CN103596953A - 吡啶并萘啶类P13K和mTOR双重抑制剂及其制备与应用 - Google Patents
吡啶并萘啶类P13K和mTOR双重抑制剂及其制备与应用 Download PDFInfo
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- CN103596953A CN103596953A CN201280016501.8A CN201280016501A CN103596953A CN 103596953 A CN103596953 A CN 103596953A CN 201280016501 A CN201280016501 A CN 201280016501A CN 103596953 A CN103596953 A CN 103596953A
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- yue
- unsubstituted
- naphthyridines
- phenyl
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- 210000000056 organ Anatomy 0.000 description 1
- 150000002891 organic anions Chemical class 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 150000004893 oxazines Chemical class 0.000 description 1
- ATYBXHSAIOKLMG-UHFFFAOYSA-N oxepin Chemical compound O1C=CC=CC=C1 ATYBXHSAIOKLMG-UHFFFAOYSA-N 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- PMJHHCWVYXUKFD-UHFFFAOYSA-N penta-1,3-diene Chemical class CC=CC=C PMJHHCWVYXUKFD-UHFFFAOYSA-N 0.000 description 1
- QYZLKGVUSQXAMU-UHFFFAOYSA-N penta-1,4-diene Chemical class C=CCC=C QYZLKGVUSQXAMU-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- MQKPEUAOJLJUMD-UHFFFAOYSA-N phenol;piperazine Chemical compound C1C[NH2+]CCN1.[O-]C1=CC=CC=C1 MQKPEUAOJLJUMD-UHFFFAOYSA-N 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- YGDICLRMNDWZAK-UHFFFAOYSA-N quinolin-3-ylboronic acid Chemical class C1=CC=CC2=CC(B(O)O)=CN=C21 YGDICLRMNDWZAK-UHFFFAOYSA-N 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000009711 regulatory function Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- NNBZCPXTIHJBJL-UHFFFAOYSA-N trans-decahydronaphthalene Natural products C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
