Ureido-substituted aniline compounds useful as serine protease inhibitors

A compound having the formula (I),

• 45
• or a pharmaceutically-acceptable salt, hydrate or prodrug thereof, wherein:
• A is a five or six-membered saturated or unsaturated carbocyclic, heterocyclic or heteroaryl ring, said ring A being optionally substituted with up to three groups selected from R27;
• B is selected from one of
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• D is phenyl or a five to six-membered heteroaryl, heterocyclic, or cycloalkyl ring;
• R1 is hydrogen, C1-4alkyl, or C1-4alkyl substituted with one to two R21;
• R2 and R3 are attached to any available carbon atom of ring B and ring D, respectively, and at each occurrence are independently selected from halogen, cyano, NO2, C1-6alkyl, substituted C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloalkyl, haloalkoxy, —OR15, —C(═O)R15, —OC(═O)R15, —CO2R15, —OCO2R15, —C(═O)NR15R16, —OC(═O)NR15R16, —NR15R16, —NR16C(═O)R15, —NR16CO2R15, —NR16aC(═O)NR15R16, —SR15, —S(O)R15, —SO2R15, —SO2NR15R16, —SO3R15, —NR16SO2R15, and —NR16aSO2NR15R16;
• R4 and R5 are independently selected from hydrogen, halogen, hydroxy, cyano, C1-3alkoxy, —OCF3, CF3, amino, C1-6alkylamino, C1-4alkyl, and C1-4alkyl substituted with one to two R22, or alternatively, R4 and R5 taken together may form a three-to-eight membered cycloalkyl or heterocyclic Spiro ring, said ring being optionally substituted with up to three R28;
• R6 is selected from hydrogen, C1-4alkyl, and C1-4alkyl substituted with one to two R23;
• R7 and R8 are independently selected from hydrogen, halogen, hydroxy, cyano, C1-3alkoxy, OCF3, CF3, amino, C1-6alkylamino, C1-4alkyl, and C1-4alkyl substituted with one to two R24;
• or alternatively, R7 and R8 taken together may form a three-to-eight membered cycloalkyl or heterocyclic spiro ring, said ring being optionally substituted with up to three R29;
• or alternatively, one or both of R7 and R8 may be taken together with one or both of R9 and R10 to form a heterocyclic or heteroaryl ring, said ring in turn being optionally substituted with up to three R30;
• R9 and R10 are independently selected from hydrogen, C1-4alkyl, and C1-4alkyl substituted with one to two R25;
• or alternatively, R9 and R10 taken together may form a three-to-eight membered heterocyclic ring or a five to six membered heteroaryl ring, said ring being optionally substituted with up to three R30;
• or alternatively, one or both of R9 and R10 may be taken together with one or both of R7 and R8 to form a heterocyclic or heteroaryl ring optionally substituted with up to three R30;
• R11 at each occurrence is independently selected from halogen, cyano, NO2, C1-6alkyl, substituted C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloalkyl, haloalkoxy, —OR17, —C(═O)R17, —OC(═O)R17, —CO2R17, —OCO2R17, —C(═O)NR17R18, —OC(═O)NR17R18, —NR17R18, —NR18C(═O)R17, NR18aC(═O)NR17R18, —NR18CO2R17, —SR17, —S(O)R17, —SO2R17, —SO2NR17R18, —SO3R17, —NR18SO2R17, and —NR18aSO2NR17R18;
• or alternatively, two R11 groups may be taken together to form a fused benzo, heteroaryl, or heterocyclic ring, wherein said ring in turn is optionally substituted with up to one A group and/or one to two R31;
• R12 is hydrogen, C1-4alkyl, or C1-4alkyl substituted with one to two R26;
• R13 and R14 are independently selected from hydrogen, alkyl, substituted alkyl, cyano, hydroxy, alkoxy, cycloalkyl, heterocyclo, aryl and heteroaryl;
• or alternatively, R13 and R14 taken together may form a heteroaryl or heterocyclic ring;
