PAK1 inhibitors and uses thereof

1. A method of treating acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in a subject, the method comprising administering to the subject a compound of Formula I, II, III or IV in an amount effective to inhibit p21 protein (Cdc42/Rac)-activated kinase (PAK1) in a subject, wherein Formula I has the structure:

wherein R 1 , R 2 , R 3 and R 4 of Formula I are independently H, halogen, —OH, —NH 2 , C1-C6 alkyl, —OCH 3 , —COCH 3 , 5- or 6-membered cyclic or heterocyclic, 5- or 6-membered aryl or heteroaryl, wherein the heteroaryl or heterocyclic contains one or more of the same or different heteroatom, or optionally substituted phenyl or benzyl, wherein the phenyl or benzyl is optionally substituted with one or more of halogen, —OH, —NH 2 , —CH 3 , or —OCH 3 ;

wherein R 5 , R 6 , R 7 , R 8 and R 9 of Formula I are independently H, halogen, —OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , C1-C6 alkyl, —OCH 3 , —SH, —OCH 3 , —SCH 3 , 5- or 6-membered cyclic or heterocyclic, or 5- or 6-membered aryl or heteroaryl, wherein the heteroaryl or heterocyclic contains one or more of the same or different heteroatom, or optionally substituted phenyl or benzyl, wherein the phenyl or benzyl is optionally substituted with one or more of halogen, —OH, —NH 2 , —CH 3 , or —OCH 3 ;

wherein A is a heteroaryl or heterocyclic containing one or more of the same or different heteroatom, or

where ( ) represents the point of attachment to the molecular scaffold;

wherein R 10 , R 11 , R 12 , R 13 and R 14 of Formula I are independently H, halogen, —OH, —NH 2 , C1-C6 alkyl, —OCH 3 , —COCH 3 , 5- or 6-membered cyclic or heterocyclic, or 5- or 6-membered aryl or heteroaryl, wherein the heteroaryl or heterocyclic contains one or more of the same or different heteroatom, and/or R 10 and R 11 , or R 11 and R 12 , or R 12 and R 13 , or R 13 and R 14 of Formula I together form a 5- or 6-membered hetrocyclic or heteroaryl containing one or more of the same or different heteroatom;

or a pharmaceutically acceptable salt thereof;

wherein Formula II has the structure:

wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 of Formula II are independently H, halogen, —OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , C1-C6 alkyl, —OCH 3 , —COCH 3 , —SH, or —SCH 3 ,

or a pharmaceutically acceptable salt thereof;

wherein Formula III has the structure:

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 of Formula III are independently H, halogen, —OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , C1-C6 alkyl, —OCH 3 , —COCH 3 , —SH, or —SCH 3 ,

or a pharmaceutically acceptable salt thereof; and

wherein Formula IV has the structure:

wherein A1 and A2 of Formula IV are independently

where ( ) represents the point of attachment to the molecular scaffold;

wherein X 1 , X 2 , X 3 , X 4 , X 5 and X 7 of Formula IV are independently CH or N;

wherein X 6 of Formula IV is CH, N or

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 of Formula IV are independently H, halogen, —OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , C1-C6 alkyl, —OCH 3 , —COCH 3 , —SH, or —SCH 3 ;

wherein A3 of Formula IV is O or N, and when A3 is N, R 6 is a C2 alkyl that bonds to the N of A3;

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein one or both of R 2 and R 6 of Formula I is halogen.

3. The method of claim 1 , wherein one or more of R 1 , R 4 , R 10 and R 14 of Formula I is —CH 3 .

4. The method of claim 1 , wherein R 7 of Formula I is —OH, —OCH 3 , —N(CH 3 ) 2 or —SCH 3 .

5. The method of claim 1 , wherein R 6 or R 7 of Formula I is —OCH 3 .

6. The method of claim 1 , wherein A of Formula I is a pyridine, pyrimidine or pyrazine.

7. The method of claim 1 , wherein the compound of Formula I has the formula

wherein R 1 , R 2 , R 3 and R 4 are independently H, halogen, —OH, —NH 2 , —CH 3 or —OCH 3 ;

wherein R 5 , R 6 , R 7 , R 8 and R 9 are independently H, halogen, —OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —CH 3 , —OCH 3 , —SH or —SCH 3 ,

wherein R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently H, halogen, —OH, —NH 2 , —CH 3 or —OCH 3 ,

wherein any X is independently CH 2 , NH, O or S, or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein in the compound of Formula IV, X 1 , X 2 , X 3 and X 4 are CH; or

