WO2023025109A1 - 一类Toll样受体抑制剂及其制备和应用 - Google Patents
一类Toll样受体抑制剂及其制备和应用 Download PDFInfo
- Publication number
- WO2023025109A1 WO2023025109A1 PCT/CN2022/114038 CN2022114038W WO2023025109A1 WO 2023025109 A1 WO2023025109 A1 WO 2023025109A1 CN 2022114038 W CN2022114038 W CN 2022114038W WO 2023025109 A1 WO2023025109 A1 WO 2023025109A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- alkyl
- group
- methyl
- mmol
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 190
- 229940125970 Toll-Like Receptor inhibitor Drugs 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 762
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 10
- 208000037976 chronic inflammation Diseases 0.000 claims abstract description 4
- 208000037893 chronic inflammatory disorder Diseases 0.000 claims abstract description 3
- -1 C 1 -C 6 alkoxy Chemical group 0.000 claims description 143
- 125000000217 alkyl group Chemical group 0.000 claims description 78
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 41
- 229910052757 nitrogen Inorganic materials 0.000 claims description 38
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 229910052799 carbon Inorganic materials 0.000 claims description 31
- 125000003545 alkoxy group Chemical group 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 25
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 24
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 21
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 125000005842 heteroatom Chemical group 0.000 claims description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 229920006395 saturated elastomer Polymers 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 16
- 239000000126 substance Substances 0.000 claims description 16
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 125000002950 monocyclic group Chemical group 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000003003 spiro group Chemical group 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 9
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 8
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 8
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000004043 oxo group Chemical group O=* 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 4
- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 4
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 229910052701 rubidium Inorganic materials 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 4
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims description 4
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
- 208000005777 Lupus Nephritis Diseases 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 101000669402 Homo sapiens Toll-like receptor 7 Proteins 0.000 abstract description 17
- 102100039390 Toll-like receptor 7 Human genes 0.000 abstract description 16
- 101000800483 Homo sapiens Toll-like receptor 8 Proteins 0.000 abstract description 13
- 102100033110 Toll-like receptor 8 Human genes 0.000 abstract description 12
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 580
- 238000004949 mass spectrometry Methods 0.000 description 283
- 239000007787 solid Substances 0.000 description 199
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 175
- 238000005481 NMR spectroscopy Methods 0.000 description 142
- 230000015572 biosynthetic process Effects 0.000 description 105
- 238000003786 synthesis reaction Methods 0.000 description 105
- 239000011541 reaction mixture Substances 0.000 description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 65
- 239000012074 organic phase Substances 0.000 description 65
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 65
- 239000012043 crude product Substances 0.000 description 64
- 238000006243 chemical reaction Methods 0.000 description 59
- 239000000243 solution Substances 0.000 description 59
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 52
- 238000010898 silica gel chromatography Methods 0.000 description 51
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- 239000005457 ice water Substances 0.000 description 39
- 238000003756 stirring Methods 0.000 description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 35
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 31
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 30
- 238000010791 quenching Methods 0.000 description 28
- 238000000605 extraction Methods 0.000 description 27
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 25
- 239000003921 oil Substances 0.000 description 24
- 235000019198 oils Nutrition 0.000 description 24
- JUIKUQOUMZUFQT-UHFFFAOYSA-N 2-bromoacetamide Chemical compound NC(=O)CBr JUIKUQOUMZUFQT-UHFFFAOYSA-N 0.000 description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 17
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 15
- CIIFKVFOVFJZDM-UHFFFAOYSA-N quinoline-8-carbonitrile Chemical compound C1=CN=C2C(C#N)=CC=CC2=C1 CIIFKVFOVFJZDM-UHFFFAOYSA-N 0.000 description 15
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 12
- QPIOVNJLOVNTMW-UHFFFAOYSA-N 2-bromo-n,n-dimethylacetamide Chemical compound CN(C)C(=O)CBr QPIOVNJLOVNTMW-UHFFFAOYSA-N 0.000 description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical group C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 10
- 230000014759 maintenance of location Effects 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 9
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 102000002689 Toll-like receptor Human genes 0.000 description 9
- 108020000411 Toll-like receptor Proteins 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
- KIDIJBYYGAEULX-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound N#CC1=CC=CC2=CC=NN12 KIDIJBYYGAEULX-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- DAYKHFAZOORREQ-UHFFFAOYSA-N 5-bromoquinoline-8-carbonitrile Chemical compound C1=CC=C2C(Br)=CC=C(C#N)C2=N1 DAYKHFAZOORREQ-UHFFFAOYSA-N 0.000 description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 5
- QYMGRIFMUQCAJW-UHFFFAOYSA-N 1,2-dihydropyrazine Chemical compound C1NC=CN=C1 QYMGRIFMUQCAJW-UHFFFAOYSA-N 0.000 description 5
- VXACJVJUOOZPGX-UHFFFAOYSA-N 3,4-difluoropyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound FC=1C=NN2C=1C(=CC=C2C#N)F VXACJVJUOOZPGX-UHFFFAOYSA-N 0.000 description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- BASAHWQUEPWGSA-VIFPVBQESA-N (2s)-1-[(4-methoxyphenyl)methylamino]propan-2-ol Chemical compound COC1=CC=C(CNC[C@H](C)O)C=C1 BASAHWQUEPWGSA-VIFPVBQESA-N 0.000 description 4
- HXKKHQJGJAFBHI-VKHMYHEASA-N (2s)-1-aminopropan-2-ol Chemical compound C[C@H](O)CN HXKKHQJGJAFBHI-VKHMYHEASA-N 0.000 description 4
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 4
- OKRZRAGANCLTGI-UHFFFAOYSA-N 4-fluoropyrazolo[1,5-a]pyridine-7-carbonitrile Chemical compound Fc1ccc(C#N)n2nccc12 OKRZRAGANCLTGI-UHFFFAOYSA-N 0.000 description 4
- BPGWWRPPLVFBGK-UHFFFAOYSA-N 5-chloro-8-iodo-[1,2,4]triazolo[1,5-a]pyridine Chemical compound ClC1=CC=C(I)C2=NC=NN12 BPGWWRPPLVFBGK-UHFFFAOYSA-N 0.000 description 4
- YQXNCQIIKGZOMK-UHFFFAOYSA-N 6-[4-[7-tert-butyl-5-(4-chloro-3-fluorophenyl)furo[3,2-b]pyridine-2-carbonyl]-3,3-dimethylpiperazin-1-yl]-2,4-dimethylpyridine-3-carboxylic acid Chemical compound C(C)(C)(C)C1=C2C(=NC(=C1)C1=CC(=C(C=C1)Cl)F)C=C(O2)C(=O)N1C(CN(CC1)C1=CC(=C(C(=N1)C)C(=O)O)C)(C)C YQXNCQIIKGZOMK-UHFFFAOYSA-N 0.000 description 4
- QDQJIDDXPACPKY-UHFFFAOYSA-N 6-bromo-1h-indazole-3-carboxylic acid Chemical compound BrC1=CC=C2C(C(=O)O)=NNC2=C1 QDQJIDDXPACPKY-UHFFFAOYSA-N 0.000 description 4
- YMKMENRYNAOOGP-UHFFFAOYSA-N 7-bromo-3,4-difluoropyrazolo[1,5-a]pyridine Chemical compound BrC1=CC=C(C=2N1N=CC=2F)F YMKMENRYNAOOGP-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 108700003601 dimethylglycine Proteins 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 4
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- 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 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 4
- WTMZYKCXBXPVPT-LURJTMIESA-N (2s)-4,4-difluoro-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1C(O)=O WTMZYKCXBXPVPT-LURJTMIESA-N 0.000 description 3
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 3
- LNAHWKUKPHEFST-UHFFFAOYSA-N 1-(6-bromo-1h-indazol-3-yl)ethanone Chemical compound BrC1=CC=C2C(C(=O)C)=NNC2=C1 LNAHWKUKPHEFST-UHFFFAOYSA-N 0.000 description 3
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 3
- GGXIOSCUHASSOL-UHFFFAOYSA-N 6-chloro-3-iodopyridin-2-amine Chemical compound NC1=NC(Cl)=CC=C1I GGXIOSCUHASSOL-UHFFFAOYSA-N 0.000 description 3
- GXXHPFBEHKCPMC-UHFFFAOYSA-N 7-bromo-4-fluoropyrazolo[1,5-a]pyridine Chemical compound Fc1ccc(Br)n2nccc12 GXXHPFBEHKCPMC-UHFFFAOYSA-N 0.000 description 3
- GPIFQUNBVBLVBH-UHFFFAOYSA-N 7-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carboxylic acid Chemical compound BrC1=CC=C(C=2N1N=CC=2C(=O)O)F GPIFQUNBVBLVBH-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 3
- 101150003085 Pdcl gene Proteins 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 239000006143 cell culture medium Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- IYTUPCRBGNFVOI-UHFFFAOYSA-N ethyl 7-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carboxylate Chemical compound CCOC(=O)c1cnn2c(Br)ccc(F)c12 IYTUPCRBGNFVOI-UHFFFAOYSA-N 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 3
- 230000008506 pathogenesis Effects 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 239000011698 potassium fluoride Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- UWNNZXDNLPNGQJ-UHFFFAOYSA-N tert-butyl 2-ethylhexanoate Chemical compound CCCCC(CC)C(=O)OC(C)(C)C UWNNZXDNLPNGQJ-UHFFFAOYSA-N 0.000 description 3
- FCRTVZBUJDHXNR-UHFFFAOYSA-N tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC2NC1C2 FCRTVZBUJDHXNR-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 125000001425 triazolyl group Chemical group 0.000 description 3
- 229910052720 vanadium Inorganic materials 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- WTRIMJTZOOLIFZ-UHFFFAOYSA-N 2-bromo-2-methylpropanamide Chemical compound CC(C)(Br)C(N)=O WTRIMJTZOOLIFZ-UHFFFAOYSA-N 0.000 description 2
- JLVWULWMWNADPD-UHFFFAOYSA-M 2-bromo-5-fluoropyridin-1-ium-1-amine 2,4,6-trimethylbenzenesulfonate Chemical compound CC1=C(C(=CC(=C1)C)C)S(=O)(=O)[O-].BrC1=[N+](C=C(C=C1)F)N JLVWULWMWNADPD-UHFFFAOYSA-M 0.000 description 2
- LBVZINOLAFTARU-UHFFFAOYSA-N 2-bromo-n-methylacetamide Chemical compound CNC(=O)CBr LBVZINOLAFTARU-UHFFFAOYSA-N 0.000 description 2
- LAQJGAKLLZAETL-UHFFFAOYSA-N 2h-pyrazin-3-one Chemical compound O=C1CN=CC=N1 LAQJGAKLLZAETL-UHFFFAOYSA-N 0.000 description 2
- DPGSPRJLAZGUBQ-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane Substances CC1(C)OB(C=C)OC1(C)C DPGSPRJLAZGUBQ-UHFFFAOYSA-N 0.000 description 2
- OIUXEDBYFWPCLF-UHFFFAOYSA-N 6-bromo-5-fluoro-1h-indole Chemical compound C1=C(Br)C(F)=CC2=C1NC=C2 OIUXEDBYFWPCLF-UHFFFAOYSA-N 0.000 description 2
- WJQWKNTUPQCTRF-UHFFFAOYSA-N 6-bromo-N-methoxy-N-methyl-1H-indazole-3-carboxamide Chemical compound CON(C)C(=O)c1n[nH]c2cc(Br)ccc12 WJQWKNTUPQCTRF-UHFFFAOYSA-N 0.000 description 2
- DZDYYVVNKYKPBE-UHFFFAOYSA-N 6-chloro-3-iodo-1-(oxan-2-yl)pyrazolo[3,4-b]pyridine Chemical compound C12=NC(Cl)=CC=C2C(I)=NN1C1CCCCO1 DZDYYVVNKYKPBE-UHFFFAOYSA-N 0.000 description 2
