ZA200109907B

ZA200109907B - Method for treating chronic pain using MEK inhibitors.

Info

Publication number: ZA200109907B
Application number: ZA200109907A
Authority: ZA
Inventors: Alistair Dixon; Robert Denham Pinnock; Kevin Lee
Original assignee: Warner Lambert Co
Priority date: 1999-07-16
Filing date: 2001-11-30
Publication date: 2003-02-28
Also published as: KR20020012315A; CN1373660A; HUP0202623A3; AR024732A1; AU5786000A; EP1202726A2; PE20010545A1; PL352684A1; WO2001005392A2; JP2003504400A; CO5300398A1; CA2374052A1; NZ515567A; TR200200082T2; WO2001005392A3; IL147619A0; HUP0202623A2

Description

METHOD FOR TREATING CHRONIC PAIN

USING MEK INHIBITORS

BACKGROUND

The invention features a method for treating chronic pain using MEK inhibitors. Chronic pain includes neuropathic pain, and chronic inflammatory pain.

Abnormality anywhere in a nerve pathway disrupts nerve signals, which in turn are abnormally interpreted in the brain, causing neuropathic pain.

Neuropathic pain may be, for example, a deep ache, a burning sensation, or _ hypersensitivity to touch. Diseases or conditions associated with neuropathic pain include; without limitation, diabetic neuropathy, causalgia, plexus avulsion, neuroma, vasculitis, crush injury, viral infections (e.g., herpes virus infection or HIV), constriction injury, tissue injury, nerve injury from the periphery to the central nervous system, limb amputation, hypothyroidism, uremia, chronic alcoholism, post-operative pain, arthritis, back pain, and . vitamin deficiencies,

Infections such as herpes zoster (shingles) can cause nerve } inflammation and produce postherpetic neuralgia, a chronic burning localized to the area of viral infection. Hyperalgesia is when an already noxious . stimulus becomes more painful, and allodynia, when a previously non-noxious stimulus becomes painful (such as contact of clothing or a breeze). Reflex sympathetic dystrophy is accompanied by swelling and sweating or changes in local blood flow, tissue atrophy, or osteoporosis. Causalgia, including severe burning pain and swelling, sweating, and changes in blood flow, may follow an injury or disease of a major nerve such as the sciatic nerve. Some types of chronic low back pain can have a neuropathic component (e.g, on : sciatica, postpoliomyelitis and CPRM). Neuropathic pain may also be induced by cancer or chemotherapy.

Neuropathic pain is currently treated with anticonvulsants such as carbamazepine and antidepressants such as amitryptaline. NSAIDS and opioids generally have little effect (Fields et al 1994 Textbook of Pain p 391- . 996 (pub: Churchill Livingstone), James & Page 1994

J Am.Pediatr.Med.Assoc, 8: 439-447, Galer, 1995 Neurology 45 S17-S25.

Neuropathic conditions that have been treated with gabapentin include: postherpetic neuralgia, postpoliomyelitis, CPRM, HIV-related neuropathy, trigeminal neuralgia, and reflex sympathetic dystrophy (RSD).

The generally weak efficacy of antiinflammatory agents suggests that the mechanism for chronic pain is separate from hyperalgesia.

SUMMARY OF THE INVENTION

The invention features a method for treating chronic pain, which method includes the step of administering a composition including a MEK inhibitor to a patient in need of such treatment. Chronic pain includes neuropathic pain, idiopathic pain, and pain associated with vitamin deficiencies, uremia, hypothyroidism post-operative pain, arthritis, back pain, ’ and chronic alcoholism. The invention also features compounds as disclosed, formulated for the treatment of chronic pain. Such a composition may include - one or more MEK inhibitor compounds having a structure disclosed in patent applications PCT/US98/13106, international filing date June 24, 1998, and :

PCT/US98/13105, international filing date June 24, 1998.

Examples of MEK inhibitors include 4-bromo and 4-iodo.phenylamino benzhydroxamic acid derivatives which are kinase inhibitors and as such are useful for treating proliferative diseases such as cancer, psoriasis, and restenosis. The compounds are defined by Formula | : 2 Ts 2 C-N=-O—R,

R

N

Jom + I 5

Brorl R] R,

wherein: oe

R1 is hydrogen, hydroxy, C4-Cg alkyl, C4-Cg alkoxy, halo, trifluoromethyl, or

CN;

Ra is hydrogen,

Ras, Rg, and Rg independently are hydrogen, hydroxy, halo, trifluoromethyl,

C1-Cg alkyl, C1-Cg alkoxy, nitro, CN, or (O or NH)m-(CH2)n-Rg, where

Rg is hydrogen, hydroxy, CO2H or NR1gR11; nis Oto 4; mis 0 or 1;

Rqg and R14 independently are hydrogen or C1-Cg alkyl, or taken together with the nitrogen to which they are attached can complete a 3- to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or N-C4-Cg alkyl; 0] i

Reg is hydrogen, C1-Cg alkyl, C-C1-Cg alkyl, aryl, aralkyl, or

C3-C1p cycloalkyl,

Ry is hydrogen, C4-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl,

C3-C10 (cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NRg); or Rg and R7 taken together with the N-O : to which they are attached can complete a 5- to 10-membered cyclic ring, optionally containing one, two, or three additional heteroatoms selected from O, S, or NR1poR11; and wherein any of the foregoing alkyl, alkenyl, and alkynyl groups can be unsubstituted or substituted by cycloalkyl (or cycloalkyl optionally containing a heteroatom selected from O, S, or NRg), aryl, aryloxy, heteroaryl, or heteroaryloxy.

Preferred compounds have Formula i

O R n 19

R, H

N

I

Rs

Brorl

Rs Ry where R1, R3, R4, Rs, Rg, and Ry are as defined above. Especially preferred ara ncomnaunde wherein Ra ie methvl ar halo and Ra Ra and Re are halo are compounds wherein R4 is methyl or halo, and R3, Ra, and Rg are halo such as fluoro or bromo.

Another preferred group of compounds have Formula Ili 0

I

C —NHOR 1 H 7

N in

Brorl Ry Rs }

R4 wherein R{, R3, Rg, Rs, and Ry are as defined above.

The most preferred compounds are those wherein R14 is methyl! or halo oo © 10 suchas F, Br, Cl, and |, R3 is hydrogen or halo such as fluoro, R4 is halo such as fluoro, and Rg is hydrogen or halo such as fluoro or bromo. Such compounds have the formulas i 0 a

H; or halo C—NHOR, CH; or halo C—NHOR4 os or

Brorl Ol Brorl be

F F

0 o :

CH; or halo c —NHOR, CH; or hato c —NHOR, or jon

Brorl pol Br Brorl po! F

F F

Specific compounds provided by the invention include the following: 3,4,5-Trifluoro-N-hyd roxy-2-(d-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide;

N-Hydroxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro-benzamide; 3,4,5-Trifluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide; 5-Chloro-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide; 2-(2-Fluoro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy-benzamide; 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide; 5-Bromo-2-(2-bromo-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-methyl-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-3,4,5-trifluoro-N-hydroxy-benzamide;

2-(2-Bromo-4-iodo-phenylamino)-5-chloro-3,4-difluoro-N-hydroxy- benzamide; 2-(2-Bromo-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide; 4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide; 3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy-benzamide,

N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluocro-4-iodo- phenylamino)-benzamide;

N-Cyclopropylmethoxy-2-(4-iodo-2-methyl-phenylamino)-4-nitro- benzamide;

N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(2-fluoro-4-iodo-phenylamino)-

A benzamide; 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo- oo phenylamino)-benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4-diflucro-benzamide;

N-Cyclopropylmethoxy-2-(2-fluoro-4-iodo-phenylamino)-4-nitro- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4,5-trifluoro- benzamide; 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- 3,4-difluoro-benzamide; 5-Bromo-2-(2-bromo-4-iodo-phenylamino)-N-ethoxy-3,4-difluoro- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-ethoxy-4-nitro-benzamide;

2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4,5-trifluoro- benzamide; 2-(2-Bromo-4-iodo-phenylamino)-5-chloro-N-cyclopropylmethoxy- 3,4-difluoro-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylimethoxy-4-nitro- benzamide;

N-Cyclopropyimethoxy-4-fluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide;

N-Cyclopropylmethoxy-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide; 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro- benzamide; : 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide; 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-N-isopropyl- benzamide;

N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl-phenylamino)- : benzamide; 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-N-methyl- benzamide; 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide; 3,4-Difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide (HCI salt); 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-(tetrahydro-pyran-2-yloxy)- benzamide;

] A WO 01/05392 PCT/US00/18347 3,4-Difluoro-2-(2-chloro-4-iodo-phenylamino)-N-cyclobutylmethoxy- benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N-(2-dimethylamino-ethoxy)- 3,4-difluoro-benzamide monohydrochloride salt; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide; 3,4-Difluoro-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy- benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3.4- difluoro-benzamide; 5-Bromo-N-cyclohexylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-N-cyclopentylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; and 5-Bromo-N-cyclobutylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide. - Other aspects of the invention are provided in the description, examples and claims below. :

Further examples of MEK inhibitors include 4-bromo and 4-iodo : . 20 phenylamino benzoic acid derivatives which are selective MEK kinase inhibitors. The compounds are defined by Formula 1(A)

Ry 4

R,

N

Rm

Brorl R} R, wherein:

R1 is hydrogen, hydroxy, C1-Cg alkyl, C4-Cg alkoxy, halo, trifluoromethyl, or

CN;

Ro is hydrogen;

Ra, R4, and Rg independently are hydrogen, hydroxy, halo, trifluoromethyl, CC

C1-Cg alkyl, C4-Cg alkoxy, nitro, CN, or -(O or NH), -(CH2)p-Rg, where Rg is hydrogen, hydroxy, CO2H, or NR1gR11; nis 0-4, misOor1; . R10 and R41 independently are hydrogen or C4-Cg alkyl, or taken together with the nitrogen to which they are attached, can complete a 3-10 member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or N-C1-Cg alkyl;

Zis COORy7, tetrazolyl, CONRgR7, CONHNR1gR11 or CH20R7;

Re and R7 independently are hydrogen, C1-Cg alkyl, C2-Cg alkenyl, oO

C2-Cg alkynyl, C - C1-Cg alkyl, aryl, heteroaryl,

C3-C1( cycloalkyl, or C3-C1p (cycloalkyl optionally containing one, two, or three heteroatoms selected from O, S, NH, or N alkyl); or Rg and R7 together with the nitrogen to which they are attached complete a 3-10 member cyclic ring optionally . containing 1, 2, or 3 additional heteroatoms selected from O, S, - NH, or N alkyl; and wherein any of the foregoing alkyl, alkenyl, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, and the pharmaceutically acceptable salts thereof.

Preferred compounds have Formula lI(A) 0

C—0—Ry

R, H oh

Brorl Rr, R,

where R1, R3, R4, Rs, Rg, and Ry are as defined above. Especially preferred are compounds wherein R1 is methyl or halo, and R3, R4, and Rs are halo such as fluoro or bromo.

The compounds of Formula lI(A) are carboxylic acids when R7 is hydrogen, and are esters when R7 is other than hydrogen. Compounds which are analogous to the acids in physical and biological properties are tetrazolyl derivatives of Formula lla

N=N / \

NN

Ry

Ry H

N

Brorl

R, Ry - Ha - / Ro

N-—N nooo : N__N

R H

- 1 N . Rs

Brorl

Ry Ry

Another preferred group of compounds are amides Formula H(A) 0

C—NRR

R, H 67

N

HI(A)

Brorl Rj Rs

R4 and hydrazides of Formula lila i

C—NHNR sR

R, H 10711

N la

Brorl Ry Rg

Ry

The benzyl alcohols of the invention have Formula IV(A)

H,OR 2V7

R, H oY fs VE

Brorl

Rg Ry

Among this group, the most preferred compounds are those wherein

R1 is methyl, R3 is hydrogen or halo such as fluoro, Ry is halo such as fluoro, and Rg is hydrogen or halo such as fluoro, bromo, or chloro. Representative compounds have the formulas

CH z CH z 3 4 3 4 : JN. : 5 N

Brorl Brorl F

F F

CH yA CH z

N N

Brorl F < Brorl F F

F F F .

Preferred embodiments for this invention include methods using one or more of the following compounds: (a) said MEK inhibitor has a structure selected from: 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide;

N-Cyclopropylmethoxy-3,4,5-trifuoro-2-(4-iodo-2-methyl-phenylamino)- benzamide;

N-Cyclopropyimethoxy-3 4 5-trifuoro-2-(4-iodo-2-methvl-nhenvlamino)- benzamide, potassium salt; 2-(2-Chloro-4-iodo-phenylamino)-N-cyclobutylmethoxy-3,4-difluoro- benzamide,; 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-fluoro- benzamide, 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy- benzamide;

R 3,4-Difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- ’ benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- : benzamide;

N-Cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-N-cyclobutylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Bromo-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyi- phenylamino)-benzamide; 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4- difluoro-benzamide; 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide;

4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide, Co hydrochloride salt; 5-Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)- benzamide; 3,4-Difluoro-N-(2-hydroxy-ethoxy)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-(3-hydroxy- propoxy)-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-N-(3-hydroxy-propoxy)- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-N-[2-(2-methoxy- ethoxy)-ethoxy]-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-(3-hydroxy-propoxy)- benzamide; 5-Bromo-3,4-difluoro-N-(3-hydroxy-propoxy)-2-(4-iodo-2-methyi- phenylamino)-benzamide; 3,4,5-Trifluoro-N-(3-hydroxy-propoxy)-2-(4-iodo-2-methyl- . phenylamino)-benzamide; 3,4,5-Trifluoro-N-(2-hydroxy-ethoxy)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)- benzamide; and 3,4-Difluoro-N-(2-hydroxy-ethoxy)-2-(4-iodo-2-methyl-phenylamino)- benzamide; (b) said MEK inhibitor has a structure selected from: 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide;

N-Cyclopropylmethoxy-3,4,5-trifuoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)- benzamide;

3,4-Difluoro-N-(2-hydroxy-ethoxy)-2-(4-iodo-2-methyl-phenylamino)- benzamide, (c) said MEK inhibitor has a structure selected from: 2-(2-Chloro-4-iodo-phenylamino)-3,4difluoro-benzoic acid; 3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid, 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid, 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2-(2-Chloro-4-iodo-pyenylamino)-3,4-difluoro-5-nitro-benzoic acid; 2-(2-Chloro-4-iodo-phenylamino)-3,4,5-trifluoro-benzoic acid; 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)1 H-benzoimidazole-5- carboxylic acid cyclopropylmethoxy-amide; 5-Chloro-3,4-difluoro-2-(4-iodo-2-methyi-phenylamino)-benzoic acid; and . 15 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid, and .. (d) said MEK inhibitor has a structure selected from: 2-(2-Chloro-4-iodo-phenylamino)-3,4difluoro-benzoic acid; and : 7-Fluoro-6-(4-iodo-2-methyl-phenylamino)1 H-benzoimidazole-5- carboxylic acid cyclopropylmethoxy-amide.

This invention also provides pharmaceutical formulations adapted for : the treatment of chronic pain, said formalities comprising a disclosed compound together with a pharmaceutically acceptable excipient, diluent, or carrier. Preferred formulations include any of the foregoing preferred compounds together with an excipient, diluent, or carrier.

The disclosed compounds are potent and selective inhibitors of kinase enzymes, particularly MEK and MEK3>.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a bar graph representing the paw withdrawal threshold (PWT) in grams as a function of time in days. The empty, cross-hatched, and single-

S hatched bars are vehicle, PD 198306, and pregabalin, respectively. The arrows indicate time of drug administration (30 mg/kg, p.o.).

FIG 2. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days.

Baseline (BL) measurements were taken before treatment. Animals received a single p.o. administration of PD 198306 (3-30mg/kg), or pregabalin (30mg/kg) and withdrawal thresholds were re-assessed 1h after treatment.

Treatments were repeated twice a day for two days. Results are expressed median + 1% and 3"™ quartiles. *P<0.05, **P<0.01, ***P<0.001 significantly different from vehicle treated animals (Mann-Whitney t test; n=7-8).

FIG. 3. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days.

Baseline (BL) measurements were taken before treatment. Animals received : a single p.o. administration of PD 198306 (3-30mg/kg), or pregabalin (30mg/kg) and withdrawal thresholds were re-assessed 1h after treatment. .

Treatments were repeated twice a day for two days. Results are expressed median + 1% and 3" quartiles. **P<0.01 significantly different from vehicle treated animals (Mann-Whitney t test; n=6).

FIG. 4. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days.

Baseline (BL) measurements were taken before treatment. Animals received a single i.t. administration of PD 198306 (1-30ug/10ul), or pregabalin (100ug/10ul) and withdrawal thresholds were re-assessed at 30min, 1h and 2h after treatment. Results are expressed median + 1% and 3" quartiles. *P<0.05, ***P<0.001 significantly different from vehicle treated animals (Mann-

Whitney t test; n=7-9).

FIG. 5. is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days.

Baseline (BL) measurements were taken before treatment. Animals received asingle i.t. administration of PD 198306 (1-30ug/10ul), or pregabalin 4 00pg/10pul) and withdrawal thresholds were re-assessed at 30min, 1h and 2h after treatment. Results are expressed median + 1% and 3" quartiles. *P<0.05, **P<0.01, ***P<0.001 significantly different from vehicle treated animals (Mann-Whitney t test; n=6-8). ’ .

FIG. 6 is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments as a function of time in days .

Animals received a single intraplantar (i.pl.) administration of PD 198306 (3mg/100pl), or an intrathecal injection of PD 198306 (30ug/10ul) and withdrawal thresholds were re-assessed 1h after treatment. Results are expressed median + 1% and 3™ quartiles. **P<0.01 significantly different from : vehicle treated animals (Mann-Whitney t test; n=6-9).

FIG. 7. is a bar graph representing the force required in grams to elicit * 20 paw withdrawal using von Frey hair filaments as a function of time in days. 7 ’ Animals received a single intraplantar (i.pl.) administration of PD 198306 = (3mg/100u), or an intrathecal injection of PD 198306 (30ug/10ul) and withdrawal thresholds were re-assessed 1h after treatment. Results are ' expressed median + 1% and 3™ quartiles. **P<0.01 significantly different from vehicle treated animals (Mann-Whitney t test; n=6).

FIG. 8 is a bar graph representing the force required in grams to elicit paw withdrawal using von Frey hair filaments. Baseline (BL) measurements were taken before treatment. Animals received a single i.t. administration of

PD219622, PD297447, PD 184352, or PD 254552 (30ug/10ul), or pregabalin (100ug/10ul) and withdrawal thresholds were re-assessed at 30min, 1h and 2h after treatment. Results are expressed median + 1% and 3" quartiles.

*P<0.05, **P<0.01, ***P<0.001 significantly different from vehicle treated animals (Mann-Whitney t test; n=7-8).

DETAILED DESCRIPTION

The compounds disclosed herein are pharmaceutically active, for example, they inhibit MEK. MEK enzymes are dual specificity kinases involved in, for example, immunomodulation, inflammation, and proliferative diseases such as cancer and restenosis, as well as pair.

Proliferative diseases are caused by a defect in the intracellular signaling system, or the signal transduction mechanism of certain proteins.

Defects include a change either in the intrinsic activity or in the cellular concentration of one or more signaling proteins in the signaling cascade . The cell may produce a growth factor that binds to its own receptors, resulting in an autocrine loop, which continually stimulates proliferation. Mutations or overexpression of intracellular signaling proteins can lead to spurious mitogenic signals within the cell. Some of the most common mutations occur in genes encoding the protein known as Ras, a G-protein that is activated when bound to GTP, and inactivated when bound to GDP. The above- mentioned growth factor receptors, and many other mitogenic receptors, when activated, lead to Ras being converted from the GDP-bound state to the GTP- bound state. This signal is an absolute prerequisite for proliferation in most cell types. Defects in this signaling system, especially in the deactivation of . the Ras-GTP complex, are common in cancers, and lead to the signaling cascade below Ras being chronically activated.

Activated Ras leads in turn to the activation of a cascade of serine/threonine kinases. One of the groups of kinases known to require an active Ras-GTP for its own activation is the Raf family. These in turn activate

MEK (e.g.. MEK4 and MEK>) which then activates MAP kinase, ERK (ERK, and ERK). Activation of MAP kinase by mitogens appears to be essential for : proliferation; constitutive activation of this kinase is sufficient to induce cellular transformation. Blockade of downstream Ras signaling, for example by use of a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants.

Although Ras is not itself a protein kinase, it participates in the activation of

Raf and other kinases, most likely through a phosphorylation mechanism.

Once activated, Raf and other kinases phosphorylate MEK on two closely oC adjacent serine residues, S218 and S222 in the case of MEK-1, which are the prerequisite for activation of MEK as a kinase. MEK in turn phosphorylates

MAP kinase on both a tyrosine, Y185, and a threonine residue, T183, separated by a single amino acid.

This double phosphorylation activates MAP kinase at least 100-fold.

Activated MAP kinase can then catalyze the phosphorylation of a large number of proteins, including several transcription factors and other kinases.

Many of these MAP kinase phosphorylations are mitogenically activating for the target protein, such as a kinase, a transcription factor, or another cellular protein. In addition to Raf-1 and MEKK, other kinases activate MEK, and

MEK itself appears to be a signal integrating kinase. Current understanding is that MEK is highly specific for the phosphorylation of MAP kinase. In fact, no substrate for MEK other than the MAP kinase , ERK, has been demonstrated to date and MEK does not phosphorylate peptides based on the MAP kinase phosphorylation sequence, or even phosphorylate denatured

MAP kinase. MEK also appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK may require a prior strong interaction between the two proteins. Both this requirement and the unusual specificity of MEK are suggestive that it may have enough difference in its mechanism of action to other protein : kinases that selective inhibitors of MEK, possibly operating through allosteric mechanisms rather than through the usual blockade of the ATP binding site, may be found.

The effect of the MEK inhibitor PD 198306 has been investigated in two animal models of neuropathic pain by assessing static allodynia with von Frey hairs.

