WO2010145197A1

WO2010145197A1 - Novel 6-arylamino pyridone sulfonamides and 6-arylamino pyrazinone sulfonamdies as mek inhibitors

Info

Publication number: WO2010145197A1
Application number: PCT/CN2010/000851
Authority: WO
Inventors: Dengming Xiao; Li Zhu; Shixin Wang; Zhi LIANG; Wei Hu
Original assignee: CHEMIZON (BEIJING) Ltd
Current assignee: CHEMIZON (BEIJING) Ltd
Priority date: 2009-06-15
Filing date: 2010-06-13
Publication date: 2010-12-23
Anticipated expiration: 2011-12-15
Also published as: KR20120034736A; WO2010145197A8; CN102134218A; JP2012530079A

Abstract

The invention provides novel substituted 6-arylamino pyridone sulfonamides and 6 arylamino pyrazinone sulfonamides represented by Formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, and a composition comprising these compounds. The compounds provided can be used as inhibitors of MEK and are useful in the treatment of inflammatory diseases, cancer and other hyperproliferative diseases. The invention further provides a method of treatment for inflammatory diseases, cancer and other hyperproliferative diseases in mammals, especially humans.

Description

NOVEL 6-ARYLAMINO PYRIDONE SULFONAMIDES AND 6-ARYLAMINO PYRAZINONE SULFONAMDIES AS MEK INHIBITORS

FIELD OF THE INVENTION

[001] This invention relates to a series of substituted 6-arylamino pyridone sulfonamide and 6- arylamino pyrazinone sulfonamides which are inhibitors of MEK and are useful in the treatment of inflammatory diseases, cancer and other hyperproliferative diseases. This invention also relates to a pharmaceutical composition comprising the compound of the invention, use of the compound in the preparation of a medicament, and method of treatment for hyperproliferative diseases in mammals, especially humans by administering the compound thereof.

BACKGROUND OF THE INVENTION

[002]Protein kinases constitute a large family of structurally related enzymes that effect the transfer of a phosphate group from a nucleoside triphosphate to a Ser, Thr or Tyr residue on a protein acceptor. A vast array of cellular functions, including DNA replication, cell cycle progression, energy metabolism, and cell growth and differentiation, are regulated by reversible protein phosphorylation events mediated by protein kinases. Additionally, protein kinase activity has been implicated in a number of diseases, including cancers. Of the >100 dominant oncogenes known to date, many encode receptor and cytoplasmic protein kinases known to be mutated and/or over expressed in human cancers (Blume- Jensen and Hunter, Nature, 411:355- 365 (2001)). Accordingly, protein kinase targets have attracted substantial drug discovery efforts in recent years, with several protein kinase inhibitors achieving regulatory approval (reviewed in Fischer, Curr. Med. Chem., 11 : 1563 (2004); Dancey and Sausville, Nature Rev. Drug Disc., 2:296 (2003)).

[003] The Ras/Raf7MEK/ERK pathway is a central signal transduction pathway, which transmits signals from multiple cell surface receptors to transcription factors in the nucleus which regulate gene expression. This pathway is frequently referred to as the MAP kinase pathway as MAPK stands for mitogen-activated protein kinase indicating that this pathway can be stimulated by mitogens, cytokines and growth factors (Steelman et al., Leukemia 2004, 18, 189-218). Depending upon the stimulus and cell type, this pathway can transmit signals, which result in the prevention or induction of apoptosis or cell cycle progression. The Ras/Raf/MEK/ERK pathway has been shown to play important roles in cell proliferation and the prevention of apoptosis. Aberrant activation of this pathway is commonly observed in malignantly transformed cells. Amplification of ras proto-oncogenes and activating mutations that lead to the expression of constitutively active Ras proteins are observed in approximately 30% of all human cancers (Stirewalt et al., Blood 2001, 97, 3589-95). Mutated, oncogenic forms of Ras are found in 50% of colon and >90% pancreatic cancers as well as many other types of cancers (Kohl et al., Science 1993, 260, 1834-1837). The effects of Ras on proliferation and tumorigenesis have been documented in immortal cell lines (McCubrey et al., Int J Oncol 1995, 7, 295-310). bRaf mutations have been identified in more than 60% of malignant melanoma (Davies, H et al., Nature 2002, 417, 949954). Given the high level of mutations that have been detected at Ras, this pathway has always been considered a key target for therapeutic intervention (Chang et al., Leukemia 2003, 17, 1263-93).

[004] As constitutive or overactivation of MAP kinase cascade plays a pivotal role in cell proliferation and differentiation, inhibition of this pathway is believed is to be beneficial in hyperproliferative diseases. MEK is a key player in this pathway as it is downstream of Ras and Raf. Additionally, it is an attractive therapeutic target because the only known substrates of MEK phosphorylation are the MAP kinases, ERKl and ERK2. Inhibition of MEK has been shown to have potential therapeutic benefit in several studies. For example, small molecule MEK inhibitors have been shown to inhibit human tumor growth in mouse xenografts, (Seebolt-Leopold et. al., Nature-Medicine, 1999 5(7), 810-816; Trachet et al. AACR April 6-10, 2002, Poster & num; 5426) and inhibit growth of acute myeloid leukemia cells (Milella et. al., J. Clin. Invest., 2001, 108 (6) 851-859).

[005] Compounds suitable as MEK inhibitors are also disclosed in WO 00/41994; WO 00/42022; WO 00/42029; WO 00/68201; WO 01/68619; WO 02/06213, WO 03/077914, WO 05/023251, WO

05/121142, WO07/014011, WO 07/071951, WO 07/123939, WO 08/ 021389, WO 08/078086, WO

08/120004, WO 08/124085, WO 08/125180, WO 09/018233, WO07/044084, WO07/121481 and WO

09/018238.

SUMMARY OF THE INVENTION

[006] This invention provides a compound of formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof:

wherein

[007] R₀ is H, Ci-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₅-C₆ cycloalkenyl or C₂-C₆ alkynyl; wherein each alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C₁-C₄ alky, Ci-C₄ alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, andone or two ring carbon atoms of said C₃-C₆ cycloalkyl groups are optionally replaced with, independently, O, N, or S; and

[008] Ri is H, C₁-C₄ alkoxy, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₅-C₆ cycloalkenyl C₂- C₆ alkynyl, or halogen; wherein each alkoxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C₁-C₄ alky, Ci-C₄ alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, or Ri is 5 or 6-atom heterocyclic group, which group may be saturated, unsaturated, or aromatic, containing 1-5 heteroatoms selected independently from the group consisting of O, N, and S, which heterocyclic group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C₁ -C₄ alky, Ci-C₄ alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl; or

[009] Ri is -CH₂X'where X' represents a group according to formula (H)

wherein [010] Yi and Y₂ may be the same or different, each represents a single bond, -CO-, -COO, -O-, - OCO-, -NR_a or-SO₂-;

[011] Y₃ represents a Cj_-5 alkyl which may be substituted by one to three groups represented by Z;

[012]Z may be the same or different and represent a C₁.₅ alky group, halogen atom; an oxo group, -OR_a, -COOR₃, -COOCOR_a, -CO-halogen atom, -OCOR₃, -CONR₃Rb, -SR₃, -SO₂R₃, -NR₃Rb, - NR₃COR_b, NR₃SO₂R_b, -SO₂NR_aR_b, a 5 or 6 membered monocyclic or 9 to 13 membered bicyclic heterocyclic group, or a 5 or 6 membered monocyclic or 9 to 13 membered bicyclic heteroaryl group which may be optionally substituted with one or more substituents selcted from the group consisting of a Ci-₅ alkyl group, -OR₃, and NR₃Rb; the alkyl group may be substituted by a hydroxyl group, a C_1-S alkoxy group, or an amino group; the above substituents except the oxo group and the halogen may be linked to each other to form a cycloalkyl group or a heterocyclic group which may has one or more substituents selected from the group consisting Of-OR₃, NR₃R_b, and a Ci_-5 alkyl group that may be substituted with- OR₃;

[013] R₃ and R_b may be the same or different and each represents a hydrogen atom or a C_1-S alkyl group which may be substituted by one to three groups selected from the group consisting of a hydroxyl group, a Ci-₅ alkoxy group and an amino group

[014] The symbol "•" used in formula II implies the site of bonding; and

[015] X is C or N;

[016] R₂ is H, C₁-C₄ alkoxy, Ci-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₅-C₆ cycloalkenyl or C₂-C₆ alkynyl; wherein each alkoxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C₁-C₄ alky, C₁-C₄ alkoxy, cyano, cyanomethyl, trifluorornethyl, difluoromethoxy and phenyl, or R₂ is 5 or 6-atom heterocyclic group, which group may be saturated, unsaturated, or aromatic, containing 1-5 heteroatoms selected independently from the group consisting of O, N, and S, which heterocyclic group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C₁-C₄ alky, C₁-C₄ alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl when X = C or R₂ = nothing when X = N; or

R₁ and R₂ taken together form a 5 or 6 membered heterocyclic group which group may be unsaturated or aromatic containing 1-3 heteroatoms selected independently from the group consisting of O, N or S which heterocyclic group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxyl, Ci-C₄ alkyl, Ci -C₄ alkoxy, cyano, cyanomethyl, trifluormethyl, difluroomethoxy and phenyl; and

[017] R₃ is selected from the group consisting of trifluoromethyl, Ci-Ci₀ alkyl, C₂-Ci₀ alkenyl, C₂-Ci₀ alkynyl, C₃-Ci₀ cycloalkyl, C₃-Ci₀ cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarycycloalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, heteroarycycloalkyl, and heterocyclyl is unsubstituted or substituted with 1-3 substituents selected independently from halogen, hydroxyl, C₁- C₄ alkyl, Ci- C₄ alkoxy, cyano, trifluoromethyl, difluoromethoxy, phenyl or substituted phenyl with 1-3 substituents selected independently from halogen, hydroxyl, Ci- C₄ alkyl, Ci- C₄ alkoxy, cyano trifluoromethyl, or difluoromethoxy,

[018] R₄, Rs, R₆, R₇, and Rg are independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, S R ₉ , O R ₉ , C ( O ) R ₉ , NRi₀C(O)ORi₂, OC(O)R₉, NRi₀ S(O)j R_n, S (O)jNR₉ Ri₀, S(O)jNR,₀C(O)R₉, C(O)NRi₀S (0)j R₁₂, S (O^ Ri₂, NRi₀C(O)R₉, C(O)NR₉Ri₀, NRi ₁C(O)NR₉Ri_O, NRi₁C(NCN)NR₉R₁₀, NR₉Ri₀ and Ci-Ci₀ alkyl, C₂-Ci₀ alkenyl, C₂-Ci₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, S(O)J(C₁-C₆ alkyl), S(O)J(CRi₀R₁ i)_m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, ©(CRioRioWaryl, NR₁₀(CRI₀RI i)_m-aryl, 0(CR₁₀R₁ i)_m-heteroaryl, NR₁₀(CRi₀R₁ O_m-heteroaryl, 0(CR₁₀R₁ i)_m-heterocyclyl, NR₁₀(CR₁₀R₁ O_m-heterocyclyl, and S(C₁-C₂ alkyl) optionally substituted with 1-5 fluorine atoms;

[019] R₉ is selected from the group consisting of hydrogen, trifluoromethyl, C₁ - C₁₀ alkyl, C₂- C₁₀ alkenyl, C₂ - C₁₀ alkynyl, C₃ - C₁₀ cycloalkyl, C₃ - C₁₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halogen, C₁ - C₄ alkyl, hydroxyl and amino;

[020] Ri₀ is selected from hydrogen or Ci-C₆ alkyl where alkyl may be unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halogen, C₁- C₄ alkyl, hydroxyl and amino; or

[021] R₉ and Ri₀ can be taken together with the atom to which they are attached to form a 4 to 10 membered heteroaryl or heterocyclic ring, each of which is unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halogen, C₁-C₄ alkyl, hydroxyFand amino; [022] R₁₁ is selected from hydrogen or C₁-C₆ alkyl where alkyl may be unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halogen, C₁- C₄ alkyl, hydroxyl and amino; or

[023] R_1O and R₁₁ can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is unsubstituted orsubstituted with 1 -3 substituents independently selected from the group consisting of halogen, C₁- C₄ alkyl, hydroxyl and amino;

[024] R₁₂ is selected from trifluoromethyl, CfC₁₀ alkyl, C₃-Q₀ cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl unsubstituted or substituted with 1 -3 substituents independently selected from the group consisting of halogen, C₁-C₄ alkyl, hydroxyl and amino;

[025] m is 0, 1 £3,4, or 5; and

[026] j is l or 2.

[027] In another aspect, the present invention provides some preferable compounds of Formula I, wherein Ro is H or C₁-C₆ alkyl; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

[028]In another aspect, the present invention provides some preferable compounds of Formula I, wherein R₁ is H or C₁-C₆ alkyl; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

[029] In another aspect, the present invention provides some preferable compounds of Formula I, wherein R₂ is nothing when X is N; or H or Cj-C₆ alkoxy when X is C; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

[030] In another aspect, the present invention provides some preferable compounds of Formula I , wherein R₂ is Ci-C₄ alkoxy; or 5 or 6-atom heterocyclic group, which group may be saturated, unsaturated, or aromatic, containing 1-5 heteroatoms selected independently from O, N, and S, which heterocyclic group is optionally substituted with 1-3 substituents selected independently from halogen, hydroxy, Ci-C₄ alky, Ci-C₄ alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl when X is C; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. [031] In another aspect, the present invention provides some preferable compounds of Formula I, wherein R₃ is selected from the group consisting OfC₁-Q alkyl optionally substituted with one or more halogen or hydroxyl; C₂-C₆ alkenyl; Q-Q cycloalkyl optionally substituted with C₁-C₆ alkyl or C₂-C₆ alkenyl; 5 or 6 membered monocyclic or 9 to 13 membered bicyclic heteroaryl with O, N, or S as the hetero atom; 5 or 6 membered monocyclic or 9 to 13 membered bicyclic aryl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, C₁-QaIkOXy and hydroxyl; arylcycloalkyl in which aryl is 5 or 6 membered monocyclic or 9 to 13 membered bicyclic aryl and cycloalkyl has 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, Ci-Q alkoxy and hydroxyl; heteroarylcycloalkyl in which heteroaryl is 5 or 6 membered monocyclic or 9 to 13 membered bicyclic aryl and cycloalkyl has 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, Cj-C₆ alkoxy and hydroxyl; and Ci-C₆ alkyl Ci-Q cycloalkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, Ci-Q alkoxy and hydroxyl; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

[032] In another aspect, the present invention provides some preferable compounds of Formula I, wherein R₄, R₅, R₆, R₇, and R₈ are independently selected from H or halogen; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

[033] In another aspect, the present invention provides some preferable compounds of Formula I, wherein one of R₄ and R₈ is fluoro, and R₆ is iodo; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

[034] In another aspect, the present invention provides some more preferable compounds of Formula I, wherein Ro is H or Ci-C₆ alkyl; Ri is H or Ci-C₆ alkyl; R₂ is nothing when X is N, and is H or Ci-C₆ alkoxy when X is C; R₃ is selected from the group consisting of Ci-C₆ alkyl optionally substituted with one or more halogen or hydroxyl; C₂-C₆ alkenyl; C₃-C₆ cycloalkyl optionally substituted with Ci-C₆ alkyl or C₂-C₆ alkenyl; 5 or 6 membered monocyclic or 9 to 13 membered bicyclic heteroaryl with O, N, or S as the hetero atom; 5 or 6 membered monocyclic or 9 to 13 membered bicyclic aryl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, Ci-C₆ alkoxy and hydroxyl; arylcycloalkyl in which aryl is 5 or 6 membered monocyclic or 9 to 13 membered bicyclic aryl and cycloalkyl has 1 to 6 carbon atoms; and Ci-C₆ alkyl Ci-C₆ cycloalkyl; and R₄, R₅, R₆, R₇, and R₈ are independently selected from H or halogen ; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

[035] In another aspect, the present invention provides compounds represented by the following Formula:

wherein

[036] R₀, Ri₅R₂, R4~R₈ are defined as Formula I;

[037] Rn is selected from the group consisting of H, C₂-C₆ alkenyl and Ci-C₆ alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxyl;

R_H is selected from the group consisting of H, CpC₆ alkyl, 5 or 6 membered monocyclic or 9 to 13 membered bicyclic aryl and 5 or 6 membered monocyclic or 9 to 13 membered bicyclic heteroaryl with O, N, or S as the hetero atom, optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, Ci-C₆ alkyl optionally substituted with halogen, and Ci-C₆ alkoxy;

or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

[038] In another aspect, R₀ is H or Ci-C₆ alkyl; Ri is H, Ci-C₆ alkyl or halogen; R₂ is H or Ci-C₆ alkoxy; R₃ is selected from the group consisting of C₁-C₆ alkyl optionally substituted with one or more halogen or hydroxyl; C₂-C₆ alkenyl; C₃-C₆ cycloalkyl optionally substituted with Ci-C₆ alkyl or C₂-C₆ alkenyl; 5 or 6 membered monocyclic or 9 to 13 membered bicyclic heteroaryl with O, N, or S as the hetero atom; 5 or 6 membered monocyclic or 9 to 13 membered bicyclic aryl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, Ci-C₆ alkoxy and hydroxyl; arylcycloalkyl in which aryl is 5 or 6 membered monocyclic or 9 to 13 membered bicyclic aryl and cycloalkyl has 1 to 6 carbon atoms; and Ci-C₆ alkyl Ci-C₆ cycloalkyl; and R₄, R₅, R₆, R₇, and Rg are independently selected from H or halogen; and

Ru and Rj₄ are defined as above; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

[039] In another aspect, the present invention provides compounds represented by the following Formula:

wherein,

[040] Ri is H, Ci-C₆ alkyl or haloge; R₂ is H or Ci-C₆ alkoxy; Rn is selected from the group consisting of H, C₂-C₆ alkenyl and Ci-C₆ alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxyl; Ri₄ is selected from the group consisting of H, Q-C₆ alkyl, 5 or 6 membered monocyclic or 9 to 13 membered bicyclic aryl and 5 or 6 membered monocyclic or 9 to 13 membered bicyclic heteroaryl with O, N, or S as the hetero atom, optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, Ci-C₆ alkyl optionally substituted with halogen, and Q- C₆ alkoxy;

[041 ] In another aspect, the present invention provides compounds represented by the following Formula:

wherein, [042] Rn is selected from the group consisting of H, C₂-C₆ alkenyl and Ci-C₆ alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxyl; R_H is selected from the group consisting of H, Cj-C₆ alkyl, 5 or 6 membered monocyclic or 9 to 13 membered bicyclic aryl and 5 or 6 membered monocyclic or 9 to 13 membered bicyclic heteroaryl with O, N, or S as the hetero atom, optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, Ci-C₆ alkyl optionally substituted with halogen, and Ci-C₆ alkoxy;

[043] In other embodiments, the present invention provides compounds represented by the following Formulae:

[044] hi another aspect, the present invention provides compounds represented by the following Formula:

wherein

[045] Rn is selected from the group consisting of H, C₂-C₆ alkenyl and C₁-C₆ alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxyl; R^ is selected from the group consisting of H, C₁-C₆ alkyl, 5 or 6 membered monocyclic or 9 to 13 membered bi cyclic aryl and 5 or 6 membered monocyclic or 9 to 13 membered bicyclic heteroaryl with O, N, or S as the hetero atom, optionally substituted with one or more substituents selected from the group consisting of halogen, cyano and Cj-C₆ alkoxy;

[046] In other embodiments, the present invention provides compounds represented by the following Formulae:

[047]Compounds of present invention are inhibitors of MEK and, consequently, are useful for treating cancers and other hyperproliferative diseases.

[048] In other aspects, the present invention is directed to a pharmaceutical composition comprising an effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvants and/or excipients. In some embodiments, such a composition may contain at least one of preservatives, agents for delaying absorption, fillers, binders, adsorbents, buffers, disintegrating agents, solubilizing agents, and other carriers, adjuvants and/or excipients as inert ingredients. The composition may be formulated with a method well-known in the art.

[049] In some aspects, the present invention is directed to a method of treating a disease in an individual suffering from said disease comprising administering to said individual a therapeutically effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

[050] In other aspects, the present invention is directed to a method of treating a disorder in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or pro- drug thereof.

[051] In other aspects, the present invention is directed to a method of treating a disorder in a human, comprising administering to said human a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or pro- drug thereof.

[052] In other aspects, the present invention is directed to a method of treating an inflammatory disease, condition, or disorder in a mammal, including a human, comprising administering to said mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt, ester, prodrug, solvate, such as hydrate, polymorph or tautomer thereof.

[053] In other aspects, the present invention is directed to a method of treating a disorder or condition which is modulated by the MEK cascade in a mammal, including a human, comprising administering to said mammal an amount of the compound of formula I, or a pharmaceutically acceptable salt, ester, prodrug, solvate, such as hydrate, polymorph or tautomer thereof, effective to modulate said cascade. The appropriate dosage for a particular patient can be determined, according to known methods, by those skilled in the art.

[054] In other aspects, the present invention is directed to use of compound of formula I or a pharmaceutically acceptable salt, ester, prodrug, solvate, such as hydrate, polymorph or tautomer thereof in the preparation of a pharmaceutical composition. The pharmaceutical composition can be used for treating a disorder or condition which is modulated by the MEK cascade in a mammal, including a human. The pharmaceutical composition is useful for treating cancer, inflammatory disease and other hyperproliferative diseases.

[055] In other aspects, the present invention is directed to a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. In some embodiments, the pharmaceutical composition is in a form suitable for oral administratioa In further or additional embodiments, the pharmaceutical composition is in the form of a tablet, capsule, pill, powder, sustained release formulation, solution and suspension. In some embodiments, the pharmaceutical composition is in a form suitable for parenteral injection, such as a sterile solution, suspension or emulsion; for topical administration as an ointment or cream or for rectal administration as a suppository. In further or additional embodiments, the pharmaceutical composition is in unit dosage forms suitable for single administration of precise dosages. In further or additional embodiments the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.002 to about 6 g/day. In further or additional embodiments Ihe amount of compound of formula I is about 0.005 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required. In further or additional embodiments the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. hi further or additional embodiments the compound of formula I is administered more than four times per day. In some embodiments, the pharmaceutical composition is for administration to a mammal. In further or additional embodiments, the mammal is human. In further or additional embodiments, the pharmaceutical composition further comprises a pharmaceutical carrier, excipient and/or adjuvant. In further or additional embodiments, the pharmaceutical composition further comprises at least one therapeutic agent. In further or additional embodiments, the therapeutic agent is selected from the group consisting of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents. In further or additional embodiments, the antineoplastic agent is selected from the group consisting of alkylating agents, anti-metabolites, epidophyl- lotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors. In further or additional embodiments, the therapeutic agent is taxol, bortezomib or both. In further or additional embodiments, the pharmaceutical composition is administered in combination with an additional therapy. In farther or additional embodiments, the additional therapy is radiation therapy, chemotherapy or a combination of both. In further or additional embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of a compound of formula I.

[056] In other aspects, the present invention is directed to a method for inhibiting a MEK enzyme. The method comprises contacting said MEK enzyme with an amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, sufficient to inhibit said enzyme, wherein said enzyme is inhibited, hi some embodiments, the present invention is directed to a method for selectively inhibiting a MEK enzyme.

[057] In other aspects, the present invention is directed to use of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof in the preparation of a pharmaceutical composition for inhibiting a MEK enzyme.

[058] In further or additional embodiments the enzyme is at least about 1% inhibited. In further or additional embodiments the enzyme is at least about 2% inhibited In further or additional embodiments the enzyme is at least about 3% inhibited. In further or additional embodiments the enzyme is at least about 4% inhibited. In further or additional embodiments the enzyme is at least about 5% inhibited. In further or additional embodiments the enzyme is at least about 10% inhibited, hi further or additional embodiments the enzyme is at least about 20% inhibited. In further or additional embodiments the enzyme is at least about 25% inhibited, hi further or additional embodiments the enzyme is at least about 30% inhibited, hi further or additional embodiments the enzyme is at least about 40% inhibited. In further or additional embodiments the enzyme is at least about 50% inhibited, hi further or additional embodiments the enzyme is at least about 60% inhibited. In further or additional embodiments the enzyme is at least about 70% inhibited, hi further or additional embodiments the enzyme is at least about 75% inhibited, hi further or additional embodiments the enzyme is at least about 80% inhibited. In further or additional embodiments the enzyme is at least about 90% inhibited, hi further or additional embodiments the enzyme is essentially completely inhibited. In further or additional embodiments the MEK enzyme is MEK kinase. In further or additional embodiments the MEK enzyme is MEKl . In further or additional embodiments the MEK enzyme is MEK2. In some embodiments, the compounds of this invention can selectively inhibit a MEKl enzyme or MEK2 enzyme. Ln some other embodiments, the compounds of this invention may not have a selectivity between a MEKl enzyme and MEK2 enzyme, hi further or additional embodiments the contacting occurs within a cell. La further or additional embodiments the cell is a mammalian cell. Ln further or additional embodiments the mammalian cell is a human cell, hi further or additional embodiments, the MEK enzyme is inhibited with a composition comprising a pharmaceutically acceptable salt of a compound of formula I.

[059] In other aspects, the present invention is directed to a method of treatment of a MEK mediated disorder in an individual suffering from said disorder comprising administering to said individual an effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

[060] In other aspects, the present invention is directed to use of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof in the preparation of a pharmaceutical composition for treating a MEK mediated disorder.

[061] In some embodiments, the composition comprising a compound of formula I is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally. In some embodiments, the pharmaceutical composition is in a form suitable for oral administration. In further or additional embodiments, the pharmaceutical composition is in the form of a tablet, capsule, pill, powder, sustained release formulations, solution and suspension for oral administration, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream, or for rectal administration as a suppository. In further or additional embodiments, the pharmaceutical composition is in unit dosage forms suitable for single administration of precise dosages. In further or additional embodiments, the pharmaceutical composition further comprises a pharmaceutical carrier, excipient and/or adjuvant. In further or additional embodiments the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required. In further or additional embodiments the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day. In some embodi- ments, the individual suffering from the MEK mediated disorder is a mammal. In further or additional embodiments, the individual is a human. In some embodiments, the composition comprising a compound of formula I is administered in combination with an additional therapy. In further or additional embodiments, die additional therapy is radiation therapy, chemotherapy or a combination of both. In further or additional embodiments, the composition comprising a compound of formula I is administered in combination with at least one therapeutic agent. In further or additional embodiments, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents. In further or additional embodiments, the anti-neoplastic agent is selected from the group of consisting of alkylating agents, anti-metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors. In further or additional embodiments, the therapeutic agent is selected from taxol, bortezomib or both. In some embodiments, the MEK mediated disorder is selected from the group consisting of inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorder, neurological disorders, fibrogenic disorders, proliferative disorders, hyperproliferative disorders, non-cancer hyper- proliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases, malignant disease, vascular restenosis, psoriasis, atherosclerosis, rheumatoid arthritis, osteoarthritis, heart failure, chronic pain, neuropathic pain, dry eye, closed angle glaucoma and wide angle glaucoma. In further or additional embodiments, the MEK mediated disorder is an inflammatory disease. In further or additional embodiments, the MEK mediated disorder is a hyperproliferative disease. In further or additional embodiments, the MEK mediated disorder is selected from the group consisting of tumors, leukemias, neoplasms, cancers, carcinomas and malignant disease. In further or additional embodiments, the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer or leukemia. In further or additional embodiments, the fibrogenetic disorder is scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis. Li further or additional embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula is administered.

[062] In other aspects, the present invention is directed to a method for degrading, inhibiting the growth of or killing a cancer cell comprising contacting said cell with an amount of a composition effective to degrade, inhibit the growth of or to kill said cell, the composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

[063] In other aspects, the present invention is directed to use of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof in the preparation of a pharmaceutical composition for degrading and/or inhibiting the growth of or killing a cancer cell.

[064] In some embodiments, the cancer cells comprise brain, breast, lung, ovarian, pancreatic, prostate, renal, or colorectal cancer cells. In further or additional embodiments, the composition is administered with at least one therapeutic agent In further or additional embodiments, the therapeutic agent is taxol, bortezomib or both. In further or additional embodiments, the therapeutic agent is selected from the group consisting of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents. In further or additional embodiments, the anti-neoplastic agents selected from the group of consisting of alkylating agents, anti-metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors. In some embodiments, the cancer cells are degraded. In further or additional embodiments, 1% of the cancer cells are degraded. In further or additional embodiments, 2% of the cancer cells are degraded. In further or additional embodiments, 3% of the cancer cells are degraded. In further or additional embodiments, 4% of the cancer cells are degraded. In further or additional embodiments, 5% of the cancer cells are degraded. In further or additional embodiments, 10% of the cancer cells are degraded. In further or additional embodiments, 20% of the cancer cells are degraded. In further or additional embodiments, 25% of the cancer cells are degraded. In further or additional embodiments, 30% of the cancer cells are degraded. In further or additional embodiments, 40% of the cancer cells are degraded. In further or additional embodiments, 50% of the cancer cells are degraded. In further or additional embodiments, 60% of the cancer cells are degraded. In further or additional embodiments, 70% of the cancer cells are degraded. In further or additional embodiments, 75% of the cancer cells are degraded. In further or additional embodiments, 80% of the cancer cells are degraded. In further or additional embodiments, 90% of the cancer cells are degraded. In further or additional embodiments, 100% of the cancer cells are degraded. In further or additional embodiments, essentially all of the cancer cells are degraded. In some embodiments, the cancer cells are killed. In further or additional embodiments, 1% of the cancer cells are killed. In further or additional embodiments, 2% of the cancer cells are killed. In further or additional embodiments, 3% of the cancer cells are killed. In further or additional embodiments, 4% of the cancer cells are killed. In further or additional embodiments, 5% of the cancer cells are killed. In further or additional embodiments, 10% of the cancer cells are killed. In further or additional embodiments, 20% of the cancer cells are killed. In further or additional embodiments, 25% of the cancer cells are killed. In further or additional embodiments, 30% of the cancer cells are killed. In further or additional embodiments, 40% of the cancer cells are killed. In further or additional embodiments, 50% of the cancer cells are killed. In further or additional embodiments, 60% of the cancer cells are killed. In further or additional embodiments, 70% of the cancer cells are killed. In further or additional embodiments, 75% of the cancer cells are killed, hi further or additional embodiments, 80% of the cancer cells are killed. In further or additional embodiments, 90% of the cancer cells are killed. In further or additional embodiments, 100% of the cancer cells are killed. In further or additional embodiments, essentially all of the cancer cells are killed. In further or additional embodiments, the growth of the cancer cells is inhibited. In further or additional embodiments, the growth of the cancer cells is about 1% inhibited. In further or additional embodiments, the growth of the cancer cells is about 2% inhibited. In further or additional embodiments, the growth of the cancer cells is about 3% inhibited. In further or additional embodiments, the growth of the cancer cells is about 4% inhibited. In further or additional embodiments, the growth of the cancer cells is about 5% inhibited. In further or additional embodiments, the growth of the cancer cells is about 10% inhibited. In further or additional embodiments, the growth of the cancer cells is about 20% inhibited. In further or additional embodiments, the growth of the cancer cells is about 25% inhibited. In further or additional embodiments, the growth of the cancer cells is about 30% inhibited. In further or additional embodiments, the growth of the cancer cells is about 40% inhibited. In further or additional embodiments, the growth of the cancer cells is about 50% inhibited. In further or additional embodiments, the growth of the cancer cells is about 60% inhibited. In further or additional embodiments, the growth of the cancer cells is about 70% inhibited. In further or additional embodiments, the growth of the cancer cells is about 75% inhibited. In further or additional embodiments, the growth of the cancer cells is about 80% inhibited. In further or additional embodiments, the growth of the cancer cells is about 90% inhibited. In further or additional embodiments, the growth of the cancer cells is about 100% inhibited. In further or additional embodiments, a composition comprising a pharmaceutically acceptable salt of a compound of formula I is used.

[065] In other aspects, the present invention is directed to a method for the treatment or prophylaxis of a proliferative disease in an individual comprising administering to said individual an effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or pro- drug thereof.

[066] In other aspects, the present invention is directed to use of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof in the preparation of a pharmaceutical composition for the treatment or prophylaxis of a proliferative disease.

[067] In some embodiments, the proliferative disease is cancer, psoriasis, restenosis, autoimmune disease, or atherosclerosis. In further or additional embodiments, the proliferative disease is a hyperproliferative disease. In further or additional embodiments, the proliferative disease is selected from the group consisting of tumors, leukemias, neoplasms, cancers, carcinomas and malignant disease. In further or additional embodiments, the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer or leukemia. In further or additional embodiments, the fibrogenetic disorder is scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis. In further or additional embodiments, the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer or leukemia. In further or additional embodiments, the cancer is brain cancer or adreno- cortical carcinoma. In further or additional embodiments, the cancer is breast cancer. In further or additional embodiments, the cancer is ovarian cancer. In further or additional embodiments, tlie cancer is pancreatic cancer. In further or additional embodiments, the cancer is prostate cancer. In further or additional embodiments, the cancer is renal cancer. In further or additional embodiments, the cancer is colorectal cancer. In further or additional embodiments, the cancer is myeloid leukemia. In further or additional embodiments, the cancer is glioblastoma. In further or additional embodiments, the cancer is follicular lymphoma. In further or additional embodiments, the cancer is pre-B acute leukemia. In further or additional embodiments, the cancer is chronic lymphocytic B-leukemia. In further or additional embodiments, the cancer is mesothelioma. In further or additional embodiments, the cancer is small cell line cancer. In some embodiments, the composition comprising a compound of formula I is administered in combination with an additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy or a combination of both. In further or additional embodiments, the composition comprising a compound of formula I is administered in combination with at least one therapeutic agent. In further or additional embodiments, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents. In further or additional embodiments, the antineoplastic agent is selected from the group of consisting of alkylating agents, anti-metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors. In further or additional embodiments, the therapeutic agent is selected from taxol, bortezomib or both. In some embodiments, the composition is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally. In further or additional embodiments the amount of compound of formulal is in the range of about 0.001 to about 1000 mg/kg body weighi/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg body weight /day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required. In further or additional embodiments the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional ^: embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. hi further or additional embodiments the compound of formula I is administered more than four times per day. In some embodiments, the individual suffering from the proliferative disease is a mammal. In further or additional embodiments, the individual is a human. In further or additional embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.

[068] In other aspects, the present invention is directed to a method for the treatment or prophylaxis of an inflammatory disease in an individual comprising administering to said individual an effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. [069] In other aspects, the present invention is directed to use of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof in the preparation of a pharmaceutical composition for the treatment or prophylaxis of an inflammatory disease.

[070] In further or additional embodiments, the inflammatory disease is selected from chronic inflammatory diseases, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis, acute rheumatic arthritis, enteropathic arthritis, neuropathic arthritis, psoriatic arthritis, pyogenic arthritis, atherosclerosis, systemic lupus erythematosus, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, reflux esophagitis, Crohn's disease, gastritis, asthma, allergies, respiratory distress syndrome, pancreatitis, chronic obstructive pulmonary disease, pulmonary fibrosis, psoriasis, eczema or scleroderma, hi some embodiments, the composition comprising a compound of formula is administered in combination with an additional therapy. In further or additional embodiments, the composition comprising a compound of formula is administered in combination with at least one therapeutic agent. In some embodiments, the composition is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally. In further or additional embodiments the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg body weight /day. In further or additional embodiments the amount of compound of formula is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required. In further or additional embodiments the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or addi- tional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day. In some embodiments, the individual suffering from the inflammatory disease is a mammal. In further or additional embodiments, the individual is a human. In further or additional embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.

[071] In other aspects, the present invention is directed to a method for the treatment or prophylaxis of cancer in an individual comprising administering to said individual an effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

[072] In other aspects, the present invention is directed to use of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof in the preparation of a pharmaceutical composition for the treatment or prophylaxis of a cancer.

[073] In further or additional embodiments, the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer or leukemia In further or additional embodiments, the fibrogenetic disorder is scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis. In further or additional embodiments, the cancer is brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, colorectal cancer or leukemia. In further or additional embodiments, the cancer is brain cancer or adrenocortical carcinoma. In further or additional embodiments, the cancer is breast cancer. In further or additional embodiments, the cancer is ovarian cancer. In further or additional embodiments, the cancer is pancreatic cancer. In further or additional embodiments, the cancer is prostate cancer. In further or additional embodiments, the cancer is renal cancer. In further or additional embodiments, the cancer is colorectal cancer. In further or additional embodiments, the cancer is myeloid leukemia. In further or additional embodiments, the cancer is glioblastoma. In further or additional embodiments, the cancer is follicular lymphoma. In further or additional embodiments, the cancer is pre- B acute leukemia. In further or additional embodiments, the cancer is chronic lymphocytic B-leukemia. In further or additional embodiments, the cancer is mesothelioma. In further or additional embodiments, the cancer is small cell line cancer. In some embodiments, the composition comprising a compound of formula I is administered in combination with an additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy or a combination of both. In further or additional embodiments, the composition comprising a compound of formula I is administered in combination with at least one therapeutic agent. In further or additional embodiments, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents. In further or additional embodiments, the anti-neoplastic agent is selected from the group of consisting of alkylating agents, anti- metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors. In further or additional embodiments, the therapeutic agent is selected from taxol, bortezomib or both. In some embodiments, the composition is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally. In further or additional embodiments the amount of compound of formula is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg body weight /day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required. In further or additional embodiments the compound of formula is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day. In some embodiments, the individual suffering from cancer is a mammal. In further or additional embodiments, the individual is a human. In further or additional embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.

[074] In other aspects, the present invention is directed to a method of reducing the size of a tumor, inhibiting tumor size increase, reducing tumor proliferation or preventing tumor proliferation in an individual, comprising administering to said individual an effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. [075] In other aspects, the present invention is directed to use of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof in the preparation of a pharmaceutical composition for reducing the size of a tumor, inhibiting tumor size increase, reducing tumor proliferation or preventing tumor proliferation.

[076] In some embodiments, the size of a tumor is reduced. In further or additional embodiments, the size of a tumor is reduced by at least 1%. In further or additional embodiments, the size of a tumor is reduced by at least 2%. hi further or additional embodiments, the size of a tumor is reduced by at least 3%. In further or additional embodiments, the size of a tumor is reduced by at least 4%. In further or additional embodiments, the size of a tumor is reduced by at least 5%. In further or additional embodiments, the size of a tumor is reduced by at least 10%. In further or additional embodiments, the size of a tumor is reduced by at least 20%. hi further or additional embodiments, the size of a tumor is reduced by at least 25%. hi further or additional embodiments, the size of a tumor is reduced by at least 30%. In further or additional embodiments, the size of a tumor is reduced by at least 40%. hi further or additional embodiments, the size of a tumor is reduced by at least 50%. In further or additional embodiments, the size of a tumor is reduced by at least 60%. In further or additional embodiments, the size of a tumor is reduced by at least 70%. hi further or additional embodiments, the size of a tumor is reduced by at least 75%. hi further or additional embodiments, the size of a tumor is reduced by at least 80%. In further or additional embodiments, the size of a tumor is reduced by at least 85%. In further or additional embodiments, the size of a tumor is reduced by at least 90%. hi further or additional embodiments, the size of a tumor is reduced by at least 95%. In further or additional embodiments, the tumor is eradicated. In some embodiments, the size of a tumor does not increase, hi some embodiments, tumor proliferation is reduced. In some embodiments, tumor proliferation is reduced by at least 1%. In some embodiments, tumor proliferation is reduced by at least 2%. hi some embodiments, tumor proliferation is reduced by at least 3%. hi some embodiments, tumor proliferation is reduced by at least 4%. In some embodiments, tumor proliferation is reduced by at least 5%. In some embodiments, tumor proliferation is reduced by at least 10%. hi some embodiments, tumor proliferation is reduced by at least 20%. In some embodiments, tumor proliferation is reduced by at least 25%. hi some embodiments, tumor proliferation is reduced by at least 30%. hi some embodiments, tumor proliferation is reduced by at least 40%. hi some embodiments, tumor proliferation is reduced by at least 50%. In some embodiments, tumor proliferation is reduced by at least 60%. hi some embodiments, tumor proliferation is reduced by at least 70%. hi some embodiments, tumor proliferation is reduced by at least 75%. hi some embodiments, tumor proliferation is reduced by at least 80%. hi some embodiments, tumor proliferation is reduced by at least 90%. In some embodiments, tumor proliferation is reduced by at least 95%. In some embodiments, tumor proliferation is prevented. In some embodiments, the composition comprising a compound of formula I is administered in combination with an additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy or a combination of both. In further or additional embodiments, the composition comprising a compound of formula I is administered in combination wilh at least one therapeutic agent In further or additional embodiments, the therapeutic agent is selected from the group of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents. In further or additional embodiments, the anti-neoplastic agent is selected from the group of consisting of alkylating agents, anti-metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors. In further or additional embodiments, the therapeutic agent is selected from taxol, bortezomib or both. In some embodiments, the composition is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally. In further or additional embodiments the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg body weight /day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required. In further or additional embodiments the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In further or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day. In some embodiments, the individual suffering from cancer is a mammal. In further or additional embodiments, the individual is ? human. In further or additional embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.

