Compounds for treatment of cancer

1. A method for treating cancer characterized by expression of an R-spondin fusion in a subject that has been diagnosed as having an R-spondin fusion and has been diagnosed with the cancer being treated, comprising:

administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein

X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are independently —CR 4 or N;

X 8 is —CR 4 ;

Y 1 is hydrogen or —C(R 4 ) 3 ;

Y 2 and Y 3 are independently hydrogen, halogen or —C(R 3 ) 3 where each R 3 is same or different;

R 1 is hydrogen, halogen, C 1-6 alkyl, quinolinyl,

C 6-30 aryl, 3 to 6 membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O and S, or 5 or 6 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, wherein each of quinolinyl,

C 6-30 aryl, 3 to 6 membered heterocycloalkyl, and 5 or 6 membered heteroaryl can be optionally substituted with one or two, and same or different R 4 ;

R 2 is halogen, C 1-6 alkyl, quinolinyl,

C 6-30 aryl, 3 to 6 membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O and S, or 5 or 6 membered heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, wherein each of quinolinyl,

C 6-30 aryl, 3 to 6 membered heterocycloalkyl, and 5 or 6 membered heteroaryl can be optionally substituted with one or two, and same or different R 4 ;

each R 3 is independently hydrogen, halogen, cyano, C 1-6 alkyl, or C 1-6 alkoxy, wherein each of the C 1-6 alkyl, and C 1-6 alkoxy can be optionally substituted with halo, amino, hydroxyl, alkoxy, C 1-6 alkoxy or cyano;

each R 4 is independently hydrogen, halogen, oxide, C 1-6 alkoxy, —S(O) 2 R 5 , —C(O)OR 5 , —C(O)R 5 , —C(O)NR 6 R 7 , C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein each of C 1-6 alkoxy, —S(O) 2 R 5 , —C(O)OR 5 , —C(O)R 5 , —C(O)NR 6 R 7 , C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl can be optionally substituted with halo, amino, hydroxyl, C 1-6 alkoxy or cyano;

R 5 , R 6 and R 7 are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, in which each of the C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl can be optionally substituted with halo, amino, hydroxyl, C 1-6 alkoxy or cyano;

wherein the core structure defined by X 5 , X 6 , X 7 and X 8 is:

2. The method of claim 1 , wherein said 5 or 6 membered heteroaryl is:

wherein,

R 4 is hydrogen, halogen, C 1-6 alkoxy, —S(O) 2 R 5 , —C(O)OR 5 , —C(O)R 5 , —C(O)NR 6 R 7 , C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, each of which can be optionally substituted with halo, amino, hydroxyl, alkoxy or cyano;

R 5 , R 6 and R 7 are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, each of which may be optionally substituted with halo, amino, hydroxyl, alkoxy or cyano; and

R 8 is hydrogen or C 1-6 alkyl.

3. The method of claim 1 , wherein R 1 and R 2 is independently substituted with 1 or 2 R 4 groups.

4. The method of claim 1 , wherein an atom in any said substituent groups is H, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 35 S, 18 F, 36 Cl, or 123 I.

5. A method for treating cancer characterized by expression of an R-spondin fusion in a subject that has been diagnosed as having an R-spondin fusion and has been diagnosed with the cancer being treated, comprising:

administering to the subject a compound, having a structure:

6. The method of claim 1 , wherein said pharmaceutical composition is for topical application and is an aqueous solution, an ointment, a cream or a gel.

7. The method of claim 1 , wherein the therapeutically effective amount of the compound is about 0.03 to 2.5 mg/kg of body weight at daily dosages.

8. The method of claim 7 , wherein the therapeutically effective amount of the compound is about 0.5 mg to about 100 mg for human.

9. The method of claim 1 , wherein said pharmaceutical composition is administrated enterally, orally, parenterally, topically or in a nasal or suppository form.

10. The method of claim 1 , wherein said R-spondin fusion comprises a gene fusion between PTPRK and Rspo3 genes.

11. The method of claim 10 , wherein said R-spondin fusion results in expression of R-spondin gene driven by a promoter of said PTPRK gene.

12. The method of claim 10 , wherein said R-spondin fusion comprises a gene fusion between PTPRK exon 1 and Rspo3 exon 2, or between PTPRK exon7 and Rspo3 exon 2.

13. The method of claim 1 , wherein said R-spondin fusion comprises a gene fusion between EIF3E and Rspo3 genes.

14. The method of claim 13 , wherein said R-spondin fusion results in expression of R-spondin gene driven by a promoter of said EIF3E gene.

15. The method of claim 10 , wherein said R-spondin fusion comprises a gene fusion between EIF3E exon 1 and Rspo2 exon 2 or between EIF3E exon 1 and Rspo2 exon 3.

16. The method of claim 1 , wherein said cancer is colorectal cancer, gastric cancer, liver cancer, or esophageal cancer.

