CN114728987A - 用于治疗自身免疫性疾病的1,8-萘啶-2-酮化合物 - Google Patents
用于治疗自身免疫性疾病的1,8-萘啶-2-酮化合物 Download PDFInfo
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- CN114728987A CN114728987A CN202080079547.9A CN202080079547A CN114728987A CN 114728987 A CN114728987 A CN 114728987A CN 202080079547 A CN202080079547 A CN 202080079547A CN 114728987 A CN114728987 A CN 114728987A
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- Prior art keywords
- methyl
- amino
- naphthyridin
- group
- pyrazino
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- 238000011282 treatment Methods 0.000 title claims description 14
- 208000023275 Autoimmune disease Diseases 0.000 title description 4
- ZFRUGZMCGCYBRC-UHFFFAOYSA-N 1h-1,8-naphthyridin-2-one Chemical class C1=CC=NC2=NC(O)=CC=C21 ZFRUGZMCGCYBRC-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 179
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 13
- -1 oxazinyl group Chemical group 0.000 claims description 125
- 238000002360 preparation method Methods 0.000 claims description 59
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 125000004193 piperazinyl group Chemical group 0.000 claims description 27
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 claims description 26
- 102000008235 Toll-Like Receptor 9 Human genes 0.000 claims description 25
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 claims description 25
- 102100039390 Toll-like receptor 7 Human genes 0.000 claims description 25
- 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 claims description 24
- 125000003386 piperidinyl group Chemical group 0.000 claims description 23
- 102100033110 Toll-like receptor 8 Human genes 0.000 claims description 22
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 20
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 14
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- 239000005557 antagonist Substances 0.000 claims description 13
- BQIYCRMYUHKTPK-WOVIWESZSA-N 4-[(4R,10bS)-8-[(3R,4R)-3-amino-4-methoxypyrrolidin-1-yl]-4-methyl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]-1-ethyl-1,8-naphthyridin-2-one Chemical compound CCN1C2=NC=CC=C2C(N(C2)C[C@@H](C)N(CC3=C4)[C@H]2C3=CC=C4N(C[C@H]2N)C[C@H]2OC)=CC1=O BQIYCRMYUHKTPK-WOVIWESZSA-N 0.000 claims description 12
- QCKGUUWXRFHBDP-MZNJEOGPSA-N C[C@@H]1CN(C[C@H]2N1CC3=C2C=CC(=C3)C4CCNCC4)C5=CC(=O)N(C6=C5C=CC=N6)C Chemical compound C[C@@H]1CN(C[C@H]2N1CC3=C2C=CC(=C3)C4CCNCC4)C5=CC(=O)N(C6=C5C=CC=N6)C QCKGUUWXRFHBDP-MZNJEOGPSA-N 0.000 claims description 10
- 208000005777 Lupus Nephritis Diseases 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 150000003254 radicals Chemical class 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 claims description 8
- NZWUZDHXHYAKIH-OPAMFIHVSA-N C1(C)(CN(C1)C1=CC=C2[C@H]3CN(C[C@H](N3CC2=C1)C)C1=CC(=O)N(C2=C1C=CC=N2)C)N Chemical compound C1(C)(CN(C1)C1=CC=C2[C@H]3CN(C[C@H](N3CC2=C1)C)C1=CC(=O)N(C2=C1C=CC=N2)C)N NZWUZDHXHYAKIH-OPAMFIHVSA-N 0.000 claims description 6
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000002393 azetidinyl group Chemical group 0.000 claims description 5
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- UXAWXZDXVOYLII-UHFFFAOYSA-N tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate Chemical compound C1C2N(C(=O)OC(C)(C)C)CC1NC2 UXAWXZDXVOYLII-UHFFFAOYSA-N 0.000 claims description 5
- FGBYPAVTEXWXFM-USMGDQGLSA-N C[C@H](CN(C1)C(C2=CC=CN=C2N2C)=CC2=O)N2[C@H]1C1=CC=C([C@H](CC3)CC[C@@H]3N3CCOCC3)C=C1C2 Chemical compound C[C@H](CN(C1)C(C2=CC=CN=C2N2C)=CC2=O)N2[C@H]1C1=CC=C([C@H](CC3)CC[C@@H]3N3CCOCC3)C=C1C2 FGBYPAVTEXWXFM-USMGDQGLSA-N 0.000 claims description 4
- FGBYPAVTEXWXFM-JWTSJRFNSA-N C[C@H](CN(C1)C(C2=CC=CN=C2N2C)=CC2=O)N2[C@H]1C1=CC=C([C@H](CC3)CC[C@H]3N3CCOCC3)C=C1C2 Chemical compound C[C@H](CN(C1)C(C2=CC=CN=C2N2C)=CC2=O)N2[C@H]1C1=CC=C([C@H](CC3)CC[C@H]3N3CCOCC3)C=C1C2 FGBYPAVTEXWXFM-JWTSJRFNSA-N 0.000 claims description 4
- 238000006069 Suzuki reaction reaction Methods 0.000 claims description 4
- 102000002689 Toll-like receptor Human genes 0.000 claims description 4
- 108020000411 Toll-like receptor Proteins 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- HTNOIALXTJFHHK-HOYKHHGWSA-N 4-[(4R,10bS)-4-methyl-8-(5-oxa-2,8-diazaspiro[3.5]nonan-8-yl)-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]-1-methyl-1,8-naphthyridin-2-one Chemical compound C[C@H](CN(C1)C(C2=CC=CN=C2N2C)=CC2=O)N(CC2=C3)[C@H]1C2=CC=C3N1CC2(CNC2)OCC1 HTNOIALXTJFHHK-HOYKHHGWSA-N 0.000 claims description 3
- RRVINODMTJIOHO-QZTZHPFYSA-N 4-[(4R,10bS)-4-methyl-8-[(2R)-2-methylpiperazin-1-yl]-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]-1-methyl-1,8-naphthyridin-2-one Chemical compound C[C@H](CN(C1)C(C2=CC=CN=C2N2C)=CC2=O)N(CC2=C3)[C@H]1C2=CC=C3N1[C@H](C)CNCC1 RRVINODMTJIOHO-QZTZHPFYSA-N 0.000 claims description 3
- ICSQJAGCGVHHKM-QZTZHPFYSA-N 4-[(4R,10bS)-4-methyl-8-[(3R)-3-methylpiperazin-1-yl]-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]-1-methyl-1,8-naphthyridin-2-one Chemical compound C[C@H](C1)NCCN1C1=CC=C([C@@H](C2)N(C3)[C@H](C)CN2C(C2=CC=CN=C2N2C)=CC2=O)C3=C1 ICSQJAGCGVHHKM-QZTZHPFYSA-N 0.000 claims description 3
- ICSQJAGCGVHHKM-HOOSLVGPSA-N 4-[(4R,10bS)-4-methyl-8-[(3S)-3-methylpiperazin-1-yl]-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]-1-methyl-1,8-naphthyridin-2-one Chemical compound C[C@@H](C1)NCCN1C1=CC=C([C@@H](C2)N(C3)[C@H](C)CN2C(C2=CC=CN=C2N2C)=CC2=O)C3=C1 ICSQJAGCGVHHKM-HOOSLVGPSA-N 0.000 claims description 3
- KTODYWZEASDFMB-UZUQRXQVSA-N 4-[(4R,10bS)-4-methyl-8-piperazin-1-yl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]-1-methyl-1,8-naphthyridin-2-one Chemical compound C[C@H](CN(C1)C(C2=CC=CN=C2N2C)=CC2=O)N(CC2=C3)[C@H]1C2=CC=C3N1CCNCC1 KTODYWZEASDFMB-UZUQRXQVSA-N 0.000 claims description 3
- DEBRJSOSHKNWKF-HOYKHHGWSA-N 4-[(4R,10bS)-8-(4-amino-4-methylpiperidin-1-yl)-4-methyl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]-1-methyl-1,8-naphthyridin-2-one Chemical compound C[C@H](CN(C1)C(C2=CC=CN=C2N2C)=CC2=O)N(CC2=C3)[C@H]1C2=CC=C3N(CC1)CCC1(C)N DEBRJSOSHKNWKF-HOYKHHGWSA-N 0.000 claims description 3
- WAPYVKMRZGBYCW-UKWAKIAUSA-N 4-[(4R,10bS)-8-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-4-methyl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]-1-methyl-1,8-naphthyridin-2-one Chemical compound C[C@H](CN(C1)C(C2=CC=CN=C2N2C)=CC2=O)N(CC2=C3)[C@H]1C2=CC=C3N1[C@H](C2)CN[C@H]2C1 WAPYVKMRZGBYCW-UKWAKIAUSA-N 0.000 claims description 3
- YPVNCTXLNZNBEU-DHTSOJEISA-N 4-[(4R,10bS)-8-[(2S)-2-(methoxymethyl)piperazin-1-yl]-4-methyl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]-1-methyl-1,8-naphthyridin-2-one Chemical compound C[C@H](CN(C1)C(C2=CC=CN=C2N2C)=CC2=O)N(CC2=C3)[C@H]1C2=CC=C3N1[C@H](COC)CNCC1 YPVNCTXLNZNBEU-DHTSOJEISA-N 0.000 claims description 3
- PMXMBTDQZDKTMO-KMBRJESTSA-N 4-[(4R,10bS)-8-[(3R,4R)-3-amino-4-methoxypyrrolidin-1-yl]-4-methyl-3,4,6,10b-tetrahydro-1H-pyrazino[2,1-a]isoindol-2-yl]-1-methyl-1,8-naphthyridin-2-one Chemical compound C[C@H](CN(C1)C(C2=CC=CN=C2N2C)=CC2=O)N(CC2=C3)[C@H]1C2=CC=C3N(C[C@H]1N)C[C@H]1OC PMXMBTDQZDKTMO-KMBRJESTSA-N 0.000 claims description 3
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- BTUDOGSWFVKTQU-ZYPQTRCHSA-N [C@H]1(F)CN(C[C@H]1N)C1=CC=C2[C@H]3CN(C[C@H](N3CC2=C1)C)C1=CC(=O)N(C2=C1C=CC=N2)C Chemical compound [C@H]1(F)CN(C[C@H]1N)C1=CC=C2[C@H]3CN(C[C@H](N3CC2=C1)C)C1=CC(=O)N(C2=C1C=CC=N2)C BTUDOGSWFVKTQU-ZYPQTRCHSA-N 0.000 claims description 3
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- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
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- 239000000203 mixture Substances 0.000 abstract description 31
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- 238000001819 mass spectrum Methods 0.000 description 58
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- 239000000243 solution Substances 0.000 description 41
- 238000005160 1H NMR spectroscopy Methods 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 34
