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 particularly a composition comprising 40% PEG 400 and 60% water or saline. The choice of carrier will be determined in part by the particular compound chosen, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention.

[72] The following formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, rectal, and vaginal administration are merely exemplary and are in no way limiting. [73] The pharmaceutical compositions can be administered parenterally, e.g., intravenously, intraarterially, subcutaneously, intradermally, intrathecally, or intramuscularly. Thus, the invention provides compositions for parenteral administration that comprises a solution of the compound of the invention dissolved or suspended in an acceptable carrier suitable for parenteral administration, including aqueous and non-aqueous, isotonic sterile injection solutions.

[74] Overall, the requirements for effective pharmaceutical carriers for parenteral compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J. B. Lippincott Company, Philadelphia, Banker and Chalmers, pages 238-250 ( 1982) , and ASHP Handbook on Injectable Drugs, 4^th ed. , Lawrence A. Trissel, pages 622-630 ( 1986). Such compositions include solutions containing an ti- oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol (for example in topical applications), or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, dimethylsulfoxide, glycerol ketals, such as 2,2-dimethyl- l ,3-dioxolane-4-methanol, ethers, such as polyfethyleneglyco 1)400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.

[75] Oils useful in parenteral formulations include petroleum, animal, vegetable, and synthetic oils. Specific examples of oils useful in such formulations include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral oil. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. [76] Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl^-aminopropionates, 2-alkyl- imidazoline quaternary ammonium salts, and (e) mixtures thereof. [77] The parenteral formulations typically will contain from about 0.5% or less to about 25% or more by weight of a compound of the invention in solution. Preservatives and buffers can be used. In order to minimize or eliminate irritation at the site of injection, such compositions can contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules or vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets. [78] Topical formulations, including those that are useful for transdermal drug release, are well known to those of skill in the art and are suitable in the context of the present invention for application to skin.

[79] Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of a compound of the invention dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a pre-determined amount of a compound of the invention, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations can include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients. Lozenge forms can comprise the compound ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising a compound of the invention in an inert base, such as gelatin and glycerin, or sucrose and acacia. Lozenge forms can also comprise emulsions, gels, and the like containing, in addition to a compound of the invention, such excipients as are known in the art.

[80] A compound of the present invention, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. A compound or epimer of the invention is preferably supplied in finely divided form along with a surfactant and propellant. Typical percentages of the compound of the invention can be about 0.01% to about 20% by weight, preferably about 1% to about 10% by weight. The surfactant must, of course, be nontoxic, and preferably soluble in the propellant. Representative of such surfactants are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric, and oleic acids, with an aliphatic polyhydric alcohol or its cyclic anhydride. Mixed esters, such as mixed or natural glycerides can be employed. The surfactant can constitute from about 0. 1% to about 20% by weight of the composition, preferably from about 0.25% to about 5%. The balance of the composition is ordinarily propellant. A carrier can also be included as desired, e.g., lecithin, for intranasal delivery. These aerosol formulations can be placed into acceptable pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer. Such spray formulations can be used to spray mucosa.

[81] Additionally, a compound of the invention can be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the compound ingredient, such carriers as are known in the art to be appropriate. [82] The concentration of a compound in the pharmaceutical formulations can vary, e.g., from less than about 1% to about 10%, to as much as about 20% to about 50% or more by weight, and can be selected primarily by fluid volumes, and viscosities, in accordance with the particular mode of administration selected. [83] For example, a typical pharmaceutical composition for intravenous infusion could be made up to contain 250 ml of sterile Ringer's solution, and 100 mg of at least one compound of the invention. Actual methods for preparing parenterally administrable compounds of the invention will be known or apparent to those skilled in the art and are described in more detail in, for example, Remington's Pharmaceutical Science ( 17^th ed., Mack Publishing Company, Easton, PA, 1985).

[84] It will be appreciated 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 an inclusion complexe, such as a cyclodextrin inclusion complexe, or a liposome. Liposomes can serve to target a compound of the invention to a particular tissue, such as lymphoid tissue or cancerous hepatic cells. Liposomes can also be used to increase the half-life of a compound of the invention. Many methods are available for preparing liposomes, as described in, for example, Francis Szoka et al., Ann. Rev. Biophys. Bioeng., 1980, 9, 467-508 and U.S. Patents 4,235,871 ; 4,501 ,728; 4,837,028; and 5,019,369.

[85] The compounds of the invention can be administered in a dose sufficient to treat the disease, condition, or disorder. Such doses are known in the art (see, for example, the Physicians' Desk Reference, 58^th Edition, 2004). The compounds can be administered using techniques such as those described in, for example, Todd H. Wasserman et al., Cancer, 36: 1258- 1268, 1975 and Physicians' Desk Reference, 58^th ed. , Thomson PDR (2004).

[86] Suitable doses and dosage regimens can be determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of a compound of the present invention. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. The methods disclosed herein can involve the administration of about 0. 1 ig to about 50 mg of at least one compound of the invention per kg body weight of the subject. For a 70 kg patient, dosages of from about 10 ig to about 200 mg of the compound of the invention would be more commonly used, depending on a patient's physiological response.

[87] By way of example and not intended as limiting, 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, about 0.002 mg, about 0.005 mg, about 0.010 mg, about 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0. 1 mg, about 0. 15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg/kg body weight per day. The dose of the pharmaceutically active agent(s) described herein can be about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 0.020 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg/kg body weight per day. [88] The terms "treat," "prevent," "ameliorate," and "inhibit," as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disease or disorder in a subject (e.g. a mammal) . For example, a disease or disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, prevention, amelioration, or inhibition provided by the inventive method can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disease or disorder, e.g., cancer. Also, for purposes herein, "treatment," "prevention," "amelioration," or "inhibition" can encompass delaying the onset of the disease or disorder, or a symptom or condition thereof.

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

General Method of preparation [90] A compound of formula (I) where R^x-R⁵ are as defined earlier can be prepared by the exemplary methods given in below schemes 1 , 2, and 3 or the examples illustrated herein below.

[91] However, the disclosure should not be construed to limit the scope of the invention arriving at compound of formula (I) disclosed hereinabove.

Scheme 1:

[92] A compound of formula (I) where R¹ is hydrogen and R²-R⁵ are as defined herein, can be prepared by following the process depicted in Scheme 1.

cheme

[93] A compound of formula (II), where R¹ is a N-protecting group, Z is any suitable leaving group like CI, Br, I, -0(SO)₂(4-MePh), -0(SO)₂CH₃, -0(SO)₂CF₃ etc., and R³-R⁵ are as defined herein, can be converted to a compound of formula (III) , by reacting a compound of formula (II) with corresponding aniline in the presence of a suitable base like 2,6-Lutidine, l ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), K2CO3, Cs₂C0₃, NaH, KH, n-BuLi, lithium bis(trimethylsilyl)amide (LiHMDS) etc., in a solvent like THF, DMF, DMSO etc., at a temperature ranging from about -78°C to about 150°C. A compound of formula (II) can be prepared by following the chemistry disclosed in WO 2005/ 121 142.

[94] A compound of formula (III) , where R¹ is a N-protecting group and R²-R⁵ are as defined herein, can be converted to a compound of formula (IV) , wherein R¹ is a N-protecting group and R²-R⁵ are as defined herein, by reacting a compound of formula (III) with a suitable base such as NaOMe, K₂CO3 etc., in a solvent like Methanol, Ethanol, THF, DMF etc. , at a temperature ranging from about -78°C to about 150°C.

[95] A compound of formula (IV) , where R¹ is a N-protecting group and R²-R⁵ are as defined herein, can be converted to a compound of formula (I), where R¹ is hydrogen and R²-R⁵ are as defined herein, by reacting a compound of formula (IV) with a suitable N-deprotection agent such as AICI3, Pd-C/ H2 etc. , in a solvent like Anisole, Toluene, Xylene, THF, DMF, DMSO etc., at a temperature ranging from about -78°C to about 150°C.

Scheme 2: [96] A compound of formula (I) , where R¹ is substituted- or unsubstituted- alkyl and R²-R⁵ are as defomed herein, can be prepared by following the process depicted in Scheme 2.

[97] A compound of formula (lb) , where R¹ is H and R²-R⁵ are as defined herein, can be converted to a compound of formula (I) , where R¹ is substituted- or unsubstituted- alkyl and R²-R⁵ are as defined herein, by reacting a compound of formula (lb) with R^XZ, wherein R¹ is H and Z is any suitable leaving group like CI, Br, I, -0(SO)₂(4-MePh), -0(SO)₂CH₃, -0(SO)₂CF₃ etc. , in presence of a suitable base like 2,6-Lutidine, l ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) , K₂CO3, Cs₂CC NaH, KH, n-BuLi, lithium bis (trimethylsilyl) amide (LiHMDS) etc., in a solvent like THF, DMF, DMSO etc., at a temperature ranging from about -78°C to about 150°C.

Scheme 3: [98] A compound of formula (I) , where R¹ is substituted- or unsubstituted- alkyl and R²-R⁵ are as defined herein, can be prepared by following the process depicted in Scheme 3.

Scheme 3

[99] A compound of formula (II), where R¹ is substituted- or unsubstituted- alkyl, Z is any suitable leaving group like CI, Br, I, -0(SO)₂(4-MePh) , -0(SO)₂CH₃, - 0(SO)₂CF3 etc., and R³-R⁵ are as defined herein, can be converted to compound of formula (III), where R¹ is substituted- or unsubstituted- alkyl and R²-R⁵ are as defined herein, by reacting compound of formula (II) with corresponding aniline in presence of a suitable base like 2,6-Lutidine, l ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), K2CO3, Cs₂C0₃, NaH, KH, n-BuLi, lithium bis(trimethylsilyl)amide (LiHMDS) etc., in a solvent like THF, DMF, DM SO, and the like, at a temperature ranging from about -78°C to about 150°C.

[ 100] A compound of formula (III) , where R¹ is substituted- or unsubstituted- alkyl and R²-R⁵ are as defined herein, can be converted to a compound of formula (I), where R¹ is substituted- or unsubstituted- alkyl and R²- R⁵ are as defined herein, by reacting a compound of formula (III) with a suitable base such as NaOMe, K₂CO3 etc., in a solvent like Methanol, Ethanol, THF, DMF etc., at a temperature ranging from about -78°C to about 150°C.

[ 101] The intermediates and the compounds of the present invention are obtained in pure form in a manner known per se, for example by distilling off the solvent in vacuum and re-crystallizing the residue obtained from a suitable solvent, such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone, or their combinations or subjecting it to one of the purification methods, such as column chromatography (e.g. flash chromatography) on a suitable support material such as alumina or silica gel using eluent such as dichloromethane, ethyl acetate, hexane, methanol, acetone, and their combinations. Preparative LC-MS method may also be used for the purification of compounds described herein.

