Wnt signaling pathway inhibitors and therapeutic applications thereof

A compound of Formula I:

• or a pharmaceutically acceptable salt, solvate, stereoisomer or a tautomer thereof, wherein
• A is A1, A2, A3 or A4;
• U is U1, U2, U3 or U4;
• L is L, L2, or L3;
• Q is Q1, Q2, Q3 or Q4;
• Z is Z1, Z2, Z3 or Z4;
• A1 is
• wherein X1 to X7 are independently selected from N and C—R13;
• A2 is
• A3 is
• A4 is
• wherein X13 and X15 are independently O, N, S or C—R4c, and X14 is N or C;
• U1 is
• wherein X8 to X10 are independently selected from N and C—R14;
• G1 and G2 are independently selected from N and C;
• V1 and V2 are independently selected from N, O, S and C—R15;
• W is V3, V4—V5 or V4═V5, wherein V3 to V5 are independently selected from N, O, S and C—R16, wherein V4 connects with V1;
• and
• V5 connects with V2;
• U2 is C6-C10 aryl, 5-12 membered heteroaryl, 11-13 membered heterocyclophenyl or 10-13 membered heterocycloheteroaryl, wherein heterocyclo and heteroaryl comprises 1 to 4 heteroatoms independently selected from N, O and S;
• and
• C6-C10 aryl, 5-12 membered heteroaryl, 11-13 membered heterocyclophenyl and 10-13 membered heterocycloheteroaryl are unsubstituted or substituted with 1 to 4 R6a groups;
• U3 is —OR14b, —NR14bR15b, C6-C12 aryl unsubstituted or substituted with 1-6 R13b group, 5-14 membered heteroaryl unsubstituted or substituted with 1-6 R13b group, 11-13 membered heterocyclophenyl unsubstituted or substituted with 1-6 R13b group, 10-13 membered heterocycloheteroaryl unsubstituted or substituted with 1-6 R13b group, C2-C8 alkenyl substituted with 5-6 membered aryl or heteroaryl, C2-C8 alkynyl substituted with 5-6 membered aryl or heteroaryl, or
• unsubstituted or substituted with 1 to 2 R13b groups, wherein heterocyclo and heteroaryl comprises 1 to 4 heteroatoms independently selected from N, O and S;
• and
• X11 is N or C—R13b;
• U4 is
• wherein X8 to X10 are independently selected from N and C—R15c;
• G1 and G2 are independently selected from N and C;
• V1 and V2 are independently selected from N, O, S and C—R16c;
• W is V3, V4—V5 or V4═V5, wherein V3 to V5 are independently selected from N, O, S and C—R17c, wherein V4 connects with V1;
• and
• V5 connects with V2;
• L1 is
• L2 is
• wherein Y2 is blank, —O—, —S—, —N(R18b)— or —C(R18b)(R19b)—;
• L3 is —C(R2c)(R3c)— or —NHCH2CH2—;
• Q1 is C6-C10 arylene or 5-12 membered heteroarylene, wherein 5-12 membered heteroarylene comprises 1 to 4 heteroatoms independently selected from N, O and S;
• and
• C6-C10 aryl and 5-12 membered heteroarylene are unsubstituted or substituted with 1 to 4 R17 groups;
• Q2 is C6-C10 arylene or 5-10 membered heteroarylene, wherein 5-10 membered heteroarylene comprises 1 to 4 heteroatoms independently selected from N, O and S;
• and
• C6-C10 arylene and 5-10 membered heteroarylene are unsubstituted or substituted with 1 to 4 R4a groups;
• Q3 is C6-C12 arylene unsubstituted or substituted with 1-6 R6b group, 5-14 membered heteroarylene unsubstituted or substituted with 1-6 R6b group, C3-C6 cycloalkylene unsubstituted or substituted with 1-6 R6b group, C3-C6 heterocylene unsubstituted or substituted with 1-6 R6b group, or
• unsubstituted or substituted with 1 to 2 R6b groups, wherein heterocyclene and heteroarylene comprises 1 to 4 heteroatoms independently selected from N, O and S;
• and
• X12 is N or C—R6b;
• Q4 is C6-C10 arylene or 5-12 membered heteroarylene, wherein 5-12 membered heteroarylene comprises 1 to 4 heteroatoms independently selected from N, O and S;
• and
• C6-C10 arylene and 5-12 membered heteroarylene are unsubstituted or substituted with 1 to 4 R5c groups;
• Z1 is —CN, C6 aryl, 5-6 membered heteroaryl, or
• wherein 5-6 membered heteroaryl comprises 1 to 3 heteroatoms independently selected from N, O and S;