[077] In other aspects, the present invention is directed to a method for achieving an effect in a patient comprising the administration of an effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, to a patient, wherein the effect is selected from the group consisting of inhibition of various cancers, immunological diseases, and inflammatory diseases. In some embodiments, the effect is inhibition of various cancers. In further or additional embodiments, the effect is inhibition of immunological diseases. In further or additional embodiments, the effect is inhibition inflammatory diseases.

[078] In other aspects, the present invention is directed to use of a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof in the preparation of a pharmaceutical composition for the inhibiting various cancers, immunological diseases, and/or inflammatory diseases.

[079] In some embodiments, the composition comprising a compound of formula I is administered in combination with an additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy or a combination of both. In further or additional embodiments, the composition comprising a compound of formula I is administered in combination with at least one therapeutic agent. In some embodiments, the composition is administered orally, intraduodenally, parenterally (including intravenous, subcutaneous, intramuscular, intravascular or by infusion), topically or rectally. In further or additional embodiments the amount of compound of formula I is in the range of about 0.001 to about 1000 mg/kg body weight/day. In further or additional embodiments the amount of compound of formula I is in the range of about 0.5 to about 50 mg/kg body weight /day. In further or additional embodiments the amount of compound of formula I is about 0.001 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.01 to about 7 g/day. In further or additional embodiments the amount of compound of formula I is about 0.02 to about 5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.05 to about 2.5 g/day. In further or additional embodiments the amount of compound of formula I is about 0.1 to about 1 g/day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate. In further or additional embodiments, dosage levels above the upper limit of the aforesaid range may be required. In further or additional embodiments the compound of formula I is administered in a single dose, once daily. In further or additional embodiments the compound of formula I is administered in multiple doses, more than once per day. In further or additional embodiments the compound of formula I is administered twice daily. In farther or additional embodiments the compound of formula I is administered three times per day. In further or additional embodiments the compound of formula I is administered four times per day. In further or additional embodiments the compound of formula I is administered more than four times per day. In some embodiments, the individual suffering from cancer is a mammal. In further or additional embodiments, the individual is a human. In further or additional embodiments, an effective amount of a composition comprising a pharmaceutically acceptable salt of a compound of formula I is administered.

[080] In other aspects, the present invention is directed to a process for preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

DETAILED DESCRIPTION

[081] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized.

[082] While preferred embodiments of the present invention have been shown and described herein such embodiments are provided by way of example only. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. Those ordinary skilled in the art will appreciate that numerous variations, changes, and substitutions are possible without departing from the invention. It is intended that the following claims define the scope of aspects of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[083] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, without limitation, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose.

Certain Chemical Terminology

[084] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. All patents, patent applications, published materials referred to throughout the entire disclosure herein, unless noted otherwise, are incorporated by reference in their entirety. In the event that there is a plurality of definitions for terms herein, those in this section prevail. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet or other appropriate reference source. Reference thereto evidences the availability and public dissemination of such information.

[085] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that use of "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes", and "included" is not limiting. Likewise, use of the term "comprising" as well as other forms, such as "comprise", "comprises", and "comprised" is not limiting.

[086] Definition of standard chemistry terms may be found in reference works, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4™ ED." VoIs. A (2000) and B (2001), Plenum Press,

New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, IR and UV/Vis spectroscopy and pharmacology, within the skill of the art are employed. Unless specific definitions are provided, the nomenclature employed in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those known in the art. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients. Reactions and purification techniques can be performed e.g., using kits of manufacturer's specifications or as commonly accomplished in the art or as described herein. The foregoing techniques and procedures can be generally performed of conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. Throughout the specification, groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds.

[087] Where substituent groups are specified by their conventional chemical formulas, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left. As a non-limiting example, CH₂O is equivalent to OCH₂ . [088] Unless otherwise noted, the use of general chemical terms, such as though not limited to "alkyl," "amine," "aryl," are equivalent to their optionally substituted forms. For example, "alkyl," as used herein, includes optionally substituted alkyl.

[089] The compounds presented herein may possess one or more stereocenters and each center may exist in the R or S configuration, or combinations thereof. Likewise, the compounds presented herein may possess one or more double bonds and each may exist in the E (trans) or Z (cis) configuration, or combinations thereof. Presentation of one particular stereoisomer, regioisomer, diastereomer, enantiomer or epimer should be understood to include all possible stereoisomers, regioisomers, diastereomers, enantiomers or epimers and mixtures thereof. Thus, the compounds presented herein include all separate configurational stereoisomeric, regioisomeric, diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. Techniques for inverting or leaving unchanged a particular stereocenter, and those for resolving mixtures of stereoisomers are well known in the art and it is well within the ability of one of skill in the art to choose an appropriate method for a particular situation. See, for example, Fumiss et al. (eds.), VOGEL¹S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; and Heller, Ace. Chem. Res. 1990, 23, 128.

[090] The terms "moiety", "chemical moiety", "group" and "chemical group", as used herein refer to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[091 ] The term "bond" or "single bond" refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.

[092] The term "catalytic group" refers to a chemical functional group that assists catalysis by acting to lower the activation barrier to reaction.

[093] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted alkyl" means either "alkyl" or

"substituted alkyl" as defined below. Further, an optionally substituted group may be un-substituted

(e.g., CH₂CH₃), fully substituted (e.g.,CF₂CF₃),mono-substituted (e.g.,CH₂CH₂F) or substituted at a level anywhere in-between fully substituted and mono- substituted (e.g. ,CH₂CHF_2, CF₂CH₃₅CFHCHF₂, etc). It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infϊnitum) that are sterically impractical and/or synthetically non-feasible. Thus, any substituents described should generally be understood as having a maximum molecular weight of about 1 ,000 daltons, and more typically, up to about 500 daltons (except in those instances where macromolecular substituents are clearly intended, e.g., polypeptides, polysaccharides, polyethylene glycols, DNA, RNA and the like).

[094] As used herein, Ci-Cn, includes Ci-C₂, C₁-C₃ .. . Ci-Cn. By way of example only, a group designated as "C₁-C₄" indicates that there are one to four carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms, as well as the ranges Ci-C₂ and C₁-C₃. Thus, by way of example only, "C₁-C₄ alkyl" indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range; e.g., "1 to 10 carbon atoms" means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

[095] The term "hydrocarbon" as used herein, alone or in combination, refers to a compound or chemical group containing only carbon and hydrogen atoms.

[096] The terms "heteroatom" or "hetero" as used herein, alone or in combination, refer to an atom other than carbon and hydrogen. Heteroatoms are independently selected from among oxygen, nitrogen, sulfur, phosphorous, silicon, selenium and tin but are not limited to these atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms can be the same as each another, or some or all of the two or more heteroatoms can each be different from the others.

[097] The term "alkyl" as used herein, alone or in combination, refers to an optionally substituted straight- chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-l-propyl, 2-methyl-2 -propyl, 2-methyl-l-butyl, 3 - methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-l-pentyl, 3 -methyl- 1 -pentyl, 4- methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2 -dimethyl-1-butyl, 3,3 - dimethyl- 1 -butyl, 2 -ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert- amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as "Ci-C₆ alkyl" or "C_{1 6} alkyl", means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although Ihe present definition also covers the occurrence of the term "alkyl" where no numerical range is designated.

[098] The term "alkylene" as used herein, alone or in combination, refers to a diradical derived from the above-defined monoradical, alkyl. Examples include, but are not limited to methylene (-CH₂), ethylene (-CH₂CH₂), propylene (-CH₂CH₂CH₂), isopropylene (-CH(CH₃)CH₂ ) and the like.

[099] The term "alkenyl" as used herein, alone or in combination, refers to an optionally substituted straight- chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double- bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers. Examples include, but are not limited to ethenyl ( CH — CH₂), 1-propenyl ( CH₂CH=CH₂), isopropenyl [ C(CH₃)=CH₂], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as "C₂-C₆ alkenyl" or "C₂_₆ alkenyl", means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl" where no numerical range is designated.

[0100] The term "alkenylene" as used herein, alone or in combination, refers to a diradical derived from the above- defined monoradical alkenyl. Examples include, but are not limited to ethenylene (CH — CH ), the propenylene isomers (e.g., CH₂CH=CH and C(CHa)=CH ) and the like.

[0101] The term "alkynyl" as used herein, alone or in combination, refers to an optionally substituted straight- chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3- butadiynyl and the like. Whenever it appears herein, a numerical range such as "C₂-C₆ alkynyl" or "C_{2 6} alkynyl", means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl" where no numerical range is designated.

[0102] The term "alkynylene" as used herein, alone or in combination, refers to a diradical derived from the above- defined monoradical, alkynyl. Examples include, but are not limited to ethynylene ( -CC-), propargylene ( -CH₂CC-) and the like.

[0103] The term "aliphatic" as used herein, alone or in combination, refers to an optionally substituted, straight- chain or branched-chain, non-cyclic, saturated, partially unsaturated, or fully unsaturated nonaromatic hydrocarbon. Thus, the term collectively includes alkyl, alkenyl and alkynyl groups.

[0104] The terms "heteroalkyl", "heteroalkenyl" and "heteroalkynyl" as used herein, alone or in combination, refer to optionally substituted alkyl, alkenyl and alkynyl structures respectively, as described above, in which one or more of the skeletal chain carbon atoms (and any associated hydrogen atoms, as appropriate) are each independently replaced with a heteroatom (Le. an atom other than carbon, such as though not limited to oxygen, nitrogen, sulfur, silicon, phosphorous, tin or combinations thereof.

[0105] The terms "haloalkyl", "haloalkenyl" and "haloalkynyl" as used herein, alone or in combination, refer to optionally substituted alkyl, alkenyl and alkynyl groups respectively, as defined above, in which one or more hydrogen atoms is replaced by fluorine, chlorine, bromine or iodine atoms, or combinations thereof. In some embodiments two or more hydrogen atoms may be replaced with halogen atoms that are the same as each another (e.g. difluoromethyl); in other embodiments two or more hydrogen atoms may be replaced with halogen atoms that are not all the same as each other (e.g. 1-chloro-l-fluoro- 1 -iodoethyl). Non-limiting examples of haloalkyl groups are fluoromethyl and bromoethyl. A non-limiting example of a haloalkenyl group is bromoethenyl. A non-limiting example of a haloalkynyl group is chloroethynyl.

[0106] The term "perhalo" as used herein, alone or in combination, refers to groups in which all of the hydrogen atoms are replaced by fluorines, chlorines, bromines, iodines, or combinations thereof. Thus, as a non-limiting example, the term "peihaloalkyl" refers to an alkyl group, as defined herein, in which all of the H atoms have been replaced by fluorines, chlorines, bromines or iodines, or combinations thereof. A non-limiting example of a perhaloalkyl group is bromo, chloro, fluoromethyl. A non-limiting example of a perhaloalkenyl group is trichloroethenyl. A non-limiting example of a perhaloalkynyl group is tribromopropynyl.

[0107] The term "carbon chain" as used herein, alone or in combination, refers to any alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl or heteroalkynyl group, which is linear, cyclic, or any combination thereof. If the chain is part of a linker and that linker comprises one or more rings as part of the core backbone, for purposes of calculating chain length, the "chain" only includes those carbon atoms that compose the bottom or top of a given ring and not both, and where the top and bottom of the ring(s) are not equivalent in length, the shorter distance shall be used in determining the chain length. If the chain contains heteroatoms as part of the backbone, those atoms are not calculated as part of the carbon chain length.

[0108] The terms "cycle", "cyclic", "ring" and "membered ring" as used herein, alone or in combination, refer to any covalently closed structure, including alicyclic, heterocyclic, aromatic, heteroaromatic and polycyclic fused or non-fused ring systems as described herein. Rings can be optionally substituted. Rings can form part of a fused ring system. The term "membered" is meant to denote the number of skeletal atoms that constitute the ring. Thus, by way of example only, cyclohexane, pyridine, pyran and pyrimidine are six-membered rings and cyclopentane, pyrrole, tetrahydrofuran and thiophene are fϊve-membered rings.

[0109] The term "fused" as used herein, alone or in combination, refers to cyclic structures in which two or more rings share one or more bonds.

[0110] The term "cycloalkyl" as used herein, alone or in combination, refers to an optionally substituted, saturated, hydrocarbon monoradical ring, containing from three to about fifteen ring carbon atoms or from three to about ten ring carbon atoms, though may include additional, non-ring carbon atoms as substituents (e.g. methylcyclopropyl).

[0111] A non-limiting example of "cycloalkyl" includes azinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo [4. 1.0]heptyl, 3H-indolyl and quinolizinyl and the like. The terms also include all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.

[0112] The term "aromatic" as used herein, refers to a planar, cyclic or polycyclic, ring moiety having a delocalized at-electron system containing 4n+2 n electrons, where n is an integer. Aromatic rings can be formed by five, six, seven, eight, nine, or more than nine atoms. Aromatics can be optionally substituted and can be monocyclic or fused- ring polycyclic. The term aromatic encompasses both all carbon containing rings (e.g., phenyl) and those rings containing one or more heteroatoms (e.g., pyridine). [0113] The term "aryl" as used herein, alone or in combination, refers to an optionally substituted aromatic hydrocarbon radical of six to about twenty ring carbon atoms, and includes fused and non-fused aryl rings. A fused aryl ring radical contains from two to four fused rings where the ring of attachment is an aryl ring, and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof. Further, the term aryl includes fused and non-fused rings containing from six to about twelve ring carbon atoms, as well as those containing from six to about ten ring carbon atoms. A non-limiting example of a single ring aryl group includes phenyl; a fused ring aryl group includes naphthyl, phenanthrenyl, anthracenyl, azulenyl; and a non-fused bi-aryl group includes biphenyl.

[0114] The term "arylene" as used herein, alone or in combination, refers to a diradical derived from the above- defined monoradical, aryl. Examples include, but are not limited to 1,2-phenylene, 1,3- phenylene, 1,4-phenylene, 1,2-naphthylene and the like.

[0115] The term "heteroaryl" as used herein, alone or in combination, refers to optionally substituted aromatic mono- radicals containing from about five to about twenty skeletal ring atoms, where one or more of the ring atoms is a heteroatom independently selected from among oxygen, nitrogen, sulfur, phosphorous, silicon, selenium and tin but not limited to these atoms and with the proviso that the ring of said group does not contain two adjacent 0 or S atoms, hi embodiments in which two or more heteroatoms are present in the ring, the two or more heteroatoms can be the same as each another, or some or all of the two or more heteroatoms can each be different from the others. The term heteroaryl includes optionally substituted fused and non- fused heteroaryl radicals having at least one heteroatom. The term heteroaryl also includes fused and non-fused heteroaryls having from five to about twelve skeletal ring atoms, as well as those having from five to about ten skeletal ring atoms. Bonding to a heteroaryl group can be via a carbon atom or a heteroatom. Thus, as a non-limiting example, an imidiazole group may be attached to a parent molecule via any of its carbon atoms (imidazol-2-yl, imidazol-4-yl or imidazol-5-yl), or its nitrogen atoms (imidazol-1-yl or imidazol-3-yl). Likewise, a heteroaryl group may be further substituted via any or all of its carbon atoms, and/or any or all of its heteroatoms. A fused heteroaryl radical may contain from two to four fused rings where the ring of attachment is a heteroaromatic ring and the other individual rings may be alicyclic, heterocyclic, aromatic, heteroaromatic or any combination thereof. A non-limiting example of a single ring heteroaryl group includes pyridyl; fused ring heteroaryl groups include benzimidazolyl, quinolinyl, acridinyl; and a non-fused bi-heteroaryl group includes bipyridinyl. Further examples of heteroaryls include, without limitation, furanyl, thienyl, oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl, benzotriazolyl, imidazolyl, indolyl, isoxazolyl, isoquinolinyl, indolizinyl, isothiazolyl, isoindolyloxadiazolyl, indazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrazolyl, purinyl, phthalazinyl, pteridinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazolyl, tetrazolyl, thiazolyl, triazinyl, thiadiazolyl and the like, and their oxides, such as for example pyridyl-iV-oxide and the like.

[0116] The term "heteroarylene" as used herein, alone or in combination, refers to a diradical derived from the above- defined monoradical heteroaryl. Examples include, but are not limited to pyridinylene and pyrimidinylene.

[0117] The term "heterocyclyl" as used herein, alone or in combination, refers collectively to heteroalicyclyl and heteroaryl groups. Herein, whenever the number of carbon atoms in a heterocycle is indicated (e.g., C₁-C₆ heterocycle), at least one non-carbon atom (the heteroatom) must be present in the ring. Designations such as "C₁-C₆ heterocycle" refer only to the number of carbon atoms in the ring and do not refer to the total number of atoms in the ring. Designations such as "4-6 membered heterocycle" refer to the total number of atoms that are contained in the ring (i.e., a four, five, or six membered ring, in which at least one atom is a carbon atom, at least one atom is a heteroatom and the remaining two to four atoms are either carbon atoms or heteroatoms). For heterocycles having two or more heteroatoms, those two or more heteroatoms can be the same or different from one another. Heterocycles can be optionally substituted. Non-aromatic heterocyclic groups include groups having only three atoms in the ring, while aromatic heterocyclic groups must have at least five atoms in the ring. Bonding (i.e. attachment to a parent molecule or further substitution) to a heterocycle can be via a heteroatom or a carbon atom.

[0118] The term "carbocyclyl" as used herein, alone or in combination, refers collectively to alicyclyl and aryl groups; i.e. all carbon, covalently closed ring structures, which may be saturated, partially unsaturated, fully unsaturated or aromatic. Carbocyclic rings can be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. Carbocycles can be optionally substituted. The term distin- guishes carbocyclic from heterocyclic rings in which the ring backbone contains at least one atom which is different from carbon.[0119] The terms "halogen", "halo" or "halide" as used herein, alone or in combination refer to fluoro, chloro, bromo and iodo.

[0120] The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether radical,

0-alkyl, including the groups O-aliphatic and 0-carbocyclyl, wherein the alkyl, aliphatic and carbocyclyl groups may be optionally substituted, and wherein the terms alkyl, aliphatic and carbocyclyl are as defined herein. Non-limiting examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tertbutoxy and the like.

[0121] The term "sulfinyl" as used herein, alone or in combination, refers to the diradical -S(-O)

[0122] The term "sulfonyl" as used herein, alone or in combination, refers to the diradical -S(-O)₂

[0123] The terms "sulfonamide", "sulfonamido" and "sulfonamidyl" as used herein, alone or in combination, refer to the diradical groups -S(-O)_2-NH- and -NH-S( = O ) ₂

[0124] The terms "sulfamide", "sulfamido" and "sulfamidyl" as used herein, alone or in combination, refertothe diradical group NHS(-O)₂NH .

Certain Pharmaceutical Terminology

[0125] The term "MEK inhibitor" as used herein refers to a compound that exhibits an IC50, with respect to MEK activity, of no more than about 100 M or not more than about 50 M, as measured in the Mekl kinase assay described generally herein. "IC₅₀" is that concentration of inhibitor which reduces the activity of an enzyme (e.g., MEK) to half-maximal level. Compounds described herein have been discovered to exhibit inhibition against MEK. Compounds of the present invention preferably exhibit an IQo with respect to MEK of no more than about 10 M, more preferably, no more than about 5 M, even more preferably not more than about 1 M, and most preferably, not more than about 200 nM, as measured in the Mekl kinase assay described herein.

[0126] The term "selective," "selectively," or "selectivity" as used herein refers to a compound of this invention having a lower IC₅₀ value for a MEK enzyme as compared to any other enzymes (e.g., at least 2, 5, 10 or more-fold lower). The term may also refer to a compound of this invention having a lower IC₅₀ value for a MEKl enzyme as compared to a MEK2 enzyme (e.g., at least 2, 5, 10 or more-fold) or alternatively having a lower IC₅₀ value for a MEK2 enzyme as compared to a MEKl enzyme (e.g., at least 2, 5, 10 or more-fold lower).

[0127] The term "subject", "patient" or "individual" as used herein in reference to mdividuals suffering from a disorder, a disorder, a condition, and the like, encompasses mammals and non- mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non- mammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0128] The terms "treat," "treating" or "treatment," and other grammatical equivalents as used herein, include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition, and are intended to include prophylaxis. The terms further include achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[0129] The terms "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" as used herein, refer to a sufficient amount of at least one agent or compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in a disease. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study.

[0130] The terms "administer," "administering", "administration," and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodcnal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein, e.g., as discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Eastern, Pa. In preferred embodiments, the compounds and compositions described herein are administered orally.

[0131] The term "acceptable" as used herein, with respect to a formulation, composition or ingredient, means having no persistent detrimental effect on the general health of the subject being treated.

[0132] The term "pharmaceutically acceptable" as used herein, refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds described herein, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0133] The term "pharmaceutical composition," as used herein, refers to a biologically active compound, optionally mixed with at least one pharmaceutically acceptable chemical component, such as, though not limited to carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.

[0134] The term "carrier" as used herein, refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.

[0135] The term "agonist," as used herein, refers to a molecule such as a compound, a drug, an enzyme activator or a hormone modulator which enhances the activity of another molecule or the activity of a receptor site.

[0136] The term "antagonist," as used herein, refers to a molecule such as a compound, a drug, an enzyme inhibitor, or a hormone modulator, which diminishes, or prevents the action of another molecule or the activity of a receptor site.

[0137] The term "modulate," as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.

[138] The term "modulator," as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist and an antagonist.

[139] The term "pharmaceutically acceptable salt" as used herein, refers to salts that retain the biological effectiveness of the free acids and bases of the specified compound and that are not biologically or otherwise undesirable. Compounds described herein may possess acidic or basic groups and therefore may react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral or organic acid or an inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-l,6-dioate, hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate. metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate undeconate and xylenesulfonate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts (See examples at Berge et al., J Pharm. Sd. 1977, 66, 1-19.). Further, those compounds described herein which may comprise a free acid group may react with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, IV (Ci_₄ alkyl)₄, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogen- containing groups they may contain. Water or oil-soluble or dispersible products may be obtained by such quatemization. See, for example, Berge et al., supra.

[0140] The term "solvate" as used herein refers to a combination of a compound of this invention with a solvent molecule formed by solvation. In some situations, the solvate refers to a hydrate, i.e., the solvent molecule is a water molecule, the combination of a compound of this invention and water forms a hydrate.

[0141] The term "polymorph" or "polymorphism" as used herein refers to a compound of this invention present in different crystal lattice forms.

[0142] The term "ester" as used herein refers to a derivative of a compound of this invention derived from an oxoacid group and a hydroxyl group, either one of which can be present at the compound of this invention.

[0143] The term "tautomer" as used herein refers to an isomer readily interconverted from a compound of this invention by e.g., migration of a hydrogen atom or proton.

[0144] The term "pharmaceutically acceptable derivative or prodrug" as used herein, refers to any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention, which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or a pharmaceutically active metabolite or residue thereof. Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing orally administered compound to be more readily absorbed into blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system).

[0145] Pharmaceutically acceptable prodrugs of the compounds described herein include, but are not limited to, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, metal salts and sulfonate esters. Various forms of prodrugs are well known in the art. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook ofDrug Design and Development, Krosgaard-Larsen and H. Bundgaard, Ed, 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. The prodrugs described herein include, but are not limited to, the following groups and combinations of these groups; amine derived prodrugs: Hydroxy prodrugs include, but are not limited to acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters and disulfide containing esters.

[146] The terms "enhance" or "enhancing," as used herein, means to increase or prolong either in potency or duration of a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.

[0147] An "enhancing-effective amount," as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[148] The terms "pharmaceutical combination", "administering an additional therapy", "administering an additional therapeutic agent" and the like, as used herein, refer to a pharmaceutical therapy resulting from mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that at least one of the compounds described herein, and at least one co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that at least one of the compounds described herein, and at least one co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the patient. These also apply to cocktail therapies, e.g. the administration of three or more active ingredients.

[149] The terms "co-administration", "administered in combination with" and their grammatical equivalents or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times. In some embodiments the compounds described herein will be co-administered with other agents. These terms encompass administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composi- tion in which both agents are present Thus, in some embodiments, the compounds of the invention and the other agent (s) are administered in a single composition.

[150] The term "metabolite," as used herein, refers to a derivative of a compound which is formed when the compound is metabolized.

[151] The term "active metabolite," as used herein, refers to a biologically active derivative of a compound that is formed when the compound is metabolized.

[152] The term "metabolized," as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulphydryl groups. Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996).

Compounds

[153] Described herein are compounds of formula I, pharmaceutically acceptable salts, solvates, polymorphs, esters, tautomers or prodrugs thereof,

wherein

[154] R₀ is H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₅-C₆ cycloalkenyl or C₂-C₆ alkynyl; wherein each alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, CpC₄ alky, C₁-C₄ alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, or one or two ring carbon atoms of said C₃-C₆ cycloalkyl groups are optionally replaced with, independently, O, N, or S; and

[155] R₁ is H, C₁-C₄ alkoxy, Ci-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₅-C₆ cycloalkenyl or C₂-C₆ alkynyl; wherein each alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C₁-C₄ alky, C₁-C₄ alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, or

[156] Ri is 5 or 6-atom heterocyclic group, which group may be saturated, unsaturated, or aromatic, containing 1-5 heteroatoms selected independently from the group consisting of O, N, and S, which heterocyclic group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, Q-C₄ alky, Ci-C₄ alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl; or

[0157] Ri is -CH₂X' where X' represents a group according to formula (II)

wherein

[0158] Yi and Y₂ may be the same or different, each represents a single bond, -CO-, -COO, -O-, -OCO-, -NR₃ Or-SO₂-;

[0159] Y₃ represents a Ci_-5 alkyl which may be substituted by one to three groups represented by Z;

[160] Z may be the same or different and represent a Ci_-5 alky group, halogen atom, an oxo group, -OR₃, -COOR₃, -COOCOR₃, -CO-halogen atom, -OCOR₃, -CONR₉R_b. -SR₃, -SO₂R₃, - NR₃Rb, -NR₃CORb, NR₃SO₂Rb, -SO₂NR₃Rb, a monocyclic or bicyclic heterocyclic group, or a heteroaryl group which may be optionally substituted with one or more substituents selcted from the group consisting of a Ci_-5 alkyl group, -OR₃, and NR₃R_b; the alkyl group maybe substituted by a hydroxyl group, a C_1-5 alkoxy group, or an amino group; the above substituents except the oxo group and the halogen may be linked to each other to form a cycloalkyl group or a heterocyclic group which may has one or more substituents selected from the group consisting of -ORa, NR₃Rb, and a C_1-5 alkyl group that may be substituted with -OR₃;

[ 161 ] R_a and R_b may be the same or different and each represents a hydrogen atom or a C_1-5 alkyl group which may be substituted by one to three groups selected from the group consisting of a hydroxyl group, a C_1-5 alkoxy group and an amino group;

[162] The symbol "•" used in formula II implies the site of bonding; and

[163] Xis CorN;

[164] R₂ is H, C₁-C₄ alkoxy, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₅-C₆ cycloalkenyl or C₂-C₆ alkynyl; wherein each alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents selected independently from halogen, hydroxy, C₁-C₄ alky, C₁-C₄ alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, or R₂ is 5 or 6-atom heterocyclic group, which group may be saturated, unsaturated, or aromatic, containing 1-5 heteroatoms selected independently from O, N, and S, which heterocyclic group is optionally substituted with 1-3 substituents selected independently from halogen, hydroxy, C₁-C₄ alky, C₁-C₄ alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl when X = C or

R₂ = nothing when X = N; or

Ri and R₂ taken together form a 5 or 6 membered heterocyclic group which group may be unsaturated or aromatic containing 1-3 heteroatoms selected independently from the group consisting of O, N or S which heterocyclic group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxyl, Ci-C₄ alkyl, C₁-C₄ alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl; and

[165] R₃ is selected from the group consisting of trifluoromethyl, Ci-Cio alkyl, C₂-C₁₀ alkenyl, C₂-Ci₀ alkynyl, C₃-C₁₀ cycloalkyl, C₃-Ci₀ cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarycycloalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, heteroarycycloalkyl, and heterocyclyl is unsubstituted or substituted with 1-3 substituents selected independently from halogen, hydroxyl, Ci- C₄ alkyl, Ci- C₄ alkoxy, cyano, trifluoromethyl, difluoromethoxy, phenyl or substituted phenyl with 1-3 substituents selected independently from halogen, hydroxyl, C₁- C₄ alkyl, Ci- C₄ alkoxy, cyano trifluoromethyl, or difluoromethoxy, and

[166] R₄, R₅, R₆, R₇, and R₈ are independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, S R _{9 ,} O R ₉ , C ( O ) R ₉ , NRi₀C(O)OR₁₂, OC(O)R₉, NRi₀ S(O)j Ri₂, S (O)jNR₉ Ri₀, S(O)_jNR,₀C(O)R₉, C(O)NRi₀S (0)j R₁₂, S (O), R₁₂, NR₁₀C(O)R₉, C(O)NR₉R₁₀, NR₁₁C(O)NR₉R₁₀, NR_πC(NCN)NR₉Rio, NR₉Ri₀ and Ci-Ci₀ alkyl, C₂-Ci₀ alkenyl, C₂-Ci₀ alkynyl, C₃-Ci₀ cycloalkyl, C₃-Ci₀ cycloalkylalkyl, S(O)j(Ci-C₆ alkyl), S(0)_j(CRioRii)_m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylaUcyl, O(CRi₀Ri₀)_m-aryl, NRi_O(CRi₀Ri i)_m-aryl, 0(CRi₀Ri i)_m-heteroaryl, NRi_O(CRioRn)_m-heteroaryl, 0(CRi₀Ri i)_m-heterocyclyl, NRio(CRioRii)_m-heterocyclyl, and S(Ci-C₂ alkyl) optionally substituted with 1-5 fluorine atoms and [167] R₉ is selected from hydrogen, trifluoromethyl, Ci - Ci₀ alkyl, C₂- Ci₀ alkenyl, C₂- Cio alkynyl, C₃- Ci₀ cycloalkyl, C₃- Ci₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or substituted with 1 -3 substituents independently selected from halogen, Ci - C₄ alkyl, hydroxyl and amino;

[168] Ri₀ is selected from hydrogen and Ci-C₆ alkyl where alkyl may be unsubstituted or substituted with 1 -3 substituents independently selected from halogen, Ci-C₄ alkyl, hydroxyl and amino; or

[169] R₉ and Ri₀ can be taken together with the atom to which they are attached to form a 4 to 10 membered heteroaryl or heterocyclic ring, each of which is unsubstituted or substituted with 1 -3 substituents independently selected from halogen, Ci-C₄ alkyl, hydroxyl and amino;

[170] Rn is selected from hydrogen and Ci -C^ alkyl where alkyl may be unsubstituted or substituted with 1 -3 substituents independently selected from halogen, Ci-C₄ alkyl, hydroxyl and amino; or

[171] Rio and Rn can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is unsubstituted or substituted with 1 -3 substituents independently selected from halogen, Ci - C₄ alkyl, hydroxyl and amino;

[172] Ri₂ is selected from trifluoromethyl, CfCio alkyl, C₃-Ci₀ cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl unsubstituted or substituted with 1 -3 substituents independently selected from halogen, C₁ - C₄ alkyl, hydroxyl and amino;

[173] mis 0,1,2,3,4, or 5 and;

[174] j is l or 2.

[175] Methods for synthesizing the compounds described herein are provided. In some embodiments, the compounds described herein can be prepared by the methods described below. The procedures and examples below are intended to illustrate those methods. Neither the procedures nor the examples should be construed as limiting the invention in any way. Compounds described herein may also be synthesized using standard synthetic techniques known to those of skill in the art or using methods known in the art in combination with methods described herein.

[176] Synthetic Procedures and Examples

The preparation of compounds of formula I is outlined below:

Scheme 1

[177] Scheme 1 above illustrates the preparation of pyridone sulfonamide derivatives of (10). Dichloropyridine derivative (3) can be prepared in two steps from oxidation of chloropyridine (1) followed by chlorination of pyridine oxide (2). Nitration of dichloro pyridine (3) followed by SN _Ar reaction with aniline (5) forms intermediate 6. The pyridone derivatives (7) obtained from hydrolysis of chloropyridine (6) can be alkylated to provide nitro pyridine (8). After reduction, the amino pyridine (9) was treated with sulfonyl chlorides to give the desired pyridone sulfonamides (10).

Scheme 2

[178] Scheme 2 illustrates the preparation of cyclopropyl sulfonyl chloride (17). Cyclopropyl sulfonyl chloride (11) reacted with alkyl alcohol (12) in the presence of base such as pyridine to give sulfonate (13). The following lithiation and alkylation with alkylhalide (14) provided the substituted cyclopropyl sulfonate (15). The potassium salt (16) prepared from the treatment of compound (15) with KSCN was reacted with thionyl chloride to give the sulfonyl chlorides (17).

Scheme 3

[179] Scheme 3 illustrates the preparation of dihydroxypropyl cyclopropyl sulfonyl chlorides (23). Isopropyl cyclopropylsulfonate (18) was treated with epoxide (19) after lithiation to give hydroxylpropyl sulfonate (20). Protection of the secondary hydroxyl group and hydrolysis of sulfonate (21) gave the sulfonate salt (22). Treatment of compound 22 with thionyl chloride provided the protected dihydroxypropyl cyclopropyl sulfonyl chlorides (23).

Scheme 4

[180] Scheme 4 illustrates the preparation of dioxolanone protected cyclopropyl sulfonyl chloride (27). Dihydroxypropyl cyclopropyl sulfonate (24) from deprotection of protected hydroxylpropyl cyclopropyl sulfonate (20; Scheme 3) was treated with CDI or bis(trichloromethyl)carbonate to form dioxolanone propyl cyclopropylsulfonate (25). Hydrolysis of compound (25) under mild condition such as Nal/acetone or Bu₄NI gave the sulfonate salt (26). Treatment of compound (26) with sulfuryl chloride in the presence of PPh₃ or thionyl chloride provided dioxolanone protected cyclopropyl sulfonyl chloride (27).

Typical procedure A for the synthesis of sulfonamides:

[181] Procedure A: To a stirred solution of the amine (9) (leq) in anhydrous pyridine (ImI) at O⁰C - 5⁰C was added the sulfonyl chloride (2-3 eq) followed by the addition of dimethylaminopyridine (DMAP) (O.leq). The mixture was stirred at O⁰C - 5⁰C for 1-2 hours. The reaction was concentrated under reduced pressure and dichloromethane added. The mixture was washed with water and the organic phase dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to yield the desired product.

Example 1

iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)cyclopropanesulfonamide

[182] Step A: 2-chloro-5-methylpyridine 1 -oxide

To a mixture of 2-chloro-5-methylpyridine (200 g, 1.57 mol), and urea hydrogen peroxide addition compound (310 g, 3.29 mol) in dichloromethane (2L) was added anhydrous trifluoroacetic acid (619%, 5.96 mol) dropwise at O⁰C, and the mixture was stirred at O⁰C for 1 hour.

After stirring for 48 hours while elevating the reaction temperature to room temperature, an aqueous solution of sodium hydrosulfite (326 g, 3.14 mol) was added, and the reaction mixture was stirred for 4 hours. The reaction was neutralized with sodium hydroxide, extracted with dichloromethane, washed with brine, and the organic phase dried over magnesium sulfate.

Filtration, and removal of solventunder reduced pressure afforded the title compound(189 g, 84%) as a brown SOhU¹H NMR (400MHz, CDCl₃) δ 8.21 (s, IH), 7.39 (d, J= 8.4Hz, IH), 7.06 (d, J = 8.4Hz, IH), 2.32 (s, 3H); m/z = 144 [M+l]⁺.

[183] Step B: 2.6-dichloro-3-methylpyridine

A solution of phosphorus oxychloride (10OmL, 1087mmol) in dichloromethane (500 ml) was added to a mixture of 2-chloro-5-methylpyridine 1-oxide (130g, 905mmol) and triethylamine (11Og, 1087mmol) in dichloromethane (1.5L) at O⁰C. After stirring at O⁰C for 2 hours and then at room temprature for 24 hours, water was added and the mixture was neutralized with a sodium hydroxide solution. The organic layer was washed with a saturated brine solution and the aqueous layer extracted with ethylacetate and washed with a saturated brine solution. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford a dark red solid as a mixture of 2,6-dichloro-3-methyl-pyridine and 2,4- dichloro-5-methyl-pyridine (138g, 94%,3:1 ratio by ¹H NMR)-¹H NMR (400MHz, CDCl₃) δ 7.50 (d, J= 8.0Hz, IH), 7.17 (d, J= 8.4Hz, IH), 2.33 (s, 3H); m/z = 161 [M+l]⁺.

[184] Step C: 2. ό-dichloroO-methyl-S-nitropyridine

The mixture of 2,6-dichloro-3-methyl-pyridine and 2,4- dichloro-5-methyl-pyridine (26g,

160mmol, leq) was added slowly under constant stirring to concentrated sulfuric acid (294g, 3mol,

18eq) at O⁰C. To this solution, nitric acid (95.0 percent, 74g, 1.17mol, 7eq) was added slowly while maintaining the reaction temperature at O⁰C for 0.5 hours. After the addition, the resulting mixture was heated to 100⁰C for 3.5 hours. The reaction mixture was cooled to 5O⁰C, and poured into ice water. The resulting precipitate was filtered and washed with water. The yellow solid obtained was dried to give the title compound (17.6g, 51⁰Zo)₁ ¹H NMR (400MHz, CDCl₃) δ 8.14 (s, IH), 2.47 (s, 3H).

[185] Step D: 6-chloro-N-(^'2-fluoro-4-iodophenyl^')-5-methyl-3-nitropyridin-2-amine

To a mixture of NaH (3.55g, 148mmol, 3eq) in THF (tetrahydrogenfuran, 500ml) was added 2-fluoro-4-iodoaniline (11.68g, 49.3mmol, leq) at room temperature. After stirring for 30 minutes, 2,6-dichloro-3-methyl-5-nitropyridine (10.2g, 49.3mmol, leq) was added and the mixture was heated to reflux for 0.5 hours. After cooling to room temperature, water was slowly added, and the solution was extracted with ethylacetate and washed with a saturated brine solution. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure, thereby yielding the title compound as brown solid which was used in the next step without further purification. ¹H NMR (400MHz, CDCl₃) δ 10.24 (br, IH), 8.40 (s, IH), 8.18 (t, J = 8.4Hz, IH),, 7.50-7.54 (m, 2H), 2.37 (s, 3H);

[186] Step E; 6-(2-fluoro-4-iodophenylamino^')-3-methyl-5-nitropyridin-2(lH)-one

6-Chloro-N-(2-fluoro-4-iodophenyl)-5-methyl-3-nitropyridin-2-amine (2Og, 49.1 mmol) was dissolved in EtOH (400ml) , then aqueous KOΗ (55g, 980mmol, dissolved in 200ml water) was slowly added, and the mixture was refluxed for 4 hours. The mixture was cooled to room temperature and the yellow suspension was filtered, washed with water, and dried to afford the desired product (11.3g, 59⁰Zo)-¹H NMR (400MHz, DMSO) δ 11.61 (s, IH), 8.84 (t, J= 8.8Hz, IH), 7.61-7.66 (m, 2H), 7.50 (d, J= 8.8Hz, IH), 1.85 (s, 3H);

[187] Step F: 6-(2-fluoro-4-iodophenylaminoV1.3-dimethyl-5-nitropyridin-2(lH)-one

To the solution of NaH (1.2 eq.) in dry dimethylformamide (DMF) (0.2 mol/L) was added 6-(2-fluoro-4-iodophenylamino)-3-methyl-5-nitropyridin-2(7H_y)-one (1 eq.) at room temperature and stirred for 35 minutes followed by the addition of methyliodide (1.05 eq.) to the dark red mixture. After stirring at room temperature for 1 hour, the reaction was quenched with sat. NH₄Cl and the mixture extracted with ethylacetate. The organic phase was washed with water and brine then dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via column chromatography on silica gel using DCM:PE=1:1 to DCM as eluent gave the desired product (yield = 63%).Η NMR (400MHZ, CDCl₃) δ 10.35 (s, IH), 8.10 (d, J= 1.2Hz_; IH), 7.54 (dd, J= 1.6 & 9.6Hz, IH), 7.47-7.50 (m, IH), 6.71 (t, J= 8.0Hz, IH), 3.22 (s, 3H), 2.16 (s, 3H) ;

[188] Step G: 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3-dimethylpyridin-2(lH)-one

6-(2-Fluoro-4-iodophenylamino)-l,3-dimethyl-5-nitropyridin-2fiH_/)-one (510 mg) and

Na₂S₂O₄ (1.96 g, 8 eq.) was dissolved in dioxane and water (30 mL, 1:1) then NH₄OH (1 mL) was added at room temperature. After 2 hours 40 minutes, the mixture was diluted with 100 mL ethylacetate, washed with water and brine. The aqueous layer was extracted with ethylacetate twice and washed with brine. The organic layers were combined, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. Purification of the residue via column chromatography on silica using using PE:EA(petroleum etheπethyl acetate)=l:l to DCM:MeOH (dichloromethane:methanol)=20: 1 as eluent, gave the title compound (378 mg, yield = 80%) as a gray-green solid. ¹H NMR (400MHz, CDCl₃) δ 7.40 (dd, J= 2.0 & 10.8Hz, IH), 7.25 (d, J= 6.8Hz, IH), 7.02 (s, IH), 6.18 (t, J= 8.4Hz, IH), 5.45 (br, IH), 3.43 (s, 3H), 2.85 (br, 2H), 2.18 (s, 3H); m/z = 373 [M+l]⁺.

