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Ep 2569287 B1 (19) TZZ _T (11) EP 2 569 287 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 413/04 (2006.01) C07D 239/46 (2006.01) 09.07.2014 Bulletin 2014/28 (86) International application number: (21) Application number: 11731562.2 PCT/US2011/036245 (22) Date of filing: 12.05.2011 (87) International publication number: WO 2011/143425 (17.11.2011 Gazette 2011/46) (54) COMPOUNDS USEFUL AS INHIBITORS OF ATR KINASE VERBINDUNGEN ALS HEMMER DER ATR-KINASE COMPOSÉS UTILISABLES EN TANT QU’INHIBITEURS DE LA KINASE ATR (84) Designated Contracting States: • VIRANI, Aniza, Nizarali AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Abingdon GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Oxfordshire OX144RY (GB) PL PT RO RS SE SI SK SM TR • REAPER, Philip, Michael Abingdon (30) Priority: 12.05.2010 US 333869 P Oxfordshire OX144RY (GB) (43) Date of publication of application: (74) Representative: Coles, Andrea Birgit et al 20.03.2013 Bulletin 2013/12 Kilburn & Strode LLP 20 Red Lion Street (73) Proprietor: Vertex Pharmaceuticals Inc. London WC1R 4PJ (GB) Boston, MA 02210 (US) (56) References cited: (72) Inventors: WO-A1-2010/054398 WO-A1-2010/071837 • CHARRIER, Jean-Damien Abingdon • C. A. HALL-JACKSON: "ATR is a caffeine- Oxfordshire OX144RY (GB) sensitive, DNA-activated protein kinase with a • DURRANT, Steven, John substrate specificity distinct from DNA-PK", Abingdon ONCOGENE, vol. 18, 1999, pages 6707-6713, Oxfordshire OX144RY (GB) XP002665425, cited in the application • KNEGTEL, Ronald, Marcellus Alphonsus Abingdon Oxfordshire OX144RY (GB) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 569 287 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 569 287 B1 Description BACKGROUND OF THE INVENTION 5 [0001] ATR ("ATM and Rad3 related") kinase is a protein kinase involved in cellular responses to DNA damage. ATR kinase acts with ATM ("ataxia telangiectasia mutated") kinase and many other proteins to regulate a ce ll’s response to DNA damage, commonly referred to as the DNA Damage Re sponse ("DDR"). The DDR stimulates DNA repair, promotes survival and stalls cell cycle progression by activating cell cycle checkpoints, which provide time for repair. Without the DDR, cells are much more sensitive to DNA damage and readily die from DNA lesions induced by endogenous cellular 10 processes such as DNA replication or exogenous DNA damaging agents commonly used in cancer therapy. [0002] Healthy cells can rely on a host of different proteins for DNA repair including the DDR kinase ATR. In some cases these proteins can compensate for one another by activating functionally redundant DNA repair processes. On the contrary, many cancer cells harbour defects in some of their DNA repair processes, such as ATM signaling, and therefore display a greater reliance on their remaining intact DNA repair proteins which include ATR. 15 [0003] In addition, many cancer cells express activated oncogenes or lack key tumour suppressors, and this can make these cancer cells prone to dysregulated phases of DNA replication which in turn cause DNA damage. ATR has been implicated as a critical component of the DDR in response to disrupted DNA replication. As a result, these cancer cells are more dependent on ATR activity for survival than healthy cells. Accordingly, ATR inhibitors may be useful for cancer treatment, either used alone or in combination with DNA damaging agents, because they shut down a DNA repair 20 mechanism that is more important for cellular survival in many cancer cells than in healthy normal cells. [0004] In fact, disruption of ATR function (e.g. by gene deletion) has been shown to promote cancer cell death both 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. [0005] ATR peptide can be expressed and isolated using a variety of methods known in the literature ( see e.g., Ünsal- 25 Kaçmaz et al, PNAS 99: 10, pp6673-6678, May 14, 2002; see also Kumagai et al. Cell 124, pp943-955, March 10, 2006; Unsal-Kacmaz et al. Molecular and Cellular Biology, Feb 2004, p1292-1300; and Hall-Jackson et al. Oncogene 1999, 18, 6707-6713). WO 2010/071837 relates to pyrazine derivatives useful as inhibitors of ATR protein kinase, pharmaceutically acceptable compositions comprising these compounds and their use in treating various diseases. 