Heterocyclic inhibitors of PTPN11

Patent metadata

Field	Value
Publication number	US-11466017-B2
Application number	US-202016989211-A
Country	US
Kind code	B2
Filing date	Aug 10, 2020
Priority date	Mar 10, 2011
Publication date	Oct 11, 2022
Grant date	Oct 11, 2022

Abstract

The present invention relates to compounds which may be useful as inhibitors of PTPN11 for the treatment or prevention of cancer and other PTP-mediated diseases. Disclosed herein are new compounds and compounds based on pyrazolopyrazines and their application as pharmaceuticals for the treatment of disease.

First claim

What is claimed is:

1. A compound of structural Formula I:

or a salt or tautomer thereof, wherein:
a is selected from 0 and 1;
b is selected from 0 and 1;
R 1 is selected from halo, C 6-10 aryl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms or groups independently selected from N, C(O), O, and S;
said aryl or heteroaryl of R 1 is optionally substituted with 1 to 5 R 12 groups independently selected from halo, hydroxy, amino, C 1-4 alkylamino, C 1-4 dialkylamino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 aminoalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, NR 15 C(O)R 13 , NR 15 C(O)OR 13 , NR 13 C(O)NR 15 R 16 , NR 15 S(O)R 13 , NR 15 S(O) 2 R 13 , C(O)NR 15 R 16 , S(O)NR 15 R 16 , S(O) 2 NR 15 R 16 , C(O)R 13 , C(O)OR 13 , SR 13 , S(O)R 13 , and S(O) 2 R 13 ;
R 2 , R 3 , R 10 , and R 11 are independently selected from hydrogen, C 1-4 alkyl, and C 3-8 cycloalkyl;
R 4 , R 5 , R 8 , and R 9 are independently selected from hydrogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, amino, hydroxy, C 3-8 cycloalkyl, halo, and C 1-4 alkylamino;
R 6 is selected from amino, C 1-4 aminoalkyl, and C 1-4 alkylamino;
R 7 is selected from hydrogen, cyano, amido, halo, and hydroxy, or is selected from C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl, and 5- or 6-membered heteroaryl, any of which is optionally substituted with one or more R 17 groups;
or R 6 and R 7 together with the carbon atom to which they are both attached form a 3- to 7-membered saturated or unsaturated ring that can contain 1 to 3 heteroatoms or groups independently selected from N, C(O), O, and S(O) m , and that is optionally substituted with one R 17 group, and that is optionally substituted with one or more R 18 groups;
m is selected from 0, 1, and 2;
any two groups selected from R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 and R 11 can form a 5- to 6-membered ring, optionally containing a N, O or S heteroatom;
any two groups selected from R 2 , R 4 , R 6 , R 8 and R 10 can form a direct bond, or a 1 or 2 atom carbon bridge;
R 13 , R 15 , and R 16 are independently selected from hydrogen, C 1-4 alkyl, and C 3-8 cycloakyl, wherein said alkyl or cycloalkyl is optionally substituted by one or more substituents selected from hydroxy, cyano and halo; and
each R 17 and R 18 is independently selected from amino, halo, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C 1-4 alkyl, and C 1-4 alkoxy.

2. The compound as recited in claim 1 wherein:
R 1 is selected from C 6-10 aryl and a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms or groups independently selected from N, C(O), O, and S;
said aryl or heteroaryl of R 1 is optionally substituted with 1 to 5 R 12 groups independently selected from halo, hydroxy, amino, C 1-4 alkylamino, C 1-4 dialkylamino, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 1-4 aminoalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, NR 15 C(O)R 13 , NR 15 C(O)OR 13 , NR 13 C(O)NR 15 R 16 , NR 15 S(O)R 13 , NR 15 S(O) 2 R 13 , C(O)NR 15 R 16 , S(O)NR 15 R 16 , S(O) 2 NR 15 R 16 , C(O)R 13 , C(O)OR 13 , SR 13 , S(O)R 13 , and S(O) 2 R 13 ; and
R 13 , R 15 , and R 16 are independently selected from hydrogen, C 1-4 alkyl, and C 3-8 cycloakyl, wherein said alkyl or cycloalkyl is optionally substituted by one or more substituents selected from hydroxy, cyano and halo.