Description
Claims (1)
- 权 利 要 求1. 通式 (I)所示的化合物、 其药学上可接受的盐、 它们的立体异构 体或它们的氘代物:X为 0;R1为氢, 或者为未被取代或被 1-3个 R8取代的 d.6烷基、 C2.6烯 基、 C2_6炔基、 3-14元环烷基、 6-14元芳基、 3-14元杂环基、 7-12元 螺环基或 7-12元桥环基;R2为氢, 或者为未被取代或被 1-3个 R8'取代的 C1-6烷基、 C2-6烯 基、 C2.6炔基、 3-14元环烷基、 6-14元芳基、 3-14元杂环基、 7-12元 螺环基或 7-12元桥环基;R3和 R4各自独立地选自下列一组基团: 氢, 素, 氰基, 氨基, 羟基,磺酰基, -S02C^6烷基, 以及未被取代或被 1-3个选自 1¾素原子、 羟基和 /或羧基的取代基取代的 d.6烷基和(^_6烷氧基;R5选自下列一组基团: 氢, 氰基, 氨基, 磺酰基, -SOzC^烷基, 以及未被取代或被 1-3个选自 1¾素原子、 羟基和 /或羧基的取代基取代 的 d_6烷基和 C1-6烷氧基;R6和 R7各自独立地选自下列一组基团: 氢, 羟基, 卤素, 氨基, 以及未被取代或被 1-3个选自 素原子、 羟基和 /或羧基的取代基取代 的 _6烷基和 d_6烷氧基;R8和 R8'各自独立地选自下列一组基团:(1) 羟基, 素, 氨基, 氰基, -(CH2)nNRaRb, -(CH2)nC(0)Rc , -(CH2)nS(0)mRc , -(CH2)nS(0)mNRaRb , -(CH2)nNRaS(0)mRc , -(CH2)nC(0)(CH2)nNRaRb, -(CH2)nOC(0)Rc, -(CH2)nNRaC(0)Rc, 和 -(CH2)nNRaC(0)NRaRb,(2) 未被取代或被 1-3个选自氰基、 卤素和 /或羟基的取代基取代的 d.6 烷基、 C2-6烯基、 C2-6炔基和 c1-6烷氧基, 以及(3) 未被取代或被 1-3 个选自氰基、 三氟曱基、 卤素、 d_6烷基、 C2-8 烯基、 C2-8炔基、 d.6烷氧基、 -(CH2)nNRaRb、 -(CH2)nC(0)Re'、 -(CH2)nC(0)(CH2)nNRaRb、 _(CH2)nS(0)mRc'、 -(CH2)nS(0)mNRaRb、 _(CH2)nNRaS(0)mRc'、 -(CH2)nOC(0)Rc,、 -(CH2)nNRaC(0)Rc,和 /或 -(CH2)nNRaC(0)NRaRb的取代基取代的 3-14元环烷基、 6-14元芳基 和 3-14元杂环基;其中Ra和 Rb各自独立地选自氢, 或者未被取代或被 1-3个选自羟基、 卤素和 /或氰基的取代基取代的 6烷基;Re为未被取代或被 1-3个选自羟基、 卤素、 氰基和 /或三氟曱基的 取代基取代的 d.6烷基或 d-6烷氧基;Re'为未被取代或被 1-3个选自羟基、 1¾素和 /或氰基的取代基取代 的 C1-6烷基、 C1-6烷氧基、 3-8元单环环烷基或 3-8元单杂环基;m为 0、 1或 2; 以及n为 0〜4。2. 如权利要求 1所述的化合物、 其药学上可接受的盐、 其立体异 构体或其氘代物, 其中R1为未被取代或被 1-3个 R8取代的 3-14元环烷基、 6-14元芳基、 3-14元杂环基、 7-12元螺环基或 7-12元桥环基;R2为未被取代或被 1-3个 R8'取代的 3-14元环烷基、 6-14元芳基 或 3-14元杂环基;R3和 R4各自独立地选自下列一组基团: 氢, 素, 氰基, 氨基, 羟基, 三氟曱基以及三氟曱氧基; R5为氢, 氰基或氨基;R6和 R7各自独立地选自下列一组基团: 氢, 羟基, 卤素, 氨基, 以及 