Non-covalent inhibitors of urokinase and blood vessel formation

A compound of the formula:

• wherein:
• (a) X is selected from the group consisting of —S(O)2—, N(R)—S(O)2—, —(C═O)—, —OC(═O)—, —NH—C(═O)—, —P(O)(R′)—, and a direct link, wherein R′ is independently hydrogen, alkyl of 1 to 4 carbon atoms, aryl of 6 to 14 carbon atoms or aralkyl of 7 to 16 carbon atoms, with the proviso that when X is —P(O)(R′)—, then R′ is not hydrogen;
• (b) R1 is selected from the group consisting of:
• (1) alkyl of 1 to 12 carbon atoms which is optionally substituted with Y1 and/or Y2,
• (2) alkyl of 1 to 3 carbon atoms substituted with cycloalkyl of 3 to 8 carbon atoms which is optionally mono-, di- or tri-substituted with Y1, Y2, and/or Y3,
• (3) cycloalkyl of 3 to 15 carbon atoms, which is optionally mono-, di-, or tri-substituted on the ring with Y1, Y2, and/or Y3,
• (4) heterocycloalkyl of 4 to 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O)i, wherein i is 0, 1 or 2, which is optionally mono-, di-, or tri-substituted on the ring with Y1, Y2, and/or Y3,
• (5) heterocyclo of 4 to 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen nitrogen, and S(O)i wherein i is 0, 1, or 2, including,
• wherein
• is a 5 to 7 member heterocycle having 3 to 6 ring carbon atoms, where V is —CH2—, —O—, —S(═O)—, —S(O)2— or —S—, which is optionally mono-, di-, or tri-substituted on the ring carbons with Y1, Y2, and/or Y3,
• (6) alkenyl of 2 to 6 carbon atoms which is optionally substituted with cycloalkyl of 3 to 8 carbon atoms, which is optionally mono-, di-, or tri-substituted on the ring with Y1, Y2, and/or Y3,
• (7) aryl of 6 to 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y1, Y2, and/or Y3,
• (8) heteroaryl of 5 to 14 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur, and which is optionally mono-, di- or tri-substituted with Y1, Y2, and/or Y3,
• (9) aralkyl of 7 to 15 carbon atoms which is optionally substituted on the alkyl chain with hydroxy or halogen and which is optionally mono-, di-, or tri-substituted on the aryl ring with Y1, Y2 and/or Y3,
• (10) heteroaralkyl of 5 to 14 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur, which is optionally substituted on the alkyl chain with hydroxy or halogen and optionally mono-, di- or tri-substituted on the ring with Y1, Y2 and/or Y3,
• (11) aralkenyl of 8 to 16 carbon atoms which is optionally mono-, di-, or tri-substituted on the aryl ring with Y1, Y2 and/or Y3,
• (12) heteroaralkenyl of 5 to 14 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur, and which is optionally mono-, di- or tri-substituted on the ring carbons with Y1, Y2 and/or Y3,
• (17) fused carbocyclic alkyl of 9 to 15 carbon atoms,
• (18) difluoromethyl or perfluoroalkyl of 1 to 12 carbon atoms,
• (19) perfluoroaryl of 6 to 14 carbon atoms,
• (20) perfluoroaralkyl of 7 to 15 carbon atoms, and
• (21) hydrogen when X is a direct link;
• wherein each Y1, Y2, and Y3 is independently selected and is
• (i) selected from the group consisting of halogen, cyano, nitro, tetrazolyl, guanidino, amidino, methylguanidino, —CF3, —CF2CF3, —CH(CF3)2, —C(OH)(CF3)2, —OCF3, —OCF2H, —OCF2CF3, —OC(O)NH2, —OC(O)NHZ1, —OC(O)NX1Z2, —NHC(O)Z1, —NHC(O)NH2, —NHC(O)NZ1, —NHC(O)NZ1Z2, —C(O)OH, —C(O)OZ1, —C(O)NH2, —C(O)NHZ1, —C(O)NZ1Z2, —P(O)3H2, —P(O)3(Z1)2, —S(O)3H, —S(O)mZ1, —Z1, —OZ1, —OH, —NH2, —NHZ1, —NZ1Z2, —N-morpholino, and S(O)m(CF2)qCF3, wherein m is 0, 1 or 2, q is an integer from 0 to 5, and Z1 and Z2 are independently selected from the group consisting of alkyl of 1 to 12 carbon atoms, aryl of 6 to 14 carbon atoms, heteroaryl of 5 to 14 ring atoms, aralkyl of 7 to 15 carbon atoms, and heteroaralkyl of 5 to 14 ring atoms, or
