Allenic aryl sulfonamide hydroxamic acids as matrix metalloproteinase and TACE inhibitors

1. A compound of Formula (I):

wherein:

X is —S—, —SO—, —SO 2 — or —P(O)—R 8 ;

Y is aryl or heteroaryl, with the proviso that X and Z may not be bonded to adjacent atoms of Y;

Z is —O—, —NH—, —CH 2 — or —S—;

R 1 is hydrogen, aryl, heteroaryl, C 5 -C 8 cycloheteroalkyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms;

R 2 is hydrogen, aryl, heteroaryl, cycloalkyl of 3 to 6 carbon atoms, C 5 -C 8 cycloheteroalkyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms;

or R 1 and R 2 , taken together with the atoms to which they are attached, may form a 3 to 7 membered cycloalkyl or cycloheteroalkyl ring;

R 3 is hydrogen, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms;

or R 1 and R 3 , together with the atoms to which they are attached, may form a 5 to 8 membered ring wherein R 1 and R 3 represent divalent moieties of the formulae:

A is aryl or heteroaryl;

Q is a C—C single or double bond, —O—, —S—, —SO—, —SO 2 —, —NR 11 , or —CONR 12 ;

s is an integer of 0 to 3;

u is an integer of 1 to 4;

m is an integer of 1 to 3;

R 4 and R 5 are each, independently, hydrogen or alkyl of 1 to 6 carbon atoms;

R 6 and R 7 are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, heteroaryl or C 5 -C 8 -cycloheteroalkyl;

or R 6 and R 7 , together with the atom to which they are attached, may form 3 to 7 membered cycloalkyl or cycloheteroalkyl ring;

R 8 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or heteroaryl;

R 9 and R 10 are each, independently, selected from H, —OR 13 , —NR 13 R 14 , alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, heteroaryl, —COOR 13 ; or —CONR 13 R 14 ; or R 9 and R 10 taken together form a C 3 -C 6 -cycloalkyl of 3 to 6 carbon atoms or a C 5 -C 8 -cycloheteroalkyl ring; or R 9 and R 10 taken together with the carbon to which they are attached, form a carbonyl group;

R 11 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloheteroalkyl of 3 to 6 carbon atoms, aryl, heteroaryl, —S(O) n R 13 , —COOR 13 , —CONR 13 R 14 , —SO 2 NR 13 R 14 or —COR 13 , and n is an integer of 0 to 2;

R 12 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms; and

R 13 and R 14 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl or C 5 -C 8 -cycloheteroalkyl;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 wherein Y is aryl and X is —SO 2 — or a pharmaceutically acceptable salt thereof.

3. A compound of claim 2 wherein Y is phenyl or a pharmaceutically acceptable salt thereof.

4. A compound of claim 1 wherein Y is aryl and X is —SO 2 —, Z is oxygen and R 4 , R 5 and R 6 are hydrogen or a pharmaceutically acceptable salt thereof.

5. A compound of claim 4 wherein Y is phenyl or a pharmaceutically acceptable salt thereof.

6. A compound of claim 1 wherein Y is aryl and X is —SO 2 — and Z is oxygen, R 4 , R 5 and R 6 are hydrogen, R 7 is hydrogen or methyl and R 2 is isopropyl or a pharmaceutically acceptable salt thereof.

7. A compound of claim 6 wherein Y is phenyl or a pharmaceutically acceptable salt thereof.

8. A compound of claim 1 wherein Y is aryl and R 1 and R 3 together with the atoms to which each is attached form a thiomorpholine ring or a pharmaceutically acceptable salt thereof.

9. A compound of claim 8 wherein Y is phenyl or a pharmaceutically acceptable salt thereof.

10. A compound of claim 9 wherein the absolute stereochemistry is shown by the formula:

or a pharmaceutically acceptable salt thereof.

11. A compound of claim 1 selected from the group consisting of:

2-({[4-(2,3-Butadienyloxy)phenyl]sulfonyl}amino)-N-hydroxy-3-methylbutanamide,

2-[{[4-(2,3-Butadienyloxy)phenyl]sulfonyl}(methyl)amino]-N-hydroxy-3-methylbutanamide,

N-Hydroxy-3-methyl-2-({[4-(2,3-pentadienyloxy)phenyl]sulfonyl}amino)butanamide,

N-Hydroxy-3-methyl-2-(methyl{[4-(2,3-pentadienyloxy)phenyl]sulfonyl}amino)butanamide,

(3S)-4-{[4-(2,3- Butadienyloxy)phenyl]sulfonyl}-N-hydroxy-2,2-dimethyl-3-thiomorpholinecarboxamide,

(3S)-N-Hydroxy-2,2-dimethyl-4-{[4-(2,3-pentadienyloxy)phenyl]sulfonyl}-3-thiomorpholinecarboxamide,

1-Acetyl-4-{[4-(2,3-butadienyloxy)phenyl]sulfonyl}-N-hydroxy-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-3-carboxamide,

1-Benzoyl-4-(4-buta-2,3-dienyloxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-3-carboxylic acid hydroxyamide and

1-Benzoyl-N-hydroxy-4-{[4-(2,3-pentadienyloxy)phenyl]sulfonyl}-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-3-carboxamide.

