METHOD OF TREATING ARTHRITIS
Methods of preventing or treating arthritis is disclosed.
1 . A method for treating arthritis in a mammal comprising administering to a mammal in need of such a treatment a therapeutically effective amount of a compound having Formula (I)
or a therapeutically acceptable salt thereof, wherein
A 1 is N or C(A 2 );
one or two or three or each of A 2 , B 1 , D 1 and E 1 are independently selected R 1 , OR 1 , SR 1 , S(O)R 1 , SO 2 R 1 , C(O)R 1 , C(O)OR 1 , OC(O)R 1 , NHR 1 , N(R 1 ) 2 , C(O)NHR 1 , C(O)N(R 1 ) 2 , NHC(O)R 1 , NHC(O)OR 1 , NR 1 C(O)NHR 1 , NR 1 C(O)N(R 1 ) 2 , SO 2 NHR 1 , SO 2 N(R 1 ) 2 , NHSO 2 R 1 , NHSO 2 NHR 1 or N(CH 3 )SO 2 N(CH 3 )R 1 , and the remainder are independently selected H, F, Cl, Br, I, CN, CF 3 , C(O)OH, C(O)NH 2 or C(O)OR 1A ; and
Y 1 is H, CN, NO 2 , C(O)OH, F, Cl, Br, I, CF 3 , OCF 3 , CF 2 CF 3 , OCF 2 CF 3 , R 17 , OR 17 , C(O)R 17 , C(O)OR 17 , SR 17 , NH 2 , NHR 17 , N(R 17 ) 2 , NHC(O)R 17 , C(O)NH 2 , C(O)NHR 17 , C(O)N(R 17 ) 2 , NHS(O)R 17 or NHSO 2 R 17 ;
or
B 1 and Y 1 , together with the atoms to which they are attached, are imidazole or triazole; and
one or two or each of A 2 , D 1 and E 1 are independently selected R 1 , OR 1 , SR 1 , S(O)R 1 , SO 2 R 1 , C(O)R 1 , C(O)OR 1 , OC(O)R 1 , NHR 1 , N(R 1 ) 2 , C(O)NHR 1 , C(O)N(R 1 ) 2 , NHC(O)R 1 , NHC(O)OR 1 , NHC(O)NHR 1 , N(CH 3 )C(O)N(CH 3 )R 1 , SO 2 NHR 1 , SO 2 N(R 1 ) 2 , NHSO 2 R 1 , NHSO 2 NHR 1 or N(CH 3 )SO 2 N(CH 3 )R 1 , and the remainder are independently selected H, F, Cl, Br, I, CF 3 , CF 2 CF 3 , CF 2 CF 2 CF 3 , C(O)OH, C(O)NH 2 or C(O)OR 1A ;
R 1 is R 2 , R 3 , R 4 or R 5 ;
R 1A is alkyl, C 3 -C 6 -alkenyl or C 3 -C 6 -alkynyl;
R 2 is phenyl which is unfused or fused with benzene, heteroarene or R 2A ; R 2A is cycloalkane or heterocycloalkane;
R 3 is heteroaryl which is unfused or fused with benzene, heteroarene or R 3A ; R 3A is cycloalkane or heterocycloalkane;
R 4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 4A ; R 4A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 5 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 6 , NC(R 6A )(R 6B ), R 7 , OR 7 , SR 7 , S(O)R 7 , SO 2 R 7 , NHR 7 , N(R 7 ) 2 , C(O)R 7 , C(O)NH 2 , C(O)NHR 7 , NHC(O)R 7 , NHSO 2 R 7 , NHC(O)OR 7 , SO 2 NH 2 , SO 2 NHR 7 , SO 2 N(R 7 ) 2 , NHC(O)NH 2 , NHC(O)NHR 7 , OH, (O), C(O)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br or I;
R 6 is C 2 -C 5 -spiroalkyl which is unsubstituted or substituted with OH, (O), N 3 , CN, CF 3 , CF 2 CF 3 , F, Cl, Br, I, NH 2 , NH(CH 3 ) or N(CH 3 ) 2 ;
R 6A and R 6B are independently selected alkyl or, together with the N to which they are attached, R 6C ;
R 6C is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, each of which has one CH 2 moiety unreplaced or replaced with O, C(O), CNOH, CNOCH 3 , S, S(O), SO 2 or NH;
R 7 is R 8 , R 9 , R 10 or R 11 ;
R 8 is phenyl which is unfused or fused with benzene, heteroarene or R 8A ; R 8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 9 is heteroaryl which is unfused or fused with benzene, heteroarene or R 9A ; R 9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 10 is C 3 -C 10 -Cycloalkyl, C 4 -C 10 -Cycloalkenyl, C 3 -C 10 -heterocycloalkyl or C 4 -C 10 -heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 10A ; R 10A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 11 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 12 , OR 12 , NHR 12 , N(R 12 ) 2 , C(O)NH 2 , C(O)NHR 12 , C(O)N(R 12 ) 2 , OH, (O), C(O)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br or I;