Oral administration of PD 198306 (3-30mg/kg) had no effect in the model of chronic constriction injury of the sciatic nerve (CCl). However, after repeated administration (3 doses over two days) it had a transient effect in the diabetic neuropathy model (streptozocin). This may be due to disorders of the blood- brain barrier induced by the diabetic condition in these animals, thus allowing central action of the compound. Intrathecal administration of PD 198306 (1-

30ug) dose-dependently blocked static allodynia in both the streptozocin and the

CCI models of neuropathic pain, with minimum effective doses (MED) of 3 and 10pg respectively. The highest dose used (30ug) totally blocked the maintenance of static allodynia, for up to 1h. Intraplantar administration of PD 198306 (3mg/100ul) at a dose 100-fold higher than the dose shown to be effective intrathecally (30ug/10pl) had no effect on static allodynia in either of the neuropathic pain models. This finding confirms the. lack of effect seen after systemic administration and suggests a central site of action for the compound.

This study suppoits the use of MEK inhibilors as potential new therapeutic tools for chronic pain. The study of potential side-effects, especially related to memory, of future brain-penetrant MEK inhibitors will further support the therapeutic window for this novel class of compounds in the treatment of pain.

A. Terms oC

Certain terms are defined below and by their usage throughout this disclosure. .

Alkyl groups include aliphatic (i.e., hydrocarbyl or hydrocarbon radical structures containing hydrogen and carbon atoms) with a free valence. Alkyl groups are understood to include straight chain and branched structures.

Examples include methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, t- butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, 2,3-dimethylhexyl, 1,1- dimethylpentyl, heptyl, and octyl. Cycloalkyl groups include cyclopropyl, - cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

Alkyl groups can be substituted with 1, 2, 3 or more substituents which are independently selected from halo (fluoro, chloro, bromo, or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy. Specific examples include fluoromethyl, hydroxyethyl, 2,3-dihydroxyethyl, (2- or 3-furanyl)methyt, cyclopropylmethyi, benzyloxyethyl, (3-pyridinyl)methyl, (2- or 3-furanyl)methyl, (2-thienyl)ethyl, hydroxypropyl, aminocyclohexyi, 2-dimethylaminobutyl, methoxymethyl, N-pyridinylethyl, diethylaminoethyl, and cyclobutyimethyl.

Alkenyl groups are analogous to alkyl groups, but have at least one : double bond (two adjacent sp? carbon atoms). Depending on the placement of a double bond and substituents, if any, the geometry of the double bond . may be entgegen (E), or zusammen (Z), cis, or trans. Similarly, alkynyl groups have at least one triple bond (two adjacent sp carbon atoms).

Unsaturated alkenyl or alkynyl groups may have one or more double or triple bonds, respectively, or a mixture thereof; like alkyl groups, unsaturated groups may be straight chain or branched, and they may be substituted as described both above for alkyl groups and throughout the disclosure by example.

Examples of alkenyls, alkynyls, and substituted forms include 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-butynyl, 3-(3-fluorophenyl)-2-propynyl, and 2-methyl-2- propenyl. In formula (1), alkenyls and alkynyls can be C 24 or C 2, for example, and are preferably C 34 or C 33.

More general forms of substituted hydrocarbon radicals include hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryi, and corresponding forms for the prefixes amino-, halo- (e.g., fluoro-, chloro-, or bromo-), nitro-, alkyl-, phenyl-, cycloalkyl- and so on, or combinations of substituents. According to formula (1), therefore, substituted alkyls include hydroxyalkyl, aminoalkyl, nitroalkyl, haloalkyl, alkylalkyl (branched alkyls, such x as methylpentyl), (cycloalkyl)alkyl, phenylalkyl, alkoxy, alkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, (heterocyclic radical)alkvl, and (heterocyclic radical)oxyalkyl. Rs thus includes hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocycloalkyl, aminoaryl, alkylalkenyl, (alkylaryl)alkyl, (haloaryl)alkyl, (hydroxyaryl)alkynyl, and so forth.

Similarly, Ra includes hydroxyalkyl and aminoaryl, and Rg includes hydroxyalkyl, aminoalkyl, and hydroxyalkyl(heterocyclic radical)alky!.

Heterocyclic radicals, which include but are not limited to heteroaryls, = include: furyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, pyrrolyl, imidazolyl, g 1,3.4-triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, and their ” nonaromatic counterparts. Further examples of heterocyclic radicals include piperidyl, quinolyl, isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyrrolyl, pyrrolidinyl, octahydroindolyl, : octahydrobenzothiofuranyl, and octahydrobenzofuranyl. “ Selective MEK 1 or MEK 2 inhibitors are those compounds which : inhibit the MEK 1 or MEK 2 enzymes, respectively, without substantially inhibiting other enzymes such as MKK3, PKC, Cdk2A, phosphorylase kinase,

EGF, and PDGF receptor kinases, and C-src. In general, a selective MEK 1 or MEK 2 inhibitor has an ICsg for MEK 1 or MEK 2 that is at least one-fiftieth (1/50) that of its ICs, for one of the above-named other enzymes. Preferably, a selective inhibitor has an ICs that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000, or less than that of its ICsp or one or more of the above-named enzymes.

B. Compounds

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

The term “aryloxy” means an aryl group bonded through an oxygen atom, for example phenoxy, 3-bromophenoxy, naphthyloxy, and 4-methyl- 1-fluorenyloxy. “Heteroaryl” means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from four to eleven carbon atoms and one, two, or three heteroatoms selected from O, S, or N. Examples include furyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, thiazolyl, xanthenyl, pyronyl, indolyl, pyrimidyl, naphthyridyl, pyridyl, and triazinyl. The heteroaryl groups can be unsubstituted or substituted by one, two, or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, or amino. Examples of substituted heteroaryl groups include chloropyranyl, methyithienyl, fluoropyridyl, amino-1,4-benzisoxazinyt, - nitroisoquinolinyl, and hydroxyindolyl.

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

The term “C4-Cg alkyl” means straight and branched chain aliphatic groups having from one to eight carbon atoms. Typical C4-Cg alkyl groups include methyl, ethyl, isopropyl, tert.-butyl, 2,3-dimethylhexyl, and 1,1-dimethylpentyl. The alkyl groups can be unsubstituted or substituted by cycloalkyl, cycloalkyl containing a heteroatom selected from O, S, or NRg, aryl, aryloxy, heteroaryl, or heteroaryloxy, as those terms are defined above.

Examples of aryl and aryloxy substituted alkyl groups include phenylmethyl, 2-phenylethyl, 3-chlorophenylmethyl, 1,1-dimethyl-3-(2-nitrophenoxy)butyl, and 3,4,5-trifluoronaphthylmethyl. Examples of alkyl groups substituted by a heteroaryl or heteroaryloxy group include thienylmethyl, 2-furylethyl, 6-furyloxyoctyl, 4-methylquinolyloxymethyl, and 6-isothiazolylhexyl. Cycloalkyi substituted alkyl groups include cyclopropyimethyl, 2-cyclopentylethyl, 2-piperidin-1-ylethyl, 3-(tetrahydropyran-2-yl)propyl, and cyclobutyimethyl.

S “Cp-Cg Alkenyl” means a straight or branched carbon chain having one or more double bonds. Examples include but-2-enyl, 2-methyl-prop-2-enyl, 1,1-dimethyl-hex-4-enyl, 3-ethyl-4-methyi-pent-2-enyl, and 3-isopropyl-pent- 4-enyl. The alkenyl groups can be substituted with aryl, aryloxy, heteroaryl, or heteroyloxy, for example 2-phenylnrop-2-enyl, 8-thienyl-hex-2-enyl, 2-furyloxy- but-2-enyl, and 4-naphthyloxy-hex-2-enyl. “Co-Cg Alkynyl” means a straight or branched carbon chain having from two to eight carbon atoms and at least one triple bond. Typical alkynyl groups include prop-2-ynyl, 2-methyl-hex-5-ynyl, 3,4-dimethyl-hex-5-ynyl, and 2-ethyl-but-3-ynyl. The alkynyl groups can be substituted by aryl, aryloxy, heteroaryl, or heteroaryloxy, for example 4-(2-fluorophenyl)-but-3-ynyl, - 3-methyl-5-thienylpent-4-ynyl, 3-phenoxy-hex-4-ynyl, and 2-furyloxy-3-methyl- = hex-4-ynyl.

The alkenyl and alkynyl groups can have one or more double bonds or triple bonds, respectively, or a combination of double and triple bonds. For example, typical groups having both double and triple bonds include hex-2-en- } 4-ynyl, 3-methyl-5-phenylpent-2-en-4-ynyl, and 3-thienyloxy-hex-3-en-5-ynyl. g The term “C3-C10 cycloalkyl” means a non-aromatic ring or fused rings containing from three to ten carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopenyl, cyclooctyl, bicycloheptyl, adamantyl, and cyclohexyl.

The ring can optionally contain a heteroatom selected from O, S, or NRg.

Such groups include tetrahydrofuryl, tetrahydropyrrolyl, octahydrobenzofuranyl, octahydroindolyl, and octahydrobenzothiofuranyl.

R3, Rg, and Rs can include groups defined by the term (O or NH)m- (CH2)n-Rg. Examples of such groups are aminomethyl, 2-aminoethyl, 2-aminoethylamino, 3-aminopropoxy, N,N-diethylamino, 3-(N-methyl-N- isopropylamino)-propylamino, 2-(N-acetylamino)-ethoxy, 4-(N- dimethylaminocarbonylamino)-butoxy, and 3-(N-cyclopropylamino)-propoxy.

As used herein, the term “aryl” means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from five to twelve carbon atoms. Examples of typical aryl groups include phenyl, naphthyl, and fluorenyl. The aryl may be substituted by one, two, or three groups selected from fluoro, chloro, bromo,

S iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino. Typical substituted aryl groups include 3-fluorophenyl, 3,5-dimethoxyphenyl, 4-nitronaphthyl, 2-methyl-4-chloro-7-aminofluorenyl, and the like.

The term "aryloxy” means an aryl group bonded through an oxygen atom, for example phenoxy, 3-bromophenoxy, naphthyloxy, and 4-methyl- 1-fluorenyloxy. “Heteroaryl” means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from four to eleven carbon atoms and one, two, or three heteroatoms selected from O, S, or N. Examples include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, xanthenyl, pyronyl, indolyl, pyrimidyl, naphthyridyl, pyridyl, benzinnidazolyl, and triazinyl. The heteroaryl groups can - be unsubstituted or substituted by cone, two, or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino. Examples of substituted heteroaryl groups include chloropyranyl, methylthienyl, fluoropyridyl, amino-1,4-benzisoxazinyl, : nitroisoquinolinyl, and hydroxyindolyl.

The term “C1-Cg alkyl’ means straight and branched chain aliphatic groups having from one to eight carbon atoms, preferably one to four. Typical

C1-Cg alkyl groups include methyl, ethyl, isopropyl, tert.-butyl, 2,3-dimethylhexyl, and 1,1-dimethylpentyl. The alkyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, as those terms are defined herein. Typical substituted alkyl groups include chloromethyl, 3-hydroxypropyl, 2-dimethylaminobutyl, and 2-(hydroxymethylamino)ethyl. Examples of aryl and aryloxy substituted alkyl groups include phenylimethyl, 2-phenylethyl, 3-chlorophenylmethyl,

1,1-dimethyl-3-(2-nitrophenoxy)butyl, and 3,4,5-trifluoronaphthylmethyl.

Examples of alkyl groups substituted by a heteroaryl or heteroaryloxy group include thienylmethyl, 2-furylethyl, 6-furyloxyoctyl, 4-methylquinolyloxymethyl, and 6-isothiazolylhexyl. Cycloalkyl substituted alkyl groups include cyclopropylmethyl, 2-cyclohexyethyl, piperidyl-2-methyl, 2-(piperidin-1-yl)- ethyl, 3-(morpholin-4-yl)propyl. “Co-Cg Alkenyl” means a straight or branched carbon chain having one or more double bonds. Examples include but-2-enyl, 2-methyl-prop-2-enyl, 1,1-dimethyl-hex-4-eny! 3-ethyl-4-methyl-nent-2-enyl, and 3-isopropyl-nent. 4-enyl. The alkenyl groups can be substituted with halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy, heteroaryl, or heteroyloxy, for example 2-bromoethenyl, 3-hydroxy-2-butenyl, 1-aminoethenyl, 3-phenylprop- 2-enyl, 6-thienyl-hex-2-enyl, 2-furyloxy-but-2-enyl, and 4-naphthyloxy-hex- 2-enyl. “Co-Cg Alkynyl” means a straight or branched carbon chain having ) from two to eight carbon atoms and at least one triple bond. Typical alkynyi . groups include prop-2-ynyl, 2-methyl-hex-5-ynyl, 3,4-dimethyl-hex-5-ynyl, and 2-ethyl-but-3-ynyl. The alkynyl groups can be substituted as the alkyl and alkenyl groups, for example, by aryl, aryloxy, heteroaryl, or heteroaryloxy, for example 4-(2-fluorophenyl)-but-3-ynyl, 3-methyl-5-thienyipent-4-ynyl, 3-phenoxy-hex-4-ynyl, and 2-furyloxy-3-methyl-hex-4-ynyl. : The alkenyl and alkynyl groups can have one or more double bonds or triple bonds, respectively, or a combination of double and triple bonds. For example, typical groups having both double and triple bonds include hex-2-en- 4-ynyl, 3-methyl-5-phenylpent-2-en-4-ynyl, and 3-thienyloxy-hex-3-en-5-ynyl.

The term “C3-C1 cycloalkyl” means a nonaromatic ring or fused rings containing from three to ten carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopenyl, cyclooctyl, bicycloheptyl, adamantyl, and cyclohexyl.

The ring can optionally contain one, two, or three heteroatoms selected from 0, S, or NRg. Such groups include tetrahydrofuryl, tetrahydropyrrolyl, octahydrobenzofuranyl, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, octahydroindolyl, and octahydrobenzothiofuranyl. The cycloalkyl groups can be substituted with the same substituents as an alkyl and alkenyl! groups, for example, halo, hydroxy, aryl, and heteroaryloxy. Examples include 3-hydroxycyclohexyl, 2-aminocyclopropyl, 2-phenylpyrrolidinyl, and 3-thienylmorpholine-1-yl.

Rg and R7 can be taken together with the nitrogen to which they are attached to complete a cyclic ring having from 3 to 10 members, which may contain 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl. Examples of such cyclic rings include piperazinyl, piperidyl, pyrrolidinyl, morpholino, N-methylpiperazinyl, aziridynyl, and the like. Such rings can be substituted with halo, hydroxy, alkyl, alkoxy, amino, alkyl, and dialkylamino, aryl, aryloxy, heteroaryl, and heteroaryloxy. Typical examples include 3-hydroxy-pyrrolidinyl, 2-fluoro-piperindyl, 4-(2-hydroxyethyl)-piperidinyl, and 3-thienylmorpholino.

C. Synthesis

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

Scheme 1.

Scheme 1 : 0) ) I

R, f C—OH

NH L

+ Rs

Brorl K, R, [pase 0

R22 c-oH

R,

N

Rs

Brorl

Ry R, fo

HN—-O —R4 6) Re

R, 1]

N

Rs

Brorl

R, Ry where L is a leaving group, for example halo such as fluoro, chloro, bromo or iodo, or an activated hydroxy group such as a diethylphosphate, : trimethylsilyloxy, p-nitrophenoxy, or phenylsulfonoxy.

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

The phenylamino benzoic acid next is reacted with a hydroxylamine derivative HNRgOR7 in the presence of a peptide coupling reagent.

Hydroxylamine derivatives that can be employed include methoxylamine,

N-ethyl-isopropoxy amine, and tetrahydro-oxazine. Typical coupling reagents include 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), 1,3-dicyclohexylcarbodiimide (DCC), bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP) and (benzotriazolyloxy)tripyrrolidino phosphonium hexafluorophosphate (PyBOP). The phenylamino benzoic acid and hydroxylamino derivative normally are mixed in approximately equimolar quantities in an unreactive organic solvent such as dichloromethane, tetrahydrofuran, chloroform, or xylene, and an equimolar quantity of the coupling reagent is added. A base such as triethylamine or diisopropylethylamine can be added to act as an acid scavenger if desired.

The coupling reaction generally is complete after about 10 minutes to 2 hours, and the product is readily isolated by removing the reaction solvent, for instance by evaporation under reduced pressure, and purifying the product by standard methods such as chromatography or crystallizations from solvents such as acetone, diethyl ether, or ethanol.

An alternative method for making the invention compounds involves first converting a benzoic acid to a hydroxamic acid derivative, and then reacting the hydroxamic acid derivative with an aniline. This synthetic sequence is depicted in Scheme 2.

Scheme 2 0 0 Rg i" H J

C—OH gr C-N-O—Ry !

EE

, od Rs | / Se Rg

Pa IN

R4 Ry Ry Ry

NHR,

Jr, a Brorl 0] Rg

R THE

2 C—-N-O0—R4

R, “ Se N

Rs = Brorl

Rj Ry4 where L is a leaving group. The general reaction conditions for both of the steps in Scheme 2 are the same as those described above for Scheme 1.

Yet another method for making invention compounds comprises reacting a phenylamino benzhydroxamic acid with an ester forming group as depicted in Scheme 3.

Scheme 3

Oo Rg

R TH

2 C—N—OH

R,

N

Rs + L-Ry

Brorl

Rj Ry [use 0 Te

R20 c-N-0—R

R, 7

N

Rg

Brorl

Rj, R, where L is a leaving group such as halo, and a base is triethylamine or diisopropylamine.

The synthesis of invention compounds of Formula | is further illustrated : by the following detailed examples numbers 1 to 102.

The 2-(4-bromo and 4-iodo phenylamino)-benzoic acid derivatives of

Formula I(A) can be prepared from commercially available starting materials utilizing synthetic methodologies well-known to those skilled in organic chemistry and illustrated in synthetic examples 1A - 224A below. A typical synthesis is carried out by reacting a 4-bromo or 4-iodo aniline with a benzoic acid having a leaving group at the 2-position to give a 2-(phenylamino)- benzoic acid. This process is depicted in Scheme 1(A).

Scheme 1(A)

I

2 C—OH

Ry

NH L

+ Rg

Brorl

Ry Ry pes n

Ry» c-oH : R,

N

R,

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

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

The 2-(phenylamino)-benzoic acid (eg, Formula IA, where R7 is hydrogen) can be reacted with an organic or inorganic base such as pyridine, triethylamine, calcium carbonate, or sodium hydroxide to produce a pharmaceutically acceptable salt. The free acids can also be reacted with an alcohol of the formula HOR7 (where Ry is other than hydrogen, for example methyl) to produce the corresponding ester. Reaction of the benzoic acid with an alcohol can be carried out in the presence of a coupling agent. Typical coupling reagents include 2-ethoxy-1-ethoxycarbonyi-1,2-dihydroquinoline (EEDQ), 1,3-dicyclohexylcarbodiimide (DCC), bromo-tris(pyrrolidino)- phosphonium hexafluorophosphate (PyBrOP), and (benzotriazolyloxy) tripyrrolidino phosphonium hexafluorophosphate (PyBOP). The phenylamino benzoic acid and alcohol derivative normally are mixed in approximately equimolar quantities in an unreactive organic solvent such as dichloromethane, tetrahydrofuran, chloroform, or xylene, and an equimolar quantity of the coupling reagent is added. A base such as triethylamine or diisopropylethylamine can be added to act as an acid scavenger if desired.

The coupling reaction generally is complete after about 10 minutes to 2 hours, : and the product is readily isolated by removing the reaction solvent, for instance by evaporation under reduced pressure, and purifying the product by standard methods such as chromatography or crystallizations from solvents such as acetone, diethyl ether, or ethanol.

The benzamides of the invention, Formula (A) where Z is CONRgR7, are readily prepared by reacting the foregoing benzoic acids with an amine of the formula HNRgR7. The reaction is carried out by reacting approximately equimolar quantities of the benzoic acid and amine in an unreactive organic solventin the presence of a coupling reagent. Typical solvents are chloroform, dichloromethane, tetrahydrofuran, benzene, toluene, and xylene. Typical coupling reagents include DCC, EEDQ, PyBrOP, and PyBOP. The reaction is i WO 01/05392 PCT/US00/18347 generally complete after about 10 minutes to about 2 hours when carried out at a temperature of about 0°C to about 60°C. The product amide is readily isolated by removing the reaction solvent, for instance by evaporation, and further purification can be accomplished by normal methods such as chromatography, crystallization, or distillation. The hydrazides (z= CONHNR1gR11) are similarly prepared by coupling a benzoic acid with a hydrazine of the formula HopHNR1gR 141.

The benzyl alcohols of the invention, compounds of Formula I(A) where

Z is CHoORg and Rg is hydrogen, are readily prepared by reduction of the corresponding benzoic acid according to the following scheme 0 % [* C—-OH | X, f2 H,OH reducing N

Bror | %, Ry Brorl & Ry . Typical reducing agents commonly employed include borane in tetrahydrofuran. The reduction normally is carried out in an unreactive organic - solvent such as tetrahydrofuran, and generally is complete within about 2 hours to about 24 hours when conducted at a temperature of about 0°C to - about 40°C.

The following detailed examples 1A to 224A illustrate specific compounds provided by this invention.

D. Uses oC

The disclosed compositions are useful as both prophylactic and therapeutic treatments for diseases or conditions relating to chronic pain, including neuropathic pain, as provided in the Summary section, as well as - 5 diseases or conditions modulated by the MEK cascade. For example, in one embodiment, the disclosed method relates to postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, crush injury, constriction injury, tissue injury, post-surgical pain, arthritis pain, or limb amputation

For example, local injuries can be treated with local or topical administration. Chronic pain affecting the entire body, such as diabetic neuropathy can be treated with systemic administration (injection or orally) of a disclosed composition. Treatment for chronic pain (e.g., post-operative pain) confined to the lower body can be administered centrally, e.g., epidurally. Formulations and methods of administration can include the use of more than one MEK inhibitor, or a combination of a MEK inhibitor and another ] pharmaceutical agent, such as an anti-inflammatory, analgesic, muscle relaxing, or anti-infective agent. Preferred routes of administration are oral, intrathecal or epidural, subcutaneous, intravenous, intramuscular, and, for non-human mammals, intraplantar, and are preferably epidural. 1. Dosages

Those skilled in the art will be able to determine, according to known methods, the appropriate dosage for a patient, taking into account factors such as age, weight, general health, the type of pain requiring treatment, and the presence of other medications. In general, an effective amount will be between 0.1 and 1000 mg/kg per day, preferably between 1 and 300 mg/kg body weight, and daily dosages will be between 10 and 5000 mg for an adult subject of normal weight. Commercially available capsules or other

A WO 01/05392 PCT/US00/18347 formulations (such as liquids and film-coated tablets) of 100 mg, 200 mg, 300 mg, or 400 mg can be administered according to the disclosed methods. 2. Formulations

Dosage unit forms include tablets, capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted for subdivision into individual doses.

