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US 6,204,384 B1Granted
Substituted 3-amino-2-hydroxyphenylacetamide derivatives as enzyme inhibitors (II)
AssigneeCorvas International, Inc.
InventorsJoseph Edward Semple, Marguerita S. Lim-Wilby, Terence K. Brunck
Life of this patent
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Abstract
The present invention provides peptide aldehydes having an 3-amino-2-hydro yenyl acetamide group as part of the peptide backbone d an arginine group or analog at P1. These compounds e potent and specific or inhibitors of thrombin. Ther pharmaceutically acceptable salts, pharmaceutic ly acceptable compositions thereof, and methods of using t as therapeutic agents for disease states in mammals charachterized by abnormal thrombosis are also described. Also described are 3-amino-2-hydroxyphenyl-acetamide derivatives having in history activity towards proteases of the trypsin/chymotrypsin class.
Claims28
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 hydrogen, alkyl of 1 to about 4 carbon atoms, aryl of about 6 to about 14 carbon atoms or aralkyl of about 6 to about 16 carbon atoms, and R″ is —NHR′, —OR′, —R′, or —SR′;
- (b) R1 is selected from the group consisting of:
- (1) alkyl of 1 to about 12 carbon atoms,
- (2) alkyl of 1 to about 3 carbon atoms substituted with cycloalkyl of about 5 to about 8 carbon atoms, which optionally is substituted on the ring carbons with hydroxyl, amino, guanidino, amidino, C1 to C3 alkyl, C1 to C3 alkoxy, or —CO2R′,
- (3) cycloalkyl of 3 to about 15 carbon atoms, which optionally is substituted on the ring carbons with hydroxyl, amino, guanidino, amidino, C1 to C3 alkyl, C1 to C3 alkoxy, or —CO2R′,
- (4) heterocycloalkyl of 4 to about 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, and which is optionally substituted on the ring carbons with hydroxyl, amino, guanidino, amidino, C1 to C3 alkyl, C1 to C3 alkoxy, or —CO2R′,
- (5) heterocyclo of 4 to about 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, and which is optionally substituted on the ring carbons with hydroxyl, amino, guanidino, amidino, C1 to C3 alkyl, C1 to C3 alkoxy, or —CO2R′,
- (6) alkenyl of 2 to about 6 carbon atoms which is optionally substituted with cycloalkyl of about 3 to about 8 carbon atoms, which optionally is substituted on the ring carbons with hydroxyl, amino, guanidino, amidino, C1 to C3 alkyl, C1 to C3 alkoxy, or —CO2R′,
- (7) aryl of about 6 to about 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 S(O)i, and which is optionally mono-, di- or tri-substituted on the ring carbons with Y1, Y2, and/or Y3,
- (9) aralkyl of about 7 to about 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 S(O)i, which is optionally substituted on the alkyl chain with hydroxy or halogen and which is optionally mono-, di- or tri-substituted on the ring carbons with Y1, Y2, and/or Y3,
- (11) aralkenyl of about 8 to about 16 carbon atoms having 6 to about 14 ring 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 S(O)i, and which is optionally mono-, di- or tri-substituted on the ring carbons with Y1, Y2, and/or Y3,