[ 102] Salts of a compound of formula (I) or (la) can be obtained by dissolving the compound in a suitable solvent, for example, in a chlorinated hydrocarbon, such as methyl chloride or chloroform, or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol, which is then treated with the desired acid or base as described in Stephen M. Berge et al., "Pharmaceutical Salts, a review article in Journal of Pharmaceutical Sciences, vol. 66, No. 1 , page 1- 19, 1977" and in Handbook of Pharmaceutical Salts, Properties, Selection, and Use by P. Heinrich Stahl and Camille G. Wermuth, Wiley- VCH (2002) . Lists of suitable salts can also be found in Remington'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 salt can be of an alkali metal (e.g., sodium or potassium), an alkaline earth metal (e.g., calcium), or ammonium. [ 103] A compound of the invention or a composition thereof can potentially be administered as a pharmaceutically acceptable acid- addition, base neutralized or addition salt, formed by reaction with inorganic acids, such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base, such as sodium hydroxide or potassium hydroxide. The conversion to a salt is accomplished by treatment of the base compound with at least a stoichiometric amount of an appropriate acid. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol, methanol, and the like, and the acid is added in a similar solvent. The mixture is maintained at a suitable temperature (e.g., between 0°C and 50°C). The resulting salt precipitates spontaneously or can be brought out of solution with a less polar solvent. [ 104] The stereoisomers of a compound of formula (I) or (la) of the present invention may be prepared by stereo specific syntheses or resolution of the achiral compound using an optically active amine, acid or complex forming agent, and separating the diastereomeric salt/ complex by fractional crystallization or by column chromatography. [ 105] A compound of formula (I) or (la) of the present invention can exist in tautomeric forms, such as keto-enol tautomers. Such tautomeric forms are contemplated as an objective of this invention and such tautomers may be in equilibrium or predominant in one of the forms.

[ 106] Prodrugs can be prepared in situ during the isolation and purification of a compound, or by separately reacting a purified compound with a suitable derivatizing agent. For example, hydroxy groups can be converted into esters via treatment with a carboxylic acid in the presence of a catalyst. Examples of cleavable alcohol prodrug moieties include substituted or unsubstituted, branched or unbranched lower alkyl ester moieties, e.g., ethyl esters, lower alkenyl esters, di-lower alkylamino lower- alkyl esters, e.g., dimethylaminoethyl ester, acylamino lower alkyl esters, acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester) , aryl esters, e.g., phenyl ester, aryl- lower alkyl esters, e.g., benzyl ester, substituted- or unsubstituted-, e.g., with methyl, halo, or methoxy substituents aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy amides.

[ 107] The term "prodrug" as used herein, denotes a derivative of a compound, which derivative, when administered to warm-blooded animals, e.g. humans, is converted into the compound (drug). The enzymatic and/ or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a manner that the proven drug form is released, and the moiety or moieties split off remain nontoxic or are metabolized so that nontoxic metabolic products are produced.

Examples [ 108] The following examples are provided to further illustrate the present invention and therefore should not be construed in any way to limit the scope of the present invention. All ^XHNMR spectra were determined in the solvents indicated and chemical shifts are reported in δ units downfield from the internal standard tetramethylsilane (TMS) and interproton coupling constants are reported in Hertz (Hz) .

[ 109] Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers, drying the organic layer over sodium sulphate, filtration, and evaporation of the solvent. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, generally using a mobile phase with suitable polarity. The following abbreviations are used in the text: DMSO-d6: Hexadeuterodimethyl sulfoxide; DMSO: Dimethylsulfoxide, DMF: N,N- dimethyl formamide, DMA: Dimethylacetamide, TFA: Trifluoroacetic acid, THF: Tetrahydrofuran, DCM: Dichloromethane, EDC: l-Ethyl-3-(3- dimethylaminopropyljcarbodiimide, Boc: tert-butoxycarbonyl, Bn: benzyl, Ts: tosyl, Tf: trifluoromethanesulfonyl, DIPEA: Ν,Ν-Diisopropyl ethyl amine, HOBT: 1-Hydroxy- lH-benzotriazole, PMB: p-methoxybenzyl, DAST: Diethylamino sulfur trifluoride, PyBOP: (benzotriazol- 1-yl-oxytripyrrolidinophosphonium hexafluorophosphate) , J: Coupling constant in units of Hz, and hr. or h: hour(s). [ HO] The term "room temperature" denotes any temperature ranging between about 20°C to about 40°C, unless it is specifically mentioned as otherwise. [ 1 1 1] The following examples demonstrate preparation of representative compounds embodied in formula (I) ; however, the same should not be construed as limiting the scope of the invention.

[ 1 12] Example 1: Synthesis of N-(3-aminophenyl)-l-(hydroxymethyl) cyclopropane- 1-sulfonamide. oc

[ 1 13] Step 1: Syntheis of tert-butyl (3-(l-((benzyloxy)methyl)

cyclopropanesulfonamidojphenyl) carbamate.

[ 1 14] To a stirred solution of tert-butyl (3-aminophenyl) carbamate (2 g,

9.60 mmol) in dry pyridine (20 ml) was added l-((benzyloxy)methyl)cyclopropane- 1-sulfonyl chloride (2.50 g, 9.60 mmol) under nitrogen atmosphere and stirred continuously for 16 hrs at room temperature. Solvent was removed under vacuum. The reaction was quenched with water ( 100 ml). The aqueous layer was extracted with ethyl acetate (2 x 100 ml) . The combined organic layers were dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography on silica gel by eluting with ethyl acetate (0- 50%) in hexane to afford tert-butyl (3^_( 1^_

((benzyloxy)methyl)cyclopropanesulfonamido)phenyl) carbamate (3.5 g, 84%).

[ 1 15] ⁱH NMR (400 MHz, DMSO-cfe) : δ 9.71 (s, 1H) , 9.39 (s, 1H), 7.50 (s,

1H) , 7. 19 - 7.37 (m, 5H) , 7.05 - 7. 15 (m, 2H) , 6.79 (ddd, J = 5.3, 3.4, 2. 1 Hz, 1H) , 4.42 (s, 2H), 3.73 (s, 2H), 1.46 (s, 9H), 1.21 (p, J= 4.8, 4.4 Hz, 2H), 0.92 - 1.00 (m, 2H).

[116] Step 2: Synthesis of tert-butyl (3-(l-(hydroxymethyl)

cyclopropanesulfonamidojphenyl) carbamate. [117] To a solution of tert-butyl (3-(l-((benzyloxy)methyl)

cyclopropanesulfonamidojphenyl) carbamate (3 g, 6.94 mmol) in methanol (20 ml) was added 10% Pd-C (0.3 g). The reaction mixture was stirred under hydrogen atmosphere at room temperature for 3 hrs. The reaction mixture was filtered through celite bed and filtrate was concentrated under vacuum to give tert-butyl (3-(l-hydroxymethyl)cyclopropanesulfonamido)phenyl) carbamate (2.3 g, 97%) as a brownish liquid which was solidified overnight.

[118] ⁱH NMR (400 MHz, Chloroform- d): 67.34 - 7.40 (m, 1H), 7.14 - 7.27

(m, 2H), 6.98 - 7.08 (m, 2H), 6.64 (s, 1H), 3.91 (s, 2H), 2.19 (s, 1H), 1.52 (s, 9H), 1.23 - 1.37 (m, 2H), 0.82 - 0.92 (m, 2H). [119] MS: m/z: 343 (M+l).

[120] Step 3: Synthesis of N-(3-aminophenyl)-l-(hydroxymethyl) cyclopropane- 1-sulfonamide.

[121] To a solution of tert-butyl (3-(l-(hydroxymethyl) cyclopropanesulfonamidojphenyl) carbamate (2.30 g, 6.72 mmol) in DCM (20 ml) was added TFA (2.59 ml, 33.6 mmol) drop-wise at 0°C under nitrogen atmosphere. Once the addition was complete, the reaction mixture was stirred for another 18 hrs at room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate solution. Separated organic layer, and the aqueous layer was extracted with ethyl acetate (2 x 25 ml). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to afford N-(3- aminophenyl)- l-(hydroxymethyl) cyclopropane- 1-sulfonamide (1.3 g, 80%).

[122] MS: m/z: 243 (M+l). [123] Example 2: Synthesis of (l-((3-aminophenyl)sulfonyl)cyclopropyl) methanol.

[124] Step 1: Synthesis of ethyl 2-((3-nitrophenyl)thio)acetate. [125] To a solution of 3-nitrobenzenethiol (1.3 g, 8.38 mmol) and ethyl 2- bromoacetate (1.40 g, 8.38 mmol) in DMF (15 ml) was added K₂C0₃ (2.89 g, 20.94 mmol) at room temperature in a sealed tube. After stirring at 65°C for 1 hr, water (30 ml) was added and reaction mixture was extracted with ethyl acetate (2 x 25 ml). Organic layer was washed with brine (25 ml) and solvent was evaporated under vacuum to give ethyl 2-((3-nitrophenyl)thio)acetate (1.43 g, 71%) as a pale yellow liquid.

[126] Ή NMR (DMSO-de): 68.15 (t, J = 2.1 Hz, 1H), 8.04 (ddd, J = 8.2, 2.2,

0.9 Hz, 1H), 7.79 (ddd, J = 7.9, 1.9, 1.0 Hz, 1H), 7.61 (t, J = 8.1 Hz, 1H), 4.11 (d, J = 6.6 Hz, 4H), 1.15 (t, J = 7.1 Hz, 3H). [127] MS: m/z: 242 (M+l).

[128] Step 2: Synthesis of ethyl 2-((3-nitrophenyl)sulfonyl)acetate.

[129] To a solution of ethyl 2-((3-nitrophenyl)thio)acetate (1.4 g, 5.80 mmol) in ethyl acetate (10 ml) were added tetrabutylammonium hydrogen sulfate (9.85 mg, 0.029 mmol), sodium tungstate dihydrate (0.191 g, 0.580 mmol), and hydrogen peroxide (0.89 ml, 29.0 mmol) at 0°C and stirred at room temperature for 18 hrs. The reaction was quenched with water ( 10 ml). The aqueous layer was extracted with ethyl acetate (2 x 15 ml) . The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give ethyl 2-((3- nitrophenyl) sulfonyl) acetate ( 1.5 g, 95%) as an off white solid. [ 130] ⁱH NMR (DMSO-de) : 6 8.70 - 8.57 (m, 2H), 8.38 (ddd, J = 7.9, 1.8, 1.0

Hz, 1H) , 7.99 (t, J = 8.0 Hz, 1H) , 4.91 (s, 2H), 4.06 (q, J = 7. 1 Hz, 2H) , 1.07 (t, J = 7. 1 Hz, 3H) .

[ 131] Step 3: Synthesis of ethyl l-((3-nitrophenyl)sulfonyl) cyclopropanecarboxylate. [ 132] To a stirred solution of ethyl 2-((3-nitrophenyl)sulfonyl)acetate (4 g,

14.64 mmol) , 1 ,2-dibromoethane (3.78 ml, 43.9 mmol) and 18-crown-6 ( 1.935 g, 7.32 mmol) in acetone (250 ml) was added K2CO3 ( 10. 12 g, 73.2 mmol) and the mixture was heated under reflux for 18 hrs. The reaction mixture was filtered and the acetone layer was concentrated under vacuum. The obtained residue was added to in water (30 ml) . Extraction with chloroform (3 x 30 ml) was performed and the organic layer was washed with water (2 x 30 ml) . The obtained organic layer was dried over sodium sulfate and concentrated under vacuum to afford crude product which was purified by column chromatography eluting with 0 to 30% ethyl acetate in hexane to give ethyl l-((3-nitrophenyl) sulfonyl) cyclopropanecarboxylate (3 g, 69%) as an off white solid.

[ 133] ⁱH NMR (DMSO-d₆) : 6 8.67 (t, J = 2.0 Hz, 1H), 8.60 (ddd, J = 8.3, 2.3,

1.0 Hz, 1H), 8.44 (ddd, J = 7.9, 1.8, 1.0 Hz, 1H) , 7.97 (t, J = 8.0 Hz, 1H) , 4.03 (q, J = 7. 1 Hz, 2H) , 2.07 - 1.95 (m, 2H) , 1.84 - 1.68 (m, 2H), 1.07 (t, J = 7. 1 Hz, 3H) .

