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 . In some various cancer cell lines cases these proteins can compensate for one another by [0013 ] FIG . 5 : Cancer -selective synergistic effects for the activating functionally redundant DNA repair processes. On combination of VE -822 with PARP inhibitor Rucaparib in a the contrary, many cancer cells harbour defects in some of cancer cell compared to a normal cell their DNA repair processes , such as ATM signaling , and [0014 ] FIG . 6a : Cancer- selective synergistic effects for the therefore display a greater reliance on their remaining intact combination of VE -822 , the PARP inhibitor Rucaparib and DNA repair proteins which include ATR . Ionizing radiation ( IR ) [0004 ] In addition , many cancer cells express activated [0015 ] FIG . 66 : Cancer - selective synergistic effects for the oncogenes or lack key tumour suppressors, and this can combination of VE - 822 , the PARP inhibitor Rucaparib and make these cancer cells prone to dysregulated phases of cisplatin . DNA replication which in turn cause DNA damage. ATR has been implicated as a critical component of the DDR in DETAILED DESCRIPTION OF THE response to disrupted DNA replication . As a result , these INVENTION cancer cells are more dependent on ATR activity for survival [0016 ] One aspect of the invention provides a compound than healthy cells . Accordingly, ATR inhibitors may be of Formula I : useful for cancer treatment, either used alone or in combi nation with DNA damaging agents , because they shut down a DNA repair mechanism that is more important for cellular I survival in many cancer cells than in healthy normal cells . NH2 [0005 ] In fact , disruption of ATR function ( e.g. by gene ( L )n - R ! deletion ) hasbeen shown to promote cancer cell death both N in the absence and presence of DNA damaging agents . This suggests that ATR inhibitors may be effective both as single agents and as potent sensitizers to radiotherapy or genotoxic chemotherapy . R2 [0006 ] ATR peptide can be expressed and isolated using a variety of methods known in the literature ( see e.g., Ünsal or a pharmaceutically acceptable salt thereof, Kaçmaz et al, PNAS 99: 10 , pp 6673-6678 , May 14 , 2002 ; [0017 ] wherein see also Kumagai et al . Cell 124 , pp 943-955 ,Mar. 10 , 2006 ; [0018 ] R ' is a 5-6 membered monocyclic aryl or het Unsal- Kacmaz et al. Molecular and Cellular Biology, Feb eroaryl ring having 0-4 heteroatoms independently ruary 2004 , p 1292-1300 ; and Hall- Jackson et al. Oncogene selected from nitrogen , oxygen , or sulfur , wherein said 1999 , 18 , 6707-6713 ). monocyclic aryl or heteroaryl ring is optionally fused to [0007 ] For all of these reasons, there is a need for the another ring to form an 8-10 membered bicyclic aryl or development of potent and selective ATR inhibitors for the heteroaryl ring having 0-6 heteroatoms independently treatment of cancer , either as single agents or as part of selected from nitrogen , oxygen , or sulfur ; each R ' is combination therapies . optionally substituted with 1-5 J ' groups ; US 2020/0222392 A1 Jul. 16 , 2020 2

[ 0019 ] R2 is a 5-6 membered monocyclic aryl or het 0-6 heteroatoms independently selected from nitrogen , eroaryl ring having 0-3 heteroatoms independently oxygen , or sulfur; each Q4 is optionally substituted with selected from nitrogen , oxygen , or sulfur, wherein said 1-5 j24 ; monocyclic aryl or heteroaryl ring is optionally fused to [0033 ] jQ4 is halo , CN , or C - alkyl wherein up to 2 another ring to form an 8-10 membered bicyclic aryl or methylene units are optionally replaced with O , NR * , heteroaryl ring having 0-4 heteroatoms independently S , C ( O ), S ( O ), or S ( O ) 2 ; selected from nitrogen , oxygen , or sulfur ; each R² is [ 0034 ] R is H or C - alkyl wherein said C - alkyl is optionally substituted with 1-5 J2 groups; optionally substituted with 1-4 halo ; [0020 ] L is C ( O ) NH or C ( O ) N ( C -galkyl ) [0035 ] R ', R " , and R * are each independently H , [0021 ] n is 0 or 1 ; C1- alkyl, or is absent; wherein said C1- alkyl is option [0022 ] Each Ji and J ? is independently halo , CN , ally substituted with 1-4 halo . NO , V —R , or (V2 )m - Q ; [0036 ] Another embodiment provides a compound of For [0023 ] Vl is a C1-10aliphatic chain wherein 0-3 meth mula I for use in treating cancer with a defect in the ATM ylene units are optionally and independently replaced signaling cascade or a base excision repair protein . with O , NR " , S , C ( O ) , S ( O ) , or S ( O ) 2 ; V1 is optionally [0037 ] In some embodiments , L is C (O )NH— ; and R ! substituted with 1-6 occurrences of J " ; and R2 are phenyl. [0024 ] V2 is a C1-10aliphatic chain wherein 0-3 meth [ 0038 ] Another embodiment provides a compound of For ylene units are optionally and independently replaced mula IA - iii : with O , NR " , S , C (O ), S (O ), or S (O )2 ; V2 is optionally substituted with 1-6 occurrences of JV2; IA - Hii [0025 ] m is 0 or 1 ; LO [0026 ] Q is a 3-8 membered saturated or unsaturated monocyclic ring having 0-4 heteroatoms independently NH2 selected from nitrogen , oxygen , or sulfur , or a 9-10 A -Jop membered saturated or unsaturated bicyclic ring having N 0-6 heteroatoms independently selected from nitrogen , oxygen , or sulfur; each Q is optionally substituted with 0-5 JQ ; [0027 ] each J or j” ? is independently halogen , CN , -J20 NH , NO2, C - aliphatic , NH ( C - aliphatic ), N ( C - ali phatic ) 2, OH , O (C - aliphatic ), CO , H , CO2 (C - ali phatic ), C (O )NH2 , C ( O )NH (C1-4aliphatic ), C (O ) N (C1 * J? m 4aliphatic )2 , NHCO (C1-4aliphatic ), N (C2-4aliphatic ) CO (C1 - aliphatic ) , SO2( C1-4aliphatic ) , NHSO2( C1 J p or & 4aliphatic ), N (C1-4aliphatic )SO2 ( C1 - aliphatic ), wherein said Caliphatic is optionally substituted wherein with halo ; [ 0039 ] Ring A is [ 0028 ] R is H or Cl- Galiphatic wherein said Cl- ali phatic is optionally substituted with 1-4 occurrences of NH , NH (C -4aliphatic ), NC - aliphatic )2 , halogen , C .aliphatic , OH , O (C - aliphatic ) , NO2, CN , CO H , CO2( C -4aliphatic ), CO (C1.4aliphatic ) , O (haloC .ali phatic ) , or haloC1-4aliphatic ; Ky toy [0029 ] each JQ is independently halo , oxo , CN , NO2, X - R , or (X ), - Q +; [0030 ] p is 0 or 1 ; [0040 ] Pois H , F , CI, Caliphatic , O ( C ) -zaliphatic ), or [0031 ] X is C -10aliphatic ; wherein 1-3 methylene units OH ; of said C -galiphatic are optionally replaced with [0041 ] Jp is —NR , 0 , S— , C (O ), S (O ) 2, or S (O ); wherein X is optionally and independently substituted with 1-4 occurrences of NH2, NH (C1-4aliphatic ) , N ( C1-4ali HNJJp1; phatic ) 2, halogen, C1- aliphatic , OH , O (C1-4aliphatic ), NO2, CN , CO (C1-4aliphatic ) , CO H , CO2 (C1-4ali Jp2 phatic ) , C ( O ) NH2, C ( O )NH ( C1-4aliphatic ) , C (O ) N (C1 4aliphatic )2 , SO (C1-4aliphatic ), SO2( C1-4aliphatic ), SO ,NH ( C14aliphatic1 ), SO, N (Caliphatic ) , NHC ( O ) [0042 ] ?pl is H ,Caliphatic , oxetanyl, tetrahydro (C1-4aliphatic ), N (C1-4aliphatic ) C (O )( C1-4aliphatic ), furanyl, tetrahydropyranyl ; wherein J pl is optionally wherein said C1-4aliphatic is optionally substituted substituted with 1-2 occurrences of OH or halo ; with 1-3 occurrences of halo ; [ 0043 ] p2 is H , methyl, ethyl, CH F , CF3 , or CH2OH ; [0032 ] Q4 is a 3-8 membered saturated or unsaturated [0044 ] Po is H , CN , or SO2CH3; monocyclic ring having 0-4 heteroatoms independently [0045 ] J? m is H , F, C1, or methyl ; selected from nitrogen , oxygen , or sulfur , or a 8-10 [0046 ] Jp is - SO2( C1 - alkyl) , -SO2( C3-6cycloalkyl) , membered saturated or unsaturated bicyclic ring having SO2( 4-6 membered heterocyclyl ), SO2 (C1-4alkyl ) US 2020/0222392 A1 Jul. 16 , 2020 3

N (C1-4alkyl ) 2, or SO2 (C1 - alkyl )- (4-6 membered [0052 ] Compounds of this invention include those heterocyclyl) , wherein said heterocyclyl contains 1 described generally herein , and are further illustrated by the heteroatom selected from oxygen , nitrogen , or sulfur ; classes, subclasses , and species disclosed herein . As used and wherein said Jp is optionally substituted with 1-3 herein , the following definitions shall apply unless otherwise occurences halo , OH , or O (C1-4alkyl ) . indicated . For purposes of this invention , the chemical [ 0047 ] In some embodiments , Ring A is elements are identified in accordance with the Periodic Table of the Elements , CAS version , Handbook of Chemistry and Physics , 75th Ed . Additionally , general principles of organic N chemistry are described in “ Organic Chemistry " , Thomas Sorrell, University Science Books, Sausalito : 1999, and “ March's Advanced Organic Chemistry ” , 5th Ed ., Ed .: Smith , M. B. and March , J. , John Wiley & Sons, New York : 2001, the entire contents of which are hereby incorporated by reference . [ 0048 ] In other embodiments , Ring A is [0053 ] As described herein , a specified number range of atoms includes any integer therein . For example , a group having from 1-4 atoms could have 1 , 2 , 3 , or 4 atoms. N [ 0054 ] As described herein , compounds of the invention may optionally be substituted with one or more substituents , such as are illustrated generally herein , or as exemplified by particular classes, subclasses , and species of the invention . It will be appreciated that the phrase " optionally substituted ” is used interchangeably with the phrase " substituted or [ 0049] Another embodiment provides a compound unsubstituted .” In general, the term “ substituted ” , whether selected from the following : preceded by the term “ optionally ” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise VE - 821 indicated , an optionally substituted group may have a sub NH2 stituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a N specified group , the substituent may be either the same or N different at every position . Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds . [0055 ] Unless otherwise indicated , a substituent con nected by a bond drawn from the center of a ring means that the substituent can be bonded to any position in the ring . In example i below , for instance, Jl can be bonded to any O = S = O position on the pyridyl ring . For bicyclic rings , a bond drawn through both rings indicates that the substituent can be VE - 822 bonded from any position of the bicyclic ring. In example ii below , for instance , Jl can be bonded to the 5 -membered ring NH2 N (on the nitrogen atom , for instance ) , and to the 6 -membered HN ring . N

- (J )s

O - (J ! ) 0-5

[0056 ] The term “ stable ” , as used herein , refers to com [ 0050 ] In yet another embodiment , the compound is pounds that are not substantially altered when subjected to selected from a compound described in WO 2010/071837 . conditions to allow for their production , detection , recovery , [0051 ] In some embodiments , the variables are as depicted purification , and use for one or more of the purposes in the compounds of the disclosure including compounds in disclosed herein . In some embodiments , a stable compound the tables herein . or chemically feasible compound is one that is not substan US 2020/0222392 A1 Jul. 16 , 2020 4 tially altered when kept at a temperature of 40 ° C. or less , in any oxidized form of nitrogen , sulfur , phosphorus , or sili the absence of moisture or other chemically reactive condi con ; the quaternized form of any basic nitrogen or; a tions , for at least a week . substitutable nitrogen of a heterocyclic ring, for example N [0057 ] The term “ aliphatic ” or “ aliphatic group ” , as used (as in 3,4 -dihydro - 2H -pyrrolyl ) , NH (as in pyrrolidinyl) or herein , means a straight- chain (i.e. , unbranched ), branched , NR + ( as in N -substituted pyrrolidinyl) ) . or cyclic , substituted or unsubstituted hydrocarbon chain [0064 ] The term “ unsaturated ” , as used herein , means that that is completely saturated or that contains one or more a moiety has one or more units of unsaturation . As would be units of unsaturation that has a single point of attachment to known by one of skill in the art, unsaturated groups can be the rest of the molecule . partially unsaturated or fully unsaturated . Examples of par [0058 ] Unless otherwise specified , aliphatic groups con tially unsaturated groups include, but are not limited to , tain 1-20 aliphatic carbon atoms. In some embodiments , butene , cyclohexene, and tetrahydropyridine . Fully unsatu aliphatic groups contain 1-10 aliphatic carbon atoms. In rated groups can be aromatic , anti -aromatic , or non -aro other embodiments , aliphatic groups contain 1-8 aliphatic matic . Examples of fully unsaturated groups include, but are carbon atoms. In still other embodiments , aliphatic groups not limited to , phenyl, cyclooctatetraene, pyridyl, thienyl, contain 1-6 aliphatic carbon atoms, and in yet other embodi and 1 -methylpyridin - 2 (1H ) -one. ments aliphatic groups contain 1-4 aliphatic carbon atoms. [0065 ] The term " alkoxy" , or " thioalkyl” , as used herein , Aliphatic groups may be linear or branched , substituted or refers to an alkyl group , as previously defined , attached unsubstituted alkyl, alkenyl, or alkynyl groups. Specific through an oxygen (“ alkoxy ” ) or sulfur ( “ thioalkyl” ) atom . examples include , but are not limited to , methyl, ethyl, [0066 ] The terms “ haloalkyl ”, “ haloalkenyl” , “ haloali isopropyl, n -propyl , sec -butyl , vinyl, n -butenyl , ethynyl, and phatic ” , and “ haloalkoxy” mean alkyl, alkenyl or alkoxy, as tert -butyl . Aliphatic groups may also be cyclic , or have a the case may be, substituted with one or more halogen combination of linear or branched and cyclic groups . atoms. This term includes perfluorinated alkyl groups, such Examples of such types of aliphatic groups include, but are as CF3 and CF CF3. not limited to cyclopropyl, cyclobutyl , cyclopentyl, cyclo [0067 ] The terms“ halogen ” , “ halo ” , and “ hal” mean F , C1, hexyl, cyclohexenyl , CH2- cyclopropyl, CH CH.CH Br, or I. ( CH3) -cyclohexyl. [0068 ] The term “ aryl” used alone or as part of a larger [ 0059 ] The term " cycloaliphatic " (or " carbocycle " or " car moiety as in “ aralkyl” , “ aralkoxy " , or " aryloxyalkyl” , refers bocyclyl" ) refers to a monocyclic Cz -C , hydrocarbon or to monocyclic , bicyclic , and tricyclic ring systems having a bicyclic C8- C12 hydrocarbon that is completely saturated or total of five to fourteen ring members , wherein at least one that contains one or more units of unsaturation , but which is ring in the system is aromatic and wherein each ring in the not aromatic , that has a single point of attachment to the rest system contains 3 to 7 ring members. The term “ aryl” may of the molecule wherein any individual ring in said bicyclic be used interchangeably with the term “ aryl ring ”. ring system has 3-7 members . Examples of cycloaliphatic [0069 ] The term " heteroaryl” , used alone or as part of a groups include , but are not limited to , cycloalkyl and larger moiety as in " heteroaralkyl” or “ heteroarylalkoxy ” , cycloalkenyl groups. Specific examples include, but are not refers to monocyclic , bicyclic , and tricyclic ring systems limited to , cyclohexyl, cyclopropenyl, and cyclobutyl. having a total of five to fourteen ring members, wherein at [ 0060 ] The term " heterocycle " , " heterocyclyl" , or " het least one ring in the system is aromatic , at least one ring in erocyclic ” as used herein means non - aromatic , monocyclic , the system contains one or more heteroatoms, and wherein bicyclic , or tricyclic ring systems in which one or more ring each ring in the system contains 3 to 7 ring members . The members are an independently selected heteroatom . In some term “ heteroaryl ” may be used interchangeably with the embodiments , the “ heterocycle ” , “ heterocyclyl” , or “ hetero term “ heteroaryl ring " or the term " heteroaromatic ” . cyclic ” group has three to fourteen ring members in which Examples of heteroaryl rings include , but are not limited to , one or more ring members is a heteroatom independently 2 -furanyl , 3 - furanyl, N - imidazolyl, 2 -imidazolyl , 4 - imida selected from oxygen , sulfur, nitrogen , or phosphorus, and zolyl , 5 - imidazolyl, benzimidazolyl, 3 - isoxazolyl , 4 - isox each ring in the system contains 3 to 7 ring members. azolyl, 5 - isoxazolyl , 2 - oxazolyl, 4 - oxazolyl , 5 - oxazolyl, [0061 ] Examples of heterocycles include , but are not lim N -pyrrolyl , 2 -pyrrolyl , 3 - pyrrolyl, 2 - pyridyl, 3 - pyridyl, ited to , 3-1H -benzimidazol - 2 -one , 3- ( 1 - alkyl) -benzimida 4 -pyridyl , 2 -pyrimidinyl , 4 -pyrimidinyl , 5 -pyrimidinyl , zol - 2 - one, 2 - tetrahydrofuranyl, 3 - tetrahydrofuranyl, 2 -tetra pyridazinyl ( e.g., 3 -pyridazinyl ) , 2 - thiazolyl, 4 -thiazolyl , hydrothiophenyl, 3 - tetrahydrothiophenyl, 2 -morpholino , 5 - thiazolyl, tetrazolyl ( e.g., 5 - tetrazolyl) , triazolyl ( e.g., 3 -morpholino , 4 -morpholino , 2 -thiomorpholino , 3 - thiomor 2 - triazolyl and 5- triazolyl ), 2 - thienyl , 3- thienyl, benzofuryl , pholino, 4 - thiomorpholino , 1 -pyrrolidinyl , 2 -pyrrolidinyl , benzothiophenyl, indolyl ( e.g., 2 - indolyl) , pyrazolyl ( e.g., 3 -pyrrolidinyl , 1 -tetrahydropiperazinyl , 2- tetrahydropiper 2 -pyrazolyl ) , isothiazolyl, 1,2,3 -oxadiazolyl , 1,2,5 - oxadiaz azinyl, 3 -tetrahydropiperazinyl , 1- piperidinyl , 2 -piperidinyl , olyl , 1,2,4 -oxadiazolyl , 1,2,3 - triazolyl, 1,2,3 -thiadiazolyl , 3 -piperidinyl , 1 - pyrazolinyl, 3- pyrazolinyl , 4 - pyrazolinyl, 1,3,4 -thiadiazolyl , 1,2,5 - thiadiazolyl , purinyl, pyrazinyl , 5 -pyrazolinyl , 1 - piperidinyl, 2 -piperidinyl , 3 - piperidinyl, 1,3,5 - triazinyl, quinolinyl ( e.g., 2 -quinolinyl , 3 - quinolinyl, 4 - piperidinyl, 2 - thiazolidinyl, 3 - thiazolidinyl, 4 - thiazolidi 4 -quinolinyl ), and isoquinolinyl (e.g. , 1 -isoquinolinyl , 3- iso nyl, 1- imidazolidinyl, 2 -imidazolidinyl , 4 - imidazolidinyl, quinolinyl, or 4 - isoquinolinyl) . 5 - imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahy [0070 ] It shall be understood that the term " heteroaryl ” droisoquinolinyl, benzothiolane , benzodithiane , and 1,3 - di includes certain types of heteroaryl rings that exist in hydro - imidazol- 2 -one . equilibrium between two different forms. More specifically , [0062 ] Cyclic groups, ( e.g. cycloaliphatic and hetero for example , species such hydropyridine and pyridinone cycles ), can be linearly fused , bridged , or spirocyclic . (and likewise hydroxypyrimidine and pyrimidinone) are [0063 ] The term " heteroatom ” means one or more of meant to be encompassed within the definition of " het oxygen , sulfur, nitrogen , phosphorus, or silicon ( including , eroaryl. ” US 2020/0222392 A1 Jul. 16 , 2020 5

