BACKGROUND OF THE INVENTION Asthma is a heterogeneous disorder of the airways that afflicts millions of people. Airway inflammation, hyperresponsiveness, and obstruction characterize the condition. The disease often causes spasms of the bronchial smooth muscle system, and affects both the upper and lower respiratory tracts. There are several forms of asthma, characterized by varying degrees of severity. Mild asthma, for example, is defined as brief episodes of wheezing, with or without dyspnea or cough. Moderately severe asthma is defined as wheezing and dyspnea, and can be with or without cough and expectoration, but generally interferes with daily activities and/or sleeping. Severe asthma is characterized by incapacitation due to dyspnea, and the afflicted patient typically is unable to eat or sleep normally, is very anxious, and is often exhausted. A condition known as status asthmaticus is the most severe form of asthma, and generally requires intensive hospital care, and may even prove fatal. The disease may occur as a result of both allergic and nonallergic mechanisms.

While there are several treatments available for relieving the symptoms and discomfort associated with asthma, there are no cures. Moreover, the current treatments often cause side effects that exacerbate the discomfort and precipitate other debilitating conditions. Mild asthma generally is treated with beta- adrenergic drugs, as well as antihistamines, especially in the case of children, to prevent or abort sporadic episodes. Moderately severe and severe asthma are

generally treated with adrenergic agents and bronchodilators, as well as corticosteroids. Other actions caused by antiasthmatic agents which limit their widespread use include headache, fatigue, dry mouth, nervousness, and in some cases addiction and substance abuse. Recent advances in the understanding of the pathogenesis and treatment of asthma is discussed more fully by Grayson et al., The MountSinai Journal of Medicine, Sept. 1998; 65 (4): 246-256.

Because asthma is so prevalent in both children and adults, there is an on- going need for agents that can treat the disease, or at least relieve the symptoms that accompany the disease, without causing undesirable side effects. We have now discovered that MEK inhibitors are particularly useful for treating asthma and relieving the symptoms that accompany the disease. An object of this invention is therefore to provide a new method for preventing and treating asthmatic conditions.

SUMMARY OF THE INVENTION This invention provides a method of preventing and treating asthma, said method comprising the step of administering to a patient an antiasthmatic- effective amount of a MEK inhibitor. Selective MEK inhibitors are those compounds which inhibit the MEK 1 and MEK 2 enzymes without substantial inhibition of other such enzymes. In a preferred embodiment, the invention provides a method for preventing or treating asthma by administering a MEK inhibitor. In a further embodiment, the invention provides a method for preventing and/or treating asthma comprising administering an effective amount of the selective MEK inhibitor described in US 5,525,625, incorporated herein by reference, which selective MEK inhibitor is 2- (2-amino-3-methoxyphenyl)-4-oxo- 4H- [1] benzopyran.

In another preferred embodiment, the MEK inhibitor to be administered is a phenyl amine derivative of Formula I:

In Formula (I), Ri is hydrogen, hydroxy, Ci-Cg alkyi, Ci-Cg alkoxy, halo, trifluoromethyl, or CN. R2 is hydrogen. R3, R4, and Rs are independently selected from hydrogen, hydroxy, halo, trifluoromethyl, Ci-Cg alkyi, Cl-Cg alkoxy, nitro, CN, and- (O orNH) m-(CH2) n-Rg. Rg is hydrogen, hydroxy, <BR> <BR> <BR> <BR> COOH, or NR1 oRl 1; n is 0-4; m is 0 or 1. Each of RI 0 and R1 1 is independently selected from hydrogen and C 1-C8 alkyl, or taken together with the nitrogen to which they are attached can complete a 3-10 member cyclic ring optionally containing 1,2, or 3 additional heteroatoms selected from 0, S, NH, or N-(Cl-Cg alkyl). Z is COOR7, tetrazolyl, CONR6R7, CONHNRIOR1 1, or CH20R7. R6 and R7 independently are hydrogen, Cl-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, (CO)-Cl-Cg alkyl, aryl, heteroaryl, C-Cio cycloalkyi, or C3-Clo (cycloalkyl optionally containing one, two, or three heteroatoms selected from 0, S, NH, or N alkyl); or R6 and R7 together with the nitrogen to which they are attached complete a 3-10 member cyclic ring optionally containing 1,2, or 3 additional heteroatoms selected from 0, S, NH, or N alkyl. In formula (I), any of the foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, Cl-C6 alkoxy, amino, nitro, Cl-C4 alkylamino, di (Cl-C4) alkylamino, C3-C6 cycloalkyl, phenyl, phenoxy, C3-Cs heteroaryl or heterocyclic radical, or C3-C5 heteroaryloxy or heterocyclic radical- oxy. The invention also provides a pharmaceutically acceptable salt, ester, amide, or prodrug of each of the disclosed MEK inhibitors.

Preferred embodiments of Formula (I) have a structure wherein: (a) Rl is hydrogen, methyl, methoxy, fluoro, chloro, or bromo; (b) R2 is hydrogen; (c) R3, R4, and R5 independently are hydrogen, fluoro, chloro, bromo, iodo, methyl, methoxy, or nitro; (d) Rio and Rl l independently are hydrogen or methyl; (e) Z is COORs, tetrazolyl, CONR6R7, CONHNRIORI l, or CH20R7; R6 and R7

independently are hydrogen, C 14 alkyl, heteroaryl, or C 3-5 cycloalkyl optionally containing one or two heteroatoms selected from 0, S, or NH; or R6 and Rv together with the nitrogen to which they are attached complete a 5-6 member cyclic ring optionally containing 1 or 2 additional heteroatoms selected from 0, NH or N-alkyl; and wherein any of the foregoing alkyl or aryl groups can be unsubstituted or substituted by halo, hydroxy, methoxy, ethoxy, or heteroaryloxy (such as 2,3,4,5,6-pentafluorophenyl); (f) Z is COORy; (g) Ra is H, pentafluorophenyl, or tetrazolyl; (h) R3, R4, and Rs are independently H, fluoro, or chloro; (i) R4 is fluoro; (j) two of R3, R4, and Rs are fluoro; or (k) or combinations of the above. In another preferred embodiment of Formula (I), R, is methyl, fluoro, chloro, or bromo.

In a more preferred embodiment, the MEK inhibitor is selected from a compound in Formula (I) Compound Table below.

FORMULA (I) COMPOUND TABLE (page 1 of 10) [4-Chloro-2-(1 H-tetrazol-5-yl)-phenyl- (4-iodo-2-methyl-phenyl)-amine (4-iodo-2-methyl-phenyl)- [2- ( 1 H-tetrazol-5-yl)-phenyl] amine [4-nitro-2- (l H-tetrazol-5-yl)-phenyl- (4-iodo-2-methyl-phenyl)-amine 4-Fluoro-2- (4-iodo-2-methylphenylamino) benzoic acid 3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino)-benzoic acid 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-benzoic acid 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-benzoicacid 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-benzoic acid Sodium5-Chloro-2- (4-iodo-2-methyl-phenylamino)-benzoate 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-benzoic acid 2- (4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid 4-Chloro-2- (4-iodo-2-methyl-phenylamino)-benzoic acid 2- (4-Iodo-2-methyl-phenylamino)-benzoic acid 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-benzoic acid 5-Iodo-2- (4-iodo-2-methyl-phenylamino)-benzoic acid 2,3,5-Trifluoro-4- (4-iodo-2-methyl-phenylamino)-benzoic acid 2- (4-Iodo-phenylamino)-5-methoxy-benzoic acid 5-Methyl-2- (4-iodo-2-methyl-phenylamino)-benzoic acid 2- (4-Iodo-2-methyl-phenylamino)-4-nitro-benzoic acid 2- (4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic acid 2- (2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic acid 2- (4-Bromo-2-methyl-phenylamino)-3,4-difluoro-benzoic acid <BR> <BR> <BR> 5-Chloro-N- (2-hydroxyethyl)-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N-methyl-benzamide<BR> <BR> <BR> <BR> N-Ethyl-4-fluoro-2- (4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N, N-dimethyl-benzamide <BR> <BR> <BR> 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- ( 1 H-tetrazol-5-yl)-benzamide

FORMULA (I) COMPOUND TABLE (continued, page 2 of 10) 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N, N-dimethyl-benzamide <BR> <BR> [5-Chloro-2- (4-iodo-2-methyl-phenylamino)-benzoylamino]-aceticacid<BR > <BR> 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N-propyl-benzamide<BR> <BR> 5-Bromo-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)- benzamide N,N-Diethyl-4-fluoro-2- (4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-N- {3- [4- (2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-2- (4-iodo- 2-methyl-phenylamino)-benzamide N,N-Diethyl-2- (4-iodo-2-methyl-phenylamino)-5-nitro-benzamide N-Butyl-4-fluoro-2- (4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-N, N-diethyl-2- (4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N, N-dimethyl-benzamide 5-Bromo-3,4-difluoro-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl- phenylamino)-benzamide N- (2,3-Dihydroxy-propyl)-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-piperidin-1- yl-ethyl)-benzamide 3,4-Difluoro-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)- benzamide N- (2, 3-Dihydroxy-propyl)-4-fluoro-2- (4-iodo-2-methyl-phenylamino)- benzamide 3,4-Difluoro-N- (3-hydroxy-propyl)-2- (4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-pyrrolidin-1- yl-ethyl)-benzamide 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-pyridin-4-yl- ethyl)-benzamide

FORMULA (I) COMPOUND TABLE (continued, page 3 of 10) <BR> <BR> <BR> <BR> <BR> 4-Fluoro-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> 5-Bromo-N- (3-dimethylamino-propyl)-3, 4-difluoro-2- (4-iodo- 2-methylphenylamino)-benzamide 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-morpholin-4- yl-ethyl)-benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-morpholin-4-yl-ethyl)- benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-pyrrolidin-1-yl-ethyl)- benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-pyridin-4-yl-ethyl)- benzamide <BR> <BR> <BR> <BR> N- (3-Dimethylamino-propyl)-3, 4-difluoro-2- (4-iodo-2-methyl-<BR> <BR> <BR> <BR> <BR> <BR> phenylamino)-benzamide<BR> <BR> <BR> <BR> <BR> N-Benzyl-4-fluoro-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> <BR> 2- (4-Bromo-2-methyl-phenylamino)-3, 4-difluoro-N- (2-hydroxy-ethyl)- benzamide 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-morpholin-4-yl-ethyl)- benzamide 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (3-piperidin-1-yl-propyl)- benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (3-piperidin-1-yl-propyl)- benzamide 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-thiophen-2-yl-ethyl)- benzamide 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-pyrrolidin-1-yl-ethyl)- benzamide 2- (4-Bromo-2-methyl-phenylamino)-3, 4-difluoro-N- (2-morpholin-4-yl- ethyl)-benzamide

FORMULA (I) COMPOUND TABLE (continued, page 4 of 10) 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N-pyridin-4- ylmethyl-benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide 2- (4-Bromo-2-methyl-phenylamino)-N- (3-dimethylamino- propyl) -3,4-difluoro-benzamide <BR> <BR> <BR> <BR> 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl-enzamide& lt;BR> <BR> <BR> <BR> <BR> <BR> 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-pyridin-4-yl-ethyl)- benzamide <BR> <BR> <BR> <BR> 2- (4-Bromo-2-methyl-phenylamino)-3, 4-difluoro-N- (2-pyridin-4-yl-ethyl)- benzamide 2- (4-Bromo-2-methyl-phenylamino)-3, 4-difluoro-N- (3-hydroxy-propyl)- benzamide <BR> <BR> <BR> <BR> 2- (4-Bromo-2-methyl-phenylamino)-3, 4-difluoro-N- (2-pyrrolidin-1-yl-<BR> <BR> <BR> <BR> <BR> ethyl)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N-phenethyl-benzamide<BR> ; <BR> <BR> <BR> <BR> <BR> 2- (4-Bromo-2-methyl-phenylamino)-3, 4-difluoro-N- (2-thiophen-2-yl- ethyl)-benzamide 2- (4-Bromo-2-methyl-phenylamino)-3, 4-difluoro-N-pyridin-4-ylmethyl- benzamide 2- (4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-phenethyl-benz amide 2- (4-Bromo-2-methyl-phenylamino)-3, 4-difluoro-N- (2-piperidin-1-yl- ethyl)-benzamide 5-Chloro-N- {3- [4- (2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-2- (4-iodo-2- <BR> <BR> <BR> <BR> methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> <BR> 5-Fluoro-N- {3- [4- (2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-2- (4-iodo-2- methyl-phenylamino)-benzamide 2- (4-lodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methyl-benzamide

FORMULA (I) COMPOUND TABLE (continued, page 5 of 10) 5-Bromo-N-3- [4- (2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-2- (4-iodo-2- methyl-phenylamino)-benzamide <BR> <BR> <BR> <BR> 5-Chloro-N- (2-diethylamino-ethyl)-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> <BR> 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N- (2-piperidin-1-yl-ethyl)- benzamide <BR> <BR> <BR> <BR> <BR> (3-Hydroxy-pyrrolidin-1-yl)- [5-nitro-2- (4-iodo-2-methyl-phenylamino)-phenyl}- methanone 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N- (2-pyrrolidin-1-yl-ethyl)- benzamide 5-Bromo-N- (2-diethylamino-ethyl)-2- (4-iodo-2-methyl-phenylamino)- benzamide N-{2- [Bis- (2-hydroxy-ethyl)-amino]-ethyl}-5-chloro-2- (4-iodo-2-methyl- phenylamino)-benzamide <BR> <BR> <BR> <BR> N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-bromo-2-(4-iodo- 2-methyl-<BR> <BR> <BR> <BR> <BR> <BR> <BR> phenylamino)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> N- {3- [4- (2-Hydroxy-ethyl)-piperazin-1-yl]-propyl}-2- (4-iodo-2-methyl- phenylamino)-benzamide 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- benzamide 5-Bromo-2- (4-iodo-2-ethyl-phenylamino)-N- (2-pyrrolidin-1-yl-ethyl)- benzamide 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N- (2-piperidin-1-yl-ethyl)- benzamide 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-pyrrolidin-1-yl-ethyl)- benzamide 5-Chloro-N- (3-dimethylamino-propyl)-2- (4-iodo-2-methyl-phenylamino)- benzamide N- {2- [Bis- (2-hydroxy-ethyl)-amino]-ethyl}-5-fluoro-2- (4-iodo-2-methyl- phenylamino)-benzamide

FORMULA (I) COMPOUND TABLE (continued, page 6 of 10) 5-Chloro-N- (3-hydroxy-propyl)-2- (4-iodo-2-methyl-phenylamino)- benzamide <BR> <BR> 5-Chloro-N- (3-diethylamino-2-hydroxy-propyl)-2- (4-iodo-2-methyl-<BR> <BR> <BR> phenylamino)-benzamide<BR> <BR> 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-piperidin-1-yl-ethyl)- benzamide 5-Bromo-N- (3-hydroxy-propyl)-2- (4-iodo-2-methyl-phenylamino)- benzamide <BR> <BR> 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N- (3-piperidin-1-yl-propyl)- benzamide N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-2-(4-iodo-2-methyl - <BR> <BR> phenylamino)-5-nitro-benzamide<BR> <BR> 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N- (2-morpholin-4-yl-ethyl)- benzamide 5-Chloro-N- (3-diethylamino-propyl)-2- (4-iodo-2-methyl-phenylamino)- benzamide <BR> <BR> 5-Chloro-N- (2-diisopropylamino-ethyl)-2- (4-iodo-2-methyl-phenylamino)- benzamide <BR> <BR> 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N- (3-piperidin-1-yl-propyl)- benzamide 2- (4-Iodo-2-methyl-phenylamino)-5-nitro-N- (2-piperidin-1-yl-ethyl)- benzamide 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N- (2-piperazin-1-yl-ethyl)- benzamide N- (2-Diethylamino-ethyl)-5-fluoro-2- (4-iodo-2-methyl-phenylamino)- benzamide <BR> <BR> 5-Bromo-N- (3-dimethylamino-propyl)-2- (4-iodo-2-methyl-phenylamino)- benzamide <BR> <BR> N- (3-Hydroxy-propyl)-2- (4-iodo-2-methyl-phenylamino)-5-nitro-benzamide