12. A method of treating a pathological condition mediated by TNF-α converting enzyme (TACE) in a mammal in need thereof which comprises administering to said mammal a therapeutically effective amount of a compound having the formula

wherein:

X is —S—, —SO—, —SO 2 — or —P(O)—R 8 ;

Y is aryl or heteroaryl, with the proviso that X and Z may not be bonded to adjacent atoms of Y;

Z is —O—, —NH—, —CH 2 — or —S—;

R 1 is hydrogen, aryl, heteroaryl, C 5 -C 8 cycloheteroalkyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms;

R 2 is hydrogen, aryl, heteroaryl, cycloalkyl of 3 to 6 carbon atoms, C 5 -C 8 cycloheteroalkyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms;

R 1 and R 2 , taken together with the atoms to which they are attached, may form a 3 to 7 membered cycloalkyl or cycloheteroalkyl ring;

R 3 is hydrogen, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, or alkenyl of 2 to 6 carbon atoms;

or R 1 and R 3 , together with the atoms to which they are attached, may form a 5 to 8 membered ring wherein R 1 and R 3 represent divalent moieties of the formulae:

A is aryl or heteroaryl;

Q is a C—C single or double bond, —O—, —S—, —SO—, —SO 2 —, —NR 11 , or —CONR 12 ;

s is an integer of 0 to 3;

u is an integer of 1 to 4;

m is an integer of 1 to 3;

R 4 and R 5 are each, independently, hydrogen or alkyl of 1 to 6 carbon atoms;

R 6 and R 7 are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, aryl, heteroaryl or C 5 -C 8 -cycloheteroalkyl;

or R 6 and R 7 , together with the atom to which they are attached, may form 3 to 7 membered cycloalkyl or cycloheteroalkyl ring;

R 8 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or heteroaryl;

R 9 and R 10 are each, independently, selected from H, —OR 13 , —NR 13 R 14 , alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, heteroalryl, —COOR 13 ; or —CONR 13 R 14 ; or R 9 and R 10 taken together form a C 3 -C 6 -cycloalkyl of 3 to 6 carbon atoms or a C 5 -C 8 -cycloheteroalkyl ring; or R 9 and R 10 taken together with the carbon to which they are attached, form a carbonyl group;

R 11 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, heteroalryl, —S(O) n R 13 , —COOR 13 , —CONR 13 R 14 , —SO 2 NR 13 R 14 or —COR 13 , and n is an integer of 0 to 2;

R 12 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms; and

R 13 and R 14 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl or C 5 -C 8 -cycloheteroalkyl;

or a pharmaceutically acceptable salt thereof;

wherein the condition treated is rheumatoid arthritis, ulcerative colitis, multiple sclerosis, graft rejection, cachexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease of HIV.

13. A pharmaceutical composition comprising a compound having the formula

wherein:

X is —S—, —SO—, —SO 2 — or —P(O)—R 8 ;

Y is aryl or heteroaryl, with the proviso that X and Z may not be bonded to adjacent atoms of Y;

Z is —O—, —NH—, —CH 2 — or —S—;

R 1 is hydrogen, aryl, heteroaryl, C 5 -C 8 cycloheteroalkyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms;

R 2 is hydrogen, aryl, heteroaryl, cycloalkyl of 3 to 6 carbon atoms, C 5 -C 8 cycloheteroalkyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms;

or R 1 and R 2 , taken together with the atoms to which they are attached, may form a 3 to 7 membered cycloalkyl or cycloheteroalkyl ring;

R 3 is hydrogen, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms;

or R 1 and R 3 , together with the atoms to which they are attached, may form a 5 to 8 membered ring wherein R 1 and R 3 represent divalent moieties of the formulae:

A is aryl or heteroaryl;

Q is a C—C single or double bond, —O—, —S—, —SO—, —SO 2 —, —NR 11 , or —CONR 12 ;

s is an integer of 0 to 3;

u is an integer of 1 to 4;

m is an integer of 1 to 3;

R 4 and R 5 are each, independently, hydrogen or alkyl of 1 to 6 carbon atoms;

