US 10,472,341 B2 · Bicyclic tetrahydrothiazepine derivatives useful for the treatment of neoplastic and/or infectious diseases

Abstract

The present invention relates to bicyclic tetrahydrothiazepine of formula (I), wherein R1 to R3, X1, X2 and R18 have the meaning as indicated in the description and claims. The invention further relates to pharmaceutical compositions comprising such compounds as well as their use as medicaments, especially in methods for the treatment or prevention of a neoplastic and/or infectious disease and in vitro methods.

A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein
X1 is S;
S(O);
or S(O)2;
X2 is N;
or C(R4);
R1 is H;
or methyl;
R2 is phenyl;
3 to 7 membered heterocyclyl;
or 7 to 11 membered heterobicyclyl, wherein R2 is optionally substituted with one or more R5, which are the same or different;
R5 is halogen;
CN;
C(O)OR6;
OR6;
C(O)R6;
C(O)N(R6R6a);
S(O)2N(R6R6a);
S(O)N(R6R6a);
S(O)2R6;
S(O)R6;
N(R6)S(O)2N(R6aR6b);
SR6;
N(R6R6a);
OC(O)R6;
N(R6)C(O)R6a;
N(R6)S(O)2R6a;
N(R6)S(O)R6a;
N(R6)C(O)OR6a;
N(R6)C(O)N(R6aR6b);
OC(O)N(R6R6a);
oxo (═O), where the ring is at least partially saturated;
T1;
C1-6 alkyl;
C2-6 alkenyl;
or C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R6, R6a, and R6b are independently selected from the group consisting of H;
C1-6 alkyl, C2-6 alkenyl;
and C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
T1 is phenyl;
C3-7 cycloalkyl;
or 3 to 7 membered heterocyclyl, wherein T1 is optionally substituted with one or more R7, which are the same or different;
R7 is halogen;
CN;
C(O)OR8;
OR8;
C(O)R8;
C(O)N(R8R8a);
S(O)2N(R8R8a);
S(O)N(R8R8a);
S(O)2R8;
S(O)R8;
N(R8)S(O)2N(R8aR8b);
SR8;
N(R8R8a);
OC(O)R8;
N(R8)C(O)R8a;
N(R8)S(O)2R8a;
N(R8)S(O)R8a;
N(R8)C(O)OR8a;
N(R8)C(O)N(R8aR8b);
OC(O)N(R8R8a);
oxo (═O), where the ring is at least partially saturated;
C1-6 alkyl;
C2-6 alkenyl;
or C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R8, R8a, and R8b are independently selected from the group consisting of H;
C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R3 is R3a;
OR3a;
NHR3a;
or NHC(O)R3a;
R3a is T2;
C1-12 alkyl;
C2-12 alkenyl;
or C2-12 alkynyl, wherein C1-12 alkyl;
C2-12 alkenyl;
and C2-12 alkynyl are optionally substituted with one or more R9, which are the same or different;
R9 is halogen;
CN;
C(O)OR10;
OR10;
C(O)R10;
C(O)N(R10R10a);
S(O)2N(R10R10a);
S(O)N(R10R10a);
S(O)2R10;
S(O)R10;
N(R10)S(O)2N(R10aR10b);
SR10;
N(R10R10a);
OC(O)R10;
N(R10)C(O)R10a;
N(R10)S(O)2R10a;
N(R10)S(O)R10a;
N(R10)C(O)N(R10aR10b);
N(R10)C(O)OR10a;
OC(O)N(R10R10a);
T2;
C1-12 alkyl;
C2-12 alkenyl;
or C2-12 alkynyl, wherein C1-12 alkyl;
C2-12 alkenyl;
and C2-12 alkynyl are optionally substituted with one or more R11, which are the same or different;
R10, R10a, and R10b are independently selected from the group consisting of H;
T2;
C1-12 alkyl;
C2-12 alkenyl;
and C2-12 alkynyl, wherein C1-12 alkyl;
C2-12 alkenyl;
and C2-12 alkynyl are optionally substituted with one or more R11, which are the same or different;
T2 is phenyl;
