Substituted 4-amino-pyrrolotriazine derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis

1. A method of treating breast cancer with a compound of formula (I)

wherein

X 0 represents C or N;

R 1 represents

1.1) phenyl or a bicyclic carbocycle of 9-10 ring members, in which at least one ring is aromatic, R 1 optionally bearing up to 4 substituents independently selected from the group consisting of

1.1.a) (C 1 -C 4 )alkyl, which may optionally bear up to 3 substituents independently selected from

1.1.a1) halogen;

1.1.a2) OR 5 wherein R 5 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen or —(C 1 -C 3 )mono- or di-alkylamino;

1.1.a3) —NR 6 R 7 in which R 6 and R 7 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen or OR 7a wherein R 7a represents H or (C 1 -C 3 )alkyl, or R 6 and R 7 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 8 wherein R 8 represents H or (C 1 -C 3 )alkyl; and

1.1.a4) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;

1.1.b) —(C 3 -C 6 )cycloalkyl which may optionally bear up to 2 substituents independently selected from

1.1.b1) halogen; and

1.1.b2) OR 9 wherein R 9 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen or (C 1 -C 3 )mono- or di-alkylamino;

1.1.c) OR 10 wherein

R 10 represents H; phenyl; benzyl; (C 3 -C 6 )cycloalkyl; or (C 1 -C 4 )alkyl which may optionally bear up to 3 substituents independently selected from

1.1.c1) halogen;

1.1.c2) OR 11 wherein R 11 represents H or (C 1 -C 3 )alkyl which may optionally bear (C 1 -C 3 )mono- or di-alkylamino; and

1.1.c3) NR 12 R 13 in which R 12 and R 13 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 12 and R 13 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 14 wherein R 14 represents H or (C 1 -C 3 )alkyl;

1.1.d) —C(O)—OR 15 wherein R 15 represents H or —(C 1 -C 4 )alkyl which may optionally bear up to 3 halogens;

1.1.e) —C(O)—NR 16 R 17 wherein

R 16 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen; and

R 17 represents H or —(C 1 -C 4 )alkyl which is optionally substituted with

1.1.e1) halogen;

1.1.e2) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;

1.1.e3) phenyl;

1.1.e4) —SO 2 CH 3 ;

1.1.e5) —OR 18 wherein R 18 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen; or

1.1.e6) —NR 19 R 20 in which R 19 and R 20 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 19 and R 20 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 21 wherein R 21 represents H or (C 1 -C 3 )alkyl;

1.1.f) —N(R 22 )—C(O)—R 23 wherein

R 22 represents H or (C 1 -C 3 )alkyl; and

R 23 represents optionally substituted phenyl, or (C 1 -C 4 )alkyl which is optionally substituted with

1.1.f1) optionally substituted phenyl,

1.1.f2) OR 24 wherein R 24 represents H or (C 1 -C 3 )alkyl, or

1.1.f3) NR 25 R 26 wherein R 25 and R 26 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 25 and R 26 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 27 wherein R 27 represents H or (C 1 -C 3 )alkyl;

1.1.g) —SO 2 NR 28 R 29 wherein

R 28 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen; and

R 29 represents H or —(C 1 -C 4 )alkyl which is optionally substituted with:

1.1.g1) halogen;

1.1.g2) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;

1.1.g3) phenyl;

1.1.g4) —SO 2 CH 3 ;

1.1.g5) —OR 30 wherein R 30 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen; or

1.1.g6) —NR 31 R 32 in which R 31 and R 32 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 31 and R 32 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 33 wherein R 33 represents H or (C 1 -C 3 )alkyl;

1.1.h) —N(R 34 )—SO 2 —R 35 wherein

R 34 represents H or (C 1 -C 3 )alkyl, and

R 35 represents optionally substituted phenyl, or (C 1 -C 4 )alkyl which is optionally substituted with

1.1.h1) halogen;

1.1.h2) optionally substituted phenyl,

1.1.h3) OR 36 wherein R 36 represents H or (C 1 -C 3 )alkyl, or

1.1.h4) NR 37 R 38 wherein R 37 and R 38 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 37 and R 38 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 39 wherein R 39 represents H or (C 1 -C 3 )alkyl;

1.1.i) —NR 40 R 41 in which R 40 and R 41 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen or OR 42 in which R 42 represents H or (C 1 -C 3 )alkyl, or R 40 and R 41 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 43 wherein R 43 represents H or (C 1 -C 3 )alkyl;

1.1.j) halogen;

1.1.k) optionally substituted phenyl;

1.1.l) NO 2 ;

1.1.m) CN; and

1.1.n) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;