[ 134] MS: m/z: 300 (M+ l) . [ 135] Step 4: Synthesis of (l-((3-aminophenyl)sulfonyl)cyclopropyl) methanol.

[ 136] To a solution of ethyl l-((3-nitrophenyl) sulfonyl) cyclopropanecarboxylate (3.0 g, 10.02 mmol) in tetrahydrofuran (50 ml) was added L1BH4 (15.54 ml, 31.1 mmol) dropwise at -16°C. Reaction mixture was allowed to attain -6°C and maintained for 6 hrs and left at room temperature overnight. Reaction mixture was quenched with saturated ammonium chloride (20 ml) carefully and extracted with ethyl acetate (2 x 15 ml). Separated organic layer was dried over sodium sulfate and concentrated to afford crude compound which was further purified by column chromatography eluting with ethyl acetate (0 to 50%) in hexane to give (l-((3-aminophenyl)sulfonyl)cyclopropyl)methanol (2.0 g, 88%).

[137] ⁱH NMR (400 MHz, DMSO-d6): 68.73 (d, J = 2.1 Hz, 1H), 8.64 (d, J =

2.0 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.27 (t, J = 2.0 Hz, 1H), 7.16 - 7.22 (m, 1H), 7.06 - 7.13 (m, 1H), 4.91 (t, J = 6.3 Hz, 1H), 3.61 (d, J = 6.2 Hz, 2H), 1.26 - 1.31 (m, 2H), 1.02 - 1.08 (m, 2H).

[138] GCMS: 227 (M+).

Synthesis of 2-((3-aminophenyl)sulfonyl)-2-

[140] Step 1: Synthesis of ethyl 2-methyl-2-((3-nitrophenyl)thio) propanoate.

[141] To a solution of 3-nitrobenzenethiol (1 g, 6.44 mmol) in ethanol (10 ml) was added ethyl 2-bromo-2-methylpropanoate (2.51 g, 12.89 mmol) and KOH (0.723 g, 12.89 mmol) at room temperature under nitrogen atmosphere and continued stirring for 6 hrs at 80°C. Ethanol was removed under vacuum; residue was suspended in water (25 ml) and extracted with ethyl acetate (2 x 50 ml). Separated organic layer was dried over sodium sulfate and concentrated under vacuum to give ethyl 2-methyl-2-((3-nitrophenyl)thio)propanoate (1.4 g, 81 %).

[142] Ή NMR (400 MHz, DMSO-d6): 68.31 (ddd, J = 8.3, 2.3, 1.0 Hz, 1H),

8.18 (t, J = 2.0 Hz, 1H), 7.90 (ddd, J = 7.7, 1.7, 1.0 Hz, 1H), 7.72 (t, J = 8.0 Hz, 1H), 4.07 (q, J = 7.1 Hz, 2H), 1.46 (s, 6H), 1.14 (t, J = 7.1 Hz, 3H). [143] MS: m/z: 270 (M+l).

[144] Step 2: Synthesis of ethyl 2-methyl-2-((3- nitrophenyl)sulfonyl)propanoate.

[145] To a solution of ethyl 2-methyl-2-((3-nitrophenyl)thio)propanoate (1.4 g, 5.20 mmol) in ethyl acetate (10 ml) were added tetrabutylammonium hydrogen sulfate (8.83 mg, 0.026 mmol), sodium tungstate dihydrate (0.171 g, 0.520 mmol), and hydrogen peroxide (0.78 ml, 26.0 mmol) at 0°C and stirred at room temperature for 18 hrs. The reaction was quenched with water (10 ml). The aqueous layer was extracted with ethyl acetate (2 x 15 ml). The combined organic layers were dried with sodium sulfate and concentrated under vacuum to give ethyl 2-methyl-2-((3-nitrophenyl)sulfonyl)propanoate (1.5 g, 99%).

[146] ⁱH NMR (400 MHz, DMSO-d₆): 68.65 (ddd, J= 8.3, 2.3, 1.0 Hz, 1H),

8.44 (t, J= 2.0 Hz, 1H), 8.28 (ddd, J= 7.9, 1.8, 1.0 Hz, 1H), 7.99 (t, J= 8.1 Hz, 1H), 4.08 (q, J= 7.1 Hz, 2H), 1.55 (s, 6H), 1.10 (t, J= 7.1 Hz, 3H).

[147] MS: m/z: 302 (M+l). [148] Step 3: synthesis of 2-methyl-2-((3-nitrophenyl)sulfonyl) propanamide. [ 149] To a solution of ethyl 2-methyl-2-((3-nitrophenyl)sulfonyl)propanoate

(0.5 g, 1.66 mmol) and ammonia (0.359 ml, 16.59 mmol) in a sealed tube was heated at 1 10°C for 18 hrs. Reaction mixture was concentrated under vacuum to give 2-methyl-2-((3-nitrophenyl)sulfonyl)propanamide (0.2 g, 44%) as a crude compound.

[ 150] LCMS: m/z: 273 (M+ l).

[ 151] Step 4: Synthesis of 2-((3-aminophenyl)sulfonyl)-2- methylpropanamide .

[ 152] To a solution of 2-methyl-2-((3-nitrophenyl)sulfonyl)propanamide (0.3 g, 1. 10 mmol) in methanol ( 10 ml) was added 10% Pd-C (0. 12 g) at room temperature and the reation mixture was stirred under hydrogen atmosphere for 2 hrs. Reaction mixture was filtered through celite bed and washed with methanol (2 x 15 ml). Filtrate was collected and solvent was evaporated under vacuum to give 2-((3-aminophenyl)sulfonyl)-2-methylpropanamide (0. 15 g, 56%) as an off white solid.

[ 153] Ή NMR (400 MHz, DMSO-d6) : δ 7.52 (s, 1H) , 7.43 (s, 1H), 7.28 (s,

1H) , 7.21 (d, J = 7.9 Hz, 1H), 6.97 (t, J = 2.0 Hz, 1H) , 6.85 (dd, J = 8.0, 2. 1 Hz, 2H) , 5.66 (s, 2H), 1.41 (s, 6H) .

[ 154] MS: m/z: 243 (M+ l) . [ 155] Example 4: Synthesis of (3-aminophenyl)methanesulfonamide.

[ 156] Step 1: Synthesis of N,2-dimethyl-2-((3-nitrophenyl)sulfonyl) propanamide. [157] A solution of methyl amine in methanol 30% (10 ml, 0.83 mmol) and ethyl 2-methyl-2-((3-nitrophenyl)sulfonyl)propanoate (0.25 g, 0.83 mmol) in a sealed tube was heated at 110°C for 18 hrs. Reaction mixture was concentrated under vacuum to give N,2-dimethyl-2-((3-nitrophenyl)sulfonyl)propanamide (0.2 g, 84%).

[158] ⁱH NMR (400 MHz, DMSO-d₆): 68.61 (ddd, J= 8.3, 2.3, 1.0 Hz, 1H),

8.38 (t, J= 2.0 Hz, 1H), 8.17 (dt, J= 7.8, 1.3 Hz, 1H), 8.05 (q, J= 4.7 Hz, 1H), 7.95 (t, J= 8.1 Hz, 1H), 2.58 (d, J= 4.4 Hz, 3H), 1.51 (s, 6H).

[159] LCMS: m/z: 287 (M+l). [160] Step 2: Synthesis of 2-((3-aminophenyl)sulfonyl)-N,2- dimethylpropanamide.

[161] To a solution of N,2-dimethyl-2-((3-nitrophenyl)sulfonyl)propanamide

(0.2 g, 0.70 mmol) in methanol (10 ml) was added 10% Pd-C (0.04 g) at room temperature and the reation mixture was stirred under hydrogen atmosphere for 1 hr. Reaction mixture was filtered through celite bed and washed with methanol (2 x 15 ml). Filtrate was collected and solvent was evaporated under vacuum to give 2-((3-aminophenyl)sulfonyl)-N,2-dimethylpropanamide (0.15 g, 84%) as an off white solid.

[162] Ή NMR (400 MHz, DMSO-d6): 67.82 (q, J = 4.5 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.92 (t, J = 2.0 Hz, 1H), 6.88 - 6.75 (m, 2H), 5.66 (s, 2H), 2.60 (d, J = 4.5 Hz, 3H), 1.42 (s, 6H).

[163] LCMS: m/z: 256 (M+).

[164] Example 5: Synthesis of 2-((3-aminophenyl)sulfonyl)-N,N,2- trimethylpropanamide .

[165] Step 1: Synthesis of 2-methyl-2-((3- nitrophenyl)sulfonyl)propanoic acid.

[166] Ethyl 2-methyl-2-((3-nitrophenyl)sulfonyl)propanoate (1.2 g, 3.98 mmol) was added to a mixture of THF (9 ml) , methanol (6 ml) , and water (3 ml) . To the reaction mixture was added lithium hydroxide monohydrate (0.286 g, 11.95 mmol) and stirred at room temperature for 1 hr. Reaction mixture was diluted with water (20 ml) and acidified with IN HC1. Obtained white precipitate was filtered and dried to give 2-methyl-2-((3-nitrophenyl)sulfonyl)propanoic acid (1 g, 92%) as an off white solid.

[167] ⁱH NMR (400 MHz, DMSO-d₆): 6 13.75 (s, 1H), 8.62 (ddd, J= 8.3, 2.3,

1.0 Hz, 1H), 8.46 (t, J= 2.0 Hz, 1H), 8.27 (ddd, J= 7.9, 1.8, 1.0 Hz, 1H), 7.97 (t, J = 8.0 Hz, 1H), 1.52 (s, 6H).

[168] LCMS: m/z: 274 (M+l). [169] Step 2: Synthesis of N,N,2-trimethyl-2-((3-nitrophenyl)sulfonyl) propanamide.

[170] Under nitrogen, to a mixture of 2-methyl-2-((3- nitrophenyl)sulfonyl)propanoic acid (0.8 g, 2.93 mmol) and dimethylamine hydrochloride (0.716 g, 8.78 mmol) in pyridine (7 ml) was added EDC.HC1 (1.684 g, 8.78 mmol). Reaction mixture was stirred at room temperature for 10 hrs, diluted with cold water ( 100 ml) , and extracted with ethyl acetate (2 x 25 ml). Separated organic layer was washed with dil. HC1 (50 ml) , saturated aqueous sodium bicarbonate solution (50 ml) , and brine (20 ml). Organic layer was dried over sodium sulfate and concentrated under vacuum to give N,N,2-trimethyl-2- ((3-nitrophenyl)sulfonyl)propanamide (0.75 g, 85%) as a pale yellow solid.

[ 171] MS: m/z: 301 (M+ l) .

[ 172] Step 3: Synthesis of 2-((3-aminophenyl)sulfonyl)-N,N,2- trimethylpropanamide .

[ 173] To a solution of N,N,2-trimethyl-2-((3-nitrophenyl)sulfonyl) propanamide (0.7 g, 2.33 mmol) in methanol (20 ml) was added 10% Pd-C (0.2 g) at room temperature and the reation mixture was stirred under hydrogen atmosphere for 3 hrs. Reaction mixture was filtered through celite bed and washed with methanol (2 x 5 ml) . Filtrate was collected and solvent was evaporated under vacuum to give 2-((3-aminophenyl)sulfonyl)-N,N,2- trimethylpropanamide (0.5 g, 79%) as a brownish liquid which was solidified overnight.