• C6 aryl and 5-6 membered heteroaryl are unsubstituted or substituted with 1 to 3 R18 groups;
• Y1 is O or NR20;
• and
• q is 0, 1, 2, or 3;
• Z2 is H, —CN, halide, —OH, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkylsulfonyl, C1-C8 acyl, aminoacyl, C1-C8 acylamino, C1-C8 alkylcarbamoylamino, C1-C8 alkoxycarbamoyl, C1-C8 alkylsulfonamido, C1-C8 alkylaminosulphonyl, C1-C8 alkoxy, C2-C8 alkoxyacyl, phenyl, 5-6 membered heteroaryl, or 5-7 membered heterocyclo, wherein 5-6 membered heteroaryl and 5-7 membered heterocyclo comprise one or more hetero atoms independently selected from N, O and S;
• and
• phenyl, 5-6 membered heteroaryl and 5-7 membered heterocycle are unsubstituted or substituted with 1 to 3 R5a groups;
• Z3 is H, —CN, halide, —OH, C1-C8 alkyl unsubstituted or substituted with 1 to 3 R12b groups, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkylsulfonyl, C1-C8 acyl, aminoacyl, C1-C8 acylamino, C1-C8 alkylcarbamoylamino, C1-C8 alkoxycarbamoyl, C1-C8 alkylsulfonamido, C1-C8 alkylaminosulphonyl, C1-C8 alkoxy, C2-C8 alkoxyacyl, —N(R7b)(R8b) unsubstituted or substituted with 1 to 3 R12b groups, phenyl unsubstituted or substituted with 1 to 3 R9b groups, 5-6 membered heteroaryl unsubstituted or substituted with 1 to 3 R10b groups, or 5-7 membered heterocyclo unsubstituted or substituted with 1 to 3 R11b groups, wherein 5-6 membered heteroaryl and 5-7 membered heterocyclo comprises 1-3 hetero atoms independently selected from N, O and S;
• Z4 is —CN, C6 aryl, 5-6 membered heteroaryl, or
• wherein 5-6 membered heteroaryl comprises 1 to 3 heteroatoms independently selected from N, O and S;
• C6 aryl and 5-6 membered heteroaryl are unsubstituted or substituted with 1 to 3 R6c groups;
• Y3 is O or NR8c;
• and
• q is 0, 1, 2, or 3;
• R1 to R3 are independently selected from H and C1-C6 alkyl, wherein C1-C6 alkyl is unsubstituted or substituted with 1 to 3 halide, —CN, —OH, C1-C3 alkyl, C3-C5 cycloalkyl, or C1-C3 alkoxy groups;
• R4 is H, halide, —CN, —OH, —NO2, C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 alkoxy, wherein C1-C6 alkyl, C3-C8 cycloalkyl and C1-C6 alkoxy are unsubstituted or substituted with 1 to 3 halide;
• R5 and R6 are independently selected from H, halide, —CN, —OH, amino, C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 alkoxy, wherein C1-C6 alkyl, C3-C6 cycloalkyl and C1-C6 alkoxy are unsubstituted or substituted with 1 to 3 halide;
• R7 and R8 are independently selected from H and C1-C6 alkyl, or R7 and R8 together are oxo (═O);
• R9 to R12 are independently selected from H, C1-C6 alkyl;
• R13 is H, halide, —CN, —OH, amino, —NO2, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio or 1-pyrrolidino, wherein amino, C1-C6 alkyl and C1-C6 alkoxy are unsubstituted or substituted with 1 to 3 halide, C1-C3 alkyl or C3-C6 cycloalkyl groups;
• R14 to R17 are independently selected from H, halide, —CN, —OH, amino, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy and C1-C6 alkylthio, wherein amino, C1-C6 alkyl and C1-C6 alkoxy are unsubstituted or substituted with 1 to 3 halide, C1-C3 alkyl or C3-C6 cycloalkyl groups;
• R18 is H, halide, —CN, —OH, amino, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy, wherein amino, C1-C6 alkyl and C1-C6 alkoxy are unsubstituted or substituted with 1 to 3 halide, C1-C3 alkyl or C3-C6 cycloalkyl groups;
• R19 and R20 are independently selected from H and C1-C3 alkyl, or R19 and R20 together, with adjacent atoms they attached to, form a cyclic structure;