- (17) perfluoroalkyl of 1 to about 12 carbon atoms,
- (18) perfluoroaryl of about 6 to about 14 carbon atoms,
- (19) perfluoroaralkyl of about 7 to about 15 carbon atoms,
- (20) hydrogen, and
- wherein
- is a 5 to 7 membered heterocyclic ring having 3 to 6 ring carbon atoms, where V is —CH2—, —O—, —S(═O)—, —S(O)2— or —S—, and wherein Y1, Y2, and Y3 are
- (i) independently selected from the group consisting of hydrogen, halogen, cyano, nitro, tetrazolyl, amino, guanidino, amidino, methylamino, methylguanidino, —CF3, —CF2CF3, —CF2H, —CH(CF3)2, —C(OH)(CF3)2, —OCF3, —OCF2CF3, —OC(O)NH2, —OC(O)NHZ1, —OC(O)NZ1Z2, —NHC(O)Z1, —NHC(O)NH2, —NHC(O)NHZ1, —NHC(O)NZ1Z2, —C(O)OH, —C(O)NH2, —C(O)NHZ1, —C(O)NZ1Z2, —C(O)OZ1, —P(O)3H, —P(O)3H2, —PH(O)OH, —P(O)3(Z1)2, —S(O)3H , —S(O)mZ1, —Zi, —OZi, —OH, —NH2, —NHZ1, and —NZ1Z2, wherein m is 0, 1 or 2, and Z, and Z2 are independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms, heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms, or
- (ii) Y1 and Y2 are selected together to be —OC[ (Z3) (Z4)]qO—, wherein q is an integer from 1 to 4 and Z3 and Z4 are independently selected from the group consisting of hydrogen, alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms,
- (c) R2 is selected from the group consisting of hydrogen, alkyl of 1 to about 4 carbon atoms, and alkenyl of about 2 to about 4 carbon atoms,
- (d) R3 is
- where d is an integer from 0 to 5;
- (e) R4 is selected from the group consisting of
- (i) —R1, —OR1, —NHR1, —S(O)nR1, wherein n is 0, 1 or 2, and R1 is a defined above, with the proviso that R1 is not a camphor derivative or
- heterocycle,
- (ii) —CF3, —CF2H, —OCF3, or —OCF2H,
- (iii) halogen,
- (iv) alkyl of 1 to 6 carbon atoms substituted with Z5, wherein Z5 is selected from the group consisting of hydrogen, —OH, —OR8, —CH3, halogen, —C(O)OH, —C(O)OR8 and —S(O)pR8, wherein R8 is alkyl of 1 to about 6 carbon atoms, and p is 0, 1 or 2,
- (v) alkyl of 1 to 3 carbon atoms substituted with cycloalkyl of 3 to 5 carbon atoms,
- (vi) alkenyl of about 3 to about 6 carbon atoms,
- (vii) cycloalkyl of about 3 to about 10 carbon atoms,
- (viii) heteroaryl of about 5 to about 10 ring atoms having 1 to about 9 ring carbon atoms and the remainder of the ring atoms heteroatoms selected from oxygen, sulfur and nitrogen, and
- (ix) heteroaralkyl of about 5 to about 10 ring atoms having 2 to about 15 carbon atoms which include 1 to about 9 ring carbon atoms and the remainder of the ring atoms heteroatoms selected from oxygen, sulfur and nitrogen;
- (f) R5 is selected from the group consisting of
- (i) —R1, —OR1, —NHR1, —S(O)nR1, wherein R1 is as defined above, with the proviso that R1 is not a camphor derivative or
- heterocycle,
- (ii) —CF3, —CF2H, —OCF3, or OCF2H, and
- (iii) halogen;
- (g) R6 is selected from the group consisting of
- (i) —R1, —OR1, —NHR1, or —S(O)nR1, wherein R1 is as defined above, with the proviso that R1 is not a camphor derivative or
- heterocycle,
- (ii) —CF3, —CF2H, —OCF3,or —OCF2H,
- (iii) halogen,
