3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands

A method of treating a chemokine-mediated disease, in a patient in need of such treatment, wherein the chemokine binds to a CXCR2 and/or CXCR1 receptor in said patient, comprising administering to said patient an effective amount of at least one compound of formula IA:

• 2450
• and the pharmaceutically acceptable salts and solvates thereof, wherein:
• A is selected from the group consisting of:
• 2451 2452 2453
• wherein the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of:
• R9 groups;
• 2454
• wherein one or both of the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of:
• R9 groups;
• 2455
• wherein the above phenyl rings of said A groups are substituted with 1 to 3 substituents each independently selected from the group consisting of:
• R9 groups;
• and
• 2456
• B is:
• 2457
• n is 0 to 6;
• p is 1 to 5;
• X is O, NH, or S;
• Z is 1 to 3;
• R2 is selected from the group consisting of:
• hydrogen, OH, —C(O)OH, —SH, —SO2NR13R14, —NHC(O)R13, —NHSO2NR13R14, —NHSO2R13, —NR13R14—C(O)NR13R14, —C(O)NHOR13, —C(O)NR13OH, —S(O2)OH, —OC(O)R13, an unsubstituted heterocyclic acidic functional group, and a substituted heterocyclic acidic functional group;
• wherein there are 1 to 6 substituents on said substituted heterocyclic acidic functional group each substituent being independently selected from the group consisting of:
• R9 groups;
• each R3 and R4 is independently selected from the group consisting of:
• hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF3, —OCF3, —NO2, —C(O)R13, —C(O)OR13, —C(O)NHR17, —SO(t)NR13R14, —SO(t)R13, —C(O)NR13OR14, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl;
• wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of:
• R9 groups;
• and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of:
• R9 groups;
• each R5 and R6 are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF3, —OCF3, —NO2, —C(O)R3, —C(O)OR13, —C(O)NR13R14, —SO(t)NR13R14, —C(O)NR13OR14, cyano, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl group;
• wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of:
• R9 groups;
• and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of:
• R9 groups;
• each R7 and R8 is independently selected from the group consisting of:
• H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, —CO2R13, —CONR13R14, alkynyl, alkenyl, and cycloalkenyl;
• and wherein there are one or more substituents on said substituted R7 and R8 groups, wherein each substituent is independently selected from the group consisting of:
• a) halogen,
• b) —CF3,
• c) —COR13,
• d) —OR13,
• e) —NR13R14,
• f) —NO2,
• g) —CN,
• h) —SO2OR13,
• i) —Si(alkyl)3, wherein each alkyl is independently selected,
• j) —Si(aryl)3, wherein each alkyl is independently selected,
• k) —(R13)2R14Si, wherein each R13 is independently selected,
• l) —CO2R13,
• m) —C(O)NR13R14,
• n) —SO2NR13R14,
• o) —SO2R13,
• p) —OC(O)R13,
• q) —OC(O)NR13R14,
• r) —NR13C(O)R14, and
• s) —NR13CO2R14;
• R8a is selected from the group consisting of:
• hydrogen, alkyl, cycloalkyl and cycloalkylalkyl;
• each R9 is independently selected from the group consisting of:
• a) —R13,
• b) halogen,
• c) —CF3,
• d) —COR13,
• e) —OR13,
• f) —NR13R14,
• g) —NO2,
• h) —CN,
• i) —SO2R13,
• j) —SO2NR13R14,
• k) —NR13COR14,
• l) —CONR13R14,
• m) —NR3CO2R14,
• n) —CO2R13,
• 2458
• p) alkyl substituted with one or more —OH groups,
• q) alkyl substituted with one or more —NR13R14 group, and
• r) —N(R13)SO2R14;
• R12 is selected from the group consisting of:
• hydrogen, —C(O)OR13, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkylalkyl, and unsubstituted or substituted heteroarylalkyl group;