Dosage unit forms can also be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implants.

Administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, : intravesical, local (drops, powders, ointments, gels, or cream), and by inhalation (a buccal or nasal spray).

Parenteral formulations include pharmaceutically acceptable aqueous or nonaqueous solutions, dispersion, suspensions, emulsions, and sterile powders for the preparation thereof. Examples of carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils, and d injectable organic esters such as ethyl oleate. Fluidity can be maintained by

E the use of a coating such as lecithin, a surfactant, or maintaining appropriate particle size. Carriers for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption acccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, : and (j) propellants.

Compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents; antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid; isotonic agents such as a sugar or sodium chloride; absorption-prolonging agents such as aluminum monostearate and gelatin; and absorption-enhancing agents. 3. Related compounds

The invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, hydrates or solvated forms thereof; masked or protected forms; and racemic mixtures, or enantiomerically or optically pure forms.

Pharmaceutically acceptable salts, esters, and amides include carboxylate salts (e.g., C 1.a alkyl, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic), amino acid addition salts, esters, and amides which are within a reasonable benefit/risk ratio, pharmacologically effective, and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate. These may include alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine. See, for example, S.M. Berge, et al., “Phamaceutical Salts,” J. Pharm. Sci., 1977, : 66:1-19 which is incorporated herein by reference. Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C 1. alkyl amines 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 between 1 and 2 additional heteroatoms. Preferred amides are derived from ammonia, C 1.3 alkyl primary amines, and di (C 1 alkyl)amines.

Representative pharmaceutically acceptable esters of the invention include

C 1.7 alkyl, C s.7 cycloalkyl, phenyl, and phenyl(C 1.s)alkyl esters. Preferred esters include methyl esters.

The invention also includes disclosed compounds having one or more functional groups (e.g., hydroxyl, amino, or carboxyl) masked by a protecting group. Some of these masked or protected compounds are pharmaceutically acceptable; others will be useful as intermediates. Synthetic intermediates and processes disclosed herein, and minor modifications thereof, are also within the scope of the invention.

HYDROXYL PROTECTING GROUPS

Hydroxy! protecting groups include: ethers, esters, and protection for 1,2- and 1,3-diols. The ether protecting groups include: methyl, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, silyl ethers and conversion of silyl ethers to other functional groups.

Substituted Methyl Ethers

Substituted methyl ethers include: methoxymethyl, methyithiomethyl, t- utylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p- ethoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolmethyl, ¢- butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyi, 2,2 2-trichloroethoxymethyl, bis(2-chloro- ethoxy)methyl, 2- (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydro-pyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4- methoxytetrahydrothio-pyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxido, 1-[(2-chioro-4-methyl)phenyl]-4-methoxypiperidin-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 Ethers

Substituted ethyl ethers include: 1-ethoxyethyl, 1-(2,chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyi-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2- ; fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilyethyl, 2-(phenylselenyl)ethyl, t-

EN butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.

Substituted Benzyl Ethers : Substituted benzyl ethers include: p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyi, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p, p-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-naphthyldiphenyl- methyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri-(p-methoxyphenyl)methyl, 4-(4’-bromophenacyloxy)phenyldiphenylmethyl, 4,4’ 4"-tris(4,5-dichlorophthalimidophenyl)methyi, 4,4’,4"- tris(levulinoyloxyphenyl) methyl, 4,4’ 4"tris(benzoyloxyphenyl)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- dioxido.

Silyl Ethers

Silyl ethers include: trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropyisilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethyisilyl, and t-butylmethoxyphenyisilyl.

ESTERS

Esters protecting groups include: esters, carbonates, assisted cleavage, miscellaneous esters, and sulfonates.

Esters

Examples of protective esters include: formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p- chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio) pentanoate, pivaloate, adamantoate,crotonate,4-methoxycrotonate, benzoate, p-phenylbenzoate, and 2,4,6-trimethylbenzoate (mesitoate). .

Carbonates

Carbonates include: methyl, S-fluorenylmethyl, ethyl, 2,2 2-trichloroethyl, . 2-(trimethylsilyl) ethyl, 2-(phenylsuifonyl) ethyl, 2-(triphenylphosphonio) ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4- dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4- ethoxy-1-naphthyl, and methyl dithiocarbonate.

Assisted Cleavage

Examples of assisted cleavage protecting groups include: 2-iodobenzoate, 4- azido-butyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl) benzoate, 2- formylbenzene-suifonate, 2-(methylthiomethoxy) ethyl carbonate, 4- (methylthiomethoxymethyl) benzoate, and 2-(methyithiomethoxymethyl) benzoate.

Miscellaneous Esters

In addition to the above classes, miscellaneous esters include: 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro4-(1,1,3,3-tetramethylbutyl) phenoxyacetate, 2,4-bis(1,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monasuccinoate, (E)-2-methyl-2- butenoate (tigloate), o-(methoxycarbonyl) benzoate, p-P-benzoate, a- naphthoate, nitrate, alkyl N,N,N’ N ‘-tetramethylphosphorodiamidate, N- phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4- dinitrophenylsulfenate.

Sulfonates

Protective sulfates includes: sulfate, methanesulfonate(mesylate), benzylsulfonate, and tosylate.

PROTECTION FOR 1,2- AND 1,3-DIOLS

The protection for 1,2 and 1,3-diols group includes: cyclic acetals and ketals, ~ cyclic ortho esters, and silyl derivatives.

Cyclic Acetals and Ketals : Cyclic acetals and ketals include: methylene, ethylidene, 1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, : cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4- a dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and 2-nitrobenzylidene.

Cyclic Ortho Esters

Cyclic ortho esters include: methoxymethylene, ethoxymethylene, dimethoxy- methylene, 1-methoxyethylidene, 1-ethoxyethylidine, 1,2- dimethoxyethylidene, a-methoxybenzylidene, 1-(N,N- dimethylamino)ethylidene derivative, a~(N,N-dimethylamino) benzylidene derivative, and 2-oxacyclopentylidene.

PROTECTION FOR THE CARBOXYL GROUP

ESTERS

Ester protecting groups include: esters, substituted methyl esters, 2- substituted ethyl esters, substituted benzyl esters, silyl esters, activated esters, miscellaneous derivatives, and stannyl esters.

Substituted Methyl Esters

Substituted methyl esters include: 9-fluorenylmethyl, methoxymethyl, methyithiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxy-methyl, benzyloxymethyl, phenacyl, p-bromophenacyl, a-methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N- phthalimidomethyi. 2-Substituted Ethyl Esters 2-Substituted ethyl esters include: 2,2,2-trichloroethyl, 2-haloethyl, a- chloroalkyl, 2-(trimethylsily)ethyl, 2-methylthioethy!, 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-(trimethylsily)-2-buten-1-yl, cinnamyl, a- methylcinnamyl, phenyl, p-(methylmercapto)-phenyl, and benzyl.

Substituted Benzyl Esters )

Substituted benzyl esters include: triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 8-anthrylmethyl, 2-(9,10-dioxo)anthryimethyi, 5- : dibenzo-suberyl, 1-pyrenylmethyl,2-(trifluoromethyl)-6-chromylmethyl, 2,4,6- trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p- methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl, and 4-P-benzyl.

Silyl Esters

Silyt esters include: trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, i propyldimethyisilyl, phenyldimethylsilyl, and di- t-butylmethyilsilyl.

Miscellaneous Derivatives

Miscellaneous derivatives includes: oxazoles, 2-alkyl-1,3-oxazolines, 4-alkyl- 5-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1,3-dioxolanes, ortho esters, phenyl group, and pentaaminocobalt(lll) complex.

Stannyl Esters

Examples of stannyl esters include: triethylstannyl and tri-n-butylstannyl.

AMIDES AND HYDRAZIDES

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

PROTECTION FOR THE AMINO GROUP

CARBAMATES

Carbamates include: carbamates, substituted ethyl, assisted cleavage, photolytic cleavage, urea-type derivatives, and miscellaneous carbamates.

Carbamates o 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-10,10,10,10-tetrahydro- thioxanthyl)Jmethyl, and 4-methoxyphenacyl.

Substituted Ethyl

Substituted ethyl protective groups include: 2,2,2-trichloroethyl, 2- . trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1,1-dimethyi-

Pa 2-haloethyl, 1,1dimethyl-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-icyclohexylcarboxamido)- ethyl, t-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, connamyl, 4-nitrocinnamyl, quinolyl, N- hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p- bromobenzyl, p-chlorobenzyl, 2,4dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, and diphenylmethyl.

Assisted Cleavage

Protection via assisted cleavage includes: 2-methylthioethy!, 2-methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethyl-thiophenyl, 2-phosphonioethyl,

2-triphenylphosphonioisopropyl, 1,1-dimethyl-2cyanoethyl, m-chioro-p- acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolyl-methyl, and 2-(trifluoromethyl)-6-chromonylmethyl.

Photolytic Cleavage

Photolytic cleavage methods use groups such as: m-nitrophenyl, 3,5- dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o- nitrophenyl)methyl.

Urea-Type Derivatives

Examples of of urea-type derivatives include: phenothiazinyl-(10)-carbonyl derivative, N '-p-toluenesuifonylaminocarbonyl, and N ’- phenylaminothiocarbonyl.

Miscellaneous Carbamates

In addition to the above, miscellaneous carbamates include: f-amyl, S-benzy! thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxy-benzyl, diisopropylmethyl, 2,2- dimethoxycarbonylvinyl, o-(N,N-dimethyl-carboxamido)-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-henylazophenyl)- 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.

AMIDES

Amides

Amides includes: N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl,

N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3- pyridyl-carboxamide, N-benzoylphenylalany! derivative, N-benzoyl, and N-p- phenylbenzoyl.

Assisted Cleavage

Assisted cleavage groups include: N-o-nitrophenylacetyl, N-o- nitrophenoxyacetyl, N-acetoacetyl, (N~dithiobenzyloxycarbonylamino)acetyt,

oo ) WO 01/05392 PCT/US00/18347

N-3-(p-hydroxphenyl) propionyl, N-3-(o-nitrophenyl)propionyl, N-2-methyl-2- (o-nitrophenoxy)propionyl, N-2-methyl-2-(o-phenylazophenoxy)propionyt, N-4- chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N- acetylmethionine derivative, N-o-nitrobenzoyl, N-o- (benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3-oxazolin-2-one.

Cyclic Imide Derivatives

Cyclic imide derivatives include: N-phthalimide, N-dithiasuccinoyl,

N-2,3-diphenyl-maleoyl, N-2,5-dimethylpyrrolyl,

N-1.1.4 4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzy!- 1,3,5-triazacyclohexan-2-one, and 1-substituted 3,5-dinitro-4-pyridonyl.

SPECIAL -NH PROTECTIVE GROUPS

Protective groups for — NH include: N-alkyl and N-aryl amines, imine 8 derivatives, enamine derivatives, and N-hetero atom derivatives (such as N- - metal, N-N, N-P, N-Si, and N-S), N-sulfenyl, and N-sulfonyl.

N-Alkyl and N-Aryl Amines

N-alkyl and N-aryl amines include: N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxyl]-methyl, N-3-acetoxypropy!,

N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, . N-benzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl,

N-triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl,

N-2,7-dichloro-9-fluorenyimethylene, N-ferrocenylmethyl, and N-2-picolylamine N '-oxide.

Imine Derivatives

Imine derivatives include: N-1,1-dimethylthiomethylene, N-benzylidene,

N-p-methoxybenzylidene, N-diphenylmethylene,

N-[(2-pyridyl)mesityllmethylene, N-(N',N '-dimethylaminomethylene),

N,N -isopropylidene, N-p-nitrobenzylidene, N-salicyiidene,

N-5-chlorosalicylidene, N-(5-chloro-2-hydroxyphenyl)phenyl-methylene, and

N-cyclohexylidene.

An example of an enamine derivative is N- (5,5-dimethyl-3-oxo-1-cyclohexenyl).

N-Hetero Atom Derivatives

N-metal derivatives include: N-borane derivatives, N-diphenylborinic acid derivative, N-[phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, and

N-copper or N-zinc chelate. Examples of N-N derivatives include: N-nitro,

N-nitroso, and N-oxide. Examples of N-P derivatives include:

N-diphenylphosphinyl, N-dimethyithiophosphinyl, N-diphenyithiophosphinyl,

N-dialkyl phosphoryl, N-dibenzyl phosphoryl, and N-diphenyl phosphoryl.

Examples of N-suifenyl derivatives include: N-benzenesulifenyl,

N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl,

N-pentachlorobenzenesulfenyl, N-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-methoxybenzenesulifonyl,

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-pg-trimethylsilylethanesulfonyl, N-9-anthracenesulfonyl,

N-4-(4',8'-dimethoxynaphthyimethyl)-benzenesulfonyl, N-benzylisulfonyl, N-trifluoromethylsulfonyl, and N-phenacylsuifonyl.

Disclosed compounds which are masked or protected may be prodrugs, compounds metabolized or otherwise transformed in vivo to yield a disclosed compound, e.g., transiently during metabolism. This transformation may be a hydrolysis or oxidation which results from contact with a bodily fluid such as blood, or the action of acids, or liver, gastrointestinal, or other enzymes.

Features of the invention are further described in the examples below.

} WO (11/05392 PCT/US00/18347

E. Examples

BIOLOGICAL EXAMPLES

EXAMPLE 1

Effect of PD 198306 on streptozocin-induced static allodynia

Animals :

Male Sprague Dawley rats (250-300g), obtained from Bantin and

Kingman, (Hull, U.K.) were housed in groups of 3. All animals were kept under a 12h light/dark cycle (lights on at 07h 00min) with food and water ad libitum.

All experiments were carried out by an observer blind to drug treatments.

Development of diabetes in the rat

Diabetes was induced in rats by a single i.p. injection of streptozocin (50 mg/kg) as described previously (Courteix et al., 1993). : Evaluation of static allodynia

Mechanical hypersensitivity was measured using Semmes-Weinstein von Frey hairs (Stoelting, lllinois, U.S.A.). Animals were placed into wire mesh bottom cages allowing access to the underside of their paws. Animals were habituated to this environment prior to the start of the experiment. Mechanical = hypersensitivity was tested by touching the plantar surface of the animals right hind paw with von Frey hairs in ascending order of force ( 0.7, 1.2, 1.5, 2, 3.6, 5.5, 8.5, 11.8, 15.1 and 29g) for up to 6 sec. Once a withdrawal response was established, the paw was re-tested, starting with the next descending von

Frey hair until no response occurred. The highest force of 29 g lifted the paw as well as eliciting a response, thus represented the cut off point. The lowest amount of force required to elicit a response was recorded as the paw withdrawal threshold (PWT) in grams.

Drugs

PD 198306 [N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide] and CI-1008 (pregabalin) were synthesized at

Parke-Davis (Ann Arbor, MI, USA). PD 198306 was suspended in

S cremophor:ethanol:water (1:1:8) vehicle. Pregabalin was dissolved in water.

Both compounds were administered orally. Streptozocin (Aldrich, UK) was dissolved in 0.9% w/v NaCl and administered intraperitoneally. Drug administrations were made in a volume of 1 ml/kg.

Statistics

The static allodynia data were analysed using a Kruskall-Wallis ANOVA for non-parametric results, followed when significant by Mann-Whitney’s t test.

Experimental protocol

Static allodynia was assessed with von Frey hairs, before (baseline,

BL) and 1h after oral administration of PD 198306 (30mg/kg, p.0.), vehicle (cremophor:ethanol:water, 1:1:8) or pregabalin (30mg/kg, p.o.) (test).

Animals were administered again the same compounds on the following day, both in the morning and the afternoon. Static allodynia was assessed only before and 1h after the afternoon administration, in order to minimise the habituation of the animals to the testing conditions. Animals treated with pregabalin received water in the morning administration, in order to avoid the potential development of tolerance to the compound with repeated administration.

Day 1: Day 2: a.m... PD 198306

Water

Vehicle p.m.: BL p.m.: BL

PD 198306 PD 198306

PCT/US00/18347 (

Pregabalin Pregabalin

Vehicle Vehicle

Test " Test

RESULTS

A single administration of pregabalin (30mg/kg, p.o.) significantly blocked streptozocin-induced static allodynia 1h after administration. In contrast, a single administration of PD 198306 (30mg/kg, p.o) had no effect on oo streptozocin-induced static allodynia 1h after administration (see below).

However, after the compound had been administered twice more on the ] following day, it significantly blocked streptozocin-induced static allodynia 1h oo after the third administration. The effects had disappeared by the following day (see FIG. 1). 15 . EXAMPLE 2 : a MATERIALS AND METHODS )

Animals oo Male Sprague Dawley rats (250-300g), obtained from Charles River, oo : Margate, U.K.) were housed in groups of 3-6. All animals were kept under a <20 12h light/dark cycle (lights on at 07h 00min) with food and water ad libitum. All experiments were carried out by an observer blind to drug treatments.

Development of Chronic Constriction Injury in the rat

Animals were anaesthetised with 2% isoflurane 1:4 O2/N,0 mixture maintained during surgery via a nose cone. The sciatic nerve was ligated as previously described by Bennett and Xie, 1988. Animals were placed on a homeothermic blanket for the duration of the procedure. After surgical preparation the common sciatic nerve was exposed at the middie of the thigh by blunt dissection through biceps femoris. Proximal to the sciatic trifurcation, about 7mm of nerve was freed of adhering tissue and 4 ligatures (4-0 silk) 48

AMENDED SHEET were tied loosely around it with about 1mm spacing. The incision was closed in layers and the wound treated with topical antibiotics.

Intrathecal injections

PD 198306 and pregabalin were administered intrathecally in a volume of 10 pl using a 100 pl Hamilton syringe by exposing the spine of the rats under brief isoflurane anaesthesia. Injections were made into the intrathecal space between lumbar region 5-6 with a 10 mm long 27 gauge needle. Penetrations were judged successful if there was a tail flick response. The wound was sealed with an autoclip and rats appeared fully awake within 2-3 min following injection.

Evaluation of static allodynia

Mechanical hypersensitivity was measured using Semmes-Weinstein von Frey hairs (Stoelting, Illinois, U.S.A.). Animals were placed into wire mesh bottom cages allowing access to the underside of their paws. Animals were habituated to this environment prior to the start of the experiment. Mechanical hypersensitivity was tested by touching the plantar surface of the animals right hind paw with von Frey hairs in ascending order of force ( 0.7, 1.2, 1.5, 2, 3.6, 5.5, 8.5, 11.8, 15.1 and 29g) for up to 6sec. Once a withdrawal response was established, the paw was re-tested, starting with the next descending von

Frey hair until no response occurred. The highest force of 29g lifted the paw as well as eliciting a response, thus represented the cut off point. The lowest amount of force required to elicit a response was recorded as the paw withdrawal threshold (PWT) in grams.

Experimental protocol

Static allodynia was assessed with von Frey hairs, before (baseline,

BL) and 0.5h, 1h and 2h after intrathecal or intraplantar administration of PD 198306 (1-30ug, i.t.), vehicle (cremophor.ethanol:water, 1:1:8) or pregabalin (10ug, it). For oral administration experiments, static allodynia was assessed with von Frey hairs, before (baseline, BL) and 1h after oral administration of

PD 198306 (3-30mg/kg, p.o.), vehicle (cremophor:ethanol:water, 1:1:8) or pregabalin (30mg/kg, p.o.). Animals were administered again the same compounds on the following day, both in the morning and the afternoon. Static allodynia was assessed before and 1h after the morning administration. In the afternoon static allodynia was assessed before, 1h, 2h and 3h after administration for streptozocin treated animals. CCl animals were assessed before, 1h and 2h after administration

Drugs used

PD 198306 and pregabalin were synthesised at Parke-Davis (Ann

Arbor, MI, USA). PD 198306 was suspended in cremophor:ethanol:water (1:1:8) vehicle. Pregabalin was dissolved in water. Both compounds were administered orally, intrathecally or intraplantar in volumes of 1mi/kg, 10ul and 100i respectively. Streptozocin (Aldrich, UK) was dissolved in 0.9% w/v NaCl and administered intraperitoneally in a volume of 1ml/kg.

Statistics : . Data were analysed using a Kruskall-Wallis ANOVA for non-parametric - ’ results, followed when significant by Mann-Whitney's t test vs vehicle group. ‘ RESULTS 1. Effects of PD 198306 on static allodynia, following systemic . . . administration - i 1.1. Effect of PD198306 on streptozocin-induced static allodynia

A single administration of pregabalin (30mg/kg, p.o.) significantly blocked streptozocin-induced static allodynia 1h after administration. In contrast, a single administration of PD 198306 (3-30mg/kg, p.o) had no effect on streptozocin-induced static allodynia 1h after administration (FIG. 2).

However, after the compound had been administered twice more on the following day, PD 198306 (30mg/kg) significantly blocked streptozocin- induced static allodynia for 2h after the third administration (FIG. 2). 1.2. Effect of PD198306 on CCl-induced static allodynia

A single administration of pregabalin (30mg/kg, p.o.) significantly blocked CCI- induced static allodynia 1h after administration. in contrast, neither a single or multiple administration of PD 198306 (3-30mg/kg, p.o) had any effect on CCI- . induced static allodynia (FIG. 3). 2. Effects of PD 198306 on static allodynia, following intrathecal administration

Intrathecally administered PD198306 (1-30pg) dose-dependently blocked the maintenance of static allodynia in both streptozocin (FIG. 4) and CCl animals (FIG. 5) with respective MEDs of 3 and 10 ug. This antiallodynic effect lasted for 1h. 3. Effects of PD 198306 on static allodynia, following intraplantar administration

An intrathecal administration of PD 198306 (30ug) significantly blocked static allodynia in both neuropathic pain models (FIGS. 6,7). In contrast, a single - administration of PD 198306 at a dose 100-fold higher (3mg/100pl) directly . into the paw had no effect on streptozocin (FIG. 6) or CCl-induced static allodynia (FIG. 7).

