JP2000212157A - Diarylamine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new diarylamine compound useful for treating proliferative disorders, such as psoriasis, restenosis, autoimmune diseases and atherosclerosis. SOLUTION: A compound of formula I [W is OR1, NR2OR1 (R1 is H, a 1-8C alkyl or the like, R2 is H, phenyl or the like) or the like; R3 is H, F, Cl or the like; R4 is H or F; R5 is H, methyl or Cl; R6 and R7 are each H, a 1-4C alkyl or the like], a pharmaceutically acceptable salt or a 1-6C ester of the compound, for example, methyl 2-(2-chloro-4-iodo-phenylamino)-5- dimethylsulfamoyl-3,4-difluorobenzoate. The compound is formed through intermediates such as 1-dimethylsulfamoyl-2,3,4-trifluorobenzene which is obtained by reacting 2,3,4-trifluorobenzenesulfonyl chloride of formula II with dimethylamine in dichloroethane.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to sulfamoyldiarylamines and derivatives thereof.

[0002]

MEK enzymes are dual specificity kinases that are involved, for example, in immunomodulation, inflammatory and proliferative disorders, such as cancer and restenosis. Proliferative disorders are caused by defects in the intracellular signaling system or the signal transduction mechanism of certain proteins. Defects include alterations in the cellular activity of one or more signaling proteins in an intrinsic activity or signaling cascade. Cells can produce growth factors that bind to their own receptors, resulting in an autocrine loop that continuously stimulates growth. Mutations or overexpression of intracellular signaling proteins can lead to pseudomitogenic signals in cells. Some of the most common mutations occur in genes encoding a protein known as Ras, a G-protein that is activated when bound to GTP and inactivated when bound to GDP. The growth factor receptor and many other mitogen receptors described above, when activated, change from GDP-bound to GTP-
This results in Ras being converted to a bound state. This signal is an absolute requirement for growth in most cell types. In this signaling system, especially Ras
Deficiencies in GTP complex inactivation are common in cancer and result in a downstream signaling cascade in which Ras is chronically active.

Activated Ras then leads to activation of the serine / threonine kinase cascade. One group of kinases known to require active Ras-GTP for its own activation is Raf
Family. These are then MEK (eg, M
Activates EK ₁ and MEK ₂ ) and then activates the MAP kinase, ERK (ERK ₁ and ERK ₂ ).
Activation of MAP kinase by mitogen appears to be essential for proliferation; constitutive activation of this kinase is sufficient to trigger cell transformation. Blockade of downstream Ras signaling, for example by use of a predominant negative Raf-1 protein, completely inhibits mitogenesis induced by cell surface receptors or induced by oncogenic Ras mutants. be able to.
Although Ras is not itself a protein kinase, it is involved in the activation of Raf and other kinases, probably by a phosphorylation mechanism. Once activated, Raf and other kinases phosphorylate MEK with respect to two very adjacent serine group of S ²¹⁸ and S ²²² in the case of MEK-1. This is a prerequisite for the activation of MEK as a kinase. MEK then phosphorylates MAP kinase for both tyrosine, Y ¹⁸⁵ and the threonine group, T ¹⁸³ , separated by a single amino acid. This dual phosphorylation activates MAP kinase at least 100-fold. Activated MAP kinase can then catalyze the phosphorylation of a number of proteins, including some transcription factors and other kinases.
Many of these MAP kinase phosphorylations mitogenically activate target proteins, such as kinases, transcription factors or other cellular proteins. In addition to Raf-1 and MEKK, other kinases activate MEK, and MEK itself appears to be a signal-integrating kinase. The current understanding is that MEK is very specific for MAP kinase phosphorylation. In fact, no substrates for MEKs other than MAP kinase, ERK have been proven to date, and MEK
It does not phosphorylate peptides based on the kinase phosphorylation sequence or additionally does not phosphorylate denatured MAP kinase. MEK is also strongly associated with MAP kinase before phosphorylation, and phosphorylation of MAP kinase by MEK requires a previous strong interaction between the two proteins. This requirement and unusual specificity of MEK is such that the ability to find selective inhibitors of MEK that is manipulated by an allosteric mechanism rather than by ordinary blockade of the ATP binding site suggests that It suggests that there is a sufficient difference in the mechanism of action.

[0004]

BRIEF SUMMARY OF THE INVENTION

Embedded image And a compound having the formula:

In the above equation, W is OR₁, NR_TwoOR
₁, NR_AR_B, NR_TwoNR_AR_B, Or NR_Two(CH_Two)_{2- Four}
NR_AR_BIt is. R₁Is H, C_1-8Alkyl, C_3-8A
Lucenyl, C_3-8Alkynyl, C_3-8Cycloalkyl,
Phenyl, (phenyl) C_1-4Alkyl, (phenyl) C_3-4A
Lucenyl, (phenyl) C_3-4Alkynyl, (C_3-8Cyclo
Alkyl) C_1-4Alkyl, (C_3-8Cycloalkyl) C_3-4
Alkenyl, (C_3-8Cycloalkyl) C_3-4Alkynyl,
C _3-8A heterocyclic group, (C_3-8Heterocyclic group) C_1-4Alkyl,
(C_3-8Heterocyclic group) C_3-4Alkenyl, (C_3-8Heterocyclic
Group) C_3-4Alkynyl or (CH_Two)_2-4NR_AR_BIt is.

R ₂ is H, phenyl, C _1-4 alkyl, C
_3-4 alkenyl, C _3-8 alkynyl, C _3-8 cycloalkyl or (C _3-8 cycloalkyl) C _1-4 alkyl.
_RA is H, C _1-6 alkyl, C _3-8 alkenyl, C _3-8 alkynyl, C _3-8 cycloalkyl, phenyl, (C _3-8 cycloalkyl) C _1-4 alkyl, (C _{3 -8} cycloalkyl)
C _3-4 alkenyl, (C _3-8 cycloalkyl) C _3-4 alkynyl, C _3-8 heterocyclic group, (C _3-8 heterocyclic group) C _1-4 alkyl, (aminosulfonyl) phenyl , [(aminosulfonyl) phenyl] C _1-4 alkyl, (aminosulfonyl) C _1-6 alkyl, (aminosulfonyl) C _3-6 cycloalkyl, or [(aminosulfonyl) C _{3 -6} cycloalkyl] C _{1- 4} alkyl.

R _B is H, C _1-8 alkyl, C _3-8 alkenyl, C _3-8 alkynyl, C _3-8 cycloalkyl or C _3-8
6-8 aryl. R ₃ is H, F, Cl, Br or NO ₂ . R ₄ is H or F. R ₅ is H,
Methyl or Cl. R ₆ is H, C _1-4 alkyl,
Hydroxyethyl, hydroxypropyl, (CH ₂ )
_2-4 (NR _C R _D), phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or CH ₂ Ar (wherein, Ar is phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl) It is.

R ₇ is H, C _1-4 alkyl, hydroxyethyl, hydroxypropyl, (CH ₂ ) _2-4 (NR _C R _D ), phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or CH ₂ Ar, wherein Ar is phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl.
Each of R _C and R _D is independently H, C _1-6 alkyl, C _3-4 alkenyl, C _3-4 alkynyl, C _3-6 cycloalkyl, C _3-6 heterocyclic and phenyl. Is selected from NR _C R _D can also be selected morpholinyl, piperazinyl, pyrrolidinyl or piperidinyl.

Each of the above-mentioned hydrocarbon groups or heterocyclic groups may optionally be independently halogen, C _1-4 alkyl, C _3-6 cycloalkyl, C _2-4 alkenyl, C _2-4 alkenyl,
_2-4 alkynyl, phenyl, hydroxy, amino, it may be substituted by one to three substituents selected from (amino) sulfonyl, and NO _2; and each substituent alkyl, cycloalkyl, alkenyl,
The alkynyl or phenyl may be optionally substituted independently with 1 to 3 substituents selected from halogen, C _1-2 alkyl, hydroxy, amino and NO ₂ . The invention also features pharmaceutically acceptable salts and C _1-7 esters thereof. The present invention also relates to a pharmaceutical composition comprising (a) a compound of formula (I) and (b) a pharmaceutically acceptable carrier.

[0010] The invention further relates to a method of treating a proliferative disease, such as cancer, restenosis, psoriasis, autoimmune disease and atherosclerosis. Another aspect of the invention is directed to solid or hematopoietic MEK-related (ras-
(Including related) methods of treating cancer. Examples of cancer include colorectal cancer, cervical cancer, breast cancer, ovarian cancer, brain cancer, acute leukemia, gastric cancer, non-small cell lung cancer,
Includes pancreatic and lung cancer. Other aspects of the invention include xenograft (organ or bone marrow transplant) rejection, osteoarthritis,
Rheumatoid arthritis, cystic fibrosis, diabetes (including diabetic retinopathy), hepatoma, cardiac hypertrophy, stroke (e.g., acute vocal ischemic stroke and global cerebral ischemia), heart failure, septic shock, asthma and Methods for treating or reducing the symptoms of Alzheimer's disease are included. The compounds of the present invention
Also antiviral agents for treating viral infections such as HIV, hepatitis (B) virus (HBV), human papilloma virus (HPV), reovirus, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) Useful as These methods involve administering a pharmaceutically effective amount of a disclosed compound or pharmaceutical composition thereof to a patient in need of such treatment or suffering from such a disease or condition.

The present invention also relates to a combination treatment method, such as a method for treating cancer, wherein the method further comprises radiation or chemotherapy, for example using a mitotic inhibitor such as a taxane or vinca alkaloid. It is. Chemotherapy or radiation therapy can be given before, during or after administration of the disclosed compounds, depending on the needs of the patient. The invention also features the synthetic methods disclosed herein. Other aspects of the invention are as set forth in the following description and examples, and in the claims.

[0012]

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to sulfamoyl diarylamine compounds, pharmaceutical compositions thereof, and methods of using such compounds and compositions. According to one aspect of the invention, the compound is a MEK inhibitor.
The MEK inhibition assay is an in vitro cascade assay for inhibitors of the MAP kinase pathway described in US Pat. Includes the in vitro MEK assay described on line 27. The entire disclosures of these patents are incorporated herein by reference (and also
See Examples 5 to 10 below).

A. Terminology Certain terms are defined throughout the specification as follows. Alkyl groups include aliphatic groups having a free valence (ie, a hydrocarbyl or hydrocarbon group structure containing hydrogen and carbon atoms). Obviously, alkyl groups include straight-chain and branched-chain structures. Examples are methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, 2,3-dimethylhexyl, 1,1-dimethylpentyl, Includes heptyl and octyl. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Alkyl groups are independently halogen (fluorine,
One selected from chlorine, bromine or iodine), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic group and (heterocyclic group) oxy, It may be substituted by two, three or more substituents. Specific examples are fluoromethyl, hydroxyethyl, 2,3-dihydroxyethyl,
(2- or 3-furanyl) methyl, cyclopropylmethyl, benzyloxyethyl, (3-pyridinyl) methyl, (2- or 3-furanyl) methyl, (2-thienyl) ethyl, hydroxypropyl, aminocyclohexyl, 2- Dimethylaminobutyl, methoxymethyl, N-
Includes pyridinylethyl, diethylaminoethyl and cyclobutylmethyl.

An alkenyl group is similar to an alkyl group except that it has at least one double bond (two adjacent SP ² carbon atoms). Depending on the configuration of the double bond and the substituent (if present), the geometry of the double bond
Entogen (E) or Tuzanmen (Z), cis or trans. Similarly, an alkynyl group has at least one triple bond (two adjacent SP carbon atoms). Unsaturated alkenyl or alkynyl groups can have one or more double or triple bonds, respectively, or a mixture thereof. Like the alkyl groups, the unsaturated groups can be straight-chain or branched and they are substituted as described above for alkyl and as described by the disclosure according to the examples. Is also good. Examples of alkenyl, alkynyl and substituted forms are cis-2-butenyl, trans-2-butenyl, 3-butynyl, 3-phenyl-2-
Propynyl, 3- (2'-fluorophenyl) -2-propynyl, 3-methyl (5-phenyl) -4-pentynyl, 2-hydroxy-2-propynyl, 2-methyl-2
-Propynyl, 2-propenyl, 4-hydroxy-3-
Includes butynyl, 3- (3-fluorophenyl) -2-propynyl and 2-methyl-2-propenyl. In formula (I), the alkenyl and alkynyl groups can be, for example, C _2-4 or C _2-8 , preferably C _3-4 or C _3-8 .

The more common forms of substituted hydrocarbon groups are hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, and the prefix amino-, halo- (eg, fluoro-, chloro- or Bromo-), nitro-,
Includes forms corresponding to combinations of alkyl-, phenyl-, cycloalkyl-, etc. or substitutions. Therefore, according to formula (1), the substituted alkyl may be hydroxyalkyl, aminoalkyl, nitroalkyl, haloalkyl, alkylalkyl (branched alkyl, for example methylpentyl), (cycloalkyl) alkyl, phenyl Includes alkyl, alkoxy, alkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, (heterocyclic) alkyl, and (heterocyclic) oxyalkyl. That is, R ₁ is hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocycloalkyl, aminoaryl, alkylalkenyl, (alkylaryl) alkyl, (haloaryl) Alkyl, (hydroxyaryl) alkynyl and the like. Similarly, R _A includes hydroxyalkyl and aminoaryl and R _B includes hydroxyalkyl, aminoalkyl, hydroxyalkyl (heterocyclic) alkyl, and the like.

Heterocyclic groups, including but not limited to heteroaryl, include furyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, pyrrolyl, imidazolyl, 1,3,4-triazolyl, tetrazolyl,
Includes pyridinyl, pyrimidinyl, pyridazinyl, indolyl and their non-aromatic equivalents. Other examples of heterocyclic groups include piperidyl, quinolyl, isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyrrolyl, pyrrolidinyl, octahydroindolyl, octahydrobenzothiofuranyl and octahydrobenzofuranyl. I do.