• R4a, R5a and R6a are independently selected from halide, —CN, and —OH, or R4a, R5a and R6a are independently selected from C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkylsulfonyl, C1-C8 acyl, aminoacyl, C1-C8 acylamino, C1-C8 alkylcarbamoylamino, C1-C8 alkoxycarbamoyl, C1-C8 alkylsulfonamido, C1-C8 alkylaminosulphonyl, C2-C8 alkoxyacyl, and 3-8 membered heterocycle, all of which are unsubstituted or substituted with 1-3 halide, —OH, —CN, C1-C3 alkyl, C1-C3 alkoxyl or C3-C8 cycloalkyl groups, wherein 3-8 membered heterocycle comprises one or more hetero atoms from N, O or S;
• R2m is H, deuterium, tritium, halide, —OH, —CN, C1-C8 alkyl, C3-C8 cycloalkyl or C1-C5 alkoxy;
• R2b and R3b are independently selected from H, C1-C6 alkyl unsubstituted or substituted with 1-3 groups selected from halide, —CN, —OH, C1-C6 alkyl, C3-C5 cycloalkyl and C1-C3 alkoxy;
• R4b and R5b are independently selected from H, halide, —CN, amino, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, and C1-C3 alkylamino;
• R6b is H, halide, —CN or —OH, or R6b is selected from amino, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, and C1-C3 alkylamino, all of which are unsubstituted or substituted with 1-3 halide, C1-C3 alkyl, or C3-C6 cycloalkyl groups;
• R7b and R8b are independently selected from H, C1-C8 alkyl and C3-C8 cycloalkyl, the latter two of which are unsubstituted or substituted with 1-3 R12b, or R7 and R8 together, with adjacent atoms they attached to, form a cyclic structure;
• R9b and R10b are independently selected from H, halide, —CN and —OH, or R9b and R10b are independently selected from amino, C1-C6 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy, all of which are unsubstituted or substituted with 1-3 halide, C1-C3 alkyl, or C3-C6 cycloalkyl groups;
• R11b is H, halide, —CN, —OH, amino, C1-C6 alkyl unsubstituted or substituted with halide, C3-C6 cycloalkyl, oxo, or C1-C6 alkoxy;
• R12b is H, —CN, —OH, amino, C1-C6 alkyl unsubstituted or substituted with halide, C3-C6 cycloalkyl, oxo, or C1-C6 alkoxy;
• R13b is H, halide, —CN, —OH, amino, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C2-C6 alkylcarbamoylamino, C2-C6 alkoxycarbamoyl, C1-C3 alkylsulphonyl, —N(R16b)S(O)2—C1-C3 alkyl, or —N(R16b)C(O)—C1-C3 alkyl;
• R14b and R15b are independently selected from H, C3-C6 cycloalkyl unsubstituted or substituted with 1 to 3 R20b groups, C1-C6 alkyl unsubstituted or substituted with 1 to 3 R20b groups, 5-6 membered aryl unsubstituted or substituted with 1 to 3 R20b groups, 5-6 membered heteroaryl unsubstituted or substituted with 1 to 3 R20b groups, and 5-6 membered heterocyclo unsubstituted or substituted with 1 to 3 R20b groups, wherein 5-6 membered heteroaryl and 5-7 membered heterocyclo comprise 1 to 3 hetero atoms independently selected from N, O and S, or R14b and R15b together, with adjacent atoms they attached to, form a cyclic structure;
• R16b to R19b are independently selected from H and C1-C6 alkyl unsubstituted or substituted with halide;
• R20b is H, —CN, —OH, amino, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, 5-6 membered aryl, or 5-6 membered heteroaryl, wherein 5-6 membered heteroaryl comprises 1 to 3 hetero atoms independently selected from N, O and S;
• R21b is H or C1-C6 alkyl;
• R2c and R3c are independently selected from H and C1-C6 alkyl unsubstituted or substituted with 1-3 halide;
• R4c is H, halide, C1-C3 alkyl, C3-C5 cycloalkyl, or C1-C3 alkoxy;
• R5c and R6c are independently selected from H, halide, —CN, —OH, amino, C1-C6 alkyl unsubstituted or substituted with 1-3 halide, C3-C5 cycloalkyl, and C1-C6 alkoxy;
• R7c and R8c are independently selected from H and C1-C6 alkyl, or R7c and R8c together, with adjacent atoms they attached to, form a cyclic structure;
• R9c to R14c are independently selected from H, C1-C6 alkyl and —CF3;
• R15c to R17c are independently selected from H, halide, —CN, —OH, amino, C1-C6 alkyl unsubstituted or substituted with 1-3 halide, C3-C5 cycloalkyl, and C1-C6 alkoxy.