“ methylene unit” would result in dimethylamine [—N (CH3 ) 2 ] . In instances such as these , one of skill in the art would understand that the nitrogen atom will not have any addi tional atoms bonded to it , and the “ R ” from “ NR ” would be absent in this case . NH [0074 ] Unless otherwise indicated , the optional replace ments form a chemically stable compound . Optional OH replacements can occur both within the chain and / or at either end of the chain ; i.e. both at the point of attachment and /or [0071 ] The term " protecting group " and " protective also at the terminal end . Two optional replacements can also group ” as used herein , are interchangeable and refer to an be adjacent to each other within a chain so long as it results agent used to temporarily block one or more desired func in a chemically stable compound . For example , a Cz ali tional groups in a compound with multiple reactive sites . In phatic can be optionally replaced by 2 nitrogen atoms to certain embodiments , a protecting group has one or more , or form C – N = N . The optional replacements can also com preferably all , of the following characteristics : a ) is added pletely replace all of the carbon atoms in a chain . For selectively to a functional group in good yield to give a example , a Cz aliphatic can be optionally replaced by protected substrate that is b ) stable to reactions occurring at NR- , -C ( O ) - , and -NR- to form - NRC ( O )NR one or more of the other reactive sites; and c ) is selectively (a urea ). removable in good yield by reagents that do not attack the [0075 ] Unless otherwise indicated , if the replacement regenerated , deprotected functional group . As would be occurs at the terminal end , the replacement atom is bound to understood by one skilled in the art, in some cases , the a hydrogen atom on the terminal end . For example , if a reagents do not attack other reactive groups in the com methylene unit of_CH , CH ,CH ; were optionally replaced pound . In other cases, the reagents may also react with other with — O— , the resulting compound could be - OCH , CH3, reactive groups in the compound . Examples of protecting CH_OCH3, or CH2CH2OH . It should be understood groups are detailed in Greene , T. W., Wuts , P. G in “ Pro that if the terminal atom does not contain any free valence tective Groups in Organic Synthesis ” , Third Edition , John electrons, then a hydrogen atom is not required at the Wiley & Sons, New York : 1999 ( and other editions of the terminal end ( e.g., _CH , CH , CH = O or — CH , CH_C = N ) . book ), the entire contents of which are hereby incorporated [0076 ] Unless otherwise indicated , structures depicted by reference . The term “ nitrogen protecting group ” , as used herein are also meant to include all isomeric (e.g. , enantio herein , refers to an agent used to temporarily block one or meric , diastereomeric , geometric , conformational, and rota more desired nitrogen reactive sites in a multifunctional tional) forms of the structure . For example , the R and S compound . Preferred nitrogen protecting groups also pos configurations for each asymmetric center , (2 ) and (E ) sess the characteristics exemplified for a protecting group double bond isomers , and ( Z ) and ( E ) conformational iso above, and certain exemplary nitrogen protecting groups are mers are included in this invention . As would be understood also detailed in Chapter 7 in Greene , T. W., Wuts , P. G in to one skilled in the art , a substituent can freely rotate around “ Protective Groups in Organic Synthesis ” , Third Edition , any rotatable bonds. For example , a substituent drawn as John Wiley & Sons, New York : 1999 , the entire contents of which are hereby incorporated by reference . [0072 ] In some embodiments , a methylene unit of an alkyl mm or aliphatic chain is optionally replaced with another atom or group . Examples of such atoms or groups include , but are N not limited to , nitrogen , oxygen , sulfur, C (O ) - , _CCN CN ) CE= NR ) , CENOR ) , SO— 2 and S02— . These atoms or groups can be combined to form larger groups. Examples of such larger groups include , but are not limited to , -OC (O ) C ( O ) CO CO2 also represents C ( O )NR- , Ce= N / CN ) , - NRCO , NRC (0 ) 0 SONR -NRSO , -NRC ( O )NR— OC ( O ) NR— , and —NRSO NR— , wherein R is , for example , H or Cl- Galiphatic . It should be understood that these groups can be bonded to the methylene units of the aliphatic chain via N single , double , or triple bonds. An example of an optional replacement (nitrogen atom in this case ) that is bonded to the aliphatic chain via a double bond would be CH2CH = N G CHz. In some cases, especially on the terminal end , an optional replacement can be bonded to the aliphatic group [0077 ] Therefore , single stereochemical isomers as well as via a triple bond . One example of this would be enantiomeric , diastereomeric , geometric , conformational , CH ,CH ,CH , CEN . It should be understood that in this and rotationalmixtures of the present compounds are within situation , the terminal nitrogen is not bonded to another the scope of the invention . atom . [0078 ] Unless otherwise indicated , all tautomeric forms of [ 0073 ] It should also be understood that, the term “meth the compounds of the invention are within the scope of the ylene unit” can also refer to branched or substituted meth invention . ylene units . For example , in an isopropyl moiety [ CH [ 0079 ] Additionally , unless otherwise indicated , structures ( CH3) 2 ] , a nitrogen atom ( e.g. NR ) replacing the first recited depicted herein are also meant to include compounds that US 2020/0222392 A1 Jul. 16 , 2020 6

differ only in the presence of one or more isotopically [0085 ] Further pharmaceutically acceptable salts include, enriched atoms. For example , compounds having the present when appropriate , nontoxic ammonium , quaternary ammo structures except for the replacement of hydrogen by deu nium , and amine cations formed using counterions such as terium or tritium , or the replacement of a carbon by a 13C halide, hydroxide , carboxylate , sulfate , phosphate , nitrate , or 14C - enriched carbon are within the scope of this inven loweralkyl sulfonate and aryl sulfonate . Other acids and tion . Such compounds are useful, for example , as analytical bases , while not in themselves pharmaceutically acceptable , tools or probes in biological assays. may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention Pharmaceutically Acceptable Salts and their pharmaceutically acceptable acid or base addition [0080 ] The compounds of this invention can exist in free salts . form for treatment, or where appropriate, as a pharmaceu tically acceptable salt. ABBREVIATIONS [ 0081] A “ pharmaceutically acceptable salt” means any [0086 ] The following abbreviations are used : non - toxic salt of a compound of this invention that , upon [0087 ] DMSO dimethyl sulfoxide administration to a recipient, is capable of providing, either [0088 ] ATP adenosine triphosphate directly or indirectly , a compound of this invention or an [0089 ] " HNMR proton nuclear magnetic resonance inhibitorily active metabolite or residue thereof As used [ 0090 ] HPLC high performance liquid chromatography herein , the term “ inhibitorily active metabolite or residue [ 0091 ] LCMS liquid chromatography -mass spectrometry thereof” means that a metabolite or residue thereof is also an [0092 ] TLC thin layer chromatography inhibitor of the ATR protein kinase. [ 0082 ] Pharmaceutically acceptable salts are well known [0093 ] Rt retention time in the art. For example, S. M. Berge et al. , describe phar maceutically acceptable salts in detail in J. Pharmaceutical Compound Uses Sciences , 1977 , 66 , 1-19 , incorporated herein by reference . [0094 ] One aspect of this invention provides compounds Pharmaceutically acceptable salts of the compounds of this that are inhibitors of ATR kinase , and thus are useful for invention include those derived from suitable inorganic and treating or lessening the severity of a disease , condition , or organic acids and bases. These salts can be prepared in situ disorder where ATR is implicated in the disease , condition , during the final isolation and purification of the compounds . or disorder. Acid addition salts can be prepared by 1 ) reacting the [0095 ] Another aspect of this invention provides com purified compound in its free -based form with a suitable pounds that are useful for the treatment of diseases , disor organic or inorganic acid and 2 ) isolating the salt thus ders , and conditions characterized by excessive or abnormal formed . cell proliferation . Such diseases include, a proliferative or [ 0083 ] Examples of pharmaceutically acceptable , non hyperproliferative disease . Examples of proliferative and toxic acid addition salts are salts of an amino group formed hyperproliferative diseases include, without limitation , can with inorganic acids such as hydrochloric acid , hydrobromic cer and myeloproliferative disorders . acid , phosphoric acid , sulfuric acid and perchloric acid or [0096 ] In some embodiments, said compounds are with organic acids such as acetic acid , oxalic acid , maleic selected from the group consisting of a compound of for acid , tartaric acid , citric acid , succinic acid or malonic acid mula I. The term “ cancer " includes, but is not limited to the or by using other methods used in the art such as ion following types of cancers : oral , lung, gastrointestinal , geni exchange . Other pharmaceutically acceptable salts include tourinary tract, liver , bone, nervous system , gynecological , adipate , alginate , ascorbate , aspartate , benzenesulfonate , skin , thyroid gland , or adrenal gland . More specifically , benzoate , bisulfate , borate , butyrate , camphorate , camphor " cancer ” includes , but is not limited to the following can sulfonate , citrate , cyclopentanepropionate , digluconate , cers : Oral : buccal cavity , lip , tongue, mouth , pharynx ; dodecylsulfate , ethanesulfonate , formate , fumarate , gluco Cardiac : sarcoma ( angiosarcoma, fibrosarcoma, rhab heptonate , glycerophosphate , glycolate , gluconate , glyco domyosarcoma, liposarcoma ), myxoma, rhabdomyoma, late , hemisulfate , heptanoate , hexanoate , hydrochloride , fibroma, lipoma and teratoma; Lung : bronchogenic carci hydrobromide, hydroiodide, 2- hydroxy -ethanesulfonate , noma ( squamous cell or epidermoid , undifferentiated small lactobionate , lactate , laurate , lauryl sulfate ,malate , maleate , cell, undifferentiated large cell, adenocarcinoma) , alveolar malonate , methanesulfonate , 2 -naphthalenesulfonate , nico (bronchiolar ) carcinoma, bronchial adenoma, sarcoma, lym tinate , nitrate , oleate , oxalate , palmitate , palmoate , pectinate , phoma, chondromatous hamartoma, mesothelioma; Gastro persulfate, 3 -phenylpropionate , phosphate , picrate , pivalate , intestinal : esophagus (squamous cell carcinoma , larynx , propionate , salicylate , stearate , succinate , sulfate , tartrate , adenocarcinoma, leiomyosarcoma, lymphoma) , stomach thiocyanate , p - toluenesulfonate , undecanoate , valerate salts , ( carcinoma, lymphoma , leiomyosarcoma) , pancreas (ductal and the like . adenocarcinoma, insulinoma, glucagonoma, gastrinoma, [0084 ] Base addition salts can be prepared by 1 ) reacting carcinoid tumors, vipoma) , small bowel or small intestines the purified compound in its acid form with a suitable (adenocarcinoma , lymphoma, carcinoid tumors , Karposi's organic or inorganic base and 2 ) isolating the salt thus sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, formed . Salts derived from appropriate bases include alkali fibroma) , large bowel or large intestines ( adenocarcinoma, metal ( e.g., sodium , lithium , and potassium ) , alkaline earth tubular adenoma, villous adenoma, hamartoma, leio metal ( e.g., magnesium and calcium ), ammonium and myoma) , colon , colon -rectum , colorectal; rectum , Genito N + (C1 - alkyl) 4 salts . This invention also envisions the quat urinary tract: kidney ( adenocarcinoma, Wilm's tumor [neph ernization of any basic nitrogen -containing groups of the roblastoma] , lymphoma, leukemia ), bladder and urethra compounds disclosed herein . Water or oil- soluble or dis (squamous cell carcinoma , transitional cell carcinoma, persible products may be obtained by such quaternization . adenocarcinoma) , prostate ( adenocarcinoma, sarcoma ), tes US 2020/0222392 A1 Jul. 16 , 2020 7

