US 12,251,387 B2
Substituted quinoxalines and benzo[c][1,2,5]oxadiazoles as DNA-PK inhibitors
John Patrick Maxwell, Hingham, MA (US); Paul S. Charifson, Framingham, MA (US); Qing Tang, Boston, MA (US); Steven M. Ronkin, Watertown, MA (US); Katrina Lee Jackson, Cambridge, MA (US); Albert Charles Pierce, Cambridge, MA (US); David J. Lauffer, Stow, MA (US); Pan Li, Lexington, MA (US); Simon Giroux, Cambridge, MA (US); Jinwang Xu, Boston, MA (US); Kevin Michael Cottrell, Cambridge, MA (US); Mark A. Morris, Somerville, MA (US); Nathan D. Waal, Cambridge, MA (US); John J. Court, Littleton, MA (US); Wenxin Gu, Concord, MA (US); and Hongbo Deng, Southborough, MA (US)
Assigned to Vertex Pharmaceuticals Incorporated, Boston, MA (US)
Filed by Vertex Pharmaceuticals Incorporated, Boston, MA (US)
Filed on Feb. 27, 2023, as Appl. No. 18/175,515.
Application 15/965,489 is a division of application No. 15/133,378, filed on Apr. 20, 2016, granted, now 9,987,284.
Application 15/133,378 is a division of application No. 14/205,657, filed on Mar. 12, 2014, granted, now 9,340,557.
Application 18/175,515 is a continuation of application No. 17/171,061, filed on Feb. 9, 2021, abandoned.
Application 17/171,061 is a continuation of application No. 16/372,080, filed on Apr. 1, 2019, granted, now 10,973,830.
Application 16/372,080 is a continuation of application No. 15/965,489, filed on Apr. 27, 2018, abandoned.
Claims priority of provisional application 61/777,816, filed on Mar. 12, 2013.
Prior Publication US 2023/0277547 A1, Sep. 7, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 241/44 (2006.01); A61K 31/506 (2006.01); A61K 31/5377 (2006.01); A61K 31/5386 (2006.01); C07D 241/40 (2006.01); C07D 241/42 (2006.01); C07D 271/12 (2006.01); C07D 401/12 (2006.01); C07D 401/14 (2006.01); C07D 403/12 (2006.01); C07D 403/14 (2006.01); C07D 405/12 (2006.01); C07D 405/14 (2006.01); C07D 413/04 (2006.01); C07D 413/12 (2006.01); C07D 413/14 (2006.01); C07D 417/12 (2006.01); C07D 471/04 (2006.01); C07D 473/40 (2006.01); C07D 475/00 (2006.01); C07D 487/04 (2006.01); C07D 491/048 (2006.01); C07D 491/052 (2006.01); C07D 491/056 (2006.01); C07D 491/08 (2006.01); C07D 498/08 (2006.01); C07D 513/04 (2006.01)
CPC A61K 31/5377 (2013.01) [A61K 31/506 (2013.01); A61K 31/5386 (2013.01); C07D 241/40 (2013.01); C07D 241/42 (2013.01); C07D 241/44 (2013.01); C07D 271/12 (2013.01); C07D 401/12 (2013.01); C07D 401/14 (2013.01); C07D 403/12 (2013.01); C07D 403/14 (2013.01); C07D 405/12 (2013.01); C07D 405/14 (2013.01); C07D 413/04 (2013.01); C07D 413/12 (2013.01); C07D 413/14 (2013.01); C07D 417/12 (2013.01); C07D 471/04 (2013.01); C07D 473/40 (2013.01); C07D 475/00 (2013.01); C07D 487/04 (2013.01); C07D 491/048 (2013.01); C07D 491/052 (2013.01); C07D 491/056 (2013.01); C07D 491/08 (2013.01); C07D 498/08 (2013.01); C07D 513/04 (2013.01)] 20 Claims
 
1. A method for inhibiting cancer cell growth in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof,
wherein:
Ring A is:

OG Complex Work Unit Chemistry
each R3 is independently hydrogen, fluoro, chloro, cyano, C1-4 alkyl, C(O)H, C(O)NH2, C(O)NHC1-2 alkyl, C(O)OH, C(O)OC1-2 alkyl, or OC1-2 alkyl, wherein each C1-4 alkyl, C(O)NHC1-2 alkyl, C(O)OC1-2 alkyl, and OC1-2 alkyl is optionally and independently substituted with one, two, or three fluoro substituents, one or two hydroxy substituents, or one or two independently selected OC1-2 alkyl substituents;