• (ii) Y1 and Y2 are selected together to be —O[C(Z3)(Z4)]rO— or —O[C(Z3)(Z4)]r+1—, wherein r is an integer from 1 to 4 and Z3 and Z4 are independently selected from the group consisting of hydrogen, alkyl of 1 to 12 carbon atoms, aryl of 6 to 14 carbon atoms, heteroaryl of 5 to 14 ring atoms, aralkyl of 7 to 15 carbon atoms, and heteroaralkyl of 5 to 14 ring atoms;
• (c) R2 is selected from the group consisting of —CH3, —C2H5, —(CH2)2OH, —(CH2)2OA1, —CH(R5)OH, —CH(R5)OA1 and —CH2NH—X′—R6 wherein A1 is —C(═O)OR6, —C(═O)R6 or —C(═O)NR5R6;
• X′ is selected from the group consisting of —S(O)2—, —S(O)2—N(R″)—, —(C═O)—, —C(═O)—O—, —C(═O)—NH—, —P(O)(R″)—, and a direct link, wherein R″ is hydrogen, alkyl of 1 to 4 carbon atoms, aryl of 6 to 14 carbon atoms or aralkyl of 7 to 16 carbon atoms with the proviso that when X′ is —P(O) (R″)—, then R″ is not hydrogen;
• R5 is selected from the group consisting of:
• (1) alkyl of 1 to 4 carbon atoms, optionally substituted with Y1 and/or Y2,
• (2) alkyl of 1 to 3 carbon atoms substituted with cycloalkyl of 3 to 6 carbon atoms, which is optionally mono-, di-, or tri-substituted on the ring with Y1, Y2, and/or Y3,
• (3) cycloalkyl of 3 to 6 carbon atoms, which is optionally mono-, di-, or trisubstituted on the ring with Y1, Y2, and/or Y3,
• (4) heterocycloalkyl of 4 to 6 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O)i, wherein i is 0, 1 or 2, which is optionally mono-, di-, or tri-substituted on the ring with Y1, Y2 and/or Y3,
• (5) heterocyclo of 4 to 6 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O)i, wherein i is 0, 1, or 2, including
• wherein
• is a 5 to 6 member heterocycle having 3 to 5 ring carbon atoms, where V is —CH2—, —O—, —S(═O)—, —S(O)2— or —S—, which is optionally mono-, di-, or tri-substituted on the ring carbons with Y1, Y2 and/or Y3,
• (6) alkenyl of 2 to 6 carbon atoms which is optionally substituted with cycloalkyl of 3 to 6 carbon atoms, which is optionally mono-, di-, or tri-substituted on the ring with Y1, Y2 and/or Y3,
• (7) phenyl which is optionally mono-, di- or tri-substituted with Y1, Y2 and/or Y3,
• (8) heteroaryl of 5 to 6 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur, and which is optionally mono-, di- or tri-substituted with Y1, Y2 and/or Y3,
• (9) alkyl of 1 to 4 carbon atoms substituted with phenyl and which is optionally mono-, di-, or tri-substituted on the phenyl ring with Y1, Y2 and/or Y3,
• (10) heteroaralkyl of 5 to 6 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur, and which is optionally substituted on the alkyl chain with hydroxy or halogen and optionally mono-, di- or tri-substituted on the ring with Y1, Y2 and/or Y3,
• (11) aralkenyl of 8 to 12 carbon atoms which is optionally mono-, di-, or tri-substituted on the aryl ring with Y1, Y2 and/or Y3,
• (12) heteroalkenyl of 5 to 6 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur, and which is optionally mono-, di- or tri-substituted on the ring carbons with Y1, Y2 and/or Y3, and
• (13) hydrogen;