tis ( seminoma, teratoma, embryonal carcinoma, teratocarci Pharmaceutically Acceptable Derivatives or noma, choriocarcinoma, sarcoma, interstitial cell carcinoma , Prodrugs fibroma, fibroadenoma, adenomatoid tumors, lipoma ); Liver : hepatoma (hepatocellular carcinoma) , cholangiocar [0100 ] In addition to the compounds of this invention , cinoma, hepatoblastoma, angiosarcoma, hepatocellular pharmaceutically acceptable derivatives or prodrugs of the adenoma, hemangioma, biliary passages; Bone: osteogenic compounds of this invention may also be employed in sarcoma ( osteosarcoma) , fibrosarcoma, malignant fibrous compositions to treat or prevent the herein identified disor histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant ders. lymphoma (reticulum cell sarcoma) , multiple myeloma, [0101 ] The compounds of this invention can also exist as malignant giant cell tumor chordoma, osteochronfroma (os pharmaceutically acceptable derivatives . teocartilaginous exostoses ), benign chondroma, chondro [0102 ] A " pharmaceutically acceptable derivative " is an blastoma, chondromyxofibroma, osteoid osteoma and giant adduct or derivative which , upon administration to a patient cell tumors; Nervous system : skull (osteoma , hemangioma, in need , is capable of providing, directly or indirectly , a granuloma, xanthoma, osteitis deformans) , meninges (men compound as otherwise described herein , or a metabolite or ingioma , meningiosarcoma , gliomatosis ), brain ( astrocy residue thereof. Examples of pharmaceutically acceptable toma, medulloblastoma, glioma, ependymoma, germinoma derivatives include , but are not limited to , esters and salts of [pinealoma ) , glioblastoma multiform , oligodendroglioma, such esters . schwannoma, retinoblastoma, congenital tumors ), spinal [0103 ] A “ pharmaceutically acceptable derivative or pro cord neurofibroma, meningioma, glioma, sarcoma) ; Gyne drug ” means any pharmaceutically acceptable ester , salt of cological : uterus ( endometrial carcinoma) , cervix ( cervical an ester or other derivative or salt thereof of a compound , of carcinoma , pre- tumor cervical dysplasia ), ovaries (ovarian this invention ich , upon administration to a recipient, is carcinoma ( serous cystadenocarcinoma, mucinous cystade capable of providing , either directly or indirectly , a com nocarcinoma, unclassified carcinoma) , granulosa -thecal cell pound of this invention or an inhibitorily active metabolite tumors , Sertoli -Leydig cell tumors , dysgerminoma, malig or residue thereof. Particularly favoured derivatives or pro nant teratoma) , vulva (squamous cell carcinoma, intraepi drugs are those that increase the bioavailability of the thelial carcinoma, adenocarcinoma, fibrosarcoma, mela compounds of this invention when such compounds are noma) , vagina (clear cell carcinoma, squamous cell administered to a patient ( e.g ., by allowing an orally admin carcinoma, botryoid sarcoma ( embryonal rhabdomyosar istered compound to be more readily absorbed into the coma) , fallopian tubes (carcinoma ) , breast ; Hematologic : blood ) or which enhance delivery of the parent compound to blood (myeloid leukemia (acute and chronic ], acute lym a biological compartment ( e.g. , the brain or lymphatic phoblastic leukemia , chronic lymphocytic leukemia ,myelo system ) relative to the parent species. proliferative diseases, multiple myeloma , myelodysplastic [0104 ] Pharmaceutically acceptable prodrugs of the com syndrome) , Hodgkin's disease , non -Hodgkin's lymphoma pounds of this invention include, without limitation , esters , [malignant lymphoma) hairy cell ; lymphoid disorders ; Skin : amino acid esters, phosphate esters ,metal salts and sulfonate malignant melanoma, basal cell carcinoma, squamous cell esters . carcinoma, Karposi's sarcoma, keratoacanthoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids , Pharmaceutical Compositions psoriasis, Thyroid gland : papillary thyroid carcinoma, fol [0105 ] The present invention also provides compounds licular thyroid carcinoma, undifferentiated thyroid cancer , and compositions that are useful as inhibitors of ATR kinase . medullary thyroid carcinoma , multiple endocrine neoplasia [0106 ] One aspect of this invention provides pharmaceu type 2A , multiple endocrine neoplasia type 2B , familial tically acceptable compositions that comprise any of the medullary thyroid cancer, pheochromocytoma, paragan compounds as described herein , and optionally comprise a glioma ; and Adrenal glands : neuroblastoma. pharmaceutically acceptable carrier, adjuvant or vehicle. [0097 ] In some embodiments , the cancer is selected from [0107 ] The pharmaceutically acceptable carrier , adjuvant, a cancer of the lung or the pancreas. In other embodiments , or vehicle , as used herein , includes any and all solvents , the cancer is selected from lung cancer, head and neck diluents , or other liquid vehicle , dispersion or suspension cancer, pancreatic cancer, gastric cancer, or brain cancer. In aids, surface active agents , isotonic agents, thickening or yet other embodiments , the cancer is selected from non emulsifying agents , preservatives , solid binders , lubricants small cell lung cancer, small cell lung cancer, pancreatic and the like , as suited to the particular dosage form desired . cancer, biliary tract cancer , head and neck cancer, bladder Remington's Pharmaceutical Sciences, Sixteenth Edition , E. cancer, colorectal cancer , glioblastoma, esophageal cancer, W. Martin (Mack Publishing Co., Easton , Pa. , 1980 ) dis breast cancer , hepatocellular carcinoma, or ovarian cancer . closes various carriers used in formulating pharmaceutically [ 0098 ] Thus , the term " cancerous cell ” as provided herein , acceptable compositions and known techniques for the includes a cell afflicted by any one of the above - identified preparation thereof Except insofar as any conventional car conditions . In some embodiments , the cancer is selected rier medium is incompatible with the compounds of the from colorectal, thyroid , or breast cancer. invention , such as by producing any undesirable biological [0099 ] The term “myeloproliferative disorders ” , includes effect or otherwise interacting in a deleterious manner with disorders such as polycythemia vera , thrombocythemia , any other component( s ) of the pharmaceutically acceptable myeloid metaplasia with myelofibrosis , hypereosinophilic composition , its use is contemplated to be within the scope syndrome, juvenile myelomonocytic leukemia , systemic of this invention . mast cell disease, and hematopoietic disorders , in particular, [0108 ] Some examples of materials which can serve as acute -myelogenous leukemia ( AML ), chronic -myelogenous pharmaceutically acceptable carriers include , but are not leukemia (CML ) , acute -promyelocytic leukemia (APL ) , and limited to , ion exchangers , alumina, aluminum stearate , acute lymphocytic leukemia (ALL ) . lecithin , serum proteins , such as human serum albumin , US 2020/0222392 A1 Jul. 16 , 2020 8 buffer substances such as phosphates , glycine, sorbic acid , or [0112 ] Examples of DNA - damaging agents that may be potassium sorbate , partial glyceride mixtures of saturated used in combination with compounds of this invention vegetable fatty acids, water , salts or electrolytes , such as include , but are not limited to Platinating agents , such as protamine sulfate , disodium hydrogen phosphate , potassium Carboplatin , Nedaplatin , Satraplatin and other derivatives; hydrogen phosphate , sodium chloride, zinc salts , colloidal Topo I inhibitors , such as Topotecan , irinotecan /SN38 , silica , magnesium trisilicate , polyvinyl pyrrolidone , poly rubitecan and other derivatives ; Topo II inhibitors , such as acrylates, waxes, polyethylene -polyoxypropylene - block Etoposide (VP - 16 ) , Daunorubicin , Doxorubicin , Mitoxan polymers , wool fat, sugars such as lactose , glucose and trone , Aclarubicin , Epirubicin , Idarubicin , Amrubicin , sucrose ; starches such as corn starch and potato starch ; Amsacrine , Pirarubicin , Valrubicin , Zorubicin , Teniposide cellulose and its derivatives such as sodium carboxymethyl and other derivatives ; Antimetabolites, such as Folic family cellulose , ethyl cellulose and cellulose acetate ; powdered (Methotrexate , Pemetrexed and relatives ); Purine antago tragacanth ; malt ; gelatin ; talc ; excipients such as cocoa nists and Pyrimidine antagonists ( Thioguanine, Fludarabine , butter and suppository waxes ; oils such as peanut oil, Cladribine, Cytarabine, Gemcitabine , 6 -Mercaptopurine , cottonseed oil ; safflower oil; sesame oil ; olive oil ; corn oil 5 -Fluorouracil (5FU ) and relatives) ; Alkylating agents , such and soybean oil ; glycols , such a propylene glycol or poly as Nitrogen mustards ( Cyclophosphamide, Melphalan , ethylene glycol; esters such as ethyl oleate and ethyl laurate ; Chlorambucil , mechlorethamine , Ifosfamide and relatives ) ; agar ; buffering agents such as magnesium hydroxide and nitrosoureas (eg Carmustine ) ; Triazenes ( Dacarbazine , aluminum hydroxide ; alginic acid ; pyrogen - free water ; iso temozolomide ); Alkyl sulphonates (eg Busulfan ); Procarba tonic saline ; Ringer's solution ; ethyl alcohol, and phosphate zine and Aziridines ; Antibiotics , such as Hydroxyurea , buffer solutions, as well as other non - toxic compatible Anthracyclines (doxorubicin , daunorubicin , epirubicin and lubricants such as sodium lauryl sulfate and magnesium other derivatives ); Anthracenediones (Mitoxantrone and stearate , as well as coloring agents , releasing agents , coating relatives ); Streptomyces family (Bleomycin , Mitomycin C , agents , sweetening , flavoring and perfuming agents , preser actinomycin ); and Ultraviolet light. vatives and antioxidants can also be present in the compo [0113 ] Other therapies or anticancer agents that may be sition , according to the judgment of the formulator. used in combination with the inventive agents of the present invention include surgery , radiotherapy ( in but a few Combination Therapies examples, gamma- radiation , neutron beam radiotherapy, [ 0109 ] Another aspect of this invention is directed towards electron beam radiotherapy , proton therapy, brachytherapy , a method of treating cancer in a subject in need thereof, and systemic radioactive isotopes, to name a few ), endocrine comprising administration of a compound of this invention therapy, biologic response modifiers ( interferons, interleu or a pharmaceutically acceptable salt thereof, and an addi kins, and tumor necrosis factor ( TNF ) to name a few ) , tional therapeutic agent. In some embodiments , said method hyperthermia and cryotherapy, agents to attenuate any comprises the sequential or co - administration of the com adverse effects ( e.g., antiemetics ) , and other approved che pound or a pharmaceutically acceptable salt thereof, and the motherapeutic drugs, including , but not limited to , the DNA additional therapeutic agent. damaging agents listed herein , spindle poisons ( Vinblastine, [0110 ] In some embodiments , said additional therapeutic Vincristine, Vinorelbine, Paclitaxel) , podophyllotoxins agent is an anti - cancer agent. In other embodiments , said (Etoposide , Irinotecan , Topotecan ) , nitrosoureas (Carmus additional therapeutic agent is a DNA -damaging agent. It tine, Lomustine ) , inorganic ions (Cisplatin , Carboplatin ) , shall be understood that the additional therapeutic agentmay enzymes (Asparaginase ), and hormones ( Tamoxifen , Leu comprise one or more therapies . In yet other embodiments , prolide, Flutamide , and Megestrol) , GleevecTM , adriamycin , said additional therapeutic agent is selected from radiation dexamethasone , and cyclophosphamide . therapy , chemotherapy, or other agents typically used in [0114 ] A compound of the instant invention may also be combination with radiation therapy or chemotherapy, such useful for treating cancer in combination with any of the as radiosensitizers and chemosensitizers . In yet other following therapeutic agents : abarelix (Plenaxis depot ); embodiments , said additional therapeutic agent is ionizing aldes leukin (Prokine® ); Aldesleukin ( Proleukin® ) ; Alemtu radiation . In some embodiments , said additional therapeutic zumabb ( Campath® ); alitretinoin (Panretin® ); allopurinol agent comprises ionizing radiation and a DNA - damaging ( Zyloprim® ) ; altretamine (Hexalen ) ; amifostine agent. ( Ethyol® ) ; anastrozole ( Arimidex® ) ; arsenic trioxide [0111 ] As would be known by one of skill in the art , ( Trisenox ) ; asparaginase ( Elspar® ); azacitidine radiosensitizers are agents that can be used in combination (Vidaza® ); bevacuzimab (Avastin® ); bexarotene capsules with radiation therapy . Radiosensitizers work in various ( Targretin® ) ; bexarotene gel ( Targretin® ) ; bleomycin ( Ble different ways, including, but not limited to ,making cancer noxane® ) ; bortezomib (Velcade® ); busulfan intravenous cells more sensitive to radiation therapy, working in synergy (Busulfex® ) ; busulfan oral (Myleran® ); calusterone with radiation therapy to provide an improved synergistic (Methosarb® ); capecitabine ( Xeloda® ), carboplatin (Para effect, acting additively with radiation therapy , or protecting platin® ) ; carmustine (BCNU? , BICNU? ); carmustine surrounding healthy cells from damage caused by radiation (Gliadel® ); carmustine with Polifeprosan 20 Implant (Glia therapy. Likewise chemosensitizers are agents that can be del Wafer® ) ; celecoxib (Celebrex® ); cetuximab (Erbitux® ) ; used in combination with chemotherapy. Similarly , chemo chlorambucil (Leukeran® ) ; cisplatin (Platinol® ) ; cladribine sensitizers work in various different ways, including, but not (Leustatin® , 2 -CdA® ) ; clofarabine (Clolar® ) ; cyclophos limited to , making cancer cells more sensitive to chemo phamide (Cytoxan , Neosar ); cyclophosphamide (Cy therapy , working in synergy with chemotherapy to provide toxan Injection ) ; cyclophosphamide (Cytoxan Tablet® ) ; an improved synergistic effect , acting additively to chemo cytarabine (Cytosar -U? ) ; cytarabine liposomal (Depo therapy, or protecting surrounding healthy cells from dam Cyt® ) ; dacarbazine (DTIC -Dome® ) ; dactinomycin , actino age caused by chemotherapy . mycin D (Cosmegen® ) ; Darbepoetin alfa ( Aranesp® ) ; US 2020/0222392 A1 Jul. 16 , 2020 9 daunorubicin liposomal (DanuoXome® ); daunorubicin , tions for administration to animals or humans. These phar daunomycin (Daunorubicin® ) ; daunorubicin , daunomycin maceutical compositions, which comprise an amount of the (Cerubidine® ) ; Denileukin diftitox ( Ontak® ) ; dexrazoxane ATR inhibitor effective to treat or prevent the diseases or (Zinecard® ); docetaxel ( Taxotere® ) ; doxorubicin (Adri conditions described herein and a pharmaceutically accept amycin PFS® ) ; doxorubicin (Adriamycin® , Rubex® ) ; able carrier , are another embodiment of the present inven doxorubicin (Adriamycin PFS Injection® ); doxorubicin tion . liposomal (Doxil® ) ; dromostanolone propionate (dromo [0118 ] The exact amount of compound required for treat stanolone® ) ; dromostanolone propionate (masterone injec ment will vary from subject to subject, depending on the tion® ) ; Elliott's B Solution (Elliott's B Solution® ) ; epiru species , age , and general condition of the subject, the bicin (Ellence ) ; Epoetin alfa ( epogen ) ; erlotinib severity of the infection , the particular agent, its mode of ( Tarceva® ) ; estramustine (Emcyt® ) ; etoposide phosphate administration , and the like . The compounds of the inven ( Etopophos® ) ; etoposide , VP - 16 (Vepesid® ) ; exemestane tion are preferably formulated in dosage unit form for ease (Aromasin® ); Filgrastim (Neupogen® ) ; floxuridine ( in of administration and uniformity of dosage. The expression traarterial) (FUDR® ) ; fludarabine ( Fludara® ) ; fluorouracil, “ dosage unit form ” as used herein refers to a physically 5 -FU ( Adrucil® ) ; fulvestrant (Faslodex® ); gefitinib discrete unit of agent appropriate for the patient to be ( Iressa® ) ; gemcitabine (Gemzar® ) ; gemtuzumab ozogami treated . It will be understood , however , that the total daily cin (Mylotarg® ) ; goserelin acetate ( Zoladex Implant® ); usage of the compounds and compositions of the present goserelin acetate (Zoladex® ) ; histrelin acetate (Histrelin invention will be decided by the attending physician within implant ); hydroxyurea (Hydrea ); Ibritumomab Tiuxetan the scope of sound medical judgment. The specific effective ( Zevalin® ) ; idarubicin (Idamycin ); ifosfamide ( IFEX® ); dose level for any particular patient or organism will depend imatinib mesylate (Gleevec® ); interferon alfa 2a ( Roferon upon a variety of factors including the disorder being treated A® ); Interferon alfa -2b (Intron AC ) ; irinotecan (Camp and the severity of the disorder ; the activity of the specific tosar® ); lenalidomide (Revlimid® ) ; letrozole (Ferrara® ); compound employed ; the specific composition employed ; leucovorin (Wellcovorin® , Leucovorin® ) ; Leuprolide the age, body weight, general health , sex and diet of the Acetate (Eligard® ) ; levamisole (Ergamisol® ) ; lomustine , patient; the time of administration , route of administration , CCNU (CeeBU® ) ; meclorethamine, nitrogen mustard and rate of excretion of the specific compound employed ; ( Mustargen® ) ; megestrol acetate (Megace® ) ; melphalan , the duration of the treatment; drugs used in combination or L - PAM (Alkeran® ) ; mercaptopurine , 6 -MP (Purinethol® ) ; coincidental with the specific compound employed , and like mesna (Mesnex® ) ; mesna (Mesnex tabs® ) ; methotrexate factors well known in the medical arts . The term “ patient ” , (Methotrexate® ); methoxsalen (Uvadex® ) ; mitomycin C as used herein , means an animal , preferably a mammal, and (Mutamycin® ); mitotane (Lysodren® ) ; mitoxantrone (No most preferably a human . vantrone® ) ; nandrolone phenpropionate ( Durabolin - 50 % ) ; [0119 ] In some embodiments , these compositions option nelarabine (Arranon® ); Nofetumomab (Verluma® ) ; ally further comprise one or more additional therapeutic Oprelvekin (Neumega® ); oxaliplatin (Eloxatin® ); pacli agents . For example , chemotherapeutic agents or other anti taxel (Paxene ) ; paclitaxel ( Taxol® ) ; paclitaxel protein proliferative agents may be combined with the compounds bound particles (Abraxane® ); palifermin (Kepivance® ); of this invention to treat proliferative diseases and cancer . pamidronate ( Aredia® ) ; pegademase (Adagen (Pegademase Examples of known agents with which these compositions Bovine ) ® ) ; pegaspargase (Oncaspar ) ; Pegfilgrastim (Neu can be combined are listed above under the “ Combination lasta® ) ; pemetrexed disodium ( Alimta® ) ; pentostatin (Ni Therapies” section and also throughout the specification . pent® ) ; pipobroman ( Vercyte® ) ; plicamycin , mithramycin Some embodiments provide a simultaneous , separate or (Mithracin® ) ; porfimer sodium ( Photofrin® ); procarbazine sequential use of a combined preparation . (Matulane® ) ; quinacrine (Atabrine® ); Rasburicase (Eli tek® ); Rituximab (Rituxan® ); sargramostim (Leukine® ); Modes of Administration and Dosage Forms Sargramostim (Prokiner ) ; sorafenib (Nexavar ); strepto [0120 ] The pharmaceutically acceptable compositions of zocin (Zanosar® ); sunitinib maleate (Sutent® ); talc (Scle this invention can be administered to humans and other rosol® ) ; tamoxifen (Nolvadex® ) ; temozolomide ( Temo animals orally , rectally , parenterally , intracisternally , intra dar® ) ; teniposide, VM - 26 (Vumon® ) ; testolactone vaginally , intraperitoneally , topically ( as by powders , oint ( Teslac® ) ; thioguanine , 6 - TG Thioguanine ) ; thiotepa ments , or drops) , bucally , as an oral or nasal spray, or the ( Thioplex® ) ; topotecan (Hycamtin® ) ; toremifene (Fares like , depending on the severity of the infection being treated . ton® ) ; Tositumomab (Bexxar® ) ; Tositumomab/ I - 131 tosi In certain embodiments , the compounds of the invention tumomab (Bexxar® ) ; Trastuzumab (Herceptin® ) ; tretinoin , may be administered orally or parenterally at dosage levels ATRA ( Vesanoid® ) ; Uracil Mustard (Uracil Mustard Cap of about 0.01 mg/ kg to about 50 mg/ kg and preferably from sules® ) ; valrubicin (Valstar® ) ; vinblastine (Velban® ) ; vin about 1 mg/ kg to about 25 mg/ kg , of subject body weight per cristine (Oncovin® ) ; vinorelbine ( Navelbine® ); zoledronate day, one or more times a day, to obtain the desired thera ( Zometar ) and vorinostat (Zolinza® ) . peutic effect. [0115 ] For a comprehensive discussion of updated cancer [0121 ] Liquid dosage forms for oral administration therapies see, http://www.nci.nih.gov/ , a list of the FDA include , but are not limited to , pharmaceutically acceptable approved oncology drugs at http://www.fda.gov/cder/can emulsions, microemulsions, solutions , suspensions, syrups cer/ druglistframe.htm , and The Merck Manual, Seventeenth and elixirs . In addition to the active compounds, the liquid Ed . 1999 , the entire contents of which are hereby incorpo dosage formsmay contain inert diluents commonly used in rated by reference . the art such as , for example , water or other solvents , [0116 ] Compositions for Administration into a Subject solubilizing agents and emulsifiers such as ethyl alcohol, [ 0117 ] The ATR kinase inhibitors or pharmaceutical salts isopropyl alcohol, ethyl carbonate , ethyl acetate , benzyl thereof may be formulated into pharmaceutical composi alcohol, benzyl benzoate , propylene glycol, 1,3 -butylene US 2020/0222392 A1 Jul. 16 , 2020 10