REFERENCES

Bennett GJ, Xie Y-K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33:87-107. :

Courteix C, Eschalier A and Lavarenne J. Streptozocin —induced rats: behavioural evidence for a model of chronic pain. Pain 1993;53:81-8

EXAMPLE 3

Effect of other MEK inhibitors in a neuropathic pain model in the rat

SUMMARY

The effect of several MEK inhibitors, with different binding affinities, has been investigated in the CCl model of neuropathic pain in the rat, by assessing static allodynia with von Frey hairs. Intrathecal administration of PD219622 or

PD297447 (30ug) had no significant effect on allodynia. This lack of effect

Co . WO 01/05392 PCT/USO0/18347 may reflect the low affinity or solubility of the compounds. However, intrathecal administration of PD 254552 or PD 184352 (30ug), which posses higher binding affinities, blocked the maintenance of static allodynia in CCl animals. The antiallodynic effect was only evident for 30min post-injection and thus, shorter than the one observed for pregabalin (100ng). The magnitude of the effect was similar for 30ug of PD 184352 and 100ug of pregabalin. From this study it is concluded that MEK inhibitors exert an antiallodynic effect in

CCl-induced neuropathic rats when administered intrathecally, and that the antiallodynic effect correlates with the affinity of the compounds.

The animals and methods for developing chronic constriction injury in the rat, injecting test compounds, and evaluation of static allodynia were according to Example 2 above. PD219622, PD297447, PD 184352, PD 254552 and pregabalin were administered intrathecally at doses of 30 g for all

PD compounds and 100ug for pregabalin. Static allodynia was assessed with : E von Frey hairs, before (baseline, BL) and 0.5h, 1h and 2h after intrathecal administration of the compounds

Drugs used

PD297447, PD219622, PD 254552, PD 184352 (CI-1040), and pregabalin were synthesised at Parke-Davis (Ann Arbor, MI, USA). PD297447,

PD219622, PD 254552 and PD 184352 were suspended in cremophor:ethanol:water (1:1:8) vehicle. Pregabalin was dissolved in water. All compounds were administered intrathecally in a 10pl volume.

Statistics

Data were analysed using a Kruskall-Wallis ANOVA for non-parametric results, followed when significant by Mann-Whitney’s t test vs vehicle group.

RESULTS

Intrathecally administered PD297447 or PD219622 (30ug) had no significant effect on allodynia. This lack of effect may reflect the low affinity of the compounds (965nM and 100nM respectively). However, intrathecal administration of PD 184352 or PD 254552 (30ug) blocked the maintenance of static allodynia in CCl animals (see FIG. 8). These compounds possess higher affinity (2 and 5 nM respectively). The antiallodynic effect was only evident for 30min post-injection and thus, shorter than the one observed for pregabalin (100ug). The magnitude of the effect was similar for 30ug of PD 184352 and 100ug of pregabalin.

The results indicate that MEK inhibitors exert an antiallodynic effect in

CHEMICAL EXAMPLES

EXAMPLE 1 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide (@) Preparation of 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid

To a stirred solution containing 3.16 g (0.0133 mol) of 2-amino- 5-iodotoluene in 5 mL of tetrahydrofuran at -78°C was added 10 mL (0.020 mol) of a 2.0 M lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (Aldrich) solution. The resulting green suspension was stirred vigorously for 15 minutes, after which time a solution of 1.00 g (0.00632 mol) of 2,4-difluorobenzoic acid in 10 mL of tetrahydrofuran was added. The reaction temperature was allowed to increase slowly to room temperature, at which temperature the mixture was stirred for 2 days. The reaction mixture was concentrated by evaporation of the solvent under reduced pressure. Aqueous HCI (10%) was added to the concentrate, and the solution was extracted with dichloromethane. The organic phase was dried (MgSQOg4) and then concentrated over a steambath to low volume (10 mL) and - cooled to room temperature. The off-white fibers which formed were collected by vacuum filtration, rinsed with hexane, and dried in a vacuum-oven (76°C;

To ca. 10 mm of Hg) to afford 1.10 g (47%) of the desired material, mp 224-229.5°C; : 1H NMR (400 MHz, DMSO): 8 9.72 (s, 1H), 7.97 (dd, 1H, J=7.0, 8.7 Hz), 7.70 (d, 1H, J=1.5 Hz), 7.57 (dd, 1H, J=8.4, 1.9 Hz), 7.17 (d, 1H, J=8.2 Hz), 6.61-6.53 (m, 2H), 2.18 (s, 3H); 13C NMR (100 MHz, DMSO): § 169.87, 166.36 (d, Jo.F=249.4 Hz), 150.11 (d, Jo-F=11.4 Hz), 139.83, 138.49, 136.07, 135.26 (d, J;-F=11.5 Hz), 135.07, 125.60, 109.32, 104.98 (d, Jc.F=21.1 Hz), 99.54 (d, Jc-F=26.0 Hz), 89.43, 17.52; 19F NMR (376 MHz, DMSO): 3 -104.00 to -104.07 (m);

IR (KBr) 1670 (C=0 stretch)cm-1:

MS (Cl) M+1 = 372.

Analysis calculated for C14H11FINO2:

C, 45.31; H, 2.99; N, 3.77.

Found: C, 45.21; H, 2.77; N, 3.64. (b) Preparation of 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide

To a stirred solution of 4-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzoic acid (0.6495 g, 0.001750 mol), O-(tetrahydro-2H-pyran-2-yl)- hydroxylamine (0.2590 g, 0.002211 mol), and diisopropylethylamine (0.40 mL, 0.0023 mol) in 31 mL of an equivolume tetrahydrofuran-dichloromethane solution was added 1.18 g (0.00227 mol) of solid PyBOP ([benzotriazolyloxyltripyrrolidino phosphonium hexafluorophosphate,

Advanced ChemTech) directly. The reaction mixture was stirred for 30 minutes after which time it was concentrated in vacuo. The brown oil was treated with 10% aqueous hydrochloric acid. The suspension was extracted with ether. The organic extraction was washed with 10% sodium hydroxide followed by another 10% hydrochloric acid wash, was dried (MgSQO4) and concentrated in vacuo to afford 1.0 g of a light-brown foam. This intermediate was dissolved in 25 mL of ethanolic hydrogen chloride, and the solution was . allowed to stand at room temperature for 15 minutes. The reaction mixture was concentrated in vacuo to a brown oil that was purified by flash silica . chromatography. Elution with dichloromethane — dichloromethane-methanol (166:1) afforded 0.2284 g of a light-brown viscous oil. Scratching with pentane-hexanes and drying under high vacuum afforded 0.1541 g (23%) of an off-white foam; mp 61-75°C;

TH NMR (400 MHz, DMSO): 8 11.34 (s, 1H), 9.68 (s, 1H), 9.18 (s, 1H), 7.65 (d, 1H, J=1.5 Hz), 7.58 (dd, 1H, J=8.7, 6.8 Hz), 7.52 (dd, 1H, J=8.4, 1.9 Hz), 7.15 (d, 1H, J=8.4 Hz), 6.74 (dd, 1H, J=11.8, 2.4 Hz), 6.62 (ddd, 1H,

J=8.4, 8.4, 2.7 Hz), 2.18 (s, 3H); 13C NMR (100 MHz, DMSO): 3 165.91, 164.36 (d, Jo_F=247.1 Hz), 146.78, 139.18, 138.77, 135.43, 132.64, 130.60 (d, Jc.F=11.5 Hz), 122.23, 112.52, 104.72 (d, J=22.1 Hz), 100.45 (d, Jc.F=25.2 Hz), 86.77, 17.03;

oo ) WO 01/05392 PCT/USO0/18347 19F NMR (376 MHz, DMSO): 8 -107.20 to -107.27 (m);

IR (KBr) 3307 (broad, O-H stretch), 1636 (C=0 stretch) cm-1;

MS (CI) M+1 = 387.

Analysis calculated for C14H{2FIN202:

C,43.54; H, 3.13; N, 7.25.

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

EXAMPLE 2 8-BRromo-3,4-difluoro-N-hvdroxy-2-(4-iodo-2-methyl-phenvlamino)- benzamide (a) Preparation of 5-Bromo-2,3,4-trifluorobenzoic acid

To a stirred solution comprised of 1-bromo-2,3,4-trifluorobenzene (Aldrich, 99%; 5.30 g, 0.0249 mol) in 95 mL of anhydrous tetrahydrofuran cooled to -78°C was slowly added 12.5 mL of 2.0 M lithium diisopropylamide in heptaneftetrahydrofuran/ethylbenzene solution (Aldrich). The mixture was © 15 stirred for 1 hour and transferred by canula into 700 mL of a stirred saturated ethereal carbon dioxide solution cooled to -78°C. The cold bath was removed, and the reaction mixture was stirred for 18 hours at ambient temperature. ’ Dilute (10%) aqueous hydrochloric acid (ca. 500 mL) was poured into the reaction mixture, and the mixture was subsequently concentrated on a rotary ’ 20 evaporator to a crude solid. The solid product was partitioned between diethyl - ether (150 mL) and aq. HCI (330 mL, pH 0). The aqueous phase was extracted with a second portion (100 mL) of diethyl ether, and the combined ethereal extracts were washed with 5% aqueous sodium hydroxide (200 mL) and water (100 mL, pH 12). These combined alkaline aqueous extractions were acidified to pH 0 with concentrated aqueous hydrochloric acid. The resulting suspension was extracted with ether (2 x 200 mL). The combined organic extracts were dried (MgSO4), concentrated in vacuo, and subjected to high vacuum until constant mass was achieved to afford 5.60 g (88% yield) of an off-white powder; mp 139-142.5°C;

TH NMR (400 MHz, DMSO): & 13.97 (broad s, 1H, 8.00-7.96 (m, 1H);

13C NMR (100 MHz, DMSO): 5 162.96, 129.34, 118.47, 104.54 (d,

Je-F=22.9 Hz); 19F NMR (376 MHz, DMSO): 5 -120.20 to -120.31 (m), -131.75 to -131.86 (m), -154.95 to -155.07 (m);

IR (KBr) 1696 (C=0 stretch)cm-1;

MS (Cl) M+1 = 255.

Analysis calculated for C74H21BrF302:

C, 32.97; H, 0.79; N, 0.00; Br, 31.34; F, 22.35.

Found: C, 33.18; H, 0.64; N, 0.01; Br, 30.14; F, 22.75. (b) Preparation of 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- phenylamino)-benzoic acid

To a stirred solution comprised of 1.88 g (0.00791 mol) of 2-amino- 5-iodotoluene in 10 mL of tetrahydrofuran at -78°C was added 6 mL (0.012 mol) of a 2.0 M lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (Aldrich) solution. The resulting green suspension was stirred vigorously for 10 minutes, after which time a solution of 1.00 g (0.00392 mol) of 5-bromo-2,3,4-trifluorobenzoic acid in 15 mL of tetrahydrofuran was added. The cold bath was subsequently removed, and the reaction mixture stirred for 18 hours. The mixture was concentrated, and the concentrate was treated with 100 mL of dilute (10%) aqueous hydrochloric acid. The resulting suspension was extracted with ether (2 x 150 mL), and the combined organic extractions were dried (MgSO4) and concentrated in vacuo to give an orange solid. The solid was triturated with boiling dichloromethane, cooled to ambient temperature, and collected by filtration. The solid was rinsed with dichloromethane, and dried in the vacuum-oven (80°C) to afford 1.39 g (76%) of a yellow-green powder; mp 259.5-262°C;

TH NMR (400 MHz, DMSO): 59.03 (s, 1H), 7.99 (dd, 1H, J=7.5, 1.9 Hz), 7.57 (dd, 1H, J=1.5 Hz), 7.42 (dd, 1H, J=8.4, 1.9 Hz), 6.70 (dd, 1H, J=8.4, 6.0 Hz), 2.24 (s, 3H); 19F NMR (376 MHz, DMSO): 6 -123.40 to -123.47 (m); -139.00 to -139.14 (m):

IR (KBr) 1667 (C=0 stretch)em-1;

MS (Cl) M+1 = 469.

Analysis calculated for C14HgBrF2INO>:

C, 35.93; H, 1.94; N, 2.99; Br, 17.07; F, 8.12; |, 27.11.

Found: C, 36.15; H, 1.91; N, 2.70; Br, 16.40; F, 8.46; |, 26.05. (c) Preparation of 5-Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide

To a stirred solution comprised of 5-brome-3 4-diflucro-2-(4-icde- 2-methyl-phenylamino)-benzoic acid (0.51 g, 0.0011 mol), O-(tetrahydro-2H- pyran-2-yl)-hydroxylamine (0.15 g, 0.0013 mol), and diisopropylethylamine (0.25 mL, 0.0014 mol) in 20 mL of an equivolume tetrahydrofuran- dichloromethane solution was added 0.6794 g (0.001306 mol) of solid PyBOP (Advanced ChemTech) directly. The reaction mixture was stirred at 24°C for 10 minutes, and then was concentrated to dryness in vacuo. The concentrate was suspended in 100 mL of 10% aqueous hydrochloric acid. The suspension was extracted with 125 mL of diethyl ether. The ether layer was separated, washed with 75 mL of 10% aqueous sodium hydroxide, and then with 100 mL of dilute acid. The ether solution was dried (MgSQO4) and concentrated in vacuo to afford 0.62 g (100%) of an off-white foam. The foam was dissolved in ca. 15 mL of methanolic hydrogen chloride. After 5 minutes, the solution was concentrated in vacuo to an oil, and the oil was purified by flash silica chromatography. Elution with dichloromethane — dichloromethane-methanol (99:1) afforded 0.2233 g (42%) of a yellow powder. The powder was dissolved in diethyl ether and washed with dilute hydrochloric acid. The organic phase was dried (MgSOg4) and concentrated in vacuo to afford 0.200 g of a foam.

This product was triturated with pentane to afford 0.1525 g of a powder that was repurified by flash silica chromatography. Elution with dichloromethane afforded 0.0783 g (15%) of an analytically pure title compound, mp 80-90°C;

TH NMR (400 MHz, DMSO): 8 11.53 (s, 1H), 9.38 (s, 1H), 8.82 (s, 1H), 7.70 (dd, 1H, J=7.0, 1.9 Hz), 7.53 (s, 1H), 7.37 (dd, 1H, J=8.4, 1.9 Hz), 6.55 (dd, 1H, J=8.2, 6.5 Hz), 2.22 (s, 3H);

19F NMR (376 MHz, DMSO): 5 -126.24 to -126.29 (m), -137.71 to -137.77 (m);

IR (KBr) 3346 (broad, O-H stretch), 1651 (C=O stretch)em-1;

MS (Cl) M+1 = 484.

Analysis calculated for C14H1gBrF2IN2O2:

C, 34.81; H, 2.09; N, 5.80.

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

Examples 3 to 12 and 78 to 102 in the table below were prepared by the general procedures of Examples 1 and 2.

EXAMPLES 13-77

Examples 13 to 77 were prepared utilizing combinatorial synthetic methodology by reacting appropriately substituted phenylamino benzoic acids

Re (e.g., as shown in Scheme 1) and hydroxylamines (e.g., HN-O-R7) A general method is given below:

To a 0.8 mL autosampler vial in a metal block was added 40 pL of a 0.5 M solution of the acid in DMF and 40 pL of the hydroxylamine (2 M ) solution in Hunig’s base and 1 M in amine in DMF). A 0.5 M solution of

PyBrop was freshly prepared, and 50 uL were added to the autosampler vial.

The reaction was allowed to stand for 24 hours.

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

The residue was taken up in 2 mL of 50% acetonitrile in water and injected on a semi-prep reversed phase column (10 mm x 25 cm, 5 pM spherical silica, pore Size 115 A derivatised with C-18, the sample was eluted at4.7 mL/min with a linear ramp to 100% acetonitrile over 8.5 minutes. Elution with 100% acetonitrile continued for 8 minutes.) Fractions were collected by monitoring at 214 nM. The desired fractions were evaporated using a Zymark

Co i} WO 01/05392 PCT/US00/18347

Turbovap. The product was dissolved in chloroform and transferred to a preweighed vial, evaporated, and weighed again to determine the yield. The structure was confirmed by mass spectroscopy.

EXAMPLES 3-102

Example Compound Melting MS

No. Point (°C) (M-H*) 3 2-(4-bromo-2-methyl-phenylamino)-4-fluoro- 56-75 dec 523

N-hydroxy-benzamide 4 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl- 65 dec phenylamino)-benzamide 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl- 62-67 phenylamino)-N-methyl-benzamide 6 5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 105-108 . N-(terahydropyran-2-yloxy)benzamide } 7 5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 64-68

N-methoxybenzamide 8 4-Fluoro-N-hydroxy-2-(4-fluoro-2-methyl- 119-135 phenylamino)-benzamide 9 4-Fluoro-N-hydroxy-2-(2-methyl 101-103 phenylamino)-benzamide 4-Fluoro-2-(4-fluor-2-methyl-phenylamino)- 142-146

N-(terahydropyran-2-yloxy)benzamide

Example Compound Melting MS

No. Point (°C) (M-H+) 11 4-Fluoro-N-hydroxy-2-(4-cluoro-2-methyi- 133.5-135 phenylamino)-benzamide 12 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 107-109.5

N-phenylmethoxy-benzamide 13 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 399

N-methoxy-benzamide 14 3,4-Difluoro-2-(4-iodo-2-methyl- 417 phenylamino)-N-methoxy-benzamide 2-(4-Bromo-2-methyl-phenylamino)- 369 3,4-difluoro-N-methoxy-benzamide 16 2-(4-Bromo-2-methyl-phenylamino)-N- 342* ethoxy-3,4-difluoro-benzamide (M-EtO) ) 17 5-Bromo-N-ethoxy-3,4-difluoro-2-(4-iodo- 509 : 2-methyl-phenylamino)-benzamide 18 3,4-Difluoro-2-(4-iodo-2-methyl- 445 phenylamino)-N-isopropoxy-benzamide 19 2-(4-Bromo-2-methyl-phenylamino)- 397 3,4-difluoro-N-isopropoxy-benzamide 4-Fluoro-N-(furan-3-ylmethoxy)-2-(4-iodo- 465 2-methyl-phenylamino)-benzamide

Example Compound Melting MS

No. Point (°C) (M-H+) 21 3,4-Difluoro-N-(furan-3-ylmethoxy)- 483 2-(4-iodo-2-methyl-phenylamino)-benzamide 22 2-(4-Bromo-2-methyl-phenylamino)- 435 3,4-difluoro-N-(furan-3-ylmethoxy)- : benzamide 23 5-Bromo-3,4-difluoro-N-(furan-3-ylmethoxy)- 561 2-(4-iodo-2-methyl-phenylamino)-benzamide 24 5-Bromo-N-(but-2-enyloxy)-3,4-difluoro- 536 2-(4-iodo-2-methyl-phenylamino)-benzamide 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 423

N-(prop-2-ynyloxy)-benzamide 26 3,4-Difluoro-2-(4-iodo-2-methyl- 441 phenylamino)-N-(prop-2-ynyloxy)- ‘ benzamide 27 3,4-Difluoro-2-(4-iodo-2-methyl- 455 phenylamino)-N-(1-methyl-prop-2-ynyloxy)- benzamide 28 2-(4-Bromo-2-methyl-phenylamino)- 407 3,4-difluoro-N-(1-methyl-prop-2-ynyloxy)- benzamide 29 N-(But-3-ynyloxy)-3,4-difluoro-2-(4-iodo- 455 2-methyl-phenylamino)-benzamide

Example Compound Melting MS

No. Point (°C) (M-H+) 2-(4-Bromo-2-methyl-phenylamino)-N-(but- 407 3-ynyloxy)-3,4-difluoro-benzamide 31 5-Bromo-N-(but-3-ynyloxy)-3,4-difluoro- 533 2-(4-iodo-2-methyl-phenylamino)-benzamide 32 3,4-Difluoro-2-(4-iodo-2-methyl- 517 phenylamino)-N-(3-phenyl-prop-2-ynyloxy)- benzamide 33 3,4-Difluoro-2-(4-bromo-2-methyl- 469 phenylamino)-N-(3-phenyl-prop-2-ynyloxy)- benzamide 34 3,4-Difluoro-N-[3-(3-fluoro-phenyl)-prop- 535 2-ynyloxy]-2-(4-iodo-2-methyl-phenylamino)- benzamide ) 2-(4-Bromo-2-methyl-phenylamino)- 487 3,4-difluoro-N-{3-(3-fluoro-phenyt)-prop- 2-ynyloxyl-benzamide 36 3,4-Difluoro-N-[3-(2-fluoro-phenyl)-prop- 535 2-ynyloxy]-2-(4-iodo-2-methyl-phenylamino)- benzamide 37 5-Bromo-3,4-difluoro-N-[3-(2-fluoro-phenyl)- 613 prop-2-ynyloxyl-2-(4-iodo-2-methyl- phenylamino)-benzamide oo } WO 01/05392 PCT/US00/18347

Example Compound Melting MS

No. Point (°C) (M-H+) 39 2-(4-Bromo-2-methyl-phenylamino)- 510 3,4-difluoro-N-(3-methyl-5-phenyl-pent-2-en- 4-ynyloxy)-benzamide 40 N-Ethoxy-3,4-difluoro-2-(4-iodo-2-methyl- 431 phenylamino)-benzamide 41 2-(4-Bromo-2-methyi-phenylamino)-N- 383 ethoxy-3,4-difluoro-benzamide 42 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 427

N-propoxy-benzamide 43 3,4-Difluoro-2-(4-iodo-2-methyl- 445 g phenylamino)-N-propoxy-benzamide ) 44 2-(4-Bromo-2-methyl-phenylamino)- 397 3,4-difluoro-N-propoxy-benzamide : 45 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 523 phenylamino)-N-propoxy-benzamide 46 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 427