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 235000019439 ethyl acetate Nutrition 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- BFHSUIWEPMCBQR-UHFFFAOYSA-N tert-butyl n-(3-methylazetidin-3-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1(C)CNC1 BFHSUIWEPMCBQR-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 14
- 239000007832 Na2SO4 Substances 0.000 description 13
- 239000003054 catalyst Substances 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 13
- 229910052938 sodium sulfate Inorganic materials 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
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- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
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Classifications
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- C07D498/10—Spiro-condensed systems
Abstract
Description
本发明涉及可用于哺乳动物的治疗和/或预防的有机化合物,尤其涉及可用于治疗系统性红斑狼疮或狼疮性肾炎的TLR7和/或TLR8和/或TLR9的拮抗剂。
技术领域
自身免疫性结缔组织病(CTD)包括典型的自身免疫综合征,诸如系统性红斑狼疮(SLE)、原发性干燥综合征(pSjS)、混合性结缔组织病(MCTD)、皮肌炎/多发性肌炎(DM/PM)、类风湿关节炎(RA)和系统性硬化症(SSc)。除RA以外,对患者来说,没有真正有效且安全的疗法。SLE代表典型的CTD,其患病率为20-150/100,000,并在不同器官引起广泛的炎症和组织损伤,从皮肤和关节的常见症状到肾、肺或心力衰竭。传统上,SLE已使用非特异性抗炎药或免疫抑制剂进行治疗。但是,长期使用免疫抑制药物,例如,皮质类固醇仅部分有效,并伴有非预期毒性和副作用。贝利尤单抗是过去50年中唯一获得FDA批准的用于狼疮的药物,尽管仅对部分SLE患者具有适度延迟的疗效(Navarra,S.V.等人,Lancet 2011,377,721.)。其他生物制剂,诸如抗CD20 mAb、抗特定细胞因子的mAb或其可溶受体,在大多数临床研究中均失败了。因此,需要新型疗法,其在更大比例的患者群组中提供持续改善,并且对于在许多自身免疫以及自身炎症性疾病中的长期使用而言更安全。
Toll样受体(TLR)是模式识别受体(PRR)的重要家族,可以引发多种免疫细胞产生广泛的免疫应答。核内体TLR 7、TLR8和TLR9作为天然的宿主防御传感器,可识别衍生自病毒、细菌的核酸;具体地,TLR7/TLR8和TLR9分别识别单链RNA(ssRNA)和单链CpG-DNA。然而,TRL7、TRL8、TRL9的异常核酸传感被认为是广泛的自身免疫和自身炎性疾病的关键节点(Krieg,A.M.等人,Immunol.Rev.2007,220,251.Jim é nez-Dalmaroni,M.J.等人,Autoimmun Rev.2016,15,1.Chen,J.Q.等人,Clinical Reviews in Allergy&Immunology2016,50,1.)。抗RNA和抗DNA抗体是SLE的公认诊断标志,这些抗体可以将自身RNA和自身DNA两者传递至内体。自身RNA复合物可以被TLR7和TLR8识别,而自身DNA复合物可以触发TLR9激活。实际上,在SLE(系统性红斑狼疮)患者中,自身RNA和自身DNA从血液和/或组织中的缺陷清除很明显。据报道,TLR7和TLR9在SLE组织中被上调,并分别与狼疮性肾炎的慢性和活性有关。在SLE患者的B细胞中,TLR7表达与抗RNP抗体的产生相关,而TLR9表达与IL-6和抗dsDNA抗体水平相关。一致地,在狼疮小鼠模型中,抗RNA抗体需要TLR7,抗核小体抗体需要TLR9。另一方面,小鼠中TLR7或人TLR8的过度表达会促进自身免疫和自身炎症。此外,TLR8的激活特别有助于mDC/巨噬细胞的炎症性细胞因子分泌,嗜中性粒细胞胞外捕网过程(NETosis),Th17细胞的诱导和Treg细胞的抑制。除了描述的TLR9在促进B细胞自身抗体产生中的作用外,pDC中通过自身DNA激活TLR9还会导致诱导I型IFN和其他炎症性细胞因子。考虑到pDC和B细胞两者中TLR9的这些作用,它们都是自身免疫性疾病发病机理的关键因素,而且在许多自身免疫性疾病患者中大量存在可轻易激活TLR9的自身DNA复合物,在抑制TLR7和TLR8途径基础之上,它对于进一步阻断自身DNA介导的TLR9途径可能具有额外益处。总之,TLR7、8和9途径代表了治疗自身免疫性疾病和自身炎症性疾病的新治疗靶点,针对这些疾病,不存在有效的不含类固醇和无细胞毒性的口服药物,并且从非常上游就抑制了所有这些途径可能会带来令人满意的治疗效果。因此,我们发明了靶向和抑制TLR7、TLR8和TLR9的口服化合物,用于治疗自身免疫性疾病和自身炎症性疾病。
发明内容
本发明涉及式(I)和(Ia)的新型化合物,
其中
R1为C1-6烷基;
R2为C1-6烷基;
R3为(C1-6烷氧基C1-6烷基)哌嗪基;(C1-6烷基)2氨基C1-6烷氧基;2,5-二氮杂双环[2.2.1]庚烷基;3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪基;3,8-二氮杂双环[3.2.1]辛烷基;3-氧杂-9-氮杂双环[3.3.1]壬烷基;5-氧杂-2,8-二氮杂螺[3.5]壬烷基;氨基(C1-6烷氧基)哌啶基;氨基(C1-6烷氧基)吡咯烷基;氨基(C1-6烷基)氮杂环丁烷基;氨基(C1-6烷基)哌啶基;氨基(C1-6烷基)吡咯烷基;氨基-1,4-氧氮杂环庚烷基;氨基卤代吡咯烷基;氨基哌啶基;C1-6烷基-2,6-二氮杂螺[3.3]庚烷基;C1-6烷基哌嗪基;吗啉基C3-7环烷基;哌嗪基;哌啶基或吡咯烷基;
或其药用盐。
本发明的另一目的涉及式(I)或(Ia)的新型化合物、其生产、基于根据本发明化合物的药物及其制备以及式(I)或(Ia)的化合物作为TLR7和/或TLR8和/或TLR9拮抗剂的用途,及用于治疗或预防系统性红斑狼疮或狼疮性肾炎的用途。式(I)或(Ia)的化合物显示出优异的TLR7和/或TLR8和/或TLR9拮抗活性。另外,式(I)或(Ia)化合物还显示出良好的hPBMC、细胞毒性、溶解性、人微粒体稳定性和SDPK特征,以及低CYP抑制。
具体实施方式
定义
术语“C1-6烷基”表示含有1至6个,特别是1至4个碳原子的饱和、直链或支链烷基,例如,甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基等。特别地,“C1-6烷基”基团为甲基、乙基和正丙基。
术语“C3-7环烷基”表示含有3至7个碳原子、特别是3至6个碳原子的饱和碳环,例如环丙基、环丁基、环戊基、环己基、环庚基等。特别的“C3-7环烷基”基团是环丙基、环戊基和环己基。
术语“卤素”和“卤基”在本文中可互换使用,表示氟、氯、溴或碘。
术语“C1-6烷氧基”表示C1-6烷基-O-。
术语“卤代吡咯烷基”表示被卤素取代一次、两次或三次的吡咯烷基。卤代吡咯烷基的实例包括但不限于二氟吡咯烷基和氟吡咯烷基。
术语“药用盐”表示在生物学上或其他方面不是不期望的盐。“药用盐”包括酸加成盐和碱加成盐两者。
“药用酸加成盐”是指与无机酸和有机酸形成的那些药用盐,所述无机酸诸如盐酸、氢溴酸、硫酸、硝酸、碳酸、磷酸等,所述有机酸可以选自脂肪族、脂环族、芳族、芳脂族、杂环、羧酸和磺酸类有机酸,诸如甲酸、乙酸、丙酸、乙醇酸、葡萄糖酸、乳酸、丙酮酸、草酸、苹果酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、天冬氨酸、抗坏血酸、谷氨酸、邻氨基苯甲酸、苯甲酸、肉桂酸、扁桃酸、双羟萘酸、苯乙酸、甲磺酸、乙磺酸、对甲苯磺酸、和水杨酸等。
术语“药用碱加成盐”表示与有机或无机碱形成的那些药用盐。可接受的无机碱的示例包括钠、钾、铵、钙、镁、铁、锌、铜、锰和铝盐。衍生自药用有机无毒碱的盐包括伯胺、仲胺和叔胺,取代胺(包括天然存在的取代胺)、环胺和碱性离子交换树脂(诸如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二乙氨基乙醇、氨丁三醇、二环己胺,赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、哈胺(hydrabamine)、胆碱、甜菜碱、乙二胺、葡糖胺、甲基葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶和多胺树脂)的盐。
术语“药物活性代谢物”表示通过特定化合物或其盐在体内的代谢产生的药理活性产物。进入人体后,大多数药物均是化学反应的底物,可能改变其物理性质和生物学效应。这些通常影响本发明化合物极性的代谢转化改变了药物在体内分布和从体内排泄的方式。然而,在某些情况下,药物代谢是治疗效果所必需的。
术语“治疗有效量”是表示本发明的化合物或分子的量,当将其施用于受试者时,(i)治疗或预防特定疾病、病症或疾患,(ii)减弱、改善或消除特定疾病、病症或疾患的一种或多种症状,或(iii)预防或延迟本文所述的特定疾病、病症或疾患的一种或多种症状的发作。治疗有效量取决于化合物,所治疗的疾病状态,所治疗疾病的严重程度,受试者的年龄和相对健康状况,施用途径和形式,主治医学或兽医的判断和其他因素。
术语“药物组合物”表示包含治疗有效量的活性药物成分和一起施用于有此需要的哺乳动物(例如人)的药用赋形剂的混合物或溶液。
TLR7和/或TLR8和/或TLR9的拮抗剂
本发明涉及(i),其是式(I)化合物,
其中
R1为C1-6烷基;
R2为C1-6烷基;
R3为(C1-6烷氧基C1-6烷基)哌嗪基;(C1-6烷基)2氨基C1-6烷氧基;2,5-二氮杂双环[2.2.1]庚烷基;3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪基;3,8-二氮杂双环[3.2.1]辛烷基;3-氧杂-9-氮杂双环[3.3.1]壬烷基;5-氧杂-2,8-二氮杂螺[3.5]壬烷基;氨基(C1-6烷氧基)哌啶基;氨基(C1-6烷氧基)吡咯烷基;氨基(C1-6烷基)氮杂环丁烷基;氨基(C1-6烷基)哌啶基;氨基(C1-6烷基)吡咯烷基;氨基-1,4-氧氮杂环庚烷基;氨基卤代吡咯烷基;氨基哌啶基;C1-6烷基-2,6-二氮杂螺[3.3]庚烷基;C1-6烷基哌嗪基;吗啉基C3-7环烷基;哌嗪基;哌啶基或吡咯烷基;
或其药用盐。
本发明的另一个实施例是(ii)具有式(Ia)的化合物,
其中
R1为C1-6烷基;
R2为C1-6烷基;
R3为(C1-6烷氧基C1-6烷基)哌嗪基;(C1-6烷基)2氨基C1-6烷氧基;2,5-二氮杂双环[2.2.1]庚烷基;3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪基;3,8-二氮杂双环[3.2.1]辛烷基;3-氧杂-9-氮杂双环[3.3.1]壬烷基;5-氧杂-2,8-二氮杂螺[3.5]壬烷基;氨基(C1-6烷氧基)哌啶基;氨基(C1-6烷氧基)吡咯烷基;氨基(C1-6烷基)氮杂环丁烷基;氨基(C1-6烷基)哌啶基;氨基(C1-6烷基)吡咯烷基;氨基-1,4-氧氮杂环庚烷基;氨基卤代吡咯烷基;氨基哌啶基;C1-6烷基-2,6-二氮杂螺[3.3]庚烷基;C1-6烷基哌嗪基;吗啉基C3-7环烷基;哌嗪基;哌啶基或吡咯烷基;
或其药用盐。
本发明的进一步实施方案是(iii)根据(i)或(ii)的式(I)或(Ia)化合物,或其药用盐,其中
R1为甲基或乙基;
R2为甲基;
R3为2-(二甲基氨基)乙氧基;2-(甲氧基甲基)哌嗪-1-基;2,5-二氮杂双环[2.2.1]庚烷-2-基;2-甲基哌嗪-1-基;3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-6-基;3,8-二氮杂双环[3.2.1]辛烷-3-基;3-氨基-1-哌啶基;3-氨基-3-甲基-1-哌啶基;3-氨基-3-甲基-氮杂环丁烷-1-基;3-氨基-3-甲基-吡咯烷-1-基;3-氨基-4-氟-吡咯烷-1-基;3-氨基-4-甲氧基-1-哌啶基;3-氨基-4-甲氧基-吡咯烷-1-基;3-甲基哌嗪-1-基;3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基;3-哌啶基;4-氨基-3-甲氧基-1-哌啶基;4-氨基-4-甲基-1-哌啶基;4-吗啉代环己基;4-哌啶基;5-氧杂-2,8-二氮杂螺[3.5]壬烷-2-基;5-氧杂-2,8-二氮杂螺[3.5]壬烷-8-基;6-氨基-1,4-氧氮杂环庚烷-4-基;6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基;哌嗪-1-基或吡咯烷-3-基;
或其药用盐。
本发明的进一步实施方案是(iv)根据(i)至(iii)中任一项的式(I)或(Ia)化合物,或其药用盐,其中R3为氨基(C1-6烷氧基)吡咯烷基;氨基(C1-6烷基)哌啶基;氨基-1,4-氧氮杂环庚烷基;氨基哌啶基;C1-6烷基-2,6-二氮杂螺[3.3]庚烷基;C1-6烷基哌嗪基;C1-6烷基哌嗪基;吗啉基C3-7环烷基;哌嗪基;哌啶基或3-氧杂-9-氮杂双环[3.3.1]壬烷基。
本发明的进一步实施方案是(v)根据(i)至(iv)中任一项的式(I)或(Ia)化合物,或其药用盐,其中R3为3-氨基-1-哌啶基;3-氨基-3-甲基-1-哌啶基;3-氨基-4-甲氧基-吡咯烷-1-基;3-甲基哌嗪-1-基;4-氨基-4-甲基-1-哌啶基;4-吗啉代环己基;4-哌啶基;6-氨基-1,4-氧氮杂环庚烷-4-基;6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基;哌嗪-1-基或3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基。
本发明的进一步实施方案是(vi)根据(i)至(v)中任一项的式(I)或(Ia)化合物,或其药用盐,其中
R1为C1-6烷基;
R2为C1-6烷基;
R3为氨基(C1-6烷氧基)吡咯烷基;氨基(C1-6烷基)哌啶基;氨基-1,4-氧氮杂环庚烷基;氨基哌啶基;C1-6烷基-2,6-二氮杂螺[3.3]庚烷基;C1-6烷基哌嗪基;C1-6烷基哌嗪基;吗啉基C3-7环烷基;哌嗪基;哌啶基或3-氧杂-9-氮杂双环[3.3.1]壬烷基;
或其药用盐。
本发明的进一步实施方案是(vii)根据(i)至(vi)中任一项的式(I)或(Ia)化合物,或其药用盐,其中
R1为甲基;
R2为甲基;
R3为3-氨基-1-哌啶基;3-氨基-3-甲基-1-哌啶基-3-氨基-4-甲氧基-吡咯烷-1-基;3-甲基哌嗪-1-基;4-氨基-4-甲基-1-哌啶基;4-吗啉代环己基;4-哌啶基;6-氨基-1,4-氧氮杂环庚烷-4-基;6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基;哌嗪-1-基或3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基;
或其药用盐。
本发明的另一个实施方案是(viii)式(I)或(Ia)化合物选自以下:
4-[(4R,10bS)-8-(3-氨基-3-甲基-氮杂环丁烷-1-基)-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-(6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-(5-氧杂-2,8-二氮杂螺[3.5]壬烷-2-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(3R)-3-氨基-3-甲基-吡咯烷-1-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(4aR,7aR)-3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-6-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(3R,4S)-3-氨基-4-氟-吡咯烷-1-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(3S,4S)-4-氨基-3-甲氧基-1-哌啶基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(3S,4S)-3-氨基-4-甲氧基-1-哌啶基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(2S)-2-(甲氧基甲基)哌嗪-1-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-(5-氧杂-2,8-二氮杂螺[3.5]壬烷-8-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-哌嗪-1-基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-[(3S)-3-甲基哌嗪-1-基]-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-[(3R)-3-甲基哌嗪-1-基]-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(3S)-3-氨基-3-甲基-1-哌啶基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(3R)-3-氨基-1-哌啶基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-[(2R)-2-甲基哌嗪-1-基]-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-(4-氨基-4-甲基-1-哌啶基)-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(1R,4R)-2,5-二氮杂双环[2.2.1]庚烷-2-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(6R)-6-氨基-1,4-氧氮杂环庚烷-4-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[2-(二甲基氨基)乙氧基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-(4-哌啶基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-(3-哌啶基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-吡咯烷-3-基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-(反式-4-吗啉代环己基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-(顺式-4-吗啉代环己基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-(内型-3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-(外型-3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;和