[189] Step H: JV-(2-(2-fluoro-4-iodophenylamino)- 1 ,5-dimethyl-6-oxo- 1 ,6-dihvdropyridin-3- vDcvclopropanesulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H)-one was reacted with cyclopropanesulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.44 (dd, J = 1.6Hz & 10.8 Hz, IH), 7.28-7.29 (m, 2H), 7.14 (s, IH), 6.13 (t, J = 8.4Hz, IH), 6.02 (s, IH), 3.44 (s, 3H), 2.42 (m, IH), 2.17 (s, 3H), 1.15-

1.17 (m, 2H), 1.00-1.02 (m, 2H); m/z = 478 [M+ 1]⁺.

Example 2

l-allyl-iV-(2-(2-fluoro-4-iodophenylainino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)cyclopropanesulfonamide

[190] Step A: 1-Butyl cvclopropanesulfonate

Cyclopropanesulfonyl chloride (25g,178 mmol, leq) was dissolved in an excess of n-BuOH (80ml) and the reaction mixture was cooled at O⁰C, followed by the dropwise addition of pyridine (13.3ml, 160 mmol, 0.9eq). The mixture was slowly warmed to room temperature and stirred for 36 hours. The solvent was removed under reduced pressure and the resulting white solid was dissolved in chloroform. The organic phase was washed with water, brine and dried (MgSO₄) and then concentrated to give an oil (24.5g, 77%).¹H NMR (400MHz, CDCl₃) δ 4.25 (t, J= 6.4Hz, 2H), 2.47 (heptet, 2H), 1.74 (quintet, 2H), 1.43 (sextet, 2H), 1.24 (m, 2H), 1.08 (m, 2H), 0.96 (t, J = 7.6Hz, 3H);

[191] Step B: Butyl 1-allylcvclopropane-l -sulfonate

To a solution of 1 -butyl cyclopropanesulfonate (6Og, 337mmol ) in THF (500ml) at -78⁰C was slowly added butyllithium (150ml, 2.5M in hexane, 404mmol) under a nitrogen atmosphere. After stirring 15 minutes, allyl iodide (31ml, 337mmol) in THF (100ml) was added. The reaction mixture was stirred for 2 hours at -78⁰C and 30 minutes at room temperature. The volatiles were evaporated under reduced pressure and the residue extracted with dichloromethane. The extract was washed with water, dried (MgSO₄) and evaporated. The residue was purified via column chromatography on silica gel (eluent: PE/EA=10:l) to obtain the titled compound (5Og, yield:

68%) as a colorless oil. ¹H NMR (400MHz, CDCl₃) δ 5.71-5.81 (m, IH), 5.09-5.14 (m, 2H), 4.22

(t, J= 6.4Hz, 2H), 2.65 (d, J= 7.2Hz, 2H), 1.74 (m, 2H), 1.42 (m, 4H), 0.91 (m, 5H);

[192] Step C: Potassium 1 -allylcvclopropane- 1 -sulfonate

A mixture of butyl 1-allylcyclopropane-l -sulfonate (5Og, 229mmol) and potassium thiocyanate (23.4g, 240mmol) in dimethyl ether (DME, 350ml) and water (350ml) was heated at reflux overnight. The mixture was extracted with ethylacetate, and the aqueous phase was evaporated under reduce pressure to obtain the crude product which was used in the next reaction without further purification. ¹H NMR (400MHz, DMSO) δ 5.83-5.90 (m, IH), 4.90-4.94 (m, 2H), 2.45 (d, J= 7.6Hz, 2H), 0.82 (dd, J= 3.6 Hz & 6.0Hz, 2H), 0.36 (dd, J= 3.2Hz & 6.4Hz, 2H) ; [193] Step D; l-Allylcyclopropane-l-sulfonyl chloride:

A solution of potassium 1-allylcyclopropane-l -sulfonate (44g, 220mmol), thionyl chloride (500ml) and DMF (5ml) was heated at reflux for 1.5 hours. The volatiles were evaporated under reduced pressure and water was slowly added. The mixture was extracted with ethylacetate, dried over MgSO₄ filtered and concentrated under reduced pressured. The residue was purified over silica gel chromatography (eluants: PE/EA=10:l) to obtain the title compound (33g, 83%).¹H NMR (400MHz, CDCl₃) 65.69-5.78 (m, IH), 5.17-5.23 (m, 2H)₅ 2.89 (d, J = 7.6Hz, 2H), 1.71- 1.75 (m, 2H), 1.18-1.21(m, 2H) ;

[194] Step E: 1 -Allyl-N-f 2-f 2-fluoro-4-iodophenylaminoV 1.5.-dimethyl-6-oxo- 1.6- dihvdropyridin-3-vOcvclopropanesuIfonamide

According to general procedure A, 5-amino-6-(2-fiuoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H_>)-one was reacted with 1-allylcyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.44 (dd, J= 2.0Hz, & 10.0Hz, IH), 7.26 (m, IH),

7.09 (s, IH), 6.10 (t, J= 8.4Hz, IH), 5.88 (s, IH), 5.73-5.79 (m, IH), 5.14-5.19 (m, 2H), 3.43 (s,

3H), 2.67 (d, J= 7.2Hz, 2H), 2.17 (s, 3H), 1.25 (m, 2H), 0.83-0.87 (m, 2H); m/z = 517 [M+lf.

Example 3

[195] 2,2,2-trifluoro-N-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)ethanesulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H)-one was reacted with 2,2,2-trifluoroethanesulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.45 (dd, J = 2.0Hz & 6.4Hz, IH), 7.28 (d, J = 8.4Hz, IH), 1.23-1.26 (m, IH), 7.01 (s, IH), 6.62 (s, IH), 6.13 (t, J= 8.4Hz, IH), 3.79 (q, J =

8.8Hz, 2H), 3.44 (s, 3H), 2.18 (s, 3H) ; m/z = 520 [M+l]⁺.

Example 4

[196] iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)propane-2-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H}-one was reacted with propane-2-sulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.44 (dd, J= 2.0Hz & 9.6Hz, IH), 7.28 (m, IH), 7.18 (m,

2H), 6.11 (t, J= 8.4Hz, IH), 5.30 (s, IH), 3.44 (s, 3H), 3.22 (m, IH), 2.18 (s, 3H), 1.26 (m, 2H); m/z = 452 [M+l]⁺.

Example 5

[197] Λ^r-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)ethanesulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H^-one was reacted with ethanesulfonyl chloride to obtain the desired product. ¹R NMR (400MHz, CDCl₃) δ 7.44 (dd, J= 1.2Hz & 10.0Hz, IH), 7.28 (m, IH), 7.15 (d, J= 9.2Hz, 2H), 6.12 (t, J= 8.4Hz, IH), 5.30 (s, IH), 3.09 (q, J= 7.2Hz, 2H), 2.18 (s, 3H), 1.43 (t, J= 7.6Hz, 3H) ; m/z = 464 [M+l]⁺.

Example 6

[198] N^2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)cyclohexanesulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H_>)-one was reacted with cyclohexanesulfonyl chloride to obtain the desired product. ¹U NMR (400MΗz, CDCl₃) δ 7.44 (dd, J= 2.0Hz & 10.4Hz, IH), 7.26 (m, IH), 7.18 (m, IH), 6.11 ( t, J= 8.8Hz, IH), 5.73 (s, IH), 3.44 (s, 3H), 2.90 (m, IH), 2.18 (s, 3H), 1.20-2.14 (m, 10H); m/z = 520 [M+l]⁺.

Example 7

[199] N-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)butane- 1-sulf onamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H_>)-one was reacted with butane- 1-sulfonyl chloride to obtain the desired product. ¹U NMR (400MΗz, CDCl₃) δ 7.44 (dd, J= 1.2Hz & 10.0Hz, IH), 7.29 (m, IH), 7.16 (m, IH), 6.12 (t, J= 8.4Hz, IH), 5.75 (s, IH), 3.45 (s, 3H), 3.04 (t, J= 7.6Hz, 2H), 2.19 (s, 3H), 1.79-

1.81 (m, 2H), 1.42-1.48 (m, 2H), 0.95 (t, J= 7.22Hz, 3H); m/z = 494 [M+l]⁺.

Example 8

[200] 3-chIoro-iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)propane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H_/)-one was reacted with 3-chloropropane- 1-sulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.45 (dd, J = 1.6Hz & 9.6Hz, IH), 7.30 (m, IH), 7.23 (m, IH), 7.04 (s, IH), 6.13 (t, J= 8.4Hz, IH), 5.77 (s, IH), 3.68 (t , J= 6.4Hz, 2H), 3.45 (s, 3H), 3.25 (t, J= 8.0Hz, 2H), 2.31-2.36 (m, 2H), 2.18 (m, 3H); m/z = 514 [M+l]⁺.

Example 9

[201] iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)methanesulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7HJ-one was reacted with methanesulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.44 (dd, J = 1.6Hz & 10.0Hz, IH), 7.29 (m, IH), 7.21 (m,lH), 7.12 (s, IH), 6.13 (t, J = 8.8Hz, IH), 5.91 (s, IH), 3.45 (s, 3H), 2.99 (s, 3H), 2.18 (S, 3H); m/z = 452 [M+l]⁺.

Example 10

[202] l-chloro-N-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)methanesulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H_>)-one was reacted with chloromethanesulfonyl chloride to obtain the desired product. ¹H NMR (400MΗz, CDCl₃) δ 7.45 (dd, J = 1.2Hz & 10.0Hz, 7.30 (m , 2H), 6.90 (s, IH), 6.13 (m, 2H), 4.51 (s, 2H), 3.44 (s, 3H), 2.19 (m, 3H); m/z = 486 [M+l]⁺.

Example 11

[203] N-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)cyclopentanesulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H)-one was reacted with cyclopentanesulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.44 (dd, J= 1.6Hz & 10.0Hz, IH), 7.30 (m, 2H), 7.17 (s, IH), 6.11 (t, J= 8.4Hz, IH), 5.77 (s, IH), 3.51 (quintet, IH), 3.44 (s, 3H), 2.18 (s, 3H), 2.00-2.15

(m, 4H), 1.82-1.85 (m, 2H), 1.65-1.68 (m, 2H); m/z = 506 [M+l]⁺.

Example 12

[204] iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyI-6-oxo-l,6-dihydropyridin-3- yl)thiophene-2-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H^-one was reacted with thiophene-2-sulfonyl chloride to obtain the desired product. ¹H NMR (400MΗz, CDCl₃) δ 7.65 ( dd, J= 1.2Hz & 4.8Hz, IH), 7.50 (dd, J= 1.6Hz &

4.0Hz, IH), 7.42-7.45 (dd, J= 1.6Hz & 10.0Hz, IH), 7.250-7.27 (m, 2H), 7.09 (m, IH), 6.79 (s, IH), 6.65 (s, IH), 6.01 ( t, J= 4.0Hz, IH), 3.41 (s, 3H), 2.05 (s, 3H); m/z = 520 [M+lf.

Example 13

[205] N-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)benzenesulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H^-one was reacted with benzenesulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) 67.73 (d, J = 7.6Hz, 2H), 7.62 (m, IH), 7.49 (t, J = 8.0Hz, 2H), 7.43 (dd, J= 1.6Hz & 10.0Hz, IH), 7.20 (d, J= 8.0Hz, IH), 6.71 (s, IH), 6.65 (s, IH), 5.98 (m, IH), 3.39 (s, 3H), 2.05 (s, 3H); m/z = 514 [M+l]⁺.

Example 14

[206] N-(2-(2-fluoro-4-iodophenyIamino)-l,5-dimethyI-6-oxo-l,6-dihydropyridin-3-yl)-4- methylbenzenesulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H^-one was reacted with 4-methylbenzene-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) 67.58 (d, J = 8.4Hz, 2H), 7.41 (dd, J = 1.6Hz & 9.6Hz, IH), 7.23-7.26 (m, 2H), 7.18 (d, J = 8.4Hz, IH), 6.80 (s, IH), 6.64 (s, IH), 5.99 (s, IH), 5.94 (t, J = 8.8Hz, IH), 3.38 (s, 3H), 2.44 (s, 3H), 2.04 (s, 3H); m/z = 528 [M+l]⁺.

Example 15

[207] 4-fluoro-Λ^r-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)benzenesulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7Hj-one was reacted with 4-fluorobenzene-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.73-7.76 (m, 2H), 7.43 (dd, J = 1.6Hz & 10.0Hz, IH), 7.21 (d, J = 8.4Hz, IH), 7.13 (t, J = 8.4Hz, 2H), 6.76 (d, J = 6.0Hz, 2H), 6.16 (s, IH), 5.96 (t,

J = 8.8Hz, IH), 3.40 (s, IH), 2.04 (s, 3H); m/z = 532 [M+l]⁺.

Example 16

[208] Λ^r-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)thiophene-3-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H)-one was reacted with thiophene-3-sulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.85 (dd, J= 1.2Hz & 6.8Hz, IH), 7.41-7.45 (m, 2H), 7.22- 7.26 (m, 2H), 6.77 (s, 2H), 6.16 (s, IH), 6.01 (t, J= 8.4Hz, IH), 3.40 (s, 3H), 2.05 (s, 3H); m/z = 520 [M+l]⁺.

Example 17

[209] N-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-2- isopropylcyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H^-one was reacted with 2-isopropylcyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.43 (dd, J= 1.6Hz & 10.0Hz, IH), 7.26 (m, 2H), 7,16 (s, IH), 6.12 ( t, J= 8.4Hz, IH), 5.84 (s, IH), 3.44 (s, 3H), 2.19-2.22 (m, IH), 2.18

(s, 3H), 1.22-1.26 (m, IH), 1.17-1.21 (m, 2H), 0.96 (m, 6H), 0.84-0.99 (m, IH); m/z = 520 [M+l]⁺.

Example 18

[210] iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-2- isoburylcyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H_>)-one was reacted with 2-isobutylcyclopropane-l-sulfonyl chloride chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.45 (dd, J= 1.2Hz & 10.0Hz, IH), 7.28-7.30 (m, 2H), 7.17 (s, IH), 6.14 (t, J = 8.8Hz, IH), 5.81 (s, IH), 3.47 (s, 3H), 2.21 (s, 3H),2.16-2.19 (m, IH), 1.67-1.73 (m, IH), 1.33-1.38 (m, 2H), 1.27-1.31 (m, IH), 1.08-1.15 (m, 6H), 0.93-0.95 (m, IH); m/z = 534 [M+l]⁺.

Example 19

[211] 2-(4-ethoxyphenyl)-N-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)cyclopropane-l-sulfonamide

According to general procedure A, 5-arnino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H)-one was reacted with 2-(4-ethoxyphenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.44 (dd, J = 1.6Hz & 10.0Hz, IH), 7.24-7.26 (m, 2H), 7.09 (s, IH), 6.85 (q, J = 8.8Hz, 4H), 6.76 (s, IH), 6.08 (t, J= 8.4Hz, IH), 5.81 (s, IH), 4.01 (q, 6.8Hz, 2H), 3.39 (s, 3H), 2.57-2.59 (m, IH), 2.50 (m, IH), 2.01 (s, 3H), 1.70-1.73 (m, IH), 1.38-1.43 (m, 4H); m/z = 598 [M+lf.

Example 20

[212] Λ^2-(2-fluoro-44odophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyriuin-3-yl)-2- phenylcyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H)-one was reacted with 2-phenylcyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.42 (dd, J = 1.6Hz & 10.0Hz, IH), 7.24- 7.35(m, 4H), 7.07 (s, IH), 6.96 (d, J= 7.2Hz, 2H), 6.82 (s, IH), 6.08 (t, J = 8.8Hz, IH), 6.01 (s, IH), 3.38 (s, 3H), 2.62-2.65 (m, IH), 2.53-2.55 (m, IH), 2.04 (s, 3H), 1.75-1.77 (m, IH), 1.45 (m, lH); m/z = 554 [M+l]⁺.

Example 21

[213] 2-(3,4-difluorophenyl)-iV-(2-(2-fluoro-4-iodophenyIamino)-l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7/ζ)-one was reacted with 2-(3,4-difluorophenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.44 (dd, J= 2.0Hz & 10.0Hz, IH), 7.29 (m, IH), 7.11-7.13 (m, IH), 7.07 (s, IH), 6.74-6.77 (m, IH), 6.12 (t, J = 8.4Hz, IH), 5.30 (s, IH), 3.43 (s, 3H), 2.57-2.63 (m, 2H), 2.05 (s, 3H), 1.73-1.75 (m, IH), 1.38-1.42 (m, lH); ); m/z = 590 [M+l]⁺.

Example 22

[214] iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-2- (thiophen-2-yl)cyclopropane-l-suIfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H,)-one was reacted with 2-(thiophen-2-yl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.43 (dd, J = 2.0Hz & 10.4Hz, IH), 7.23 (d, J= 5.6Hz, 2H), 7.16 (d, J= 5.2Hz, IH), 6.98 (s, IH), 6.94 (dd, J= 3.6Hz & 5.2Hz, IH), 6.75 (d, J = 3.2HZ, IH), 6.09 (t, J= 8.4Hz, IH), 3.41 (s, 3H), 2.67-2.80 (m, IH), 2.63-2.66 (m, IH), 2.04 (d, J= 2.0Hz, 3H), 1.76-1.81 (m, IH), 1.39-1.44 (m, IH); m/z = 560 [M+l]⁺.

Example 23

[215] 2-(2,4-difluorophenyl)-/V-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H)-one was reacted with 2-(2,4-difluorophenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400MΗz, CDCl₃) δ 7.43 (dd, J= 1.6Hz & 10.0Hz, IH), 7.26 (m, IH), 7.09 (s, IH), 7.04 (s, IH), 6.82-6.89 (m, 3H), 6.12 (t, J= 8.8Hz, IH), 5.94 (s, IH), 3.43 (s, 3H), 2.68-2.74 (m, 2H), 2.01 (s, 3H), 1.72-1.78 (m, IH), 1.47-1.49 (m, IH); ); m/z = 590 [M+l]⁺.

Example 24

[216] 2-(4-cyanophenyl)-iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7H_y)-one was reacted with 2-(4-cyanophenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.62 (d, J= 8.4HZ, 2H), 7.44 (dd, J = 1.6Hz & 10.0Hz, IH), 7.29 (m, IH), 7.10 (d, J= 8.4Hz, 2H), 7.03 (s, IH), 6.91 (s, IH), 6.12 (t, J= 8.4Hz, IH), 5.84 (s, IH), 3.43 (s, 3H), 2.64-2.71 (m, 2H), 2.01 (s, 3H), 1.78-1.84 (m, IH), 1.46- 1.49 (m, IH); m/z = 579 [M+l]⁺.

Example 25

N-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-J- methylcyclopropane-l-sulfonamide

[217] Step A; Isopropyl cyclopropanesulfonate

Cyclopropanesulfonyl chloride (21.6g, 154 mmol, 1 eq.) was dissolved in excess /-PrOH (50ml) and the reaction mixture was cooled at O⁰C. Pyridine (12.15g, 154 mmol, leq) was added drop wise and the mixture was slowly warmed to room temperature and stirred for 94 hours. The solvent was removed under reduced pressure and the resulting white solid was dissolved in dichloromethane. The organic phase was washed with water, brine and dried (MgSO₄), filtered and concentrated to give an oil (17.8g, 71%).1H NMR (400MHz, CDCl₃) δ 4.91-4.97 (m, IH), 2.42- 2.48 (m, IH), 1.41-1.44 (m, 6H), 1.24-1.28 (m, 2H), 1.04-1.10 (m, 2H);

[218] Step B: Isopropyl 1 -methylcvclopropane- 1 -sulfonate

To a solution of isopropyl cyclopropanesulfonate (2g, 12.18mmol ) in THF (40ml) at -78°C was slowly added butyllithium (6.1ml, 2.5M in hexane, 15.22mmol) under a nitrogen atmosphere. After stirring 30 minutes, a solution of methyliodide (1.44g, 10.15 mmol) in THF (5ml) was added. The reaction mixture was stirred 2 hours at -60⁰C. The solution was quenched with water and was allowed to warm to room temperature. The volatiles were evaporated under reduced pressure and the residue extracted with ethylacetate. The organic phase was washed with water, dried (MgSO₄), filtered and evaporated under reduce pressure. The residue was purified over silica gel chromatography (eluant: PE/EA=5: 1) to obtain the titled product (830mg, yield: 46%) as a yellow oil. ¹H NMR (400MHz, CDCl₃) δ 4.91-4.96 (m, IH), 1.54-1.56 (m, 2H), 1.41-1.48 (m, 2H), 0.83- 0.88 (m, 2H);

[219] Step C: Potassium 1 -methylcvclopropane- 1 -sulfonate

A mixture of isopropyl 1-methylcyclopropane-l -sulfonate (810mg, 4.54mmol) and potassium thiocyanate (442mg, 4.54mmol) in DME (12.5ml) and water (12.5ml) was heated at reflux overnight. The residue was extracted with ethylacetate, and the aqueous phase was evaporated under reduce pressure to obtain the crude product which was used in the next reaction without further purification.

[220] Step D: 1 -Methylcvclopropane- 1 -sulfonyl chloride

A solution of potassium 1-methylcyclopropane-l -sulfonate (349mg, 2mmol), thionyl chloride (5ml) and DMF (5drops) was heated at reflux for 1.5 hours. The volatiles were evaporated under reduce pressure and water was slowly added. The residue was extracted with ethylacetate, dried over MgSO₄, filtered, and evaporated to obtain the crude product as a yellow oil which was used in the next reaction without further purification.

[221] Step E: N-(2-( 2-fluoro-4-iodophenylamino> 1.S-dimethyl-ό-oxo- 1 ,6-dihvdropyridin-3-yl)- 1 -methylcvclopropane- 1 -sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7.fi9-one was reacted with 1-methylcyclopropane-l -sulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.43 (dd, J = 2.0Hz & 10.4Hz, IH), 7.28 (m,

IH), 7.08 (s, IH), 6.11 (t, J = 8.4Hz, IH), 5.73 (s, IH), 3.44 (s, 3H), 2.05 (s, 3H), 1.58 (s, 3H),

1.26-1.32 (m, 2H), 0.78-0.80 (m, 2H); m/z = 492 [M+l]⁺.

Example 26

N-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyI-6-oxo-l,6-dihydropyridin-3- yl)cyclobutanesulfonamide

[222] Step A: Cvclobutanesulfonyl chloride

To a suspension of Mg turnings (0.405g, 16.67mmol) in 5ml of anhydrous THF was added

0.3g bromocyclobutane, and a catalytic amount of iodine. The mixture was heated using an electric blower. As the solution turned to colorless, another 1.2g bromocyclobutane dissolved in 15ml of THF was slowly added. The mixture was heated at reflux for 1 hour, then cooled to room temperature and the supernatant was added in small portions to an ice-cold solution of sulfuryl chloride (4.5g, 33.3mmol) in 10ml of anhydrous dichlormethane,. After complete addition, the suspension was warmed to room temperature and the volatiles were removed in vacuo. The residue was dissolved in hexane (25ml). The suspension was filtered, and the solution was evaporated to give the crude product (1.55g, 90%) as a yellow oil which was used in the next reaction without further purification.

[223] Step B: A/-(2-(2-fluoro-4-iodophenylamino)- 1.5-dimethyl-6-oxo- 1.6-dihvdropyridin-3- vDcyclobutanesulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(7/()-one was reacted with cyclobutanesulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.44 (dd, J= 2.0Hz & 10.0Hz, IH), 7.28 (m, IH), 7.20 (s, IH), 7.08 (s, IH), 6.11 ( t, J= 8.4Hz, IH), 5.61 (s, IH), 3.84-3.88 (m, IH), 3.43 (s, 3H), 2.52-2.57 (m, 2H), 2.29-2.35 (m, 2H), 2.17 (s, 3H), 2.03-2.08 (m, 2H); ); m/z = 492 [M+l]⁺.

Example 27

l-(2,3-dihydroxypropyl)-iV-(2-(2-fluoro-4-iodophenylainino)-l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)cyclopropane-l-sulfonamide

[224] Step A: Tert-butyl 1 -allylcvclopropylsulfonyl(2-(2-fluoro-4-iodophenylamino)- 1,5- dimethyl-6-oxo- 1.6-dihvdropyridin-3-yl^*)carbamate

To a solution of l-allyl-iV-(2-(2-fluoro-4-iodophenylamino)-l,5,-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)cyclopropanesulfonamide (182 mg, 0.352 mmol) and di-tert-butyl dicarbonate (84 mg, 0.387 mmol, 1.1 eq.) in 3 mL of dry THF was added NaH (60%wt, 31 mg, 2.2 eq.) in one portion at 0 ⁰C, then stirred at room temperature overnight (14 hours). After quenching with water, ethylacetate was added. The organic phase was washed with water and the aqueous phase extracted with ethylacetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica using PE:EA=2:1 as eluent to afford the title compound (138 mg, yield = 63%) as a light yellow oil. ¹K NMR (400MHz, CDCl₃) δ 7.45-7.50 (m, 2 H), 7.32 (s, IH), 7.12 (t, J= 8.4Hz, IH), 5.68-5.78 (m, IH), 5.54 (s, IH), 5.08-5.15 (m, 2H), 3.39 (s, 3H), 2.68 (d, J = 7.6Hz, 2H), 2.16 (s, 3H), 1.15 (s, 9H), 1.30-1.35 (m, IH), 1.23-1.27 (m, IH), 0.85- 0.92 (m, 2H); m/z = 618 [M+l]⁺.

[225] Step B: Tert-butyl 1 -(2.3-dihvdroxypropyDcvclopropylsulfonyl(2-(2-fluoro-4- iodophenylamino)- 1.S-dimethyl-ό-oxo- 1.6-dihydropyridin-3-yl)carbamate

To solution of tert-butyl l-allylcyclopropylsulfonyl(2-(2-fluoro-4-iodophenylamino)-l,5- dimethyl-6-oxo-l,6-dihydropyridin-3-yl)carbamate (lOOmg, 0.162mmol), was added N- methylmorpholine iV-oxide (19 mg, 0.162 mmol) at O⁰C, followed by osmium( VIII) oxide (4%wt, 103 mg, 0.1 eq.) at O⁰C. The mixture was stirred at room temperature for 18 hours, then quenched with aq.Na₂S₂O₄, extracted with dichloromethane, dried over magnesium sulfate and filtered. The solvent was removed and the residue was purified by flash column chromatography on silica using DCM:MeOH=10:l as eluent, to give the title compound (96mg, 91%) as a gray solid. ¹H NMR (400MHz, CDCl₃) δ 7.46-7.48 (m, 2 H), 7.35 (s, IH), 7.16 (t, J = 8.4Hz, IH), 6.31 (d, J = 5.2Hz, IH), 4.00 (m, IH), 3.59 (d, J= 11.2Hz, IH), 3.41 (s, 3H), 3.40-3.49 (m, IH), 3.23 (s, IH), 2.26 (dd, J = 15.6&9.6Hz, IH), 2.16 (s, 3H), 1.77 (dd, J = 15.6&45.2Hz, IH), 1.15 (s, 9H), 1.25(m, 2H), 1.00 (m, 2H); m/z = 652 [M+l]⁺.

[226] Step C: 1 -(2,3-DihvdroxypropylVN-(2-(2-fluoro-4-iodophenylamino)- 1.5-dimethyl-6-oxo- 1 ,6-dihvdropyridin-3-yl)cyclopropane- 1 -sulfonamide

Trifluoroacetic acid (0.5mL) was added to a solution of tert-butyl l-(2,3-dihydroxypropyl) cyclopropylsulfonyl(2-(2-fluoro-4-iodophenylamino)- 1 ,5-dimethyl-6-oxo- 1 ,6-dihydropyridin -3- yl) carbamate (43 mg, 0.066 mmol) in 1 mL of dichloromethane at room temperature and stirred for 1 hour. The reaction was quenched with sat.Na₂CO₃ and stirred for 0.5 hours. After extraction with dichloromethane (3x), sodium chloride was added to the water phase and extracted with dichloromethane (3x). The combined organic layers were dried over MgSO₄ and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica using DCMrMeOH=IO: 1 as eluent, to afford the title compound (24 mg, yield = 66%) as a gray solid. ¹U NMR (400MHz, CDCl₃) δ 7.49 (s, IH), 7.39-7.42 (dd, J =

1.6&11.2HZ, IH), 7.42 (s, IH), 7.24-7.26 (m, 2H), 6.10 (t, J= 8.0Hz, IH), 3.92 (m, IH), 3.66 (s,

IH), 3.57-3.60 (m, IH), 3.42-3.46 (m, IH), 3.42 (s, 3H), 2.72 (s, IH), 2.25 (dd, J= 9.6&15.2Hz, IH), 2.15 (s, 3H), 1.63 (d, J= 14.4Hz, IH), 1.37-1.42 (m, IH), 1.22-1.33 (m, IH), 0.81-0.90 (m,

2H); m/z = 552 [M+l]⁺.

Example 28

(R)-l-(2,3-dihydroxypropyl)-Λ'-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)cyclopropane-l-suIfonamide

[227] Step A: lftVIsopropyl 1 -(^'3-(benzyloxy^')-2-hvdroxypropyl^*)cvclopropane- 1 -sulfonate

n-Butyllithium (2.5 M, 91 mL, 228 mmol) was added to isopropyl cyclopropanesulfonate (30 g, 183 mmol) in 450 mL of dry THF and 50 mL of HMPA(hexamethyl phosphoramide) at -78⁰C over 25 min (ethylacetate/N₂ bath) and stirred for 30 min. The black solution was then stirred at - 40°C( acetonitrile/N₂ bath) and (Λ)-2-(benzyloxymethyl)oxirane (25g, 152 mmol) in 50 mL THF added and stirred at -4O⁰C for 3 hours. The reaction was quenched with water, extracted with ethylacetate (2x), washed with sat.NaCl, dried over MgSO₄ and filtered. The solvent was removed under reduced pressured and the residue purified via column chromatography on silica gel using petroleum, ether: ethylacetate=5:l -to 2:1 as eluent to afford the title compound (37.9 g, yield = 76%) as a brown oil. ¹H NMR (400MHz, CDCl₃) δ 7.30-7.37 (m, 5H), 4.95 (sept, 6.OHz₅IH), 4.55 (s, 2H), 4.16-4.20 (m, IH), 3.51 (dd, J = 9.6Hz&4.8Hz ,1H), 3.42 (dd, J = 9.6Hz&6.0Hz ,1H), 2.70 (d, J = 4.0Hz, IH), 2.08 (dd, J =15.6Hz&3.6Hz,lH) , 1.88 (dd, J = 15.2Hz&8.8Hz, IH), 1.44-1.46 (m, 2H) ,1.43 (d, J = 6.0Hz, 3H), 1.15-1.18 (m, IH), 0.93-0.97 (m,lH); m/z = 329 [M+l]⁺.

[228] Step B: IRVIsopropyl l-(2.3-bis(benzyloxy)propy0cvclopropane-l -sulfonate

(i?)-Isopropyl l-(3-(benzyloxy)-2-hydroxypropyl)cyclopropane-l -sulfonate (1.38 g, 4.2 mmol) was added to a mixture of NaH (60% wt, 210 mg, 5.25 mmol) in DMF at O⁰C and stirred for 30 minuntes. Benzylbromide (0.75 mL, 6.3 mmol) was added to the reaction mixture at O⁰C and stirred at room temperature overnight (13 hours), then quenched with water, extracted with ethylacetate, washed with water (2x) and sat. brine, dried over MgSO₄ and filtered. The solvent was removed under reduced pressure and the residue purified via column chromatography on silica gel using petroleum ether:ethylacetate=10:l-to 5:1 as eluent to afford the title compound (1.145 g, yield = 65%) as a brown oil. ¹H NMR (400MHz, CDCl₃) δ 7.26-7.34 (m, 10H), 4.89 (sept, J = 6.OHz₅IH), 4.63 (dd, J = 36.4 Hz&11.2Hz, 2H), 4.55 (s, 3H), 4.13-4.16 ( m, IH), 4.15(dd, J =8.4Hz&4.4Hz,2H), 3.56 (dd, J =4.4Hz,&1.2Hz ,1H), 2.32 (dd, J = 15.6Hz & 4.4Hz ,1H), 1.40-1.45 (m, 2H), 1.37 (dd, J = 8.0Hz & 6.0Hz, 6H), 1.18-1.22 (m, IH), 0.87-0.92 (m, lH); m/z = 419 [M+l]⁺.

[229] Step C: Potassium (R)- 1 -(2,3-bis(benzyloxy)propyl)cvclopropane- 1 -sulfonate

(i?)-Isopropyl l-(2,3-bis(benzyloxy)propyl)cyclopropane-l -sulfonate) (450 mg, 1.075 mmol) and potassium thiocyanate (115 mg, 1.183 mmol) were dissolved in a solution of diethyl ether and water (10 mL, 2:1 v/v). The reaction mixture was heated at reflux overnight, and then the mixture was evaporated under reduced pressure. The residue was washed with ether to give the title compound as a sticky solid.

[230] Step D: (R)- 1 -(2.3 -BisfbenzyloxytoropyDcvclopropane- 1 -sulfonyl chloride

Potassium (/?)-l-(2,3-bis(benzyloxy)propyl)cyclopropane-l -sulfonate) was dissolved in 7 mL sulfurous dichloride and 1 mL of DMF. The reaction mixture was heated at reflux for 1 hour, and then the mixture was evaporated under reduced pressure.. The yellow residue was purified by column chromatography on silica gel using an elution gradient of ethylacetate: petroleum ether =

1:5 to give the title compound (250 mg, 60% for two steps) as a yellow oil. ¹H NMR (400MHz, CDCl₃) δ 7.29-7.37(m, 10H), 4.60 (dd, J = 57.6Hz&l 1.6Hz, 2H ) 4.56 (s, 2H), 4.14-4.20 ( m, IH), 3.54-3.62 ( m, 2H), 2.63 (dd, J =16.4Hz&3.6Hz,lH), 2.17( s, 3H), 2.02 (dd, J =16.4Hz&9.2Hz ,lH), 1.75-1.81(m, IH), 1.65-1.71 (m, IH), 1.52-1.57 (m, IH), 1.14-1.19 (m, IH).

[231] Step E: f/?Vl-(23-Bis(beiizyloxy)propyiyN-f2-f2-fluoro-4-iodophenylaminoπ,5- dimethyl-6-oxo- 1 ,6-dihvdropyridin-3-yl)cyclopropane- 1 -sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with (/?)-l-(2,3-bis(benzyloxy)propyl) cyclopropane- 1- sulfonyl chloride to obtain the desired product. ¹H NMR (400MHz, CDCl₃) δ 7.22-7.41 (m, 1 IH), 7.00 (s, IH), 6.87 (s, IH), 6.55 (s, IH), 5.99 (t, J = 8.8Hz, IH), 4.57(dd, J= 72.4Hz&10.8Hz, 2H), 4.52(s, 2H), 3.89-3.92 (m, IH), 3.60 (dd, J = 9.6Hz&4.0Hz, IH), 3.50 (dd, J =9.6Hz&5.6Hz,lH), 3.31 (s, 3H), 2.18-2.20 (m, 2H), 2.08 (s, 3H), 1.38-1.42 (m, IH), 1.24-1.30 (m, IH), 0.84-0.97 (m, IH), 0.84-0.87 (m, IH); m/z = 732 [M+l]⁺.

[232] Step F: (R)- 1 -(2.3-DihvdroxypropylVN-f 2-Q-fluoro-4-iodophenylamino^')- 1.5-dimethyl-6- oxo- 1.ό-dihvdropyridin-S-vDcvclopropane- 1 -sulfonamide

Boron trichloride (1 M in dichloromethane, 0.8 mL) was added to (/?)-l-(2,3-bis(benzyloxy) propyl)-N-(2-(2-fluoro-4-iodophenylamino)- 1 ,5-dimethyl-6-oxo- 1 ,6-dihydropyridin-3- yl)cyclopropane-l -sulfonamide (61 mg, 0.083 mmol) in 8 mL of dichloromethane at O⁰C. After stirring at room temperature for 10 minutes, 1 N HCl was added, and the mixture extracted with dichloromethane. The organic phase was washed with sat. NaHCO₃, sat. NaCl, and dried over MgSO₄. Filtration, removal of solvent and column chromatography of the residue on silica gel using dichloromethane:methanol=15:l as eluent gave the title compound (41mg, 90%) as a gray solid. ¹H NMR (400MHz, CDCl₃) δ 7.43 (d, J= 10.4Hz, IH), 7.35 (s, IH), 7.26 (s, IH), 7.12 (s, IH), 6.84 (s, IH), 6.10 (t, J= 8.8Hz, IH), 3.96 (m, IH), 3.65 (m, IH), 3.50 (m, IH), 3.44 (s, 3H), 3.16 (s, IH), 2.34 (dd, J= 10.0&15.6Hz, IH), 2.18 (s, 3H), 1.97 (s, IH), 1.67 (d, J= 15.6Hz, IH), 1.46-1.49 (m, IH), 1.26-1.30 (m, IH), 0.88-0.95 (m, 2H); ¹H NMR (400MHz, CDCl₃+2 drops of DMSO-d6) δ 8.64 (s, IH), 7.68 (s, IH), 7.49 (s, CDCl₃), 7.37 (s, 1 H), 7.32 (dd, J= 10.4&2.0Hz, IH), 7.17 (d, J = 8.4Hz,lH), 6.05 (t, J = 8.8Hz, IH), 4.04 (m, IH), 3.90 (m, IH), 3.72 (m, IH), 3.31 (s, 3H), 3.22-3.34 (m, IH), 2.50 (DMSO-d6), 1.68-1.80 (m, 2H), 1.10-1.18 (m, IH), 0.99- 1.03 (m, IH), 0.80-0.82 (m, IH), 0.73-0.76 (m, IH); m/z = 552 [M+l]⁺.

Example 29

(5^r)-l-(2,3-dihydroxypropyl)-Λ^?-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6- dihydropyridin-S-ylJcyclopropane-l-sulfonaniide

[233] Step A: (.SVIsopropyl 1 -(3 -(benzyloxy)-2-hvdroxypropyl)cvclopropane- 1 -sulfonate

Following the procedure as step A in example 28 described above, gave the title compound.

¹H NMR (400MHz, CDCl₃) δ 7.30-7.37 (m, 5H), 4.95 (sept, 6.OHz₁IH), 4.55 (s, 2H), 4.16-4.20 (m, IH), 3.51 (dd, J= 9.6Hz&4.8Hz ,1H), 3.42 (dd, J= 9.6Hz&6.0Hz ,1H), 2.70 (d, J= 4.0Hz, IH),

2.08 (dd, J=15.6Hz&3.6Hz,lH) , 1.88 (dd, J = 15.2Hz&8.8Hz, IH), 1.44-1.46 (m, 2H) ,1.43 (d, J

= 6.0Hz, 3H), 1.15-1.18 (m, IH), 0.93-0.97 (m, IH); m/z = 329 [M+l]⁺.

