Acid derivatives useful as serine protease inhibitors

A compound having a formula (IA):

• or a pharmaceutically-acceptable salt, hydrate or prodrug thereof, wherein:
• W is —C(═O)NR4R5;
• X1 is selected (i) from —CR9R10—, —C(═O)—, —NR9a—, —O— and —S— when the bond between X1 and the adjacent carbon atom to which R27 is attached (or when r is 0, the carbon atom to which R26 is attached) is a single bond, and (ii) from —CR9— and —N— when said bond is a double bond;
• X3 is selected (i) from —CR11R12—, —C(═O)—, —NR11a—, —O— and —S— when the bond between X3 and the carbon atom to which R26 is attached is a single bond, and (ii) from —CR11— and —N— when said bond is a double bond;
• Y is selected from —C(═O)NR13—, —NR13C(═O)—, —NR13CR14R15—, —CR14R15—NR13—, and —CR13R14—CR15R16—, or Y may be —C(═O)—, when Z is
• Z is selected from a 5 to 7-membered monocyclic or 8 to 11-membered bicyclic aryl, heteroaryl, heterocyclo, or cycloalkyl, wherein each Z group is optionally substituted with up to two R20 and/or up to one R21;
• R1 and R2 (ii) are taken together to form a five-to-seven membered heterocyclo;
• wherein when R1 and R2 together form a cyclic group, said cyclic group is optionally substituted with up to two R26;
• R3 is hydrogen, alkyl, or substituted alkyl;
• R4, R4a and R5 are (i) independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, aryl, heteroaryl, heterocyclo, and cycloalkyl;
• or alternatively (ii) R4 and R5 may be taken together to form a five-to-seven membered heteroaryl or heterocyclo ring, except when W is —S(O)pR4, then R4 is not hydrogen;
• R6 is C2-6alkyl, phenyl, or benzyl;
• R8, R9, R10, R11, R12, R26 and R27 (i) are at each occurrence independently selected from hydrogen, OR30, NR31R32, NR31SO2R32a, alkyl, alkenyl, substituted alkyl, substituted alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, alkylthio, —C(═O)H, acyl, —CO2H, alkoxycarbonyl, sulfonamido, sulfonyl, and phenyl, or (ii) when r is 1, R26 and R27 may be taken together to form a fused benzo ring, provided that when R26 and R27 form a fused benzo ring then Z is not phenyl substituted in the para position with cyano or a five-membered heterocycle or heteroaryl;
• R9a and R11a are selected from hydrogen, OR30, NR31R32, alkyl, alkenyl, substituted alkyl, substituted alkenyl, —C(═O)H, acyl, alkoxycarbonyl, sulfonamido, sulfonyl, and phenyl,
• R13, R14, R15, and R16 are selected from hydrogen, lower alkyl, hydroxy, or lower alkyl substituted with hydroxy or halogen;
• R20 and R21 are independently selected from hydrogen, halogen, alkyl, substituted alkyl, haloalkyl, haloalkoxy, cyano, nitro, —C(═O)NR22R23, —OR22, —CO2R22, —C(═O)R22, —SR22, —S(O)qR22a, —NR22R23, —NR22SO2R23, —NR22CO2R23, —NR22C(═O)R23, —SO2NR22R23, —NR22C(═O)NR23R33, —NR22SO2NR23R33, five or six membered heterocyclo or heteroaryl, phenyl, and four to seven membered cycloalkyl, wherein when R20 and/or R21 comprise a cyclic group, each cyclic group is in turn optionally substituted with up to three lower alkyl, halogen, hydroxy, haloalkyl, haloalkoxy, amino, aminoalkyl, or cyano;
• R22, R23, and R33 are independently selected from hydrogen, halogen, alkyl, and substituted alkyl;
• R30 at each occurrence is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, and phenyl;
• R31 and R32 at each occurrence are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, and cycloalkyl;
• R22a and R32a at each occurrence are independently selected from alkyl, substituted alkyl, and cycloalkyl;
• m is 0, 1 or 2;
• p and q are independently 1 or 2;
• r is 0 or 1;
• and
• s is 0 or 1.

A compound having the formula (IA):

• or a pharmaceutically-acceptable salt, hydrate or prodrug thereof, wherein:
• W is —C(═O)NR4R5;
• X1 is selected (i) from —CH2—, —NH—, —O— and —S— when the bond between X1 and the carbon atom to which R27 is attached (or when r is 0, the bond between X1 and the carbon atom to which R26 is attached) is a single bond;
• and (ii) from —CH— and —N— when said bond is a double bond;
• X3 is selected (i) from —CH2—, —NH—, —O— and —S— when the bond between X3 and the carbon atom to which R26 is attached is a single bond, and (ii) from —CH— and —N— when said bond is a double bond;
• Y is selected from —NHC(═O)—, —NH—CH2—, and —CH2—CH2—, or Y may be —C(═O)— when Z is
• Z is selected from:
• R1 and R2 (ii) are taken together to form a five-to-seven membered heterocyclo;
• R3 is hydrogen or C1-4alkyl;
• R4 is selected from hydrogen, C1-4alkyl, and C1-4alkyl substituted with hydroxy;
• R5 is selected from:
• i) C1-10alkyl or C1-10alkenyl;
• ii) C1-6alkyl or C1-10alkenyl substituted with one to three of:
• a) OH, keto (═O), —OC1-4alkyl;
• b) partially or fully saturated cycloalkyl in turn optionally substituted with C1-4alkyl or hydroxy;
• c) phenyl in turn optionally substituted with halogen, hydroxy, methoxy, C1-4alkyl, —SO2NH2, or —NO2;
• d) heteroaryl in turn optionally substituted with methyl;
• e) heterocyclo;
• and/or
• f) NHPhenyl;
• iii) heteroaryl or heterocyclo optionally substituted with NH2;
• alternatively, R4 and R5 together form a heterocyclo or heteroaryl optionally substituted with hydroxy, C1-4alkyl, and C1-4alkyl substituted with one or more of hydroxy and/or phenyl;
• R6 is selected from C2-4alkyl, phenyl and benzyl;
• R26 and R27 at each occurrence are independently selected of each other from the group consisting of hydrogen, C1-4alkyl, C2-4alkenyl, OR30, NR31R32, phenyloxy, and benzyloxy, or when r is 1, R26 and R27 may be taken together to form a fused benzo ring, provided that when R26 and R27 form a fused benzo ring then Z is not phenyl substituted in the para position with a five-membered heterocycle or heteroaryl;
• R20 and R21 are independently selected from hydrogen, halogen, —C(═O)NH2, —C(═O)C1-4alkyl, —NH2, —NHC1-4alkyl, —S—C1-4alkyl, —O—C1-4alkyl, C1-4alkyl, C1-4alkyl substituted with NH2, and five or six membered heterocyclo or heteroaryl;
• R30 at each occurrence is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, and phenyl;
• R31 and R32 at each occurrence are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, and cycloalkyl;
• n is 0, 1 or 2;
• r is 0 or 1;
• and
• s is 0 or 1.