Combinations of phosphoinositide 3-kinase inhibitor compounds and chemotherapeutic agents for the treatment of hematopoietic malignanciesCombinations of PI3K inhibitor compounds having Formula (I) and chemotherapeutic agents, including stereoisomers, geometric isomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for treating hematopoietic malignancies. Methods of using such combinations for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.Treat the method for hematopoietic malignancies, including to mammal, drug treatment is combined in combination preparation form or in turn, one or more chemotherapeutants of the compound and therapeutically effective amount of wherein described therapeutic combination comprising therapeutically effective amount with formulas i, the chemotherapeutant is selected from dexamethasone, phosphinothioylidynetrisaziridine, doxorubicin, vincristine, rituximab, endoxan, metacortandracin, melphalan, lenalidomide, bortezomib, rapamycin and cytarabine；its compounds of formula i has following formula and its stereoisomer, geometric isomer, dynamic isomer or officinal salt：wherein：r1selected from h, f, cl, br, i, cn ,-(cr14r15)mnr10r11、-c(r14r15)nnr12c (=y) r10、-(cr14r15)nnr12s(o)2r10、-(cr14r15)mor10、-(cr14r15)ns(o)2r10、-(cr14r15)ns(o)2nr10r11、-c(or10)r11r14,-c (=y) r10,-c (=y) or10,-c (=y) nr10r11,-c (=y) nr12or10,-c (=o) nr12s(o)2r10,-c (=o) nr12(cr14r15)mnr10r11、-no2、-nr12c (=y) r11、-nr12c (=y) or11、-nr12c (=y) nr10r11、-nr12s(o)2r10、-nr12so2nr10r11、-sr10、-s(o)2r10、-s(o)2nr10r11,-sc (=y) r10,-sc (=y) or10、c1-c12alkyl, c2-c8alkenyl, c2-c8alkynyl, c3-c12carbocylic radical, c2-c20heterocyclic radical, c6-c20aryl and c1-c20heteroaryl；r2selected from h, f, cl, br, i, cn, cf3、-no2,-c (=y) r10,-c (=y) or10,-c (=y) nr10r11、-(cr14r15)mnr10r11、-(cr14r15)nor10、-(cr14r15)m-nr12c (=o) (cr14r15)nnr10r11、-nr12c (=y) r10、-nr12c (=y) or10、-nr12c (=y) nr10r11、-nr12so2r10、or10,-oc (=y) r10,-oc (=y) or10,-oc (=y) nr10r11、-os(o)2(or10) ,-op (=y) (or10)(or11)、-op(or10)(or11)、sr10、-s(o)r10、-s(o)2r10、-s(o)2nr10r11、-s(o)(or10)、-s(o)2(or10)、 - sc (=y) r10,-sc (=y) or10,-sc (=y) nr10r11、c1-c12alkyl, c2-c8alkenyl, c2-c8alkynyl, c3-c12carbocylic radical, c2-c20heterocyclic radical, c6-c20aryl and c1-c20heteroaryl；r3for carbon receipts or other documents in duplicate ring heteroaryl, carbon connection fused bicyclic c3-c20heterocyclic radical or carbon connection fused bicyclic c1-c20heteroaryl, wherein the bicyclic heteroaryl, fused bicyclic