C1-6烷基;R8和 R8'各自独立地选自下列一组基团:(1) 羟基, 1¾素, 氨基, 氰基, -(CH2)nC(0)Rc,-(CH2)nNRaRb , -(CH2)nS(0)mRc , -(CH2)nS(0)mNRaRb , -(CH2)nNRaS(0)mRc , -(CH2)nC(0)(CH2)nNRaRb, -(CH2)nOC(0)Rc , -(CH2)nNRaC(0)Rc和 -(CH2)nNRaC(0)NRaRb,(2) 未被取代或被 1-3个选自氰基、 素和 /或羟基的取代基取代的 d_6 烷基和 0^6烷氧基, 以及(3) 未被取代或被 1-3 个选自氰基、 三氟甲基、 卤素、 d_6烷基、 C1-6 烷氧基、 -(CH2)nNRaRb、 -(CH2)nC(0)Rc'、 -(CH2)nC(0)(CH2)nNRaRb、 -(CH2)nS(0)mRc' 、 -(CH2)nS(0)mNRaRb 、 -(CH2)nNRaS(0)mRc' 、 -(CH2)nOC(0)Rc'、 _(CH2)nNRaC(0)Rc'和 /或 _(CH2)nNRaC(0)NRaRb的 取代基取代的 3-8元单环环烷基、 6-14元芳基和 3-8元单杂环基; 其中Ra和 Rb各自独立地选自氢, 或者未被取代或被 1-3个选自羟基、 卤素和 /或氰基的取代基取代的 烷基;Re为未被取代或被 1-3个选自羟基、 卤素、 氰基和 /或三氟甲基的 取代基取代的 d_6烷基和 C^6烷氧基;Re'为未被取代或被 1-3个选自羟基、 素和 /或氰基的取代基取代 的 烷基或 d.6烷氧基;m为 0、 1或 2; 以及n为 0、 1、 2或 3。3. 如权利要求 1所述的化合物、 其药学上可接受的盐、 其立体异 构体或其氘代物, 其中R1为未被取代或被 1-3个 R8取代的 3-8元单环环烷基、 6-14元芳 基或 3-8元单杂环基; R2为未被取代或被 1-3个 R8'取代的 3-8元单环环烷基、 6-14元芳 基或 5-10元杂环基;R3、 R4和 R5各自为氢;R6和 R7各自独立地为氢或 d_4烷基;R8选自下列一组基团:(1) 羟基, 卤素, 氰基, 氨基, 和 -(CH2)nC(0)Rc,(2) 未被取代或被 1-3个选自氰基、 1¾素和 /或羟基的取代基取代的 d.4 烷基和 d_4烷氧基, 以及(3) 未被取代或被 1-3个选自氰基、 三氟曱基、 卤素、 -(CH2)nC(0)Rc'、 -(CH2)nC(0)(CH2)„NRaRb和 /或 _(CH2)nS(0)mRe'的取代基取代的 5-8 元饱和单杂环基;R8'选自下列一组基团:(1) 羟基, 1¾素, 氰基, 氨基, -(CH2)nC(0)Re , -(CH2)nNRaRb , -(CH2)nS(0)mRc , -(CH2)nS(0)mNRaRb , -(CH2)nNRaS(0)mRc , -(CH2)nC(0)(CH2)nNRaRb , -(CH2)nOC(0)Rc , -(CH2)nNRaC(0)Rc和 -(CH2)nNRaC(0)NRaRb,(2) 未被取代或被 1-3个选自氰基、 素和 /或羟基的取代基取代的 CM 烷基和 CM烷氧基, 以及(3) 未被取代或被 1-3 个选自氰基、 三氟曱基、 卤素、 CM烷基、 d_4 烷氧基、 -(CH2)nNRaRb、 -(CH2)nC(0)Rc'、 -(CH2)nC(0)(CH2)nNRaRb、-(CH2)nS(0)mRc' 、 -(CH2)nS(0)mNRaRb 、 -(CH2)nNRaS(0)mRc' 、 -(CH2)nOC(0)Rc\ _(CH2)nNRaC(0)Rc'和 /或 _(CH2)nNRaC(0)NRaRb的 取代基取代的 5-8元单杂环基;Ra和 Rb各自独立地为氢,或未被取代或被 1-3个选自羟基和 /或卤 素的取代基取代的 d_4烷基;Re为未被取代或被 1-3个选自羟基、 素和 /或氰基的取代基取代 的 CM烷基或 d_4烷氧基;Re'为未被取代或被 1-3个选自羟基和 /或 素的取代基取代的 d.4 烷基或 CM烷氧基;m为 0、 1或 2; 以及n为 0、 1、 2或 3。