3. The compound as recited in claim 2 wherein:
R 1 is selected from C 6-10 aryl and a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms or groups independently selected from N, C(O), O, and S;
said aryl or heteroaryl of R 1 is optionally substituted with 1 to 5 R 12 groups independently selected from halo, hydroxy, amino, C 1-4 alkylamino, C 1-4 dialkylamino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 aminoalkyl; and
R 17 is selected from amino, halo, and hydroxy.

4. The compound as recited in claim 2 wherein:
R 1 is C 6-10 aryl or a 5- to 9-membered heteroaryl group containing 1 to 4 heteroatoms or groups independently selected from N, C(O), O, and S;
said aryl or heteroaryl of R 1 is optionally substituted with 1 to 5 R 12 groups independently selected from the group consisting of halo, hydroxy, amino, C 1-4 alkylamino, C 1-4 dialkylamino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 aminoalkyl; and
R 6 is amino, C 1-4 aminoalkyl, or C 1-4 alkylamino; and
R 7 is hydrogen, cyano, amido, halo, hydroxy, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more R 17 groups.

5. The compound as recited in claim 1 wherein R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 and R 11 are hydrogen.

6. The compound as recited in claim 1 , wherein R 6 and R 7 together with the carbon atom to which they are both attached forms a 3- to 7-membered saturated or unsaturated ring that can contain 1 to 3 heteroatoms or groups independently selected from N, C(O), O, and S(O) m , and that is optionally substituted with one R 17 group, and that is optionally substituted with one or more R 18 groups.

7. The compound as recited in claim 1 , wherein R 6 and R 7 together with the carbon atom to which they are both attached forms a 3- to 7-membered cycloalkyl ring that is optionally substituted with one R 17 group, and that is optionally substituted with one or more R 18 groups.

8. The compound as recited in claim 1 , wherein R 6 and R 7 together with the carbon atom to which they are both attached form a 3- to 6-membered heterocycloalkyl ring that is optionally substituted with one R 17 group, and that is optionally substituted with one or more R 18 groups.

9. The compound as recited in claim 1 , wherein
R 1 is selected from C 6-10 aryl and a 5-9 membered heteroaryl group containing 1 to 4 heteroatoms or groups independently selected from N, C(O), O, and S;
said aryl or heteroaryl of R 1 is optionally substituted with 1 to 5 R 12 groups independently selected from halo, hydroxy, alkoxy, amino, C 1-4 alkylamino, C 1-4 dialkylamino, cyano, C 1-4 alkyl.

10. The compound as recited in claim 1 , wherein R 1 is selected from:

and
each R 12 is independently selected from halo, hydroxy, amino, methylamino, dimethylamino, cyano, C 1-4 alkyl, and C 1-4 alkoxy.

11. The compound as recited in claim 1 , wherein R 1 is selected from pyridyl, piperazinyl, pyrimidinyl, pyrazolyl, and pyridazinyl.

12. The compound as recited in claim 1 , wherein R 1 is pyridyl.

13. The compound as recited in claim 1 , wherein the structure is selected from:

14. The compound as recited in claim 13 , wherein
R 6 is selected from amino, C 1-4 aminoalkyl, and C 1-4 alkylamino;
R 7 is selected from hydrogen, cyano, amido, halo, and hydroxy, or is selected from C 1-4 alkyl, and C 1-4 hydroxyalkyl, any of which is optionally substituted with one or more R 17 groups; and
each R 17 is independently selected from amino, halo, and hydroxy.

15. The compound as recited in claim 1 wherein the structure is selected from:

Assignees

• Univ Texas

Inventors

• Jones Philip
• Czako Barbara
• Cross Jason
• Leonard Paul
• Mseeh Faika
• Parker Connor

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/501

  not condensed and containing further heterocyclic rings · CPC title