1.1.o) —C(O)—R 209 wherein R 209 represents H or —(C 1 -C 4 )alkyl which may optionally bear up to 3 halogens;

or

R 1 represents

1.2) a 5-6 membered aromatic heterocycle containing up to 3 heteroatoms independently selected from the group consisting of N, O, and S; or a bicyclic heterocycle of 8-10 ring members in which at least one ring is aromatic and contains up to 3 moieties independently selected from the group consisting of N, N→O, O, and S, and any non-aromatic ring of said bicyclic heterocycle optionally contains up to three moieties independently selected from the group consisting of O, S, S(O), S(O) 2 , and NR 44 wherein R 44 represents H or —(C 1 -C 3 )alkyl; said R 1 heterocycle optionally bearing up to 4 substituents independently selected from the group consisting of

1.2.a) (C 1 -C 4 )alkyl, which may optionally bear up to 3 substituents independently selected from

1.2.a1) halogen;

1.2.a2) OR 45 wherein R 45 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen or —(C 1 -C 3 )mono- or di-alkylamino;

1.2.a3) —NR 46 R 47 in which R 46 and R 47 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen or OR 47a wherein R 47a represents H or (C 1 -C 3 )alkyl, or R 46 and R 47 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 48 wherein R 48 represents H or (C 1 -C 3 )alkyl; and

1.2.a4) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;

1.2.b) —(C 3 -C 6 )cycloalkyl which may optionally bear up to 2 substituents independently selected from

1.2.b1) halogen; and

1.2.b2) OR 49 wherein R 49 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen or —(C 1 -C 3 )mono- or di-alkylamino;

1.2.c) OR 50 wherein

R 50 represents H; phenyl; benzyl; —(C 3 -C 6 )cycloalkyl; or —(C 1 -C 4 )alkyl which may optionally bear up to 3 substituents independently selected from

1.2.c1) halogen;

1.2.c2) OR 51 wherein R 51 represents H or (C 1 -C 3 )alkyl which may optionally bear —(C 1 -C 3 )mono- or di-alkylamino; and

1.2.c3) —NR 52 R 53 in which R 52 and R 53 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 52 and R 53 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 54 wherein R 54 represents H or (C 1 -C 3 )alkyl;

1.2.d) —C(O)—OR 55 wherein R 55 represents H or —(C 1 -C 4 )alkyl which may optionally bear up to 3 halogens;

1.2.e) —C(O)—NR 56 R 57 wherein

R 56 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen; and

R 57 represents H or —(C 1 -C 4 )alkyl which is optionally substituted with

1.2.e1) halogen;

1.2.e2) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from 0, S, and N;

1.2.e3) phenyl;

1.2.e4)—SO 2 CH 3 ;

1.2.e5) —OR 58 wherein R 58 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen; or

1.2.e6) —NR 59 R 60 in which R 59 and R 60 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 59 and R 60 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 61 wherein R 61 represents H or (C 1 -C 3 )alkyl;

1.2.f) —N(R 62 )—C(O)—R 63 wherein

R 62 represents H or (C 1 -C 3 )alkyl; and

R 63 represents optionally substituted phenyl, or (C 1 -C 4 )alkyl which is optionally substituted with

1.2.f1) optionally substituted phenyl,

1.2.f2) OR 64 wherein R 64 represents H or (C 1 -C 3 )alkyl, or

1.2.f3) NR 65 R 66 wherein R 65 and R 66 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 65 and R 66 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 67 wherein R 67 represents H or (C 1 -C 3 )alkyl;

1.2.g) —SO 2 NR 68 R 69 wherein

R 68 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen; and

R 69 represents H or —(C 1 -C 4 )alkyl which is optionally substituted with

1.2.g1) halogen;

1.2.g2) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from 0, S, and N;

1.2.g3) phenyl;

1.2.g4) —SO 2 CH 3 ;

1.2.g5) —OR 70 wherein R 70 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen; or

1.2.g6 —NR 71 R 72 in which R 71 and R 72 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 71 and R 72 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 73 wherein R 73 represents H or (C 1 -C 3 )alkyl;

1.2.h) —N(R 74 )—SO 2 —R 75 wherein

R 74 represents H or (C 1 -C 3 )alkyl, and

R 75 represents optionally substituted phenyl, or (C 1 -C 4 )alkyl which is optionally substituted with

1.2.h1) halogen;

1.2.h2) optionally substituted phenyl,

1.2.h3) OR 76 wherein R 76 represents H or (C 1 -C 3 )alkyl, or

1.2.h4) NR 77 R 78 wherein R 77 and R 78 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 77 and R 78 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 79 wherein R 79 represents H or (C 1 -C 3 )alkyl;