- ZMQMWKWEXIQSJF-UHFFFAOYSA-N 6-chloro-3-iodo-2h-pyrazolo[3,4-b]pyridine Chemical compound ClC1=CC=C2C(I)=NNC2=N1 ZMQMWKWEXIQSJF-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 101000831496 Homo sapiens Toll-like receptor 3 Proteins 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 102100024324 Toll-like receptor 3 Human genes 0.000 description 2
- 241000009298 Trigla lyra Species 0.000 description 2
- JOSCNYCOYXTLTN-GFCCVEGCSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-[(3R)-3-(hydroxymethyl)pyrrolidin-1-yl]methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1C[C@@H](CC1)CO JOSCNYCOYXTLTN-GFCCVEGCSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- NHCGQXPQGHFCPN-UHFFFAOYSA-N amino methanesulfonate Chemical compound CS(=O)(=O)ON NHCGQXPQGHFCPN-UHFFFAOYSA-N 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- VEZXCJBBBCKRPI-UHFFFAOYSA-N beta-propiolactone Chemical compound O=C1CCO1 VEZXCJBBBCKRPI-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052750 molybdenum Inorganic materials 0.000 description 2
- 239000011733 molybdenum Substances 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 2
- FSDNTQSJGHSJBG-UHFFFAOYSA-N piperidine-4-carbonitrile Chemical compound N#CC1CCNCC1 FSDNTQSJGHSJBG-UHFFFAOYSA-N 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 235000003270 potassium fluoride Nutrition 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- OZIIJRIDLMERFZ-UHFFFAOYSA-N pyrazolo[1,5-a]pyrazine Chemical compound N1=C[CH]N2N=C=CC2=C1 OZIIJRIDLMERFZ-UHFFFAOYSA-N 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- DVMUNQAGXAMHOR-UHFFFAOYSA-N tert-butyl 2,2-dimethylpiperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1(C)C DVMUNQAGXAMHOR-UHFFFAOYSA-N 0.000 description 2
- XNLYPHAMXHERHS-UHFFFAOYSA-N tert-butyl 4,7-diazaspiro[2.5]octane-4-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC11CC1 XNLYPHAMXHERHS-UHFFFAOYSA-N 0.000 description 2
- UEYNRRQJJHZENW-UHFFFAOYSA-N tert-butyl n-(6-chloropyridin-2-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CC(Cl)=N1 UEYNRRQJJHZENW-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- BHHYHSUAOQUXJK-UHFFFAOYSA-L zinc fluoride Chemical compound F[Zn]F BHHYHSUAOQUXJK-UHFFFAOYSA-L 0.000 description 2
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- JRHPOFJADXHYBR-HTQZYQBOSA-N (1r,2r)-1-n,2-n-dimethylcyclohexane-1,2-diamine Chemical compound CN[C@@H]1CCCC[C@H]1NC JRHPOFJADXHYBR-HTQZYQBOSA-N 0.000 description 1
- LKKCSUHCVGCGFA-KGZKBUQUSA-N (1r,2r)-2-aminocyclohexan-1-ol;hydrochloride Chemical compound Cl.N[C@@H]1CCCC[C@H]1O LKKCSUHCVGCGFA-KGZKBUQUSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 description 1
- YGWZXQOYEBWUTH-BQBZGAKWSA-N (2s,4s)-4-fluoro-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1C(O)=O YGWZXQOYEBWUTH-BQBZGAKWSA-N 0.000 description 1
- ZWHOTPNCEFWATE-CQSZACIVSA-N (3R)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylpyrrolidine-1-carboxamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@H]1CN(CC1)C(=O)NC1=CC=CC=C1 ZWHOTPNCEFWATE-CQSZACIVSA-N 0.000 description 1
- MAYZWDRUFKUGGP-VIFPVBQESA-N (3s)-1-[5-tert-butyl-3-[(1-methyltetrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-yl]pyrrolidin-3-ol Chemical compound CN1N=NN=C1CN1C2=NC(C(C)(C)C)=NC(N3C[C@@H](O)CC3)=C2N=N1 MAYZWDRUFKUGGP-VIFPVBQESA-N 0.000 description 1
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- MOWXJLUYGFNTAL-DEOSSOPVSA-N (s)-[2-chloro-4-fluoro-5-(7-morpholin-4-ylquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl)methanol Chemical compound N1=NC(OC)=CC=C1[C@@H](O)C1=CC(C=2C3=CC=C(C=C3N=CN=2)N2CCOCC2)=C(F)C=C1Cl MOWXJLUYGFNTAL-DEOSSOPVSA-N 0.000 description 1
- HDPNBNXLBDFELL-UHFFFAOYSA-N 1,1,1-trimethoxyethane Chemical compound COC(C)(OC)OC HDPNBNXLBDFELL-UHFFFAOYSA-N 0.000 description 1
- OQJVXNHMUWQQEW-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrazine Chemical compound C1CNC=CN1 OQJVXNHMUWQQEW-UHFFFAOYSA-N 0.000 description 1
- YUCBLVFHJWOYDN-HVLQGHBFSA-N 1,4-bis[(s)-[(2r,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]phthalazine Chemical compound C1=C(OC)C=C2C([C@H](OC=3C4=CC=CC=C4C(O[C@H]([C@@H]4N5CC[C@H]([C@H](C5)CC)C4)C=4C5=CC(OC)=CC=C5N=CC=4)=NN=3)[C@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 YUCBLVFHJWOYDN-HVLQGHBFSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- APWRZPQBPCAXFP-UHFFFAOYSA-N 1-(1-oxo-2H-isoquinolin-5-yl)-5-(trifluoromethyl)-N-[2-(trifluoromethyl)pyridin-4-yl]pyrazole-4-carboxamide Chemical compound O=C1NC=CC2=C(C=CC=C12)N1N=CC(=C1C(F)(F)F)C(=O)NC1=CC(=NC=C1)C(F)(F)F APWRZPQBPCAXFP-UHFFFAOYSA-N 0.000 description 1
- YJYMYJRAQYREBT-UHFFFAOYSA-N 1-(4-methylphenyl)sulfonylimidazole Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C=NC=C1 YJYMYJRAQYREBT-UHFFFAOYSA-N 0.000 description 1
- RAVIQFQJZMTUBX-AWEZNQCLSA-N 1-[(3S)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxypiperidin-1-yl]-2-(3,4-dichlorophenyl)ethanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@@H]1CN(CCC1)C(CC1=CC(=C(C=C1)Cl)Cl)=O RAVIQFQJZMTUBX-AWEZNQCLSA-N 0.000 description 1
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 1
- XFQPQSJDMJVOBN-UHFFFAOYSA-N 1-[4-amino-2-(ethylaminomethyl)imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F.C1=CC=CC2=C(N(C(CNCC)=N3)CC(C)(C)O)C3=C(N)N=C21 XFQPQSJDMJVOBN-UHFFFAOYSA-N 0.000 description 1
- OZHIYEINSCNALY-UHFFFAOYSA-N 1-aminobutan-1-ol Chemical compound CCCC(N)O OZHIYEINSCNALY-UHFFFAOYSA-N 0.000 description 1
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical compound C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 description 1
- DKWNYTKOLIZNAX-UHFFFAOYSA-N 1-chloro-2-methylsulfonylethane Chemical compound CS(=O)(=O)CCCl DKWNYTKOLIZNAX-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZHXUWDPHUQHFOV-UHFFFAOYSA-N 2,5-dibromopyridine Chemical compound BrC1=CC=C(Br)N=C1 ZHXUWDPHUQHFOV-UHFFFAOYSA-N 0.000 description 1
- XNIOWJUQPMKCIJ-UHFFFAOYSA-N 2-(benzylamino)ethanol Chemical compound OCCNCC1=CC=CC=C1 XNIOWJUQPMKCIJ-UHFFFAOYSA-N 0.000 description 1
- UXALHMXBHIKAJM-UHFFFAOYSA-N 2-bromo-1-(3,3-difluoroazetidin-1-yl)ethanone Chemical compound BrCC(=O)N1CC(C1)(F)F UXALHMXBHIKAJM-UHFFFAOYSA-N 0.000 description 1
- SPHXSIXITGVYAA-UHFFFAOYSA-N 2-bromo-1-pyrrolidin-1-ylethanone Chemical compound BrCC(=O)N1CCCC1 SPHXSIXITGVYAA-UHFFFAOYSA-N 0.000 description 1
- USOQQXOBLQDCDD-UHFFFAOYSA-N 2-bromo-5-fluoropyridin-1-ium-1-amine Chemical compound BrC1=[N+](C=C(C=C1)F)N USOQQXOBLQDCDD-UHFFFAOYSA-N 0.000 description 1
- UODINHBLNPPDPD-UHFFFAOYSA-N 2-bromo-5-fluoropyridine Chemical compound FC1=CC=C(Br)N=C1 UODINHBLNPPDPD-UHFFFAOYSA-N 0.000 description 1
- DEJUUKULVAIMNF-UHFFFAOYSA-N 2-chloro-5-iodopyridin-4-amine Chemical compound NC1=CC(Cl)=NC=C1I DEJUUKULVAIMNF-UHFFFAOYSA-N 0.000 description 1
- REEJIAYBFVLNQD-UHFFFAOYSA-N 2-chloro-N-(3,3-difluorocyclobutyl)acetamide Chemical compound ClCC(=O)NC1CC(C1)(F)F REEJIAYBFVLNQD-UHFFFAOYSA-N 0.000 description 1
- SVDDJQGVOFZBNX-UHFFFAOYSA-N 2-chloroethyl carbonochloridate Chemical compound ClCCOC(Cl)=O SVDDJQGVOFZBNX-UHFFFAOYSA-N 0.000 description 1
- PGHKJMVOHWKSLJ-UHFFFAOYSA-N 2-methoxyethyl n-(2-methoxyethoxycarbonylimino)carbamate Chemical compound COCCOC(=O)N=NC(=O)OCCOC PGHKJMVOHWKSLJ-UHFFFAOYSA-N 0.000 description 1
- JGHDTAFOBLEIFK-UHFFFAOYSA-N 2-pyrrolidin-1-ylacetyl chloride Chemical compound ClC(=O)CN1CCCC1 JGHDTAFOBLEIFK-UHFFFAOYSA-N 0.000 description 1
- WJKMUGYQMMXILX-UHFFFAOYSA-N 2-trimethylsilylacetonitrile Chemical compound C[Si](C)(C)CC#N WJKMUGYQMMXILX-UHFFFAOYSA-N 0.000 description 1
- VQEHZPGBDDJXAO-UHFFFAOYSA-N 2h-pyrazolo[3,4-b]pyridine-3-carboxamide Chemical compound C1=CC=C2C(C(=O)N)=NNC2=N1 VQEHZPGBDDJXAO-UHFFFAOYSA-N 0.000 description 1
- IKMRMBZUQPSGDF-UHFFFAOYSA-N 3,4,5-trimethylbenzenesulfonyl chloride Chemical compound CC1=CC(S(Cl)(=O)=O)=CC(C)=C1C IKMRMBZUQPSGDF-UHFFFAOYSA-N 0.000 description 1
- YVHBSYTYLQYTOU-UHFFFAOYSA-N 3,6-diazabicyclo[3.1.1]heptane Chemical compound C1NCC2CC1N2 YVHBSYTYLQYTOU-UHFFFAOYSA-N 0.000 description 1
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 1
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 1
- WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 1
- XZZXVOBSGWDZQY-UHFFFAOYSA-N 4-bromo-1-methyl-1,8-naphthyridin-2-one Chemical compound N1(C)C(=O)C=C(C2=C1N=CC=C2)Br XZZXVOBSGWDZQY-UHFFFAOYSA-N 0.000 description 1
- IMOLPSNRLZLWQR-UHFFFAOYSA-N 4-bromo-2,3-difluorobenzaldehyde Chemical compound FC1=C(F)C(C=O)=CC=C1Br IMOLPSNRLZLWQR-UHFFFAOYSA-N 0.000 description 1
- BAQKUNMKVAPWGU-UHFFFAOYSA-N 4-bromopyridin-2-amine Chemical compound NC1=CC(Br)=CC=N1 BAQKUNMKVAPWGU-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- IRPVABHDSJVBNZ-RTHVDDQRSA-N 5-[1-(cyclopropylmethyl)-5-[(1R,5S)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl]pyrazol-3-yl]-3-(trifluoromethyl)pyridin-2-amine Chemical compound C1=C(C(F)(F)F)C(N)=NC=C1C1=NN(CC2CC2)C(C2[C@@H]3CN(C[C@@H]32)C2COC2)=C1 IRPVABHDSJVBNZ-RTHVDDQRSA-N 0.000 description 1
- AMJVXOOGGBPVCZ-UHFFFAOYSA-N 5-bromo-1h-indazole-3-carboxylic acid Chemical compound C1=C(Br)C=C2C(C(=O)O)=NNC2=C1 AMJVXOOGGBPVCZ-UHFFFAOYSA-N 0.000 description 1
- KCBWAFJCKVKYHO-UHFFFAOYSA-N 6-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1-[[4-[1-propan-2-yl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrazolo[3,4-d]pyrimidine Chemical compound C1(CC1)C1=NC=NC(=C1C1=NC=C2C(=N1)N(N=C2)CC1=CC=C(C=C1)C=1N(C=C(N=1)C(F)(F)F)C(C)C)OC KCBWAFJCKVKYHO-UHFFFAOYSA-N 0.000 description 1
- IRWREYGFJOJLFT-UHFFFAOYSA-N 6-bromo-5-chloro-1h-indole Chemical compound C1=C(Br)C(Cl)=CC2=C1NC=C2 IRWREYGFJOJLFT-UHFFFAOYSA-N 0.000 description 1
- YLLZDOJZLKUKEA-UHFFFAOYSA-N 6-bromo-5-methyl-1h-indazole Chemical compound C1=C(Br)C(C)=CC2=C1NN=C2 YLLZDOJZLKUKEA-UHFFFAOYSA-N 0.000 description 1
- NWYLBGYCSAJFCB-UHFFFAOYSA-N 6-chloro-1h-pyrazolo[3,4-b]pyridine Chemical compound ClC1=CC=C2C=NNC2=N1 NWYLBGYCSAJFCB-UHFFFAOYSA-N 0.000 description 1
- OBYJTLDIQBWBHM-UHFFFAOYSA-N 6-chloropyridin-2-amine Chemical compound NC1=CC=CC(Cl)=N1 OBYJTLDIQBWBHM-UHFFFAOYSA-N 0.000 description 1
- HJSGTNVPWFFHOJ-UHFFFAOYSA-N 7-bromo-2h-indazole-3-carboxylic acid Chemical compound BrC1=CC=CC2=C(C(=O)O)NN=C21 HJSGTNVPWFFHOJ-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 1
- 125000003466 9 membered carbocyclic group Chemical group 0.000 description 1
- 229910001148 Al-Li alloy Inorganic materials 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- DWOXIPZVDPMGNU-UHFFFAOYSA-N C1CC11N(CCNC1)C(=O)O Chemical compound C1CC11N(CCNC1)C(=O)O DWOXIPZVDPMGNU-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 206010052805 Drug tolerance decreased Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 101000801643 Homo sapiens Retinal-specific phospholipid-transporting ATPase ABCA4 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102100026720 Interferon beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 102000019223 Interleukin-1 receptor Human genes 0.000 description 1
- 108050006617 Interleukin-1 receptor Proteins 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- 108010085220 Multiprotein Complexes Proteins 0.000 description 1
- 102000007474 Multiprotein Complexes Human genes 0.000 description 1
- GSCCALZHGUWNJW-UHFFFAOYSA-N N-Cyclohexyl-N-methylcyclohexanamine Chemical compound C1CCCCC1N(C)C1CCCCC1 GSCCALZHGUWNJW-UHFFFAOYSA-N 0.000 description 1
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 1