B. Compounds One aspect of the present invention is characterized in the summary section of the invention by the compounds represented by formula (1). Examples of compounds of formula (1) are
(a) the sulfamoyl group is meta to W (CO)-and para to the bridged NH; (b) the sulfamoyl group is para to W (CO)-and to the bridged NH (C) R ₄ is fluorine; (d) R ₃
(E) R ₃ is H; (f) W is OH; (g) W is NR ₂ OR ₁ ; (h) each of R ₃ and R ₄ is fluorine (I) R ₁ has at least one hydroxy substitution; (k) R ₁ is H, methyl, ethyl,
Propyl, isopropyl, isobutyl, benzyl, phenethyl, allyl, C _2-5 alkenyl, C _2-5 alkynyl,
C _3-6 cycloalkyl, (C _3-5 cycloalkyl) C _1-2 alkyl, (C _3-5 heterocyclic group) C _1-2 alkyl or (C
H ₂₎ be a _{2-4 NR A R B; (l} ) R 1 is H or (C _3-4 cycloalkyl) C _1-2 alkyl; (m) R ₂ is H, methyl, C _{2- 4} alkynyl, C _3-5 cycloalkyl or (C _3-5 cycloalkyl) methyl; (n) _RA is H,
Methyl, ethyl, isobutyl, hydroxyethyl, hydroxypropyl, cyclopropylmethyl, cyclobutylmethyl, _C3-4 alkynyl, phenyl, 2-piperidin-1-yl-ethyl, 2,3-dihydroxy-propyl, 3- [4 -(2-hydroxyethyl) -piperazin-1-yl] -propyl, 2-pyrrolidin-1-yl-
Ethyl or 2-diethylamino-ethyl; and R _B is H; or R _B is methyl and R _A
Is phenyl; (o) R ₇ is (CH ₂ ) _2-4 (NR _C R _D ); (p) NR _C R _D is morpholinyl, piperazinyl,
(Q) R _C is methyl, ethyl, hydroxyethyl or hydroxypropyl; (r) R ₅ is methyl or chlorine; (s) R _D is methyl , Ethyl, hydroxyethyl or hydroxypropyl; (t) or a combination thereof, for example having a structure wherein each of R _C and R _D is methyl or ethyl.

When _one of R ₁ , R ₂ , R _A , R _B , R _C or R _D is an alkenyl or alkynyl group, the double or triple bond, respectively, is not adjacent to the point of attachment. . For example, when W is NR ₂ OR ₁ , R ₂ is preferably prop-2-ynyl or but-2- or 3
-Enyl and, more preferably, prop-1-ynyl or but-1-enyl.

Examples of the compound of the formula (1) are 2- (2-chloro-4-iodo-phenylamino) -4-sulfamoyl-benzoic acid; 2- (2-chloro-4-iodo-phenylamino)- N-hydroxy-4-sulfamoyl-benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-4-sulfamoyl-benzamide; 2- (2-chloro-4-iodo-
Phenylamino) -4- (2-morpholin-4-yl-
Ethylsulfamoyl) -benzoic acid; 2- (2-chloro-4-iodo-phenylamino) -N-hydroxy-4
-(2-morpholin-4-yl-ethylsulfamoyl) -benzamide; 2- (2-chloro-4-iodo-
Phenylamino) -N-cyclopropylmethoxy-4-
(2-morpholin-4-yl-ethylsulfamoyl)
-Benzamide; 2- (2-chloro-4-iodo-phenylamino) -3,4-difluoro-5-sulfamoyl-benzoic acid (APK IC ₅₀ = 749 ± 344 nM);
-(2-chloro-4-iodo-phenylamino) -3,
4-difluoro-N-hydroxy-5-sulfamoyl-benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-
Difluoro-5-sulfamoyl-benzamide; 2-
(2-chloro-4-iodo-phenylamino) -3,4
-Difluoro-5- (2-morpholin-4-yl-ethylsulfamoyl) -benzoic acid; 2- (2-chloro-4
-Iodo-phenylamino) -3,4-difluoro-N
-Hydroxy-5- (2-morpholin-4-yl-ethylsulfamoyl) -benzamide; and 2- (2-
Chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5- (2-morpholin-4-yl-ethylsulfamoyl) -benzamide.

Other examples are 5- [bis (4-methoxy-benzyl) sulfamoyl] -2- (2-chloro-4-iodo-phenylamino) -3,4-difluoro-benzoic acid; and 2- ( 2-chloro-4-iodo-phenylamino) -5-dimethylsulfamoyl-3,4-difluoro-benzoic acid methyl ester.

An additional example is 5- (bis-pyridine-3)
-Ylmethyl-sulfamoyl) -3,4-difluoro-2- (4-iodo-phenylamino) -benzoic acid; 5
-(Bis-pyridin-3-ylmethyl-sulfamoyl) -N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro- 2- (4-Iodo-phenylamino) -5- (methyl-pyridin-3-ylmethyl-sulfamoyl) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-phenylamino)- 5-
[(Pyridin-3-ylmethyl) -sulfamoyl] -benzamide; N-cyclopropylmethoxy-5-[(3
-Diethylamino-propyl) -pyridin-3-ylmethyl-sulfamoyl] -3,4-difluoro-2-
(4-iodo-phenylamino) -benzamide; N-
Cyclopropylmethoxy-3,4-difluoro-5-
[(3-hydroxy-propyl) -pyridin-3-ylmethyl-sulfamoyl] -2- (4-iodo-phenylamino) -benzamide; N-cyclopropylmethoxy-5- (ethyl-pyridin-3-ylmethyl-sulfamoyl) -3,4-difluoro-2- (4-iodo-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-
Ethyl) -pyridin-3-ylmethyl-sulfamoyl] -2- (4-iodo-phenylamino) -benzamide; 5- (bis-pyridin-2-ylmethyl-sulfamoyl) -3,4-difluoro-2- (4- Iodine
Phenylamino) -benzoic acid; 5- (bis-pyridine-
2-ylmethyl-sulfamoyl) -N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-
N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-phenylamino) -5- (methyl-pyridin-2-ylmethyl-sulfamoyl) -benzamide; N-cyclopropylmethoxy -3,4-difluoro-2- (4-iodo-phenylamino) -5-[(pyridin-2-ylmethyl) -sulfamoyl] -benzamide; 5- (bis-pyridin-3-ylmethyl-sulfamoyl) -3,
4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid; 5- (bis-pyridine-3-
Ylmethyl-sulfamoyl) -N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-2-
Methyl-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -5- (methyl-
Pyridin-3-ylmethyl-sulfamoyl) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -5-[(pyridin-3-ylmethyl) -sulfamoyl ] -Benzamide; N-cyclopropylmethoxy-
5-[(3-diethylamino-propyl) -pyridine-3
-Ylmethyl-sulfamoyl] -3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-
Benzamide; N-cyclopropylmethoxy-3,4-
Difluoro-5-[(3-hydroxy-propyl) -pyridin-3-ylmethyl-sulfamoyl] -2- (4-
Iodo-2-methyl-phenylamino) -benzamide; N-cyclopropylmethoxy-5- (ethyl-pyridin-3-ylmethyl-sulfamoyl) -3,4-difluoro-2- (4-iodo-2-methyl-phenyl Amino) -benzamide; N-cyclopropylmethoxy-
3,4-difluoro-5-[(2-hydroxy-ethyl)
-Pyridin-3-ylmethyl-sulfamoyl) -2-
(4-Iodo-2-methyl-phenylamino) -benzamide; 5- (bis-pyridin-2-ylmethyl-sulfamoyl) -3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)- Benzoic acid; 5- (bis-pyridin-2-ylmethyl-sulfamoyl) -N
-Cyclopropylmethoxy-3,4-difluoro-2-
(4-Iodo-2-methyl-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -5- (methyl-pyridine-2 -Ylmethyl-sulfamoyl) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -5-[(pyridin-2-ylmethyl) -sulfamoyl] -benzamide 5- (bis-pyridin-3-ylmethyl-sulfamoyl) -2
-(2-chloro-4-iodo-phenylamino) -3,
4-difluoro-benzoic acid; 5- (bis-pyridine-3
-Ylmethyl-sulfamoyl) -2- (2-chloro-
4- (iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide; 2- (2
-Chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5- (methyl-pyridin-3-ylmethyl-sulfamoyl) -benzamide; 2- (2-chloro-4-iodo- Phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5-[(pyridin-3-ylmethyl) -sulfamoyl] benzamide; 2- (2-chloro-4-iodo-
Phenylamino) -N-cyclopropylmethoxy-5-
[(3-Diethylamino-propyl) -pyridin-3-ylmethyl-sulfamoyl] -3,4-difluoro-benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4 -Difluoro-5-[(3-hydroxy-propyl) -pyridin-3-ylmethyl-sulfamoyl] benzamide;
2- (2-chloro-4-iodo-phenylamino) -N
-Cyclopropylmethoxy-5- (ethyl-pyridine-
3-ylmethyl-sulfamoyl) -3,4-difluoro-benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4
-Difluoro-5-[(2-hydroxy-ethyl) -pyridin-3-ylmethyl-sulfamoyl] benzamide; 5- (bis-pyridin-2-ylmethyl-sulfamoyl) -2- (2-chloro-4-iodo-phenyl Amino) -3,4-difluoro-benzoic acid; 5- (bis-
Pyridin-2-ylmethyl-sulfamoyl) -2-
(2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3, 4-difluoro-5- (methyl-pyridin-2-ylmethyl-sulfamoyl) -benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5- [ (Pyridin-2-ylmethyl) -sulfamoyl] benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(3-hydroxy-propyl) -pyridin-2-ylmethyl-sulfamoyl] -2- (4-iodo -Phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydro [Xy-ethyl) -pyridin-2-ylmethyl-sulfamoyl] -2- (4-iodo-phenylamino) -benzamide; 5- (benzyl-pyridin-2-ylmethyl-sulfamoyl) -N-
Cyclopropylmethoxy-3,4-difluoro-2-
(4-iodo-phenylamino) -benzamide; N-
Cyclopropylmethoxy-3,4-difluoro-2-
(4-iodo-phenylamino) -5-[(pyridine-
4-ylmethyl) -sulfamoyl] -benzamide;
N-cyclopropylmethoxy-5- (ethyl-pyridin-4-ylmethyl-sulfamoyl) -3,4-difluoro-2- (4-iodo-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro -2- (4-Iodo-phenylamino) -5- (methyl-pyridin-4-ylmethyl-sulfamoyl) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(3-hydroxy-propyl) -Pyridin-4-ylmethyl-sulfamoyl] -2- (4-iodo-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl) -pyridine-4- Ylmethyl-sulfamoyl] -2- (4-iodo-phenylamino) -benzamide; N-cyclo Ropirumetokishi -3,4-difluoro-2- (4-iodo - phenyl) -5-
(Methyl-phenyl-sulfamoyl) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-phenylamino) -5-phenylsulfamoyl-benzamide; N-cyclopropylmethoxy-3, 4-difluoro-2- (4-iodo-phenylamino) -5- (pyridin-3-ylsulfamoyl) -benzamide; N-cyclopropylmethoxy-
3,4-difluoro-5-[(3-hydroxy-propyl) -pyridin-2-ylmethyl-sulfamoyl]-
2- (4-iodo-2-methyl-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl) -pyridin-2-ylmethyl-sulfamoyl] -2 -(4-iodo-2-methyl-phenylamino) -benzamide; 5
-(Benzyl-pyridin-2-ylmethyl-sulfamoyl) -N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzamide; N-cyclopropylmethoxy-
3,4-difluoro-2- (4-iodo-2-methyl-
Phenylamino) -5-[(pyridin-4-ylmethyl)
-Sulfamoyl] -benzamide; N-cyclopropylmethoxy-5- (ethyl-pyridin-4-ylmethyl-sulfamoyl) -3,4-difluoro-2- (4-
Iodo-2-methyl-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-
5- (methyl-pyridin-4-ylmethyl-sulfamoyl) -benzamide; N-cyclopropylmethoxy-
3,4-difluoro-5-[(3-hydroxy-propyl) -pyridin-4-ylmethyl-sulfamoyl]-
2- (4-iodo-2-methyl-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl) -pyridin-4-ylmethyl-sulfamoyl] -2 -(4-iodo-2-methyl-phenylamino) -benzamide; N
-Cyclopropylmethoxy-3,4-difluoro-2-
(4-Iodo-2-methyl-phenylamino) -5
(Methyl-phenyl-sulfamoyl) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino)-
5-phenylsulfamoyl-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-
2-iodo-2-methyl-phenylamino) -5- (pyridin-3-ylsulfamoyl) -benzamide; 2-
(2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5-[(3
-Hydroxy-propyl) -pyridin-2-ylmethyl-sulfamoyl] -benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5-[(2- (Hydroxy-ethyl) pyridin-2-ylmethyl-sulfamoyl] -benzamide; 5- (benzyl-pyridin-2-
Ylmethyl-sulfamoyl) -2- (2-chloro-4
-Iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide; 2- (2-
Chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5-[(pyridin-4-ylmethyl) -sulfamoyl] -benzamide; 2- (2-chloro-4-iodo-phenyl) amino)
-N-cyclopropylmethoxy-5- (ethyl-pyridin-4-ylmethyl-sulfamoyl) -3,4-difluoro-benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-
3,4-difluoro-5- (methyl-pyridin-4-ylmethyl-sulfamoyl) -benzamide; 2- (2
-Chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5-[(3-hydroxy-propyl) -pyridin-4-ylmethyl-sulfamoyl] -benzamide; 2- (2- Chloro-4
-Iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl) -pyridin-4-ylmethyl-sulfamoyl]
-Benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-
Difluoro-5- (methyl-phenyl-sulfamoyl) -benzamide; 2- (2-chloro-4-iodo-
Phenylamino) -N-cyclopropylmethoxy-3,
4-difluoro-5-phenylsulfamoyl-benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5- (pyridin-3-ylsulfamoyl N-cyclopropylmethoxy-2- (4-iodo-phenylamino) -4-phenylsulfamoyl-benzamide; N-cyclopropylmethoxy-2-
(4-Iodo-phenylamino) -4- (pyridine-3
-Ylsulfamoyl) -benzamide; N-cyclopropylmethoxy-2- (4-iodo-phenylamino)
4-[(pyridin-3-ylmethyl) -sulfamoyl] -benzamide; 4- (bis-pyridin-3-ylmethyl-sulfamoyl) -N-cyclopropylmethoxy-2- (4-iodo-phenylamino) -benzamide; N-cyclopropylmethoxy-4-[(2-hydroxy-ethyl) -pyridin-4-ylmethyl-sulfamoyl] -2- (4-iodo-phenylamino) -benzamide; N-cyclopropylmethoxy-2- (4- Iodo-phenylamino) -4- (methyl-pyridine-3
-Ylmethyl-sulfamoyl) -benzamide; N-
Cyclopropylmethoxy-4-[(3-diethylamino-propyl) -pyridin-3-ylmethyl-sulfamoyl] -2- (4-iodo-phenylamino) -benzamide; N-cyclopropylmethoxy-2- (4-iodo- 2-methyl-phenylamino) -4-phenylsulfamoyl-benzamide; N-cyclopropylmethoxy-2- (4-iodo-2-methyl-phenylamino)
-4- (pyridin-3-ylsulfamoyl) -benzamide; N-cyclopropylmethoxy-2- (4-iodo-2-methyl-phenylamino) -4-[(pyridin-3-ylmethyl) -sulfamoyl]- 4- (bis-pyridin-3-ylmethyl-sulfamoyl) -N-cyclopropylmethoxy-2- (4-iodo-2-methyl-phenylamino) -benzamide;
N-cyclopropylmethoxy-4-[(2-hydroxy-ethyl) -pyridin-4-ylmethyl-sulfamoyl] -2- (4-iodo-2-methyl-phenylamino) -benzamide; N-cyclopropylmethoxy-2
-(4-Iodo-2-methyl-phenylamino) -4-
(Methyl-pyridin-3-ylmethyl-sulfamoyl) -benzamide; N-cyclopropylmethoxy-4
-[(3-diethylamino-propyl) -pyridine-3-
Ylmethyl-sulfamoyl] -2- (4-iodo-2
-Methyl-phenylamino) -benzamide; 2- (2
-Chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-4-phenylsulfamoyl-benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-4- ( Pyridin-3-ylsulfamoyl) -benzamide; 2- (2
-Chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-4-[(pyridin-3-ylmethyl)
-Sulfamoyl] -benzamide; 4- (bis-pyridin-3-ylmethyl-sulfamoyl) -2- (2-
Chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-benzamide; 2- (2-chloro-4
-Iodo-phenylamino) -N-cyclopropylmethoxy-4-[(2-hydroxy-ethyl) -pyridine-4
-Ylmethyl-sulfamoyl] -benzamide; 2-
(2-Chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-4- (methyl-pyridine-3-
Ylmethyl-sulfamoyl) -benzamide; and 2- (2-chloro-4-iodo-phenylamino) -N
-Cyclopropylmethoxy-4-[(3-diethylamino-propyl) -pyridin-3-ylmethyl-sulfamoyl] -benzamide.