c3-c20heterocyclic radical and fused bicyclic c1-c20heteroaryl is optionally substituted with one or more groups, and the group is selected from f, cl, br, i ,-cn ,-nr10r11、-or10、-c(o)r10、-nr10c(o)r11、-n(c(o)r11)2、-nr10c(o)nr10r11、-nr12s(o)2r10,-c (=o) or10,-c (=o) nr10r11、c1-c12alkyl and (c1-c12alkyl)-or10；r10、r11and r12it independently is h, c1-c12alkyl, c2-c8alkenyl, c2-c8alkynyl, c3-c12carbocylic radical, c2-c20heterocyclic radical, c6-c20aryl or c1-c20heteroaryl,or r10and r11nitrogen in connection forms the c for being optionally substituted with one or more groups together2-c20miscellaneous cyclic rings, the group is independently selected from oxo, (ch2)mor12、nr12r12、cf3、f、cl、br、i、so2r12, c (=o) r12、nr12c (=y) r12、nr12s(o)2r12, c (=y) nr12r12、c1-c12alkyl, c2-c8alkenyl, c2-c8alkynyl, c3-c12carbocylic radical, c2-c20heterocyclic radical, c6-c20aryl and c1-c20heteroaryl；r14and r15independently selected from h, c1-c12alkyl or-(ch2)n- aryl,or, r14and r15atom in connection forms saturation or part unsaturation c together3-c12carbocyclic ring；wherein described alkyl, alkenyl, alkynyl, carbocylic radical, heterocyclic radical, aryl and heteroaryl are optionally substituted with one or more groups, and the group is independently selected from f, cl, br, i, cn, cf3、-no2, oxo, r10,-c (=y) r10,-c (=y) or10,-c (=y) nr10r11、-(cr14r15)nnr10r11、-(cr14r15)nor10、-nr10r11、-nr12c (=y) r10、-nr12c (=y) or11、-nr12c (=y) nr10r11、-(cr14r15)mnr12so2r10,=nr12、or10,-oc (=y) r10,-oc (=y) or10,-oc (=y) nr10r11、-os(o)2(or10) ,-op (=y) (or10)(or11)、-op(or10)(or11)、-sr10、-s(o)r10、-s(o)2r10、-s(o)2nr10r11、-s(o)(or10)、-s(o)2(or10) ,-sc (=y) r10,-sc (=y) or10,-sc (=y) nr10r11、c1-c12alkyl, c2-c8alkenyl, c2-c8alkynyl, c3-c12carbocylic radical, c2-c20heterocyclic radical, c6-c20aryl and c1-c20heteroaryl；y is o, s or nr12；m is 0,1,2,3,4,5 or 6；withn is 1,2,3,4,5 or 6.
조혈 악성종양의 치료를 위한 포스포이노시티드 ３-키나제 억제제 화합물 및 화학요법제의 조합물하기 화학식 I을 갖는 PDK 억제제 화합물 및 화학요법제의 조합물 (이들의 입체이성질체, 기하 이성질체, 호변이성질체, 대사물 및 제약상 허용되는 염 포함)은 조혈 악성종양을 치료하는데 유용하다. 포유동물 세포에서 이러한 장애 또는 관련된 병리 상태를 시험관내, 계내 및 생체내에서 진단, 예방 또는 치료하기 위한 이러한 조합물의 사용 방법이 개시된다. <화학식 I>치료 유효량의, 하기 구조식을 갖는 화학식 I의 화합물 및 그의 입체이성질체, 기하 이성질체, 호변이성질체 또는 제약상 허용되는 염, 및치료 유효량의, 덱사메타손, 티오테파, 독소루비신, 빈크리스틴, 리툭시맙, 시클로포스파미드, 프레드니손, 멜팔란, 레날리도미드, 보르테조밉, 라파마이신 및 시타라빈으로부터 선택된 하나 이상의 화학요법제를 포함하는 치료 조합물을 포유동물에게 조합된 제제로 또는 교대로 투여하는 것을 포함하는, 조혈 악성종양의 치료 방법.