R 6 and R 7 are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, aryl, heteroaryl or C 5 -C 8 -cycloheteroalkyl;

or R 6 and R 7 , together with the atom to which they are attached, may form 3 to 7 membered cycloalkyl or cycloheteroalkyl ring;

R 8 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or heteroaryl;

R 9 and R 10 are each, independently, selected from H, —OR 13 , —NR 13 R 14 , alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, aryl, heteroaryl, —COOR 13 ; or —CONR 13 R 14 ; or R 9 and R 10 taken together form a C 3 -C 6 -cycloalkyl of 3 to 6 carbon atoms or a C 5 -C 8 -cycloheteroalkyl ring; or R 9 and R 10 taken together with the carbon to which they are attached, form a carbonyl group;

R 11 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloheteroalkyl of 3 to 6 carbon atoms, aryl, heteroaryl, —S(O) n R 13 , —COOR 13 , —CONR 13 R 14 , —SO 2 NR 13 R 14 or —COR 13 , and n is an integer of 0 to 2;

R 12 is hydrogen, aryl, heteroaryl, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms; and

R 13 and R 14 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, aryl, heteroaryl or C 5 -C 8 -cycloheteroalkyl;

or a pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable carriers.

14. A process for preparing a compound of Formula (I):

wherein:

Y is aryl or heteroaryl, with the proviso that X and Z may not be bonded to adjacent atoms of Y;

Z is —O—, —NH—, —CH 2 — or —S—;

R 1 is hydrogen, aryl, heteroaryl, C 5 -C 8 cycloheteroalkyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms;

R 2 is hydrogen, aryl, heteroaryl, cycloalkyl of 3 to 6 carbon atoms, C 5 -C 8 cycloheteroalkyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms;

or R 1 and R 2 , taken together with the atoms to which they are attached, may form a 3 to 7 membered cycloalkyl or cycloheteroalkyl ring;

R 3 is hydrogen, cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms;

or R 1 and R 3 , together with the atoms to which they are attached, may form a 5 to 8 membered ring wherein R 1 and R 3 represent divalent moieties of the formulae:

A is aryl or heteroaryl;

Q is a C—C single or double bond, —O—, —S—, —SO—, —SO 2 —, —NR 11 , or —CONR 12 ;

s is an integer of 0 to 3;

u is an integer of 1 to 4;

m is an integer of 1 to 3;

R 4 and R 5 are each, independently, hydrogen or alkyl of 1 to 6 carbon atoms;

R 6 and R 7 are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, aryl, heteroaryl or C 5 -C 8 -cycloheteroalkyl;

or R 6 and R 7 , together with the atom to which they are attached, may form 3 to 7 membered cycloalkyl or cycloheteroalkyl ring;

R 8 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl or heteroaryl;

R 9 and R 10 are each, independently, selected from H, —OR 13 , —NR 13 R 14 , alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, aryl, heteroaryl, —COOR 13 ; or —CONR 13 R 14 ; or R 9 and R 10 taken together form a C 3 -C 6 -cycloalkyl of 3 to 6 carbon atoms or a C 5 -C 8 -cycloheteroalkyl ring; or R 9 and R 10 taken together with the carbon to which they are attached, form a carbonyl group;

R 11 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloheteroalkyl of 3 to 6 carbon atoms, aryl, heteroaryl, —S(O) n R 13 , —COOR 13 , —CONR 13 R 14 , —SO 2 NR 13 R 14 or —COR 13 , and n is an integer of 0 to 2;

R 12 is hydrogen, aryl, heteroaryl, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms; and

R 13 and R 14 are each, independently, hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, aryl, heteroaryl or C 5 -C 8 -cycloheteroalkyl;

or a pharmaceutically acceptable salt thereof

which comprises:

reacting a compound of the formula V:

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, Y and Z are as hereinbefore defined with an activating reagent forming an activating agent which is further reacted with hydroxylamine to give a corresponding compound of formula (I).

15. The process of claim 14 wherein the activating reagent is a chlorinating agent selected from the group consisting of thionyl chloride, chlorosulfonic acid, oxalyl chloride, and phosphorous pentachloride, or a halogenating agent selected from the group consisting of fluorosulfonic acid and thionyl bromide, a peptide coupling reagent selected from the group consisting of N,N′-Dicyclohexylcarbodiimide plus 1-hydroxybenzotriazole; Benzotriazol-1-yloxytris (dimethylamino)phosphonium hexafluorophosphate (BOP-reagent); N,N′-Bis[2-oxo-3-oxazolidinyl]phosphorodiamidic chloride (BOB-Cl); Diphenylphosphinyl chloride (DPP-Cl); Diethoxyphosphoryl cyanide; 2-Chloro-1-methylpyridinium iodide; Phenyldichlorophosphate plus imidazole; and ethyl chloroformate.