• R15 at each occurrence independently of each other R15 is selected from hydrogen, C1-6alkyl, substituted C1-6alkyl, C2-8alkenyl, C2-8alkynyl, C3-10cycloalkyl(C0-4alkyl), aryl(C0-4alkyl), heterocyclo(C0-4alkyl), and heteroaryl(C0-4alkyl), wherein each of said cycloalkyl, aryl, heterocyclo, and heteroaryl groups are optionally substituted with up to two substituents independently selected from R32;
• provided, however, that when R15 is attached to a sulfonyl group as in —SO2R15, —S(═O)R15, and —SO3R15, then R15 is not hydrogen;
• and
• R16 and R16a at each occurrence independently of each other R16 and R16a are selected from hydrogen, C1-6alkyl, substituted C1-6alkyl, C2-6alkenyl, C2-6alkynyl, —OR19, —C(═O)R19, —CO2R19, —SO2R19, C3-10cycloalkyl(C0-4alkyl), aryl(C0-4alkyl), heterocyclo(C0-4alkyl), and heteroaryl(C0-4alkyl), wherein R19 is C1-6alkyl, C3-10cycloalkyl, aryl, heterocyclo, or heteroaryl, and each of said RI19, cycloalkyl, aryl, heterocyclo, and heteroaryl groups are in turn optionally substituted with up to two substituents independently selected from R33;
• alternatively, R15 and R16 can be taken together with the nitrogen atom to which they are attached to form a heterocyclo or heteroaryl, said ring being in turn optionally substituted with up to three groups selected from R33;
• R17 at each occurrence independently of each other R17 is selected from hydrogen, C1-6alkyl, substituted C1-6alkyl, C2-8alkenyl, C2-8alkynyl, C3-10cycloalkyl(C0-4alkyl), aryl(C0-4alkyl), heterocyclo(C0-4alkyl), and heteroaryl(C0-4alkyl), wherein each of said cycloalkyl, aryl, heterocyclo, and heteroaryl groups in turn are optionally substituted with up to two substituents independently selected from R34;
• provided, however, that when R17 is attached to a sulfonyl group as in —SO2R17, —S(═O)R17, and —SO3R17, then R17 is not hydrogen;
• and
• R18 and R18a at each occurrence independently of each other R18 and R18a are selected from hydrogen, C1-6alkyl, substituted C1-6alkyl, C2-6alkenyl, C2-6alkynyl, —OR20, —C(═O)R20, —CO2R20, —SO2R20, C3-10cycloalkyl(C0-4alkyl), aryl(C0-4alkyl), heterocyclo(C0-4alkyl), and heteroaryl(C0-4alkyl), wherein R20 is C1-6alkyl, C3-10cycloalkyl, aryl, heterocyclo, or heteroaryl, and each of said R20, cycloalkyl, aryl, heterocyclo, and heteroaryl groups are in turn optionally substituted with up to two substituents independently selected from the group consisting of R35;
• or, alternatively, R17 and R18 when both groups are attached to the same nitrogen atom can be taken together with the nitrogen atom to which they are attached to form a heterocyclo or heteroaryl, said ring in turn being optionally substituted with up to three groups selected from R35;
• R21, R22, R23, R24, R25, and R26 are independently selected from halogen, cyano, hydroxy, C1-3alkoxy, OCF3, CF3, amino, and C1-6alkylamino;
• R27, R28, R29, R30, R31, R32, R33, R34, and R35 are at each occurrence independently selected from C1-4alkyl, C2-6alkenyl, C2-6alkynyl, oxo (═O), halo(C0-4alkyl), NO2(C0-4alkyl), hydroxy(C0-4alkyl), CF3(C0-4alkyl), OCF3(C0-4alkyl) cyano(C0-4alkyl), amino(C0-4alkyl), C1-4alkoxy(C0-4alkyl), C1-6alkylamino(C0-4alkyl), C1-4alkylthio(C0-4alkyl), carbamyl(C0-4alkyl), —C(═O)C1-4alkyl, —CO2C1-4alkyl, —S(O)(C1-4alkyl), —SO2(C1-4alkyl), —SO2NH2, —SO2NH(C1-4alkyl), —SO2N(C1-4alkyl)2, SO3H, SO3(C1-4alkyl), —NHC(═O)(C1-6alkyl), and —C(═O)NH(C1-4alkyl), provided, however, that when R26, R27, R30, R31, R32, R33, R34 and R35 are substituents attached to an aryl or heteroaryl ring, said groups are not selected from oxo (═O);
• provided further, that when R26, R27, R30, R31, R32, R33, R34 and R35 are hydroxy and attached to an aryl or heteroaryl ring, the ring may undergo tautomerization to an oxo species, or exist as an equilibrium mixture of both tautomers;
• a is 0 or 1;
• m is 0, 1,or 2;
• n is 0, 1, 2, 3, or 4;
• p is 0, 1 or 2;
• q is 0, 1, 2, 3 or 4;
• and
• r is 0, 1 or 2.