- CWLQUGTUXBXTLF-YFKPBYRVSA-N N-methylproline Chemical compound CN1CCC[C@H]1C(O)=O CWLQUGTUXBXTLF-YFKPBYRVSA-N 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- JTMGSIPKZABLBT-UHFFFAOYSA-N NOS(=O)(=O)S(=O)(=O)C Chemical compound NOS(=O)(=O)S(=O)(=O)C JTMGSIPKZABLBT-UHFFFAOYSA-N 0.000 description 1
- IDRGFNPZDVBSSE-UHFFFAOYSA-N OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F Chemical compound OCCN1CCN(CC1)c1ccc(Nc2ncc3cccc(-c4cccc(NC(=O)C=C)c4)c3n2)c(F)c1F IDRGFNPZDVBSSE-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 102100033617 Retinal-specific phospholipid-transporting ATPase ABCA4 Human genes 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical compound CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 108091005906 Type I transmembrane proteins Proteins 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- LXRZVMYMQHNYJB-UNXOBOICSA-N [(1R,2S,4R)-4-[[5-[4-[(1R)-7-chloro-1,2,3,4-tetrahydroisoquinolin-1-yl]-5-methylthiophene-2-carbonyl]pyrimidin-4-yl]amino]-2-hydroxycyclopentyl]methyl sulfamate Chemical compound CC1=C(C=C(S1)C(=O)C1=C(N[C@H]2C[C@H](O)[C@@H](COS(N)(=O)=O)C2)N=CN=C1)[C@@H]1NCCC2=C1C=C(Cl)C=C2 LXRZVMYMQHNYJB-UNXOBOICSA-N 0.000 description 1
- RWQJLIWMOBYOTI-AWEZNQCLSA-N [(3S)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxypiperidin-1-yl]-pyridin-3-ylmethanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@@H]1CN(CCC1)C(=O)C=1C=NC=CC=1 RWQJLIWMOBYOTI-AWEZNQCLSA-N 0.000 description 1
- ABRVLXLNVJHDRQ-UHFFFAOYSA-N [2-pyridin-3-yl-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound FC(C1=CC(=CC(=N1)C=1C=NC=CC=1)CN)(F)F ABRVLXLNVJHDRQ-UHFFFAOYSA-N 0.000 description 1
- JWSIZPAOIFLWKM-UHFFFAOYSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-[3-(dimethylamino)-4-hydroxypyrrolidin-1-yl]methanone Chemical compound CN(C)C1CN(CC1O)C(=O)c1cccc(Oc2cc(CN)cc(n2)C(F)(F)F)c1 JWSIZPAOIFLWKM-UHFFFAOYSA-N 0.000 description 1
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 210000005006 adaptive immune system Anatomy 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- OTJZCIYGRUNXTP-UHFFFAOYSA-N but-3-yn-1-ol Chemical compound OCCC#C OTJZCIYGRUNXTP-UHFFFAOYSA-N 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- QOPVNWQGBQYBBP-UHFFFAOYSA-N chloroethyl chloroformate Chemical compound CC(Cl)OC(Cl)=O QOPVNWQGBQYBBP-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 210000005220 cytoplasmic tail Anatomy 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000008482 dysregulation Effects 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000005966 endogenous activation Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- JMIAPORGEDIDLT-UHFFFAOYSA-N ethyl ethanimidate Chemical compound CCOC(C)=N JMIAPORGEDIDLT-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229940124670 gardiquimod Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 102000045715 human TLR7 Human genes 0.000 description 1
- 102000045720 human TLR8 Human genes 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000015788 innate immune response Effects 0.000 description 1
- 210000005007 innate immune system Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000002514 liquid chromatography mass spectrum Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- UIUXUFNYAYAMOE-UHFFFAOYSA-N methylsilane Chemical compound [SiH3]C UIUXUFNYAYAMOE-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- ATHHXGZTWNVVOU-UHFFFAOYSA-N monomethyl-formamide Natural products CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 1
- HWWVAHCWJLGKLW-UHFFFAOYSA-N n,n-dimethylhydroxylamine;hydron;chloride Chemical compound Cl.CN(C)O HWWVAHCWJLGKLW-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- VLWJKVNMRMHPCC-UHFFFAOYSA-N n-benzyl-2-chloro-n-(2-chloroethyl)ethanamine Chemical compound ClCCN(CCCl)CC1=CC=CC=C1 VLWJKVNMRMHPCC-UHFFFAOYSA-N 0.000 description 1
- RRPKGUUYTHFUPN-UHFFFAOYSA-N n-hydroxy-2,4,6-trimethylbenzenesulfonamide Chemical compound CC1=CC(C)=C(S(=O)(=O)NO)C(C)=C1 RRPKGUUYTHFUPN-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- BFSQJYRFLQUZKX-UHFFFAOYSA-L nickel(ii) iodide Chemical compound I[Ni]I BFSQJYRFLQUZKX-UHFFFAOYSA-L 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- JMJRYTGVHCAYCT-UHFFFAOYSA-N oxan-4-one Chemical compound O=C1CCOCC1 JMJRYTGVHCAYCT-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 229940074439 potassium sodium tartrate Drugs 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- SWWHCQCMVCPLEQ-UHFFFAOYSA-N propan-2-yl methanesulfonate Chemical compound CC(C)OS(C)(=O)=O SWWHCQCMVCPLEQ-UHFFFAOYSA-N 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- BXNMTOQRYBFHNZ-UHFFFAOYSA-N resiquimod Chemical compound C1=CC=CC2=C(N(C(COCC)=N3)CC(C)(C)O)C3=C(N)N=C21 BXNMTOQRYBFHNZ-UHFFFAOYSA-N 0.000 description 1
- 229950010550 resiquimod Drugs 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011257 shell material Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- IWUZDBAVKRNONF-UHFFFAOYSA-N sodium bis(trimethylsilyl)azanide [dimethyl-(trimethylsilylamino)silyl]methane Chemical compound C[Si]([N-][Si](C)(C)C)(C)C.C[Si](N[Si](C)(C)C)(C)C.[Na+] IWUZDBAVKRNONF-UHFFFAOYSA-N 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- DATRVIMZZZVHMP-MRVPVSSYSA-N tert-butyl (2r)-2-methylpiperazine-1-carboxylate Chemical compound C[C@@H]1CNCCN1C(=O)OC(C)(C)C DATRVIMZZZVHMP-MRVPVSSYSA-N 0.000 description 1
- PGZCVLUQTJRRAA-DTWKUNHWSA-N tert-butyl (2r,5s)-2,5-dimethylpiperazine-1-carboxylate Chemical compound C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1 PGZCVLUQTJRRAA-DTWKUNHWSA-N 0.000 description 1
- RBOGBIZGALIITO-DTORHVGOSA-N tert-butyl (2s,6r)-2,6-dimethylpiperazine-1-carboxylate Chemical compound C[C@H]1CNC[C@@H](C)N1C(=O)OC(C)(C)C RBOGBIZGALIITO-DTORHVGOSA-N 0.000 description 1
- FYUVLZRRIRGSTE-UHFFFAOYSA-N tert-butyl 2,3,3a,4,6,6a-hexahydro-1h-pyrrolo[3,4-c]pyrrole-5-carboxylate Chemical compound C1NCC2CN(C(=O)OC(C)(C)C)CC21 FYUVLZRRIRGSTE-UHFFFAOYSA-N 0.000 description 1
- KVOUHLVOTMOJBS-UHFFFAOYSA-N tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC11CNC1 KVOUHLVOTMOJBS-UHFFFAOYSA-N 0.000 description 1
- OUFBVDKNEWUFHP-UHFFFAOYSA-N tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate Chemical compound C1C2N(C(=O)OC(C)(C)C)C1CNC2 OUFBVDKNEWUFHP-UHFFFAOYSA-N 0.000 description 1
- PSDAEKDIOQXLLC-UHFFFAOYSA-N tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC2CCC1N2 PSDAEKDIOQXLLC-UHFFFAOYSA-N 0.000 description 1
- HNINFCBLGHCFOJ-UHFFFAOYSA-N tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate Chemical compound C1NCC2CCC1N2C(=O)OC(C)(C)C HNINFCBLGHCFOJ-UHFFFAOYSA-N 0.000 description 1
- RGWGRRBHQUREDE-UHFFFAOYSA-N tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1 RGWGRRBHQUREDE-UHFFFAOYSA-N 0.000 description 1
- FCMLWBBLOASUSO-UHFFFAOYSA-N tert-butyl 3-oxopiperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNC(=O)C1 FCMLWBBLOASUSO-UHFFFAOYSA-N 0.000 description 1
- HONNWTDYWUAZJF-UHFFFAOYSA-N tert-butyl 4-[2-[4-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyindol-1-yl]acetyl]piperazine-1-carboxylate Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC1=C2C=CN(C2=CC=C1)CC(=O)N1CCN(CC1)C(=O)OC(C)(C)C HONNWTDYWUAZJF-UHFFFAOYSA-N 0.000 description 1
- LZRDHSFPLUWYAX-UHFFFAOYSA-N tert-butyl 4-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)CC1 LZRDHSFPLUWYAX-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- XUBOHMHNNCJPHN-UHFFFAOYSA-N tert-butyl N-(6-chloro-3-iodopyridin-2-yl)carbamate Chemical compound CC(C)(C)OC(=O)Nc1nc(Cl)ccc1I XUBOHMHNNCJPHN-UHFFFAOYSA-N 0.000 description 1
- NZEASWFMIYVAAZ-SSDOTTSWSA-N tert-butyl N-[(3R)-5,5-difluoropiperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CNCC(F)(F)C1 NZEASWFMIYVAAZ-SSDOTTSWSA-N 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- BZSDDSIFAGBZLT-UHFFFAOYSA-N tert-butyl n-(4-fluoropyrrolidin-3-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CNCC1F BZSDDSIFAGBZLT-UHFFFAOYSA-N 0.000 description 1
- CGEBPOMWRHSMLI-UHFFFAOYSA-N tert-butyl n-(5-azaspiro[2.4]heptan-7-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1CNCC11CC1 CGEBPOMWRHSMLI-UHFFFAOYSA-N 0.000 description 1
- PIGDOXPNNMFBNA-HTQZYQBOSA-N tert-butyl n-[(3r,4r)-4-methoxypyrrolidin-3-yl]carbamate Chemical compound CO[C@@H]1CNC[C@H]1NC(=O)OC(C)(C)C PIGDOXPNNMFBNA-HTQZYQBOSA-N 0.000 description 1
- BZSDDSIFAGBZLT-NKWVEPMBSA-N tert-butyl n-[(3r,4s)-4-fluoropyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CNC[C@@H]1F BZSDDSIFAGBZLT-NKWVEPMBSA-N 0.000 description 1
- CUNVTZVWJLBPQS-JGVFFNPUSA-N tert-butyl n-[(3r,5s)-5-(trifluoromethyl)piperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CNC[C@@H](C(F)(F)F)C1 CUNVTZVWJLBPQS-JGVFFNPUSA-N 0.000 description 1
- DQQJBEAXSOOCPG-ZETCQYMHSA-N tert-butyl n-[(3s)-pyrrolidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@H]1CCNC1 DQQJBEAXSOOCPG-ZETCQYMHSA-N 0.000 description 1
- CGEBPOMWRHSMLI-MRVPVSSYSA-N tert-butyl n-[(7s)-5-azaspiro[2.4]heptan-7-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CNCC11CC1 CGEBPOMWRHSMLI-MRVPVSSYSA-N 0.000 description 1
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ZXUCBXRTRRIBSO-UHFFFAOYSA-L tetrabutylazanium;sulfate Chemical compound [O-]S([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC ZXUCBXRTRRIBSO-UHFFFAOYSA-L 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- LENLQGBLVGGAMF-UHFFFAOYSA-N tributyl([1,2,4]triazolo[1,5-a]pyridin-6-yl)stannane Chemical compound C1=C([Sn](CCCC)(CCCC)CCCC)C=CC2=NC=NN21 LENLQGBLVGGAMF-UHFFFAOYSA-N 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 1
- XPDWGBQVDMORPB-UHFFFAOYSA-N trifluoromethane acid Natural products FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- WVLBCYQITXONBZ-UHFFFAOYSA-N trimethyl phosphate Chemical compound COP(=O)(OC)OC WVLBCYQITXONBZ-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- DYWSVUBJGFTOQC-UHFFFAOYSA-N xi-2-Ethylheptanoic acid Chemical compound CCCCCC(CC)C(O)=O DYWSVUBJGFTOQC-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4162—1,2-Diazoles 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- 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
- C07D471/02—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 two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
Definitions
- the present invention relates to the field of small molecule pharmaceutical compounds, specifically, the present invention provides a class of Toll-like receptor inhibitors and their preparation and application.
- TLRs Toll-like receptors
- TLRs are a class of structurally conserved proteins that form the first barrier in the innate immune response. By recognizing various conserved pathogen-associated molecular patterns (PAMPs), TLRs can recognize invasive microorganisms and endogenous molecules released after tissue damage or non-physiological cell death, and activate signaling cascades, resulting in the production of pro-inflammatory cytokines.
- PAMPs pathogen-associated molecular patterns
- TLRs can recognize invasive microorganisms and endogenous molecules released after tissue damage or non-physiological cell death, and activate signaling cascades, resulting in the production of pro-inflammatory cytokines.
- There are 10 known members of the human TLRs family which are type I transmembrane proteins characterized by a leucine-rich extracellular domain and containing the conserved Toll/interleukin-1 receptor (Toll/interleukin (IL) -1 receptor, TIR) domain cytoplasmic tail.