• wherein there are 1 to 6 substituents on the substituted R12 groups and each substituent is independently selected from the group consisting of:
• R9 groups;
• each R13 and R14 is independently selected from the group consisting of:
• H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl;
• wherein there are 1 to 6 substituents on said substituted R13 and R14 groups and each substituent is independently selected from the group consisting of:
• alkyl, —CF3, —OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, —N(R40)2, —C(O)OR15, —C(O)NR15R16, —S(O)tNR15R16, —C(O)R15, —SO2R15 provided that R15 is not H, halogen, and —NHC(O)NR15R16;
• or
• R13 and R14 taken together with the nitrogen they are attached to in the groups —NR13R14, —C(O)NR13R14, —SO2NR13R14, —OC(O)NR13R14, —CONR13R14—NR13C(O)NR13R14, —SOtNR13R14, —NHSO2NR13R14 form an unsubstituted or substituted saturated heterocyclic ring, said ring optionally containing one additional heteroatom selected from the group consisting of:
• O, S and NR18;
• wherein there are 1 to 3 substituents on the substituted cyclized R13 and R14 groups and each substituent is independently selected from the group consisting of:
• alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR15, —C(O)NR15R16, —SOtNR15R16, —C(O)R15, —SO2R15 provided that R15 is not H, —NHC(O)NR15R16, —NHC(O)OR15, halogen, and a heterocycloalkenyl group;
• each R15 and R16 is independently selected from the group consisting of:
• H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;
• R17 is selected from the group consisting of:
• —SO2alkyl, —SO2aryl, —SO2cycloalkyl, and —SO2heteroaryl;
• R18 is selected from the group consisting of:
• H, alkyl, aryl, heteroaryl, —C(O)R19, —SO2R19 and —C(O)NR19R20;
• each R19 and R20 is independently selected from the group consisting of:
• alkyl, aryl and heteroaryl;
• each R40 is independently selected from the group consisting of:
• H, alkyl and cycloalkyl;
• and
• t is 0, 1 or 2.

A method of treating cancer in a patient in need of such treatment comprising administering to said patient an effective amount of at least one compound of formula IA:

• 2459
• and the pharmaceutically acceptable salts and solvates thereof, wherein:
• A is selected from the group consisting of:
• 2460 2461 2462
• wherein the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of:
• R9 groups;
• 2463
• wherein one or both of the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of:
• R9 groups;
• 2464
• wherein the above phenyl rings of said A groups are substituted with 1 to 3 substituents each independently selected from the group consisting of:
• R9 groups;
• and
• 2465
• B is:
• 2466
• n is 0 to 6;
• p is 1 to 5;
• X is O, NH, or S;
• Z is 1 to 3;
• R2 is selected from the group consisting of:
• hydrogen, OH, —C(O)OH, —SH, —SO2NR13R14, —NHC(O)R13, —NHSO2NR13R14, —NHSO2R13, —NR13R14, —C(O)NR13R14—C(O)NHOR13, —C(O)NR13OH, —S(O2)OH, —OC(O)R13, an unsubstituted heterocyclic acidic functional group, and a substituted heterocyclic acidic functional group;
• wherein there are 1 to 6 substituents on said substituted heterocyclic acidic functional group each substituent being independently selected from the group consisting of:
• R9 groups;
• each R3 and R4 is independently selected from the group consisting of:
• hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF3, —OCF3, —NO2, —C(O)R13, —C(O)OR13, —C(O)NHR17, —SO(t)NR13R14, —SO(t)R13, —C(O)NR3OR14, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl;
• wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of:
• R9 groups;
• and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of:
• R9 groups;