4. 如权利要求 1所述的化合物、 其药学上可接受的盐、 其立体异 构体或其氘代物, 其中R1为未被取代或被 1-3个 R8取代的 6-10元芳基、 3-8元饱和单杂 环基或 5-6元芳香性单杂环基;R2为未被取代或被 1-3个 R8'取代的 6-10元芳基或 5-10元单杂环 基;R3、 R4和 R5各自为氢;R6和 R7各自独立地为氢或 CM烷基;R8为(1) 羟基, 1¾素, 氰基, 氨基或 -C(0)RE,(2) 未被取代或被 1-3个选自氰基、 1¾素和 /或羟基的取代基取代的 CM 烷基或 CM烷氧基, 或者(3) 未被取代或被 1-3 个选自氰基、 三氟曱基、 1¾素、 -C(0)Re'、 -C(0)(CH2)NNRARB和 /或 -S(0)2RE'的取代基取代的 5-6元饱和单杂环 基;R8'为(1) 羟基, 素, 氰基, 氨基, -(CH2)NNRAC(0)RE或- (CH2)NS(0)MRE,(2) 未被取代或被 1-3个选自氰基、 素和 /或羟基的取代基取代的 CM 烷基或 d.4烷氧基, 或者(3) 未被取代或被氰基、 三氟曱基、 面素、 d-4烷基或 d_4烷氧基取代 的 5-6元单杂环基;RA和 RB各自独立地为氢,或未被取代或被 1-3个选自羟基和 /或卤 素的取代基取代的 CM烷基;RE为未被取代或被 1-3个选自羟基、 1¾素和 /或氰基的取代基取代 的 d_4烷基或 CM烷氧基; RE'为未被取代或被 1-3个选自羟基和 /或 I¾素的取代基取代的 CM 烷基或 CM烷氧基;m为 0、 1或 2; 以及n为 0、 1、 2或 3。5. 如权利要求 4所述的化合物、 其药学上可接受的盐、 其立体异 构体或其氘代物, 其中R1为未被取代或被 1-3个 R8取代的苯基、 萘基或 5-6元饱和单杂 环基;R2为未被取代或被 1-3个 R8'取代的苯基、 吡啶基、 嘧啶基、 哒嗪 基、 吡嗪基、 吡唑基、 咪唑基、 吡咯基、 哺唑基、 异哺唑基、 噻唑基、 异噻唑基、 吲唑基、 喹啉基、 异喹啉基、 吲哚基、 吡咯并吡啶、 二氢 吡咯并吡淀或吡唑并吡 ff定基;R6和 R7各自独立地为氢或曱基;R8为(1) 氨基或 -C(0)Re, Re为未被取代或羟基或面素取代的 d.4烷基,(2) 未被取代或者被氰基或 1-3个氟取代的 CM烷基或 d_4烷氧基, 或 者(3) 未被取代或者被氰基或三氟曱基取代的哌嗪基或哌啶基;R8'为(1) 羟基, 卤素, 氨基, 氰基, -NHC(0)Re或 -S(0)mRc, 其中 m为 0或 2, Rc为 d.4烷基,(2) 未被取代或被羟基或 1-3个氟取代的 d.4烷基或 d_4烷氧基, 或者(3) 未被取代或被氰基、 三氟曱基、 1¾素、 CM烷基或 CM烷氧基取代 的吡啶基、 哌啶基、 嘧啶基、 哒嗪基、 吡。秦基、 哌嗪基、 吡唑基、 咪 唑基、 吡咯基、 吡咯烷基或吗啉基。6. 如权利要求 4所述的化合物、 其药学上可接受的盐、 其立体异 构体或其氘代物, 其中R1为未被取代或被 1-3个 R8取代的 6-10元芳基或 5-6元单杂环基, 其中 R8为(1) 氨基或 -C(0)RE, RE为未被取代或羟基或卤素取代的 CM 烷基, (2) 未被取代或者被氰基或 1-3个 素取代的 d_4烷基或 d.4烷 氧基,或者 (3) 未被取代或者被氰基或三氟曱基取代的 5-6元单杂环基; 和 /或R2为未被取代或被 1-3个 R8'取代的 6-10元芳基、 5-6元部分饱和 单杂环基、 5-6元芳香性单杂环基或 9-10元稠杂环基,其中 R8'为(1)羟 基, 素, 氨基, 氰基, -NHC(0)Re或 -S(0)mRe, 其中 m为 0、 1或 2, RE为 CM烷基, (2) 未被取代或被羟基或 1-3个 素取代的 d_4烷基或 CL4烷氧基, 或者 (3) 未被取代或被氰基、 三氟曱基、 素、 CM烷基 或 CM烷氧基取代的 5-6元单杂环基。