3-substituted pyrrolidines useful as inhibitors of matrix metalloproteinases

A compound of the formula

• wherein
• e is an integer from 0 to 2;
• A is selected from the group consisting of —OH and —NRR′;
• wherein
• R and R′ are independently selected from the group consisting of hydrogen and C1-C6 alkyl or R and R′ taken together with the nitrogen atom to which they are attached form a N-morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl;
• R1 is selected from the group consisting of hydrogen, C1-C6 alkyl, —(CH2)a—CO2R5, —(CH2)a—C(O)NH2, —(CH2)4NH2, —(CH2)3—NH—C(NH)NH2, —(CH2)2—S(O)b—CH3, —CH2—OH, —CH(OH)CH3, —CH2—SH, —(CH2)d—Ar1, and —CH2—Ar2;
• wherein
• a is 1 or 2;
• b is 0, 1,or 2;
• d is an integer from 0 to 4;
• R5 is selected from the group consisting of hydrogen, C1-C4 alkyl, and benzyl;
• Ar1 is a radical selected from the group consisting of
• wherein
• R6 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, hydroxy, and C1-C4 alkoxy;
• R7 is selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, and C1-C4 alkoxy;
• Ar2 is a radical selected from the group consisting of
• R2 is a radical selected from the group consisting of
• wherein
• wherein
• R2′ is from 1 to 2 substituents selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, and C1-C4 alkoxy;
• R3 is selected from the group consisting of C1-C6 alkyl, —(CH2)m—W, —(CH2)p—Ar3, —(CH2)k—CO2R9, —(CH2)m—NR8′SO2—Y1, and —(CH2)m—Z—Q
• wherein
• m is an integer from 2 to 8;
• p is an integer from 0-10;
• k is an integer from 1 to 9;
• W is phthalimido;
• Ar3 is selected from the group consisting of
• wherein
• R23 is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, and C1-C4 alkoxy;
• R8′ is hydrogen or C1-C6 alkyl;
• R9 is hydrogen or C1-C6 alkyl;
• Y1 is selected from the group consisting of hydrogen, —(CH2)j—Ar4, and —N(R24)2
• wherein
• j is 0 or 1;
• R24 each time selected is independently hydrogen or C1-C6 alkyl or are taken together with the nitrogen to which they are attached to form N-morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl;
• Ar4 is
• wherein
• R25 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, and C1-C4 alkoxy;
• Z is selected from the group consisting of —O—, —NR8—, —C(O)NR8—, —NR8C(O)—, —NR8C(O)NH—, —NR8C(O)O—, and —OC(O)NH—;
• wherein
• R8 is hydrogen or C1-C6 alkyl;
• Q is selected from the group consisting of hydrogen, —(CH2)n—Y2, and —(CH2)x—Y3;
• wherein
• n is an integer from 0 to 4;
• Y2 is selected from the group consisting of hydrogen, —(CH2)h—Ar5 and —(CH2)t—C(O)OR27
• wherein
• Ar5 is selected from the group consisting of
• wherein
• R26 is from 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, and C1-C4 alkoxy;
• h is an integer from 0 to 6;
• t is an integer from 1 to 6;
• R27 is hydrogen or C1-C6 alkyl;
• x is an integer from 2 to 4;
• Y3 is selected from the group consisting of —N(R28)2, N-morpholino, N-piperidino, N-pyrrolidino, and N-isoindolyl;
• wherein
• R28 each time taken is independently selected from the group consisting of hydrogen and C1-C6 alkyl;
• R4 is selected from the group consisting of hydrogen, —C(O)R10, —C(O)—(CH2)q—K and —S—G
• wherein
• R10 is selected from the group consisting of hydrogen, C1-C4 alkyl, phenyl, and benzyl;
• q is 0, 1, or 2;
• K is selected from the group consisting of
• wherein
• V is selected from the group consisting of a bond, —CH2—, —O—, —S(O)r—, —NR21—, and —NC(O)R22—;
• wherein
• r is 0, 1, or 2;
• R21 is selected from the group consisting of hydrogen, C1-C4 alkyl, and benzyl;
• R22 is selected from the group consisting of hydrogen, —CF3, C1-C10 alkyl, phenyl , and benzyl;
• R11 is selected from the group consisting of hydrogen, C1-C4 alkyl, and benzyl;
• R11′ is selected from the group consisting of hydrogen, C1-C4 alkyl, and benzyl;
• G is selected from the group consisting of
• wherein
• w is an integer from 1 to 3;
• R12 is selected from the group consisting of hydrogen, C1-C6 alkyl, —CH2CH2S(O)fCH3, and benzyl;
• wherein f is 0, 1, or 2;
• R13 is selected from the group consisting of hydrogen, hydroxy, amino, C1-C6 alkyl, N-methylamino, N,N-dimethylamino, —CO2R17, and —OC(O)R18;
• wherein
• R17 is hydrogen, —CH2O—C(O)C(CH3)3, C1-C4 alkyl, benzyl, or diphenylmethyl;
• R18 is hydrogen, C1-C6 alkyl or phenyl;
• R14 is 1 or 2 substituents independently selected from the group consisting of hydrogen, C1-C4 alkyl, C1-C4 alkoxy, or halogen;
• V1 is selected from the group consisting of —O—, —S—, and —NH—;
• V2 is selected from the group consisting of —N— and —CH—;
• V3 is selected from the group consisting of a bond and —C(O)—;
• V4 is selected from the group consisting of —O—, —S—, —NR19—, and —NC(O)R20—;
• wherein
• R19 is hydrogen, C1-C4 alkyl, or benzyl;
• R20 is hydrogen, —CF3, C1-C10 alkyl, or benzyl;
• R15 is selected from the group consisting of hydrogen, C1-C6 alkyl and benzyl;
• R16 is selected from the group consisting of hydrogen and C1-C4 alkyl;
• and stereoisomers, pharmaceutically acceptable salt, and hydrate thereof.