- (iv) alkyl of 1 to about 12 carbon atoms substituted with Z6, wherein Z6 is selected from the group consisting of hydrogen, hydroxy, halogen, —OR9, —NHR9, —C(O)OH, —C(O)OR9, and —S(O)pR9, wherein R9 is alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 10 carbon atoms, aralkyl of about 7 to about 12 carbon atoms, heteroaryl of about 5 to about 10 ring atoms having 1 to about 9 ring carbon atoms and the remainder of the ring atoms heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally mono-, di- or tri- substituted on the ring with Y1, Y2 and/or Y3, or heteroaralkyl of about 5 to about 10 ring atoms having about 2 to about 15 carbon atoms which include 1 to about 9 ring carbon atoms and the remainder of the ring atoms heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally mono-, di- or tri- substituted on the ring with Y1, Y2 and/or Y3,
- (v) alkyl of 1 to about 3 carbon atoms substituted with cycloalkyl of about 3 to about 8 carbon atoms,
- (vi) alkenyl of 2 to about 6 carbon atoms which is optionally substituted with cycloalkyl of about 3 to about 8 carbon atoms, aryl of about 6 to about 10 carbon atoms or heteroaryl of about 5 to about 10 ring atoms having 1 to about 9 ring carbon atoms,
- (vii) aralkyl of about 7 to about 15 carbon atoms which is optionally substituted on the alkyl chain with hydroxy or halogen, and optionally mono-, di- or tri-substituted on the aryl ring with Y1, Y2 and/or Y3,
- (viii) heteroaralkyl of about 5 to about 10 ring atoms having 1 to about 9 ring carbon atoms and the remainder of the ring atoms heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally substituted on the alkyl chain with hydroxy or halogen, and optionally mono-, di- or tri-substituted on the ring carbons with Y1, Y2 and/or Y3,
- (ix) aralkenyl of about 6 to 15 carbon atoms which is optionally mono-, di- or tri-substituted on the aryl ring with Y1, Y2 and/or Y3, and
- (x) heteroaralkenyl of about 5 to about 10 ring atoms having 1 to 9 ring carbon atoms and the remainder of the ring atoms heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally mono-, di- or tri- substituted on the ring carbons with Y1, Y2 and/or Y3;
- and
- (h) R7 is selected from the group consisting of
- (i) R1, wherein R1 is as defined above with the proviso that R1 is not an camphor derivative or
- heterocycle,
- (ii) —CF3 or CF2H,
- (iii) alkyl of 1 to about 10 carbon atoms, optionally substituted with —CH2OR10, —CO2R10, —SO2R10, or —CONR10R11, wherein each of R10 and R11 is independnetly selected and is alkyl of 1 to about 4 carbon atoms or hydrogen,
- (iv) alkenyl of about 3 to about 10 carbon atoms, optionally substituted with —CH2OR10, —CO2R10, —SO2R10,or —CONR10R11,
- (v) cycloalkyl of 3 to about 10 carbon atoms, optionally substituted with —CH2OR10, —CO2R10, —SO2R10, or —CONR10R11,
- (vi) heteroaryl of about 5 to about 10 ring atoms having about 1 to about 9 ring carbon atoms, optionally substituted with —CH2OR10, —CO2R10, —SO2R10, or —CONR10R11, and
- (vii) alkyl of 1 to about 3 carbon atoms substituted with heteroaryl of about 5 to about 10 ring atoms having about 1 to about 9 carbon atoms, optionally substituted with —CH2OR10, —CO2R10, —SO2R10, or —CONR10R11, or pharmaceutically acceptable salts thereof.