R 12 is R 13 , R 14 , R 15 or R 16 ;
R 13 is phenyl which is unfused or fused with benzene, heteroarene or R 13A ; R 13A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 14 is heteroaryl, each of which is unfused or fused with benzene, heteroarene or R 14A ; R 14A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 15 is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene, each of which is unfused or fused with benzene, heteroarene or R 15A ; R 15A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 16 is alkyl, alkenyl or alkynyl;
R 17 is R 18 , R 19 , R 20 or R 21 ;
R 18 is phenyl which is unfused or fused with benzene, heteroarene or R 18A ; R 18A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 19 is heteroaryl which is unfused or fused with benzene, heteroarene or R 19A ; R 19A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 20 is C 3 -C 10 -cycloalkyl, C 4 -C 10 -cycloalkenyl, C 3 -C 10 -heterocycloalkyl or C 4 -C 10 -heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 20A ; R 20A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 21 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 22 , OR 22 , NHR 22 , N(R 22 ) 2 , C(O)NH 2 , C(O)NHR 22 , C(O)N(R 22 ) 2 , OH, (O), C(O)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br or I;
R 22 is R 23 , R 24 or R 25 ;
R 23 is phenyl which is unfused or fused with benzene, heteroarene or R 23A ; R 23A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 24 is heteroarene which is unfused or fused with benzene, heteroarene or R 24A ; R 24A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 25 is C 3 -C 6 -cycloalkyl, C 4 -C 6 -cycloalkenyl, C 3 -C 6 -heterocycloalkyl or C 4 -C 6 -heteroycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 25A ; R 25A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
Z 1 is R 26 or R 27 , each of which is substituted with R 28 , R 29 or R 30 , each of which is substituted with F, Cl, Br, I, CH 2 R 37 , CH(R 31 )(R 37 ), C(R 31 )(R 31A )(R 37 ), C(O)R 37 , OR 37 , SR 37 , S(O)R 37 , SO 2 R 37 , NHR 37 or N(R 32 )R 37 ;
R 26 is phenyl which is unfused or fused with benzene or heteroarene;
R 27 is heteroarene which is unfused or fused with benzene or heteroarene;
R 28 is phenyl which is unfused or fused with benzene, heteroarene or R 28A ; R 28A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 29 is heteroaryl or R 29A ; R 29A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 30 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 30A ; R 30A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 31 and R 31A are independently selected F, Cl, Br or independently selected alkyl or are taken together and are C 2 -C 5 -spiroalkyl;
R 32 is R 33 , C(O)R 33 or C(O)OR 33 ;
R 33 is R 34 or R 35 ;
R 34 is phenyl which is unfused or fused with aryl, heteroaryl or R 34A ; R 34A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 35 is alkyl which is unsubstituted or substituted with R 36 ;
R 36 is phenyl which is unfused or fused with benzene, heteroarene or R 36A ; R 36A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 37 is R 38 , R 39 or R 40 , each of which is substituted with F, Cl, Br, I, R 41 , OR 41 , NHR 41 , N(R 41 ) 2 , NHC(O)OR 41 , SR 41 , S(O)R 41 or SO 2 R 41 ;