C. Synthesis The disclosed compounds can be synthesized according to the following four schemes or variations thereof. These synthetic methods suitable for conventional or combinatorial real synthetic methods are further illustrated in Examples 1-4 below.

[0024]

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[0025]

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[0026]

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[0027]

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Amine reagents such as R ₆ R ₇ NH in the above scheme are commercially available or can be obtained by simple modifications of commercially available intermediates. Examples of such amine reagents that can be reacted with appropriate intermediates in the combinatorial or matrix method are described below. For example, in section B (compound) starting on page 8, line 16, 3
There are three sets of 0 (one set each for R ₅ = H, Me and Cl). The following table shows the numbers (corresponding to the order in which the names are found in the text; for example "1"
Correspond to compounds 1, 31 and 61 in the list of 90 compounds); amine reagent names; and chemical abstract numbers. Where a PD number is given, the amine reagent was prepared from commercially available starting materials.

[0029]

[Table 1]

The additional compounds in claim 1 can be prepared using the following amine reagents. Corresponding CAS
Enter the number. 2- (methylamino) pyridine 4597-87-9 2-benzylaminopyridine 6935-27-9 2-allylaminopyridine 5866-28-4 2,2'-dipyridylamine 1202-34-2 2-anilinopyridine 6631 -37-4 2-aminopyridine 504-29-0 4-aminopyridine 504-24-5 2-benzylaminopyridine 6935-27-9 2- (4-methoxybenzyl) aminopyridine 52818-63-0 2-methyl Aminopyridine 4597-87-9

D. Uses The disclosed compositions are useful for prophylactic and therapeutic treatment of diseases or conditions as described in the Summary of the Invention, as well as diseases or conditions modulated by the MEK cascade. Examples of diseases include stroke, heart failure, osteoarthritis, rheumatoid arthritis, organ transplant rejection and various tumors such as ovarian, lung, pancreatic, brain, prostate and colorectal tumors.

1. A person skilled in the art will be aware of suitable dosages for a patient by known methods, taking into account such factors as age, weight, general health, type of pain requiring treatment and the presence of other medications. Can be determined. Generally, an effective amount will be between 0.1 and 1000 mg / kg body weight per day, preferably between 1 and 300 mg / kg body weight and the daily dose will be 10 to 10 for normal weight adult patients. ~ 500
Between 0 mg. 100 mg, 200 mg, 300 mg or 400 mg of commercially available capsules or other formulations (eg, liquid and film-coated tablets)
Can be administered by the disclosed methods.

2. Formulation Dosage unit forms include tablets, capsules, pills, powders, granules, aqueous and non-aqueous oral solutions and suspensions, and non-aqueous tablets filled into individual doses. Oral solutions are included. Dosage unit forms may also be adapted for various modes of administration, including controlled release formulations, such as subcutaneous implantation. The method of administration is oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, vaginal, intraperitoneal, intravesical, topical (drip, powder, ointment) , Gels or creams) administration and inhalation (buccal or nasal spray).

Parenteral formulations include pharmaceutically acceptable aqueous or non-aqueous solutions, dispersions, suspensions, emulsions and sterile powders for producing them. Examples of carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils and injectable organic esters such as ethyl oleate.
Fluidity can be maintained through the use of a coating such as lecithin, a surfactant, or by maintaining an appropriate particle size. Carriers for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrants, (e) solution retarders,
(F) an absorption promoter, (g) an adsorbent, (h) a lubricant,
(I) a buffer and (j) a propellant. The compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants; antimicrobial agents, such as parabens, chlorobutanol, phenol and sorbic acid; isotonic agents, such as sugar or sodium chloride; For example, aluminum monostearate and gelatin; and absorption-enhancing agents can be included.

3. Related Compounds The present invention relates to the disclosed compounds and closely related pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, hydrated or solvated forms thereof; masked or protected forms And a racemic mixture or enantiomerically or optically pure form is provided.

Pharmaceutically acceptable salts, esters and amides are within reasonable benefit / risk ratios, are pharmacologically effective and come into contact with the patient's tissues without undue toxicity, irritation or allergic response. Carboxylate salts (eg, C _1-8 alkyl, cycloalkyl, aryl, hefroaryl, non-aromatic heterocyclic) that are suitable for:
Includes amino acid addition salts, esters and amides. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate,
Borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate,
Includes tartrate, naphthylate, mesylate, glucoheptonate, lacthiobionate and lauryl sulfonate. These include alkali metal and alkaline earth metal cations such as sodium, potassium, calcium and magnesium, and non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethylammonium, methylamine, trimethylamine and ethylamine. Can be included.
For example, SM Berge, which is incorporated herein by reference.
“Pharmaceutical Salts”, J. Pharm. Sci., 197
See 7, 66: 1-19. Representative pharmaceutically acceptable amides of the present invention are those derived from ammonia, primary C _1-6 alkylamines and secondary di (C _1-6 alkyl) amines. Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally 1-2 additional heteroatoms. Preferred amides are derived from ammonia, C _1-3 alkyl primary amines and di (C _1-2 alkyl) amines. Representative pharmaceutically acceptable esters of the invention include C _1-7 alkyl, C _5-7 cycloalkyl, phenyl and phenyl (C _1-6) alkyl esters. Preferred esters include methyl esters.

The present invention also includes the disclosed compounds having one or more functional groups (eg, hydroxyl, amino or carboxyl) masked by a protecting group. Some of these masked or protected compounds are pharmaceutically acceptable and others are useful as intermediates. Synthetic intermediates and methods disclosed herein and slight modifications thereof are also within the scope of the invention.

Hydroxyl protecting groups Hydroxyl protecting groups include ethers, esters and 1,1
Includes protection against 2- and 1,3-diols.
Ether protecting groups include the conversion of silyl ethers to methyl, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, silyl ethers and other functional groups.

Substituted methyl ethers Substituted methyl ethers include methoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl,
-Ethoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis (2 -Chloro-ethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydro-pyranyl,
Tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxide, 1-[(2-chloro-4-methyl) Phenyl] -4-methoxypiperidine-
4-yl, 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, and 2,3,
3a, 4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-ethanobenzofuran-2-yl.

Substituted ethyl ether Substituted ethyl ether is 1-ethoxyethyl, 1-ethoxyethyl,
-(2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl , 2-trimethylsilylethyl, 2- (phenylselenyl) ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.

Substituted benzyl ethers The substituted benzyl ethers are p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-
Dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-
Picolyl N-oxide, diphenylmethyl, p, p'-
Dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenyl-methyl, p
-Methoxyphenyldiphenylmethyl, di (p-methoxyphenyl) phenylmethyl, tri- (p-methoxyphenyl) methyl, 4- (4'-bromophenacyloxy) phenyldiphenylmethyl, 4,4 ', 4 "-tris (4,5-dichlorophthalimido-phenyl) methyl,
4,4 ', 4 "-tris (levulinoyloxy-phenyl) methyl, 4,4', 4" tris (benzoyloxy-
Phenyl) methyl, 3- (imidazol-1-ylmethyl) -bis (4 ', 4 "-dimethoxyphenyl) -methyl, 1,1-bis (4-methoxyphenyl) -1'-pyrenylmethyl, 9-anthryl, 9 -(9-phenyl)
Xanthenyl, 9- (9-phenyl-10-oxo) anthryl, 1,3-benzodithiolan-2-yl, and benzisothiazolyl S, S-dioxide.

Silyl ethers Silyl ethers include trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethyl texylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p -Xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and t-butylmethoxy-phenylsilyl.

Ester ester protecting groups include esters, carbonates, assisted cleavage, miscellaneous esters and sulfonic esters. Examples of ester protected esters are formate, benzoyl formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,
Methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio) pentanoate, Includes pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, and 2,4,6-trimethylbenzoate (mesitate).

Carbonate carbonate is methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl,
2- (triphenylphosphonio) ethyl, isobutyl,
Vinyl, allyl, p-nitrophenyl, benzyl, p-
Methoxybenzyl, 3,4-dimethoxybenzyl, o-
Includes nitrobenzyl, p-nitrobenzyl, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl, and methyldithiocarbonate.

Examples of auxiliary cleavage auxiliary cleavage protecting groups are 2-iodobenzoate, 4-iodobenzoate,
Azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzene-sulfonate, 2- (methylthiomethoxy) ethyl carbonate, 4- (methylthiomethoxymethyl) benzoate, and 2 -(Methylthiomethoxymethyl) benzoate.

Miscellaneous Esters In addition to the classes described above, miscellaneous esters are 2,2
6-dichloro-4-methylphenoxyacetate, 2,
6-dichloro-4- (1,1,3,3-tetramethylbutyl) phenoxyacetate, 2,4-bis (1,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate,
(E) -2-methyl-2-butenoate (tigroate), o- (methoxycarbonyl) benzoate, p-
P-benzoate, α-naphthoate, nitrate,
Includes alkyl N, N, N'N'-tetramethyl-phosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate. Sulfonate protected sulfates include sulfate, methanesulfonate (mesylate), benzylsulfonate and tosylate.

The protection for 1,2- and 1,3-diols
Protection against the 1,2- and 1,3-diol groups includes cyclic acetals and ketals, cyclic orthoesters and silyl derivatives. Cyclic acetals and ketals Cyclic acetals and ketals are methylene, ethylidene, 1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-
Includes trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and 2-nitrobenzylidene. I do.

Cyclic orthoesters Cyclic orthoesters include methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidene, 1,2-dimethoxyethylidene, α-methoxybenzylidene, 1- (N, N-dimethyl Amino) ethylidene derivatives, α- (N, N-dimethylamino) benzylidene derivatives, and 2-oxacyclopentylidene.

Protective esters for carboxyl groups Ester protecting groups include esters, substituted methyl esters, 2-substituted ethyl esters, substituted benzyl esters, silyl esters, activated esters,
Includes miscellaneous derivatives, and stannyl esters.

Substituted methyl esters The substituted methyl esters are 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxy-methyl, benzyloxy Methyl, phenacyl, p-bromophenacyl, α-methylphenacyl, p-methoxyphenacyl,
Carboxamidomethyl, and N-phthalimidomethyl.

2-Substituted Ethyl Esters 2-Substituted ethyl esters are 2,2,2-trichloroethyl, 2-haloethyl, ω-chloroalkyl, 2-
(Trimethylsilyl) ethyl, 2-methylthioethyl,
1,3-dithianyl-2-methyl, 2 (p-nitrophenylsulfenyl) -ethyl, 2- (p-toluenesulfonyl) ethyl, 2- (2'-pyridyl) ethyl, 2-
(Diphenylphosphino) ethyl, 1-methyl-1-phenylethyl, t-butyl, cyclopentyl, cyclohexyl, allyl, 3-buten-1-yl, 4- (trimethylsilyl) -2-buten-1-yl, cinnamyl, α
-Methylcinnamyl, phenyl, p- (m-methylmercapto) -phenyl, and benzyl.

Substituted benzyl esters The substituted benzyl esters are triphenylmethyl,
Diphenylmethyl, bis (o-nitrophenyl) methyl, 9-anthrylmethyl, 2- (9,10-dioxo) anthrylmethyl, 5-dibenzo-suberyl, 1-
Pyrenylmethyl, 2- (trifluoromethyl) -6-chromylmethyl, 2,4,6-trimethyl-benzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl , 4- (methylsulfinyl) benzyl, 4-sulfobenzyl, piperonyl, and 4-P-benzyl. Silyl esters Silyl esters include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, i-propyldimethylsilyl, phenyldimethylsilyl, and di-t-butylmethylsilyl.

Miscellaneous Derivatives Miscellaneous derivatives include oxazole, 2-alkyl-
1,3-oxazoline, 4-alkyl-5-oxo-1,
3-oxazolidine, 5-alkyl-4-oxo-1,
Includes 3-dioxolane, orthoester, phenyl, and pentaaminocobalt (III) complexes. Examples of stannyl esters stannyl esters include triethyl stannyl and tri -n- butylstannyl.