4-[(4R,10bS)-8-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-乙基-1,8-萘啶-2-酮;
或其药用盐、对映体或非对映体。
合成
本发明的化合物可以通过任何常规方法制备。在以下方案和示例中提供了合成这些化合物及其原料的合适方法。除非另有说明,否则所有取代基,特别是R1至R6如上所定义。此外,除非另有明确说明,否则所有反应、反应条件、缩写和符号均具有有机化学领域普通技术人员众所周知的含义。
制备式(I)化合物的一般合成路线在以下流程1中显示。
方案1
其中X和Y为卤素或离去基团,例如,OTf或OMs;R4和R5为保护基,例如,R4为Boc,并且R5为苄基;R6为烷基甲硅烷基,例如三甲基甲硅烷基。
可以使用偶联剂(诸如HATU和DIPEA),实现被保护的氨基酸(II)和甲硅烷基胺(III)的酰胺偶联,以得到中间体(IV)。在通过选择性脱保护除去R4之后,可以在还原条件下(诸如LAH的处理)还原所得中间体(V)中的酰胺键,以得到二胺(VI)。可以在典型的脱水条件下通过醛(VII)和二胺(VI)缩合形成的亚胺(VIII)在光-氧化还原条件下环化,该环化由蓝光和Ir型催化剂(诸如[Ir(dtbbpy)(ppy)2][PF6]),以得到三环内酰胺(IX)。当用还原试剂如LAH处理时,内酰胺(IX)可被还原成式(X)化合物。具有式(X)的化合物可用作金属催化的偶联条件下(诸如Buchwald-Hartwig胺化、Suzuki偶联、Negishi偶联,Stille偶联或Pd催化的C=O插入)进一步官能化的常用中间体。例如,在Buchwald-Hartwig胺化条件下(参考文献:Acc.Chem.Res.1998,31,805-818;Chem.Rev.2016,116,12564-12649;Topics inCurrent Chemistry,2002,219,131-209;和其中引用的文献),用催化剂(诸如Ruphos Pd-G2)和碱(Cs2CO3),可以由具有式(X)的化合物生成式(XI)的化合物。在典型条件下(例如,通过在催化量碳载钯上加氢而脱除苄基保护基)对R5基团进行选择性脱保护后,可以将所得的式(XII)化合物置于亲核芳族取代条件(例如,在DMSO中在DIEPA存在下与卤化物(XIII)加热)或Buchwald-Hartwig胺化条件(例如,在催化剂(诸如Ruphos Pd-G2)和碱(诸如Cs2CO3)存在下与卤化物(XIII)加热,以得到式(I)或(Ia)化合物。在一些实施方案中,式(XII)化合物可以包含保护基,例如Boc,将其除去之后会得到最终的式(I)或(Ia)化合物。
方案2
可替代地,如方案2所示,在通过选择性脱保护从式(X)中除去R5后,所得的式(XIV)化合物可在碱(诸如DIEPA)存在下通过亲核芳族取代与卤化物(XIII)反应,以得到式(XV)化合物。式(I)或(Ia)化合物可通过金属催化的偶联条件从式(XV)化合物获得:在催化剂(诸如Ruphos Pd-G2)和碱(诸如Cs2CO3)存在下进行Buchwald-Hartwig胺化;在钯催化剂(诸如四(三苯基膦)钯(0)或[1,1'-双(二苯基膦基)二茂铁]二氯钯(II)二氯甲烷络合物)和碱(诸如在溶剂中的碳酸钾)存在下,与R3-有机硼酸或R3-有机硼酸酯进行Suzuki偶联;在钯(0)催化剂(诸如四(三苯基膦)钯(0))存在下,与有机锡试剂进行Stille偶联;或在钯(0)催化剂(诸如四(三苯基膦)钯(0)或[1,1'-双(二苯基膦基)二茂铁]二氯钯(II))存在下,与有机锌试剂进行Negishi偶联。在一些实施方案中,式(XII)化合物可以包含保护基,例如Boc,将其除去之后会得到最终的式(I)或(Ia)化合物。
本发明的化合物可以以非对映体或对映体的混合物形式获得,它们可以通过本领域熟知的方法分离,例如,(手性)HPLC或SFC。
本发明还涉及用于制备式(I)或(Ia)化合物的方法,所述方法包括以下步骤中的任一者:
b)式(XV)化合物,
与胺HR3的Buchwald-Hartwig胺化反应;或式(IX)化合物与R3-有机硼酸或R3-有机硼酸酯之间的Suzuki偶联反应;
根据上述方法用非手性或手性起始原料制备的式(I)或(Ia)化合物也是本发明的目的。
适应症和治疗方法
本发明提供了可以用作TLR7和/或TLR8和/或TLR9拮抗剂的化合物,其抑制通过TLR7和/或TLR8和/或TLR9通路的活化以及相应的下游生物学事件,包括但不限于通过产生所有类型的细胞因子和各种形式的自身抗体介导的先天性和适应性免疫应答。因此,本发明的化合物可用于在表达此类受体的所有类型的细胞中阻断TLR7和/或TLR8和/或TLR9,所述细胞包括但不限于浆细胞样树突细胞、B细胞、T细胞、巨噬细胞、单核细胞、中性粒细胞、角质形成细胞、上皮细胞。如此,该化合物可用作系统性红斑狼疮和狼疮性肾炎的治疗剂或预防剂。
本发明提供了治疗或预防有需要的患者的系统性红斑狼疮和狼疮性肾炎的方法。
另一实施例包括治疗或预防需要这种治疗的哺乳动物中系统性红斑狼疮和狼疮性肾炎的方法,其中所述方法包括向所述哺乳动物施用治疗有效量的式(I)的化合物、其立体异构体、互变异构体、前药或药用盐。
实例
通过参考以下实施例将更全面地理解本发明。但是,它们不应被解释为限制本发明的范围。
缩写
通过参考以下实施例将更全面地理解本发明。但是,它们不应被解释为限制本发明的范围。
本文使用的缩写如下:
ACN: 乙腈
DCM: 二氯甲烷
DIPEA 二乙基异丙基胺
EA或EtOAc: 乙酸乙酯
FA: 甲酸
HATU 1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐
hr 小时
hrs 小时
IC50: 半抑制浓度
MS: 质谱
prep-HPLC: 制备型高效液相色谱
RT: 保留时间
RuPhos Pd G2: 氯(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯)[2-(2'-氨基-1,1'-联苯)]钯(II)第二代
SFC: 超临界流体色谱
TFA: 三氟乙酸
v/v 体积比
一般实验条件
使用以下仪器之一通过快速色谱法纯化中间体和最终化合物:i)Biotage SP1系统和Quad 12/25Cartridge模块。ii)ISCO combi-flash色谱仪。硅胶品牌和孔径:i)KP-SIL粒径:40-60μm;ii)CAS登录号:硅胶:63231-67-4,粒径:47-60微米硅胶;iii)青岛海洋化学有限公司的ZCX,孔:200-300或300-400。
中间体和最终化合物在反相色谱柱上通过制备型HPLC纯化,反相色谱柱使用XBridgeTM Prep-C18(5μm,OBDTM 30×100mm)色谱柱,SunFireTM Prep-C18(5μm,OBDTM 30×100mm)色谱柱,Phenomenex Synergi-C18(10μm,25×150mm)或Phenomenex Gemini-C18(10μm,25×150mm)。Waters AutoP纯化系统(样品管理器2767,泵2525,检测器:Micromass ZQ和UV 2487,溶剂体系:ACN和0.1%氢氧化铵水溶液;ACN和0.1%FA水溶液或ACN和0.1%TFA水溶液)。或Gilson-281纯化系统(泵322,检测器:UV 156,溶剂体系:ACN和0.05%氢氧化铵水溶液;ACN和0.225%FA水溶液;ACN和0.05%HCl水溶液;ACN和0.075%TFA水溶液;或ACN和水)。
为了进行SFC手性分离,中间体分离通过手性柱(Daicel chiralpak IC,5μm,30×250mm)、AS(10μm,30×250mm)或AD(10μm,30×250mm),使用Mettler Toledo MultigramIII系统SFC、Waters 80Q制备型SFC或Thar 80制备型SFC,溶剂系统:CO2和IPA(0.5%TEA的IPA溶液)或CO2和MeOH(0.1%NH3·H2O的MeOH溶液),背压100bar,在254或220nm处检测UV。
使用LC/MS(WatersTM Alliance 2795-Micromass ZQ、Shimadzu Alliance 2020-Micromass ZQ或Agilent Alliance 6110-Micromass ZQ)获得化合物的LC/MS光谱,LC/MS条件如下(运行时间3或1.5分钟):
酸性条件I:A:0.1%TFA在H2O中的溶液;B:0.1%TFA的ACN溶液;
酸性条件II:A:0.0375%TFA在H2O中的溶液;B:0.01875%TFA的ACN溶液;
碱性条件I:A:0.1%NH3·H2O在H2O中的溶液;B:ACN;
碱性条件II:A:0.025%NH3·H2O在H2O中的溶液;B:ACN;
中性条件:A:H2O;B:ACN。
质谱(MS):通常仅报告表示母体质量的离子,除非另有说明,否则所引用的质量离子为正质量离子(MH)+。
使用Bruker Avance 400MHz获得NMR谱。
微波辅助反应在Biotage Initiator Sixty微波合成仪中进行。所有涉及对空气敏感的试剂的反应均在氩气或氮气气氛下进行。除非另有说明,否则试剂按原样购自商业供应商,未经进一步纯化。
制备实例
以下实例旨在说明本发明的含义,但绝不代表对本发明含义的限制:
中间体A
(4R,10bS)-2-苄基-8-溴-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚
根据以下方案合成标题化合物:
步骤1:制备N-[(1R)-2-[苄基(三甲基甲硅烷基甲基)氨基]-1-甲基-2-氧代-乙基]氨基甲酸叔丁酯(化合物A2)
向(2R)-2-(叔丁氧基羰基氨基)丙酸(化合物A1,10g,52.9mmol)的DMF(40mL)溶液中加入N-苄基-1-(三甲基甲硅烷基)甲胺(10.2g,52.9mmol)、HATU(20.1g,52.9mmol)和DIEA(6.8g,9.2mL,52.9mmol)。将反应混合物在室温搅拌过夜,然后用水(150mL)猝灭,并用DCM(100mL)萃取3次。将合并的有机层用盐水洗涤,经Na2SO4干燥、过滤并真空浓缩。残余物通过快速色谱法纯化(硅胶,40g,在PE中的0%至30%的EtOAc),得到化合物A2(13.1g,68%收率)。MS:calc’d 365[(M+H)+],测量值为365[(M+H)+]。
步骤2:制备(2R)-2-氨基-N-苄基-N-(三甲基甲硅烷基甲基)丙酰胺(化合物A3)
将TFA(10mL)加入至N-[(1R)-2-[苄基(三甲基甲硅烷基甲基)氨基]-1-甲基-2-氧代-乙基]氨基甲酸叔丁酯(化合物A2,13.0g,35.7mmol)的DCM(60mL)溶液,并将混合物在室温搅拌4小时。将反应真空浓缩,并将残余物用饱和NaHCO3(aq)和EA分配。分离有机层,并将碱性水层用DCM(80mL)萃取两次。合并的有机层经Na2SO4干燥,过滤并真空浓缩,得到化合物A3(9.1g,96%收率),无需进一步纯化。MS:calc’d 265[(M+H)+],测量值为265[(M+H)+]。
步骤3:制备(2R)-N1-苄基-N1-(三甲基甲硅烷基甲基)丙烷-1,2-二胺(化合物A4)
向(2R)-2-氨基-N-苄基-N-(三甲基甲硅烷基甲基)-丙酰胺(化合物A3,9.0g,34mmol)在无水THF(100mL)中的冰冷却溶液中缓慢加入LiAlH4(3.9g,102mmol)。添加完成后,将混合物在回流下加热过夜。将反应冷却至室温,用20%NaOH(aq)猝灭,然后过滤并用EtOAc洗涤。真空浓缩合并的滤液,得到化合物A4(5.7g,67%收率),无需进一步纯化。MS:calc’d 251[(M+H)+],测量值为251[(M+H)+]。
步骤4:制备(4R,10bS)-2-苄基-8-溴-4-甲基-1,3,4,10b-四氢吡嗪并[1,2-b]异吲哚-6-酮(化合物A6)
将N2下的(2R)-N1-苄基-N1-(三甲基硅烷基甲基)丙烷-1,2-二胺(化合物A4,3g,12mmol)、5-溴-2-甲酰基苯甲酸甲酯(2.9g,12mmol)和4A MS(5.0g)在MeCN(80mL)中的混合物在室温搅拌过夜。通过硅藻土过滤反应,并用DCM洗涤。将滤液真空浓缩,得到中间体化合物A5,将残余物重新溶于MeCN/TFE(45mL/5mL)中,随后加入[Ir(dtbbpy)(ppy)2][PF6](CAS:676525-77-2,TCI,目录:D4887,42.9mg,46.9μmol)。将反应物混合物于室温在蓝色LED(synLED-16A Discover,12W,波长465-470nm,购自SYNLED公司)的曝光下搅拌2天。真空除去溶剂后,将残余物通过快速色谱法纯化(硅胶,80g,在PE中的20%至70%EA),得到化合物A6(1.85g,42%收率)。立体化学由NOESY确认。MS:计算的371和373[(M+H)+],测得的371和373[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 7.75(d,J=1.71Hz,1H)7.63(dd,J=8.01,1.77Hz,1H)7.19-7.35(m,6H)4.43(dd,J=10.88,3.67Hz,1H)3.67-3.86(m,1H)3.56(s,2H)3.41-3.45(m,1H)2.79-2.87(m,1H)1.86(t,J=11.07Hz,1H)1.67(d,J=6.97Hz,3H)1.64(t,J=11.07Hz,1H)。
步骤5:制备(4R,10bS)-2-苄基-8-溴-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚(中间体A)
将(4R,10bS)-2-苄基-8-溴-4-甲基-1,3,4,10b-四氢吡嗪并[1,2-b]异吲哚-6-酮(化合物A6,1.9g,5.0mmol)和BH3溶液(1M与THF中,40mL,40mmol)的混合物在搅拌下于80℃加热5小时。于0℃向反应混合物缓慢加入HCl溶液(6N,10mL)。将所得混合物在室温搅拌过夜,然后将混合物用NaOH溶液(2N)碱化至pH 10。将混合物用EtOAc萃取两次。合并的有机层经MgSO4干燥,过滤并真空浓缩。残余物通过快速色谱法纯化(硅胶,40g,在PE中的30%至100%的EtOAc),得到中间体A(1.5g,85%收率)。立体化学由NOESY确认。MS:calc’d 357和359[(M+H)+],测量值为357和359[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 7.49(s,1H)7.32-7.43(m,5H)7.26-7.32(m,1H)7.05(d,J=7.95Hz,1H)4.18(d,J=12.59Hz,1H)3.71(br d,J=10.51Hz,1H)3.55(dd,J=12.47,2.32Hz,1H)3.36-3.31(m,1H)2.97-2.89(m,1H)2.77-2.87(m,1H)2.12(t,J=10.64Hz,1H)2.00(t,J=10.64Hz,1H)1.14(d,J=6.48Hz,3H)。
中间体B
4-氯-1-甲基-1,8-萘啶-2-酮
根据以下方案合成标题化合物:
步骤(a):制备2-(甲基氨基)吡啶-3-甲酸(化合物B2)
将2-氯烟酸(化合物B1,1.0kg,6.3mol)溶于33%单甲胺(386.3mol)的乙醇溶液中。将反应混合物在高压釜中在80℃搅拌80小时,然后真空浓缩,得到化合物A2.2(1.4kg,粗产物)。MS:calc’d 153[(M+H)+],测量值为153[(M+H)+]。
步骤(b):制备(1-甲基-2-氧代-1,8-萘啶-4-基)乙酸酯(化合物B3)
将2-(甲基氨基)吡啶-3-甲酸(化合物B2,1.4kg,粗产物)在乙酸酐(10.0L,105789mmol)和乙酸(5.0L)中的溶液加热回流2小时。将反应混合物真空浓缩,得到化合物B3(1.8kg,粗产物)。MS:calc’d 219[(M+H)+],测量值为219[(M+H)+]。
步骤(c):制备4-羟基-1-甲基-1,8-萘啶-2-酮(化合物B4)
向(1-甲基-2-氧代-1,8-萘啶-4-基)乙酸酯(化合物B3,1.8kg,粗产物)在甲醇(12.0L)中的溶液中加入碳酸钾(1.9kg,13.7mol)在水(3.6L)中的溶液。将混合物在25℃搅拌2小时。然后将反应混合物减压浓缩以除去MeOH。将残余物用HCl溶液(6N)酸化至pH 4-5,用EA(1500mL)萃取三次。将合并的有机层用饱和盐水(1500mL)洗涤,经Na2SO4干燥,并且真空浓缩,得到化合物B4(450g,40.2%收率)。MS:计算值为177[(M+H)+],测量值为177[(M+H)+];1H NMR(400MHz,DMSO-d6)δppm11.68(s,1H),8.63(dd,J=4.60,1.80Hz,1H),8.22(dd,J=7.80,1.80Hz,1H),7.27(dd,J=7.80,4.60Hz,1H),5.93(s,1H),3.59(s,3H)