glycol, dimethylformamide , oils ( in particular , cottonseed , vinylpyrrolidinone , sucrose , and acacia , c ) humectants such groundnut, corn , germ , olive , castor, and sesame oils ), as glycerol, d ) disintegrating agents such as agar- agar, glycerol, tetrahydrofurfuryl alcohol , polyethylene glycols calcium carbonate , potato or tapioca starch , alginic acid , and fatty acid esters of sorbitan , and mixtures thereof. certain silicates, and sodium carbonate , e ) solution retarding Besides inert diluents , the oral compositions can also agents such as paraffin , f) absorption accelerators such as include adjuvants such as wetting agents , emulsifying and quaternary ammonium compounds, g ) wetting agents such suspending agents , sweetening , flavoring, and perfuming as, for example , cetyl alcohol and glycerolmonostearate , h ) agents . absorbents such as kaolin and bentonite clay, and i) lubri [0122 ] Injectable preparations, for example , sterile inject cants such as talc , calcium stearate , magnesium stearate , able aqueous or oleaginous suspensions may be formulated solid polyethylene glycols , sodium lauryl sulfate , and mix according to the known art using suitable dispersing or tures thereof In the case of capsules , tablets and pills , the wetting agents and suspending agents. The sterile injectable dosage form may also comprise buffering agents . preparation may also be a sterile injectable solution , sus [0127 ] Solid compositions of a similar type may also be pension or emulsion in a nontoxic parenterally acceptable employed as fillers in soft and hard - filled gelatin capsules diluent or solvent, for example , as a solution in 1,3 -butane using such excipients as lactose or milk sugar as well as high diol. Among the acceptable vehicles and solvents that may molecular weight polyethylene glycols and the like . The be employed are water , Ringer's solution , U.S.P. and iso solid dosage forms of tablets , dragees, capsules, pills , and tonic sodium chloride solution . In addition , sterile , fixed oils granules can be prepared with coatings and shells such as are conventionally employed as a solvent or suspending enteric coatings and other coatings well known in the medium . For this purpose any bland fixed oil can be pharmaceutical formulating art. They may optionally con employed including synthetic mono- or diglycerides. In tain opacifying agents and can also be of a composition that addition , fatty acids such as oleic acid are used in the they release the active ingredient( s ) only , or preferentially , in preparation of injectables. a certain part of the intestinal tract, optionally , in a delayed [0123 ] The injectable formulations can be sterilized , for manner. Examples of embedding compositions that can be example , by filtration through a bacterial- retaining filter, or used include polymeric substances and waxes. Solid com by incorporating sterilizing agents in the form of sterile solid positions of a similar type may also be employed as fillers compositions which can be dissolved or dispersed in sterile in soft and hard - filled gelatin capsules using such excipients water or other sterile injectable medium prior to use . as lactose or milk sugar as well as high molecular weight [0124 ] In order to prolong the effect of a compound of the polethylene glycols and the like . present invention , it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injec [0128 ] The active compounds can also be in microencap tion . This may be accomplished by the use of a liquid sulated form with one or more excipients as noted above . suspension of crystalline or amorphous material with poor The solid dosage forms of tablets, dragees , capsules , pills , water solubility . The rate of absorption of the compound and granules can be prepared with coatings and shells such then depends upon its rate of dissolution that , in turn , may as enteric coatings, release controlling coatings and other depend upon crystal size and crystalline form . Alternatively , coatings well known in the pharmaceutical formulating art . delayed absorption of a parenterally administered compound In such solid dosage forms the active compound may be form is accomplished by dissolving or suspending the com admixed with at least one inert diluent such as sucrose , pound in an oil vehicle . Injectable depot forms are made by lactose or starch . Such dosage formsmay also comprise , as forming microencapsule matrices of the compound in bio is normal practice , additional substances other than inert degradable polymers such as polylactide -polyglycolide . diluents , e.g. , tableting lubricants and other tableting aids Depending upon the ratio of compound to polymer and the such a magnesium stearate and microcrystalline cellulose . In nature of the particular polymer employed , the rate of the case of capsules , tablets and pills , the dosage formsmay compound release can be controlled . Examples of other also comprise buffering agents . They may optionally contain biodegradable polymers include poly ( orthoesters ) and poly opacifying agents and can also be of a composition that they ( anhydrides ) . Depot injectable formulations are also pre release the active ingredient( s ) only , or preferentially , in a pared by entrapping the compound in liposomes or micro certain part of the intestinal tract, optionally , in a delayed emulsions that are compatible with body tissues . manner . Examples of embedding compositions that can be [0125 ] Compositions for rectal or vaginal administration used include polymeric substances and waxes . are preferably suppositories which can be prepared by [ 0129 ] Dosage forms for topical or transdermal adminis mixing the compounds of this invention with suitable non tration of a compound of this invention include ointments , irritating excipients or carriers such as cocoa butter, poly pastes , creams, lotions, gels , powders , solutions, sprays , ethylene glycol or a suppository wax which are solid at inhalants or patches. The active component is admixed ambient temperature but liquid at body temperature and under sterile conditions with a pharmaceutically acceptable therefore melt in the rectum or vaginal cavity and release the carrier and any needed preservatives or buffers as may be active compound . required . Ophthalmic formulation , eardrops, and eye drops [ 0126 ] Solid dosage forms for oral administration include are also contemplated as being within the scope of this capsules , tablets , pills , powders , and granules . In such solid invention . Additionally , the present invention contemplates dosage forms, the active compound is mixed with at least the use of transdermal patches , which have the added one inert, pharmaceutically acceptable excipient or carrier advantage ofproviding controlled delivery of a compound to such as sodium citrate or dicalcium phosphate and /or a ) the body. Such dosage forms can be made by dissolving or fillers or extenders such as starches , lactose, sucrose , glu dispensing the compound in the proper medium . Absorption cose , mannitol, and silicic acid , b ) binders such as, for enhancers can also be used to increase the flux of the example , carboxymethylcellulose, alginates , gelatin , poly compound across the skin . The rate can be controlled by US 2020/0222392 A1 Jul. 16 , 2020 11

either providing a rate controlling membrane or by dispers the skin , or the lower intestinal tract . Suitable topical for ing the compound in a polymer matrix or gel. mulations are readily prepared for each of these areas or organs . [0130 ] The compositions of the present invention may be [0135 ] Topical application for the lower intestinal tract can administered orally , parenterally , by inhalation spray , topi be effected in a rectal suppository formulation (see above) or cally , rectally , nasally , buccally , vaginally or via an in a suitable enema formulation . Topically - transdermal implanted reservoir . The term “ parenteral ” as used herein patches may also be used . includes , but is not limited to , subcutaneous, intravenous , [0136 ] For topical applications, the pharmaceutical com intramuscular, intra -articular , intra -synovial , intrasternal, positions may be formulated in a suitable ointment contain intrathecal, intrahepatic , intralesional and intracranial injec ing the active component suspended or dissolved in one or tion or infusion techniques . Preferably , the compositions are more carriers . Carriers for topical administration of the administered orally , intraperitoneally or intravenously . compounds of this invention include, but are not limited to , [0131 ] Sterile injectable forms of the compositions of this mineral oil, liquid petrolatum , white petrolatum , propylene invention may be aqueous or oleaginous suspension . These glycol, polyoxyethylene, polyoxypropylene compound , suspensions may be formulated according to techniques emulsifying wax and water . Alternatively , the pharmaceuti known in the art using suitable dispersing or wetting agents cal compositions can be formulated in a suitable lotion or and suspending agents . The sterile injectable preparation cream containing the active components suspended or dis may also be a sterile injectable solution or suspension in a solved in one or more pharmaceutically acceptable carriers . non - toxic parenterally - acceptable diluent or solvent, for Suitable carriers include , but are not limited to , mineral oil, example as a solution in 1,3 - butanediol. Among the accept sorbitan monostearate , polysorbate 60 , cetyl esters wax , able vehicles and solvents that may be employed are water, cetearyl alcohol, 2 -octyldodecanol , benzyl alcohol and Ringer's solution and isotonic sodium chloride solution . In water . addition , sterile , fixed oils are conventionally employed as a [0137 ] For ophthalmic use , the pharmaceutical composi solvent or suspending medium . For this purpose , any bland tions may be formulated as micronized suspensions in fixed oil may be employed including synthetic mono- or isotonic , pH adjusted sterile saline , or, preferably , as solu di- glycerides. Fatty acids, such as oleic acid and its glycer tions in isotonic , pH adjusted sterile saline, either with or ide derivatives are useful in the preparation of injectables, as without a preservative such as benzylalkonium chloride. are natural pharmaceutically -acceptable oils , such as olive Alternatively , for ophthalmic uses, the pharmaceutical com oil or castor oil, especially in their polyoxyethylated ver positions may be formulated in an ointment such as petro sions . These oil solutions or suspensions may also contain a latum . long - chain alcohol diluent or dispersant, such as carboxym [0138 ] The pharmaceutical compositions of this invention ethyl cellulose or similar dispersing agents which are com may also be administered by nasal aerosol or inhalation . monly used in the formulation of pharmaceutically accept Such compositions are prepared according to techniques able dosage forms including emulsions and suspensions . well -known in the art of pharmaceutical formulation and Other commonly used surfactants , such as Tweens, Spans may be prepared as solutions in saline , employing benzyl and other emulsifying agents or bioavailability enhancers alcohol or other suitable preservatives, absorption promoters which are commonly used in the manufacture of pharma to enhance bioavailability , fluorocarbons, and/ or other con ceutically acceptable solid , liquid , or other dosage forms ventional solubilizing or dispersing agents . may also be used for the purposes of formulation . [ 0139 ] The amount of protein kinase inhibitor that may be combined with the carrier materials to produce a single [0132 ] The pharmaceutical compositions of this invention dosage form will vary depending upon the host treated , the may be orally administered in any orally acceptable dosage particular mode of administration . Preferably , the composi form including , butnot limited to , capsules, tablets , aqueous tions should be formulated so that a dosage of between suspensions or solutions. In the case of tablets for oral use , 0.01-100 mg/kg body weight/ day of the inhibitor can be carriers commonly used include , but are not limited to , administered to a patient receiving these compositions. lactose and corn starch . Lubricating agents , such as magne [0140 ] It should also be understood that a specific dosage sium stearate , are also typically added . For oral administra and treatment regimen for any particular patient will depend tion in a capsule form , useful diluents include lactose and upon a variety of factors, including the activity of the dried cornstarch . When aqueous suspensions are required specific compound employed , the age , body weight, general for oral use , the active ingredient is combined with emul health , sex , diet , time of administration, rate of excretion , sifying and suspending agents . If desired , certain sweeten drug combination , and the judgment of the treating physi ing , flavoring or coloring agents may also be added . cian and the severity of the particular disease being treated . [ 0133 ] Alternatively , the pharmaceutical compositions of The amount of inhibitor will also depend upon the particular this invention may be administered in the form of supposi compound in the composition . tories for rectal administration . These can be prepared by mixing the agent with a suitable non - irritating excipient that Administering with Another Agent is solid at room temperature but liquid at rectal temperature [0141 ] Depending upon the particular protein kinase- me and therefore will melt in the rectum to release the drug . diated conditions to be treated or prevented , additional Such materials include , but are not limited to , cocoa butter , drugs , which are normally administered to treat or prevent beeswax and polyethylene glycols . that condition ,may be administered together with the com [0134 ] The pharmaceutical compositions of this invention pounds of this invention . may also be administered topically , especially when the [0142 ] Those additional agents may be administered sepa target of treatment includes areas or organs readily acces rately , as part of a multiple dosage regimen , from the protein sible by topical application , including diseases of the eye , kinase inhibitor -containing compound or composition . US 2020/0222392 A1 Jul. 16 , 2020 12