61 more elements
A compound of the formula:
- wherein,
- (a) X is selected from the group consisting of —S(O)2—, —N(R′)—S(O)2—, —O(C═O)—, —OC(═O)—, —NH—C(═O)—, —P(O)(R″)— and a direct link, wherein R1 is hydrogen, alkyl of 1 to about 4 carbon atoms, aryl of about 6 to about 14 carbon atoms or aralkyl of about 6 to about 16 carbon atoms, and R″ is —NR′, —OR′, —R′, or —SR′;
- (b) R1 is selected from the group consisting of:
- (1) alkyl of 1 to about 12 carbon atoms,
- (2) alkyl of 1 to about 3 carbon atoms substituted with cycloalkyl of about 5 to about 8 carbon atoms, which optionally is substituted in the ring carbons with hydroxyl, amino, guanidino, amidino, C1 to C3 alkyl, C1 to C3 alkoxy, or CO2R′,
- (3) cycloalkyl of 3 to about 15 carbon atoms, which optionally is substituted in the ring carbons with hydroxyl, amino, guanidino, amidino, C1 to C3 alkyl, C1 to C3 alkoxy, or CO2R′,
- (4) heterocycloalkyl of 4 to about 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, and which is optionally substituted on the ring carbons with hydroxyl, amino, guanidino, amidino, C1 to C3 alkyl, C1 to C3 alkoxy, or CO2R′,
- (5) heterocyclo of 4 to about 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, and which is optionally substituted on the ring carbons with hydroxyl, amino, guanidino, amidino, C1 to C3 alkyl, C1 to C3 alkoxy, or CO2R′,
- (6) alkenyl of about 2 to about 6 carbon atoms which is optionally substituted with cycloalkyl of about 3 to about 8 carbon atoms, which optionally is substituted on the ring carbons with hydroxyl, amino, guanidino, amidino, C1 to C3 alkyl, C1 to C3 alkoxy, or CO2R′,
- (7) aryl of about 6 to about 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 S(O)i, and which is optionally mono-, di- or tri-substituted on the ring carbons with Y1, Y2, and/or Y3,
- (9) aralkyl of about 7 to about 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 S(O)i, which is optionally substituted on the alkyl chain with hydroxy or halogen and which is optionally mono-, di- or tri-substituted on the ring carbons with Y1, Y2, and/or Y3, respectively,
- (11) aralkenyl of about 8 to about 16 carbon atoms having 6 to about 14 ring carbons which is optionally mono-, di-, or tri-substituted on the aryl ring with Y1, Y2, and/or Y3, respectively,
- (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 S(O)i, and which is optionally mono-, di- or tri-substituted on the ring carbons with Y1, Y2, and/or Y3, respectively,
- (17) perfluoroalkyl of 1 to about 12 carbon atoms,
- (18) perfluoroaryl of about 6 to about 14 carbon atoms,
- (19) perfluoroaryl alkyl of about 7 to about 15 carbon atoms,
- (20) hydrogen, and
- wherein
- is a 5 to 7 member heterocyclic ring having 3 to 6 ring carbon atoms, where V is —CH2—, —O—, —S(═O)—, —S(O)2— or —S—, wherein Y1, Y2, and Y3 are
- (i) independently selected from the group consisting of hydrogen, halogen, cyano, nitro, tetrazolyl, amino, guanidino, amidino, methylamino, methylguanidino, —CF3, —CF2CF3, —CF2H, CH(CF3)2, —C(OH)(CF3)2, —OCF3, —OCF2CF3, —OC(O)NH2, —OC(O)NHZ1, —OC(O)NZ1Z2, —NHC(O)Z1, —NHC(O)NH2, —NHC(O)NZ1, —NHC(O)NZ1Z2, —C(O)OH, —C(O)NH2, —C(O)NHZ1, —C(O)NZ1Z2, —C(O)OZ1, —P(O)3H, —P(O)3H2, —PH(O)OH, —P(O)3(Z1)2, —S(O)3H , —S(O)mZ1, —Z1, —OZ1, —OH, —NH2, —NHZ1, and —NZ1Z2, wherein m is 0, 1 or 2, and Z1and Z2 are independently selected from the group consisting of alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms, heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms, or
