Claims for Patent: 9,169,235

Summary for Patent: 9,169,235

Title:	Phthalazinone derivatives
Abstract:	Compounds of the formula (I): ##STR00001## wherein A and B together represent an optionally substituted, fused aromatic ring; X can be NR.sup.X or CR.sup.XR.sup.Y; if X.dbd.NR.sup.X then n is 1 or 2 and if X.dbd.CR.sup.XR.sup.Y then n is 1; R.sup.X is selected from the group consisting of H, optionally substituted C.sub.1-20 alkyl, C.sub.5-20 aryl, C.sub.3-20 heterocyclyl, amido, thioamido, ester, acyl, and sulfonyl groups; R.sup.Y is selected from H, hydroxy, amino; or R.sup.X and R.sup.Y may together form a spiro-C.sub.3-7 cycloalkyl or heterocyclyl group; R.sup.C1 and R.sup.C2 are both hydrogen, or when X is CR.sup.XR.sup.Y, R.sup.C1, R.sup.C2, R.sup.X and R.sup.Y, together with the carbon atoms to which they are attached, may form an optionally substituted fused aromatic ring; and R.sup.1 is selected from H and halo.
Inventor(s):	Martin; Niall Morrison Barr (Cambridge, GB), Smith; Graeme Cameron (Cambridge, GB), Jackson; Stephen Philip (Cambridge, GB), Loh; Vincent Junior M (Horsham, GB), Cockcroft; Xiao-Ling Fan (Horsham, GB), Matthews; Ian Timothy Williams (Horsham, GB), Menear; Keith Allan (Horsham, GB), Kerrigan; Frank (Tintagel, GB), Ashworth; Alan (London, GB)
Assignee:	KUDOS PHARMACEUTICALS LIMITED (Cambridge, Cambridgeshire, GB)
Application Number:	14/483,663
Patent Claims:	1. A method of treatment for prostate or pancreatic cancer deficient in a HR dependent DNA DSB repair pathway comprising administering to a subject a therapeutically effective amount of a compound of formula (Ib): ##STR00441## or an isomer or salt thereof, or a mixture of any thereof, wherein: A and B together represent a fused aromatic ring, optionally substituted with one or more substituent groups selected from halo, nitro, hydroxyl, ether, thiol, thioether, amino, C.sub.1-7 alkyl, C.sub.5-1 aryl and a heterocyclyl group having from 3 to 7 ring atoms, of which from 1 to 4 are selected from nitrogen, oxygen and sulfur; R.sup.X is selected from H, C.sub.1-7 alkyl, C.sub.5-7 aryl, amido, thioamido, ester, acyl, sulfonyl groups and a heterocyclyl group having from 3 to 7 ring atoms, of which from 1 to 4 are selected from nitrogen, oxygen and sulfur, wherein the acyl, C.sub.1-7 alkyl, C.sub.5-7 aryl or heterocyclyl group is optionally substituted with one or more substituent groups selected from C.sub.1-7 alkyl, C.sub.5-7 aryl, halo, hydroxyl, ether, nitro, cyano, acyl, carboxy, ester, amido, amino, acylamido, ureido, acyloxy, thiol, thioether, sulfoxide, sulfonyl, thioamido, sulfonamido and a heterocyclyl group having from 3 to 7 ring atoms, of which from 1 to 4 are selected from nitrogen, oxygen and sulfur; R.sup.C1 and R.sup.C2 are both hydrogen; and R.sup.1 is selected from H and halo; wherein the cancer is prostate or pancreatic cancer; and wherein the cancer comprises one or more cancer cells having a reduced or abrogated ability to repair DNA DSB by HR relative to normal cells. 2. The method of claim 1, wherein the fused aromatic ring represented by A and B together is benzene. 3. The method of claim 1, wherein R.sup.1 is selected from H, Cl, and F. 4. The method of claim 1, wherein R.sup.X is selected from H, C.sub.1-7 alkyl, C.sub.5-7 aryl, acyl, sulfonyl, amido, and thioamido groups, wherein the acyl, C.sub.1-7 alkyl or C.sub.5-7 aryl group is optionally substituted with one or more substituent groups selected from C.sub.1-7 alkyl, C.sub.5-7 aryl, halo, hydroxyl, ether, nitro, cyano, acyl, carboxy, ester, amido, amino, acylamido, ureido, acyloxy, thiol, thioether, sulfoxide, sulfonyl, thioamido, sulfonamido and a heterocyclyl group having from 3 to 7 ring atoms, of which from 1 to 4 are selected from nitrogen, oxygen and sulfur. 5. The method of claim 1, wherein the compound of formula (Ib) or an isomer or salt thereof, or a mixture of any thereof, is a compound of formula (II): ##STR00442## or an isomer or salt thereof, or a mixture of any thereof, wherein: R.sup.C3 is selected from C.sub.1-7 alkyl, C.sub.5-7 aryl, and a heterocyclyl group having from 3 to 7 ring atoms, of which from 1 to 4 are selected from nitrogen, oxygen and sulfur, wherein the C.sub.1-7 alkyl, C.sub.5-7 aryl or heterocyclyl group is optionally substituted with one or more substituent groups selected from C.sub.1-7 alkyl, C.sub.5-7 aryl, halo, hydroxyl, ether, nitro, cyano, acyl, carboxy, ester, amido, amino, acylamido, ureido, acyloxy, thiol, thioether, sulfoxide, sulfonyl, thioamido, sulfonamido and a heterocyclyl group having from 3 to 7 ring atoms, of which from 1 to 4 are selected from nitrogen, oxygen and sulfur. 6. The method of claim 1, wherein the compound of formula (Ib) or an isomer or salt thereof, or a mixture of any thereof, is a compound of formula (III): ##STR00443## or an isomer or salt thereof, or a mixture of any thereof, wherein R is selected from: ##STR00444## 7. The method of claim 1, wherein the compound of formula (Ib) or an isomer or salt thereof, or a mixture of any thereof, is a compound of formula (IV), ##STR00445## or an isomer or salt thereof, or a mixture of any thereof. 8. The method of claim 1, further comprising identifying the subject as having a cancer condition that is deficient in a HR dependent DNA DSB repair pathway. 9. The method of claim 1, further comprising administering ionizing radiation, a chemotherapeutic agent, or a combination thereof to the subject. 10. The method of claim 1, wherein the one or more cancer cells has a BRCA1 or BRCA2 deficient phenotype. 11. The method of claim 10, wherein the one or more cancer cells are deficient in BRCA1 or BRCA2. 12. The method of claim 1, wherein the subject is heterozygous for a mutation in a gene encoding a component of the HR dependent DNA DSB repair pathway.