步骤(d):制备4-氯-1-甲基-1,8-萘啶-2-酮(中间体A5)
将4-羟基-1-甲基-1,8-萘啶-2-酮(化合物B4,150g,0.85mol)在三氯氧磷(300mL)中的溶液在100℃搅拌2小时。减压浓缩反应混合物以除去三氯氧磷。通过在室温加入饱和NaHCO3水溶液,将残余物中和至pH 7-8,并且将混合物用DCM(1000mL)萃取两次。将合并的有机层用饱和盐水(500mL)洗涤,经Na2SO4干燥,并且真空浓缩以得到粗产物,通过硅胶色谱法(PE/EtOAc=1:0至7:1)纯化该粗产物,得到中间体B(39g,24%收率)。MS:计算值为195[(M+H)+],测量值为195[(M+H)+];1H NMR(400MHz,DMSO-d6)δppm 8.75(dd,J=4.60,1.60Hz,1H),8.32(dd,J=7.90,1.70Hz,1H),7.44(dd,J=8.00,4.60Hz,1H),7.03(s,1H),3.66(s,3H)。
中间体C
4-溴-1-乙基-1,8-萘啶-2-酮
根据以下方案合成标题化合物:
步骤(a):制备4-溴-1-乙基-1,8-萘啶-2-酮(中间体C)
向4-溴-1,8-萘啶-2(1H)-酮(化合物C1,500mg,2.2mmol)的DMF(20mL)溶液加入碘乙烷(3.47g,22.2mmol)和Cs2CO3(1.45g,4.44mmol)。将反应混合物在80℃下搅拌过夜。冷却至室温后,通过加入冰水(30mL)猝灭反应。将所得的混合物用PE/EA=1/1(30mL)萃取三次。合并的有机层用饱和盐水洗涤,经Na2SO4干燥,并真空浓缩。残余物通过快速色谱法纯化(硅胶,12g,在PE中的10%至30%的EA),得到中间体C(490mg,87%收率)。MS:calc’d 253和255[(M+H)+],测量值为253和255[(M+H)+]。
实例1
4-[(4R,10bS)-8-(3-氨基-3-甲基-氮杂环丁烷-1-基)-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
根据以下方案合成标题化合物:
步骤1:制备(4R,10bS)-8-溴-4-甲基-1,2,3,4,6,10b-六氢吡嗪并[2,1-a]异吲哚(化合物1.1)
向(4R,10bS)-2-苄基-8-溴-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚(中间体A,900mg,2.4mmol)的DCE(30mL)溶液中,室温搅拌下加入1-氯乙基碳酰氯(1.7g,12.1mmol)。将反应混合物在回流下加热过夜,并冷却至室温,然后真空浓缩。将残余物溶解在MeOH(20mL)中,并将所得混合物在回流下加热另外2小时,然后真空浓缩。残余物用水(10mL)稀释,溶液用NaHCO3水溶液碱化,并且混合物用EtOAc萃取两次。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并真空浓缩,得到化合物化合物1.1(660mg,98%收率),其直接用于下一步。MS:calc’d 267和269[(M+H)+],测量值为267和269[(M+H)+]。
步骤2:制备1-甲基-4-[(4R,10bS)-8-溴-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1,8-萘啶-2-酮(化合物1.2)
向(4R,10bS)-8-溴-4-甲基-1,2,3,4,6,10b-六氢吡嗪并[2,1-a]异吲哚(化合物1.1,0.70g,2.62mmol)的DMSO(20mL)溶液加入CsF(1.19g,7.86mmol)和4-氯-1-甲基-1,8-萘啶-2(1H)-酮(中间体B,0.54g,2.75mmol)。将反应混合物在120℃下搅拌20小时。冷却至室温后,将反应用水(50mL)猝灭,并用DCM(50mL)萃取两次。将合并的有机层用盐水洗涤,经Na2SO4干燥、过滤并真空浓缩。残余物通过快速色谱法纯化(硅胶,40g,在DCM中的0%至100%的EtOAc),得到化合物1.2(0.63g,56.5%收率)。MS:calc’d 425和427[(M+H)+],测量值为425和427[(M+H)+]。
步骤3:制备N-[3-甲基-1-[(4R,10bS)-4-甲基-2-(1-甲基-2-氧代-1,8-萘啶-4-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-8-基]氮杂环丁烷-3-基]氨基甲酸叔丁酯(化合物1.3)
向1-甲基-4-[(4R,10bS)-8-溴-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1,8-萘啶-2-酮(化合物1.2,60mg,141μmol)的甲苯(8mL)溶液加入(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯(31.5mg,169μmol)、Cs2CO3(138mg,423μmol)和RuPhos Pd G2(CAS:1375325-68-0,Aldrich,目录号:753246,21.9mg,28.2μmol)。将所得混合物在100℃加热20小时。冷却至室温后,用水(50mL)稀释,并用DCM(50mL)萃取三次。将合并的有机层用盐水洗涤,经Na2SO4干燥、过滤并真空浓缩。残余物通过快速色谱法纯化(硅胶,40g,在PE中的0%至100%的EtOAc),得到化合物1.3(40mg,53.4%收率)。MS:calc’d 531[(M+H)+],测量值为531[(M+H)+]。
步骤4:制备4-[(4R,10bS)-8-(3-氨基-3-甲基-氮杂环丁烷-1-基)-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮(实例1)
向N-[3-甲基-1-[(4R,10bS)-4-甲基-2-(1-甲基-2-氧代-1,8-萘啶-4-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-8-基]氮杂环丁烷-3-基]氨基甲酸叔丁酯(化合物1.3,40mg,75.4μmol)的DCM(5mL)溶液加入TFA(2mL)。将反应混合物在室温搅拌2小时,然后浓缩,得到粗产物将其通过制备型HPLC纯化,得到实例1(15mg,46.3%产率)。)。MS:calc’d431[(M+H)+],测量值为431[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.75-8.59(m,1H),8.43-8.23(m,1H),7.48-7.37(m,1H),7.32(d,J=8.3Hz,1H),6.68(d,J=1.7Hz,1H),6.60-6.48(m,1H),6.28(s,1H),5.15-5.03(m,1H),4.81(d,J=13.6Hz,1H),4.49(d,J=13.6Hz,1H),4.26-4.11(m,1H),4.04(d,J=8.4Hz,2H),3.98-3.86(m,3H),3.78(s,3H),3.65(br d,J=13.1Hz,1H),3.20-3.08(m,1H),3.04-2.90(m,1H),1.70(s,3H),1.51(d,J=6.7Hz,3H)。
实例2
4-[(4R,10bS)-4-甲基-8-(6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用2-甲基-2,6-二氮杂螺[3.3]庚烷(CAS:1203567-11-6,PharmaBlock,目录号:PBLJ2831)代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例2。MS:calc’d 457[(M+H)+],测量值为457[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.74-8.62(m,1H),8.39-8.23(m,1H),7.42-7.31(m,1H),7.27(d,J=8.2Hz,1H),6.60(d,J=1.7Hz,1H),6.54-6.43(m,1H),6.26(s,1H),5.05-4.95(m,1H),4.76(d,J=13.6Hz,1H),4.50-4.30(m,5H),4.12-4.08(m,1H),4.08(s,4H),3.93-3.86(m,1H),3.77(s,3H),3.66-3.55(m,1H),3.15-3.05(m,1H),3.01-2.88(m,1H),2.94(s,3H),1.47(d,J=6.7Hz,3H)。
实例3
4-[(4R,10bS)-4-甲基-8-(5-氧杂-2,8-二氮杂螺[3.5]壬烷-2-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用5-氧杂-2,8-二氮杂螺[3.5]壬烷-8-甲酸叔丁酯(CAS:1251005-61-4,PharmaBlock,目录号:PBN20111065)代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例3。MS:calc’d 473[(M+H)+],测量值为473[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.74-8.65(m,1H),8.44-8.27(m,1H),7.46-7.36(m,1H),7.33(d,J=8.3Hz,1H),6.67(d,J=1.7Hz,1H),6.63-6.51(m,1H),6.29(s,1H),5.19-5.08(m,1H),4.85(d,J=13.7Hz,1H),4.54(d,J=13.7Hz,1H),4.29-4.14(m,1H),4.08(d,J=8.6Hz,2H),4.01-3.88(m,3H),3.82(d,J=8.4Hz,2H),3.78(s,3H),3.66(br d,J=13.1Hz,1H),3.54(s,2H),3.30-3.24(m,2H),3.21-3.11(m,1H),3.05-2.95(m,1H),1.52(d,J=6.6Hz,3H)。
实例4
4-[(4R,10bS)-8-[(3R)-3-氨基-3-甲基-吡咯烷-1-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用N-[(3R)-3-甲基吡咯烷-3-基]氨基甲酸叔丁酯(CAS:167888-15-5,PharmaBlock,目录号:PBXA3113)代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例4。MS:calc’d 445[(M+H)+],测量值为445[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.74-8.65(m,1H),8.44-8.35(m,1H),7.47-7.36(m,1H),7.32(d,J=8.3Hz,1H),6.78(d,J=1.8Hz,1H),6.72-6.59(m,1H),6.29(s,1H),5.07-4.99(m,1H),4.79(d,J=13.6Hz,1H),4.45(d,J=13.4Hz,1H),4.17-4.00(m,1H),3.99-3.87(m,1H),3.79(s,3H),3.71-3.57(m,3H),3.53-3.43(m,1H),3.39(d,J=10.6Hz,1H),3.19-3.07(m,1H),3.06-2.90(m,1H),2.37-2.20(m,2H),1.60(s,3H),1.50(d,J=6.7Hz,3H)。
实例5
4-[(4R,10bS)-8-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用N-[(3R,4R)-4-甲氧基吡咯烷-3-基]氨基甲酸叔丁酯(CAS:1932066-52-8,PharmaBlock,目录号:PBZ4728)代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例5。MS:calc’d 461[(M+H)+],测量值为461[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.73-8.68(m,1H),8.49-8.28(m,1H),7.43-7.36(m,1H),7.29(d,J=8.3Hz,1H),6.79(d,J=1.6Hz,1H),6.68-6.62(m,1H),6.28(s,1H),4.83-4.75(m,1H),4.68(d,J=13.2Hz,1H),4.28(d,J=13.2Hz,1H),4.19-4.07(m,1H),3.97-3.83(m,4H),3.80(s,3H),3.76-3.66(m,1H),3.64-3.55(m,1H),3.52-3.41(m,2H),3.49(s,3H),3.09-2.91(m,2H),1.45(d,J=6.6Hz,3H)。
实例6
4-[(4R,10bS)-8-[(4aR,7aR)-3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-6-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用(4aR,7aR)-3,4a,5,6,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-4-甲酸叔丁酯(CAS:1932337-68-2,PharmaBlock,目录号:PBXA8123)代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例6。MS:calc’d 473[(M+H)+],测量值为473[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.74-8.64(m,1H),8.40-8.31(m,1H),7.40-7.35(m,1H),7.30(d,J=8.4Hz,1H),6.72(d,J=1.8Hz,1H),6.63-6.56(m,1H),6.27(s,1H),5.05-4.94(m,1H),4.77(d,J=13.6Hz,1H),4.42(d,J=13.4Hz,1H),4.27-4.19(m,1H),4.15-3.84(m,4H),3.81-3.68(m,2H),3.77(s,3H),3.65-3.34(m,5H),3.35-3.32(m,1H),3.13-3.05(m,1H),3.02-2.88(m,1H),1.47(d,J=6.7Hz,3H)。
实例7
4-[(4R,10bS)-8-[(3R,4S)-3-氨基-4-氟-吡咯烷-1-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用N-[(3R,4S)-4-氟吡咯烷-3-基]氨基甲酸叔丁酯(CAS:1033718-91--0,PharmaBlock,目录号:PB09204)代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例7。MS:calc’d 449[(M+H)+],测量值为449[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.74-8.60(m,1H),8.40-8.30(m,1H),7.44-7.37(m,1H),7.34(d,J=8.3Hz,1H),6.79(d,J=1.5Hz,1H),6.71-6.59(m,1H),6.29(s,1H),5.62-5.41(m,1H),5.12-5.03(m,1H),4.82(d,J=13.6Hz,1H),4.49(d,J=13.6Hz,1H),4.29-4.06(m,2H),3.98-3.61(m,5H),3.78(s,3H),3.49(t,J=9.1Hz,1H),3.19-3.09(m,1H),3.07-2.93(m,1H),1.51(d,J=6.6Hz,3H)。
实例8
4-[(4R,10bS)-8-[(3S,4S)-4-氨基-3-甲氧基-1-哌啶基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用N-[(3S,4S)-3-甲氧基-4-哌啶基]氨基甲酸叔丁酯(CAS:907544-19-8,PharmaBlock,目录号:PB07429)代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例8。MS:calc’d 475[(M+H)+],测量值为475[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.73-8.66(m,1H),8.46-8.31(m,1H),7.53-7.28(m,2H),7.19(d,J=2.0Hz,1H),7.15-7.03(m,1H),6.29(s,1H),5.22-5.14(m,1H),4.88(br d,J=13.7Hz,1H),4.58(d,J=13.7Hz,1H),4.35-4.11(m,2H),4.01-3.91(m,1H),3.88-3.80(m,1H),3.77(s,3H),3.66(br d,J=13.1Hz,1H),3.55(s,3H),3.47-3.36(m,1H),3.25-3.09(m,2H),3.08-2.96(m,1H),2.94-2.80(m,1H),2.65-2.53(m,1H),2.25-2.11(m,1H),1.89-1.74(m,1H),1.54(d,J=6.7Hz,3H)。
实例9
4-[(4R,10bS)-8-[(3S,4S)-3-氨基-4-甲氧基-1-哌啶基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用N-[(3S,4S)-4-甲氧基-3-哌啶基]氨基甲酸叔丁酯(PharmaBlock,目录号:PBZ5290)代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例9。MS:calc’d 475[(M+H)+],测量值为475[(M+H)+]。1HNMR(400MHz,甲醇-d4)δppm 8.76-8.61(m,1H),8.45-8.24(m,1H),7.46-7.33(m,2H),7.17(d,J=1.8Hz,1H),7.12-7.01(m,1H),6.29(s,1H),5.26-5.08(m,1H),4.86(br d,J=13.7Hz,1H),4.55(d,J=13.7Hz,1H),4.20(br s,1H),4.06-3.88(m,2H),3.84-3.73(m,1H),3.77(s,3H),3.69-3.58(m,1H),3.48-3.39(m,1H),3.47(s,3H),3.29-3.09(m,2H),3.07-2.87(m,3H),2.48-2.29(m,1H),1.67-1.55(m,1H),1.52(d,J=6.7Hz,3H)。
