发明名称 MACROCYCLIC COMPOUNDS AS PROTEIN KINASE INHIBITORS
摘要 There is provided compounds of formula I, wherein R1, R2a, R2b, R2c, X, Y, Z, R3 and ring A/B have meanings given in the description, and pharmaceutically-acceptable esters, amides, solvates or salts thereof, which compounds are useful in the treatment of diseases in which inhibition of a protein or lipid kinase (e.g. PI3-K, particularly class I PI3K, PIM family kinase and/or mTOR) is desired and/or required, and particularly in the treatment of cancer. The invention also relates to combinations containing such compounds.;
申请公布号 US2014256717(A1) 申请公布日期 2014.09.11
申请号 US201214118009 申请日期 2012.05.18
申请人 Fernández Joaquín Pastor;Álvarez Escobar Rosa Maria;Riesco Fagundo Rosario Concepción;García García Ana Belén;Rodríguez Hergueta Antonio;Martin Hernando Jose Ignacio;Blanco Aparicio Carmen;Cebrián Muñoz David Álvaro 发明人 Fernández Joaquín Pastor;Álvarez Escobar Rosa Maria;Riesco Fagundo Rosario Concepción;García García Ana Belén;Rodríguez Hergueta Antonio;Martin Hernando Jose Ignacio;Blanco Aparicio Carmen;Cebrián Muñoz David Álvaro
分类号 C07D515/22;A61K31/4745;A61K45/06;A61K31/5383;A61K31/519;A61K31/5025;A61K31/4375;C07D513/22;C07D513/16 主分类号 C07D515/22
代理机构 代理人
主权项 1. A compound of formula I, wherein: ring A and ring B represent a fused bicyclic group of any one of the following formulae: wherein in formula IA: W1a is CH, CF or N; W2a is CH, CF or N; W3a is CR4a or N; W4a is CR5a or N; W5a is CR6a or N; in formula IB: W1b is CH, CF or N; W2b is CH, CF or N; W3b is CR4b or N; W4b is C or N; W5b is CR6b or N; W6b is C or N; W7b is C or N, and wherein when W3b represents N, W4b and W6b represent C and W5b represents C or N, then R* is hydrogen (in all other cases R* is absent); in formula IC: W1c is CH, CRt1, N, NRq1, O or S; W2c is CH, CRt2, N, NRq2, O or S; W3c is or N; W4c is CR5c or N; W5c is CR6c or N; W6c is or N; in formula ID: W1d is CH, CRt1, N, NRq1, O or S; W2d is CH, CRt2, N, NRq2, O or S; W3d is C or N; W4c is CR5c or N; W5c is C or N; W6d is C or N; each Rt1, Rt2, Rt3 and Rt4 is independently selected from halo, C1-3 alkyl (e.g. acyclic C1-3 alkyl or cyclopropyl), a 3- to 5-membered heterocycloalkyl group, —ORs1, —CN, —N(Rs2)Rs3, —S(O)w1CH3 or —C(O)CH3; W1 represents 0, 1 or 2; each Rs1, Rs2 and R3S independently represent hydrogen or C1-2 alkyl; each Rq1, Rq2, Rq3 and Rq4 is independently selected from C1-3 alkyl (e.g. acyclic C1-3 alkyl or cyclopropyl), a 3- to 5-membered heterocycloalkyl group or —C(O)CH3; each R1, R2a, R2b, R2c, R3, R4a, R5a, R6a, R4b, R6b, R5c, R6c, and R5d are independently selected from hydrogen or a substituent selected from halo, —CN, —C(O)N(Rf1)Rf2, —C(O)Rf3, —N(Rf4)Rf5, —C(O)ORf6, —ORf7, —OC(O)—Rf8, —S(O)w2CH3 or C1-8 alkyl (e.g. acyclic C1-6 alkyl or C3-7 cycloalkyl) and a 3- to 8-membered heterocycloalkyl groups, both of which (i.e. alkyl and heterocycloalkyl groups) are optionally substituted by one or more substituents selected from ═O and E1; W2 represents 0, 1 or 2; Rf1, Rf2, Rf3Rf5 and Rf7 independently represent hydrogen or C1-6 alkyl optionally substituted by one or more substituents selected from ═O and E2; or Rf1 and Rf2 and/or Rf4 and Rf5 may be linked together to form a 4- to 8-(e.g. 5- to 6-) membered ring optionally substituted by one or more substituents selected from C1-3 alkyl and halo; Rf3, Rf6 and Rf8 independently represent C1-6 alkyl optionally substituted by one or more substituents selected from ═O and E2; X represents a direct bond, —C(Ra)(Rb)—, —O—, —S—, —N(Rc)—, —N(Rd)C(O)—, —C(O)N(Re)— or —N(Rf)—C(O)—N(Rg)—; Y represents -arylene-, -heteroarylene- (which latter two groups are optionally substituted by one or more substituents selected from E3), -heterocycloalkylene- or —C1-12alkylene- (which latter two groups are optionally substituted by one or more substituents selected from ═O and E4); RN represents hydrogen or C1-6 alkyl optionally substituted by one or more substituents selected from ═O and E5; Z represents -(Ax)1-7-, wherein each Ax independently represents —C(Rx1)(Rx2)—, —N(Rx3)—, —C(O)—, —O—, —S—, —S(O)— or —S(O)2—; Rx1, Rx2 and Rx3 each independently represent hydrogen or a substituent selected from Ex; each Ex independently represents halo, —C(O)Ry1, —N(Ry2)—C(O)—N(Ry3)(Ry4), C1-6 alkyl