US 2013/0296344 A1 · CHROMENE DERIVATIVES AND THEIR ANALOGA AS WNT PATHWAY ANTAGONISTS

Abstract

Compounds according to the general formula (I) wherein X1, X2, X3 and X4 independently from each other are N or CR8 wherein R8 may be same or different, and wherein up to 3 of the group X1, X2, X3 and X4 may be N; A is a 5- or 6-membered aromatic or heteroaromtic cycle containing 1 to 3 heteroatoms selected from the group consisting of N, O and S wherein A may be substituted by 1 to 5 substituents R which may be same or different; their solvates, hydrates, and pharmaceutically acceptable salts for the treatment of a disorder or disease associated with an aberrant activation of Wnt signalling in a mammal selected from a cell proliferative disorder, rheumatoid arthritis, increased bone density, aging or age-related disorders and/or diseases or Dupuytren disease (superficial fibromatosis).

Claims16

Dependent claims

1-15. (canceled)

Method for the treatment of a disorder or disease associated with an aberrant activation of Wnt signalling in a mammal selected from a cell proliferative disorder, rheumatoid arthritis, increased bone density, aging or age-related disorders and/or diseases or Dupuytren disease (superficial fibromatosis) using a compound of formula (I)

and/or solvates;
hydrates;
and pharmaceutically acceptable salts thereof
wherein
X1, X2, X3 and X4 independently from each other are N or CR8 wherein R8 may be same or different, and wherein up to 3 of the group X1, X2, X3 and X4 may be N;
A is selected from the group consisting of 5- to 6-membered aromatic or heteroaromtic cycles containing 1 to 3 heteroatoms selected from the group consisting of N, O and S wherein A is optionally substituted by 1 to 5 substituents R which may be same or different;
R is selected from 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;
C(O)R1a;
C(O)OR1a;
C(O)N(R1aR1b);
C(NR1aR1b)NOR1c;
C(NR1aR1b)NOC(O)R1c;
S(O)2N(R1a)C(O)N(R1bR1c);
N(R1a)S(O)2OR1b;
C(R1a)N(R1b);
C(R1a)NOR1b;
C(R1a)NN(R1bR1c);
C(O)N(Rla)OR1b;
C(NR1a)N(R1bR1c);
C(NR1a)N(R1b)OR1c;
C(NR1a)N(R1b)N(R1cR1d);
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)2OR;
S(O)2N(RlaR1b);
S(O)N(R1aR1b);
S(O)2R1a;
S(O)R1a;
OR1a;
OC(O)R1a;
and OC(O)N(R1aR1b);
and wherein alkyl;
alkenyl, alkinyl, cycloalkyl;
heterocyclyl;
aryl;
heteroaryl;
aralkyl;
and heteroarylalkyl are optionally substituted by one or more groups R10 which are same or different;
and
optionally two adjacent substituents R form together a 5- to 7-membered aromatic, heteroaromatic, alicyclic or heterocyclic ring optionally substituted by one or more groups R10 which are same or different;
R1a;
R1b;
R1c;
and R1d 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;
and heteroarylalkyl are 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)2N(R10a)C(O)N(R10bR10c);
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);
N(R10a)C(O)OR10b;
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 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)R6a;
C(O)OR6a;
C(O)N(R6aR6b);
C(O)N(R6a)OR6b;
C(O)N(R6a)N(R6bR6c);
C(NR6a)N(R6bR6c);
C(NR6a)N(R6b)OR6c;
C(NR6a)N(R6b)N(R6cR6d);
C(R6a)N(R6b);