- Toll/interleukin (IL) -1 receptor T
- TLR3, TLR7, TLR8 and TLR9 are located in the endosomal compartment. Endosomal TLRs recognize viral and endogenous double-stranded RNA (dsRNA; TLR3), single-stranded RNA (ssRNA; TLR7/8) or unmethylated CpG sequences (TLR9).
- dsRNA double-stranded RNA
- ssRNA single-stranded RNA
- TLR9 unmethylated CpG sequences
- TLR7 and 8 are implicated in the etiology of some autoimmune diseases that target self-RNA and DNA/protein complexes that are most likely released during normal cell death and clearance.
- a large body of scientific evidence now links inappropriate persistent endogenous activation of the TLR7/8 pathway to persistent responses to self-antigens in autoimmune diseases.
- TLR7 has been shown to play a role in the pathogenesis of systemic lupus erythematosus.
- TLR8 polymorphisms are associated with rheumatoid arthritis.
- TLR7 and/or TLR8 activity may benefit from treatments involving modulation of cytokine, interferon (IFN) production and B cell activity, as most autoimmune diseases may benefit from Provides substantial therapeutic benefit to such autoimmune patients.
- IFN interferon
- the object of the present invention is to provide a compound that can be used to regulate the activity of TLR7 and/or TLR8.
- the first aspect of the present invention provides a compound represented by the following formula I, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixtures thereof:
- Dashed lines are chemical bonds or none; and is an aromatic ring;
- U is selected from the following group: C, or N;
- J is selected from the group: C or N;
- W is N, CR x or NR y ; wherein, said R x is selected from the following group: H, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, Or C 3-7 cycloalkyl; R y is selected from the following group: H, C 1-6 alkyl, halogenated C 1-6 alkyl, or C 3-7 cycloalkyl;
- R 1 is selected from the group consisting of substituted or unsubstituted 5-membered and 6-membered heteroaryl, substituted or unsubstituted 6-membered and 6-membered heteroaryl;
- R 2 and R 3 with their attached carbon atoms, R 4 and R 5 with their attached carbon atoms, R 6 and R 7 with their attached carbon atoms together form a substituted or unsubstituted 3- to 6-membered ring Alkyl, or a substituted or unsubstituted 3- to 6-membered heterocyclic group;
- R 8 is selected from the group consisting of H, halogen, OH, NH 2 , cyano, C(O)NH 2 , substituted or unsubstituted 3- to 9-membered carbocyclyl (saturated, unsaturated monocyclic, spiro ring, ring or bridging ring), or substituted or unsubstituted 3- to 9-membered heterocyclyl (saturated, unsaturated monocyclic, spiro, and bridging ring or bridging ring);
- X, Y, Z and V are each independently selected from the following group: N or C(R 15 ); said LR 8 is located on any atom of X, Y, Z and V, and when LR 8 is located on X, Y , Z or V, the corresponding atom is C(R 15 ), and at this time R 15 is replaced by LR 8 ;
- R 15 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 3-7 cycloalkyl or halogen;
- said R is selected from the following group:
- a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , B 1 , B 2 , B 3 , B 4 are each independently selected from the following group: CR, N, NR 14 ;
- a 7 and A 8 are each independently selected from the following group: C, N;
- the R 14 is selected from the group consisting of H, C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 3-7 cycloalkyl;
- Each R is independently selected from the group consisting of H, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, Ra substituted C 1-6 alkyl, Or C 1-6 alkoxy substituted by Rb; wherein, said Ra and Rb are each independently selected from the following group: OH, halogen, cyano, C 1-3 alkyl or C 1-3 alkoxy.
- said R is selected from the following group:
- R 9 , R 10 , R 11 , R 12 and R 13 are each independently selected from the following group: H, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkane group, C 1-6 alkyl substituted by Ra, or C 1-6 alkoxy substituted by Rb; wherein, the Ra and Rb are each independently selected from the following group: OH, halogen, cyano, C 1- 3 alkyl or C 1-3 alkoxy;
- R 14 is selected from the group consisting of H, C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 3-7 cycloalkyl;
- M is selected from the group: CH or N.
- M is CH.
- the compound of formula I has the structure shown in formula II below:
- Has a structure selected from the following group (substituent R 15 and LR 8 structures are not shown):
- the R 8 is selected from the group consisting of H, halogen, OH, NH 2 , cyano, C(O)NH 2 , CH 2 C(O)NH 2 , substituted or unsubstituted 5- to 9-membered carbocyclic group, substituted or unsubstituted 5- to 9-membered heterocyclic group.
- the R 8 is selected from the group consisting of H, halogen, OH, NH 2 , cyano, C(O)NH 2 , CH 2 C(O)NH 2 , substituted or unsubstituted 5- to 9-membered carbocyclyl, substituted or unsubstituted 5- to 9-membered nitrogen heterocyclyl.
- the R 8 is selected from the group consisting of H, halogen, OH, NH 2 , cyano, C(O)NH 2 , CH 2 C(O)NH 2 , or substituted or unsubstituted A group selected from the group consisting of:
- the compound of formula I has the structure shown in the following formula III-1 or III-2:
- the compound of formula I has the structure shown in the following formula IV-1 or IV-2;
- the R 8 is selected from the following group: substituted or unsubstituted 3- to 9-membered carbocyclyl (saturated, unsaturated monocyclic, parallel ring or bridged ring), or substituted or Unsubstituted 3- to 9-membered heterocyclic group (saturated, unsaturated monocyclic, branched or bridged ring).
- the second aspect of the present invention provides a pharmaceutical composition, which includes: the compound of formula I as described in the first aspect of the present invention, its pharmaceutically acceptable salt, racemate, R- One or more of isomers, S-isomers or mixtures thereof, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients and/or diluents.
- the third aspect of the present invention provides a compound of formula I as described in the first aspect of the present invention, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or their Use of the mixture for preparing a pharmaceutical composition for treating or preventing autoimmune diseases or chronic inflammatory diseases.
- the disease is selected from the group consisting of Sjogren's syndrome, systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, systemic sclerosis, psoriasis, systemic lupus erythematosus, lupus nephritis .
- the present invention provides a conjugate obtained by chemically linking the compound as described in the present invention with a biological small molecule or a monoclonal antibody.
- the present inventors After long-term and in-depth research, the present inventors have discovered a class of small molecular compounds with TLR7 and/or TLR8 inhibitory activity.
- the compounds are novel in structure and have comparable or better inhibitory effects than similar compounds in the prior art. active. Based on the above findings, the inventors have accomplished the present invention.
- the halogen is F, Cl, Br or I.
- C 1 -C 6 alkyl refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, including without limitation methyl, ethyl, propyl, isopropyl , butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
- C 1 -C 6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy base, isopropoxy and butoxy, etc.
- C 3 -C 7 cycloalkyl refers to a cyclic alkyl group having 3 to 7 carbon atoms in the ring, including without limitation cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, cycloheptyl, cyclooctyl, etc.
- the terms “C 5 -C 6 cycloalkyl”, and “C 3 -C 6 cycloalkyl” have similar meanings.
- aryl ring or “aryl” has the same meaning, preferably "aryl” is “C 6 -C 12 aryl” or “C 6 -C 10 aryl”.
- C 6 -C 12 aryl refers to an aromatic ring group having 6 to 12 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl and the like.
- C 6 -C 10 aryl has a similar meaning.
- heteroaryl has the same meaning and refers to a heteroaromatic group containing one to more heteroatoms.
- the heteroatoms referred to herein include oxygen, sulfur and nitrogen.
- the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is a heteroaryl ring.
- Heteroaryl groups can be optionally substituted or unsubstituted.
- 3-9 membered carbocyclic group refers to a 3-9 membered ring group in the form of saturated or unsaturated (non-aromatic rings, including monocyclic rings, double rings, spiro rings, bridged rings, etc.) , whose ring skeleton structure includes only carbon atoms, such as cyclopentyl, cyclohexyl, etc.
- 3-9 membered heterocyclic group refers to a saturated or unsaturated (non-aromatic ring, including monocyclic ring) containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen on the ring. , and rings, spiro rings, bridged rings, etc.) 3-9-membered ring groups, such as dioxolyl and the like.
- 3-7 membered heterocyclyl has a similar meaning.
- substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
- the specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment.
- a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position.
- a cyclic substituent, such as a heterocycloalkyl can be attached to another ring, such as a cycloalkyl, to form a spirobicyclic ring system, eg, two rings having a common carbon atom.
- substituents contemplated by this invention are those that are stable or chemically feasible.
- the substituents are for example (but not limited to): C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl , aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 aldehyde, C 2-10 acyl, C 2-10 ester, amino, alkoxy, C 1-10 sulfonyl wait.
- the present invention provides a compound represented by the following formula I, its pharmaceutically acceptable salt, racemate, R-isomer, S-isomer or mixtures thereof:
- Dashed lines are chemical bonds or none; and is an aromatic ring;
- U is selected from the following group: C or N;
- J is selected from the group: C or N;
- W is N, CR x or NR y ; wherein, said R x is selected from the following group: H, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, Or C 3-7 cycloalkyl; R y is selected from the following group: H, C 1-6 alkyl, halogenated C 1-6 alkyl, or C 3-7 cycloalkyl;
- R 1 is selected from the group consisting of substituted or unsubstituted 5-membered and 6-membered heteroaryl, substituted or unsubstituted 6-membered and 6-membered heteroaryl;
- R 2 and R 3 with their attached carbon atoms, R 4 and R 5 with their attached carbon atoms, R 6 and R 7 with their attached carbon atoms together form a substituted or unsubstituted 3- to 6-membered ring Alkyl, or a substituted or unsubstituted 3- to 6-membered heterocyclic group;
- R 8 is selected from the group consisting of H, halogen, OH, NH 2 , cyano, C(O)NH 2 , substituted or unsubstituted 3- to 9-membered carbocyclyl (saturated, unsaturated monocyclic, spiro ring, ring or bridging ring), or substituted or unsubstituted 3- to 9-membered heterocyclyl (saturated, unsaturated monocyclic, spiro, and bridging ring or bridging ring);
- X, Y, Z and V are each independently selected from the following group: N or C(R 15 ); said LR 8 is located on any atom of X, Y, Z and V, and when LR 8 is located on X, Y , Z or V, the corresponding atom is C(R 15 ), and at this time R 15 is replaced by LR 8 ;
- R 15 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, C 3-7 cycloalkyl or halogen;
- (CH 2 ) n SO 2 NH 2 nitro, cyano, unsubstituted or halogenated C 1 -C 6 alkyl, C 2 -C 10 alkenyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl-amino group, C 6 -C 10 aryl, five-membered or six-membered heteroaryl, -O-(C 6 -C 10 aryl), -O-(five-membered or six-membered heteroaryl aryl), substituted or unsubstituted C 3-7 heterocycloalkyl; n is 0, 1 or 2.
- the present invention also provides the above-mentioned preparation method of the compound shown in formula I, which is any of the following methods:
- Method 1 which comprises the following steps: in a solvent, under the action of a base, the compound shown in formula III and the compound shown in formula IV react to obtain the compound shown in formula I
- Q 1 is fluorine, chlorine or bromine
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, Y, Z, U, V, W and L are as defined above said;
- Method 2 which comprises the following steps: in a solvent, under the action of a base, the compound shown in formula VIII and the compound shown in formula I-1 undergo a substitution reaction to obtain the compound shown in formula I;
- Q 2 is OMs, fluorine, chlorine or bromine
- R 8' is "one or more heteroatoms selected from N, O and S, and a 3-9 membered heterocycloalkyl group with 1-3 heteroatoms ”
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, Y, Z, U, V, W and L are as defined above.
- R 8-1 is "the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 3-7 membered heterocycloalkyl", and the number of heteroatoms is 1-4 C 1 to C 10 heteroaryl", C 1 to C 6 alkyl with 1 to 3 substituted or unsubstituted heteroatoms, C 3 to C 7 substituted or unsubstituted heteroatoms with 1 to 3 Cycloalkyl, C 1 -C 6 alkoxycarbonyl, (CH 2 ) n NH 2 , (CH 2 ) n C(O)NH 2 , (CH 2 ) n C(O)OH, C 1 -C 6 Amide, C 1 -C 6 sulfonamide, C(O)(CH 2 ) n NH 2 , SO 2 (CH 2 ) n NH 2 , (CH 2 ) n SO 2 NH 2 , unsubstituted or halogenated C 1 -C 6 alkyl, C 2
- Method 3 which comprises the following steps: in a solvent, under the action of a base, the compound shown in formula III and the compound shown in formula V are reacted to compound VI, and compound VI is deprotected to obtain the compound shown in formula I compound of
- Q 1 is fluorine, chlorine or bromine
- T is chlorine or bromine
- R 8-2 is R protected by protecting groups such as tert-butoxycarbonyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, etc. 8 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, Y, Z, U, V, W and L are as defined above.
- compositions containing active ingredients are provided.
- the compound of the present invention has excellent Toll-like receptor inhibitory activity
- the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are the main
- the pharmaceutical composition of the active ingredients can be used to prevent and/or treat (stabilize, alleviate or cure) Toll-like receptors (especially TLR7, 8) abnormal expression or activation-related diseases or conditions, such as autoimmune diseases or chronic inflammation Disease; preferably, the autoimmune disease is selected from the group consisting of Sjogren's syndrome, systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, systemic sclerosis, psoriasis, systemic lupus erythematosus , Lupus nephritis.
- the pharmaceutical composition of the present invention comprises the compound of the present invention and pharmaceutically acceptable excipients or carriers in a safe and effective amount range.
- safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
- the pharmaceutical composition contains 0.01-99.99% by weight of the compound/dose of the present invention, more preferably, contains 0.1-99.9% of the compound/dose of the present invention.
- the "one dose” is a capsule or tablet.
- “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low toxicity. "Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
- Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
- cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
- gelatin such as talc
- solid lubricants such as stearic acid , magnesium stearate
- calcium sulfate such
- the administration method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous).
- Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
- the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
- Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
- coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
- Examples of usable embedding components are polymeric substances and waxy substances.
- the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
- liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
- inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
- compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
- suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
- compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
- the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds such as anti-HBV agents.
- the pharmaceutical composition When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds.
- One or more (2, 3, 4, or more) of these other pharmaceutically acceptable compounds can be used simultaneously, separately or sequentially with the compound of the present invention for the prevention and/or treatment of Toll Diseases or disorders associated with abnormal expression or activation of TLR-like receptors (especially TLR7, 8).
- a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage is a pharmaceutically effective dosage.
- a mammal such as a human
- the dosage is a pharmaceutically effective dosage.
- factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
- the structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm).
- the determination of NMR is carried out with Bruker AVANCE-400 nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is four Methylsilane (TMS).
- SHIMADZU LC system (column: CSH TM Prep-C18, 19*150mm, liquid handler LH-40, pump LC-20AP, detector SPD-20A, system controller CBM-20A, solvent system: acetonitrile and 0.05% trifluoroacetic acid aqueous solution).
- LC/MS spectra of compounds were obtained using LC/MS (Agilent Technologies 1200 Series). LC/MS conditions were as follows (10 min run time):
- Acidic conditions A: 0.05% trifluoroacetic acid in water; B: 0.05% trifluoroacetic acid in acetonitrile;
- intermediates and final compounds are purified using silica gel column chromatography, or using Purified by preparative HPLC on a CSH TM Prep-C18 (5 ⁇ m, OBD TM 19*150 mm) column or on a reverse phase column using XBridgeTM Prep Phenyl (5 ⁇ m, OBD TM 30*100 mm).
- Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
- the CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
- Thin-layer chromatography (TLC) silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
- the specifications of the silica gel plates used for TLC detection products are 0.15mm to 0.2mm.
- the specifications of TLC separation and purification products are 0.4mm ⁇ 0.5mm.
- the known starting materials of the present invention can be used or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui chemical companies.
- Step 1 Preparation of (S)-1-((4-methoxybenzyl)amino)propan-2-ol (Intermediate A1-2)
- Step 2 Preparation of (S)-6-bromo-N-(2-hydroxypropyl)-N-(4-methoxybenzyl)-1H-indazole-3-carboxamide (intermediate A1-4 )
- 6-Bromo-1H-indoleazole-3-carboxylic acid (5.00 g, 20.74 mmol), N-ethyl-N-isopropyl-2-amine (16.09 g, 124 mmol), DMAP (0.507 g, 4.15 mmol) and 2.5 g of 4A molecular sieves (4A MS) were added to DMF (5 mL).
- HATU (7.89 g, 20.74 mmol) was slowly added under stirring at 15 degrees.
- reaction mixture was stirred at 15 degrees for 2 hours, and then (S)-1-((4-methoxybenzyl) Amino)propan-2-ol (4.86 g, 24.89 mmol) was added to the above reaction mixture, and after the addition was complete, the reaction mixture was stirred at 15° C. for 3 hours. Then ice water was added to quench the reaction, and the extraction was diluted with ethyl acetate.
- Step 5 Preparation of (R)-8-bromo-4-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazole (Intermediate A1)
- reaction mixture was slowly raised to 100°C under the protection of nitrogen and stirred for 16 hours, then the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (R)-4-(4-methyl-1,2,3 , tert-butyl 4-tetrahydropyrazino[1,2-b]indazol-8-yl)piperazine-1-carboxylate (100 mg, 17.9%). MS: 372.1 (M+H) + .
- Step 1 (R)-4-(4-Methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)-3,6-dihydropyridine - Preparation of tert-butyl 1(2H)-carboxylate (intermediate A7-2)
- Step 1 Preparation of ethyl (E)-N-((methylsulfonylsulfonyloxy)oxy)acetimidate (intermediate A8-1)
- Ethyl (E)-N-((methylsulfonylsulfonyl)oxy)acetimidate (220 g, 771.0 mmol) was dissolved in anhydrous 1,4-dioxane (600 mL), Perchloric acid (120 mL) was slowly added with stirring at 0°C. After dropping, the reaction mixture was stirred at 0 °C for 1 hour, then ice water was added to quench the reaction, and the extraction was diluted with ethyl acetate.
- Step 3 Preparation of 1-amino-2-bromo-5-fluoropyridin-1-ium 2,4,6-trimethylbenzenesulfonate (Intermediate A8-3)
- Step 4 Preparation of ethyl 7-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carboxylate (intermediate A8-4)
- Step 5 Preparation of 7-bromo-4-fluoropyrazolo[1,5-a]pyridine (Intermediate A8-5)
- Ethyl 7-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carboxylate (4.0 g, 13.9 mmol) was dissolved in acetic acid (24 mL) and water (24 mL) in Concentrated hydrochloric acid (18 mL, 216 mmol) was added with stirring. After dropping, the reaction mixture was slowly raised to 100°C and stirred for 18 hours, then water and saturated aqueous sodium bicarbonate were added to adjust the pH to 8, and extracted with ethyl acetate.
- Step 1 Preparation of 7-bromo-4-fluoropyrazolo[1,5-a]pyridine-3-carboxylic acid (Intermediate A9-1)
- Step 2 Preparation of 7-bromo-3,4-difluoropyrazolo[1,5-a]pyridine (Intermediate A9-2)
- intermediate A10 refers to intermediate A7, and intermediate A10 is prepared by using intermediate A2 instead of intermediate A1.
- Step 1 Preparation of tert-butyl (6-chloropyridin-2-yl)aminocarboxylate (Intermediate A13-1)
- 6-Chloropyridin-2-amine (10 g, 77.8 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml), and slowly added bis(trimethylsilyl)amide sodium bis(trimethylsilyl)amide (2M THF solution, 77.8 ml). After dropping, the reaction mixture was stirred at -30°C for 30 minutes, and a solution of tert-butoxycarbonyl tert-butyl carbonate (18.8 g, 86.1 mmol) in tetrahydrofuran (100 ml) was slowly added to the reaction solution.
- Step 2 Preparation of tert-butyl (6-chloro-3-iodopyridin-2-yl)aminocarboxylate (Intermediate A13-2)
- 6-Chloro-3-iodopyridin-2-yl) tert-butyl aminocarboxylate (16 g, 45.1 mmol) was dissolved in methanolic hydrochloric acid (30 ml), and the reaction mixture was stirred at room temperature for 48 hours, then added Dilute with ice water and extract with ethyl acetate. The organic phase was washed with saturated aqueous sodium carbonate, saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 6-chloro-3-iodopyridin-2-amine (11.4 g, 99.3%) as a white solid. MS: 254.9 (M+H) + .
- Step 4 Preparation of (Z)-N'-(6-chloro-3-iodopyridin-2-yl)-N,N-dimethylformamide (Intermediate A13-4)
- Step 5 Preparation of (Z)-N'-(6-chloro-3-iodopyridin-2-yl)-N-hydroxycarboximide (Intermediate A13-5)
- Step 1 Preparation of 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (intermediate A14-1)
- Step 2 Preparation of 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (intermediate A14-2)
- Step 3 Preparation of 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid methyl ester (intermediate A14- 3)
- Step 4 Preparation of 6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (intermediate A14-4)
- Step 5 6-Chloro-N-((S)-2-hydroxypropyl)-N-(4-methoxybenzyl)-1-(tetrahydro-2H-pyran-2-yl)-1H -
- pyrazolo[3,4-b]pyridine-3-carboxamide (intermediate A14-5)
- Step 6 (S)-6-Chloro-N-(2-hydroxypropyl)-N-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-3-methanol Preparation of Amides (Intermediate A14-6)
- Step 7 (R)-2-Chloro-6-(4-methoxybenzyl)-8-methyl-7,8-dihydropyridin[2',3':3,4]pyrazol[1 ,5-a] Preparation of pyrazin-5(6H)-one (intermediate A14-7)
- Step 8 (R)-2-(4-benzylpiperazin-1-yl)-6-(4-methoxybenzyl)-8-methyl-7,8-dihydropyridine[2', 3': Preparation of 3,4]pyrazol[1,5-a]pyrazin-5(6H)-one (Intermediate A14)
- intermediate A14 refers to intermediate A6, and intermediate A14 is prepared by using intermediate A14-7 instead of intermediate A1 and 1-benzylpiperazine instead of piperazine-1-carboxylate tert-butyl. MS: 497.1 (M+H) + .
- Step 3 Preparation of (2S)-1-((1-(6-bromo-1H-indazol-3-yl)ethyl)amino)propanol (Intermediate A15-3)
- Step 4 Preparation of tert-butyl (1-(6-bromo-1H-indazol-3-yl)ethyl)((S)-2-hydroxypropyl)carbamate (Intermediate A15-4)
- Step 5 Preparation of (2S)-1-((1-(6-bromo-1H-indazol-3-yl) ethyl) (tert-butoxycarbonyl) amino) prop-2-yl methanesulfonate ( Intermediate A15-5)
- the intermediate A5 was chirally resolved by SFC (column model: CHIRALPAK IA, 3cm ⁇ 25cm, 5 ⁇ m chromatographic column, mobile phase: 35% methanol in carbon dioxide) to obtain the first component peak intermediate A5 which was a white solid -a (retention time is 2.14 minutes) and the second component peak intermediate A5-b (retention time is 2.50 minutes).
- Step 1 Preparation of tert-butyl 7-chloro-1,3,4,5-tetrahydro-2H-pyrrole[3,2-c:4,5-c']bipyridine-2-carboxylate (A16- 1)
- tert-butyl 4-oxopiperidine-1-carboxylate (3132 mg, 15.72 mmol), ethyl orthosilicate (1801 mg, 8.65 mmol), 2-chloro-5-iodopyridin-4-amine ( 2000 mg, 7.86 mmol), TsOH (299 mg, 1.572 mmol), N-cyclohexyl-N-methylcyclohexylamine (1996 mg, 10.22 mmol) and Pd(Ph 3 P) 4 (272 mg, 0.236 mmol) was dissolved in pyridine (15 ml). The reaction mixture was slowly raised to 160°C under the protection of nitrogen and stirred for 40 minutes, then the reaction mixture was diluted with water and extracted with ethyl acetate.
- tert-butyl 7-chloro-1,3,4,5-tetrahydro-2H-pyrrole[3,2-c:4,5-c']bipyridine-2-carboxylate (990 mg, 3.22 mmol ) was dissolved in THF (20 mL). The reaction mixture was slowly added NaH (618 mg, 25.7 mmol) under the protection of nitrogen at 0 degrees, and continued stirring at 0 degrees for 30 minutes, then methyl iodide (3.65 grams, 25.7 mmol) was added to the reaction solution, and Ask to stir the reaction for 16 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate.
- the intermediate A17 was chirally resolved by SFC (column model: CHIRALPAK AD, 3cm ⁇ 25cm, 5 ⁇ m chromatographic column, mobile phase: 15% methanol in carbon dioxide) to obtain the first component peak intermediate A17 which is a white solid -a (retention time is 1.67 minutes) and the second component peak intermediate A17-b (retention time is 1.93 minutes).
- intermediate A18 refers to intermediate A7, and intermediate A18 is prepared by using intermediate A18-1 instead of intermediate A7-1.
- intermediate A19 refers to intermediate A7, and intermediate A19 is prepared by using intermediate A19-1 instead of intermediate A7-1.
- intermediate A20 refers to intermediate A22, and intermediate A20 is prepared by using intermediate A20-1 instead of intermediate A22-1.
- intermediate A21 refers to intermediate A7, and intermediate A21 is prepared by using intermediate A20 instead of intermediate A1. MS: 389.1 (M+H) + .
- Step 2 Preparation of (S)-1-(((6-bromo-5-fluoro-1H-indazol-3-yl)methyl)(4-methoxybenzyl)amino)propan-2-ol (Intermediate A22-2)
- Step 3 (R)-8-Bromo-9-fluoro-2-(4-methoxybenzyl)-4-methyl-1,2,3,4-tetrahydropyrazine[1,2-b ] Preparation of indazole (intermediate A22-3)
- Step 4 Preparation of (R)-8-bromo-9-fluoro-4-methyl-1,2,3,4-tetrahydropyrazine[1,2-b]indazole (Intermediate A22)
- intermediate A22 refers to intermediate A1, and intermediate A22 is prepared by using intermediate A22-3 instead of intermediate A1-6.
- intermediate A23 refers to intermediate A7, and intermediate A23 is prepared by using intermediate A22 instead of intermediate A1. MS: 389.1 (M+H) + .
- intermediate A25 refers to intermediate A23, and intermediate A25 is prepared by using intermediate A24 instead of intermediate A22.
- Step 1 Preparation of tert-butyl 7-bromo-3,4-dihydroimidazo[1,2-a:5,4-c']bipyridine-2(1H)-carboxylate (Intermediate A26-1)
- Step 2 Preparation of 7-bromo-1,2,3,4-tetrahydroimidazo[1,2-a:5,4-c']bipyridyl (intermediate A26-2)
- Step 3 Preparation of tert-butyl 4-(1,2,3,4-tetrahydroimidazo[1,2-a:5,4-c']bipyridin-7-yl)piperidine-1-carboxylate (Intermediate A26)
- intermediate A26 refers to intermediate A23, and intermediate A26 is prepared by using intermediate A26-2 instead of intermediate A22. MS: 357.1 (M+H) + .
- intermediate A27 refers to intermediate A22, and intermediate A27 is prepared by using intermediate A27-1 instead of intermediate A22-1. MS: 223.1 (M+H) + .
- intermediate A28 refers to intermediate A23, and intermediate A28 is prepared by using intermediate A27 instead of intermediate A22. MS: 372.1 (M+H) + .