• and R6 is selected from the group consisting of:
• (1) alkyl of 1 to 12 carbon atoms, optionally substituted with Y1 and/or Y2,
• (2) alkyl of 1 to 3 carbon atoms substituted with cycloalkyl of 3 to 8 carbon atoms, which is optionally mono-, di-, or tri-substituted on the ring with Y1, Y2 and/or Y3,
• (3) cycloalkyl of 3 to 15 carbon atoms, which is optionally mono-, di-, or trisubstituted on the ring with Y1, Y2, and/or Y3,
• (4) heterocycloalkyl of 4 to 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O)i, wherein i is 0, 1 or 2, which is optionally mono-, di-, or tri-substituted on the ring with Y1, Y2 and/or Y3,
• (5) heterocyclo of 4 to 10 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from the group consisting of oxygen, nitrogen, and S(O)i, wherein i is 0, 1, or 2, including
• wherein
• is a 5 to 7 member heterocycle having 3 to 6 ring carbon atoms, where V is —CH2—, —O—, —S(═O)—, —S(O)2— or —S—, which is optionally mono-, di-, or tri-substituted on the ring carbons with Y1, Y2 and/or Y3,
• (6) aryl of 6 to 14 carbon atoms which is optionally mono-, di- or tri-substituted with Y1, Y2 and/or Y3,
• (7) heteroaryl of 5 to 14 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur, and which is optionally mono-, di- or tri-substituted with Y1, Y2 and/or Y3,
• (8) aralkyl of 7 to 15 carbon atoms which is optionally mono-, di-, on tri-substituted on the aryl ring with Y1, Y2 and/or Y3,
• (9) heteroaralkyl of 5 to 14 ring atoms with the ring atoms selected from carbon and heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur, and which is optionally substituted on the alkyl chain with hydroxy or halogen and optionally mono-, di- or tri-substituted on the ring with Y1, Y2 and/or Y3, and
• (10) hydrogen, with the proviso that R6 is not hydrogen when A1 is —C(═O)OR6;
• (d) R3 is selected from H and methyl, or R3 and R4 are selected together as set forth in (f);
• (e) the carbon bearing R4 is of the S configuration and is selected from the group consisting of H, —CH2—S—CH3, —CH2OH, —CH2CN, lower alkyl of 1 to 3 carbon atoms, —CH2C≡CH, —CH2CH═CH2 and —CH═CH2 or R3 and R4 are selected together as set forth in (f);
• (f) alternatively, the carbon bearing R4 is of the S configuration and R3 and R4 are selected together to give a group at P2 selected from the group consisting of prolyl, pipecolyl, azetidine-2-carbonyl, 4-hydroxyprolyl, 3-hydroxyprolyl, 3,4-methanoprolyl and 3,4-dehydroprolyl;
• (g) R7 is hydrogen or alkyl of 1 to 4 carbon atoms;
• and
• (h) E is selected from
• wherein R8 and R9 are independently selected from hydrogen, hydroxy, halogen, alkyl of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms substituted with alkoxy of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, and trifluoromethyl;
• R10 and R11 are independently hydrogen, hydroxy, alkoxy of 1 to 3 carbon atoms, trihydrocarbylsilyl of 3 to 16 carbon atoms, alkyl of 1 to 3 carbon atoms or —C(═O)R12;
• R11 is hydrogen or alkyl of 1 to 3 carbon atoms with the proviso that R10 and R11 are not both hydroxy or alkoxy;
• R12 is hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or (CF2)jCF3 wherein j is 0, 1, 2 or 3;
• each of R13 and R14 is independently selected from hydrogen or lower alkyl of 1 to 3 carbon atoms;
• and t is an integer from 0 to 6;
• and pharmaceutically acceptable salts thereof.