Heterocyclic inhibitors of PTPN11

Patent metadata

Field	Value
Publication number	US-11840536-B2
Application number	US-202217876958-A
Country	US
Kind code	B2
Filing date	Jul 29, 2022
Priority date	May 31, 2016
Publication date	Dec 12, 2023
Grant date	Dec 12, 2023

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 pharmaceutically acceptable salt or tautomer thereof, wherein:
a is 1;
b is 1;
R 1 is phenyl or 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms or groups independently selected from N, C(O), O, and S;
said phenyl or heteroaryl of R 1 is 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, and C 1-4 aminoalkyl;
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 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 contains 1 to 3 heteroatoms or groups independently selected from N, C(O), O, and S(O) m , and said 3- to 7-membered saturated ring is optionally substituted with one R 17 group, and 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 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 8 and R 10 can form a direct bond, or a 1 or 2 atom carbon bridge; 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 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 and R 11 are each hydrogen.

3. 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 ring that contains 1 to 3 heteroatoms or groups independently selected from N, C(O), O, and S(O) m , and said 3- to 7-membered saturated ring is optionally substituted with one R 17 group, and is optionally substituted with one or more R 18 groups.

4. 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 saturated ring that contains a heteroatom of N or O, and said 3- to 6-membered saturated ring is substituted with one R 17 group and one or more R 18 groups.

5. 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 saturated ring that contains a heteroatom of O, and said 3- to 6-membered saturated ring is substituted with one R 17 group and one or more R 18 groups.

6. The compound as recited in claim 1 , wherein
R 1 is phenyl or 5- to 6-membered heteroaryl group containing 1 to 4 heteroatoms or groups independently selected from N, C(O), O, and S; and
said phenyl 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, and C 1-4 alkyl.

7. 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.

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

9. The compound as recited in claim 1 , wherein R 1 is phenyl.

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

or a pharmaceutically acceptable salt or tautomer thereof.

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

or an enantiomer of any one of the above structures,
or a pharmaceutically acceptable salt or tautomer of any one of the above structures,
or a pharmaceutically acceptable salt or tautomer of the enantiomer of any one of the above structures.

12. A pharmaceutical composition comprising a compound as recited in claim 1 together with a pharmaceutically acceptable carrier.

13. A method of inhibition of PTPN11 comprising contacting PTPN11 with a compound as recited in claim 1 .

14. A method of treatment of a PTPN11-mediated disease comprising the administration of a therapeutically effective amount of a compound of Formula I as recited in claim 1 to a patient in need thereof, wherein the patient has the PTPN11-mediated disease; and the PTPN11-mediated disease is a Noonan Syndrome, LEOPARD Syndrome, or cancer selected from the group consisting of breast cancer, colon cancer, lung cancer, leukemia, and melanoma.

15. The method as recited in claim 14 , wherein the PTPN11-mediated disease is cancer selected from the group consisting of breast cancer, colon cancer, lung cancer, leukemia, and melanoma.

16. The method as recited in claim 14 , wherein the PTPN11-mediated disease is Noonan Syndrome or LEOPARD Syndrome.

17. The method of claim 14 further comprising a second therapeutic agent.

18. The method of claim 14 , wherein the compound is selected from:

or a pharmaceutically acceptable salt or tautomer thereof.

Assignees

• Univ Texas

Inventors

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

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · 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

• A61P35/00

  Antineoplastic agents · CPC title

• 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