Alternatively , those agents may be part of a single dosage known as AZD2281 or KU - 0059436 ), Iniparib ( also known form , mixed together with the protein kinase inhibitor in a as BSI- 201 or SAR240550 ), Veliparib (also known as ABT single composition . 888 ) , Rucaparib ( also known as PF -01367338 ), CEP - 9722, [0143 ] Another aspect of this invention is directed towards INO - 1001, MK -4827 , E7016 , BMN673 , or AZD2461 . a method of treating cancer in a subject in need thereof, [0147 ] Another embodiment provides a method of treating comprising the sequential or co -administration of a com cancer comprising administering a compound of this inven pound of this invention or a pharmaceutically acceptable salt tion with a DNA damaging agent selected from ionizing thereof, and one or more additional therapeutic agents . radiation or cisplatin and an agent that inhibits or modulates Examples of additional therapeutic agents include, but are PARP1 or PARP2 . In some embodiments the DNA -damaing not limited to , DNA - damaging agents , anti -cancer agents , agent is cisplatin . In other embodiments , the DNA damaging and agents that inhibit or modulates a base excision repair agent is ionizing radiation . In some embodiments the com protein . pound is VE- 821 . In other embodiments , the compound is [0144 ] Another aspect of this invention is directed towards VE - 822 . a method of treating cancer in a subject in need thereof, [0148 ] Another embodiment provides a method of treating comprising the sequential or co -administration of a com cancer comprising administering a compound of Formula I; pound of this invention or a pharmaceutically acceptable salt thereof, and an anti- cancer agent. In some embodiments , said anti -cancer agent is selected from Platinating agents, such as Cisplatin , Oxaliplatin , Carboplatin , Nedaplatin , or NH2 Satraplatin and other derivatives ; Topo I inhibitors , such as ( L )n - R Camptothecin , Topotecan , irinotecan /SN38 , rubitecan and N other derivatives; Topo II inhibitors , such as Etoposide ( VP - 16 ), Daunorubicin , Doxorubicin , Mitoxantrone , Acla N rubicin , Epirubicin , Idarubicin , Amrubicin , Amsacrine, Pira rubicin , Valrubicin , Zorubicin , Teniposide and other deriva R2 G tives ; Antimetabolites , such as Folic family (Methotrexate , Pemetrexed and relatives ) ; Purine family ( Thioguanine , or a pharmaceutically acceptable salt thereof, wherein the Fludarabine , Cladribine, 6 -Mercaptopurine and relatives ) ; variables are as defined herein with an agent that inhibits or Pyrimidine family (Cytarabine , Gemcitabine, 5 -Fluorouracil modulates PARP1 or PARP2. and relatives ) ; Alkylating agents , such as Nitrogen mustards [0149 ] In some embodiments , said method further com (Cyclophosphamide , Melphalan , Chlorambucil, mechlore prises administering a DNA damaging agent to the patient . thamine , Ifosfamide, and relatives ); nitrosoureas ( e.g. Car In some embodiments , the DNA -damaging agent is cispla mustine ); Triazenes (Dacarbazine , temozolomide ) ; Alkyl tin . In other embodiments , the DNA -damaging agent is sulphonates ( e.g. Busulfan ); Procarbazine and Aziridines ; ionizing radiation . Antibiotics, such as Hydroxyurea ; Anthracyclines (doxoru [0150 ] In some embodiments , the agent that inhibits or bicin , daunorubicin , epirubicin and other derivatives ) ; modulates PARP1 or PARP2 is selected from Olaparib ( also Anthracenediones (Mitoxantrone and relatives ); Streptomy known as AZD2281 or KU - 0059436 ) , Iniparib ( also known ces family (Bleomycin , Mitomycin C , actinomycin ) and as BSI- 201 or SAR240550 ), Veliparib ( also known as ABT Ultraviolet light. 888 ) , Rucaparib ( also known as PF -01367338 ), CEP - 9722, [0145 ] Another embodiment provides a method of treating INO - 1001, MK -4827 , E7016 , BMN673 , or AZD2461. In cancer in a subject in need thereof, comprising administer other embodiments , the agent that inhibits or modulates ing a compound of this invention with an additional thera PARP1 or PARP2 is Veliparib ( also known as ABT- 888 ) or peutic agent that inhibits or modulates a base excision repair Rucaparib . protein . In some embodiments , the base excision repair protein is selected from UNG , SMUG1, MBD4 , TDG , [0151 ] In some embodiments , the compound is VE -821 or OGG1, MYH , NTHI, MPG , NEIL1, NEIL2 , NEIL3 (DNA VE 822 . glycosylases) ; APE1, APEX2 (AP endonucleases ); LIGI, LIG3 (DNA ligases I and III) ; XRCC1 (LIG3 accessory ); Biological Samples PNK , PNKP (polynucleotide kinase and phosphatase ); [0152 ] As inhibitors of ATR kinase , the compounds and ARP1, PARP2 (Poly (ADP - Ribose ) Polymerases ) ; PolB , compositions of this invention are also useful in biological PolG (polymerases ) ; FEN1 ( endonuclease ) or Aprataxin . In samples . One aspect of the invention relates to inhibiting other embodiments , the base excision repair protein is ATR kinase activity in a biological sample , which method selected from PARP1, PARP2 , or PolB . In yet other embodi comprises contacting said biological sample with a com ments , the base excision repair protein is selected from pound described herein or a composition comprising said PARP1 or PARP2 . compound . The term “ biological sample ” , as used herein , [014 ] In some embodiments , the compound of this inven means an in vitro or an ex vivo sample , including , without tion and the therapeutic agent that inhibits or modulates a limitation , cell cultures or extracts thereof; biopsied material base excision repair protein are further administered with an obtained from a mammal or extracts thereof; and blood , additional therapeutic agent. In some embodiments , the saliva, urine , feces, semen , tears , or other body fluids or additional therapeutic agent is a DNA damaging agent extracts thereof. The term " compounds described herein ” selected from ionizing radiation or cisplatin . In some includes compounds of formula I. embodiments , the base excision repair protein PARP1 or [0153 ] Inhibition of ATR kinase activity in a biological PARP2 . In other embodiments , the agent that inhibits or sample is useful for a variety of purposes that are known to modulates PARP1 or PARP2 is selected from Olaparib ( also one of skill in the art. Examples of such purposes include, US 2020/0222392 A1 Jul. 16 , 2020 13 but are not limited to , blood transfusion , organ - transplanta pharynx ; Cardiac : sarcoma (angiosarcoma , fibrosarcoma, tion , and biological specimen storage . rhabdomyosarcoma, liposarcoma ) ,myxoma , rhabdomyoma, fibroma, lipoma and teratoma; Lung : bronchogenic carci Study of Protein Kinases noma (squamous cell or epidermoid , undifferentiated small [0154 ] Another aspect of this invention relates to the study cell , undifferentiated large cell, adenocarcinoma) , alveolar of protein kinases in biological and pathological phenom (bronchiolar ) carcinoma, bronchial adenoma, sarcoma, lym phoma, chondromatous hamartoma, mesothelioma; Gastro ena ; the study of intracellular signal transduction pathways intestinal: esophagus ( squamous cell carcinoma, larynx , mediated by such protein kinases; and the comparative adenocarcinoma, leiomyosarcoma, lymphoma) , stomach evaluation of new protein kinase inhibitors . Examples of ( carcinoma, lymphoma, leiomyosarcoma ), pancreas (ductal such uses include , but are not limited to , biological assays adenocarcinoma, insulinoma, glucagonoma, gastrinoma, such as enzyme assays and cell -based assays . carcinoid tumors , vipoma ), small bowel or small intestines [0155 ] The activity of the compounds as protein kinase (adenocarcinoma , lymphoma, carcinoid tumors , Karposi's inhibitors may be assayed in vitro , in vivo or in a cell line. sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, In vitro assays include assays that determine inhibition of fibroma ), large bowel or large intestines (adenocarcinoma , either the kinase activity or ATPase activity of the activated tubular adenoma, villous adenoma, hamartoma, leio kinase . Alternate in vitro assays quantitate the ability of the myoma) , colon , colon -rectum , colorectal; rectum , Genito inhibitor to bind to the protein kinase and may be measured urinary tract: kidney ( adenocarcinoma, Wilm's tumor [neph either by radiolabelling the inhibitor prior to binding, iso roblastoma] , lymphoma) , bladder and urethra ( squamous lating the inhibitor/ kinase complex and determining the cell carcinoma, transitional cell carcinoma, adenocarci amount of radiolabel bound , or by running a competition noma) , prostate (adenocarcinoma , sarcoma) , testis ( semi experiment where new inhibitors are incubated with the noma, teratoma, embryonal carcinoma , teratocarcinoma , kinase bound to known radioligands. Detailed conditions for choriocarcinoma, sarcoma , interstitial cell carcinoma, assaying a compound utilized in this invention as an inhibi fibroma, fibroadenoma, adenomatoid tumors , lipoma) ; tor of ATR is set forth in the Examples below . Liver : hepatoma (hepatocellular carcinoma) , cholangiocar [0156 ] Another aspect of the invention provides a method cinoma, hepatoblastoma, angiosarcoma, hepatocellular for modulating enzyme activity by contacting a compound adenoma, hemangioma, biliary passages ; Bone: osteogenic described herein with ATR kinase . sarcoma (osteosarcoma ) , fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant Methods of Treatment lymphoma (reticulum cell sarcoma) , multiple myeloma, [ 0157 ] In one aspect , the present invention provides a malignant giant cell tumor chordoma, osteochronfroma (os method for treating or lessening the severity of a disease , teocartilaginous exostoses ), benign chondroma, chondro condition , or disorder where ATR kinase is implicated in the blastoma, chondromyxofibroma, osteoid osteoma and giant disease state . In another aspect, the present invention pro cell tumors ; Nervous system : skull (osteoma , hemangioma, vides a method for treating or lessening the severity of an granuloma, xanthoma, osteitis deformans) , meninges (men ATR kinase disease , condition , or disorder where inhibition ingioma, meningiosarcoma, gliomatosis) , brain (astrocy of enzymatic activity is implicated in the treatment of the toma, medulloblastoma, glioma, ependymoma, germinoma disease . In another aspect, this invention provides a method [pinealoma ) , glioblastoma multiform , oligodendroglioma, for treating or lessening the severity of a disease, condition , schwannoma, retinoblastoma, congenital tumors ) , spinal or disorder with compounds that inhibit enzymatic activity cord neurofibroma, meningioma, glioma, sarcoma) ; Gyne by binding to the ATR kinase . Another aspect provides a cological: uterus ( endometrial carcinoma) , cervix ( cervical method for treating or lessening the severity of a kinase carcinoma, pre - tumor cervical dysplasia ), ovaries (ovarian disease , condition , or disorder by inhibiting enzymatic activ carcinoma (serous cystadenocarcinoma , mucinous cystade ity of ATR kinase with an ATR kinase inhibitor. nocarcinoma, unclassified carcinoma) , granulosa - thecal cell [0158 ] One aspect of the invention relates to a method of tumors , Sertoli- Leydig cell tumors , dysgerminoma, malig inhibiting ATR kinase activity in a patient, which method nant teratoma) , vulva ( squamous cell carcinoma, intraepi comprises administering to the patient a compound thelial carcinoma, adenocarcinoma, fibrosarcoma, mela described herein , or a composition comprising said com noma) , vagina (clear cell carcinoma, squamous cell pound . In some embodiments , said method is used to treat or carcinoma, botryoid sarcoma ( embryonal rhabdomyosar prevent a condition selected from proliferative and hyper coma) , fallopian tubes ( carcinoma) , breast ; Skin : malignant proliferative diseases, such as cancer. melanoma, basal cell carcinoma, squamous cell carcinoma, [0159 ] Another aspect of this invention provides a method Karposi's sarcoma, keratoacanthoma, moles dysplastic nevi, for treating, preventing, or lessening the severity of prolif lipoma, angioma , dermatofibroma, keloids, psoriasis , Thy erative or hyperproliferative diseases comprising adminis roid gland : papillary thyroid carcinoma, follicular thyroid tering an effective amount of a compound , or a pharmaceu carcinoma; medullary thyroid carcinoma , multiple endo tically acceptable composition comprising a compound , to a crine neoplasia type 2A , multiple endocrine neoplasia type subject in need thereof In some embodiments , said subject 2B , familial medullary thyroid cancer , pheochromocytoma , is a patient. The term “ patient” , as used herein , means an paraganglioma; and Adrenal glands: neuroblastoma. animal, preferably a human . [0161 ] In some embodiments , the cancer is selected from [0160 ] In some embodiments , said method is used to treat the cancers described herein . In some embodiments, said or prevent cancer. In some embodiments , said method is cancer is lung cancer , head and neck cancer, pancreatic used to treat or prevent a type of cancer with solid tumors . cancer, gastric cancer , or brain cancer . In other embodi In yet another embodiment, said cancer is selected from the ments , the cancer is selected from a cancer of the lung or the following cancers : Oral: buccal cavity , lip , tongue, mouth , pancreas . In some embodiments , the lung cancer is non US 2020/0222392 A1 Jul. 16 , 2020 14 small cell lung cancer or small cell lung cancer, such [0172 ] Examples of alkylating agents include Nitrogen squamous non small cell lung cancer. In other embodiments , mustards, Triazenes , alkyl sulphonates , Procarbazine and the cancer is selected from a cancer of the breast , such as Aziridines . Examples of Nitrogen mustards include Cyclo triple negative breast cancer. phosphamide , Melphalan , Chlorambucil and relatives; [0162 ] In yet other embodiments , the cancer is selected examples of nitrosoureas include Carmustine ; examples of from non - small cell lung cancer, small cell lung cancer, triazenes include Dacarbazine and temozolomide ; examples pancreatic cancer, biliary tract cancer, head and neck cancer, of alkyl sulphonates include Busulfan . bladder cancer, colorectal cancer, glioblastoma, esophageal [0173 ] Other specific examples of alkylating agents cancer, breast cancer, hepatocellular carcinoma, or ovarian include Mechlorethamine , Cyclophosphamide, Ifosfamide , cancer . Trofosfamide, Chlorambucil, Melphalan , Prednimustine, [0163 ] In certain embodiments , an “ effective amount” of Bendamustine, Uramustine , Estramustine , Carmustine , the compound or pharmaceutically acceptable composition Lomustine, Semustine , Fotemustine , Nimustine, Rani is that amount effective in order to treat said disease . The mustine, Streptozocin , Busulfan , Mannosulfan , Treosulfan , compounds and compositions, according to the method of Carboquone , ThioTEPA , Triaziquone , Triethylen the present invention , may be administered using any emelamine , Procarbazine , Dacarbazine, Temozolomide, amount and any route ofadministration effective for treating Altretamine , Mitobronitol, Actinomycin , Bleomycin , Mito or lessening the severity of said disease . mycin and Plicamycin . [0164 ] One aspect provides a method for inhibiting ATR in [0174 ] Examples of antibiotics include Mitomycin , a patient comprising administering a compound described Hydroxyurea; Anthracyclines , Anthracenediones , Strepto herein as described herein . Another embodiment provides a myces family . Examples of Anthracyclines include doxoru method of treating cancer comprising administering to a bicin , daunorubicin , epirubicin and other derivatives ; patient a compound described herein , wherein the variables examples of Anthracenediones include Mitoxantrone and are as defined herein . relatives; examples of Streptomyces family inclue Bleomy [0165 ] Some embodiments comprising administering to cin , Mitomycin C , and actinomycin . said patient an additional therapeutic agent selected from a [0175 ] In certain embodiments , said platinating agent is DNA -damaging agent; wherein said additional therapeutic Cisplatin or Oxaliplatin ; said Topo I inhibitor is Camptoth agent is appropriate for the disease being treated ; and said ecin ; said Topo II inhibitor is Etoposide; and said antibiotic additional therapeutic agent is administered together with is Mitomycin . In other embodiments , said platinating agent said compound as a single dosage form or separately from is selected from Cisplatin , Oxaliplatin , Carboplatin , Neda said compound as part of a multiple dosage form . platin , or Satraplatin ; said Topo I inhibitor is selected from [0166 ] In some embodiments , said DNA -damaging agent Camptothecin , Topotecan , irinotecan /SN38 , rubitecan ; said is selected from ionizing radiation , radiomimetic neocar Topo II inhibitor is selected from Etoposide ; said antime zinostatin , a platinating agent, a Topo I inhibitor, a Topo II tabolite is selected from a member of the Folic Family , the inhibitor, an antimetabolite , an alkylating agent, an alkyl Purine Family , or the Pyrimidine Family ; said alkylating sulphonates , an antimetabolite , or an antibiotic . In other agent is selected from nitrogen mustards, nitrosoureas , tri embodiments , said DNA - damaging agent is selected from azenes , alkyl sulfonates , Procarbazine , or aziridines ; and ionizing radiation , a platinating agent, a Topo I inhibitor , a said antibiotic is selected from Hydroxyurea , Anthracy Topo II inhibitor , or an antibiotic . clines , Anthracenediones, or Streptomyces family . [0167 ] Examples of Platinating agents include Cisplatin , [0176 ] In some embodiments , the additional therapeutic Oxaliplatin , Carboplatin , Nedaplatin , Satraplatin and other agent is ionizing radiation . In other embodiments , the addi derivatives . Other platinating agents include Lobaplatin , and tional therapeutic agent is Cisplatin or Carboplatin . In yet Triplatin . Other platinating agents include Tetranitrate , Pico other embodiments , the additional therapeutic agent is platin , Satraplatin , ProLindac and Aroplatin . Etoposide . In yet other embodiments , the additional thera [0168 ] Examples of Topo I inhibitor include Camptoth peutic agent is Temozolomide . ecin , Topotecan , irinotecan /SN38 , rubitecan and other ( 0177 ] In certain embodiments , the additional therapeutic derivatives. Other Topo I inhibitors include Belotecan . agent is selected from one or more of the following : Cis [0169 ] Examples of Topo II inhibitors include Etoposide, platin , Carboplatin , gemcitabine, Etoposide , Temozolomide, Daunorubicin , Doxorubicin , Mitoxantrone , Aclarubicin , or ionizing radiation . Epirubicin , Idarubicin , Amrubicin , Amsacrine , Pirarubicin , [ 0178 ] In other embodiments , the additional therapeutic Valrubicin , Zorubicin and Ten oside. agents are selected from one or more of the following : [0170 ] Examples of Antimetabolites include members of gemcitabine, cisplatin or carboplatin , and etoposide. In yet the Folic family , Purine family (purine antagonists ) , or other embodiments, the additional therapeutic agents are Pyrimidine family (pyrimidine antagonists ) . Examples of selected from one or more of the following : cisplatin or the Folic family include methotrexate , pemetrexed and rela carboplatin , etoposide, and ionizing radiation . In some tives; examples of the Purine family include Thioguanine , embodiments , the cancer is lung cancer . In some embodi Fludarabine, Cladribine, 6 -Mercaptopurine , and relatives ; ments , the lung cancer is non - small cell lung cancer or small examples of the Pyrimidine family include Cytarabine , cell lung cancer. gemcitabine , 5 - Fluorouracil (5FU ) and relatives. [0179 ] Another embodiment provides a method of treating [0171 ] Some other specific examples of antimetabolites small cell lung cancer comprising administering to a patient include Aminopterin , Methotrexate , Pemetrexed , Ralti a compound of the invention in combination with cisplatin trexed , Pentostatin , Cladribine , Clofarabine , Fludarabine , and etoposide. Thioguanine, Mercaptopurine , Fluorouracil , Capecitabine , [0180 ] Another embodiment provides a method of treating Tegafur, Carmofur, Floxuridine , Cytarabine , Gemcitabine , non - small cell lung cancer comprising administering to a Azacitidine and Hydroxyurea . patient a compound of Formula I in combination with US 2020/0222392 A1 Jul. 16 , 2020 15