[ 174] LCMS: m/z: 271 (M+ l).

[ 175] Example 6: Synthesis of 2-((3-aminophenyl)sulfonyl)acetamide.

[ 176] Step 1: Synthesis of 2-((3-nitrophenyl)thio)acetamide.

[ 177] To a solution of 3-nitrobenzenethiol ( 1.3 g, 8.38 mmol) in DMSO ( 15 ml) was added 2-chloroacetamide ( 1.959 g, 20.94 mmol) and K₂C0₃ (2.89 g, 20.94 mmol) . Reaction mixture was heated at 60°C for 6 hrs. Reaction mixture was cooled to room temperature, water was added (20 ml) and extracted with ethyl acetate (2 x 10 ml) . Combined organic layers were dried over sodium sulfate and concentrated under vacuum to afford 2-((3-nitrophenyl)thio)acetamide (1.4 g, 79%).

[178] ⁱH NMR (400 MHz, DMSO-d6): 68.15 (t, J = 2.1 Hz, 1H), 8.01 (ddd, J

= 8.2, 2.3, 1.0 Hz, 1H), 7.78 (ddd, J = 7.9, 1.9, 0.9 Hz, 1H), 7.55 - 7.69 (m, 2H), 7.25 (s, 1H), 3.78 (s, 2H).

[179] LCMS: m/z: 213 (M+l).

[180] Step 2: Synthesis of 2-((3-nitrophenyl)sulfonyl)acetamide.

[181] To a solution of 2-((3-nitrophenyl)thio)acetamide (1.4 g, 6.60 mmol) in ethyl acetate (10 ml) were added sodium tungstate dihydrate (0.28 g, 0.84 mmol), tetrabutylammonium hydrogensulfate (0.28 g, 0.84 mmol) and hydrogen peroxide (0.26 ml, 8.38 mmol). Reaction mixture was stirred overnight at room temperature and obtained solid was filtered to give 2-((3- nitrophenyl)sulfonyl)acetamide (0.85 g, 53%) as a white solid.

[182] Ή NMR (400 MHz, DMSO-d6): 68.71 - 8.53 (m, 2H), 8.32 (d, J = 7.8 Hz, 1H), 7.96 (t, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.44 (s, 1H), 4.45 (s, 2H).

[183] LCMS: m/z: 245 (M+l).

[184] Step 3: Synthesis of 2-((3-aminophenyl)sulfonyl)acetamide.

[185] To a solution of 2-((3-nitrophenyl)sulfonyl)acetamide (0.85 g, 3.48 mmol) in methanol (10 ml) was added 10% Pd-C (0.2 g) at room temperature and the reation mixture was stirred under hydrogen atmosphere for 24 hrs. Reaction mixture was filtered through celite bed and washed with methanol (2 x 5 ml). Filtrate was collected and solvent was evaporated under vacuum to give 2-((3- aminophenyl)sulfonyl)acetamide (0.52 g, 70%).

[186] ⁱH NMR (400 MHz, DMSO-d6): 6 7.57 - 7.52 (m, 1H), 7.33 (s, 1H), 7.23 (t, J = 7.9 Hz, IH), 7.03 (t, J = 2.0 Hz, IH), 7.00 - 6.90 (m, IH), 6.82 (ddd, J = 8.1, 2.3, 1.0 Hz, IH), 5.67 (s, 2H), 4.08 (s, 2H). [ 187] LCMS: m/z: 215 (M+ l).

[ 188] Example 7: Synthesis

aminophenyl)thio)azetidine-l-carboxylate

[ 189] Step 1: Synthesis of tert-butyl 3-((3-nitrophenyl)thio)azetidine-l- carboxylate.

[ 190] To a stirred solution of 3-nitrobenzenethiol ( 1 g, 6.44 mmol) in DMF

( 10 ml) was added K₂C0₃ (2.23 g, 16. 1 1 mmol) followed by tert-butyl 3- iodoazetidine- 1-carboxylate ( 1.82 g, 6.44 mmol). Reaction mixture was stirred overnight and diluted with water (30 ml) and ethyl acetate (30 ml) . The aqueous layer was separated and extracted with ethyl acetate (3 x 20 ml) . The combined organic layers were washed with water (3 x 20 ml) and brine (20 ml), dried over Na2S0₄, and concentrated to give oil. The oily compound was purified by column chromatography on silica gel eluting with 0 - 10% ethyl acetate in hexane to afford tert-butyl 3- ((3-nitrophenyl)thio)azetidine- 1-carboxylate ( 1.4 g, 70%) as a pale yellow liquid.

[ 191] ⁱH NMR (400 MHz, DMSO-d6) 6 8.05 (ddd, J = 7.9, 2.2, 1.2 Hz, 1H) ,

7.99 (t, J = 2.0 Hz, 1H) , 7.71 - 7.59 (m, 2H), 4.54 - 4.28 (m, 3H) , 3.72 (d, J = 9.6 Hz, 2H), 1.37 (s, 9H) .

[ 192] Step 2: tert-butyl 3-((3-aminophenyl)thio)azetidine-l-carboxylate.

[ 193] To a solution of tert-butyl 3-((3-nitrophenyl)thio)azetidine- 1- carboxylate ( 1.5 g, 4.83 mmol) in ethanol (20 ml) was added iron ( 1.35 g, 24. 16 mmol) , cone. HC1 ( 1.47 ml, 48.3 mmol) and water (0.87 ml, 48.3 mmol). Reaction mixture was heated at 85°C for 2 hrs. Reaction mixture was concentrated until dry. Residue was added to the mixture of ethyl acetate: saturated aqueous sodium bicarbonate solution (10 ml: 10 ml) and filtered through celite. Separated organic layer was dried over sodium sulfate and concentrated under vacuum to give crude product which was purified by column chromatography eluting with ethyl acetate (0 - 17%) in hexane to afford tert-butyl 3- ((3- aminophenyl)thio)azetidine- 1 -carboxylate (1.25 g, 92%) as a liquid.

[194] ⁱH NMR (400 MHz, Chloroform- d): 67.14 (t, J= 8.0 Hz, 1H), 6.68 -

6.77 (m, 3H), 4.35 (dd, J= 9.0, 7.6 Hz, 2H), 4.01 (tt, J= 7.6, 5.3 Hz, 1H), 3.88 (dd, J= 9.0, 5.3 Hz, 2H), 2.85-3.50 (bs, 2H), 1.45 (s, 9H). [195] MS: m/z: 281 (M+l).

[196] Example 8: Synthesis of l-(2-fluoro-4-iodophenyl)-3-(4- methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-l,2,3,4,7,8-hexahydropyrido[2,3- d]pyrimidin-5-yl 4-methylbenzenesulfonate.

[197] Under nitrogen atmosphere, to a solution of l-(2-fluoro-4- iodophenyl)-5-hydroxy-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine- 2,4,7(lH,3H,8H)-trione (41 g, 72.8 mmol) (Prepared as per reference WO 2005/121142) in acetonitrile (300 ml), triethylamine (30.4 ml, 218 mmol) and trimethylamine hydrochloride (3.48 g, 36.4 mmol) was added drop-wise p- toluensulfonylchloride (27.8 g, 146 mmol) in acetonitrile (300 ml) at 0°C, and the mixture was stirred under ice cooling for 1 hr, and at room temperature for 24 hrs. To the reaction mixture was added methanol (220 ml), and the mixture was stirred at room temperature for 1 hr. The precipitated crystals were collected by filtration and dried under vacuum to afford the titled compound (40.5 g, 78%).

[198] ⁱH NMR(400 MHz,DMSO-d₆) 6: 7.95 (dd, J = 1.6 and 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 = 16Hz, 1H), 4.77 (d, J = 16 Hz, 1H), 3.71 (s, 3H), 2.76 (s, 3H), 2.42 (s, 3H), 1.53 (s, 3H).

[199] MS (ESI): m/z: 718 (M+l).

[200] Example 9: Synthesis of l-(2-fluoro-4-iodophenyl)-3-(4- methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-l,2,3,4,7,8-hexahydropyrido[2,3- d]pyrimidin-5-yl trifluoromethanesulfonate.

[201] Under nitrogen atmosphere, to an ice cooled solution of l-(2-fluoro-4- iodophenyl)-5-hydroxy-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine- 2,4,7(lH,3H,8H)-trione (14.1 g) in chloroform (70 ml) was added 2,6-lutidine (3.79 ml) and trifluoromethanesulfonic anhydride (5.47 ml) and stirred for 1 hr. Ice bath was removed and stirred at room temperature for 1.5 hrs. To the reaction mixture was added saturated aqueous sodium bicarbonate solution (20 ml) and chloroform (20 ml) to allow partitioning. The organic layer was washed once with saturated aqueous sodium bicarbonate solution (20 ml), twice with IN HC1 (10 ml), once with saturated aqueous sodium chloride solution (20 ml), and dried over sodium sulfate. After filtration, the filtrate was concentrated under vacuum. To the obtained crude product was added isopropyl alcohol (35 ml), and the mixture was stirred with heating at 95°C for 30 min. After allowing cooling with stirring to room temperature, isopropyl alcohol (35 ml) was added, and mixture was stirred for 1 hr. The precipitated crystals were collected by filtration, washed with isopropyl alcohol (20 ml) and dried under vacuum to afford l-(2- fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo- 1 ,2,3,4,7,8- hexahydropyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate ( 14 g, 81%) .

[202] Ή NMR (400 MHz, DMSO-d6) : 6 7.97 (dd, J = 9.5, 1.8 Hz, 1H) , 7.79 -

7.69 (m, 1H) , 7.38 (t, J = 8. 1 Hz, 1H) , 7.32 - 7.24 (m, 2H), 6.94 - 6.83 (m, 2H), 5.06 (d, J = 14.4 Hz, 1H) , 4.92 (d, J = 14.4 Hz, 1H), 3.72 (s, 3H), 2.77 (s, 3H) , 2.03 (s, 3H).

[203] MS (ESI): m/z: 696 (M+ l).

[204] Example 10: Synthesis of l-(3-(azetidin-3-ylsulfonyl)phenyl)-5-((2- fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine- 2,4,7(lH,3H,6H)-trione (Compound 11).

[205] Step 1: Synthesis of tert-butyl 3-((3-((l-(2-fluoro-4-iodophenyl)-3-

(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-l,2,3,4,7,8- hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl)thio)azetidine-l- carboxylate.

[206] To a mixture of l-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8- dimethyl-2,4,7-trioxo- 1 ,2, 3,4,7, 8-hexahydropyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate (1.61 g, 2.32 mmol) and tert-butyl 3-((3- aminophenyl)thio)azetidine- 1 -carboxylate (0.71 g, 2.55 mmol) in DMA (3 ml) was added 2,6-lutidine (0.81 ml, 6.94 mmol). The resulting reaction mixture was heated at 130°C for 6 hrs. To the reaction mixture was added water (10 ml) and extracted with ethyl acetate (2 x 10 ml). Separated organic layer was dried over sodium sulfate and concentrated under vacuum to afford crude product, which was purified by column chromatography eluting with ethyl acetate (0 - 28%) in hexane to afford tert-butyl 3-((3-((l-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)- 6,8-dimethyl-2,4,7-trioxo- 1,2, 3,4,7, 8-hexahydropyrido[2,3-d]pyrimidin-5- yl)amino)phenyl)thio)azetidine- 1-carboxylate as a white solid (1.13 g, 59%).