[234] Step B: (.SVIsopropyl l-(2.3-bis(benzyloxy)propyl)cvclopropane-l -sulfonate

Following the same procedure as step B, example 28 described, gave the title compound. ¹H

NMR (400MHz, CDCl₃) δ 7.26-7.34 (m, 10H), 4.89 (sept, J = 6.0Hz₅IH), 4.63 (dd, J = 36.4

Hz&11.2Hz, 2H), 4.55 (s, 3H), 4.13-4.16 ( m, IH), 4.15(dd, J =8.4Hz&4.4Hz,2H), 3.56 (dd, J

=4.4Hz,&1.2Hz ,1H), 2.32 (dd, J =15.6Hz&4.4Hz ,1H), 1.40-1.45 (m, 2H), 1.37 (dd, J = 8.0Hz&6.0Hz, 6H), 1.18-1.22 (m, IH), 0.87-0.92 (m, IH); m/z = 419 [M+l]⁺.

[235] Step C: Potassium (S)- 1 -(2,3-bis(ben2yloxy)propyl)cvclopropane- 1 -sulfonate

Following the same procedure as step C, example 28 described, gave the title compound.

[236] Step D: (S)- 1 -(2.3-Bis(benzyloxy)propyl)cyclopropane- 1 -sulfonyl chloride

Following the same procedure as step D, example 28 described, gave the title compound. ¹H NMR (400MHz, CDCl₃) δ 7.29-7.37(m, 10H), 4.60 (dd, J = 57.6Hz&11.6Hz, 2H ) 4.56 (s, 2H), 4.14-4.20 ( m, IH), 3.54-3.62 ( m, 2H), 2.63 (dd, J=16.4Hz&3.6Hz,lH), 2.17( s, 3H), 2.02 (dd, J =16.4Hz&9.2Hz ,1H), 1.75-1.81(m, IH), 1.65-1.71 (m, IH), 1.52-1.57 (m, IH), 1.14-1.19 (m, IH).

[237] Step E: (5Vl-(23-Bis(benzyloxy^ρropyl)-N-f2-(2-fluoro-4-iodophenylaminoπ.5- dimethyl-6-oxo- 1 ,6-dihvdropyridin-3-yl)cvclopropane- 1 -sulfonamide

Following the same procedure as step E, example 28 described, gave the title compound. ¹H NMR (400MHz, CDCl₃) δ 7.22-7.41 (m, HH), 7.00 (s, IH), 6.87 (s, IH), 6.55 (s, IH), 5.99 (t, J = 8.8Hz, IH), 4.57(dd, J = 72.4Hz&10.8Hz, 2H), 4.52(s, 2H), 3.89-3.92 (m, IH), 3.60 (dd, J = 9.6Hz&4.0Hz, IH), 3.50 (dd, J=9.6Hz&5.6Hz,lH), 3.31 (s, 3H), 2.18-2.20 (m, 2H), 2.08 (s, 3H),, 1.38-1.42 (m, IH), 1.24-1.30 (m, IH), 0.84-0.97 (m, IH), 0.84-0.87 (m, IH); m/z = 732 [M+l]⁺.

[238] Step F: (S)- 1 -(23-dihvdroxypropylVN-(2-Q-fluoro-4-iodophenylamino)- 1.5-dimethyl-6- oxo- 1.ό-dihydropyridin-S-vDcvclopropane- 1 -sulfonamide

Following the same procedure as step F, example 28 described, gave the title compound. ¹H

NMR (400MHz, CDCl₃) δ 7.43 (d, J= 10.4Hz, IH), 7.35 (s, IH), 7.26 (s, IH), 7.12 (s, IH), 6.84

(s, IH), 6.10 (t, J= 8.8Hz, IH), 3.96 (m, IH), 3.65 (m, IH), 3.50 (m, IH), 3.44 (s, 3H), 3.16 (s, IH), 2.34 (dd, J= 10.0&15.6Hz, IH), 2.18 (s, 3H), 1.97 (s, IH), 1.67 (d, J= 15.6Hz, IH), 1.46-

1.49 (m, IH), 1.26-1.30 (m, IH), 0.88-0.95 (m, 2H); m/z = 552 [M+ 1]⁺.

Example 30

[239] N-(2-(2-Fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-l-(3- hydroxypropyl)cyclopropane-l-sulfonamide

A mixture of tert-butyl 1-allylcyclopropylsulfonyl (2-(2-fluoro-4-iodophenylamino)-l,5- dimethyl-6-oxo-l,6-dihydropyridin-3-yl)carbamate (lOOmg, 0.162mmol) and THF (2ml) was stirred in a three-necked round bottom flask, under a nitrogen atmosphere. Using a syringe, BH₃-

THF (ImI, lmmol) was slowly added into the reaction flask. The reaction was stirred at room temperature for 48 hours, and aqueous NaOH ( 3M, ImI) and 30% aqueous H₂O₂ (3ml) were added to the reaction flask while cooling with an ice-bath. After the addition, the mixture was stirred at room temperature for 2 hours, and then extracted with ethylacetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (eluant: ethylacetate) to obtain the title product 1-OH (66mg, 64%) and byproduct 2-OH (27mg, 26%). The 1-OH product (60mg, 0.094mmol) was dissolved in 2ml of dichloromethane, and excess TFA (0.5ml) was slowly added. The mixture was stirred at room temperature for 2 hours, and the volatiles were removed in vacuo. The residue was purified via silica gel chromatography (eluant: dichlormethane:methanol = 20:1) to obtain the desire product (44mg, 87%). ¹H NMR (400MHz, DMSO) δ 8.86 (s, IH), 7.98 (s, IH), 7.58 (dd, J= 1.6Hz & 10.8Hz, IH), 7.33-7.36 (m, 2H), 6.27 (t, J= 8.8Hz, IH), 4.18 (br, IH), 3.22- 3.33 (m, 5H), 2.03 (s, 3H), 1.61-1.65 (m, 2H), 1.28-1.32 (m, 2H), 0.86-0.92 (m, 2H), 0.63-0.66 (m, 2H); m/z = 535 [M+l]⁺.

Example 31

[240] iV-(2-(2-FIuoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-l-(2- hydroxypropyl)cyclopropane-l-sulfonamide

According to the same procedure as example 30, the desired product was obtained. ¹H NMR (400MHz, DMSO-D6) δ 8.82 (br, IH), 7.94 (s, IH), 7.57 (dd, J= 2.0Hz & 10.8Hz, IH), 7.39 (s, IH), 7.31 (d, J= 8.4Hz, IH), 6.25 (t, J= 8.4Hz, IH), 4.45 (d, J= 5.6Hz, IH), 3.60 (br, IH), 3.26 (s, 3H), 2.00 (s, 3H), 1.78-1.83 (m, IH), 1.52-1.58 (m, IH), 0.81-0.94 (m, 5H); m/z = 535 [M+l]⁺.

Example 32

N-(2-(2-Fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)butane-l-sulfonamide:

[241] Step A: 2-Chloro-4-nitropyridine 1 -oxide:

Into a mixture of 2-chloro-5-methylpyridine, urea hydrogen peroxide addition compound and dichloromethane was added anhydrous trifluoroacetic acid dropwise at O⁰C, and the mixture was stirred at O⁰C for 1 hour. After stirring for 3 days while elevating the reaction temperature to room temperature, an aqueous solution (250 mL) of sodium hydrosulfite (45 g) was added, and the reaction mixture was stirred for 15 minutes. Hydrochloric acid (0.5N, 400 mL) was added and the mixture was extracted with dichloromethane (400 mL). The organic phase was washed with sodium bicarbonate solution, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to afford the title compound which was used in the next step without further purification as a yellow solid. Yield=90%. ¹H NMR (400 MHz, CDCl₃): δ= 8.422-8.404 (t, 1 H, J= 3.6 Hz), 8.399-8.375 (t, 1 H, J= 4.8 Hz), 8.067-8.049 (t, 1 H, J= 3.6 Hz).

[242] Step B: 2-Chloro-4-methoxypyridine 1 -oxide:

A solution of sodium methoxide, prepared by dissolving sodium (21 g) in dry MeOH (1000 ml), was quickly poured into a stirred solution of 2-chloro-4-nitropyridine 1 -oxide (151 g) in MeOH (1000 ml). Dissolution was complete within 5 minutes and the reaction was left stirring in a stoppered flask overnight. Partial concentration of the yellow solution produced a precipitate, which was filtered and washed with MeOH (2 x 100 mL). The filtrate and washings were evaporated to dryness, and the solid that remained was extracted with boiling dichloromethane to give (after filtration and concentration) a yellow-brown solid which was used in the next step without further purification. Yield= 95%. ¹H NMR (400 MHz, CDCl₃): δ= 8.256-8.237 (d, 1 H, J= 7.6 Hz), 7.026-7.018 (d, 1 H, J= 3.2 Hz), 6.804-6.777 (dd, 1 H, J= 3.6 & 3.2 Hz), 3.875 (s, 3 H).

[243] Step C: 2,6-Dichloro-4-methoxypyridine:

A solution of phosphorus oxychloride (151 g) in 250 ml of dichloromethane was added to a mixture of 2-chloro-4-methoxypyridine 1 -oxide (13Og) and triethylamine (151 ml) in dichloromethane (1000 ml) at O⁰C. After stirring at O⁰C for 2 hours and then room temperature for 1 hour, water was added and the mixture was neutralized with a sodium hydroxide solution (6N), and the separated organic layer was washed with a saturated brine solution. The aqueous layer of the reaction solution was extracted with ethylacetate, and washed with a saturated brine solution. The combined organic layers were dried over Na₂SO₄ and concentrated in vacuum to afford the crude product which was purified via silica gel chromatography (petroleum ether/ethylacetate=10/l) to give the desired compound. Yield= 38.3%. ¹H NMR (400 MHz, CDCl₃): δ= 6.794 (s, 2 H), 3.877 (s, 3 H); m/z= 178 [M+l]⁺.

[244] Step D: 2,6-Dichloro-4-methoxy-3-nitropyridine:

To a solution of 2,6-dichloro-4-methoxypyridine (40 g) in concentrated sulfuric acid was added concentrated nitric acid (95%) at O⁰C. The mixture was heated to 100⁰C for 3.5 hours. After cooling to 5O⁰C, the mixture was poured into ice. The resulting precipitate was filter and washed with water. The white solid was dissolved in dichloromethane, dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford the title compound as white solid which was used without further purification. Yield=82%. ¹H NMR (400 MHz, CDCl₃): δ= 6.994 (s, 1 H), 4.023 (s, 3 H); m/z= 223 [M+l]⁺.

[245] Step E: 6-Chloro-N-(2-fluoro-4-iodophenyl)-4-methoxy-3-nitropyridin-2-amine:

To a mixturre of NaH (3.0 eq.) in THF was added 2-fluoro-4-iodoaniline (1.0 eq.) at room temperature. The mixture was heated at 60 ⁰C for 15 minutes followed by the addition of 2,6- dichloro-4-methoxy-3-nitropyridine. After heating at reflux for 0.5 hours, the reaction was cooled and water was added. The suspension was filtered and dried to afford the title compound. Yield=50%. ¹H NMR (400 MHz, CDCl₃): δ= 9.529 (bra, 1 H), 8.032-7.998 (t, 1 H, J= 8.8 Hz), 7.493-7.463 (m, 2 H), 6.523 (s, 1 H), 3.974 (s, 3 H); m/z=424 [M+ 1]⁺.

[246] Step F: 6-(2-Fluoro-4-iodophenylammo)-4-methoxy-5-nitropyridin-2(7/#-one:

To aq. KOH (14.4g in 52 ml water) was added 6-chloro-iV-(2-fluoro-4-iodophenyl)-4-methoxy-3- nitropyridin-2-amine (2 g), followed by MeOH (150 ml). The mixture was heated at reflux for 1.5 hours. Cold water was added, and the yellow suspension was filtered and dried to afford the title compound. The filtrate solution was adjusted to pH 7 with cone. HCl, to yield additional yellow precipitate which was filtered and dried to afford the title compound as a red solid which was used in the next step without further purification. Yield=99%. ¹H NMR (400 MHz, CDCl₃): δ= 10.257 (bra, 1 H), 7.564-7.490 (m, 2 H), 7.174-7.133 (t, 1 H, J= 8.4 Hz), 6.523 (s, 1 H), 3.974 (s, 3 H); m/z=405 [M+l]⁺.

[247] Step G: 6-(2-Fluoro-4-iodophenylamino)-4-methoxy-l-methyl-5-nitropyridin-2(7Hj-one:

To a solution of NaH (2.5 eq.) in dry DMF (0.2 mol/L) was added 6-(2-fluoro-4- iodophenylamino)-4-methoxy-5-nitropyridin-2(7H>one (1 eq.) at room temperature. After stirring for 25 minutes, methyliodide (1.3 eq.) was added to the dark red mixture and stirring continued for 1 hour followed by the addition of sat. NH₄Cl. The mixture was extracted with ethylacetate, washed with water and brine. The organic layer was dried over MgSO₄ , filtered and concentrated in vacuo to give the crude product which was purified via silica gel chromatography (from petroleum ether 100% to petroleum ether/ethylacetate~l/2) to afford the title compound as a yellow solid. Yield=50%. ¹H NMR (400 MHz, CDCl₃): δ= 8.799 (brs, 1 H), 7.525-7.268 (dd, 2 H, J= 10 & 7.6 Hz), 6.593-6.551 (t, 1 H, J= 8.4 Hz), 5.810 (s, 1 H), 3.912 (s, 3 H), 3.230 (s, 3 H); m/z= 420 [M+l]⁺.

[248] Step H: 5-Amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methylpyridin-2(7HJ-one:

6-(2-Fluoro-4-iodophenylamino)-4-methoxy-l-methyl-5-nitropyridin-2(7H^-one (220 mg) and Na₂S₂O₄ (1.96 g, 16 eq.) was dissolved in dioxane and water (30 mL, 1:1) followed by the addition of NΗ₄OΗ (1 mL) at room temperature. After 1 hour, the mixture was diluted with 100 mL ethylacetate, washed with water and brine. The aqueous layer was extracted with ethylacetate (2x), and washed with brine. The combined organic layeres were dried over Na₂SO₄, filtered, and concentrated in vacuo to give the crude product which was purified via preparative TLC to afford the title compound. Yield=50%.Η NMR (400 MHz, CDCl₃): δ= 7.525-7.268 (dd, 2 H, J= 10 & 7.6 Hz), 6.593-6.551 (t, 1 H, J= 8.4 Hz), 5.810 (s, 1 H), 3.912 (s, 3 H), 3.230 (s, 3 H); m/z= 390 [M+l]⁺.

[249] Step I: N-(2-(2-Fluoro-4-iodophenylamino)-4-methoxy- 1 -methyl-6-oxo- 1.6- dihvdropyridin-3-yPbutane-l-sulfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7H)-one was reacted with butane- 1-sulfonyl chloride to obtain the desired compound. Yield= 76.6%. ¹H NMR (400 MHz, CDCl₃): δ= 7.750 (brs, 1 H), 7.424-7.420 (d, 1 H,

J= 1.6 Hz), 7.399-7.395 (d, 1 H, J= 1.6 Hz), 6.511 (brs, 1 H), 6.226-6.183 (t, 1 H, J= 8.6 Hz), 5.926 (s, 1 H), 3.849 (s, 3 H), 3.299 (s, 1 H), 3.048-3.008 (t, 3 H, J= 8.6 Hz), 1.866-1.809 (m, 2 H), 1.455-1.399 (m, 2 H), 0.994-0.960 (t, 3 H, J= 6.8 Hz); m/z= 509.92 [M+l]⁺.

Example 33

[250] Λ^r-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)benzenesulfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7H,)-one was reacted with benzenesulfonyl chloride to obtain the desired compound. Yield= 25%. ¹H NMR (400 MHz, CDCl₃): δ= 7.749-7.713 (t, 3 H, J= 7.2 Hz), 7.598-7.561 (t, 1 H, J= 5.8 Hz), 7.472-7.424 (t, 3 H, J= 9.6 Hz), 6.239-6.196 (t, 1 H, J= 8.6 Hz), 5.602 (s, 1 H), 3.340 (s, 3 H), 3.162 (s, 3 H); m/z= 529.79 [M+l]⁺..

Example 34

[251] Λ^r-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)cyclohexanesulf onamide :

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7H^-one was reacted with cyclohexanesulfonyl chloride to obtain the desired compound. Yield= 9.45%. ¹H NMR (400 MHz, CDCl₃): δ= 7.828 (brs, 1 H), 7.451-7.422 (d, 1 H, J= 2 Hz), 7.289-7.269 (d, 1 H, J= 8 Hz), 6.203-6.168 (t, 1 H, J= 7 Hz), 5.903 (s, 1 H), 5.722 (brs, 1 H), 3.826 (s, 3 H), 3.339 (s, 1 H), 2.895 (m, 1 H), 2.245-2.216 (brd, 2 H, J= 11.6 Hz), 1.933-1.920 (m, 2 H), 1.724-1.714 (br, 1 H), 1.614-1.555 (m, 3 H), 1.277-1.218 (m, 2 H); m/z= 535.95 [M+l]⁺.

Example 35

[252] N-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)cyclopropanesulfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7H^-one was reacted with cyclopropanesulfonyl chloride to obtain the desired compound. Yield= 19.72%. ¹U NMR (400 MHz, CDCl₃): δ= 7.663(brs, 1 H), 7.434-7.409 (d, 1 H, J= 10 Hz), 7.289-7.273 (d, 1 H, J= 6.4 Hz), 6.218-6.178 (t, 1 H, J= 8.4 Hz), 5.913 (s, 1 H), 3.865 (s, 3 H), 3.324 (s, 1 H), 2.437 (bra, 1 H), 1.116 (brs, 2 H), 0.946 (brs, 2 H); m/z= 493.96 [M+l]⁺.

Example 36

[253] N-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yI)thiophene-3-sulfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7H,)-one was reacted with thiophene-3-sulfonyl chloride to obtain the desired compound. Yield= 34.1%. ¹H NMR (400 MHz, CDCl₃): δ= 7.897-7.880 (d, 1 H, J= 6.8 Hz), 7.719-7.699 (d, 1 H, J= 8 Hz), 7.497-7.391 (m, 2 H), 7.333-7.264 (m, 2 H), 6.238-6.216 (d, 1 H,

J= 8.8 Hz), 5.689-5.666 (d, 1 H, J= 9.2 Hz), 3.392-3.375 (q, 6 H, J= 4 Hz); m/z= 535.95 [M+l]⁺.. Example 37

[254] S-chloro-TV-CZ-Cl-fluoro^-iodophenylaminoJ^-methoxy-l-methyl-ό-oxo-ljβ- dihydropyridin-3-yl)propane-l-sulfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7H)-one was reacted with 3-chloropropane-l-sulfonyl chloride to obtain the desired compound. Yield=29.8%. ¹H NMR (400 MHz, CDCl₃): δ = 7.678(brs, 1 H), 7.462-7.432 (dd, 1 H, J= 1.6 & 2 Hz), 7.306-7.267 (dd, 1 H, J= 8.4 & 0.4 Hz), 6.227-6.185 (t, 1 H, J= 8.4 Hz), 5.916 (s, 1 H), 5820 (brs, 1 H), 3.895 (s, 3 H), 3.687-3.657 (t, 2 H, J= 6 Hz), 3.337 (s, 3 H), 3.262-3.224 (t, 2 H, J= 7.6 Hz), 2.366-2.297 (m, 2 H); m/z= 529.75 [M+l]⁺..

Example 38

[255] N-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)propane-2-sulfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7H?-one was reacted with propane-2-sulfonyl chloride to obtain the desired compound. Yield= 10.21%. ¹H NMR (400 MHz, CDCl₃): δ = 7.850 (brs, 1 H), 7.455-7.426 (dd, 1 H, J= 1.6 & 2 Hz), 7.292-7.264 (dd, 1 H, J= 8.4 & 0.4 Hz), 6.202-6.159 (t, 1 H, J= 8.8 Hz), 5.895 (s, 1 H), 5.716 (brs, 1 H), 3.873 (s, 3 H), 3.340 (s, 3 H), 3.231-3.196 (m, 1 H), 1.439-1.413 (t, 6 H, J= 7.2 Hz); m/z= 495.96 [M+l]⁺..

Example 39 [256] Λ^r-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)thiophene-2-sulfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7Λ9-one was reacted with thiophene-2-sulfonyl chloride to obtain the desired compound. Yield= 17.89%. ¹H NMR (400 MHz, CDCl₃): δ= 7.648-7.633 (q, 1 H, J= 1.6 Hz), 7.511-7.499 (q, 1 H, J= 1.2 Hz), 7.479-7.449 (dd, 1 H, J= 2 & 2 Hz), 7.314-7.293 (d, 2 H, J= 8.4 Hz), 7.090-7.078 (t, 1 H, J= 4 Hz), 6.242-6.199 (t, 1 H, J= 8.4 Hz), 5.667 (s, 1 H), 3.364-3.360 (d, 6 H, J= 1.6 Hz); m/z= 535.93 [M+l]⁺..

Example 40

[257] l-chIoro-iV-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6- dihydropyridin-3-yl)methanesulfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7/#-one was reacted with chloromethanesulfonyl chloride to obtain the desired compound. Yield=29.8%. ¹K NMR (400 MHz, CDCl₃): δ = 7.463-7.433 (dd, 1 H, J= 1.6 & 2 Hz), 7.318-7.266 (dd, 1 H, J= 8.4 & 0.4 Hz), 6.260-6.218 (t, 1 H, J= 8.4 Hz), 5.991 (s, 1 H), 4.252 (s, 2 H), 3.887 (s, 3 H), 3.323 (s, 3 H); m/z= 501.91 [M+l]⁺..

Example 41 [258] 4-fluoro-iV-(2-(2-fluoro-4-iodophenyIamino)-4-methoxy-l-methyl-6-oxo-l,6- dihydropyridin-3-yl)benzenesuIfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7H)-one was reacted with 4-fluorobenzene-l-sulfonyl chloride to obtain the desired compound. Yield= 27.3%. ¹H NMR (400 MHz, CDCl₃): δ= 7.790-7.760 (m, 2 H), 7.677 (s, 1 H), 7.485-7.460 (d, 1 H, J= 10 Hz), 7.319-7.299 (d, 1 H, J= 8 Hz), 7.185-7.146 (t, 2 H, J= 8 Hz), 6.241-6.199 (t, 1 H, J= 8.4 Hz), 5.911 (brs, 1 H), 5.623 (s. 1 H), 3.358 (s, 3 H), 3.279 (s, 3 H); m/z= 547.99 [M+l]⁺..

Example 42

[259] iV-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridiii-3- yl)methanesulfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7.HJ-one was reacted with methanesulfonyl chloride to obtain the desired compound. Yield=30%. ¹U NMR (400 MHz, CDCl₃): δ = 7.660 (brs, 1 H), 7.454-7.429 (d, 1 H, J= 10 Hz), 7.304-7.270 (dd, 1 H, J= 8.4 & 1.2 Hz), 6.236-6.194 (t, 1 H, J= 8.4 Hz), 5.922 (s, 1 H)₅ 3.889 (s, 3 H), 3.332 (s, 3 H); m/z= 464.97 [M+l]⁺..

Example 43

[260] 2,2,2-trifluoro-iV-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6- dihydropyridin-3-yl)ethanesulfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7.H)-one was reacted with 2,2,2-trifluoroethanesulfonyl chloride to obtain the desired compound. Yield=48.7%. ¹H NMR (400 MHz, CDCl₃): δ = 7.446-7.416 (dd, 1 H, J= 2 & 1.6 Hz), 7.310-7.291 (d, 2 H, J= 7.6 Hz), 6.264-6.221 (t, 1 H, J= 8.6 Hz), 5.940 (s, 1 H), 3.873 (s, 3 H), 3.398 (s, 3 H); m/z= 535.95 [M+l]⁺..

Example 44

[261] iV-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)-2-phenylcyclopropane-l-sulfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2('i/-9-one was reacted with 2-phenylcyclopropane-l-sulfonyl chloride to obtain the desired compound. Yield=44%. ¹H NMR (400 MHz, CDCl₃): δ = 7.661 (brs, 1 H), 7.450-7.424 (dd, 1 H, J= 1.6 & 2 Hz), 7.321-7.219 (m, 4 H), 6.934-6.913 (t, 1 H, J= 8.4 Hz), 6.206-6.213 (t, 1 H, J= 8.4 Hz), 5.971 (brs, 1 H), 5.617 (s, 1 H), 3.357 (s, 3 H), 3.109 (s, 3 H), 2.724-2.678 (m, 1 H), 2.527-2.475 (m, 1 H), 1.782-1.729 (m, 1 H), 1.424-1.372 (m, 1 H); m/z= 569.96 [M+l]⁺..

Example 45

[262] 2-(4-ethoxyphenyl)-iV-(2-(2-fluoro-4-iodopheiiylamino)-4-methoxy-l-methyl-6-oxo-l,6- dihydropyridin-3-yl)cyclopropane-l-sulfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7H_>)-one was reacted with 2-(4-ethoxyphenyl)cyclopropane-l-sulfonyl chloride to obtain the desired compound. Yield=13.32%. ¹H NMR (400 MHz, CDCl₃): δ = 7.673 (brs, 1 H), 7.460-7.430 (dd, 1 H, J= 1.6 & 2 Hz), 7.297-7.235 (dd, 1 H, J= 8.8 & 2.8 Hz), 6.206-6.163 (t, 1 H, J= 8.6 Hz), 5.648 (s, 1 H), 4.028-3.975 (q, 2 H, J= 7.1 Hz), 3.488 (s, 3 H), 3.202 (s, 3 H), 2.632-2.612 (m, 1 H), 2.473-2.463 (m, 1 H), 1.719-1.681 (m, 1 H), 1.358-1.3337 (m, 1 H), 1.251-1.241 (t, 3 H, J= 7.1 Hz); m/z= 614.05 [M+l]⁺..

Example 46

[263] 2-(3,4-difluorophenyl)-Λ^r-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo- l,6-dihydropyridin-3-yl)cyclopropane-l-sulfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7H)-one was reacted with 2-(3,4-difluorophenyl)cyclopropane-l-sulfonyl chloride to obtain the desired compound. Yield=5.79%. ¹H NMR (400 MHz, CDCl₃): δ = 7.619 (brs, 1 H), 7.438-7.408 (dd, 1 H, J= 1.6 & 2 Hz), 7.290-7.226 (dd, 1 H, J= 8.8 & 2.8 Hz), 7.101-7.077 (t, 1 H, J= 8.6 Hz), 6.811-6.806 (d, 1 H, J= 2 Hz), 6.221-6.178 (t, 1 H, J= 8.6 Hz), 5.736 (s, 1 H), 3.387 (s, 3 H), 3.333 (s, 3 H), 2.674-2.663 (m, 1 H), 2.549-2.525 (m, 1 H), 1.752-1.698 (m, 1 H), 1.347-1.310 (m, 1 H); m/z= 605.99 [M+ 1]⁺.

Example 47 [264] N-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)-2-isopropylcyclopropane-l-sulfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7H^-one was reacted with 2-isopropylcyclopropane-l-sulfonyl chloride to obtain the desired compound. Yield=40%. ¹H NMR (400 MHz, CDCl₃): δ = 7.743 (brs, 1 H),

7.445-7.415 (dd, 1 H, J= 1.6 & 2 Hz), 7.291-7.269 (dd, 1 H, J= 8.8 & 2.8 Hz), 6.209-6.166 (t, 1

H, J= 8.6 Hz), 5.896 (brs, 2 H), 3.876 (s, 3 H), 3.336 (s, 3 H), 2.237-2.193 (m, 1 H), 1.499-1.438

(m, 1 H), 1.198-1.152 (m, 1 H), 0.997-0.981 (d, 3 H, J= 6.4 Hz), 0.943-0.926 (d, 3 H, J= 6.8 Hz), 0.819-0.783 (m, 1 H); m/z= 536.02 [M+l]⁺..

Example 48

[265] iV-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)-2-isobutylcyclopropane-l-sulfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7//)-one was reacted with 2-isobutylcyclopropane-l-sulfonyl chloride to obtain the desired compound. Yield=35.4%. ¹H NMR (400 MHz, CDCl₃): δ = 7.752 (brs, 1 H), 7.444-7.4154 (dd, 1 H, J= 1.6 & 2 Hz), 7.291-7.270 (dd, 1 H, J= 8.8 & 2.8 Hz), 6.209-6.166 (t, 1 H, J= 8.6 Hz), 5.958 (brs, 1 H), 5.914 (s, 1 H), 3.878 (s, 3 H), 3.332 (s, 3 H), 2.169-2.126 (m, 1 H), 1.694-1.627 (m, 1 H), 1.559-1.516 (m, 1 H), 1.327-1.229 (m, 2 H), 1.053-0.999 (m, 1 H), 0.919-0.900 (m, 6 H), 0.943-0.926 (d, 3 H, J= 6.8 Hz), 0.774-0.724 (m, 1 H); m/z= 550.06 [M+l]⁺.. Example 49

[266] JV-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridiii-3- yl)-2-(thiophen-2-yl)cyclopropane-l-suIfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7H^-one was reacted with 2-(thiophen-2-yl)cyclopropane-l-sulfonyl chloride to obtain the desired compound. Yield=6.76%. ¹U NMR (400 MHz, CDCl₃): δ = 7.763 (brs, 1 H), 7.456-7.426 (dd, 1 H, J= 1.6 & 2 Hz), 7.299-7.269 (d, 1 H, J= 8.4 Hz), 7.130-7.128 (d, 1 H, J= 8.4 Hz), 6.929-6.907 (d, 1 H, J= 8.4 Hz), 6.216-6.273 (t, 1 H, J= 8.4 Hz), 5.737 (s, 1 H), 3.379 (s, 3 H), 3.337 (s, 3 H), 2.780-2.716 (m, 2 H), 1.796-1.782 (m, 1 H), 1.396-1.375 (m, 1 H); m/z= 575.91 [M+l]⁺..

Example 50

[267] 2-(2,4-difluorophenyI)-iV-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo- l,6-dihydropyridin-3-yl)cyclopropane-l-sulfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7H^-one was reacted with 2-(2,4-difluorophenyl)cyclopropane-l-sulfonyl chloride to obtain the desired compound. Yield=41.8%. ¹H NMR (400 MHz, CDCl₃): δ = 7.662 (brs, 1 H), 7.456-7.426 (dd, 1 H, J= 1.6 & 2 Hz), 7.300-7.273 (dd, 1 H, J= 8.8 & 2.8 Hz), 6.850-6.804 (m, 3 H), 6.226-6.184 (t, 1 H, J= 8.6 Hz), 5.665 (s, 1 H), 3.386 (s, 3 H), 3.351 (s, 3 H), 2.785-2.751 (m, 1 H), 2.694-2.665 (m, 1 H), 1.742-1.703 (m, 1 H), 1.486-1.448 (m, 1 H); m/z= 605.99 [M+l]⁺..

Example 51

[268] 2-(3,5-difluorophenyl)-iV-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo- l,6-dihydropyridin-3-yl)cyclopropane-l-sulfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7H_>)-one was reacted with 2-(3,5-difluorophenyl)cyclopropane-l-sulfonyl chloride to obtain the desired compound. Yield=28.9%. ¹H NMR (400 MHz, CDCl₃): δ = 7.607 (JbTS, 1 H), 7.455-7.425 (dd, 1 H, J= 1.6 & 2 Hz), 7.300-7.265 (dd, 1 H, J= 8.8 & 2.8 Hz), 6.738-6.685 (m, 1 H), 6.553-6.516 (m, 2 H, J= 8.6 Hz), 6.219-6.177 (t, 1 H, J= 8.6 Hz), 5.752 (s, 1 H), 3.420 (s, 3 H), 3.323 (s, 3 H), 2.742-2.709 (m, 1 H), 2.695-2.543 (m, 1 H), 1.798-1.745 (m, 1 H), 1.391-1.338 (m, 1 H); m/z= 605.99 [M+l]⁺.

Example 52

[269] 2-(4-cyanophenyl)-iV-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6- dihydropyridin-3-yl)cyclopropane-l-sulfonamide:

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(7H)-one was reacted with 2-(4-cyanophenyl)cyclopropane-l-sulfonyl chloride to obtain the desired compound. Yield=2%. ¹H NMR (400 MHz, CDCl₃): δ = 7.630-7.593 (t, 3 H, J=

7.4 Hz), 7.472-7.443 (dd, 1 H, J= 1.6 & 1.6 Hz), 7.312-7.270 (m, 1 H), 7.083-7.083 (d, 2 H, J= 8 Hz), 6.219-6.176 (t, 1 H, J= 8.6 Hz), 5.781 (s, 1 H), 5.664 (s, 1 H), 3.357 (s, 3 H), 3.236 (s, 3 H), 2.768-2.735 (m, 1 H), 2.612-2.592 (m, 1 H), 1.866-1.828 (m, 1 H), 1.460-1.423 (m, i H); m/z= 594.96 [M+l]⁺.

Example 53

N-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-l-(2- hydroxyethyl)cyclopropane-l-sulfonamide

[270] Step A: tert-butyl 2-(2-fluoro-4-iodophenylaminoV 1 ,5-dimethyl-6-oxo- 1 ,6- dihydropyridin-3- yl( 1 -(2-oxoethyl)cyclopropylsulfonyl)carbamate

A solution of the tert-butyl l-(2,3-dihydroxypropyl)cyclopropylsulfonyl(2-(2-fluoro-4- iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)carbamate (230 mg, 0.353 mmol) in THF:H₂O (1:1, 3ml), was treated with NaIO₄ (151mg, 0.706 mmol) at 0 ⁰C. After stirring overnight, the mixture was diluted with water, and the aqueous phase was extracted with CH₂Cl₂. The combined organic layers were dried over MgSO₄ and concentrated to afford a gray solid which was used in the next reaction without further purification, m/z = 620 [M+l]⁺.

[271] Step B: fert-butyl 2-(2-fluoro-4-iodophenylarninoV 1 ,5-dimethyl-6-oxo- 1 ,6- dihvdropyridin-3-yl(l-(2-hvdroxyethyl)cvclopropylsulfonyl^*)carbamate

The aldehyde (210mg, 0.339mmol) was dissolved in 3ml MeOH, and NaBH₄ (33 mg) was added to the solution. The mixture was stirred overnight. Water was added, and the mixture extracted with EtOAc, dried over MgSO₄, and concentrated to afford the desired product which was used without further purification, m/z = 622 [M+ 1]⁺.

[272] Step C: N-(2-(2-fluoro-4-iodophenylamino)- 1.5-dimethyl-6-oxo- 1.6-dihydropyridin-3-yl)- 1 -(2-hvdroxyethyl)cyclopropane- 1 -sulfonamide

The 1-OH product (150mg, 0.241mmol) was dissolved in 2ml CH₂Cl₂, and excessive TFA (0.8ml) was slowly added. The mixture was stirred at room temperature for 2 h, and the volatiles were removed in vacuum. The residue was purified over silica gel chromatography (eluent: EtOAc) to obtain the desire product (85mg, 68%). ¹H NMR (400 MHz, DMS0-D6) δ 8.86 (s, IH), 7.93 (s, IH), 7.59 (dd, J = 2.0 & 10 Hz), 7.31-7.35 (m, 2H), 6.25 (t, J = 8.8 Hz, IH), 4.45 (br, IH), 3.16-3.26 (m, 5H), 2.01 (s, 3H), 1.81 (t, J = 7.2 Hz, 2H), 0.87-0.89 (m, 2H), 0.77-0.78 (m, 2H); m/z = 522 [M+l]⁺.

Example 54

[273] iV-(2-(2-chloro-4-iodophenylamino)-l,5-dimethyI-6-oxo-l,6-dihydropyridin-3- yl)cyclopropanesulfonamide

According to general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with cyclopropanesulfonyl chloride to obtain the desired product.¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J = 1.6 Hz, IH), 7.27 (dd, J = 1.6 & 9.6 Hz, IH), 7.26 (m, 2H), 6.05 (d, J = 8.4 Hz, IH), 5.70 (s, IH), 3.42 (s, 3H), 2.45 (m, IH), 2.19 (s, 3H), 1.17-

1.19 (m, 2H), 1.03-1.05 (m, 2H); m/z = 494 [M+l]⁺.

Example 55 [274] Λ^r-(2-(4-bromo-2-chIorophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)cyclopropanesulfonamide

According to general procedure A, 5-amino-6-(4-bromo-2-chlorophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with cyclopropanesulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, J = 2.4 Hz, IH), 7.29 (m, 2H), 7.19-7.22 (m, IH),

6.18 (dd, J = 2.4 & 8.4 Hz, IH), 5.73 (s, IH), 3.41 (d, J = 2.0 Hz, 3H), 2.43-2.46 (m, IH), 2.19 (s,

3H), 1.18-1.19 (m, 2H), 1.03-1.05 (m, 2H); m/z = 446 [M+ 1]⁺.

Example 56

[275] iV-(2-(4-bromo-2-fluorophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)cyclopropanesulfonamide

According to general procedure A, 5-amino-6-(4-bromo-2-fluorophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with cyclopropanesulfonyl chloride to obtain the desired product. ¹U NMR (400 MHz, CDCl₃) δ 7.30 (d, J = 2.4 Hz, IH), 7.27 (m, IH), 7.26 (dd, J = 2.4

& 4.0 Hz, IH), 7.08-7.11 (m, IH), 6.26 (t, J = 8.8 Hz, IH), 5.66 (s, IH), 5.30 (s, IH), 3.45 (s, 3H),

2.44-2.48 (m, IH), 2.19 (s, 3H), 1.17-1.19 (m, 2H), 1.04-1.08 (m, 2H); m/z = 430 [M+l]⁺.

Example 57

[276] iV-(2-(2,4-difluorophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridiii-3- yl)cyclopropanesulfonamide

According to general procedure A, 5-amino-6-(2,4-difluorophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with cyclopropanesulfonyl chloride to obtain the desired product. ¹K NMR (400 MHz, CDCl₃) δ 6.89-6.94 (m, 2H), 6.73 (m, IH), 6.35-6.41 (m, IH), 5.68 (s, IH), 3.42 (s, 3H), 2.45-2.49 (m, IH), 2.18 (s, 3H), 1.17-1.20 (m, 2H), 1.04-1.08 (m, 2H); m/z = 370 [M+l]⁺. Example 58

[277] allyl-iV-(2-(2-chloro-4-iodophenyIainino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-chloro-4-iodophenylεmino)-l,3- dimethylpyridin-2(lH)-one was reacted with 1-allylcyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, J = 2.0 Hz, IH), 7.36 (dd, J = 2.0 & 8.4 Hz, IH), 7.23 (s, IH), 6.02 (d, J = 8.4 Hz, IH), 5.76-5.82 (m, IH), 5.61 (s, IH), 5.17-.521 (m, 2H), 3.41 (s, 3H), 2.69 (d, J = 7.6 Hz, 2H), 2.19 (s, 3H), 1.24-1.29 (m, 2H), 0.85-0.87 (, 2H); m/z = 534 [M+l]⁺.

Example 59

[278] allyl-Λ'-(2-(4-bromo-2-chlorophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridiii-3- yl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(4-brorno-2-chlorophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with 1-allylcyclopropane-l-sulfonyl chloride to obtain the desired product. ¹U NMR (400 MHz, CDCl₃) δ 7.54 (d, J = 2.4 Hz, IH), 7.18-7.26 (m, 2H), 6.15 (d, J = 8.8 Hz, IH), 5.76-5.80 (m, IH), 5.63 (s, IH), 5.18 (dd, J = 2.0 & 9.6 Hz, 2H), 3.41 (s, 3H), 2.69 (d, J= 7.2 Hz, 2H), 2.19 (s, 3H), 1.26-1.30 (m, 2H), 0.86-0.88 (m, 2H); m/z = 488 [M+ 1]⁺.

Example 60

[279] allyl-iV-(2-(4-bromo-2-fluorophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(4-bromo-2-fluorophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with 1-allylcyclopropane-l-sulfonyl chloride to obtain the desired product. ¹K NMR (400 MHz, CDCl₃) δ 7.30 (d, J = 2.4 Hz, IH), 7.27 (m, IH), 7.09-7.12 (m, IH), 7.08 (m, IH), 6.23 (t, J = 8.8 Hz, IH), 5.76-5.79 (m, IH), 5.62 (s, IH), 5.17-5.21 (m, 2H), 3.44 (s, 3H), 2.69 (d, J = 7.2 Hz, 2H), 2.19 (s, 3H)), 1.27-1.30 (m, 2H), 0.86-0.89 (m, 2H); m/z = 470 [M+l]⁺.