gemcitabine and cisplatin . In some embodiments , the non [ 0191 ] Another aspect provides a method of inhibiting small cell lung cancer is squamous non -small cell lung phosphorylation of Chkl ( Ser 345 ) in a pancreatic cancer cell cancer . comprising administering a compound described herein [ 0181] Another embodiment provides a method of treating after treatment with gemcitabine ( 100 nM ) and /or radiation breast cancer comprising administering to a patient a com (6 Gy ) to a pancreatic cancer cell. pound of Formula I in combination with cisplatin . In some [0192 ] Another aspect provides method of radiosensitiz embodiments , the breast cancer is triple negative breast ing hypoxic PSN - 1 , MiaPaCa- 2 or PancM tumor cells by cancer . administering a compound described herein to the tumor cell [0182 ] In some embodiments , the compound is a com in combination with radiation therapy . pound of Formula I. In other embodiments , the compound is [0193 ] Yet another aspect provides a method of sensitizing VE -821 . In other embodiments , the compound is VE- 822 . hypoxic PSN -1 , MiaPaCa - 2 or PancM tumor cells by [ 0183 ] Another embodiment provides methods for treating administering a compound described herein to the tumor cell pancreatic cancer by administering a compound described in combination with gemcitabine . herein in combination with another known pancreatic cancer [0194 ] Another aspect provides a method of sensitizing treatment. One aspect of the invention includes administer PSN - 1 and MiaPaCa - 2 tumor cells to chemoradiation by ing a compound described herein in combination with administering a compound described herein to the tumor gemcitabine . In some embodiments , the pancreatic cancer cells in combination with chemoradiation . comprises one of the following cell lines : PSN - 1 , [0195 ] Another aspect provides a method of disrupting MiaPaCa -2 or Panc - 1. According to another aspect , the damage- induced cell cycle checkpoints by administering a cancer comprises one of the following primary tumor lines : compound described herein in combination with radiation Panc - M or MRCS . therapy to a pancreatic cancer cell . [0184 ] Another embodiment provides a method of treating breast cancer with a compound described herein in combi [0196 ] Another aspect provides a method of inhibiting nation with a platinating agent. In some embodiments , the repair of DNA damage by homologous recombination in a breast cancer is triple negative breast cancer. In other pancreatic cancer cell by administering a compound embodiments , the platinating agent is cisplatin . Another described herein in combination with one or more of the embodiment provides a method of treating triple negative following treatments : chemoradiation , chemotherapy , and breast cancer with a compound described herein in combi radiation therapy . nation with cisplatin . [0197 ] In some embodiments , the chemotherapy is gem [0185 ] Another embodiment provides a method of treating citabine. small cell lung cancer with a compound described herein in [0198 ] Another aspect provides a method of inhibiting combination with cisplatin and etoposide . repair of DNA damage by homologous recombination in a [0186 ] Another embodiment provides a method of treating pancreatic cancer cell by administering a compound non - small cell lung cancer with a compound described described herein in combination with gemcitabine and radia herein in combination with cisplatin and gemcitabine . In tion therapy. some embodiments , the non -small cell lung cancer is [0199 ] In some embodiments , the pancreatic cancer cells squamous non - small cell lung cancer. In some embodiments , are derived from a pancreatic cell line selected from PSN - 1, the compound is a compound of Formula I. In other embodi MiaPaCa - 2 or Panc - 1 . ments , the compound is VE -822 . [0200 ] In other embodiments , the pancreatic cancer cells [0187 ] Another aspect of the invention includes adminis are in a cancer patient. tering a compound described herein in combination with [ 0201 ] Another aspect of the invention provides a method radiation therapy. Yet another aspect provides a method of of treating non - small cell lung cancer comprising adminis abolishing radiation - induced G2/ M checkpoint by adminis tering to a patient a compound described herein in combi tering a compound described herein in combination with nation with one or more of the following additional thera radiation treatment . peutic agents : Cisplatin or Carboplatin , Etoposide, and [0188 ] Another aspect provides a method of treating pan ionizing radiation . Some embodiments comprise adminis creatic cancer by administering to pancreatic cancer cells a tering to a patient a compound described herein in combi compound described herein in combination with one or nation with Cisplatin or Carboplatin , Etoposide, and ioniz more cancer therapies. In some embodiments , the compound ing radiation . In some embodiments the combination is is combined with chemoradiation , chemotherapy, and /or Cisplatin , Etoposide, and ionizing radiation . In other radiation therapy. As would be understood by one of skill in embodiments the combination is Carboplatin , Etoposide, the art , chemoradiation refers to a treatment regime that and ionizing radiation . includes both chemotherapy ( such as gemcitabine ) and [0202 ] Another embodiment provides a method of pro radiation . In some embodiments , the chemotherapy is gem moting cell death in cancer cells comprising administering citabine . to a patient a compound described herein , or a composition [0189 ] Yet another aspect provides a method of increasing comprising said compound . the sensitivity of pancreatic cancer cells to a cancer therapy [0203 ] Yet another embodiment provides a method of selected from gemcitabine or radiation therapy by adminis preventing cell repair of DNA damage in cancer cells tering a compound described herein in combination with the comprising administering to a patient a compound described cancer therapy. herein , or a composition comprising said compound . Yet [0190 ] In some embodiments , the cancer therapy is gem another embodiment provides a method of preventing cell citabine. In other embodiments , the cancer therapy is radia repair caused by of DNA damage in cancer cells comprising tion therapy . In yet another embodiment the cancer therapy administering to a patient a compound of formula I , or a is chemoradiation . composition comprising said compound . US 2020/0222392 A1 Jul. 16 , 2020 16

[0204 ] Another embodiment provides a method of sensi [0211 ] Yet another embodiment provides use of a com tizing cells to DNA damaging agents comprising adminis pound described herein as a radio - sensitizer or a chemo tering to a patient a compound described herein , or a sensitizer . composition comprising said compound . [0212 ] Yet other embodiment provides use of a compound [0205 ] In some embodiments , the method is used on a of formula I as a single agent (monotherapy ) for treating cancer cell having defects in the ATM signaling cascade . In cancer . In some embodiments , the compounds of formula I some embodiments , said defect is altered expression or are used for treating patients having cancer with a DNA activity of one or more of the following : ATM , p53 , CHK2, damage response (DDR ) defect. In other embodiments , said MRE11, RAD50 , NBS1, 53BP1, MDC1, H2AX , MCPH1/ defect is a mutation or loss of ATM , p53 , CHK2, MRE11 , BRIT1 , CTIP , or SMC1. In other embodiments , said defect RAD50 , NBS1, 53BP1 , MDC1, or H2AX . According to is altered expression or activity of one or more of the another embodiment , the method is used on a cancer, cancer following : ATM , p53 , CHK2, MRE11, RAD50, NBS1, cell , or cell expressing DNA damaging oncogenes . 53BP1 ,MDC1 or H2AX . In another embodiment, the cell is a cancer cell expressing DNA damaging oncogenes . In some Compounds and Compositions for Use embodiments , said cancer cell has altered expression or [0213 ] One embodiment provides a compound or compo activity of one or more of the following: K - Ras, N - Ras , sition as described herein for use as a radio - sensitizer or a H -Ras , Raf ,Myc , Mos, E2F , Cdc25A , CDC4 , CDK2 , Cyclin chemo -sensitizer . Another embodiment provides a com E , Cyclin A and Rb . pound or composition as described herein for use as a single [ 0206 ] According to another embodiment, the method is agent (monotherapy ) for treating cancer . used on a cancer , cancer cell, or cell has a defect in a protein [0214 ] Another embodiment provides a compound or involved in base excision repair (“ base excision repair composition as described herein for treating patients having protein ” ) . There are many methods known in the art for cancer with a DNA -damage response (DDR ) defect. In some determining whether a tumor has a defect in base excision embodiments , said defect is a mutation or loss of ATM , p53 , repair. For example , sequencing of either the genomic DNA CHK2, MRE11, RAD50 , NBS1 , 53BP1, MDC1, or H2AX . or mRNA products of each base excision repair gene ( e.g., In other embodiments , said defect is a mutation or loss of UNG , PARP1 , or LIG1) can be performed on a sample of the ATM , p53 , CHK2 , MRE11, RAD50 , NBS1 , 53BP1, MDC1, tumor to establish whether mutations expected to modulate H2AX , MCPH1/ BRIT1 , CTIP , or SMC1 . the function or expression of the gene product are present [0215 ] Another embodiment provides compounds or com (Wang et al. , Cancer Research 52: 4824 ( 1992 ) ) . In addition positions described herein for treating cancer . In some to the mutational inactivation , tumor cells can modulate a embodiments , the compound or composition is further com DNA repair gene by hypermethylating its promoter region , bined with an additional therapeutic agent described herein . leading to reduced gene expression . This is most commonly In some embodiments , the compound or composition is assessed using methylation - specific polymerase chain reac further combined with a DNA damaging agent described tion (PCR ) to quantify methylation levels on the promoters herein . of base excision repair genes of interest. Analysis of base excision repair gene promoter methylation is available com [0216 ] In some embodiments , the cancer has a defect in a mercially (http://www.sabiosciences.com/dnamethylation pathway described herein . product/ HTML /MEAH - 421A.html) . Manufacture of Medicaments [0207 ] Finally, the expression levels of base excision [0217 ] One embodiment provides the use of a compound repair genes can be assessed by directly quantifying levels of or composition described herein for the manufacture of a the mRNA and protein products of each gene using standard medicament for use as a radio - sensitizer or a chemo- sensi techniques such as quantitative reverse transcriptase tizer . Another embodiment provides the use of a compound coupled polymerase chain reaction (RT - PCR ) and immun or composition described herein for the manufacture of a hohistochemistry ( IHC ) , respectively ( Shinmura et al ., Car medicament for the manufacture of a medicament for use as cinogenesis 25 : 2311 (2004 ); Shinmura et al ., Journal of a single agent (monotherapy ) for treating cancer . Pathology 225: 414 ( 2011 ) ) . [ 0218 ] Yet another embodiment provides the use of a [0208 ] In some embodiments , the base excision repair compound or composition described herein for the manu protein is UNG , SMUG1, MBD4 , TDG , OGG1, MYH , facture of a medicament for the manufacture of a medica NTHI, MPG , NEIL1, NEIL2, NEIL3 (DNA glycosylases ); ment for treating patients having cancer with a DNA APE1, APEX2 ( AP endonucleases ) ; LIG1, LIG3 (DNA damage response (DDR ) defect . ligases I and III ) ; XRCC1 (LIG3 accessory ) ; PNK , PNKP [0219 ] In some embodiments , said defect is a mutation or (polynucleotide kinase and phosphatase ) ; PARP1, PARP2 loss of ATM , p53 , CHK2, MRE11 , RAD50 , NBS1 , 53BP1 , ( Poly (ADP -Ribose ) Polymerases) ; PolB , PolG (poly MDC1, or H2AX . In other embodiments , said defect is a merases ) ; FEN1 (endonuclease ) or Aprataxin . mutation or loss of ATM , p53 , CHK2, MRE11, RAD50 , [ 0209 ] In some embodiments , the base excision repair NBS1, 53BP1 , MDC1 , H2AX , MCPH1/ BRIT1 , CTIP , or protein is PARP1, PARP2 , or PolB . In other embodiments , SMC1. the base excision repair protein is PARP1 or PARP2 . [0220 ] Another embodiment provides the use of a com [ 0210 ] The methods described above ( gene sequence , pro pound or composition described herein for the manufacture moter methylation and mRNA expression ) may also be used of a medicament for treating cancer . In some embodiments , to characterize the status ( e.g., expression or mutation ) of the compound or composition is combined with an addi other genes or proteins of interesting, such DNA -damaging tional therapeutic agent , such as a DNA damaging agent, oncogenes expressed by a tumor or defects in the ATM described herein . In another embodiment, the cancer has a signaling cascade of a cell . defect in a pathway described herein . US 2020/0222392 A1 Jul. 16 , 2020 17

SCHEMES AND EXAMPLES carboxylic acid group is engaged in a coupling reaction with [0221 ] The compounds of the disclosure may be prepared an amine to lead to cyclic amide compounds of the Formula according to steps generally known to those of ordinary skill IA - 1 . in the art. More specifically , the compounds may be prepared according to the schemes and examples described in WO Scheme I - A2 : Preparation of Compounds wherein -L - R 2010/071837 , the contents of which are hereby incorporated by reference . Those compoundsmay be analyzed by known is an Aromatic Amide methods, including but not limited to LCMS ( liquid chro matography mass spectrometry ) and NMR (nuclear mag NH2 netic resonance ). The following generic schemes illustrate CO2Me how to prepare the compounds of the present disclosure . Any examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way. ' H -NMR spectra were recorded at 400 MHz using a Bruker DPX 400 instrument. Mass spec . samples were Br analyzed on a MicroMass Quattro Micro mass spectrometer operated in single MS mode with electrospray ionization .

Scheme I -A1 : Preparation of Compounds wherein - -L - R NH2 is an Aromatic Amide CO2H -( Jlha NH2 HN (4 ) CO2Me Br 3

Br 1 NH2 NH2 CO2H N H?N ( 4 ) N

Br - (J2 ) Go4 NH2 (L— NR'R ) - ( J !) ? 2 ( 4 ) NH2 (J ) NH -( J2) ? ( L - NR'R ) -( J2) IA - 2 (L - NR'R ), [0223 ] Alternatively , compounds of the present disclosure wherein -L - R is an aromatic amide can be prepared accord IA - 1 ing to methods similar to the one depicted in Scheme 1 - A2, a variation of the synthetic sequence depicted in scheme [0222 ] Cyclic amides compounds of the present disclosure I -A1 which consists in starting from methyl ester 1. Ester 1 wherein -L - R is an aromatic amide can be prepared accord is transformed into carboxylic acid 3 which is engaged in a ing to methods similar to the one depicted in Scheme 1 -A1 : coupling reaction with an amine to give amide 4. This is Commercially available ester 1 is reacted with a boronic reacted with a boronic acid under Suzuki conditions to lead acid under Suzuki conditions to give intermediate 2. The to compounds of formula IA - 2 . US 2020/0222392 A1 Jul. 16 , 2020 18

Scheme I- B1: preparation of compounds Scheme I - B2 : preparation of compounds where Ring A is a 1,3,4 - oxadiazole where Ring A is a 1,3,4 -oxadiazole

NH2 NH2 CO2Me N N NHNH2 AYR5 , ?? Br ( or R = S ) 3 NH2 X COOH R 5 --N R5

NH2 X

-N R5 8 NH2 X NH R5

9

9 NH2 NH2 R5 N R5 N

R

R I - B2 I - B1 wherein R is (L— NR'R ?) p or - (12 ) wherein R is (L— NR'R ?) p or -( J2) , [0225 ] Alternatively , compounds of the present disclosure [0224 ] Compounds of the present disclosure where Ring A is a 1,3,4 -oxadiazole can be prepared according to methods where Ring A is a 1,3,4 - oxadiazole can be prepared accord similar to the one depicted in Scheme 1 - B1 : methyl ester 3 ing to methods similar to the one depicted in Scheme I -B2 , is reacted with a boronic acid under Suzuki conditions to a variation of the synthetic sequence depicted in scheme give intermediate 8. The carboxylic acid in 8 is then engaged I -B1 . The hydrazide 5 is engaged in a coupling reaction with into a coupling reaction with an hydrazide ( X = 0 ) or a carboxylic acid functional group to form intermediate 9 thiohydrazide ( X = S ) to form 9. Finally , the the acylhydraz ( X = O ) . As in scheme I- B1 the acylhydrazide then under ide in 9 undergoes a cyclodehydration to lead to compounds goes a cyclodehydration to lead to compounds of formula of the present disclosure ( formula I in Scheme I -B1 ) . Trans IB - 2 . When R5 is a moiety bound to the oxadiazole ring formation of intermediate 8 into compounds of formula IB - 1 through a C — N bond , then an thioisocyanate can be used to has also been performed in a one -pot procedure using generate intermediate 9 ( X = S ); the thioacylhydrazide then reagents serving two purposes ( coupling and cyclodehydra undergoes a cyclodehydration to lead to compounds of tion ). formula IB - 2 . US 2020/0222392 A1 Jul. 16 , 2020 19

has been constructed . Transformation of starting point 10 or Scheme I -B3 : preparation of 6 into intermediate 12 has also been performed in a one -pot compounds where Ring A ia a 1,3,4 - oxadizole procedure using reagents serving two purposes ( coupling and cyclodehydration ) . The bromo handle in oxadiazole 12 NH2 is then reacted with a boronic acid under Suzuki conditions to give compounds of formula 1B -3 . When R group in N Formula IB - 3 contains a carboxylic acid moiety, it can be further transformed ( eg into an amide ) using conditions N known in the art .

