0001US 20200222392A1 IN (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No .: US 2020/0222392 A1 Pollard et al. (43 ) Pub . Date : Jul. 16 , 2020 (54 ) COMPOUNDS USEFUL AS INHIBITORS OF (52 ) U.S. CI. ATR KINASE AND COMBINATION CPC A61K 31/496 ( 2013.01) ; A61K 31/4965 THERAPIES THEREOF (2013.01 ) ; A61K 31/497 ( 2013.01) ; C07D 413/04 ( 2013.01 ) ; A61K 33/24 ( 2013.01 ) ; (71 ) Applicant: Vertex Pharmaceuticals Incorporated , A61K 45/06 ( 2013.01) ; A61K 31/55 ( 2013.01) Boston , MA (US ) (57 ) ABSTRACT The present invention relates to compounds useful as inhibi ( 72 ) Inventors : John Robert Pollard , Abingdon (GB ) ; tors of ATR protein kinase and combination therapies Philip Michael Reaper, Abingdon thereof The invention also relates to pharmaceutically (GB ) ; Mohammed Asmal, Newton , acceptable compositions comprising the compounds of this MA (US ) invention ;methods of treating of various diseases, disorders , and conditions using the compounds of this invention ; ( 21) Appl. No .: 16 /507,139 processes for preparing the compounds of this invention ; intermediates for the preparation of the compounds of this ( 22 ) Filed : Jul. 10 , 2019 invention ; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and Related U.S. Application Data pathological phenomena ; the study of intracellular signal (60 ) Continuation of application No. 14 / 816,432 , filed on transduction pathways mediated by such kinases ; and the Aug. 3 , 2015 , now Pat . No. 10,478,430 , which is a comparative evaluation of new kinase inhibitors. division of application No. 13 /857,658 , filed on Apr. The compounds of this invention have formula I: 5 , 2013 , now abandoned . (60 ) Provisional application No.61 / 620,717 , filed on Apr. 5 , 2012 . NH2 Publication Classification (L )n - R N (51 ) Int. Ci. A61K 31/496 ( 2006.01 ) A61K 31/4965 ( 2006.01 ) A61K 31/497 (2006.01 ) ?R2 A61K 31/55 ( 2006.01 ) A61K 33/24 ( 2006.01) A61K 45/06 (2006.01 ) wherein the variables are as defined herein . CO7D 413/04 ( 2006.01 ) Specification includes a Sequence Listing. Patent Application Publication Jul. 16 , 2020 Sheet 1 of 18 US 2020/0222392 A1 uimarisha 2 FreeMonta99.9 ABT288-w 1 0,1 1FIGURE MDA-MB231ABT888CombinationwithVE821andIrradiation triglisering 2 VEAB 10 1 survival Melanogenic Patent Application Publication Jul. 16 , 2020 Sheet 2 of 18 US 2020/0222392 A1 ?? FIGURE1(continued) CombinationwithVE-821andIrradiationMDAMB231ABT888 .121012 TWD| Patent Application Publication Jul. 16 , 2020 Sheet 3 of 18 US 2020/0222392 A1 ABT 0.0005<*p DMSOVE-322A8-588+ wwwwwwwwwwwwwwww FIGURE2 OMSOVEABT-888 Patent Application Publication Jul. 16 , 2020 Sheet 4 of 18 US 2020/0222392 A1 r 0.05*** 4GY IB ??? survival Plogerne ** ABT DMSOVE-22ABT888 FIGURE2(continued) 2Gy OL ABT OGY BAX BUBU Patent Application Publication Jul. 16 , 2020 Sheet 5 of 18 US 2020/0222392 A1 