FORMULA (I) COMPOUND TABLE (continued, page 7 of 10) 5-Fluoro-N- (3-hydroxy-propyl)-2- (4-iodo-2-methyl-phenylamino)- benzamide N- (3-Diethylamino-propyl)-5-fluoro-2- (4-iodo-2-methyl-phenylamino)- benzamide N- (3-Diethylamino-propyl)-2- (4-iodo-2-methyl-phenylamino)-5-nitro- benzamide <BR> <BR> 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N- (2-morpholin-4-yl-ethyl)- benzamide 2- (4-Iodo-2-methyl-phenylamino)-5-nitro-N- (3-piperidin-1-yl-propyl)- benzamide <BR> <BR> [5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-phenyl]- (2 or 3-hydroxy-<BR> <BR> pyrrolidin-1-yl)-methanone<BR> <BR> 5-Bromo-N- (2-diisopropylamino-ethyl)-2- (4-iodo-2-methyl-phenylamino)- benzamide 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-morpholin-4-yl-ethyl)- benzamide <BR> <BR> 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (3-piperidin-1-yl-propyl)- benzamide <BR> <BR> [5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-phenyl]-4- (2-hydroxy-ethyl)-<BR> <BR> piperazin-1-yl)-methanone<BR> <BR> N- (3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2- (4-iodo-2-methyl- phenylamino)-benzamide <BR> <BR> N-Cyclopropyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> 5-Chloro-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)- benzamide <BR> <BR> 5-Fluoro-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> N-Benzyloxy-5-fluoro-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> N-Benzyloxy-5-bromo-2- (4-iodo-2-methyl-phenylamino)-benzamide

FORMULA (I) COMPOUND TABLE (continued, page 8 of 10) 2- (4-Iodo-2-methyl-phenylamino)-5-nitro-N- (4-sulfamoyl-benzyl)- benzamide 5-Bromo-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)- benzamide <BR> <BR> <BR> <BR> N- (2-Hydroxy-ethyl)-5-iodo-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> N- (2-Hydroxy-ethyl)-2- (4-iodo-2-ethyl-phenylamino)-5-nitro-benzamide 2- (4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl-benz amide <BR> <BR> <BR> <BR> 5-Chloro-N-cyclopropyl-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide< ;BR> <BR> <BR> <BR> <BR> N-Allyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> N-Benzyloxy-5-iodo-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (4-sulfamoyl-benzyl)- benzamide <BR> <BR> <BR> <BR> N-Allyl-5-chloro-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> N-Cyclopropyl-2- (4-iodo-2-methyl-phenylamino)-5-nitro-benzamide<BR> <BR> <BR> <BR> <BR> <BR> 5-Bromo-N-cyclopropyl-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide 5-Iodo-2- (4-iodo-2-methyl-phenylamino)-N- (4-sulfamoyl-benzyl)- benzamide 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N- (4-sulfamoyl-benzyl)- benzamide <BR> <BR> <BR> <BR> N-Allyl-2- (4-iodo-2-methyl-phenylamino)-5-nitro-benzamide<BR> <BR> <BR> <BR> <BR> <BR> 2- (4-Iodo-2-methyl-phenylamino)-5-nitro-N- (4-sulfamoyl-benzyl)- benzamide <BR> <BR> <BR> <BR> N-Allyl-5-bromo-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (3-methyl-benzyl)- benzamide N-Cyclopropyl-5-iodo-2- (4-iodo-2-methyl-phenylamino)-benzamide

FORMULA (I) COMPOUND TABLE (continued, page 9 of 10) <BR> <BR> 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide< ;BR> <BR> N-Benzyloxy-2- (4-iodo-2-methyl-phenylamino)-5-nitro-benzamide<BR> <BR> N-Cyclohexyl-5-iodo-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> N-Allyl-5-iodo-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> 5-Iodo-2- (4-iodo-2-methyl-phenylamino)-N- (3-methyl-benzyl)-benzamide<BR> <BR> 2- (4-Iodo-2-methyl-phenylamino)-N- (3-methyl-benzyl)-5-nitro-benzamide<BR> <BR> 5-Iodo-2- (4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide N-Cyclohexyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino)-benzamide <BR> <BR> 5-Chloro-N-cyclohexyl-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N- (3-methyl-benzyl)- benzamide <BR> <BR> 5-Bromo-N-cyclohexyl-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N- (3-methyl-benzyl)- benzamide <BR> <BR> N-Cyclohexyl-2- (4-iodo-2-methyl-phenylamino)-5-nitro-benzamide<BR> <BR> N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamid e<BR> <BR> N-Benzyloxy-5-fluoro-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> 5-Chloro-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)- benzamide 2- (4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl-benz amide <BR> <BR> 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide< ;BR> <BR> N- (2-Hydroxy-ethyl)-5-iodo-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> 5-Chloro-N-cyclopropyl-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> N-Allyl-5-chloro-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide

FORMULA (I) COMPOUND TABLE (continued, page 10 of 10) <BR> <BR> <BR> <BR> <BR> N- (2-Hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)-5-nitro-benzamide<BR> <BR> <BR> <BR> 5-Fluoro-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> 5-Bromo-N-cyclopropyl-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> <BR> N-Cyclopropyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (4-sulfamoyl-benzyl)- benzamide <BR> <BR> <BR> <BR> N-Cyclopropyl-2- (4-iodo-2-methyl-phenylamino)-5-nitro-benzamide<BR> <BR> <BR> <BR> N-Allyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> N-Benzyloxy-5-iodo-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> N-Allyl-5-bromo-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> <BR> 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N- (4-sulfamoyl-benzyl)- benzamide <BR> <BR> <BR> <BR> N-Allyl-2- (4-iodo-2-methyl-phenylamino)-5-nitro-benzamide<BR> <BR> <BR> <BR> <BR> 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-benzyl alcohol<BR> <BR> <BR> <BR> [5-Chloro-2- (4-iodo-2-methyl-phenylamino)-phenyl]-methanol<BR> <BR> <BR> <BR> [2- (4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl]-methanol<BR > <BR> <BR> <BR> [5-Bromo-2- (4-iodo-2-methyl-phenylamino)-phenyl]-methanol<BR> <BR> <BR> <BR> <BR> N-Allyl-2- (4-iodo-2-methyl-phenylamino)-5-nitro-benzamide.

In another preferred embodiment, the MEK inhibitor is a compound of Formula II In Formula (II), Rl a is hydrogen, hydroxy, Cl-Cg alkyl, Cl-Cg alkoxy, halo, trifluoromethyl, or CN. R2a is hydrogen. Each of R3a R4a and Rsa is

independently selected from hydrogen, hydroxy, halo, trifluoromethyl, Cl-Cg alkyl, Cl-Cg alkoxy, nitro, CN, and (O or NH) m- (CH2) n-R9a. R9a is hydrogen, hydroxy, C02H or NRlOaRl la ; n is 0-4 and and is 0 or 1. Each of RlOa and RI 1 a is independently hydrogen or C1-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3-to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from 0, S, NH, or N- (C l-Cg alkyl). R6a is hydrogen, C 1-C8 alkyl, (CO)-(C 1-C8 alkyl), aryl, aralkyl, or C3-Clo cycloalkyl. R7a is hydrogen, Cl-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C 10 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from 0, S, or NRga). In Formula (II), any of the foregoingany of the foregoing alkyl, alkenyl, aryl, heteroaryl, heterocyclic, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, C I-C6 alkoxy, amino, nitro, C-C4 alkylamino, di (Ci-C4) alkylamino, C3-C6 cycloalkyl, phenyl, phenoxy, C3-Cs heteroaryl or heterocyclic radical, or C3-C5 heteroaryloxy or heterocyclic radical-oxy; or R6a and R7a taken together with the N to which they are attached can complete a 5-to 10-membered cyclic ring, optionally containing one, two, or three additional heteroatoms selected from 0, S, or NRloaRl la. The invention also encompasses pharmaceutically acceptable salts, esters, amides or prodrugs of each of the disclosed compounds.

Preferred embodiments of Formula (II) are those structures wherein: (a) Rla is H, methyl, fluoro, or chloro; (b) R2a is H; R3a, R4a, and Rsaare each H, Cl, nitro, or F; (c) R6a is H; (d) R7a is methyl, ethyl, 2-propenyl, propyl, butyl, pentyl, hexyl, cyclopropylmethyl, cyclobutyl methyl, cyclopropylmethyl, or cyclopropylethyl; (e) the 4'position is I, rather than Br; (f) R4a is F at the 4 position, para to the CO-N-R6a-ORa group and meta to the bridging nitrogen; (f) R3a or Rsa is F; (g) at least one of R3a, R4a, and Rsa is F; (h) Rla is methyl or chloro; or (i) or a combination of the above.

In a more preferred embodiment the MEK inhibitor is a compound selected from Formula (II) Compound Table below.

FORMULA (II) COMPOUND TABLE (page 1 of 7) 4-Fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino)-benzamide <BR> <BR> <BR> <BR> 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (methoxy)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (prop-2-ynyloxy)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-phenoxyethoxy)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-thienylmethoxy)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (prop-2-enyloxy)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> <BR> 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (cyclopentoxy)-benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (3-furylmethoxy)-benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N-ethoxy-benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (but-2-enyloxy)-benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)- benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- ( 1-methylprop-2-ynyloxy)- benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (3-phenylprop-2-ynyloxy)- benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (3-methyl-5-phenylpent-2-en- 4-ynyloxy)-benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (prop-2-ynyloxy)-benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (propoxy)-benzamide

FORMULA (II) COMPOUND TABLE (continued, page 2 of 7) 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (cyclobutyloxy)-benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-thienylmethoxy)-benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-methyl-prop-2-enyloxy)- benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-phenoxyethoxy)-benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (but-2-enyloxy)-benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (but-3-ynyloxy)-benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (cyclopentyloxy)-benzamide 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (3- (2-fluorophenyl)-prop- 2-ynyloxy)-benzamide 5-Bromo-3,4-difluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (n-propoxy)- benzamide 5-Bromo-3,4-difluoro-N- (furan-3-ylmethoxy)-2- (4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-N- (but-2-enyloxy)-3, 4-difluoro-2- (4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-N-butoxy-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (3-methyl-but- 2-enyloxy)-benzamide 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (3-methyl-pent-2-en- 4-ynyloxy)-benzamide

FORMULA (II) COMPOUND TABLE (continued, page 3 of 7) 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-benzyl)-N- [5- (3-methoxy-phenyl)- 3-methyl-pent-2-en-4-ynyloxy]-benzamide 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (prop-2-ynyloxy)- benzamide 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- [3- (3-methoxy- phenyl)-prop-2-ynyloxy]-benzamide 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (thiopen- 2-ylmethoxy)-benzamide 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (pyridin- 3-ylmethoxy)-benzamide <BR> <BR> 5-Bromo-3-4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (3- (2-fluorophenyl)- prop-2-ynyloxy)-benzamide 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (ethoxy)-benzamide 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)-benzamide 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (isopropoxy)- benzamide 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N-but-3-ynyloxy)- benzamide <BR> <BR> 5-Chloro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N- (tetrahydro-pyran-2-yloxy)- benzamide <BR> <BR> 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N-methoxy-benzamide<BR> <BR> 4-Bromo-2- (4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide<B R> <BR> 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide<B R> <BR> 5-Fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino)-benzamide<BR> <BR> 5-Iodo-2- (4-iodo-2-methyl-phenylamino)-N-phenylmethoxy-benzamide<B R> <BR> 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (tetrahydropyran-2-yloxy)- benzamide

FORMULA (II) COMPOUND TABLE (continued, page 4 of 7) 3,4-Difluoro-2- (4-bromo-2-methyl-phenylamino)-N- (3-phenylprop-2-ynyloxy)- benzamide 3,4-Difluoro-2- (4-bromo-2-methyl-phenylamino)-N- (3-furylmethoxy)-benzamide 3,4-Difluoro-2- (4-bromo-2-methyl-phenylamino)-N- (2-thienylmethoxy)- benzamide 3,4-Difluoro-2- (4-bromo-2-methyl-phenylamino)-N- (but-3-ynyloxy)-benzamide 3,4-Difluoro-2- (4-bromo-2-methyl-phenylamino)-N- (2-methyl-prop-2-enyloxy)- benzamide 3,4-Difluoro-2- (4-bromo-2-methyl-phenylamino)-N- (but-2-enyloxy)-benzamide 3,4-Difluoro-2- (4-bromo-2-methyl-phenylamino)-N- (methoxy)-benzamide 3,4-Difluoro-2- (4-bromo-2-methyl-phenylamino)-N- (ethoxy)-benzamide 3,4-Difluoro-2- (4-bromo-2-methyl-phenylamino)-N- (cyclobutoxy)-benzamide 3,4-Difluoro-2- (4-bromo-2-methyl-phenylamino)-N- (isopropoxy)-benzamide 3,4-Difluoro-2- (4-bromo-2-methyl-phenylamino)-N- (2-phenoxyethoxy)- benzamide 3,4-Difluoro-2- (4-bromo-2-methyl-phenylamino)-N- (cyclopropylmethoxy)- benzamide 3,4-Difluoro-2- (4-bromo-2-methyl-phenylamino)-N- (n-propoxy)-benzamide 3,4-Difluoro-2- (4-bromo-2-methyl-phenylamino)-N- ( 1-methyl-prop-2-ynyloxy)- benzamide 3,4-Difluoro-2- (4-bromo-2-methyl-phenylamino)-N- (3- (3-fluorophenyl)-prop- 2-ynyloxy)-benzamide 3,4-Difluoro-2- (4-bromo-2-methyl-phenylamino)-N- (4,4-dimethylpent- 2-ynyloxy)-benzamide

FORMULA (II) COMPOUND TABLE (continued, page 5 of 7) 3,4-Difluoro-2- (4-bromo-2-methyl-phenylamino)-N- (cyclopentoxy)-benzamide 3,4,5-Trifluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino)-benzamide 5-Chloro-3,4-difluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino)-benzamide 5-Bromo-3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide N-Hydroxy-2- (4-iodo-2-methyl-phenylamino)-4-nitro-benzamide 3,4,5-Trifluoro-2- (2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide 5-Chloro-3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide <BR> <BR> <BR> 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3, 4-difluoro-N-hydroxy-benzamide<BR> <BR> <BR> <BR> <BR> 2- (2-Fluoro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide 2- (2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy-benz amide <BR> <BR> <BR> <BR> 5-Chloro-2- (2-chloro-4-iodo-phenylamino)-3, 4-difluoro-N-hydroxy-benzamide<BR> <BR> <BR> <BR> <BR> <BR> 5-Bromo-2- (2-bromo-4-iodo-phenylamino)-3, 4-difluoro-N-hydroxy-benzamide<BR> <BR> <BR> <BR> <BR> 2- (2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-methyl-benzamide&l t;BR> <BR> <BR> <BR> <BR> 2- (2-Bromo-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy-benza mide<BR> <BR> <BR> <BR> <BR> <BR> 2- (2-Bromo-4-iodo-phenylamino)-5-chloro-3, 4-difluoro-N-hydroxy-benzamide<BR> <BR> <BR> <BR> <BR> 2- (2-Bromo-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide 4-Fluoro-2- (2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide 3,4-Difluoro-2- (2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide 2- (2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benzami de <BR> <BR> <BR> 2- (2-Bromo-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide< ;BR> <BR> <BR> <BR> <BR> 2- (2-Bromo-4-iodo-phenylamino)-3, 4-difluoro-N-hydroxy-benzamide

