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

A compound of formula (I)

• wherein
• R1 represents
• 1.1) phenyl or a bicyclic carbocycle of 9-10 ring members, in which at least one ring is aromatic, R1 optionally bearing up to 4 substituents independently selected from the group consisting of
• 1.1.a) (C1-C4)alkyl, which may optionally bear up to 3 substituents independently selected from
• 1.1.a1) halogen;
• 1.1.a2) OR5 wherein R5 represents H or (C1-C3)alkyl which may optionally bear halogen or —(C1-C3)mono- or di-alkylamino;
• 1.1.a3) —NR6R7 in which R6 and R7 are independently H or —(C1-C3)alkyl which may optionally bear halogen or OR7a wherein R7a represents H or (C1-C3)alkyl, or R6 and R7 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 NR8 wherein R8 represents H or (C1-C3)alkyl;
• and
• 1.1.a4) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;
• 1.1.b) —(C3-C6)cycloalkyl which may optionally bear up to 2 substituents independently selected from
• 1.1.b1) halogen;
• and
• 1.1.b2) OR9 wherein R9 represents H or (C1-C3)alkyl which may optionally bear halogen or (C1-C3)mono- or di-alkylamino;
• 1.1.c) OR10 wherein
• R10 represents H;
• phenyl;
• benzyl;
• (C3-C6)cycloalkyl;
• or (C1-C4)alkyl which may optionally bear up to 3 substituents independently selected from
• 1.1.c1) halogen;
• 1.1.c2) OR11 wherein R11 represents H or (C1-C3)alkyl which may optionally bear (C1-C3)mono- or di-alkylamino;
• and
• 1.1.c3) NR12R13 in which R12 and R13 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R12 and R13 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 NR14 wherein R14 represents H or (C1-C3)alkyl;
• 1.1.d) —C(O)—OR15 wherein R15 represents H or —(C1-C4)alkyl which may optionally bear up to 3 halogens;
• 1.1.e) —C(O)—NR16R17 wherein
• R16 represents H or (C1-C3)alkyl which may optionally bear halogen;
• and
• R17 represents H or —(C1-C4)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) —SO2CH3;
• 1.1.e5) —OR18 wherein R18 represents H or (C1-C3)alkyl which may optionally bear halogen;
• or
• 1.1.e6) —NR19R20 in which R19 and R20 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R19 and R20 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 NR21 wherein R21 represents H or (C1-C3)alkyl;
• 1.1.f) —N(R22)—C(O)—R23 wherein
• R22 represents H or (C1-C3)alkyl;
• and
• R23 represents optionally substituted phenyl, or (C1-C4)alkyl which is optionally substituted with
• 1.1.f1) optionally substituted phenyl,
• 1.1.f2) OR24 wherein R24 represents H or (C1-C3)alkyl, or
• 1.1.f3) NR25R26 wherein R25 and R26 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R25 and R26 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 NR27 wherein R27 represents H or (C1-C3)alkyl;
• 1.1.g) —SO2NR28R29 wherein
• R28 represents H or (C1-C3)alkyl which may optionally bear halogen;
• and
• R29 represents H or —(C1-C4)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) —SO2CH3;
• 1.1.g5) —OR30 wherein R30 represents H or (C1-C3)alkyl which may optionally bear halogen;
• or
• 1.1.g6) —NR31R32 in which R31 and R32 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R31 and R32 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 NR33 wherein R33 represents H or (C1-C3)alkyl;
• 1.1.h) —N(R34)—SO2—R35 wherein
• R34 represents H or (C1-C3)alkyl, and
• R35 represents optionally substituted phenyl, or (C1-C4)alkyl which is optionally substituted with
• 1.1.h1) halogen;
• 1.1.h2) optionally substituted phenyl,
• 1.1.h3) OR36 wherein R36 represents H or (C1-C3)alkyl, or
• 1.1.h4) NR37R38 wherein R37 and R38 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R37 and R38 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 NR39 wherein R39 represents H or (C1-C3)alkyl;