Amides and hydrazide amides include N, N-dimethyl, pyrrolidinyl, piperidinyl, 5,6-dihydrophenanthridinyl, o-nitroanilide, N-7-nitroindolyl, N-8-nitro-1, 2,3,4-tetrahydroquinolyl, and p-
P-benzenesulfonamide. Hydrazides include N-phenyl, N, N'-diisopropyl and other dialkyl hydrazides.

Protected carbamate carbamates for amino groups include carbamates, substituted ethyls, assisted cleavage, photolytic cleavage, urea-type derivatives, and miscellaneous carbamates. Carbamates Carbamates include methyl and ethyl, 9-fluorenylmethyl, 9- (2-sulfo) fluorenylmethyl, 9-
-(2,7-dibromo) fluorenylmethyl, 2,7-di-t-butyl- [9- (10,10-dioxo-10,1
0,10,10-tetrahydro-thioxanthyl) methyl, and 4-methoxyphenacyl.

Substituted ethyl Substituted ethyl protecting groups include 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1- (1-adamantyl) -1-methylethyl,
1,1-dimethyl-2-haloethyl, 1,1-dimethyl-
2,2-dibromoethyl, 1,1-dimethyl-2,2,2-
Trichloroethyl, 1-methyl-1- (4-biphenylyl) ethyl, 1- (3,5-di-t-butylphenyl)
-1-methylethyl, 2- (2'- and 4'-pyridyl) ethyl, 2- (N, N-dicyclohexylcarboxamide) -ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, Cinnamil,
4-nitrocinnamyl, quinolyl, N-hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, p
-Chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, and diphenylmethyl.

[0057] Protection by auxiliary Cleavage auxiliary cleavage include 2-methylthioethyl, 2-methylsulfonylethyl, 2- (p-toluenesulfonyl) ethyl, [2- (1,3-dithianyl)] methyl, 4
-Methylthiophenyl, 2,4-dimethyl-thiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1,1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p- (dihydroxyboryl) benzyl , 5-benzisoxazolyl-methyl, and 2- (trifluoromethyl) -6
Chromonylmethyl.

[0058] photolytic cleavage photolysis cleavage methods are, m- nitrophenyl, 3,5-dimethoxybenzyl, o- nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl (o-nitrophenyl) methyl Use such groups. Examples of the urea type derivatives urea type derivatives, phenothiazinyl - including carbonyl derivative, N'-p-toluenesulfonyl aminocarbonyl, and N'- phenylaminothiocarbonyl - (10).

Miscellaneous carbamates In addition to the above, miscellaneous carbamates include t-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl,
Cyclopropylmethyl, p-decyloxy-benzyl,
Diisopropylmethyl, 2,2-dimethoxy-carbonylvinyl, o- (N, N-dimethyl-carboxamide)
-Benzyl, 1,1-dimethyl-3 (N, N-dimethylcarboxamido) propyl, 1,1-dimethyl-propynyl, di (2-pyridyl) methyl, 2-furanylmethyl,
2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p (p'-methoxyphenyl-azo) benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropyl-methyl, 1-methyl- (3 , 5-Dimethoxyphenyl) ethyl, 1-methyl-1 (p-phenylazophenyl) -ethyl, 1-methyl-1-phenylethyl, 1-methyl-1- (4-pyridyl) ethyl, phenyl, p- ( Phenylazo) benzyl, 2,4,6-tri-t-butylphenyl, 4- (trimethylammonium) benzyl, and 2,4,6-trimethylbenzyl.

[0060] Amide Amide amide, N- formyl, N- acetyl, N- chloroacetyl, N- trichloroacetyl, N- trifluoroacetyl, N- phenylacetyl, N-3- phenylpropionyl, N- picolinoyl, N- 3-pyridyl-carboxamide, N-benzoylphenylalanyl derivative,
N-benzoyl, and Np-phenylbenzoyl.

Auxiliary Cleavage The auxiliary cleavable group is No-nitrophenylacetyl, N-
o-nitrophenoxyacetyl, N-acetoacetyl,
(N'-dithiobenzyloxycarbonylamino) acetyl, N-3- (p-hydroxyphenyl) propionyl, N-3- (o-nitrophenyl) propionyl, N
-2-methyl-2- (o-nitrophenoxy) propionyl, N-2-methyl-2- (o-phenylazophenoxy) propionyl, N-4-chlorobutyryl, N-3
-Methyl-3-nitrobutyryl, No-nitrocinnamoyl, N-acetylmethionine derivative, No-nitrobenzoyl, No- (benzoyloxymethyl) benzoyl, and 4,5-diphenyl-3-oxazoline- 2-one.

Cyclic imide derivatives Cyclic imide derivatives include N-phthalimide, N-dithiasuccinoyl, N-2,3-diphenyl-maleoil,
-2,5-dimethylpyrrolyl, N-1,1,4,4-tetramethyl-disilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane -2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, and 1-substituted 3,5-dinitro-4-pyridonyl.

Specific -NH protecting groups -NH protecting groups include N-alkyl and N-arylamines, imine derivatives, enamine derivatives, and N-
-Heteroatom derivatives (e.g. N-metals, N-N, N-
P, N-Si, and NS), N-sulfenyl, and N-sulfonyl.

N-alkyl and N-arylamines N-alkyl and N-arylamine are N-methyl, N-allyl,-[2- (trimethylsilyl) ethoxyl] -methyl, N-3-acetoxypropyl, N-
(1-isopropyl-4-nitro-2-oxo-3-pyrolin-3-yl), quaternary ammonium salt, N-benzyl, N-di (4-methoxyphenyl) methyl, N-5
-Dibenzosuberyl, N-triphenylmethyl, N-
(4-methoxyphenyl) diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, and N
-2-picolylamine N'-oxide.

Imine Derivatives Imine derivatives include N-1,1-dimethylthiomethylene,
N-benzylidene, Np-methoxybenzylidene, N
-Diphenylmethylene, N-[(2-pyridyl) mesityl] methylene, N- (N ', N'-dimethylaminomethylene), N, N'-isopropylidene, Np-nitrobenzylidene, N-salicylidene, N- -5-chlorosalicylidene, N- (5-chloro-2-hydroxyphenyl) phenyl-methylene, and N-cyclohexylidene. Enamine derivatives Examples of enamine derivatives include N- (5,5-dimethyl-3-
Oxo-1-cyclohexenyl).

N-heteroatom derivatives N-metal derivatives include N-borane derivatives, N-diphenylborinic acid derivatives, N- [phenyl (pentacarbonylchromium- or -tungsten)] carbenyl, and N-copper or N-zinc Includes chelates. N, N-
Examples of derivatives include N-nitro, N-nitrone and N-oxide. Examples of NP derivatives include N-diphenylphosphinyl, N-dimethylthiophosphinyl, N-
Includes diphenylthiophosphinyl, N-dialkylphosphoryl, N-dibenzylphosphoryl, and N-diphenylphosphoryl. Examples of N-sulfenyl derivatives include N-benzenesulfenyl, No-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl,
2-nitro-4-methoxy-benzenesulfenyl, N
-Triphenylmethylsulfenyl, and N-3-nitropyridinesulfenyl. N-sulfonyl derivatives include N-p-toluenesulfonyl, N-benzenesulfonyl, N-2,3,6-trimethyl-4-methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzenesulfonyl, N-2 , 6-Dimethyl-4-methoxy-benzenesulfonyl, N-pentamethylbenzenesulfonyl, N-2,3,5,6-tetramethyl-4-methoxybenzene-sulfonyl, N-4-methoxybenzenesulfonyl, N-2 , 4,6-Trimethylbenzenesulfonyl, N-2,6-dimethoxy-4-methylbenzenesulfonyl, N-2,2,5,7,8-pentamethylchroman-
6-sulfonyl, N-methanesulfonyl, N-β-trimethyl-silylethanesulfonyl, N-9-anthracenesulfonyl, N-4- (4 ′, 8′-dimethoxynaphthylmethyl) -benzenesulfonyl, N-benzylsulfonyl, N-trifluoromethylsulfonyl, and N
-Phenacylsulfonyl.

The disclosed compounds that are masked or protected can be prodrugs that are metabolized or otherwise converted in vivo to yield, for example, the compounds disclosed in the short term during metabolism. This conversion can be hydrolysis or oxidation resulting from the action of body fluids such as blood or acids or from contact with the liver, gastrointestinal or other enzymes. The features of the present invention will be further described by the following examples.

E. Examples Example 1 2- (2-chloro-4-iodo-phenylamino) -5
Preparation of -dimethylsulfamoyl-3,4-difluorobenzoic acid methyl ester (APK IC ₅₀ = 222 nM) Step a: Preparation of 1-dimethylsulfamoyl-2,3,4-trifluorobenzene 1,2-dichloroethane (200 ml) in 2,3,4-trifluorobenzenesulfonyl chloride (5.70).
g, 0.0247 mol) of gaseous anhydrous dimethylamine was bubbled into the gently stirred solution. The mixture turned cloudy after a few minutes. The mixture was then combined with water (200 mL), 6N aqueous hydrochloric acid, brine (200 mL).
Washed in l), dried over anhydrous magnesium sulfate and concentrated in vacuo to give a yellow oil. The crude product was purified by flash chromatography. Elution with dichloromethane gave 3.40 g of a white solid. Yield 58%. ¹ H-NMR (400 MHz; CDCl ₃ ) δ 7.63-7.56 (m, 1
H), 7.12-7.04 (m, 1H), 2.812 (s, 3H), 2.807 (s, 3H);
¹⁹ F-NMR (376 MHz; CDCl ₃ ) δ -124.91 to -125.03 (m), -12
7.98 to -128.03 (m), -156.41 to -156.53.

Step b: 5-dimethylsulfamoyl-
Preparation of 2,3,4-trifluoro-benzoic acid in anhydrous tetrahydrofuran (60 ml) under a nitrogen atmosphere
1-dimethylsulfamoyl-2,3,4-trifluoro
Commercially available chilled (-78 ° C) stirred solution consisting of benzene
Diisopropylamide available at
Solution (Aldrich, tetrahydrofuran / heptane / ethyl
(2.0 M in benzene). After stirring for about 10 minutes
The purple solution via cannula and diethyl ether
Solution (200 ml) cooled and stirred with saturated carbon dioxide
Transferred to liquid. The reaction mixture is dull Burgundy red
How about the color of sake. Remove the cooling bath and remove the reaction mixture
Was warmed to ambient temperature for 1 hour. then,
The mixture is carefully quenched with 10% aqueous hydrochloric acid (200 ml).
I got it. The layers were separated. Organic phase is 10% by weight aqueous
2 times with sodium hydroxide (200ml, 100ml each)
Extracted. The combined aqueous alkaline extracts are concentrated with concentrated aqueous hydrochloric acid.
(100 ml) to pH 0. White precipitate formed
Was done. Cool the suspension, then add diethyl ether
(600 ml). Extract the organic extract with anhydrous
Dry over gnesium and concentrate in vacuo to give an off-white
2.70 g of a solid were obtained. Yield 67.5%. Melting point 225-2
28 ° C. ¹ H-NMR (400MHz; DMSO) δ 14.08 (broad s, 1H), 8.0
2-7.97 (m, 1H), 2.75 (s, 3H), 2.74 (s, 3H),¹⁹F-NMR (37
6 MHz; DMSO) δ -122.50 to -122.63 (m), -122.95 to -123.
08 (m), -154.49 to -154.61 (m); MS (APCI +) 284 (M + 1, 2
2), 238 (100); (APCI-) 282 (M-1, 85), 259 (94), 238 (4
6), 216 (91), 195 (100); IR (KBr) 1702cm^-1; Analytical value. C
₉H₈F_ThreeNO_FourCalculated / found for S: C, 38.17 / 38.40; H,
 2.85 / 2.90; N, 4.95 / 4.80; F, 20.12 / 19.75; S, 1
1.32 / 11.12.

Step c: 5-dimethylsulfamoyl-
Preparation of 2,3,4-trifluoro-benzoic acid methyl ester The acid catalyst (17.1 mg) was dissolved in methanol (125 ml). The stirred mixture is
The mixture was refluxed for 51 hours under a nitrogen atmosphere. The reaction mixture was concentrated in vacuo to give a solid. The product was partitioned between diethyl ether (200ml) and saturated aqueous potassium carbonate (75ml). The layers are separated and the organic phase is separated with water (75
ml), brine (75 ml), dried over anhydrous potassium carbonate and concentrated in vacuo to give 0.15 g of an off-white solid. Yield 10%. ¹ H-NMR (400 MHz; CDCl ₃ )
δ 8.23-8.19 (m, 1H), 3.92 (s, 3H), 2.83 (s, 6H); ¹⁹
F-NMR (376 MHz; CDCl ₃ ) δ -120.79 to -121.02 (m), -153.
69-153.80.

Step d: 2- (2-chloro-4-iodo-
Phenylamino) -5-dimethylsulfamoyl-3,
Preparation of 4-difluoro-benzoic acid methyl ester 2 in anhydrous tetrahydrofuran (5 ml) under a nitrogen atmosphere
-Chloro-4-iodoaniline (0.143 g, 5.64
× 10 ⁻⁴ mol) into a stirred, cooled (−78 ° C.) solution of a commercially available solution of lithium diisopropylamide (Aldrich, 2.0M in tetrahydrofuran / heptane / ethylbenzene, 0.300 ml, 6.30 ml). 0
× 10 ^-4 mol). After stirring for 5 minutes, a solution of 5-dimethylsulfamoyl-2,3,4-trifluoro-benzoic acid methyl ester (0.15 g, 5.0 × 10 ⁻⁴ mol) in tetrahydrofuran (10 ml) was added. , Added via syringe. The cooling bath was removed and the reaction mixture was stirred for 2 hours. The reaction mixture was then partitioned between diethyl ether (125ml) and saturated aqueous sodium bicarbonate (125ml). The aqueous bicarbonate phase was further extracted with diethyl ether (125ml). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated in vacuo to give a yellow oil. This oil is heptane-
Crystallized from ethyl acetate to give an off-white powder 0.060.
g was obtained. Yield 23%. Mp 154-156 ° C. ¹ H-NMR
(400MHz; CDCl ₃ ) δ 9.74 (s, 1H), 8.30 (d, 1H, J = 7.1H
z), 7.72 (s, 1H), 7.49 (d, 1H, J = 8.3Hz), 6.73-6.69 (m,
1H), 3.92 (s, 3H), 2.84 (s, 3H), 2.83 (s, 3H); ¹⁹ FN
MR (376 MHz; CDCl ₃ ) δ -123.90 (d), -139.55 (d).