[207] ⁱH NMR (400 MHz, DMSO-d6): 6 10.09 (s, 1H), 7.97 (dd, J = 9.4, 1.9

Hz, 1H), 7.75 (dd, J = 8.4, 1.8 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.31 - 7.26 (m, 3H), 6.91 - 6.83 (m, 3H), 6.83 - 6.76 (m, 2H), 5.11 - 4.87 (m, 2H), 4.25 - 4.35 (m, 2H), 4.17 (tt, J = 7.7, 5.0 Hz, 1H), 3.70 (s, 3H), 3.66 (dd, J = 8.9, 4.8 Hz, 2H), 2.76 (s, 3H), 1.52 (s, 3H), 1.36 (s, 9H).

[208] MS (ESI): m/z: 826 (M+l).

[209] Step 2: Synthesis of tert-butyl 3-((3-((l-(2-fluoro-4-iodophenyl)-3-

(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-l,2,3,4,7,8- hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl)sulfonyl)azetidine-l- carboxylate.

[210] To a solution of tert-butyl 3-((3-(( l-(2-fluoro-4-iodophenyl)-3-(4- methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo- l ,2,3,4,7,8-hexahydropyrido[2,3- d]pyrimidin-5-yl)amino)phenyl)thio)azetidine- 1-carboxylate ( 1. 13 g, 1.37 mmol) in ethyl acetate ( 15 ml) was added sodium tungstate dihydrate (0.76 g, 2.32 mmol) , tetrabutylammonium hydrogen sulfate (0.79 g, 2.32 mmol) , and hydrogen peroxide ( 1.0 ml) . The reaction mixture was stirred overnight at room temperature. Separated organic layer was dried over sodium sulfate and concentrated to afford crude compound which was further purified by column chromatography eluting with ethyl acetate (0 - 50%) in hexane to afford tert-butyl 3-((3-(( l-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo- l ,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5- yl) amino) phenyl) sulfonyl)azetidine- 1-carboxylate ( 1. 16 g, 99%) as an off white solid.

[21 1] Ή NMR (400 MHz, DMSO-cfc) : 6 10.20 (s, 1H) , 7.98 (dd, J = 9.4, 1.9 Hz, 1H), 7.73 - 7.79 (m, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.48 - 7.54 (m, 1H), 7.22 - 7.42 (m, 5H) , 7. 1 1 - 7.21 (m, 1H) , 6.83 - 6.91 (m, 1H), 4.87 - 5. 1 1 (m, 2H), 4.42 (td, J = 8.3, 4. 1 Hz, 1H) , 3.88 - 4.20 (m, 4H) , 3.70 (s, 3H) , 2.78 (s, 3H) , 1.55 (s, 3H) , 1.37 (s, 9H).

[212] MS (ESI): m/z: 858 (M+ l). [213] Step 3: Synthesis of tert-butyl 3-((3-(5-((2-fluoro-4- iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)sulfonyl)azetidine-l- carboxylate.

[214] To a solution of tert-butyl 3-((3-((l-(2-fluoro-4-iodophenyl)-3-(4- methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo- l,2,3,4,7,8-hexahydropyrido[2,3- d]pyrimidin-5-yl)amino)phenyl)sulfonyl)azetidine- 1 -carboxylate (1.15 g, 1.35 mmol) in THF (10 ml) was added NaOMe in methanol (30% solution, 0.58 ml) at 0°C and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 30 min. Reaction mixture was quenched with 0.5 ml acetic acid and concentrated to afford crude compound which was purified by column chromatography eluting with ethyl acetate (0 - 50%) in hexane to afford tert-butyl 3-((3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7- trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin- 1(2H)- yl) phenyl) sulfonyl)azetidine- 1-carboxylate (0.88 g, 76%) as an off white solid.

[215] ⁱH NMR (400 MHz, DMSO-d6): 6 11.09 (s, 1H), 8.12 (t, J = 1.9 Hz,

1H), 7.99 (dt, J = 7.7, 1.4 Hz, 1H), 7.85 - 7.93 (m, 1H), 7.73 - 7.85 (m, 2H), 7.51 - 7.63 (m, 1H), 7.22 - 7.35 (m, 2H), 7.01 (t, J = 8.6 Hz, 1H), 6.81 - 6.92 (m, 2H), 4.97 (s, 2H), 4.48 (ddd, J = 13.6, 8.4, 5.2 Hz, 1H), 3.90 - 4.22 (m, 4H), 3.71 (s, 3H), 3.11 (d, J = 1.7 Hz, 3H), 1.37 (s, 9H), 1.14 (s, 3H).

[216] MS (ESI): m/z: 858 (M+l).

[217] Step 4: Synthesis of l-(3-(azetidin-3-ylsulfonyl)phenyl)-5-((2- fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine- 2,4,7(lH,3H,6H)-trione (Compound 11).

[218] To a solution of tert-butyl 3-((3-(5-((2-fluoro-4-iodophenyl)amino)-3-

(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3- d]pyrimidin- l (2H)-yl)phenyl)sulfonyl)azetidine- l-carboxylate (0.3 g, 0.35 mmol) in anisole (2 ml) was added aluminum chloride (0.47 g, 3.50 mmol) at 0°C and stirred at room temperature for 12 hrs. Methanol (2 ml) was added and concentrated under vacuum to afford sticky material. Sticky material was added to the mixture of THF and ethyl acetate ( 1 : 1 , 10 ml) and water was added ( 10 ml) . Separated organic layer dried over sodium sulfate and concentrated under vacuum. Residue was dissolved in 10% methanol in DCM ( 10 ml) and adsorbed on silica gel. Column chromatographic purification was performed eluting with methanol (0 - 4%) in DCM to afford impure compound (0.07 g) which was again suspended in methanol (2 ml) and filtered to give l-(3-(azetidin-3- ylsulfonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3- d]pyrimidine-2,4,7( lH,3H,6H)-trione (0.04 g, 15%) as an off white solid.

[219] ⁱH NMR (400 MHz, DMSO-d6) : 6 1 1.20 (s, 1H) , 7.75 - 8.04 (m, 6H) ,

7.54 - 7.61 (m, 1H) , 6.97 (t, J = 8.6 Hz, 1H) , 4.66 (tt, J = 8.7, 6.6 Hz, 1H) , 3.97 (dd, J = 10.2, 6.6 Hz, 2H) , 3.86 (t, J = 9.5 Hz, 2H), 3.07 (s, 3H), 1. 14 (s, 3H).

[220] MS (ESI): m/z 638 (M+ l).

[221] The following compounds were prepared using a similar experimental procedure as given above, using appropriate starting material/ intermediates. [222] 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin- l(2H)-yl)phenyl)sulfonyl)-2- methylpropanamide (Compound 9).

[223] ⁱH NMR (400 MHz, DMSO-d6): 6 11.65 (s, 1H), 11.18 (s, 1H), 7.85 (t,

J = 1.9 Hz, 1H), 7.76 - 7.84 (m, 3H), 7.72 (t, J = 7.8 Hz, 1H), 7.53 - 7.61 (m, 2H), 7.49 (s, 1H), 6.96 (t, J = 8.6 Hz, 1H), 3.07 (s, 3H), 1.48 (s, 3H), 1.44 (s, 3H), 1.20 (s, 3H).

[224] MS (ESI) m/z: 668 (M+l).

[225] 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin- l(2H)-yl)phenyl)sulfonyl)-N,2- dimethylpropanamide (Compound 8).

[226] ⁱH NMR (400 MHz, DMSO-d6): 6 11.64 (s, 1H), 11.17 (s, 1H), 7.97 (q,

J = 4.4 Hz, IH), 7.69 - 7.85 (m, 5H), 7.53 - 7.59 (m, IH), 6.96 (t, J = 8.6 Hz, IH), 3.07 (s, 3H), 2.59 (d, J = 4.4 Hz, 3H), 1.48 (d, J = 12.9 Hz, 6H), 1.22 (s, 3H).

[227] MS (ESI) m/z: 682 (M+l).

[228] 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-yl)phenyl)sulfonyl)-N,N,2- trimethylpropanamide (Compound 3).

[229] ⁱH NMR (400 MHz, DMSO-d6): 6 11.64 (s, IH), 11.17 (s, IH), 7.95 -

7.67 (m, 5H), 7.57 (d, J = 8.3 Hz, IH), 6.96 (t, J = 8.6 Hz, IH), 3.07 (bs, 9H), 1.60 (d, J = 19.0 Hz, 6H), 1.22 (s, 3H).

[230] MS (ESI): m/z: 696 (M+l).

[231] The following compounds were prepared using a similar experimental procedure as given above, using the intermediate as prepared in example 8 and corresponding aniline. [232] 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin- l(2H)-yl) phenyl) sulfonyl) acetamide (Compound 4).

[233] ⁱH NMR (400 MHz, DMSO-d6): 6 11.67 (s, 1H), 11.18 (s, 1H), 7.88 - 7.97 (m, 2H), 7.77 - 7.83 (m, 2H), 7.74 (t, J = 7.9 Hz, 1H), 7.62 (s, 1H), 7.53 - 7.59 (m, 1H), 7.39 (s, 1H), 6.96 (t, J = 8.6 Hz, 1H), 4.32 (d, J = 9.8 Hz, 2H), 3.07 (s, 3H), 1.20 (s, 3H).

[234] MS (ESI): m/z: 640 (M+l).

[235] 5- ((2-fluoro-4-iodophenyl) amino) - 1 - (3- (( 1 - (hydroxymethyl) cyclopr opyl) sulfonyl) phenyl) -6,8- dimethylpyrido [4 , 3- d] pyrimidine- 2,4,7(lH,3H,6H)-trione (Compound 10).

[236] ⁱH NMR (400 MHz, DMSO-d6): 6 11.66 (s, 1H), 11.21 (s, 1H), 7.90

(dd, J = 6.9, 1.5 Hz, 2H), 7.76 - 7.83 (m, 2H), 7.69 - 7.76 (m, IH), 7.53 - 7.59 (m, IH), 6.97 (t, J = 8.6 Hz, IH), 4.97 (t, J = 6.1 Hz, IH), 3.69 (d, J = 11.3 Hz, 2H), 3.07 (s, 3H), 1.30 - 1.41 (m, 2H), 1.17 (s, 3H), 1.06 (d, J = 10.1 Hz, 2H).

[237] MS (ESI): m/z: 653 (M+l).

[238] N-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin- l(2H)-yl) phenyl)- 1- (hydroxymethyl) cyclopropane- 1- sulfonamide (Compound 16). [239] ⁱH NMR (400 MHz, DMSO-d6): 6 11.58 (s, IH), 11.21 (s, IH), 9.86 (s,

IH), 7.79 (dd, J = 10.3, 1.9 Hz, IH), 7.51 - 7.59 (m, IH), 7.37 (t, J = 8.0 Hz, IH), 7.19 - 7.32 (m, 2H), 7.05 - 7.13 (m, IH), 6.94 (t, J = 8.6 Hz, IH), 4.98 (t, J = 6.2 Hz, IH), 3.77 (dd, J = 6.4, 2.7 Hz, 2H), 3.34 - 3.50 (m, 10H), 3.06 (s, 3H), 1.26 (s, 3H), 0.98 - 1.12 (m, 2H), 0.89 (bs, 2H). [240] MS (ESI): m/z: 668 (M+l). [241] N-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin- l(2H)-yl) phenyl)- 1- (methoxymethyl) cyclopropane- 1- sulfonamide (Compound 15).