X 1 is N, and X 2 , X 3 and X 4 are CH; or

X 2 is N, and X 1 , X 3 and X 4 are CH; or

X 1 and X 3 are N, and X 2 and X 4 are CH; or

X 5 is N, and X 6 and X 7 are CH; or

X 5 and X 7 are N, and X 6 is CH; or

X 6 is N, and X 5 and X 7 are CH; or

X 5 is N, X 7 is CH, and X 6 is

9. The method of claim 1 , wherein the compound of Formula IV has the formula

or a pharmaceutically acceptable salt thereof.

10. The method of claim 1 , wherein any halogen is independently Br, Cl or I.

11. The method of claim 1 , wherein any C1-C6 alkyl is independently —CH 3 or —CH 2 CH 3 .

12. The method of claim 1 , wherein the compound of Formula I is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein the compound of Formula II has the structure

or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 , wherein the compound of Formula III has the structure

or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 , wherein the compound of Formula IV has the structure

or a pharmaceutically acceptable salt thereof.

16. The method of claim 1 , wherein the compound causes only

0-5% reduction in the activity of PAK2, PAK3, PAK4, PAK5, PAK6 or PAK7 at the same dose that is used to inhibit PAK1; or

only 0-10% reduction in the activity of PAK2, PAK3, PAK4, PAK5, PAK6 or PAK7 at the same dose that is used to inhibit PAK1;

or 0-15% reduction in the activity of PAK2, PAK3, PAK4, PAK5, PAK6 or PAK7 at the same dose that is used to inhibit PAK1;

or 0-30% reduction in the activity of PAK2, PAK3, PAK4, PAK5, PAK6 or PAK7 at the same dose that is used to inhibit PAK1.

17. The method of claim 1 , wherein the compound

reduces proliferation of AML or MDS cells; and/or

induces apoptosis in AML or MDS cells; and/or

reduces colony formation of AML or MDS cells; and/or

is effective to increase survival of the subject compared to untreated controls.

18. A method of inhibiting PAK1 in a subject, the method comprising administering to the subject a compound of Formula I, II, III or IV in an amount effective to inhibit PAK1 in a subject,

wherein Formula I has the structure:

wherein R 1 , R 2 , R 3 and R 4 of Formula I are independently H, halogen, —OH, —NH 2 , C1-C6 alkyl, —OCH 3 , —COCH 3 , 5- or 6-membered cyclic or heterocyclic, 5- or 6-membered aryl or heteroaryl, wherein the heteroaryl or heterocyclic contains one or more of the same or different heteroatom, or optionally substituted phenyl or benzyl, wherein the phenyl or benzyl is optionally substituted with one or more of halogen, —OH, —NH 2 , —CH 3 , or —OCH 3 ;

wherein R 5 , R 6 , R 7 , R 8 and R 9 of Formula I are independently H, halogen, —OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , C1-C6 alkyl, —OCH 3 , —SH, —COCH 3 , —SCH 3 , 5- or 6-membered cyclic or heterocyclic, 5- or 6-membered aryl or heteroaryl, wherein the heteroaryl or heterocyclic contains one or more of the same or different heteroatom, or optionally substituted phenyl or benzyl, wherein the phenyl or benzyl is optionally substituted with one or more of halogen, —OH, —NH 2 , —CH 3 , or —OCH 3 ;

wherein A is a heteroaryl or heterocyclic containing one or more of the same or different heteroatom, or

where ( ) represents the point of attachment to the molecular scaffold;

wherein R 10 , R 11 , R 12 , R 13 and R 14 of Formula I are independently H, halogen, —OH, —NH 2 , C1-C6 alkyl, —OCH 3 , —COCH 3 , and/or R 10 and R 11 , or R 11 and R 12 , or R 12 and R 13 , or R 13 and R 14 of Formula I together form a 5- or 6-membered hetrocyclic or heteroaryl containing one or more of the same or different heteroatom;

or a pharmaceutically acceptable salt thereof;

wherein Formula II has the structure:

wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 of Formula II are independently H, halogen, —OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , C1-C6 alkyl, —OCH 3 , —COCH 3 —SH, or —SCH 3 ,

or a pharmaceutically acceptable salt thereof;

wherein Formula III has the structure:

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 of Formula III are independently H, halogen, —OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , C1-C6 alkyl, —OCH 3 , —COCH 3 , —SH, or —SCH 3 ,

or a pharmaceutically acceptable salt thereof; and

wherein Formula IV has the structure:

wherein A1 and A2 of Formula IV are independently

wherein X 1 , X 2 , X 3 , X 4 , X 5 and X 7 of Formula IV are independently CH or N;

wherein X 6 of Formula IV is CH, N or

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 of Formula IV are independently H, halogen, —OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , C1-C6 alkyl, —OCH 3 , —COCH 3 , —SH, or —SCH 3 ;

wherein A3 of Formula IV is O or N, and when A3 is N, R 6 is a C2 alkyl that bonds to the N of A3;

or a pharmaceutically acceptable salt thereof.

19. The method of claim 18 , wherein the subject has elevated expression of PAK1 and/or increased PAK1 activity.

20. A compound having the structure

or a pharmaceutically acceptable salt thereof.

21. The method of claim 18 , wherein one or both of R 2 and R 6 of Formula I is halogen.

22. The method of claim 18 , wherein one or more of R 1 , R 4 , R 10 and R 14 of Formula I is —CH 3 .

23. The method of claim 18 , wherein R 7 of Formula I is —OH, —OCH 3 , —N(CH 3 ) 2 or —SCH 3 .

24. The method of claim 18 , wherein R 6 or R 7 of Formula I is —OCH 3 .

25. The method of claim 18 , wherein A of Formula I is a pyridine, pyrimidine or pyrazine.

26. The method of claim 18 , wherein the compound of Formula I has the formula

wherein R 1 , R 2 , R 3 and R 4 are independently H, halogen, —OH, —NH 2 , —CH 3 or —OCH 3 ;

wherein R 5 , R 6 , R 7 , R 8 and R 9 are independently H, halogen, —OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —CH 3 , —OCH 3 , —SH or —SCH 3 ,

wherein R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are independently H, halogen, —OH, —NH 2 , —CH 3 or —OCH 3 ,

wherein any X is independently CH 2 , NH, O or S, or a pharmaceutically acceptable salt thereof.

27. The method of claim 18 , wherein in the compound of Formula IV, X 1 , X 2 , X 3 and X 4 are CH; or

X 1 is N, and X 2 , X 3 and X 4 are CH; or

X 2 is N, and X 1 , X 3 and X 4 are CH; or

X 1 and X 3 are N, and X 2 and X 4 are CH; or

X 5 is N, and X 6 and X 7 are CH; or

X 5 and X 7 are N, and X 6 is CH; or

X 6 is N, and X 5 and X 7 are CH; or

X 5 is N, X 7 is CH, and X 6 is

28. The method of claim 18 , wherein the compound of Formula IV has the formula

or a pharmaceutically acceptable salt thereof.

29. The method of claim 18 , wherein any halogen is independently Br, Cl or I.

30. The method of claim 18 , wherein any C1-C6 alkyl is independently —CH 3 or —CH 2 CH 3 .

31. The method of claim 18 , wherein the compound of Formula I is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

32. The method of claim 18 , wherein the compound of Formula II has the structure

or a pharmaceutically acceptable salt thereof.

33. The method of claim 18 , wherein the compound of Formula III has the structure

or a pharmaceutically acceptable salt thereof.

34. The method of claim 18 , wherein the compound of Formula IV has the structure

or a pharmaceutically acceptable salt thereof.