FIGURE3 10 Patent Application Publication Jul. 16 , 2020 Sheet 6 of 18 US 2020/0222392 A1 Synergy/Antagonism 45 40 35 30 25 20 15 10 5 Rucaparib(UM) 1.3 90 0.3 0.2 FIGURE4 0.1 0.0 31.25 62.5 Cancer-selectivesynergisticeffectsofVE822withRucaparib 125 250 5007 VE-822 (UM) Patent Application Publication Jul. 16 , 2020 Sheet 7 of 18 US 2020/0222392 A1 SynergyAntagonism/ 40 35 30 ? ? -5 10.0 Rucaparib(UM) 5.0 2.5 1.3 0.3 0.2 FIGURE4(continued) 0.1 0.0 31.25 62.5 125 OSZ 009 VE-822 (wm) 1000 2000 juared uonezyddy iqnd ?uoge Jul. 16 , 2020 Sheet 8 of 18 US 2020/0222392 A1 SynergyAntagonism/ 30 å å då or -5 10.0 Rucaparib(UM) 5.0 2.5 1.3 0.6 0.3 0.2 FIGURE4(continued) 0.1 0.0 31.25 62.5 125 250 500 VE-822 (wm) 1000 2000 Patent Application Publication Jul. 16 , 2020 Sheet 9 of 18 US 2020/0222392 A1 SynergyAntagonism/ 40 35 30 i à 1008 10.0 Rucaparib(UM) 5.0 2.5 1.3 0.6 0.3 0.2 FIGURE4(continued) 0.1 0.0 31.25 62.5 125 OSZ 009 VE-822 (wm) 2000Loool juared uonezyddy iqnd ?uoge Jul. 16 , 2020 Sheet 10 of 18 US 2020/0222392 A1 AntagonismSynergy/ 40 35 30 å å å à or -5 10.0 Rucaparib(UM) 5.0 2.5 1.3 0.3 0.2 FIGURE4(continued) 0.1 0.0 31.25 62.5 125 250 500 VE-822 (wm) 1000 2000 juared uonezyddy iqnd ?uoge Jul. 16 , 2020 Sheet 11 of 18 US 2020/0222392 A1 SynergyAntagonism/ 40 35 30 ? ? ? ?? 10.0 Rucaparib(UM) 5.0 2.5 1.3 0.6 0.3 0.2 FIGURE4(continued) 0.1 0.0 31.25 62.5 125 250 500 VE822- (wm) 100012000 Patent Application Publication Jul. 16 , 2020 Sheet 12 of 18 US 2020/0222392 A1 SynergyAntagonism/ 40 35 30 25 20 uno? 0 o á 10.0 Rucaparib(UM) 5.0 2.5 1.3 0.3 0.2 FIGURE4(continued) 0.1 0.0 31.25 62.5 125 250 500 VE-822 (wm) 1000 2000 Patent Application Publication Jul. 16 , 2020 Sheet 13 of 18 US 2020/0222392 A1 2.00 VE-822UM)( 0.40 0.080 0.016 0.003 0.031 er FIGURE5 cellsCancerandNon-SynergisticwithRucaparibineffectsofVE822 0.125 0.50 Rucaparib(UM) 2.0 8.0 35.0 30.0 25.0 20.0 15.0 10.0 5.0 0.0 -5.0 ) % ( Synergy Patent Application Publication Jul. 16 , 2020 Sheet 14 of 18 US 2020/0222392 A1 2.00 VE-822 WT)( 0.40 0.080 0.016 0.003 0 0.031 FIGURE5(continued) 0.125 0.50 Rucaparib(UM) 2.0 8.0 35.0 30.0 25.0 20.0 15.0 10.0 5,0 0.0 -5.0 ) % ( Synergy Patent Application Publication Jul. 16 , 2020 Sheet 15 of 18 US 2020/0222392 A1 2.0 0.40 0.08 0.016 +2GYIR 0.0032 0.031 FIGURE6A 0.125 lonizingRadiationSynergisticeffectsofVE-822withRucapariband 0.50 2.0 Ruc(UM) 30.0 25.0 20.0 15.0 10.0 5.0 0.0 -5,0 -10.0 ) %( Synergy Patent Application Publication Jul. 16 , 2020 Sheet 16 of 18 US 2020/0222392 A1 2.0 0.08 0.016 +2GYIR 0.0032 0.031 FIGURE6A(continued) 0.125 0.50 2.0 Ruc(UM) 8.0 30.0 25.0 20.0 15.0 10.0 5,0 -5,0 -10.0 ) % ( Synergy Patent Application Publication Jul. 16 , 2020 Sheet 17 of 18 US 2020/0222392 A1 VE-822 (UM) 2.0 0.40 0.08 0.016 +BonMCis. 