Example 61

[280] alIyl-iV-(2-(2,4-difluorophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2,4-difluorophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with 1-allylcyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.25-7.26 (m, IH), 6.90-6.94 (m, 2H), 6.71-6.73 (m, IH), 6.32-6.37 (m, IH), 5.77-5.81 (m, IH), 5.63 (s, IH), 5.17-5.21 (m, 2H), 3.41 (s, 3H), 2.70 (d, J = 7.2 Hz, 2H), 2.18 (s, 3H), 1.25-1.30 (m, 2H), 0.86-0.89 (m, 2H); m/z = 410 [M+l]⁺.

Example 62

[281] N-(2-(4-bromo-2-chlorophenyIamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)benzenesulfonamide

According to general procedure A, 5-amino-6-(4-bromo-2-chlorophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with benzenesulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.74 (dd, J = 1.2 & 8.4 Hz, 2H), 7.61-7.63 (m, IH), 7.48-

7.53 (m, 3H), 7.13 (dd, J = 2.0 & 8.4 Hz, IH), 6.79 (s, IH), 6.74 (s, IH), 6.03 (d, J = 8.4 Hz, IH), 5.83 (s, IH), 3.35 (s, 3H), 2.03 (s, 3H); m/z = 484 [M+l]⁺.

Example 63

[282] iV-(2-(4-bromo-2-chlorophenylamino)-l,5-dimethyl-6-oxo-l,6-diliydropyridin-3- yl)butane-l-sulfonamide

According to general procedure A, 5-amino-6-(4-bromo-2-chlorophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with butane- 1-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, J = 2.0 Hz, IH), 7.29 (s, IH), 7.19-7.22 (m, 2H),

6.17 (d, J = 8.8 Hz, IH), 5.65 (s, IH), 3.41 (s, 3H), 3.04 (t, J = 7.6 Hz, 2H), 2.19 (s, 3H), 1.80- 1.83 (m, 2H), 1.45-1.47 (m, 2H), 0.95 (t, J= 7.6 Hz, 3H); m/z = 464 [M+l]⁺.

Example 64

[283] (R)-N-(2-(2-chloro-4-iodophenylainino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)- l-(2,3-dihydroxypropyI)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(4-bromo-2-chlorophenylatnino)-l,3- dimethylpyridin-2-(lH)-one was reacted with (/?)-l-(2,3-dihydroxypropyl) cyclopropane- 1- sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, DMS0-D6) δ 8.98 (s, IH), 7.77 (d, J = 2.0 Hz, 2H), 7.44-7.48 (m, 2H), 6.18 (d, J = 8.8 Hz, IH), 4.56-4.59 (m, 2H), 3.47 (br, IH), 3.18-3.23 (m, 5H), 2.10-2.13 (m, IH), 2.09 (s, 3H), 1.60-1.63 (m, IH), 0.93-1.00 (m, 4H); m/z = 568 [M+l]⁺.

Example 65

[284] (S)-N-(2-(2-chloro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)- l-(2,3-dihydroxypropyl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(4-bromo-2-chlorophenylamino)-l,3- dimethylpyridin-2(l//)-one was reacted with (S)-I -(2,3-dihydroxypropyl) cyclopropane- 1- sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, DMSO-D6) δ 8.98 (s, IH), 7.77 (d, J = 2.0 Hz, 2H), 7.44-7.48 (m, 2H), 6.18 (d, J = 8.4 Hz, IH), 4.56-4.60 (m, 2H), 3.47 (br, IH), 3.18-3.22 (m, 5H), 2.10-2.13 (m, IH), 2.09 (s, 3H), 1.60-1.63 (m, IH), 0.93-0.99 (m, 4H); m/z = 568 [M+l]⁺.

Example 66

[285] iV-(2-(2-chloro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)benzenesulfonamide

According to general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with benzenesulfonyl chloride to obtain the desired product. ¹K NMR (400 MHz, CDCl₃) δ 7.74 (d, J = 2.0 Hz, 2H), 7.72 (d, J = 1.2 Hz, IH), 7.68-

7.69 (m, IH), 7.53 (t, J = 7.6 Hz, 2H), 7.29 (dd, J = 2.0 & 8.4 Hz, IH), 6.80 (s, IH), 6.77 (s, IH),

5.94 (s, IH), 5.89 (d, J = 8.4 Hz, IH), 3.35 (s, 3H), 2.04 (d, J = 5.6 Hz, 3H); m/z = 530 [M+l]⁺.

Example 67

[286] Λ^r-(2-(2-chloro-4-iodophenyIamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)butane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with butane- 1-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J = 2.0 Hz, 2H), 7.37 (dd, J = 2.0 & 8.4 Hz, IH), 7.31 (s, IH), 7.20 (s, IH), 6.05 (d, J = 8.8 Hz, IH), 5.77 (s, IH), 3.41 (s, 3H), 3.03 (t, J = 8.0 Hz, 2H), 2.19 (s, 3H), 1.80-1.84 (m, 2H), 1.42-1.47 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); m/z = 510 [M+l]⁺. Example 68

[287] iV-(2-(2-chloro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)cyclobutanesulfonamide

According to general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with cyclobutanesulfonyl chloride to obtain the desired product. ¹U NMR (400 MHz, CDCl₃) δ 7.71 (d, J = 2.0 Hz, 2H), 7.37 (m, IH), 7.35 (d, J = 2.0 Hz, IH), 7.10 (s, IH), 6.03 (d, J = 8.4 Hz, IH), 5.63 (s, IH), 3.83-3.88 (m, IH), 3.40 (s, 3H), 2.52-2.57 (m, 2H), 2.31-2.34 (m, 2H), 2.18 (s, 3H), 2.03-2.08 (m, 2H); m/z = 508 [M+l]⁺.

Example 69

[288] iV-(2-(2-chloro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)cyclohexanesulfonamide

According to general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with cyclohexanesulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, J = 2.0 Hz, 2H), 7.37 (dd, J = 2.0 & 8.4 Hz, IH), 7.28 (s, IH), 7.20 (s, IH), 6.04 (d, J = 8.8 Hz, IH), 5.64 (s, IH), 3.41 (s, 3H), 2.86-2.92 (m, IH), 2.19 (s, 3H), 2.14 (m, 2H), 1.85-1.91 (m, 2H), 1.55-1.72 (m, 2H), 1.21-1.26 (m, 3H); m/z = 536 [M+l]⁺.

Example 70 [289] 7V-(2-(2-chloro-4-iodophenyIamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-2- isobutylcyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with 2-isobutylcyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, J = 2.0 Hz, 2H), 7.36 (dd, J = 2.0 & 8.4 Hz, IH), 7.32 (s, IH), 7.26 (s, IH), 6.05 (d, J = 8.4 Hz, IH), 5.68 (s, IH), 3.42 (s, 3H), 2.20 (s, 3H), 2.15-2.17 (m, IH), 1.62-1.69 (m, IH), 1.24-1.33 (m, 3H), 1.12 (m, IH), 0.92-0.94 (m, 6H), 0.82-0.86 (m, IH); m/z = 550 [M+l]⁺.

Example 71

[290] iV-(2-(2-chloro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yI)-2- (2,4-difluorophenyl)cycIopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with 2-(2,4-difluorophenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (d, J = 2.0 Hz, 2H), 7.35 (dd, J = 2.0 & 8.4 Hz, IH), 7.18 (s, IH), 7.12 (s, IH), 6.82-6.90 (m, 3H), 6.04 ( d, J = 8.4 Hz, IH), 5.88 (s, IH), 4.10-4.15 (m, IH), 3.40 (s, 3H), 2.72 (t, J = 7.2 Hz, IH), 2.04 (s, 3H), 1.73-1.78 (m, IH), 1.48-1.52 (m, IH); m/z = 606 [M+l]⁺.

Example 72

[291] N-(2-(2-chloro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yI)thiophene-2-sulfonamide

According to general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with thiophene-2-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (d, J = 2.0 Hz, IH), 7.65 (dd, J = 1.6 & 8.8 Hz, IH), 7.50 (dd, J = 2.0 & 4.0 Hz, IH), 7.27-7.34 (m, IH), 7.09 (dd, J = 3.6 & 9.2 Hz, IH), 6.82-6.84 (m, 2H), 5.93-5.97 (m, 2H), 3.37 (s, 3H), 2.07 (s, 3H); m/z = 536 [M+l]⁺.

Example 73

[292] N-(2-(2-chIoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridiii-3- yI)thiophene-3-sulfonamide

According to general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with thiophene-3-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.88 (dd, J = 1.6 & 3.2 Hz, IH), 7.70 (d, J = 1.6 Hz, IH), 7.44 (dd, J = 3.2 & 8.8 Hz, IH), 7.32 (m, IH), 7.25-7.26 (m, IH), 6.88 (s, IH), 6.80 (d, J = 1.6 Hz, IH), 5.94-5.96 (m, 2H), 3.37 (s, 3H), 2.06 (s, 3H); m/z = 536 [M+l]⁺.

Example 74

[293) N-(2-(2-chloro-4-iodophenylamino)-l,5-dimethyI-6-oxo-l,6-dihydropyridin-3- yI)propane-2-suIfonamide

According to general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with propane-2-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, J = 2.0 Hz, IH), 7.35-7.38 (m, 2H), 7.20 (s, IH), 6.03 (d, J = 7.2 Hz, IH), 5.66 (s, IH), 3.41 (s, 3H), 3.21-3.24 (m, IH), 2.18 (s, 3H), 1.42 (d, J = 7.2 Hz, 6H); m/z = 496 [M+l]⁺.

Example 75

[294] 3-chIoro-iV-(2-(2-chloro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin- 3-yl)propane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with 3-chloropropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.17 (d, J = 2.0 Hz, IH), 7.37 (dd, J = 2.0 & 8.4 Hz, IH), 7.23-7.26 (m, 2H), 6.05 (d, J = 8.4 Hz, IH), 5.86 (s, IH), 3.67 (t, J = 6.0 Hz, 2H), 3.42 (s, 3H), 3.24 (t, J = 7.6 Hz, 2H), 2.30-2.34 (m, 2H), 2.19 (s, 3H); m/z = 530 [M+l]⁺.

Example 76

[295] 2-(3,5-difluorophenyl)-iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with 2-(3,5-difluorophenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.46 (m, IH), 7.26-7.27 (m, IH), 7.05 (s, IH), 6.91 (m, IH), 6.71-6.74 (m, IH), 6.54 (dd, J = 2.0 & 8.0 Hz, 2H), 6.12 (t, J = 8.8 Hz, IH), 5.77 (s, IH), 3.42 (s, 3H), 2.66-2.68 (m, IH), 2.58-2.61 (m, IH), 2.04 (s, 3H), 1.77- 1.79 (m, IH), 1.42-1.46 (m, IH); m/z = 590 [M+l]⁺.

Example 77

[296] iV-(2-(2-chloro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)ethanesulfonamide

According to general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with ethanesulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J = 1.6 Hz, IH), 7.37 (dd, J = 2.0 & 8.4 Hz, IH), 7.32 (s, IH), 7.19 (s, IH), 6.04 (d, J = 8.4 Hz, IH), 5.73 (s, IH), 3.41 (s, 3H), 3.06-3.10 (m, 2H), 2.19 (s, IH), 1.43 (t, J = 7.2 Hz, 3H); m/z = 482 [M+l]⁺.

Example 78

[297] (/?)-N-(2-(4-bromo-2-chlorophenyIamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)-l-(2,3-dihydroxypropyI)cyclopropane-l-sulfonamide

According to general procedure A, step E & F, example 28, 5-amino-6-(4-bromo-2- chlorophenylamino)-l,3-dimethylpyridin-2(lH)-one was reacted the same sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.52 (d, J = 4.4 Hz, IH), 7.29 (s, IH), 7.20 (dd, J = 2.4 & 8.8 Hz, IH), 6.96 (br, IH), 6.15 (d, J = 8.8 Hz, IH), 3.99 (br, IH), 3.64-3.70 (m, IH), 3.48-3.52 (m, IH), 3.41 (s, 3H), 3.17 (br, IH), 2.35-2.41 (m, IH), 2.19 (s, 3H), 1.98 (m, IH), 1.63-1.67 (m, IH), 1.47-1.51 (m, IH), 1.31-1.35 (m, IH), 0.88-0.97 (m, 2H); m/z = 522 [M+l]⁺.

Example 79 [298] (^-iV-Cl^Z^-difluorophenylamino^ljS-dimethyl-o-oxo-ljo-dihydropyridin-S-yl)-!- (2,3-dihydroxypropyl)cyclopropane-l-sulfonamide

According to general procedure A, , step E & F, example 28, 5-amino-6-(2,4- difluorophenylamino)-l,3-dimethylpyridin-2(lH)-one was reacted with the same sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.34(s, IH), 7.00 (s, lH),6.74-6.88 (m, 2H), 6.70-6.72 (m, IH), 6.32 (t, J = 5.6 Hz, IH), 3.99 (br, IH), 3.65-3.66 (m, IH), 3.48-3.53 (m, IH), 3.41 (s, 3H), 2.32-2.39 (m, IH), 2.18 (s, 3H), 1.46-1.50 (m, 2H), 1.28-1.33 (m, 2H), 0.84- 0.97 (m, 3H); m/z = 444 [M+l]⁺.

Example 80 [299] (R)-N-(2-(4-bromo-2-fluorophenyIamino)-l,5-dimethyI-6-oxo-l,6-dihydropyridin-3- yl)-l-(2,3-dihydroxypropyl)cyclopropane-l-sulfonamide

According to general procedure A, , step E & F, example 28, 5-amino-6-(4-bromo-2- fluorophenylamino)-l,3-dimethylpyridin-2(lH)-one was reacted with the same sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.35 (s, IH), 7.29 (s, IH), 7.08-7.11 (m, 2H), 6.85 (s, IH), 6.23 (t, J = 8.8 Hz, IH), 3.97 (br, IH), 3.65-3.68 (m, IH), 3.47-3.53 (m, IH), 3.44 (s, 3H), 3.16 (d, J = 4.0 Hz, IH), 2.32-2.38 (m, IH), 2.19 (s, 3H), 1.97 (t, J = 5.2 Hz, IH), 1.65-1.68 (m, IH), 1.45-1.51 (m, IH), 1.26-1.32 (m, 2H), 0.86-0.97 (m, 2H); m/z = 506 [M+l]⁺.

Example 81

[300] iV-(2-(4-bromo-2-chIorophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)thiophene-2-sulfonamide

According to general procedure A, 5-amino-6-(4-bromo-2-chlorophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with thiophene-2-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.64 (dd, J = 1.2 & 5.2 Hz, IH), 7.51 (dd, J = 1.2 & 6.0 Hz, IH), 7.50 (t, J = 1.6 Hz, IH), 7.15 (dd, J = 2.0 & 8.4 Hz, IH), 7.08-7.09 (m, IH), 6.85-6.87

(m, 2H), 6.15 (s, IH), 6.06 (d, J= 8.8 Hz, IH), 3.37 (s, 3H), 2.06 (s, 3H); m/z = 490 [M+l]⁺.

Example 82

[301] Λ^r-(2-(4-bromo-2-chlorophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)thiophene-3-sulfonamide

According to general procedure A, 5-amino-6-(4-bromo-2-chlorophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with thiophene-3-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, J = 1.2 Hz, IH), 7.54 (d, J = 2.4 Hz, IH), 7.44- 7.46 (m, IH), 7.17 (dd, J = 2.0 & 8.4 Hz, IH), 6.89 (s, IH), 6.79 (s, IH), 6.08 (d, J = 8.8 Hz, IH), 5.93 (s, IH), 3.37 (s, 3H), 2.06 (s, 3H); m/z = 490 [M+l]⁺.

Example 83

[302] iV-(2-(4-bromo-2-chIorophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-4- fluorobenzenesulfonamide

According to general procedure A, 5-amino-6-(4-bromo-2-chlorophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with 4-fluorobenzene-l-sulfonyl chloride to obtain the desired product. ¹R NMR (400 MHz, CDCl₃) δ 7.73-.77 (m, 2H), 7.53 (d, J = 2.4 Hz, IH), 7.12- 7.16 (m, 3H), 6.91 (s, IH), 6.17 (s, IH), 6.00 (d, J= 8.8 Hz, IH), 3.36 (s, 3H), 2.05 (d, J = 1.2 Hz, 3H); m/z = 502 [M+l]⁺.

Example 84

[303] iV-(2-(2-chloro-4-iodophenyIamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-4- fluorobenzenesulfonamide

According to general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with 4-fluorobenzene-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.73-7.76 (m, 2H), 7.69 (d, J = 2.0 Hz, IH), 7.30 (dd, J = 2.0 & 8.4 Hz, IH), 7.14 (t, J = 8.8 Hz, 2H), 6.88 (s, IH), 6.81 (s, IH), 6.10 (s, IH), 5.88 (d, J = 8.8 Hz, IH), 3.36 (s, 3H), 2.05 (s, 3H); m/z = 502 [M+l]⁺.

Example 85

[304] 7V-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-2- (hydroxymethyl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with (2-(chlorosulfonyl)cyclopropyl)methyl pivalate to obtain the sulfonyl amide which was used without further purification. The intermediate was hydrolyzed with LiOH. The solvent was removed under reduced pressure and the residue was purified over silica gel chromatography (eluent:CH₂Cl₂:CH₃OH = 15:1) to obtain the desire product. ¹H NMR (400 MHz, CDCl₃) δ 7.68 (s, IH), 7.43 (dd, J = 2.0 & 10.4 Hz, IH), 7.39 (s, IH), 7.25-7.26 (m, IH), 6.11 (t, J = 8.8 Hz, IH), 4.06 (dd, J = 4.0 & 11.2 Hz, IH), 3.42 (s, 3H), 3.15 (dd, J = 8.8 & 11.2 Hz, IH), 2.42-2.44 (m,lH), 2.17 (s, 3H), 1.72-1.73 (m, IH), 1.40-1.44 (m, 2H), 0.99 (dd, J = 2.0 & 6.0 Hz, IH); m/z = 508 [M+l]⁺.

Example 86

[305] iV-(2-(4-bromo-2-fluorophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-2- (hydroxymethyl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(4-bromo-2-fluorophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with (2-(chlorosulfonyl)cyclopropyl)methyl pivalate to obtain the sulfonyl amide which was used without further purification. The intermediate was hydrolyzed with LiOH. The solvent was removed under reduced pressure and the residue was purified over silica gel chromatography (eluent:CΗ₂Cl₂:CΗ₃θΗ = 15:1) to obtain the desire product. ¹H NMR (400 MHz, CDCl₃) δ 7.49 (s, IH), 7.28 (dd, J = 2.0 & 11.2 Hz, IH), 7.25-7.26 (m, IH), 7.09-7.11 (m, IH), 6.24 (t, J = 8.8 Hz, IH), 5.83 (br, IH), 4.05 (dd, J = 4.4 & 11.2 Hz, IH), 3.42 (s, 3H), 3.18 (dd, J = 8.4 & 11.2 Hz, IH), 2.42-2.46 (m, IH), 2.17 (s, 3H), 1.73-1.76 (m, IH), 1.41-1.44 (m, IH), 0.98-1.03 (m, IH); m/z = 460 [M+l]⁺.

Example 87

[306] N-(2-(2,4-difluorophenylamino)-l,5-dimethyI-6-oxo-l,6-dihydropyridin-3-yl)-2- (hydroxymethyl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2,4-difluorophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with (2-(chlorosulfonyl)cyclopropyl)methyl pivalate to obtain the sulfonyl amide which was used without further purification. The intermediate was hydrolyzed with LiOH. The solvent was removed under reduced pressure and the residue was purified over silica gel chromatography (eluent:CΗ₂Cl₂:CΗ₃0Η=15:l) to obtain the desire product. ¹H NMR (400 MHz, CDCl₃) δ 7.50 (s, IH), 7.16 (s, IH), 6.89-6.95 (m, IH), 6.71-6.75 (m, IH), 6.30-6.36 (m, IH), 4.03 (dd, J = 4.4 & 11.2 Hz, IH), 3.41 (s, 3H), 3.20-3.25 (m, IH), 2.44-2.48 (m, IH), 2.17 (s, 3H), 1.73-1.79 (m, IH), 1.39-1.43 (m, IH), 1.00-1.05 (m, IH); m/z = 400 [M+l]⁺.

Example 88 [307) iV-(2-(2-chloro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-2- (hydroxymethyl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with (2-(chlorosulfonyl)cyclopropyl)methyl pivalate to obtain the sulfonyl amide which was used without further purification. The intermediate was hydrolyzed with LiOH. The solvent was removed under reduced pressure and the residue was purified over silica gel chromatography (eluent:CH₂Cl₂:CH₃OH=15:l) to obtain the desire product. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, J = 2.0 Hz, IH), 7.51 (d, J = 7.2 Hz, 2H), 7.36 (dd, J = 2.0 & 8.8 Hz, IH), 6.04 (d, J = 8.8 Hz, IH), 5.82 (br, IH), 4.03-4.07 (m, IH), 3.39 (s, 3H), 3.15-3.18 (m, IH), 2.44-2.47 (m, IH), 2.17 (s, 3H), 1.55 (m, IH), 1.38-1.41 (m, IH), 0.98-1.01 (m, IH); m/z = 524 [M+l]⁺.

Example 89

[308] N-(2-(4-bromo-2-chlorophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-2- (hydroxymethyOcyclopropane-l-suIfonamide

According to general procedure A, 5-amino-6-(4-bromo-2-chlorophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with (2-(chlorosulfonyl)cyclopropyl)methyl pivalate to obtain the sulfonyl amide which was used without further purification. The intermediate was hydrolyzed with LiOH. The solvent was removed under reduced pressure and the residue was purified over silica gel chromatography (eluent:CΗ₂Cl₂:CΗ₃θΗ=15:l) to obtain the desire product. ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, J = 2.0 Hz, IH), 7.51 (s, 2H), 7.20 (dd, J = 2.0 & 8.4 Hz, IH), 6.16 (d, J = 8.4 Hz, IH), 5.90 (br, IH), 4.06 (dd, J = 4.0 & 11.2 Hz, IH), 3.39 (s, 3H), 3.12- 3.17 (m, IH), 2.44-2.48 (m, IH), 2.17 (s, 3H), 1.70-1.72 (m, IH), 1.37-1.42 (m, IH), 0.98-1.01 (m, lH); m/z = 478 [M+l]⁺.

Example 90

[309] butyl-Λ^2-(2-fluoro-44odophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- y^cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with 1-butylcyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.43 (dd, J = 2.0 & 10.0 Hz, IH), 7.25-7.27 (m, 2H), 7.05 (s, IH), 6.11 (t, J = 8.4 Hz, IH), 5.69 (s, IH), 3.44 (s, 3H), 2.18 (s, 3H), 1.89 (t, J = 8.8

Hz, 2H), 1.24-1.54 (m, 7H), 0.88-0.92 (t, J = 7.2 Hz, 3H), 0.81-0.84 (m, 2H); m/z = 534 [M+l]⁺.

Example 91

[310] (5)-iV-(2-(2,4-difluorophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-l- (2,3-dihydroxypropyl)cyclopropane-l-sulfonamide

According to general procedure A, step E & F, example 28, 5-amino-6-(2,4- difluorophenylamino)-l,3-dimethylpyridin-2(lH)-one was reacted with (5)-l-(2,3- bis(benzyloxy)propyl) cyclopropane- 1-sulfonyl chloride. The benzyl group was removed with BBr₃ to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.58 (s, IH), 7.39 (s, IH), 7.15 (s, IH), 6.86-6.91 (m, IH), 6.69-6.73 (m, IH), 6.31-6.37 (m, IH), 3.96 (m, IH), 3.76 (s, IH), 3.58- 3.61 (m, IH), 3.43-3.47 (m, IH), 3.39 (s, 3H), 2.25 (dd, J = 9.6 & 15.6 Hz, IH), 2.14 (s, 3H), 1.84 (s,lH), 1.66 (d, J = 15.2 Hz, IH), 1.37-1.40 (m, IH), 1.22-1.30 (m, IH), 0.84-.090 (m, 2H); m/z 444 [M+l]⁺.

Example 92

[311] (S)-N-(2-(4-bromo-2-fluorophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)-l-(2,3-dihydroxypropyl)cyclopropane-l-suIfonamide

According to general procedure A, step E & F, example 28, 5-amino-6-(4-bromo-2- fluorophenylamino)-l,3-dimethylpyridin-2(lH)-one was reacted with (S)- 1 -(2,3- bis(benzyloxy)propyl) cyclopropane- 1-sulfonyl chloride. The benzyl group was removed with BCl₃ to obtain the desired product. ¹H NMR (400 MHz, DMSO-D6) δ 8.81 (s, IH), 7.92 (s, IH), 7.49 (dd, J = 2.0 & 10.8 Hz, IH), 7.16 (dd, J = 1.6 & 9.6 Hz, IH), 6.39 (t, J = 9.2 Hz, IH), 4.55 (s, 2H), 3.45 (s, IH), 3.25 (s, 3H), 3.15 (m, 2H), 2.04 (dd, J = 2.0 8c 15.2 Hz, IH), 2.00 (s, 3H), 1.56 (dd, J = 9.6 & 14.8 Hz, IH), 0.84-.097 (m, 4H); m/z = 504 [M+l]⁺.

Example 93

[312] l-aIlyl-Λ^r-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3- yl)-2-(3-fluorophenyl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with l-allyl-2-(3-fluorophenyl)cyclopropane- 1-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.44 (dd, J = 1.6 & 10.4 Hz, IH), 7.24-7.31 (m, 3H), 7.09 (s, IH), 7.00 (dd, J = 6.4 & 8.4 Hz, IH), 6.93 (d, J = 6.4 Hz, IH), 6.78 (d, J = 9.6 Hz, IH), 6.12 (t, J = 6.4 Hz, IH), 5.75-5.85 (m, 2H), 5.04-5.11 (m, 2H), 3.46 (s, 3H), 3.00 (dd, J = 8.0 & 10.0 Hz, IH), 2.64 (dd, J = 6.4 & 15.6 Hz, IH), 2.20 (s, 3H), 2.12 (dd, J = 7.6 & 15.6 Hz, IH), 1.77 (dd, J = 6.4 & 10.0 Hz, IH), 1.39 (t, J = 6.8 Hz, IH); m/z = 612 [M+l]⁺.

Example 94

[313] iV-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)-2-(3-fluorophenyl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(lH)-one was reacted with 2-(3-fluorophenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.64 (s, IH), 7.45 (dd, J = 1.6 & 10.0 Hz, IH), 7.26-7.30 (m, 2H), 6.96 (t, J = 8.4 Hz, IH), 6.77 (d, J = 8.0 Hz, IH), 6.42 (d, J = 10.0 Hz, IH), 6.19 (t, J = 8.0 Hz, IH), 5.81 (s, IH), 5.67 (s, IH), 3.36 (s, 3H), 3.27 (s, 3H), 2.68-2.72 (m, IH), 2.53-2.56 (m, IH), 1.75-1.81 (m, IH), 1.36-1.42 (m, IH); m/z = 588 [M+l]⁺.

Example 95 l-(2,3-dihydroxypropyl)-iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)-2-(3-methoxyphenyl)cyclopropane-l-sulfonamide

[314] Step A: 1 -allyl-iV-(2-(2-fluoro-4-iodophenylamino)- 1 ,5-dimethyl-6-oxo- 1.6- dihydropyridin-3-yl)-2-(3-methoxyphenyl)cycIopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with l-allyl-2-(3-methoxyphenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J = 10.4 Hz, IH), 7.22-7.28 (m, 2H), 7.07 (s, IH), 6.82 (dd, J = 2.4 & 8.4 Hz, IH), 6.65 (d, J = 8.4 Hz, IH), 6.61 (s, IH), 6.09 (t, J = 8.8 Hz, IH), 5.76-5.87 (m, IH), 5.75 (s, IH), 5.06-5.10 (m, 2H), 3.80 (s, 3H), 3.46 (s, 3H), 2.99 (dd, J = 7.6 & 10.0, IH), 2.63 (dd, J = 7.2 & 16.0 Hz, IH), 2.20 (s, 3H), 2.13 (dd, J = 7.6 & 16.0 Hz, IH), 1.74 (dd, J = 6.0 & 9.6 Hz, IH), 1.39 (t, J = 6.8 Hz, IH); m/z = 624 [M+l]⁺. [315] Step B: 1 -(23-dihvdrox\τ>ropylVN-(2-f2-fluoro-4-iodophenylamino)- 1.5-dimethyl-6-oxo- 1 ,6-dihvdropyridin-3-yl)-2-(3-methoxyphenvπcvclopropane- 1 -sulfonamide

According to the same procedure as example 27 described, the desired product was obtained. ¹H NMR (400 MHz, DMSO-D6, two isomer 1:1) δ 8.95 (s, IH), 8.93 (s, IH), 7.91 (s, 2H), 7.52- 7.56 (m, 2H), 7.40 (s, IH), 7.35 (s, IH), 7.15-7.21 (m, 3H), 7.03 (d, J = 8.0 Hz, IH), 6.81-6.85 (m, 2H), 6.58-6.60 (m, 2H), 6.52 (s, IH), 6.48 (d, J = 7.6 Hz, IH), 6.14 (t, J = 8.8 Hz, IH), 5.88 (t, J = 8.8 Hz, IH), 4.64 (d, J = 4.8 Hz, IH), 4.54 (J = 5.2 Hz, IH), 4.43-4.48 (m, 2H), 3.71 (s, 3H), 3.70 (s, 3H), 3.26 (s, 3H), 3.22 (s, 3H), 2.00 (s, 6H), 1.27-3.90 (m, 16H); m/z = 658 [M+l]⁺.

Example 96

[316] 2-(4-chlorophenyl)-iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with 2-(4-chlorophenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.44 (dd, J = 1.6 & 10.0 Hz, IH), 7.25-7.31 (m, 3H), 7.05 (s, IH), 6.91-6.93 (m, 2H), 6.12 (s, IH), 6.10 (t, J = 8.4 Hz, IH), 5.91 (s, IH), 3.41 (s, 3H), 2.54-2.63 (m, 2H), 2.01 (s, 3H), 1.72-1.77 (m, IH), 1.40-1.43 (m, IH); m/z = 588 [M+l]⁺.

Example 97

[317] N-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-2-(2- fluoro-4-methoxyphenyl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with 2-(2-fluoro-4-methoxyphenyl) cyclopropane- 1- sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J = 10.0 Hz, IH), 7.25-7.27 (m, IH), 7.09 (s, IH), 6.88-6.92 (m, 2H), 6.70-6.73 (m, 2H), 6.10 (t, J = 8.4 Hz, IH), 5.98 (s, IH), 3.88 (s, 3H), 3.42 (s, 3H), 2.50-2.60 (m, 2H), 2.03 (s, 3H), 1.70-1.72 (m, IH), 1.35-1.39 (m, IH); m/z = 602 [M+l]⁺.

Example 98

[318] 2-(2,4-dichlorophenyI)-iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6- dihydropyridin-S-yOcyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridui-2(lH)-one was reacted with 2-(2,4-dichlorophenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹U NMR (400 MHz, CDCl₃) δ 7.41-7.44 (m, 2H), 7.21-7.27 (m, 2H), 7.09 (s, IH), 7.01 (s, IH), 6.82 (d, J = 8.4 Hz, IH), 6.12 (t, J = 8.4 Hz, IH), 5.87 (s, IH), 3.43 (s, 3H), 2.91-2.97 (m, IH), 2.58-2.63 (m, IH), 2.02 (s, 3H), 1.77-1.82 (m, IH), 1.42-1.48 (m, lH); m/z = 622 [M+l]⁺.

Example 99

[319] iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-2-(3- fluoro-4-methoxyphenyl)cycIopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylainino)-l,3- dimethylpyridin-2(lH)-one was reacted with 2-(3-fluoro-4-methoxyphenyl) cyclopropane- 1- sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.43 (dd, J = 1.6 & 10.0 Hz, IH), 7.25-7.27 (m, IH), 7.10 (s, IH), 6.99 (s, IH), 6.80 (t, J = 8.8 Hz, IH), 6.61-6.67 (m, 2H), 6.11 (t, J = 8.8 Hz, IH), 5.84 (s, IH), 3.80 (s, 3H), 3.42 (s, 3H), 2.67 (t, J = 7.2 Hz, 2H), 1.74 (dd, J = 7.2 & 13.6 Hz, IH), 1.50 (dd, J = 7.2 & 13.6 Hz, IH); m/z = 602 [M+l]⁺.

Example 100

[3201 iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-2-(3- fluorophenyl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(l//)-one was reacted with 2-(3-fluorophenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J = 10.4 Hz, IH), 7.25-7.32 (m, 2H), 7.06 (s, IH), 6.96-7.00 (m, IH), 6.93 (s, IH), 6.77 (d, J = 8.0 Hz, IH), 6.68 (d, J = 10.0 Hz, IH), 6.10 (t, J = 8.4 Hz, IH), 6.02 (s, IH), 3.41 (s, 3H), 2.63-2.68 (m, IH), 2.55-2.59 (m, IH), 1.99 (s, 3H), 1.74-1.80 (m, IH), 1.40-1.46 (m, IH); m/z = 572 [M+l]⁺.

Example 101

(R)-l-(2-fluoro-3-hydroxypropyl)-Λ^r-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo- l,6-dihydropyridin-3-yl)cyclopropane-l-sulfonamide

[321] Step A: (7?Visopropyl 1 -(3-(benzyloxyV2-fluoropropyl^')cvclopropane- 1 -sulfonate

To a stirred solution of (5)-isopropyl l-(3-(benzyloxy)-2-hydroxypropyl)cyclopropane-l- sulfonate (2.0 g, 6.7mmol) in 30ml THF was slowly added diethylaminosulphur trifluoride (1.806ml, 14.75mmol) at O⁰C. The mixture was stirred at room temperature for 1.5 hr, then saturated NaHCO₃ solution was added. The mixture was extracted with EtOAc, dried over MgSO₄, filtered, concentrated , and purified over column chromatography (eluent petroleum ether : EtOAc = 8:1) to afford the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.37 (m, 5H), 5.54-5.59 (m, 0.5H), 5.02-5.06 (m, 0.5H), 4.94 (sept., J = 6.4 Hz, IH), 4.50-4.61 (m, 2H), 3.58-4.13 (m, 2H), 2.36-2.48 (m, IH), 1.96-2.05 (m, IH), 1.42-1.46 (m, 2H), 1.40 (d, J = 6.0Hz, 6H), 1.13-1.20 (m, IH), 0.86-0.94 (m, IH).

[322] Step B: potassium (R)- 1 -(3-(benzyloxV)-2-fluoroprop vDcvclopropane- 1 -sulfonate

A mixture of (/?)-isopropyl l-(3-(benzyloxy)-2-fluoropropyl)cyclopropane-l -sulfonate (682mg, 2.27mmol) and potassium thiocyanate (232mg, 2.38mmol) in DME (6ml) and water (6ml) was heated at reflux overnight. The residue was extracted with EtOAc, and the aqueous phase was evaporated under reduce pressure to obtain the crude product which was used in the next reaction without further purification.

[323] Step C: (R)- 1 -(3-(benzyloxyV2-fluoropropyl)cvclopropane- 1 -sulfonyl chloride

A solution of sulfonate (670 mg, 2.26 mmol), thionyl chloride (5 ml) and N₁N- dimethylformamide (5 drops) was heated at reflux for 15min. The volatiles were evaporated under reduce pressure and water was slowly adde., The residue was extracted with EtOAc (2x), and the combined organic layers dried over MgSO₄, filtered, and evaporated to obtain a yellow oil as the crude product which was purified over silica gel chromatography (eluent petroleum ether :

EtOAc = 8:1) to afford the desire product. ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.38 (m, 5H), 5.17- 5.19 (m, 0.5H), 5.05-5.07 (m, 0.5 H), 4.54-4.62 (m, 2H), 3.49-3.74 (m, 2H), 2.64-2.76 (m, IH),

2.17-2.27 (m, IH), 1.83-1.88 (m, IH), 1.72-1.78 (m, IH), 1.51-1.57 (m, IH), 1.20-1.26 (m, IH).

[324] Step D: (R)- 1 -(3-rbenzyloxy^")-2-fluoropropylVN-(2-(2-fluoro-4-iodophenylamino) - 1 ,5- dimethyl-6-oxo- 1 ,6-dihvdropyridin-3-yl)cyclopropane- 1 -sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with (/?)-l-(3-(benzyloxy)-2-fluoropropyl)cyclopropane- 1-sulfonyl chloride to obtain the desired product. [325] Step E: (J?yi-(2-fluoro-3-hvdroxypropyl)-N-(2-f2-fluoro-4-iodophenylaminoV1.5- dimethyl-6-oxo- 1 ,6-dihvdrop yridin-3 - vDcvclopropane- 1 -sulfonamide

(R)- 1 -(3-(benzyloxy)-2-fluoropropyl)-iV-(2-(2-fluoro-4-iodophenylamino)- 1 ,5-dimeihyl-6- oxo-l,6-dihydropyridin-3-yl)cyclopropane-l -sulfonamide (61 mg, 0.095 mmol) was dissolved in dried CH₂Cl₂ (2 ml), and BCl₃ (16.66 mg, 0.142 mmol, 1.5 eq.) was slowly added at O⁰C. The mixture was stirred at room temperature for 2 h, followed by the addition of water.. The organic phase was separated and the aqueous phase extracted with CH₂Cl₂. The combined organic layers were washed with sat. brine, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified over silica gel chromatography (eluants: EtOAc) to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.44 (d, J = 10.0 Hz, IH), 7.26-7.30 (m, 2H), 7.02 (s, IH), 6.11 (t, J = 8.4 Hz, IH), 6.06 (s, IH), 4.84-5.04 (m, IH), 3.64-3.86 (m, 2H), 3.44 (s, 3H), 2.18 (s, 3H), 2.11-2.40 (m, 2H), 1.93 (s, IH), 1.38-1.43 (m, IH), 1.23-1.33 (m, IH), 1.04-1.13 (m, IH), 0.94-1.00 (m, IH); m/z = 554 [M+lf.

Example 102

(/?)-l-(2,3-difluoropropyl)-iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yI)cycIopropane-l-sulfonamide

[326] Step A: (5)-isopropyl 1 -(2,3-dihvdroxypropyl)cyclopropane- 1 -sulfonate

To the solution of (5)-isopropyl l-(3-(benzyloxy)-2-hydroxypropyl)cyclopropane-l -sulfonate

(3.2 g, 9.74 mol) was added BCl₃ (12.7 ml, lmol/L, 12.67 mol) at 0⁰C and the mixture was stirred at it for 0.5 h, then quenched with aq. NaHCO₃. The mixture was extracted with CH₂Cl₂, washed with sat. brine, and dried over Na₂SO₄. Filtration, removal of solvent under reduced pressure and purification of the residue via column chromatography (silica gel, eluent EtOAc :petroleum ether = 10: l)gave the desired product. ¹H NMR (400M Hz, CDCl₃) δ 4.98 (sept, J = 6.4 Hz, IH), 4.11- 4.14 (m, IH), 3.66 (dd, J = 10.8 Hz&4.0 Hz, IH), 3.49 (dd, J = 10.8 Hz&6.0 Hz, IH), 1.90-1.94 (m, 2H), 1.49-1.51 (m, 2H), 1.44 (d, J = 6.4 Hz, 6H), 1.09-1.12 (m, IH), 0.93-0.96 (m, IH).

[327] Step B: (.RVisopropyl 1 -(2,3-difluoropropyl)cvclopropane- 1 -sulfonate

To a stirred solution of diol (1.75 g, 7.34 mmol) in 30ml THF was slowly added diethylaminosulphur trifluoride (4.5 ml, 36.7 mmol) at O⁰C. The mixture was stirred at room temperature overnight, then saturated NaHCO₃ solution was added. The organic phase was separated and the aqueous phaseextracted with EtOAc. The combined organic layers were washed with sat. NaCl, and dried over Na₂SO₄. Filtration, removal of solvent and purification of the residue via column chromatography (silica gel, eluent EtOAc:petroleum ether = 8:l)afforded the desired product. ¹H NMR (400 MHz, CDCl₃) δ 5.06-5.29 (m, IH), 4.96 (sept., J = 6.0 Hz, IH), 4.01-4.74 (m, 2H), 2.31-2.42 (m, IH), 2.00-2.10 (m, IH), 1.49-1.53 (m, 2H), 1.43 (d, J = 6.0 Hz, 6H), 1.14-1.22 (m, IH), 0.94-1.00 (m, IH).

[328] Step C: potassium (R)- 1 -(2.3-difluoropropyl')cvclopropane- 1 -sulfonate

Following the same procedure as step B, example 101 afforded the desired product which was used directly in the next step.