实例10
4-[(4R,10bS)-8-[(2S)-2-(甲氧基甲基)哌嗪-1-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用(3S)-3-(甲氧基甲基)哌嗪-1-甲酸叔丁酯(CAS:955400-16-5,Bide Pharmatech,目录号:BD293888)代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例10。MS:calc’d 475[(M+H)+],测量值为475[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.73-8.65(m,1H),8.43-8.29(m,1H),7.41-7.30(m,2H),7.17(d,J=1.7Hz,1H),7.09-7.00(m,1H),6.28(s,1H),4.98-4.94(m,1H),4.77(br d,J=13.4Hz,1H),4.40(br d,J=13.4Hz,1H),4.28-4.17(m,1H),4.10-3.99(m,1H),3.98-3.87(m,1H),3.77(s,3H),3.68-3.41(m,8H),3.30(s,3H),3.28-3.19(m,1H),3.13-2.93(m,2H),1.46(d,J=6.6Hz,3H)。
实例11
4-[(4R,10bS)-4-甲基-8-(5-氧杂-2,8-二氮杂螺[3.5]壬烷-8-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用5-氧杂-2,8-二氮杂螺[3.5]壬烷-2-甲酸叔丁酯(CAS:1251011-05-8,PharmaBlock,目录号:PBN20111063)代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例11。MS:calc’d 473[(M+H)+],测量值为473[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.73-8.64(m,1H),8.40-8.30(m,1H),7.42-7.31(m,2H),7.16(d,J=1.7Hz,1H),7.11-7.00(m,1H),6.27(s,1H),5.01-4.94(m,1H),4.76(d,J=13.4Hz,1H),4.40(d,J=13.4Hz,1H),4.17-4.00(m,5H),3.96-3.90(m,1H),3.90-3.84(m,2H),3.77(s,3H),3.62(br d,J=12.8Hz,1H),3.40(s,2H),3.17-3.13(m,2H),3.12-2.94(m,2H),1.47(d,J=6.6Hz,3H)。
实例12
4-[(4R,10bS)-4-甲基-8-哌嗪-1-基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用哌嗪-1-甲酸叔丁酯代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例12。MS:calc’d 431[(M+H)+],测量值为431[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.73-8.66(m,1H),8.41-8.31(m,1H),7.42-7.37(m,1H),7.31(d,J=8.3Hz,1H),7.16(d,J=1.8Hz,1H),7.05-6.98(m,1H),6.27(s,1H),4.57(br d,J=13.0Hz,2H),4.11(d,J=12.8Hz,1H),3.99-3.88(m,1H),3.82-3.69(m,1H),3.79(s,3H),3.61-3.54(m,1H),3.49-3.38(m,8H),3.03-2.89(m,2H),1.39(d,J=6.5Hz,3H)。
实例13
4-[(4R,10bS)-4-甲基-8-[(3S)-3-甲基哌嗪-1-基]-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用(2S)-2-甲基哌嗪-1-甲酸叔丁酯代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例13。MS:calc’d445[(M+H)+],测量值为445[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.77-8.62(m,1H),8.40-8.27(m,1H),7.40-7.28(m,2H),7.17(d,J=1.8Hz,1H),7.08-6.99(m,1H),6.26(s,1H),4.85-4.79(m,1H),4.69(d,J=13.3Hz,1H),4.30(d,J=13.2Hz,1H),3.98-3.71(m,4H),3.77(s,3H),3.64-3.56(m,1H),3.54-3.45(m,2H),3.34-3.25(m,3H),3.11-2.93(m,3H),2.89-2.80(m,1H),1.44(d,J=6.7Hz,3H),1.41(d,J=6.6Hz,3H)。
实例14
4-[(4R,10bS)-4-甲基-8-[(3R)-3-甲基哌嗪-1-基]-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用(2R)-2-甲基哌嗪-1-甲酸叔丁酯代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例14。MS:calc’d445[(M+H)+],测量值为445[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.73-8.65(m,1H),8.41-8.30(m,1H),7.40-7.35(m,1H),7.32(d,J=8.3Hz,1H),7.17(d,J=2.0Hz,1H),7.08-6.98(m,1H),6.26(s,1H),4.76-4.68(m,1H),4.64(d,J=13.2Hz,1H),4.23(d,J=13.1Hz,1H),3.96-3.90(m,1H),3.89-3.74(m,3H),3.78(s,3H),3.63-3.56(m,1H),3.55-3.42(m,2H),3.34-3.28(m,1H),3.11-2.92(m,3H),2.88-2.74(m,1H),1.42(d,J=6.7Hz,3H),1.40(d,J=6.6Hz,3H)。
实例15
4-[(4R,10bS)-8-[(3S)-3-氨基-3-甲基-1-哌啶基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用N-[(3S)-3-甲基-3-哌啶基]氨基甲酸叔丁酯(CAS:1363378-21-5,PharmaBlock,目录号:PBN20120294)代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例15。MS:calc’d 459[(M+H)+],测量值为459[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.72-8.64(m,1H),8.40-8.31(m,1H),7.40-7.34(m,1H),7.32(d,J=8.3Hz,1H),7.19(d,J=1.8Hz,1H),7.10-6.98(m,1H),6.26(s,1H),4.83-4.77(m,1H),4.68(d,J=13.2Hz,1H),4.29(d,J=13.1Hz,1H),3.97-3.86(m,2H),3.78(s,3H),3.65-3.58(m,1H),3.45(br d,J=12.8Hz,2H),3.06-2.93(m,2H),2.90(d,J=12.7Hz,2H),2.04-1.77(m,3H),1.72-1.68(m,1H),1.44(d,J=6.6Hz,3H),1.41(s,3H)。
实例16
4-[(4R,10bS)-8-[(3R)-3-氨基-1-哌啶基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用N-[(3R)-3-哌啶基]氨基甲酸叔丁酯(CAS:309956-78-3,PharmaBlock,目录号:PB00803)代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例16。MS:计算值为445[(M+H)+],测量值为445[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.70-8.64(m,1H),8.40-8.30(m,1H),7.47-7.32(m,2H),7.16(d,J=1.8Hz,1H),7.08-6.99(m,1H),6.28(s,1H),5.19-5.07(m,1H),4.84(d,J=13.7Hz,1H),4.53(d,J=13.7Hz,1H),4.25-4.09(m,1H),3.99-3.88(m,1H),3.76(s,3H),3.69-3.60(m,1H),3.60-3.53(m,1H),3.52-3.42(m,1H),3.34(br d,J=3.3Hz,1H),3.20-3.07(m,3H),3.05-2.93(m,1H),2.10-1.90(m,2H),1.84-1.67(m,2H),1.51(d,J=6.7Hz,3H)。
实例17
4-[(4R,10bS)-4-甲基-8-[(2R)-2-甲基哌嗪-1-基]-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用(3R)-3-甲基哌嗪-1-甲酸叔丁酯(CAS:163765-44-4,PharmaBlock,目录号:PB07855)代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例17。MS:calc’d445[(M+H)+],测量值为445[(M+H)+]。1HNMR(400MHz,甲醇-d4)δppm8.75-8.64(m,1H),8.39-8.33(m,1H),7.43-7.32(m,2H),7.21(d,J=1.6Hz,1H),7.14-7.04(m,1H),6.28(s,1H),5.08-5.01(m,1H),4.83(d,J=13.6Hz,1H),4.47(d,J=13.6Hz,1H),4.17-4.00(m,2H),3.99-3.90(m,1H),3.77(s,3H),3.65(brd,J=13.0Hz,1H),3.48-3.36(m,3H),3.29-3.18(m,3H),3.15-2.97(m,2H),1.48(d,J=6.7Hz,3H),1.10(d,J=6.6Hz,3H)。
实例18
4-[(4R,10bS)-8-(4-氨基-4-甲基-1-哌啶基)-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用N-(4-甲基-4-哌啶基)氨基甲酸叔丁酯代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例18。MS:calc’d 459[(M+H)+],测量值为459[(M+H)+]。1HNMR(400MHz,甲醇-d4)δppm 8.70-8.65(m,1H),8.40-8.29(m,1H),7.47-7.29(m,2H),7.15(d,J=1.8Hz,1H),7.07-6.99(m,1H),6.28(s,1H),5.27-5.12(m,1H),4.90(d,J=13.7Hz,1H),4.59(d,J=13.7Hz,1H),4.33-4.17(m,1H),4.11-3.83(m,1H),3.76(s,3H),3.69-3.50(m,3H),3.23-3.09(m,3H),3.09-2.94(m,1H),2.01-1.85(m,4H),1.52(d,J=6.7Hz,3H),1.46(s,3H)。
实例19
4-[(4R,10bS)-8-[(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(CAS:113451-59-5,PharmaBlock,目录号:PBN20120579)代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例19。MS:calc’d 443[(M+H)+],测量值为443[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.71-8.63(m,1H),8.38-8.32(m,1H),7.42-7.30(m,2H),6.83(s,1H),6.76-6.64(m,1H),6.27(s,1H),5.16-5.06(m,1H),4.86-4.68(m,2H),4.60-4.49(m,2H),4.27-4.11(m,1H),3.92(br d,J=11.2Hz,1H),3.79-3.72(m,1H),3.75(s,3H),3.64(br d,J=13.2Hz,1H),3.43-3.33(m,3H),3.23-3.11(m,1H),3.06-2.92(m,1H),2.29(br d,J=11.1Hz,1H),2.09(br d,J=11.1Hz,1H),1.51(d,J=6.7Hz,3H)。
实例20
4-[(4R,10bS)-8-[(1R,4R)-2,5-二氮杂双环[2.2.1]庚烷-2-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用(1R,4R)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯(CAS:134003-84-2,PharmaBlock,目录号:PBN20120578)代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例20。MS:calc’d 443[(M+H)+],测量值为443[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.74-8.63(m,1H),8.42-8.29(m,1H),7.43-7.32(m,2H),6.83(d,J=1.8Hz,1H),6.75-6.62(m,1H),6.27(s,1H),5.23-5.03(m,1H),4.84-4.69(m,2H),4.61-4.47(m,2H),4.31-4.09(m,1H),3.92(br d,J=12.7Hz,1H),3.82-3.70(m,1H),3.76(s,3H),3.65(br d,J=13.1Hz,1H),3.45-3.33(m,3H),3.23-3.09(m,1H),3.07-2.89(m,1H),2.29(br d,J=11.1Hz,1H),2.09(br d,J=11.1Hz,1H),1.51(d,J=6.7Hz,3H)。
实例21
4-[(4R,10bS)-8-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(CAS:149771-44-8,PharmaBlock,目录号:PBN20120001)代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例21。MS:calc’d 457[(M+H)+],测量值为457[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.59-8.53(m,1H),8.27-8.18(m,1H),7.30-7.22(m,1H),7.18(d,J=8.4Hz,1H),6.97(d,J=1.8Hz,1H),6.88-6.77(m,1H),6.14(s,1H),4.63-4.56(m,1H),4.51(d,J=13.2Hz,1H),4.09(br t,J=6.3Hz,3H),3.84-3.76(m,1H),3.75-3.69(m,1H),3.66(s,3H),3.65-3.58(m,2H),3.46(br d,J=12.6Hz,1H),3.04(d,J=12.0Hz,2H),2.92-2.76(m,2H),2.03(s,4H),1.30(d,J=6.6Hz,3H)。
实例22
4-[(4R,10bS)-8-[(6R)-6-氨基-1,4-氧氮杂环庚烷-4-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用N-[(6R)-1,4-氧氮杂环庚烷-6-基]氨基甲酸叔丁酯(PharmaBlock,目录号:PB97932)代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例22。MS:calc’d461[(M+H)+],测量值为461[(M+H)+]。1HNMR(400MHz,甲醇-d4)δppm8.75-8.67(m,1H),8.43-8.32(m,1H),7.44-7.37(m,1H),7.35(d,J=8.6Hz,1H),7.03(d,J=2.0Hz,1H),6.95-6.84(m,1H),6.29(s,1H),5.19-5.07(m,1H),4.85(d,J=13.7Hz,1H),4.54(d,J=13.6Hz,1H),4.29-4.12(m,2H),4.09-3.74(m,6H),3.79(s,3H),3.70-3.47(m,4H),3.22-3.10(m,1H),3.08-2.96(m,1H),1.52(d,J=6.7Hz,3H)。
实例23