R 38 is phenyl which is unfused or fused with benzene, heteroarene or R 38A ; R 38A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 39 is heteroaryl which is unfused or fused with benzene, heteroarene or R 39A ; R 39A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 40 is C 3 -C 5 -cycloalkyl, C 4 -C 5 -cycloalkenyl, C 3 -C 5 -heterocycloalkyl or C 4 -C 5 -heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 40A ; R 40A cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 41 is R 42 , R 43 , R 44 or R 45 ;
R 42 is phenyl which is unfused or fused with benzene, heteroarene or R 42A ; R 42A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 43 is heteroaryl which is unfused or fused with benzene, heteroarene or R 43A ; R 43A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 44 is C 3 -C 6 -cycloalkyl, C 4 -C 6 -cycloalkenyl, C 3 -C 6 -heterocycloalkyl or C 4 -C 6 -heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 44A ; R 44A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 45 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two independently selected R 46 , OR 46 , NHR 46 , N(R 46 ) 2 , C(O)NH 2 , C(O)NHR 46 , C(O)N(R 46 ) 2 , OH, (O), C(O)OH, N 3 , CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br or I substituents;
R 46 is R 47 , R 48 or R 49 ;
R 47 is phenyl which is unfused or fused with benzene, heteroarene or R 47A ; R 47A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 48 is heteroaryl or R 48A ; R 48A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 49 is C 3 -C 6 -cycloalkyl, C 4 -C 6 -cycloalkenyl, C 3 -C 6 -heterocycloalkyl or C 4 -C 6 -heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 49A ; R 49A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
wherein each foregoing cyclic moiety is independently unsubstituted, further unsubstituted, substituted or further substituted with one or two or three or four or five of independently selected R 50 , OR 50 , SR 50 , S(O)R 50 , SO 2 R 50 , C(O)R 50 , CO(O)R 50 , OC(O)R 50 , OC(O)OR 50 , NH 2 , NHR 50 , N(R 50 ) 2 , C(O)NH 2 , C(O)NHR 50 , C(O)N(R 50 ) 2 , C(O)NHOH, C(O)NHOR 50 , C(O)NHSO 2 R 50 , C(O)NR 55 SO 2 R 50 , SO 2 NH 2 , SO 2 NHR 50 , SO 2 N(R 50 ) 2 , CF 3 , CF 2 CF 3 , C(O)H, C(O)OH, C(N)NH 2 , C(N)NHR 50 , C(N)N(R 50 ) 2 , OH, (O), N 3 , NO 2 , CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , F, Cl, Br or I;
R 50 is R 51 , R 52 , R 53 or R 54 ;
R 51 is phenyl which is unfused or fused with benzene, heteroarene or R 51A ; R 51A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 52 is heteroaryl or R 52A ; R 52A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 53 is C 3 -C 6 -cycloalkyl, C 4 -C 6 -cycloalkenyl, C 3 -C 6 -heterocycloalkyl or C 4 -C 6 -heteroycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 53A ;
R 53A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 54 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three or independently selected R 55 , OR 55 , SR 55 , S(O)R 55 , SO 2 R 55 , NHR 55 , N(R 55 ) 2 , C(O)R 55 , C(O)NH 2 , C(O)NHR 55 , NHC(O)R 55 , NHSO 2 R 55 , NHC(O)OR 55 , SO 2 NH 2 , SO 2 NHR 55 , SO 2 N(R 55 ) 2 , NHC(O)NH 2 , NHC(O)NHR 55 , OH, (O), C(O)OH, (O), N 3 , CN, NH 2 , CF 3 , OCF 3 , CF 2 CF 3 , OCF 2 CF 3 , F, Cl, Br or I;
and
R 55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, C 3 -C 6 -cycloalkyl, C 4 -C 6 -cycloalkyl, C 3 -C 6 -heterocycloalkyl or C 4 -C 6 -heterocycloalkyl.