Example 2 5- [Bis- (4-methoxy-benzyl) -sulfamo
Yl] -2- (2-chloro-4-iodo-phenylamido
G) -3,4-difluoro-benzoic acid (APK IC₅₀=
163 ± 33 nM) Step a: 2,3,4-trifluoro-N, N-bis- (4
Preparation of -methoxy-benzyl) benzenesulfonamide bis-4-methoxybenz in dichloromethane (10 ml)
Ziramine (2.5 g, 9.7 mmol) and diisoprop
From propylethylamine (1.7 ml, 9.7 mmol)
Liquid solution with 2,3,4-trifluorobenzenesulfur
Honyl chloride (2.24 g, 9.7 mmol) directly
added. The reaction is quite exothermic. Release reaction mixture overnight
And then with diethyl ether (250 ml)
Partition between saturated aqueous ammonium chloride (250 ml)
Was. The organic phase is dried (MgSO _Four) And concentrate in vacuum
Compression yielded 4.6 g of a yellow oil. This oil, at ambient temperature,
Crystallizes gradually on standing. Quantitative yield. Melting point 70-
79 ° C.¹H-NMR (400 MHz; CDCl_Three) δ 7.66-7.60 (m, 1H),
 7.07-7.02 (m, 1H), 7.02-6.74 (AB quadruple, 8H, J = 8.7H
z), 4.35 (s, 4H), 3.78 (s, 6H);¹⁹F-NMR (376 MHz; CDCl
_Three) δ -125.52〜-125.62 (m), -128.62〜-128.74 (m), -1
56.92 to -157.10 (m); MS (APCI +) 121 (M-330,100); (APCI
-) 330 (M-121, 18), 195 (M-256, 100); IR (KBr) 2954,
2835, 1613,1511, 1504, 1243, 1160, 1033cm^-1; C_{twenty two}H
₂₀F_ThreeNO_FourCalculated / found for S: C, 58.53 / 57.04; H,
4.47 / 4.34; N, 3.10 / 2.91; F, 12.62 / 13.35; S, 7.1
0 / 7.00.

Step b: Preparation of 5- [bis- (4-methoxy-benzyl) -sulfamoyl] -2,3,4-trifluoro-benzoic acid Tetrahydrofuran (50 ml) at -78 ° C. under a nitrogen atmosphere.
2,3,4-trifluoro-N, N-bis- (4-methoxy-benzyl) benzenesulfonamide (4.38
g, 9.7 mmol) in a lithium diisopropylamide solution (Aldrich, 2.0 M in tetrahydrofuran / heptane / ethylbenzene, 5.0 ml, 1 ml).
0 mmol) was added. The dark mixture was stirred for 15 minutes,
It was then transferred to a reaction flask containing a cooled (−78 ° C.) stirred carbon dioxide ether solution (200 ml). The cooling bath was removed and the reaction mixture was stirred at room temperature for 5 days.
The mixture was treated with dilute aqueous acid and the layers were separated. The organic phase was treated with 10% by weight aqueous sodium hydroxide to pH 14 to give a white suspension. This suspension was filtered. The solid was suspended in dilute aqueous hydrochloric acid. Diethyl ether was added and the layers were shaken vigorously. The resulting suspension was filtered and the solid was aspirated to give 1.0584 g of a white powder. Yield 2
2%. 158-161 ° C. ¹ H-NMR (400 MHz; DMSO)
δ 7.80-7.76 (m, 1H), 7.05-6.74 (AB quartet, 8H, J = 8.6
Hz), 4.33 (s, 4H), 3.66 (s, 6H); ¹⁹ F-NMR (376 MHz; DMS
O) δ -123.28 to -123.36 (m), -124.12 to -124.21 (m), -1
55.41-155.53 (m); MS (APCI +) 495 (M, 1), 121 (100);
(APCI-) 494 (M-1, 47), 216 (89), 195 (100); IR (KBr) 32
40 (broad), 2954, 2838, 1695 (C = O stretch), 16
13, 1512, 1347, 1238, 1152, 1079cm -1; C 23 H 20 F 3 NO 6 S
Calculated / found: C, 55.76 / 55.85; H, 4.07 / 4.0
2; N, 2.83 / 2.71; F, 11.50 / 11.41; S, 6.47 / 6.25.

Step c: 5- [bis- (4-methoxy-benzyl) -sulfamoyl] -2- (2-chloro-4-
Preparation of (iodo-phenylamino) -3,4-difluoro-benzoic acid Tetrahydrofuran (10 ml) at -78 ° C under nitrogen atmosphere
2-chloro-4-iodoaniline (0.5300)
g, 2.050 mmol) was added lithium bis (trimethylsilyl) amide (Aldrich, 1.0 M in tetrahydrofuran, 4.1 ml, 4.1 mmol). Within minutes, the green solution became a dark, light green suspension. The suspension is added via cannula to 5
-A cooled (-78 ° C) solution of lithium [bis- (4-methoxy-benzyl) -sulfamoyl] -2,3,4-trifluorobenzoate [2.0 ml of a 1.0 M lithium bis (trimethylsilyl) amide solution ( 2.0 mmol)
With 5- [bis- (4-methoxy-benzyl) -sulfamoyl] -2,3,4-trifluorobenzoic acid (1.0
0 g, 2.02 mmol). The reaction mixture became clear and homogeneous within minutes. The reaction mixture was stirred for 15 minutes. The mixture was concentrated in vacuo to give a crude semi-solid.
The crude product was partitioned between diethyl ether (250ml) and very dilute (~ 1%) aqueous hydrochloric acid (150ml). The ether phase was then combined with water (200 ml, pH 4 after washing), a second portion of water (200 ml, pH 6 after washing) and brine (20 ml) to help neutralize the ether phase.
0 ml). Dry the ether phase (MgSO ₄ )
And concentrated in vacuo to give 1.88 g of a viscous residue. Upon standing overnight, the viscous product partially solidified. The amorphous solid was dissolved in dichloromethane and re-concentrated to give a semi-solid again. This semi-solid was dissolved in boiling toluene (500 ml). The clear yellow solution was left at room temperature as it slowly cooled. Further crystallization does not occur even when cooled in a cooler. Heptane (70 ml) was added to the cooled yellow solution. An oily suspension precipitates, but violent and persistent scratching causes solidification. The solid is collected by vacuum filtration and suctioned off off-white powder 1.1180
g was obtained. Yield 76%. 162-166 ° C. ¹ H-NMR
(400MHz; DMSO) δ 9.86 (s, 1H), 7.92 (d, 1H, J = 6.8H
z), 7.86 (d, 1H, J = 8.5, 1.7Hz), 7.06-7.04 / 6.78-6.7
5 (AB quad, 8H, J = 8.5Hz), 6.93-6.89 (m, 1H), 4.31
(s, 4H), 3.66 (s, 6H); ¹⁹ F-NMR (376 MHz; DMSO) δ -12
7.22 (d),-141.36 (d); MS (APCI +) 729 (M + 1, 1), 256 (5
0), 121 (100); (APCI-) 727 (M-1,100), 601 (19), 192 (1
4), 127 (92); IR (KBr) 1698, 1673, 1513, 1251 cm ^-1 ; C
Calculated / found for ₂₉ H ₂₄ ClF ₂ IN ₂ O ₆ S: C, 47.78 / 47.
93; H, 3.32 / 3.33; N, 3.84 / 3.80; Cl, 4.86 / 4.84;
F, 5.21 / 5.46; I, 17.41 / 17.16; S, 4.40 / 4.29.

Example 3 2- (2-chloro-4-iodo-phenylamino) -5
-Sulfamoyl-3,4-difluoro-benzoic acid (A
Preparation of PK IC ₅₀ = 749 ± 344 nM) Compound “2- (2-chloro-4-iodo-phenylamino) -3,4-difluoro-5-[(bis-4-methoxybenzyl) -sulfamoyl] -benzoic acid "(0.099
(5 g, 0.136 mmol) was placed in a reaction flask. The system was evacuated and flushed twice with nitrogen. Trifluoroacetic acid (5 ml) was added via syringe and within minutes the reaction mixture changed from a clear light yellow to a clear magenta. The reaction mixture is brought to ambient temperature under nitrogen gas at 65
Stirred for hours. A white solid precipitated from the reaction mixture.
This was collected by vacuum filtration. Rinse with hexane and aspirate to give 55.2 mg of a white powder. The product was recrystallized from boiling chloroform (200 ml). The solution was boiled. At a volume of 75 ml, the recrystallization solution becomes slightly hazy. In a volume of 15 ml, the suspension was cooled slightly and it was filtered. Suction-drying gave 31.8 mg of a fluffy white solid. Yield 48%. Melting point 295-
296 ° C. ¹ H-NMR (400 MHz; DMSO) δ 9.77 (s, 1H), 8.1
6 (d, 1H, J = 7.3Hz), 7.82 (s, 3H), 7.56 (d, 1H, J = 8.5H
z), 6.97-6.92 (m, 1H); ¹⁹ F-NMR (376 MHz; DMSO) δ -12
8.47, -141.13 (d, J = 19.8Hz); MS (APCI +) 489 (M + 1, 5),
102 (100); (APCI-) 491 (32), 490 (18), 489 (100), 488
(18), 487 (M-1, 75); IR (KBr) 3372 (m, NH), 3244 (m,
NH stretch), 1688 (s, C = O stretch) cm ^-1 ; C ₁₃ H
₈ ClF ₂ IN ₂ O ₄ calculated for S / Found: C, 31.96 / 32.19;
H, 1.65 / 1.81; N, 5.73 / 5.37.

Example 4 2- (2-chloro-4-iodo-phenylamino) -N
Preparation of 4-hydroxy-4-dimethylsulfamoyl-benzamide Step a: Preparation of 4-methyl-benzene-N, N-dimethylsulfonamide To a stirred solution of para-toluenesulfonyl chloride in dichloromethane at 0 ° C. was added excess Gaseous dimethylamine is introduced. The precipitate was removed by filtration and the filtrate was concentrated in vacuo to give the product.

Step b: Preparation of 4-methyl-3-nitro-benzene-N, N-dimethylsulfonamide A gently stirred solution of 1 molar equivalent of fuming nitric acid in excess concentrated sulfuric acid is added to 4-methyl- Benzene-N, N-
One molar equivalent of dimethylsulfonamide is added in small portions.
The mixture is stirred for 1 hour and then poured into cold water. The mixture is extracted with a suitable solvent, for example diethyl ether or dichloromethane. The organic phase into a suitable drying agent,
Dry over, for example, magnesium sulfate and concentrate in vacuo to give the crude product. This product is prepared in the usual way,
It can be purified, for example, by chromatography or crystallization from a solvent such as chloroform or heptane.

Step c: Preparation of 3-amino-4-methyl-benzene-N, N-dimethylsulfonamide The compound 4-methyl-3-nitro-benzene-N, N-dimethylsulfonamide is dissolved in ethanol. A catalyst such as Raney nickel is added and the mixture is hydrogenated in a shaker. The catalyst is removed by filtration. The solvent is removed in vacuo to give the product. This product can be purified, if necessary, by chromatography or crystallization from a suitable solvent such as chloroform or heptane-ethyl acetate.

Step d: Preparation of 3-fluoro-4-methyl-benzene-N, N-dimethylsulfonamide The compound 3-amino-4-methyl-benzene-N, N-dimethylsulfonamide is converted to a compound such as tetrahydrofuran or dichloromethane. Diazotization with an alkyl nitrite such as tert-butyl nitrite under anhydrous conditions in a suitable non-reactive solvent. The intermediate diazonium compound is then treated with pyridinium fluoride to give the product. This product can be purified by chromatography or crystallization.

Step e: 4-dimethylsulfamoyl-2
Preparation of -Fluoro-benzoic acid 3-Fluoro-4-methyl-benzene-N, N- in water
A mixture of dimethyl sulfonamide and potassium permanganate (2.2 molar equivalents) is refluxed for 4 hours. The reaction mixture is filtered through celite. The filtrate is treated with activated carbon and refiltered through fresh celite. The second filtrate is acidified to pH 0 with concentrated hydrochloric acid. The mixture is cooled and extracted with diethyl ether. The organic phase,
Dry over a desiccant such as magnesium sulfate and concentrate in vacuo. The product can be purified by recrystallization from a suitable solvent such as ethanol or chloroform.

Step f: 2- (2-chloro-4-iodo-
Preparation of phenylamino) -4-dimethylsulfamoyl-benzoic acid To a stirred, cooled (-78 ° C.) solution of 2-chloro-4-iodoaniline (1 molar equivalent) in anhydrous tetrahydrofuran under a nitrogen atmosphere, commercial Lithium diisopropylamide solution (Aldrich, 2.0 in tetrahydrofuran / heptane / ethylbenzene)
M, 1 molar equivalent). After stirring for 5 minutes, a solution of 4-dimethylsulfamoyl-2-fluoro-benzoic acid (1 molar equivalent) in tetrahydrofuran is added. The cooling bath is removed and the reaction mixture is stirred for 2 hours. The reaction mixture is then partitioned between diethyl ether and dilute aqueous hydrochloric acid. The organic phase is washed with brine,
Dry over magnesium sulfate and concentrate in vacuo to give the product. The product can be purified by chromatography or recrystallization from a suitable solvent such as chloroform or heptane-ethanol.

Step g: 2- (2-chloro-4-iodo-
Phenylamino) -4-dimethylsulfamoyl-benzoic acid O- (tetrahydro-2H-pyran-2-yl)-
Preparation of Oxyamide 2- (2-chloro-4-iodo-phenylamino) -4-dimethylsulfamoyl-benzoic acid in 1: 1 (v / v) tetrahydrofuran-dichloromethane, O-
(Tetrahydro-2H-pyran-2-yl) -hydroxylamine (1.25 molar equivalents), benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (1.25 molar equivalents) and diisopropylethylamine (1.25 molar equivalents) (3 molar equivalents) is stirred for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using dichloromethane as eluent to give the desired product. The product can be recrystallized from a suitable solvent such as methanol if further purification is required.