C3-7 cycloalkyl;
3 to 7 membered heterocyclyl;
or 7 to 11 membered heterobicyclyl, wherein T2 is optionally substituted with one or more R12, which are the same or different;
R12 is halogen;
CN;
C(O)OR13;
OR13;
C(O)R13;
C(O)N(R13R13a);
S(O)2N(R13R13a);
S(O)N(R13R13a);
S(O)2R13;
S(O)R13;
N(R13)S(O)2N(R13aR13b);
SR13;
N(R13R13a);
OC(O)R13;
N(R13)C(O)R13a;
N(R13)S(O)2R13a;
N(R13)S(O)R13a;
N(R13)C(O)OR13a;
N(R13)C(O)N(R13aR13b);
OC(O)N(R13R13a);
oxo (═O), where the ring is at least partially saturated;
T3;
C1-6 alkyl;
C2-6 alkenyl;
or C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more R14, which are the same or different;
R13, R13a, and R13b are independently selected from the group consisting of H;
C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more R14, which are the same or different;
R11 and R14 are independently selected from the group consisting of halogen;
CN;
C(O)OR15;
OR15;
C(O)R15;
C(O)N(R15R15a);
S(O)2N(R15R15a);
S(O)N(R15R15a);
S(O)2R15;
S(O)R15;
N(R15)S(O)2N(R15aR15b);
SR15;
N(R15R15a);
OC(O)R15;
N(R15)C(O)R15a;
N(R15)S(O)2R15a;
N(R15)S(O)R15a;
N(R15)C(O)OR15a;
N(R15)C(O)N(R15aR15b);
OC(O)N(R15R15a);
and T3;
R15, R15a, and R15b are independently selected from the group consisting of H;
T3;
C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
T3 is phenyl;
C3-7 cycloalkyl;
or 3 to 7 membered heterocyclyl, wherein T3 is optionally substituted with one or more R16, which are the same or different;
R16 is halogen;
CN;
C(O)OR17;
OR17;
C(O)R17;
C(O)N(R17R17a);
S(O)2N(R17R17a);
S(O)N(R17R17a);
S(O)2R17;
S(O)R17;
N(R17)S(O)2N(R17aR17b);
SR17;
N(R17R17a);
OC(O)R17;
N(R17)C(O)R17a;
N(R17)S(O)2R17a;
N(R17)S(O)R17a;
N(R17)C(O)OR17a;
N(R17)C(O)N(R17aR17b);
OC(O)N(R17R17a);
oxo (═O), where the ring is at least partially saturated;
C1-6 alkyl;
C2-6 alkenyl;
or C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R17, R17a, and R17b are independently selected from the group consisting of H;
C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl, wherein C1-6 alkyl;
C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
R4 is H;
F;
Cl;
or N(CH3)2;
R18 is H;
C1-6 alkyl;
C2-6 alkenyl;
or C2-6 alkynyl;
wherein C1-6 alkyl, C2-6 alkenyl;
and C2-6 alkynyl are optionally substituted with one or more R19, which are the same or different;
R19 is halogen;
CN;
C(O)OR20;
OR20;
C(O)R20;
C(O)N(R20R20a);
S(O)2N(R20R20a);
S(O)N(R20R20a);
S(O)2R20;
S(O)R20;
N(R20)S(O)2N(R20aR20b);
SR20;
N(R20R20a);
NO2;
OC(O)R20;
N(R20)C(O)R20a;
N(R20)SO2R20a;
N(R20)S(O)R20a;
N(R20)C(O)N(R20aR20b);
N(R20)C(O)OR20a;
or OC(O)N(R20R20a);
and
R20, R20a, and R20b are independently selected from the group consisting of H;
and C1-6 alkyl, wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.

252 more elements

Bicyclic tetrahydrothiazepine derivatives useful for the treatment of neoplastic and/or infectious diseases

Life of this patent

Bicyclic tetrahydrothiazepine derivatives useful for the treatment of neoplastic and/or infectious diseases

Life of this patent

Abstract

Claims30