- (ii) Y1 and Y2 are selected together to be —OC[(Z3)(Z4)]qO—, wherein q is an integer from 1 to 4 and Z3 and Z4 are independently selected from the group consisting of hydrogen, alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 14 carbon atoms heteroaryl of about 5 to about 14 atoms having 1 to about 9 carbon atoms, aralkyl of about 7 to about 15 carbon atoms, and heteroaralkyl of about 6 to about 11 atoms having about 3 to about 9 carbon atoms;
- (c) R2 is selected from the group consisting of hydrogen, alkyl of 1 to about 4 carbon atoms, and alkenyl of about 2 to about 4 carbon atoms;
- (d) R4 is selected from the group consisting of
- (i) —R1, —OR1, —NHR1, —S(O)nR1, wherein n is 0, 1 or 2, and R1 is as defined above , with the proviso that R1 is X not a camphor derivative or
- heterocycle,
- (ii) —CF3, —CF2H, —OCF3, —OCF2H,
- (iii)halogen,
- (iv) alkyl of 1 to 6 carbon atoms substituted with Z5, wherein Z5 is selected from the group consisting of hydrogen, —OH, —OR8, —CH3, halogen, —C(O)OH, —C(O)OR8 and —S(O)pR8, wherein R8 is alkyl of 1 to about 6 carbon atoms, and p is 0, 1 or 2,
- (v) alkyl of 1 to 3 carbon atoms substituted with cyclic alkyl of 3 to 5 carbon atoms,
- (vi) alkenyl of about 3 to about 6 carbon atoms,
- (vii) cycloalkyl of about 3 to about 10 carbon atoms,
- (viii) heteroaryl of about 5 to about 10 ring atoms having 1 to about 9 ring carbon atoms and the remainder of the ring atoms heteroatoms selected from oxygen, sulfur and nitrogen, and
- (ix) heteroaralkyl of about 5 to about 10 ring atoms having 2 to about 15 carbon atoms which include 1 to about 9 ring carbon atoms and the remainder of the ring atoms heteroatoms selected from oxygen, sulfur and nitrogen;
- (e) R5 is selected from the group consisting of
- (i) —R1, —OR1, —NHR1, —S(O)nR1, wherein R1 is as defined above, with the proviso that R1 is not a camphor derivative or
- heterocycle,
- (ii) —CF3, —CF2H, —OCF3, —OCF2H, and
- (iii) halogen;
- (f) R6 is selected from the group consisting of
- (i) —R1, —OR1, —NHR1, —S(O)nR1, wherein R1 is as defined above, with the proviso that R1 is not a camphor derivative or
- heterocycle,
- (ii) —CF3, —CF2H, —OCF3, —OCF2H,
- (iii) halogen,
- (iv) alkyl of 1 to about 12 carbon atoms substituted with Z6, wherein Z6 is selected from the group consisting of hydrogen, hydroxy, halogen, —OR9, —NHR9, —C(O)OH, —C(O)OR9, and —S(O)pR9, wherein R9 is alkyl of 1 to about 12 carbon atoms, aryl of about 6 to about 10 carbon atoms, aralkyl of about 7 to about 12 carbon atoms, heteroaryl of about 5 to about 10 ring atoms 1 to about 9 ring carbon atoms and the remainder of the ring atoms heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally mono-, di- or tri- substituted in the ring carbons with Y1, Y2 and/or Y3, and heteroaralkyl of about 5 to about 10 ring atoms having about 2 to about 15 carbon atoms which include 1 to about 9 ring carbon atoms and the remainder of the ring atoms heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally mono-, di- or tri-substituted in the ring carbons with Y1, Y2 and/or Y3,
- (v) alkyl of 1 to about 3 carbon atoms substituted with cycloalkyl of about 3 to about 8 carbon atoms,
- (vi) alkenyl of 2 to about 6 carbon atoms which is optionally substituted with cycloalkyl of about 3 to about 8 carbon atoms, aryl of about 6 to about 10 carbon atoms, or heteroaryl of about 5 to about 10 ring atoms having 1 to about 9 ring carbon atoms,
- (vii) aralkyl of about 7 to about 15 carbon atoms which is optionally substituted on the alkyl chain with hydroxy or halogen, and optionally mono-, di- or tri-substituted with Y1, Y2 and/or Y3,