• 1.1.i) —NR40R41 in which R40 and R41 are independently H or —(C1-C3)alkyl which may optionally bear halogen or OR42 in which R42 represents H or (C1-C3)alkyl, or R40 and R41 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 NR43 wherein R43 represents H or (C1-C3)alkyl;
• 1.1.j) halogen;
• 1.1.k) optionally substituted phenyl;
• 1.1.l) NO2;
• 1.1.m) CN;
• and
• 1.1.n) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;
• or
• R1 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 NR44 wherein R44 represents H or —(C1-C3)alkyl;
• said R1 heterocycle optionally bearing up to 4 substituents independently selected from the group consisting of
• 1.2.a) (C1-C4)alkyl, which may optionally bear up to 3 substituents independently selected from
• 1.2.a1) halogen;
• 1.2.a2) OR45 wherein R45 represents H or (C1-C3)alkyl which may optionally bear halogen or —(C1-C3)mono- or di-alkylamino;
• 1.2.a3) —NR46R47 in which R46 and R47 are independently H or —(C1-C3)alkyl which may optionally bear halogen or OR47a wherein R47a represents H or (C1-C3)alkyl, or R46 and R47 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 NR48 wherein R48 represents H or (C1-C3)alkyl;
• and
• 1.2.a4) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;
• 1.2.b) —(C3-C6)cycloalkyl which may optionally bear up to 2 substituents independently selected from
• 1.2.b1) halogen;
• and
• 1.2.b2) OR49 wherein R49 represents H or (C1-C3)alkyl which may optionally bear halogen or —(C1-C3)mono- or di-alkylamino;
• 1.2.c) OR50 wherein
• R50 represents H;
• phenyl;
• benzyl;
• —(C3-C6)cycloalkyl;
• or —(C1-C4)alkyl which may optionally bear up to 3 substituents independently selected from
• 1.2.c1) halogen;
• 1.2.c2) OR51 wherein R51 represents H or (C1-C3)alkyl which may optionally bear —(C1-C3)mono- or di-alkylamino;
• and
• 1.2.c3) —NR52R53 in which R52 and R53 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R52 and R53 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 NR54 wherein R54 represents H or (C1-C3)alkyl;
• 1.2.d) —C(O)—OR55 wherein R55 represents H or —(C1-C4)alkyl which may optionally bear up to 3 halogens;
• 1.2.e) —C(O)—NR56R57 wherein
• R56 represents H or (C1-C3)alkyl which may optionally bear halogen;
• and
• R57 represents H or —(C1-C4)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 O, S, and N;
• 1.2.e3) phenyl;
• 1.2.e4) —SO2CH3;
• 1.2.e5) —OR58 wherein R58 represents H or (C1-C3)alkyl which may optionally bear halogen;
• or
• 1.2.e6) —NR59R60 in which R59 and R60 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R59 and R60 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 NR61 wherein R61 represents H or (C1-C3)alkyl;
• 1.2.f) —N(R62)—C(O)—R63 wherein
• R62 represents H or (C1-C3)alkyl;
• and
• R63 represents optionally substituted phenyl, or (C1-C4)alkyl which is optionally substituted with
• 1.2.f1) optionally substituted phenyl,
• 1.2.f2) OR64 wherein R64 represents H or (C1-C3)alkyl, or
• 1.2.f3) NR65R66 wherein R65 and R66 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R65 and R66 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 NR67 wherein R67 represents H or (C1-C3)alkyl;
• 1.2.g) —SO2NR68R69 wherein
• R68 represents H or (C1-C3)alkyl which may optionally bear halogen;
• and
• R69 represents H or —(C1-C4)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 O, S, and N;
• 1.2.g3) phenyl;
• 1.2.g4) —SO2CH3;
• 1.2.g5) —OR70 wherein R70 represents H or (C1-C3)alkyl which may optionally bear halogen;
• or