• each R5 and R6 are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF3, —OCF3, —NO2, —C(O)R13—C(O)OR13, —C(O)NR13R14, —SO(t)NR13R14, —C(O)NR13OR14, cyano, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl group;
• wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of:
• R9 groups;
• and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of:
• R9 groups;
• each R7 and R8 is independently selected from the group consisting of:
• H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, —CO2R13, —CONR13R14, alkynyl, alkenyl, and cycloalkenyl;
• and wherein there are one or more substituents on said substituted R7 and R8 groups, wherein each substituent is independently selected from the group consisting of:
• a) halogen,
• b) —CF3,
• c) —COR13,
• d) —OR13,
• e) —NR13R14,
• f) —NO2,
• g) —CN,
• h) —SO2OR13,
• i) —Si(alkyl)3, wherein each alkyl is independently selected,
• j) —Si(aryl)3, wherein each alkyl is independently selected,
• k) —(R13)2R14Si, wherein each R13 is independently selected,
• l) —CO2R13,
• m) —C(O)NR13R14,
• n) —SO2NR13R14,
• o) —SO2R13,
• p) —OC(O)R13,
• q) —OC(O)NR13R14,
• r) —NR13C(O)R14, and
• s) —NR13CO2R14;
• R8a is selected from the group consisting of:
• hydrogen, alkyl, cycloalkyl and cycloalkylalkyl;
• each R9 is independently selected from the group consisting of:
• a) —R13,
• b) halogen,
• c) —CF3,
• d) —COR13,
• e) —OR13,
• f) —NR13R14,
• g) —NO2,
• h) —CN,
• i) —SO2R13,
• j) —SO2NR13R14,
• k) —NR13COR14,
• l) —CONR13R14,
• m) —NR13CO2R14,
• n) —CO2R13,
• 2467
• p) alkyl substituted with one or more —OH groups,
• q) alkyl substituted with one or more —NR13R14 group, and
• r) —N(R13)SO2R14;
• R12 is selected from the group consisting of:
• hydrogen, —C(O)OR13, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkylalkyl, and unsubstituted or substituted heteroarylalkyl group;
• wherein there are 1 to 6 substituents on the substituted R12 groups and each substituent is independently selected from the group consisting of:
• R9 groups;
• each R13 and R14 is independently selected from the group consisting of:
• H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl;
• wherein there are 1 to 6 substituents on said substituted R13 and R14 groups and each substituent is independently selected from the group consisting of:
• alkyl, —CF3, —OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, —N(R40)2, —C(O)OR15, —C(O)NR15R16, —S(O)tNR15R16, —C(O)R15, —SO2R15 provided that R15 is not H, halogen, and —NHC(O)NR15R16;
• or
• R13 and R14 taken together with the nitrogen they are attached to in the groups —NR13R14, —C(O)NR13R14, —SO2NR13R14, —OC(O)NR13R14, —CONR13R14—NR13C(O)NR13R14, —SOtNR13R14, —NHSO2NR13R14 form an unsubstituted or substituted saturated heterocyclic ring, said ring optionally containing one additional heteroatom selected from the group consisting of:
• O, S and NR18;
• wherein there are 1 to 3 substituents on the substituted cyclized R13 and R14 groups and each substituent is independently selected from the group consisting of:
• alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR15, —C(O)NR15R16, —SOtNR15R16, —C(O)R15, —SO2R15 provided that R15 is not H, —NHC(O)NR15R16, —NHC(O)OR15, halogen, and a heterocycloalkenyl group;
• each R15 and R16 is independently selected from the group consisting of:
• H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;
• R17 is selected from the group consisting of:
• —SO2alkyl, —SO2aryl, —SO2cycloalkyl, and —SO2heteroaryl;
• R18 is selected from the group consisting of:
• H, alkyl, aryl, heteroaryl, —C(O)R19, —SO2R19 and —C(O)NR19R20;
• each R19 and R20 is independently selected from the group consisting of:
• alkyl, aryl and heteroaryl;
• each R40 is independently selected from the group consisting of:
• H, alkyl and cycloalkyl;
• and
• t is 0, 1 or 2.

A method of inhibiting angiogenesis, in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of formula IA:

• 2468
• and the pharmaceutically acceptable salts and solvates thereof, wherein:
• A is selected from the group consisting of:
• 2469 2470 2471
• wherein the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of:
• R9 groups;
• 2472
• wherein one or both of the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of:
• R9 groups;
• 2473
• wherein the above phenyl rings of said A groups are substituted with 1 to 3 substituents each independently selected from the group consisting of:
• R9 groups;
• and
• 2474
• B is:
• 2475
• n is 0 to 6;
• p is 1 to 5;
• X is O, NH, or S;
• Z is 1 to 3;
• R2 is selected from the group consisting of:
• hydrogen, OH, —C(O)OH, —SH, —SO2NR13R14, —NHC(O)R13, —NHSO2N R13R14, —NHS O2R13, —NR13R14, —C(O)NR13R14,
• —C(O)NH O R13, —C(O)NR13 OH, —S(O2)OH, —OC(O)R13, an unsubstituted heterocyclic acidic functional group, and a substituted heterocyclic acidic functional group;
• wherein there are 1 to 6 substituents on said substituted heterocyclic acidic functional group each substituent being independently selected from the group consisting of:
• R9 groups;
• each R3 and R4 is independently selected from the group consisting of:
• hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF3, —OCF3, —NO2, —C(O)R13, —C(O)OR13, —C(O)NHR17, —SO(t)NR13R14, —SO(t)R3, —C(O)NR13OR14, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl;
• wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of:
• R9 groups;
• and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of:
• R9 groups;
• each R5 and R6 are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF3, —OCF3, —NO2, —C(O)R13—C(O)OR13, —C(O)NR13R14, —SO(t)NR13R14, —C(O)NR13OR14, cyano, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl group;
• wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of:
• R9 groups;
• and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of:
• R9 groups;
• each R7 and R8 is independently selected from the group consisting of:
• H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, —CO2R13, —CONR13R14, alkynyl, alkenyl, and cycloalkenyl;
• and wherein there are one or more substituents on said substituted R7 and R8 groups, wherein each substituent is independently selected from the group consisting of:
• a) halogen,
• b) —CF3,
• c) —COR13,
• d) —OR13,
• e) —NR13R14,
• f) —NO2,
• g) —CN,
• h) —SO2OR13,
• i) —Si(alkyl)3, wherein each alkyl is independently selected,
• j) —Si(aryl)3, wherein each alkyl is independently selected,
• k) —(R13)2R14Si, wherein each R13 is independently selected,
• l) —CO2R13,
• m) —C(O)NR13R14,
• n) —SO2NR13R14,
• o) —SO2R13,
• p) —OC(O)R13,
• q) —OC(O)NR13R14,
• r) —NR3C(O)R14, and
• s) —NR13CO2R14;
• R8a is selected from the group consisting of:
• hydrogen, alkyl, cycloalkyl and cycloalkylalkyl;
• each R9 is independently selected from the group consisting of:
• a) —R13,
• b) halogen,
• c) —CF3,
• d) —COR13,
• e) —OR13,
• f) —NR13R14,
• g) —NO2,
• h) —CN,
• i) —SO2R13,
• j) —SO2NR13R14,
• k) —NR13COR14,
• l) —CONR13R14,
• m) —NR3CO2R14,
• n) —CO2R13,
• 2476
• p) alkyl substituted with one or more —OH groups,
• q) alkyl substituted with one or more —NR13R14 group, and
• r) —N(R13)SO2R14;
• R12 is selected from the group consisting of:
• hydrogen, —C(O)OR13, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkylalkyl, and unsubstituted or substituted heteroarylalkyl group;
• wherein there are 1 to 6 substituents on the substituted R12 groups and each substituent is independently selected from the group consisting of:
• R9 groups;
• each R13 and R14 is independently selected from the group consisting of:
• H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl;
