Substituted cyclic hydroxamates as inhibitors of matrix metalloproteinases

1. A method of treating rheumatoid arthritis in a mammalian subject by administering to said mammal in need of such treatment an effective amount of a compound according to the following formula:

or pharmaceutically acceptable salt thereof, wherein:

P is -D-E-G-Q-L-T-X-Y;

D is C(O);

E is absent or is selected from the group consisting of C 1-10 alkylene, C 2-10 alkenylene, and C 2-10 alkynylene;

G is absent or is selected from the group consisting of O, NR a1 , S(O) p , and C(O);

Q is absent or is selected from the group consisting of a C 3-13 carbocycle substituted with 0-5 R b , and a heterocycle wherein said heterocycle is piperazine substituted with 0-5 R b ;

L is absent or is selected from the group consisting of O, NR a1 , C(O), C(O)O, OC(O), C(O)NR a1 , NR a1 C(O), OC(O)NR a1 , NR a1 C(O)O, S(O) p , S(O) p NR a1 , and NR a1 S(O) p ;

T is absent or is selected from the group consisting of C 1-10 alkylene, C 2-10 alkenylene, and C 2-10 alkynylene;

X is absent or is selected from the group consisting of O, NR a1 , S(O) p , and C(O);

Y is selected from the group consisting of H and a C 3-10 carbocycle substituted with 0-5 R c ,

provided that E, G, Q, L, T, X and Y do not combine to form a N—N, N—O, O—N, O—O, S(O) p —O, O—S(O) p or S(O) p —S(O) p group;

M is an aromatic heterocycle selected from the group consisting of pyridyl, quinolyl, and isoquinolyl and substituted with 0-5 R d ;

R b at each occurrence is independently selected from the group consisting of C 1-6 alkyl optionally substituted with R c1 , O (primary, secondary, or tertiary)C 1 -C 8 alkyl, OH, Cl, F, —CN, NO 2 , NR a R a1 , C(O)R a , C(O)OR a , C(O)NR a R a1 , R a NC(O)NR a R a1 , OC(O)NR a R a1 , R a NC(O)OR a1 , S(O) 2 NR a R a1 , NR a S(O) 2 R a2 , NR a S(O) 2 NR a R a1 , OS(O) 2 NR a R a1 , S(O) p R a2 , CF 3 , CH 2 F, CHF 2 , CF 2 CH 3 , C(CH 3 ) 2 F, OCF 3 , OCHF 2 , OCH 2 CF 3 , a C 3-10 carbocyclic residue and C 3 -C 10 carbocyclyl(C 1-8 )alkyl, wherein said C 3-10 carbocyclic residue, and C 3 -C 10 carbocyclyl(C 1-8 )alkyl are optionally substituted with R c1 ;

R a , R a1 , and R a2 at each occurrence are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, wherein said alkyl, alkenyl and alkynyl groups are optionally substituted with O (primary, secondary, or tertiary)C 1 -C 8 , OH, Cl, F, —CN, alkylamino, dialkylamino, alkarylamino, arylamino, alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, carboxyl, alkylcarboxylate, alkylamido, dialkylamido, alkylureidoalkyl, alkylureidodialkyl, carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl, sulfonamidodialkyl, N-alkylsulfonamidoalkyl, N-alkylsulfonamidoalkyl, N-alkylsufonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate, alkylsulfinyl, alkylsulfonyl, CF 3 , CF 2 CF 3 , CH 2 F, CHF 2 , CF 2 CH 3 , C(CH 3 ) 2 F, OCF 3 , and OCH 2 CF 3 ; C 3 -C 10 carbocycle, C 3 -C 10 carbocyclylalkyl, and wherein said C 3 -C 10 carbocycle and C 3 -C 10 carbocyclylalkyl may be optionally substituted with one or more substituents selected from the group consisting of C 1 -C 8 alkyl, O (primary, secondary, or tertiary)C 1 -C 8 alkyl, OH, Cl, F, Br, ═O, —CN, NO 2 , alkylamino, dialkylamino, alkarylamino, arylamino, alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, carboxyl, alkylcarboxylate, alkylamido, dialkylamido, alkylureidoalkyl, alkylureidodialkyl, carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl, sulfonamidodialkyl, N-alkylsulfonamidoalkyl, N-alkylsulfonamidoalkyl, N-alkylsufonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate, alkylsulfinyl, alkylsulfonyl, CF 3 , CH 2 F, CHF 2 , CF 2 CH 3 , C(CH 3 ) 2 F, OCF 3 , and OCH 2 CF 3 ;

R c at each occurrence is independently selected from the group consisting of C 1-6 alkyl optionally substituted with R c1 , OR a , Cl, F, —CN, NO 2 , NR a R a1 , C(O)R a , C(O)OR a , C(O)NR a R a1 , R a NC(O)NR a R a , OC(O)NR a R a1 , R a NC(O)OR a1 , S(O) 2 NR a R a1 , NR a S(O) 2 R a2 , NR a S(O) 2 NR a R a1 , S(O) p R a2 , CF 3 , CH 2 F, CHF 2 , CF 2 CH 3 , C(CH 3 ) 2 F, OCF 3 , OCHF 2 , OCH 2 CF 3 , a C 3-10 carbocyclic residue and C 3 -C 10 carbocyclyl(C 1-8 )alkyl, wherein said C 3-10 carbocyclic residue and C 3 -C 10 carbocyclyl(C 1-8 )alkyl are optionally substituted with R c1 ;