FORMULA (II) COMPOUND TABLE (continued, page 6 of 7) N-Cyclopropylmethoxy-3,4,5-trifluoro-2- (4-iodo-2-methyl-phenylamino)- benzamide 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)- benzamide 5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)- benzamide N-Cyclopropylmethoxy-2- (4-iodo-2-methyl-phenylamino)-4-nitro-benzamide N-Cyclopropylmethoxy-3,4,5-trifluoro-2- (2-fluoro-4-iodo-phenylamino)- benzamide <BR> <BR> 5-Chloro-N-cyclopropylmethoxy-3, 4-difluoro-2- (2-fluoro-4-iodo-phenylamino)- benzamide <BR> <BR> 5-Bromo-2- (2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-diflu oro- benzamide <BR> <BR> N-Cyclopropylmethoxy-2- (2-fluoro-4-iodo-phenylamino)-4-nitro-benzamide<BR> <BR> 2- (2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4,5-tri fluoro- benzamide 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethox y-3,(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3, 4-difluoro- benzamide <BR> <BR> 5-Bromo-2- (2-bromo-4-iodo-phenylamino)-N-ethoxy-3,4-difluoro-benzamide <BR> <BR> 2- (2-Chloro-4-iodo-phenylamino)-N-ethoxy-4-nitro-benzamide< BR> <BR> 2- (2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4,5-trif luoro- benzamide <BR> <BR> 2- (2-Bromo-4-iodo-phenylamino)-5-chloro-N-cyclopropylmethoxy-3 , 4-difluoro- benzamide 2- (2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-nitro-be nzamide

FORMULA (II) COMPOUND TABLE (continued, page 7 of 7) N-Cyclopropylmethoxy-4-fluoro-2- (2-fluoro-4-iodo-phenylamino)-benzamide N-Cyclopropylmethoxy-3,4-difluoro-2- (2-fluoro-4-iodo-phenylamino)-benzamide <BR> <BR> <BR> <BR> 2- (2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro- benzamide<BR> <BR> <BR> <BR> <BR> <BR> 2- (2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-diflu oro-benzamide<BR> <BR> <BR> <BR> <BR> <BR> 2- (2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro-b enzamide<BR> <BR> <BR> <BR> <BR> <BR> 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3, 4-difluoro- benzamide.

In the most preferred embodiment of this invention, a compound selected from the following is administered to a patient (ie, a mammal) in an amount that is effective to prevent or treat rheumatoid arthritis or osteoarthritis: 2-(2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4-difluorobenzamide (PD184352); 2- (2-Methyl-4-iodophenylamino)-N- hydroxy-4-fluorobenzamide (PD 170611); 2- (2-Methyl-4-iodophenylamino)-N- hydroxy-3,4-difluoro-5-bromobenzamide (PD171984); 2- (2-Methyl- 4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluoro-5-bromo benzamide (PD 177168); 2- (2-Methyl-4-iodophenylamino)-N-cyclobutylmethoxy- 3,4-difluoro-5-bromobenzamide (PD 180841); 2- (2-Chloro-4-iodophenylamino)- N-cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide (PD 184161) ; 2- (2-Chloro-4-iodophenylamino)-N-hydroxy-3,4-difluoro-5-bromob enzamide (PD184386); 2- (2-Chloro-4-iodophenylamino)-N-cyclobutylmethoxy- 3,4-difluorobenzamide (PD 185625) ; 2- (2-Chloro-4-iodophenylamino)-N- hydroxy-4-fluorobenzamide (PD 185848); 2-(2-Methyl-4-iodophenylamino)-N- hydroxy-3,4-difluorobenzamide (PD 188563); 2- (2-Methyl-4-iodophenylamino)- N-cyclopropylmethoxy-3,4,5-trifluorobenzamide (PD 198306); and 2- (2-Chloro- 4-iodophenylamino)-N-cyclopropylmethoxy-4-fluorobenzamide (PD 203311); and the benzoic acid derivatives thereof. For example, the benzoic acid derivative of PD 198306 is 2- (2-Methyl-4-iodophenylamino)-3,4,5-trifluorobenzoic acid.

Additional preferred compounds include 2- (2-chloro-4-iodophenylamino)-5- chloro-N-cyclopropylmethoxy-3,4-difluorobenzamide (PD 297189), 2- (4-

iodophenylamino)-N-cyclopropylmethoxy-5-chloro-3,4-difluorob enzamide (PD 297190), 2- (4-iodophenylamino)-5-chloro-3,4-difluorobenzoic acid (PD 296771), 2- (2-chloro-4-iodophenylamino)-5-chloro-3,4-difluorobenzoic acid (PD 296770), 5-chloro-3,4-difluoro-2- (4-iodo-2-methylphenylamino)-benzoic acid (PD 296767); and 5-chloro-N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-2- methylphenylamino)-benzamide (PD 298127).

The invention further provides methods of synthesis and synthetic intermediates.

Other features and advantages of the invention are apparent from the detailed description, examples, and claims set forth.

In a further preferred embodiment of this invention, a mitotic inhibitor is administered to a patient suffering from cancer and in need of treatment in combination with a selective MEK inhibitor selected from: 2- (2-Chloro- 4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamid e (PD 184352); 2- (2-Methyl-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD 170611); 2- (2-Methyl-4-iodophenylamino)-N-hydroxy-3,4-difluoro-5-bromob enzamide (PD 171984), a more preferred compound; 2- (2-Methyl-4-iodophenylamino)-N- cyclopropylmethoxy-3,4-difluoro-5-bromobenzamide (PD 177168); 2- (2-Methyl- 4-iodophenylamino)-N-cyclobutylmethoxy-3,4-difluoro-5-bromob enzamide (PD 180841); 2- (2-Chloro-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-5-bromobenzamide (PD 184161); 2- (2-Chloro-4-iodophenylamino)- N-hydroxy-3,4-difluoro-5-bromobenzamide (PD 1843 86); 2- (2-Chloro- 4-iodophenylamino)-N-cyclobutylmethoxy-3,4-difluorobenzamide (PD 185625); 2- (2-Chloro-4-iodophenylamino)-N-hydroxy-4-fluorobenzamide (PD 185848); 2- (2-Methyl-4-iodophenylamino)-N-hydroxy-3,4-difluorobenzamide (PD 188563); 2- (2-Methyl-4-iodophenylamino)-N-cyclopropylmethoxy- 3,4,5-trifluorobenzamide (PD 198306); and 2- (2-Chloro-4-iodophenylamino)-N- cyclopropylmethoxy-4-fluorobenzamide (PD 203311); and the benzoic acid derivatives thereof. For example, the benzoic acid derivative of PD 198306 is 2- (2-Methyl-4-iodophenylamino)-3,4,5-trifluorobenzoic acid.

DETAILED DESCRIPTION OF THE INVENTION This invention provides a method of preventing or treating asthma in a patient which comprises administering to a patient suffering from asthma and in need of treatment, or to a patient at risk for developing an asthmatic attack, an anti-asthmatic effective amount of a MEK inhibitor. The invention provides a method of preventing and treating all forms of asthma and relieving the symptoms that accompany the disease. The invention is preferably practiced by administering a phenyl amine MEK inhibitor of Formula I or Formula II. Such MEK phenyl amine compounds are specific MEK 1 and MEK 2 inhibitors, meaning that they inhibit these enzymes without inhibiting other enzymes to a great extent.

The compounds of the present invention, which can be used to treat septic shock, are MEK inhibitors. A MEK inhibitor is a compound that shows MEK inhibition when tested in the assays titled"Enzyme Assays"in United States Patent Number 5,525,625, column 6, beginning at line 35. The complete disclosure of United States Patent Number 5,525,625 is hereby incorporated by reference. An example of a MEK inhibitor is 2- (2-amino-3-methoxyphenyl)- 4-oxo-4H- [1] benzopyran. Specifically, a compound is a MEK inhibitor if a compound shows activity in the assay titled"Cascade Assay for Inhibitors of the MAP Kinase Pathway,"column 6, line 36 to column 7, line 4 of the United States Patent Number 5,525,625 and/or shows activity in the assay titled"In Vitro MEK Assay"at column 7, lines 4 to 27 of the above-referenced patent.

A. Terms Some of the terms used herein are defined below and by their usage throughout this disclosure.

The term"patient"means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, horses, and pigs. The mammals to be treated according to this invention are patients who have developed asthma and are suffering from the symptoms associated with disease, or who are at risk for developing the disease, for example having a family history of asthma. Those skilled in the medical art are readily able to identify individual patients, particularly children, who are afflicted with asthma, as well as those who

are susceptible to developing the disease.

As used herein, the term"aryl"means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from five to twelve carbon atoms. Examples of typical aryl groups include phenyl, naphthyl, and fluorenyl. The aryl may be substituted by one, two, or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino. Typical substituted aryl groups include 3-fluorophenyl, 3,5-dimethoxyphenyl, 4-nitronaphthyl, 2-methyl-4-chloro-7-aminofluorenyl, and the like.

The term"aryloxy"means an aryl group bonded through an oxygen atom, for example phenoxy, 3-bromophenoxy, naphthyloxy, and 4-methyl- 1-fluorenyloxy.

"Heteroaryl"means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from four to eleven carbon atoms and one, two, or three heteroatoms selected from O, S, or N. Examples include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, xanthenyl, pyronyl, indolyl, pyrimidyl, naphthyridyl, pyridyl, benzinnidazolyl, and triazinyl. The heteroaryl groups can be unsubstituted or substituted by one, two, or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino. Examples of substituted heteroaryl groups include chloropyranyl, methylthienyl, fluoropyridyl, amino-1,4-benzisoxazinyl, nitroisoquinolinyl, and hydroxyindolyl.

The heteroaryl groups can be bonded through oxygen to make heteroaryloxy groups, for example thienyloxy, isothiazolyloxy, benzofuranyloxy, pyridyloxy, and 4-methylisoquinolinyloxy.

The term"alkyl"means straight and branched chain aliphatic groups.

Typical alkyl groups include methyl, ethyl, isopropyl, tert.-butyl, 2,3-dimethylhexyl, and 1,1-dimethylpentyl. The alkyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, as those terms are defined herein. Typical substituted alkyl groups include chloromethyl, 3-hydroxypropyl, 2-dimethylaminobutyl, and 2- (hydroxymethylamino) ethyl. Examples of aryl and aryloxy substituted alkyl groups include phenylmethyl, 2-phenylethyl, 3-chlorophenylmethyl, 1,1-dimethyl-3- (2-nitrophenoxy) butyl, and

3,4,5-trifluoronaphthylmethyl. Examples of alkyl groups substituted by a heteroaryl or heteroaryloxy group include thienylmethyl, 2-furylethyl, 6-furyloxyoctyl, 4-methylquinolyloxymethyl, and 6-isothiazolylhexyl. Cycloalkyl substituted alkyl groups include cyclopropylmethyl, 2-cyclohexyethyl, piperidyl- 2-methyl, 2- (piperidin-1-yl)-ethyl, 3- (morpholin-4-yl) propyl.

"Alkenyl"means a straight or branched carbon chain having one or more double bonds. Examples include but-2-enyl, 2-methyl-prop-2-enyl, 1,1-dimethyl- hex-4-enyl, 3-ethyl-4-methyl-pent-2-enyl, and 3-isopropyl-pent-4-enyl. The alkenyl groups can be substituted with halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy, heteroaryl, or heteroyloxy, for example 2-bromoethenyl, 3-hydroxy-2-butenyl, 1-aminoethenyl, 3-phenylprop-2-enyl, 6-thienyl-hex-2-enyl, 2-furyloxy-but-2-enyl, and 4-naphthyloxy-hex-2-enyl.

"Alkynyl"means a straight or branched carbon chain having at least one triple bond. Typical alkynyl groups include prop-2-ynyl, 2-methyl-hex-5-ynyl, 3,4-dimethyl-hex-5-ynyl, and 2-ethyl-but-3-ynyl. The alkynyl groups can be substituted as the alkyl and alkenyl groups, for example, by aryl, aryloxy, heteroaryl, or heteroaryloxy, for example 4- (2-fluorophenyl)-but-3-ynyl, 3-methyl-5-thienylpent-4-ynyl, 3-phenoxy-hex-4-ynyl, and 2-furyloxy-3-methyl- hex-4-ynyl.

The alkenyl and alkynyl groups can have one or more double bonds or triple bonds, respectively, or a combination of double and triple bonds. For example, typical groups having both double and triple bonds include hex-2-en- 4-ynyl, 3-methyl-5-phenylpent-2-en-4-ynyl, and 3-thienyloxy-hex-3-en-5-ynyl.

The term"cycloalkyl"means a nonaromatic ring or fused rings. Examples include cyclopropyl, cyclobutyl, cyclopenyl, cyclooctyl, bicycloheptyl, adamantyl, and cyclohexyl. The ring can optionally contain one, two, or three heteroatoms selected from O, S, or N. Such groups include tetrahydrofuryl, tetrahydropyrrolyl, octahydrobenzofuranyl, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, octahydroindolyl, and octahydrobenzothiofuranyl. The cycloalkyl groups can be substituted with the same substituents as an alkyl and alkenyl groups, for example, halo, hydroxy, aryl, and heteroaryloxy. Examples include 3-hydroxycyclohexyl, 2-aminocyclopropyl, 2-phenylpyrrolidinyl, and 3-thienylmorpholine-1-yl.

Selective MEK 1 or MEK 2 inhibitors are those compounds which inhibit the MEK 1 or MEK 2 enzymes, respectively, without substantially inhibiting other enzymes such as MKK3, PKC, Cdk2A, phosphorylase kinase, EGF, and PDGF receptor kinases, and C-src. In general, a selective MEK 1 or MEK 2 inhibitor has an IC5o for MEK 1 or MEK 2 that is at least one-fiftieth (1/50) that of its IC50 for one of the above-named other enzymes. Preferably, a selective inhibitor has an IC$o that is at least 1/100, more preferably 1/500, and even more preferably 1/1000,1/5000, or less than that of its In50 or one or more of the above- named enzymes.

B. Administration and Formulation The MEK inhibitors of the present method can be administered to a patient as part of a pharmaceutically acceptable composition. The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the

like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well- known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers,

as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols, and fatty acid esters of sorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalamic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.

The compounds of the present method can be administered to a patient at dosage levels in the range of about 0.1 to about 1000 mg per day. For a normal human adult having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kg of body weight per day is preferable. The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well-

known to those skilled in the art.

The compounds of the present method can be administered as pharmaceutically acceptable salts, esters, amides, or prodrugs. The term "pharmaceutically acceptable salts, esters, amides, and prodrugs"as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.

The term"salts"refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts, and the like.

These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, S. M. Berge, et al., "Pharmaceutical Salts,"J. Pharm. Sci., 1977; 66: 1-19 which is incorporated herein by reference.) Examples of pharmaceutically acceptable, non-toxic esters of the compounds of this invention include C 1-C6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include Cs-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C 1-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.

Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C1-C6 alkyl amines and secondary C1-C6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5 or 6 membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amines and C1-C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.

The term"prodrug"refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella,"Pro-drugs as Novel Delivery Systems,"Vol. 14 of the A. C. S.

Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B.

Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

In addition, the compounds of the present method can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

Some of the compounds of the present method can exist in different stereoisometric forms by virtue of the presence of chiral centers. It is contemplated that all stereoisometric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of this invention.

