DNA-damaging agents are among the most frequently used anticancer drugs. However, they provide only modest benefit in most cancers. This may be attributed to a genome maintenance network, the DNA damage response (DDR), that recognizes and repairs damaged DNA. ATR is a major regulator of the DDR and an attractive anticancer target. Herein, we describe the discovery of a series of aminopyrazines with potent and selective ATR inhibition. Compound 45 inhibits ATR with a K(i) of 6 nM, shows >600-fold selectivity over related kinases ATM or DNA-PK, and blocks ATR signaling in cells with an IC(50) of 0.42 μM. Using this compound, we show that ATR inhibition markedly enhances death induced by DNA-damaging agents in certain cancers but not normal cells. This differential response between cancer and normal cells highlights the great potential for ATR inhibition as a novel mechanism to dramatically increase the efficacy of many established drugs and ionizing radiation.

Interleukin-2 inducible T-cell kinase (Itk) plays a role in T-cell functions, and its inhibition potentially represents an attractive intervention point to treat autoimmune and allergic diseases. Herein we describe the discovery of a series of potent and selective novel inhibitors of Itk. These inhibitors were identified by structure-based design, starting from a fragment generated de novo, the 3-aminopyrid-2-one motif. Functionalization of the 3-amino group enabled rapid enhancement of the inhibitory activity against Itk, while introduction of a substituted heteroaromatic ring in position 5 of the pyridone fragment was key to achieving optimal selectivity over related kinases. A careful analysis of the hydration patterns in the kinase active site was necessary to fully explain the observed selectivity profile. The best molecule prepared in this optimization campaign, 7v, inhibits Itk with a K(i) of 7 nM and has a good selectivity profile across kinases.

The regiodivergent palladium-catalyzed C–H arylation of pyrazolo[1,5-a]pyrimidine has been achieved, wherein the switch in regioselectivity between positions C3 and C7 is under complete catalyst control. A phosphine-containing palladium catalyst promotes the direct arylation at the most acidic position (C7), whereas a phosphine-free catalyst targets the most electron-rich position (C3).

The regiodivergent palladium-catalyzed C À Ha rylation of pyrazolo [1,5-a]pyrimidine has been achieved, wherein the switch in regioselectivity between positions C3 and C7 is under complete catalyst control. Ap hosphinecontaining palladium catalyst promotes the direct arylation at the most acidic position (C7), whereas ap hosphine-free catalyst targets the most electron-rich position (C3).The direct CÀHa rylation of heterocyclics ubstrates (Scheme 1) is ap owerful synthetic tool for the construction of functionalized heterocycles.I tm aintains the expediency associated with simple cross-coupling reactions,b ut with greater step economy and lower waste production.[1] In heterocycles with multiple C À Hg roups,i tw ould be highly advantageous to be able to choose which CÀHg roup is functionalized, ideally with complete selectivity and with the ability to "switch" regioselectivity at will.[2] Seminal examples of this approach include the vinylation or arylation of pyrroles and indoles at either C2 or C3, where the outcome is driven by achange in substrate derivatization, [3,4] solvent, [5] or oxidant.[6]In these cases,the site selectivity is typically controlled by prohibiting or encouraging migration between positions C3 and C2. By contrast, we were interested to find out whether site selectivity could be engendered in the arylation of remote CÀHg roups,a nd whether catalyst "tuning" could be employed to drive this selectivity. [7] We report herein the catalyst-controlled switching in regioselectivity between the remote positions C3 and C7 of pyrazolo[1,5-a]pyrimidine (1; Figure 1). We chose this motif [8] because it forms the core of ar ange of biologically active compounds.S pecifically,a ryl-substituted pyrazolo[1,5-a]pyrimidines show antitumor [9] and anti-inflammatory properties, [10] have been examined as hepatitis Cvirus inhibitors and estrogen receptor ligands, [11,12] and are found in the approved sedative agents zaleplon and indiplon as well as in the anxiolytic agent ocinaplon.We began our study with the optimization of the coupling of compound 1 with bromobenzene in the presence of av ariety of palladium sources,w ith and without phosphines, changing solvents,bases,additives,and conditions.The results from this survey are summarized in the Supporting Information, and Scheme 2highlights the optimized conditions. Theu se of the monodentate phosphine ligand SPhos proved crucial to achieving site selectivity at C7, giving the desired product 2a in good yield.[13] NMR and UHPLC/ES-MS analyses of the crude reaction mixture showed at race amount (4 %) of the 3,7-diphenylated product (4a)b ut none of the 3-arylated species 3a,t hus indicating that arylation at C3 can only occur (to avery limited extent) after arylation at C7. [14] Conveniently,the reaction works just as well under air as under an inert atmosphere.The relatively high air stability of SPhos is obviously apivotal factor here.

The DNA damage response (DDR) is a DNA damage surveillance and repair mechanism that can limit the effectiveness of radiotherapy and DNA-damaging chemotherapy, commonly used treatment modalities in cancer. Two related kinases, ataxia telangiectasia mutated (ATM) and ATM and Rad3-related kinase (ATR), work together as apical proteins in the DDR to maintain genome stability and cell survival in the face of potentially lethal forms of DNA damage. However, compromised ATM signaling is a common characteristic of tumor cells, which places greater reliance on ATR to mediate the DDR. In such circumstances, ATR inhibition has been shown to enhance the toxicity of DNA damaging chemotherapy to many cancer cells in multiple preclinical studies, while healthy tissue with functional ATM can tolerate ATR inhibition. ATR therefore represents a very attractive anticancer target. Herein we describe the discovery of VX-970/M6620, the first ATR inhibitor to enter clinical studies, which is based on a 2-aminopyrazine core first reported by Charrier Charrier 10.1021/jm101488zJ. Med. Chem.20115423202330).

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The palladium-catalyzed ortho-arylation of diethyl carbamate-protected estrone and estriol with aryl iodides gives the 2-arylated analogues. Subsequent removal of the carbamate directing group furnishes 2-arylated estrone, estradiol, or estriol depending on the method used.

Halides. -Easily accessible 5-pyridyl boronate (V) smoothly reacts with a range of aryl and hetaryl halides with varying electronic properties to furnish 5-arylated pyridones (VII) (8 examples). Derivative (VIId) is elaborated to the cardiotonic agent amrinone (VIII). -(DURRANT*, S. J.; et al.; Heterocycles 70 (2006) 1, 509-517; Vertex Pharm. (Europe) Ltd., Abingdon, Oxfordshire OX14 4RY, UK; Eng.) -R. Staver 22-130