0.0032 0 0.031 FIGURE6B 0.125 0.50 SynergisticeffectsofVE-822withRucaparibandCisplatin Rucaparib(UM) 2.0 8.0 50.0 45.0 40.0 35.0 30.0 25.0 20.0 15.0 10.0 5.0 -5.0 -10.0 -15.0 ) % ( Synergy Patent Application Publication Jul. 16 , 2020 Sheet 18 of 18 US 2020/0222392 A1 VE-822 (WT) 2.0 0.40 0.08 80NMCis 0.016 0.0032 + 1800 FIGURE6B(continued) 0.125 0.50 Rucaparib(UM) 2.0 8.0 5,0 50.0 45.0 40,0 35.0 30.0 25.0 20.0 15.0 10.0 -5.0 -10.0 -15.0 ) %( Synergy US 2020/0222392 A1 Jul. 16 , 2020 1 COMPOUNDS USEFUL AS INHIBITORS OF SUMMARY OF THE INVENTION ATR KINASE AND COMBINATION [0008 ] The present invention relates to compounds useful THERAPIES THEREOF as inhibitors of ATR protein kinase . The invention also relates to pharmaceutically acceptable compositions com CROSS REFERENCE TO RELATED prising the compounds of this invention ; methods of treating APPLICATIONS of various diseases, disorders, and conditions using the compounds of this invention ; processes for preparing the [ 0001 ] This present invention claims the benefit, under 35 compounds of this invention ; intermediates for the prepa U.S.C. § 119 , of U.S. Provisional Application No. 61/620 , ration of the compounds of this invention ; and methods of 717 , filed Apr. 5 , 2012 , the entire contents of which are using the compounds in in vitro applications, such as the incorporated herein by reference . study of kinases in biological and pathological phenomena ; the study of intracellular signal transduction pathways medi BACKGROUND OF THE INVENTION ated by such kinases; and the comparative evaluation of new [ 0002 ] ATR ( “ ATM and Rad3 related ” ) kinase is a protein kinase inhibitors . kinase involved in cellular responses to DNA damage. ATR [0009 ] The compounds of the invention are very potent kinase acts with ATM (“ ataxia telangiectasia mutated ” ) ATR inhibitors . kinase and many other proteins to regulate a cell's response to DNA damage, commonly referred to as the DNA Damage BRIEF DESCRIPTION OF THE FIGURES Response (“ DDR ” ) . The DDR stimulates DNA repair, pro [0010 ) FIG . 1 : Clonogenic survival of cancer cells from motes survival and stalls cell cycle progression by activating MDA -MB - 231 breast cancer cell line when treated with cell cycle checkpoints , which provide time for repair. With VE - 821, ABT- 888 , and ionizing radiation out the DDR , cells are much more sensitive to DNA damage [0011 ] FIGS . 2 and 3 : Clonogenic survival of cancer cells and readily die from DNA lesions induced by endogenous from RKO and MDA -MB - 231 breast cancer cell line when cellular processes such as DNA replication or exogenous treated with VE - 822 , ABT- 888 , and ionizing radiation DNA damaging agents commonly used in cancer therapy. [0012 ] FIG . 4 : Cancer - selective synergistic effects for the [0003 ] Healthy cells can rely on a host of different proteins combination of VE - 822 with PARP inhibitor Rucaparib in for DNA repair including the DDR kinase ATR .