C(NR6aR6b)NOR6c;
C(NR6aR6b)NOC(O)R6c;
C(R6a)NN(R6bR6c);
CR6aNOR6b;
OR6a;
OC(O)R6a;
OC(O)N(R6aR6b);
SR6a;
S(O)R6a;
S(O)2R6a;
S(O)2OR6a;
S(O)2N(R6aR6b);
S(O)N(R6aR6b);
S(O)2N(R6a)C(O)N(R6bR6c);
N(R6a)S(O)2N(R6bR6c);
N(R6a)S(O)2R6b;
N(R6a)S(O)R6b;
N(R6a)S(O)2OR6b;
N(R6aR6b);
N(R6a)C(O)R6b;
N(R6a)C(O)N(R6bR6c);
and N(R6a)C(O)OR6b;
wherein alkyl;
cycloalkyl;
heterocyclyl;
alkenyl;
alkinyl;
aryl;
heteroaryl;
aralkyl;
and heteroarylalkyl are optionally substituted by one or more R11, which are same or different;
R6a;
R6b;
R6c;
and R6d 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);
S(O)2N(R11a)C(O)N(R11bR11c);
N(R11a)S(O)2N(R11bR11c);
N(R11a)S(O)2R11b;
N(R11a)S(O)R11b;
N(R11a)C(O)N(R11bR11c);
N(R11a)C(O)OR11b;
and OC(O)N(R11aR11b);
wherein C1-C6 alkyl is optionally substituted with one or more R18 which are same or different;
(a)
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);
S(O)2N(R11a)C(O)N(R1bR11c);
N(R11a)S(O)2N(R11bR11c);
N(R11a)S(O)2R11b;
N(R11a)S(O)R11b;
N(R11a)C(O)N(R11bR11c);
N(R11a)C(O)OR11b;
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;
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)R7a;
C(O)OR7a;
C(O)N(R7a)OR7b;
C(NR7a)N(R7bR7c);
C(NR7a)N(R7b)OR7c;
C(O)N(R7aR7b);
C(O)N(R7a)N(R7bR7c);
C(NR7a)N(R7b)N(R7cR7d);
C(R7a)N(R7b);
C(R7a)NN(R7bR7c);
C(R7a)NOR7b;
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);
SR7a;
S(O)R7a;
S(O)2R7a;
S(O)2OR7a;
S(O)N(R7aR7b);
S(O)2N(R7aR7b);
S(O)2N(R7a)C(O)N(R7bR7c);
C(NR7aR7b)NOR7c;
and C(NR7aR7b)NOC(O)R7c;
wherein alkyl;
cycloalkyl;
alkenyl;
alkinyl;
aryl;
aralkyl;
and heteroarylalkyl are optionally substituted by one or more R12, which are same or different;
R7a;
R7b;
R7c, and R7d 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(O)N(R8a)OR8b;
C(O)N(R8a)N(R8bR8c);
C(NR8a)N(R8bR8c);
C(NR8a)N(R8b)OR8c;
C(NR8a)N(R8b)N(R8CR8d);
C(R8a)N(R8b);
C(R8a)NN(R8bR8c);
C(R8a)NOR8b;
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);
N(R8a)C(O)OR8b;
C(NR8aR8b)NOR8c;
C(NR8aR8b)NOC(O)R8c;
C(O)NR8aN(R8bR8c);
and N(R8a)C(S)N(R8bR8c);
wherein alkyl;
cycloalkyl;
heterocyclyl;
alkenyl;
alkinyl;
aryl;
heteroaryl;
aralkyl;
and heteroarylalkyl are optionally substituted by one or more R16, which are same or different;
and
optionally two adjacent R8 form together a substituted or unsubstituted 5- or 6 membered saturated or unsaturated hydrocarbon ring containing up to 3 N-atoms in the ring or a substituted or unsubstituted 5- to 7-membered cyclic monoether or diether;
R8a;
R8b;
R8c;
and R8d 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);
N(R16a)C(O)OR16b;
OC(O)N(R16aR16);
and S(O)2N(R16a)C(O)N(R16bR16c);
wherein C1-C6 alkyl is optionally substituted with one or more halogen which are same or different;
R16a;
R16b and R16c are independently from each other selected from H;
and C1-6 alkyl;
wherein C1-6 alkyl is optionally substituted with one or more halogen which are the same or different.

406 more elements

Dependencies are inferred from the claim text.

Chromene derivatives and their analoga as wnt pathway antagonists

Life of this patent

Chromene derivatives and their analoga as wnt pathway antagonists

Life of this patent

Abstract

Claims16