- intermediate A29 refers to intermediate A22, and intermediate A29 is prepared by using intermediate A29-1 instead of intermediate A22-1. MS: 223.1 (M+H) + .
- the intermediate I-48-3 was subjected to chiral resolution by SFC (column type: CHIRALPAK IF, 2cm ⁇ 25cm, 5 ⁇ m chromatographic column, mobile phase: 20% ethanol in carbon dioxide) to obtain the first component, both of which were white solids Peak intermediate I-48-3a (retention time 1.318 minutes) and the second component peak intermediate I-48-3c (retention time 1.578 minutes) and the third component peak intermediate I-48-3b (retention time is 1.770 minutes) and the fourth component peak intermediate I-48-3d (retention time is 2.48 minutes). MS: 548.1 (M+H) + .
- Step 1 the preparation of intermediate A30-1
- Step 2 (R)-3-(4-Methyl-1,2,3,4-tetrahydropyrazine[1,2-b]indazol-8-yl)azetidine-1-carboxy Preparation of tert-butyl acid ester (intermediate A30)
- Step 1 the preparation of intermediate A31-1
- intermediate A31 refers to intermediate A23, and intermediate A31 is prepared by using intermediate A31-6 instead of intermediate A22. MS: 357.1 (M+H) + .
- Step 1 the preparation of intermediate A32-1
- intermediate A32-3 refers to intermediate A1-6, and intermediate A32-3 is prepared as a yellow oil by using intermediate A32-2 instead of intermediate A1-5. MS: 318.2 (M+H) + .
- intermediate A34 refers to intermediate A7, and intermediate A34 is prepared by using intermediate A33 instead of intermediate A1. MS: 389.1 (M+H) + .
- intermediate A36 refers to intermediate A7, and intermediate A36 is prepared by using intermediate A35 instead of intermediate A1. MS: 385.1 (M+H) + .
- Step 1 the preparation of intermediate A37-1
- intermediate A38 refers to intermediate A37, and yellow solid intermediate A38 is prepared by using intermediate A22 instead of intermediate A1. MS: 404.1(M+1) + .
- Step 1 the preparation of intermediate A39-1
- 1,1,1-Trimethoxyethane (1.45 g, 12.09 mmol) was slowly added to intermediate A39-2 (1.4 g, 4.03 mmol) in dichloromethane (12 ml ) solution, then trimethylchlorosilane (1.13 g, 12.09 mmol) was slowly added to the above reaction mixture.
- the reaction mixture was stirred at 20°C for 1 hour, then concentrated to give a white solid, which was reacted with a solution of potassium carbonate (1.11 g, 8.06 mmol) in methanol (10 mL) at room temperature for 1 hour.
- intermediate A39 refers to intermediate A32, and yellow solid intermediate A39 is prepared by using intermediate A39-3 instead of intermediate A32-5.
- intermediate A40 refers to intermediate A39, and yellow solid intermediate A40 is prepared by using AD-mix-beta instead of AD-mix-alfa. MS:363.1(M+1) +
- Step 1 (R)-5-(8-Bromo-4-methyl-3,4-dihydropyrazino[1,2-b]indazol-2(1H)-yl)quinoline-8- Preparation of Nitrile (Intermediate I-1-1)
- Pd2 (dba) 3 (0.017 g, 0.019 mmol), sodium tert-butoxide (0.054 g, 0.564 mmol), BINAP (0.023 g, 0.038 mmol), 5-bromo-8-cyanoquinoline ( Intermediate D1, 0.219 g, 0.939 mmol) and (R)-8-bromo-4-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazole (intermediate A1, 50 mg, 0.188 mmol) was dissolved in toluene (5 mL).
- reaction mixture was slowly raised to 80°C under the protection of nitrogen and stirred for 1.5 hours, then the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (R)-5-(8-bromo-4-methyl-3 , 4-dihydropyrazino[1,2-b]indazol-2(1H)-yl)quinoline-8-carbonitrile (40 mg, 51%). MS: 418&420(M+H) + .
- Step 2 (R)-4-(2-(8-cyanoquinolin-5-yl)-4-methyl-1,2,3,4-tetrahydropyrazino[1,2-b] Preparation of indazol-8-yl)piperazine-1-carboxylate tert-butyl ester (intermediate I-1-2)
- Step 3 (R)-5-(4-methyl-8-(piperazin-1-yl)-3,4-dihydropyrazino[1,2-b]indazole-2(1H)- Base) the preparation of quinoline-8-carbonitrile
- Step 1 (R)-4-(2-(8-cyanoquinolin-5-yl)-4-methyl-1,2,3,4-tetrahydropyrazino[1,2-b] Preparation of tert-butyl indazol-8-yl)-3,6-dihydropyridine-1(2H)-carboxylate (intermediate I-2-1)
- Step 2 (R)-5-(4-methyl-8-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydropyrazine[1,2-b] Preparation of indazol-2(1H)-yl)quinoline-8-carbonitrile
- Step 2 (R)-3-fluoro-4-(4-methyl-8-(piperazin-1-yl)-3,4-dihydropyrazine[1,2-b]indazole-2( 1H)-yl)pyrazol[1,5-a]pyridine-7-carbonitrile
- Compound I-13 was synthesized with reference to compound I-1 by using 6-bromo-8-methyl-[1,2,4]triazol[1,5-a]pyridine (intermediate D2) instead of 5-bromo- 8-cyanoquinoline (intermediate D1) was prepared to obtain white solid compound I-13.
- Step 1 (R)-4-(2-(8-cyanoquinolin-5-yl)-4-methyl-1,2,3,4-tetrahydropyrazino[1,2-b] Preparation of tert-butyl indazole-8-carbonyl)piperazine-1-carboxylate (intermediate I-15-1)
- reaction mixture was microwaved at 140°C for 15 minutes, then ice water was added to quench the reaction, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow solid (R)-4-(2-(8-cyanoquinoline- 5-yl)-4-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazole-8-carbonyl)piperazine-1-carboxylic acid tert-butyl ester (20 mg , 30%), MS: 552.1 (M+H) + .
- Step 2 (R)-5-(4-Methyl-8-(piperazine-1-carbonyl)-3,4-dihydropyrazine[1,2-b]indoleazole-2(1H)- Base) quinoline-8-carbonitrile
- white solid compound I-16 was prepared by using tert-butyl 4-aminopiperidine-1-carboxylate instead of tert-butyl piperazine-1-carboxylate.
- Synthetic reference compound I-1 of compound I-17 by using 8-bromo-4-ethyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazole (intermediate A5)
- Compound I-17 was prepared as a white solid by replacing (R)-8-bromo-4-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazole (Intermediate A1).
- Step 1 (R)-8-bromo-2-(8-iodo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-4-methyl-1, Preparation of 2,3,4-tetrahydropyrazine[1,2-b]indazole (Intermediate I-19-1)
- intermediate I-19-1 refers to intermediate I-8-1, by using 5-chloro-8-iodo-[1,2,4]triazolo[1,5-a]pyridine (intermediate A13 ) instead of 3,4-difluoropyrazolo[1,5-a]pyridine-7-carbonitrile (Intermediate A9) to prepare Intermediate I-19-1.
- Compound I-23 was synthesized with reference to Compound I-1 by using (5-oxo-2,8-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester instead of piperazine-1-carboxylic acid tert-butyl
- the butyl ester was prepared to give compound 1-23 as a white solid.
- Compound I-29 was synthesized with reference to Compound I-25, and Compound I-29 was prepared as a white solid by using Compound I-6 instead of Compound I-1.
- Step 1 (R)-4-(2-(8-Iodo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-4-methyl-1,2 , Preparation of 3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)piperidine-1-carboxylic acid tert-butyl ester (intermediate I-30-1)
- intermediate I-30-1 refers to intermediate I-19-1, by using (R)-4-(4-methyl-1,2,3,4-tetrahydropyrazino[1,2- b] Indazol-8-yl)piperidine-1-carboxylate tert-butyl ester (Intermediate A7) instead of (R)-8-bromo-4-methyl-1,2,3,4-tetrahydropyrazine And [1,2-b] indazole (intermediate A1) prepared intermediate I-30-1. MS: 614.1 (M+H) + .
- Step 2 (R)-2-(8-iodo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-4-methyl-8-(piperidine- Preparation of 4-yl)-1,2,3,4-tetrahydropyrazine[1,2-b]indazole
- Compound I-31 was synthesized with reference to Compound I-8 by using 4-fluoropyrazolo[1,5-a]pyridine-7-carbonitrile (Intermediate A8) instead of 3,4-difluoropyrazolo[1,5 -a] Pyridine-7-carbonitrile (Intermediate A9) to prepare compound I-31 as a yellow solid.
- Step 1 (R)-4-(2-(8-cyano-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-4-methyl-1,2 , Preparation of 3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)piperidine-1-carboxylic acid tert-butyl ester (intermediate I-32-1)
- intermediate I-32-1 refers to intermediate A9, by using (R)-4-(2-(8-iodo-[1,2,4]triazolo[1,5-a]pyridine- 5-yl)-4-methyl-1,2,3,4-tetrahydropyrazino[1,2-b]indazol-8-yl)piperidine-1-carboxylic acid tert-butyl ester (intermediate I-30-1) was substituted for 7-bromo-3,4-difluoropyrazolo[1,5-a]pyridine (intermediate A9-2) to prepare compound I-32-1.
- Step 2 (R)-5-(4-Methyl-8-(piperidin-4-yl)-3,4-dihydropyrazin[1,2-b]indazol-2(1H)-yl )-[1,2,4]triazolo[1,5-a]pyridine-8-carbonitrile
- Step 1 (R)-2-(4-Benzylpiperazin-1-yl)-8-methyl-7,8-dihydropyridin[2',3':3,4]pyrazolo[1 ,5-a] Preparation of pyrazin-5(6H)-one (intermediate I-33-1)
- Step 2 (R)-4-(2-(4-Benzylpiperazin-1-yl)-8-methyl-5-oxo-7,8-dihydropyridine[2',3':3 ,4] Preparation of pyrazolo[1,5-a]pyrazin-6(5H)-yl)-3-fluoropyrazolo[1,5-a]pyridine-7-carbonitrile (intermediate I-33 -2)
- Step 3 (R)-3-fluoro-4-(8-methyl-5-oxo-2-(piperazin-1-yl)-7,8-dihydropyridine[2',3':3 ,4] Preparation of pyrazolo[1,5-a]pyrazin-6(5H)-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile (compound I-33)
- Compound I-34a and Compound I-34b 5-((1S,4R)-1,4-dimethyl-8-(piperazin-1-yl)-3,4-dihydropyrazino[1, 2-b]indazole-2(1H)-yl)quinoline-8-carbonitrile and 5-((1R,4R)-1,4-dimethyl-8-(piperazin-1-yl)- 3,4-Dihydropyrazino[1,2-b]indazole-2(1H)-yl)quinoline-8-carbonitrile
- Step 1 4-(7-Chloro-5-methyl-1,3,4,5-tetrahydro-2H-pyrrole[3,2-c:4,5-c']bipyridin-2-yl) -3-fluoropyrazolo[1,5-a]pyridine-7-carbonitrile (I-36-1)
- Step 2 4-(2-(7-cyano-3-fluoropyrazol[1,5-a]pyridin-4-yl)-5-methyl-2,3,4,5-tetrahydro-1H -pyrrole
- Step 3 3-fluoro-4-(5-methyl-7-(piperidin-4-yl)-1,3,4,5-tetrahydro-2H-pyrrole[3,2-c:4,5 -c']bipyridin-2-yl)pyrazol[1,5-a]pyridine-7-carbonitrile (I-36)
- Compound I-45 was synthesized with reference to compound I-44 by using ((3R,5S)-5-fluoropiperidin-3-yl)carbamate tert-butyl ester instead of ((3R,5S)-5-(trifluoroform yl) piperidin-3-yl) tert-butyl carbamate to obtain compound I-45 as a white solid. MS: 463.2 (M+H) + .
- Step 1 3-Hydroxy-4-((R)-4-methyl-1,2,3,4-tetrahydropyrazin[1,2-b]indazole-8-yl)piperidine-1 - Preparation of tert-butyl carboxylate (intermediate I-48-1)
- Step 2 4-((R)-2-(7-cyano-3-fluoropyrazol[1,5-a]pyridin-4-yl)-4-methyl-1,2,3,4- Preparation of tert-butyl tetrahydropyrazine[1,2-b]indazol-8-yl)-3-hydroxypiperidine-1-carboxylate (intermediate I-48-2)
- Step 3 4-((R)-2-(7-cyano-3-fluoropyrazol[1,5-a]pyridin-4-yl)-4-methyl-1,2,3,4- Preparation of tetrahydropyrazine[1,2-b]indazol-8-yl)-3-fluoropiperidine-1-carboxylate tert-butyl ester (intermediate I-48-3)
- Step 4 3-fluoro-4-((4R)-8-(3-fluoropyridin-4-yl)-4-methyl-3,4-dihydropyrazine[1,2-b]indazole- Preparation of 2(1H)-yl)pyrazolo[1,5-a]pyridine-7-carbonitrile (Compound I-48)
- Step 1 (S)-2-(4-((R)-2-(7-cyano-3-fluoropyrazol[1,5-a]pyridin-4-yl)-4-methyl-1 ,2,3,4-Tetrahydropyrazine[1,2-b]indazol-8-yl)piperidine-1-carbonyl)-4,4-difluoropyrrolidine-1-carboxylic acid tert-butyl ester Preparation (I-57-1)
- Step 2 4-((R)-8-(1-((S)-4,4-difluoropyrrolidine-2-carbonyl)piperidin-4-yl)-4-methyl-3,4- Preparation of Dihydropyrazine[1,2-b]indazol-2(1H)-yl)-3-fluoropyrazol[1,5-a]pyridine-7-carbonitrile (I-57)
- Step 2 (R)-2-(4-(2-(7-cyano-3-fluoropyrazol[1,5-a]pyridin-4-yl)-4-ethyl-1,2,3 , Preparation of 4-tetrahydropyrazine [1,2-b] indazol-8-yl) piperidin-1-yl) acetamide (I-61)
- Compound I-101 was synthesized with reference to compound I-44 by using (2R, 5S)-2,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester instead of ((3R, 5S)-5-(trifluoro Methyl)piperidin-3-yl)carbamate tert-butyl ester to obtain white solid compound I-101.