17. The method of claim 1 , wherein the ring in Formula I defined by X 1 , X 2 , X 3 and X 4 is:

18. The method of claim 1 , wherein R 1 and R 2 are independently hydrogen, fluorine, chlorine, methyl,

phenyl, morpholinyl, piperazinyl, or the 5 or 6 membered heteroaryl selected from:

19. The method of claim 1 , wherein the core structure defined by X 5 , X 6 , X 7 and X 8 is:

20. A method for treating cancer characterized by expression of an R-spondin fusion in a subject that has been diagnosed as having an R-spondin fusion and has been diagnosed with the cancer being treated, comprising:

administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound, having the structure of Formula I:

or a pharmaceutically acceptable salt thereof, wherein

X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and X 7 are independently CR 4 or N;

X 8 is CR 4 ;

Y 1 is hydrogen or —C(R 4 ) 3 , each R 4 is same or different;

Y 2 and Y 3 are independently hydrogen, halogen or —C(R 3 ) 3 , each R 3 is same or different;

R 1 is hydrogen, halogen, C 1-6 alkyl, quinolinyl,

C 6-30 aryl, 3 to 6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S, or 5 or 6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein each of quinolinyl,

C 6-30 aryl, 3 to 6 membered heterocycloalkyl, and 5 or 6 membered heteroaryl can be optionally substituted with one or two, and same or different R 4 ;

R 2 is hydrogen, halogen, C 1-6 alkyl, quinolinyl,

3 to 6 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O and S, or 5 or 6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, wherein each of quinolinyl,

3 to 6 membered heterocycloalkyl, and 5 or 6 membered heteroaryl can be optionally substituted with one or two, and same or different R 4 ;

each R 3 is independently hydrogen, halogen, cyano, C 1-6 alkyl, or C 1-6 alkoxy, wherein each of the C 1-6 alkyl and C 1-6 alkoxy can be optionally substituted with halo, amino, hydroxyl, C 1-6 alkoxy or cyano; and

each R 4 is independently hydrogen, halogen, oxide, C 1-6 alkoxy, —S(O) 2 R 5 , —C(O)OR 5 , —C(O)R 5 , —C(O)NR 6 R 7 , C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein each of C 1-6 alkoxy, —S(O) 2 R 5 , —C(O)OR 5 , —C(O)R 5 , —C(O)NR 6 R 7 , C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl can be optionally substituted with halo, amino, hydroxyl, C 1-6 alkoxy or cyano;

R 5 , R 6 and R 7 are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein each of the C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl can be optionally substituted with halo, amino, hydroxyl, C 1-6 alkoxy or cyano; and

wherein the core structure of Formula I defined by X 5 , X 6 , X 7 and X 8 is

21. The method of claim 20 , wherein said 5 or 6 membered heteroaryl is:

wherein,

R 4 is hydrogen, halogen, C 1-6 alkoxy, —S(O) 2 R 5 , —C(O)OR 5 , —C(O)R 5 , —C(O)NR 6 R 7 , C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, each of which can be optionally substituted with halo, amino, hydroxyl, alkoxy or cyano;

R 5 , R 6 and R 7 are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, each of which may be optionally substituted with halo, amino, hydroxyl, alkoxy or cyano; and

R 8 is hydrogen or C 1-6 alkyl.

22. The method of claim 20 , wherein R 1 and R 2 is independently substituted with 1 or 2 R 4 groups.

23. The method of claim 20 , wherein an atom in any said substituent groups is H, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 35 S, 18 F, 36 Cl, or 123 I.

24. The method of claim 20 , wherein said pharmaceutical composition is for topical application and is an aqueous solution, an ointment, a cream or a gel.

25. The method of claim 20 , wherein the therapeutically effective amount of the compound is about 0.03 to about 2.5 mg/kg of body weight at daily dosage.

26. The method of claim 25 , wherein the therapeutically effective amount of the compound is about 0.5 mg to about 100 mg for human.

27. The method of claim 20 , wherein said pharmaceutical composition is administrated enterally, orally, parenterally, topically or in a nasal or suppository form.

28. The method of claim 20 , wherein said R-spondin fusion comprises a gene fusion between PTPRK and Rspo3 genes.

29. The method of claim 28 , wherein said R-spondin fusion results in expression of R-spondin gene driven by a promoter of said PTPRK gene.

30. The method of claim 28 , wherein said R-spondin fusion comprises a gene fusion between PTPRK exon 1 and Rspo3 exon 2, or between PTPRK exon7 and Rspo3 exon 2.

31. The method of claim 20 , wherein said R-spondin fusion comprises a gene fusion between EIF3E and Rspo3 genes.

32. The method of claim 31 , wherein said R-spondin fusion results in expression of R-spondin gene driven by a promoter of said EIF3E gene.

33. The method of claim 28 , wherein said R-spondin fusion comprises a gene fusion between EIF3E exon 1 and Rspo2 exon 2 or between EIF3E exon 1 and Rspo2 exon 3.

34. The method of claim 20 , wherein said cancer is colorectal cancer, gastric cancer, liver cancer, or esophageal cancer.

35. The method of claim 20 , wherein the ring in Formula I defined by X 1 , X 2 , X 3 and X 4 is:

36. The method of claim 20 , wherein R 1 and R 2 are independently hydrogen, fluorine, chlorine, methyl,

phenyl, morpholinyl, piperazinyl, or the 5 or 6 membered heteroaryl selected from: