Substituted pyridines for modulating the WNT signaling pathway

1. A compound having Formula (1):

or a pharmaceutically acceptable salt thereof, wherein:

A is

X is CH or CR 6 ;

one of X 1 , X 2 , X 3 and X 4 is N and the others are CR 11 ;

one of X 5 , X 6 , X 7 and X 8 is N and the others are CR 12 ;

Z is a 5-6 membered heteroaryl, wherein said heteroaryl contains 1-2 nitrogen atoms, and Z is unsubstituted or substituted by 1-2 R 7 groups;

R 1 , R 2 , R 3 and R 4 are hydrogen or C 1-6 alkyl;

R 5 and R 6 are independently halo, cyano, C 1-6 alkoxy, S(O) 2 R 10 , or a C 1-6 alkyl unsubstituted or substituted with halo;

R 7 is hydrogen, halo, cyano, C 1-6 alkoxy; C 1-6 alkyl, which is unsubstituted or substituted by halo, amino, hydroxy, alkoxy or cyano; -L-W, NR 8 R 9 , -L-C(O)R 10 , -L-C(O)OR 10 , -L-C(O)NR 8 R 9 , OR 9 , -L-S(O) 2 R 10 or -L-S(O) 2 NR 8 R 9 ;

R 8 and R 9 are independently hydrogen or -L-W; or C 1-6 alkyl, which is unsubstituted or substituted by halo, amino, hydroxy, alkoxy or cyano; or alternatively, R 8 and R 9 together with the nitrogen atom to which they are attached may form pyrrolidinyl, 2-oxopyrrolidinyl or piperidinyl;

R 10 is C 1-6 alkyl or -L-W;

R 11 and R 12 are independently hydrogen, halo, cyano, C 1-6 alkoxy, or a C 1-6 alkyl unsubstituted or substituted by halo;

L is a single bond or (CR 2 ) 1-4 wherein each R is independently H or C 1-6 alkyl;

W is C 3-7 cycloalkyl or a 5-6 membered heterocyclic ring; and

n and q are independently 0, 1, 2 or 3.

2. The compound of claim 1 , wherein Z is pyridinyl unsubstituted or substituted by C 1-6 alkyl or NR 8 R 9 ; or pyridazinyl, pyrazinyl, or pyrimidinyl;

R 8 and R 9 are independently hydrogen or C 1-6 alkyl; or alternatively, R 8 and R 9 together with the nitrogen atom to which they are attached form 2-oxopyrrolidinyl;

R 10 is C 1-6 alkyl; and

L is a single bond.

3. The compound of claim 2 , wherein Z is pyridinyl, pyridazinyl, pyrazinyl or pyrimidinyl.

4. The compound of claim 1 , wherein A is

X is CH or CR 6 ;

R 1 , R 2 and R 3 are hydrogen;

R 4 is hydrogen or C 1-6 alkyl;

R 5 and R 6 are independently halo, or a C 1-6 alkyl unsubstituted or substituted with halo;

R 7 is halo, cyano, C 1-6 alkyl, NR 8 R 9 , -L-C(O)R 10 , -L-C(O)OR 10 or -L-S(O) 2 R 10 wherein L is a single bond;

R 8 and R 9 are independently hydrogen or C 1-6 alkyl; or alternatively, R 8 and R 9 together with the nitrogen atom to which they are attached form pyrrolidinyl, 2-oxopyrrolidinyl or piperidinyl;

R 10 is C 1-6 alkyl;

R 11 and R 12 are independently hydrogen, halo or C 1-6 alkyl; and

n and q are independently 0 or 1.

5. The compound of claim 1 , wherein said compound is of Formula (2):

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein said compound is of Formula (2A):

or a pharmaceutically acceptable salt thereof, wherein:

X is CH or CR 6 ;

R 1 , R 2 and R 3 are hydrogen;

R 5 and R 6 are independently halo, or a C 1-6 alkyl unsubstituted or substituted with halo;

q is 0;

R 7 is halo, cyano, C 1-6 alkyl, NR 8 R 9 , -L-C(O)R 10 , -L-C(O)OR 10 or -L-S(O) 2 R 10 wherein L is a single bond;

R 8 and R 9 are independently hydrogen or C 1-6 alkyl; or alternatively, R 8 and R 9 together with the nitrogen atom to which they are attached form pyrrolidinyl, 2-oxopyrrolidinyl or piperidinyl;

R 10 is C 1-6 alkyl;

R 11 is hydrogen, halo or methyl; and

R 12 is hydrogen or methyl.

7. The compound of claim 1 , wherein X is CH or CR 6 ; and R 6 is halo, methyl or trifluoromethyl.

8. The compound of claim 1 , wherein said compound is selected from:

wherein said compound is selected from:

a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 8 and a pharmaceutically acceptable carrier.

11. A combination comprising a therapeutically effective amount of a compound of claim 1 and a chemotherapeutic agent.

12. A combination comprising a therapeutically effective amount of a compound of claim 8 and a chemotherapeutic agent.

13. A method for inhibiting Wnt signaling in a cell, comprising contacting the cell with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

14. A method for inhibiting a porcupine gene in a cell, comprising contacting the cell with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

15. A process for the production of a compound of Formula (2A),

comprising reacting a compound of Formula (5)

 with a compound of Formula (6)

wherein X is CH or CR 6 ;

Z is 5-6 membered heteroaryl containing 1-2 nitrogen atoms, wherein said heteroaryl is unsubstituted or substituted by 1-2 R 7 groups;

R 1 , R 2 and R 3 are hydrogen;

R 5 and R 6 are independently halo, or a C 1-6 alkyl unsubstituted or substituted by halo;

q is 0;

R 7 is halo, cyano, C 1-6 alkyl, NR 8 R 9 , -L-C(O)R 10 , -L-C(O)OR 10 or -L-S(O) 2 R 10 wherein L is a single bond;

R 8 and R 9 are independently hydrogen or C 1-6 alkyl; or alternatively, R 8 and R 9 together with the nitrogen atom to which they are attached form pyrrolidinyl, 2-oxopyrrolidinyl or piperidinyl;

R 10 is C 1-6 alkyl;

R 11 is hydrogen, halo or methyl; and

R 12 is hydrogen or methyl;

Q is an organic acid or inorganic acid; and

recovering the compound of Formula (2A) or a pharmaceutically acceptable salt thereof, and (i) optionally converting the compound of Formula (2A) into a pharmaceutically acceptable salt thereof, or (ii) optionally converting the pharmaceutically acceptable salt of the compound of formula (2A) into another pharmaceutically acceptable salt.