7. 如权利要求 5所述的化合物、 其药学上可接受的盐、 其立体异 构体或其氘代物, 其中R1为未被取代或被 1-2个 R8取代的苯基、 哌啶基或哌嗪基; R2为未被取代或被 1-2个 R8'取代的苯基、 吡啶基、 嘧啶基、 哒嗪 基、 吡嗪基、 吡唑基、 咪唑基、 吡咯基、 哺唑基、 异11恶唑基、 噻唑基、 异噻唑基、 喹啉基、 异喹啉基、 吡咯并吡啶、 二氢吡咯并吡啶或吲哚 基;R8为(1) 氨基或 -C(0)R°, RE为未被取代或被羟基取代的 CM烷基,(2) 未被取代或者被氰基或三个氟取代的 CM烷基, 或者(3) 未被取代或者被氰基或三氟曱基取代的哌嗪基或哌啶基;R8'为(1) 卤素, 氨基, 氰基, -NHC(0)Rc或 -S(0)mRc, 其中 m为 0或 2, Rc(2) 未被取代或者被羟基或三个氟取代的 d.4烷基或 CM烷氧基,或者(3) 未被取代或被 CM烷基取代的哌嗪基、 吡唑基、 哌啶基、 吗啉 基、 嘧啶基、 哒嗪基、 吡嗪基、 吡咯基或吡咯烷基。8. 如权利要求 1所述的化合物、 其药学上可接受的盐、 其立体异 构体或其氘代物, 所述化合物选自:2-(6-氨基吡啶 -3-基) -10-(3- (三氟曱基)苯基)吡啶并 [3,2-c][l,5]萘啶 -9(腿)-酮,2-(6-甲氧基吡啶 -3-基) -10-(4- (哌嗪 -1-基) -3- (三氟甲基)苯基)吡啶 并 [3,2-c][l,5]萘啶 -9(10H)-酮,(R)-2-(6-氨基吡啶 -3-基) -10-(1-(2-羟基丙酰基)哌啶 -4-基)吡啶并 [3,2-c][l,5]萘啶 -9(10H)-酮,(R)-10-(l-(2-羟基丙酰基)哌啶 -4-基) -2-(6-曱氧基吡啶 -3-基)吡啶并 [3,2-c][l,5]萘啶 -9(10H)-酮,2-曱基 -2-(4-(9-氧代 -2- (喹啉 -3-基)吡啶并 [3,2-c][l,5]萘啶 -10(9H)- 基)苯基)丙腈,2-(6-氨基吡啶 -3-基) -10-(4- (哌嗪 -1-基) -3- (三氟曱基)苯基)吡啶并 [3,2-c][l,5]萘啶 -9(10H)-酮,2-(4-(2-(6-氨基吡啶 -3-基) -9-氧代吡啶并 [3,2-c][l,5]萘啶 -10(9H)- 基)苯基) -2-曱基丙腈,2-(6-甲氧基吡啶 -3-基) -10-(3- (三氟曱基)苯基)吡啶并 [3,2-c][l,5]萘 啶 -9(10H)-酮,2-(喹啉 -3-基 )-10-(3-(三氟甲基)苯基)吡啶并 [3,2-c][l ,5]萘啶 -9(丽)-酮,10-(4-(哌嗪 -1-基)-3-(三氟曱基)苯基)-2-(喹啉 -3-基)吡啶并[3,2-c][l,5]萘啶 -9(10H)-酮,(R)-10-(l-(2-羟基丙酰基)哌啶 -4-基 )-2-(喹啉 -3-基)吡啶并 [3,2-c][l,5]萘啶 -9(10H)-酮,2-(4-(2-(6-曱氧基吡啶 -3-基 )-9-氧代吡啶并 [3,2-c][l,5]萘啶 -10(9H)-基)苯基) -2-曱基丙腈,2-(2-氨基嘧啶 -5-基) -10-(3- (三氟甲基)苯基)吡啶并 [3,2-c][l,5]萘啶 -9(腿)-酮,2-(2-甲氧基嘧啶 -5-基) -10-(3- (三氟曱基)苯基)吡啶并 [3,2-c][l,5]萘 啶 -9(10H)-酮,N-(5-(9-氧代 -10-(3- (三氟曱基)苯基) -9,10-二氢吡啶并 [3,2-c][l,5] 