N-isopropoxy-benzamide 47 3,4-Difluoro-2-(4-iodo-2-methyl- 445 phenylamino)-N-isopropoxy-benzamide 48 2-(4-Bromo-2-methyl-phenylamino)- 397 3,4-difluoro-N-isopropoxy-benzamide

Example Compound Melting MS

No. Point (°C) (M-H+) 49 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 523 phenylamino)-N-isopropoxy-benzamide 50 N-Cyclobutyloxy-3,4-difluoro-2-(4-iodo- 457 2-methyl-phenylamino)-benzamide 51 2-(4-Bromo-2-methyl-phenylamino)-N- 409 cyclobutyloxy-3,4-difluoro-benzamide 52 N-Cyclopentyloxy-4-fluoro-2-(4-iodo- 453 2-methyl-phenylamino)-benzamide 53 N-Cyclopentyloxy-3,4-difluoro-2-(4-iodo- 471 2-methyl-phenylamino)-benzamide 54 2-(4-Bromo-2-methyl-phenylamino)-N- 423 cyclopentyloxy-3,4-difluoro-benzamide 55 N-Cyclopropylmethoxy-4-fluoro-2-(4-iodo- 439 . 2-methyl-phenylamino)-benzamide 56 N-Cyclopropylmethoxy-3,4-difluoro- 457 2-(4-iodo-2-methyl-phenylamino)-benzamide 57 2-(4-Bromo-2-methyl-phenylamino)-N- 409 cyclopropylmethoxy-3,4-difluoro-benzamide 58 5-Bromo-N-cyclopropylmethoxy-3,4-difluoro- 435 2-(4-iodo-2-methyl-phenylamino)

Example Compound Melting MS

No. Point (°C) (M-H+) 59 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 505

N-(2-phenoxy-ethoxy)-benzamide 60 3.4-Difluoro-2-(4-iodo-2-methyl- 523 phenylamino)-N-(2-phenoxy-ethoxy)- obenzamide 61 2-(4-Bromo-2-methyl-phenylamino)- 475 3,4-difluoro-N-(2-phenoxy-ethoxy)- benzamide 62 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 481 . N-(thiophen-2-yimethoxy)-benzamide 63 3,4-Difluoro-2-(4-iodo-2-methyl- 499 ) phenylamino)-N-(thiophen-2-yimethoxy)- benzamide

E 64 2-(4-Bromo-2-methyl-phenylamino)- 451 3,4-difluoro-N-(thiophen-2-ylmethoxy)- benzamide 65 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 439

N-(2-methyl-allyloxy)-benzamide 66 3,4-Difluoro-2-(4-iodo-2-methyl- : 457 phenylamino)-N-(2-methyl-allyloxy)- benzamide

Example Compound Melting MS

No. Point (°C) (M-H+) 67 2-(4-Bromo-2-methyl-phenylamino)- 410 3,4-difluoro-N-(2-methyl-allyloxy)-benzamide 68 N-(But-2-enyloxy)-4-fluoro-2-(4-iodo- 438 2-methyl-phenylamino)-benzamide 69 N-(But-2-enyloxy)-3,4-difluoro-2-(4-iodo- 457 2-methyl-phenylamino)-benzamide 70 2-(4-Bromo-2-methyl-phenylamino)-N-(but- 410 2-enyloxy)-3,4-difluoro-benzamide 71 3,4-Difluoro-2-(4-iodo-2-methyl- 441 phenylamino)-N-(prop-2-ynyloxy)- benzamide 72 N-(But-3-ynyloxy)-3,4-difluoro-2-(4-iodo- 455 ) 2-methyl-phenylamino)-benzamide 73 2-(4-Bromo-2-methyl-phenylamino)-N- 449 (4,4-dimethyl-pent-2-ynyloxy)-3,4-difluoro- benzamide 74 N-(But-2-enyloxy)-3,4-difluoro-2-(4-iodo- 457 2-methyl-phenylamino)-benzamide 75 2-(4-Bromo-2-methyl-phenylamino)-N-(but- 410 2-enyloxy)-3,4-difluoro-benzamide

Example Compound Melting MS

No. Point (°C) (M-H+) 76 N-(3-tert.-butyl-propyn-2-yl)oxy-4-fluoro- 479 2-(4-iodo-2-methyl-phenylamino)-benzamide 77 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 577*

N-phenylmethoxy-benzamide *Cl 78 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl- oil phenylamino)-N-isopropyl-benzamide 79 N-Cyclopropyimethoxy-3,4,5-trifluoro-2-(4- 125-127 iodo-2-methyl-phenylamino)-benzamide 80 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyi- 45-55 phenylamino)-N-methyl-benzamide ) 81 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl- 208-209 phenylamino)-5-nitro-benzamide (GLASS) : 82 2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy- 199-200 4-pitro-benzamide 83 3,4-Difluoro-2-(4-iodo-2-methyl- 163-165 phenylamino)-N-(tetrahydro-pyran-2-yloxy)- benzamide 84 3,4-Difluoro-N-hydroxy-2-(4-iodo-2-methyl- 65-75 phenylamino)-benzamide

Example Compound Melting MS

No. Point (°C) (M-H+) 85 3,4-Difluoro-5-bromo-2-(4-iodo-2-methyl- 95 phenylamino)-N-(2-piperidin-1-yl-ethoxy)- benzamide 86 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 167-169 phenylamino)-N-(tetrahydro-pyran-2-yloxy)- benzamide 87 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N- 165-169 hydroxy-benzamide (HCI salt) 88 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N- 166-167.5 (tetrahydro-pyran-2-yloxy)-benzamide 89 3,4-Difluoro-2-(2-chioro-4-iodo- 173-174 phenylamino)-N-cyclobutylmethoxy- benzamide : 90 3,4-Difluoro-2-(2-chloro-4-iodo- 121-122 - phenylamino)-N-(tetrahydro-pyran-2-yloxy)- benzamide 91 5-Bromo-2-(2-chloro4-iodo-phenylamino)- 206-211.5

N-(2-dimethylamino-ethoxy)-3,4-difluoro- DEC benzamide monohydrochloride salt 92 5-Bromo-N-(2-dimethylamino-propoxy)-3,4- 95-105 difluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide

Example Compound Melting MS

No. Point (°C) (M-H+) 93 5-Bromo-2-(2-chloro-4-iodo-phenylamino)- 266-280 3,4-difluoro-N-hydroxy-benzamide DEC 94 5-Bromo-2-(2-chloro-4-iodo-phenylamino)- 167.5-169.5 3,4-difluoro-N-(tetrahydro-pyran-2-yloxy)- benzamide a5 3,4-Difluoro-2-(2-chloro-4-iodo- 172.5-173.5 phenylamino)-N-cyclopropylmethoxy- benzamide 96 5-Bromo-2-(2-chloro4-iodo-phenylamino)- 171-172.5

N-cyclopropylmethoxy-3,4-difluoro- . benzamide ) 97 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 173.5-175 : phenylamino)-N-(2-morpholin-4-yl-ethoxy)- : benzamide 98 5-Bromo-N-(2-diethylamino-ethoxy)-3,4- 81 DEC difluoro-(4-iodo-2-methyl-phenylamino)- benzamide 99 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 126-128 phenylamino)-N-isobutoxy-benzamide 100 5-Bromo-N-cyclohexylmethoxy-3,4-difluoro- ~~ 139-142 2-(4-iodo-2-methyl-phenylamino)-benzamide

Example Compound Melting MS

No. Point (°C) (M-H+) "101 5-Bromo-N-cyclopentylmethoxy-3,4-difluoro- 113-115 2-(4-iodo-2-methyl-phenylamino)-benzamide 102 5-Bromo-N-cyclobuty!lmethoxy-3,4-difluoro- ~~ 138-139 2-(4-iodo-2-methyl-phenylamino)-benzamide

The invention compounds are useful in treating chronic pain proliferative diseases by virtue of their selective inhibition of the dual specificity protein kinases MEK4 and MEK2. The invention compound has been evaluated in a number of biological assays which are normally utilized to

S establish inhibition of proteins and kinases, and to measure mitogenic and metabolic responses to such inhibition.

EXAMPLE 1A 4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid

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

The reaction mixture was concentrated. Aqueous HCI (10%) was added to the concentrate, and the solution was extracted with dichloromethane. The organic phase was dried (MgSO4) and then boiled over a steambath to low volume and cooled to room temperature. The off-white fibers were collected by vacuum filtration, rinsed with hexanes, and vacuum-oven dried. (76°C; ca. 10 mm of Hg) to afford 1.10 g (47%) of the desired material; mp 224-229.5°C;

1H NMR (400 MHz; DMSO): 8 9.72 (s, 1H), 7.97 (dd, 1H, J = 7.0, 8.7 Hz), 7.70 (d, 1H, J = 1.5 Hz), 7.57 (dd, 1H, J = 8.4, 1.9 Hz), 7.17 (d, 1H,

J = 8.2 Hz), 6.61-6.53 (m, 2H), 2.18 (s, 3H); 13C NMR (100 MHz; DMSO): § 169.87, 167.60, 165.12, 150.17, 150.05, 139.83, 138.49, 136.07, 135.31, 135.20, 135.07, 125.60, 109.32, 105.09, 104.87, 99.72, 99.46, 89.43, 17.52; 19F NMR (376 MHz; DMSO): § -104.00 to -104.07 (m);

IR (KBr) 1670 (C = O stretch) cm-1;

MS (Cl) M+1 = 372.

Analysis calculated for C14H41FINO2:

C,4531; H,299; N, 3.77.

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

EXAMPLES 2A-30A

By following the general procedure of Example 1A, the following benzoic acids and salts were prepared:

Example Compound MP °C

No. 2A 3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)- 206-210 ; benzoic acid 3A 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)- 240.5-244.5 . benzoic acid 4A 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 259.5-262 phenylaminoc)-benzoic acid :

BA 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-benzoic 255-260 acid ]

BA 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic 234-238 acid

Example Compound MP °C

No.

TA Sodium 5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 310-320 DE benzoate C 8A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic 239.5-240 acid 9A 2-(2-Chloro-4-iodo-phenylamino)-5-nitro-benzoic 289-293 acid 10A 4-Fluoro-2-(3-fluoro-4-iodo-2-methyl-phenylamino)- 233-235 benzoic acid 11A 2-(4-lodo-2-methyl-phenylamino)-5-nitro-benzoic 264-267 acid 12A 2-(2-Fluoro-4-iodo-phenylamino)-5-nitro-benzoic 256-258 acid 13A 2-(4-Bromo-2-methyl-phenylamino)-4-fluoro- 218.5-220 benzoic acid ; 14A 2-(2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic 285-288 DE acid Cc 15A 2-(4-Bromo-2-methyl-phenylamino)-3,4-diflucro- 230-234 benzoic acid 16A 3-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic 218-221 acid 17A 3,4-Difluoro-2-(4-iodo-2-methoxy-phenylamino)- 230-233 benzoic acid

Example Compound MP °C

No. 18A 4-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic 245-255 DE acid C 19A 2-(4-lodo-2-methyl-phenylamino)-benzoic acid 218-223 20A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic 243-46 acid 21A 5-lodo-2-(4-iodo-2-methyl-phenylamino)-benzoic 241-245 acid 26A 2-Fluoro-6-(4-iodo-2-methyl-phenylamino)-benzoic 179-182 acid 27A 4-Fluoro2-(2,3-dimethyl-4-iodo-2-methyl- 258-261 : : phenylamino)-benzoic acid 28A 5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic 209.5-211 , acid 29A 2-Chloro-6-(4-iodo-2-methyl-phenylamino)-benzoic 171-175 acid 30A 2-(4-lodo-2-methyl-phenylamino)-4-nitro-benzoic 251-263 acid

EXAMPLE 31A 5-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide

To a stirring solution comprised of 0.1020 g (0.2632 mmol) of 5-chloro- 2-(4-iodo-2-methyl-phenylamino)-benzoic acid, 0.1 mL (1.7 mmol) of ethanolamine, and 0.05 mL (0.29 mmol) of diisopropylethylamine in 5 mL of a

1:1 (viv) tetrahydrofuran-dichloromethane solution was added 0.15 g (0.29 mmol) of solid PyBOP powder directly. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The crude residue was partitioned between ether (50 mL) and 10% aqueous hydrochloric acid (50 mL). The organic phase was washed with 10% aqueous sodium hydroxide (50 mL), dried (MgSQO4) and concentrated in vacuo to afford a yellow-brown oil which was crystallized from hexanes-ether to afford 0.0831 g (73%) of a green-yellow powder; mp 120-121°C;

TH NMR (400 MHz; CDCI3): § 9.11 (s, 1H); 7.56 (d, 1H, J = 1.4 Hz), 7.46-7.41 (m, 2H), 7.20 (dd, 1H, J = 8.9, 2.4 Hz), 7.00 (t, 2H, J = 9.6 Hz), 6.55 (broad t, 1H), 3.86 (t, 2H, J = 5.0 Hz), 3.61 (dd, 2H, J = 10.1, 5.5 Hz), 2.23 (s, 3H), 1.56 (broad s, 1H);

IR (KBr) 3297 (O-H stretch), 1627 (C = O stretch) cm-1;

MS (Cl) M+1 = 431.

Analysis calculated for C1gH16CIIN202:

C, 4462; H, 3.74; N, 6.50.

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

EXAMPLES 32-48A

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

oo. . WO 01/05392 PCT/USO0/18347 “Example Compound MP°C

No.

T 32A 4-Methoxy-N-(4-methoxy-phenyl)-3-nitro- ~~ 153.5-156 benzamide 33A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 158 benzamide 34A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 102.5-104.5 methyl-benzamide 35A N-Ethyl-4-fluoro-2-(4-iodo-2-methyl- 90-91 phenylamino)-benzamide 36A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N- oil dimethyl-benzamide 37A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 285-288 DE (1H-tetrazol-5-yl)-benzamide C 38A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)- 180-182 benzamide 39A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N- 137-138 dimethyl-benzamide 40A [5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 170-173 } benzoylamino]-acetic acid 41A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 69-71 propyl-benzamide ) 42A 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo- 132-133.4 oo ’ 2-methyl-phenylamino)-benzamide 43A N,N-Diethyi-4-fluoro-2-(4-iodo-2-methyl- oil phenylamino)-benzamide 44A 4-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin- 122-124 1-yl]-propyi}-2-(4-iodo-2-methyl-phenylamino)- benzamide 45A N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)- 91-93 5-nitro-benzamide 46A N-Butyl-4-fluoro-2-(4-iodo-2-methyl- 97-99 phenylamino)-benzamide

“Bamps Compound mPC

No. phenylamino)-benzamide 48A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N- 142.5-144 dimethyl-benzamide

EXAMPLE 49A

A4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohol4-Fluoro- 2-(4-iodo-2-methyl-phenylamino)-benzoic acid (0.50 g, 1.35 mmol) was dissolved in 6 mL (6 mmol) of cold 1.0 M borane-tetrahydrofuran complex in tetrahydrofuran solution. The reaction mixture was stirred under nitrogen atmosphere at room temperature overnight. The reaction was quenched with 80 mL of methanol. Concentration in vacuo produced a clear tan oil which was purified by MPLC. Elution with dichloromethane afforded 0.4285 g (89%) of a white solid; mp 99-100.5°C,;

TH NMR (400 MHz; DMSO): 5 7.57 (d, 1H, J=1.7 Hz), 7.45 (dd, 1H, J=8.4, 1.9 Hz), 7.39 (s, 1H), 7.29 (t, 1H, J=7.5 Hz), 6.89 (d, 1H, J=8.4 Hz), 6.67-6.60 (m, 1H), 5.47 (t, 1H, J=5.5 Hz), 4.49 (d, 2H, 5.1 Hz), 2.14 (s, 3H),

IR (KBr) 3372 (O-H stretch) cm-1;

MS (CI) M+1 = 358.

Analysis calculated for C14H43FINO:

C, 47.08; H, 3.67; N, 3.92.

Found: C,4717; H, 3.75; N, 3.72.

EXAMPLE 50A-52A

The following benzyl alcohols were prepared by the general procedure of Example 49A.

Co WO 01/05392 PCT/US00/18347 “Example Compound MP°C

No. phenyl}-methanol

S51A [2-(4-lodo-2-methyl-phenylamino)-5-nitro- 126.5-128. phenyi]-methanol 5 52A [5-Bromo-2-(4-iocdo-2-methyl-phenylamino)- 60.5-63.5 phenyi]-methanol

Several invention compounds of Formula I(A) were prepared utilizing combinatorial synthetic techniques. The general procedure is as follows:

To a 0.8-mL autosampler vial in a metal block was added 40 pl of a 0.5 M solution of the acid in DMF and 40 ul of the reagent amine (2M solution in Hunig's base and 1 M in amine in DMF). A 0.5M solution of PyBrop was - freshly prepared and 50 ul were added to the autosampler vial. The reaction was allowed to stand for 24 hours.

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

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

EXAMPLES 53A-206A

The following compounds of Formula | were prepared by combinatorial methodology: “Example Compound MS

No. M-H ~ 53A 5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(d-iodo- 510 2-methyl-phenylamino)-benzamide 54A N-(2,3-Dihydroxy-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- 462 phenylamino)-benzamide 55A 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 577 (2-piperidin-1-yl-ethyl)-benzamide 56A 3,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 432 phenylamino)-benzamide 57A N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl- 444 phenylamino)-benzamide 58A 3,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 446 phenylamino)-benzamide 59A 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 564 (2-pyrrolidin-1-yl-ethyl)-benzamide 60A 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 571 (2-pyridin-4-yl-ethyl)-benzamide 61A 4-Fluoro-N-(2-hydroxy-ethyl}-2-(4-iodo-2-methyl- 414 phenylamino)-benzamide 62A 5-Bromo-N-(3-dimethylamino-propyl)-3,4-difluoro-2-(4-iodo- 551 2-methyl-phenylamino)-benzamide

B3A 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 580 : (2-morpholin-4-yl-ethyl)-benzamide

B4A 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 501 (2-morpholin-4-yl-ethyl)-benzamide

B5A 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 485 (2-pyrrolidin-1-yl-ethyl)-benzamide

Co A WO 01/05392 PCT/USNN/18347 “Exampe Compound WMS

No. M-H

TT B6A 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin- 493 4-yl-ethyl)-benzamide 867A N-(3-Dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl- 473 phenylamino)-benzamide 68A N-Benzyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)- 460 benzamide 69A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 384 (2-hydroxy-ethyi)-benzamide 70A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin- ~~ 483 4-yl-ethyl)-benzamide 71A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 495 1-yl-propyl)-benzamide 72A 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 513 1-yl-propyl)-benzamide . 73A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen- 480 2-yl-ethyl)-benzamide 74A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 467 } 1-yl-ethyl)-benzamide 75A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 453 (2-morpholin-4-yl-ethyl)-benzamide ) 76A 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 557 pyridin-4-ylmethyi-benzamide 77A 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin- 479 4-ylmethyl-benzamide 78A 2-(4-Bromo-2-methyl-phenylamino)-N-(3-dimethylamino- 425 propyl)-3,4-difluoro-benzamide 79A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin- 461 4-ylmethyl-benzamide 80A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl- 475 ethyl)-benzamide 81A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyridin- 445 4-yl-ethyl)-benzamide 82A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 400 (3-hydroxy-propyl)-benzamide

“Exampe Compound MS

No. M-H

T 83A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 437 (2-pyrrolidin-1-yl-ethyl)-benzamide 84A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl- 474 benzamide 85A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 450 (2-thiophen-2-yl-ethyl)-benzamide 86A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyridin- 431 4-ylmethyl-benzamide 87A 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 444 phenethyl-benzamide 88A 2-(4-Bromo-2-methyi-phenylamino)-3,4-difluoro-N- 451 : (2-piperidin-1-yl-ethyl)-benzamide 89A 5-Chloro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-y(]-propyl}- 557* 2-(4-iodo-2-methyl-phenylamino)-benzamide 90A 5-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl}-propyl}- 541* 2-(4-iodo-2-methyl-phenylamino)-benzamide 91A 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl 487 methyl-benzamide 92A 5-Bromo-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl}-propyl}- 601* 2-(4-iodo-2-methyl- phenylamino)-benzamide 93A 5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- 486* : phenylamino)-benzamide 94A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-{2-piperidin- 497+ 1-yl-ethy!)-benzamide 95A (3-Hydroxy-pyrrolidin-1-yl)-[2-(4-iodo-2-methyl- 466 phenylamino)-5-nitro-phenyl]- 96A 5-Chloro-2-(4-iodo-2-methyt-phenylamino)-N-(2-pyrrolidin- 484* 1-yl-ethyl)-benzamide 97A 5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl- 5307 phenylamino)-benzamide 98A N-{2-[Bis-(2-hydroxy-ethyl)}-amino}-ethyl}-5-chloro-2-(4-iodo- 518* 2-methyi- phenylamino)-benzamide

“Exampe Compound MS

No. M-H

TT 99A N-{2-[Bis-(2-hydroxy-ethyl)-amino}-ethyl}-5-bromo-2-(4-iodo- 562° 2-methyl- phenylamino)-benzamide 100A [5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]- 499 (3-hydroxy-pyrrolidin-1-yl)- 101A 2-(4-1odo-2-methyl-phenylamino)-5-nitro-benzoic acid 501 phenethyl ester 102A N-{3-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-propyl}-2-(4-iodo- ~~ 568* 2-methyl-phenylamino)-benzamide 103A [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- 455 : (3-hydroxy-pyrrolidin-1-yi)- 104A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin- 460 4-ylmethyl-benzamide 105A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 528* 1-yl-ethyl)-benzamide : 106A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 542* 1-yl-ethyl)-benzamide 107A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 468* 1-yl-ethyl)-benzamide 108A 5-Chloro-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- 472% phenylamino)-benzamide 109A N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-fluoro-2-(4-iodo- 502* 2-methyl-phenylamino)-benzamide 110A 5-Chloro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 445* phenylamino)-benzamide 111A 5-Chloro-N-(3-diethylamino-2-hydroxy-propyl)-2-(4-iodo- 516 2-methyl-phenylamino)-benzamide 112A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- 482* 1-yl-ethyl)-benzamide 113A 5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 489* phenylamino)-benzamide 114A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 556* 1-yl-propyl)-benzamide