1.2.i) —NR 80 R 81 in which R 80 and R 81 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen or OR 81a wherein R 81a represents H or (C 1 -C 3 )alkyl, or R 80 and R 81 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 82 wherein R 82 represents H or (C 1 -C 3 )alkyl;

1.2.j) halogen;

1.2.k) optionally substituted phenyl;

1.2.l) NO 2 ;

1.2.m) CN; and

1.2.n) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;

1.2.o) —C(O)—R 210 wherein R 210 represents H or —(C 1 -C 4 )alkyl which may optionally bear up to 3 halogens;

R 2 represents hydrogen; halogen; —(C 1 -C 5 )alkyl which may optionally bear halogen; or —O(C 1 -C 3 )alkyl which may optionally bear halogen;

R 3 represents hydrogen; halogen; —(C 1 -C 5 )alkyl which may optionally bear halogen; or —O(C 1 -C 3 )alkyl which may optionally bear halogen;

R 4 represents

4.1) —(C 1 -C 5 )alkyl which is optionally substituted with

4.1.a) —(C 3 -C 5 )cycloalkyl which may optionally bear halogen or OR 109 wherein R 109 represents H or (C 1 -C 3 )alkyl;

4.1.b)-halogen;

4.1.c) —OR 110 wherein R 110 represents H or —(C 1 -C 3 )alkyl which may optionally bear up to 3 substituents independently selected from

4.1.c1) halogen;

4.1.c2) phenyl;

4.1.c3) —S(O) 2 CH 3 ;

4.1.c4) OR 111 wherein R 111 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen; and

4.1.c5) —NR 112 R 113 in which R 112 and R 113 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 112 and R 113 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from 0, S, and NR 114 wherein R 114 represents H or (C 1 -C 3 )alkyl;

4.1.d) —NR 115 R 116 wherein

R 115 represents H or —(C 1 -C 3 )alkyl which may optionally bear halogen and

R 116 represents H, optionally substituted phenyl, or —(C 1 -C 5 )alkyl which may optionally bear up to 3 substituents independently selected from

 4.1.d1) halogen;

 4.1.d2) —S(O) 2 CH 3 ;

 4.1.d3) OR 117 wherein R 117 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen; and

 4.1.d4) —NR 118 R 119 in which R 118 and R 119 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 118 and R 119 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 120 wherein R 120 represents H or (C 1 -C 3 )alkyl;

4.1.e) optionally substituted phenyl; or

4.1.f) a 5-6 membered aromatic heterocycle containing up to two heteroatoms selected from O, S, and N;

4.2)

 wherein R 121 represents —(C 1 -C 3 )alkyl which may optionally bear halogen or —OR 122 in which R 122 represents H or —(C 1 -C 3 )alkyl;

d represents 1, 2, or 3;

e represents 0 or 1;

f represents 0, 1, or 2;

4.3)

 wherein R 123 represents —(C 1 -C 3 )alkyl which may optionally bear halogen or —OR 124 in which R 124 represents H or —(C 1 -C 3 )alkyl;

g represents 1, 2, or 3;

h represents 0, 1, or 2;

4.4)

 wherein

R 125 represents

4.4.a) H;

4.4.b) —(C 1 -C 3 )alkyl which may optionally bear halogen or —OR 126 in which R 126 represents H or —(C 1 -C 3 )alkyl which in turn is optionally substituted with halogen;

4.4.c) —SO 2 R 127 wherein R 127 represents optionally substituted phenyl, or —(C 1 -C 3 )alkyl which may optionally bear halogen or OR 128 wherein R 128 represents H or (C 1 -C 3 )alkyl;

4.4.d) —C(O)R 129 wherein

 R 129 represents

 4.4.d1) optionally substituted phenyl,

 4.4.d2) —(C 1 -C 3 )alkyl which may optionally bear up to 3 substituents independently selected from

 4.4.d2.1) halogen;

 4.4.d2.2) optionally substituted phenyl;

 4.4.d2.3) —S(O) 2 —(C 1 -C 4 )alkyl which may optionally bear halogen;

 4.4.d2.4) —OR 130 wherein R 130 represents H or (C 1 -C 4 )alkyl which may optionally bear halogen; and

 4.4.d2.5) —NR 131 R 132 in which R 131 and R 132 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 131 and R 132 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 133 wherein R 133 represents H or (C 1 -C 3 )alkyl;

4.4.d3) —OR 134 wherein R 134 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen; or

4.4.d4) NR 135 R 136 wherein R 135 and R 136 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 135 and R 136 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 137 wherein R 137 represents H or (C 1 -C 3 )alkyl; and

j represents 1, 2, or 3;