萘啶 -2-基)吡啶 -2-基)乙酰胺,5-(9-氧代 -10-(3- (三氟曱基)苯基) -9,10-二氢吡啶并 [3,2-c][l,5]萘啶 -2-基) -2-氰基吡啶,2-( 1 H-吡咯并 [2,3-b]吡啶 -3-基) - 10-(3-(三氟曱基)苯基)吡啶并 [3,2-c][l,5]萘啶 -9(10H)-酮,2-(6- (羟曱基)吡啶 -3-基) -10-(3- (三氟曱基)苯基)吡啶并 [3,2-c][l,5] 萘啶 -9(10H)-酮,2-(6-(4-曱基哌嗪 -1-基)吡啶 -3-基) -10-(3- (三氟曱基)苯基)吡啶并[3,2-c][l,5]萘啶 -9(10H)-酮,2-(6-(1Η-吡唑 -1-基)吡啶 -3-基) -10-(3- (三氟曱基)苯基)吡啶并 [3,2-c][l,5]萘啶 -9(10H)-酮,2-(4-(2-(2-曱氧基嘧啶 -5-基 )-9-氧代吡啶并 [3,2-c][l,5]萘啶 -10(9H)-基)苯基) -2-甲基丙腈,2-(6- (曱基磺酰基)吡啶 -3-基) -10-(3- (三氟曱基)苯基)吡啶并 [3,2-c][l,5]萘啶 -9(10H)-酮,2-(6-甲氧基吡啶 -3-基) -10-(3- (三氟曱基)苯基)吡啶并 [3,2-c][l,5]萘 啶 -9(10H)-酮,2-(6-吗啉代吡啶 -3-基) -10-(3- (三氟甲基)苯基)吡啶并 [3,2-c][l,5]萘 啶 -9(10H)-酮,2-(5-曱氧基吡啶 -3-基) -10-(3- (三氟曱基)苯基)吡啶并 [3,2-c][l,5]萘 啶 -9(10H)-酮,2-(2-曱氧基吡啶 -3-基) -10-(3- (三氟曱基)苯基)吡啶 [3,2-c][l,5]萘啶 -9(匪)-酮,10-(3-(三氟曱基)苯基)-2-(6-(三氟甲基)吡啶 -3-基)吡啶并 [3,2-c][l,5]萘啶 -9(10H)-酮,2-(6-曱基吡啶 -3-基) -10-(3- (三氟曱基)苯基)吡啶并 [3,2-c][l,5]萘啶 -9(腿)-酮,2-(3,5-二甲基异11恶唑 -4-基)-10-(3-(三氟曱基)苯基)吡啶并 [3,2-c][l,5]萘啶 -9(10H)-酮,2-(5-氟吡啶 -3-基) -10-(3_ (三氟曱基)苯基)吡啶并 [3,2_c][l ,5]萘啶 -9(匪)-酮,10-(3- (三氟曱基)苯基 -2-(5- (三氟曱基)吡啶 -3-基)吡啶并 [3,2-c][l,5] 萘啶 -9(10H)-酮,2- (1-甲基 -1H-吡唑 -5-基) -10-(3- (三氟曱基)苯基)吡啶并 [3,2-c][l,5] 萘啶 -9(10H)-酮,2-(噻唑 -5-基 )-10-(3-(三氟曱基)苯基)吡啶并 [3,2-c][l,5]萘啶-9(腿)-酮,3-甲基 -5-(9-氧代 -10-(3-(三氟曱基)苯基 )-9,10-二氢吡啶并 [3,2-c][l,5 ]萘啶 -2-基) _2_氰基吡啶,5-(9-氧代 -10-(3- (三氟曱基)苯基) -9,10-二氢吡啶并 [3,2-c][l,5]萘啶 -2-基) -3-氰基吡啶,2-(6- (吡咯烷 -1-基)吡啶 -3-基) -10-(3- (三氟曱基)苯基)吡啶并 [3,2-c][l,5]萘啶 -9(10H)-酮,2-(1-曱基 -1H-吡唑 -4-基) -10-(3- (三氟曱基)苯基)吡啶并 [3,2-c][l,5] 萘啶 -9(10H)-酮,2-(6- (曱硫基)吡啶 -3-基) -10-(3- (三氟曱基)苯基)吡啶并 [3,2-c][l,5] 萘啶 -9(1 OH)-酮,2-( 1 H-吡咯并 [2,3-b]吡啶 -5-基) - 10-(3-(三氟曱基)苯基)吡啶并 [3,2-c][l,5]萘啶 -9(10H)-酮,2-(6- (曱基磺酰基)吡啶 -3-基) -10-(4- (哌嗪 -1-基) -3- (三氟甲基)苯基) 吡啶并 [3,2-c][l,5]萘啶 -9(10H)-酮,(R)-10-(l-(2-羟基丙酰基)哌啶 -4-基) -2-(6- (甲基磺酰基)吡啶 -3-基) 吡啶并 [3,2-c][l,5]萘啶 -9(10H)-酮,2-曱基 -2-(4-(2-(6-(甲基磺酰基)吡啶 -3-基 )-9-氧代吡啶并 [3,2-c][l,5]萘啶 -10(9H)-基)苯基)丙腈,N-(5-(9-氧代 -10-(4- (哌嗪 -1-基) -3- (三氟曱基)苯基) -9,10-二氢吡啶 并 [3 ,2-c] [ 1,5 ]萘啶 _2_基)吡啶 _2_基)乙酰胺,(R)-N-(5-(10-(l-(2-羟基丙酰基)哌啶 -4-基) -9-氧代 -9,10-二氢吡啶 并 [3 ,2-c] [ 1,5 ]萘啶 -2-基)吡啶 -2-基)乙酰胺,N-(5 -( 10-(4-(2-氰基丙基 -2-基)苯基)-9-氧代 -9, 10-二氢吡啶并 [3,2-c][l ,5 ]萘啶 -2-基)吡啶 -2-基)乙酰胺,5-(9-氧代 -10-(4- (哌嗪 -1-基) -3- (三氟曱基)苯基) -9,10-二氢吡啶并 [3,2-c] [ 1 ,5 ]萘啶 -2-基) -2-氰基吡啶 ,(R)-(5-(10-(l-(2-羟基丙酰基)哌啶 _4_基) -9-氧代 -9,10-二氢吡啶并[3,2-c][l,5]萘啶 -2-基) -2-氰基吡啶,5-(10-(4-(2-氰基丙基 -2-基)苯基 )-9-氧代 -9,10-二氢吡啶并 [3,2-c][l,5]萘啶 -2-基) -2-氰基吡啶,2-(6- (甲硫基)吡啶 -3-基) -10-(4- (哌嗪 -1-基) -3- (三氟曱基)苯基)吡啶 并 [3,2-c][l,5]萘啶 -9(10H)-酮,(R)-10-(l-(2-羟基丙酰基)哌啶 -4-基) -2-(6- (甲硫基)吡啶 -3-基)吡啶 并 [3,2-c][l,5]萘啶 -9(10H)-酮, 和2-曱基 -2-(4-(2-(6- (曱硫基)吡啶 -3-基) -9-氧代吡啶并 [3,2-c][l,5]萘 啶 -10(9H)-基)苯基)丙腈。9、 含有权利要求 1 ~ 8任一项所述的化合物、 其药学上可接受的 盐、 其立体异构体或其氘代物的药物组合物。10.如权利要求 9 所述的组合物, 还包括一种或多种抗肿瘤剂和 / 或免疫抑制剂, 所述的抗肿瘤剂和免疫抑制剂为抗代谢物, 选自卡培 他滨、 吉西他滨、 培美曲塞二钠; 为生长因子抑制剂, 选自帕唑帕尼、 伊马替尼、 埃罗替尼、 拉帕替尼、 吉非替尼、 凡德他尼; 为抗体, 选 自赫赛汀、 贝伐单抗; 为有丝分裂抑制剂, 选自紫杉醇、 长春瑞滨、 多西他赛、 多柔比星; 为抗肿瘤激素类, 选自来曲唑、 他莫西芬、 氟 维司群、 氟他胺、 曲普瑞林; 为烷化剂类, 选自环磷酰胺、 氮芥、 马 法兰、 瘤可宁、 卡莫司汀; 为金属铂类, 选自卡铂、 顺铂、 奥沙利铂; 为拓朴异构酶抑制剂, 选自拓朴特肯喜树碱、 拓朴替康、 依立替康; 为免疫抑制类, 选自依维莫司、 西罗莫司、 特癌适; 为嘌呤类似物, 选自 6-巯基嘌呤、 6-硫鸟嘌呤、 硫唑嘌呤; 为抗生素类, 选自菌素 D、 柔红霉素、 阿霉素、 米托蒽醌、 争光霉素、 普卡霉素; 为铂配合物, 选自顺铂、 卡波铂; 为肾上腺皮质抑制剂类, 选自氨鲁米特。11. 含有权利要求 1 ~ 8任一项所述的化合物、 其药学上可接受的 盐、 其立体异构体或其氘代物与一种或多种药用载体的药物制剂, 为 临床上或药学上可接受的任一剂型。12. 权利要求 1 ~ 8任一项所述的化合物、 其药学上可接受的盐、 用途。13. 