“Example Compound MS

No. M-H

TT115A N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-2-(4-iodo-2-methyl- 529" phenylamino)-5-nitro-benzamide 116A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin- 500" 4-yl-ethyl)-benzamide 117A 5-Chioro-N-(3-diethylamino-propyl)-2-(4-iodo-2-methyl- 500 phenylamino)-benzamide 118A 5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- 514* phenylamino)-benzamide 119A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 512* 1-yl-propyl)-benzamide 120A 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin-1-yl- 509* ethyl)-benzamide 121A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin- 544» 1-yl-ethyl)-benzamide 122A N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl- 470" phenylamino)-benzamide 123A 5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl- 516* phenylamino)-benzamide 124A N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- 456" 5-nitro-benzamide 125A 5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl- 429* : phenylamino)-benzamide 126A N-(3-Diethylamino-propyl)-5-fluoro-2-(4-iodo-2-methyl- 4B84* phenylamino)-benzamide 127A N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- 511* 5-nitro-benzamide 128A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin- 544* 4-yl-ethyl)-benzamide 129A 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin-1-yl- 523* propyl)-benzamide 130A [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- 439 (3-hydroxy-pyrrolidin-1-yl)-

oo . WO 01/05392 PCT/US00/18347 “Example Compound MS

No. M-H 131A 5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl- 558" phenylamino)-benzamide 132A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin- 484" 4-yl-ethyl)-benzamide 133A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin- 496" 1-yl-propyl)-benzamide 134A [5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]- 482 [4-(2-hydroxy-ethyi)-piperazin-i- 135A N-(3-Diethylamino-2-hydroxy-propyl)-S-fluoro-2-(4-iodo- 500" 2-methyl-phenylamino)-benzamide 136A [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoylamino}- 443 acetic acid 137A 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(2-pyrrolidin-1-yl- 495* ethyl)-benzamide “ 138A N-(3-Dimethylamino-propyl)-2-(4-icdo-2-methyl- 483" phenylamino)-5-nitro-benzamide : 139A N-(2-Diisopropylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl- 498* } phenylamino)-benzamide 140A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid 490

S-phenethyl ester ’ 141A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid 506 } S-phenethyl ester 142A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid 536

S-benzyl ester 143A 2-(4-lodo-2-methyl-phenylamino)-5-nitro-thiobenzoic acid 503

S-benzyl ester 144A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid 476

S-benzyl ester 145A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-thiobenzoic acid 492

S-benzyl ester 146A N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 409 benzamide

“Example Compound MS

No. M-H "147A 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 429 phenylamino)-benzamide 148A 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 413 phenylamino)-benzamide 149A N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 475 benzamide 150A N-Benzyloxy-5-bromo-2-(4-iodo-2-methyi-phenylamino)- 593" benzamide 151A 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl- 567 benzyl)-benzamide 152A 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 473 phenylamino)-benzamide 183A N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl- 521 phenylamino)-benzamide 154A N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 440 5-nitro-benzamide 155A 2-(4-lodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- 486 benzamide 156A 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 425 benzamide 157A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N- 459 : phenyl-benzamide 158A N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 409 159A N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 583 benzamide 160A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 538 benzyl)-benzamide 161A N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylaming)- 425 benzamide 162A N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 436 benzamide 163A 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 469 benzamide

“Example Compound MS

No. M-H "184A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N- 475 phenyl-benzamide 165A 5-lodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 646 benzyl)-benzamide 166A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 598 benzyl)-benzamide 187A N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 436 168A 2-(4-iodo-Z-methyi-phenyiamino}-5-niiro-N-{4-suifamoyi- 565 benzyl)-benzamide 169A N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)- 469 benzamide : 170A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl- 473 benzyl)-benzamide 171A N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 517 benzamide : 172A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N- 519 phenyl-benzamide 173A N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 502 benzamide 174A N-Cyclohexyi-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 559 benzamide 175A N-Allyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide ~~ 517 176A 5-lodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl- 581 benzyl)-benzamide 177A 2-(4-lodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- 500 5-nitro-benzamide 178A 5-lodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- 567 benzamide 179A N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 451 benzamide 180A 5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- 467 benzamide 181A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl- 533 benzyl)-benzamide

“Example Compound MS

No. M-H "182A 5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- 511 benzamide 183A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl- 489 benzyl)-benzamide 184A N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 478 benzamide 185A N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)- 538 benzamide : 186A N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 477 benzamide 187A 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyi- 431 phenylamino)-benzamide 188A 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 475 phenylamino)-benzamide 189A 2-(4-lodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl- 488 benzamide 190A 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N- 477 phenyl-benzamide 191A N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl- 523 phenylamino)-benzamide 192A 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 425 : benzamide 183A N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)- 427 benzamide 194A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N- 461 phenyl-benzamide 195A N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- 442 5-nitro-benzamide 196A 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 415 phenylamino)-benzamide 197A 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 472 benzamide 198A N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 411 benzamide

Co . WO 01/05392 PCT/US00/18347 ~ Exampe Compound MS

No. M-H "199A 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- 540 benzyl)-benzamide 200A N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro- 438 benzamide 201A N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 411 202A N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)- 585 benzamide 203A N-Ailyi-5-bromo-2-(4-iodo-2-methyi-phenyiaminoj- 472 benzamide 204A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl- ~~ 601 benzyl)-benzamide 205A 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N- 522 phenyl-benzamide 206A N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 438 . --w+a

EXAMPLE 207A

Preparation of [4-Chloro-2-(1H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)-amine : Step a: Preparation of 5-Chloro-2-fluoro-benzaldehyde

To a solution of 1-chloro-4-fluorobenzne (13.06 g, 0.1 mol) in THF -S (180 mL), at -78°C, LDA (2 M solution in THF, 50 mL, 0.1 mol) was added dropwise. After stirring at -78°C for 1.5 hours, DMF (8 mL) was added to the : reaction mixture and allowed to warm up to room temperature overnight. The reaction mixture was partitioned between water and Et2O. The Et20 layer was dried (MgSO4) and the solvent removed in vacuum to give 14.95 g (94%) yield of crude aldehyde:

TH NMR (CDCI3): 8, 10.3 (s, -C(=0)H).

Step b: Preparation of 5-Chloro-2-fluoro-benzaldehyde oxime

A solution of 5-chloro-2-fluoro-benzaldehyde (10 g, 0.0631 mol), hydroxylamine hydrochloride (6.57 g, 0.0946 mol) and pyridine (8.3 mL, 0.1010 mol) in EtOH (100 mL) was heated at 75°C (oil bath temperature) for 1 hour and the solvent removed under vacuum to give an oil. The oil was partitioned between water and CH2Cl2. The CHCl layer was dried (MgSOg4) and the solvent removed under vacuum to give crude aldoxime as a solid. The solid was purified by medium pressure liquid chromatography on silica. Elution ~ with CH2Clo gave 4.87 g (28%) of the aldoxime as white solid: mp 95-97°C;

Analysis calculated for C7H5NOFCI:

C, 48.44; H, 2.90; N, 8.07.

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

Step c: Preparation of 5-Chloro-2-fluoro-benzonirile

A solution of the 5-chloro-2-fluoro-benzaldehyde oxime (3.15 g, 0.0182 mol) in acetic anhydride (150 mL) was refluxed for 16 hours. The reaction mixture was cooled to room temperature and poured into saturated aqueous NaHCO3 (200 mL) solution. The mixture was extracted with Eto0.

The Et20 layer was dried (K2CQO3) and the solvent removed to give the product as an oily solid. The product was used without further purification in the next step.

Step d: Preparation of 5-(5-Chloro-2-fluoro-phenyl)-1H-tetrazole

A mixture of 5-chloro-2-fluoro-benzonitrile (2.84 g, 0.01823 mol), butanol (15 mL), sodium azide (1.543 g, 0.0237 mol), acetic acid (1.36 mL, 0.0237 mol) was refluxed for 24 hours. The reaction mixture was cooled to room temperature, additional 1.543 g sodium azide added, and the reaction mixture refluxed for additional 24 hours. After cooling to room temperature,

EtoO (100 mL) and 10% aqueous NaOH (200 mL) were added sequentially.

The mixture was vigorously stirred. The aqueous layer was separated, cooled with ice-methanol bath (-15°C) and acidified to pH 1 with conc. HCI. A gray solid precipitated. The solid was dried in vacuum at 50°C to give 1.76 g (48%)

oo . WO 01/05392 PCT/US00/18347 of 5-(5-chloro-2-fluoro-phenyl)-1H-tetrazole: mp partial melt at 110°C, complete melting at 124°C); 1H (400 Mz, CDCI3): 5 8.19-8.08 (m, 1H), 7.77-7.71 (m, 1H), 7.61-7.52 (m, 1H); 13C (100 Mz, CDCl3): § 159.00, 156.49, 140.88, 133.02, 132.93, 130.73, 129.23, 129.21, 129.08, 126.05, 118.96, 118.73, 114.50;

MS (Cl) M+1 = 199 (100), M = 198 (6).

Step e: Preparation of [4-Chloro-2-(1H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)- amine

To a solution of 2-methyl-4-iodoaniline (3.52 g, 0.0151 mol) in THF (25 mL) at -78°C, LDA (2 molar solution in THF, 11.33 mL, 0.02267 mol) was added dropwise. After stirring for 0.5 hours, a solution of 1-(tetrazol-5-yl)- 2-fluoro-5-chlorobenzene (1.5 g, 0.00756 mol) in THF (15 mL) was added dropwise. The reaction was stirred for 16 hours as it warmed up to room temperature. The reaction mixture was quenched with aqueous conc. NH4Cl solution and extracted with CH2Cls. The organic layer was dried (MgSQOg4) and the solvent removed giving a crude product as an oil. The oil with

Bn CH2Clz->CH2Clp:MeOH (9.7:0.3) gave 1.5 g (48%) of the desired product: mp 205-208; 1H (400 Mz, DMSO): & 9.13 (s, 1H), 8.00-7.99 (s, 1H), 7.69 (s, ) 1H), 7.65-7.52 (m, 1H), 7.43-7.40 (m, 1H), 7.12-7.05 (m, 1H), 2.24 (s, 3H); 13C (100 Mz, CDCl3): 5 141.87, 139.28, 138.88, 135.47, 133.71, 131.65, 128.15, 123.69, 121.94, 116.68, 87.79, 17.22;

MS (Cl) M+2 = 413 (44), M+1 = 412 (85), M = 411 (100).

Analysis calculated for C414H11N5CIl-0.5H20:

C, 39.97; H, 2.87; N, 16.65.

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

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

EXAMPLE 208A (4-lodo-2-methyl-phenyl)-[2-(1H-tetrazol-5-yl)-phenyllamine, mp 231°C (dec)

EXAMPLE 209A [4-Nitro-2-(1H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)-amine, mp 205-208°C.

EXAMPLES 210A-224A

Additional invention compounds which were prepared by the general methods described above are: “Example Compound MP °C

No. ~ 210A 2-(2-Chloro-4-iodo-phenylamino)-3-fluoro-4-(2- 239-241 morpholin-4-yl-ethylamino)-5-nitro-benzoic acid DEC 211A 4-Amino-2-(2-chloro-4-iodo-phenylamino)-3- >270 - fluoro-5-nitro-benzoic acid : : 212A 2,4-Bis-(2-chloro-4-iodo-phenylamino)-3-fluoro- >265 DEC 5-nitro-benzoic acid 213A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-5- 218-225 nitro-benzoic acid DEC : 214A 2-(2,6-Difluoro-4-iodo-phenylamino)-3,4- 247-249 difluoro-benzoic acid } 215A 2-(2-Chloro-4-iodo-phenylamino)-4-nitro- 267-269 benzoic acid 216A 2-(2,4-Diiodo-phenylamino)-4-fluoro-benzoic 260-261 acid 217A 2-(2-Bromo-4-iodo-phenylamino)-4-fluoro- 259-262 benzoic acid 218A 4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)- 215-217 benzoic acid

Co . WO 01/05392 PCT/US00/18347 “Example Compound MP°C

No. "219A 2-(2-Chioro-4-iodo-phenylamino)4-flucro- 242-247 benzoic acid 220A 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4- 312.5-318 difluoro-benzoic acid 221A 2,3,5-Trifluoro-6-(4-iodo-2-methyl-phenylamino)- 118-121 4-(4-methyl-piperazin-1-yl)-benzoic acid methyl ester dihydrofluoride salt 222A §-Bromo-3,4-diflucrs-2-{4-icdo-2-methyl- 214.217 phenylamino)-N-(4-methyl-piperazin-1-yl)- DEC benazmide 223A 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 154-175 phenylamino)-benzoic acid N’,N’-dimethy!- DEC hydrazide 224A 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 153.5-156 benzoic acid hydrazide

F. Other Embodiments

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

Publications cited herein are hereby incorporated by reference in their entirety.

What is claimed is:

Claims

SE. | PCT/US00/18347 @® Chime :

1. Use of a MEK inhibitor of Formula 1 i Re r2 C-N-0—R, R, NE Brorl = i . : R; Ry oo wherein: R41 is hydrogen, hydroxy, C1-Cg alkyl, C1-Cg alkoxy, halo, oo | | trifluoromethyl, or CN: - | ’ Ro is hydrogen; . : oo N : R3, R4, and Rs independently are hydrogen, hydroxy, halo, a | = : trifluoromethyl, C4-Cg alkyl, C4-Cg alkoxy, nitro, CN, or a (O or NH)rm-(CHo)n-Rg. where Rg is hydrogen, hydroxy, COH : Le ~ orNRigR11: | | - nis Oto 4; oo Co ~~ misOort; | oo oo R10 and R14 independently are hydrogen or C1-Cg alkyl, or taken tegether with the: nitrogen to which they are attached can : complete a 3- to 10-member cyclic ring optionally containing one, two, or three additional heteroatoms selected from 0, S, NH, or N-C4-Cg alkyl; : ~ Rg is hydrogen, C1-Cg alkyl, C-C4-Cg alkyl, aryl, aralkyl, or C3-C1g cycloalkyl: AMENDED SHEET

® PCT/US00/18347 R- is hydrogen, C41-Cg alkyl, C,-Cg alkenyl, Co-Cg alkynyl, or C3-C4 cycloalkyl optionally containing a heteroatom selected from O, S, or NRg; and wherein any of the foregoing alkyl, alkenyl, and alkynyl groups can be unsubstituted or substituted by cycloalkyl or cycloalkyl optionally containing a heteroatom selected from O, S, or NRg, aryl, aryloxy, heteroaryl, or heteroaryloxy; or Re and Ry taken together with the N-O to which they are attached can complete a 5- to 10- membered cyclic ring, optionally containing one, two, or three additional heteroatoms selected from O, S, or NRqgRq1. in the manufacture of a medicament to treat chronic pain.

2. The use of claim 1, wherein said chronic pain is selected from neuropathic pain, idiopathic pain, and pain associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism.

3. The use of claim 2, wherein said chronic pain is a type of neuropathic pain.

4. The use of claim 3, wherein said neuropathic pain is associated with one of the following:- inflammation, postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, viral infection, crush injury, constriction injury, tissue injury, limb amputation, arthritis pain, and any other nerve injury between the peripheral nervous system and the central nervous system, inclusively.

5. The use of claim 2, wherein said chronic pain is associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism. AMENDED SHEET

PCT/US00/18347

6. The use of claim 2, wherein said chronic pain is associated with idiopathic pain.

7. The use of claim 1, wherein said chronic pain is associated with inflammation.

8. The use of claim 1, wherein said chronic pain is associated with . : arthritis.

9. The use of claim 1, wherein said chronic pain is associated with post- operative pain. : 10. The use of claim 1, wherein Rq is C4-Cg alkyl or halo. : N 11. The use according to claim 1 wherein Rg is hydrogen.

12. The use according to claim 11 wherein R1 is methyl.

13. The use according to claim 12 wherein the MEK inhibitor has the formula O : Li N : yy _ : | I RS Rs Ry oo

14. The use of claim 13 wherein Rg is fluoro, and Rg and Rg are hydrogen. AMENDED SHEET

® PCT/US00/18347

15. The use of claim 14, wherein said MEK inhibitor has a structure selected from: 4-Fluoro-N-hydroxy-2- (4-iodo-2-methyl-phenylamino)-benzamide; . 4-F luoro-2-(4-iodo-2-methyl-phenylamino)-N-(methoxy)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamine)-N-(prop-2-ynyloxy)- oo benzamide; : 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-phenoxyethoxy)- benzamide; Co oo E 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thienylmethoxy)- benzamide; : 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop-2-enyloxy)- - : benzamide; | ’ - 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- oo (cyclopropytmethoxy)-benzamide; oo 4 Fluoro-2-(4-iodo-2-methyl-phenylamine)-N-(cyclopentoxy)- - benzamide; oo : 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-N-

A. isopropyl-benzamide; and 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)}-N-methyi- benzamide. : ~ 16. The use of claim 13 wherein Rg and Ry are fluoro, and Rg is hydrogen.

17. The use of claim 16, wherein said MEK inhibitor has a structure selected from: | : AMENDED SHEET 97 oo

PCT/US00/18347 ] ® 3,4-Diflucro-2-(4-iodo-2-methyi-phenylamino)-N- (3-furylmethoxy)-benzamide; 25 3,4-Difluoro-2-(4-iodo-2-methyl-phenyiamino)-N-sthoxy- : : benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(but-2-enyloxy)- benzamide; : 3,4-Difiuoro-2-{4-iodo-2-methyl-phenylamino)-N-(cyclopropyl- 30 methoxy)-benzamide; 3,4-Diflucro-2-(4-iod o-2-methyl-phenylamine)-N-(1 -methyiprop- ~ 2-ynyloxy)-benzamide; : 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamina)-N-(3-phenyiprop- : : 2-ynyloxy)-benzamide; : ~ 3,4-Diflucro-2-{4-iodo-2-methyl-phenylzmine)-N~(3-methyl- 5-phenyipent-2-en-4-ynyloxy)-benzamide; . a. 3,4-Difluoro-2-{4-iodo-2-methyi-phenylamino)-N-(prop- oo 2-ynyloxy)-benzamide: | a. : 3,4-Diflucro-2-(4-icdo-2-methyl-phenylamino)-N-(propoxy)- benzamide:; . 3,4-Difiuoro-2-(4-iodo-2-methyl-phenylamino)-N-(cyclobutyloxy)- benzamide; oo 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (2-thienyimethoxy)-benzamide: 3,4-Difluoro-2-{4-iod o-2-methyi-phenylamino)-N-(2-methyi-p rop- 2-enyloxy)-benzamide; . : 3,4-Difluoro-2-{4-iodo-2-methyl-phenylamino)-N- oo (2-phenoxyethoxy)-benzamide; a 3,4-Difluoro-2-(4-icdo-2-methy-phenylamino)-N-(but-2-enyloxy)- benzamide; CC 3,4-Difluoro-2-{4-iodo-2-methyl-phenylamino)-N-{but-3-ynyloxy)- benzamide; | : Co E 3,4-Difluoro-2-{4-iodo-2-methyil-phenylamino)-N- : (cyciopentyloxy)-benzamide; AMENDED SHEET

PCT/US00/18347 ® 3,4-Difluoro-2-(4-iodo- 2-methyl-phenylamino)-N-(3-(2- : fluorophenyl)-prop-2-ynyloxy)-benzamide;

3.4 Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydro- pyran-2-yloxy)-benzamide; and : : 3,4-Difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide.

18. The use of claim 13 wherein R3 and Ra are fluoro, and Rg is bromo.

19. The use according to claim 18, wherein said MEK inhibitor has a structure selected from: . | 5-Bromo-3 4-difiuoro-N-hydroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide: 5-Bromo-3,4-difluoro-2-(4-iodo-2-methy-phenylaming)-N- - (n-propoxy)-benzamide; : 5-Bromo-3,4-difluoro-N-(furan-3-yimethoxy}-2-(4-iodo-2-methyl- - phenylamino)-benzamide; oo : E oC 8-Bromo-N-(but-2-enyloxy)-3,4-diflucro-2-(4-iodo-2-methyl- phenylamino)-benzamide CL - 5-Bromo-N-butoxy-3,4-diflucro-2-(4-iodo-2-methyl- phenylamino)-benzamide: S-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (3-methyl-but-2-enyloxy)-benzamide: : S-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- : (3-methyl-pent-2-en-4-ynyloxy)-benzamide: >-Bromo-3, 4difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(prop- 2-ynyloxy)-benzamide; : 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyi-phenylamino)-N- [3-(3-methoxy-phenyl)-prop-2-ynyioxyl-benzamide: 5-Bromo-3,4difluoro-2-(4-icdo-2-methyi-phenyiamino)-N- (thiopen-2-yimethoxy)-benzamide: AMENDED SHEET

) PCT/US00/18347 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N- (pyridin-3-yimethoxy)-benzamide; 5-Bromo-3-4-difluoro-2-(4-iode-2-methyl-phenylamino)-N- (3-(2-fluorophenyl)-prop-2-ynyloxy)-benzamide; : : 5-Bromo-3,4difluorc-2-(4-iodo-2-methyl-phenylamino)-N- (ethoxy)-benzamide; ! : 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyi-phenylamino)-N- (cyclopropylmethoxy)-benzamide; 5-Bromo-3, 4-diflucro-2-(4-iodo-2-methyl-phenylamino)-N- (isopropoxy)-benzamide; : 5-Bromo-3.4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-but- 3-ynyloxy)-benzamide; 5-Bromo-3,4difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2- piperidin-1-yl-ethoxy)-benzamide; 5-Bromo-3,4-difluoro-2-{4-iodo-2-methyl-phenylamino)-N- - (tetrahydro-pyran-2-yloxy)-benzamide; | : oo | '5-Bromo-3,4-difluora-2-(4-icdo-2-methyl-phenylamina)-N-(2- morpholin—4-yl-ethoxy)-benzamide; oo 5-Bromo-N-(2-diethylamino-ethoxy)-3,4-difluoro~(4-iodo-2- methyl-phenylaminc)-benzamide; a : 5-Bromo-3,4-difluoro-2-(4-iado-2-methyl-phenylamino)-N- isobutoxy-benzamide; 5-Bromo-N-cyclohexylmethoxy-3,4difluoro-2-(4-iodo-2-methyl- : phenylamino)-benzamide; | | : : 5-Bromo-N-cyclopentyimethoxy-3,4-difluore-2-(4-iode-2-methyi- phenylamino)-benzamide; 5-Bromo-N-cyclobutylmethoxy-3,4-difluoro-2-(4-icdo-2-methyl- phenylamino)-benzamide; and 5-Bromo-N-(2-dimethylamino-propoxy)-3 4-difluoro—2-(4-iodo- 2-methyl-phenytamino)-benzamide; : AMENDED SHEET

PCT/US00/18347 . 20. The use of claim 13 wherein R4 and Ry are hydrogen, and Rg is halo.