[329] Step D: (R)- 1 -(2,3-difluoropropyl)cyclopropane- 1 -sulfonyl chloride

Following the same procedure as step C, example 101 afforded the desired product. ¹H NMR (400 MHz, CDCl₃) δ 5.11-5.32 (m, IH), 4.42-4.78 (m, 2H), 2.63-2.75 (m, IH), 2.17-2.27 (m, IH), 1.90-1.96 (m, IH), 1.78-1.84 (m, IH), 1.54-1.60 (m, IH), 1.23-1.29 (m, IH).

[3301 Step E: (R)- 1 -(2.3-difluoropropylViV-(2-(2-fluoro-4-iodθDhenylamino^')- 1.5-dimethyl-6- oxo- 1 ,6-dihvdropyridin-3-yl)cvclopropane- 1 -sulfonamide

According to general procedure A, 5-amino-6-(2-fiuoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with (/?)-l-(2,3-difluoropropyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.45 (dd, J = 2.0 & 10.0 Hz, IH), 7.25-7.29 (m, 2H), 6.94 (s, IH), 6.11 (t, J = 8.4 Hz, IH), 5.79 (s, IH), 4.96-5.20 (m, IH), 4.40-4.70 (m, 2H), 3.45 (s, 3H), 2.22-2.42 (m, 2H), 2.18 (s, 3H), 1.40-1.44 (m, IH), 1.28-1.34 (m, IH), 1.09-1.14 (m, IH), 0.92-0.96 (m, IH); m/z = 556 [M+l]⁺.

Example 103

[331] (R)-l-(2,3-difluoropropyl)-N-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6- oxo-ljδ-dihydropyridin-S-yOcyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fiuoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(lH)-one was reacted with (/?)-l-(2,3-difluoropropyl) cyclopropane- 1-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (s, IH), 7.44 (d, J = 10.0 Hz, IH), 7.29 (d, J = 8.4 Hz, IH), 6.18 (t, J = 8.4 Hz, IH), 5.90 (s, IH), 5.84 (s, IH), 4.95- 5.18 (m, IH), 4.40-4.72 (m, 2H), 3.88 (s, 3H), 3.34 (s, 3H), 2.21-2.48 (m, 2H), 1.40-1.46 (m, IH), 1.25-1.32 (m, IH), 1.01-1.12 (m, IH), 0.87-0.92 (m, IH); m/z = 572 [M+l]⁺.

Example 104 l-(2,2-difluoro-3-hydroxypropyl)-Λ'-(2-(2-fluoro-4-iodophenylainino)-l,5-dimethyl-6-oxo-l,6- dihydropyridin-S-yOcyclopropane-l-sulfonamide

[332] Step A: isopropyl 1 -(3-(benzyloxy)-2-oxopropyl)cvclopropane- 1 -sulfonate

To a solution of (S)-isopropyl l-(3-(benzyloxy)-2-hydroxypropyl)cyclopropane-l -sulfonate (2.05 g, 6.24 mmol) in 50 ml CH₂Cl₂ was added Dess-Martin periodinane (5.29 g, 14.27 mmol) and the mixture was then stirred at room temperature for 3.5. The reaction was quenched with sat.NaHCC>₃, extraced with EtOAc, dried, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether:EtOAc:CH₂Cl₂=2:l:l) to yield the desired product (1.788 g, 88%)as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.31-7.36 (m, 5H), 4.91 (sept., J = 6.0 Hz, IH), 4.60 (s, 2H), 4.16 (s, 2H), 2.90 (s, 2H), 1.51-1.54 (m, 2H), 1.38 (d, J = 6.0 Hz, 6H), 1.14-1.18 (m, 2H).

[333] Step B: isopropyl 1 -(3-(benzyloxy^')-2.2-difluoropropyl)cvclopropane- 1 -sulfonate

The ketone (0.96 g, 2.94 mmol) was dissolved in 10 ml dry methylene chloride and the mixture cooled down to 0⁰C. To this solution was added dropwise, under nitrogen, DAST (1 ml, 7.76 mmol) and stirred for 6 h, followed by additional DAST (1 ml, 7.76 mmol). The solution was stirred at rt for 3 days, then poured into aqueous sodium bicarbonate. The organic layer was separated, concentrated and the residue purified on silica gel (petroleum ether:EtOAc=10:l) to afford the desired product (623 mg, 60.8%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.31-

7.36 (m, 5H), 4.94 (sept., J = 6.0 Hz, IH), 4.61 (s, 2H), 3.68 (t, J = 12.4 Hz, 2H), 2.65 (t, J = 17.6 Hz, 2H), 1.51-1.54 (m, 2H), 1.39 (d, J = 6.0 Hz, 6H), 1.23-1.26 (m, 2H). [334] Step C: potassium 1 -(3-(benzyloxy)-2.2-difluoropropyl^')cvclopropane- 1 -sulfonate

Following the same procedure as step B, example 101 the desired product was obtained and utilized directly in the next step .

[335] Step D: 1 -(3-(benzyloxyV2,2-difluoropropyncvclopropane- 1 -sulfonyl chloride

Following the same procedure as step C, example 101 the desired product was obtained and utilized directly in the next step. ¹H NMR (400 MHz, CDCl₃) δ 7.26-7.38 (m, 5H), 4.62 (s, 2H), 3.68 (t, J = 12.4 Hz, 2H), 2.92 (t, J = 17.6 Hz, 2H), 1.84-1.86 (m, 2H), 1.57-1.60 (m, 2H).

[336] Step E: 1 -C3-(benzyloxy^')-2.2-difluoropropyD-N-f 2-(2-fluoro-4-iodophenylamino) -1.5- dimethyl-6-oxo-l,6-dihvdropyridin-3-yl)cyclopropane-l -sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with the sulfonyl chloride to obtain the desired product, which was used without further purification.

[337] Step F: 1 -(2.2-difluoro-3-hvdroxypropylVN-(2-(2-fluoro-4-iodophenylamino)- 1 ,5- dimethyl-6-oxo- 1 ,6-dihydropyridin-3-yl)cyclopropane- 1 -sulfonamide

To a solution of l-(3-(benzyloxy)-2,2-difluoropropyl)-N-(2-(2-fluoro-4-iodophenylamino)- l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)cyclopropane-l -sulfonamide (100 mg, 0.151 mmol) in 3 ml dry CH₂Cl₂ was added BCl₃ (0.45 ml, 1 mol/L, 0.45 mmol.) at -1O⁰C and stirred for 2 h at rt. Additional BCl₃ (0.9 ml, 0.9 mmol.) was added at -1O⁰C and the mixture was stirred for 15 min, followed by the addition of water. The organic was separated and the aqueous phase was extracted with CH₂Cl₂, and washed with sat.NaHCO₃. The combinedorganic layers were washed with sat. brine, dried (MgSO₄), filtered, and concentrated under reduced presssure. The residue was purified by flash column chromatography on silica gel (CH₂Cl₂:MeOH=20:l to 10:1) to yield the desired product (56 mg, 65%) as yellow crystal. ¹H NMR (400 MHz, acetone-D6) δ 7.54 (dd, J = 2.0 & 10.8 Hz, IH), 7.52 (s, IH), 7.48 (s, IH), 7.39 (d, J = 8.4 Hz, IH), 6.38 (t, J = 8.4 Hz, IH), 3.72 (t, J = 13.6 Hz, 2H), 3.40 (s, 3H), 2.76 (t, J = 18.0 Hz, 2H), 2.09 (s, 3H), 1.24-1.27 (m, 2H), 1.19-1.21 (m, 2H); m/z = 572 [M+l]⁺.

Example 105

[338] iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-2-(3- methoxyphenyl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with 2-(3-methoxyphenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d, J = 10.0 Hz, IH),

7.23-7.27 (m, 2H), 7.07 (s, IH), 6.81 (dd, J = 2.0 & 8.0 Hz, IH), 6.69 (s, IH), 6.55 (d, J = 8.0 Hz, IH), 6.51 (t, J = 2.0 Hz, IH), 6.08 (t, J = 8.4 Hz, IH), 5.77 (s, IH), 3.80 (s, 3H), 3.38 (s, 3H), 2.66-2.69 (m, IH), 2.49-2.51 (m, IH), 1.99 (s, 3H), 1.74-1.79 (m ,1H), 1.43-1.48 (m, IH); m/z = 584 [M+l]⁺.

Example 106 [339] N-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)-2-(3-methoxyphenyI)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(lH)-one was reacted with 2-(3-methoxyphenyl) cyclopropane- 1-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.66 (s, IH), 7.45 (d, J = 10.0 Hz, IH), 7.29 (d, J = 8.8 Hz, IH), 7.21 (t, J = 8.0 Hz, IH), 6.78 (d, J = 8.0 Hz, IH), 6.51 (d, J = 8.0 Hz, IH), 6.47 (s, IH), 6.18 (t, J= 8.8 Hz, IH), 5.76 (s, IH), 5.65 (s, IH), 3.79 (s, 3H), 3.36 (s, 3H), 3.20 (s, 3H), 2.68-2.72 (m, IH), 2.46-2.53 (m, IH), 1.72-1.78 (m, IH), 1.37-1.42 (m, IH); m/z = 600 [M+l]⁺.

Example 107

[340] 2-(3-fluoro-4-hydroxyphenyl)-Λ'-(2-(2-fluoro-4-iodophenyIamino)-l,5-dimethyl-6-oxo- l,6-dihydropyridin-3-yl)cyclopropane-l-sulfonamide

N-(2-(2-fluoro-4-iodophenylamino)- 1 ,5-dimethyl-6-oxo- 1 ,6-dihydropyridin-3-yl)-2-(3- fluoro-4-methoxyphenyl)cyclopropane-l -sulfonamide was treated with BBr₃ to obtain the desired product. ¹H ΝMR (400 MHz, DMSO-D6) δ 9.85 (s, IH), 8.92 (s, IH), 7.95 (s, IH), 7.60 (d, J = 10.8 Hz, IH), 7.31 (d, J = 8.0 Hz, IH), 7.23 (s, IH), 6.50-6.62 (m, 3H), 6.34 (t, J = 8.8 Hz, IH), 3.27 (s, 3H), 2.64-2.67 (m, IH), 2.41-2.45 (m, IH), 1.91 (s, 3H), 1.32-1.34 (m, IH), 0.99-1.03 (m, lH); m/z = 588 [M+l]⁺.

Example 108

[341] iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-2-(3- hydroxyphenyl)cyclopropane-l-sulfonamide

N-(2-(2-fluoro-4-iodophenylamino)- 1 ,5-dimethyl-6-oxo- 1 ,6-dihydropyridin-3-yl)-2-(3- methoxyphenyl)cyclopropane-l -sulfonamide was treated with BBr₃ to obtain the desired product. ¹H NMR (400 MHz, DMSO-D6) δ 9.37 (s, IH), 8.88 (s, IH), 7.91 (s, IH), 7.58 (dd, J = 1.6 & 10.8 Hz, IH), 7.31 (d, J = 7.6 Hz, IH), 7.17 (s, IH), 7.05 (t, J = 7.6 Hz, IH), 6.60 (dd, J = 2.0 & 8.0 Hz, IH), 6.47 (s, IH), 6.32 (t, J = 8.8 Hz, IH), 6.29 (d, J = 8.0 Hz, IH), 3.26 (s, 3H), 2.59- 2.62 (m, IH), 2.31-2.33 (m, IH), 1.86 (s, 3H), 1.34-1.37 (m, IH), 1.02-1.05 (m, IH); m/z = 570 [M+l]⁺.

Example 109

[342] 2-(4-fluoro-3-methoxyphenyl)-iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo- l,6-dihydropyridin-3-yl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fiuoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with 2-(4-fluoro-3-methoxyphenyl) cyclopropane- 1- sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, DMSO-D6) δ 8.92 (s, IH),

7.93 (s, IH), 7.57-7.61 (dd, J = 1.6 & 10.8 Hz, IH), 7.30-7.32 (d, J = 8.4 Hz, IH), 7.20 (s, IH), 7.06-7.12 (dd, J = 8.4 & 11.6 Hz, IH), 6.83-6.85 (d, J = 6.8 Hz, IH), 6.49-6.50 (d, J = 6.4 Hz, IH), 6.32-6.36 (t, J = 8.8 Hz, IH), 3.81 (s, 3H), 3.28 (s, 3H), 2.78-2.83 (m, IH), 2.43-2.46 (m, IH), 1.86 (s, 3H), 1.36-1.39 (m, IH), 1.04-1.07 (m, IH); m/z = 602 [M+l]⁺.

Example 110 [343] 2-(4-chloro-2-fluorophenyl)-iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo- l,6-dihydropyridin-3-yl)cycIopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with 2-(4-chloro-2-fluorophenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, DMSO-D6) δ 8.98 (s, IK), 7.94 (s, IH), 7.56-7.59 (dd, J = 1.6 & 10.6 Hz, IH), 7.40-7.41 (d, J = 2.0 Hz, IH), 7.38-7.39 (d, J = 2.0 Hz, IH), 7.31 (s, IH), 7.28-7.29 (d, J = 1.6 Hz, IH), 7.21-7.23 (d, J = 8.4 Hz, IH), 6.89-6.93 (t, J = 8.4 Hz, IH), 6.32-6.36 (t, J = 8.4 Hz, IH), 3.28 (s, 3H), 2.86-2.90 (m, IH), 2.46-2.48 (m, IH), 1.88 (s, 3H), 1.40-1.46 (m, IH), 1.11-1.16 (m, IH); m/z = 607 [M+ 1]⁺.

Example 111

[344] 2-(4-fluoro-3-methoxyphenyl)-iV-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methyl-ό-oxo-l.ό-dihydropyridin-S-yOcyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2( lH)-one was reacted with 2-(4-fluoro-3-methoxyphenyl) cyclopropane- 1 -sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, DMSO-D6) δ 8.75 (s, IH), 7.89 (s,

IH), 7.56-7.61 (d, J = 11.2 Hz, IH), 7.36-7.38 (d, J = 8.0 Hz, IH) , 7.07-7.12 (dd , J = 8.4 & 11.2 Hz, IH), 6.86-6.88 (d, J = 7.2 Hz, IH), 6.61 (s, IH), 6.37-6.41 (t, J = 8.4 Hz, IH), 5.60 (s, IH), 3.82 (s, 3H), 3.24 (s, 3H), 3.23 (s, 3H), 2.85-2.89 (m, IH), 2.35-2.39 (m, IH), 1.33-1.44 (m, 2H); m/z = 618 [M+l]⁺.

Example 112 [345] 2-(4-chloro-2-fluorophenyl)-7V-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl- 6-oxo-l,6-dihydropyridin-3-yl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(lH)-one was reacted with 2-(4-chloro-2-fluorophenyl) cyclopropane- 1-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, DMSO-D6) δ 8.81 (s, IH), 7.91 (s, IH), 7.57-7.59 (dd , J = 1.6 & 10.8 Hz, IH), 7.39-7.40 (d, J = 2.0 Hz, IH), 7.35-7.37 (d, J = 8.4 Hz, IH), 7.23-7.25 (d, J = 8.4 Hz, IH), 7.07-7.11 (t, J = 8.4 Hz, IH), 6.37-6.42 (t, J = 8.8 Hz, IH), 5.64 (s, IH), 3.26 (s, 3H), 3.24 (s, 3H), 2.94-2.98 (m, IH), 2.42-2.46 (m, IH), 1.41-1.50 (m, 2H); m/z = 623 [M+l]⁺.

Example 113

[346] 2-(4-fluoro-2-hydroxyphenyl)-N-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo- l,6-dihydropyridin-3-yl)cydopropane-l-sulfonamide

2-(4-fluoro-2-methoxyphenyl)-N-(2-(2-fluoro-4-iodophenylamino)- 1 ,5-dimethyl-6-oxo- 1 ,6- dihydropyridin-3-yl)cyclopropane-l -sulfonamide was treated with BBr₃ to obtain the desired product. ¹H NMR (400 MHz, DMSO-D6) δ 9.86 (s, IH), 8.93 (s, IH), 7.96 (s, IH), 7.68-7.71 (d, J =13.6 Hz, IH), 7.59-7.61 (d, J = 10.4 Hz, IH), 7.30-7.32 (d, J = 8.0 Hz, IH), 7.24 (s, IH), 6.50- 6.62 (m, 3H), 6.32-6.36 (t, J = 8.6 Hz, IH), 3.28 (m, 3H), 2.63-2.65 (m, IH), 2.42-2.45 (m, IH), 1.91 (s, 3H), 1.34-1.36 (m, IH), 1.04-1.06 (m, IH); m/z = 588 [M+l]⁺.

Example 114

[347] iV-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)-2-(3-hydroxyphenyl)cydopropane-l-sulfonamide

To a solution of N-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6- dihydropyridin-3-yl)-2-(3-methoxyphenyl)cyclopropane-l -sulfonamide in 3 ml dichloromethane was added BBr₃ at -15⁰C. After completion of reaction (monitored by TLC), the solution was quenched with water, extracted with EtOAc and washed with brine. The organic phase wasdried over MgSO₄. Filtration, removal of solvent and purification of the residue via column chromatography on silica gel ga ve the desired product. ¹H NMR (400 MHz, DMSO-D6) δ 9.39 (s, IH), 8.74 (s, IH), 7.91 (s, IH), 7.60 (d, J = 10.8 Hz, IH), 7.37 (d, J = 8.0 Hz, IH), 7.06 (t, J = 8.0 Hz, IH), 6.62 (d, J = 8.0 Hz, IH), 6.45-6.48 (m, IH), 6.37-6.42 (t, J = 8.8 Hz, IH), 5.65 (s, IH), 3.25 (s, 3H), 3.23 (s, 3H), 2.70-2.73 (m, IH), 2.29-2.33 (m, IH), 1.38-1.40 (m, IH), 1.27-1.29 (m, lH); m/z = 586 [M+l]⁺.

Example 115

[348] iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-2-(4- methoxypheny^cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with 2-(4-methoxyphenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.44 (dd, J = 2.0 & 10.0 Hz, IH), 7.24-7.26 (m, IH), 7.10 (s, IH), 6.83-6.90 (m, 5H), 6.06-6.11 (t, J = 8.6 Hz, IH), 5.98 (s, IH), 3.80 (s, 3H), 3.39 (s, 3H), 2.47-2.58 (m, 2H), 2.00 (s, 3H), 1.68-1.73 (m, IH), 1.36- 1.40 (m, IH); m/z = 584 [M+l]⁺.

Example 116

[349] 2-(4-chloro-3-(trifluoromethyl)phenyl)-N-(2-(2-fluoro-4-iodophenylamino)-l,5- dimethyl-6-oxo-l,6-dihydropyridin-3-yl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with 2-(4-chloro-3-(trifluoromethyl) phenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, IH), 7.43-7.46 (dd, J = 1.6 & 10.0 Hz, IH), 7.34-7.35 (d, J = 2.4 Hz, IH), 7.25- 7.28 (m, IH), 7.08-7.13 (m, 2H), 7.01 (s, IH), 6.12-6.14 (t, J = 8.2 Hz, IH), 6.08 (s, IH), 3.43 (s, 3H), 2.66-2.69 (m, 2H), 2.03 (s, 3H), 1.75-1.80 (m, IH), 1.40-1.45 (m, IH); m/z = 656 [M+l]⁺.

Example 117

[350] 2-(3,4-dimethoxyphenyl)-N-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with 2-(3,4-dimethoxyphenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.44 (d, J = 10.0 Hz, IH), 7.24-7.27 (d, J = 9.2 Hz, IH), 7.13 (s, IH), 6.81-6.83 (d, J = 8.0 Hz, IH), 6.72 (s, IH), 6.49- 6.51 (d, J = 10.0 Hz, IH), 6.47 (s, IH), 6.06-6.11 (t, J = 8.6 Hz, IH), 5.93-5.94 (d, J = 2.4 Hz, IH), 3.87 (s, 3H), 3.86 (s, 3H), 3.38 (s, 3H), 2.60-2.62 (m, IH), 2.50-2.52 (m, IH), 2.03 (s, 3H), 1.70-1.72 (m, IH), 1.38-1.40 (m, IH); m/z = 614 [M+l]⁺.

Example 118

[351] 2-(4-fluoro-3-hydroxyphenyl)-iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo- l,6-dihydropyridin-3-yI)cyclopropane-l-suIfonamide

2-(4-fluoro-3-methoxyphenyl)-N-(2-(2-fluoro-4-iodophenylamino)- 1 ,5-dimethyl-6-oxo- 1 ,6- dihydropyridin-3-yl)cyclopropane-l -sulfonamide was treated with BBr₃ to obtain the desired product. ¹K NMR (400 MHz, DMSO-D6) δ 9.81 (s, IH), 8.90 (s, IH), 7.92 (s, IH), 7.58-7.61 (dd, J = 1.6 & 10.8 Hz, IH), 7.32-7.34 (d, J = 8.4 Hz, IH), 7.19 (s, IH), 6.99-7.05 (dd, J = 8.6 & 11.4 Hz, IH), 6.37-6.70 (dd, J = 2.0 & 8.4 Hz, IH), 6.32-6.37 (t, J = 8.8 Hz, IH), 6.30-6.32 (m, IH), 3.30 (s, 3H), 2.64-2.67 (m, IH), 2.36-2.38 (m, IH), 1.88 (s, 3H), 1.34-1.37 (m, IH), 1.03-1.05 (m, lH); m/z = 588 [M+l]⁺.

Example 119 [3521 iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-2-(4- hydroxyphenyl)cyclopropane-l-sulfonamide

N-(2-(2-fiuoro-4-iodophenylamino)- 1 ,5-dimethyl-6-oxo- 1 ,6-dihydropyridin-3-yl)-2-(4- methoxyphenyl)cyclopropane-l -sulfonamide was treated with BBr₃ to obtain the desired product. ¹H NMR (400 MHz, DMSO-D6) δ 9.33 (s, IH), 8.88 (s, IH), 7.98 (s, IH), 7.62 (d, J = 8.8 Hz, IH), 7.34 (d, J = 8.8 Hz, IH), 7.22 (s, IH), 6.72-6.74 (m, 2H), 6.65-6.67 (m, 2H), 6.33 (t, J = 9.2 Hz, IH), 3.31 (s, 3H), 2.44-2.51 (m, IH), 2.29-2.39 (m, IH), 1.90 (s, 3H), 1.22-1.36 (m, IH), 0.88- 0.95 (m, IH); m/z = 570 [M+l]⁺.

Example 120

[353] 2-(3,4-dihydroxyphenyl)-N-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)cyclopropane-l-sulfonamide

2-(3,4-dimethoxyphenyl)-iV-(2-(2-fluoro-4-iodophenylamino)- 1 ,5-dimethyl-6-oxo- 1 ,6- dihydropyridin-3-yl)cyclopropane-l -sulfonamide was treated with BBr₃ to obtain the desired product. ¹H NMR (400 MHz, DMSO-D6) δ 9.03 (s, IH), 8.90 (s, IH), 8.86 (s, IH), 8.12 (s, IH), 7.60 (d, J = 8.4 Hz, IH), 7.33 (d, J = 8.4 Hz, IH), 7.24 (s, IH), 6.65 (d, J = 8.0 Hz, IH), 6.49 (s, IH), 6.33 (t, J = 8.8 Hz, IH), 6.08 (d, J = 8.0 Hz, IH), 3.27 (s, 3H), 2.30-2.43 (m, IH), 2.22- 2.30(m, IH), 1.91 (s, 3H), 1.24-1.36 (m, IH), 0.86-0.92 (m, IH); m/z = 586 [M+l]⁺.

Example 121

[354] N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2-(2-fluoro-4- methoxyphenyl)cyclopropane-l-sulfonamide

According to general procedure A, 5,6-difluoro-N¹-(2-fluoro-4-iodophenyl)benzene-l,2- diamine was reacted with 2-(2-fluoro-4-methoxyphenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.42 (m, 2H), 7.07-7.17 (m, 2H),

6.76-6.80 (m, IH), 6.72 (s, IH), 6.34-6.57(m, 2H), 6.15 (t, J = 8.4 Hz, IH), 5.67 (s, IH), 3.79 (s, 3H), 2.67-2.71 (m, 2H), 1.68-1.72 (m, IH), 1.42-1.50 (m, IH); m/z = 592 [M+l]⁺.

Example 122

[355] iV-(5-fluoro-2-(2-fluoro-4-iodophenyIamino)-4-methoxy-l-methyl-6-oxo-l,6- dihydropyridin-3-yl)cyclopropanesulfonamide

A mixture of N-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-0-oxo-l,6- dihydropyridin-3-yl)cyclopropanesulfonamide (190 mg, 0.385 mmol) and selectfluor (177 mg,

0.501 mmol) in 5 ml MeCN wad stirred at -10 ⁰C for 15 min. The solution was concentrated under reduced pressure and the residue was purified via silica gel chromatography (petroleum ether:EtOAc=3: 1-EtOAc) to obtain the product. ¹H NMR (400 MHz, CDCl₃) δ 7.55 (s, IH), 7.43 (d, J = 8.4 Hz, IH), 7.28 (d, J = 8.4 Hz, IH), 6.12 (t, J = 8.4 Hz, IH), 5.93 (s, IH), 4.30 (s, 3H), 3.40 (s, 3H), 2.43-2.47 (m, IH), 1.14-1.20 (m, 2H), 0.92-1.10 (m, 2H); m/z = 496 [M+l]⁺.

Example 123

[356] 2-(2,4-dichlorophenyl)-7V-(3,4-difluoro-2-(2-fluoro-4-iodophenyIamino)phenyl) cyclopropane- 1-sulfonamide

According to general procedure A, 5,6-difluoro-iV¹-(2-fluoro-4-iodophenyl)benzene-l,2- diamine was reacted with 2-(2,4-dichlorophenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.41 (m, 3H), 7.16-7.20 (m, 2H), 7.06-7.12

(m, IH), 6.78-6.83(m, 2H), 6.19 (t, J = 8.4 Hz, IH), 5.80 (s, IH), 2.91-2.97 (m, IH), 2.6T-2.91 (m, IH), 1.60-1.79 (m, IH), 1.36-1.41 (m, IH); m/z = 613 [M+l]⁺.

Example 124

[357] N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2-(2-fluoro-4- hydroxyphenyl)cyclopropane-l-sulfonamide

According to example 114, iV-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-2-(2- fluoro-4-methoxyphenyl)cyclopropane-l -sulfonamide was treated with BBr₃ to obtain the desired. 1H NMR (400 MHz, CDCl₃) δ 7.38-7.41 (m, 2H), 7.17 (d, J = 8.8 Hz, IH), 7.07 (d, J = 8.8 Hz, IH), 6.80 (s, IH), 6.69-6.74 (m, IH), 6.55-6.58 (m, 2H), 6.15-6.18 (m, 2H), 5.75 (s, IH), 2.60- 2.69 (m, 2H), 1.64-1.72 (m, IH), 1.40-1.48 (m, IH); m/z = 579 [M+l]⁺.

Example 125 iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyI-6-oxo-l,6-dihydropyridin-3-yl)-l-(3- hydroxy-2-oxopropyl)cyclopropane-l-sulfonamide

[358] Step A: (S)- 1 -(benzyloxy)-3-( 1 -(isopropoxysulfonyl)cvclopropyl)propan-2-yl divagate

A mixture of (.S)-isopropyl l-(3-(benzyloxy)-2-hydroxypropyl)cyclopropane-l -sulfonate (5.0 g, 15.22 mmol), pivaloyl chloride (2.25 ml, 18.27 mmol), Et₃N (2.64 ml, 18.87 mmol), and DMAP (186 mg, 1.522 mmol) in 40 ml CH₂Cl₂ were heated under reflux for 15.5 h. The mixture was quenched with water, extracted with EtOAc, washed with water (x2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum etheπEtOAc = 8:1 to 5:1) to yield the desired product (4.75 g, 76%) as colorless oil. ¹R NMR (400 MHz, CDCl₃) δ 7.28-7.36 (m, 5H), 5.34-5.37 (m, IH), 4.95-5.00 (sept., J = 6.0 Hz, IH), 4.52 (s, 2H), 3.55-3.63 (m, 2H), 2.37 (dd, J = 4.8 Sr 15.2 Hz, IH), 2.04 (dd, J = 8.4 & 15.2 Hz, IH), 1.40 (dd, J = 6.4 & 11.2 Hz, 6H), 1.24-1.26 (m, 2H), 1.20 (s, 9H), 1.02-1.05 (m, IH), 0.92-0.96 (m, IH).

[359] Step B: sodium (S)- 1 -(3-(benzyloxy)-2-(pivaloyloxy)prop vDcvclopropane- 1 -sulfonate

(<y)-l-(benzyloxy)-3-(l-(isopropoxysulfonyl)cyclopropyl)propan-2-yl divagate (4.75 g, 11.51 mmol) and NaI (2.07 g, 13.81 mmol) in 60 ml acetone were heated under reflux for 64 h, then concentrated and dried over P₂O₅ under reduced pressure to yield4.758 g of a yellow sticky which was utilized without further purificaiton. ¹H NMR (400 MHz, DMSO-D6) δ 7.28-7.35 (m, 5H), 5.50 (m, IH), 4.40-4.49 (m, 2H), 3.56-3.64 (m, 2H), 1.82-1.93 (m, 2H), 1.11 (s, 9H), 0.87 (m, 2H), 0.45 (m, 2H).

[360] Step C: (S)- 1 -(benzyloxy)-3-( 1 -(chlorosulfonyl)cvclopropyl)propan-2-yl pivalate

To a solution of sodium (1.48 g, 3.58 mmol) in 5 ml SOCl₂ was added 4 drops of N,N- dimethylformamide, and the mixture heated to reflux for 1.5 h, and then concentrated under reduced pressure. The residue was , diluted with EtOAc, washed with water, and the aqueous layer extracted with EtOAc (x2), The combined organic layers were washed with sat.NaCl, dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether:EtOAc=8:l) to yield the desired product (1.218 g, 87%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.38 (m, 5H), 5.33-5.37 (m, IH), 4.53 (s, 2H), 3.57-3.62 (m, 2H), 2.61 (dd, J = 4.0 & 16.0 Hz, IH), 2.31 (dd, J = 9.2 & 16.0 Hz, IH), 1.73-1.80 (m, 2H), 1.33-1.36 (m, IH), 1.21-1.25 (m, IH), 1.21 (s, 9H). [361] Step D: (S)- 1 -(benzyloxy)-3-( 1 -(N-(2-( 2-fluoro-4-iodophenylaminoV 1.5-dimethyl-6-oxo- l,6-dihvdropyridin-3-vDsulfamoyl)cvclopropyDpropan-2-yl pivalate

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with (5)-l-(benzyloxy)-3-(l-

(chlorosulfonyl)cyclopropyl)propan-2-yl pivalate to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.39 (dd, J = 2.0 & 10.4 Hz, IH), 7.24-7.36 (m, 7H), 7.10 (s, IH), 6.74 (s, IH), 6.10 (t, J = 8.8 Hz, IH), 5.36-5.39 (m, IH), 4.48-4.56 (m, 2H), 3.66 (dd, J = 4.0 & 10.S Hz, IH), 3.52 (dd, J = 4.0 & 10.8 Hz, IH), 3.42 (s, 3H), 2.16 (s, 3H), 2.14-2.16 (m, 2H), 1.32-1.36 (m, IH), 1.22-1.28 (m, IH), 1.18 (s, 9H), 0.85-0.89 (m, IH), 0.78-0.82 (m, IH).

[362] Step E: (S)- 1 -fbenzyloxyV3-( 1 -(N-ftert-butoxycarbonylVN-(2-(2-fluoro-4- iodophenylamino)- 1 ,5-dimethyl-6-oxo- 1 ,6-dihvdropyridin-3-yl)sulfamoyl)cyclopropyl^') propan-2- yl pivalate

To a solution of (5)-l-(benzyloxy)-3-(l-(iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6- oxo-l,6-dihydropyridin-3-yl)sulfamoyl)cyclopropyl)propan-2-yl pivalate and (Boc)₂O in 15 ml THF was added NaH at once at -45⁰C and then stirred at room temperature overnight (17 h). The mixture was quenched with ice-water, extracted with EtOAc, washed with satNϊLiCl, dried of Na₂SO₄, filtered and concentrated under reduced pressure to yield, 1.379 g of crude product as a brown solid which was used without further purification..

[363] Step F: (.S^-fert-butyl l-(3-(benzyloxy)-2-hvdroxypropyl^*)cvclopropylsulfonyl(2-(2-fluoro- 4-iodophenylamino)- 1 ,5-dimethyl-6-oxo- 1.6-dihvdropyridin-3-yl)carbamate

Lithium hydroxide monohydrate (175 mg, 4.17 mmol) was added to the turbid solution of crude (S)- 1 -(benzyloxy)-3-( 1 -(N-(tert-butoxycarbonyl)-iV-(2-(2-fluoro-4-iodophenylamino)- 1 ,5- dimethyl-6-oxo-l,6-dihydropyridin-3-yl)sulfamoyl)cyclopropyl) propan-2-yl pivalate (689 mg, 92% purity from step E, 0.768 mmol) in MeOH (6 ml) and H₂O (2 ml). The clear solution was then stirred at rt for 3 h. After heating to 6O⁰C overnight (17 h), additional LiOHH₂O (156 mg, 3.72 mmol) was added and the mixture was heated for 4 h. The solution was concentrated under reduced pressure, extracted with EtOAc, washed with water and brine, dried, filtered and concentrated under reduced pressure to afford 505 mg of crude product (89%) as a yellow solid which was utilized without further purification.. [364] Step G: fert-butyl l-(3-(benzyloxV)-2-oxopropyl^*)cyclopropylsulfonyl(2-(2-fluoro-4- iodophenylamino)- 1.S-dimethyl-ό-oxo- 1 ,6-dihvdropyridin-3-yl)carbamate

To a solution of (S)-tert-butyl l-(3-(benzyloxy)-2-hydroxypropyl)cyclopropylsulfonyl(2-(2- fluoro-4-iodophenylamino)- 1 ,5-dimethyl-6-oxo- 1 ,6-dihydropyridin-3-yl)carbamate (500 mg, 0.674 mmol) in 7 ml CH₂Cl₂ was added Dess-Martin periodinane (572 mg, 1.348 mmol) and the mixture was then stirred at room temperature for 16.5 h. The mixture was quenched with sat.NaHCC>₃, extraced with CH₂Cl₂, dried, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum etheπEtOAc =1:1) to yield the desired product (181 mg, 36%) as a yellow crystalline solid. ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.47 (m, 2H), 7.31-7.40 (m, 6H), 7.18 (t, J = 8.4 Hz, IH), 6.23 (s, IH), 4.57 (s, 2H), 4.08 (s, 2H), 3.46 (s, 3H), 3.15 (d, J = 15.6 Hz, IH), 2.96 (d, J = 15.6 Hz, IH), 2.15 (s, 3H), 1.52- 1.55 (m, IH), 1.47 (s, 9H), 1.41-1.47 (m, IH), 0.97-1.08 (m, 2H).

[365] Step H: N-(2-(2-fluoro-4-iodophenylamino)- 1.5-dimethyl-6-oxo- 1.6-dihvdropyridin-3-ylV 1 -(3-hvdroxy-2-oxopropyl)cvclopropane- 1 -sulfonamide

To a solution of tert-butyl l-(3-(benzyloxy)-2-oxopropyl)cyclopropylsulfonyl(2-(2-fluoro-4- iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)carbamate (175 mg, 0.237 mmol) in 5 ml CH₂Cl₂ was added 1 ml BCl₃ (1 M) at O⁰C and the mixture was stirred at O⁰C for 10 min, then quenched with water, extracted with CH₂Cl₂ (x3), washed with sat. brine and dried over MgSCvPurification of the residue via column chromatography on silica gel (CH₂Cl₂ :MeOH=20: 1) afforded 64 mg (49%) of product as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.45 (m, 2H), 7.26-7.28 (m, IH), 7.04 (s, IH), 6.63 (s, IH), 6.11 (t, J = 8.4 Hz, IH), 4.31 (s, 2H), 3.44 (s, 3H), 2.98 (s, 2H), 2.90 (s, IH), 2.19 (s, 3H), 2.46-2.52 (m, 2H), 0.94-1.04 (m, 2H); m/z = 550 [M+l]⁺.

Example 126

(S)-l-(3-fluoro-2-hydroxypropyl)-iV-(2-(2-fluoro-4-iodophenyIamino)-l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yI)cycIopropane-l-sulfonamide

[366] Step A: (-?)-l-hvdroxy-3-(l-(isopropoxysulfonyl^')cvclopropyl)propan-2-yl pivalate

(S)-l-(benzyloxy)-3-(l-(isopropoxysulfonyl)cyclopropyl)propan-2-yl pivalate (1.5g,

3.92mmol) was dissolved in dried CH₂Cl₂ (30ml), and BCl₃ (5.1ml, 1 mol/L, 5.10 mmol) was slowly added while cooling the reaction in an ice-bath. The mixture was stirred at room temperature for 2 h, then water was added. The mixture was extracted with CH₂Cl₂,washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum ether:EtOAc = 4:1) to obtain the desire product (1.04g, 91%). ¹H NMR (400 MHz, CDCl₃) δ 5.25-5.28 (m, IH), 5.00 (sept., J =

6.4 Hz, IH), 3.80 (dd, J = 3.2 & 12.0 Hz, IH), 3.70 (dd, J = 4.4 & 12.0 Hz, IH), 2.32 (dd, J = 5.6 & 15.6 Hz, IH), 1.99 (dd, J = 8.0 & 15.6 Hz, IH), 1.46-1.50 (m, 2H), 1.42 (dd, J = 6.4 & 6.8 Hz,

6H), 1.22 (s, 9H), 1.03-1.06 (m, IH), 0.97-1.00 (m, IH).

[367] Step B: (S)- 1 -fluoro-3-( 1 -(isopropoxysulfonyl)cvclopropyl)propan-2-yl

To a stirred solution of the alcohol (1.04g, 3.56mmol) in 20 ml of THF was slowly added DAST (1.26g, 0.958ml, 7.83mmol) at O⁰C. The mixture was stirred at room temperature for 24 h, then saturated NaHCO₃ was added, and the mixture extracted with EtOAc. The organic phase was dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to yield the desired product. ¹H NMR (⁴OO MHz,

CDCl₃) δ 5.21-5.23 (m, 0.5H), 5.09-5.11 (m, 0.5H), 4.96 (sept., J = 6.4 Hz, IH), 4.12-4.29 (m, 2H), 2.37-2.49 (m, IH), 1.63-1.96 (m, IH), 1.48-1.51 (m, 2H), 1.42 (d, J = 6.4 Hz, 6H), 1.19-1.22

(m, 10H), 0.88-0.92 (m, IH).

[368] Step C: sodium (S)- 1 -(3-fluoro-2-(pivaloyloxy)propyl)cvclopropane- 1 -sulfonate

A mixture of (5)-l-fluoro-3-(l-(isopropoxysulfonyl)cyclopropyl)propan-2-yl pivalate (295 mg, 1.00 mmol) and sodium iodide (165 mg, 1.10 mmol) in acetone 10 ml was refluxed overnight. The residue was extracted with EtOAc, and the aqueous phase was evaporated under reduce pressure to obtain the crude product which was used in the next reaction without further purification.

[369] Step D: (S)- 1 -( 1 -(chlorosuIfonyDcyclopropyD-S-fluoropropan-Σ-yl pivalate

A solution of the sodium salt (260 mg, 0.948 mmol), thionyl chloride (5 ml) and N,N- dimethylformamide (5 drops) was refluxed for 1 h. The volatiles were evaporated under reduced pressure and water was slowly added. The residue was extracted with EtOAc, dried over MgSO₄, filtered, and evaporated to obtain a yellow oil which was purified over silica gel chromatography (eluants: petroleum ether:EtOAc=10:l) to afford the desired product (216 mg, 79%). ¹H NMR (400 MHz, CDCl₃) δ 5.24-5.26 (m, 0.5 H), 5.11-5.14 (m, 0.5 H), 4.25-4.28 (m, IH), 4.21-4.23 (m, IH), 2.75 (dd, J = 16.4 & 34.8 Hz, IH), 2.00-2.11 (m, IH), 1.88-1.94 (m, IH), 1.76-1.82 (m, IH), 1.56-1.60 (m, IH), 1.19-1.25 (m, 10H).

[370] Step E: CSV 1 -fluoro-3-( 1 -(N-(2-(2-fluoro-4-iodophenylamino)- 1.5-dimethyl-6-oxo- 1.6- dihvdropyridin-3-yl)sulfamoyl)cvclopropyl)propan-2-yl pivalate

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one was reacted with (S)-I -(I -(chlorosulfonyl)cyclopropyl)-3- fluoropropan-2-yl pivalate to obtain the desired product.