• 1.2.g6 —NR71R72 in which R71 and R72 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R71 and R72 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 NR73 wherein R73 represents H or (C1-C3)alkyl;
• 1.2.h) —N(R74)—SO2—R75 wherein
• R74 represents H or (C1-C3)alkyl, and
• R75 represents optionally substituted phenyl, or (C1-C4)alkyl which is optionally substituted with
• 1.2.h1) halogen;
• 1.2.h2) optionally substituted phenyl,
• 1.2.h3) OR76 wherein R76 represents H or (C1-C3)alkyl, or
• 1.2.h4) NR77R78 wherein R77 and R78 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R77 and R78 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 NR79 wherein R79 represents H or (C1-C3)alkyl;
• 1.2.i) —NR80R81 in which R80 and R81 are independently H or —(C1-C3)alkyl which may optionally bear halogen or OR81a wherein R81a represents H or (C1-C3)alkyl, or R80 and R81 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 NR82 wherein R82 represents H or (C1-C3)alkyl;
• 1.2.j) halogen;
• 1.2.k) optionally substituted phenyl;
• 1.2.l) NO2;
• 1.2.m) CN;
• and
• 1.2.n) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;
• R2 represents hydrogen;
• halogen;
• —(C1-C5)alkyl which may optionally bear halogen;
• or —O(C1-C3)alkyl which may optionally bear halogen;
• R3 represents
• 3.1) —(C1-C5)alkyl which is substituted with
• 3.1.a) -halogen;
• 3.1.b) phenyl optionally substituted with halogen, —(C1-C3)alkyl, or —(C1-C3)alkoxy,
• 3.1.c) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N, optionally substituted with halogen or —(C1-C3)alkyl,
• 3.1.d) —CN,
• 3.1.e) —OR83 wherein R83 represents H or —(C1-C3)alkyl which may optionally bear up to 3 substituents independently selected from
• 3.1.e1) halogen;
• 3.1.e2) optionally substituted phenyl;
• 3.1.e3) —S(O)2CH3;
• 3.1.e4) OR84 wherein R84 represents H or (C1-C3)alkyl which may optionally bear halogen or —(C1-C3)mono- or di-alkylamino;
• and
• 3.1.e5) —NR85R86 in which R85 and R86 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R85 and R86 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 NR87 wherein R87 represents H or (C1-C3)alkyl;
• 3.1.f) —(C3-C5)cycloalkyl which may optionally bear halogen or OR88 wherein R88 represents H or (C1-C3)alkyl;
• or
• 3.1.g) —NR89R90 wherein
• R89 represents H or —(C1-C3)alkyl which may optionally bear halogen;
• and
• R90 represents H or —(C1-C4)alkyl which is optionally substituted with
• 3.1.g1) halogen;
• 3.1.g2) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;
• 3.1.g3) phenyl;
• 3.1.g4) —SO2CH3;
• 3.1.g5) —OR91 wherein R91 represents H or (C1-C3)alkyl which may optionally bear halogen;
• or
• 3.1.g6) —NR92R93 in which R92 and R93 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R92 and R93 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 NR94 wherein R94 represents H or (C1-C3)alkyl;
• or
• 3.1.g7) R89 and R90 may be joined and taken together with the N to which they are attached form an aromatic or nonaromatic 5-6 membered ring which may optionally contain a ring member selected from O, S, and NR95 wherein R95 represents H or (C1-C3)alkyl;
• 3.2)
• wherein
• R96 represents
• 3.2.a) H,
• 3.2.b) —(C3-C5)cycloalkyl which may optionally bear halogen or —(C1-C3)alkoxy;
• or
• 3.2.c) —(C1-C5)alkyl which may optionally bear up to 3 substituents independently selected from
• 3.2.c1) halogen;
• 3.2.c2) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;
• 3.2.c3) phenyl;
• 3.2.c4) —S(O)2CH3;
• 3.2.c5) —OR97 wherein R97 represents H or (C1-C3)alkyl which may optionally bear halogen or —(C1-C3)mono- or di-alkylamino;
• and
• 3.2.c6) —NR98R99 in which R98 and R99 are independently H or —(C1-C3)alkyl which may optionally bear halogen or OR99a wherein R99a represents H or (C1-C3)alkyl, or R98 and R99 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 NR100 wherein R100 represents H or (C1-C3)alkyl;