‘21. The use according to claim 20, wherein said MEK inhibitor has a structure selected from: 5-Chloro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- . benzamide; : 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydro-pyran- 2-yloxy)-benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy- ~ benzamide; 5-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-lodo-2-(4-iodo-2-methyl-phenylamino}-N-phenylmethoxy- “benzamide; and | . : 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydropyran-2- yloxy)-benzamide. AMENDED SHEET

® : PCT/US00/18347

22. The use of claim 12 wherein the MEK inhibitor has the formula:

i . : = Br RZ : Rs 3 J Ry :

23. The use of claim 22 wherein R3 and Ry, are fluoro, and Rg is "hydrogen. 24, | The use according to claim 23, wherein said MEK inhibitor has . C selected from: oo } : : h 3,4-Difluoro-2-(4-bromo-2-methyi-phenylamine)-N- (3-phenyiprop-2-ynyloxy)-benzamide: 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- BE a. (3-furylmethoxy)-benzamide: 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (2-thienyimethoxy)-benzamide: : : 3,4-Difluoro-2-(4-bromo-2-methyi-p henylamino)-N-{but- 3-ynyloxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(2-methyl- prop-2-enyjoxy)-benzamide; 3,4-Difluoro-2-(4-bromo-2-methyi-phenytamino)}-N-(but- : 2-enyloxy)-benzamide; AMENDED SHEET

: PCT/US00/18347 ® 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(methoxy)- benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(ethoxy)- benzzamide;

3.4-Difluoro-2-(4-bromo-2-methyi-phenylamino)-N-(cyclobutoxy)- benzamide; 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamina)-N-(isopropoxy)- oo benzamide; Co : 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (2-phenoxyethoxy)-benzamide: | SE 3,4-Diflucra-2-(4-bromo-2-methyl-phenylamino)-N-(cyciopropyl- : methoxy)-benzamide: 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N-(n-propoxy)- : benzamide; . 3,4-Difl uoro-2-(4-bromo-2-methyl-p henylamino)-N-(1-methyl- prop-2-ynyloxy)-benzamide: : 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (3~(3-fluorophenyl)-prop-2-ynyloxy)-benzamide: 3,4-Difluoro-2-(4-bromo-2-methyl-phenyiamino)-N- : (4,4-dimethylpent-2-ynyloxy)-benzamide: and 3,4-Difluoro-2-(4-bromo-2-methyl-phenylamino)-N- (cyclopentoxy)-benzamide. - :

25. The use according to claim 1, wherein said MEK inhibitor has a structure selected from: ~ 3,4,5-Trifluoro-N-hydroxy-2-(4-iodo-2-methyi-phenylamino)- benzamide; 5-Chloro-3, 4-difluoro-N-hydroxy-2-(4-iodo-2-methyl- phenylamino)-benzamide: 5-Bromo-3,4-difluoro-2-({2-flucro-4-iodo-phenylamino)-N- hydroxy-benzamide; N-Hydroxy-2-{4-iodo-2-methyl-phenylamino)-4-nitro-benzamide: AMENDED SHEET

PCT/US00/18347 ® 3,4,5-Trifluoro-2-(2-flucro-4-iode-phenylamino)-N-hydraxy- benzzmide; 5-Chioro-3, 4-difiuoro-2-(2-fluoro—-iodo-phenylaming)-N- hydroxy-benzamide: : 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4difiuoro-N- : hydroxy-benzamide: : 2-(2-Fluoro-4-iodo-phenylamino)-N-hydroxy—4-nitro-benzamide: 2-(2-Chioro-4-iodo-phenylamino)-3,4, 5-trifluoro-N-hydroxy- benzamide; 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro- - benzamide; 2-(2-Chloro—4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide: 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N- hydroxy-benzamide; - 5-Bromo-2-(2-bromo-4-iode-phenyiamino)-3 4-difluoro-N- hydroxy-benzamide; . 2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-methyi- benzamide; : oo Co | 2-(2-Bromo-4-iodo-phenylamino)-3,4,5-triflucro-N-hydroxy- benzamide; 2-(2-Bromo-4-icdo-phenylamino)-5-chloro-3. 4-difluoro-N- hydroxy-benzamide: : : 2-(2-Bromo-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide: 4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy-benzamide; 3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-hydroxy- benzamide; . 2-(2-Chioro-4-iodo-phenylamino)-<4-fluoro-N-hydroxy-benzamide: 2-(2-Chloro-4-iodo-phenylamine)-3,4-ifluoro-N-hydroxy- benzamide; Ea | oo 2-(2-Bromo-4-iodo-phenylamino)<4-flucro-N-hydroxy-benzamide: 2-(2-Bromo-4-icdo-phenylamino)-3, 4-difluoro-N-hydroxy- benzamide; AMENDED SHEET

PCT/US00/18347 ® N-Cyclopropyimethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyi- phenylamino)-benzamide: | ‘ S-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(4-iodo-2-methyi- phenylamino)-benzamide; Co 5-Bromo-N-cyciopropylmethoxy-3,4-difluoro-2-(2-flucro4-iodo- phenylamino)-benzamide; N-Cyclopropyimethoxy-2-(4-iodo-2-methyl-phenytamino)-4-nitro- benzamide; : N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(2-fluoro-4-iodo- : : phenylamino)-benzamide; 5-Chloro-N-cyclopropylmethoxy-3,4-difluoro-2-(2-flucro-4-iodo- phenylamino)-benzamide; : 5-Bromo-2-(2-chiofb-4-iodo-phenylamino)-N- cyclopropylmethoxy-3,4-difluoro-benzamide; N-Cyclopropyimethoxy-2-(2-flucro4-iodo-phenylamino)-<4-nitro- benzamide; 2-(2-Chloro4-iodo-phenylamino)-N-cyclopropyimethoxy- 3,4,5-triflucro-benzamide; 5-Chioro-2-(2-chloro-4-iodo-phenylaming)-N- cyclopropyimethoxy-3,4-diflucro-benzamide; S-Bromo-2-(2-bromo-4-iodo-phenylamino)-N-ethoxy-3,4-difluoro- benzamide; 2-(2-Chioro-4-iodo-phenylamino)-N-ethoxy-4-nitro-benzamide; 2-(2-Bromo-4-icdo-phenytamino)-N-cyclopropyimethoxy- : 3,4, 5-trifluoro-benzamide: - 2-(2-Bromo-4-iodo-phenylamino)-5-chloro-N- cyclopropyimethoxy-3,4-difluoro-benzamide 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy-4-nitro- benzamide; N-Cyclopropylmethoxy-4-flucro-2-(2-flucro-4-icdo-phenytamino)- benzamide; : N-Cyciopropyimethoxy-3,4-difluoro-2-(2-flucro-4-iodo- phenylamino)-benzamide; AMENDED SHEET -

PCT/US00/18347 @® 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropyimethoxy- 4-fluoro-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropyimethoxy- 3,4-difluoro-benzamide: 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropylmethoxy- 4-fluoro-benzamide; 2-(2-Bromo-4-iodo-phenylamino)-N-cyclopropyimethoxy- 3,4-difluoro-benzamide; - N-Cyclopropylmethoxy-3,4, 5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-N-hydroxy-4-nitro-benzamide: 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(tetrahydro- pyran-2-yloxy)-benzamide: 3,4-Difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenyiamino)- benzamide; 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-N-hydroxy-benzamide (HCI salt): oo : 2-(2-Chloro-4-iodo-phenylamino)-4-fluaro-N-(tetrahydro-pyran-2- yloxy)-benzamide; 2-(2-Chioro-4-icdo-phenylamino)-N-cyclobutylmethoxy-3,4- difluoro-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3,4-difluoro-N-(tetrahydro- : pyran-2-yloxy)-benzamide; 5-Bromo-2-(2-chioro-4-iodo-phenylamino)-N-(2-dimethylamino- ~~ ethoxy)-3,4-difluoro-benzamide monohydrochicride sait: 5-Bromo-N-(2-dimethylamino-propoxy)-3,4-difluoro-2-(4-iodo- 2-methyl-phenylamino)-benzamide; oo } 5-Bromo-2-(2-chloro-4-iodo-phenyiamine)-3,4-difluoro-N- hydroxy-benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenyiamino)-3,4-difluoro-N- ) (tetrahydro-pyran-2-yloxy)-benzamide; AMENDED SHEET

PCT/US00/18347 . 3,4 Difluoro-2-(2-chloro-4-iodo-phenylamino}-N-cyclobutylmethoxy- : benzamide; 3,4-Difluoro-2-(2-chloro-4-iodo-phenylamino)-N-(tetrahydo-pyran-2- yloxy)-benzamide; 3,4-Difluoro-2-(2-chloro-4-iodo-phenylamino)-N-(cyclopropylmethoxy- benzamide; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N-(2-dimethylamino-ethoxy)- 3,4-difluoro-benzamide monohydrochloride salt; : 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide; 5-Bromo-2-{2-chloro-4-iodo-phenylamino)-3,4-difluoro-N-(tetrahydo- pyfan-2-yloxy)-benzamide; | - ’ 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4- difluoro-benzamide; Co : 4-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- 3 benzamide; and - - 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenylmethoxy- oo - benzamide. - | . oo EE

26. - Use of a MEK inhibitor of Formula I{A) BN oo fz AN Brorl R; R, wherein: : : oo R4 is hydrogen, hydroxy, C4-Cg alkyl, C4-Cg alkoxy, halo, trifluoromethyl, or CN; ‘Rp is hydrogen; AMENDED SHEET

® PCT/US00/18347 -R3, R4, and Rs independently are hydrogen, hydroxy, halo, trifluoromethyl, C4-Cg alkyl, C4-Cg alkoxy, nitro, CN, or -(O or NH)m ~(CH2)n-Rg, where Rg is hydrogen, hydroxy, : : COOH, or NR4gR 11: nis 04; mis 0 or 1; | Co R1g and R11 independently are hydrogen or C41-Cg alkyl, or taken : : together with the nitrogen to which they are attached can complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or oo ~ N-C4-Cg alkyl; © Zis COORy, tetrazolyl, CONRgR7, CONHNR1gR 11. or CHoOR7; : Rg and Ry independently are hydrogen, Ci-Cg alkyl, C,-Cg alkenyl, | : Cy-Cg alkynyl, C - &.-cq alkyl, aryl, heteroaryl, or : oe C3-C1 cycloalkyl, optionally containing one, two, or three Co : "heteroatoms selected from O, S, NH, or N alkyl); or Rg and Ry h together with the nitrogen to which they are attached complete ~ a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl; and wherein any of the foregoing alkyl, alkenyl, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or : heteroaryloxy, and the pharmaceutically acceptable salts thereof, in the manufacture of a medicament to treat chronic pain.

27. The use of claim 26, wherein said chronic pain is selected from neuropathic pain, idiopathic pain, and pain associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism. AMENDED SHEET

PCT/US00/18347

28. The use of claim 27, wherein said chronic pain is a type of neuropathic pain.

29. The use of claim 28, wherein said neuropathic pain is associated with one of the following:- inflammation, postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, viral infection, crush injury, constriction injury, tissue injury, limb amputation, . arthritis pain, and any other nerve injury between the peripheral nervous system and the central nervous system, inclusively.

30. The use of claim 27, wherein said chronic pain is associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism. :

31. The use of claim 27, wherein said chronic pain is associated with idiopathic pain. - oo

32. The use of claim 26, wherein said chronic pain is associated with inflammation.

33. The use of claim 26, wherein said chronic pain is associated with arthritis.

34. The use of claim 26, wherein said chronic pain is associated with oo post-operative pain. :

35. The use of claim 26, wherein R1 is CH or halo. ~ 36. The use according to claim 35, wherein Z is COOR5, tetrazolyl, or a salt thereof. AMENDED SHEET

PS PCT/US00/18347

37. The use according to claim 36, wherein said MEK inhibitor has a structure selected from: ) [4-Chloro-2-(1H-tetrazol-5-yl)-phenyl-(4-iodo-2-methyl-phenyl)-amine; (4-lodo-2-methyl-phenyl)-[2-(1H-tetrazol-5-yl)-phenyllamine; and [4-Nitro-2-(1H-tetrazol-5-yl)-phenyl-(4-iodo-2-methyl-phenyl)-amine.

38. The use according to claim 35, wherein the MEK inhibitor has the formula : CH; H - OH : : Jogo! oo I Ry. | Rs oo Ry | oo

39. The use of claim 38 wherein R3 is hydrogen, fluoro, or chloro; Rg is hydrogen, fluoro, chloro, or nitro; and Rg is hydrogen, chloro, fluoro, bromo, nitro, or methoxy. :

40. The use of claim 39, wherein said MEK inhibitor has a structure selected from: 4-Fluaro-2-(4-iodo-2-methyiphenylamino)benzoic acid; 3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; ) 3 4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid: ~~ 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid, Sodium 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoate; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2-(4-lodo-2-methyl-phenylamino)-5-nitro-benzoic acid; : - 4 Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2-(4-lodo-2-methyk-phenylamino)-benzoic acid; . 5-F luoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; AMENDED SHEET

PS PCT/US00/18347 2-(4-lodo-2-methyl-phenylamino)-4-nitro-benzoic acid; 4-Fluoro-2-(4-iodo-2-methyi-phenylamino)-5-nitro-benzoic acid; and 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-methyl- : piperazin-1-yl)-benzamide.

41. The use of claim 35, wherein the MEK inhibitor has the formula © CH C-OH : > H : N N R,

42. The use of claim 41 wherein R3 is hydrogen, chloro, or fluoro; R4 is . hydrogen, chloro, fluoro, or nitro; Rg is hydrogen, chloro, fluoro, bromo, nitro, or methoxy. Co

43. The use of claim 26, wherein said MEK inhibitor has a structure - a selected from: | : : 2-(4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic acid: 2-(2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic acid; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-benzoic acid; : 2-(2-Chloro-4-iodo-phenylamino)-3-fluoro4-(2-morpholin-4-yI- - ethylamino)-5-nitro-benzoic acid; © 4-Aminor2-(2-chioro-4-iodo-phenylamino)-3-fluoro-5-nitro-benzoic acid, : | 2-(2-Chloro—4-iodo-phenyiamino)-4-nitro-benzoic acid: 2-(2,4-Diiodo-phenylamino)-4-fluoro-benzoic acid; 2-(2-Bromo-4-iodo-phenylamino)-4-fluoro-benzoic acid; 4-Fluoro-2-(2-fluoro<4-iodo-phenylamino)-benzoic acid; 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-benzoic acid; 5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid; : AMENDED SHEET

PCT/US00/18347 5-lodo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2-(4-lodo-phenylamino)-5-methoxy-benzoic acid; : 5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; : 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid N’,N’-dimethyl-hydrazide; and . 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide.

44. The use of claim 35 wherein Z is CONRgR5.

45. The use of claim 44, wherein the MEK inhibitor has the formula : 0 iH C—NR/R jos oo Brorl | Rq | Rg = Rg wherein: oo Co R; is CH3 or halo. ~ 46. The use of claim 45 wherein R3 is hydrogen, chloro, or fluoro; Rg is hydrogen, chloro, fluoro, or nitro; and Rg is hydrogen, chloro, fluoro, bromo, nitro, or methoxy. . 47. The use of claim 26, wherein said MEK inhibitor has a structure selected from: AMENDED SHEET ’

® PCT/US00/18347 5-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide, 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; : 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-benzamide; N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 4 Fluoro-2-(4-iodo-2-methyl-phenylamine)-N,N-dimethyl-benzamide; 4-Fluoro-2-(4-iodo-2-methyi-phenylamino)-N-(1H-tetrazol-5-y1)- benzamide: | i 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide; [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-hydroxycarbonylmethyl- : benzamide: | Sa

: . 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-propyl-benzamide; : 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- } benzamide; . N,N-Diethyl4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; -4-Fluoro-N-{3-{4-(2-hydroxy-ethyl)-piperazin-1-yi]-propyl}-2-(4-iodo- 2-methyi-phenylamino)-benzamide; N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; : N-Butyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; : 5-Chloro-N,N-diethyi-2-{4-iodo-2-methyl-phenylamino)-benzamide; oo 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N, N-dimethyl-benzamide; ~*~ 5.Bromo-3,4-difluaro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- phenylamino)-benzamide; N-(2,3-Dihydroxy-propyl)-3,4-diflucro-2-(4-icdo-2-methyl-phenylamino)- : benzamide; 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin- - 1-yl-ethyl)-benzamide; AMENDED SHEET

PCT/US00/18347 ® 3,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; Co 3,4-Difluoro-N-{3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- : benzamide; 5-Brome-3,4-difluoro-2-{4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin- 1-yl-ethyl)-benzamide; 5-Bromo-3,4-difiluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin- 4-yl-ethyl)-benzamide; 4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; : : 5-Bromo-N-(3dimethylamino-propyl)-3,4-difiucro-2-(4-iodo-2-methyl- phenylamino)-benzamide; : Co 5_Bromo-3, 4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin- SE 4-yl-ethyl)-benzamide; | - oo : 3,4-Difluoro-2-(4-iodo-2-methyl-phenytamino)-N-(2-morpholin4-yi- oo ethy)-benzamide; oo : oo 3 4-Difiuoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrolidin-1-y- ~~ ethyl)-benzamide; : - 3,4-Difluoro-2-(4-iodo-2-methyl-phenylaminec)-N-(2-pyridin-4-yl-ethyl)- benzamide; N-(3-Dimethylamino-propyl)-3,4-diflucro-2-(4-icdo-2-methyl- phenyiamino)-benzamide; E N-Benzyi-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-diflucro-N-(2-hydroxy-ethyl)- benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N~(2-morpholin-4-yl-ethyf)- benzamide; : 4-Fluoro-2-4-iodo-2-methyl-phenytamino)-N~3-piperidin-1-yl-propyl)- oo benzamide; | . 3,4-Difluoro-2-{4-iodo-2-methyl-phenylamino}-N-(3-piperidin-1 -yl- propyf)-benzamide; AMENDED SHEET a

PCT/USC0/18347 ® 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen-2-yl-ethyi)- benzamide, , 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)- benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-morpholin-4-yi- ethyl)-benzamide;

' 5.Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin- 4-ylmethyl-benzamide; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-yimethyi- benzamide; y 2-(4-Bromo-2-methyl-phenylamino)-N-(3-dimethylaminoc- propyl)-3,4-difluoro-benzamide;

a. 4-Fluoro-2-(4-iodo-2-methyl-phenylamin)-N-pyridin-4-yimelhyl- benzamide; . ! 4-F luoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrid in-4-yl-ethyl)- . benzamide; ’ 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluo ro-N-(2-pyridin4-yl-ethyl)- benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(3-hydroxy-propyl)- benzamide; 2-(4-B romo-2-methyl-phenylaminc)-3 ,4-difluoro-N-(2-pyrrolidin-1-yi- ethyl)-benzamide; 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyi-benzamide: 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-thiophen-2-yi- : ethyl)-benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyridin-4-yimethyk- benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-phenethyl- benzamide; 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-piperidin-1-yl- ethyl)-benzamide; 5-Chloro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1 -y{]-propyl}-2-(4-icdo- 2-methyl- phenylamino)- benzamide; AMENDED SHEET

® | PCT/US00/18347 5-Fluoro-N-{3-[4-(2-hyd roxy-ethyl)-piperazin-1-yl}-propyl}-2-(4-iodo- 2-methyl- phenylamino)- benzamide; 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methyl- benzamide; : 5-Bromo-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yi}-pro pyl}-2-(4-iodo- 2-methyl- phenylamino)- benzamide; 5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5_Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl-ethyl)- benzamide; (3-Hydroxy-pyrrolidin-1 -yD-[2-(4-iodo-2-methyl-p henylamino)-5-nitro- : phenyl]-methanone; | : 5-Chloro-2-(4-iodo-2-methyl-phénylamino)-N-(2-pyrrolidin-1 -yl-ethyi)- benzamide; | » 5-Bromo-N-(2-diethylamino-ethyf)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-chloro-2-(4-iodo-2-methyl- ‘phenylamino)- benzamide; : N~{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-bromo-2-(4-iodo-2-methyl- i | phenylamino)- benzamide; . : N-{3-[4-(2-Hyd roxy-ethyl)-piperazin-1-yi}-pro pyi}-2-(4-iodo-2-methyl- phenylamino)- benzamide; = 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-yimethy- benzamide; 5-Bromo-2-(4-iodo-2-ethyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)- benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl-ethyl)- benzamide; 5-F Juoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1 -yl-ethyl)- benzamide; 5-Chloro-N~(3-dimethylamino-propyl)-2-(4-iodo-2-methyl-phenytamino)- benzamide; AMENDED SHEET CL

