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1. WO2020163598 - INHIBITEURS DÉPENDANTS D'IMMUOPHILINE ET LEURS UTILISATIONS

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

WHAT IS CLAIMED IS:

1. A compound having the formula:

A-L1-R1;

wherein

A is an immunophilin-binding moiety;

L1 is a bond or a covalent linker; and

R1 is a kinase inhibitor, a pseudokinase inhibitor, a GTPase inhibitor, a histone-modifying enzyme inhibitor, or a monovalent anti-viral agent; wherein the compound is not

2. The compound of claim 1, wherein R1 is not a monovalent human immunodeficiency (HIV) protease inhibitor or an amyloid β aggregation inhibitor.

3. The compound of claim 1, wherein the immunophilin-binding moiety is a cyclophilin-binding moiety or an FKBP-binding moiety.

4. The compound of claim 1, wherein the immunophilin-binding moiety is



or an analog thereof.

5. The compound of claim 1, wherein the immunophilin-binding moiety is

or an
analog thereof.

6. The compound of claim 1, wherein L1 is L2-L3-L4-L5-L6;

L2 is connected directly to the moiety of an immunophilin-binding compound;

L2 is a bond, -S(O)2-, -N(R2)-, -O-, -S-, -C(O)-, -C(O)N(R2)-, -N(R2)C(O)-, -N(R2)C(O)NH-, -NHC(O)N(R2)-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

L3 is a bond, -S(O)2-, -N(R3)-, -O-, -S-, -C(O)-, -C(O)N(R3)-, -N(R3)C(O)-, -N(R3)C(O)NH-, -NHC(O)N(R3)-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

L4 is a bond, -S(O)2-, -N(R4)-, -O-, -S-, -C(O)-, -C(O)N(R4)-, -N(R4)C(O)-, -N(R4)C(O)NH-, -NHC(O)N(R4)-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

L5 is a

bond, -S(O)2-, -N(R5)-, -O-, -S-, -C(O)-, -C(O)N(R5)-, -N(R5)C(O)-, -N(R5)C(O)NH-, -NHC( O)N(R5)-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and

L6 is a

bond, -S(O)2-, -N(R6)-, -O-, -S-, -C(O)-, -C(O)N(R6)-, -N(R6)C(O)-, -N(R6)C(O)NH-, -NHC( O)N(R6)-, -C(O)O-, -OC(O)-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and

R2, R3, R4, R5, and R6 are independently hydrogen,

halogen, -CCl3, -CBr3, -CF3, -CI3,

-CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -SO4H, -SO2NH2, ‒NHNH2, ‒ONH2, ‒NHC(O)NHNH2, ‒NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OC

I3,

-OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

7. The compound of claim 6, wherein L3, L4, L5, and L6 are a bond.

8. The compound of claim 6, wherein L2 is a substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene;

L3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene;

L4 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

L5 is a bond; and

L6 is a bond.

9. The compound of claim 6, wherein L2 is an unsubstituted C3-C7 alkylene, an oxo-substituted C3-C7 alkylene, an unsubstituted 3 to 17 membered heteroalkylene, or an oxo-substituted 3 to 17 membered heteroalkylene;

L3 is a bond, an unsubstituted C3-C7 alkylene, an oxo-substituted C3-C7 alkylene, an unsubstituted 3 to 17 membered heteroalkylene, an oxo-substituted 3 to 17 membered heteroalkylene, or an unsubstituted 5 to 6 membered heterocycloalkylene, and

L4 is a bond, an unsubstituted C3-C7 alkylene, an oxo-substituted C3-C7 alkylene, an unsubstituted 3 to 17 membered heteroalkylene, or an oxo-substituted 3 to 17 membered heteroalkylene;

L5 is a bond; and

L6 is a bond.

10. The compound of claim 1, wherein L1 is a bond, an unsubstituted C3- C7 alkylene, an oxo- substituted C3-C7 alkylene, an unsubstituted 3 to 17 membered heteroalkylene, or an oxo-substituted 3 to 17 membered heteroalkylene.

11. The compound of claim 1, wherein L1 is

12. The compound of claim 1, wherein L1 is a bond.

13. The compound of claim 1, wherein L1 is a substituted or unsubstituted alkylene or substituted or unsubstituted heteroalkylene.

14. The compound of claim 1, wherein R1 is a monovalent kinase inhibitor.

15. The compound of claim 14, wherein the kinase is not mTOR.

16. The compound of claim 14, wherein the monovalent kinase inhibitor is a monovalent Src kinase inhibitor.

17. The compound of claim 14, wherein the monovalent Src kinase inhibitor is a monovalent dasatinib or monovalent dasatinib derivative.

18. The compound of claim 17, wherein the monovalent dasatinib derivative has the formula:


19. The compound of claim 14, wherein the monovalent kinase inhibitor is a monovalent Raf inhibitor, VEGFR inhibitor, PDGFR inhibitor, or c-Kit inhibitor.

20. The compound of claim 19, wherein the monovalent Raf inhibitor, VEGFR inhibitor, PDGFR inhibitor, or c-Kit inhibitor is a monovalent sorafenib or monovalent sorafenib derivative.

21. The compound of claim 20, wherein the monovalent sorafenib derivative has the formula:


22. The compound of claim 14, wherein the monovalent kinase inhibitor is a monovalent EGFR inhibitor.

23. The compound of claim 22, wherein the monovalent EGFR inhibitor is a monovalent lapatinib, monovalent lapatinib derivative, monovalent erlotinib, monovalent erlotinib derivative, monovalent gefitinib, or monovalent gefitinib derivative.

24. The compound of claim 23, wherein the monovalent EGFR inhibitor has the formula:

25. The compound of claim 14, wherein the monovalent kinase inhibitor is a monovalent LRRK2 inhibitor.

26. The compound of claim 25, wherein the monovalent LRRK2 inhibitor is a monovalent GNE-7915 or monovalent GNE-7915 derivative.

27. The compound of claim 26, wherein the monovalent GNE-7915 derivative has the formula:


28. The compound of claims 14, wherein the monovalent kinase inhibitor is a monovalent MAP4K inhibitor.

29. The compound of claim 28, wherein the monovalent MAP4K inhibitor is a monovalent HGK inhibitor.

30. The compound of claim 29, wherein the monovalent HGK inhibitor has the formula:


31. The compound of claims 14, wherein the monovalent kinase inhibitor is a monovalent MAP3K inhibitor.

32. The compound of claim 31, wherein the monovalent MAP3K inhibitor is a monovalent DLK inhibitor.

33. The compound of claim 32, wherein the monovalent DLK inhibitor has

the formula:


34. The compound of claim 1, wherein R1 is a monovalent KRAS inhibitor.

35. The compound of claim 34, wherein the monovalent KRAS inhibitor is a monovalent KRAS G12C inhibitor or a monovalent KRAS M72C inhibitor.

36. The compound of claim 35, wherein the monovalent KRAS inhibitor has the formula:

37. The compound of one of claims 1 to 36, wherein the compound is not a calcineurin inhibitor.

38. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of one of claims 1 to 36.

39. A method of treating a disease associated with aberrant enzyme activity in a subject in need of such treatment, comprising administering a compound of one of claims 1 to 36 to the subject.

40. The method of claim 39, wherein the enzyme activity is a kinase activity.

41. The method of claim 40, wherein the kinase activity is in the CNS of the subject.

42. A method of treating a disease in a subject in need of such treatment, comprising administering a compound of one of claims 1 to 36 to the subject, wherein the disease is a viral disease, cancer, or a neurodegenerative disease.

43. The method of claim 42, wherein the disease is cancer.

44. The method of claim 43, wherein the cancer is glioblastoma or glioma.

45. The method of claim 42, wherein the disease is a neurodegenerative disease.

46. The method of claim 45, wherein the neurodegenerative disease is

Parkinson’s Disease.

47. The method of claim 45, wherein the disease is Amyotrophic lateral sclerosis (ALS).

48. The method of claim 45, wherein the disease is Alzheimer’s disease.