2 . The method of claim 1 , wherein A 1 is C(A 2 );
one or two or three or each of A 2 , B 1 , D 1 and E 1 are independently selected R 1 , OR 1 , SR 1 , S(O)R 1 , SO 2 R 1 , C(O)R 1 , C(O)OR 1 , OC(O)R 1 , NHR 1 , N(R 1 ) 2 , C(O)NHR 1 , C(O)N(R 1 ) 2 , NHC(O)R 1 , NHC(O)OR 1 , NR 1 C(O)NHR 1 , NR 1 C(O)N(R 1 ) 2 , SO 2 NHR 1 , SO 2 N(R 1 ) 2 , NHSO 2 R 1 , NHSO 2 NHR 1 or N(CH 3 )SO 2 N(CH 3 )R 1 , and the remainder are independently selected H, F, Cl, Br, I, CN, CF 3 , C(O)OH, C(O)NH 2 or C(O)OR 1A ;
Y 1 is H, CN, NO 2 , C(O)OH, F, Cl, Br, I, CF 3 , OCF 3 , CF 2 CF 3 , OCF 2 CF 3 , R 17 , OR 17 , C(O)R 17 , C(O)OR 17 , SR 17 , NH 2 , NHR 17 , N(R 17 ) 2 , NHC(O)R 17 , C(O)NH 2 , C(O)NHR 17 , C(O)N(R 17 ) 2 , NHS(O)R 17 or NHSO 2 R 17 ;
R 1 is R 2 , R 4 or R 5 ;
R 1A is alkyl, C 3 -C 6 -alkenyl or C 3 -C 6 -alkynyl;
R 2 is phenyl which is unfused or fused with benzene or heteroarene;
R 4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene or heteroarene;
R 5 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected NC(R 6A )(R 6B ), R 7 , OR 7 , SR 7 , S(O)R 7 , SO 2 R 7 , NHR 7 , N(R 7 ) 2 , C(O)R 7 , C(O)NH 2 , C(O)NHR 7 , NHC(O)R 7 , NHSO 2 R 7 , NHC(O)OR 7 , NHC(O)NH 2 , OH, (O), C(O)OH, CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br or I;
R 6A and R 6B are independently selected alkyl or, together with the N to which they are attached, R 6C ;
R 6C is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl;
R 7 is R 8 , R 9 , R 10 or R 11 ;
R 8 is phenyl which is unfused or fused with benzene, heteroarene or R 8A ; R 8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 9 is heteroaryl which is unfused or fused with benzene or heteroarene;
R 10 is C 3 -C 10 -Cycloalkyl, C 4 -C 10 -Cycloalkenyl, C 3 -C 10 -heterocycloalkyl or C 4 -C 10 -heterocycloalkenyl, each of which is unfused or fused with benzene or heteroarene;
R 11 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 12 , OR 12 , NHR 12 , N(R 12 ) 2 , C(O)NH 2 , C(O)NHR 12 , C(O)N(R 12 ) 2 , OH, (O), C(O)OH, CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br or I;
R 12 is R 13 , R 14 , R 15 or R 16 ;
R 13 is phenyl which is unfused or fused with heterocycloalkane;
R 14 is heteroaryl, each of which is unfused or fused with benzene or heteroarene;
R 15 is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 16 is alkyl, alkenyl or alkynyl;
R 17 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R 22 , OR 22 , NHR 22 , N(R 22 ) 2 , C(O)NH 2 , C(O)NHR 22 , C(O)N(R 22 ) 2 , OH, (O), C(O)OH, CN, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br or I;
Z 1 is R 26 or R 27 , each of which is substituted with R 28 , R 29 or R 30 , each of which is substituted with F, Cl, Br, I, CH 2 R 37 , C(R 31 )(R 31A )(R 37 ), C(O)R 37 , OR 37 , SR 37 , S(O)R 37 , SO 2 R 37 , NHR 37 or N(R 32 )R 37 ;
R 26 is phenyl which is unfused or fused with benzene or heteroarene;
R 27 is heteroarene which is unfused or fused with benzene or heteroarene;
R 28 is phenyl which is unfused or fused with benzene or heteroarene
R 29 is heteroaryl or R 29A ; R 29A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 30 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R 30A ; R 30A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R 31 and R 31A are taken together and are C 2 -C 5 -spiroalkyl;
R 37 is R 38 , R 39 or R 40 , each of which is substituted with F, Cl, Br, I, R 41 , OR 41 , NHR 41 , N(R 41 ) 2 , NHC(O)OR 41 , SR 41 , S(O)R 41 or SO 2 R 41 ;
R 38 is phenyl which is unfused or fused with benzene or heteroarene;
R 39 is heteroaryl which is unfused or fused with benzene or heteroarene;
R 40 is C 3 -C 5 -cycloalkyl, C 4 -C 5 -cycloalkenyl, C 3 -C 5 -heterocycloalkyl or C 4 -C 5 -heterocycloalkenyl;
R 41 is R 42 , R 43 , R 44 or R 45 ;