[242] Ή NMR (400 MHz, DMSO-d6): 6 11.61 (s, 1H), 11.22 (s, 1H), 7.79

(dd, J = 10.3, 1.9 Hz, 1H), 7.41 - 7.61 (m, 4H), 7.28 - 7.38 (m, 1H), 6.95 (t, J = 8.6 Hz, 1H), 5.23 (t, J = 5.9 Hz, 1H), 3.74 (q, J = 3.9 Hz, 2H), 3.32 (s, 3H), 3.06 (s, 3H), 1.25 (s, 3H), 0.97 (d, J = 11.1 Hz, 4H).

[243] MS (ESI): m/z: 682 (M+l).

[244] 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin- l(2H)-yl)phenyl)sulfonyl)-N- methylpropanamide (Compound 7).

[245] ⁱH NMR (400 MHz, DMSO-d6): 6 11.66 (s, 1H), 11.19 (s, 1H), 8.19 (s,

1H), 7.69 - 7.93 (m, 5H), 7.56 (dt, J = 8.3, 1.3 Hz, 1H), 6.97 (t, J = 8.6 Hz, 1H), 4.18 (q, J = 6.9 Hz, 1H), 3.07 (s, 3H), 2.57 (d, J = 4.6 Hz, 3H), 1.31 (d, J = 7.0 Hz, 3H), 1.20 (s, 3H).

[246] MS (ESI): m/z: 668 (M+l).

[247] 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin- l(2H)-yl)phenyl)sulfonyl)-N,N- dimethylpropanamide (Compound 12).

[248] ⁱH NMR (400 MHz, DMSO-d6): 6 11.66 (s, 1H), 11.19 (s, 1H), 7.94 (s,

OH), 7.70 - 7.88 (m, 5H), 7.52 - 7.60 (m, IH), 6.97 (t, J = 8.6 Hz, IH), 4.94 (dd, J = 13.6, 7.2 Hz, IH), 3.06 (d, J = 8.4 Hz, 6H), 2.81 (s, 3H), 1.31 (d, J = 6.7 Hz, 3H), 1.21 (s, 3H).

[249] MS (ESI): m/z: 682 (M+l).

[250] 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin- l(2H)-yl)phenyl)sulfonyl)propanamide (Compound 5). [251] ⁱH NMR (400 MHz, DMSO-d6): 6 1 1.67 (s, 1H), 1 1.20 (s, 1H) , 7.90 -

7.71 (m, 5H), 7.67 (d, J = 16.2 Hz, 1H) , 7.57 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H) , 6.97 (t, J = 8.5 Hz, 1H) , 4.21 (d, J = 8.5 Hz, 1H) , 3.08 (s, 3H) , 1.30 (d, J = 8. 1 Hz, 3H) , 1.21 (s, 3H). [252] MS (ESI): m/z: 654 (M+ l).

[253] Example 11: 5-((2-fluoro-4-iodophenyl)amino)-l-(3-((l-

(fluoromethyl)cyclopropyl)sulfonyl)phenyl)-6,8-dimethylpyrido[4,3-d] pyrimidine-2,4,7( lH,3H,6H)-trione (Compound 1).

[254] To a solution of 5-((2-fluoro-4-iodophenyl)amino)- l-(3-(( l-

(hydr oxymethyl) cy clopropyl) sulfonyl) phenyl) - 6 ,8 - dimethylpyrido [4,3- d]pyrimidine-2,4,7( lH,3H,6H)-trione (0.05 g, 0.07 mmol) in dichloromethane (6 ml) was added DAST (0.02 ml, 0. 14 mmol) at -78°C. The reaction mixture was stirred at a temperature from -78°C to -30°C for 3 hrs. Reaction mixture was diluted with saturated bicarbonate solution (5 ml). Separated organic layer was dried over sodium sulfate and concentrated to afford crude product which was purified by column chromatography eluting with methanol (0 - 1.7%) in DCM to afford 5-((2-fluoro-4-iodophenyl)amino)- 1-(3-(( l-(fluoromethyl)cyclopropyl) sulfonyl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7( lH,3H,6H)-trione (0.01 g, 23%) as an off white solid.

[255] ⁱH NMR (400 MHz, DMSO-d6): 6 1 1.66 (s, 1H), 1 1.20 (s, 1H) , 7.89 -

7.99 (m, 2H), 7.80 (ddt, J = 7.3, 4.0, 1.7 Hz, 2H) , 7.74 (t, J = 7.8 Hz, IH), 7.53 - 7.60 (m, 1H), 6.97 (t, J = 8.6 Hz, 1H), 4.64 (dd, J = 48.4, 10.7 Hz, 2H), 3.07 (s, 3H), 1.18 - 1.35 (m, 4H), 1.16 (s, 3H).

[256] MS (ESI): m/z: 655 (M+l).

[257] The following compound was prepared using the same experimental procedure as given above.

[258] N-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin- l(2H)-yl) phenyl)- 1- (fluoromethyl) cyclopropane- 1- sulfonamide (Compound 14).

[259] ⁱH NMR (400 MHz, DMSO-d6): 6 11.57 (s, 1H), 11.23 (d, J = 10.8 Hz,

1H), 10.20 (s, 1H), 7.79 (dd, J = 10.2, 1.9 Hz, 1H), 7.52 - 7.58 (m, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.26 - 7.31 (m, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.10 (dd, J = 8.1, 1.7 Hz, 1H), 6.94 (t, J = 8.6 Hz, 1H), 4.66 (d, J = 48.6 Hz, 2H), 3.06 (s, 3H), 1.25 (d, J = 8.6 Hz, 5H), 1.08 (s, 2H).

[260] MS (ESI): m/z: 670 (M+l).

[261] Example 12: Synthesis of 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-

3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)- yl)phenyl)sulfonyl)acetamide (Compound 2).

[262] Step 1: Synthesis of 2-((3-((l-(2-fluoro-4-iodophenyl)-3,6,8- trimethyl-2,4,7-trioxo- 1,2, 3,4,7, 8-hexahydropyxido[2,3-d]pyrimidin-5- yl)amino)phenyl)sulfonyl)acetamide.

[263] To a mixture of l-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-2,4,7-trioxo- l ,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate (0.2 g, 0.34 mmol) and 2-((3-aminophenyl)sulfonyl)acetamide (0.08 g, 0.37 mmol) was added DMA ( 1 ml) and 2,6-lutidine (0.08 ml, 0.71 mmol). The resulting mixture was stirred under nitrogen atmosphere at 130°C for 4 hrs. The reaction mixture was cooled to room temperature. Water ( 10 ml) was added to the reaction mixture and extracted with ethyl acetate (2 x 10 ml) . Organic layer was dried over sodium sulfate and concentrated to afford crude compound which was further purified by column chromatography eluting with methanol (0 - 4%) in DCM to afford 2-((3- (( l-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-2,4,7-trioxo- 1 ,2,3,4,7,8- hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl)sulfonyl)acetamide (0. 1 g, 45%) .

[264] 1H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H) , 7.99 (dd, J = 9.4, 1.9

Hz, 1H) , 7.79 - 7.73 (m, 1H) , 7.58 (dd, J = 16.2, 8.3 Hz, 2H) , 7.52 - 7.45 (m, 1H) , 7.37 (s, 1H) , 7.35 - 7.23 (m, 2H) , 7.20 - 7. 12 (m, 1H) , 4.24 (s, 2H), 3.24 (s, 3H) , 2.78 (s, 3H), 1.56 (s, 3H) .

[265] MS (ESI): m/z: 654 (M+ l).

[266] Step 2: Synthesis of 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8- trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)- yl)phenyl)sulfonyl) acetamide (Compound 2).

[267] To a solution of 2-((3-(( l-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-

2,4,7-trioxo- 1 ,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5- yl) amino) phenyl) sulfonyljacetamide (0.06 g, 0.08 mmol) in THF (2 ml) was added sodium methoxide (0.04 ml, 25% solution in methanol). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 4 hrs. Reaction mixture was quenched by addition of (0.04 ml) of acetic acid. The resulting mixture was adsorbed on silica gel. Column purification was performed by eluting with methanol (0 - 2%) in DCM to afford titled compound 2-((3-(5-((2-fluoro-4- iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3- d]pyrimidin-l(2H)-yl) phenyl) sulfonyljacetamide (0.02 g, 35%).

[268] ⁱH NMR (400 MHz, DMSO-d6): δ 11.16 (s, 1H), 7.88 - 7.97 (m, 2H), 7.72 - 7.85 (m, 3H), 7.63 (s, 1H), 7.53 - 7.59 (m, 1H), 7.38 (s, 1H), 6.96 (t, J = 8.6 Hz, 1H), 4.32 (d, J = 6.8 Hz, 2H), 3.22 (s, 3H), 3.10 (s, 3H), 1.21 (s, 3H).

[269] MS (ESI): m/z: 654 (M+l).

[270] The following compound was prepared using a similar experimental procedure as given above, using appropriate starting material/ intermediates. [271] N-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin- l(2H)-yl) phenyl)- 1- (hydroxymethyl) cyclopropane- 1- sulfonamide (Compound 13).

[272] Ή NMR (400 MHz, DMSO-d6): 6 11.20 (s, 1H), 9.84 - 9.89 (m, 1H),

7.79 (dd, J = 10.3, 1.9 Hz, 1H), 7.51 - 7.59 (m, 1H), 7.29 - 7.42 (m, 2H), 7.20 - 7.27 (m, 1H), 7.05 - 7.13 (m, 1H), 6.93 (t, J = 8.6 Hz, 1H), 4.98 (t, J = 6.2 Hz, 1H), 3.77 (d, J = 5.2 Hz, 2H), 3.21 (s, 3H), 3.08 (s, 3H), 1.27 (s, 3H), 0.99 - 1.10 (m, 2H), 0.90 (s, 2H).

[273] MS (ESI): m/z: 682 (M+l).

[274] Example 13: Synthesis of l-((3-(5-((2-fluoro-4-iodophenyl)amino)- 6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)- yl)phenyl)sulfonyl)cyclopropanecarboxamide (Compound 6).

[275] Step 1: Synthesis of ethyl 2-((3-aminophenyl)thio)acetate

[276] Prepared using the same procedure as in example 2, step 4.

[277] MS (ESI): m/z: 212 (M+ l).

[278] Step 2: Synthesis of ethyl 2-((3-((l-(2-fluoro-4-iodophenyl)-3-(4- methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-l,2,3,4,7,8-hexahydropyrido[2,3- d]pyrimidin-5-yl)amino)phenyl)thio)acetat

[279] Prepared using the same procedure as in example 10, step 1. [280] 1H NMR (400 MHz, DMSO-d6): 6 10. 14 (s, 1H) , 7.98 (dd, J = 9.4, 1.9

Hz, 1H), 7.75 (dd, J = 8.3, 1.8 Hz, 1H) , 7.38 (t, J = 8. 1 Hz, 1H) , 7.20 - 7.33 (m, 3H) , 6.95 - 7.03 (m, 1H), 6.84 - 6.94 (m, 3H), 6.79 (dd, J = 7.8, 2. 1 Hz, 1H), 4.92 - 5.06 (m, 2H) , 4.05 - 4. 10 (m, 2H) , 3.88 (s, 2H) , 3.70 (s, 3H) , 2.76 (s, 3H) , 1.52 (s, 3H) , 1. 12 (t, J = 7. 1 Hz, 3H).