[371] Step F: (S)- 1 -(3-fluoro-2-hvdroxypropyl)-N-(2-(2-fluoro-4-iodophenylamino)- 1.5- dimethyl-6-oxo- 1.6-dihvdropyridin-3- vDcvclopropane- 1 -sulfonamide

A mixture of (5)-l-fluoro-3-(l-(iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6- dihydropyridin-3-yl)sulfamoyl)cyclopropyl)propan-2-yl pivalate (163 mg, 0.256 mmol) and

LiOHH₂O (53.6 mg, 1.278 mmol) in 4 ml MeOH-H₂O (v/v: 3:1) was heated to 6O⁰C for 2 h, and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether:EtOAc = 1:1 to 1:3) to yield the desired product (65 mg, 46%). ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.46 (m, IH), 7.25-7.30 (m, 2H), 6.13 (s, IH), 6.11 (t, J = 8.8 Hz, IH), 5.28-5.40 (m, 2H), 3.68-3.83 (m, 2H), 3.44 (s, 3H), 2.05-2.36 (m, 5H), 1.31-1.43 (m, 2H), 1.25-1.31 (m, 2H), 1.06-1.09 (m, IH), 0.92-0.98 (m, IH); m/z = 554 [M+l]⁺.

Example 127

[372] iV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-2-(3- methoxyphenyl)-7V-methylcycIopropane-l-suIfonamide

To a solution of N-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin- 3-yl)-2-(3-methoxyphenyl)-N-methylcyclopropane-l -sulfonamide (100 mg, 0.171 mmol) and

CH₃I (0.012 ml, 0.188 mmol) in 2 ml THF was added K₂CO₃ (36 mg, 0.26 mmol) at O⁰C. The reaction was stirred for 2.5h, quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure.

Purificaiton of the residue via column chromatography on silica gel (petroleum ether:EtOAc=l:l) afforded the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.45 (m, IH), 7.25-7.28 (m, IH),

6.94-7.00 (m, 2H), 6.78-6.88 (m, IH), 6.42-6.70 (m, 2H), 6.14 (t, J = 8.4 Hz, IH), 3.80 (s, 3H), 3.45 (s, 3H), 3.08 (s, 3H), 2.60-2.74 (m, IH), 2.40-2.50 (m, IH), 1.95 (s, 3H), 1.70-1.80 (m, IH), 1.40-1.50 (m, IH); m/z = 598 [M+lf.

Example 128

[373] N-(5-chloro-2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6- dihydropyridin-3-yl)-2-(3-methoxyphenyI)cyclopropane-l-sulfonamide

N-(2-(2-fluoro-4-iodophenylamino)-4-methoxy- 1 -methyl-6-oxo- 1 ,6-dihydropyridin-3-yl)-2- (3-methoxyphenyl)cyclopropane-l -sulfonamide (77 mg, 0.128 mmol) was dissolved in 2 ml CH₃CN at O⁰C, followed by the addition of N-Chlorosuccinimide (20.6 mg, 0.154 mmol). After stirring for 2 h, the mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether: EtOAc = 2:1) to obtain the desired product (50 mg, 61%). ¹K NMR (400 MHz, CDCl₃) δ 7.61 (s, IH), 7.44 (d, J = 8.4 Hz, IH), 7.20- 7.31(m, 2H), 6.79 (d, J = 5.6 Hz, IH), 6.51-6.55(m, 2H), 6.18 (t, J = 8.4 Hz, IH), 6.00 (s, IH), 3.91 (s, 3H), 3.79 (s, 3H), 3.43 (s, 3H), 2.60-2.68 (m, IH), 2.51-2.59(m, IH), 1.60-1.71 (m, IH), 1.43-1.45 (m, IH); m/z = 634 [M+l]⁺.

Example 129

[374] N-(4-fluoro-5-(2-fluoro-4-iodophenylamino)-l-methyl-lH-benzo [d]imidazol-6-yI)-2- (3-fluorophenyl)cyclopropane-l-sulfonamide

l-(2-fluoro-4-iodophenylamino)-8-fluoro-5-methyl-benzimidazo[6,5-rf] imidazole (WO2008089459 Al, example 1) was treated with LiHMDS at -78 ⁰C, followed by the addition of 2-(3-fluorophenyl)cyclopropane-l-sulfonyl chloride at O ⁰C as in step K (WO2008089459 Al, example 1) utilizing potassium trimethylsilanolate (step I) to obtain the desired product. H NMR (400 MHz, CDCl₃) δ 7.89 (s, IH), 7.57 (s, IH), 7.38-7.41(d, J = 10.4 Hz, IH), 7.19-7.25 (m, IH), 7.04-7.06 (d, J = 8.8 Hz, IH), 6.92-6.96 (t, IH), 6.62-6.64 (d, IH), 6.55-6.58 (d, J = 8.8 Hz, IH), 5.95-5.99 (t, J = 8.8 Hz, IH), 5.39 (s, IH), 4.30-4.32 (m, IH), 4.12-4.16 (m, IH), 3.86 (s, 3H), 2.62-2.66 (s, 3H); m/z = 599 [M+l]⁺.

Example 130

[375] 2-(6-chloropyridin-3-yI)-JV-(2-(2-fluoro-4-iodophenylamino)-l,5-dimethyI-6-oxo-l,6- dihydropyridin-3-yl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fiuoro-4-iodophenylamino)-l,3- dimethylpyridin-2(l/-^r)-one was reacted with thiophene-3-sulfonyl chloride to obtain the desired product. ¹K NMR (400 MHz, DMSO-D6) δ 8.95 (s, IH), 8.17 (s, IH), 7.90 (s, IH), 7.51-7.54 (d, J

= 10.4 Hz, IH), 7.38 (s, 2H), 7.28-7.30 (d, J = 8.4 Hz, IH), 7.14 (s, IH), 6.30-6.32 (t, IH), 3.24 (s, 3H), 2.91-2.93 (m, 2H), 1.82 (s, 3H), 1.42-1.45 (m, 2H); m/z = 589 [M+l]⁺.

Example 131

N-(2-(2-fluoro-4-iodophenyIamino)-4-methoxy-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)- 2-(3-fluorophenyl)cyclopropane-l-sulfonamide

[376] Step A: diethyl 2-methyl-3 -oxopentanedioate

To a solution of diethyl 3 -oxopentanedioate (2.32 g, 11.48 mmol) in 10 ml THF was added NaH (60%, 0.48 g, 1.045 mmol) and the mixture was stirred at rt for 30 min, followed by the addition of MeI (0.715 ml, 11.48 mmol). The mixture was stirred for 2 days, quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO₄,. Filtered and concentrated undere reduced pressure. The residue was purified by column chromatography on silica gel to give the desired product (1.01 g, 41%). ¹H NMR (400 MHz, CDCl₃) δ 4.18-4.24 (m, 4H), 3.36-3.75 (m, 3H), 1.25-1.40 (m, 9H).

[377] Step B: l-(2-fluoro-4-iodophenyl)-3-methylurea

To ΛζΛf-carbonyldiimidazole (30 g) in 150 ml N,N-dimethylforrnarnide was added triethylamine (26 ml), followed by the dropwise addition of 2-fluoro-4-iodoaniline (38 g) in 30 ml iV.iV-dimethylformamide at O⁰C. After complete addition, the mixture was stirred at it for 5 h, followed by the addition of 30 ml 30% methylamine in methanol dropwise at O⁰C. After stirring at rt overnight, the white precipitate was diluted with water-toluene, then filtered and driod to give the desired product as a white solid (92%). ^ι≡ NMR (400 MHz, DMSO-D6) δ 8.39 (s, IH), 7.90- 7.94 (t, J = 8.6 Hz, IH) , 7.52-7.55 (dd, J = 1.8 & 10.6 Hz, IH), 7.38-7.40 (d, J = 10.4 Hz, IH), 6.46-6.48 (d, J = 4.8 Hz, IH), 2.62 (s, 3H).

[378] Step C: 2-fluoro-4-iodo-N-((methylimino^*lmethylene)aniline

To a solution of urea (0.8 mmol), PPh₃ (420 mg, 1.6 mmol) and Et₃N (0.45 ml, 3.20 mmol) in CH₂Cl₂ (8.0 ml) was added a solution of CBr₄ (530 mg, 1.6 mmol) in CH₂Cl₂ (2.0 ml) at 0⁰C. The reaction mixture was stirred for 30 min at r.t., and concentrated to dryness. The residue was purified by flash column chromatograph on silica gel (petroleum ether:EtOAc = 10:1) to give the carbodiimide. ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.41 (m, 2H), 6.76-6.81 (t, J = 8.6 Hz, IH), 3.17 (s, 3H).

[379] Step D: ethyl 2-(2-fluoro-4-iodophenylamino^')-4-hvdroxy- 1.5-dimethyl-6-oxo- 1.6- dihvdrop yridine-3 -carboxylate

To a stirred solution of diethyl 2-methyl-3-oxopentanedioate (1.0 eq) in anhydrous THF, was added NaH (l.leq, 60%) portion- wise at O⁰C. 2-Fluoro-4-iodo-iV-((methylimino)methylene aniline

(l.leq) in THF was then added slowly with an addition funnel at room temperature and the mixture was then stirred at rt overnight. After quenching with water, the mixture was washed with

EtOAc and theaqueous layer separated and neutralized with 2 N HCl The aqueous phase was extracted with EtOAc. The combined organic layers were washed with sat.NaCl, dried over

MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the desired product. ¹H NMR (400 MHz, CDCI3) δ 11.21 (s, IH), 8.28 (s, IH), 7.48-7.51 (dd, J = 1.8 & 10.2 Hz, IH), 7.35-7.37 (d, J = 8.4 Hz, IH),

6.31-6.35 (t, J= 8.6 Hz, IH), 4.38-4.43 (m, 2H), 3.35 (s, 3H), 2.05 (s, 3H), 1.32-1.38 (m, 3H).

[380] Step E: ethyl 2-(2-fluoro-4-iodophenylaminoV4-methoxy- 1.5-dimethyl-6-oxo- 1.6- dihvdropyridine-3-carboxvlate

A mixture of the hydroxyl derivative above (6.54 mmol), Me₂SO₄ (0.37 ml, 3.93 mmol) and

K₂CO₃ (1.085 g, 7.85 mmol) in 40 ml acetone was heated to reflux for 17 h. The reqaction was quenched with water,, and extracted with EtOAc. The organic phase was dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether:EtOAc=3:l to 1:1) to give the desired product (50%). ¹H NMR (400 MHz, CDCl₃) δ 8.87 (s, IH), 7.46 (d, J = 8.4 Hz, IH), 7.33 (d, J = 8.4 Hz, IH), 6.35 (t, J = 8.4 Hz, IH), 4.31 (q, J = 7.2 Hz, 2H), 3.78 (s, 3H), 3.32 (s, 3H), 2.09 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H). [381] Step F: 2-(2-fluoro-4-iodophenylamino)-4-methoxy- 1 ,5-dimethyl-6-oxo- 1.6- dihvdropyridine-3-carboxylic acid

To the ester (1.908 mmol) in MeOH-water-THF (14 ml, 5:1:1) was added LiOHH₂O (120 mg, 2.86 mmol), and the mixture heated to reflux for 1.5 h, and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (CH₂Cl₂:Me0H=6:l) afforded the desired product (11%). ¹U NMR (400 MHz, DMSO-D6) δ 7.60 (d, J = 8.0 Hz, IH), 7.35 (d, J = 8.0 Hz, IH), 6.39 (t, J = 9.2 Hz, IH), 3.72 (s, 3H), 3.20 (s, 3H), 1.90 (s, 3H).

[382] Step G: 3-(2-fluoro-4-iodophenyl)-7-methoxy-4,6-dimethyl-lH-imidazor4,5-&1pyridine- 2.5(3H.4H)-dione

DPPA (0.1 ml, 0.46 mmol) was added to the acid (100 mg, 0.23 mmol) and triethylamine (0.14 ml, 0.93 mmol) in 5 ml N,iV-dimethylformamide at rt and stirred for 2.25 h (1.5 h turn muddy), then heated to 5O⁰C overnight. After adding EtOAc, the mixture was washed with water (x3), and the aqueous phase extracted with EtOAc. The combined organic phaseq were dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc to CH₂Cl₂MeOH=I 5:1) to give the desired product (40 mg, 40%) as a gray solid. ¹K NMR (400 MHz, CDCl₃) δ 9.24 (s, IH), 7.67-7.71 (m, 2H), 7.19 (t, J = 8.0 Hz, IH), 3.97 (s, 3H), 3.21 (s, 3H), 2.10 (s, 3H).

[383] Step H: 3-(2-fluoro-4-iodophenylVl-(2-π-fluorophenv0cyclopropylsulfonylV7-methoxy- 4.6-dimethyl-lH-imidazor4.5-61pyridine-2.5(3H.4HVdione

LiHMDS (0.1 ml, 1 M, 0.1 mmol) was added to 3-(2-fiuoro-4-iodophenyl)-7-methoxy-4,6- dimethyl-lH-imidazo[4,5-6]pyridine-2,5(3H,4H)-dione (37 mg, 0.086 mmol) in TΗF overr 20 min at -78⁰C, followed by the addition of 2-(3-fluorophenyl)cyclopropane-l-sulfonyl chloride (30 mg, 0.129 mmol) in TΗF at -78⁰C. After stirring for 4 h at rt, the mixture was quenched with sat. NH₄Cl, extracted with EtOAc, and dried ov er MgSO₄., Filtration, removal of solvent and purification of the residue by column chromatography on silica gel (petroleum ether:EtOAc=2: l)gave the desired product (17 mg, 32%). ¹H NMR (400 MHz, CDCl₃) δ 7.65-7.71 (m, 2H), 7.18 (t, J = 8.0 Hz, IH), 7.12 (t, J = 8.0 Hz, IH), 6.89-6.99 (m, 2H), 6.78-6.84 (m, IH), 4.00 (s, 3H), 3.47-3.52 (m, IH), 3.17 (s, 3H), 3.06-3.12 (m, IH), 2.13 (s, 3H), 2.07-2.12 (m, IH), 1.60-1.67 (m, IH).

[384] Step I: iV-(2-(2-fluoro-4-iodophenylamino)-4-methoxy- 1.5-dimethyl-6-oxo- 1 ,6- dihvdropyridin-3-yl)-2-(3-fluorophenyl)cvclopropane-l-sulfonamide

3-(2-fluoro-4-iodophenyl)- 1 -(2-(3-fluorophenyl)cyclopropylsulfonyl)-7-methoxy-4,6- dimethyl-lH-imidazo[4,5-b]pyridine-2,5(3H,4H)-dione (17 mg) in aq. NaOH (0.3 ml, 1 N) and dioxane (1 ml) was heated to 5O⁰C for 15 min. The mixture was quenched with sat.NH₄Cl, and the aqueous phase extracted with EtOAc. The combined organic layers were washed with sat. brine, dried over MgSO₄, filtered, and concentrated under reduced pressure. Purification of the residue via column chromatography on silica gel afforded the desired product (50%). ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.44 (m, 2H), 7.22-7.28 (m, 2H), 6.92-6.96 (m, IH), 6.74-6.76 (d, J = 8.0 Hz, IH), 6.64-6.67 (dd, J = 1.8 &11.4 Hz, IH), 6.12-6.16 (t, J = 8.6 Hz, IH), 6.04 (s, IH), 4.09-4.15 (q, IH), 3.41 (s, 3H), 2.69-2.74 (m, H), 2.53-2.58 (m, IH), 1.98 (s, 3H), 1.67-1.72 (m, IH), 1.34-1.40 (m, lH),; m/z = 602 [M+l]⁺.

Example 132

N-(6-(2-fluoro-4-iodophenylamino)-5-methyl-4-oxo-4,5-dihydrofuro[3,2-c]pyridin-7-yl)-2-(3- fluoropheny^cyclopropane-l-sulfonamide

[385] Step A: ethyl 2-(2-fluoro-4-iodophenylamino)-4-hvdroxy- 1 -methyl-6-oxo- 1 ,6- dihvdropyridine-3-carboxylate

To a stirred solution of diethyl 3-oxopentanedioate (1.0 eq) in anhydrous THF, was added NaH (l.leq, 60%) portion-wise at O⁰C. 2-Fluoro-4-iodo-7V-((methylimino)methylene aniline

(l.leq) in THF was then added slowly using an additon funnel at room temperature. The mixture was stirred at it overnight. After quenching with water, the mixture was washed with EiOAc and the aqueous layer separated and neutralized with 2 N HCl. The aqueous phase was extracted with

EtOAc and the combined organic layers washed with sat.NaCl, dried over MgSO₄, filtered, and concentratedunder reduced pressure. The residue was purified by flash column chromatography on silica gel to yield the desired product. ¹H NMR (400 MHz, CDCl₃) δ 10.96 (s, IH), 8.75 (s, IH),

7.52 (dd, J = 2.0 & 10.0 Hz, IH), 7.41 (d, J = 8.4 Hz, IH), 6.44 (t, J = 8.4 Hz, IH), 5.84 (s, IH),

4.43 (q, J = 7.2 Hz, 2H), 3.28 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H).

[386] Step B: ethyl 6-(2-fluoro-4-iodophenylaminoV5-methyl-4-oxo-4,5-dihydrofuro|^"3,2- clpyridine-7-carboxylate

To a solution of ethyl 2-(2-fluoro-4-iodophenylamino)-4-hydroxy-l-methyl-6-oxo-l,6- dihydropyridine-3-carboxylate (3.47 mmol) and K₂CO₃ (0.720 g, 5.21 mmol) in 20 ml acetone was added 2-chloroacetaldehyde (0.409 g, 5.21 mmol) at rt. The mixture was stirred at room temperature for 30 min, then quenched with IN HCl, and extracted with EtOAc. The organic phase was dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give the desired product (66%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.85 (s, IH), 7.53 (d, J = 2.4 Hz, IH), 7.49 (dd, J = 2.0 & 10.0 Hz, IH), 7.37 (d, J = 8.4 Hz, IH), 6.96 (d, J = 2.0 Hz, IH), 6.44 (t, J = 8.4 Hz, IH), 4.41 (q, J = 7.2 Hz, 2H), 3.36 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H).

[387] Step C: 6-(2-fluoro-4-iodophenylamino)-5-methyl-4-oxo-4.5-dihvdrofuro[3,2-c]pyridine- 7-carboxylic acid

Following the same procedure as step F, example 131, afforded the desired product. ¹H NMR (400 MHz, DMSO-D6) δ 7.82 (d, J = 2.0 Hz, IH), 7.65 (dd, J = 2.0 & 10.8 Hz, IH), 7.38 (d, J = 8.4 Hz, IH), 6.90 (d, J = 2.0 Hz, IH), 6.57 (t, J = 8.4 Hz, IH), 3.20 (s, 3H).

[388] Step D: 3-f2-fluoro-4-iodophenvn-4-methyl-lH-furor2.3-fflimidazor4.5-^lpyridine- 2.5(3H,4H)-dione

Following the same procedure as step G, example 131, afforded the desired product. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, IH), 7.71 (d, J = 8.8 Hz, IH), 7.69 (d, J = 10.4 Hz, IH), 7.45 (d, J = 1.6 Hz, IH), 7.23 (t, J= 8.4 Hz, IH), 7.04 (d, J = 1.6 Hz, IH), 3.27 (s, 3H). [389] Step E: 3-(2-fluoro-4-iodophenyl)-l-(2-(3-fluorophenvπcyclopropylsulfonylV4-methyl- lH-furor2.3-c/limidazor4.5-61pyridine-2.5f3H.4H)-dione

Folowing the same procedure as step Η, example 131, afforded the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.68-7.74 (m, 2H), 7.54 (d, J = 2.4 Hz, IH), 7.17-7.28 (m, 2H), 7.03 (d, J = 2.0 Hz, IH), 6.93-6.98 (m, IH), 6.89 (d, J = 7.6 Hz, IH), 6.80 (d, J = 7.6 Hz, IH), 3.35-3.39 (m, IH), 3.23 (s, 3H), 3.10-3.23 (m, IH), 2.10-2.19 (m, IH), 1.65-1.69 (m, IH).

[390] Step F: N-(6-(2-fluoro-4-iodophenylamino)-5-methyl-4-oxo-4,5-dihvdrofuro|^"3,2- c1pyridin-7-yl^')-2-(3-fluorophenyl)cvclopropane- 1 -sulfonamide

Following the same procedure as step I, example 131, afforded the desired product.. ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.47 (m, 2H), 7.17-7.22 (m, IH), 6.98-6.99 (d, J = 3Hz, IH), 6.90-6.93 (m, IH), 6.64-6.66 (d, J = 3.6 Hz, IH), 6.55-6.66 (m, IH), 6.12-6.17 (m, 2H), 2.75-2.79 (m, 2H), 2.54-2.59 (m, 2H), 1.73-1.78 (m, 2H), 1.26-1.41 (m, 2H); m/z = 598 [M+l]⁺.

Example 133

[391] iV-(2-(4-bromo-2-fluorophenyIamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin- 3-yl)butane-l-sulfonamide

According to the general procedure A, 5-amino-6-(4-bromo-2-fluorophenylamino)-4- methoxy-l-methylpyridin-2(lH)-one was reacted with butane- 1-sulfonyl chloride to obtain the desired compound. Yield = 76.6%. ¹H NMR (400 MHz, CDCl₃) δ = 7.76 (brs, IH), 7.297-7.266 (dd, IH, J = 2.0 & 2.4 Hz), 7.123-7.102 (d, IH, J = 8.4 Hz), 6.356-6.313 (t, IH, J = 8.6 Hz), 5.909-5.875 (brs, 2H), 3.875 (s, 3H), 3.316 (s, IH), 3.058-3.018 (t, 3H, J = 8.6 Hz), 1.882-1.805 (m, 2H), 1.474-1.415 (m, 2H), 0.997-0.965 (t, 3H, J = 6.8 Hz); m/z = 463.33 [M+l]⁺.

Example 134

[392] 7V-(2-(2-chIoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)butane-l-sulfonamide

According to the general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-4-methoxy- l-methylpyridin-2(lH)-one was reacted with butane- 1-sulfonyl chloride to obtain th*; desired compound. Yield = 35.5%. ¹H NMR (400 MHz, CDCl₃) δ = 7.948 (brs, IH), 7.709-7.704 (d, IH, J = 2.0 Hz), 7.390-7.394 (dd, IH, J = 2 & 2.0 Hz), 6.118-6.097 (d, IH, J = 8.4 Hz), 5.926 (s, IH), 5.842 (brs, IH), 3.880 (s, 3H), 3.296 (s, IH), 3.054-3.015 (t, 3H, J = 7.8 Hz), 1.866-1.827 (m, 2H), 1.474-1.418 (m, 2H), 1.274-1.240 (t, 3H, J = 7.2 Hz); m/z = 525.79 [M+l]⁺.

Example 135

[393] N-(2-(2-chloro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)thiophene-3-sulfonamide

According to the general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-4-methoxy- l-methylpyridin-2(lH)-one was reacted with thiophene-3-sulfonyl chloride to obtain the desired compound. Yield = 34.1%. ¹H NMR (400 MHz, CDCl₃) δ = 7.920-7.879 (dd, 2H, J = 6.0 & 6.0 Hz), 7.738-7.733 (d, IH, J = 2.0 Hz), 7.409-7.379 (m, 2H), 7.285-7.275 (m, IH), 6.129-6.108 (d, IH, J= 4.4 Hz), 5.684 (s, IH), 3.375 (s, 3H), 3.331 (s, 3H); m/z = 551.92 [M+l]⁺.

Example 136

[394] iV-(2-(2-chloro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)benzenesulfonamide

According to the general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-4-methoxy- l-methylpyridin-2(lH)-one was reacted with benzenesulfonyl chloride to obtain the desired compound. Yield = 25%. ¹H NMR (400 MHz, CDCl₃) δ = 7.945 (brs, IH), 7.768-7.732 (m, 3H), 7.620-7.583 (t, IH, J = 7.4 Hz), 7.501-7.462 (t, 2H, J = 7.8 Hz), 7.403-7.377 (t, IH, J = 8.6 Hz), 6.130-6.109 (d, IH, J = 8.4 Hz), 5.933 (brs, IH), 5.609 (s, IH), 3.332 (s, 3H), 3.187 (s, 3H); m/z = 545.78 [M+l]⁺.

Example 137

[395] N-(2-(2-chloro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)-2,2,2-trifluoroethanesulfonamide

According to the general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-4-methoxy- l-methylpyridin-2(lH)-one was reacted with 2,2,2-trifluoroethanesulfonyl chloride to obtain the desired compound. Yield = 48.7%. ¹H NMR (400 MHz, CDCl₃) δ = 7.727-7.720 (dd, IH, J = 1.2 & 1.2 Hz), 7.484 (s, IH), 7.411-7.386 (dd, IH, J = 1.2 & 1.2 Hz), 6.142-6.120 (d, IH, J = 8.8 Hz), 5.945 (s, IH), 3.898-3.848 (m, 5 H), 3.299 (s, 3H); m/z = 551.94[M+1]⁺.

Example 138

[396] N-(2-(2-chloro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)cyclopropanesulfonamide

According to the general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-4-methoxy- l-methylpyridin-2(lH)-one was reacted with cyclopropanesulfonyl chloride to obtain the desired compound. Yield = 19.72%. ¹H NMR (400 MHz, CDCl₃) δ = 7.868 (brs, IH), 7.714-7.709 (d, IH, J = 2.0 Hz), 7.398-7.372 (dd, IH, J = 2 & 2.0 Hz), 6.120-6.099 (d, IH, J = 8.4 Hz), 5.928 (s, IH), 3.890 (s, 3H), 3.22 (s, IH), 2.467-2.427 (m, IH), 1.166-1.143 (m, 2H), 0.984-0.957 (m, 2H); m/z = 510.75 [M+ 1]⁺.

Example 139

[397] N-(2-(2-chloro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)-4-fluorobenzenesulfonamide

According to the general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-4-methoxy- l-methylpyridin-2(lH)-one was reacted with 4-fluorobenzene-l-sulfonyl chloride to obtain the desired compound. Yield = 27.3%. ¹H NMR (400 MHz, CDCl₃) δ = 7.885 (s, IH), 7.798-7.764 (m, 2H), 7.734-7.729 (d, IH, J = 2.0 Hz), 7.404-7.378 (dd, IH, J = 2 & 2.0 Hz), 7.197-7.136 (m, 2H), 6.128-6.107 (d, 2H, J = 3.6 Hz), 5.648 (s, IH), 3.319 (s, 3H), 3.280 (s, 3H); m/z = 563.96 [M+l]⁺.

Example 140

[398] l-chloro-iV-(2-(2-chloro-4-iodophenylainino)-4-methoxy-l-methyl-6-oxo-l,6- dihydropyridin-3-yl)methanesulfonamide

According to the general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-4-methoxy- l-methylpyridin-2(lH)-one was reacted with chloromethanesulfonyl chloride to obtain the desired compound. Yield = 29.8%. ¹H NMR (400 MHz, CDCl₃) δ = 7.710 -7.705 (d, IH, J = 2.0 Hz),

7.477 (s, IH,), 7.406-7.380 (dd, IH, J = 1.6 & 2.0 Hz), 6.154-6.133 (t, IH, J = 8.4 Hz), 5.936 (s, IH), 4.529 (s, 2H), 3.886 (s, 3H), 3.278 (s, 3H); m/z = 517.91 [M+l]⁺.

Example 141

[399] iV-(2-(2-chloro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridiii-3- yl)methanesulfonamide

According to the general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-4-methoxy- l-methylpyridin-2(lH)-one was reacted with methanesulfonyl chloride to obtain the desired compound. Yield = 30%. ¹H NMR (400 MHz, CDCl₃) δ = 7.849 (brs, IH), 7.713-7.708 (d, IH, J = 2.0 Hz), 7.399-7.373 (dd, IH₅ J = 2 & 2.0 Hz), 6.135-6.114 (d, IH, J= 8.4 Hz), 5.938 (brs, 2H),

3.895 (s, 3H), 3.297 (s, 3H), 2.973 (s, 3H); m/z = 483.95 [M+l]⁺.

Example 142

[400] iV-(2-(2-chloro-4-iodophenyIamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)ethanesulfonamide

According to the general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-4-methoxy- l-methylpyridin-2(lH)-one was reacted with butane- 1-sulfonyl chloride to obtain the desired compound. Yield = 35.5%. ¹H NMR (400 MHz, CDCl₃) δ = 7.931 (brs, IH), 7.704-7.699 (d, IH, J = 2.0 Hz), 7.389-7.363 (dd, IH, J = 2 & 2.0 Hz), 6.122-6.100 (d, IH, J = 8.8 Hz), 5.923 (s, IH), 3.875 (s, 3H), 3.286 (s, 3H), 3.098-3.043 (q, 2H, J = 7.2 Hz), 1.437-1.399 (t, 3H, J = 7.6 Hz); m/z = 526.00 [M+l]⁺.

Example 143

[401] N-(2-(2-chloro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)thiophene-2-sulfonamide

According to the general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-4-methoxy- l-methylpyridin-2(lH)-one was reacted with thiophene-2-sulfonyl chloride to obtain the desired compound. Yield = 17.89%. ¹H NMR (400 MHz, CDCl₃) δ = 7.868 (brs, IH), 7.738-7.733 (d, IH, J = 2.0 Hz), 7.652-7.636 (dd, 1H, J= 1.2 & 1.6 Hz), 7.521-7.508 (dd, IH₅ J = 2 & 1.6 Hz), 7.409- 7.382 (dd, IH, J = 2 & 2.0 Hz), 7.095-7.073 (t, IH, J = 4 Hz), 6.135-6.114 (t, IH, J - 8.4 Hz), 5.687 (s, IH), 3.364-3.360 (d, 6 H, J= 1.6 Hz); m/z = 551.92 [M+l]⁺.

Example 144

[402] N-(2-(4-bromo-2-fluorophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin- 3-yl)thiophene-3-suIfonamide

According to the general procedure A, 5-amino-6-(4-bromo-2-fluorophenylamino)-4- methoxy-l-methylpyridin-2(lH)-one was reacted with thiophene-3-sulfonyl chloride to obtain the desired compound. Yield = 34.1%. ¹K NMR (400 MHz, CDCl₃) δ = 7.887-7.876 (d, IH, J = 4.4 Hz), 7.680 (brs, IH), 7.413-7.392 (d, IH, J = 8.4 Hz), 7.329-7.298 (m, IH), 7.149-7.119 (m, 2H), 6.382-6.338 (t, IH, J = 8.8 Hz), 5.670 (s, IH), 3.378-3.346 (d, 6 H, J = 12.8 Hz); m/z = 489.35 [M+ 1]⁺.

Example 145

[403] N-(2-(4-bromo-2-fluorophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin- 3-yI)benzenesulfonamide

According to the general procedure A, 5-amino-6-(4-bromo-2-fluorophenylamino)-4- methoxy-l-methylpyridin-2(lH)-one was reacted with benzenesulfonyl chloride to obtain the desired compound. Yield = 25%. ¹U NMR (400 MHz, CDCl₃) δ = 7.768-7.741 (t, 3H, J = 5.4 Hz), 7.621-7.580 (t, IH, J = 2 & 2.4 Hz), 7.502-7.463 (t, 2H, J = 7.8 Hz), 7.327-7.296 (dd, IH, J = 8.6 Hz), 7.145-7.115 (d, IH, J = 12.0 Hz), 6.381-6.337 (t, IH, J = 8.8 Hz), 5.590 (s, IH), 3.358 (s, 3H), 3.162 (s, 3H); m/z = 483.32 [M+l]⁺.

Example 146

[404] N-(2-(4-bromo-2-fluorophenyIamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin- 3-yl)-2,2,2-trifluoroethanesulfonamide

According to the general procedure A, 5-amino-6-(4-bromo-2-fluorophenylamino)-4- methoxy-l-methylpyridin-2(lH)-one was reacted with 2,2,2-trifluoroethanesulfonyl chloride to obtain the desired compound. Yield = 48.7%. ¹H NMR (400 MHz, CDCl₃) δ = 7.312-7.281 (dd, IH, J = 2 & 2.0 Hz), 7.146-7.125 (d, IH, J = 8.4 Hz), 6.397-6.354 (t, IH, J = 8.6 Hz), 5.922 (s,

IH), 3.733-3.661 (t, 2H, J= 14.4 Hz), 3.497 (s, 3H), 3.308 (s, 3H); m/z = 489.25 [M+l]⁺.

Example 147

[405] iV-(2-(4-bromo-2-fluorophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin- 3-yl)cyclopropanesulfonamide

According to the general procedure A, 5-amino-6-(4-bromo-2-fluorophenylamino)-4- methoxy-l-methylpyridin-2(lH)-one was reacted with cyclopropanesulfonyl chloride to obtain the desired compound. Yield = 19.72%. ¹H NMR (400 MHz, CDCl₃) δ = 7.643(brs, IH), 7.291-7.261 (d, IH, J = 12.0 Hz), 7.126-7.096 (d, IH, J = 12.0 Hz), 6.356-6.313 (t, IH, J = 8.6 Hz), 5.910 (s, IH), 3.875 (s, 3H), 3.329 (s, 3H), 2.437-2.410 (m, IH), 1.155-1.116 (m, 2H), 0.997-0.929 (m, 2H); m/z = 447.29 [M+l]⁺.

Example 148

[406] N-(2-(4-bromo-2-fluorophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin- 3-yl)-4-fluorobenzenesulfonamide

According to the general procedure A, 5-amino-6-(4-bromo-2-fluorophenylamino)-4- methoxy-l-methylpyridin-2(lH)-one was reacted with 4-fluorobenzene-l-sulfonyl chloride to obtain the desired compound. Yield = 27.3%. ¹H NMR (400 MHz, CDCl₃) δ = 7.798-7.760 (m, 2H), 7.655 (s, IH), 7.328-7.297 (d, IH₅ J = 12.4 Hz), 7.184-7.118 (m, 3H), 6.381-6.337 (t, IH, J =

8.4 Hz), 5.623 (s. IH), 3.350 (s, 3H), 3.267 (s, 3H); m/z = 501.31 [M+l]⁺.

Example 149

[407] N-(2-(4-bromo-2-fluorophenyIamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin- 3-yl)ethanesulfonamide

According to the general procedure A, 5-amino-6-(4-bromo-2-fluorophenylamino)-4- methoxy-l-methylpyridin-2(lH)-one was reacted with ethanesulfonyl chloride to obtain the desired compound. Yield = 48.7%. ¹H NMR (400 MHz, CDCl₃) δ = 7.744 (brs, IH), 7.297-7.267 (dd, IH, J = 2 & 2.0 Hz), 7.127-7.098 (d, IH₅ J = 11.6 Hz), 6.360-6.317 (t, IH, J = 8.8 Hz), 5.905 (s, IH), 3.875 (s, 3H), 3.310 (s, 3H), 3.104-3.048 (q, 2H, J = 7.6 Hz), 1.440-1.402 (t, 3H, J = 7.6 Hz); m/z = 435.29 [M+ 1]⁺.

Example 150

[408] N-(2-(2-fluoro-4-iodophenyIamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)cyclobutanesulfonamide

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy- l-methylpyridin-2(lH)-one was reacted with cyclobutanesulfonyl chloride to obtain the desired compound. Yield = 36.6%. ¹H NMR (400 MHz, CDCl₃) δ = 7.852 (brs, IH), 7.462-7.432 (d, IH, J = 16 Hz), 7.296-7.263 (d, IH, J = 13.2 Hz), 6.204-6.162 (t, IH, J = 8.4 Hz), 5.890 (s, IH), 3.875 (s, 3H), 3.330 (s, IH), 2.577-2.523 (m, 2H), 2.299-2.232 (m, 2H), 2.074-2.011 (m, 2H); m/z = 508.32 [M+l]⁺.

Example 151

[409] N-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)ethanesulfonamide

According to the general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy- l-methylpyridin-2(lH)-one was reacted with ethanesulfonyl chloride to obtain the desired compound. Yield = 26.6%. ¹H NMR (400 MHz, CDCl₃) δ = 7.767 (brs, IH), 7.458-7.428 (d, IH, J = 12.0 Hz), 6.221-6.179 (d, IH, J = 8.4 Hz), 5.930 (s, IH), 3.878 (s, 3H), 3.332 (s, IH), 3.104- 3.048 (q, 2H, J = 7.6 Hz), 1.443-1.409 (t, 3H, J = 7.6 Hz); m/z = 482.28 [M+l]⁺.

Example 152

[410] 3-chloro-7V-(2-(2-chloro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6- dihydropyridin-3-yl)propane-l-sulfonamide

According to the general procedure A, 5-amino-6-(2-chloro-4-iodophenylamino)-4-methoxy- l-methylpyridin-2(lH)-one was reacted with 3-chloropropane-l-sulfonyl chloride to obtain the desired compound. ¹H NMR (400 MHz, CDCl₃): Yield = 29.8%. δ = 7.868 (brs, IH), 7.720-7.716 (d, IH, J = 2.0 Hz), 7.402-7.376 (dd, IH, J = 2 & 1.6 Hz), 6.126-6.105 (d, IH, J = 4.4 Hz), 5.933 (s, IH), 5620 (brs, IH), 3.903 (s, 3H), 3.692-3.662 (t, 2H, J = 6 Hz), 3.307 (s, 3H), 3.263-3.226 (t, 2H, J = 7.6 Hz), 2.372-2.304 (m, 2H); m/z = 545.94 [M+lf.

Example 153

[411] N-(2-(4-bromo-2-fluorophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin- 3-yl)-3-chloropropane-l-sulfonamide

According to the general procedure A, 5-amino-6-(4-bromo-2-fluorophenylamino)-4- methoxy-l-methylpyridin-2(lH)-one was reacted with 3-chloropropane-l-sulfonyl chloride to obtain the desired compound. ¹H NMR (400 MHz, CDCl₃): Yield = 29.8%. δ = 7.666 (brs, IH), 7.311-7.283 (dd, IH, J = 2 & 1.2 Hz), 7.140-7.116 (dd, IH₅ J = 3.2 & 3.6 Hz), 6.369-6.325 (t, IH, J = 8.8 Hz), 5.918 (brs, 2H), 3.900 (s, 3H), 3.692-3.662 (t, 2H, J = 6 Hz), 3.337 (s, 3H), 3.268- 3.230 (t, 2H, J = 7.6 Hz), 2.371-2.303 (m, 2H); m/z = 483.75 [M+l]⁺.

Example 154

[412] iV-(2-(4-bromo-2-fluorophenylamino)-4-methoxy- l-methyl-6-oxo- 1 ,6-dihydropyridin- 3-yl)-l-chloromethanesulfonamide

According to the general procedure A, 5-amino-6-(4-bromo-2-fluorophenylamino)-4- methoxy-l-methylpyridin-2(lH)-one was reacted with chloromethanesulfonyl chloride to obtain the desired compound. Yield = 10.1%. ¹H NMR (400 MHz, CDCl₃) δ = 7.337-7.304 (d, IH, J = 2.4 Hz), 7.173-7.164 (dd, IH, J = 1.6 & 2.0 Hz), 6.455-6.411 (t, IH, J = 8.8 Hz), 5.925 (s, IH),

4.439 (s, 2H), 3.869 (s, 3H), 3.371 (s, 3H); m/z = 517.91 [M+l]⁺.

Example 155

N-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-2- (hydroxymethyl)cyclopropane-l-sulfonamide

[413] Step A: sodium but-3-ene-l -sulfonate

4-bromobut-l-ene and sodium sulfite were dissolved in water and heated at 7O⁰C overnight. After cooling to rt, the solvent was removed under reduced pressure to afford the crude product which was used in the next step without further purification. Yield=100%.

[414] Step B: but-3-ene-l-sulfonyl chloride

Sodium 3-butenesulfonate (8.3 g) and phosphorus oxychloride (16 ml) were placed in a 100 ml flask and heated at 115⁰C for 1.5 hours with vigorous stirring. The gray mass was then poured into 100 ml of ice water and allowed to stand for 20 minutes so as to hydrolyze the unreacted phosphorus oxychloride. The two layers were separated and the aqueous layer was extracted with CH₂Cl₂. The organic layer was dried over sodium sulfate and concentrated in vacuum to afford the crude product as brown oil. Yield= 33 %. ¹H NMR (400 MHz, CDCl₃) δ = 5.860-5.792 (m, IH), 5.303-5.194 (m, 2H), 3.762-3.737 (t, 2H, J = 5.6 Hz), 2.826-2.763 (m, 2H).

