3,4-di-substituted pyridazinediones as CXC chemokine receptor antagonists

A compound of the formula (I):

• 990
• or pharmaceutically acceptable salts or solvates thereof wherein:
• R1 and R15 are the same or different and each is independently selected from the group consisting of:
• a) H,
• b) aryl,
• c) heteroaryl,
• d) alkyl,
• e) arylalkyl,
• f) heteroarylalkyl,
• g) cycloalkyl,
• h) heterocycloalkyl,
• i) cycloalkylalkyl and
• j) heterocycloalkylalkyl,
• wherein said aryl, heteroaryl, alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, and heterocycloalkylalkyl groups are optionally substituted with one or more substituents selected from the group consisting of:
• a) halogen,
• b) CF3,
• c) COR13,
• d) OH,
• e) NR13R14,
• f) NO2,
• g) cyano,
• h) SO2OR13,
• i) —Si(alkyl),
• j) —Si(aryl)
• k) CO2R13
• l) CONR13R14,
• m) SO2NR13R14,
• n) SO2R13,
• o) —OR13,
• p) —O(C═O)R13,
• q) —O(C═O)NR13R14,
• r) —NR13COR14, and
• s) —NR13CO2R14;
• A is selected from the group consisting of:
• 991 992 993
• B is selected from the group consisting of:
• 994
• wherein:
• R2 is selected from the group consisting of:
• a) hydrogen,
• b) OH,
• c) C(O)OH,
• d) SH,
• e) SO2NR13R14,
• f) NHC(O)R13,
• g) NHSO2NR13R14,
• h) NR13R14,
• i) NHSO2R13,
• j) C(O)NR13R14,
• k) C(O)NHOR13,
• l) C(O)NR13OH,
• m) OC(O)R13 and
• n) an optionally substituted heterocyclic acidic functional group, with the proviso that if R2 is SO2NR13R14, then at least one of R13 and R14 must be hydrogen;
• R3 and R4 are the same or different and each is independently selected from the group consisting of:
• a) hydrogen,
• b) halogen,
• c) alkyl,
• d) alkoxy,
• e) OH,
• f) CF3,
• g) OCF3,
• h) NO2,
• i) C(O)R13,
• j) C(O)OR13,
• k) C(O)NR13R14,
• l) SO(t)NR13R14,
• m) SO(t)R13,
• n) C(O)NR13OR14,
• 995
• p) cyano,
• q) aryl and
• r) heteroaryl,
• wherein said aryl or heteroaryl group is optionally substituted with one or more R9 group;
• R5 and R6 are the same or different and each is independently selected from the group consisting of
• a) hydrogen,
• b) halogen,
• c) alkyl,
• d) alkoxy,
• e) CF3,
• f) OCF3,
• g) NO2,
• h) C(O)R13,
• i) C(O)OR13,
• j) C(O)NR13R14,
• k) SO(t)NR13R14,
• l) C(O)NR13OR14,
• m) cyano,
• n) aryl and
• o) heteroaryl,
• wherein said aryl or heteroaryl group is optionally substituted with one or more R9 group;
• R7 and R8 are the same or different and each is independently selected from the group consisting of
• a) H,
• b) alkyl,
• c) aryl,
• d) heteroaryl,
• e) arylalkyl,
• f) heteroarylalkyl,
• g) cycloalkyl,
• h) cycloalkylalkyl,
• i) CO2R13,
• j) CONR13R14,
• k) fluoroalkyl,
• l) alkynyl,
• m) alkenyl,
• n) alkynylalkyl,
• o) alkenylalkyl and
• p) cycloalkenyl,
• wherein said alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, fluoroalkyl, alkynyl, alkenyl, alkynylalkyl, alkenylalkyl, and cycloalkenyl groups are optionally substituted with one or more substituents selected from the group consisting of:
• a) halogen,
• b) CF3,
• c) COR13,
• d) OH,
• e) NR13R14,
• f) NO2,
• g) cyano,
• h) SO2OR13,
• i) —Si(alkyl),
• j) —Si(aryl),
• k) (R13)2R14Si,
• l) CO2R13,
• m) C(O)NR13R14,
• n) SO2NR13R14,
• o) SO2R13,
• p) —OR13,
• q) —O(C═O)R13,
• r) —O(C═O)NR13R14,
• s) —NR13C(O)R14 and
• t) —NR13CO2R14;
• R9 is selected from the group consisting of:
• a) R13,
• b) halogen,
• c) —CF3,
• d) —COR13,
• e) —OR13,
• f) —NR13R14,
• g) —NO2,
• h) cyano,
• i) —SO2R13,
• j) —SO2NR13R14,
• k) —NR13COR14,
• l) —CONR13R14,
• m) —NR13CO2R14,
• n) CO2R13 and
• 996
• R10 and R11 are the same or different and each is independently selected from the group consisting of:
• a) hydrogen,
• b) halogen,
• c) CF3,
• d) OCF3,
• e) NR13R14,
• f) NR13C(O)NR13R14,
• g) OH,
• h) C(O)OR13,
• i) SH,
• j) SO(t)NR13R14,
• k) SO2R13,
• l) NHC(O)R13,
• m) NHSO2NR13R14,
• n) NHSO2R13,
• o) C(O)NR13R14,
• p) C(O)NR13OR14,
• q) OC(O)R13 and
• r) cyano;
• R12 is selected from the group consisting of:
• a) hydrogen,
• b) OC(O)R13,
• c) aryl,
• d) heteroaryl,
• e) arylalkyl,
• f) cycloalkyl,
• g) alkyl,
• h) cycloalkylalkyl and
• i) heteroarylalkyl,
• wherein said aryl, heteroaryl, arylalkyl, cycloalkyl, alkyl, cycloalkylalkyl and heteroarylalkyl groups are optionally substituted with one or more R9 group;
• R13 and R14 are the same or different and each is independently selected from the group consisting of:
• a) H,
• b) alkyl,
• c) aryl,
• d) heteroaryl,
• e) arylalkyl,
• f) heteroarylalkyl,
• g) cycloalkyl,
• h) cycloalkylalkyl and
• i) fluoroalkyl,
• wherein said alkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, and fluoroalkyl groups are optionally substituted with one or more substituents selected from the group consisting of:
• a) alkyl,
• b) aryl,
• c) arylalkyl,
• d) fluoroalkyl,
• e) cycloalkyl,
• f) cycloalkylalkyl,
• g) heteroaryl,
• h) heteroarylalkyl,
• i) amino,
• j) carbonyl and
• k) halogen;
• or
• R13 and R14 when taken together with the atoms to which they are attached form a 3 to 7 membered heterocyclic ring wherein when the ring formed is a 6 or 7 membered heterocyclic ring, said ring optionally contains one to two additional heteroatoms independently selected from the group consisting of O, S and N and wherein said heterocyclic ring can be substituted with one or more substituents selected from the group consisting of:
• a) alkyl,
• b) aryl,
• c) arylalkyl,
• d) fluoroalkyl,
• e) cycloalkyl,
• f) cycloalkylalkyl,
• g) heteroaryl,
• h) heteroarylalkyl,
• i) amino,
• j) carbonyl and
• k) halogen;
• n is 0-6;
• m is 1-5;
• p is 0-4 and
• t is 1 or 2.