US 2016/0355496 A1 · CHROMENE DERIVATIVES AND THEIR ANALOGS AS WNT PATHWAY ANTAGONISTS

Abstract

Compounds of formula (IIc); wherein X3 and X4 independently from each other are N or CR8 wherein R8 may be same or different; Y1, Y2, Y3 and Y4 independently from each other are N or CR9 wherein R9 may be same or different and wherein up to 3 of the group Y1, Y2, Y3 and Y4 may be N; their solvates, hydrates, and pharmaceutically acceptable salts, their use for modulating the Wnt signalling pathway activity and their use as a medicament, preferably for the treatment of cancer.

A compound of formula (Ic)

wherein
X3 and X4 independently from each other are N or CR8 wherein R8 may be same or different;
Y1, Y2, Y3 and Y4 independently from each other are N or CR9 wherein R9 may be same or different and wherein up to 3 of the group Y1, Y2, Y3 and Y4 may be N;
R1;
R2;
R3;
R4 and R5 are selected from H, OH;
halogen;
CN;
C1-C6 alkyl;
C2-C6 alkenyl;
C2-C6 alkinyl;
C3-C7 aryl;
C3-C7 heteroaryl;
C4-C15 aralkyl;
C4-C15 heteroarylalkyl;
C(O)R1a;
C(O)OR1a;
C(O)N(R1aR1b);
N(R1a)S(O)2OR1b;
N(R1aR1b);
N(R1a)S(O)2N(R1bR1c);
N(R1a)C(O)R1b;
N(R1a)S(O)2R1b;
N(R1a)S(O)R1b;
N(R1a)C(O)N(R1bR1c);
N(R1a)C(O)OR1b;
SR1a;
S(O)2OR1a;
S(O)2N(R1aR1b);
S(O)N(R1aR1b);
S(O)2R1a;
S(O)R1a;
OR1a;
OC(O)R1a;
and OC(O)N(R1aR1b);
and wherein alkyl;
alkenyl, alkinyl, aryl;
heteroaryl;
aralkyl;
and heteroarylalkyl are/is optionally substituted by one or more groups R10 which are same or different;
optionally two adjacent substituents R1;
R2;
R3;
R4 and R5 form together a 5- to 7-membered heterocyclic ring optionally substituted by one or more groups R10 which may be same or different;
and wherein at least 3 of the group of R1;
R2;
R3;
R4;
and R5 are not H;
R1a;
R1b;
and R1c are independently from each other selected from H;
C1-C6 alkyl;
C3-C7 cycloalkyl;
C3-C7 heterocyclyl;
C2-C6 alkenyl;
C2-C6 alkinyl;
C3-C7 aryl;
C3-C7 heteroaryl;
C4-C16 aralkyl;
and C4-C15 heteroarylalkyl;
wherein alkyl;
cycloalkyl;
heterocyclyl;
alkenyl;
alkinyl;
aryl;
heteroaryl;
aralkyl;
and heteroarylalkyl are/is optionally substituted with one or more R10 which are same or different;
R10 is selected from halogen;
CN;
OH, C1-C6 alkyl;
OR10a;
C(O)R10a;
C(O)OR10a;
C(O)N(R10aR10b);
N(R10aR10b);
OC(O)R10a;
N(R10a)C(O)R10b;
S(O)2N(R10aR10b);
S(O)N(R10aR10b);
S(O)2R10a;
S(O)R10a;
S(O)2OR10a;
N(R10a)S(O)2N(R10bR10c);
SR10a;
N(R10a)S(O)2R10b;
N(R10a)S(O)R10b;
N(R10a)C(O)N(R10bR10c);
and OC(O)N(R10aR10b);
wherein C1-C6 alkyl is optionally substituted with one or more halogen which are same or different;
R10a;
R10b and R10c are independently from each other selected from H;
and C1-C6 alkyl;
wherein C1-C6 alkyl is optionally substituted with one or more halogen which are same or different;
R6 is selected from CN;
C(O)R6a;
C(O)OR6a;
C(O)N(R6aR6b);
C(NR6a)N(R6bR6c);
CR6aNOR6b;
SR6a;
S(O)R6a;
S(O)2R6a;
S(O)2OR6a;
S(O)2N(R6aR6b);
and S(O)N(R6aR6b);
R6a;
R6b;
and R6c are independently from each other selected from H;
C1-C6 alkyl;
C3-C7 cycloalkyl;
C3-C7 heterocyclyl;
C2-C6 alkenyl;
C2-C6 alkinyl;
C3-C7 aryl;
C3-C7 heteroaryl;
C4-C15 aralkyl;
and C4-C15 heteroarylalkyl which are optionally substituted with one or more R11, which are the same or different;
R11 is selected from halogen;
CN;
OH;
C1-C6 alkyl;
OR11a;
C(O)R11a;
C(O)OR11a;
C(O)N(R11aR11b);
N(R11aR11b);
OC(O)R11a;
N(R11a)C(O)R11b;
SR11a;
S(O)R11a;
S(O)2R11a;
S(O)2OR11a;
S(O)2N(R11aR11b);
S(O)N(R11aR11b);
N(R11a)S(O)2N(R11bR11c);
N(R11a)S(O)2R11b;
N(R11a)S(O)R11b;
N(R11a)C(O)N(R11bR11c);
and OC(O)N(R11aR11b);
wherein C1-C6 alkyl is optionally substituted with one or more R18 which are the same or different;
R18 is selected from halogen, CN, OH;
OR11a;
C(O)R11a;
C(O)OR11a;
C(O)N(R11aR11b);
N(R11aR11b);
OC(O)R11a;
N(R11a)C(O)R11b;
SR11a;
S(O)R11a;
S(O)2R11a;
S(O)2OR11a;
S(O)2N(R11aR11b);
S(O)N(R11aR11b);
N(R11a)S(O)2N(R11bR11c);
N(R11a)S(O)2R11b;
N(R11a)S(O)R11b;
N(R11a)C(O)N(R11bR11c);
and OC(O)N(R11aR11b);
R11a;
R11b;
and R11c are independently from each other selected from H;
and C1-C6 alkyl;
wherein C1-C6 alkyl is optionally substituted with one or more halogen which are the same or different;
R7 is selected from H;
OH;
OR7a;
OC(O)R7a;
OC(O)N(R7aR7b);
N(R7aR7b);
N(R7a)C(O)R7b;
N(R7a)C(O)N(R7bR7c);
N(R7a)C(O)OR7b;
N(R7a)S(O)2OR7b;
N(R7a)S(O)R7b;
N(R7a)S(O)2R7b;
N(R7a)S(O)2N(R7bR7c);
R7a;
R7b;
and R7c are independently from each other selected from H;
C1-C6 alkyl;
C3-C7 cycloalkyl;
C3-C7 heterocyclyl;
C2-C6 alkenyl;
C2-C6 alkinyl;
C3-C7 aryl;
C3-C7 heteroaryl;
C4-C15 aralkyl;
and C4-C15 heteroarylalkyl wherein alkyl;
cycloalkyl;
heterocyclyl;
alkenyl;
alkinyl;
aryl;
heteroaryl;
aralkyl;
heteroarylalkyl are optionally substituted with one or more R12, which are same or different;
R12 is selected from halogen;
CN;
OH;
C1-C6 alkyl;
OR12a;
C(O)R12a;
C(O)OR12a;
C(O)N(R12aR12b);
N(R12aR12b);
OC(O)R12a;
N(R12a)C(O)R12b;
S(O)2N(R12aR12b);
S(O)N(R12aR12b);
S(O)2R12a;
S(O)R12a;
S(O)2OR12a;
N(R12a)S(O)2N(R12bR12c);
SR12a;
N(R12a)S(O)2R12b;
N(R12a)S(O)R12b;
N(R12a)C(O)N(R12bR12c);
N(R12a)C(O)OR12b;
OC(O)N(R12aR12b);
and S(O)2N(R11a)C(O)N(R11bR11c);
wherein C1-C6 alkyl is optionally substituted with one or more halogen which are same or different;
R12a;
R12b and R12c are independently from each other selected from H;
and C1-C6 alkyl;
wherein C1-C6 alkyl is optionally substituted with one or more halogen which are same or different;
R8 is selected from H;
OH;
CN, halogen, C1-C6 alkyl;
C3-C7 cycloalkyl;
C3-C7 heterocyclyl;
C2-C6 alkenyl;
C2-C6 alkinyl;
C3-C7 aryl;
C3-C7 heteroaryl;
C4-C15 aralkyl;
C4-C15 heteroarylalkyl;
C(O)R8a;
C(O)OR8a;
C(O)N(R8aR8b);
C(NR8a)N(R8bR8c);
C(R8a)N(R8b);
OR8a;
OC(O)R8a;
OC(O)N(R8aR8b);
SR8a;
S(O)R8a;
S(O)2R8a;
S(O)2OR8a;
S(O)2N(R8aR8b);
S(O)N(R8aR8b);
S(O)2N(R8a)C(O)N(R8bR8c);
N(R8a)S(O)2N(R8bR8c);
N(R8a)S(O)2R8b;
N(R8a)S(O)R8b;
N(R8a)S(O)2OR8b;
N(R8aR8b);
N(R8a)C(O)R8b;
N(R8a)C(O)N(R8bR8c);
and N(R8a)C(S)N(R8bR8c);
wherein alkyl;