[281] MS (ESI): m/z: 757 (M+ l).

[282] Step 3: Synthesis of ethyl 2-((3-((l-(2-fluoro-4-iodophenyl)-3-(4- methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-l,2,3,4,7,8-hexahydropyrido[2,3- d]pyrimidin-5-yl)amino)phenyl)sulfonyl)acetat [283] To a solution of ethyl 2-((3-(( l-(2-fluoro-4-iodophenyl)-3-(4- methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo- l ,2,3,4,7,8-hexahydropyrido[2,3- d]pyrimidin-5-yl)amino)phenyl)thio)acetate (0.9 g, 1. 190 mmol) in ethyl acetate (20 ml) was added tetrabutylammonium hydrogensulfate (0.202 g, 0.595 mmol) and sodium tungstate dihydrate (0. 196 g, 0.595 mmol). The reaction mixture was stirred at room temperature for 15 hrs. To the reaction mixture water (20 ml) was added. Organic layer was saparated, dried over sodium sulfate, and concentrated under vacuum to afford crude product, which was purified by column chromatography eluting with ethyl acetate (0-50%) in hexane to afford ethyl 2-((3- (( l-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo- l ,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl)sulfonyl)acetate (0.560 g, 59.7%) as an off white solid.

[284] 1H NMR (400 MHz, DMSO-d6): 6 10.25 (s, 1H) , 7.98 (dd, J = 9.4, 1.9

Hz, 1H), 7.75 (dd, J = 8.3, 1.9 Hz, 1H) , 7.58 (t, J = 7.8 Hz, 1H) , 7.54 - 7.47 (m, 1H) , 7.43 - 7.35 (m, 2H), 7.30 (dd, J = 1 1.3, 8.3 Hz, 3H), 6.90 - 6.83 (m, 2H), 5.05 - 4.92 (m, 2H) , 4.63 (s, 2H) , 4.02 (q, J = 7. 1 Hz, 2H) , 3.70 (s, 3H), 2.78 (s, 3H), 1.55 (s, 3H), 1.03 (t, J = 7. 1 Hz, 3H) .

[285] MS (ESI): m/z: 789 (M+ l). [286] Step 4: Synthesis of ethyl 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-

3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3- d]pyrimidin-l(2H)-yl)phenyl)sulfonyl)acetate.

[287] Prepared using the same procedure as in example 10, step 3. [288] 1H NMR (400 MHz, DMSO-d6) : 6 1 1.06 (s, 1H) , 8.03 (t, J = 1.9 Hz,

1H) , 7.94 - 8.00 (m, 1H) , 7.87 (dt, J = 7.0, 1.2 Hz, 1H), 7.73 - 7.82 (m, 2H), 7.53 - 7.59 (m, 1H), 7.23 - 7.29 (m, 2H) , 7.01 (t, J = 8.6 Hz, 1H), 6.82 - 6.89 (m, 2H), 4.96 (s, 2H) , 4.73 (s, 2H) , 4.02 (qd, J = 7. 1 , 5.3 Hz, 2H) , 3.70 (s, 3H) , 3. 1 1 (s, 3H) , 1. 18 (s, 3H), 1.05 (t, J = 7. 1 Hz, 3H) . [289] MS (ESI): m/z: 789 (M+ l).

[290] Step 5: Synthesis of ethyl l-((3-(5-((2-fluoro-4-iodophenyl)amino)-

3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3- d]pyrimidin-l(2H)-yl)phenyl)sulfonyl)cyclopropanecarboxylate.

[291] To a stirred solution of ethyl ethyl 2-((3-(5-((2-fluoro-4- iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- l (2H)-yl)phenyl)sulfonyl)acetate (0.48 g, 0.609 mmol) , 1 ,2-dibromoethane (0.063 ml, 0.730 mmol), and 18-crown-6 (0.080 g, 0.304 mmol) in acetone (250 ml) was added K₂C0₃ (0.210 g, 1.522 mmol) and the mixture was refluxed for 24 hrs. The reaction mixture was filtered and concentrated under vacuum. The obtained residue was extracted with chloroform ( 10 ml), washed with water ( 10 ml) , dried over sodium sulphate, filtered, and concentrated under vacuum. Obtained crude product was purified by silica gel column chromatography by eluting with (0-35%) ethyl acetate in hexane to afford tilted compound (0. 140 g, 28.2%) an off white solid. [292] 1H NMR (400 MHz, DMSO-d6): 6 1 1. 12 (s, 1H) , 8.00 - 8.07 (m, 2H) ,

7.85-7.90 (m, 1H) , 7.83 - 7.72 (m, 2H), 7.56 (dd, J = 8.9, 1.9 Hz, 1H), 7.24 - 7.30 (m, 2H), 7.00 (t, J = 8.6 Hz, 1H) , 6.82- 6.89 (m, 2H), 4.97 (s, 2H) , 3.96 - 4.06 (m, 2H) , 3.70 (s, 3H), 3. 10 (s, 3H) , 1.94 (s, 2H) , 1.68 (s, 2H) , 1. 13 (s, 3H), 1.03 (t, J = 7. 1 Hz, 3H) .

[293] MS (ESI): m/z: 815 (M+ l).

[294] Step 6: Synthesis of l-((3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4- methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3- d]pyrimidin-l(2H)-yl)phenyl)sulfonyl)cyclopropanecarboxylic acid.

[295] To a solution of ethyl l-((3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4- methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3- d]pyrimidin- l (2H)-yl) phenyl) sulfonyljcyclopropanecarboxylate (0. 137 g, 0. 168 mmol) in the mixture of tetrahydrofuran (3 ml) , methanol (2 ml) , and water ( 1 ml) was added lithium hydroxide monohydrate (0.024 g, 1.01 mmol) and stirred at room temperature for 3 hrs. Reaction mixture was concentrated under vacuum and obtained residue was partitioned in water (4 ml) and ethyl acetate ( 10 ml). Organic layer was dried over sodium sulfate and concentrated under vacuum to afford l-((3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl- 2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin- 1 (2H)- yl) phenyl) sulfonyl)cyclopropanecarboxy lie acid (0. 125 g, 94%) as a white solid.

[296] MS (ESI): m/z: 787 (M+ l) .

[297] Step 7: Synthesis of l-((3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4- methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3- d]pyrimidin-l(2H)-yl)phenyl)sulfonyl)cyclopropanecarboxamide.

[298] To a mixture of l-((3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4- methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3- d]pyrimidin- l (2H)-yl) phenyl) sulfonyl)cyclopropanecarboxylic acid (0.090 g, 0. 1 14 mmol) , HOBT (0.026 g, 0. 172 mmol) , DIPEA (0.080 ml, 0.458 mmol) , and ammonium chloride (0.012 g, 0.229 mmol) in DMF ( 1 ml) was added PyBOP (0.089 g, 0. 172 mmol) and stirred at room temperature. After 1 hr, the reaction mixture was poured into water (5 ml) and extracted with ethyl acetate (2 x 5 ml) . Organic layer was dried over sodium sulfate and concentrated to afford crude compound which was further purified by column chromatography by eluting with ethyl acetate (0-50%) in hexane to afford l-((3-(5-((2-fluoro-4-iodophenyl)amino)- 3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3- djpyrimidin- l (2H)-yl) phenyl) sulfonyl)cyclopropanecarboxamide (0.084 g, 93%) as an off white solid.

[299] MS (ESI): m/z: 786 (M+ l).

[300] Step 8: Synthesis of l-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8- dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)- yl)phenyl)sulfonyl)cyclopropanecarboxamide (Compound 6).

[301] Prepared using the same procedure as in example 10, step 4.

[302] 1H NMR (400 MHz, DMSO-d6) : 6 1 1.67 (s, 1H), 1 1.21 (s, 1H), 7.94 -

8.02 (m, 2H) , 7.68 - 7.86 (m, 3H), 7.56 (dd, J = 8.1 , 1.8 Hz, 1H), 7.51 (s, 1H) , 7.38 (s, 1H), 6.97 (t, J = 8.6 Hz, 1H), 3.07 (s, 3H) , 1.71 (q, J = 4.7 Hz, 2H) , 1.53 (t, J = 4.0 Hz, 2H) , 1. 16 (s, 3H) .

[303] MS (ESI): m/z: 666 (M+ l).

[304] Example 14: Synthesis of of 2-((3-aminophenyl)sulfonyl) propanamide.

[305] Step 1: Synthesis of of methyl 2-((3-nitrophenyl)thio)propanoate.

[306] Prepared using the same procedure as in example 3, step 1.

[307] Ή NMR (400 MHz, Chloroform-d): 6 8.32 (t, J = 2.0 Hz, 1H), 8.14

(ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 7.76 (ddd, J = 7.8, 1.8, 1.0 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 3.92 (q, J = 7.2 Hz, 1H), 3.73 (s, 3H), 1.56 (d, J = 7.2 Hz, 3H).

[308] MS (ESI): m/z: 242 (M+l).

[309] Step 2: Synthesis of methyl 2-((3- nitrophenyl)sulfonyl)propanoate.

[310] Prepared using the same procedure as in example 3, step 2. [311] ⁱH NMR (400 MHz, DMSO-d6): 68.63 (ddd, J = 8.3, 2.3, 1.0 Hz, 1H),

8.57 (t, J = 2.0 Hz, 1H), 8.32 (ddd, J = 7.9, 1.8, 1.0 Hz, 1H), 7.99 (t, J = 8.0 Hz, 1H), 4.84 (d, J = 7.1 Hz, 1H), 3.59 (s, 3H), 1.46 (d, J = 7.1 Hz, 3H).

[312] Step 3: Synthesis of 2-((3-nitrophenyl)sulfonyl)propanoic acid.

[313] Prepared using the same procedure as in example 3, step 3. [314] Step 4: Synthesis of 2-((3-nitrophenyl)sulfonyl)propanamide.

[315] To an ice cooled solution of 2-((3-nitrophenyl)sulfonyl)propanoic acid

(1.2 g, 4.63 mmol) in THF (20 ml) was added oxalyl chloride (0.810 ml, 9.26 mmol) drop wise over 2 min using a syringe. Once the addition was complete, few drops of DMF was added and the mixture was stirred for another 3 hrs at room temprature. Solvent was removed under vacuum. Ammonia solution (0.334 ml, 4.63 mmol) was added to the solution of above obtained compound in THF (20 ml). The reaction mixture was stirred for another 1 hr at 0°C. Extraction was carried out using ethyl acetate (2 x 100 ml). The combined organic layer was dried over sodium sulfate and concentrated under vacuum to afford crude compound which was further purified by column chromatography by eluting with ethyl acetate (0- 100%) in hexane to afford afford 2-((3- nitrophenyl)sulfonyl)propanamide (0.9g, 75%) .

[316] GCMS: 257 (M⁺) .

[317] Step 5: Synthesis of 2-((3-aminophenyl)sulfonyl)propanamide.

[318] Prepared using the same procedure as in example 3, step 4.

[319] MS (ESI): m/z: 229 (M+ l).

[320] Example 15: Synthesis of 2-((3-aminophenyl)sulfonyl)-N- methylpropanamide .

[321] Step 1: Synthesis of N-methyl-2-((3-nitrophenyl)sulfonyl) propanamide.

[322] Prepared using the same procedure as in example 5, step 2.

[323] Step 2: Synthesis of 2-((3-aminophenyl)sulfonyl)-N- methylpropanamide .

[324] Prepared using the same procedure as in example 3, step 4.