R c1 at each occurrence is independently selected from the group consisting of C 1-6 alkyl, OR a , Cl, F, Br, ═O, —CN, NO 2 , NR a R a1 , C(O)R a , C(O)OR a , C(O)NR a R a1 , OC(O)NR a R a1 , R a NC(O)OR a , S(O) 2 NR a R a1 , NR a S(O) 2 R a2 , S(O) p R a2 , CF 3 , and CH 2 F, and CHF 2 ;

R d at each occurrence is independently selected from the group consisting of H, C 1-6 alkyl optionally substituted with R c1 , OR a , Cl, F, Br, ═O, —CN, NO 2 , NR a R a1 , C(O)R a , C(O)OR a , C(O)NR a R a1 , R a NC(O)NR a R a , OC(O)NR a R a1 , R a NC(O)OR a1 , S(O) 2 NR a R a1 , NR a S(O) 2 R a2 , OS(O) 2 NR a R a1 , S(O) p R a2 , CF 3 , CF 2 CF 3 , CH 2 F, CHF 2 , CF 2 CH 3 , C(CH 3 ) 2 F, OCF 3 , OCHF 2 , OCH 2 CF 3 , a C 3-10 carbocyclic residue and C 3 -C 10 carbocyclyl(C 1-8 )alkyl wherein said C 3-10 carbocyclic residue and C 3 -C 10 carbocyclyl(C 1-8 )alkyl are optionally substituted with R c1 ;

and p at each occurrence is 0, 1, and 2.

2. The method according to claim 1 , wherein the compound is according to the formula:

wherein:

Q is absent or is selected from the group consisting of a C 3-13 carbocycle substituted with 0-5 R b , and a heterocycle wherein said heterocycle is piperazine substituted with 0-5 R b ; and

Y is C 3-13 carbocycle substituted with 0-5 R c .

3. The method according to claim 1 , wherein the compound exists in the form of a single enantiomer or diastereomer.

4. The method according to claim 1 , wherein the compound is selected from the group consisting of:

(1S,2S,5R)-N-hydroxy-5-[(6-methylpyridin-3-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide;

(1S,2S,5R)-N-hydroxy-5-[(6-methylpyridin-2-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide;

(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-[(2-methylquinolin-4-yl)oxy]cyclohexanecarboxamide;

(1S,2S,5R)-5-[(5-chloropyridin-3-yl)oxy]-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide;

(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-3-yloxy)cyclohexanecarboxamide;

(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-6-yloxy)cyclohexanecarboxamide;

(1S,2S,5R)-N-hydroxy-5-[(4-methylpyridin-2-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide;

(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(pyridin-4-yloxy)cyclohexanecarboxamide;

(1S,2S,5R)-N-hydroxy-5-[(2-methylpyridin-3-yl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide; and

(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-4-yloxy)cyclohexanecarboxamide;

or a pharmaceutically acceptable salt thereof.

5. The method according to claim 1 , wherein the compound is selected from the group consisting of

(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-6-yloxy)cyclohexanecarboxamide,

(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-{[2-(trifluoromethyl)quinolin-4-yl]oxy}cyclo hexanecarboxamide,

(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-2-yloxy)cyclohexanecarboxamide,

(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-3-yloxy)cyclohexanecarboxamide,

(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-5-yloxy)cyclohexanecarboxamide,

(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-7-yloxy)cyclohexanecarboxamide,

(1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-8-yloxy)cyclohexanecarboxamide,

(1S,2S,5R)-N-hydroxy-5-(isoquinolin-1-yloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide,

(1S,2S,5R)-N-hydroxy-5-(isoquinolin-3-yloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide,

(1S,2S,5R)-N-hydroxy-5-(isoquinolin-5-yloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide, and

(1S,2S,5R)-N-hydroxy-5-(isoquinolin-7-yloxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexanecarboxamide,

or a pharmaceutically acceptable salt thereof.

6. The method according to claim 1 , wherein the compound is (1S,2S,5R)-N-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(quinolin-6-yloxy)cyclohexanecarboxamide, or

a pharmaceutically acceptable salt thereof.

7. The method according to claim 1 , wherein Q is:

Y is phenyl substituted with 0-5 R c .

8. The method according to claim 1 , wherein -Q-Y is 4-phenylpiperazinyl.

9. The method according to claim 1 , wherein the compound is selected from the group consisting of:

(1S,2S,5R)-N-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-2-yloxy)cyclohexanecarboxamide,

(1S,2S,5R)-N-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(pyridin-4-yloxy)cyclohexanecarboxamide, and

(1S,2S,5R)-N-hydroxy-2-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]-5-(quinolin-6-yloxy)cyclohexanecarboxamide,

or a pharmaceutically acceptable salt thereof.