cycloalkyl;
heterocyclyl;
alkenyl;
alkinyl;
aryl;
heteroaryl;
aralkyl;
and heteroarylalkyl are/is optionally substituted by one or more R16, which are same or different;
R8a and R8b;
and R8c are independently from each other selected from H;
C1-C6 alkyl;
C3-C7 cycloalkyl;
C3-C7 heterocyclyl;
C2-C6 alkenyl;
C2-C6 alkinyl;
C3-C7 aryl;
C3-C7 heteroaryl;
C4-C15 aralkyl;
and C4-C15 heteroarylalkyl which are optionally substituted with one or more R16, which are same or different;
R16 is selected from halogen;
CN;
OH;
C1-C6 alkyl;
OR16a;
C(O)R16a;
C(O)OR16a, C(O)N(R16aR16b);
N(R16aR16b);
OC(O)R16a;
N(R16a)C(O)R16b;
S(O)2N(R16aR16b);
S(O)N(R16aR16b);
S(O)2R16a;
S(O)R16a;
S(O)2OR16a;
N(R16a)S(O)2N(R16bR16c);
SR16a;
N(R16a)S(O)2R16b;
N(R16a)S(O)R16b;
N(R16a)C(O)N(R16bR16c);
and OC(O)N(R16aR16b);
wherein C1-C6 alkyl is optionally substituted with one or more halogen which are same or different;
R16a and R16b and R16c are independently from each other selected from H;
and C1-C6 alkyl;
wherein C1-6 alkyl is optionally substituted with one or more halogen which are the same or different;
R9 is selected from H;
OH;
halogen;
CN;
C1-C6 alkyl;
C3-C7 cycloalkyl;
C3-C7 heterocyclyl;
C2-C6 alkenyl;
C2-C6 alkinyl;
C3-C7 aryl;
C3-C7 heteroaryl;
C4-C15 aralkyl;
C4-C15 heteroarylalkyl;
OR9a;
C(O)R9a;
C(O)OR9a;
C(O)N(R9aR9b);
S(O)2N(R9aR9b);
S(O)N(R9aR9b);
S(O)2R9a;
S(O)R9a;
S(O)2OR9a;
S(O)2N(R9a)C(O)N(R9bR9c);
N(R9a)S(O)2N(R9bR9c);
SR9a;
OC(O)R9a;
N(R9a)C(O)R9b;
N(R9a)S(O)2R9b;
N(R9a)S(O)R9b;
N(R9a)C(O)N(R9bR9c);
N(R9a)C(S)N(R9bR9c);
OC(O)N(R9aR9b);
C(NR9a)N(R9bR9c);
N(R9a)S(O)2OR9b;
N(R9aR9b);
and C(R9a)NR9b;
wherein alkyl;
cycloalkyl;
heterocyclyl;
alkenyl;
alkinyl;
aryl;
heteroaryl;
aralkyl;
and heteroarylalkyl are optionally substituted by one or more R13, which are same or different;
R9a;
R9b;
and R9c are independently from each other selected from H;
C1-C6 alkyl;
C3-C7 cycloalkyl;
C3-C7 heterocyclyl;
C2-C6 alkenyl;
C2-C6 alkinyl C3-C7 aryl;
C3-C7 heteroaryl;
C4-C15 aralkyl;
and C4-C15 heteroarylalkyl which are optionally substituted with one or more R13, which are same or different;
R13 is selected from halogen;
CN;
OH;
C1-C6 alkyl;
OR13a;
C(O)R13a;
C(O)OR13a;
C(O)N(R13aR13b);
N(R13aR13b);
OC(O)R13a;
N(R13a)C(O)R13b;
S(O)2N(R13aR13b);
S(O)N(R13aR13b), S(O)2R13a;
S(O)2OR13a;
S(O)R13a;
N(R13a)S(O)2N(R13bR13c), SR13a;
N(R13a)S(O)2R13b;
N(R13a)S(O)R13b;
N(R13a)C(O)N(R13bR13c);
and OC(O)N(R13aR13b);
wherein C1-C6 alkyl is optionally substituted with one or more halogen which are same or different;
R13a;
R13b and R13c are independently from each other selected from H;
and C1-C6 alkyl;
wherein C1-C6 alkyl is optionally substituted with one or more halogen which are same or different;
and pharmaceutically acceptable salts thereof.

388 more elements

Chromene derivatives and their analogs as wnt pathway antagonists

Life of this patent

Chromene derivatives and their analogs as wnt pathway antagonists

Life of this patent

Abstract

Claims15