Step h: 2- (2-chloro-4-iodo-
Phenylamino) -4-dimethylsulfamoyl-N-
Preparation of Hydroxy-benzamide The compound 2- (2-chloro-4-iodo-phenylamino) -4-dimethylsulfamoyl-benzoic acid O- (tetrahydro-2H-pyran-2-yl) -oxyamide is converted to a suitable chloride. Dissolve in a hydrogen-saturated solvent such as methanol or ethanol. Once homogeneous, the solution is concentrated in vacuo to give the desired product. The product is
If further purification is required, it can be triturated with a suitable solvent such as chloroform or dichloromethane.

Example 5 Cascade Assay for Inhibitors of the MAP Kinase Pathway Incorporation of ³² P into myelin basic protein (MBP) was determined using glutathione S-protein containing p44 MAP kinase.
Assays are performed in the presence of transferase fusion protein (GST-MAPK) and glutathione S-transferase fusion protein containing p45MEK (GST-MEK). The assay solution contains 20 mM HEPES (pH 7.4), 10 mM MgC in a final volume of 100 μl.
l ₂ , 1 mM MnCl ₂ , 1 mM EGTA, 50 μM [γ- ³² P] ATP, 10 μg GST-MEK, 0.5
Contains μg GST-MAPK and 40 μg MBP. The reaction is stopped after 20 minutes by the addition of trichloroacetic acid and filtered through a GF / C filter mat. The ³² P retained on the filter mat is
Measure using S Betaplate. Compound is 10 μM
Are evaluated for their ability to inhibit ³² P uptake.

When the compound is GST-MEK or GST-M
Two additional protocols are used to determine if they inhibit APK. In a first protocol, compounds were added to tubes containing GST-MEK, followed by GST-MAPK, MBP and [γ-
³² P] Add ATP. In a second protocol, the compounds were labeled with GST-MEK and GST-MAPK.
Is added to the tube containing both MBP and [γ-
³² P] Add ATP. Compounds showing activity in both protocols are scored as MAPK inhibitors,
On the other hand, compounds that show activity only in the first protocol score as MEK inhibitors.

Example 6 In Vitro MAP Kinase Assay Inhibitory activity can be confirmed in a direct assay. For MAP kinase, 1 μg of GST-MAPK was added to a final volume of 50 μl containing 50 mM Tris (pH 7.5), 10 μM MgCl ₂ , 2 μM EGTA and 10 μM [γ- ³² P] ATP, in a final volume of 50 μl.
Incubate with 40 μg of P at 30 ° C. for 15 minutes. The reaction is stopped by the addition of Laemmli SDS sample buffer and the phosphorylated MBP is resolved by electrophoresis on a 10% polyacrylamide gel. MBP
The radioactivity incorporated therein is measured by both autoradiography and scintillation counting of the removed bands.

Example 7 In Vitro MEK Assay For direct MEK activity evaluation, GST-ME
K, 10 μg of glutathione S-transferase fusion protein containing p44MAP kinase with a mutation of lysine to alanine at position 71 (GST-
MAPK-KA) with 5 μg.
This mutation eliminates the kinase activity of MAPK, leaving only the kinase activity attributable to added MEK. 50mM
Tris, pH 7.5, 10 μM MgCl ₂ , 2 μM E
5 containing GTA and 10 mM [γ- ³² P] ATP
Incubate at 30 ° C. for 15 minutes in a final volume of 0 μl. The reaction is stopped by the addition of Laemmli SDS sample buffer. Phosphorylated GST-MAPK
-KA is resolved by electrophoresis on a 10% polyacrylamide gel. Radioactivity incorporated into GST-MAPK-KA was measured by autoradiography and subsequent scintillation counting of the removed bands. Additionally, an artificially activated MEK containing a mutation of serine to glutamate at positions 218 and 222 (GST-MEK-2E) is used. When these two sites are phosphorylated, MEK activity is increased. Phosphorylation at these sites is mimicked by mutation of a serine residue to glutamate. In this assay, 5 μg of GST-MEK-2E was mixed with 5 μg of GST-MAPK-KA in the reaction buffer described above.
For 15 minutes at 30 ° C. The reaction is terminated and analyzed as described above.

Example 8 Whole Cell MAP Kinase Assay The following protocol is used to determine whether a compound blocks MAP kinase activation in all cells. Cells are plated in multi-well plates and grown to confluence. Cells were serum-depleted overnight (serum-de
prived). The cells are exposed to the desired concentration of compound or vehicle (DMSO) for 30 minutes and a growth factor such as PDGF (100 ng / ml) is added. 5 by growth factor
After treatment for one minute, the cells are washed with PBS and 70 mM NaC
1. Dissolve in a buffer consisting of 10 mM HEPES (pH 7.4), 50 mM glycerol phosphate and 1% Triton X-100. Lysate for 10 minutes
Clarify by centrifugation at 3,000 xg.
Five micrograms of the obtained supernatant was mixed with 50 mM Tris (pH
7.4) 10 mM MgCl ₂ , 2 mM EGTA and 3
In a final volume of 25 μl containing 0 μM [γ- ³² P] ATP, microtubule-associated protein-2 (Map2) 10
Incubate with μg at 30 ° C. for 15 minutes. The reaction is terminated by the addition of Laermmli sample buffer.
Phosphorylated Map2 is resolved on a 7.5% acrylamide gel and incorporated radioactivity is measured by scintillation counting of the removed band.

Example 9 ³ H-Thymidine Incorporation Cells are plated in multi-well plates and grown to near confluence. Then remove the medium and add 1%
With growth medium containing bovine serum albumin. 2
After 4 hours of serum starvation, test compounds and specific growth factors are added and the incubation is continued for a further 24 hours. During the last 2 hours, < ³ > H-thymidine is added to the medium. To terminate the incubation, the medium is removed and the cell layer is washed twice with ice-cold phosphate buffered saline. After the last wash, ice cold 5% trichloroacetic acid is added and the cells are incubated at room temperature for 15 minutes. Then the trichloroacetic acid solution is removed and the cell layer is washed three times with distilled water. After the last wash, the cell layer is solubilized by the addition of 2% sodium dodecyl sulfate. The radioactivity of this solution is measured by scintillation counting. This demonstrates that the inhibitors are selective between the mitogenic and metabolic effects of insulin. Generally, selective inhibitors exhibit lower toxicity than non-selective inhibitors.

Example 10 Monolayer Growth Cells were plated at 10-20,000 cells / ml in multi-well plates. Forty-eight hours after inoculation, test compounds were added to the cell growth medium and incubation was continued for another two days. The cells are then removed from the wells by incubation with trypsin and counted on a Coulter counter.

Example 11 Growth in Soft Agar Cells are inoculated into 35 mm dishes at 5-10,000 cells / dish using growth medium containing 0.3% agar. After cooling and solidifying the agar, the cells are transferred to a 37 ° C. incubator. After 7-10 days of growth, visible colonies are manually counted using a dissecting microscope.

Example 12 Collagen-induced arthritis in mice Type II collagen-induced arthritis in mice (CIA)
Is an experimental model of arthritis that has many pathological, immunological and genetic features in common with rheumatoid arthritis. The disease is induced by immunization of OBA / 1 mice with 100 μg of type II collagen, a major component of articular cartilage excreted intradermally in Complete Freund's Adjuvant. Class II susceptibility to this disease
It is regulated by the MHC locus, which
It is similar to the relationship between R4 and rheumatoid arthritis.

Progressive and inflammatory arthritis, characterized by an increase in paw width of up to 100%, appears in the majority of immunized mice. Test compound is 20, 60, 100 and 200 mg / kg body weight per day
The mice are administered in an amount in the range as described above. The duration of the exam
It can range from weeks to months, such as 40, 60 or 80 days. The clinical scoring index is used to assess the progression of the disease from erythema and edema (stage 1) to joint distortion (stage 2), joint tonicity (stage 3). The disease affects one or all paws of the animal and can be varied to give a total of 12 possible scoring scores for each mouse. Histopathology of arthritic joints indicates synovitis, pannus formation and cartilage and bone erosion. All mouse species that are sensitive to CIA are high antibody responders to type II collagen and have a marked cellular response to CII.

Example 13 SCW-Induced Single Joint Arthritis Arthritis was altered slightly by Schwab et al. [Infection an
d immunity 59: 4436-4442 (1991)]. On day 0, sonicated SCs were injected intra-articularly into the right tibiotalar joint.
Rats receive 6 μg of W [in 10 μl of Dulbecco's PBS (DPBS)]. On day 21, SC administered intravenously
Start DTH with 100 μg (250 μl) of W. For oral compound studies, compounds were suspended in vehicle (0.5% hydroxypropyl-methylcellulose / 0.2% Tween 80), sonicated and
Starting one hour before reactivation by CW, 2 per day
Administer multiple doses (10 ml / kg volume). Compounds are 20, 30,
It is administered in an amount between 10 and 500 mg / kg / day, such as 60, 100, 200 and 300 mg / kg / day. The edema measurement measures the baseline volume of sensitized hind paws prior to reactivation on day 21 and compares these to the volumes at subsequent time points, such as on days 22, 23, 24 and 25. can get. Paw volume is measured by mercury volumetric recording.

Example 14 Mouse Ear-Heart Transplant Model Fey TA et al. [J. Pharm. And Toxic. Meth. 39: 9-17 (1
998)] describes a method of transplanting a fragmented neonatal heart graft into the pinna of the mouse and rat ears. The compound is dissolved in a solution containing anhydrous ethanol, 0.2% hydroxypropylmethylcellulose in water, propylene glycol, cremophor and dextrose, or a combination of other solvents or suspending vehicles. Mice receive one, one day per day from the day of transplantation (day 0) to day 13 or until the graft is rejected.
Dosing two or three times orally or intraperitoneally. Rats are dosed one, two or three times daily from day 0 to day 13. Each animal is anesthetized and an incision is made at the base of the recipient's ear to cut only the dorsal epidermis and dermis. The incision is spread parallel to the head towards the cartilage and widened enough to accommodate a piercing device for rats or an insertion device for mice. Neonatal mouse or rat pups less than 60 hours old are anesthetized and cervical dislocation. The heart is removed from the chest, rinsed with saline, halved longitudinally with a scalpel and rinsed with sterile saline. Fragments of the donor animal's heart are placed into a preformed tunnel with an insertion tool and air or residual liquid is squeezed out of the tunnel by light pressure. No stitching, adhesive bonding, bandaging or treatment with antibiotics is required.

Without anesthesia, the implants are examined with a stereoscopic dissecting microscope at 10-20 × magnification. Recipients whose implants are not visibly beating can be anesthetized and assessed for the presence of electrical activity using Grass E2 platinum subcutaneous pin microelectrodes and tachographs placed on the pinna or directly on the implant . Implants are 10 days, 20 days
1 to 4 days per day for 30 days or more
Times can be inspected. The ability of the test compound to reduce the symptoms of transplant rejection can be compared to a reference compound such as cyclosporine, tacrolimus or orally administered lefluonamide.

Example 15 Phosphorylated ERK1 / ER in human PBMC protein extract
Western blot analysis of K2 Preparation of lysis buffer and protease inhibitor Add these components and store at 4 ° C. Raw material quantity Final concentration NaCl 2.454 g 70 mM β-glycerol phosphate 5.4 g 50 mM 1 M HEPES 5 ml 10 mM Triton X-100 5 ml 1% ddH ₂ O Sufficient to make 500 ml Prepare the following stock solution and dissolution buffer Store under recommended conditions before adding. The next solution must be added to the lysis buffer just before the lysis step. This solution should not be manufactured more than 30 minutes earlier than the time
Must be stored at ° C.

Raw material quantity final concentration storage 1.678 g of Na ₃ VO ₄ 100 mM 4 ° C. 200 ml of ddH ₂ O PMSF 17.4 mg 100 mM -20 DEG C. EtOH 1 ml Every 3 weeks, a fresh stock solution is prepared and stored protected from light. 3. Leupeptin _{5mg 1mg / ml -20 ℃ ddH 2} O 5ml 3 kinds of components added to the lysis buffer solution 25 ml.

Final concentration stock solution volume 1 mM Na ₃ VO ₄ 100 mM 250 μl 1 μM PMSF 100 mM ddH ₂ O 1: 100, then add 25 μl to lysis buffer. 1 mM leupeptin 1 mg / ml 11.9 μl

The non-adherent cells are collected in a 15 ml conical tube (on ice) and centrifuged at 800 rpm for 5 minutes at 4 ° C. to pellet the cells. Add 250 μl of lysis buffer to each well (10 × 10
⁶ cells). Lyse cells on plate by pipetting up and down repeatedly. Once the non-adherent cells have been pelleted, the supernatant is aspirated off and the pellet resuspended in lysis buffer from the corresponding wells. The buffer is repeatedly pipetted before transferring the non-adherent cell pellet to ensure that the cells are lysed and completely removed from the tissue culture dish. Lyse all cells in the volume of the pipette in the tube. The sample is centrifuged at 2500 xg for 15 minutes at 4 ° C. The supernatant is collected in a capped microcentrifuge tube and stored at -80 ° C until further use.

Gel electrophoresis 100 ml of 10X Tris / glycine / SDS buffer (No.
vex LC 2675) is diluted to 1 L with ddH ₂ O. 1.0 or 1.5 mm 10% Trisglycine pre-product from Novex
Use cast gel. The thickness of the gel used (1.0
Or 1.5 mm) depends on the volume of sample loaded per well. The following table shows the available gel capacity.

Open the gel pouch and remove the gel cassette. Release the tape from the bottom and carefully pull out the comb. Wells 1X Tris / Glycine / S
Rinse with DS running buffer. The gel is oriented in the Mini-Cell so that the well side of the cassette faces the buffer core. Fill the core with running buffer and check for leaks. Pre-energize the gel at 100 V for 15 minutes (p
re-run). Samples are prepared by adding an appropriate volume of protein and Novex Tris-glycine SDS sample buffer (LC 2676). Most ideally, load at least 10 μl of sample per lane. To calculate the required volume, determine the amount of protein required to load 3 lanes with 5 μg per lane. Once this is measured, an appropriate volume of the protein sample is aliquoted into an eppendorf tube and an equal volume of 2X Tris-glycine SDS buffer is added. The total volume is divided by 3 to determine the volume of sample loaded per lane. Heat the sample at 95 ° C. for 5 minutes.
10 μl molecular weight marker (Benchmark Prestained Prot)
ein Ladder; Gibco BRL 10748-010) is loaded in the standard lane. The gel is energized at 125 V (constant voltage) or less for about 90 minutes or until the blue staining front reaches the bottom of the gel.