Ring B is:

OG Complex Work Unit Chemistry
wherein Ring B is optionally substituted with one, two, three, or four fluoro substituents, one or two independently selected C1-4 alkyl substituents, or one or two hydroxy substituents; and
wherein each C1-4 alkyl substituent is optionally substituted with one, two, or three fluoro substituents, one or two hydroxy substituents, or one or two independently selected OC1-2 alkyl substituents;
X is —NH—, —O—, or —OC1-4 alkylene-;
Ring C is cyclobutyl or cyclohexyl;
R1 is hydrogen, C1-4 alkyl-NHR4, C(O)NHR4, C(O)OR4, NHR4, NHC(O)R4, NHC(O)NHR4, NHC(O)OR4, NHS(O)2R4, or OR4;
R2 is hydrogen, C1-4 alkyl-NHR4, C(O)NHR4, C(O)OR4, NHR4, NHC(O)R4, NHC(O)NHR4, NHC(O)OR4, NHS(O)2R4, or OR4; or
R1 and R2, together with the intervening carbon atom(s) to which they are attached, form a dioxane or dioxolane ring;
(1) each R4 is independently hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-5 cycloalkyl, or phenyl;
wherein each C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-5 cycloalkyl, and phenyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of (a), (b), (c), (d), (e), and (f):
(a) one, two, three, or four fluoro, chloro, bromo, or C1-4 alkyl;
(b) one, two, or three cyano;
(c) one or two OR5;
(d) NO2, CH2OR5, C1-4 alkyl-C(O)R5, C1-4 alkyl-C(O) NR5R5, C1-4 alkyl-C(O)OR5, C1-4 alkyl-NR5R5, C1-4 alkyl-NHC(O)R5, C1-4 alkyl-OC1-4 alkyl, C1-4 alkyl-OC1-4 alkyl-C3-5 cycloalkyl, C1-4 alkyl-O—C3-5 cycloalkyl, C1-4 alkyl-C3-5 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C(O)R5, C(O)NR5R5, C(O)NH—C1-4 alkyl-C3-5 cycloalkyl, C(O)NHC3-5 cycloalkyl, C(O)OR5, C(O)OC1-4 alkyl-C3-5 cycloalkyl, C(O)OC3-5 cycloalkyl, NR5R5, NHC(O)RS, OC1-4 alkyl, OC1-4 alkyl-C3-5 cycloalkyl, OC3-5 cycloalkyl, or C3-6 cycloalkyl;
(e) a heterocyclyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, piperazinyl, and morpholinyl; and
(f) a heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, and oxadiazolyl;
wherein each C1-4 alkyl, CH2OR5, C1-4 alkyl-C(O) R5, C1-4 alkyl-C(O) NR5R5, C1-4 alkyl-C(O)OR5, C1-4 alkyl-NR5R5, C1-4 alkyl-NHC(O)R5, C1-4 alkyl-OC1-4 alkyl, C1-4 alkyl-OC1-4 alkyl-C3-5 cycloalkyl, C1-4 alkyl-OC3-5 cycloalkyl, C1-4 alkyl-C3-5 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C(O)R5, C(O)NRSR5, C(O)NH—C1-4 alkyl-C3-5 cycloalkyl, C(O)NHC3-5 cycloalkyl, C(O)OR5, C(O)OC1-4 alkyl-C3-5 cycloalkyl, C(O)OC3-5 cycloalkyl, NR5R5, NHC(O)R5, OC1-4 alkyl, OC1-4 alkyl-C3-5 cycloalkyl, OC3-5 cycloalkyl, C3-6 cycloalkyl, heterocyclyl, and heteroaryl substituent is optionally and independently substituted with one, two, three, or four fluoro substituents, one or two independently selected C1-4 alkyl substituents, one C(O)C1-4 alkyl substituent, one C(O)OC1-4 alkyl substituent, one C(O)OC1-4 alkyl-C3-5 cycloalkyl substituent, one C(O)OC3-5 cycloalkyl substituent, one or two hydroxy substituents, one or two independently selected OC1-4 alkyl substituents, or one or two independently selected SC1-4 alkyl substituents; or
(2) each R4 is independently selected from the group consisting of:
(i) a heterocyclyl selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydroisoxazolyl, pyrimidinonyl, pyrimidin-2,4-(1H,3H)-dionyl, dihydropyrrolopyrimidinyl, dihydrofuropyrimidinyl, dihydropyranopyrimidinyl, tetrahydropteridinyl, and tetrahydropyridopyrimidinyl; and
(ii) a heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and quinolinyl;
wherein each heterocyclyl and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of (a), (b), (c), (d), (e), and (f)
(a) one, two, three, or four fluoro, chloro, bromo, or C1-4 alkyl;
(b) one, two, or three cyano;
(c) one or two OR5;
(d) NO2, CH2OR5, C1-4 alkyl-C(O)R5, C1-4 alkyl-C(O) NR5R5, C1-4 alkyl-C(O)OR5, C1-4 alkyl-NR5R5, C1-4 alkyl-NHC(O)R5, C1-4 alkyl-OC1-4 alkyl, C1-4 alkyl-OC1-4 alkyl-C3-5 cycloalkyl, C1-4 alkyl-O—C3-5 cycloalkyl, C1-4 alkyl-C3-5 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C(O)R5, C(O)NR5R5, C(O)NH—C1-4 alkyl-C3-5 cycloalkyl, C(O)NHC3-5 cycloalkyl, C(O)OR5, C(O)OC1-4 alkyl-C3-5 cycloalkyl, C(O)OC3-5 cycloalkyl, NR5R5, NHC(O)R5, OC1-4 alkyl, OC1-4 alkyl-C3-5 cycloalkyl, OC3-5 cycloalkyl, or C3-6 cycloalkyl;
(e) a heterocyclyl selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyranyl, piperazinyl, and morpholinyl; and
(f) a heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, and oxadiazolyl;
wherein each C1-4 alkyl, CH2OR5, C1-4 alkyl-C(O)R5, C1-4 alkyl-C(O)NR5R5, C1-4 alkyl-C(O)OR5, C1-4 alkyl-NR5R5, C1-4 alkyl-NHC(O)R5, C1-4 alkyl-OC1-4 alkyl, C1-4 alkyl-OC1-4 alkyl-C3-5 cycloalkyl, C1-4 alkyl-OC3-5 cycloalkyl, C1-4 alkyl-C3-5 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, C(O)R5, C(O)NR5R5, C(O)NH—C1-4 alkyl-C3-5 cycloalkyl, C(O)NHC3-5 cycloalkyl, C(O)OR5, C(O)OC1-4 alkyl-C3-5 cycloalkyl, C(O)OC3-5 cycloalkyl, NR5R5, NHC(O)R5, OC1-4 alkyl, OC1-4 alkyl-C3-5 cycloalkyl, OC3-5 cycloalkyl, C3-6 cycloalkyl, heterocyclyl, and heteroaryl substituent is optionally and independently substituted with one, two, three, or four fluoro substituents, one or two independently selected C1-4 alkyl substituents, one C(O)C1-4 alkyl substituent, one C(O)OC1-4 alkyl substituent, one C(O)OC1-4 alkyl-C3-5 cycloalkyl substituent, one C(O)OC3-5 cycloalkyl substituent, one or two hydroxy substituents, one or two independently selected OC1-4 alkyl substituents, or one or two independently selected SC1-4 alkyl substituents; and
each R5 is independently hydrogen, C1-4 alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, imidazolyl, thiazolyl, triazolyl, pyridinyl, or pyrimidinyl, wherein each C1-4 alkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, imidazolyl, thiazolyl, triazolyl, pyridinyl, and pyrimidinyl is optionally and independently substituted with one, two, or three fluoro substituents, one chloro substituent, one cyano substituent, one or two independently selected C1-2 alkyl substituents, one CH2OH substituent, one or two hydroxy substituents, one or two independently selected OC1-2 alkyl substituents, one pyrrolidinyl substituent, one spirooxetanyl substituent, or one triazolyl substituent; or
two R5, together with the intervening nitrogen atom to which they are attached, form an azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl;
with the proviso that R1 and R2 are not simultaneously hydrogen.