4-[(4R,10bS)-8-[2-(二甲基氨基)乙氧基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例1的制备,通过使用2-(二甲基氨基)乙醇代替步骤3中的N-(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯来制备标题化合物。获得实例23。MS:calc’d 434[(M+H)+],测量值为434[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.74-8.63(m,1H),8.37-8.28(m,1H),7.40-7.33(m,1H),7.28(d,J=8.3Hz,1H),7.11(d,J=2.2Hz,1H),7.00-6.92(m,1H),6.25(s,1H),4.43(d,J=12.7Hz,1H),4.39-4.32(m,2H),4.30(br d,J=9.5Hz,1H),3.96-3.86(m,2H),3.79(s,3H),3.65-3.58(m,2H),3.56-3.42(m,2H),3.00(s,6H),2.96-2.86(m,1H),2.85-2.75(m,1H),1.32(d,J=6.4Hz,3H)。
实例24
4-[(4R,10bS)-4-甲基-8-(4-哌啶基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
根据以下方案合成标题化合物:
步骤1:制备4-[(4R,10bS)-4-甲基-2-(1-甲基-2-氧代-1,8-萘啶-4-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-8-基]-3,6-二氢-2H-吡啶-1-甲酸叔丁酯(化合物24.2)
向4-[(4R,10bS)-8-溴-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮(化合物1.2,300mg,705μmol)在二噁烷(18mL)和水(2mL)中的溶液加入4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-3,6-二氢-2H-吡啶-1-甲酸叔丁酯(化合物24.1,262mg,846μmol)、K2CO3(195mg,1.41mmol)和Pd(dppf)Cl2 .DCM加合物(51.6mg,70.5μmol)。将所得混合物在100℃下加热20小时。冷却至室温后,将反应混合物用水(30mL)稀释,并用DCM(60mL)萃取两次。将合并的有机层用盐水洗涤,经Na2SO4干燥、过滤并真空浓缩。残余物通过快速色谱法纯化(硅胶,40g,在DCM中的0%至100%的EtOAc),得到化合物24.2(240mg,64.5%收率)。MS:calc’d 528[(M+H)+],测量值为528[(M+H)+]。
步骤2:制备4-[(4R,10bS)-4-甲基-2-(1-甲基-2-氧代-1,8-萘啶-4-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-8-基]哌啶-1-甲酸叔丁酯(化合物24.3)
将4-[(4R,10bS)-4-甲基-2-(1-甲基-2-氧代-1,8-萘啶-4-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-8-基]-3,6-二氢-2H-吡啶-1-甲酸叔丁酯(化合物24.2,240mg,455μmol)和Pd-C(30mg)在MeOH(50mL)中的混合物在室温用氢气球氢化30min。滤除催化剂后,将滤液真空浓缩。粗材料通过快速色谱法纯化(硅胶,40g,在DCM中的50%至100%的EtOAc),得到化合物24.3(180mg,74.7%收率)。MS:calc’d 530[(M+H)+],测量值为530[(M+H)+]。
步骤3:制备4-[(4R,10bS)-4-甲基-8-(4-哌啶基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮(实例24)
向4-[(4R,10bS)-4-甲基-2-(1-甲基-2-氧代-1,8-萘啶-4-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-8-基]哌啶-1-甲酸叔丁酯(化合物24.3,180mg,340μmol)的DCM(20mL)溶液加入TFA(5mL)。将反应混合物在室温搅拌2小时,然后浓缩,得到粗产物将其通过制备型HPLC纯化,得到实例24(101mg,69.2%产率)。MS:calc’d 430[(M+H)+],测量值为430[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.72-8.63(m,1H),8.39-8.29(m,1H),7.42-7.34(m,3H),7.31-7.23(m,1H),6.26(s,1H),4.78-4.71(m,1H),4.66(d,J=13.2Hz,1H),4.24(d,J=13.2Hz,1H),3.99-3.91(m,1H),3.88-3.82(m,1H),3.77(s,3H),3.59(br d,J=12.7Hz,1H),3.51(br d,J=12.6Hz,2H),3.23-3.09(m,2H),3.06-2.89(m,3H),2.12-2.03(m,2H),2.00-1.83(m,2H),1.41(d,J=6.6Hz,3H)。
实例25
4-[(4R,10bS)-4-甲基-8-(3-哌啶基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例24的制备,通过使用5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-3,6-二氢-2H-吡啶-1-甲酸叔丁酯代替步骤1中的4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-3,6-二氢-2H-吡啶-1-甲酸氨基甲酸叔丁酯来制备标题化合物。获得实例25。MS:calc’d 430[(M+H)+],测量值为430[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.70-8.65(m,1H),8.38-8.33(m,1H),7.47-7.41(m,2H),7.40-7.30(m,2H),6.27(s,1H),4.78-4.71(m,1H),4.74(d,J=13.3Hz,1H),4.36(d,J=13.3Hz,1H),4.01-3.92(m,2H),3.77(s,3H),3.66-3.57(m,1H),3.48-3.36(m,2H),3.15-2.96(m,5H),2.11-1.98(m,2H),1.95-1.78(m,2H),1.45(d,J=6.6Hz,3H)。
实例26
4-[(4R,10bS)-4-甲基-8-吡咯烷-3-基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
类似于实例24的制备,通过使用3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2,5-二氢吡咯-1-甲酸叔丁酯代替步骤1中的4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-3,6-二氢-2H-吡啶-1-甲酸氨基甲酸叔丁酯来制备标题化合物。获得实例26。MS:calc’d 416[(M+H)+],测量值为416[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.70-8.63(m,1H),8.38-8.30(m,1H),7.43-7.28(m,4H),6.25(s,1H),4.50(d,J=12.8Hz,1H),4.45(br d,J=10.0Hz,1H),4.01(br d,J=12.5Hz,1H),3.97-3.86(m,1H),3.78(s,3H),3.75-3.67(m,1H),3.63-3.52(m,4H),3.44-3.33(m,1H),3.25-3.16(m,1H),2.99-2.91(m,1H),2.91-2.78(m,1H),2.46(br d,J=3.3Hz,1H),2.18-2.03(m,1H),1.34(d,J=6.4Hz,3H)。
实例27A和实例27B
4-[(4R,10bS)-4-甲基-8-(反式-4-吗啉代环己基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮和
4-[(4R,10bS)-4-甲基-8-(顺式-4-吗啉代环己基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
根据以下方案合成标题化合物:
步骤1:制备4-[(4R,10bS)-8-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮(化合物27.2)
向4-[(4R,10bS)-8-溴-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮(化合物1.2,100mg,235μmol)在二噁烷(9mL)和水(1mL)中的溶液加入2-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(化合物27.1,62.6mg,235μmol)、K2CO3(65mg,470μmol)和PdCl2(dppf).DCM加合物(17.2mg,23.5μmol)。将所得混合物在100℃下加热20小时。冷却至室温后,将反应混合物用水(30mL)稀释,并用DCM(60mL)萃取两次。将合并的有机层用盐水洗涤,经Na2SO4干燥、过滤并真空浓缩。残余物通过快速色谱法纯化(硅胶,20g,在DCM中的0%至100%的EtOAc),得到化合物27.2(101mg,88.6%收率)。MS:calc’d 485[(M+H)+],测量值为485[(M+H)+]。
步骤2:制备4-[(4R,10bS)-8-(1,4-二氧杂螺[4.5]癸烷-8-基)-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮(化合物27.3)
将4-[(4R,10bS)-8-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮(化合物27.2,101mg,208μmol)和Pd-C(20mg)在乙酸乙酯(30mL)中的混合物在室温用氢气球氢化2小时。滤除催化剂后,将滤液真空浓缩,得到化合物27.3(90mg,88.7%收率),其无需进一步纯化直接用于下一步骤。MS:calc’d 487[(M+H)+],测量值为487[(M+H)+]。
步骤3:制备4-[(4R,10bS)-4-甲基-8-(4-氧代环己基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮(化合物27.4)
向4-[(4R,10bS)-8-(1,4-二氧杂螺[4.5]癸烷-8-基)-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮(化合物27.3,90mg,185μmol)的THF(10mL)溶液加入2N HCl溶液(aq,2mL,4mmol)。将所得混合物在回流下搅拌30min。冷却至室温后,将反应混合物用2N NaOH溶液(aq)碱化至pH 8,并用EtOAc萃取两次。合并的有机层经MgSO4干燥,过滤并真空浓缩,得到化合物27.4(70mg,158μmol,85.5%收率),其无需进一步纯化直接用于下一步骤。MS:calc’d 443[(M+H)+],测量值为443[(M+H)+]。
步骤4:制备4-[(4R,10bS)-4-甲基-8-(反式-4-吗啉代环己基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮和4-[(4R,10bS)-4-甲基-8-(顺式-4-吗啉代环己基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮(实例27A和实例27B)
将4-[(4R,10bS)-4-甲基-8-(4-氧代环己基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮(化合物27.4,70mg,158μmol)、吗啉(68.9mg,791μmol)和NaBH3CN(19.9mg,316μmol)在乙醇(5mL)中的混合物在回流下搅拌2小时。浓缩混合物,残余物通过制备型-HPLC纯化,得到实例27A(7.3mg,9%收率)和实例27B(3.6mg,4.4%收率),该立体化学由NOESY确定。
实例27A MS:计算值为514[(M+H)+],测量值为514[(M+H)+]。1HNMR(400MHz,甲醇-d4)δppm 8.65(dd,J=1.8,4.6Hz,1H),8.31(dd,J=1.8,8.0Hz,1H),7.34(dd,J=4.6,8.1Hz,1H),7.24(s,1H),7.2-7.1(m,1H),7.1-7.1(m,1H),6.22(s,1H),4.26(d,J=12.2Hz,1H),4.02(br d,J=10.5Hz,1H),3.89(br d,J=11.6Hz,1H),3.77(s,3H),3.7-3.7(m,4H),3.7-3.6(m,1H),3.5-3.4(m,1H),3.26(ddd,J=3.0,6.8,10.0Hz,1H),2.88(t,J=11.0Hz,1H),2.71(dd,J=10.5,12.0Hz,1H),2.7-2.6(m,4H),2.6-2.5(m,1H),2.4-2.3(m,1H),2.09(br d,J=11.1Hz,2H),1.94(br d,J=12.6Hz,2H),1.6-1.5(m,2H),1.5-1.4(m,2H),1.24(d,J=6.4Hz,3H)。
实例27B MS:计算值为514[(M+H)+],测量值为514[(M+H)+]。1HNMR(400MHz,甲醇-d4)δppm 8.65(dd,J=1.8,4.6Hz,1H),8.31(dd,J=1.7,7.9Hz,1H),7.35(dd,J=4.6,8.0Hz,1H),7.29(s,1H),7.16(d,J=0.7Hz,2H),6.22(s,1H),4.27(d,J=12.1Hz,1H),4.02(br d,J=10.4Hz,1H),3.9-3.8(m,1H),3.77(s,3H),3.72(t,J=4.7Hz,4H),3.67(dd,J=1.7,12.2Hz,1H),3.5-3.4(m,1H),3.26(ddd,J=2.8,6.7,9.9Hz,1H),2.89(t,J=11.1Hz,1H),2.8-2.6(m,2H),2.50(br s,4H),2.3-2.2(m,1H),1.97(br d,J=11.5Hz,4H),1.6-1.6(m,4H),1.25(d,J=6.5Hz,3H)。
实例28A和实例28B
4-[(4R,10bS)-4-甲基-8-(内型-3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮和4-[(4R,10bS)-4-甲基-8-(外型-3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮
根据以下方案合成标题化合物:
步骤1:制备7-[(4R,10bS)-4-甲基-2-(1-甲基-2-氧代-1,8-萘啶-4-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-8-基]-3-氧杂-9-氮杂双环[3.3.1]壬-6-烯-9-甲酸叔丁酯(化合物28.2)
向4-[(4R,10bS)-8-溴-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮(化合物1.2,350mg,823μmol)在二噁烷(18mL)和水(2mL)中的溶液加入7-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-3-氧杂-9-氮杂双环[3.3.1]壬-6-烯-9-甲酸叔丁酯(CAS:1313034-29-5,PharmaBlock,目录号:PB08083,347mg,987μmol)、K2CO3(227mg,1.65mmol)和PdCl2(dppf).DCM加合物(60.2mg,82.3μmol)。将所得混合物在100℃下加热20小时。冷却至室温后,用水(30mL)稀释,并用DCM(60mL)萃取两次。将合并的有机层用盐水洗涤,经Na2SO4干燥、过滤并真空浓缩。残余物通过快速色谱法纯化(硅胶,40g,在DCM中的0%至100%的EtOAc),得到化合物28.2(310mg,75.6%收率)。MS:calc’d570[(M+H)+],测量值为570[(M+H)+]。
步骤2:制备7-[(4R,10bS)-4-甲基-2-(内型-1-甲基-2-氧代-1,8-萘啶-4-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-8-基]-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物28.3)和7-[(4R,10bS)-4-甲基-2-(外型-1-甲基-2-氧代-1,8-萘啶-4-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-8-基]-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物28.4)
将7-[(4R,10bS)-4-甲基-2-(1-甲基-2-氧代-1,8-萘啶-4-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-8-基]-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物28.2,310mg,544μmol)和Pd-C(30mg)在MeOH(50mL)中的混合物在室温用氢气球氢化2小时。滤除催化剂后,将滤液真空浓缩,利用在OX(5μm,250×20mm I.D.)柱上的50%乙醇(0.1%NH3H2O)/CO2将其通过SFC拆分以得到两种单一异构体:化合物28.3(32mg,10.3%收率)和化合物28.4(116mg,37.4%收率)。MS:calc’d 572[(M+H)+],测量值为572[(M+H)+]。化合物28.3和化合物28.4的立体化学由NOSEY测定。
步骤3:制备4-[(4R,10bS)-4-甲基-8-(内型-3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮(实例28A)