Br 10 ( R = COOH ) Scheme I- C1 : preparation of ???6 ( R = CONHNH2 ) compounds where Ring A is a 1,2,4 -oxadiazole OH NH2 NH2 NH2 CN N NH2 N IZ R5

Br 11

R 2 13 NH2 N -R5 NH2 R5 Suzuki .N NH2

Br ??12

NH2 -R5 R 14 NH2 N -R5

R I I - B3 wherein R is - (L— NR'R ?) or - (J2 ) ? I - C1 wherein Ris - (L— NR'R ?) or - (J2 ) [0226 ] Alternatively , compounds of the present disclosure where Ring A is 1,3,4 -oxadiazole can be prepared according to methods similar to the one depicted in Scheme I -B3 : the R functional group in 10 or 6 (acid and hydrazide respec [0227 ] Compounds of the present disclosure where Ring A tively, both prepared from methyl ester 3 through hydrolysis is a 1,2,4 -oxadiazole can be prepared according to methods and hydrazinolysis respectively ) are engaged into coupling similar to the one depicted in Scheme 1- C1 : nitrile reacts with a suitable partner (RFCXNHNH , when starting from with hydroxylamine to give intermediate 13. The hydroxy 10 ; R COOH /R5 S when starting from 6 ) to form acyl group in 13 reacts with acid chlorides to lead to intermediate hydrazide intermediate 11. Subsequent cyclodehydration 14 which undergoes cyclodehydration to afford compounds leads to the compound 12 where the 1,3,4 -oxadiazole ring of formula IC - 1 . US 2020/0222392 A1 Jul. 16 , 2020 20

Scheme I- C2 : preparation of Scheme I- D1 : preparation of compounds where Ring A is a 1,2,4 - oxadiazole compounds where Ring A ia a 1,3,4 - thiadiazole OH NH2 NH2 N NH2 .CN .CO2Me NH2

Br Br Br 3 15 NH2 COOH NH2 R5 N NH2 H2N - N R5 H

Br ?16 R 8 NH2

NH2 N N - N -R , H R5 N

Br 17 no R NH2 18 -RS NH2 Rs N

R I - C2 R wherein R is - (L— NR'R ?) p or -( J2 ) I - D1 wherein R is - (L - NR'R ?) p or - (52 ) a [ 0228 ] Alternatively , compounds of the present disclosure where Ring A is a 1,2,4 -oxadiazole can be prepared accord [0229 ] Compounds of the present disclosure where Ring A ing to methods similar to the one depicted in Scheme 1 - C2 : is a 1,3,4 -thiadiazole can be prepared according to methods Commercially available nitrile 1 reacts with hydroxylamine similar to the one depicted in Scheme I -D1 : methyl ester 3 to give intermediate 15. The hydroxy group in 15 reacts with is reacted with a boronic acid under Suzuki conditions to acid chlorides to lead to intermediate 16 which undergoes give intermediate 8. The carboxylic acid in 8 is then engaged cyclodehydration to afford intermediate 17. The bromo into a coupling reaction with a thiohydrazide to form 18 . handle in 17 used to perform a Suzuki reaction with Finally , the the thioacylhydrazide in 18 undergoes a cyclo a boronic acid coupling partner to give compounds of dehydration to lead to compounds of Formula ID - 1 . Trans formula IC -2 . When R group in Formula IC - 2 contains a formation of intermediate 8 into compounds of Formula carboxylic acid moiety , it can be further transformed (eg into I- D1 can be performed in a one -pot procedure using reagents an amide ) using conditions known in the art . serving two purposes ( coupling and cyclodehydration ) US 2020/0222392 Al Jul. 16 , 2020 21

Scheme I- D2 : preparation of Scheme I- E1 : preparation of compounds where Ring A is an isoxazole compounds where Ring A is a 1,3,4 - thiadiazole NH2 NH2 TMS NH2 Br N N OH

Br Br Br 21 22 10 a NH2 NBoca TMS R5

Br 19 Br 23

N NH2 -R , NBoca N OH Suzuki

R5 Br co20 NH2 -R5 R 24 N NH2 -R5

R I - D2 wherein R is - (L - NR'R2 ), or -( J2 )

[0230 ] Alternatively , compounds of the present disclosure I - E1 where Ring A is 1,3,4- thiadiazole can be prepared according wherein Ris -( L — NR'R ?)por -( 52 ) to methods similar to the one depicted in Scheme 1 -D2 : the acid functional group in 10 is engaged into coupling with a suitable partner ( R CSNHNH2) to form the thioacylhydraz [0231 ] Compounds of the present disclosure where Ring A ide intermediate 19. Subsequent cyclodehydration leads to is an isoxazole can be prepared according to methods similar the compound 20 where the 1,3,4 - thiadiazole ring has been to the one depicted in Scheme I- E1 : Commercially available constructed . Transformation of starting point 10 into 20 has 2 -amino -3,5 -dibromo pyrazine 21 undergoes a Sonogashira been performed in a one -pot procedure using reagents coupling with TMS -acetylene to give intermediate 22, the serving two purposes (coupling and cyclodehydration ) . The amino group of which can be fully protected as the diBoc mo handle in thiadiazole 20 is then reacted wit a boronic species 23 . A Suzuki coupling with the remaining bromo acid under Suzuki conditions to give compounds of formula handle , with concommitent TMS deprotection affords inter I -D2 . When R group in Formula I- D2 contains a carboxylic mediate 24. The alkyne 24 finally reacts in a cycloconden acid moiety , it can be further transformed (eg into an amide ) sation with N -hydroxyaroyl chloride to furnish compounds using conditions known in the art . of Formula I -E1 . US 2020/0222392 A1 Jul. 16 , 2020 22

isoxazole 26 is then reacted with a boronic acid under Scheme I - E2 : preparation of compounds where Ring A is an isoxazole Suzuki conditions to give compounds 27. A final deprotec tion of N - protecting groups in 27 can reveal compounds of NBoca TMS Formula I. When R group in Formula I -E2 contains a carboxylic acid moiety , it can be further transformed ( eg into an amide ) using conditions known in the art .

Scheme I- E3 : preparation of compounds where Ring A is an isoxazole Br 23 Eto Reductive NBoca amination OH H2N— Jp1 EtO H

Eto HN - Jºp1 Protection Br Eto 25 es 2 NBoc2 PG -Rs - Eto N— J> p1 Oxime N formation hydroxylamine Eto hydrachloride 3 Br Boc Boc 26 N coN NBoc2 -R5 N

N PG Br HO - N N- Jp1 Isoxazole formation (1 or 2 steps )

4 R PG Boc 27 Boc N - Pp1 NH2 1 ) Suzuki -RS R2 - B (OH ) 2 N N 2 ) Deprotection

Br

HN - Jp1 NH2

R N I - E2 wherein Ris - (L— NR'R ?) p or (J2 ) ?

[0232 ] Alternatively , compounds of the present disclosure soaI - E3 where Ring A is an isoxazole can be prepared according to methods similar to the one depicted in Scheme I -E2 : The TMS -protected intermediate 23 , described in scheme I - E1 [0233 ] Compounds of Formula I- E3 can be made accord can be deprotected to reveal the alkyne compound 25. The ing to the steps outlined in Scheme I - E3 . Reductive amina alkyne 25 reacts in a cyclocondensation with N -hydrox tion between compound 1 and an amine (e.g. , Pp1- NH2 ) , yaroyl chloride to furnish intermediate 26 where the isox leads to compound 2. Conditions for reductive amination azole ring has been constructed . The bromo handle in include, for example , combining compound 1 with J?pl US 2020/0222392 A1 Jul. 16 , 2020 23

NH , in methanol to form an imine intermediate which is -continued reduced with NaBH4 to form compound 2. Compound 2 can then be protected with nitrogen protecting groups known to NH2 those skilled in the art. For example , compound 2 can be -R5 IZ. combined with (Boc ) 20 and EtzN in DCM to form com N pound 3 (wherein PG = Boc ) . [0234 ] Compound 3 can be combined with hydroxylamine hydrochloride under suitable oxime formation conditions to form compound 4. Suitable oxime formation conditions include either a one - step procedure or a two ep procedure . The one - step procedure comprises stirring 1 equivalent of compound 3 with a 1.1 equivalents of NH ,OH.HCl in a 10: 1 v / v mixture of THF/ water . The two step procedure com prises first deprotecting the ketal group of compound 3 into I - F1 an aldehyde under suitable deprotection conditions, and then wherein Ris - (L— NR'R ?por) -( 52 ) forming an oxime under suitable two- step oxime formation conditions to form compound 4 . [0235 ) Compound 4 can be combined with the BOC [0237 ] Alternatively , compounds of the present disclosure protected aminopyrazine shown in Scheme 1 - E3 under suit where Ring A is a 1,2,4 - triazole can be prepared according able isoxazole formation conditions to form compound 5 . to methods similar to the one depicted in Scheme 1 -F1 Compound 4 is transformed and engaged in a [ 3 + 2 ] cycload starting from methyl ester 3. Ester 3 is reacted with a boronic dition to form the isoxazole 5. This transformation can be conducted in one potbut requires two distinct steps. The first acid under Suzuki conditions to give intermediate 4. When step is an oxidation of the oxime functional group into a R group contains a carboxylic acid moiety , it can be further nitrone, or a similar intermediate with the same degree of transformed at this stage ( eg into an amide ) using conditions oxidation , for example a chlorooxime. This reactive species known in the art. The methyl ester group in 4 is then then reacts with an alkyne in a [3 + 2 ] cycloaddition to form the isoxazole adduct. transformed into an hydrazide by reaction with hydrazine to [0236 ] Finally , compound 5 undergoes a metal- assisted give 5. Finally , the hydrazide group in 5 is engaged in a coupling reaction to form compound 6. For example , com coupling reaction with a nitrile and subsequently undergoes pound 5 can be combined with a boronic acid under Suzuki a cyclodehydration to lead to compounds of Formula I -F1 . cross- coupling conditions to form the compound of formula 6 . Scheme I -F2 : preparation of compounds where Ring A is a 1,2,4 - triazole Scheme I- F1 : preparation of compounds where Ring A is a 1,2,4 - triazole NH2 NH2 R NH2 CO2Me N N CO2Me Br 1 ( R = CN ) 3 ( R = CO2Me) Br 6 ( R = CONHNH2 ) 3

NH2

–NH2 NH2 -R5 N Rs N N Suzuki

Br 7 US 2020/0222392 A1 Jul. 16 , 2020 24

-continued -continued ( Jup NH2 N R5 NH2

N N

R I -F2 I -G1 wherein R is - (L— NR'R ?) , or -( J2) wherein R is - (L— NR'R ?) , or - (J2 ) ?

[ 0238 ] Alternatively , compounds of the present disclosure [0239 ] Benzoxazole compounds of Formula VI can be where Ring A is a 1,2,4 - triazole can be prepared according prepared according to methods similar to the one depicted in Scheme I- G1 : Commercially available nitrile 1 is reacted to methods similar to the one depicted in Scheme I- F2 : the with a amino phenol to give the benzoxazole which is then R functional group in 1 or 3 (nitrile and methyl ester reacted with a boronic acid under Suzuki conditions to give respectively) are engaged into coupling (after appropriate compounds of the Formula 1- G1 . transformation of 3 into hydrazide 6 ) with a suitable cou pling partner (R , CONHNH , when starting from 1 ; R , CN if using 6 ). Subsequent cyclodehydration leads to the interme Scheme I- H1 : preparation of compounds where Ring A is a benzothiazole diate 7 where the 1,2,4 - triazole ring has been constructed . NH2 The bromo handle in triazole 7 is then reacted with a boronic .CN acid under Suzuki conditions to give compounds of formula I -F2 . When R group in Formula I- F2 contains a carboxylic acid moiety , it can be further transformed (eg into an amide ) using conditions known in the art . Br 1

NH2 Scheme I -G1 : preparation of compounds where Ring A is a benzoxazole NH2 Suzuki

SogBr N 2 (J1 ) P Br NH2 1

NH2

Suzuki I- H1 wherein Ris - (L— NR'R2) p or - (52 ) Br soo2 . [0240 ] Benzothiazole compounds of Formula VI can be prepared according to methods similar to the one depicted in US 2020/0222392 A1 Jul. 16 , 2020 25

Scheme I- H1 : Commercially available nitrile 1 is reacted -continued with a aminobenzenethiol to give the benzothiazole which is ( J1) p then reacted with a boronic acid under Suzuki conditions to give compounds of the Formula 1-11. NH2

Scheme I -H2 : preparation of compounds where benzothiazole N NH2 NH2 COOH COOMe N

Suzuki 1-11 wherein R is - (L— NR'R ?)por -( J2 ) Br 3 [0242 ] Benzimidazole compounds of Formula I can be R prepared according to methods similar to the one depicted in 8 Scheme I -H1 : methyl ester 3 is reacted with a boronic acid under Suzuki conditions to give intermediate 8. Cyclisation of internediate 8 with a benzene 1,2 -diamine will lead to compounds of the Formula 1-11. ( J1) p NH2 Scheme 1-12 : preparation of compounds where Ring A is an imidazole NH2 N COOH N

Br 3 ( J1) p I- H2 NH2 wherein Ris - - (L— NR'R ? ) or - (J2 )

Suzuki [0241 ] Alternatively, benzothiazole compounds of For mula VI can be prepared according to Scheme I -H2 ; methyl ester 3 is reacted with a boronic acid under Suzuki condi Br tions to give intermediate 8. Cyclisation of intermediate 8 9 with an amino benzenethiol will lead to compounds of the ( J1 )p Formula 1 -H2 . NH2

Scheme I- 11 : preparation of compounds where Ring A is an imidazole N NH2 NH2 COOH COOMe N N Suzuki R I - 12 Br wherein R is ( L — NR'R ? )p or - (J2 ) ? 3 [0243 ] Alternatively, benzimidazole compounds of For 8 mula I can be prepared according to methods similar to the & one depicted in Scheme 1-12 : Reaction of the acid functional US 2020/0222392 A1 Jul. 16 , 2020 26

