	US 11,993,585 B2
	Poly-ADP ribose polymerase (PARP) inhibitors
Taisuke Takahashi, Tsukuba (JP); Arthur Kluge, Lincoln, MA (US); Bharat Lagu, Acton, MA (US); and Nan Ji, Arlington, MA (US)
Assigned to Mitobridge, Inc., Cambridge, MA (US)
Filed by Mitobridge, Inc., Cambridge, MA (US)
Filed on Jun. 9, 2021, as Appl. No. 17/342,873.
Application 17/342,873 is a continuation of application No. 16/473,127, granted, now 11,034,670, issued on Jun. 15, 2021, previously published as PCT/US2017/068636, filed on Dec. 28, 2017.
Claims priority of provisional application 62/440,581, filed on Dec. 30, 2016.
Prior Publication US 2022/0033380 A1, Feb. 3, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 401/14 (2006.01); A61P 13/12 (2006.01); C07D 401/06 (2006.01); C07D 403/06 (2006.01); C07D 403/14 (2006.01); C07D 405/14 (2006.01); C07D 417/14 (2006.01); C07D 471/04 (2006.01); C07D 487/04 (2006.01); C07D 495/04 (2006.01)

CPC C07D 401/14 (2013.01) [A61P 13/12 (2018.01); C07D 401/06 (2013.01); C07D 403/06 (2013.01); C07D 403/14 (2013.01); C07D 405/14 (2013.01); C07D 417/14 (2013.01); C07D 471/04 (2013.01); C07D 487/04 (2013.01); C07D 495/04 (2013.01)]

20 Claims

1. A method of treating cell death in a subject after surgery, comprising administering to the subject an effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and wherein said compound is represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is phenyl or 5-6 membered heteroaryl; each of which is optionally substituted with one or two substituents selected from the group consisting of -halogen, —CN, —NO₂, —NR^aR^b, —S(O)_iR^a, —NR^aS(O)_iR^b, —S(O)_iNR^aR^b, —C(═O)OR^a, —OC(═O)OR^a, —C(═S)OR^a, —O(C═S)R^a, —C(═O)NR^aR^b, —NR^aC(═O)R^b, —C(═S)NR^aR^b, —NR^aC(═S)R^b, —NR^a(C═O)OR^b, —O(C═O)NR^aR^b, —NR^a(C═S)OR^b, —O(C═S)NR^aR^b, —NR^a(C═O)NR^aR^b, —NR^a(C═S)NR^aR^b, —C(═S)R^a, —C(═O)R^b, halo(C₁-C₅)alkyl and (C₁-C₅)alkyl, wherein the (C₁-C₅)alkyl is optionally substituted one or two groups selected from —CN, —NO₂, —NR^aR^b, —S(O)_iR^a, —NR^aS(O)_iR^b, —S(O)_iNR^aR^b, —C(═O)OR^a, —OC(═O)OR^a, —C(═S)OR^a, —O(C═S)R^a, —C(═O)NR^aR^b, —NR^aC(═O)R^b, —C(═S)NR^aR^b, —NR^aC(═S)R^b, —NR^a(C═O)OR^b, —O(C═O)NR^aR^b, —NR^a(C═S)OR^b, —O(C═S)NR^aR^b, —NR^a(C═O)NR^aR^b, —NR^a(C═S)NR^aR^b, —C(═S)R^a, and —C(═O)R^a;

each R^aand each R^bare independently selected from —H and (C₁-C₅)alkyl optionally substituted with hydroxyl or (C₁-C₃)alkoxy;

R^cis —H, halo(C₁-C₅)alkyl or (C₁-C₅)alkyl, wherein the (C₁-C₅)alkyl is optionally substituted with hydroxyl or (C₁-C₃)alkoxy;

i is 0, 1, or 2;

Ring B is phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, each optionally substituted with one or two substituents represented by R³;

is absent or a bond;

E is N or CH when custom character

is absent or E is C when custom character

is a bond;

is optionally substituted with (C₁-C₅)alkyl or hydroxy (C₁-C₅)alkyl;

each R³is independently selected from the group consisting of -halogen, —CN, —NO₂, —OR^d, —S(O)_iR^e, —C(═NR^e)NR^eR^f, —NR^eS(O)_iR^f, —S(O)_iNR^eR^f, —C(═O)OR^e, —OC(═O)OR^e, —C(═S)OR^e, —O(C═S)R^e, —C(═O)NR^eR^f, —NR^eC(═O)R^f, —C(═S)NR^eR^f, —NR^eC(═S)R^f, —NR^e(C═O)OR^f, —O(C═O)NR^eR^f, —NR^e(C═S)OR^f, —O(C═S)NR^eR^f, —NR^e(C═O)NR^eR^f, —NR^e(C═S)NR^eR^f, —C(═S)R^e, —C(═O)R^e, halo(C₁-C₅)alkyl, and (C₁-C₅)alkyl, wherein the (C₁-C₅)alkyl represented by R³is optionally substituted with —CN, —NO₂, —OR^e, —NR^eR^f, —S(O)_iR^e, —NR^eS(O)_iR^f, —S(O)_iNR^eR^f, —C(═O)OR^e, —OC(═O)OR^e, —C(═S)OR^e, —O(C═S)R^e, —C(═O)NR^eR^f, —NR^eC(═O)R^f, —C(═S)NR^eR^f, —NR^eC(═S)R^f, —NR^e(C═O)OR^f, —O(C═O)NR^eR^f, —NR^e(C═S)OR^f, —O(C═S)NR^eR^f, —NR^e(C═O)NR^eR^f, —NR^e(C═S)NR^eR^f, —C(═S)R^e, or —C(═O)R^e;

R^dis —H, halo(C₁-C₅)alkyl or (C₁-C₅)alkyl, wherein the (C₁-C₅)alkyl is optionally substituted with hydroxyl or (C₁-C₃)alkoxy;

each R^eis independently selected from the group consisting of —H and (C₁-C₅)alkyl optionally substituted with hydroxyl or (C₁-C₃)alkoxy;

each R^fis independently selected from the group consisting of —H, (C₁-C₅)alkyl optionally substituted with hydroxyl or (C₁-C₃)alkoxy, (C₃-C₆)cycloalkyl optionally substituted with (C₁-C₂) alkyl, and 4-6 membered oxygen-containing heterocyclyl optionally substituted with (C₁-C₂) alkyl; or

—NR^eR^ftaken together is a 4-6 membered heterocyclyl optionally substituted with (C₁-C₂) alkyl; or

—C(═NR^e)NR^eR^ftaken together is a 4-6 membered heterocyclyl optionally substituted with R^e;

R⁵is —H or (C₁-C₅)alkyl; and

i is 0, 1, or 2,

wherein 5-6 membered heteroaryl refers to a monocyclic aromatic ring group having five or six ring atoms selected from carbon and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur; and

5-6 membered heterocyclyl refers to a monocyclic non-aromatic ring radical containing 5-6 ring atoms selected from carbon atom and 1 or 2 heteroatoms, each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (NO), oxygen, sulfur, sulfoxide and sulfone.