• 3.3)
• wherein R101 represents H or —(C1-C5)alkyl which may optionally bear up to 3 substituents independently selected from
• 3.3.a) halogen;
• and
• 3.3.b) phenyl;
• 3.4)
• wherein
• R102 represents H or —(C1-C3)alkyl which may optionally bear halogen;
• and
• R103 represents H or —(C1-C5)alkyl which may optionally bear up to 3 substituents independently selected from
• 3.4.a) halogen;
• 3.4.b) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;
• 3.4.c) phenyl;
• 3.4.d) —S(O)2CH3;
• 3.4.e) OR104 wherein R104 represents H or (C1-C3)alkyl which may optionally bear halogen;
• and
• 3.4.f) —NR105R106 in which R105 and R106 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R105 and R106 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 NR107 wherein R107 represents H or (C1-C3)alkyl;
• 3.5) optionally substituted phenyl;
• 3.6) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;
• 3.7) halogen;
• 3.8) —CN;
• or
• 3.9) —CH═N—OR108 wherein R108 represents H or —C(O)—(C1-C3)alkyl;
• R4 represents
• 4.1) —(C1-C5)alkyl which is substituted with
• 4.1.a) —(C3-C5)cycloalkyl which may optionally bear halogen or OR109 wherein R109 represents H or (C1-C3)alkyl;
• 4.1.b) -halogen;
• 4.1.c) —OR110 wherein R110 represents H or —(C1-C3)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)2CH3;
• 4.1.c4) OR111 wherein R111 represents H or (C1-C3)alkyl which may optionally bear halogen;
• and
• 4.1.c5) —NR112R113 in which R112 and R113 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R112 and R113 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 NR114 wherein R114 represents H or (C1-C3)alkyl;
• 4.1.d) —NR115R116 wherein
• R115 represents H or —(C1-C3)alkyl which may optionally bear halogen and
• R116 represents H, optionally substituted phenyl, or —(C1-C5)alkyl which may optionally bear up to 3 substituents independently selected from
• 4.1.d1) halogen;
• 4.1.d2) —S(O)2CH3;
• 4.1.d3) OR117 wherein R117 represents H or (C1-C3)alkyl which may optionally bear halogen;
• and
• 4.1.d4) —NR118R119 in which R118 and R119 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R118 and R119 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 NR120 wherein R120 represents H or (C1-C3)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 R121 represents —(C1-C3)alkyl which may optionally bear halogen or —OR122 in which R122 represents H or —(C1-C3)alkyl;
• d represents 1, 2, or 3;
• e represents 0 or 1;
• f represents 0, 1, or 2;
• 4.3)
• wherein R123 represents —(C1-C3)alkyl which may optionally bear halogen or —OR124 in which R124 represents H or —(C1-C3)alkyl;
• g represents 1, 2, or 3;
• h represents 0, 1, or 2;
• 4.4)
• wherein
• R125 represents
• 4.4.a) H;
• 4.4.b) —(C1-C3)alkyl which may optionally bear halogen or —OR126 in which R126 represents H or —(C1-C3)alkyl which in turn is optionally substituted with halogen;
• 4.4.c) —SO2R127 wherein R127 represents optionally substituted phenyl, or —(C1-C3)alkyl which may optionally bear halogen or OR128 wherein R128 represents H or (C1-C3)alkyl;
• 4.4.d) —C(O)R129 wherein
• R129 represents
• 4.4.d1) optionally substituted phenyl,
• 4.4.d2) —(C1-C3)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)2CH3;
• 4.4.d2.4) —OR130 wherein R130 represents H or (C1-C3)alkyl which may optionally bear halogen;
• and
• 4.4.d2.5) —NR131R132 in which R131 and R132 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R131 and R132 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 NR133 wherein R133 represents H or (C1-C3)alkyl;