R 42 is phenyl which is unfused or fused with benzene or heteroarene;
R 43 is heteroaryl which is unfused or fused with benzene or heteroarene;
R 44 is C 3 -C 6 -cycloalkyl, C 4 -C 6 -cycloalkenyl, C 3 -C 6 -heterocycloalkyl or C 4 -C 6 -heterocycloalkenyl;
R 45 is alkyl;
wherein each foregoing cyclic moiety is independently unsubstituted, further unsubstituted, substituted or further substituted with one or two or three or four or five of independently selected R 50 , OR 50 , SR 50 , SO 2 R 50 , C(O)R 50 , CO(O)R 50 , NH 2 , NHR 50 , N(R 50 ) 2 , C(O)NHOH, C(O)NHSO 2 R 50 , C(O)OH, OH, (O), CF 3 , OCF 3 , F, Cl, Br or I;
R 50 is R 51 , R 52 , R 53 or R 54 ;
R 51 is phenyl which is unfused or fused with benzene;
R 52 is heteroaryl;
R 53 is C 3 -C 6 -cycloalkyl, C 4 -C 6 -cycloalkenyl, C 3 -C 6 -heterocycloalkyl or C 4 -C 6 -heteroycloalkenyl, each of which is unfused or fused with benzene or heteroarene;
R 54 is alkyl, which is unsubstituted or substituted with R 55 , OR 55 , SR 55 or N(R 55 ) 2 ;
and
R 55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl, C 3 -C 6 -cycloalkyl, C 4 -C 6 -cycloalkyl, C 3 -C 6 -heterocycloalkyl or C 4 -C 6 -heterocycloalkyl.
3 . The method of claim 2 , wherein A 1 is C(A 2 );
one or two or three or each of A 2 , B 1 , D 1 and E 1 are independently selected R 1 , OR 1 , SO 2 R 1 , C(O)OR 1 , NHR 1 , NR 1 C(O)N(R 1 ) 2 , and the remainder are independently selected H, F, Cl, Br, I, CF 3 , C(O)OH, C(O)NH 2 or C(O)OR 1A ; R 1A is alkyl;
Y 1 is H, CN, NO 2 , F, Cl, Br, I, CF 3 , R 17 , NH 2 , C(O)NH 2 ;
R 1 is phenyl, R 4 or R 5 ;
R 4 is cycloalkyl or heterocycloalkyl;
R 5 is alkyl which is unsubstituted or substituted with one or two of independently selected R 7 , OR 7 , SR 7 , SO 2 R 7 , NHR 7 , N(R 7 ) 2 , C(O)R 7 , C(O)NH 2 , C(O)NHR 7 , NHC(O)R 7 , NHSO 2 R 7 , NHC(O)OR 7 , NHC(O)NH 2 , (O), C(O)OH, NH 2 , CF 3 , CF 2 CF 3 , F, Cl, Br or I;
R 7 is R 8 , R 9 , R 10 or R 11 ;
R 8 is phenyl which is unfused or fused with heterocycloalkane;
R 9 is heteroaryl which is unfused or fused with benzene;
R 10 is C 3 -C 10 -Cycloalkyl, C 3 -C 10 -heterocycloalkyl or C 4 -C 10 -heterocycloalkenyl;
R 11 is alkyl, which is unsubstituted or substituted with R 12 , N(R 12 ) 2 , C(O)N(R 12 ) 2 , OH, C(O)OH, CF 3 , F, Cl, Br or I;
R 12 is R 13 , R 14 , R 15 or R 16 ;
R 13 is phenyl which is unfused or fused with heterocycloalkane;
R 14 is heteroaryl;
R 15 is heterocycloalkane;
R 16 is alkyl;
R 17 is alkyl;
Z 1 is R 26 or R 27 , each of which is substituted with R 30 , each of which is substituted with CH 2 R 37 or C(R 31 )(R 31A )(R 37 );
R 26 is phenyl;
R 27 is heteroarene;
R 30 is cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with heterocycloalkane;
R 31 and R 31A are taken together and are C 2 -C 5 -spiroalkyl;
R 37 is R 38 , R 39 or R 40 , each of which is substituted with F, Cl, Br, I, R 41 , NHC(O)OR 41 , SR 41 or SO 2 R 41 ;
R 38 is phenyl which is unfused or fused with benzene;
R 39 is heteroaryl;
R 40 is C 4 -C 5 -cycloalkenyl or C 4 -C 5 -heterocycloalkenyl;
R 41 is R 42 , R 43 , R 44 or R 45 ;
R 42 is phenyl which is unfused or fused with benzene or heteroarene;
R 43 is heteroaryl which is unfused or fused with benzene;
R 44 is C 3 -C 6 -heterocycloalkyl;
R 45 is alkyl;
wherein each foregoing cyclic moiety is independently unsubstituted, further unsubstituted, substituted or further substituted with one or two of independently selected R 50 , OR 50 , SR 50 , SO 2 R 50 , C(O)R 50 , CO(O)R 50 , NH 2 , NHR 50 , N(R 50 ) 2 , C(O)NHOH, C(O)NHSO 2 R 50 , C(O)OH, OH, (O), CF 3 , OCF 3 , F, Cl, Br or I;
R 50 is R 51 , R 52 , R 53 or R 54 ;
R 51 is phenyl fused with benzene;
R 52 is heteroaryl;
R 53 is C 3 -C 6 -cycloalkyl or C 3 -C 6 -heterocycloalkyl, each of which is unfused or fused with benzene;
