Pak1 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-2020323855-A1
Application number	US-201716095709-A
Country	US
Kind code	A1
Filing date	Apr 3, 2017
Priority date	May 6, 2016
Publication date	Oct 15, 2020
Grant date	—

Abstract

Methods are disclosed for treating acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) using compounds that inhibit p21 protein (Cdc42/Rac)-activated kinase (PAK1).

First claim

1 . A method of treating acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or a tumor having elevated expression of H2.0-like homeobox (HLX) and/or elevated expression of p21 protein (Cdc42/Rac)-activated kinase (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 R1, R2, R3 and R4 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 R5, R6, R7, R8 and R9 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 R10, R11, R12, R13 and R14 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 R10 and R11, or R11 and R12, or R12 and R13, or R13 and R14 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 R1, R2, R3, R4, R5 and R6 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 R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 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 X1, X2, X3, X4, X5 and X7 of Formula IV are independently CH or N;
wherein X6 of Formula IV is CH, N or

wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15 and R16 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, R6 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 R2 and R6 of Formula I is halogen.

3 . The method of claim 1 , wherein one or more of R1, R4, R10 and R14 of Formula I is —CH 3 .

4 . The method of claim 1 , wherein R7 of Formula I is —OH, —OCH 3 , —N(CH 3 ) 2 or —SCH 3 .

5 . The method of claim 1 , wherein R6 or R7 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 R1, R2, R3 and R4 are independently H, halogen, —OH, —NH 2 , —CH 3 or —OCH 3 ;
wherein R5, R6, R7, R8 and R9 are independently H, halogen, —OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —CH 3 , —OCH 3 , —SH or —SCH 3 ,
wherein R10, R11, R12, R13, R14 and R15 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,
X1, X2, X3 and X4 are CH; or X1 is N, and X2, X3 and X4 are CH; or X2 is N, and X1, X3 and X4 are CH; or X1 and X3 are N, and X2 and X4 are CH; or X5 is N, and X6 and X7 are CH; or X5 and X7 are N, and X6 is CH; or X6 is N, and X5 and X7 are CH; or X5 is N, X7 is CH, and X6 is

9 - 15 . (canceled)

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

or a pharmaceutically acceptable salt thereof.

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

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

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

23 . The method of claim 1 , wherein the PAK1 inhibitor 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

Assignees

• Albert Einstein College Medicine Inc

Inventors

• Steidl Ulrich
• Eckel Ashley M
• Stanley Robert F
• Rogovoy Boris
• Okun Ilya

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/541

  Non-condensed thiazines containing further heterocyclic rings · CPC title

• A61K31/519 Primary

  ortho- or peri-condensed with heterocyclic rings · CPC title