C. Synthesis The examples presented below are intended to illustrate particular embodiments of the invention and are not intended to limit the scope of the specification, including the claims, in any way. After the priority date of the present disclosure, related syntheses and MEK inhibition data were also published in WO 99/01421 and WO 99/01426, hereby incorporated by reference.

The 2- (4-bromo and 4-iodo phenylamino)-benzoic acid derivatives of Formula I can be prepared from commercially available starting materials utilizing synthetic methodologies well-known to those skilled in organic chemistry. A typical synthesis is carried out by reacting a 4-bromo or 4-iodo aniline with a benzoic acid having a leaving group at the 2-position to give a 2- (phenylamino)- benzoic acid. This process is depicted in Scheme 1.

Scheme 1 0 IR2 COH R1 L NH T J. rY " Ri or t--uH Ne L R3 R4 base 11- II Ri C-OH N I I R5 / RS Br or I v \ R3 R4

where L is a leaving group, for example halo such as fluoro.

The reaction of aniline and the benzoic acid derivative generally is accomplished by mixing the benzoic acid with an equimolar quantity or excess of the aniline in an unreactive organic solvent such as tetrahydrofuran or toluene, in the presence of a base such as lithium diisopropylamide, n-butyl lithium, sodium hydride, triethylamine, and Hunig's base. The reaction generally is carried out at a temperature of about-78°C to about 100°C, and normally is complete within about 2 hours to about 4 days. The product can be isolated by removing the solvent, for example by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.

The 2- (phenylamino)-benzoic acid (e. g., Formula I, where R7 is hydrogen) can be reacted with an organic or inorganic base such as pyridine, triethylamine, calcium carbonate, or sodium hydroxide to produce a pharmaceutically acceptable salt. The free acids can also be reacted with an alcohol of the formula HOR7

(where R7 is other than hydrogen, for example methyl) to produce the corresponding ester. Reaction of the benzoic acid with an alcohol can be carried out in the presence of a coupling agent. Typical coupling reagents include 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), 1,3-dicyclohexylcarbodiimide (DCC), bromo-tris (pyrrolidino)- phosphonium hexafluorophosphate (PyBrOP), and (benzotriazolyloxy) tripyrrolidino phosphonium hexafluorophosphate (PyBOP). The phenylamino benzoic acid and alcohol derivative normally are mixed in approximately equimolar quantities in an unreactive organic solvent such as dichloromethane, tetrahydrofuran, chloroform, or xylene, and an equimolar quantity of the coupling reagent is added. A base such as triethylamine or diisopropylethylamine can be added to act as an acid scavenger if desired. The coupling reaction generally is complete after about 10 minutes to 2 hours, and the product is readily isolated by removing the reaction solvent, for instance by evaporation under reduced pressure, and purifying the product by standard methods such as chromatography or crystallizations from solvents such as acetone, diethyl ether, or ethanol.

The benzamides of the invention, Formula I where Z is CONR6R7, are readily prepared by reacting the foregoing benzoic acids with an amine of the formula HNR6R7. The reaction is carried out by reacting approximately equimolar quantities of the benzoic acid and amine in an unreactive organic solvent in the presence of a coupling reagent. Typical solvents are chloroform, dichloromethane, tetrahydrofuran, benzene, toluene, and xylene. Typical coupling reagents include DCC, EEDQ, PyBrOP, and PyBOP. The reaction is generally complete after about 10 minutes to about 2 hours when carried out at a temperature of about 0°C to about 60°C. The product amide is readily isolated by removing the reaction solvent, for instance by evaporation, and further purification can be accomplished by normal methods such as chromatography, crystallization, or distillation. The hydrazides (z = CONHNR1 oRl l) are similarly prepared by coupling a benzoic acid with a hydrazine of the formula H2HNRioRn.

The benzyl alcohols of the invention, compounds of Formula I where Z is CH20R6 and R6 is hydrogen, are readily prepared by reduction of the corresponding benzoic acid according to the following Scheme 2.

Scheme 2 0 Ri C-OH R12 H20H Reducing , X\reducing. ><\ / (RS/ RS Br or I Br or 15 R3 R4 R3 R4 Typical reducing agents commonly employed include borane in tetrahydrofuran.

The reduction normally is carried out in an unreactive organic solvent such as tetrahydrofuran, and generally is complete within about 2 hours to about 24 hours when conducted at a temperature of about 0°C to about 40°C.

The following detailed examples illustrate specific compounds provided by this invention.

EXAMPLE 1 4-Fluoro-2- (4-iodo-2-methylphenylamino) benzoic acid To a stirring solution comprised of 3.16 g (0.0133 mol) of 2-amino-5- iodotoluene in 5 mL of tetrahydrofuran at-78°C was added 10 mL (0.020 mol) of a 2.0 M lithium diisopropylamide in tetrahydrofuran/heptane/ethenylbenzene (Aldrich) solution. The resulting green suspension was stirred vigorously for 15 minutes, after which time a solution of 1.00 g (0.00632 mol) of 2,4-difluorobenzoic acid in 10 mL of tetrahydrofuran was added. The reaction temperature was allowed to increase slowly to room temperature, at which temperature it was stirred for 2 days. The reaction mixture was concentrated.

Aqueous HCl (10%) was added to the concentrate, and the solution was extracted with dichloromethane. The organic phase was dried (MgSO4) and then boiled over a steambath to low volume and cooled to room temperature. The off-white

fibers were collected by vacuum filtration, rinsed with hexanes, and vacuum-oven dried. (76°C; ca. 10 mm of Hg) to afford 1.10 g (47%) of the desired material; mp 224-229.5°C; 1H NMR (400 MHz; DMSO): 8 9.72 (s, 1H), 7.97 (dd, 1H, J = 7.0,8.7 Hz), 7.70 (d, 1H, J= 1.5 Hz), 7.57 (dd, 1H, J=8.4,1.9 Hz), 7.17 (d, lH, J=8. 2Hz), 6.61-6.53 (m, 2H), 2.18 (s, 3H); 13C NMR (100 MHz; DMSO): S 169.87, 167.60,165.12,150.17,150.05,139.83,138.49,136.07,135.31,135. 20,135.07, 125.60,109.32,105.09,104.87,99.72,99.46,89.43,17.52; 19F NMR (376 MHz; DMSO): 8-104.00 to-104.07 (m); IR (KBr) 1670 (C = O stretch) cm~1 ; MS (CI) M+1 = 372.

Analysis calculated for C14Hl lFINO2 : C, 45.31; H, 2.99; N, 3.77.

Found: C, H, 2.77; N, 3.64.

EXAMPLES 2-30 By following the general procedure of Example 1, the following benzoic acids and salts of Formula (I) were prepared.

Example Compound MP °C No.

2 3,4,5-Trifluoro-2- (4-iodo-2-methyl-phenylamino)- 206-210 benzoic acid 3 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-benzoic 240.5-244.5 acid 4 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl- 259.5-262 phenylamino)-benzoic acid 5 5-Chloro-2- (2-chloro-4-iodo-phenylamino)-benzoic acid 255-260 6 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-benzoic acid 234-238 7 Sodium 5-Chloro-2- (4-iodo-2-methyl-phenylamino)- 310-320 DEC benzoate 8 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-benzoic acid 239.5-240 9 2- (2-Chloro-4-iodo-phenylamino)-5-nitro-benzoic acid 289-293 10 4-Fluoro-2- (3-fluoro-4-iodo-2-methyl-phenylamino)- 233-235 benzoic acid 11 2- (4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid 264-267 12 2- (2-Fluoro-4-iodo-phenylamino)-5-nitro-benzoic acid 256-258 13 2- (4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic 218.5-220 acid 14 2- (2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic acid 285-288 DEC 15 2- (4-Bromo-2-methyl-phenylamino)-3, 4-difluoro- 230-234 benzoic acid 16 3-Fluoro-2- (4-iodo-2-methyl-phenylamino)-benzoic acid 218-221 17 3,4-Difluoro-2- (4-iodo-2-methoxy-phenylamino)- 230-233 benzoic acid 18 4-Chloro-2- (4-iodo-2-methyl-phenylamino)-benzoic acid 245-255 DEC

Example Compound MP °C No.

19 2- (4-Iodo-2-methyl-phenylamino)-benzoic acid 218-223 20 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-benzoic acid 243-46 21 5-Iodo-2- (4-iodo-2-methyl-phenylamino)-benzoic acid 241-245 22 2,3,5-Trifluoro-4- (4-iodo-2-methyl-phenylamino)- 218-222 benzoic acid 23 4-Fluoro-2- (3-chloro-4-iodo-2-methyl-phenylamino)- 248-252.5 benzoic acid 24 2- (4-Iodo-phenylamino)-5-methoxy-benzoic acid 208-211 25 3-Chloro-2- (2-chloro-4-iodo-phenylamino)-benzoic acid 232-233 26 2-Fluoro-6- (4-iodo-2-methyl-phenylamino)-benzoic acid 179-182 27 4-Fluoro2- (2, 3-dimethyl-4-iodo-2-methyl- 258-261 phenylamino) benzoic acid 28 5-Methyl-2- (4-iodo-2-methyl-phenylamino)-benzoic 209.5-211 acid 29 2-Chloro-6- (4-iodo-2-methyl-phenylamino)-benzoic acid 171-175 30 2- (4-Iodo-2-methyl-phenylamino)-4-nitro-benzoic acid 251-263 EXAMPLE 31 S-Chloro-N- (2-hydroxvethyl)-2- (4-iodo-2-methyl-phenylamino)-benzamide To a stirring solution comprised of 0.1020 g (0.2632 mmol) of 5-chloro- 2- (4-iodo-2-methyl-phenylamino)-benzoic acid, 0.1 mL (1.7 mmol) of ethanolamine, and 0.05 mL (0.29 mmol) of diisopropylethylamine in 5 mL of a 1: 1 (v/v) tetrahydrofuran-dichloromethane solution was added 0.15 g (0.29 mmol) of solid PyBOP powder directly. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The crude residue was partitioned between ether (50 mL) and 10% aqueous hydrochloric acid (50 mL).

The organic phase was washed with 10% aqueous sodium hydroxide (50 mL), dried (MgSO4) and concentrated in vacuo to afford a yellow-brown oil which was crystallized from hexanes-ether to afford 0.0831 g (73%) of a green-yellow powder; mp 120-121°C;

1H NMR (400 MHz; CDCl3): 8 9. 11 (s, 1H), 7.56 (d, 1H, J = 1.4 Hz), 7.46-7.41 (m, 2H), 7.20 (dd, 1H, J = 8.9,2.4 Hz), 7.00 (t, 2H, J = 9.6 Hz), 6.55 (broad t, 1H), 3.86 (t, 2H, J = 5.0 Hz), 3.61 (dd, 2H, J = 10.1,5.5 Hz), 2.23 (s, 3H), 1.56 (broad s, 1H); IR (KBr) 3297 (O-H stretch), 1627 (C = O stretch) cm~1; MS (CI) M+1 = 431.

Analysis calculated for C16Hl6ClIN202 : C, 44.62; H, 3.74; N, 6.50.

Found: 44.63; H, 3.67; N, 6.30.

EXAMPLES 32-48 By following the general procedure of Example 31, the following benzamides were prepared by reacting the corresponding benzoic acid with the corresponding amine.

Example Compound MP °C No.

32 4-Methoxy-N- (4-methoxy-phenyl)-3-nitro- 153.5-156 benzamide 33 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)- 158 benzamide 34 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- 102.5-104.5 methyl-benzamide 35 N-Ethyl-4-fluoro-2- (4-iodo-2-methyl-phenylamino)- 90-91 benzamide 36 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N, N- oil dimethyl-benzamide 37 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (1H- 285-288 DEC tetrazol-5-yl)-benzamide 38 5-Bromo-2- (4-iodo-2-methyl-phenylamino)- 180-182 benzamide 39 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N, N- 137-138 dimethyl-benzamide

Example Compound MP °C No.

40 [5-Chloro-2- (4-iodo-2-methyl-phenylamino)- 170-173 benzoylamino]-acetic acid 41 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- 69-71 propyl-benzamide 42 5-Bromo-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl- 132-133.4 phenylamino)-benzamide 43 N, N-Diethyl-4-fluoro-2- (4-iodo-2-methyl- oil phenylamino)-benzamide 44 4-Fluoro-N- {3- [4- (2-hydroxy-ethyl)-piperazin-1-yl]- 122-124 propyl}-2- (4-iodo-2-methyl-phenylamino)- benzamide 45 N, N-Diethyl-2- (4-iodo-2-methyl-phenylamino)-5- 91-93 nitro-benzamide 46 N-Butyl-4-fluoro-2- (4-iodo-2-methyl-phenylamino)- 97-99 benzamide 47 5-Chloro-N, N-diethyl-2- (4-iodo-2-methyl- 118-120 phenylamino)-benzamide 48 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N, N- 142.5-144 dimethyl-benzamide EXAMPLE 49 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-benzyl alcohol 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-benzoic acid (0.50 g, 1.35 mmol) was dissolved in 6 mL (6 mmol) of cold 1.0 M borane- tetrahydrofuran complex in tetrahydrofuran solution. The reaction mixture was stirred under nitrogen atmosphere at room temperature overnight. The reaction was quenched with 80 mL of methanol. Concentration in vacuo produced a clear tan oil which was purified by MPLC. Elution with dichloromethane afforded 0.4285 g (89%) of a white solid; mp 99-100.5°C; 1H NMR (400 MHz; DMSO): 8 7.57 (d, 1H, J=1.7 Hz), 7.45 (dd, 1H, J=8.4, 1.9 Hz), 7.39 (s, 1H), 7.29 (t, 1H, J=7.5 Hz), 6.89 (d, 1H, J=8.4 Hz), 6.67-6.60 (m, 1H), 5.47 (t, 1H, J=5.5 Hz), 4.49 (d, 2H, 5.1 Hz), 2.14 (s, 3H);

IR (KBr) 3372 (O-H stretch) cm~1; MS (CI) M+1 = 358.

Analysis calculated for C14Hl3FINO: C, 47.08; H, 3.67; N, 3.92.

Found: C, 47.17; H, 3.75; N, 3.72.

EXAMPLE 50-52 The following benzyl alcohols were prepared by the general procedure of Example 49.

Example No. Compound MP °C 50 [5-Chloro-2- (4-iodo-2-methyl-phenylamino)- 82-85 phenyl]-methanol 51 [2- (4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl]- 126.5-128.5 methanol 52 [5-Bromo-2- (4-iodo-2-methyl-phenylamino)- 60.5-63.5 phenyl]-methanol Several invention compounds of Formula I were prepared utilizing combinatorial synthetic techniques. The general procedure is as follows: To a 0.8-mL autosampler vial in a metal block was added 40 uL of a 0.5 M solution of the acid in DMF and 40 pL of the reagent amine (2 M solution in Hunig's base and 1 M in amine in DMF). A 0.5 M solution of PyBrop was freshly prepared and 50 uL were added to the autosampler vial. The reaction was allowed to stand for 24 hours.

The reaction mixture was transferred to a 2-dram vial and diluted with 2 mL of ethyl acetate. The organic layer was washed with 3 mL of distilled water and the water layer washed again with 2 mL of ethyl acetate. The combined organic layers were allowed to evaporate to dryness in an open fume hood.

The residue was taken up in 2 mL of 50% acetonitrile in water and injected on a semi-prep reversed phase column (10 mm x 25 cm, 5 uM spherical silica, pore size 115 A derivatized with C-18, the sample was eluted at 4.7 mL/min with

a linear ramp to 100% acetonitrile over 8.5 minutes. Elution with 100% acetonitrile continued for 8 minutes). Fractions were collected by monitoring at 214 nM. The residue was dissolved in chloroform and transferred to a preweighed vial, evaporated, and weighed again to determine the yield.

