	US 7,491,724 B2
	Substituted cyclic hydroxamates as inhibitors of matrix metalloproteinases
Yun-Long Li, Wilmington, Del. (US); Jincong Zhuo, Boothwyn, Pa. (US); David Burns, Philadelphia, Pa. (US); Wenqing Yao, Kennett Square, Pa. (US); and Ravi Kumar Jalluri, Avondale, Pa. (US)
Assigned to Incyte Corporation, Wilmington, Del. (US)
Filed on Oct. 15, 2004, as Appl. No. 10/965,215.
Claims priority of provisional application 60/586646, filed on Jul. 12, 2004.
Claims priority of provisional application 60/515352, filed on Oct. 28, 2003.
Claims priority of provisional application 60/512016, filed on Oct. 17, 2003.
Prior Publication US 2005/0113344 A1, May 26, 2005
Int. Cl. A61K 31/497 (2006.01); C07D 403/00 (2006.01)

U.S. Cl. 514—252.13 [514/255.01; 514/317; 514/318; 514/326; 544/359; 544/386; 546/268.1; 546/268.4]

10 Claims

1. 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_1-10alkylene, C_2-10alkenylene, and C_2-10alkynylene;

G is absent or is selected from the group consisting of O, NR^a-1, S(O)_p, and C(O);

Q is absent or is selected from the group consisting of a C_3-13carbocycle 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, OC(O)NR^a1, NR^a1C(O)O, S(O)_p, S(O)_pNR^a1, and NR^a1S(O)_p;

T is absent or is selected from the group consisting of C_1-10alkylene, C_2-10alkenylene, and C_2-10alkynylene;

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_3-10carbocycle 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)_por S(O)_p—S(O)_pgroup;

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

R^bat each occurrence is independently selected from the group consisting of C_1-6alkyl optionally substituted with R^c1, O(primary, secondary, or tertiary)C₁-C₈alkyl, OH, Cl, F, —CN, NO₂, NR^aR^a1, C(O)R^a, C(O)OR^a, C(O)NR^aR^a1, R^aNC(O)NR^aR^a, OC(O)NR^aR^a1, R^aNC(O)O R^a1, S(O)₂NR^aR^a1NR^aS(O)₂R^a2, NR^aS(O)₂NR^aR^a1, OS(O)₂NR^aR^a1, S(O)_pR^a2, CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂CF₃, a C_3-10carbocyclic residue and C₃-C₁₀carbocyclyl(C_1-8)alkyl, wherein said C_3-10carbocyclic residue, and C₃-C₁₀carbocyclyl(C_1-8)alky are optionally substituted with R^c1;

R^a, R^a1, and R^a2at each occurrence are independently selected from the group consisting of H, C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, wherein said alkyl, alkenyl and alkynyl groups are optionally substituted with 0(primary, secondary, or tertiary)C₁-C₈, 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, CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, and OCH₂CF₃; C₃-C₁₀, carbocycle, C₃-C₁₀carbocyclylalkyl, and wherein said C₃-C₁₀carbocycle and C₃-C₁₀carbocyclylalkyl, may be optionally substituted with one or more substituents selected from the group consisting of C₁-C₈alkyl, O(primary, secondary, or tertiary)C₁-C₈alkyl, OH, Cl, F, Br, ═O, —CN, NO₂, alkylamino, dialkylamino, alkarylamino, arylamino, alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, carboxyl, alkylcarboxylate, ailcylamido, dialkylamido, alkylureidoalkyl, alkylureidodialkyl, carbamoylalkyl, carbamoyldialkyl, alkylcarbamoyl, sulfonamidoalkyl, sulfonamidodialkyl, N-alkylsulfonamidoalkyl, N-alkylsulfonamido alkyl, N-alkylsufonamidodialkyl, alkylamidosulfonate, dialkylamidosulfonate, alkylsulfinyl, alkylsulfonyl, CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, and OCH₂CF₃;

R^cat each occurrence is independently selected from the group consisting of C_1-6alkyl optionally substituted with R^c1, OR^a, Cl, F, —CN, NO₂, NR^aR^a1, C(O)R^a, C(O)OR^a, C(O)NR^aR^a1, R^aNC(O)NR^a, R^a, OC(O)NR^aR^a1R^aNC(O)OR^a1, S(O)₂NR^aR^a1, NR^aS(O)₂R^a2, NR^aS(O)₂NR^aR^a1, S(O)_pR^a2, CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, OCH₂CF₃, a C_3-10carbocyclic residue and C₃-C₁₀carbocyclyl(C_1-8)alkyl, wherein said C_3-10carbocyclic residue and C₃-C₁₀carbocyclyl(C_1-8)alkyl are optionally substituted with R^c1;

R^c1at each occurrence is independently selected from the group consisting of C_1-6alkyl, OR^a, Cl, F, Br, ═O, —CN, NO₂, NR^aR^a1, C(O)R^a, C(O)OR^a, C(O)NR^aR^a1, OC(O)NR^aR^a1, R^aNC(O)OR^a, S(O)₂NR^aR^a1, NR^aS(O)₂R^a2, S(O)_pR^a2CF₃, and CH₂F, and CHF₂;

R^dat each occurrence is independently selected from the group consisting of H, C_1-6alkyl optionally substituted with R^c1, OR^a, Cl, F, Br, ═O, —CN, NO₂, NR^aR^a1, C(O)R^a, C(O)OR^a, C(O)NR^aR^a1, R^aNC(O)NR^aR^a, OC(O)NR^aR, R^aNC(O)OR^a1, S(O)₂NR^aR^a1, NR^aS(O)₂R^a2, OS(O)₂NR^aR^a1, S(O)_pR^a2, CF₃, CF₂CF₃, CH₂F, CHF₂, CF₂CH₃, C(CH₃)₂F, OCF₃, OCHF₂, OCH₂CF₃, a C_3-10carbocyclic residue and C₃-C₁₀carbocyclyl(C_1-8)alkyl wherein said C_3-10carbocyclic residue and C₃-C₁₀carbocyclyl(C_1-8)alkyl, are optionally substituted with R^c1;

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