<화학식 I>[이미지]상기 식에서,R1은 H, F, Cl, Br, I, CN, -(CR14R15)mNR10R11, -C(R14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -(CR14R15)mOR10, -(CR14R15)nS(O)2R10, -(CR14R15)nS(O)2NR10R11, -C(OR10)R11R14, -C(=Y)R10, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NR12OR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NO2, -NR12C(=Y)R11, -NR12C(=Y)OR11, -NR12C(=Y)NR10R11, -NR12S(O)2R10, -NR12SO2NR10R11, -SR10, -S(O)2R10, -S(O)2NR10R11, -SC(=Y)R10, -SC(=Y)OR10, C1-C12 알킬, C2-C8 알케닐, C2-C8 알키닐, C3-C12 카르보시클릴, C2-C20 헤테로시클릴, C6-C20 아릴 및 C1-C20 헤테로아릴로부터 선택되고;R2는 H, F, Cl, Br, I, CN, CF3, -NO2, -C(=Y)R10, -C(=Y)OR10, -C(=Y)NR10R11, -(CR14R15)mNR10R11, -(CR14R15)nOR10, -(CR14R15)m-NR12C(=O)(CR14R15)nNR10R11, -NR12C(=Y)R10, -NR12C(=Y)OR10, -NR12C(=Y)NR10R11, -NR12SO2R10, OR10, -OC(=Y)R10, -OC(=Y)OR10, -OC(=Y)NR10R11, -OS(O)2(OR10), -OP(=Y)(OR10)(OR11), -OP(OR10)(OR11), SR10, -S(O)R10, -S(O)2R10, -S(O)2NR10R11, -S(O)(OR10), -S(O)2(OR10), -SC(=Y)R10, -SC(=Y)OR10, -SC(=Y)NR10R11, C1-C12 알킬, C2-C8 알케닐, C2-C8 알키닐, C3-C12 카르보시클릴, C2-C20 헤테로시클릴, C6-C20 아릴 및 C1-C20 헤테로아릴로부터 선택되고;R3은 탄소 연결된 모노시클릭 헤테로아릴, 탄소 연결된 융합된 비시클릭 C3-C20 헤테로시클릴 또는 탄소 연결된 융합된 비시클릭 C1-C20 헤테로아릴이고, 여기서 모노시클릭 헤테로아릴, 융합된 비시클릭 C3-C20 헤테로시클릴 및 융합된 비시클릭 C1-C20 헤테로아릴은 F, Cl, Br, I, -CN, -NR10R11, -OR10, -C(O)R10, -NR10C(O)R11, -N(C(O)R11)2, -NR10C(O)NR10R11, -NR12S(O)2R10, -C(=O)OR10, -C(=O)NR10R11, C1-C12 알킬 및 (C1-C12 알킬)-OR10으로부터 선택된 하나 이상의 기로 임의로 치환되고;R10, R11 및 R12는 독립적으로 H, C1-C12 알킬, C2-C8 알케닐, C2-C8 알키닐, C3-C12 카르보시클릴, C2-C20 헤테로시클릴, C6-C20 아릴 또는 C1-C20 헤테로아릴이거나, 또는R10 및 R11은 이들이 부착되어 있는 질소와 함께, 옥소, (CH2)mOR12, NR12R12, CF3, F, Cl, Br, I, SO2R12, C(=O)R12, NR12C(=Y)R12, NR12S(O)2R12, C(=Y)NR12R12, C1-C12 알킬, C2-C8 알케닐, C2-C8 알키닐, C3-C12 카르보시클릴, C2-C20 헤테로시클릴, C6-C20 아릴 및 C1-C20 헤테로아릴로부터 독립적으로 선택된 하나 이상의 기로 임의로 치환된 C2-C20 헤테로시클릭 고리를 형성하고;R14 및 R15는 H, C1-C12 알킬 또는 -(CH2)n-아릴로부터 독립적으로 선택되거나, 또는R14 및 R15는 이들이 부착되어 있는 원자와 함께 포화 또는 부분 불포화 C3-C12 카르보시클릭 고리를 형성하고;여기서 상기 알킬, 알케닐, 알키닐, 카르보시클릴, 헤테로시클릴, 아릴 및 헤테로아릴은 F, Cl, Br, I, CN, CF3, -NO2, 옥소, R10, -C(=Y)R10, -C(=Y)OR10, -C(=Y)NR10R11, -(CR14R15)nNR10R11, -(CR14R15)nOR10, -NR10R11, -NR12C(=Y)R10, -NR12C(=Y)OR11, -NR12C(=Y)NR10R11, -(CR14R15)mNR12SO2R10, =NR12, OR10, -OC(=Y)R10, -OC(=Y)OR10, -OC(=Y)NR10R11, -OS(O)2(OR10), -OP(=Y)(OR10)(OR11), -OP(OR10)(OR11), -SR10, -S(O)R10, -S(O)2R10, -S(O)2NR10R11, -S(O)(OR10), -S(O)2(OR10), -SC(=Y)R10, -SC(=Y)OR10, -SC(=Y)NR10R11, C1-C12 알킬, C2-C8 알케닐, C2-C8 알키닐, C3-C12 카르보시클릴, C2-C20 헤테로시클릴, C6-C20 아릴 및 C1-C20 헤테로아릴로부터 독립적으로 선택된 하나 이상의 기로 임의로 치환되고;Y는 O, S 또는 NR12이고;m은 0, 1, 2, 3, 4, 5 또는 6이고;n은 1, 2, 3, 4, 5 또는 6이다.