4.5)

 wherein

X represents C or N;

R 138 represents

4.5.a) (C 1 -C 4 )alkyl, which may optionally bear up to 3 substituents independently selected from

4.5.a1) halogen;

4.5.a2) OR 139 wherein R 139 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen or —(C 1 -C 3 )mono- or di-alkylamino;

4.5.a3) —NR 140 R 141 in which R 140 and R 141 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen or OR 141a wherein R 141a represents H or (C 1 -C 3 )alkyl, or R 140 and R 141 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 142 wherein R 142 represents H or (C 1 -C 3 )alkyl; and

4.5.a4) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;

4.5.b) —(C 3 -C 6 )cycloalkyl which may optionally bear up to 2 substituents independently selected from

4.5.b1) halogen; and

4.5.b2) OR 143 wherein R 143 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen;

4.5.c) OR 144 wherein

R 144 represents H; phenyl; benzyl; (C 3 -C 6 )cycloalkyl; or (C 1 -C 4 )alkyl which may optionally bear up to 3 substituents independently selected from

4.5.c1) halogen;

4.5.c2) OR 145 wherein R 145 represents H or (C 1 -C 3 )alkyl which may optionally bear (C 1 -C 3 )mono- or di-alkylamino; and

4.5.c3) NR 146 R 147 in which R 146 and R 1473 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 146 and R 147 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 148 wherein R 148 represents H or (C 1 -C 3 )alkyl;

4.5.d) —C(O)—OR 149 wherein R 149 represents H or —(C 1 -C 4 )alkyl which may optionally bear up to 3 halogens;

4.5.e) —C(O)—NR 150 R 151 wherein

R 150 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen; and

R 151 represents H or —(C 1 -C 4 )alkyl which is optionally substituted with

 4.5.e1) halogen;

 4.5.e2) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;

 4.5.e3) phenyl;

 4.5.e4) —SO 2 CH 3 ;

 4.5.e5) —OR 152 wherein R 152 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen; or

 4.5.e6) —NR 153 R 154 in which R 153 and R 154 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 153 and R 154 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 155 wherein R 155 represents H or (C 1 -C 3 )alkyl;

4.5.f) —N(R 156 )—C(O)—R 157 wherein

R 156 represents H or (C 1 -C 3 )alkyl; and

R 157 represents H, optionally substituted phenyl, or (C 1 -C 4 )alkyl which is optionally substituted with

 4.5.f1) optionally substituted phenyl,

 4.5.f2) OR 158 wherein R 158 represents H or (C 1 -C 3 )alkyl, or

 4.5.f3) NR 159 R 160 wherein R 159 and R 160 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 159 and R 160 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 161 wherein R 161 represents H or (C r C 3 )alkyl;

4.5.g) —SO 2 NR 162 R 163 wherein

R 162 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen; and

R 163 represents H or —(C 1 -C 4 )alkyl which is optionally substituted with

 4.5.g1) halogen;

 4.5.g2) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;

 4.5.g3) phenyl;

 4.5.g4) —SO 2 CH 3 ;

 4.5.g5) —OR 164 wherein R 164 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen; or

 4.5.g6) —NR 165 R 166 in which R 165 and R 166 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 165 and R 166 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 167 wherein R 167 represents H or (C 1 -C 3 )alkyl;

4.5.h) —N(R 168 )—SO 2 —R 169 wherein

R 168 represents represents H or (C 1 -C 3 )alkyl, and

R 169 represents H, optionally substituted phenyl, or (C 1 -C 4 )alkyl which is optionally substituted with

4.5.h1) halogen,

4.5.h2) optionally substituted phenyl,

4.5.h3) OR 170 wherein R 170 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen, or

4.5.h4) NR 171 R 172 wherein R 171 and R 172 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 171 and R 172 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 173 wherein R 173 represents H or (C 1 -C 3 )alkyl;

4.5.i) —NR 174 R 175 in which R 174 and R 175 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen or OR 175a wherein R 175a represents H or (C 1 -C 3 )alkyl, or R 174 and R 175 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 176 wherein R 176 represents H or (C 1 -C 3 )alkyl;

4.5.j) halogen;

4.5.k) optionally substituted phenyl;

4.5.l) NO 2 ;

4.5.m) CN; or

4.5.n) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from 0, S, and N; and

k represents 0, 1, or 2;

4.6)

 wherein R 177 represents H or —(C 1 -C 3 )alkyl; and

m represents 1, 2, or 3;

4.7)

 wherein

n represents 1, 2, or 3; and

p represents 0, 1, or 2;