- (viii) heteroaralkyl of about 5 to about 10 ring atoms having 1 to about 9 ring carbon atoms and the remainder of the ring atoms heteroatoms selected from oxygen, sulfur and nitrogen, 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,
- (ix) aralkenyl of about 6 to 15 carbon atoms which is optionally mono-, di- or tri-substituted on the aryl with Y1, Y2 and/or Y3, and
- (x) heteroaralkenyl ring of about 5 to about 10 ring atoms with 1 to 9 ring carbon atoms and the remainder of the ring atoms heteroatoms selected from oxygen, sulfur and nitrogen, which is optionally mono-, di- or tri- substituted with Y1, Y2 and/or Y3;
- (g) R7 is selected from the group consisting of
- (i) R1, wherein R1 is as defined above, with the proviso that R7 is not an R1 camphor derivative or
- heterocycle,
- (ii) —CF3 or CF2H,
- (iii) alkyl of 1 to about 10 carbon atoms, optionally substituted with —CH2OR10, —CO2R10, —SO2R10, —CONR10R11, wherein each of R1 and R1 is independently selected and is alkyl of 1 to about 4 carbon atoms or hydrogen,
- (iv) alkenyl of about 3 to about 10 carbon atoms, optionally substituted with —CH2OR10, CO2R10, —S02R10, CONR10R11,
- (v) cycloalkyl of 3 to about 10 carbon atoms, optionally substituted with —CH2OR10, —CO2R1O, —SO2R10, —CONR10R11,
- (vi) heteroaryl of about 5 to about 10 ring atoms, having about 1 to about 9 ring carbon atoms which is optionally substituted with —CH2OR10, CO2R10, —SO2R10, or —CONR10R11, and
- (vii) alkyl of 1 to about 3 carbon atoms substituted with heteroaryl of about 5 to about 16 atoms having 1 to about 9 carbon atoms, which is optionally substituted with —CH2OR10, CO2R10, SO2R10, CONR10R11;
- and
- (h) R2 is selected from the group consisting of
- (i) alkyl of I to about 12 carbon atoms which is optionally substituted with amino, amidino or guanidino,
- (ii) aralkyl of 7 to about 15 carbon atoms which is optionally substituted on a ring carbon with amino, amidino, or guanidino,
- (iii)aryl of about 6 to about 14 carbon atoms which is optionally substituted on a ring carbon with amino, amidino, or guanidino,
- (iv) heteroaralkyl of 5 to about 14 ring atoms having 1 to about 9 ring carbon atoms and the remainder of the ring atoms heteroatoms selected from oxygen, nitrogen and sulfur which is optionally substituted on a ring carbon with amino, amidino or guanidino;
- and
- (j) TS is selected from the group consisting of
- (i) —CHO,
- (ii) —C(O)CF3,
- (iii) —C(O)CF2CF3,
- (iv) —C(O)—C(O)—NHR3,
- (v) —C(O)—C(O)2R13,
- (vi) —C(O)—C(O)—NR13R14,
- (vii) —B(OR13)(OR4 ) ,
- (viii) —C(O)CH2Cl, and
- (ix) —C(O)—R15;
- wherein R13 and R14 are independently selected from hydrogen, lower alkyl of 1 to about 6 carbon atoms, cycloalkyl of 3 to about 10 carbon atoms, aralkyl of 7 to about 15 carbon atoms, and heteroaralkyl of about 5 to about 10 ring atoms having about 2 to about 15 carbon atoms which include 1 to about 9 ring carbon atoms and the remainder of the ring atoms heteroatoms selected from oxygen, nitrogen and sulfur;
- or when TS is —B(OR13)(OR14) then OR13 and OR14 may be taken together to be —O[C(Z3)(Z4)]qO—;
- and R15 is selected from aryl of 6 to about 14 carbon atoms or heteroaryl of 5 to about 14 ring atoms having 1 to about 13 ring carbon atoms and the remainder of the ring atoms selected from oxygen, nitrogen and sulfur;
- and pharmaceutically acceptable salts thereof.
79 more elements
Dependencies are inferred from the claim text.