• 4.4.d3) —OR134 wherein R134 represents H or (C1-C3)alkyl which may optionally bear halogen;
• or
• 4.4.d4) NR135R136 wherein R135 and R136 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R135 and R136 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 NR137 wherein R137 represents H or (C1-C3)alkyl;
• and
• j represents 1, 2, or 3;
• 4.5)
• wherein
• X represents C or N;
• R138 represents
• 4.5.a) (C1-C4)alkyl, which may optionally bear up to 3 substituents independently selected from
• 4.5.a1) halogen;
• 4.5.a2) OR139 wherein R139 represents H or (C1-C3)alkyl which may optionally bear halogen or —(C1-C3)mono- or di-alkylamino;
• 4.5.a3) —NR140R141 in which R140 and R141 are independently H or —(C1-C3)alkyl which may optionally bear halogen or OR141a wherein R141a represents H or (C1-C3)alkyl, or R140 and R141 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 NR142 wherein R142 represents H or (C1-C3)alkyl;
• and
• 4.5.a4) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;
• 4.5.b) —(C3-C6)cycloalkyl which may optionally bear up to 2 substituents independently selected from
• 4.5.b1) halogen;
• and
• 4.5.b2) OR143 wherein R143 represents H or (C1-C3)alkyl which may optionally bear halogen;
• 4.5.c) OR144 wherein
• R144 represents H;
• phenyl;
• benzyl;
• (C3-C6)cycloalkyl;
• or (C1-C4)alkyl which may optionally bear up to 3 substituents independently selected from
• 4.5.c1) halogen;
• 4.5.c2) OR145 wherein R145 represents H or (C1-C3)alkyl which may optionally bear (C1-C3)mono- or di-alkylamino;
• and
• 4.5.c3) NR146R147 in which R146 and R1473 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R146 and R147 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 NR148 wherein R148 represents H or (C1-C3)alkyl;
• 4.5.d) —C(O)—OR149 wherein R149 represents H or —(C1-C4)alkyl which may optionally bear up to 3 halogens;
• 4.5.e) —C(O)—NR150R151 wherein
• R150 represents H or (C1-C3)alkyl which may optionally bear halogen;
• and
• R151 represents H or —(C1-C4)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) —SO2CH3;
• 4.5.e5) —OR152 wherein R152 represents H or (C1-C3)alkyl which may optionally bear halogen;
• or
• 4.5.e6) —NR153R154 in which R153 and R154 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R153 and R154 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 NR155 wherein R155 represents H or (C1-C3)alkyl;
• 4.5.f) —N(R156)—C(O)—R157 wherein
• R156 represents H or (C1-C3)alkyl;
• and
• R157 represents H, optionally substituted phenyl, or (C1-C4)alkyl which is optionally substituted with
• 4.5.f1) optionally substituted phenyl,
• 4.5.f2) OR158 wherein R158 represents H or (C1-C3)alkyl, or
• 4.5.f3) NR159R160 wherein R159 and R160 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R159 and R160 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 NR161 wherein R161 represents H or (C1-C3)alkyl;
• 4.5.g) —SO2NR162R163 wherein
• R162 represents H or (C1-C3)alkyl which may optionally bear halogen;
• and
• R163 represents H or —(C1-C4)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) —SO2CH3;
• 4.5.g5) —OR164 wherein R164 represents H or (C1-C3)alkyl which may optionally bear halogen;
• or
• 4.5.g6) —NR165R166 in which R165 and R166 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R165 and R166 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 NR167 wherein R167 represents H or (C1-C3)alkyl;
• 4.5.h) —N(R168)—SO2—R169 wherein
• R168 represents H or (C1-C3)alkyl, and
• R169 represents H, optionally substituted phenyl, or (C1-C4)alkyl which is optionally substituted with
• 4.5.h1) halogen,
• 4.5.h2) optionally substituted phenyl,