- Compound I-103 was synthesized with reference to Compound I-44 by using 3,8-diazacyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester instead of ((3R,5S)-5-(trifluoro Methyl)piperidin-3-yl)carbamate tert-butyl ester to obtain white solid compound I-103.
- Compound 1-104 was synthesized with reference to compound 1-44 by using ((3R, 4S)-3-fluoropiperidin-4-yl)carbamate tert-butyl ester instead of ((3R, 5S)-5-(trifluoroform base) piperidin-3-yl) tert-butyl carbamate to obtain white solid compound I-104. MS: 463.2 (M+H) + .
- Compound I-105 was synthesized with reference to compound I-44 by using 3,8-diazacyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester instead of ((3R,5S)-5-(trifluoro Methyl)piperidin-3-yl)carbamate tert-butyl ester to obtain white solid compound I-105.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Immunology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一类Toll样受体抑制剂及其制备和应用,具体地,提供了一种式I所示的化合物,及其制备方法和作为TLR7和/或TLR8抑制剂的用途。所述的化合物可以用于制备治疗或预防自身免疫性疾病或慢性炎性疾病的药物组合物。
Description
本发明涉及小分子药物化合物领域,具体地,本发明提供了一类Toll样受体抑制剂及其制备和应用。
自身免疫疾病是一系列慢性全身性炎症性疾病,其特征是免疫系统失调,最终导致对自身抗原的耐受性下降。尽管这些疾病的确切病因和发病机制仍不清楚,但先天和适应性免疫系统的异常过程已证明参与这些疾病的发生。多个研究表明Toll样受体(Toll-like receptors,TLRs)在各种自身免疫性疾病中起着重要作用,包括干燥综合征,系统性红斑狼疮,多发性硬化症,类风湿性关节炎,系统性硬化症和牛皮癣。
TLRs是一类结构保守的蛋白质,在先天免疫反应中形成第一道屏障。通过识别各种保守的病原体相关分子模式(pathogen-associated molecular patterns,PAMP),TLRs可以识别侵入性微生物和组织损伤或非生理性细胞死亡后释放的内源性分子,并激活信号级联反应,从而产生促炎性细胞因子。人TLRs家族有10个已知成员,它们是I型跨膜蛋白,其特征是具有富含亮氨酸的胞外结构域和包含保守的Toll/白介素-1受体(Toll/interleukin(IL)-1receptor,TIR)结构域的胞质尾巴。在该家族中,TLR3、TLR7、TLR8和TLR9位于内涵体隔室。内涵体TLRs识别病毒和内源的双链RNA(dsRNA;TLR3),单链RNA(ssRNA;TLR7/8)或未甲基化的CpG序列(TLR9)。
TLR7和8与某些针对自身RNA和DNA/蛋白质复合物的自身免疫疾病的病因有关,这些RNA和DNA/蛋白质最有可能在正常细胞死亡和清除期间释放。现在,大量的科学证据将TLR7/8途径的不适当的持续内源性激活与自身免疫疾病中对自身抗原的持续反应联系起来。已经证明TLR7在系统性红斑狼疮的发病机理中起作用。此外,TLR8多态性与类风湿关节炎有关。由于多数自身免疫性疾病可能会受益于涉及调节细胞因子,干扰素(interferon,IFN)的产生和B细胞活性的治疗,因此调节TLR7和/或TLR8活性的化合物以及使用这些化合物的方法可为多种自身免疫性患者提供实质的治疗益处。
综上所述,本领域迫切需要提供一种可以用于调节TLR7和/或TLR8活性的化合物。
发明内容
本发明的目的是提供一种可以用于调节TLR7和/或TLR8活性的化合物。
本发明的第一方面,提供了一种如下式I所示的化合物,其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物:
其中,
U选自下组:C、或N;
J选自下组:C或N;
W为N、CR
x或NR
y;其中,所述的R
x选自下组:H,卤素,C
1-6烷基,C
1-6烷氧基,卤代C
1-6烷基,或C
3-7环烷基;R
y选自下组:H、C
1-6烷基,卤代C
1-6烷基,或C
3-7环烷基;
R
1选自下组:取代或未取代的5元并6元杂芳基、取代或未取代的6元并6元杂芳基;
R
2、R
3、R
4、R
5、R
6、R
7各自独立地选自下组:H、C
1-6烷氧基、卤代C
1-6烷基、C
1-6烷基、卤素、氰基、C
3-7环烷基,或R
2、R
3、R
4、R
5、R
6、R
7中位于相同碳原子上的两个共同构成=O;
或R
2和R
3与它们相连的碳原子、R
4和R
5与它们相连的碳原子、R
6和R
7与它们相连的碳原子共同形成取代或未取代的3-至6-元环烷基、或取代或未取代的3-至6-元杂环基;
L选自下组:化学键、C=O、O、S、N(La)、C
3-9环烷基、C
3-9杂环烷基或C
1-6烷基;其中,所述的La选自下组:H、C
3-9环烷基、C
3-9杂环烷基或C
1-6烷基;
R
8选自下组:H、卤素、OH、NH
2、氰基、C(O)NH
2、取代或未取代的3-至9-元碳环基(饱和、不饱和的单环、螺环、并环或桥环)、或取代或未取代的3-至9-元杂环基(饱和、不饱和的单环、螺环、并环或桥环);
X、Y、Z和V各自独立地选自下组:N或C(R
15);所述的L-R
8位于X、Y、Z和V中任一原子上,且当L-R
8位于X、Y、Z或V时,对应原子为C(R
15),且此时R
15被L-R
8替代;
R
15选自下组:H、C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷基、C
3-7环烷基或卤素;
其中,所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、羟基、羧基、苄基、氧代(=O)、-(CH
2)
nN(R
8-1R
8-2)、-(CH
2)
nC(O)N(R
8-1R
8-2)、C(CH
3)
2N(R
8-
1R
8-2)、-(CH
2)
nC(O)OH、(CH
2)
nSO
2R
8-1、-(CH
2)
nC(O)R
8-3、-C(O)(CH
2)
nR
8-3、氨基、C
1-
6烷基NHS(O)
2-、C
1-6烷基NHC(O)-、-C(O)(CH
2)
nN(R
8-1R
8-2)、-SO
2(CH
2)
nN(R
8-1R
8-2)、(CH
2)
nSO
2N(R
8-1R
8-2)、硝基、氰基、未取代或卤代的C
1-C
6烷基、C
2-C
10烯基、C
1-C
6烷氧基、C
1-C
6烷基-胺基、C
6-C
10芳基、五元或六元杂芳基、-O-(C
6-C
10芳基)、-O-(五元 或六元杂芳基)、取代或未取代的C
3-7杂环烷基;其中所述的R
8-1、R
8-2选自下组:氢、C
1-6烷基、C
1-6卤代烷基、C
3-6环烷基、4-6元杂环烷基、或R
8-1和R
8-2与它们相连接的N共同形成“杂原子为N、或者N和O,杂原子数为1个或2个的4-6元杂环烷基”,所述的环烷基和杂环烷基可以被一个或多个卤素取代;其中所述的R
8-3选自下组:氢、C
1-6烷基、C
1-6烷氧基、C
1-6卤代烷基、C
3-6环烷基、或4-6元杂环烷基,所述的环烷基和杂环烷基可以被一个或多个卤素或C
1-6烷基取代;n为0、1、2、3、4、5或6。
在另一优选例中,所述的R
1选自下组:
其中,A
1、A
2、A
3、A
4、A
5、A
6、B
1、B
2、B
3、B
4各自独立地选自下组:CR、N、NR
14;
A
7、A
8各自独立地选自下组:C、N;
所述的R
14选自下组:H、C
1-6烷基、卤素取代的C
1-6烷基、C
3-7环烷基;
各个R各自独立地选自下组:H、卤素、氰基、C
1-6烷基、C
1-6烷氧基、C
3-7环烷基、Ra取代的C
1-6烷基、或Rb取代的C
1-6烷氧基;其中,所述的Ra和Rb各自独立地选自下组:OH、卤素、氰基、C
1-3烷基或C
1-3烷氧基。
在另一优选例中,所述的R
1选自下组:
R
9、R
10、R
11、R
12和R
13各自独立地选自下组:H、卤素、氰基、C
1-6烷基、C
1-6烷氧基、C
3-7环烷基、Ra取代的C
1-6烷基、或Rb取代的C
1-6烷氧基;其中,所述的Ra和Rb各自独立地选自下组:OH、卤素、氰基、C
1-3烷基或C
1-3烷氧基;
R
14选自下组:H、C
1-6烷基、卤素取代的C
1-6烷基、C
3-7环烷基;
M选自下组:CH或N。
在另一优选例中,M为CH。
在另一优选例中,所述的式I化合物具有如下式II所示的结构:
其中,各基团的定义如本发明第一方面中所述。
在另一优选例中,所述的R
6和R
7共同构成C=O。
在另一优选例中,所述的R
8选自下组:H、卤素、OH、NH
2、氰基、C(O)NH
2、CH
2C(O)NH
2、取代或未取代的5-至9-元碳环基、取代或未取代的5-至9-元杂环基。
在另一优选例中,所述的R
8选自下组:H、卤素、OH、NH
2、氰基、C(O)NH
2、CH
2C(O)NH
2、取代或未取代的5-至9-元碳环基、取代或未取代的5-至9-元氮杂环基。
在另一优选例中,所述的式I化合物具有如下式III-1或III-2所示的结构:
各基团的定义如上文中所述。
在另一优选例中,所述的式I化合物具有如下式IV-1或IV-2所示的结构;
各基团的定义如上文中所述。
在另一优选例中,所述的式I化合物中,R
2、R
3各自独立地选自下组:C
1-6烷氧基、卤代C
1-6烷基、C
1-6烷基、氰基、C
3-7环烷基;R
6和R
7各自独立地为H或甲基;或所述的R
6和R
7共同构成C=O。
在另一优选例中,L选自下组:化学键、C=O;
R
8选自下组:取代或未取代的3-至9-元碳环基(饱和、不饱和的单环、螺环、并环或桥环)、或取代或未取代的3-至9-元杂环基(饱和、不饱和的单环、螺环、并环或桥环);其中,所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、羟基、羧基、苄基、氧代(=O)、-(CH
2)
nN(R
8-1R
8-2)、-(CH
2)
nC(O)N(R
8-1R
8-2)、C(CH
3)
2N(R
8-1R
8-2)、-(CH
2)
nC(O)OH、(CH
2)
nSO
2R
8-1、-(CH
2)
nC(O)R
8-3、-C(O)(CH
2)
nR
8-
3、C
1-6烷基NHS(O)
2-、C
1-6烷基NHC(O)-、-C(O)(CH
2)
nN(R
8-1R
8-2)、-SO
2(CH
2)
nN(R
8-1R
8-
2)、(CH
2)
nSO
2N(R
8-1R
8-2)、氰基、未取代或卤代的C
1-C
6烷基、取代或未取代的C
3-7杂环烷基;其中所述的R
8-1、R
8-2选自下组:氢、C
1-6烷基、C
1-6卤代烷基、C
3-6环烷基、4-6元杂环烷基、或R
8-1和R
8-2与它们相连接的N共同形成“杂原子为N、或者N和O,杂原子数为1个或2个的4-6元杂环烷基”,所述的环烷基和杂环烷基可以被一个或多个 卤素取代;其中所述的R
8-3选自下组:氢、C
1-6烷基、C
1-6烷氧基、C
1-6卤代烷基、C
3-6环烷基、或4-6元杂环烷基,所述的环烷基和杂环烷基可以被一个或多个卤素或C
1-6烷基取代;n为0、1或2。
在另一优选例中,所述的R
8选自下组:取代或未取代的3-至9-元碳环基(饱和、不饱和的单环、并环或桥环)、或取代或未取代的3-至9-元杂环基(饱和、不饱和的单环、并环或桥环)。
本发明的第二方面,提供了一种药物组合物,所述的药物组合物包括:如本发明第一方面所述的式I化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种,以及一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
本发明的第三方面,提供了一种如本发明第一方面所述的式I化合物,其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物的用途,其用于制备治疗或预防自身免疫性疾病或者慢性炎性疾病的药物组合物。
在另一优选例中,所述的疾病选自下组:干燥综合征,系统性红斑狼疮,多发性硬化症,类风湿性关节炎、系统性硬化症、牛皮癣、系统性红斑狼疮、狼疮肾炎。
在另一方面,本发明提供了一种缀合物,所述的缀合物是用如本发明所述的化合物和生物小分子或单抗通过化学键相连得到的。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
本发明人经过长期而深入的研究,发现了一类具有TLR7和/或TLR8抑制活性的小分子化合物,所述的化合物结构新颖,且具有与现有技术中同类化合物相当或更为优异的抑制活性。基于上述发现,发明人完成了本发明。
术语
在本发明中,所述卤素为F、Cl、Br或I。
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义。
在本发明中,术语“C
1-C
6烷基”是指具有1至6个碳原子的直链或支链烷基,非限制性地包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基和已基等;优选乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基。
在本发明中,术语“C
1-C
6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基,非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。
在本发明中,术语“C
3-C
7环烷基”是指在环上具有3至7个碳原子的环状烷基,非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。术语“C
5-C
6环烷基”、和“C
3-C
6环烷基”具有类似的含义。
在本发明中,术语“芳环”或“芳基”具有相同的含义,优选地“芳基”为“C
6-C
12芳基”或“C
6-C
10芳基”。术语“C
6-C
12芳基”是指在环上不含杂原子的具有6至12个碳原子的芳香族环基,如苯基、萘基等。术语“C
6-C
10芳基”具有类似的含义。