向7-[(4R,10bS)-4-甲基-2-(内型-1-甲基-2-氧代-1,8-萘啶-4-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-8-基]-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物28.3,30mg,52.4μmol)的DCM(10mL)溶液加入TFA(5mL)。将反应混合物在室温搅拌2小时,然后浓缩,得到粗产物将其通过制备型HPLC纯化,得到实例28A(19mg,76.9%产率)。MS:calc’d 472[(M+H)+],测量值为472[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.68(dd,J=1.6,4.6Hz,1H),8.36(dd,J=1.7,7.9Hz,1H),7.48(s,1H),7.46-7.41(m,1H),7.41-7.34(m,2H),6.28(s,1H),4.99(dd,J=3.5,10.9Hz,1H),4.79(d,J=13.3Hz,1H),4.43(d,J=13.4Hz,1H),4.21-3.92(m,7H),3.78(s,3H),3.68-3.57(m,3H),3.12-2.94(m,2H),2.29(brdd,J=1.9,8.3Hz,4H),1.47(d,J=6.6Hz,3H)。
步骤4:制备4-[(4R,10bS)-4-甲基-8-(外型-3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮(实例28B)
向7-[(4R,10bS)-4-甲基-2-(外型-1-甲基-2-氧代-1,8-萘啶-4-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-8-基]-3-氧杂-9-氮杂双环[3.3.1]壬烷-9-甲酸叔丁酯(化合物28.4,40mg,69.9μmol)的DCM(10mL)溶液加入TFA(5mL)。将反应混合物在室温搅拌2小时,然后浓缩,得到粗产物将其通过制备型HPLC纯化,得到实例28B(26mg,78.6%产率)。MS:calc’d 472[(M+H)+],测量值为472[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.80-8.53(m,1H),8.43-8.19(m,1H),7.47(s,1H),7.39-7.28(m,3H),6.26(s,1H),4.70-4.56(m,2H),4.16(d,J=13.1Hz,1H),3.99-3.92(m,1H),3.90-3.82(m,4H),3.78-3.65(m,3H),3.78(s,3H),3.61-3.52(m,1H),3.14-3.03(m,1H),3.00-2.87(m,2H),2.53-2.29(m,2H),2.22-1.94(m,2H),1.39(d,J=6.6Hz,3H)。
实例29
4-[(4R,10bS)-8-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-乙基-1,8-萘啶-2-酮
根据以下方案合成标题化合物:
步骤1:制备N-[(3R,4R)-1-[(4R,10bS)-2-苄基-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-8-基]-4-甲氧基-吡咯烷-3-基]氨基甲酸叔丁酯(化合物29.1)
向(4R,10bS)-2-苄基-8-溴-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚(中间体A,800mg,2.24mmol)的二噁烷(35mL)溶液加入((3R,4R)-4-甲氧基吡咯烷-3-基)氨基甲酸叔丁酯(508mg,2.35mmol)、Cs2CO3(2.19g,6.72mmol)和XPhos Pd G2(176mg,224μmol)。将反应混合物在95℃下搅拌过夜。冷却至室温后,将混合物用水(30mL)稀释,并用EA(30mL)萃取三次。将合并的有机层用盐水洗涤,经Na2SO4干燥、过滤并真空浓缩。残余物通过快速色谱法纯化(硅胶,80g,在PE中的50%至100%的EA),得到化合物29.1(870mg,79%收率)。MS:calc’d 493[(M+H)+],测量值为493[(M+H)+]。
步骤2:制备N-[(3R,4R)-1-[(4R,10bS)-4-甲基-1,2,3,4,6,10b-六氢吡嗪并[2,1-a]异吲哚-8-基]-4-甲氧基-吡咯烷-3-基]氨基甲酸叔丁酯(化合物29.2)
将N-[(3R,4R)-1-[(4R,10bS)-2-苄基-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-8-基]-4-甲氧基-吡咯烷-3-基]氨基甲酸叔丁酯(化合物29.1,650mg,1.32mmol)和Pd(OH)2-C(100mg)在MeOH(20mL)中的混合物在室温用氢气球氢化2小时。滤除催化剂后,将滤液真空浓缩,得到粗化合物29.2(531mg,100%收率),其无需进一步纯化直接用于下一步骤。MS:calc’d 403[(M+H)+],测量值为403[(M+H)+]。
步骤3:制备N-[(3R,4R)-1-[(4R,10bS)-2-(1-乙基-2-氧代-1,8-萘啶-4-基)-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-8-基]-4-甲氧基-吡咯烷-3-基]氨基甲酸叔丁酯(化合物29.3)
向N-[(3R,4R)-1-[(4R,10bS)-4-甲基-1,2,3,4,6,10b-六氢吡嗪并[2,1-a]异吲哚-8-基]-4-甲氧基-吡咯烷-3-基]氨基甲酸叔丁酯(化合物29.2,113mg,280μmol)的二噁烷(10mL)溶液加入4-溴-1-乙基-1,8-萘啶-2-酮(中间体C,71mg,280μmol)、Cs2CO3(274mg,840μmol)和RuPhos Pd G2(22mg,28μmol)。将反应混合物在95℃下搅拌过夜。冷却至室温后,将混合物用水(30mL)稀释,并用EA(30mL)萃取三次。将合并的有机层用盐水洗涤,经Na2SO4干燥、过滤并真空浓缩。残余物通过快速色谱法纯化,得到化合物29.3(30mg,18.6%收率)。MS:calc’d 575[(M+H)+],测量值为575[(M+H)+]。
步骤4:制备4-[(4R,10bS)-8-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-乙基-1,8-萘啶-2-酮(实例29)
向N-[(3R,4R)-1-[(4R,10bS)-2-(1-乙基-2-氧代-1,8-萘啶-4-基)-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-8-基]-4-甲氧基-吡咯烷-3-基]氨基甲酸叔丁酯(化合物29.3,30mg,52μmol)的DCM(5mL)溶液加入2,2,2-三氟乙酸(2mL)。将反应混合物在室温搅拌2小时,然后浓缩,得到粗产物将其通过制备型HPLC纯化,得到实例29(16mg,66.2%产率)。)。MS:calc’d 475[(M+H)+],测量值为475[(M+H)+]。1H NMR(400MHz,甲醇-d4)δppm 8.60(dd,J=1.7,4.6Hz,1H),8.26(dd,J=1.6,8.1Hz,1H),7.32-7.23(m,2H),6.70(s,1H),6.65-6.57(m,1H),6.18(s,1H),5.15-5.03(m,1H),4.84-4.80(m,1H),4.46(q,J=7.0Hz,3H),4.13(br d,J=1.2Hz,1H),4.06-3.99(m,1H),3.86-3.81(m,1H),3.77(dd,J=5.9,10.8Hz,1H),3.60(s,2H),3.37(s,4H),3.25(br d,J=3.3Hz,2H),3.14-2.79(m,2H),1.42(d,J=6.6Hz,3H),1.19(t,J=7.0Hz,3H)。
实例30
为了确定具有式(I)或(Ia)或(Ib)的化合物在HEK293-Blue-hTLR-7/8/9细胞测定中的活性,进行了以下测试。
HEK293-Blue-hTLR-7细胞测定:
稳定的HEK293-Blue-hTLR-7细胞系购自InvivoGen(Cat.#:hkb-htlr7,SanDiego,California,USA)。这些细胞最初设计用于通过监测NF-κB活化来研究人TLR7刺激。将SEAP(分泌的胚胎碱性磷酸酶)报告基因置于与五个NF-κB和AP-1结合位点融合的IFN-β最小启动子的控制下。通过用TLR7配体刺激HEK-Blue hTLR7细胞使NF-κB和AP-1活化以诱导SEAP。因此,在配体(诸如R848(Resiquimod))的刺激下孵育20小时,报告基因表达被TLR7拮抗剂降低。使用QUANTI-BlueTM试剂盒(Cat.#:rep-qb1,Invivogen,San Diego,Ca,USA)在640nm波长下测定细胞培养上清液SEAP报告基因的活性,在碱性磷酸酶存在的条件下该检测培养基变成紫色或蓝色。
在含有4.5g/L葡萄糖、50U/mL青霉素、50mg/mL链霉素、100mg/mL Normocin、2mML-谷氨酰胺、10%(v/v)热灭活的胎牛血清的Dulbecco's Modified Eagle培养基(DMEM)的96孔板中以170μL的体积将HEK293-Blue-hTLR7细胞以250,000~450,000个细胞/mL的密度孵育,在上述DMEM中,在最终DMSO存在的条件下以1%的最终稀释度添加20μL供试化合物和10μL的20uM R848,在37℃的CO2培养箱中进行20小时的培养。然后将每个孔中的20μL上清液与180μL Quanti-blue底物溶液在37℃下孵育2小时,并使用分光光度计在620~655nm下读取吸光度。TLR7激活导致下游NF-κB激活的信号传导途径已被广泛接受,因此对类似的报告基因检测方法进行了修改以评估TLR7拮抗剂。
HEK293-Blue-hTLR-8细胞测定:
稳定的HEK293-Blue-hTLR-8细胞系购自InvivoGen(Cat.#:hkb-htlr8,SanDiego,California,USA)。这些细胞最初设计用于通过监测NF-κB活化来研究人TLR8刺激。将SEAP(分泌的胚胎碱性磷酸酶)报告基因置于与五个NF-κB和AP-1结合位点融合的IFN-β最小启动子的控制下。通过用TLR8配体刺激HEK-Blue hTLR8细胞使NF-κB和AP-1活化以诱导SEAP。因此,在配体(诸如R848)的刺激下孵育20小时,报告基因表达被TLR8拮抗剂降低。使用QUANTI-BlueTM试剂盒(Cat.#:rep-qb1,Invivogen,San Diego,Ca,USA)在640nm波长下测定细胞培养上清液SEAP报告基因的活性,在碱性磷酸酶存在的条件下该检测培养基变成紫色或蓝色。
在含有4.5g/L葡萄糖、50U/mL青霉素、50mg/mL链霉素、100mg/mL Normocin、2mML-谷氨酰胺、10%(v/v)热灭活的胎牛血清的Dulbecco's Modified Eagle培养基(DMEM)的96孔板中以170μL的体积将HEK293-Blue-hTLR8细胞以250,000~450,000个细胞/mL的密度孵育,在上述DMEM中,在最终DMSO存在的条件下以1%的最终稀释度添加20μL供试化合物和10μL的60uM R848,在37℃的CO2培养箱中进行20小时的培养。然后将每个孔中的20μL上清液与180μL Quanti-blue底物溶液在37℃下孵育2小时,并使用分光光度计在620~655nm下读取吸光度。TLR8激活导致下游NF-κB激活的信号传导途径已被广泛接受,因此对类似的报告基因检测方法进行了修改以评估TLR8拮抗剂。
HEK293-Blue-hTLR-9细胞测定:
稳定的HEK293-Blue-hTLR-9细胞系购自InvivoGen(Cat.#:hkb-htlr9,SanDiego,California,USA)。这些细胞最初设计用于通过监测NF-κB活化来研究人TLR9刺激。将SEAP(分泌的胚胎碱性磷酸酶)报告基因置于与五个NF-κB和AP-1结合位点融合的IFN-β最小启动子的控制下。通过用TLR9配体刺激HEK-Blue hTLR9细胞使NF-κB和AP-1活化以诱导SEAP。因此,在配体(诸如ODN2006(Cat.#:tlrl-2006-1,Invivogen,San Diego,California,USA))的刺激下孵育20小时,报告基因表达被TLR9拮抗剂降低。使用QUANTI-BlueTM试剂盒(Cat.#:rep-qb1,Invivogen,San Diego,California,USA)在640nm波长下测定细胞培养上清液SEAP报告基因的活性,在碱性磷酸酶存在的条件下该检测培养基变成紫色或蓝色。
HEK293-Blue-hTLR9细胞以250,000~450,000细胞/mL的密度以170μL的体积,在96孔板中在含有4.5g/L葡萄糖、50U/mL青霉素、50mg/mL链霉素、100mg/mL Normocin、2mML-谷氨酰胺、10%(v/v)热灭活的胎牛血清的Dulbecco's Modified Eagle培养基(DMEM)中孵育,其中在1%的最终的DMSO存在下于连续稀释液中添加20μL测试化合物和10μL的20uMODN2006的以上DMEM溶液,在37℃的CO2培养箱中孵育20小时。然后将每个孔中的20μL上清液与180μL Quanti-blue底物溶液在37℃下孵育2小时,并使用分光光度计在620~655nm处读取吸光度。TLR9激活导致下游NF-κB激活的信号传导途径已被广泛接受,因此对类似的报告基因检测方法进行了修改以评估TLR9拮抗剂。
式(I)化合物具有TLR7和/或TLR8抑制活性(IC50值)<0.1μM。此外,大多数化合物还具有<0.4μM的TLR9抑制活性。表1显示了本发明化合物的活性数据。
表1:本发明化合物在HEK293-Blue-hTLR-7/8/9细胞测定中的活性
实例31
人微粒体稳定性测定
将人肝微粒体(目录号:452117,美国康宁)在37℃下于100mM磷酸钾缓冲液(pH7.4)中与受试化合物预孵育10分钟。通过添加NADPH再生系统来引发反应。最终的孵育混合物在100mM磷酸钾缓冲液(pH 7.4)中含1μM供试化合物、0.5mg/mL肝微粒体蛋白、1mMMgCl2、1mM NADP、1单位/mL异柠檬酸脱氢酶和6mM异柠檬酸。在37℃下孵育0、3、6、9、15和30分钟后,将300μL冷ACN(包括内标)添加到100μL孵育混合物中以终止反应。沉淀并离心后,取出100uL上清液并加入300uL水。通过LC-MS/MS测定样品中残留的化合物的量。还制备并分析了零和30分钟无NADPH再生系统的对照。结果分类为:低(<7.0mL/min/kg),中(7.0-16.2mL/min/kg)和高(16.2-23.2mL/min/kg)。测试结果汇总于表2中。
表2:人类微粒体稳定性结果
实例32
hERG通道抑制测定
hERG通道抑制测定是一种高度灵敏的测量,可鉴定表现出与体内心脏毒性相关的hERG抑制作用的化合物。将hERG K+通道克隆到人体内,并在CHO(中国仓鼠卵巢)细胞系中稳定表达。CHOhERG细胞用于膜片钳(电压钳,全细胞)实验。电压模式刺激细胞以激活hERG通道并传导IKhERG电流(hERG通道的快速延迟向外整流钾电流)。细胞稳定几分钟后,以0.1Hz(6bpm)的刺激频率记录IKhERG的振幅和动力学。此后,将测试化合物以增加的浓度加入制剂中。对于每种浓度,都试图达到稳态效果,通常在3-10分钟内达到此效果,此时施加下一个最高浓度。记录每种药物浓度下IKhERG的振幅和动力学,并将其与对照值进行比较(以100%计)。(参考文献:Redfern WS,Carlsson L,Davis AS,Lynch WG,MacKenzie I,PalethorpeS,Siegl PK,Strang I,Sullivan AT,Wallis R,Camm AJ,Hammond TG.2003;Relationships between preclinical cardiac electrophysiology,clinical QTinterval prolongation and torsade de pointes for a broad range of drugs:evidence for a provisional safety margin in drugdevelopment.Cardiovasc.Res.58:32-45,Sanguinetti MC,Tristani-Firouzi M.2006;hERG potassium channels and cardiac arrhythmia.Nature 440:463-469,Webster R,Leishman D,Walker D.2002;Towards a drug concentration effect relationship forQT prolongation and torsades de pointes.Curr.Opin.Drug Discov.Devel.5:116-26).hERG的结果在表3中给出。
表3:hERG结果
Claims (19)
1.一种式(I)化合物,
其中
R1为C1-6烷基;
R2为C1-6烷基;
R3为(C1-6烷氧基C1-6烷基)哌嗪基;(C1-6烷基)2氨基C1-6烷氧基;2,5-二氮杂双环[2.2.1]庚烷基;3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪基;3,8-二氮杂双环[3.2.1]辛烷基;3-氧杂-9-氮杂双环[3.3.1]壬烷基;5-氧杂-2,8-二氮杂螺[3.5]壬烷基;氨基(C1-6烷氧基)哌啶基;氨基(C1-6烷氧基)吡咯烷基;氨基(C1-6烷基)氮杂环丁烷基;氨基(C1-6烷基)哌啶基;氨基(C1-6烷基)吡咯烷基;氨基-1,4-氧氮杂环庚烷基;氨基卤代吡咯烷基;氨基哌啶基;C1-6烷基-2,6-二氮杂螺[3.3]庚烷基;C1-6烷基哌嗪基;吗啉基C3-7环烷基;哌嗪基;哌啶基或吡咯烷基;
或其药用盐。
2.一种式(Ia)化合物,
其中
R1为C1-6烷基;
R2为C1-6烷基;
