发明名称 Heteroaryls and uses thereof
摘要 This invention provides compounds of formula IA-i-a or IB-i-a and subsets thereof:; wherein Z, HY, R1, R2, R3, G1, W, n, and A and subsets thereof are as described in the specification. The compounds are inhibitors of PI3K and are thus useful for treating proliferative, inflammatory, or cardiovascular disorders.
申请公布号 US8796268(B2) 申请公布日期 2014.08.05
申请号 US201113207753 申请日期 2011.08.11
申请人 Millennium Pharmaceuticals, Inc. 发明人 Freeze Brian S.;Hirose Masaaki;Hu Yongbo;Sells Todd B.;Shi Zhan;Vyskocil Stepan;Xu Tianlin
分类号 A61K31/5377;C07D413/04;C07D413/14 主分类号 A61K31/5377
代理机构 Choate, Hall & Stewart LLP 代理人 Choate, Hall & Stewart LLP ;Reid Andrea L.C.;Klein Daniel A.
主权项 1. A compound of formula IA-i or IB-i: or a pharmaceutically acceptable salt thereof, wherein: R3 is hydrogen or an optionally substituted C1-6 aliphatic; Ring A is a group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each occurrence of R2 is independently —R12a, -T2-R12d, or —V2-T2-R12d, or two adjacent R2 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms selected from nitrogen, oxygen, and sulfur;each occurrence of R12a is independently halogen, —CN, —NO2, —R12c, —N(R12b)2, —OR12b, —SR12c, —S(O)2R12c, —C(O)R12b, —C(O)OR12b, —C(O)N(R12b)2, —S(O)2N(R12b)2, —OC(O)N(R12b)2, —N(R12e)C(O)R12b, —N(R12e)SO2R12c, —N(R12e)C(O)OR12b, —N(R12e)C(O)N(R12b)2, or —N(R12e)SO2N(R12b)2;each occurrence of R12b is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two occurrences of R12b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having O—1 additional heteroatoms selected from nitrogen,oxygen, and sulfur;each occurrence of R12c is independently an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each occurrence of R12d is independently hydrogen, —N(R7b)2, or an optionally substituted group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each occurrence of R12e is independently hydrogen or an optionally substituted C1-6 aliphatic group;each occurrence of V2 isindependently —N(R12e)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R12e)—, —S(O)2N(R12e)—, —OC(O)N(R12e)—, —N(R12e)C(O)—, —N(R12e)SO2—, —N(R12e)C(O)O—, —N(R12e) C(O)N(R12e)—, —N(R12e)SO2N(R12e)—, —OC(O)—, or —C(O)N(R12e)—O—; andT2 is an optionally substituted C1-6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R13)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R13)—, —S(O)2N(R13)—, —OC(O)N(R13)—, —N(R13)C(O)—, —N(R13)SO2—, —N(R13)C(O)O—, —N(R13)C(O)N(R13)—, —N(R13)S(O)2N(R13)—, —OC(O)—, or —C(O)N(R13)—O— or wherein T2 or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring, wherein R13 is hydrogen or an optionally substituted C1-4aliphatic group;W is —C(R7)2—, wherein one occurrence of R7 is hydrogen and the other occurrence of R7 is hydrogen, optionally substituted C1-6aliphatic, —N(R7b)2, or F; and wherein each occurrence of R7b is independently hydrogen, optionally substituted C1-6aliphatic, —C(O)R7a, or —S(O)2R7a; or wherein two occurrences of R7b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-6-membered heterocyclic ring; and each occurrence of R7a is independently hydrogen or optionally substituted C1-6aliphatic;G1 is N or —CR8, wherein R8 is H, —CN, halogen, —Z2—R9, C1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:Z2 is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R8a)—, —S—, —S(O)—, S(O)2—, —C(O)—, —CO2—, —C(O)NR8a—, —N(R8a)C(O)—, —N(R8a)CO2—, —S(O)2NR8a—, —N(R8a)S(O)2—, —OC(O)N(R8a)—, —N(R8a)C(O)NR8a—, —N(R8a)S(O)2N(R8a)—, and —OC(O)—;R8a is hydrogen or an optionally substituted C1-4 aliphatic, andR9 is hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur; andHY is represents a single bond or a double bond;wherein each occurrence of R14 is independently—R14a or -T1—R14d, wherein: each occurrence of R14a, as valency and stability permit, is independently fluorine, ═O, ═S, —CN, —NO2, —R14c, —N(R14b)2, —OR14b, —SR14c, —S(O)2R14c, —C(O)R14b, —C(O)OR14b, —C(O)N(R14b)2, —S(O)2N(R14b)2, —OC(O)N(R14b)2, —N(R14e)C(O)R14b, —N(R14e)SO2R14c, —N(R14e)C(O)OR14b, —N(R14e)C(O)N(R14b)2, or —N(R14e)SO2N(R14b)2, or two occurrences of R14b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having O—1 additional heteroatoms selected from nitrogen,oxygen, and sulfur;each occurrence of R14b is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each occurrence of R14c is independently an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen,oxygen, and sulfur, 6-10-membered aryl, and 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each occurrence of R14d is independently hydrogen or an optionally substituted from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each occurrence of R14e is independently hydrogen or an optionally substituted C1-6 aliphatic group; andT1 is an optionally substituted C1-6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R14a)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R14a)—, —S(O)2N(R14a)—, —OC(O)N(R14a)—, —N(R14a)C(O)—, —N(R14a)SO2—, —N(R14a)C(O)O—, —NR14aC(O)N(R14a)—, —N(R14a)S(O)2N(R14a)—, —OC(O)—, or —C(O)N(R14a)—O— or wherein T1 or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring; andn is 0-6;q is 0-4;m is 1 or 2; andp is 0, 1, or 2.
地址 Cambridge MA US