• wherein there are 1 to 6 substituents on said substituted R13 and R14 groups and each substituent is independently selected from the group consisting of:
• alkyl, —CF3, —OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, —N(R40)2, —C(O)OR15, —C(O)NR15R16, —S(O)tNR15R16, —C(O)R15, —SO2R15 provided that R15 is not H, halogen, and —NHC(O)NR15R16;
• or
• R13 and R14 taken together with the nitrogen they are attached to in the groups —NR13R14, —C(O)NR13R14, —SO2NR13R14, —OC(O)NR13R14, —CONR13R14—NR13C(O)NR13R14, —SOtNR13R14, —NHSO2NR13R14 form an unsubstituted or substituted saturated heterocyclic ring, said ring optionally containing one additional heteroatom selected from the group consisting of:
• O, S and NR18;
• wherein there are 1 to 3 substituents on the substituted cyclized R13 and R14 groups and each substituent is independently selected from the group consisting of:
• alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR15, —C(O)NR15R16, —SOtNR15R16, —C(O)R15, —SO2R15 provided that R5 is not H, —NHC(O)NR15R16, —NHC(O)OR15, halogen, and a heterocycloalkenyl group;
• each R15 and R16 is independently selected from the group consisting of:
• H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;
• R17 is selected from the group consisting of:
• —SO2alkyl, —SO2aryl, —SO2cycloalkyl, and —SO2heteroaryl;
• R18 is selected from the group consisting of:
• H, alkyl, aryl, heteroaryl, —C(O)R19, —SO2R19 and —C(O)NR19R20;
• each R19 and R20 is independently selected from the group consisting of:
• alkyl, aryl and heteroaryl;
• each R40 is independently selected from the group consisting of:
• H, alkyl and cycloalkyl;
• and
• t is 0, 1 or 2.

A method of treating a disease selected from the group consisting of:

• gingivitis, respiratory viruses, herpes viruses, hepatitis viruses, HIV, kaposi's sarcoma associated virus and atherosclerosis, in a patient in need of such treatment, comprising administering to said patient an effective amount of at least one compound of formula IA:
• 2477
• and the pharmaceutically acceptable salts and solvates thereof, wherein:
• A is selected from the group consisting of:
• 2478 2479 2480
• wherein the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of:
• R9 groups;
• 2481
• wherein one or both of the above rings of said A groups are substituted with 1 to 6 substituents each independently selected from the group consisting of:
• R9 groups;
• 2482
• wherein the above phenyl rings of said A groups are substituted with 1 to 3 substituents each independently selected from the group consisting of:
• R9 groups;
• and
• 2483
• B is:
• 2484
• n is 0 to 6;
• p is 1 to 5;
• X is O, NH, or S;
• Z is 1 to 3;
• R2 is selected from the group consisting of:
• hydrogen, OH, —C(O)OH, —SH, —SO2NR13R14, —NHC(O)R13, —NHSO2NR13R14, —NHSO2R13, —NR13 R14—C(O)NR13R14, —C(O)NHOR13, —C(O)N R13OH, —S(O2)OH, —OC(O)R13, an unsubstituted heterocyclic acidic functional group, and a substituted heterocyclic acidic functional group;
• wherein there are 1 to 6 substituents on said substituted heterocyclic acidic functional group each substituent being independently selected from the group consisting of:
• R9 groups;
• each R3 and R4 is independently selected from the group consisting of:
• hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF3, —OCF3, —NO2, —C(O)R13, —C(O)OR13, —C(O)NHR17, —SO(t)NR13R14, —SO(t)R13, —C(O)NR13OR14, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl;
• wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of:
• R9 groups;
• and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of:
• R9 groups;
• each R5 and R6 are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF3, —OCF3, —NO2, —C(O)R13, —C(O)OR13, —C(O)NR13R14, —SO(t)NR13R14, —C(O)NR13OR14, cyano, unsubstituted or substituted aryl, and unsubstituted or substituted heteroaryl group;
• wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of:
• R9 groups;
• and wherein there are 1 to 6 substituents on said substituted heteroaryl group and each substituent is independently selected from the group consisting of:
• R9 groups;
• each R7 and R8 is independently selected from the group consisting of:
• H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, —CO2R13, —CONR13R14, alkynyl, alkenyl, and cycloalkenyl;
• and wherein there are one or more substituents on said substituted R7 and R8 groups, wherein each substituent is independently selected from the group consisting of:
• a) halogen,
• b) —CF3,
• c) —COR13,
• d) —OR13,
• e) —NR13R14,
• f) —NO2,
• g) —CN,
• h) —SO2OR13,
• i) —Si(alkyl)3, wherein each alkyl is independently selected,
• j) —Si(aryl)3, wherein each alkyl is independently selected,
• k) —(R13)2R14Si, wherein each R13 is independently selected,
• l) —CO2R13,
• m) —C(O)NR13R14,
• n) —SO2NR13R14,
• o) —SO2R13,
• p) —OC(O)R13,
• q) —OC(O)NR13R14,
• r) —NR13C(O)R14, and
• s) —NR13CO2R14;
• R8a is selected from the group consisting of:
• hydrogen, alkyl, cycloalkyl and cycloalkylalkyl;
• each R9 is independently selected from the group consisting of:
• a) —R13,
• b) halogen,
• c) —CF3,
• d) —COR13,
• e) —OR13,
• f) —NR13R14,
• g) —NO2,
• h) —CN,
• i) —SO2R13,
• j) —SO2NR13R14,
• k) —NR13COR14,
• l) —CONR13R14,
• m) —NR13CO2R14,
• n) —CO2R13,
• 2485
• p) alkyl substituted with one or more —OH groups,
• q) alkyl substituted with one or more —NR13R14 group, and
• r) —N(R13)SO2R14;
• R12 is selected from the group consisting of:
• hydrogen, —C(O)OR13, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkylalkyl, and unsubstituted or substituted heteroarylalkyl group;
• wherein there are 1 to 6 substituents on the substituted R12 groups and each substituent is independently selected from the group consisting of:
• R9 groups;
• each R13 and R14 is independently selected from the group consisting of:
• H, unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroarylalkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkylalkyl, unsubstituted or substituted heterocyclic, unsubstituted or substituted fluoroalkyl, and unsubstituted or substituted heterocycloalkylalkyl;
• wherein there are 1 to 6 substituents on said substituted R13 and R14 groups and each substituent is independently selected from the group consisting of:
• alkyl, —CF3, —OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, —N(R40)2, —C(O)OR15, —C(O)NR15R16, —S(O)tNR15R16, —C(O)R15, —SO2R15 provided that R15 is not H, halogen, and —NHC(O)NR15R16;
• or
• R13 and R14 taken together with the nitrogen they are attached to in the groups —NR13R14, —C(O)NR13R14, —SO2NR13R14, —OC(O)NR13R14—, NHSO2NR13R14, —NR13C(O)NR13R14, —SOtNR13R14, —NHSO2NR13R14 form an unsubstituted or substituted saturated heterocyclic ring, said ring optionally containing one additional heteroatom selected from the group consisting of:
• O, S and NR18;
• wherein there are 1 to 3 substituents on the substituted cyclized R13 and R14 groups and each substituent is independently selected from the group consisting of:
• alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR15, —C(O)NR15R16, —SOtNR15R16, —C(O)R15, —SO2R15 provided that R15 is not H, —NHC(O)NR15R16, —NHC(O)OR15, halogen, and a heterocycloalkenyl group;
• each R15 and R16 is independently selected from the group consisting of:
• H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;
• R17 is selected from the group consisting of:
• —SO2alkyl, —SO2aryl, —SO2cycloalkyl, and —SO2heteroaryl;
• R18 is selected from the group consisting of:
• H, alkyl, aryl, heteroaryl, —C(O)R19, —SO2R19 and —C(O)NR19R20;
• each R19 and R20 is independently selected from the group consisting of:
• alkyl, aryl and heteroaryl;
• each R40 is independently selected from the group consisting of:
• H, alkyl and cycloalkyl;
• and
• t is 0, 1 or 2.