Transfer 40 ml of 25X Tris-glycine transfer buffer (Novex LC)
3675) to 1 L with ddH ₂ O. The gel is removed from the cassette and rinsed in IX transfer buffer for 10 minutes with gentle shaking. Nitrocellulose and filter paper (Novex LC
2001) in IX transfer buffer for 10 minutes. Soak the blotting pad (Novex EI 9052) in IX transfer buffer until saturated. Remove air pockets and bubbles by squeezing in buffer. Assemble the blot module. Fill the core with 1X transfer buffer and check for leaks. Fill the outer chamber with transfer buffer. Transfer for 1 hour 15 minutes at 250 mA max (constant current).

Example 16 Murine Ovalbumin-Induced Eosinophilia Female C57BL / 6 mice were isolated from the Jackson Laboratory (Bar
Harbor, ME). All animals received food and water ad libitum. On day 0, the mice were OVA adsorbed to alum (grade V, Sigma Chemical Company,
St. Louis, MO) (OVA 10 in 200 μl of saline)
(g + alum 9 mg) or vehicle control (9 mg alum in 200 µl saline) by a single intraperitoneal injection. On day 14, mice were sprayed with a nebulizer (small particle generator, model SPAG-2; ICN Pharmaceuticals,
1. in saline manufactured by Costa Mesa, CA).
Challenge by 12 minute inhalation of an aerosol consisting of 5% (w / v) OVA. Groups of 8 mice were dosed with oral vehicle (0.5% hydroxypropylmethylcellulose / 0.25% Tween 80) or 1% in oral vehicle.
Administer 0, 30 or 100 mg / kg of test compound (200 μl per mouse, orally). Administration is 7
Dosing once per day starting on day or day 13 and extending to day 16.

To measure eosinophilia in the lungs, mice were anesthetized by intraperitoneal injection of anesthetic (ketamine / acepromazine / xylazine) 3 days after the first OVA aerosol challenge (day 17). Expose and insert a cannula. The lungs and upper airway are washed twice with 0.5 ml of cold PBS. Part of bronchoalveolar lavage (BAL) fluid (200 μl)
l) is replaced by a Coulter counter model ZB1 (Coulter El
ectronics, Hialeah, FL). The remaining BAL fluid was then centrifuged at 300 xg for 5 minutes and cells were harvested with 0.5% fetal calf serum (HyClone) and 1%.
HBSS (Gico BRL) containing 0 mM HEPES (Gibco BRL)
bco BRL) Resuspend in 1 ml. This cell suspension was transferred to cytospin (Shandon Southern Instruments, Sewickle).
y, PA) and Diff Quick (American Scienti
fic Products, McGraw Park, IL)
L-leukocytes are divided into neutrophils, eosinophils, monocytes or lymphocyte subsets. The number of eosinophils in the BAL fluid is measured by multiplying the percentage of eosinophils by the total cell number.

F. Other Aspects The features of the present invention will be readily apparent from the foregoing disclosure and examples, and the appended claims. Also, the scope of the present invention covers various modifications within the knowledge of those skilled in the art. Examples include compounds that have been modified by the addition or removal of protecting groups, or esters, pharmaceutical salts, hydrates, acids, or amides of the disclosed compounds. The references cited are:
Incorporated herein by reference in its entirety.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification FI FI Theme Court ゛ (Reference) A61K 31/245 A61K 31/245 C07C 311/40 C07C 311/40 (72) Inventor Hale Tecul Michigan, USA 48108. Ann Arbor. Turnberg 3048 F term (reference) 4C206 AA01 AA03 JA15 MA01 MA02 MA04 MA05 NA14 ZA16 ZA36 ZA45 ZA75 ZA89 ZA96 ZB02 ZB08 ZB15 ZB26 ZB33 ZB35 ZC35 ZC55 ZC75 4H006 AA01 AA03 AB20 AB21 AB23 AB27 AB27

Claims (39)