• 4.5.h3) OR170 wherein R170 represents H or (C1-C3)alkyl which may optionally bear halogen, or
• 4.5.h4) NR171R172 wherein R171 and R172 are independently H or —(C1-C3)alkyl which may optionally bear halogen, or R171 and R172 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 NR173 wherein R173 represents H or (C1-C3)alkyl;
• 4.5.i) —NR174R175 in which R174 and R175 are independently H or —(C1-C3)alkyl which may optionally bear halogen or OR175a wherein R175a represents H or (C1-C3)alkyl, or R174 and R175 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 NR176 wherein R176 represents H or (C1-C3)alkyl;
• 4.5.j) halogen;
• 4.5.k) optionally substituted phenyl;
• 4.5.l) NO2;
• 4.5.m) CN;
• or
• 4.5.n) a 5-6 membered heteroaromatic containing up to two heteroatoms selected from O, S, and N;
• and
• k represents 0, 1, or 2;
• 4.6)
• wherein R177 represents H or —(C1-C3)alkyl;
• and
• m represents 1, 2, or 3;
• 4.7)
• 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
• R178 represents
• 4.9.a) H;
• 4.9.b) —(C1-C3)alkyl which may optionally bear halogen or —OR179 in which R179 represents H or (C1-C3)alkyl optionally substituted with halogen;
• 4.9.c) —SO2R180 wherein R180 represents optionally substituted phenyl or —(C1-C3)alkyl, which may be substituted with halogen or —OR181 wherein R181 represents H or (C1-C3)alkyl which may optionally bear halogen;
• 4.9.d) —C(O)R182 wherein R182 represents optionally substituted phenyl or —(C1-C3)alkyl which may optionally bear up to 3 substituents independently selected from
• 4.9.d1) halogen;
• 4.9.d2) optionally substituted phenyl;
• 4.9.d3) —S(O)2CH3;
• 4.9.d4) OR183 wherein R183 represents H or (C1-C3)alkyl which may optionally bear halogen;
• and
• 4.9.d5) —NR184R185 in which R184 and R185 are independently H or —(C1-C3)alkyl which may optionally bear halogen or OR185a wherein R185a represents H or (C1-C3)alkyl, or R184 and R185 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 NR186 wherein R186 represents H or (C1-C3)alkyl;
• 4.9e) —C(O)OR187 wherein R187 represents (C1-C3)alkyl;
• or
• 4.9.f) —C(O)—NR188R189 wherein R188 and R189 each independently represents H or —(C1-C3)alkyl which may optionally bear halogen, or R188 and R189 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 NR190 wherein R190 represents H or (C1-C3)alkyl;
• r represents 0, 1, or 2;
• and
• s represents 0 or 1;
• 4.10)
• wherein
• R191 represents
• 4.10.a) H;
• 4.10.b) —(C1-C3)alkyl which may optionally bear halogen or —OR192 in which R192 represents H or (C1-C3)alkyl;
• 4.10c) —SO2R193 wherein R193 represents phenyl or —(C1-C3)alkyl, both of which may be substituted with halogen or —(C1-C3)alkyl;
• 4.10.d) —C(O)R194 wherein R194 represents (C1-C3)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)2CH3;
• 4.10.d4) OR195 wherein R195 represents H or (C1-C3)alkyl which may optionally bear halogen;
• and
• 4.10.d5) —NR196R197 in which R196 and R197 are independently H or —(C1-C3)alkyl which may optionally bear halogen or OR197a wherein R197a represents H or (C1-C3)alkyl, or R196 and R197 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 NR198 wherein R198 represents H or (C1-C3)alkyl;
• 4.10.e) —C(O)OR199 wherein R199 represents (C1-C3)alkyl;
• or
• 4.10.f) —C(O)—NR200R201 wherein R200 and R201 each independently represents H or —(C1-C3)alkyl which may optionally bear halogen, or R200 and R201 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 NR202 wherein R202 represents H or (C1-C3)alkyl;
• and
• X represents O, S, S(O), S(O)2, or NR203 wherein
• R203 represents H or —(C1-C3)alkyl;
• and
• t represents 0, 1, or 2;
• 4.11) halogen;
• or
• 4.12) CN;
• or a pharmaceutically acceptable salt thereof.