治疗增殖性疾病的方法, 包括给予有需要的对象有效量的权 利要求 1 ~ 8任一项所述的通式 (I)化合物、 其药学上可接受的盐、 其立 体异构体或其氘代物或者含有所述通式 (I)化合物、 其药学上可接受的 盐、 其立体异构体或其氘代物的药物组合物的步骤。14.如权利要求 12所述的用途或权利要求 13所述的方法, 其中所 述增殖性疾病为癌症或非癌性增殖性疾病, 所述癌症选自脑瘤、 肺癌、 非小细胞性肺癌、 鳞状上皮细胞、 膀胱癌、 胃癌、 卵巢癌、 腹膜癌、 胰腺癌、 乳腺癌、 头颈癌、 子宫颈癌、 子宫内膜癌、 结直肠癌、 肝癌、 肾癌、 食管腺癌、 食管鳞状细胞癌、 实体瘤、 非霍奇金淋巴瘤、 神经 胶质瘤、 多形性胶质母细胞瘤、 胶质肉瘤、 前列腺癌、 曱状腺癌、 雌 性生殖道癌、 原位癌、 淋巴瘤、 组织细胞淋巴瘤、 神经纤维瘤病、 骨 癌、 皮肤癌、 脑癌、 结肠癌、 睾丸癌、 小细胞肺癌、 胃肠道间质瘤、 前列腺肿瘤、 肥大细胞肿瘤、 多发性骨髓瘤、 黑色素瘤、 胶质瘤、 胶 质母细胞瘤、 星形细胞瘤、 神经母细胞瘤、 肉瘤; 所述非癌性增殖性 疾病选自皮肤或前列腺的良性增生。15. 权利要求 1的通式 (I)化合物, 即下式中间体 3 式 ( I ) 其中 R R2、 R R4、 R5、 R6和 R7如前文所定义, Hal1 , Hal2和 Hal3 代表卤素, 各自独立地选自 F、 Cl、 Br和 I, 且 Hal1 , Hal2和 Hal3可以 相同或不同; Alk代表低级烷基; "酸酐" 为有机酸肝;1. 中间体 1的制备使原料 1和原料 2于醇类有机溶剂中在碱存在下加热回流反应至 原料消失, 得中间体 1 ;2. 中间体 2'的制备使中间体 1在醇类有机溶剂中与还原剂进行反应,减压除去溶剂, 向反应混合物中加入水, 用! ¾化烃类有机溶剂进行萃取, 将有机相浓 缩, 向其中加入氧化剂, 搅拌反应, 得中间体 2,;3. 中间 2的制备在氮气保护下, 将中间体 2,与格氏试剂 R6-Mg-Hal3反应, 然后氧 化, 得中间体 2;4. 中间体 3的制备方法 1 :在密封容器中,使中间体 2和原料 3于醇类有机溶剂中在 无机碱存在下于 110-180°C进行反应, 得中间体 3; 或者方法 2: 将中间体 2溶于非质子极性有机溶剂与原料 3,中, 在微 波反应器中反应至原料消失, 得中间体 3;以及5. 式 (I)化合物的制备将中间体 3和原料 4溶于有机溶剂中, 使之在催化剂和碱存在下 在氮气保护下回流反应, 得式 (I)化合物;必要时, 可对需要保护的官能团进行保护, 此后通过常规方法脱 去保护基团。
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CN115304600A (zh) * | 2022-09-29 | 2022-11-08 | 北京鑫开元医药科技有限公司 | mTOR抑制剂、制备方法及用途 |
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Cited By (3)
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CN112047937A (zh) * | 2019-06-06 | 2020-12-08 | 劲方医药科技(上海)有限公司 | 四氢吡啶并[3,4-d]嘧啶-2(1H)-酮类化合物,其制法与医药上的用途 |
CN115304600A (zh) * | 2022-09-29 | 2022-11-08 | 北京鑫开元医药科技有限公司 | mTOR抑制剂、制备方法及用途 |
CN115304600B (zh) * | 2022-09-29 | 2023-01-13 | 北京鑫开元医药科技有限公司 | mTOR抑制剂、制备方法及用途 |
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