[Claims] (1) Formula (1)Or a pharmaceutically acceptable salt thereof or C_1-6
ester. In the above formula, W is OR₁, NR_TwoOR₁, NR_AR_B, NR_TwoNR_AR_B,
Or NR_Two(CH_Two)_{2- Four}NR_AR_BAnd R₁Is H, C
_1-8Alkyl, C_3-8Alkenyl, C_3-8Alkynyl, C
_3-8Cycloalkyl, phenyl, (phenyl) C_1-4Archi
, (Phenyl) C_3-4Alkenyl, (phenyl) C_3-4Al
Kinyl, (C_3-8Cycloalkyl) C_1-4Alkyl, (C_3-8
Cycloalkyl) C_3-4Alkenyl, (C_3-8Cycloalkyl
Le) C_3-4Alkynyl, C _3-8A heterocyclic group, (C_3-8Heterocycle
Formula group) C_1-4Alkyl, (C_3-8Heterocyclic group) C_3-4Alkene
Le, (C_3-8Heterocyclic group) C_3-4Alkynyl or (CH_Two)
_2-4NR_AR_BAnd R_TwoIs H, phenyl, C_1-4Al
Kill, C_3-4Alkenyl, C_3-8Alkynyl, C_3-8Shiku
Loalkyl or (C_3-8Cycloalkyl) C_1-4Alkyl
And R_AIs H, C_1-6Alkyl, C_3-8Alkene
Le, C_3-8Alkynyl, C_3-8Cycloalkyl, phenyl
Le, (C_3-8Cycloalkyl) C_1-4Alkyl, (C_3-8Shiku
Lower alkyl) C_3-4Alkenyl, (C_3-8Cycloalkyl)
C_3-4Alkynyl, C_3-8A heterocyclic group, (C_3-8Heterocyclic
Group) C_1-4Alkyl, (aminosulfonyl) phenyl,
[(Aminosulfonyl) phenyl] C_1-4Alkyl, (A
Minosulfonyl) C_1-6Alkyl, (aminosulfonyl) C
_3-6Cycloalkyl or [(aminosulfonyl) C_{Three -6}Shi
Chloroalkyl] C_1-4Alkyl; R_BIs H, C
_1-8Alkyl, C_3-8Alkenyl, C_3-8Alkynyl, C
_3-8Cycloalkyl or C_6-8Aryl; R
_ThreeIs H, F, Cl, Br or NO_TwoAnd R_FourIs
H or F; R_FiveIs H, methyl or Cl
R;₆Is H, C_1-4Alkyl, hydroxyethyl, ar
Droxypropyl, (CH_Two)_2-4(NR_CR_D), Phenyl,
2-pyridyl, 3-pyridyl, 4-pyridyl or CH
_TwoAr (where Ar is phenyl, 2-pyridyl, 3-
Pyridyl or 4-pyridyl); R₇Is
H, C_1-4Alkyl, hydroxyethyl, hydroxyp
Ropil, (CH_Two)_2-4(NR_CR_D), Phenyl, 2-pyridi
, 3-pyridyl, 4-pyridyl or CH_TwoAr (expression
Where Ar is phenyl, 2-pyridyl, 3-pyridyl or
Or 4-pyridyl); R_CAnd R_DThat of
Each is independently H, C_1-6Alkyl, C_3-4Alkene
Le, C_3-4Alkynyl, C_3-6Cycloalkyl, C_3-6Duplicate
Selected from cyclic groups and phenyl;
And NR_CR_DAre also morpholinyl, piperazinyl,
Can be selected from loridinyl or piperidinyl
Each of the above-mentioned hydrocarbon groups or heterocyclic groups
Is optionally, independently halogen, C_1-4Archi
Le, C_3-6Cycloalkyl, C_2-4Alkenyl, C_2-4A
Ruquinyl, phenyl, hydroxy, amino, (amino)
Sulfonyl and NO_Two1 to 3 substitutions selected from
Minute; and each
Substituted alkyl, cycloalkyl, alkenyl, alkyl
Nyl or phenyl may optionally be independently halo
Gen, C_1-2Alkyl, hydroxy, amino and NO_Two
Substituted with 1 to 3 substituents selected from
You may. 2. A compound according to claim 1, wherein the sulfamoyl group is meta to W (CO) — and para to the bridging NH. 3. The sulfamoyl group is para to W (CO) — and meta to the bridging NH.
A compound as described. 4. The compound according to claim 1, wherein R ₄ is fluorine. 5. The compound according to claim 1, wherein R ₃ is fluorine. 6. The compound according to claim 1, wherein R ₃ is H. 7. The compound according to claim 1, wherein W is OH. 8. The compound according to claim ₁ , wherein W is NR ₂ OR1. 9. The compound according to claim 7, wherein each of R ₃ and R ₄ is fluorine. 10. The compound of claim 1, wherein R ₁ has at least one hydroxy substituent. 11. R ₁ is H, methyl, ethyl, propyl, isopropyl, isobutyl, benzyl, phenethyl, allyl, C _3-5 alkenyl, C _3-5 alkynyl, C
The compound according to claim 1, which is _3-6 cycloalkyl, ( _C3-5 cycloalkyl) _C1-2 alkyl or ( _C3-5 heterocyclic group) _C1-2 alkyl. 12. The compound according to claim 11, wherein R ₁ is H or (C _3-4 cycloalkyl) C _1-2 alkyl. 13. The compound according to claim 1, wherein R ₂ is H, methyl, C _3-4 alkynyl, C _3-5 cycloalkyl or (C _3-5 cycloalkyl) methyl. 14. R _A is, H, methyl, ethyl, isobutyl, hydroxyethyl, hydroxypropyl, cyclopropylmethyl, cyclobutylmethyl, C _{3- 4} alkynyl, phenyl, 2-piperidin-1-yl - ethyl,
2,3-dihydroxy-propyl, 3- [4- (2-hydroxyethyl) -piperazin-1-yl] -propyl, 2-pyrrolidin-1-yl-ethyl or 2-diethylamino-ethyl; and R _B Is H;
Or the compound of claim 1, wherein R _B is methyl and R _A is phenyl. 15. The compound according to claim 1, wherein R ₇ is (CH ₂ ) _2-4 (NR _C R _D ). 16. NR _C R _D is morpholinyl, piperazinyl, the compounds according to claim 1, wherein one selected from pyrrolidinyl or piperidinyl. 17. The compound according to claim 1, wherein R ₅ is methyl or chlorine. 18. Structure: 2- (2-chloro-4-iodo-phenylamino) -4-sulfamoyl-benzoic acid;
2- (2-chloro-4-iodo-phenylamino) -N
-Hydroxy-4-sulfamoyl-benzamide; 2
-(2-chloro-4-iodo-phenylamino) -N-
Cyclopropylmethoxy-4-sulfamoyl-benzamide; 2- (2-chloro-4-iodo-phenylamino) -4- (2-morpholin-4-yl-ethylsulfamoyl) -benzoic acid; 2- (2- Chloro-4-iodo-phenylamino) -N-hydroxy-4- (2-morpholin-4-yl-ethylsulfamoyl) -benzamide; 2- (2-chloro-4-iodo-phenylamino) -N- Cyclopropylmethoxy-4- (2-morpholin-4-yl-ethylsulfamoyl) -benzamide; 2- (2-chloro-4-iodo-phenylamino)
-3,4-difluoro-5-sulfamoyl-benzoic acid; 2- (2-chloro-4-iodo-phenylamino)
-3,4-difluoro-N-hydroxy-5-sulfamoyl-benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-
3,4-difluoro-5-sulfamoyl-benzamide; 2- (2-chloro-4-iodo-phenylamino)
-3,4-difluoro-5- (2-morpholin-4-yl-ethylsulfamoyl) -benzoic acid; 2- (2-chloro-4-iodo-phenylamino) -3,4-difluoro-N- Hydroxy-5- (2-morpholin-4-yl-ethylsulfamoyl) -benzamide; 2- (2
-Chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5- (2-morpholin-4-yl-ethylsulfamoyl) -benzamide; 5- (bis-pyridine-3) -Ylmethyl-sulfamoyl) -3,4-difluoro-2- (4-iodo-phenylamino) -benzoic acid; 5- (bis-pyridin-3-ylmethyl-sulfamoyl) -N-cyclopropylmethoxy-3,4- Difluoro-2- (4-iodo-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-
Phenylamino) -5- (methyl-pyridin-3-ylmethyl-sulfamoyl) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-phenylamino) -5-[(pyridine-3 -Ylmethyl) -sulfamoyl] -benzamide; N-cyclopropylmethoxy-5-[(3-diethylamino-propyl) -pyridin-3-ylmethyl-sulfamoyl] -3,4-difluoro-2- (4-iodo-phenylamino ) -Benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(3-hydroxy-propyl) -pyridin-3-ylmethyl-sulfamoyl]
-2- (4-Iodo-phenylamino) -benzamide; N-cyclopropylmethoxy-5- (ethyl-pyridin-3-ylmethyl-sulfamoyl) -3,4-difluoro-2- (4-iodo-phenylamino) -Benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl) -pyridine-
3-ylmethyl-sulfamoyl] -2- (4-iodo-phenylamino) -benzamide; 5- (bis-pyridin-2-ylmethyl-sulfamoyl) -3,4-difluoro-2- (4-iodo-phenylamino) -Benzoic acid; 5- (bis-pyridin-2-ylmethyl-sulfamoyl) -N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-phenylamino) -benzamide; N-cyclopropylmethoxy-3 , 4-Difluoro-2- (4-iodo-phenylamino) -5
(Methyl-pyridin-2-ylmethyl-sulfamoyl) -benzamide; N-cyclopropylmethoxy-
3,4-difluoro-2- (4-iodo-phenylamino) -5-[(pyridin-2-ylmethyl) -sulfamoyl] -benzamide; 5- (bis-pyridin-3-ylmethyl-sulfamoyl) -3,4 -Difluoro-2
-(4-Iodo-2-methyl-phenylamino) -benzoic acid; 5- (bis-pyridin-3-ylmethyl-sulfamoyl) -N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo- 2-methyl-phenylamino) -benzamide; N-cyclopropylmethoxy-
3,4-difluoro-2- (4-iodo-2-methyl-
Phenylamino) -5- (methyl-pyridin-3-ylmethyl-sulfamoyl) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -5- [ (Pyridin-3-ylmethyl) -sulfamoyl] -benzamide; N-cyclopropylmethoxy-5-[(3-diethylamino-propyl) -pyridin-3-ylmethyl-sulfamoyl] -3,4-difluoro-2- (4- Iodo-2-methyl-phenylamino) -benzamide; N
-Cyclopropylmethoxy-3,4-difluoro-5-
[(3-hydroxy-propyl) -pyridin-3-ylmethyl-sulfamoyl] -2- (4-iodo-2-methyl-phenylamino) -benzamide; N-cyclopropylmethoxy-5- (ethyl-pyridin-3- Ylmethyl-sulfamoyl) -3,4-difluoro-2- (4
-Iodo-2-methyl-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl) -pyridin-3-ylmethyl-sulfamoyl) -2- (4- Iodine-2-
Methyl-phenylamino) -benzamide; 5- (bis-pyridin-2-ylmethyl-sulfamoyl) -3,
4-difluoro-2- (4-iodo-2-methyl-phenylamino) -benzoic acid; 5- (bis-pyridine-2-
Ylmethyl-sulfamoyl) -N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-2-
Methyl-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -5- (methyl-
Pyridin-2-ylmethyl-sulfamoyl) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -5-[(pyridin-2-ylmethyl) -sulfamoyl ] -Benzamide; 5- (bis-pyridin-3-ylmethyl-sulfamoyl) -2- (2-chloro-4-
Iodo-phenylamino) -3,4-difluoro-benzoic acid; 5- (bis-pyridin-3-ylmethyl-sulfamoyl) -2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy- 3,4-difluoro-benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-
3,4-difluoro-5- (methyl-pyridin-3-ylmethyl-sulfamoyl) -benzamide; 2- (2
-Chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5-[(pyridin-3-ylmethyl) -sulfamoyl] -benzamide; 2- (2-chloro-4-iodo- Phenylamino)
-N-cyclopropylmethoxy-5-[(3-diethylamino-propyl) -pyridin-3-ylmethyl-sulfamoyl] -3,4-difluoro-benzamide; 2
-(2-chloro-4-iodo-phenylamino) -N-
Cyclopropylmethoxy-3,4-difluoro-5-
[(3-hydroxy-propyl) -pyridin-3-ylmethyl-sulfamoyl] benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-5- (ethyl-pyridin-3-ylmethyl -Sulfamoyl) -3,4-difluoro-benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl)- Pyridine-3
-Ylmethyl-sulfamoyl] benzamide; 5-
(Bis-pyridin-2-ylmethyl-sulfamoyl)
-2- (2-chloro-4-iodo-phenylamino)-
3,4-difluoro-benzoic acid; 5- (bis-pyridin-2-ylmethyl-sulfamoyl) -2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro- Benzamide; 2-
(2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5- (methyl-pyridin-2-ylmethyl-sulfamoyl)-
Benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5-[(pyridin-2-ylmethyl) -sulfamoyl] -benzamide; N-cyclopropylmethoxy -3,4-difluoro-5-[(3-hydroxy-propyl) -pyridin-2-ylmethyl-sulfamoyl]
-2- (4-Iodo-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl) -pyridin-2-ylmethyl-sulfamoyl] -2- (4 -Iodo-phenylamino) -benzamide; 5- (benzyl-pyridin-2-ylmethyl-sulfamoyl) -N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-phenylamino) -benzamide; N- Cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-phenylamino) -5-[(pyridin-4-ylmethyl) -sulfamoyl] -benzamide; N-cyclopropylmethoxy-5- (ethyl-pyridine- 4-ylmethyl-sulfamoyl) -3,4-difluoro-2-
(4-iodo-phenylamino) -benzamide; N-
Cyclopropylmethoxy-3,4-difluoro-2-
(4-iodo-phenylamino) -5- (methyl-pyridin-4-ylmethyl-sulfamoyl) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(3-hydroxy-propyl) -pyridine- 4-
Ylmethyl-sulfamoyl] -2- (4-iodo-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-
Ethyl) -pyridin-4-ylmethyl-sulfamoyl] -2- (4-iodo-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-phenylamino) -5- (Methyl-phenyl-sulfamoyl) -benzamide; N-
Cyclopropylmethoxy-3,4-difluoro-2-
(4-Iodo-phenylamino) -5-phenylsulfamoyl-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-phenylamino) -5- (pyridin-3-ylsulfa Moir)-
Benzamide; N-cyclopropylmethoxy-3,4-
Difluoro-5-[(3-hydroxy-propyl) -pyridin-2-ylmethyl-sulfamoyl] -2- (4-
Iodo-2-methyl-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl) -pyridin-2-ylmethyl-sulfamoyl] -2- (4-iodo -2-
Methyl-phenylamino) -benzamide; 5- (benzyl-pyridin-2-ylmethyl-sulfamoyl)-
N-cyclopropylmethoxy-3,4-difluoro-2
-(4-Iodo-2-methyl-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -5-[(pyridine-4 -Ylmethyl) -sulfamoyl] -benzamide; N-cyclopropylmethoxy-
5- (ethyl-pyridin-4-ylmethyl-sulfamoyl) -3,4-difluoro-2- (4-iodo-2-
Methyl-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -5- (methyl-
Pyridin-4-ylmethyl-sulfamoyl) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-5-[(3-hydroxy-propyl) -pyridine-
4-ylmethyl-sulfamoyl] -2- (4-iodo-2-methyl-phenylamino) -benzamide; N-
Cyclopropylmethoxy-3,4-difluoro-5-
[(2-hydroxy-ethyl) -pyridin-4-ylmethyl-sulfamoyl] -2- (4-iodo-2-methyl-phenylamino) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- ( 4-Iodine-
2-methyl-phenylamino) -5- (methyl-phenyl-sulfamoyl) -benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -5-phenyl Sulfamoyl-benzamide; N-cyclopropylmethoxy-3,4-difluoro-2- (4-iodo-2-methyl-phenylamino) -5- (pyridin-3-ylsulfamoyl) -benzamide; 2- ( 2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5-[(3-hydroxy-propyl) -pyridin-2-ylmethyl-sulfamoyl]-
Benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl) pyridine-
2-ylmethyl-sulfamoyl] -benzamide; 5
-(Benzyl-pyridin-2-ylmethyl-sulfamoyl) -2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-benzamide; 2- (2-chloro-4 -Iodo-phenylamino) -N-cyclopropylmethoxy-3,4
-Difluoro-5-[(pyridin-4-ylmethyl) -sulfamoyl] -benzamide; 2- (2-chloro-4
-Iodo-phenylamino) -N-cyclopropylmethoxy-5- (ethyl-pyridin-4-ylmethyl-sulfamoyl) -3,4-difluoro-benzamide; 2
-(2-chloro-4-iodo-phenylamino) -N-
Cyclopropylmethoxy-3,4-difluoro-5-
(Methyl-pyridin-4-ylmethyl-sulfamoyl) -benzamide; 2- (2-chloro-4-iodo-
Phenylamino) -N-cyclopropylmethoxy-3,
4-difluoro-5-[(3-hydroxy-propyl)-
Pyridin-4-ylmethyl-sulfamoyl] -benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5-[(2-hydroxy-ethyl) -pyridine -4-
Ylmethyl-sulfamoyl] -benzamide; 2-
(2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5- (methyl-phenyl-sulfamoyl) -benzamide; 2
-(2-chloro-4-iodo-phenylamino) -N-
Cyclopropylmethoxy-3,4-difluoro-5-phenylsulfamoyl-benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-3,4-difluoro-5- (pyridine -3
-Ylsulfamoyl) -benzamide; N-cyclopropylmethoxy-2- (4-iodo-phenylamino)
-4-phenylsulfamoyl-benzamide; N-cyclopropylmethoxy-2- (4-iodo-phenylamino) -4- (pyridin-3-ylsulfamoyl)-
Benzamide; N-cyclopropylmethoxy-2- (4
-Iodo-phenylamino) -4-[(pyridine-3-
Ylmethyl) -sulfamoyl] -benzamide; 4-
(Bis-pyridin-3-ylmethyl-sulfamoyl)
-N-cyclopropylmethoxy-2- (4-iodo-phenylamino) -benzamide; N-cyclopropylmethoxy-4-[(2-hydroxy-ethyl) -pyridine-
4-ylmethyl-sulfamoyl] -2- (4-iodo-phenylamino) -benzamide; N-cyclopropylmethoxy-2- (4-iodo-phenylamino) -4
-(Methyl-pyridin-3-ylmethyl-sulfamoyl) -benzamide; N-cyclopropylmethoxy-4
-[(3-diethylamino-propyl) -pyridine-3-
Ylmethyl-sulfamoyl] -2- (4-iodo-phenylamino) -benzamide; N-cyclopropylmethoxy-2- (4-iodo-2-methyl-phenylamino) -4-phenylsulfamoyl-benzamide; N
-Cyclopropylmethoxy-2- (4-iodo-2-methyl-phenylamino) -4- (pyridin-3-ylsulfamoyl) -benzamide; N-cyclopropylmethoxy-2- (4-iodo-2-methyl) -Phenylamino) -4-[(pyridin-3-ylmethyl) -sulfamoyl] -benzamide; 4- (bis-pyridin-3-ylmethyl-sulfamoyl) -N-cyclopropylmethoxy-2- (4-iodo-2- Methyl-phenylamino) -benzamide; N-cyclopropylmethoxy-4
-[(2-hydroxy-ethyl) -pyridin-4-ylmethyl-sulfamoyl] -2- (4-iodo-2-methyl-phenylamino) -benzamide; N-cyclopropylmethoxy-2- (4-iodo-2 -Methyl-phenylamino) -4- (methyl-pyridin-3-ylmethyl-sulfamoyl) -benzamide; N-cyclopropylmethoxy-4-[(3-diethylamino-propyl)-
Pyridin-3-ylmethyl-sulfamoyl] -2-
(4-iodo-2-methyl-phenylamino) -benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-4-phenylsulfamoyl-benzamide; 2- (2- Chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy-4- (pyridin-3-ylsulfamoyl) -benzamide; 2- (2-chloro-4-iodo-phenylamino) -N-cyclopropylmethoxy 4-[(pyridin-3-ylmethyl) -sulfamoyl] -benzamide; 4- (bis-pyridin-3-ylmethyl-sulfamoyl) -2- (2-chloro-4-iodo-phenylamino) -N-cyclopropyl Methoxy-benzamide;
2- (2-chloro-4-iodo-phenylamino) -N
-Cyclopropylmethoxy-4-[(2-hydroxy-
Ethyl) -pyridin-4-ylmethyl-sulfamoyl] -benzamide; 2- (2-chloro-4-iodo-
Phenylamino) -N-cyclopropylmethoxy-4-
(Methyl-pyridin-3-ylmethyl-sulfamoyl) -benzamide; 2- (2-chloro-4-iodo-
Phenylamino) -N-cyclopropylmethoxy-4-
[(3-Diethylamino-propyl) -pyridin-3-ylmethyl-sulfamoyl] -benzamide; 5- [bis- (4-methoxy-benzyl) -sulfamoyl]-
2- (2-chloro-4-iodo-phenylamino)-
2. A compound according to claim 1 having 3,4-difluoro-benzoic acid; and 2- (2-chloro-4-iodo-phenylamino) -5-dimethylsulfamoyl-3,4-difluoro-benzoic acid methyl ester. . 19. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier. 20. A method for treating a proliferative disorder, comprising administering a pharmaceutically effective amount of a composition containing the compound of claim 1 to a patient in need of such treatment. 21. The method according to claim 20, wherein the proliferative disease is selected from psoriasis, restenosis, autoimmune disease and atherosclerosis. 22. A method for treating cancer comprising administering a pharmaceutically effective amount of a composition containing the compound of claim 1 to a patient in need of treatment for cancer. 23. The cancer of claim 2, wherein the cancer is a MEK-related cancer.
2. The method according to 2. 24. The method according to claim 22, wherein the cancer is brain, breast, lung, ovary, pancreas, prostate or colorectal cancer. 25. A method for treating or reducing sequelae of seizures comprising administering a pharmaceutically effective amount of a composition comprising a compound of claim 1 to a patient in need of treatment for sequelae of seizures. how to. 26. A method for treating or alleviating the sequelae of heart failure, comprising administering a pharmaceutically effective amount of a composition comprising the compound of claim 1 to a patient in need of treatment for the sequelae of heart failure. how to. 27. A method for treating or reducing the symptoms of xenograft rejection, comprising administering to a patient having an organ or bone marrow transplant a pharmaceutically effective amount of a composition containing the compound of claim 1. 28. A method for treating osteoarthritis comprising administering a pharmaceutically effective amount of a composition containing the compound of claim 1 to a patient in need of such treatment. . 29. A method for treating rheumatoid arthritis, comprising administering a pharmaceutically effective amount of a composition comprising the compound of claim 1 to a patient in need of treatment for rheumatoid arthritis. 30. A method for treating cystic fibrosis comprising administering a pharmaceutically effective amount of a composition comprising the compound of claim 1 to a patient in need of treatment for cystic fibrosis. . 31. A method of treating hepatoma, comprising administering a pharmaceutically effective amount of a composition comprising the compound of claim 1 to a patient in need of treatment for hepatoma. 32. A method of treating cardiac hypertrophy comprising administering a pharmaceutically effective amount of a composition comprising a compound of claim 1 to a patient in need of such treatment. 33. A method for treating Alzheimer's disease, comprising administering a pharmaceutically effective amount of a composition containing the compound of claim 1 to a patient in need of treatment for Alzheimer's disease. 34. A method of treating diabetes, comprising administering a pharmaceutically effective amount of a composition comprising the compound of claim 1 to a patient in need of the treatment. 35. A method for treating septic shock, comprising administering a pharmaceutically effective amount of a composition comprising the compound of claim 1 to a patient in need of treatment for septic shock. 36. A method of treating a viral infection comprising administering a pharmaceutically effective amount of a composition containing the compound of claim 1 to a patient in need of the treatment. 37. The method of claim 36, wherein the viral infection is an HIV infection. 38. (a) administering to a patient in need of treatment for cancer a pharmaceutically effective amount of a composition containing the compound of claim 1; and (b) from radiation therapy and chemotherapy. A method of treating cancer comprising administering a selected treatment. 39. The method of claim 38, wherein said chemotherapy comprises a mitotic inhibitor.