[325] Example 16: Synthesis of 2-((3-aminophenyl)sulfonyl)-N,N- dimethylpropanamide.

[326] Step 1: Synthesis of N,N-dimethyl-2-((3- nitrophenyl)sulfonyl)propanamide.

[327] Prepared using the same procedure as in example 14, step 4.

[328] Step 2: Synthesis of 2-((3-aminophenyl)sulfonyl)-N,N- dimethylpropanamide

[329] Prepared using the same procedure as in example 3, step 4.

PHARMACOLOGICAL ACTIVITY

In-Vitro Experiments

[330] Example A: Identification of compounds inhibiting MEK kinase activity.

[331] In a 25 μΐ reaction, MEK enzyme (final concentration 2-4 μg/ml) and

ERK substrate (final concentration 50- 100 μg/ml) were incubated with various concentrations 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 reactions were initiated by the addition of ATP. The reactions were terminated by adding an equal volume of KinaseGlo reagent (Promega) following the manufacturer's instructions. The plates were read on a luminometer. IC50 calculations were done using GraphPad Prism 5.

[332] The IC50 values of the test compounds of inventions were below 400 nM.

[333] Example B: Analysis of ERK phosphorylation.

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

[335] 100 - {(RFU test - RFU lysis buffer control) / (RFU vehicle treated control - RFU lysis buffer control)} x 100. The compounds prepared were tested using the above assay procedure.

[336] The minimum concentration of the compounds of invention required for≥80% inhibition of pERK was 1 nM.

[337] The foregoing description is considered illustrative only. Further, since numerous modifications and changes will readily be apparent to those skilled in the art, it is not intended to limit the disclosure as described herein. Accordingly, all suitable modifications and equivalents fall within the scope of the disclosure and the claims that follow.

[338] The words "comprise", "comprising", "include", and "including" when used in this specification and in the following claims are intended to specify the presence of the stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more additional features, integers, components, or steps thereof.

Claims

1. A compound of formula (I), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof,

wherein:

R¹ is selected from hydrogen and substituted- or unsubstituted- alkyl; R² is selected from -S0₂R⁶ and -NHSO2R⁷;

R³ and R⁴ are independently selected from hydrogen and substituted- or unsubstituted- alkyl; R⁵ is substituted- or unsubstituted- aryl;

R⁶ is selected from: a) substituted- or unsubstituted- four membered heterocyclic group; b) cycloalkyl substituted with haloalkyl, hydoxyalkyl, and alkoxyalkyl; and c) -(CR^aR^b)C(=0)NR^cR^d, wherein R^a, R^b, R^c, and R^d are each independently selected from the group consisting of hydrogen and substituted- or unsubstituted- alkyl, or R^a and R^b together with carbon atom to which they are attached form a cyclopropyl ring;

R⁷ is cycloalkyl substituted with haloalkyl, hydoxyalkyl, and alkoxyalkyl; when the alkyl group is substituted, it is substituted with 1 to 3 substituents independently selected from oxo, halogen, nitro, cyano, perhaloalkyl, -S02R^8a, - C(=0)OR^8a, -OC(=0)R^8a, -C(=0)N(H)R⁸, -OR^Sb, -C(=0)N(alkyl)R⁸, -N(H)C(=0)R⁸*, - N(H)R⁸, -N(alkyl)R⁸, and -NH-S0₂-alkyl; when the aryl group is substituted, it is substituted with 1 to 3 substituents independently selected from halogen, nitro, cyano, hydroxy, alkyl, perhaloalkyl, -O-alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -NH₂, -S0₂-alkyl, -S0₂- perhaloalkyl, -S0 N(alkyl)alkyl, -S0 N(H)alkyl, and -S0 NH ; when the heterocyclic group is substituted, it is substituted either on a ring carbon atom(s) or on a ring nitrogen atom; when heterocyclic group substituted on a ring carbon atom(s), it is substituted with 1 or 2 substituents independently selected from halogen, nitro, cyano, oxo, alkyl, perhaloalkyl, - OR^8b, -C(=0)OR^8a, -C(=0)N(H)R⁸, and N(H)R⁸; and when heterocylic group substituted on a ring nitrogen, it is substituted with a substituent selected from alkyl, cycloalkyl, aryl, -S0₂R⁸*, -C(=0)R⁸*, -C(=0)OR^8a, and -C(=0)N(H)R⁸;

R⁸ is selected from hydrogen, alkyl, and cycloalkyl;

R^8a is selected from alkyl, perhaloalkyl, and cycloalkyl; and

R^8b is selected from the group consisting of hydrogen, alkyl, perhaloalkyl, and cycloalkyl.

2. The compound of claim 1 , wherein R¹ is selected from hydrogen and methyl.

3. The compound of claim 1 or 2, wherein R² is selected from

4. The compound of any one of claims 1-3, wherein R³ and R⁴ are independently substituted- or unsubstituted- alkyl.

5. The compound of any one of claims 1-4, wherein R³ and R⁴ are methyl.

6. The compound of any one of claims 1-5, wherein R⁵ is substituted- or unsubstituted- phenyl.

7. The compound of any one of claims 1-6, wherein R⁵ is 2-fluoro-4-iodobenzene.

8. The compound of any one of claims 1-7, wherein the compound is selected from the group consisting of:

5-((2-fluoro-4-iodophenyl)amino)- l-(3-(( l-

(fluoromethyl)cyclopropyl)sulfonyl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidine- 2,4,7( lH,3H,6H)-trione (Compound 1) ,

2-((3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- l (2H)-yl)phenyl)sulfonyl)acetamide

(Compound 2) ,

2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- l (2H)-yl)phenyl)sulfonyl)-N,N,2- trimethylpropanamide (Compound 3) ,

2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- l (2H)-yl)phenyl)sulfonyl)acetamide

(Compound 4) ,

2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- l (2H)-yl)phenyl)sulfonyl)propan amide

(Compound 5) ,

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

2- ((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- 1 (2H)-yl)phenyl)sulfonyl)-N- methylpropanamide (Compound 7) , 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetr ahy dropyrido [4 , 3 - d] pyrimidin- 1 (2H) -yl) phenyl) sulfonyl) - N , 2 - dimethylpropanamide (Compound 8) ,

2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- 1 (2H)-yl)phenyl)sulfonyl)-2- methylpropanamide (Compound 9) ,

5-((2-fluoro-4-iodophenyl)amino)- 1-(3-(( 1-

(hydroxymethyl) cyclopropyl) sulfonyl) phenyl) -6,8- dimethylpyrido [4,3- d]pyrimidine-2,4,7( lH,3H,6H)-trione (Compound 10) ,

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

2- ((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- l (2H)-yl)phenyl)sulfonyl)-N,N- dimethylpropanamide (Compound 12) ,

N-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- l (2H)-yl)phenyl)- 1- (hydroxymethyl) cyclopropane- 1- sulfonamide (Compound 13),

N-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- l (2H)-yl)phenyl)- 1- (fluoromethyl) cyclopropane- 1- sulfonamide (Compound 14) ,

N-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- l (2H)-yl)phenyl)- 1- (methoxymethyl) cyclopropane- 1- sulfonamide (Compound 15) , and

N-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- l (2H)-yl)phenyl)- 1- (hydroxymethyl) cyclopropane- 1- sulfonamide (Compound 16).

9. A compound of formula (la) , its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof,

wherein: R^la is selected from hydrogen and methyl;

R^2a is selected from

R^3a and R^4a are methyl; and

R^5a is 2-fluoro-4-iodobenzene.

10. The compound of claim 9, wherein the compound is selected from the group consisting of:

5-((2-fluoro-4-iodophenyl)amino)- l-(3-(( l-

(fluoromethyl)cyclopropyl)sulfonyl)phenyl)-6,8-dimethylpyrido[4,3- d]pyrimidine-2,4,7( lH,3H,6H)-trione (Compound 1), 2-((3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- 1 (2H)-yl)phenyl)sulfonyl)-2- methylpropanamide (Compound 9), 5-((2-fluoro-4-iodophenyl)amino)- l-(3-(( l-

(hydr oxymethyl) cyclopropyl) sulfonyl) phenyl) -6,8- dimethylpyrido [4,3- d]pyrimidine-2,4,7( lH,3H,6H)-trione (Compound 10) ,

N-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- 1 (2H)-yl)phenyl)- 1- (fluoromethyl) cyclopropane- 1- sulfonamide (Compound 14),

N-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- 1 (2H)-yl)phenyl)- 1- (methoxymethyl) cyclopropane- 1- sulfonamide (Compound 15) , and

N-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin- 1 (2H)-yl)phenyl)- 1- (hydroxymethyl) cyclopropane- 1- sulfonamide (Compound 16) .

11. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof of any one of claims 1- 10 and a pharmaceutically acceptable carrier, diluent, or excipient.

12. A method for inhibiting a MEK enzyme, comprising contacting said MEK enzyme with a composition comprising a compound of formula (I) or (la), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof as claimed in any one of claims 1- 10, in an amount sufficient to inhibit said enzyme.

13. The method of claim 12, wherein said MEK enzyme is MEK kinase.

14. The method of claim 12, wherein said contacting occurs within a cell.

15. A method of treatment of a MEK mediated disorder in a subject suffering from said disorder, comprising administering to said subject an effective amount of a composition comprising a compound of formula (I) or (la), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof as claimed in any one of claims 1- 10.

16. The method of claim 15, further comprising administering an an additional therapy.

17. The method of claim 16, wherein said additional therapy is radiation therapy, chemotherapy, or a combination of both.

18. The method of claim 15, further comprising administering an additional therapeutic agent.

19. The method of claim 15, 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, proliferative disorders, hyperproliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases, and malignant diseases.

20. The method of claim 15, wherein said MEK mediated disorder is a hyperproliferative disease.

21. The method of claim 15, wherein said MEK mediated disorder is cancer, tumors, leukemias, neoplasms, or carcinomas.

22. The method of claim 15, wherein said MEK mediated disorder is an inflammatory disease.

23. The method of claim 15, wherein said subject is a mammal.

24. A method for the treatment or prophylaxis of a proliferative disease in a subject suffering from said disease, comprising administering to said subject an effective amount of a composition comprising a compound of formula (I) or (la), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof as claimed in any one of claims 1- 10.

25. The method of claim 24, wherein said proliferative disease is cancer, psoriasis, restenosis, autoimmune disease, or atherosclerosis.

26. A method for the treatment or prophylaxis of an inflammatory disease in a subject suffering from said disease, comprising administering to said subject an effective amount of a composition comprising a compound of formula (I) or (la), its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof as claimed in any one of claims 1- 10.

27. The method of claim 26, wherein said inflammatory disease is rheumatoid arthritis or multiple sclerosis.

28. A method for degrading, inhibiting the growth of, or killing cancer cells comprising contacting the cells with an amount of a composition effective to degrade, inhibit the growth of, or kill the cancer cells, wherein the composition comprises a compound of formula (I) or (la) , its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof as claimed in any one of claims 1- 10.

29. A method of inhibiting tumor size increase, reducing the size of a tumor, reducing tumor proliferation, or preventing tumor proliferation in a subject in need thereof, comprising administering to said subject an effective amount of a composition to inhibit tumor size increase, reduce the size of a tumor, reduce tumor proliferation or prevent tumor proliferation, wherein the composition comprises a compound of formula (I) or (la) , its tautomeric form, its stereoisomer, or its pharmaceutically acceptable salt thereof as claimed in any one of claims 1- 10.