Processes for preparing ATR inhibitors

Patent metadata

Field	Value
Publication number	US-10822331-B2
Application number	US-201816233641-A
Country	US
Kind code	B2
Filing date	Dec 27, 2018
Priority date	Sep 30, 2011
Publication date	Nov 3, 2020
Grant date	Nov 3, 2020

Abstract

The present invention relates to processes and intermediates for preparing compounds useful as inhibitors of ATR kinase, such as aminopyrazine-isoxazole derivatives and related molecules. The present invention also relates to compounds useful as inhibitors of ATR protein kinase. The invention relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and solid forms of the compounds of this invention.
The compounds of this invention have formula I or II:

First claim

We claim:

1. A process for preparing a compound of formula I:

wherein
R 4 is

J 1 is H, halo, C 1-4 alkyl, or C 1-4 alkoxy;
Q is phenyl, pyridyl, or an N-alkylated pyridine;
J 2 is halo; CN; phenyl; oxazolyl; or a C 1 1-6 aliphatic group wherein up to 2 methylene units are optionally replaced with O, C(O), S, S(O), or S(O) 2 ; said C 1 1-6 aliphatic group is optionally substituted with 1-3 fluoro or CN;
q is 0, 1, or 2; and
R 3 is hydrogen, C 1-6 alkyl, or a 3-6 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur;
wherein the heterocyclyl is optionally substituted with 1 occurrence of halo or C 1-3 alkyl,
wherein the process comprises the step of preparing a compound of formula 4:

from a compound of formula 3:

under suitable oxime formation conditions;
wherein:
R 1 is C 1-6 alkyl;
R 2 is C 1-6 alkyl;
or R 1 and R 2 , together with the oxygen atoms to which they are attached, form an optionally substituted 5 or 6 membered saturated heterocyclic ring having two oxygen atoms;
R 3 is hydrogen, C 1-6 alkyl, or a 3-6 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur;
wherein the heterocyclyl is optionally substituted with 1 occurrence of halo or C 1-3 alkyl;

J 1 is H, halo, C 1-4 alkyl, or C 1-4 alkoxy; and
PG is a carbamate protecting group.

2. The process of claim 1 , further comprising the step of protecting a compound of formula 2:

under suitable protection conditions to form the compound of formula 3.

3. The process of claim 2 , further comprising the step of reacting a compound of formula 1:

with a suitable ligand under suitable reductive amination conditions to form the compound of formula 2.

4. The process of claim 3 , wherein the suitable ligand is an amine.

5. The process of claim 1 , comprising one or more of the following limitations:
a) R 1 is ethyl and R 2 ethyl;
b) R 3 is CH 3 or

and
c) J 1 is H.

6. The process of claim 1 , wherein R 4 is

wherein Q is phenyl, q is 1, and J 2 is a C 1-6 aliphatic group wherein up to 1 methylene unit is optionally replaced with —S(O) 2 —.

7. The process of claim 6 , wherein J 2 is —S(O) 2 —(C 1-5 alkyl).

8. The process of claim 2 , wherein
R 1 is ethyl; R 2 is ethyl;
R 3 is CH 3 or

PG is Boc or Cbz;
J 1 is H;
R 4 is

wherein Q is phenyl; J 2 is —S(O) 2 —CH(CH 3 ) 2 ; and
q is 1.

9. The process of claim 1 , wherein the suitable oxime formation conditions comprise treating the compound of formula 3 with NH 2 OH—HCl in a mixture of THF and water.

10. The process of claim 1 , wherein the suitable oxime formation conditions comprise treating the compound of formula 3 with NH 2 OH—HCl in a mixture of 2-MeTHF and water.

11. The process of claim 9 or 10 , wherein the suitable oxime formation conditions further comprise an amount of Na 2 SO 4 as buffer.

12. The process of claim 10 , wherein 1 equivalent of the compound of formula 3 is combined with 1.1 equivalents of NH 2 OH—HCl in a 10:1 v/v mixture of 2-MeTHF/water optionally buffered with Na 2 SO 4 .

13. The process of claim 1 , wherein the compound of formula 4 is a compound of formula 4-i:

and wherein the compound of formula 3 is a compound of formula 3b:

14. The process of claim 13 , further comprising reacting the compound of formula 4-i:

under suitable chlorooxime formation conditions to provide a compound of formula 4-ii:

15. The process of claim 14 , wherein the suitable chlorooxime formation conditions comprise exposing the compound of formula 4-i to N-chlorosuccinimide (NCS) in a suitable solvent.

16. The process of claim 15 , wherein the suitable solvent comprises an aprotic solvent.

17. The process of claim 15 , wherein the suitable solvent comprises an alkyl acetate.

18. The process of claim 17 , wherein the alkyl acetate is selected from isopropyl acetate and ethyl acetate.

19. The process of claim 1 , wherein the compound of formula I is:

or a pharmaceutically acceptable salt thereof.

20. A process for preparing a compound of formula 4:

comprising the step of reacting a compound of formula 3:

under suitable oxime formation conditions;
wherein:
R 1 is C 1-6 alkyl;
R 2 is C 1-6 alkyl;
or R 1 and R 2 , together with the oxygen atoms to which they are attached, form an optionally substituted 5 or 6 membered saturated heterocyclic ring having two oxygen atoms;
R 3 is hydrogen, C 1-6 alkyl, or a 3-6 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur;
wherein the heterocyclyl is optionally substituted with 1 occurrence of halo or C 1-3 alkyl;

J 1 is H, halo, C 1-4 alkyl, or C 1-4 alkoxy; and
PG is a carbamate protecting group.

21. The process of claim 20 , further comprising the step of protecting a compound of formula 2:

under suitable protection conditions to form the compound of formula 3.

22. The process of claim 21 , further comprising the step of reacting a compound of formula 1:

with a suitable ligand under suitable reductive amination conditions to form the compoun

Assignees

• Vertex Pharma

Inventors

• Charrier Jean-Damien
• Studley John
• Pierard Francoise Yvonne Theodora Marie
• Durrant Steven John
• Littler Benjamin Joseph
• Hughes Robert Michael
• Siesel David Andrew
• Angell Paul
• Urbina Armando
• Shi Yi

Classifications

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D413/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D241/20

  Nitrogen atoms (nitro radicals C07D241/16) · CPC title

• C07C251/48

  with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring · CPC title