[415] Step C: ethyl but-3-ene-l -sulfonate

TEtOAc (0.65 g, 6.47 mmol) was added to a stirred solution of but-3-ene-l -sulfonyl chloride (1 g, 6.47 mmol) in ethanol (30 ml). The solution was stirred for 2 hours at room temperature. The mixture was washed with water (10 ml) and the aqueous layer was extracted with CH₂Cl₂. The combined organic layers were dried over sodium sulfate and concentrated in vacuum to afford crude product which was purified by silica gel column chromatography (petroleum ether/EtOAc=20/l) to afford the title product. Yield= 37.7%. ¹H NMR (400 MHz, CDCl₃) δ = 5.839-5.797 (m, IH), 5.178-5.111 (m, IH), 4.332-4.278 (m, IH), 3.191-3.151 (m, 2H), 2.635- 2.576 (m, 2H), 1.435-1.374 (m, 3H).

[416] Step D: ethyl 2-(oxiran-2-yl^*)ethanesulfonate

To a solution of ethyl but-3-ene-l -sulfonate (0.4 g, 2.43 mmol) in CH₂Cl₂ was added m- CPBA (0.72g, 2.92 mmol) at room temperature. The mixture was stirred at rt for 72 hours. The excess peracid was destroyed by the addition of 10% Na₂S₂O₃. The organic phase was separated, washed with 5% NaHCO₃ water, and dried over Na₂SO₄. The solvent was removed in vacuum to give a residue that was purified by flash chromatography (petroleum ether/EtOAc=2/l) to afford the title compound. Yield=80%. ¹H NMR (400 MHz, CDCl₃) δ = 4.350-4.296 (m, 2H), 3.279- 3.232 (m, IH), 3.116-3.083 (m, IH), 2.857-2.836 (t, IH, J = 4.4 Hz), 2.589-2.572 (m, IH), 2.319- 2.254 (m, IH), 1.959-1.905 (m, IH), 1.453-1.406 (m, 3H).

[417] Step E: ethyl 2-(hvdroxymethyl)c vclopropane- 1 -sulfonate

To a solution of ethyl 2-(oxiran-2-yl)ethanesulfonate (0.32g, 1.7 mmol) in dry THF (22 ml) was added LiHMDS (4.1 ml, 1.06 M in THF) at -30⁰C under a nitrogen atmosphere. After 3 h, the reaction mixture was allowed to warm to room temperature and then quenched with aqueous NH₄Cl. The reaction mixture was extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated in vacuum to obtain a residue that was submitted to flash chromatography (EtOAc/petroleum ether=l/l) to afford the title compound. Yield=65.6%. ¹H NMR (400 MHz, CDCl₃) δ = 4.366-4.309 (m, 2H), 3.839-3.798 (m, IH), 3.586-3.538 (m, IH), 2.501-2.048 (m, IH), 1.955-1.901 (m, IH), 1.445-1.403 (m, 3H), 1.181-1.129 (m, IH).

[418] Step F: Q-fethoxysulfonvDcvclopropyDmethyl pivalate

To a solution of ethyl 2-(hydroxymethyl)cyclopropane-l -sulfonate (0.15g, 0.772 mmol) with TEtOAc (0.1 g, 0.1 mmol) and DMAP (0.01 g, 0.07 mmol) in 5 ml CH₂Cl₂ at 0⁰C was added sulfonyl chloride (0.11 g, 0.1 mmol). The resulting mixture of yellow color solution was stirred overnight at room temperature. The reaction mixture was quenched with NaHCO₃, then partitioned between CH₂Cl₂ and saturated NaHCO₃ and brine. The organic layer was dried over Na₂SO₄ and concentrated in vacuum to obtain the crude product which was purified by silica gel column chromatography (from petroleum ether/EtOAc=30/l to EtOAc 100%) to afford the title compound. Yield = 61%. ¹H NMR (400 MHz, CDCl₃) δ = 4.348-4.298 (q, 2H, J = 7.2 Hz), 4.216-4.113 (q, IH, J = 6.4 Hz), 3.960-3.912 (q, IH, J = 7.6 Hz), 2.516-2.471 (m, IH), 2.007-1.973 (m, IH), 1.516-1.465 (m, IH), 1.435-1.229 (m, 3H), 1.227-1.192 (m, 10 H), 1.164-1.112 (m, IH).

[419] Step G: ^-(chlorosulfonylicyclopropyDmethyl pivalate

To a solution of (2-(ethoxysulfonyl)cyclopropyl)methyl pivalate in acetone was added Bu₄NI.

The mixture was stirred for 2 days at reflux. After cooling, the solvent was removed in vacuum to obtain the crude product which was used in the next step without further purification. Sulfurous dichloride was added to a solution of PPh₃ in CH₂Cl₂ at 0⁰C. After stirring for 15 min, the salt from above in CH₂Cl₂ (5 ml) was added to the reaction mixture. The resulting mixture was stirred for 6 hours at room temperature. The solvent was removed under reduced pressure and the residue was purified by silica gel (EtOAc/petroleum ether=l/30) to obtain the title compound. Yield=44.8%. ¹H NMR (400 MHz, CDCl₃) δ = 4.292-4.250 (q, IH, J = 4.8 Hz), 3.968-3.919 (q, IH, J = 7.6 Hz), 3.331-3.288 (m, IH), 2.314-2.263 (m, IH), 1.840-1.787 (m, IH), 1.427-1.366 (m, IH), 1.227-1.192 (m, 10 H).

[420] Step H: (2-(N-(2-(2-fluoro-4-iodophenylaminoV4-methoxy- 1 -methyl-6-oxo- 1.6- dihvdropyridin-S-vDsulfamovDcvclopropyDmethyl pivalate

According to the general procedure A, 5-amino-6-(4-iodo-2-fluorophenylamino)-4-methoxy- l-methylpyridin-2(lH)-one was reacted with (2-(chlorosulfonyl)cyclopropyl) methyl pivalate to obtain the desired compound.

Step I: N-( 2-(2-fluoro-4-iodophenylamino)-4-methoxy- 1 -methyl-6-oxo- 1.6-dihvdropyridin-3-yl')- 2-flivdroxymethvDc vclopropane- 1 -sulfonamide

(2-(N-(2-(2-fluoro-4-iodophenylamino)-4-methoxy- 1 -methyl-6-oxo- 1 ,6-dihydropyridin-3- yl)sulfamoyl)cyclopropyl)methyl pivalate was hydrolyzed using LiOH as previously described.. The solvent was removed under reduced pressure and the residue was purified over silica gel chromatography (eluent:CH₂Cl₂:CH₃OH = 15:1) to obtain the desired product. Yield = 2.9%. ¹H NMR (400 MHz, CDCl₃) δ = 7.508-7.477 (dd, IH, J = 1.6 & 2.0 Hz); 7.382-7.361 (d, IH, J = 8.4 Hz); 6.388-6.355 (t, IH, J = 8.8 Hz); 5.956 (s, IH); 3.917 (s, 3H); 3.577-3.536 (dd, IH, J = 4.8 & 4.8 Hz); 3.432-3.389 (dd, IH, J = 5.6 & 6.0); 3.336 (s, 3H);2.481-2.448 (dd, IH, J = 4 &4.8 Hz); 1.627- 1.616 (br, IH); 1.141-1.093 (m, IH); 1.003-0.966 (m, IH); m/z = 524.32 [M+l]⁺.

Example 156

[421] N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-2-(2,4- difluorophenyl)cyclopropane-l-sulfonamide

According to general procedure A, 5,6-difluoro-iV¹-(2-iluoro-4-iodophenyl)-3- methoxybenzene-l,2-diamine was reacted with 2-(2,4-difluorophenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.38 (dd, J = 2.0 & 10.4 Hz, IH), 7.27 (d, J = 8.0 Hz, IH), 6.75-6.82 (m, 3H), 6.43-6.48 (m, IH), 6.26 (dd, J = 6.4 & 7.6 Hz, IH), 6.15 (s, IH), 3.42 (s, 3H), 2.80-2.83 (m, IH), 2.52-2.55 (m, IH), 1.66-1.71 (m, IH), 1.39- 1.44 (m, IH); m/z = 611 [M+l]⁺.

Example 157

(5)-l-(2,3-dihydroxypropyl)-Λ'-(2-(2-fluoro-4-iodophenyIamino)-4-methoxy-l-methyl-6-oxo- l,6-dibydropyridin-3-yl)cyclopropane-l-sulfonamide

[422] Step A: (iSVisopropyl 1 -f 2.3-dihvdiOxypropyl)cyclopropane- 1 -sulfonate

To a solution of (-S)-isopropyl l-(3-(benzyloxy)-2-hydroxypropyl)cyclopropane-l -sulfonate (37.9 g, 115 mmol) in /-PrOH (250 ml) was added 10% Pd/C (3.8 g). The mixture was stirred under H₂ (0.5 MPa) overnight. After filtration through a short plug of Celite, the filtrate was evaporated to afford the diol as a clear, colorless oil (24.4 g, 89%). ¹H NMR (400M Hz, CDCl₃) δ 4.98 (sept, J = 6.4 Hz, IH), 4.11-4.14 (m, IH), 3.66 (dd, J = 10.8 Hz&4.0 Hz, IH), 3.49 (dd, J = 10.8 Hz&6.0 Hz, IH), 1.90-1.94 (m, 2H), 1.49-1.51 (m, 2H), 1.44 (d, J = 6.4 Hz, 6H), 1.09-1.12 (m, IH), 0.93-0.96 (m, IH). [423] Step B: (.SVisopropyl 1 -((2-oxo- 1 ,3-dioxolan-4-yl)methyl)cyclopropane- 1 -sulfonate

To a solution of (5)-isopropyl l-(2,3-dihydroxypropyl)cyclopropane-l -sulfonate (500 mg, 2.1 mmol) in CH₂Cl₂ (Io ml) was added N.ΛP-Carbonyldiimidazole (374 mg, 2.31 mmol) in small portions over 9 min at O⁰C and stirred at this temperature for Ih. Additional iV.iV- Carbonyldiimidazole (170 mg, 1.05 mmol) was added in small portions over 9 min and stirring continued while monitoring completion of reaction by TLC (UV). The reaction was diluted with EtOAc (40 ml) and was placed in a separatory funnel. The crude mixture was washed with water and brine. After separation, the organic layer was dried over Na₂SO₄ and concentrated. The crude mixture was then purified by flash column chromatography (EtO Ac/petroleum ether = 1/2) to yield the carbonate as a clear, colorless oil in 81% yield. ¹H NMR (400M Hz, CDCl₃) δ 5.17-5.21 (m, IH), 4.96 (sept, J = 6.4 Hz, IH), 4.65 (dd, J = 8.8 Hz&8.0 Hz, IH), 4.14 (dd, J = 8.8 Hz&7.2 Hz, IH), 2.54 (dd, J = 16.0 Hz&5.2 Hz, IH), 1.94 (dd, J = 15.6 Hz&8.0 Hz, IH), 1.52- 1.54 (m, 2H), 1.43 (d, J= 6.4 Hz, 6H), 1.21-1.24 (m, IH), 0.94-0.98 (m, IH).

[424] Step C: sodium (S)- 1 -((2-oxo- 1.3-dioxolan-4- vDmethvDcyclopropane- 1 -sulfonate

A mixture of («S)-isopropyl- 1 -((2-oxo- 1 ,3-dioxolan-4-yl)methyl)cyclopropane- 1 -sulfonate (930 mg, 3.52 mmol) and NaI (670 mg, 4.47 mmol) in acetone (35 ml) was refluxed for 4 days. After concentration in vacuum, 1.0 g of a yellow solid was obtained (80% purity, contains 20% NaI) and used directly in the next step without further purification. ¹H NMR (400M Hz, DMSO- D6) δ 5.22 (m, IH), 4.57 (dd, J = 8.4 Hz&8.4 Hz, IH), 4.29 (dd, J = 8.4 Hz&7.2 Hz, IH), 2.07 (dd, J = 14.4 Hz&7.6 Hz, IH), 1.90 (dd, J = 14.4 Hz&5.6 Hz, IH), 0.86-0.88 (m, 2H), 0.48-0.51 (m, 2H).

[425] Step D: (S)- 1 -((2-oxo- 1 J-dioxolan^-vDmethvDcvclopropane- 1 -sulfonyl chloride

The yellow solid from Step C, was dissolved in 5 ml thionyl chloride and heated to reflux for

1 h. The volatiles were evaporated under reduced pressure and water was slowly added. The residue was extracted with EtOAc, dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified over silica gel chromatography (EtOAc/petroleum ether = 1/1) to obtain the title product (669 mg, 79% for two steps). ¹H NMR (400M Hz, CDCl₃) δ 5.24-5.30 (m, IH), 4.69 (dd, J = 8.4 Hz&8.4 Hz, IH), 4.15 (dd, J = 8.8 Hz&7.6 Hz, IH), 2.88 (dd, J = 16.0 Hz&2.8 Hz, IH), 2.07 (dd, J= 16.0 Hz&8.8 Hz, IH), 1.94-2.00 (m, IH), 1.79-1.85 (m, IH), 1.60- 1.67 (m, IH), 1.23-1.29 (m, IH).

Step E: (5VN-(2-(2-fluoro-4-iodophenylamino)-4-methoxy- 1 -methyl-6-oxo- 1 ,6-dihydrop yridin-3- vD- 1 -((2-oxo- 1.3-dioxolan-4-yl)methyl)cvcloρropane- 1 -sulfonamide

According to general procedure A, 5-ammo-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(lH)-one was reacted with (5)-l-((2-oxo-l,3-dioxolan-4-yl)methyl)cyclopropane- 1-sulfonyl chloride to obtain the desired product which was used for the next step directly.

Step F: CSV 1 -(2.3-dihvdroxypropyl)-N-(2-(2-fluoro-4-iodophenylaminoV4-methoxy- 1 -methyl-6- oxo- 1 ,6-dihvdropyridin-3-yl)cvclopropane- 1 -sulfonamide

A solution of (5)-iV-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6- dihydropyridin-3-yl)- 1 -((2-oxo- 1 ,3-dioxolan-4-yl)methyl)cyclopropane- 1 -sulfonamide and LiOH (2 eq.) in MeOΗ/Η₂O (5/1) was stirred at it overnight. The mixture was concentrated under reduced pressure. Purification of the residue via column chromatography (silica gel, EtOAc) gave the title compound. Yield = 22.3%. ¹H NMR (400 MHz, CDCl₃) δ = 7.552 (br, IH); 7.432-7.402 (dd, IH, J = 1.6 & 2.0 Hz); 7.285 (br, IH); 6.190-6.174 (t, IH, 8.4 Hz); 5.903 (s, IH); 3.993 (br, IH); 3.858 (s, 3H); 3.569-3.561 (d, IH, J = 3.2 Hz); 3.459-3.443 (m, IH); 3.335 (s, 3H); 2.395- 2.302 (m, 2H); 1.678-1.640 (d, 2H, J = 15.2 Hz); 1.377 (br, IH); 1.300 (br, IH); m/z = 568.37 [M+l]⁺.

Example 158

[426] N-(2-(4-bromo-2-fluorophenylamino)-4-methoxy-l-methy--6-oxo-l,6-dihydropyridin- 3-yl)-2-(hydroxymethyl)cyclopropane-l-sulfonamide

According to general procedure A, step H & I from example 155, 5-amino-6-(4-bromo-2- fluorophenylamino)-4-methoxy-l-methylpyridin-2(lH)-one was reacted with (2-

(chlorosulfonyl)cyclopropyl) methyl pivalate then hydrolyszed by LiOH. The solvent was removed under reduced pressure and the residue was purified over silica gel chromatography

(eluent:CΗ₂Cl₂:CΗ₃OΗ = 15:1) to obtain the desire product. ¹H NMR (400 MHz, CDCl₃) δ =

7.337-7.305 (dd, IH, J = 2.0 & 2.0 Hz); 7. 175-7.150(dd, IH, J = 1.6 & 1.2 Hz); 6.438-6.394 (t,

IH, J = 8.8 Hz); 5.945 (s, IH); 3.883 (s, 3H); 3.574-3.532 (dd, IH, J = 5.2 & 5.2 Hz); 3.362-3.336

(dd, IH, J = 4.4 & 6.4); 3.293 (s, 3H);2.375-2.330 (m, IH); 1.574-1.527 (br, IH); 1.077-1.042 (m, IH); 1.029-0.827(m, IH); m/z = 476.32 [M+l]⁺.

Example 159

[427] N-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)-l-(2-hydroxyethyl)cyclopropane-l-sulfonamide

According to the same procedure as example 53 described, using 5-amino-6-(2-fluoro-4- iodophenylamino)-4-methoxy-l-methylpyridin-2(lH)-one afforded the desired product. ¹H NMR (400 MHz, CDCl₃) δ = 7.457-7.426 (dd, IH, J = 2.0 & 2.4 Hz); 7.326-7.302 (dd, IH, J = 7.6 &1.2 Hz); 6.246-6.203 (t, IH, 8.4 Hz); 5.918 (s, IH); 3.869 (s, 3Hz); 3.762-3.726 (t, 2H, J = 6.4 Hz); 3.306 (s, 3H); 2.169-2.135 (t, 2H, J = 6.8 Hz); 1.086-1.058 (dd, 2H, J = 4.8 & 4.4 Hz); 0.712- 0.683 (dd, 2H, J = 4.8 & 4.8 Hz); m/z = 538.34 [M+l]⁺.

Example 160 [428] 2-(4-chlorophenyl)-iV-(2-(2-fluoro-4-iodophenylainino)-4-methoxy-l-methyl-6-oxo- l,6-dihydropyridin-3-yl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(l/-^r)-one was reacted with 2-(4-chlorophenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.63 (s, IH), 7.45 (dd, J = 2.0 & 10.0 Hz, IH), 7.26-7.30 (m, 3H), 6.88 (d, J = 8.8 Hz, 2H), 6.19 (t, J = 8.8 Hz, IH), 5.75 (s, III), 5.66 (s, IH), 3.36 (s, 3H), 3.25 (s, 3H), 2.65-2.69 (m, IH), 2.48-2.53 (m, IH), 1.74-1.79 (m, IH), 1.34- 1.39 (m, IH); m/z = 604 [M+l]⁺.

Example 161

[429] 2-(4-chloro-3-methoxyphenyl)-iV-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methyl-6-oxo-l,6-dihydropyridin-3-yl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(lH)-one was reacted with 2-(4-chloro-3-methoxyphenyl) cyclopropane- 1- sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.68 (s, IH), 7.44 (d, J = 10.4 Hz, IH), 7.24-7.31 (m, 2H), 6.73 (dd, J = 3.2 & 8.8 Hz, IH), 6.28 (d, J = 2.8 Hz, IH), 6.19 (t, J = 8.4 Hz, IH), 5.78 (s, IH), 5.65 (s, IH), 3.77 (s, 3H), 3.38 (s, 3H), 3.35 (s, 3H), 2.92- 2.98 (m, IH), 2.68-2.71 (m, IH), 1.78-1.81 (m, IH), 1.37-1.43 (m, IH); m/z = 634 [M+l]⁺.

Example 162 [430] 2-(2,4-dichlorophenyl)-N-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-metLyl-6- oxo-l,6-dihydropyridin-3-yl)cyclopropane-l-suIfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(lH)-one was reacted with 2-(2,4-dichlorophenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.67 (s, IH), 7.45 (dd, J =

2.0 & 10.0 Hz, IH), 7.43 (d, J = 2.4 Hz, IH), 7.29 (d, J = 9.6 Hz, IH), 7.20 (dd, J = 2.4 & 8.8 Hz,

IH), 6.73 (d, J = 8.0 Hz, IH), 6.20 (t, J = 8.8 Hz, IH), 5.79 (s, IH), 5.69 (s, IH), 3.43 (s, 3H),

3.35 (s, 3H), 2.92-2.98 (m, IH), 2.66-2.70 (m, IH), 1.77-1.82 (m, IH), 1.34-1.40 (m, IH); m/z = 638 [M+l]⁺.

Example 163

[431] N-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)-2-(2-fluoro-4-methoxyphenyl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(lH)-one was reacted with 2-(2-fluoro-4-methoxyphenyl)cyclopropane-l-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.68 (s, IH), 7.43-7.46 (dd, J = 2.0 & 10.0 Hz, IH), 7.23-7.29 (d, IH), 6.69-6.71 (d, IH), 6.60-6.65 (m, 2H), 6.17-6.22 (t, J = 8.6 Hz, IH), 5.79 (s, IH), 5.64(s, IH), 3.78 (s, 3H), 3.36 (s, 3H), 3.33 (s, 3H), 2.71-2.75 (m, IH), 2.62-2.64 (m, IH), 1.67-1.73 (m, IH), 1.42-1.47 (m, IH),; m/z = 618 [M+l]⁺.

Example 164 [432] N-(2-(2-fluoro-4-iodophenylamino)-4-methoxy-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)-2-(3-fluoro-4-methoxyphenyl)cyclopropane-l-sulfonamide

According to general procedure A, 5-amino-6-(2-fluoro-4-iodophenylamino)-4-methoxy-l- methylpyridin-2(l//)-one was reacted with 2-(3-fluoro-4-methoxyphenyl) cyclopropane- 1-sulfonyl chloride to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.66 (s, IH), 7.44-7.47 (dd,

J = 1.6 & 10.0 Hz, IH), 7.28-7.31 (d, IH), 6.87-6.92 (t, IH), 6.71-6.73 (d, IH), 6.63-6.67 (dd, J

= 2.0 & 8.0 Hz, IH), 6.17-6.21 (t, J = 8.4 Hz, IH), 5.77 (s, IH), 5.70 (s, IH), 3.88 (s, 3H), 3.36 (s,

3H), 3.34 (s, 3H), 2.61-2.65 (m, IH), 2.49-2.53 (m, IH), 1.70-1.75 (m, IH), 1.29-1.34 (m, IH); m/z = 618 [M+l]⁺.

Example 165

[433] N-(2-(2-chloro-4-iodophenylamino)-l,5-dimethyI-6-oxo-l,6-dihydropyridin-3-yl)-l-(2- hydroxyethyl)cyclopropane-l-sulfonamide

Following the same procedure as step E, example 2, step A&B, example 27 and step

A&B&C, example 53 described, using 5-amino-6-(2-chloro-4-iodophenylamino)-l,3- dimethylpyridin-2(lH)-one (from step D, example 54) as starting material to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (d, J= 2.0 Hz, IH), 7.35 (dd, J= 1.6 & 8.4 Hz, IH), 7.32 (s, 2H), 7.06 (s, br, IH), 6.02 (d, J = 8.8 Hz, IH), 3.88 (t, J= 5.2 Hz, 2H), 3.40 (s, 3H), 2.40 (s, br, IH), 2.19 (s, 3H), 2.12 (t, J= 5.2 Hz, 2H), 1.37 (m, 2H), 0.88 (m, 2H); m/z = 538 [M+l]⁺.

Example 166 [434] N-(2-(4-bromo-2-chlorophenylamino)-l,5-dimethyl-6-oxo-l,6-dihydropyridin-3-yl)-l- (2-hydroxyethyl)cyclopropane-l-sulfonamide

Following the same procedure as step E, example 2, step A&B, example 27 and step A&B&C, example 53 described, using 5-amino-6-(4-bromo-2-chlorophenylamino)-l,3- dimethylpyridin-2(lH)-one (from step D, example 55) as starting material to obtain the desired product. ¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J= 2.4 Hz, IH), 7.31 (s, IH), 7.29 (s, IH), 7.19

(dd, J= 2.0 & 8.8 Hz, IH), 6.90 (s, IH), 6.15 (d, J = 8.8 Hz, IH), 3.90 (t, J= 5.4 Hz, 2H), 3.40 (s,

3H), 2.19 (s, 4H, CH₃+OH), 2.14 (t, J = 5.4 Hz, 2H), 1.39 (m, 2H), 0.89 (m, 2H); m/z = 490 [M+l]⁺.

Biological Activity

Materials and preparation of reagents: [433] The Kinase GIo plus assay kit was purchased from Promega. The substrate, APT, DTT, and dimethylsulfoxide were purchased from Sigma-Aldrich.

[434] The MAP2K1 (MEKl) kinase, Europium labeled Antibody, Tracer 236 and binding buffer

A were purchased from Invitrogen.

[435] The Recombinant Human Epithelial Growth Factor (EGF) was purchased from R&D System.

[436] The SureFire Phospho-ERKl/2 Assay kit and the AlphaScreen General IgG (Protein A)

Detection kit were both purchased from PerkinElmer.

[437] Generation of IC₅₀ Data Determination of enzymatic activity:

Compounds were diluted from DMSO stocks into Ix buffer (2OmM MOPS, PH 7.4, 5mM MgCl₂, 0.5mM MnCl₂, lOOuM Sodium Orthovanadate, 0.01% Triton X-IOO, ImM DTT). A typical reaction assay contained 0.01 nanomoles MEKl kinase, 0.01 nanomoles ATP, 10 nanograms substrate. The screening assay essentially comprised four additions. 2ul of diluted compounds were dispensed to 384 well white assay plates. 6ul of kinase-substrate cocktail was then added to each well. 2ul 5x ATP was subsequently added to each well to start the reaction. A top seal was applied and the plate was incubated at 22 degree avoiding light for 60 minutes. Finally, lOul of the Kinase GIo plus reagent was added to each well to stop the reaction. Incubated at room temperature and avoid light for ten minutes. The top seal was removed and the plate was counted by the EnVision 2104 multi labeled plate reader (PerkinElmer) with a standard luminescent program. The intensity of luminescent signal was quantitated and this data was used to generate dose response curves and IC₅₀ calculations by the Prism program.

[438] Determination of kinase binding activity:

Compounds were diluted from DMSO stocks into buffer (2OmM MOPS, PH 7.4, 5mM MgCl₂, 0.5mM MnCl₂, lOOuM Sodium Orthovanadate, 0.01% Triton X-100, ImM DTT). A typical reaction assay contained 3XlO^"4 nanomoles MEKl kinase, 3xlO^"5 nanomoles Europium labeled antibody, 1.5xlO^'3 nanomoles Tracer 236. The screening assay essentially comprised three additions. 5ul of diluted compounds were dispensed to 384 well black assay plates. 5ul 3x kinase- antibody cocktail diluted in lxbuffer A was then added to each well. 5ul 3x Tracer 236 diluted in lxbuffer A was subsequently added to each well to start the reaction. A top seal was applied and the plate was incubated at 22 degree avoiding light for 60 minutes. The top seal was removed when the plate was counted by the EnVision multi labeled plate reader (PerkinElmer) with a TR- FRET program. The intensity of fluorescence signal was quantitated and this data was used to generate dose response curves and IC₅0 calculations by the Prism program.

[439] Generation of cell based IC₅₀ Data

Effects of compounds in the cell were determined by the AlphaScreen assay for phosphorylated ERK. MCF-7 breast cancer cells were plated in a 96 wells plate at 80,000 cells per well and grown in a 37 degree humidified CO₂ incubator. The following day, the growth media

(DMEM + 10% fetal bovine serum) was removed and replaced with starving media (DMEM only).

Cells were incubated in the starve media overnight and then treated with a range of compound concentrations for 60 minutes at 37 degree. After incubation with compound, cells were stimulated with EGF for 10 minutes. The cells were then lysed and 4ul of each lysate were transferred into the 384 well white reaction plate. A cocktail of AlphaScreen beads and buffer was freshly prepared and this mixture was dispensed into each well in a room with low light. A top seal was applied and the plate was incubated at 25 degree avoiding light for two hours. The top seal was removed when the plate was counted by the En Vision multi labeled plate reader (PerkinElmer) with an optimized AlphaScreen program. The intensity of signal was quantitated and this data was used to generate dose response curves and ICs₀ calculations by the Prism program.

Biological Data for Select Compounds

[440] Select compounds prepared as described above were assayed according to the biological procedures described herein. The results are given in the table below:

Claims

What is claimed is

1. A compound of formula I

wherein

Ro is H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₅-C₆ cycloalkenyl or C₂-C₆ alkynyl; wherein each alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C₁-C₄ alky, C1-C4 alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, and one or two ring carbon atoms of said C₃-C₆ cycloalkyl groups are optionally replaced with, independently, O, N, or S; and

R₁ is H, C₁-C₄ alkoxy, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₅-C₆ cycloalkenyl C₂-C₆ alkynyl or halogen; wherein each alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C₁-C₄ alky, C₁-C₄ alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, or

R₁ is 5 or 6-atom heterocyclic group, which group may be saturated, unsaturated, or aromatic, containing 1-5 heteroatoms selected independently from the group consisting of 0, N, and S, which heterocyclic group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C₁-C₄ alky, C₁-C₄ alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl; or

Ri is -CH₂X' where X' represents a group according to formula (II)

wherein

Y₁ and Y₂ may be the same or different, each represents a single bond, -CO-, -COO, -O-, - OCO-, -NR₃ or -SO₂-;

Y₃ represents a C_1-S alkyl which may be substituted by one to three groups represented by Z;

Z may be the same or different and represent a C_1-S alky group, halogen atom, an oxo group, - OR_a, -COOR₃, -COOCOR₃, -CO-halogen atom, -OCOR₃, -CONR₃Rb. -SR₃, -SO₂Ra₃ -NR₃Rb, - NR₃COR_b, NR₃SO₂R_b, -SO₂NR₃R_b, a 5 or 6 membered monocyclic or 9 to 13 membered bicyclic heterocyclic group or a heteroaryl group which may be optionally substituted with one or more substituents selcted from the group consisting of a C_1-5 alkyl group, -OR₃, and NR₃R_b; the alkyl group may be substituted by a hydroxyl group, a C_1-5 alkoxy group, or an amino group; the above substituents except the oxo group and the halogen may be linked to each other to form a cycloalkyl group or a heterocyclic group which may has one or more substituents selected from the group consisting Of-OR₃, NR₃R_b, and a C_1-5 alkyl group that may be substituted with -OR₃;

Ra and R_b may be the same or different and each represents a hydrogen atom or a Ci_-5 alkyl group which may be substituted by one to three groups selected from the group consisting of a hydroxyl group, a Q-₅ alkoxy group and an amino group

The symbol "•" used in formula II implies the site of bonding;

X is C or N;

R₂ is H, Cj-C₄ alkoxy, Ci-C₆ alkyl, C₃-C₆ cycloalkyl, C₂-C₆ alkenyl, C₅-C₆ cycloalkenyl or C₂-C₆ alkynyl; wherein each alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents selected independently from halogen, hydroxy, C₁-C₄ alky, C₁-C₄ alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, or R₂ is 5 or 6-atom heterocyclic group, which group may be saturated, unsaturated, or aromatic, containing 1-5 heteroatoms selected independently from O, N, and S, which heterocyclic group is optionally substituted with 1-3 substituents selected independently from halogen, hydroxy, C₁-C₄ alky, C₁-C₄ alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl when X = C or

R₂ = nothing when X = N; or

Ri and R₂ taken together form a 5 or 6 membered heterocyclic group which group may be unsaturated or aromatic containing 1-3 heteroatoms selected independently from the group consisting of O, N or S which heterocyclic group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxyl, C₁-C₄ alkyl, C₁-C₄ alkoxy, cyano, cyanomethyl, trifluormethyl, difluroomethoxy and phenyl; and

R₃ is selected from the group consisting of trifluoromethyl, C₁-Ci₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-Ci₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarycycloalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, heteroarycycloalkyl, and heterocyclyl is unsubstituted or substituted with 1-3 substituents selected independently from halogen, hydroxyl, Ci- C₄ alkyl, Ci- C₄ alkoxy, cyano, trifluoromethyl, difluoromethoxy, phenyl or substituted phenyl with 1-3 substituents selected independently from halogen, hydroxyl, Ci- C₄ alkyl, Ci- C₄ alkoxy, cyano trifluoromethyl, or difluoromethoxy,

R₄, R₅, R₆, R₇, and R₈ are independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, S R ₉ , O R ₉ , C ( O ) R ₉ , C ( O ) O ₉ , NR₁₀C(O)OR₁₂, OC(O)R₉, NRj₀ S(O)₁ R₁₂, S (O)Jm₉ Ri₀, S(0)jNRioC(0)R₉, C(O)NR₁₀S (0)_j R₁₂, S (0)_j Rj₂, NR₁₀C(O)R₉, C(O)NR₉Ri₀, NR_nC(O)NR₉R₁₀, NRi ₁C(NCN)NR₉R₁₀, NR₉Ri₀ and Ci-Ci₀ alkyl, C₂-C₁₀ alkenyl, C₂-Ci₀ alkynyl, C₃-Ci₀ cycloalkyl, C₃-C₁₀ cycloalkylalkyl, S(0)j(C l -C6 alkyl), S(O)_j(CRi₀Rn)_m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, O(CR₁₀R₁₀)_m-aryl, NR_1O(CRi_OR₁ Om-aryl, 0(CR₁₀R₁ Om-heteroaryl, NR₁₀(CR₁₀R₁ i)_m-heteroaryl, 0(CR₁₀R₁ !)_m-heterocyclyl, NR₁₀(CR₁₀Ri_I)_1n- heterocyclyl, and S(C₁-C₂ alkyl) optionally substituted with 1 to 5 fluorine atoms;

R₉ is selected from hydrogen, trifluoromethyljCi - C₁₀ alkyl, C₂ - C₁₀ alkenyl, C₂ - Cio alkynyl, C₃ - Ci₀ cycloalkyl, C₃ - Ci₀ cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or substituted with 1 -3 substituents independently selected from halogen, C₁-C₄ alkyl, hydroxyl and amino;

Rio is selected from hydrogen or C₁-C₆ alkyl where alkyl may be unsubstituted or substituted with 1 -3 substituents independently selected from halogen, C₁- C₄ alkyl, hydroxyl and amino; or

R.₉ and R_1O can be taken together with the atom to which they are attached to form a 4 to 10 membered heteroaryl or heterocyclic ring, each of which is unsubstituted or substituted with 1 -3 substituents independently selected from halogen, Ci- C₄ alkyl, hydroxyl and amino;

R₁₁ is selected from hydrogen or C₁-C₆ alkyl where alkyl may be unsubstituted or substituted with 1 -3 substituents independently selected from halogen, Ci- C₄ alkyl, hydroxyl and amino; or

R₁O and Rn can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is unsubstituted or substituted with 1 -3 substituents independently selected from halogen, Ci- C₄ alkyl, hydroxyl and amino;

Ri₂ is selected from trifluoromethyl, CfCio alkyl, C₃-C₁₀ cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl unsubstituted or substituted with 1 -3 substituents independently selected from halogen, Ci- C₄ alkyl, hydroxyl and amino;

m is 0,1,2,3,4, or 5; and

j is 1 or 2;

2. The compound according to claim 1, wherein the Ro is H or Ci-C₆ alkyl; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

3. The compound according to claim 1, wherein R₁ is H or Ci-C₆ alkyl; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

4. The compound according to claim 1, wherein R₂ is nothing when X is N; or is H or Ci-Q alkoxy when X is C; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

5. The compound according to claim 1 , wherein R₂ is C₁-C₄ alkoxy ; or 5 or 6-atom heterocyclic group, which group may be saturated, unsaturated, or aromatic, containing 1-5 heteroatoms selected independently from O, N, and S, which heterocyclic group is optionally substituted with 1-3 substituents selected independently from halogen, hydroxy, C₁-Gj alky, C₁-C₄ alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl when X is C; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

6. The compound according to claim 1 , wherein R₃ is selected from the group consisting OfC₁-Q alkyl optionally substituted with one or more halogen or hydroxyl; C₂-C₆ alkenyl; C₃-C₆ cycloalkyl optionally substituted with Ci-C₆ alkyl or C₂-C₆ alkenyl; 5 or 6 membered monocyclic or 9 to 13 membered bicyclic heteroaryl with O, N, or S as the hetero atom; 5 or 6 membered monocyclic or 9 to 13 membered bicyclic aryl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, Ci-C₆ alkoxy and hydroxyl; arylcycloalkyl in which aryl is 5 or 6 membered monocyclic or 9 to 13 membered bicyclic aryi and cycloalkyl has 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, Ci-C₆ alkoxy and hydroxyl; heteroarylcycloalkyl in which heteroaryl is 5 or 6 membered monocyclic or 9 to 13 membered bicyclic aryl and cycloalkyl has 1 to 6 carbon atoms optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, Ci-C₆ alkoxy and hydroxyl; and Ci-C₆ alkyl Ci-C₆ cycloalkyl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, C₁-C₆ alkoxy and hydroxyl; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

7. The compound according to claim 1 , wherein R₄, R₅, R₆, R₇, and R₈ are independently selected from

H or halogen; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

8. The compound according to claim 1, wherein R₀ is H or C₁-C₆ alkyl; Ri is H or C₁-C₆ alkyl; R₂ is nothing, H or C₁-C₆ alkoxy; R₃ is selected from the group consisting of Cj-C₆ alkyl optionally substituted with one or more halogen or hydroxyl; C₂-C₆ alkenyl; C₃-C₆ cycloalkyl optionally substituted with Ci-C₆ alkyl or C₂-C₆ alkenyl; 5 or 6 membered monocyclic or 9 to 13 membered bicyclic heteroaryl with O, N, or S as the hetero atom; 5 or 6 membered monocyclic or 9 to 13 membered bicyclic aryl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, Ci-C₆ alkoxy and hydroxyl; arylcycloalkyl in which aryl is 5 or 6 membered monocyclic or 9 to 13 membered bicyclic aryl and cycloalkyl has 1 to 6 carbon atoms; and Cj-C₆ alkyl CpC₆ cycloalkyl; and R₄, R₅, R₆, R₇, and Rg are independently selected from H and halogen; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

9. The compound according to claim 1 having the formula

wherein

Ro, R₁, R₂, R₄, R₅, R₆, R₇, and R₈ are defined as claim 1 ;

R₁₃ is selected from the group consisting of H, C₂-C₆ alkenyl, and C₁-C₆ alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and hydroxyl; and

R₁₄ is selected from the group consisting of H, C₁-C₆ alkyl, 5 or 6 membered monocyclic or 9 to 13 membered bicyclic aryl and 5 or 6 membered monocyclic or 9 to 13 membered bicyclic heteroaryl with O, N, or S as the hetero atom, optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, hydroxyl, C₁-C₆ alkyl optionally substituted with halogen, and C₁-C₆ alkoxy;

10. The compound according to claim 9, wherein R₀ is H or C₁-C₆ alkyl; Ri is H, C₁-C₆ alkyl or halogen; R₂ is H or Ci-C₆ alkoxy; R₃ is selected from the group consisting of C₁-C₆ alkyl optionally substituted with one or more halogen or hydroxyl; C₂-C₆ alkenyl; C₃-C₆ cycloalkyl optionally substituted with C₁-C₆ alkyl or C₂-C₆ alkenyl; 5 or 6 membered monocyclic or 9 to 13 membered bicyclic heteroaryl with O, N, or S as the hetero atom; 5 or 6 membered monocyclic or 9 to 13 membered bicyclic aryl optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, Ci-C₆ alkoxy and hydroxyl; arylcycloalkyl in which aryl is 5 or 6 membered monocyclic or 9 to 13 membered bicyclic aryl and cycloalkyl has 1 to 6 carbon atoms; and C₁-C₆ alkyl Ci-C₆ cycloalkyl; and R₄, R₅, R₆, R₇, and R₈ are independently selected from H and halogen; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

11. The compound according to claim 9 having the formula

wherein,

R₁, R₂, R₁₃ and R₁₄ are defined as claim 9; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

12. The compound according to claim 11 having the formula

wherein

R₁₃ and Rj₄ are defined as claim 9; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

13. The compound according to claim 12 which is selected from the following:

14. The compound according to claim 11 having the formula

wherein

R₁₃ and R₁₄ are defined as claim 9; or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

15. The compound according to claim 14 which is selected from the following:

16. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of any of claims 1 to 15 or a pharmaceutically acceptable salt, solvate, polymorphpolymorph, ester, tautomer or prodrug thereof, and a pharmaceutically acceptable carrier.

17. Use of a compound of any of claims 1 to 15 or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof in the preparation of a pharmaceutical composition for inhibiting MEK enzyme.

18. Use of a compound of any of claims 1 to 15 or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof in the preparation of a pharmaceutical composition for the treatment or prophylaxis of a MEK mediated disorder or disease.

19. Use of a compound of any of claims 1 to 15 or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof in the preparation of a pharmaceutical composition for the treatment or prophylaxis of proliferative disorders.

20. Use of claim 19, wherein the proliferative disorders are selected from the group consisting of inflammatory diseases and cancers.

21. A method for inhibiting a MEK enzyme comprising the step of contacting the MEK enzyme with an amount sufficient to inhibit said enzyme of a compound of any of claims 1 to 15 or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

22. A method for the treatment or prophylaxis of a MEK mediated disorder or disease comprising administering to an individual in need thereof an effective amount of a composition comprising a compound of any of claims 1 to 15 or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or pro- drug thereof.

23. The method of claim 22, wherein the disorder or disease is proliferative disorders.

24. The method of claim 23, wherein the proliferative disorders are selected from the group consisting of inflammatory diseases and cancers.