EXAMPLES 53-206 The following compounds of Formula I were prepared by combinatorial methodology: Example Compound MS No. M-H 53 5-Bromo-3,4-difluoro-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl- 510 phenylamino)-benzamide 54 N- (2, 3-Dihydroxy-propyl)-3, 4-difluoro-2- (4-iodo-2-methyl- 462 phenylamino)-benzamide 55 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2- 577 piperidin-I-yl-ethyl)-benzamide 56 3,4-Difluoro-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl- 432 phenylamino)-benzamide 57 N- (2, 3-Dihydroxy-propyl)-4-fluoro-2- (4-iodo-2-methyl- 444 phenylamino)-benzamide 58 3,4-Difluoro-N- (3-hydroxy-propyl)-2- (4-iodo-2-methyl- 446 phenylamino)-benzamide 59 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- 564 (2-pyrrolidin-1-yl-ethyl)-benzamide 60 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- 571 (2-pyridin-4-yl-ethyl)-benzamide 61 4-Fluoro-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)- 414 benzamide Example Compound MS No. M-H 62 5-Bromo-N- (3-dimethylamino-propyl)-3, 4-difluoro-2- (4-iodo- 551 2-methyl-phenylamino)-benzamide 63 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- 580 (2-morpholin-4-yl-ethyl)-benzamide 64 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-morpholin- 501 4-yl-ethyl)-benzamide 65 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-pyrrolidin- 485 1-yl-ethyl)-benzamide 66 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-pyridin-4-yl- 493 ethyl)-benzamide 67 N- (3-Dimethylamino-propyl)-3, 4-difluoro-2- (4-iodo-2-methyl- 473 phenylamino)-benzamide 68 N-Benzyl-4-fluoro-2- (4-iodo-2-methyl-phenylamino)-benzamide 460 69 2- (4-Bromo-2-methyl-phenylamino)-3, 4-difluoro-N- (2-hydroxy- 384 ethyl)-benzamide 70 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-morpholin-4-yl- 483 ethyl)-benzamide 71 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (3-piperidin-1-yl- 495 propyl)-benzamide 72 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N- (3-piperidin- 513 1-yl-propyl)-benzamide 73 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-thiophen-2-yl- 480 ethyl)-benzamide 74 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-y l-467 ethyl)-benzamide 75 2- (4-Bromo-2-methyl-phenylamino)-3, 4-difluoro-N- (2-morpholin- 453 4-yl-ethyl)-benzamide 76 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-N- 557 pyridin-4-ylmethyl-benzamide 77 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)-N-pyridin- 479 4-yl-methyl-benzamide 78 2- (4-Bromo-2-methyl-phenylamino)-N- (3-dimethylamino-propyl)- 425 3,4-difluoro-benzamide Example Compound MS No. M-H 79 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- 461 benzamide 80 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-pyridin-4-yl- 475 ethyl)-benzamide 81 2- (4-Bromo-2-methyl-phenylamino)-3, 4-difluoro-N- (2-pyridin- 445 4-yl-ethyl)-benzamide 82 2- (4-Bromo-2-methyl-phenylamino)-3, 4-difluoro-N- (3-hydroxy- 400 propyl)-benzamide 83 2- (4-Bromo-2-methyl-phenylamino)-3, 4-difluoro-N- (2-pyrrolidin- 437 1-yl-ethyl)-benzamide 84 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N-phenethyl- 474 benzamide 85 2- (4-Bromo-2-methyl-phenylamino)-3, 4-difluoro-N- (2-thiophen- 450 2-yl-ethyl)-benzamide 86 2- (4-Bromo-2-methyl-phenylamino)-3, 4-difluoro-N-pyridin- 431 4-ylmethyl-benzamide 87 2- (4-Bromo-2-methyl-phenylamino)-3, 4-difluoro-N-phenethyl- 444 benzamide 88 2- (4-Bromo-2-methyl-phenylamino)-3, 4-difluoro-N- (2-piperidin- 451 1-yl-ethyl)-benzamide 89 5-Chloro-N- {3- [4- (2-hydroxy-ethyl)-piperazin-1-yl]-propyl}- 557* 2- (4-iodo-2-methyl- phenylamino)-benzamide 90 5-Fluoro-N- {3- [4- (2-hydroxy-ethyl)-piperazin-1-yl]-propyl}- 541 * 2- (4-iodo-2-methyl- phenylamino)-benzamide 91 2- (4-Iodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methyl-487 benzamide 92 5-Bromo-N- {3- [4- (2-hydroxy-ethyl)-piperazin-1-yl]-propyl}- 601 * 2- (4-iodo-2-methyl- phenylamino)-benzamide 93 5-Chloro-N- (2-diethylamino-ethyl)-2- (4-iodo-2-methyl- 486* phenylamino)-benzamide Example Compound MS No. M-H 94 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N- (2-piperidin-1-yl- 497* ethyl)-benzamide 95 (3-Hydroxy-pyrrolidin-1-yl)- [2- (4-iodo-2-methyl-phenylamino)- 466 5-nitro-phenyl]-methanone 96 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N- (2-pyrrolidin- I-yl-484* ethyl)-benzamide 97 5-Bromo-N- (2-diethylamino-ethyl)-2- (4-iodo-2-methyl- 530* phenylamino)-benzamide 98 N- {2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-chloro-2-(4-iodo-5 18* 2-methyl-phenylamino)-benzamide 99 N- {2- [Bis- (2-hydroxy-ethyl)-amino]-ethyl}-5-bromo-2- (4-iodo- 562* 2-methyl-phenylamino)-benzamide 100 [5-Bromo-2- (4-iodo-2-methyl-phenylamino)-phenyl]- (3-hydroxy- 499 pyrrolidin-1-yl)-methanone 101 2- (4-lodo-2-methyl-phenylamino)-5-nitro-benzoic acid phenethyl 501 ester 102 N- {3- [4- (2-Hydroxy-ethyl)-piperazin-1-yl]-propyl}-2- (4-iodo- 568* 2-methyl-phenylamino)-benzamide 103 [5-Chloro-2- (4-iodo-2-methyl-phenylamino)-phenyl]- (3-hydroxy- 455 pyrrolidin-1-yl)-methanone 104 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl- 460 benzamide 105 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N- (2-pyrrolidin-1-yl- 528* ethyl)-benzamide 106 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N- (2-piperidin-l-yl- 542* <BR> <BR> <BR> <BR> ethyl)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> <BR> 107 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-pyrrolidin-1-yl- 468*<BR> <BR> <BR> <BR> <BR> <BR> ethyl)-benzamide 108 5-Chloro-N- (3-dimethylamino-propyl)-2- (4-iodo-2-methyl- 472* phenylamino)-benzamide 109 N- {2- [Bis- (2-hydroxy-ethyl)-amino]-ethyl}-5-fluoro-2- (4-iodo- 502* 2-methyl-phenylamino)-benzamide Example Compound MS No. M-H 110 5-Chloro-N- (3-hydroxy-propyl)-2- (4-iodo-2-methyl- 445* phenylamino)-benzamide <BR> <BR> <BR> 111 5-Chloro-N- (3-diethylamino-2-hydroxy-propyl)-2- (4-iodo- 516* 2-methyl-phenylamino)-benzamide 112 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-piperidin-1-yl- 482* ethyl)-benzamide 113 5-Bromo-N- (3-hydroxy-propyl)-2- (4-iodo-2-methyl- 489* phenylamino)-benzamide 114 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N- (3-piperidin-1-yl- 556* propyl)-benzamide 115 N-12- [Bis- (2-hydroxy-ethyl)-amino]-ethyll-2- (4-iodo-2-methyl- 529* phenylamino)-5-nitro-benzamide 116 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N- (2-morpholin-4-yl- 500* ethyl)-benzamide 117 5-Chloro-N- (3-diethylamino-propyl)-2- (4-iodo-2-methyl- 500* phenylamino)-benzamide 118 5-Chloro-N- (2-diisopropylamino-ethyl)-2- (4-iodo-2-methyl- 514* phenylamino)-benzamide 119 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N- (3-piperidin-1-yl- 512* propyl)-benzamide 120 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin-1-yl- 509* ethyl)-benzamide 121 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N- (2-piperazin-1-yl- 544* ethyl)-benzamide 122 N- (2-Diethylamino-ethyl)-5-fluoro-2- (4-iodo-2-methyl- 470* phenylamino)-benzamide 123 5-Bromo-N- (3-dimethylamino-propyl)-2- (4-iodo-2-methyl- 516* phenylamino)-benzamide 124 N- (3-Hydroxy-propyl)-2- (4-iodo-2-methyl-phenylamino)-5-nitro- 456* benzamide Example Compound MS No. M-H 125 5-Fluoro-N- (3-hydroxy-propyl)-2- (4-iodo-2-methyl- 429* phenylamino)-benzamide 126 N- (3-Diethylamino-propyl)-5-fluoro-2- (4-iodo-2-methyl- 484* phenylamino)-benzamide 127 N- (3-Diethylamino-propyl)-2- (4-iodo-2-methyl-phenylamino)- 511* 5-nitro-benzamide 128 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N- (2-morpholin-4-yl- 544* ethyl)-benzamide 129 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin-1-yl- 523 * propyl)-benzamide 130 [5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-phenyl]- (3-hydroxy- 439 pyrrol idin-I-yl)-methanone 131 5-Bromo-N- (2-diisopropylamino-ethyl)-2- (4-iodo-2-methyl- 558* phenylamino)-benzamide 132 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (2-morpholin-4-yl- 484* ethyl)-benzamide 133 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (3-piperidin- I-yl-496* propyl)-benzamide 134 [5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-phenyl]- 482 [4- (2-hydroxy-ethyl)-piperazin-1-yi]-methanone 135 N- (3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2- (4-iodo- 500* 2-methyl-phenylamino)-benzamide 136 [5-Chloro-2- (4-iodo-2-methyl-phenylamino)-benzoylamino]- 443 acetic acid <BR> <BR> <BR> <BR> <BR> 137 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-pyrrolidin-1-yl -495 * ethyl)-benzamide 138 N- (3-Dimethylamino-propyl)-2- (4-iodo-2-methyl-phenylamino)- 48 * 5-nitro-benzamide 139 N- (2-Diisopropylamino-ethyl)-5-fluoro-2- (4-iodo-2-methyl- 498* phenylamino)-benzamide 140 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-thiobenzoic acid S-490 phenethyl ester Example Compound MS No. M-H 141 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-thiobenzoic acid S-506 phenethyl ester 142 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-thiobenzoic acid S-536 benzyl ester 143 2- (4-Iodo-2-methyl-phenylamino)-5-nitro-thiobenzoic acid S-503 benzyl ester 144 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-thiobenzoic acid S-476 benzyl ester 145 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-thiobenzoic acid S-492 benzyl ester 146 N-Cyclopropyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino)- 409 benzamide 147 5-Chloro-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)- 429 benzamide 148 5-Fluoro-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)- 413 benzamide 149 N-Benzyloxy-5-fluoro-2- (4-iodo-2-methyl-phenylamino)- 475 benzamide 150 N-Benzyloxy-5-bromo-2- (4-iodo-2-methyl-phenylamino)- 593* benzamide 151 2- (4-Iodo-2-methyl-phenylamino)-5-nitro-N- (4-sulfamoyl- 567 benzyl)-benzamide 152 5-Bromo-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)- 473 benzamide 153 N- (2-Hydroxy-ethyl)-5-iodo-2- (4-iodo-2-methyl-phenylamino)- 521 benzamide Example Compound MS No. M-H 154 N- (2-Hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)-5-nitro- 440 benzamide 155 2- (4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- 486 benzamide 156 5-Chloro-N-cyclopropyl-2- (4-iodo-2-methyl-phenylamino)- 425 benzamide 157 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 459 benzamide 158 N-Allyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino)-benzamide 409 159 N-Benzyloxy-5-iodo-2- (4-iodo-2-methyl-phenylamino)- 583 benzamide 160 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (4-sulfamoyl- 538 benzyl)-benzamide 161 N-Allyl-5-chloro-2- (4-iodo-2-methyl-phenylamino)-benzamide 425 162 N-Cyclopropyl-2- (4-iodo-2-methyl-phenylamino)-5-nitro- 436 benzamide 163 5-Bromo-N-cyclopropyl-2- (4-iodo-2-methyl-phenylamino)- 469 benzamide 164 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 475 benzamide 165 5-Iodo-2- (4-iodo-2-methyl-phenylamino)-N- (4-sulfamoyl-benzyl)- 646 benzamide 166 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N- (4-sulfamoyl- 598 benzyl)-benzamide 167 N-Allyl-2- (4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 436 Example Compound MS No. M-H 168 2- (4-Iodo-2-methyl-phenylamino)-5-nitro-N- (4-sulfamoyl- 565 benzyl)-benzamide 169 N-Allyl-5-bromo-2- (4-iodo-2-methyl-phenylamino)-benzamide 469 170 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (3-methyl-benzyl)- 473 benzamide 171 N-Cyclopropyl-5-iodo-2- (4-iodo-2-methyl-phenylamino)- 517 benzamide 172 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 519 benzamide 173 N-Benzyloxy-2- (4-iodo-2-methyl-phenylamino)-5-nitro- 502 benzamide 174 N-Cyclohexyl-5-iodo-2- (4-iodo-2-methyl-phenylamino)- 559 benzamide 175 N-Allyl-5-iodo-2- (4-iodo-2-methyl-phenylamino)-benzamide 517 176 5-Iodo-2- (4-iodo-2-methyl-phenylamino)-N- (3-methyl-benzyl)- 581 benzamide 177 2- (4-Iodo-2-methyl-phenylamino)-N- (3-methyl-benzyl)-5-nitro- 500 benzamide 178 5-Iodo-2- (4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 567 benzamide 179 N-Cyclohexyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino)- 451 benzamide 180 5-Chloro-N-cyclohexyl-2- (4-iodo-2-methyl-phenylamino)- 467 benzamide 181 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N- (3-methyl-benzyl)- 533 benzamide 182 5-Bromo-N-cyclohexyl-2- (4-iodo-2-methyl-phenylamino)- 511 benzamide 183 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N- (3-methyl-benzyl)- 489 benzamide Example Compound MS No. M-H 184 N-Cyclohexyl-2- (4-iodo-2-methyl-phenylamino)-5-nitro- 478 benzamide 185 N-Benzyloxy-5-bromo-2- (4-iodo-2-methyl-phenylamino)- 538 benzamine 186 N-Benzyloxy-5-fluoro-2- (4-iodo-2-methyl-phenylamino)- 477 benzamide 187 5-Chloro-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)- 431 benzamide 188 5-Bromo-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)- 475 benzamide 189 2- (4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- 488 benzamide 190 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 477 benzamide 191 N- (2-Hydroxy-ethyl)-5-iodo-2- (4-iodo-2-methyl-phenylamino)- 523 benzamide 192 5-Chloro-N-cyclopropyl-2- (4-iodo-2-methyl-phenylamino)- 425 benzamide 193 N-Allyl-5-chloro-2- (4-iodo-2-methyl-phenylamino)-benzamide 427 194 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 461 benzamide 195 N- (2-Hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)-5-nitro-442 benzamide 196 5-Fluoro-N- (2-hydroxy-ethyl)-2- (4-iodo-2-methyl-phenylamino)- 415 benzamide 197 5-Bromo-N-cyclopropyl-2- (4-iodo-2-methyl-phenylamino)- 472 benzamide 198 N-Cyclopropyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino)- 411 benzamide 199 5-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- (4-sulfamoyl- 540 benzyl)-benzamide

Example Compound MS No. M-H 200 N-Cyclopropyl-2- (4-iodo-2-methyl-phenylamino)-5-nitro- 438 benzamide 201 N-Allyl-5-fluoro-2- (4-iodo-2-methyl-phenylamino)-benzamide 411 202 N-Benzyloxy-5-iodo-2- (4-iodo-2-methyl-phenylamino)- 585 benzamide 203 N-Allyl-5-bromo-2- (4-iodo-2-methyl-phenylamino)-benzamide 472 204 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N- (4-sulfamoyl- 601 benzyl)-benzamide 205 5-Bromo-2- (4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 522 benzamide 206 N-Allyl-2- (4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 438 * M+H EXAMPLE 207 Preparation of [4-Chloro-2- 1 H-tetrazol-5-yl)- (4-iodo-2-methyl-phenyl)-amine Step a: Preparation of 5-chloro-2-fluoro-benzaldehyde To a solution of 1-chloro-4-fluorobenzne (13.06 g, 0.1 mol) in THF (180 mL), at-78°C, LDA (2M solution in THF, 50 mL, 0.1 mol) was added drop wise. After stirring at-78°C for 1.5 hours, DMF (8 mL) was added to the reaction mixture and allowed to warm up to room temperature overnight. The reaction mixture was partitioned between water and Et20. The Et20 layer was dried (MgSO4) and the solvent removed in vacuum to give 14.95 g (94%) yield of crude aldehyde: 1H NMR (CDC13): 8,10.3 (s,-C (=O) H).