30 WO 2010/054398 relates to pyrazine compounds useful as inhibitors of ATR protein kinase, pharmaceutically acceptable compositions comprising these compounds and their use in treating various diseases, disorders and conditions. [0006] For all of these reasons, there is a need for the development of potent and selective ATR inhibitors for the treatment of cancer, either as single agents or as combination therapies with radiotherapy or genotoxic chemotherapy. 35 SUMMARY OF THE INVENTION [0007] The present invention relates to pyrazine and pyridine compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating various diseases, disorders, and conditions using the compounds of this invention; processes for 40 preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. These compounds have an unexpected ability to treat cancer as single agents. These compounds also show surprising synergy with other cancer agents, such as cisplatin, in combination therapies. 45 DETAILED DESCRIPTION OF THE INVENTION [0008] One aspect of this invention provides a compound of Formula IV: 50 55 2 EP 2 569 287 B1 5 10 15 or a pharmaceutically acceptable salt thereof, wherein R3 is H or methyl; A is N; R’ is H or C1-4alkyl; 20 m is 0 or 1; R2 is -Q or -Q-Q1; Q is a 3-8 membered monocyclic aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Q is substituted with 1 JQ group; Q is optionally fused to Q 1 to form a fused bicyclic ring Q-Q 1; or Q and Q 1 are optionally joined together at a carbon 25 atom to form a spirocyclic bicyclic ring Q-Q 1; or Q and Q 1, taken together, form a bridged bicyclic ring Q-Q 1 wherein said bridge is 1-3 atoms long; Q1 is a 3-8 membered monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Q1 is independently and optionally substituted with 1-4 JQ1 groups; L is -OCH2-, C2aliphatic, CO, -C(O)NH-, -C(O)N(C1-6alkyl)-; 30 n is 0 or 1; R1 is a 5-6 membered monocyclic aryl or heteroaryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said monocyclic aryl or heteroaryl ring is optionally fused to another ring to form a 8-10 membered bicyclic aryl or heteroaryl ring having 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R1 is optionally substituted with 1-5 J1 groups; 35 Q each J is SO2 (C1-4alkyl) wherein said C1-4alkyl is optionally substituted by 1-4 halo Q1 1 2 3 each J , and each J is independently halo, -CN, -NO2, V-R, or -(V )m-Q ; V is a C1-10aliphatic chain wherein 0-3 methylene units are optionally and independently replaced with oxygen, V nitrogen, sulfur, C(O), S(O), or S(O)2; V is optionally substituted with 1-6 occurrences of J ; 2 V is a C1-10aliphatic chain wherein 0-3 methylene units are optionally and independently replaced with oxygen, 40 V2 nitrogen, sulfur, C(O), S(O), or S(O)2; V is optionally substituted with 1-6 occurrences of J ; m is 0 or 1; Q3 is a 3-8 membered saturated or unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 8-10 membered saturated or unsaturated bicyclic ring having 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Q 3 is optionally substituted with 1-5 J Q3; 45 V V2 each J and J is independently halogen, CN, NH2, NO2, C1-4aliphatic, NH(C1-4aliphatic), N(C1-4aliphatic)2, OH, O(C1-4aliphatic), CO2H, CO2(C1-4aliphatic), C(O)NH2, C(O)NH(C1-4aliphatic), C(O)N(C1-4aliphatic)2, N- HCO(C1-4aliphatic), N(C1-4aliphatic)CO(C1-4aliphatic), 2SO(C1-4aliphatic), NHSO2(C1-4aliphatic), or N(C1-4aliphatic)SO2(C1-4aliphatic), wherein said C1-4aliphatic is optionally substituted with halo; Q3 4 each J is independently halo, oxo, CN, NO 2, X-R, or -(X)p-Q , 50 p is 0 or 1; X is C 1-10aliphatic; wherein 1-3 methylene units of said C 1-6aliphatic are optionally replaced with -NR, -O-, -S-, C(O), S(O)2, or S(O); wherein X is optionally and independently substituted with 1-4 occurrences of NH 2, NH(C1-4aliphatic), N(C1-4aliphatic)2, halogen, 1-4aCliphatic, OH, O(C1-4aliphatic), NO2, CN, CO(C1-4aliphatic), CO2H, CO2(C1-4aliphatic), C(O)NH2, C(O)NH(C1-4aliphatic), C(O)N(C1-4aliphatic)2, SO(C1-4aliphatic), SO2(C1-4aliphatic), 55 SO2NH(C1-4aliphatic), SONH(C1-4aliphatic)2, NHC(O)(C1-4aliphatic),
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