R 54 is alkyl, which is unsubstituted or substituted with R 55 , SR 55 or N(R 55 ) 2 ;
and
R 55 is alkyl, phenyl or C 3 -C 6 -heterocycloalkyl.
4 . A method for treating arthritis in a mammal comprising administering to a mammal in need of such a treatment a therapeutically effective amount of N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide or a therapeutically acceptable salt thereof.
5 . The method of claim 4 wherein said therapeutically effective amount of N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide or a therapeutically acceptable salt thereof is effective to inhibit activated T lymphocytes and activated B lymphocytes.
6 . The method for treating arthritis of claim 4 comprising co-administration with a therapeutically effective amount of a therapeutic agent selected from the group consisting of a non-steroidal anti-inflammatory agent, a corticosteroid, a cytokine suppressive anti-inflammatory agent, a human cytokine antibody, and any combination thereof.
7 . The method for treating arthritis of claim 4 wherein the therapeutically effective amount of N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide is administered in a dosage form comprising N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide in an amount from 0.001 to 200 mg/kg of body weight of the mammal.
8 . The method for treating arthritis of claim 4 wherein the therapeutically effective amount of N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide is administered in a dosage form comprising N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide in an amount from 50 to 200 mg/kg of body weight of the mammal.
9 . The method for treating arthritis of claim 4 wherein the therapeutically effective amount of N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide is administered in a dosage form comprising N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide in an amount 50 mg/kg of body weight of the mammal.
10 . A method for treating arthritis in a mammal comprising administering to a mammal in need of such a treatment a therapeutically effective amount of N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide or a therapeutically acceptable salt thereof.
11 . The method of claim 10 wherein said therapeutically effective amount of N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide or a therapeutically acceptable salt thereof is effective to inhibit activated T lymphocytes and activated B lymphocytes.
12 . The method for treating arthritis of claim 10 comprising co-administration with a therapeutically effective amount of a therapeutic agent selected from the group consisting of a non-steroidal anti-inflammatory agent, a corticosteroid, a cytokine suppressive anti-inflammatory agent, a human cytokine antibody, and any combination thereof.
13 . The method for treating arthritis of claim 10 wherein the therapeutically effective amount of N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide is administered in a dosage form comprising N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide in an amount from 0.001 to 200 mg/kg of body weight of the mammal.
14 . The method for treating arthritis of claim 10 wherein the therapeutically effective amount of N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide is administered in a dosage form comprising N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide in an amount from 50 to 200 mg/kg of body weight of the mammal.
15 . The method for treating arthritis of claim 10 wherein the therapeutically effective amount of N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide is administered in a dosage form comprising N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)-propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide in an amount 50 mg/kg of body weight of the mammal.