or heterocycloalkyl (both of which latter two groups are optionally substituted by one or more halo atoms); Ry1, Ry2, Ry3 and Ry4 each independently represent hydrogen or C1-3 alkyl optionally substituted by one or more halo atoms; each Ra, Rb, Rc, Rd, Re, Rf and Rg independently represent hydrogen or C1-6 alkyl optionally substituted by one or more halo atoms; each E1, E2, E3, E4 and E5 independently represents, on each occasion when used herein: (i) Q4; (ii) C1-12 alkyl or heterocycloalkyl, both of which are optionally substituted by one or more substituents selected from ═O and Q5; any two E1, E2, E3, E4 and/or E5 groups (for example on C1-12 alkyl groups, e.g. when they are attached to the same or adjacent carbon atoms, or, on aromatic groups, when attached to adjacent atoms), may be linked together to form a 3- to 12-membered ring, optionally containing one or more (e.g. one to three) unsaturations (preferably, double bonds), and which ring is optionally substituted by one or more substituents selected from ═O and J1; each Q4 and Q5 independently represent, on each occasion when used herein: halo, —CN, —N(R20)R21, —OR20, —C(═Y1)—R20, —C(═Y1)—OR20, C(═Y)N(R20)R21, —C(═Y1)N(R20)—O—R21a, —OC(═Y1)—R20, —OC(═Y1)—OR20, —OC(═Y1)N(R20)R21, —OS(O)2OR20, —OP(═Y1)(OR20)(OR21), —OP(OR20)(OR21), —N(R22)C(═Y1)R21, —N(R22)C(═Y1)OR21, —N(R22)C(═Y1)N(R20)R21, —NR22S(O)2R20, —NR22S(O)2N(R20)R21, —S(O)2N(R20)R21, —SC(═Y1)R20, —SC(═Y1)OR20, —SC(═Y1)N(R20)R21, —S(O)2R20, —SR20, —S(O)R20, —S(O)2OR20, C1-6 alkyl or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from ═O and J2); each Y1 independently represents, on each occasion when used herein, ═O, ═S, ═NR23 or ═N—CN; each R21a represents C1-6 alkyl or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from J4 and ═O); each R20, R21, R22 and R23 independently represent, on each occasion when used herein, hydrogen, C1-6 alkyl or heterocycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from J4 and ═O); or any relevant pair of R20, R21 and R22, may (for example, when attached to the same atom, adjacent atom (i.e. 1,2-relationship) or to atoms that are two atoms apart, i.e. in a 1,3-relationship) be linked together to form (e.g. along with the requisite nitrogen atom to which they may be attached) a 4- to 20- (e.g. 4- to 12-) membered ring, optionally containing one or more heteroatoms (for example, in addition to those that may already be present, e.g. (a) heteroatom(s) selected from oxygen, nitrogen and sulfur), optionally containing one or more unsaturations (preferably, double bonds), and which ring is optionally substituted by one or more substituents selected from J6 and ═O; each J1, J2, J4 and J6 independently represents, on each occasion when used herein: (i) Q7; (ii) C1-6 alkyl or heterocycloalkyl, both of which are optionally substituted by one or more substituents selected from ═O and Q8; each Q7 and Q8 independently represents, on each occasion when used herein: halo, —CN, —N(R50)R51, —OR50, —C(═Ya)—R50, —C(═Ya)—OR50, —C(═Ya)N(R50)R51, —N(R52)C(═Ya)R51, —NR52S(O)2R50, —S(O)2N(R50)R51, —N(R52)—C(Ya)—N(R50)R51, —S(O)2R50, —SR50, —S(O)R50, C1-6 alkyl (optionally substituted by one or more fluoro atoms) or heterocycloalkyl (optionally substituted by one or more substituents selected from halo, —OR66 and —N(R61)R62); each Ya independently represents, on each occasion when used herein, ═O, ═S, ═NR53 or ═N—CN; each R50, R51, R52 and R53 independently represents, on each occasion when used herein, hydrogen or C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, —OR60 and —N(R61)R62 or any relevant pair of R50, R51 and R52 may (for example when attached to the same or adjacent atoms) be linked together to form, a 3- to 8-membered ring, optionally containing one or more heteroatoms (for example, in addition to those that may already be present, heteroatoms selected from oxygen, nitrogen and sulfur), optionally containing one or more unsaturations (preferably, double bonds), and which ring is optionally substituted by one or more substituents selected from ═O and C1-3 alkyl; R60, R61 and R62 independently represent hydrogen or C1-6 alkyl optionally substituted by one or more fluoro atoms; or a pharmaceutically acceptable ester, amide, solvate or salt thereof.
地址 Madrid ES