R3为(C1-6烷氧基C1-6烷基)哌嗪基;(C1-6烷基)2氨基C1-6烷氧基;2,5-二氮杂双环[2.2.1]庚烷基;3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪基;3,8-二氮杂双环[3.2.1]辛烷基;3-氧杂-9-氮杂双环[3.3.1]壬烷基;5-氧杂-2,8-二氮杂螺[3.5]壬烷基;氨基(C1-6烷氧基)哌啶基;氨基(C1-6烷氧基)吡咯烷基;氨基(C1-6烷基)氮杂环丁烷基;氨基(C1-6烷基)哌啶基;氨基(C1-6烷基)吡咯烷基;氨基-1,4-氧氮杂环庚烷基;氨基卤代吡咯烷基;氨基哌啶基;C1-6烷基-2,6-二氮杂螺[3.3]庚烷基;C1-6烷基哌嗪基;吗啉基C3-7环烷基;哌嗪基;哌啶基或吡咯烷基;
或其药用盐。
3.根据权利要求1或2所述的化合物,其中
R1为甲基或乙基;
R2为甲基;
R3为2-(二甲基氨基)乙氧基;2-(甲氧基甲基)哌嗪-1-基;2,5-二氮杂双环[2.2.1]庚烷-2-基;2-甲基哌嗪-1-基;3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-6-基;3,8-二氮杂双环[3.2.1]辛烷-3-基;3-氨基-1-哌啶基;3-氨基-3-甲基-1-哌啶基;3-氨基-3-甲基-氮杂环丁烷-1-基;3-氨基-3-甲基-吡咯烷-1-基;3-氨基-4-氟-吡咯烷-1-基;3-氨基-4-甲氧基-1-哌啶基;3-氨基-4-甲氧基-吡咯烷-1-基;3-甲基哌嗪-1-基;3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基;3-哌啶基;4-氨基-3-甲氧基-1-哌啶基;4-氨基-4-甲基-1-哌啶基;4-吗啉代环己基;4-哌啶基;5-氧杂-2,8-二氮杂螺[3.5]壬烷-2-基;5-氧杂-2,8-二氮杂螺[3.5]壬烷-8-基;6-氨基-1,4-氧氮杂环庚烷-4-基;6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基;哌嗪-1-基或吡咯烷-3-基;
或其药用盐。
4.根据权利要求1或2所述的化合物,其中R3为氨基(C1-6烷氧基)吡咯烷基;氨基(C1-6烷基)哌啶基;氨基-1,4-氧氮杂环庚烷基;氨基哌啶基;C1-6烷基-2,6-二氮杂螺[3.3]庚烷基;C1-6烷基哌嗪基;C1-6烷基哌嗪基;吗啉基C3-7环烷基;哌嗪基;哌啶基或3-氧杂-9-氮杂双环[3.3.1]壬烷基。
5.根据权利要求4所述的化合物,其中R3为3-氨基-1-哌啶基;3-氨基-3-甲基-1-哌啶基;3-氨基-4-甲氧基-吡咯烷-1-基;3-甲基哌嗪-1-基;4-氨基-4-甲基-1-哌啶基;4-吗啉代环己基;4-哌啶基;6-氨基-1,4-氧氮杂环庚烷-4-基;6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基;哌嗪-1-基或3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基。
6.根据权利要求1或2所述的化合物,其中
R1为C1-6烷基;
R2为C1-6烷基;
R3为氨基(C1-6烷氧基)吡咯烷基;氨基(C1-6烷基)哌啶基;氨基-1,4-氧氮杂环庚烷基;氨基哌啶基;C1-6烷基-2,6-二氮杂螺[3.3]庚烷基;C1-6烷基哌嗪基;C1-6烷基哌嗪基;吗啉基C3-7环烷基;哌嗪基;哌啶基或3-氧杂-9-氮杂双环[3.3.1]壬烷基;
或其药用盐。
7.根据权利要求6所述的化合物,其中
R1为甲基;
R2为甲基;
R3为3-氨基-1-哌啶基;3-氨基-3-甲基-1-哌啶基3-氨基-4-甲氧基-吡咯烷-1-基;3-甲基哌嗪-1-基;4-氨基-4-甲基-1-哌啶基;4-吗啉代环己基;4-哌啶基;6-氨基-1,4-氧氮杂环庚烷-4-基;6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基;哌嗪-1-基或3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基;
或其药用盐。
8.一种化合物,其选自:
4-[(4R,10bS)-8-(3-氨基-3-甲基-氮杂环丁烷-1-基)-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-(6-甲基-2,6-二氮杂螺[3.3]庚烷-2-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-(5-氧杂-2,8-二氮杂螺[3.5]壬烷-2-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(3R)-3-氨基-3-甲基-吡咯烷-1-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(4aR,7aR)-3,4,4a,5,7,7a-六氢-2H-吡咯并[3,4-b][1,4]噁嗪-6-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(3R,4S)-3-氨基-4-氟-吡咯烷-1-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(3S,4S)-4-氨基-3-甲氧基-1-哌啶基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(3S,4S)-3-氨基-4-甲氧基-1-哌啶基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(2S)-2-(甲氧基甲基)哌嗪-1-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-(5-氧杂-2,8-二氮杂螺[3.5]壬烷-8-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-哌嗪-1-基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-[(3S)-3-甲基哌嗪-1-基]-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-[(3R)-3-甲基哌嗪-1-基]-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(3S)-3-氨基-3-甲基-1-哌啶基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(3R)-3-氨基-1-哌啶基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-[(2R)-2-甲基哌嗪-1-基]-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-(4-氨基-4-甲基-1-哌啶基)-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(1R,4R)-2,5-二氮杂双环[2.2.1]庚烷-2-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[(6R)-6-氨基-1,4-氧氮杂环庚烷-4-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-8-[2-(二甲基氨基)乙氧基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-(4-哌啶基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-(3-哌啶基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-吡咯烷-3-基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-(反式-4-吗啉代环己基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-(顺式-4-吗啉代环己基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-(内型-3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;
4-[(4R,10bS)-4-甲基-8-(外型-3-氧杂-9-氮杂双环[3.3.1]壬烷-7-基)-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-甲基-1,8-萘啶-2-酮;和
4-[(4R,10bS)-8-[(3R,4R)-3-氨基-4-甲氧基-吡咯烷-1-基]-4-甲基-3,4,6,10b-四氢-1H-吡嗪并[2,1-a]异吲哚-2-基]-1-乙基-1,8-萘啶-2-酮;
或其药用盐、对映体或非对映体。
10.根据权利要求1至8中任一项所述的化合物或药用盐、对映体或非对映体,其用作治疗活性物质。
11.一种药物组合物,其包含根据权利要求1至8中任一项所述的化合物以及治疗惰性载体。
12.根据权利要求1至8中任一项所述的化合物用于治疗或预防系统性红斑狼疮或狼疮性肾炎的用途。
13.根据权利要求1至8中任一项所述的化合物用于制备药物的用途,所述药物用于治疗或预防系统性红斑狼疮或狼疮性肾炎。
14.根据权利要求1至8中任一项所述的化合物作为TLR7或TLR8或TLR9拮抗剂的用途。
15.根据权利要求1至8中任一项所述的化合物作为TLR7和TLR8和TLR9拮抗剂的用途。
16.根据权利要求1至8中任一项所述的化合物用于制备药物的用途,所述药物用于TLR7和TLR8和TLR9拮抗剂。
17.根据权利要求1至8中任一项所述的化合物或药用盐、对映体或非对映体,其用于治疗或预防系统性红斑狼疮或狼疮性肾炎。
18.根据权利要求1至8中任一项所述的化合物或药用盐、对映体或非对映体,其根据权利要求9所述的方法制造。
19.一种用于治疗或预防系统性红斑狼疮或狼疮性肾炎的方法,所述方法包括施用治疗有效量的如权利要求1至8中任一项所定义的化合物。
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PCT/EP2020/083113 WO2021105072A1 (en) | 2019-11-26 | 2020-11-24 | 1,8-naphthyridin-2-one compounds for the treatment of autoimmune disease |
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US (1) | US20230041743A1 (zh) |
EP (1) | EP4065586A1 (zh) |
JP (1) | JP2023503165A (zh) |
KR (1) | KR20220106126A (zh) |
CN (1) | CN114728987A (zh) |
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AU (1) | AU2020393367A1 (zh) |
BR (1) | BR112022009856A2 (zh) |
CA (1) | CA3156457A1 (zh) |
CO (1) | CO2022006942A2 (zh) |
CR (1) | CR20220231A (zh) |
IL (1) | IL291640A (zh) |
MX (1) | MX2022005912A (zh) |
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US4273773A (en) * | 1979-09-24 | 1981-06-16 | American Home Products Corporation | Antihypertensive tricyclic isoindole derivatives |
WO2014123167A1 (ja) * | 2013-02-08 | 2014-08-14 | 日産化学工業株式会社 | 3環性ピロロピリジン化合物及びjak阻害剤 |
WO2017106607A1 (en) * | 2015-12-17 | 2017-06-22 | Merck Patent Gmbh | Polycyclic tlr7/8 antagonists and use thereof in the treatment of immune disorders |
US20180327411A1 (en) * | 2017-04-21 | 2018-11-15 | Kyn Therapeutics | Indole ahr inhibitors and uses thereof |
CN110475777A (zh) * | 2017-03-30 | 2019-11-19 | 豪夫迈·罗氏有限公司 | 用于治疗和预防细菌感染的新吡啶并[2,3-b]吲哚化合物 |
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2020
- 2020-11-24 BR BR112022009856A patent/BR112022009856A2/pt not_active Application Discontinuation
- 2020-11-24 US US17/780,123 patent/US20230041743A1/en active Pending
- 2020-11-24 PE PE2022000770A patent/PE20221026A1/es unknown
- 2020-11-24 MX MX2022005912A patent/MX2022005912A/es unknown
- 2020-11-24 AR ARP200103253A patent/AR120540A1/es unknown
- 2020-11-24 CA CA3156457A patent/CA3156457A1/en active Pending
- 2020-11-24 KR KR1020227017383A patent/KR20220106126A/ko unknown
- 2020-11-24 WO PCT/EP2020/083113 patent/WO2021105072A1/en unknown
- 2020-11-24 AU AU2020393367A patent/AU2020393367A1/en active Pending
- 2020-11-24 EP EP20812250.7A patent/EP4065586A1/en active Pending
- 2020-11-24 JP JP2022530733A patent/JP2023503165A/ja active Pending
- 2020-11-24 CN CN202080079547.9A patent/CN114728987A/zh active Pending
- 2020-11-25 TW TW109141393A patent/TW202134238A/zh unknown
-
2022
- 2022-03-23 IL IL291640A patent/IL291640A/en unknown
- 2022-05-25 CO CONC2022/0006942A patent/CO2022006942A2/es unknown
- 2022-11-24 CR CR20220231A patent/CR20220231A/es unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4273773A (en) * | 1979-09-24 | 1981-06-16 | American Home Products Corporation | Antihypertensive tricyclic isoindole derivatives |
WO2014123167A1 (ja) * | 2013-02-08 | 2014-08-14 | 日産化学工業株式会社 | 3環性ピロロピリジン化合物及びjak阻害剤 |
WO2017106607A1 (en) * | 2015-12-17 | 2017-06-22 | Merck Patent Gmbh | Polycyclic tlr7/8 antagonists and use thereof in the treatment of immune disorders |
CN110475777A (zh) * | 2017-03-30 | 2019-11-19 | 豪夫迈·罗氏有限公司 | 用于治疗和预防细菌感染的新吡啶并[2,3-b]吲哚化合物 |
US20180327411A1 (en) * | 2017-04-21 | 2018-11-15 | Kyn Therapeutics | Indole ahr inhibitors and uses thereof |
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CA3156457A1 (en) | 2021-06-03 |
AR120540A1 (es) | 2022-02-23 |
BR112022009856A2 (pt) | 2022-08-02 |
KR20220106126A (ko) | 2022-07-28 |
TW202134238A (zh) | 2021-09-16 |
MX2022005912A (es) | 2022-06-24 |
WO2021105072A1 (en) | 2021-06-03 |
US20230041743A1 (en) | 2023-02-09 |
JP2023503165A (ja) | 2023-01-26 |
IL291640A (en) | 2022-05-01 |
CO2022006942A2 (es) | 2022-06-10 |
EP4065586A1 (en) | 2022-10-05 |
AU2020393367A1 (en) | 2022-04-14 |
CR20220231A (es) | 2022-06-27 |
PE20221026A1 (es) | 2022-06-16 |
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