US 12,187,731 B2
Compounds useful as inhibitors of ATR kinase
Nadia Ahmad, Didcot (GB); Dean Boyall, Faringdon (GB); Jean-Damien Charrier, Wantage (GB); Chris Davis, Salisbury (GB); Rebecca Davis, Witney (GB); Steven Durrant, Abingdon (GB); Gorka Etxebarria I Jardi, Abingdon (GB); Damien Fraysse, Abingdon (GB); Juan-Miguel Jimenez, Abingdon (GB); David Kay, Purton (GB); Ronald Knegtel, Abingdon (GB); Donald Middleton, Sandwich (GB); Michael O'Donnell, Abingdon (GB); Maninder Panesar, Didcot (GB); Francoise Pierard, Abingdon (GB); Joanne Pinder, Didcot (GB); David Shaw, Oxford (GB); Pierre-Henri Storck, Abingdon (GB); John Studley, Witney (GB); and Heather Twin, Wantage (GB)
Assigned to Vertex Pharmaceuticals Incorporated, Boston, MA (US)
Filed by Vertex Pharmaceuticals Incorporated, Boston, MA (US)
Filed on Jun. 23, 2022, as Appl. No. 17/847,938.
Application 17/007,412 is a division of application No. 15/496,180, filed on Apr. 25, 2017, granted, now 10,787,452, issued on Sep. 29, 2020.
Application 15/496,180 is a division of application No. 14/201,037, filed on Mar. 7, 2014, granted, now 9,650,381, issued on May 16, 2017.
Application 17/847,938 is a continuation of application No. 17/007,412, filed on Aug. 31, 2020, granted, now 11,370,798.
Application 14/201,037 is a continuation of application No. 14/098,606, filed on Dec. 6, 2013, granted, now 9,340,546, issued on May 17, 2016.
Claims priority of provisional application 61/868,132, filed on Aug. 21, 2013.
Claims priority of provisional application 61/787,568, filed on Mar. 15, 2013.
Claims priority of provisional application 61/734,726, filed on Dec. 7, 2012.
Prior Publication US 2023/0271963 A1, Aug. 31, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 487/04 (2006.01); C07D 453/02 (2006.01); C07D 471/08 (2006.01); C07D 487/08 (2006.01); C07D 491/107 (2006.01); C07D 498/04 (2006.01); C07D 498/10 (2006.01)
CPC C07D 487/04 (2013.01) [C07D 453/02 (2013.01); C07D 471/08 (2013.01); C07D 487/08 (2013.01); C07D 491/107 (2013.01); C07D 498/04 (2013.01); C07D 498/10 (2013.01)] 19 Claims
 
1. A compound of formula I-A:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
R1 is fluoro, chloro, or —C(J1)2CN;
each J1 is independently H or C1-2alkyl; or
two occurrences of J1, together with the carbon atom to which they are attached, form a 3-4 membered optionally substituted carbocyclic ring;
R2 is H; halo; —CN; NH2; a C1-2alkyl optionally substituted with 0-3 occurrences of fluoro; or a C1-3aliphatic chain wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)n—;
R3 is H; halo; C1-4alkyl optionally substituted with 1-3 occurrences of halo; C3-4cycloalkyl; —CN; or a C1-3aliphatic chain wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)n—;
R4 is —O—, wherein —O— is substituted with one JQ;
JQ is Q2; or a C1-8aliphatic chain wherein up to three methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)n—; wherein JQ is optionally substituted by 0-3 occurrences of JR,
Q2 is a 3-7 membered fully saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen, and sulfur; or a 7-12 membered fully saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms selected from oxygen, nitrogen, and sulfur;
each JR is independently —CN; halo; ═O; →O; Q3; or a C1-6aliphatic chain wherein up to three methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)n—; wherein each JR is optionally substituted with 0-3 occurrences of JT; or
two occurrences of JR on the same atom, together with the atom to which they are joined, form a 3-6 membered ring having 0-2 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein the ring formed by two occurrences of JR is optionally substituted with 0-3 occurrences of JX; or
two occurrences of JR, together with Q2, form a 6-10 membered saturated or partially unsaturated bridged ring system;
each Q3 is independently a 3-7 membered fully saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen, and sulfur; or a 7-12 membered fully saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms selected from oxygen, nitrogen, and sulfur;
each JT is independently —CN; ═O; a C1-6aliphatic chain wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)n—; or a 3-6 membered non-aromatic ring having 0-2 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein each occurrence of J is optionally substituted with 0-3 occurrences of JM; or
two occurrences of JT on the same atom, together with the atom to which they are joined, form a 3-6 membered ring having 0-2 heteroatoms selected from oxygen, nitrogen, and sulfur; or
two occurrences of JT, together with Q3, form a 6-10 membered saturated or partially unsaturated bridged ring system;
each JX is independently-CN; halo; or a C1-4aliphatic chain wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)n—;
each JM is independently halo or C1-6aliphatic;
n is 0, 1, or 2; and
each R is independently H or C1-4aliphatic.