Step b: Preparation of 5-chloro-2-fluoro-benzaldehvde oxime A solution of 5-chloro-2-fluoro-benzaldehyde (10 g, 0.0631 mol), hydroxylamine hydrochloride (6.57 g, 0.0946 mol) and pyridine (8.3 mL, 0.1010 mol) in EtOH (100 mL) was heated at 75°C (oil bath temperature) for 1 hour and the solvent removed under vacuum to give an oil. The oil was

partitioned between water and CH2Cl2. The CH2Cl2 layer was dried (MgSO4) and the solvent removed under vacuum to give crude aldoxime as a solid. The solid was purified by medium pressure liquid chromatography on silica. Elution with CH2Cl2 gave 4.87 g (28%) of the aldoxime as white solid: mp 95-97°C; Analysis calculated for C7HSNOFCI: C, 48.44; H, 2.90; N, 8.07.

Found: C, 48.55; H, 2.69, N, 7.90.

Step c: Preparation of 5-chloro-2-fluoro-benzonirile A solution of the 5-chloro-2-fluoro-benzaldehyde oxime (3.15 g, 0.0182 mol) in acetic anhydride (150 mL) was refluxed for 16 hours. The reaction mixture was cooled to room temperature and poured into saturated aqueous NaHC03 (200 mL) solution. The mixture was extracted with Et20. The Et20 layer was dried (K2CO3) and the solvent removed to give the product as an oily solid. The product was used without further purification in the next step.

Step d: Preparation of 5- (5-chloro-2-fluoro-phenyl)-lH-tetrazole A mixture of 5-chloro-2-fluoro-benzonitrile (2.84 g, 0.01823 mol), butanol (15 mL), sodium azide (1.543 g, 0.0237 mol), acetic acid (1.36 mL, 0.0237 mol) was refluxed for 24 hours. The reaction mixture was cooled to room temperature, additional 1.543 g sodium azide added, and the reaction mixture refluxed for additional 24 hours. After cooling to room temperature, Et20 (100 mL) and 10% aqueous NaOH (200 mL) were added sequentially. The mixture was vigorously stirred. The aqueous layer was separated, cooled with ice-methanol bath (-15°C) and acidified to pH 1 with conc. HCI. A gray solid precipitated. The solid was dried in vacuum at 50°C to give 1.76 g (49%) of 5- (5-chloro-2-fluoro-phenyl)-lH- tetrazole: mp partial melt at 110°C, complete melting at 124°C); H (400 Mz, CDCl3): 8 8.19-8.08 (m, 1H), 7.77-7.71 (m, 1H), 7.61-7.52 (m, 1H); 13C (100 Mz, CDCl3): 8 159.00,156.49,140.88,133.02,132.93,130.73,129.23, 129.21,129.08,126.05,118.96,118.73,114.50; MS (CI) M+1 = 199 (100), M = 198 (6).

Step e: Preparation of [4-Chloro-2- (1 H-tetrazol-5-vl)- (4-iodo-2-methyl-phenyl)- amine To a solution of 2-methyl-4-iodoaniline (3.52 g, 0.0151 mol) in THF (25 mL) at-78°C, LDA (2 molar solution in THF, 11.33 mL, 0.02267 mol) was added dropwise. After stirring for 0.5 hours, a solution of 1- (tetrazol-5-yl)-2- fluoro-5-chlorobenzene (1.5 g, 0.00756 mol) in THF (15 mL) was added dropwise. The reaction was stirred for 16 hours as it warmed up to room temperature. The reaction mixture was quenched with aqueous conc. NH4Cl solution and extracted with CH2Cl2. The organic layer was dried (MgSO4) and the solvent removed giving a crude product as an oil. The oil with CH2Cl2- >CH2Cl2: MeOH (9.7: 0.3) gave 1.5 g (48%) of the desired product: mp 205-208°C; 1H (400 Mz, DMSO): 5 9.13 (s, 1H), 8.00-7.99 (s, 1H), 7.69 (s, 1H), 7.55-7.52 (m, 1H), 7.43-7.40 (m, 1H), 7.12-7.05 (m, 1H), 2.24 (s, 3H); 13C (100 Mz, CDC13): 8 141.87,139.28,138.88,135.47,133.71,131.65,128.15, 123.69,121.94,116.68,87.79,17.22; MS (CI) M+2 = 413 (44), M+1 = 412 (85), M = 411 (100).

Analysis calculated for C 14H11NsClI 0. 5H2O: C, 39.97; H, 2.87; N, 16.65.

Found: C, 38.87, H, 2.77; N, 16.47.

The following tetrazole substituted phenylamines were prepared by following the general procedure of Example 207.

EXAMPLE 208 (4-iodo-2-methYl-phenYl !-r2-(lH-tetrazol-5-vl !-phenYljaminen mp 231°C (dec EXAMPLE 209 r4-nitro-2-flH-tetrazol-5-vl)- (4-iodo-2-methvI-uhenvl)-amine. mD 205-208°C.

The 4-bromo and 4-iodo phenylamino benzhydroxamic acid derivatives of Formula II can be prepared from commercially available starting materials

utilizing synthetic methodologies well-known to those skilled in organic chemistry. A typical synthesis is carried out by reacting a 4-bromo or 4-iodo aniline with a benzoic acid having a leaving group at the 2-position to give a phenylamino benzoic acid, and then reacting the benzoic acid phenylamino derivative with a hydroxylamine derivative (Scheme 3), where L is a leaving group, for example halo such as fluoro, chloro, bromo or iodo, or an activated hydroxy group such as a diethylphosphate, trimethylsilyloxy, p-nitrophenoxy, or phenylsulfonoxy.

The reaction of aniline and the benzoic acid derivative generally is accomplished by mixing the benzoic acid with an equimolar quantity or excess of the aniline in an unreactive organic solvent such as tetrahydrofuran, or toluene, in the presence of a base such as lithium diisopropylamide, n-butyl lithium, sodium hydride, and sodium amide. The reaction generally is carried out at a temperature of about-78°C to about 25°C, and normally is complete within about 2 hours to about 4 days. The product can be isolated by removing the solvent, for example by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.

Scheme 3 0 2a C-OH NH L (rusa v Br or I R3a R4a base o Il la't Rua N \ \ / RSa BrorI v \ R3a R4a R6a HN--R7a O rua 2a HNOR Rla N / RSa Br or I R3a R4a

The phenylamino benzoic acid next is reacted with a hydroxylamine derivative HNR6aOR7a in the presence of a peptide coupling reagent.

Hydroxylamine derivatives that can be employed include methoxylamine, N-ethyl-isopropoxy amine, and tetrahydro-oxazine. Typical coupling reagents include 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), 1,3-dicyclohexylcarbodiimide (DCC), bromo-tris (pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP) and (benzotriazolyloxy) tripyrrolidino

phosphonium hexafluorophosphate (PyBOP). The phenylamino benzoic acid and hydroxylamino derivative normally are mixed in approximately equimolar quantities in an unreactive organic solvent such as dichloromethane, tetrahydrofuran, chloroform, or xylene, and an equimolar quantity of the coupling reagent is added. A base such as triethylamine or diisopropylethylamine can be added to act as an acid scavenger if desired. The coupling reaction generally is complete after about 10 minutes to 2 hours, and the product is readily isolated by removing the reaction solvent, for instance by evaporation under reduced pressure, and purifying the product by standard methods such as chromatography or crystallizations from solvents such as acetone, diethyl ether, or ethanol.

An alternative method for making the invention compounds involves first converting a benzoic acid to a hydroxamic acid derivative, and then reacting the hydroxamic acid derivative with an aniline. This synthetic sequence is depicted in Scheme 4, where L is a leaving group. The general reaction conditions for both of the steps in Scheme 4 are the same as those described above for Scheme 3.

Scheme 4

Yet another method for making invention compounds comprises reacting a phenylamino benzhydroxamic acid with an ester forming group as depicted in Scheme 5, where L is a leaving group such as halo, and a base is triethylamine or diisopropylamine.

Scheme 5 8 gR6a 2a C-N-OH Rua N \ \ RSa + L-R7a 37 lu Br or I R3a R4a base -11 1 6a 8 C-N-O-R N I I R5a / RSa Br or I R3a R4a

The synthesis of compounds of Formula (II) is further illustrated by the following detailed examples.

EXAMPLE la 4-Fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino)-benzamide (a) Preparation of 4-Fluoro-2-4-iodo-2-methyl-phenvlamino)-benzoic acid To a stirred solution containing 3.16 g (0.0133 mol) of 2-amino- 5-iodotoluene in 5 mL oftetrahydrofuran at-78°C was added 10 mL (0.020 mol) of a 2.0 M lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (Aldrich) solution. The resulting green suspension was stirred vigorously for 15 minutes, after which time a solution of 1.00 g (0.00632 mol) of 2,4-difluorobenzoic acid in 10 mL of tetrahydrofuran was added. The reaction temperature was allowed to increase slowly to room temperature, at which temperature the mixture was stirred for 2 days. The reaction mixture was concentrated by evaporation of the solvent under reduced pressure. Aqueous HCl

(10%) was added to the concentrate, and the solution was extracted with dichloromethane. The organic phase was dried (MgSO4) and then concentrated over a steambath to low volume (10 mL) and cooled to room temperature. The off-white fibers which formed were collected by vacuum filtration, rinsed with hexane, and dried in a vacuum-oven (76°C; ca. 10 mm of Hg) to afford 1.10 g (47%) of the desired material; mp 224-229.5°C; 1H NMR (400 MHz, DMSO): 8 9.72 (s, 1H), 7.97 (dd, 1H, J=7.0,8.7 Hz), 7.70 (d, 1H, J=1.5 Hz), 7.57 (dd, 1H, J=8.4,1.9 Hz), 7.17 (d, 1H, J=8.2 Hz), 6.61-6.53 (m, 2H), 2.18 (s, 3H); <BR> <BR> <BR> <BR> 13C NMR (100 MHz, DMSO): 8 169.87,166.36 (d, JC-F=249.4 Hz), 150.11 (d, JC F=11. 4 Hz), 139.83,138.49,136.07,135.26 (d, JC-F=l 1 5 Hz), 135.07, 125.60,109.32,104.98 (d, JC F=21. 1 Hz), 99.54 (d, JC-F=26.0 Hz), 89.43,17.52; 19F NMR (376 MHz, DMSO): 8-104.00 to-104.07 (m); IR (KBr) 1670 (C=O stretch) cm~1; MS (CI) M+1 = 372.

Analysis calculated for C14H1 lFIN02 : C, H, 2.99; N, 3.77.

Found: C, 45.21; H, 2.77; N, 3.64.

(b) Preparation of 4-Fluoro-N-hvdroxv-2- (4-iodo-2-methvl-phenvlamino- benzamide To a stirred solution of 4-fluoro-2- (4-iodo-2-methyl-phenylamino)-benzoic acid (0.6495 g, 0.001750 mol), O- (tetrahydro-2H-pyran-2-yl)-hydroxylamine (0.2590 g, 0.002211 mol), and diisopropylethylamine (0.40 mL, 0.0023 mol) in 31 mL of an equivolume tetrahydrofuran-dichloromethane solution was added 1.18 g (0.00227 mol) of solid PyBOP ( [benzotriazolyloxy] tripyrrolidino phosphonium hexafluorophosphate, Advanced ChemTech) directly. The reaction mixture was stirred for 30 minutes after which time it was concentrated in vacuo.

The brown oil was treated with 10% aqueous hydrochloric acid. The suspension was extracted with ether. The organic extraction was washed with 10% sodium hydroxide followed by another 10% hydrochloric acid wash, was dried (MgSO4)

and concentrated in vacuo to afford 1.0 g of a light-brown foam. This intermediate was dissolved in 25 mL of ethanolic hydrogen chloride, and the solution was allowed to stand at room temperature for 15 minutes. The reaction mixture was concentrated in vacuo to a brown oil that was purified by flash silica chromatography. Elution with a gradient (100 % dichloromethane to 0.6 % methanol in dichloromethane) afforded 0.2284 g of a light-brown viscous oil.

Scratching with pentane-hexanes and drying under high vacuum afforded 0.1541 g (23%) of an off-white foam; mp 61-75°C; 1H NMR (400 MHz, DMSO): 8 11.34 (s, 1H), 9.68 (s, 1H), 9.18 (s, 1H), 7.65 (d, 1H, J=1.5 Hz), 7.58 (dd, 1H, J=8.7,6.8 Hz), 7.52 (dd, 1H, J=8.4,1.9 Hz), 7.15 (d, 1H, J=8.4 Hz), 6.74 (dd, 1H, J=11.8,2.4 Hz), 6.62 (ddd, 1H, J=8.4,8.4,2.7 Hz), 2.18 (s, 3H); 13C NMR (100 MHz, DMSO): 8 165.91,164.36 (d, JC-F=247.1 Hz), 146.78, 139.18,138.77,135.43,132.64,130.60 (d, JC F=11. 5 Hz), 122.23,112.52, 104.72 (d, J=22.1 Hz), 100.45 (d, JC-F=25.2 Hz), 86.77,17.03; 19F NMR (376 MHz, DMSO): 8-107.20 to-107.27 (m); IR (KBr) 3307 (broad, O-H stretch), 1636 (C=O stretch) cm-1; MS (CI) M+1 = 387.

Analysis calculated for C14Hl2FIN202 : C, 43.54; H, 3.13; N, 7.25.

Found: C, 43.62; H, 3.24; N, 6.98.

EXAMPLE 2a <BR> <BR> <BR> <BR> 5-Bromo-3 4-difluoro-N-hydroxv-2-(4-iodo-2-methYl-phenYlamino)-benzami de (a) Preparation of 5-Bromo-23 4-trifluorobenzoic acid To a stirred solution comprised of 1-bromo-2,3,4-trifluorobenzene (Aldrich, 99%; 5.30 g, 0.0249 mol) in 95 mL of anhydrous tetrahydrofuran cooled to-78°C was slowly added 12.5 mL of 2.0 M lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene solution (Aldrich). The mixture was stirred for 1 hour and transferred by canula into 700 mL of a stirred saturated ethereal carbon dioxide solution cooled to-78°C. The cold bath was removed, and the

reaction mixture was stirred for 18 hours at ambient temperature. Dilute (10%) aqueous hydrochloric acid (ca. 500 mL) was poured into the reaction mixture, and the mixture was subsequently concentrated on a rotary evaporator to a crude solid.