group of 3 is reacted with a benzene 1,2 - diamine to give the 37538-37543 ( 1999 ) ; and Chiang et al, “ Determination of benzimidazole intermediate 9. Intermediate 9 is then reacted the catalytic activities of mTOR and other members of the with a boronic acid under Suzuki conditions to give com phosphoinositide - 3 -kinase - related kinase family " Methods pounds of the Formula 1-12 . Mol. Biol. 281 : 125-41 ( 2004 ) ) . Example 2 Example 3 Cellular ATR Inhibition Assay ATR Inhibition Assay [0244 ] Compounds can be screened for their ability to [0248 ] Compounds can be screened for their ability to inhibit intracellular ATR using an immunofluorescence inhibit ATR kinase using a radioactive- phosphate incorpo microscopy assay to detect phosphorylation of the ATR ration assay . Assays are carried out in a mixture of 50 mM substrate histone H2AX in hydroxyurea treated cells . HT29 Tris /HCl (pH 7.5 ), 10 mM MgCl2 and 1 mM DTT . Final cells are plated at 14,000 cells per well in 96 -well black substrate concentrations are 10 UM [y - 33P ]ATP (3mCi 33P imaging plates (BD 353219) in McCoy's 5A media ( Sigma ATP /mmol ATP, Perkin Elmer) and 800 uM target peptide M8403 ) supplemented with 10 % foetal bovine serum ( JRH ( ASELPASQPQPFSAKKK ) . Biosciences 12003 ) , Penicillin /Streptomycin [0249 ] Assays are carried out at 25 ° C. in the presence of diluted 1 : 100 (Sigma P7539 ) , and 2 mM L - glumtamine 5 nM full- length ATR . An assay stock buffer solution is (Sigma G7513 ), and allowed to adhere overnight at 37 ° C. prepared containing all of the reagents listed above, with the in 5 % CO2. Compounds are then added to the cell media exception of ATP and the test compound of interest. 13.5 uL from a final concentration of 25 uM in 3 - fold serial dilutions of the stock solution is placed in a 96 well plate followed by and the cells are incubated at 37 ° C. in 5 % CO2. After 15 addition of 2 uL of DMSO stock containing serial dilutions min , hydroxyurea (Sigma H8627 ) is added to a final con of the test compound (typically starting from a final con centration of 2 mM . centration of 15 ÙM with 3 - fold serial dilutions ) in duplicate [ 0245 ] After 45 min of treatment with hydroxyurea , the ( final DMSO concentration 7 % ). The plate is pre - incubated cells are washed in PBS , fixed for 10 min in 4 % formalde for 10 minutes at 25 ° C. and the reaction initiated by hyde diluted in PBS (Polysciences Inc 18814 ), washed in addition of 15 uL [ y - 33P ] ATP ( final concentration 10 uM ) . 0.2 % Tween - 20 in PBS (wash buffer ), and permeabilised for [0250 ] The reaction is stopped after 24 hours by the 10 min in 0.5 % Triton X - 100 in PBS , all at room tempera addition of 30uL 0.1M phosphoric acid containing 2 mm ture . The cells are then washed once in wash buffer and ATP. A multiscreen phosphocellulose filter 96 -well plate blocked for 30 min at room temperature in 10 % goat serum (Millipore , Cat no .MAPHNOB50 ) is pretreated with 100 uL (Sigma G9023 ) diluted in wash buffer ( block buffer ). To 0.2M phosphoric acid prior to the addition of 45 uL of the detect H2AX phosphorylation levels , the cells are then stopped assay mixture . The plate is washed with 5x200 uL incubated for 1 h at room temperature in primary antibody 0.2M phosphoric acid . After drying, 100 uL Optiphase (mouse monoclonal anti -phosphorylated histone H2AX 'SuperMix ' liquid scintillation cocktail (Perkin Elmer) is Ser139 antibody ; Upstate 05-636 ) diluted 1 : 250 in block added to the well prior to scintillation counting ( 1450 buffer. The cells are then washed five times in wash buffer Microbeta Liquid Scintillation Counter, Wallac ). before incubation for 1 h at room temperature in the dark in [0251 ] After removing mean background values for all of a mixture of secondary antibody ( goat anti -mouse Alexa the data points , Ki?app ) data are calculated from non - linear Fluor 488 conjugated antibody; Invitrogen A11029 ) and regression analysis of the initial rate data using the Prism Hoechst stain ( Invitrogen H3570 ) ; diluted 1 :500 and 1 : 5000 , software package (GraphPad Prism version 3.0cx forMacin respectively , in wash buffer. The cells are then washed five tosh , GraphPad Software , San Diego Calif ., USA ). times in wash buffer and finally 100 ul PBS is added to each well before imaging. Example 4 [ 0246 ] Cells are imaged for Alexa Fluor 488 and Hoechst intensity using the BD Pathway 855 Bioimager and Attovi Cisplatin Sensitization Assay sion software (BD Biosciences, Version 1.6 /855 ) to quantify phosphorylated H2AX Ser139 and DNA staining, respec [0252 ] Compounds can be screened for their ability to tively . The percentage of phosphorylated H2AX -positive sensitize HCT116 colorectal cancer cells to Cisplatin using nuclei in a montage of 9 images at 20x magnification is then a 96 h cell viability (MTS ) assay. HCT116 cells , which calculated for each well using BD Image Data Explorer possess a defect in ATM signaling to Cisplatin (see , Kim et software (BD Biosciences Version 2.2.15 ). Phosphorylated al.; Oncogene 21: 3864 ( 2002 ) ; see also , Takemura et al.; H2AX -positive nuclei are defined as Hoechst- positive JBC 281: 30814 ( 2006 ) ) are plated at 470 cells per well in regions of interest containing Alexa Fluor 488 intensity at 96 - well polystyrene plates (Costar 3596 ) in 150 ul of 1.75 - fold the average Alexa Fluor 488 intensity in cells not McCoy's 5A media ( Sigma M8403 ) supplemented with treated with hydroxyurea . The percentage of H2AX positive 10 % foetal bovine serum (JRH Biosciences 12003 ) , Peni nuclei is finally plotted against concentration for each com cillin /Streptomycin solution diluted 1 : 100 (Sigma P7539 ) , pound and IC50s for intracellular ATR inhibition are deter and 2 mM L - glumtamine (Sigma G7513) , and allowed to mined using Prism software (GraphPad Prism version 3.0cx adhere overnight at 37 ° C. in 5 % CO2. Compounds and for Macintosh , GraphPad Software , San Diego Calif. , USA ) . Cisplatin are then both added simultaneously to the cell [0247 ] The compounds described herein can also be tested media in 2 - fold serial dilutions from a top final concentra according to other methods known in the art ( see Sarkaria et tion of 10 uM as a full matrix of concentrations in a final cell al, “ Inhibition of ATM and ATR Kinase Activities by the volume of 200 ul, and the cells are then incubated at 37 ° C. Radiosensitizing Agent, Caffeine : Cancer Research 59 : in 5 % CO2. After 96 h , 40 ul of MTS reagent (Promega 4375-5382 ( 1999 ) ; Hickson et al, “ Identification and Char G358a ) is added to each well and the cells are incubated for acterization of a Novel and Specific Inhibitor of the Ataxia 1 h at 37 ° C. in 5 % CO2. Finally , absorbance is measured at Telangiectasia Mutated Kinase ATM ” Cancer Research 64 : 490 nm using a SpectraMax Plus 384 reader (Molecular 9152-9159 ( 2004 ); Kim et al , “ Substrate Specificities and Devices ) and the concentration of compound required to Identification of Putative Substrates of ATM Kinase Family reduce the IC50 of Cisplatin alone by at least 3 - fold ( to 1 Members” The Journal of Biological Chemistry , 274 (53 ): decimal place ) can be reported . US 2020/0222392 A1 Jul. 16 , 2020 27

Example 5 Example 8 Cancer -Selective Synergistic Effects of VE -822 Single Agent HCT116 Activity with Rucaparib [0253 ] Compounds can be screened for single agent activ [0259 ] FIG . 4. H23 non -small cell lung cancer ( a ), U2OS ity against HCT116 colorectal cancer cells using a 96 h cell osteosarcoma ( b ) , HCT116 colorectal cancer ( c ) , MCF7 viability (MTS ) assay. HCT116 are plated at 470 cells per breast cancer (d ), HT144 melanoma (e ), HT29 colorectal well in 96 - well polystyrene plates ( Costar 3596 ) in 150 ulof cancer ( f) and PSN1 pancreatic cancer ( g ) cells were treated McCoy's 5A media (Sigma M8403 ) supplemented with in triplicate with the indicated concentrations of VE - 822 and 10 % foetal bovine serum ( JRH Biosciences 12003 ) , Peni cillin / Streptomycin solution diluted 1 : 100 (Sigma P7539 ) , Rucaparib for 96 h , cell density was measured by 3-( 4,5 and 2 mM L - glumtamine (Sigma G7513 ), and allowed to dimethylthiazol- 2 - yl) -5-( 3 - carboxymethoxyphenyl) -2- ( 4 adhere overnight at 37 ° C. in 5 % CO2. Compounds are then sulfophenyl) -2H - tetrazolium (MTS ) assay and synergy was added to the cell media in 2 - fold serial dilutions from a top analyzed at the 95 % confidence interval with MacSynergy II final concentration of 10 uM as a full matrix of concentra software. A range of synergy was observed from strong ( a ) tions in a final cell volume of 200 ul, and the cells are then to negligible (g ). The synergy plots can be analyzed using incubated at 37 ° C. in 5 % CO2. After 96 h , 40 ul ofMTS methods described in Reaper et al, “ Selective Killing of reagent (Promega G358a ) is added to each well and the cells ATM- or p53 -deficient cancer cells through inhibition of are incubated for 1 h at 37 ° C. in 5 % CO2. Finally , ATR ” , Nat. Chem . Bio . 2011, April 13 ; 9 ( 7 ) :428-430 . The absorbance is measured at 490 nm using a SpectraMax Plus data demonstrates that VE -822 synergizes with the PARP 384 reader (Molecular Devices ) and IC50 values can be inhibitor Rucaparib in many ( but not all ) cancer cell lines in calculated . vitro . Example 6 Example 9 Synergistic Effects of VE -822 with Rucaparib in Pharmacokinetics Cancer and Non - Cancer Cells [0254 ] Noncompartmental pharmacokinetic parameters [0260 ] FIG . 5. H23 non - small cell lung cancer (a ) and are analyzed using Watson Bioanalytical LIMS (Version 7.4 ; HFL1 normal lung ( b ) cells were treated in triplicate with the Thermo Fisher Scientific ) from either the blood or plasma indicated concentrations of VE -822 and Rucaparib for 96 h , samples. The following parameters are estimated following cell density was measured by 3-( 4,5 - dimethylthiazol- 2 - yl) intravenous (IV ) dosing ; terminal elimination half -life ( T 5-( 3 -carboxymethoxyphenyl ) -2-( 4 - sulfophenyl) -2H -tetra 2 = ln ( 2 ) /Az , where az is the first order rate constant associ zolium (MTS ) assay and synergy was analyzed at the 95 % ated with the terminal (log - linear ) portion of the curve . confidence interval with MacSynergy II software . The syn [0255 ] The area under the curve (AUCjast area under the ergy plots can be analyzed using methods described in curve from the time of dosing to the last measurable con Reaper et al, “ Selective Killing of ATM- or p53 -deficient centration ). The area under the curve extrapolates to infinity cancer cells through inhibition of ATR ” , Nat . Chem . Bio . (AUCO- = AUClast + Ciast/ az ). The clearance (C1 : 2011, April 13 ;9 ( 7) :428-430 . The data demonstrates that C1 = Dose / AUCO... ). The area under the firstmoment curve VE -822 synergizes with the PARP inhibitor Rucaparib in ( AUMCjast area under the concentration times time versus cancer but not normal cells in vitro . time curve from the time of dosing to the last measurable concentration ) . The area under the first moment curve Example 10 extrapolates to infinity ( AUMCO- GAUMCast + Cjasext/ hz + Ciastaz ? ) . The mean residence time (MRT = AUMCO. Synergistic Effects of VE - 822 with Rucaparib and AUC ... ) and the steady state volume of distribution Ionizing Radiation ( Vdss =MRTXC1 ) . [0261 ] FIG . 6a . H23 non - small cell lung cancer ( a ) and [0256 ] Clearance and volume of distribution can also be HFL1 normal lung ( b ) cells were treated in triplicate with the obtained using methods known to one of skill in the art ( see indicated concentrations of VE - 822 and Rucaparib together e.g. , Handbook of Essential Pharmacokinetics , Pharmaco with 2 gray (Gy ) of IR , cell density was measured after 96 dynamics and Drug Metabolism for Industrial Scientists , h by 3- (4,5 -dimethylthiazol - 2 -yl ) -5-( 3 - carboxymethoxy Younggil Kwon , pp18-28 (Non -compartmental Approach ) ) . phenyl) -2-( 4 -sulfophenyl ) -2H - tetrazolium (MTS ) assay and synergy was analyzed at the 95 % confidence interval with Example 7 MacSynergy II software modified for triple combination studies (Nguyen et al, PLOS One 5 : 9332 ). The synergy plots Clonogenic Cell Survival Assay can be analyzed using methods described in Reaper et al , “ Selective Killing of ATM- or p53 - deficient cancer cells [0257 ] Compounds can be tested in a clonogenic cell through inhibition of ATR ” , Nat. Chem . Bio . 2011 , April survival assay under conditions known to one of skill in the 13 ; 9 ( 7 ): 428-430 . The data demonstrates that cancer- selec art to evaluate the effectiveness of various combination tive synergistic effects for the combination of VE -822 , the therapies on cancer cells . PARP inhibitor Rucaparib and Ionizing radiation ( IR ) . [0258 ] ATR inhibitors VE - 821 and VE -822 were tested in Example 11 a clonogenic cell survival assay with irradiation ( ionizing radiation ) alone and also in combination with ABT- 888 , a Synergistic Effects of VE -822 with Rucaparib and potent PARP1 and PARP2 inhibitor. Clonogenic survival of Cisplatin cancer cells from RKO and MDA -MB - 231 cancer cell lines [ 0262 ] FIG . 65. H23 non - small cell lung cancer ( a ) and were evaluated and results are shown in FIGS . 1 , 2 , and 3 . HFL1normal lung (b ) cells were treated in triplicate with the US 2020/0222392 A1 Jul. 16 , 2020 28

indicated concentrations of VE - 822 and Rucaparib together 107. The method of claim 106 , wherein the inhibitor of with 80 nM cisplatin , cell density was measured after 96 h PARP I and /or PARP II is Olaparib , Veliparib . Rucaparib by 3-( 4,5 -dimethylthiazol - 2 - yl) -5-( 3 -carboxymethoxyphe nyl) -2-( 4 -sulfophenyl ) -2H - tetrazolium (MTS ) assay and CEP - 9722 INO - 1001, MK -4827 , E7016 , BMN673 , or synergy was analyzed at the 95 % confidence interval with AZD2461. MacSynergy II software modified for triple combination 108. The method of claim 106 , wherein the ATR inhibitor studies (Nguyen et al, PLOS One 5 : 9332) . The synergy plots is administered concurrently with the inhibitor of PARP 1 can be analyzed using methods described in Reaper et al, and /or PARP II. “ Selective Killing of ATM- or p53 -deficient cancer cells 109. The method of claim 106 , further comprising admin through inhibition of ATR ” , Nat. Chem . Bio . 2011, April istering to the patient a therapeutically effective amount of 13 ; 9 ( 7 ) :428-430 . The data demonstrates that cancer- selec a DNA damaging agent, wherein the DNA damaging agent tive synergistic effects for the combination of VE -822 , the is a chemotherapeutic agent or radiation . PARP inhibitor Rucaparib and cisplatin . 110. The method of claim 109 , wherein the DNA dam [0263 ] While we have described a number of embodi aging agent is ionizing radiation , a platinating agent, a Topo ments of this invention , it is apparent that our basic examples may be altered to provide other embodiments that I inhibitor, a Topo II inhibitor, an anti -metabolite , an alky utilize the compounds, methods , and processes of this inven lating agent , an alkylsulphonate , or an antibiotic . tion . Therefore , it will be appreciated that the scope of this 111. The method of claim 110 , wherein the DNA dam invention is to be defined by the appended claims rather than aging agent is Cisplatin , Oxaliplatin , Carboplatin , Nedapla by the specific embodiments that have been represented by tin , Lobaplatin , Triplatin Tetranitrate , Picoplatin , Satrapla way of example herein . tin , ProLindac , Aroplatin , Camptothecin , Topotecan ,

SEQUENCE LISTING

< 160 > NUMBER OF SEQ ID NOS : 1 < 210 > SEQ ID NO 1 < 211 > LENGTH : 17 < 212 > TYPE : PRT < 213 > ORGANISM : Artificial Sequence < 220 > FEATURE : < 223 > OTHER INFORMATION : Synthetic Polypeptide < 400 > SEQUENCE : 1 Ala Ser Glu Leu Pro Ala Ser Gin Pro Gin Pro Phe Ser Ala Lys Lys 1 5 10 15 Lys

1-105. (canceled ) Irinotecan / SN38 , Rubitecan , Belotecan , Idarubicin , Amru 106. A method of treating cancer in a patient, comprising bicin , Pirarubicin , Valrubicin , Zorubicin , Teniposide, Amin administering to a patient in need thereof a therapeutically opterin , Methotrexate , Pemetrexed , Raltitrexed , Pentostatin , effective amount of an ATR inhibitor compound of formula : Cladribine , Clofarabine , Fludarabine , Thioguanine ,Mercap VE - 822 topurine , Fluorouracil, Capecitabine , Tegafur, Carmofur, Floxuridine , Cytarabine , Gemcitabine , Azacitidine, NH2 Hydroxyurea, Mechlorethamine, Cyclophosphamide, Ifosf HN amide, Trofosfamide , Chlorambucil, Melphalan , Predni mustine, Bendamustine, Uramustine, Estramustine , Car N mustine , Lomustine , Semustine , Fotemustine, Nimustine , Ranimustine , Streptozocin , Busulfan , Mannosulfan , Treo sulfan , Carboquone , Thio TEPA , Triaziquone , Triethylen emelamine , Procarbazine , Dacarbazine , Temozolomide, Altretamine, Mitobronitol , Actinomycin , Bleomycin , Mito mycin or Plicamycin . 112. The method of claim 110 , wherein the DNA dam aging agent is cisplatin , carboplatin , gemcitabine , camptoth OES ecin , topotecan , irinotecan /SN38 , rubitecan , belotecan , etoposide , or temozolomide . 113. The method of claim 110 , wherein the DNA dam aging agent is ionizing radiation . 114. The method of claim 110 , wherein the DNA dam or a pharmaceutically acceptable salt thereof; and aging agent is gemcitabine. an inhibitor of poly (ADP - ribose ) polymerase (PARP ) I 115. The method of claim 110 , wherein the DNA dam and / or II . aging agent is cisplatin or carboplatin . US 2020/0222392 A1 Jul. 16 , 2020 29

116. The method of claim 110 , wherein the DNA dam aging agent is etoposide. 117. The method of claim 110 , wherein the DNA dam aging agent is temozolomide. 118. The method of claim 109 , wherein the DNA dam aging agent is administered sequentially with the ATR inhibitor. 119. The method of claim 106 , wherein the cancer is melanoma, lung cancer, osteosarcoma, ovarian cancer, col orectal cancer or breast cancer. 120. The method of claim 119, wherein the cancer is lung cancer . 121. The method of claim 120 , wherein the lung cancer is non - small cell lung cancer. 122. The method of claim 119, wherein the cancer is colorectal cancer . 123. The method of claim 119 , wherein the cancer is ovarian cancer . 124. The method of claim 119 , wherein the cancer is breast cancer. 125. The method of claim 124 , wherein the breast cancer is triple negative breast cancer. 126. Themethod of claim 106 , wherein the cancer has one or more defects in ATM signaling cascade . 127. The method of claim 126 , wherein said defect is altered expression or activity of one or more of the follow ing : ATM , p53 , CHK2, MRE11 , RAD50 , NBS1, 53BP1 , MDC1, H2AX , MCPH1/ BRIT1 , CTIP, and SMC1.