4.8)

 wherein

q represents 1, 2, or 3;

4.9)

 wherein

R 178 represents

4.9.a) H;

4.9.b) —(C 1 -C 3 )alkyl which may optionally bear halogen or —OR 179 in which R 179 represents H or (C 1 -C 3 )alkyl optionally substituted with halogen;

4.9.c) —(C 3 -C 7 )cycloalkyl which may optionally bear halogen;

4.9.d) —(C 2 -C 5 )alkenyl which may optionally bear halogen;

4.9.e) —SO 2 R 180 wherein R 180 represents optionally substitutued phenyl or —(C 1 -C 3 )alkyl, which may be substituted with halogen or —OR 181 wherein R 181 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen;

4.9.f) —C(O)R 182 wherein R 182 represents optionally substituted phenyl or —(C 1 -C 3 )alkyl which may optionally bear up to 3 substituents independently selected from

 4.9.f1) halogen;

 4.9.f2) optionally substituted phenyl;

 4.9.f3) —S(O) 2 CH 3 ;

 4.9.f4) OR 183 wherein R 183 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen; and

 4.9.f5) —NR 184 R 185 in which R 184 and R 185 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen or OR 185a wherein R 185a represents H or (C 1 -C 3 )alkyl, or R 184 and R 185 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 186 wherein R 186 represents H or (C 1 -C 3 )alkyl;

4.9g) —C(O)OR 187 wherein R 187 represents (C 1 -C 4 )alkyl; or

4.9.h) —C(O)—NR 188 R 189 wherein R 188 and R 189 each independently represents H or —(C 1 -C 4 )alkyl which may optionally bear halogen, or R 188 and R 189 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 190 wherein R 190 represents H or (C 1 -C 3 )alkyl;

r represents 0, 1, or 2; and

s represents 0 or 1;

4.10)

 wherein

R 191 represents

4.10.a) H;

4.10.b) —(C 1 -C 3 )alkyl which may optionally bear halogen or —OR 192 in which R 192 represents H or (C 1 -C 3 )alkyl;

4.10c) —SO 2 R 193 wherein R 193 represents phenyl or —(C 1 -C 3 )alkyl, both of which may be substituted with halogen or —(C 1 -C 3 )alkyl;

4.10.d) —C(O)R 194 wherein R 194 represents (C 1 -C 3 )alkyl which may optionally bear up to 3 substituents independently selected from

 4.10.d1) halogen;

 4.10.d2) phenyl;

 4.10.d3) —S(O) 2 CH 3 ;

 4.10.d4) OR 195 wherein R 195 represents H or (C 1 -C 3 )alkyl which may optionally bear halogen; and

 4.10.d5) —NR 196 R 197 in which R 196 and R 197 are independently H or —(C 1 -C 3 )alkyl which may optionally bear halogen or OR 197a wherein R 197a represents H or (C 1 -C 3 )alkyl, or R 196 and R 197 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 198 wherein R 198 represents H or (C 1 -C 3 )alkyl;

4.10.e) —C(O)OR 199 wherein R 199 represents (C 1 -C 3 )alkyl; or

4.10.f) —C(O)—NR 200 R 201 wherein R 200 and R 201 each independently represents H or —(C 1 -C 3 )alkyl which may optionally bear halogen, or R 200 and R 201 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR 202 wherein R 202 represents H or (C 1 -C 3 )alkyl; and

X represents O, S, S(O), S(O) 2 , or NR 203 wherein

R 203 represents H or —(C 1 -C 3 )alkyl; and

t represents 0, 1, or 2;

4.11) —C(O)R 204 wherein R 204 represents optionally substituted phenyl or —(C 1 -C 3 )alkyl which may optionally bear up to 3 substituents independently selected from

4.11.a) halogen;

4.11.b) optionally substituted phenyl;

4.11.c) OR 205 wherein R 205 represents H or —(C 1 -C 3 )alkyl which may optionally bear halogen; and

4.11.d)

4.12) —C(O)—NR 206 R 207 wherein R 206 and R 207 each independently represents H or (C 1 -C 3 )alkyl, or R 206 and R 207 may be joined and taken together with the N atom to which they are attached form a 5-6 membered ring which may optionally contain a ring member selected from O and S, said alkyl or ring optionally bearing up to 3 substituents independently selected from

4.12.a) halogen;

4.12.b) optionally substituted phenyl;

4.12.c) OR 208 wherein R 208 represents H or —(C 1 -C 3 )alkyl which may optionally bear halogen; and

4.12.d)

4.13) halogen; or

4.14) CN;

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein said mammal is a human.