The solid product was partitioned between diethyl ether (150 mL) and aq. HCl (330 mL, pH 0). The aqueous phase was extracted with a second portion (100 mL) of diethyl ether, and the combined ethereal extracts were washed with 5% aqueous sodium hydroxide (200 mL) and water (100 mL, pH 12). These combined alkaline aqueous extractions were acidified to pH 0 with concentrated aqueous hydrochloric acid. The resulting suspension was extracted with ether (2 x 200 mL). The combined organic extracts were dried (MgSO4), concentrated in vacuo, and subjected to high vacuum until constant mass was achieved to afford 5.60 g (88% yield) of an off-white powder; mp 139-142.5°C; H NMR (400 MHz, DMSO): 8 13.97 (broad s, 1H, 8.00-7.96 (m, 1H); 13C NMR (100 MHz, DMSO): 8 162.96,129.34,118.47,104.54 (d, JC-F=22.9 Hz); 19F NMR (376 MHz, DMSO): 8-120.20 to-120.31 (m),-131.75 to-131.86 (m), -154.95 to-155.07 (m); IR (KBr) 1696 (C=O stretch) cm~1; MS (CI) M+1 = 255.

Analysis calculated for C74H21BrF302: C, 32.97; H, 0.79; N, 0.00; Br, 31.34; F, 22.35.

Found: C, 33.18; H, 0.64; N, 0.01; Br, 30.14; F, 22.75.

(b) Preparation of 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)- benzoic acid To a stirred solution comprised of 1.88 g (0.00791 mol) of 2-amino- 5-iodotoluene in 10 mL oftetrahydrofuran at-78°C was added 6 mL (0.012 mol) of a 2.0 M lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (Aldrich) solution. The resulting green suspension was stirred vigorously for 10 minutes, after which time a solution of 1.00 g (0.00392 mol) of 5-bromo- 2,3,4-trifluorobenzoic acid in 15 mL of tetrahydrofuran was added. The cold bath

was subsequently removed, and the reaction mixture stirred for 18 hours. The mixture was concentrated, and the concentrate was treated with 100 mL of dilute (10%) aqueous hydrochloric acid. The resulting suspension was extracted with ether (2 x 150 mL), and the combined organic extractions were dried (MgSO4) and concentrated in vacuo to give an orange solid. The solid was triturated with boiling dichloromethane, cooled to ambient temperature, and collected by filtration. The solid was rinsed with dichloromethane, and dried in the vacuum- oven (80°C) to afford 1.39 g (76%) of a yellow-green powder; mp 259.5-262°C; 1H NMR (400 MHz, DMSO): 8 9.03 (s, 1H), 7.99 (dd, 1H, J=7.5,1.9 Hz), 7.57 (dd, 1H, J=1.5 Hz), 7.42 (dd, 1H, J=8.4,1.9 Hz), 6.70 (dd, 1H, J=8.4, 6.0 Hz), 2.24 (s, 3H); 19F NMR (376 MHz, DMSO): å-123.40 to-123.47 (m);-139.00 to-139.14 (m); IR (KBr) 1667 (C=O stretch) cm~1 ; MS (CI) M+1 = 469.

Analysis calculated for C 14H9BrF2INO2 : C, 35.93; H, 1.94; N, 2.99; Br, 17.07; F, 8.12; I, 27.11.

Found: C, 36.15; H, 1.91; N, 2.70; Br, 16.40; F, 8.46; I, 26.05.

(c) Preparation of 5-Bromo-34-difluoro-N-hydroxv-2-(4-iodo-2-methYl- phenylamino)-benzamide To a stirred solution comprised of 5-bromo-3, 4-difluoro-2- (4-iodo- 2-methyl-phenylamino)-benzoic acid (0.51 g, 0.0011 mol), 0- (tetrahydro-2H- pyran-2-yl)-hydroxylamine (0.15 g, 0.0013 mol), and diisopropylethylamine (0.25 mL, 0.0014 mol) in 20 mL of an equivolume tetrahydrofuran- dichloromethane solution was added 0.6794 g (0.001306 mol) of solid PyBOP (Advanced ChemTech) directly. The reaction mixture was stirred at 24°C for 10 minutes, and then was concentrated to dryness in vacuo. The concentrate was suspended in 100 mL of 10% aqueous hydrochloric acid. The suspension was extracted with 125 mL of diethyl ether. The ether layer was separated, washed with 75 mL of 10% aqueous sodium hydroxide, and then with 100 mL of dilute acid. The ether solution was dried (MgSO4) and concentrated in vacuo to afford 0.62 g (100%) of an off-white foam. The foam was dissolved in ca. 15 mL of

methanolic hydrogen chloride. After 5 minutes, the solution was concentrated in vacuo to an oil, and the oil was purified by flash silica chromatography. Elution with dichloromethane: dichloromethane-methanol (99: 1) afforded 0.2233 g (42%) of a yellow powder. The powder was dissolved in diethyl ether and washed with dilute hydrochloric acid. The organic phase was dried (MgSO4) and concentrated in vacuo to afford 0.200 g of a foam. This product was triturated with pentane to afford 0.1525 g of a powder that was repurified by flash silica chromatography.

Elution with dichloromethane afforded 0.0783 g (15%) of an analytically pure title compound, mp 80-90°C; 1 H NMR (400 MHz, DMSO): 8 11.53 (s, 1H), 9.38 (s, 1H), 8.82 (s, 1H), 7.70 (dd, 1H, J=7.0,1.9 Hz), 7.53 (s, 1H), 7.37 (dd, 1H, J=8.4,1.9 Hz), 6.55 (dd, 1H, J=8.2, 6.5 Hz), 2.22 (s, 3H); 19F NMR (376 MHz, DMSO): 8-126.24 to-126.29 (m),-137.71 to-137.77 (m); IR (KBr) 3346 (broad, O-H stretch), 1651 (C=O stretch) cm-1; MS (CI) M+1 = 484.

Analysis calculated for C I 4H I oBrF2lN202 : C, 34.81; H, 2.09; N, 5.80.

Found: C, 34.53; H, 1.73; N, 5.52.

Examples 3a to 12a in the table below were prepared by the general procedure of Examples 1 a and 2a.

EXAMPLES 13a-77a Examples 13a to 77a were prepared utilizing combinatorial synthetic methodology by reacting appropriately substituted phenylamino benzoic acids (e. g., as shown in Scheme 1) and hydroxylamines (e. g., (NHR6a)-O-R7a). A general method is given below: To a 0.8-mL autosampler vial in a metal block was added 40 gL of a 0.5 M solution of the acid in DMF and 40 uL of the hydroxylamine (2 M solution in Hunig's base and 1 M in amine in DMF). A 0.5 M solution of PyBrOP was

freshly prepared, and 50 uL were added to the autosampler vial. The reaction was allowed to stand for 24 hours.

The reaction mixture was transferred to a 2-dram vial and diluted with 2 mL of ethyl acetate. The organic layer was washed with 3 mL of distilled water and the water layer washed again with 2 mL of ethyl acetate. The combined organic layers were allowed to evaporate to dryness in an open fume hood.

The residue was taken up in 2 mL of 50% acetonitrile in water and injected on a semi-prep reversed phase column (10 mm x 25 cm, 5 uM spherical silica, pore Size 115 A derivatized with C-18, the sample was eluted at 4.7 mL/min with a linear ramp to 100% acetonitrile over 8.5 minutes. Elution with 100% acetonitrile continued for 8 minutes.) Fractions were collected by monitoring at 214 nM. The desired fractions were evaporated using a Zymark Turbovap. The product was dissolved in chloroform and transferred to a preweighed vial, evaporated, and weighed again to determine the yield. The structure was confirmed by mass spectroscopy.

EXAMPLES 3a-77a Example Compound Melting MS No. Point (°C) (M-H+) 3a 2- (4-bromo-2-methyl-phenylamino)-4-fluoro-N- 56-75 dec 523 hydroxy-benzamide 4a 5-Chloro-N-hydroxy-2- (4-iodo-2-methyl- 65 dec phenylamino)-benzamide 5a 5-Chloro-N-hydroxy-2- (4-iodo-2-methyl- 62-67 phenylamino)-N-methyl-benzamide 6a 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N- 105-108 (terahydropyran-2-yloxy) benzamide 7a 5-Chloro-2- (4-iodo-2-methyl-phenylamino)-N- 64-68 methoxybenzamide 8a 4-Fluoro-N-hydroxy-2- (4-fluoro-2-methyl- 119-135 phenylamino)-benzamide 9a 4-Fluoro-N-hydroxy-2- (2-methyl phenylamino)-101-103 benzamide 10a 4-Fluoro-2- (4-fluor-2-methyl-phenylamino)-N- 142-146 (terahydropyran-2-yloxy) benzamide <BR> <BR> <BR> lla 4-Fluoro-N-hydroxy-2- (4-cluoro-2-methyl- 133.5-135<BR> <BR> <BR> <BR> <BR> phenylamino)-benzamide Example Compound Melting MS No. Point (°C) (M-H+) 12a 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- 107-109.5 phenylmethoxy-benzamide 13a 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- 399 methoxy-benzamide 14a 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)- 417 N-methoxy-benzamide 15a 2- (4-Bromo-2-methyl-phenylamino)- 369 3,4-difluoro-N-methoxy-benzamide 16a 2- (4-Bromo-2-methyl-phenylamino)-N-ethoxy- 342* 3,4-difluoro-benzamide (M-EtO) 17a 5-Bromo-N-ethoxy-3,4-difluoro-2- (4-iodo- 509 2-methyl-phenylamino)-benzamide 18a 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)- 445 N-isopropoxy-benzamide 19a 2- (4-Bromo-2-methyl-phenylamino)- 397 3,4-difluoro-N-isopropoxy-benzamide 20a 4-Fluoro-N- (furan-3-ylmethoxy)-2- (4-iodo- 465 2-methyl-phenylamino)-benzamide Example Compound Melting MS No. Point (°C) (M-H+) 21 a 3,4-Difluoro-N- (furan-3-ylmethoxy)-2- (4-iodo- 483 2-methyl-phenylamino)-benzamide 22a 2- (4-Bromo-2-methyl-phenylamino)- 435 3,4-difluoro-N- (furan-3-ylmethoxy)-benzamide 23a 5-Bromo-3,4-difluoro-N- (furan-3-ylmethoxy)- 561 2- (4-iodo-2-methyl-phenylamino)-benzamide 24a 5-Bromo-N- (but-2-enyloxy)-3, 4-difluoro- 536 2- (4-iodo-2-methyl-phenylamino)-benzamide 25a 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- 423 (prop-2-ynyloxy)-benzamide 26a 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)- 441 N- (prop-2-ynyloxy)-benzamide 27a 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)- 455 N- (1-methyl-prop-2-ynyloxy)-benzamide 28a 2- (4-Bromo-2-methyl-phenylamino)- 407 3,4-difluoro-N- ( 1-methyl-prop-2-ynyloxy)- benzamide 29a N- (But-3-ynyloxy)-3, 4-difluoro-2- (4-iodo- 455 2-methyl-phenylamino)-benzamide Example Compound Melting MS No. Point (°C) (M-H+) 30a 2- (4-Bromo-2-methyl-phenylamino)-N- (but- 407 3-ynyloxy)-3,4-difluoro-benzamide <BR> <BR> <BR> <BR> <BR> 31a 5-Bromo-N- (but-3-ynyloxy)-3, 4-difluoro- 533<BR> <BR> <BR> <BR> 2- (4-iodo-2-methyl-phenylamino)-benzamide 32a 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)- 517 N- (3-phenyl-prop-2-ynyloxy)-benzamide 33a 3,4-Difluoro-2- (4-bromo-2-methyl- 469 phenylamino)-N- (3-phenyl-prop-2-ynyloxy)- benzamide 34a 3,4-Difluoro-N- [3- (3-fluoro-phenyl)-prop- 535 2-ynyloxy]-2- (4-iodo-2-methyl-phenylamino)- benzamide 35a 2- (4-Bromo-2-methyl-phenylamino)- 487 3,4-difluoro-N-[3- (3-fluoro-phenyl)-prop- 2-ynyloxy]-benzamide 36a 3,4-Difluoro-N- [3- (2-fluoro-phenyl)-prop- 535 2-ynyloxy]-2- (4-iodo-2-methyl-phenylamino)- benzamide 37a 5-Bromo-3,4-difluoro-N- [3- (2-fluoro-phenyl)- 613 <BR> <BR> <BR> prop-2-ynyloxy]-2- (4-iodo-2-methyl-<BR> <BR> <BR> <BR> phenylamino)-benzamide Example Compound Melting MS No. Point (°C) (M-H+) 38a 3, 4-Difluoro-2- (4-iodo-2-methyl-phenylamino)- 557* N- (3-methyl-5-phenyl-pent-2-en-4-ynyloxy)- * (M+H) benzamide 39a 2- (4-Bromo-2-methyl-phenylamino)- 510 3,4-difluoro-N- (3-methyl-5-phenyl-pent-2-en- 4-ynyloxy)-benzamide 40a N-Ethoxy-3,4-difluoro-2- (4-iodo-2-methyl- 431 phenylamino)-benzamide 41a 2- (4-Bromo-2-methyl-phenylamino)-N-ethoxy- 383 3,4-difluoro-benzamide 42a 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- 427 propoxy-benzamide 43a 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)- 445 N-propoxy-benzamide 44a 2- (4-Bromo-2-methyl-phenylamino)- 397 3,4-difluoro-N-propoxy-benzamide 45a 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl- 523 phenylamino)-N-propoxy-benzamide 46a 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- 427 isopropoxy-benzamide Example Compound Melting MS No. Point (°C) (M-H+) 47a 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)- 445 N-i sopropoxy-benzamide 48a 2- (4-Bromo-2-methyl-phenylamino)- 397 3,4-difluoro-N-isopropoxy-benzamide 49a 5-Bromo-3,4-difluoro-2- (4-iodo-2-methyl- 523 phenylamino)-N-isopropoxy-benzamide 50a N-Cyclobutyloxy-3,4-difluoro-2- (4-iodo- 457 <BR> <BR> <BR> 2-methyl-phenylamino)-benzamide<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> 51a 2- (4-Bromo-2-methyl-phenylamino)-N- 409 cyclobutyloxy-3,4-difluoro-benzamide 52a N-Cyclopentyloxy-4-fluoro-2- (4-iodo-2-methyl- 453 phenylamino)-benzamide 53a N-Cyclopentyloxy-3,4-difluoro-2- (4-iodo- 471 2-methyl-phenylamino)-benzamide 54a 2- (4-Bromo-2-methyl-phenylamino)-N- 423 cyclopentyloxy-3,4-difluoro-benzamide 55a N-Cyclopropylmethoxy-4-fluoro-2- (4-iodo- 439 2-methyl-phenylamino)-benzamide 56a N-Cyclopropylmethoxy-3,4-difluoro-2- (4-iodo- 457 2-methyl-phenylamino)-benzamide Example Compound Melting MS No. Point (°C) (M-H+) 57a 2- (4-Bromo-2-methyl-phenylamino)-N- 409 cyclopropylmethoxy-3,4-difluoro-benzamide 58a 5-Bromo-N-cyclopropylmethoxy-3,4-difluoro- 435 2- (4-iodo-2-methyl-phenylamino) 59a 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- 505 (2-phenoxy-ethoxy)-benzamide 60a 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)- 523 N- (2-phenoxy-ethoxy)-benzamide 61a 2- (4-Bromo-2-methyl-phenylamino)- 475 3,4-difluoro-N- (2-phenoxy-ethoxy)-benzamide 62a 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- 481 (thiophen-2-ylmethoxy)-benzamide 63a 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)- 499 N- (thiophen-2-ylmethoxy)-benzamide 64a 2- (4-Bromo-2-methyl-phenylamino)- 451 3,4-difluoro-N- (thiophen-2-ylmethoxy)- benzamide 65a 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- 439 (2-methyl-allyloxy)-benzamide Example Compound Melting MS No. Point (°C) (M-H+) 66a 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)- 457 N- (2-methyl-allyloxy)-benzamide 67a 2- (4-Bromo-2-methyl-phenylamino)- 410 3,4-difluoro-N-(2-methyl-allyloxy)-benzamide 68a N- (But-2-enyloxy)-4-fluoro-2- (4-iodo-2-methyl- 439 phenylamino)-benzamide 69a N- (But-2-enyloxy)-3, 4-difluoro-2- (4-iodo- 457 2-methyl-phenylamino)-benzamide 70a 2- (4-Bromo-2-methyl-phenylamino)-N- (but- 410 2-enyloxy)-3,4-difluoro-benzamide 71 a 3,4-Difluoro-2- (4-iodo-2-methyl-phenylamino)- 441 N- (prop-2-ynyloxy)-benzamide 72a N- (But-3-ynyloxy)-3, 4-difluoro-2- (4-iodo- 455 2-methyl-phenylamino)-benzamide 73a 2- (4-Bromo-2-methyl-phenylamino)-N- 449 (4,4-dimethyl-pent-2-ynyloxy)-3,4-difluoro- benzamide 74a N- (But-2-enyloxy)-3, 4-difluoro-2- (4-iodo- 457 2-methyl-phenylamino)-benzamide