® , PCT/US00/18347 N~{2-[Bis-(2-hydroxy-ethyl)-amino}-ethyl}-5-fluoro-2-(4-iodo-2-methyi- phenylamino)- benzamide; 5-Chloro-N-(3-hydroxy-propyi}-2-(4-iodo-2-methyl-phenylamino)- benzamide, 5-Chloro-N-(3-diethylamino-2-hydroxy-propy!)-2-(4-iodo-2-methyi- phenylamino)- benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl-ethyl)- : benzamide; 5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; : 5-Bromo-2-(4-iodo-2-methyl-phenyfaminp)-N-(3-piperidin-1-yl-propyl)- ¥ benzamide: : : N-{2-[Bis~{2-hydroxy-ethyl)-amino}-ethy(}-2-(4-iodo-2-methyi- phenylamino)-5-nitro- benzamide; v 5-Chioro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)- oo - benzamide, 5-Chloro-N-(3-diethylamino-propyl)-2-{(4-iodo-2-methyl-phenylamino)- ‘benzamide; Co 5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyi- phenylamino)-benzamide; 5-Chloro-2-(4-iodo-2-methyi-phenylamino)-N-(3-piperidin-1-yl-p ropyl)- benzamide; 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(2-pipe ridin-1-yl-ethyl)- benzamide; 5-Bromo-2-4-iodo-2-methyl-phenytamino)-N-(2-piperazin-1-yi-ethyl)- benzamide; N-(2-Diethylaminc-ethyi)-5-fiuoro-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-N~3-dimethytamino-propyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N~(3-Hydroxy-propyf)-2-(4-iodo-2-methy-phenylamino)-5-nitro- : benzamide; AMENDED SHEET

PCT/US00/18347 @® 5-Fluoro-N-(3-hydroxy-propyi)-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-(3-Diethylamino-propyl)-5-flucro-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-(3-Diethylarmino-propyl)-2-(4-iodo-2-methyl-phenytamino)-5-nitro- benzamide, 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)- benzamide; : 2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin-1 -yl-propyl)- benzamide; 1-[5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-1-(3-hydroxy- pyrrolidin-1-yl)-methanone; Co 5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-metHyi- phenylamino)-benzamide; 5-Fluoro-2-(4-iod o-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)- benzamide,; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl)- benzamide, a 1-[5-Fluoro-2-{4-iodo-2-methyl-phenylamino)-phenyl]-1-[4-(2-hydroxy- ethyl)-piperazin-1 -yll-methanone; N-(3-Dietfjylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo-2-methyl- phenylamino)- benzamide; N-Cyclopropyi-5-fluoro-2-(4-iodo-2-methyl-phenytamino)-benzamide; © 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-icdo-2-methyl-phenylamino)- benzamide; 5-Fluoro-N-(2-hydroxy-ethyl)-2-{4-iodo-2-methyi-phenylamino)- benzamide; | : N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Benzyloxy-5-bromo-2-{4-iodo-2-methyi-phenylamino)-benzamide; 2-(4-lodo-2-methyl-phenylaminc)-5-nitro-N-{4-suifamoyl-benzyi)- benzamide; 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo:-2-methyl-phenylamino)- benzamide; : AMENDED SHEET

PCT/US00/18347 ® N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- benzamide; N-(2-Hydroxy-ethyl)-2-(4-iodo-2-ethyl-phenylamino)-5-nitro-benzamide; 2-(4-lodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyi- benzamide; 5-Chloro-N-cyclopropyi-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Fluoro-2-{4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyf)- benzamide; N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyil-phenylamino)-benzamide; " oo 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyi- benzamide; 5-lodo-2-{4-icdo-2-methyl-phenylamino)-N-(4-sulfamoyi-benzyl)- benzamide; : 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- benzamide:. : N-Allyl-2-(4-iodo-2-methyl-phenylaminc)-5-nitro-benzamide; 2-(4-lodo- 2-methyl-phenylamino)-5-nitro-N-{4-sulfamoyi-benzyl)- benzamide; N-Allyt-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; Fluoro-2-{4-iodo-2-methyl-phenytamino)-N-(3-methyl-benzyl)- benzamide; . N-Cyclopropyl-5-iodo-2-(4-icdo-2-methyl-phenylamino)-benzamide; 5-Bromo-2-(4-icdo-2-methyt-phenylamino)-N-methyl-N-phenyi- benzamide; oo N-Benzyloxy-2-(4-iodo-2-methyi-phenylamino)-S-nitro-benzamide; N-Cyclohexyl-5-icdo-2-{4-icdo-2-methyl-phenytamino)-benzamide; N-Allyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide; = AMENDED SHEET

PCT/US00/18347 ® 5-lodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide; 2-(4-lodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-nitro- benzamide; 5-lodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamine)-benzamide; 5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- benzamide; 5-Bromo-N-cyciohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide;

: ._. 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)- ¥ benzamide; i N-Cyclohexyt-2-(4-iodo-2-methyi-phenylamino)-5-nitro-benzamide; N-Benzyloxy-5-bromo-2-(4-iodo-2-methyi-phenylamino)-benzamide; N-Benzyloxy-5-fiuoro-2-(4-iodo-2-methyl-phenylamino)-benzamide: 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 2-(4-lodo-2-methyl-phenylamino)-N-methyi-5-nitro-N-phenyi- benzamide; 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl- benzamide; oo N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)- : benzamide; 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenytamino)-benzamide; : | N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Fluoro-2-{4-iodo-2-methyl-phenylaminc)-N-methyi-N-phenyl- ‘benzamide: N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro- benzamide; a AMENDED SHEET

PCT/US00/18347 ® 5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)- benzamide; 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenyiamino)-benzamide: N-Cyclopropyi-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Fluoro-2-{4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- ~ benzamide; - N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; : N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide; : N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide; N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide; 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)- -benzamide; : 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-rijethyl-N-phenyl- benzamide; and i N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide.

48. The use of claim 35 wherein Z is CH,OR>. oo

49. The use of claim 48, wherein the MEK ihibitor has the formula . H,OR - EE 277 R; H oY = : Brorl Ry Ry wherein: oo : Rq is CH3 halo.

50. The use of claim 49 wherein: Rs is hydrogen, chloro, or fluoro; Ra is hydrogen, chloro, fluoro, or nitro; and Rg is hydrogen, chloro, fluoro, bromo, nitro, or methoxy. AMENDED SHEET -

® PCT/US00/18347

51. The use of claim 50, said compound being 4A-Fluoro-2-{4-iodo-2-methyl-phenylamino)-benzyl alcohol; : [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol; [2-(4-lodo-2-methyl-phenylamino}-5-nitro-phenyl]-methanol; and [5-Bromo-2-{4-iodo-2-methyl-phenyiamino)-phenyl]-methanol.

52. The use of claim 1, wherein said MEK has a structure selected from: 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropyimethoxy-3, 4-difluoro- " benzamide; N-Cyclopropyimethoxy-3,4,5-trifuoro-2-(4-icde-2-methyi-phenylamino)- k benzamide; . - : N-Cyclopropylmethoxy-3,4,5-trifucro-2-(4-iodo-2-methyl-phenylamino)- : benzamide, potassium salt; ) ; 2-(2-Chloro-4-icdo-phenytamino)-N-cyclobutyimethoxy-3,4-diftuoro- benzamide; 2-(2-Chloro—4-iodo-phenyiamino)-N-cyclopropyimethoxy-4-fiucro- benzamide; 5_Bromo-3,4-difiuoro-2-(4-iodo-2-methyl-phenylamino)-N-methoxy- benzamide; 3 4-Difluoro-N-hydroxy-2-(4-iodo-2-methyk-phenyiaminc)-benzamide; : 5-Brome-2-(2-chloro—4-iodo-phenylamino)-3,4-difluoro-N-hydroxy- benzamide; 5-Bromo-2-{2-chioro-4-icde-phenylamine)-3,4-diflucro-N-hydroxy- : benzamice; . N-Cyclopropyimethoxy-3,4-difluoro-2-(4-icdo-2-methyl-phenyiamine)- benzamide; : AMENDED SHEET .

PCT/US00/18347 ® 5-Bromo-N-cyclobutylmethoxy-3,4-diflucro-2-4-iodo-2-methyi- phenylamino)-benzamide; 5-Bromo-N-cyclopropyimethoxy-3,4-diflucro-2-(4-iodo-2-methyl- phenylaminc)-benzamide; 5-Chloro-N-cyclopropylmethoxy-3,4—difiuoro-2{4-iodo-2-methyl- phenylamino)-benzamide; 5-Chloro-2-(2-chioro-4-iodo-phenylamino)-N-cyciopropyimethoxy-3,4- diflucro-benzamide; : 4-Fluoro-N-hydroxy-2-(4-icdo-2-methyl-phenyiamino)-benzamide; 4-Fluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)-benzamide, hydrochloride salt; : 5-Bromo-3,4-difluoro-N-hydroxy-2-(4-iodo-2-methyl-phenylamino)- benzamide,; I 2-(2-Chloro-4-iodo-phenytamine)-3,4-difluoro-N-(2-hydroxy-ethoxy)- : benzamide;

3. 4-Difluoro-N-(2-hydroxy-ethuxy)-2-(4-iodo-2-methyi-phenylamino)- benzamide; ’ 5-Bromo-2-(2-chioro-4-iodo-phenylamine)-3,4-difluoro-N-(3-hydroxy- propoxy)-benzamide; So 2-(2-Chloro-4-iodo-phenylamino)-3,4, 5-trifluoro-N-(3-hydroxy-propoxy)- benzamide; : 2-(2-Chlaro-4-iodo-phenylamino)-3,4,5-trifluorc-N-{2-(2-methoxy- SE ethoxy)-ethoxyl-benzamide; : 2-(2-C hloro—4-iodo-phenytamino)-3 A-difluoro-N-(3-hydroxy-propoxy)- benzamide; ) 5-Bromo-3, 4-difluoro-N-(3-hydroxy-propoxy)-2-(4-iedo-2-methyl- phenylamino)-benzamide;

3.4, 5-Trifluoro-N~(3-hydroxy-propoxy)-2-{4-icdo-2-methyk- : phenylamino)-benzamide; 3,4, 5-Trifiuoro-N-(2-hydroxy-ethoxy)-2-{4-iode-2-methyk-phenylamino)- benzamide; 2_(2-Chioro—4-iodo-phenylaming)-3,4-difiucrc-N-(2-hydroxy-sthoxy)- benzamide; and : AMENDED SHEET

PCT/US00/18347 ® 3,4-Difluoro-N-{2-hydroxy-ethoxy)-2-(4-iodo-2-methyl-phenylamino)- benzamide.

53. The use of claim 1, wherein said MEK inhibitor has a structure selected from: 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- benzamide; N-Cyclopropylmethoxy-3,4,5-trifluoro-2-(4-iodo-2-methyl- phenylamino)-benzamide; 2-(2-Chloro-4-iodo-phenylamino)-3, 4-difluoro-N-(2-hydroxy-ethoxy)- benzamide; and 3,4 Difluoro-N-(2-hydroxy-ethoxy)-2-(4-ioffo-2-methyl-phenylamino)- benzamide. . a

54. The use of claim 26, wherein said MEK inhibitor has a structure . selected from: | : 2-(2-Chloro-4-iodo-phenylamino)-3,4difluoro-benzoic acid; 3,4,5-Trifluoro-2-(4-icdo-2-methyl-phenylaminc)-benzoic acid; ~~ 5-Bromo-2-{2-chloro4-icdo-phenylamino)-3,4-difluocro-benzoic acid; 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; 5-Bromo-3,4-difluoro-2-{4-iodo-2-methyi-phenylamino)-benzoic acid; 2-(2-Chioro-4-iodo-pyenylamino)-3,4-difluoro-5-nitro-benzoic acid; 2-(2-Chloro-4-iodo-phenylamino)-3,4,5-triflucro-benzoic acid; 7-Fluoro-6-(4-iodo-2-methyl-phenyiamino)1 H-benzoimidazole-5- : : carboxylic acid cyclopropyimethoxy-amide; 5-Chloro-3,4-difluoro-2-{4-iodo-2-methyi-phenylamino)-benzoic acid; and : 5-Chioro-2-(2-chioro-4-iodo-phenylamino)-3,4-diflucro-benzoic acid.

B5. The use of claim 26, wherein said MEK inhibitor has a structure selected from: AMENDED SHEET :

PCT/US00/18347 2-(2-Chloro-4-iodo-phenylamino}-3,4-difluoro-benzoic acid; and 7-Fluoro-6-(4-iodo-2-methyl-phenylamino) 1 H-benzoimidazole-5- carboxylic acid cyclopropylmethoxy-amide.

56. The use of claim 1, wherein said MEK inhibitor is 2-(2-Chloro-4-iodo- phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide.

57. Use of a MEK inhibitor which is : 2,3,5-Trifluoro-4-(4-iodo-2-methyl-phenylamino)-benzoic acid; 2,3,5-Trifluoro-6-(4-iodo-2-methyl-phenylamino)-4-(4-methyl-piperazin- 1-yl)- benzoic acid methyl ester dihydrofluoride salt; and 2,4-Bis-(2-chloro-4-iodo-phenylamino)-3-fluoro-5-nitro-benzoic acid, in the manufacture of a medicament for treating chronic pain.

58. A substance or composition for use in a method for treating chronic oo pain, said substance or composition comprising a MEK inhibitor of Formula 1 as defined in claim 1, said method comprising administering said substance or composition to a subject in need of such treatment.

59. A substance or composition for use in a method of treatment according to claim 58, wherein said chronic pain is selected from neuropathic pain, idiopathic pain, and pain associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism.

60. A substance or composition for use in a method of treatment according to claim 59, wherein said chronic pain is a type of neuropathic “pain.

61. A substance or composition for use in a method of treatment according to claim 60, wherein said neuropathic pain is associated with one AMENDED SHEET

PCT/US00/18347 of the following: inflammation, postoperative pain, phantom limb pain, burn ° pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, viral $ infection, crush injury, constriction injury, tissue injury, limb amputation, arthritis pain, and any other nerve injury between the peripheral nervous system and the central nervous system, inclusively.

62. A substance or composition for use in a method of treatment according to claim 59, wherein said chronic pain is associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism.

63. A substance or composition for use in a method of treatment according to claim 59, wherein said chronic pain is associated with idiopathic pain.

64. A substance or composition for use in a method of treatment according to claim 58, wherein said chronic pain is associated with inflammation.

65. A substance or composition for use in a method of treatment according to claim 58, wherein said chronic pain is associated with arthritis.

66. A substance or composition for use in a method of treatment "according to claim 58, wherein said chronic pain is associated with post- operative pain.

67. A substance or composition for use in a method of treatment according to claim 58, wherein R4 is C41-Cg alkyl or halo.

68. A substance or composition for use in a method of treatment according to claim 67 wherein Rg is hydrogen. : AMENDED SHEET

PCT/US00/18347

69. A substance or composition for use in a method of treatment according to claim 68 wherein R4 is methyl. ’

70. A substance or composition for use in a method of treatment according to claim 69 wherein the MEK inhibitor has the formula § CH; -C — NHOR, B : N I” ) Rj Rs Ry -

71. A substance or composition for use in a method of treatment - according to claim 70 wherein Ry4 is fluoro, and Rg and Rg are hydrogen.

72. A substance or composition for use in a method of treatment according to claim 71, wherein said MEK inhibitor has a structure selected from the compounds listed in claim 15. :

73. A substance or composition for use in a method of treatment according to claim 70 wherein R43 and Ry are fluoro, and Rg is hydrogen. :

74. A substance or composition for use in a method of treatment oo according to claim 73, wherein said MEK inhibitor has a structure selected from the compounds listed in claim 17.

75. A substance or composition for use in a method of treatment’ according to claim 70 wherein R3 and Ra are fluoro, and Rg is bromo. AMENDED SHEET -

PS PCT/US00/18347

76. A substance or composition for use in a method of treatment according to claim 75, wherein said MEK inhibitor has a structure selected from the compounds listed in claim 19.

77. A substance or composition for use in a method of treatment according to claim 70 wherein R45 and R, are hydrogen, and:Rg is halo.

78. A substance or composition for use in a method of treatment according to claim 77, wherein said MEK inhibitor has a structure selected from the compounds listed in claim 21. : 79. A substance or composition for use in a method of treatment ) N according to claim 69, wherein the MEK inhibitor has the formula: 11 oo CH; C —NHOR, or Br Rs TT . Rs oo

80. A substance or composition for use in a method of treatment . : according to claim 79 wherein R45 and Ry are fluoro, and Rg is hydrogen.

81. A substance or composition for use in a method of treatment according to claim 80, wherein said MEK inhibitor has selected from the . compounds listed in claim 24.

82. A substance or composition for use in a method of treatment according to claim 58, wherein said MEK inhibitor has a structure selected from the compounds listed in claim 25. AMENDED SHEET

PCT/US00/18347

83. A substance or composition for use in a method for treating chronic pain, said substance or composition comprising a MEK inhibitor of Formula 1(A) as defined in claim 28, and said method comprising administering said substance or composition to a subject in need of such treatment.

84. A substance or composition for use in a method of treatment according to claim 83, wherein said chronic pain is selected from neuropathic pain, idiopathic pain, and pain associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism.

85. A substance or composition for use in a method of treatment according to claim 84, wherein said chronic pain is a type of neuropathic pain.

86. A substance or composition for use in a method of treatment according to claim 85, wherein said neuropathic pain is associated with one of the following:- inflammation, postoperative pain, phantom limb pain, burn : pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, ’ causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, viral infection, crush injury, constriction injury, tissue injury, limb amputation, arthritis pain, and any other nerve injury between the peripheral nervous system and the central nervous system, inclusively.

87. A substance or composition for use in a method of treatment ~according to claim 84, wherein said chronic pain is associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism.

88. A substance or composition for use in a method of treatment according to claim 84, wherein said chronic pain is associated with idiopathic pain. AMENDED SHEET

PCT/US00/18347

89. A substance or composition for use in a method of treatment according to claim 83, wherein said chronic pain is associated with inflammation.

90. A substance or composition for use in a method of treatment according to claim 83, wherein said chronic pain is associated with arthritis.

. 91. A substance or composition for use in a method of treatment : according to claim 83, wherein said chronic pain is associated with post- : operative pain.

92. A substance or composition for use in a method of treatment - according to claim 83, wherein Rq is CHg or halo.

93. A substance or composition for use in a method of treatment according to claim 92 wherein Z is COOR5, tetrazolyl, or a salt thereof. : 94. A substance or composition for use in a method of treatment Co _ according to claim 93, wherein said MEK inhibitor has a structure selected : from the compounds listed in claim 37.

95. A substance or composition for use in a method of treatment according to claim 92, wherein the MEK inhibitor has the formula CH, - 3 4 C-0OH BON AMENDED SHEET

PCT/US00/18347

96. A substance or composition for use in a method of treatment according to claim 85 wherein R3 is hydrogen, fluoro, or chloro; Ryq is hydrogen, fluoro, chloro, or nitro; and Rg is hydrogen, chloro, fluoro, bromo, - nitro, or methoxy. :

87. A substance or composition for use in a method of treatment according to claim 96, wherein said MEK inhibitor has a structure selected from the compounds listed in claim 40.

98. A substance or composition for use in a method of treatment according to claim 92 wherein the MEK inhibitor has the formula 0 : I - CH C-0OH 3 nu So Re | oo

99. A substance or composition for use in a method of treatment - : according to claim 98 wherein Rg is hydrogen, chloro, or fluoro; Rg is hydrogen, chloro, fluoro, or nitro; Rg is hydrogen, chloro, fluoro, bromo, oo nitro, or methoxy. :

100. A substance or composition for use in a method of treatment according to claim 83, wherein said MEK inhibitor has a structure selected So : from the compounds listed in claim 43. :

101. A substance or composition for use in a method of treatment according to claim 92 wherein Z is CONRgR-. AMENDED SHEET

: PCT/US00/18347

102. A substance or composition for use in a method of treatment according to claim 101, wherein the MEK inhibitor has the formula defined in claim 45.

103. A substance or composition for use in a method of treatment according to claim 102 wherein R4 is hydrogen, chloro, or fluoro; Ry is hydrogen, chloro, fluoro, or nitro; and Rg is hydrogen, chloro, fluoro, bromo, nitro, or methoxy. - 104. A substance or composition for use in a method of treatment according to claim 83, wherein said MEK inhibitor has a structure selected from the compounds listed in claim 47. } 105. A substance or composition for use in a method of treatment according to claim 92 wherein Z is CH,OR7.

106. A substance or composition for use in a method of treatment according to claim 105 wherein the MEK inhibitor has the formula defined in claim 49.

107. A substance or composition for use in a method of treatment according to claim 106 wherein: Rg is hydrogen, chloro, or fluoro; Ry is hydrogen, chloro, fluoro, or nitro; and Rg is hydrogen, chloro, fluoro, bromo, nitro, or methoxy.

108. A substance or composition for use in a method of treatment according to claim 107, said compound being 4-Fluoro-2-{4-iodo-2-methyl-phenylamino)-benzyl alcohol; [5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol; [2-(4-lodo-2-methyl-phenylamino)-5-nitro-phenyl]-methanol; and [5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol. AMENDED SHEET

PCT/US00/18347

109. A substance or composition for use in a method of treatment according to claim 58, wherein said MEK inhibitor has a structure selected from the compounds listed in claim 52.

110. A substance or composition for use in a method of treatment according to claim 58, wherein said MEK inhibitor has a structure selected from the compounds listed in claim 53.

111. A substance or composition for use in a method of treatment according to claim 83, wherein said MEK inhibitor has a structure selected from the compounds listed in claim 54.

112. A substance or composition for use in a method of treatment - according to claim 83, wherein said MEK inhibitor has a structure selected from the compounds listed in claim 55.

113. A substance or composition for use in a method of treatment : according to claim 58, wherein the said MEK inhibitor is: 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro- : ~ benzamide.

114. A substance or composition for use in a method for treating chronic pain, said substance or composition comprising a MEK inhibitor which is selected from: 2,3,5-Trifluoro-4-(4-iodo-2-methyl-phenylamino)-benzoic acid; : 2,3,5-Trifluoro-6-(4-iodo-2-methyl-phenylamino)-4-(4-methyl-piperazin- 1-yl)-benzoic acid methyl ester dihydrofluoride salt; and 2,4-Bis-(2-chloro-4-iodo-phenylamino)-3-fluoro-5-nitro-benzoic acid, and said method comprising administering said substance or composition to a subject in need of such treatment. AMENDED SHEET

PCT/US00/18347

115. The use of a MEK inhibitor as claimed in any one of claims 1 to 57, substantially as herein described and illustrated.

116. A substance or composition for use in a method of treatment as claimed in any one of claims 58 to 1 14, substantially as herein described and illustrated. .

117. A new use of a MEK inhibitor, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET