HSP70 modulators and methods for making and using the same

Patent metadata

Field	Value
Publication number	US-9878987-B2
Application number	US-201515310142-A
Country	US
Kind code	B2
Filing date	May 13, 2015
Priority date	May 13, 2014
Publication date	Jan 30, 2018
Grant date	Jan 30, 2018

Abstract

The present invention provides compounds I and II and compositions thereof for use in the modulation of Hsp70. In some embodiments, the present invention provides a method for inhibiting Hsp70 activity. In some embodiments, the present invention provides a method of treating a subject suffering from or susceptible to a disease, disorder, or condition responsive to Hsp70 inhibition comprising administering to the subject a therapeutically effective amount of a provided compound. In some embodiments, the present invention provides a method for treating or preventing cancer in a subject suffering therefrom, comprising administering to a patient in need thereof a therapeutically effective amount of a provided compound.

First claim

The invention claimed is:

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
X is N═ or CH═;
X 1 is —N═ or —C(R 5 )═;
R 1 is

R 1a is

or C 1-6 aliphatic optionally substituted with one or more groups independently selected from —OH, cyclopropyl, or 5-membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;
each R 1b is independently hydrogen, C 1-4 alkyl, or two R 1b groups are optionally taken together to form an oxo group;
each of R 1c and R 1d is independently hydrogen or C 1-4 alkyl;
R 2 is —O—CH 2 -Ring A, —NH—CH 2 -Ring A, or —O—CH 2 CH 2 -Ring A;
Ring A is unsubstituted phenyl, unsubstituted furanyl,

or pyridinyl optionally substituted with R A5 ;
each of R A1 is independently halogen, —CN, —C(O)N(R) 2 , —N(R) 2 , —OR, —C(O)R, —N 3 , an optionally substituted 5- or 6-membered heterocyclyl or heteroaryl having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, or C 1-4 alkyl optionally substituted with one or more halogen;
each R is independently hydrogen or C 1-4 alkyl optionally substituted with one or more halogen;
R A2 is —Cl, —Br, —I, —CN, —C(O)N(R) 2 , —N(R) 2 , —OR, —C(O)R, —N 3 , C 1-4 alkyl optionally substituted with one or more halogen, or an optionally substituted 5- or 6-membered heterocyclyl or heteroaryl having one or two heteroatoms independently selected from nitrogen, oxygen or sulfur;
n is 1 to 4;
R A3 is —H or —F;
R A4 is —F or —OR;
R A5 is —OR or —N(R) 2 ;
R 3 is —C(O)N(R 3a ) 2 , —OR 3b , —C(O)H, —C(O)OR, or —N(R 3c ) 2 ;
each R 3a is independently hydrogen or C 1 alkyl optionally substituted with one or more groups independently selected from halogen or 1-pyrrolidinyl;
R 3b is hydrogen or C 1-4 alkyl optionally substituted with one or more groups independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, oxo, or —N(R) 2 ;
each R 3c is independently hydrogen or C 1-4 alkyl optionally substituted with one or more groups independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, oxo, or —N(R) 2 ;
R 4 is R, halogen, or —N(R) 2 ; and
R 5 is hydrogen, methyl or —N(R) 2 .

2. The compound of claim 1 , wherein X is —N═.

3. The compound of claim 1 , wherein X is —CH═.

4. The compound of claim 1 , wherein R 3 is —C(O)NH 2 .

5. The compound of claim 1 , wherein R 3 is —N(R 3c ) 2 .

6. The compound of claim 1 , wherein R 4 is —CF 3 .

7. The compound of claim 1 , wherein R 4 is halogen.

8. The compound of claim 1 , wherein X 1 is —C(R 5 )═.

9. The compound of claim 1 , wherein X 1 is —N═.

10. A compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein:
Y is —S—, —O—, or —CR 2 —;
R 1 is

R 1a is

or C 1-6 aliphatic optionally substituted with one or more groups independently selected from —OH, cyclopropyl, or 5-membered heteroaryl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R 1b is independently hydrogen, C 1-4 alkyl, or two R 1b groups are optionally taken together to form an oxo group;
each of R 1c and R 1d is independently hydrogen or C 1-4 alkyl;
R 2 is —O—CH 2 -Ring A, —NH—CH 2 -Ring A, or —O—CH 2 CH 2 -Ring A;
Ring A is unsubstituted phenyl, unsubstituted furanyl,

or pyridinyl optionally substituted with R A5 ;
each of R A1 is independently halogen, —CN, —C(O)N(R) 2 , —N(R) 2 , —OR, —C(O)R, —N 3 , an optionally substituted 5- or 6-membered heterocyclyl or heteroaryl having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, or C 1-4 alkyl optionally substituted with one or more halogen;
each R is independently hydrogen or C 1-4 alkyl optionally substituted with one or more halogen;
R A2 is —Cl, —Br, —I, —CN, —C(O)N(R) 2 , —N(R) 2 , —OR, —C(O)R, —N 3 , C 1-4 alkyl optionally substituted with one or more halogen, or an optionally substituted 5- or 6-membered heterocyclyl or heteroaryl having one or two heteroatoms independently selected from nitrogen, oxygen or sulfur;
n is 1 to 4;
R A3 is —H or —F;
R A4 is —F or —OR;
R A5 is —OR or —N(R) 2 ; and
Ring B is

thienyl optionally substituted with —C(O)R, or furanyl optionally substituted with —C(O)R.

11. The compound of claim 1 , wherein R 1 is

12. The compound of claim 1 , wherein R 2 is —O—CH 2 -Ring A.

13. The compound of claim 1 , wherein Ring A is phenyl,

14. A compound selected from the group consisting of

Assignees

• Memorial Sloan Kettering Cancer Center

Inventors

• Chiosis Gabriela
• Kang Yanlong
• Patel Hardik J
• Patel Maulik
• Ochiana Stefan
• Rodina Anna
• Taldone Tony
• Shrestha Liza

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D239/42 Primary

  One nitrogen atom (nitro radicals C07D239/30) · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title