Example Compound Melting MS No. Point (°C) (M-H+) 75a 2- (4-Bromo-2-methyl-phenylamino)-N- (but- 410 2-enyloxy)-3,4-difluoro-benzamide 76a N- (3-tert-butyl-propyn-2-yl) oxy-4-fluoro- 479 2- (4-iodo-2-methyl-phenylamino)-benzamide 77a 4-Fluoro-2- (4-iodo-2-methyl-phenylamino)-N- 577 phenylmethoxy-benzamide PHYSICAL DATA FOR SELECTED COMPOUNDS PD 0171984 mp 80-90 °C PD 0184161 mp 174-175 °C PD 0203311 mp 141-144 °C PD 0297189 mp167-169 °C 'H-NMR (400 MHz; DMSO) 6 11.70 (s, 1H), 8.59 (s, 1H), 7.55 (s, 1H), 7.43 (d, 1H, J=6.5 Hz), 7.27 (d, lH, J=8.7 Hz), 6.46 (m, 1H), 3.42 (d, 2H, J=7.0 Hz), 0.84 (m, 1H), 0.27 (m, 2H), 0.00 (m, 2H)

PD 0297190 mp 125.5-133 °C <BR> <BR> <BR> <BR> 'H-NMR (400 MHz; DMSO) 8 11.48 (s, 1H), 8.32 (s, 1H), 7.34 (d, 1H, J=7.5 Hz), 7.28 (d, 2H, J=8.2 Hz), 6.48 (d, 2H, J=7.7 Hz), 3.32 (d, 2H, J=6.8 Hz), 0.81 (m, 1H), 0.28 (m, 2H), 0.00 (m, 2H) PD 0296771 mp 266.7-268.9 °C 'H-NMR (400 MHz; DMSO) b 13.85 (broad s, 1H), 8.99 (s, 1H), 7.87 (dd, 1H, J=7.9,2.1 Hz), 7.55 (d, 2H, J=8.6 Hz), 6.82 (dd, 2H, J=8.7,2.8 Hz) PD 0296770 mp 293.2-296.3 °C 'H-NMR (400 MHz; DMSO) 8 14.05 (broad s, 1H), 9.21 (s, 1H), 7.93 (dd, 1H, J=7.8,2.2 Hz), 7.82 (d, lH, J=1.9 Hz), 7.54 (dd, 1H, J=8.6,1.9 Hz), 6.82 (dd, 1H, J=8.6,6.7 Hz) PD 0296767 mp 249-251 °C 'H-NMR (400 MHz; DMSO) 8 13.99 (broad s, 1H), 9.01 (s, 1H), 7.90 (dd, 1H, J=7.9,2.3 Hz), 7.58 (d, lH, J=1.6 Hz), 7.42 (dd, 1H, J=8.4,1.9 Hz), 6.69 (dd, 1H, J=8.4,6.0 Hz), 2.24 (s, 3H) PD298127 mp 127-135 °C 5-chloro-N-cyclopropylmethoxy-3,4-difluoro-2- [4-iodo-2-methyl phenylamino] benzamide Proton NMR (440 MHz; DMSO) 8 11.64 (s, 1H), 8.28 (s, 1H), 7.38 (dd, 1H, J=7.6,1.7 Hz), 7.31 (d, 1 H, J=1.2 Hz), 7.15 (dd, 1H, J=8.5,1.7 Hz), 3.35 (d, 2H, J=7.3 Hz), 2.01 (s, 3H), 0.83 (m, 1H), 0.28 (m, 2H), 0.01 (m, 2H)

BIOLOGICAL ASSAYS The ability of MEK inhibitors described above to prevent and treat asthma has been demonstrated in three different assays: (1) inhibition of antigen-induced interleukin-5 (IL-5) production in vitro, (2) inhibition of the passive-transfer of eosinophilic lung inflammation in vivo, and (3) inhibition of active eosinophilic lung inflammation in vivo. For each of these assays, female C57BL/6 mice obtained from the Jackson Laboratory (Bar Harbor, ME) were given an intraperitoneal (i. p.) injection of ovalbumin (OVA, Grade V, Sigma Chemical Company, St. Louis, MO) adsorbed to aluminum hydroxide (10 g OVA + 9 mg aluminum hydroxide in 200 jjL saline). This sensitizes OVA-specific lymphocytes for subsequent restimulation either in vivo or in vitro.

The first set of experiments was designed to determine whether the MEK inhibitors could prevent antigen-induced production of IL-5 by the OVA-primed splenocytes in vitro. IL-5 is required for the differentiation, migration, and survival of pulmonary eosinophils, which are thought to be responsible for much of the pathology associated with human asthma. In order to examine the effects of MEK inhibitors on IL-5 production, OVA-sensitized mice were sacrificed by cervical dislocation 14 days after sensitization (Day 14), the spleens were excised and disaggregated, and the erythrocytes were lysed. The splenocytes were washed and resuspended at 5 x 106 cells/mL in complete medium consisting of RPMI 1640 (Gibco BRL, Gaithersburg, MD) with 10% heat-inactivated fetal calf serum (Hyclone, Logan, UT), 55 uM 2-mercaptoethanol, 50 U/mL penicillin G, 50 ug/mL streptomycin sulfate, and 2 mM L-glutamine (Gibco BRL). The splenocytes were then cultured at 37°C in the presence of 200, ug/mL OVA. MEK inhibitors were also added to the cultures from sterile 10 mM stock solutions (in DMSO). After 3 days, the culture medium was recovered and assayed for IL-5 by specific ELISA. The results of the analysis of IL-5 inhibition are presented in Table 1. All MEK inhibitors tested were found to potently inhibit antigen-induced IL-5 production.

Table 1. The Effects of MEK Inhibitors on Antigen- Induced IL-5 Production MEK Inhibitor IC50 (nM) PD 184386 23 PD 171984 117 PD 170611 1,121 PD 184161 1,147 PD 177168 1,205 PD 184352 1,622 PD 098059 17,440 When OVA-sensitized spleen cells are restimulated with OVA in vitro for 3 days, as described above, the spleen cells not only produce IL-5, but also acquire the ability to induce eosinophilic lung inflammation when transferred into naive recipient mice. The critical cell type responsible for this adoptively- transferred activity is thought to be IL-5-producing T lymphocytes. Because the results of the first set of experiments indicated that the MEK inhibitors inhibited IL-5 production by cultured splenocytes, a second set of experiments was initiated to determine whether the MEK inhibitor-treated cells were capable of transferring eosinophilic lung inflammation to naive mice. Splenocytes from OVA restimulation cultures, with or without the addition of MEK inhibitors were harvested after 3 days of culture, washed three times, and resuspended at 1 x 108 cells/mL in sterile saline. Groups of five naive (unsensitized) C57BL/c mice were injected i. p. with 200 L of the cell suspension (2 x 107 cells). Three days after transfer of cells, the recipient mice were challenged with a 12-minute inhalation of an aerosol formulation of 1.5% OVA in saline (weight/volume), the mist being produced by a nebulizer (small particle generator model SPAG-2, ICN Pharmaceuticals, Costa Mesa, CA). Three days after aerosol challenge, the mice were anesthetized with an i. p. injection of an anesthetic mixture comprising Ketamine, acepromazine, and xylazine. The trachea of each mouse was exposed and cannulated. The lungs and upper airways were lavaged with 0.5 mL of cold (5°C) phosphate buffered saline (PBS). The cells within a 200 pL portion of the

bronchoalveolar lavage (BAL) fluid were enumerated using a Coulter counter (Model ZB 1, Coulter Electronics, Hialeah, FL). The remaining BAL fluid was then centrifuged at 300 x g for 5 minutes, and the cells resuspended in 1 mL of Hank's balanced salt solution (HBSS, Gibco BRL), containing 0.5% fetal calf serum, and 10 mM of N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid (HEPES, Gibco BRL). The cell suspension (100 uL) was centrifuged in a cytospin (Shandon Southern Instruments, Sewickley, PA) and stained with Diff Quick to distinguish neutrophil, eosinophil, monocyte, and lymphocyte subsets. The number of eosinophils in the BAL fluid was determined by multiplying the percentage of eosinophils by the total cell count.

As shown in Table 2, OVA-sensitized splenocytes cultured in the absence of MEK inhibitor, when transferred to naive recipient mice, were able to promote eosinophilic lung inflammation in response to an aerosol challenge with OVA. In contrast, splenocytes cultured in the presence of the MEK inhibitors PD 171984, PD 184352, and PD 184386 (10 uM each) did not promote eosinophilic lung inflammation (>99% inhibition). For each of the MEK inhibitors used, a 10 uM concentration was previously found to inhibit IL-5 production by over 75% (Table 1). These results suggest that the MEK inhibitors inhibit the IL-5-producing T lymphocytes that are required to support asthma-like eosinophilic lung inflammation in mice.

Table 2. The Effects of MEK Inhibitors on the Adoptive-Transfer of Eosinophilic Lung Inflammation Treatment of Spleen Cell Culture % Inhibition of BAL Eosinophils Compound Dose (tM) None 0 PD 171984 10 99.82 PD 184386 10 99.78 PD 184352 10 99.46 The final set of experiments was designed to test whether MEK inhibitors could inhibit active OVA-induced eosinophilic lung inflammation in mice. Mice

were sensitized with OVA/aluminum hydroxide on Day 0 as described above. On Day 14, the mice were challenged by aerosol with 1.5% OVA, as described above for the adoptive-transfer recipients. One group of eight sensitized mice was dosed orally with vehicle (0.5% hydroxypropylmethylcellulose/0.25% TWEEN-80).

Other groups of sensitized mice (8 mice per group) were given oral doses of a MEK inhibitor. The test compound was dissolved in the vehicle, and the volume for each dosage was adjusted to 200 uL, so that each test animal received the same oral volume. In experiments reported in Table 3 and Table 4, the MEK inhibitor was administered starting on Day 13 (ie, 13 days after initial sensitization and 1 day prior to aerosol challenge), and continued daily through Day 16 (4 days total). In experiments reported in Table 5, the MEK inhibitor was administered starting on Day 7 (ie, 7 days after initial sensitization and 7 days prior to aerosol challenge), and continued daily through Day 16 (9 days total). On Day 17 of each experiment (17 days following the initial OVA challenge, and 3 days after the OVA aerosol challenge), all animals including controls were anesthetized, cannulated, and lavaged as previously described. The number of BAL eosinophils was determined as described above.

In the initial analysis of active OVA-induced lung inflammation, multiple MEK inhibitors (PD 171984, PD 177168, PD 184161, PD 184386, and PD 184352) were dosed orally for 4 days. Only one compound, PD 171984, demonstrated any inhibition of pulmonary eosinophilia (Table 3). PD 171984, along with PD 184352, were tested again at multiple doses, again dosing for only 4 days. The results in Table 4 essentially parallel those in Table 3 for these compounds; PD 171984 appears active, whereas PD 184352 does not. As reported in Table 5, increasing the oral dosing schedule from 4 days to 9 days (7 days prior to aerosol challenge, 2 days after) resulted in a degree of inhibitory activity for PD 184352 at 100 mg/kg (59.85% inhibition, p = 0.11). PD 171984 continued to demonstrate statistically significant inhibitory activity under this dosing regimen.

In total, these results indicate that MEK inhibitors, when used in vitro, are potent inhibitors of IL-5 production, and completely inhibit the ability of antigen- stimulated cells to adoptively transfer asthma-like symptoms to naive recipient mice. When used in vivo, some MEK inhibitors are more active than others.

However, a less potent compound (PD 184352) was shown to inhibit the asthma- like response in mice under a more rigorous dosing regimen. Thus, the foregoing data establish that the selective MEK inhibitors are active in inhibiting a model of asthma in mice. The compounds have little or no toxic effects, and accordingly are particularly well-suited for treating and controlling asthma in children, as well as adults. The compounds will be formulated for convenient oral or parenteral administration, including by aerosol delivery, transdermal delivery, or even suppositories, and will be administered in an antiasthmatic effective dose, which is that amount that is effective to treat the particular asthma severity for which treatment is needed or otherwise desired.

Table 3. The Effect of MEK Inhibitors on Eosinophilic Lung Inflammation in Mice MEK Inhibitor Dose (M) % Inhibition of BAL Eosinophilia PD 171984 100 55.26* PD 177168 100-123.38 PD 184161 100-32.53 PD 184386 100-33.24 PD 184352 150-5.41 * p=0.08 Table 4. Inhibition of BAL Eosinophils With 4-Day Compound Dosing Dose (mg/kg) % Inhibition of BAL Eosinophils by: PD 184352 PD 171984 0 0 0 10-22.7 38.4* 30-153.8 46.6* 100-8.2 58.4* * Significantly different from control (p <0.05)

Table 5. Inhibition of BAL Eosinophils With 9-Day Compound Dosing Dose (mg/kg) % Inhibition of BAL Eosinophils by: PD 184352 PD 171984 Experiment 1 Experiment 2 0 0 0 0 10-42.99-13.74 50.15* 30 1.83 80.64* 37.23* 100 59.85 88.40* 54.77* * Significantly different from control (p <0.05) The foregoing data establish that the selective MEK inhibitors are active in both inhibiting and controlling the asthmatic disease, for example, prior to actual challenge and following challenge. The compounds are therefore useful in the prophylaxis of asthma, and also in treating and alleviating the symptoms that accompany the disease during its active stage. The compounds have little or no toxic effects, and accordingly are particularly well-suited for treating and controlling asthma in children, as well as adults. The compounds will be formulated for convenient oral or parenteral administration, including by aerosol delivery, transdermal delivery, or even suppositories, and will be administered in an antiasthmatic effective dose, which is that amount that is effective to treat the particular asthma severity for which treatment is needed or otherwise desired.

D. Other Embodiments From the above disclosure and examples, and from the claims below, the essential features of the invention are readily apparent. The scope of the invention also encompasses various modifications and adaptations within the knowledge of a person of ordinary skill. Examples include a disclosed compound modified by addition or removal of a protecting group, or an ester, pharmaceutical salt, hydrate, acid, or amide of a disclosed compound. Publications cited herein are hereby incorporated by reference in their entirety.