在本发明中,术语“芳香杂环”或“杂芳基”具有相同的含义,指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂 芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中,术语“3-9元碳环基”是指在饱和或不饱和(非芳香性环,包括单环,并环,螺环,桥环等形式)的3-9元环基,其环骨架结构仅包括碳原子,例如环戊基、环己基等。
在本发明中,术语“3-9元杂环基”是指在环上含有1~3个选自氧、硫和氮中的杂原子的饱和或不饱和(非芳香性环,包括单环,并环,螺环,桥环等形式)的3-9元环基,例如二氧杂环戊基等。术语“3-7元杂环基”具有类似的含义。
在本发明中,术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基,或各实施例中所出现的取代基。除非特别说明,某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或不同的。环状取代基,例如杂环烷基,可以与另一个环相连,例如环烷基,从而形成螺二环系,例如,两个环具有一个共用碳原子。本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于):C
1-8烷基、C
2-8烯基、C
2-
8炔基、C
3-8环烷基、3-至12-元杂环基,芳基、杂芳基、卤素、羟基、羧基(-COOH)、C
1-8醛基、C
2-10酰基、C
2-10酯基、氨基、烷氧基、C
1-10磺酰基等。
具有TLR7和/或TLR8调节活性的式I化合物
本发明提供了一种如下式I所示的化合物,其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物:
其中,
U选自下组:C或N;
J选自下组:C或N;
W为N、CR
x或NR
y;其中,所述的R
x选自下组:H,卤素,C
1-6烷基,C
1-6烷氧基,卤代C
1-6烷基,或C
3-7环烷基;R
y选自下组:H、C
1-6烷基,卤代C
1-6烷基,或C
3-7环烷基;
R
1选自下组:取代或未取代的5元并6元杂芳基、取代或未取代的6元并6元杂芳基;
R
2、R
3、R
4、R
5、R
6、R
7各自独立地选自下组:H、C
1-6烷氧基、卤代C
1-6烷基、C
1-6烷基、氰基、C
3-7环烷基,或R
2、R
3、R
4、R
5、R
6、R
7中位于相同碳原子上的两个共同构成=O;
或R
2和R
3与它们相连的碳原子、R
4和R
5与它们相连的碳原子、R
6和R
7与它们相连的碳原子共同形成取代或未取代的3-至6-元环烷基、或取代或未取代的3-至6-元杂环 基;
L选自下组:化学键、C=O、O、S、N(La)、C
3-9环烷基、C
3-9杂环烷基(优选为C
3-
7环烷基、C
3-7杂环烷基)或C
1-6烷基;其中,所述的La选自下组:H、C
3-9环烷基、C
3-9杂环烷基(C
3-7环烷基、C
3-7杂环烷基)或C
1-6烷基;
R
8选自下组:H、卤素、OH、NH
2、氰基、C(O)NH
2、取代或未取代的3-至9-元碳环基(饱和、不饱和的单环、螺环、并环或桥环)、或取代或未取代的3-至9-元杂环基(饱和、不饱和的单环、螺环、并环或桥环);
X、Y、Z和V各自独立地选自下组:N或C(R
15);所述的L-R
8位于X、Y、Z和V中任一原子上,且当L-R
8位于X、Y、Z或V时,对应原子为C(R
15),且此时R
15被L-R
8替代;
R
15选自下组:H、C
1-6烷基、C
1-6烷氧基、卤代C
1-6烷基、C
3-7环烷基或卤素;
其中,所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、羟基、羧基、苄基、氧代(=O)、C
2-C
6烷氧基羰基、(CH
2)
nNH
2、(CH
2)
nC(O)NH
2、(CH
2)
nC(O)OH、氨基、C
2-C
6酰胺基(C
1-5烷基NHC(O)-)、C
1-C
6磺酰胺基(C
1-6烷基NHS(O)
2-)、C(O)(CH
2)
nNH
2、SO
2(CH
2)
nNH
2、(CH
2)
nSO
2NH
2、硝基、氰基、未取代或卤代的C
1-C
6烷基、C
2-C
10烯基、C
1-C
6烷氧基、C
1-C
6烷基-胺基、C
6-C
10芳基、五元或六元杂芳基、-O-(C
6-C
10芳基)、-O-(五元或六元杂芳基)、取代或未取代的C
3-7杂环烷基;n为0、1或2。
式I化合物的制备方法
本发明还提供了上述的如式I所示的化合物的制备方法,其为如下任一方法:
方法1,其包括以下步骤:溶剂中,在碱的作用下,如式III所示的化合物和如式IV所示的化合物进行反应,得如式I所示的化合物
Q
1为氟、氯或溴,R
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、X、Y、Z、U、V、W和L的定义如前所述;
方法2,其包括以下步骤:溶剂中,在碱的作用下,如式VIII所示的化合物和如式I-1所示的化合物进行取代反应,得如式I所示的化合物;
Q
2为OMs、氟、氯或溴,R
8’为“杂原子选自N、O和S中的一种或多种,杂原子数为1~3个的3~9元杂环烷基”;R
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、X、Y、Z、U、V、W和L的定义如前所述。
R
8-1为“杂原子选自N、O和S中的一种或多种,杂原子数为1~3个的3~7元杂环烷基”、杂原子数为1~4个的C
1~C
10杂芳基”、杂原子数为1~3个取代或未取代的C
1~C
6 烷基、杂原子数为1~3个取代或未取代的C
3~C
7环烷基,C
1-C
6烷氧基羰基、(CH
2)
nNH
2、(CH
2)
nC(O)NH
2、(CH
2)
nC(O)OH、C
1-C
6酰胺基、C
1-C
6磺酰胺基、C(O)(CH
2)
nNH
2、SO
2(CH
2)
nNH
2、(CH
2)
nSO
2NH
2、未取代或卤代的C
1-C
6烷基、C
2-C
10烯基、C
1-C
6烷氧基、C
1-C
6烷基-胺基、C
6-C
10芳基、五元或六元杂芳基;n为0、1或2。
方法3,其包括以下步骤:溶剂中,在碱的作用下,如式III所示的化合物和如式V所示的化合物进行反应的到化合物VI,化合物VI经脱保护得到如式I所示的化合物
Q
1为氟、氯或溴,T为氯或溴,R
8-2为叔丁氧羰基、苄基、4-甲氧苄基、2,4-二甲氧苄基等保护基保护的R
8,R
1、R
2、R
3、R
4、R
5、R
6、R
7、R
8、X、Y、Z、U、V、W和L的定义如前所述。
含有活性成分的药物组合物
由于本发明化合物具有优异的Toll样受体的抑制活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)Toll样受体(特别是TLR7、8)的异常表达或激活相关的疾病或病症,如自身免疫性疾病或者慢性炎性疾病;较佳地,所述的自身免疫性疾病选自下组:干燥综合征,系统性红斑狼疮,多发性硬化症,类风湿性关节炎、系统性硬化症、牛皮癣、系统性红斑狼疮、狼疮肾炎。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有0.01-99.99%重量百分比的本发明化合物/剂,更佳地,含有0.1-99.9%本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f) 吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物(例如抗-HBV剂)联合给药。
联合给药时,所述药物组合物还包括与一种或多种(2种,3种,4种,或更多种)其他药学上可接受的化合物。该其他药学上可接受的化合物中的一种或多种(2种,3种,4种,或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗Toll样受体(特别是TLR7、8)的异常表达或激活相关的疾病或病症。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
以下实施例中,化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10
-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d
6)、氘代氯仿(CDCl
3)、氘代甲醇(CD
3OD),内标为四甲基硅烷(TMS)。
SHIMADZU LC系统(色谱柱:
CSH
TM Prep-C18,19*150mm,液体处理机LH-40,泵LC-20AP,检测器SPD-20A,系统控制器CBM-20A,溶剂系统:乙腈和0.05%三氟乙酸水溶液)。
使用LC/MS(Agilent Technologies 1200 Series)获得化合物的LC/MS光谱。LC/MS条件如下(运行时间为10分钟):
酸性条件:A:0.05%三氟乙酸的水溶液;B:0.05%三氟乙酸的乙腈溶液;
碱性条件:A:0.05%NH
3·H
2O的水溶液;B:乙腈
中性条件:A:10mM NH
4OAC的水溶液;B:乙腈
如无特别说明,以下实施例中,中间体和最终化合物使用硅胶柱色谱法纯化、或使用
CSH
TM Prep-C18(5μm,OBD
TM 19*150mm)色谱柱或使用XBridgeTM Prep Phenyl(5μm,OBD
TM 30*100mm)在反相色谱柱上通过制备性HPLC纯化。
硅胶柱色谱法一般使用烟台黄海硅胶200~300目硅胶为载体。
CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。
薄层色谱法(TLC)硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层层析检测产品使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成,或可购买自ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
缩略词:Ac
2O:醋酐;AIBN:偶氮二异丁腈;BINAP:1,1'-联萘-2,2'-双二苯膦;Boc
2O:碳酸叔丁氧基羰基叔丁酯;Conc.HCl:浓盐酸;Cs
2CO
3:碳酸铯;DCM:二氯甲烷;DCE:1,2-二氯乙烷;DIAD:偶氮二甲酸二异丙酯;Dioxane:1,4-二氧六环;DIEA:N,N-二异丙基乙胺;DMAP:4-二甲氨基吡啶;DMF:二甲基甲酰胺;DMSO:二甲基亚砜;DMF-DMA:1,1-二甲氧基-N,N-二甲基-甲胺;EtOH:乙醇;Ethyl propiolate:丙酸乙酯;HOAc;醋酸;H
2:氢气;I
2:碘;K
2CO
3:碳酸钾;K
3PO
4:磷酸钾;LiAlH
4:氢化铝锂;LiHMDS:双三甲基硅基胺基锂;LiOH:氢氧化锂;mCPBA:间氯过氧苯甲酸;MeOH:甲醇;NaH:氢化钠;NaHCO
3:碳酸氢钠;NaHMDS:双(三甲基硅基)氨基钠;PPA:多聚磷酸;PCy3:三环己基膦;Pd(dppf)Cl
2:[1,1'-双(二苯基膦基)二茂铁]二氯化钯;Pd(OAc)
2:醋酸钯;Pd/C:钯碳;Pd
2(dba)
3:三(二亚苄基丙酮)二钯;Pd(PPh
3)
4:四三苯基膦钯;POCl
3:三氯氧磷;PPh
3:三苯基膦;t-BuOK:叔丁醇钾;t-BuLi:叔丁基锂;KF:氟化钾;TEA:三乙胺;TFA:三氟乙酸;TFAA:三氟乙酸酐;TfOH:三氟甲磺酸;THF:四氢呋喃;TLC:薄层层析;TMP:磷酸三甲酯;XantPhos:4,5-双(二苯基膦)-9,9-二甲基氧杂蒽;Zn:锌;ZnCl
2:氯化锌;Zn(CN)
2:氰化锌。
制备例 中间体A1(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑的制备
步骤1:(S)-1-((4-甲氧基苄基)氨基)丙-2-醇的制备(中间体A1-2)
将(S)-1-氨基丙烷-2-醇(10.00克,133毫摩尔)和4-甲氧基苯甲醛(18.13克,133毫摩尔)溶于乙醇(200毫升)中。在20度搅拌下缓慢加入NaBH
4(7.56克,200毫摩尔),加完后,将反应混合物在20度继续搅拌3小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃 取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到浅黄色油状物(S)-1-((4-甲氧基苄基)氨基)丙-2-醇(20克,77%)。MS:196.1(M+H)
+。
步骤2:(S)-6-溴-N-(2-羟丙基)-N-(4-甲氧基苄基)-1H-吲唑-3-甲酰胺的制备(中间体A1-4)
将6-溴-1H-吲哚唑-3-羧酸(5.00克,20.74毫摩尔),N-乙基-N-异丙基-2-胺(16.09克,124毫摩尔),DMAP(0.507克,4.15毫摩尔)和2.5克4A分子筛(4A MS)加到DMF(5毫升)中。在15度搅拌下缓慢加入HATU(7.89克,20.74毫摩尔),加完后,将反应混合物在15度继续搅拌2小时,然后将(S)-1-((4-甲氧基苄基)氨基)丙-2-醇(4.86克,24.89毫摩尔)加入到上述反应混合物中,加完后,将反应混合物在15度继续搅拌3小时。然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色油状物(S)-6-溴-N-(2-羟丙基)-N-(4-甲氧基苄基)-1H-吲唑-3-甲酰胺(3.66克,42.2%)。MS:418.1&420.1(M+H)
+。
步骤3:(R)-8-溴-2-(4-甲氧基苄基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-1(2H)-酮的制备(中间体A1-5)
将(S)-6-溴-N-(2-羟丙基)-N-(4-甲氧基苄基)-1H-吲唑-3-甲酰胺(3.66克,8.75毫摩尔)和三苯基膦(3.44克,13.12毫摩尔)溶于THF(80毫升)中。在20度搅拌下缓慢加入偶氮二甲酸二异丙酯(2.65克,13.12毫摩尔),加完后,将反应混合物在25度继续搅拌16小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色油状物(R)-8-溴-2-(4-甲氧基苄基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-1(2H)-酮(3.1克,89%)。MS:400.1&402.1(M+H)
+。
步骤4:(R)-8-溴-2-(4-甲氧基苄基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑的制备(中间体A1-6)
将(R)-8-溴-2-(4-甲氧基苄基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-1(2H)-酮(6.64克,16.59毫摩尔)溶于无水四氢呋喃(5毫升)中,在0度搅拌缓慢加入铝锂氢(33.2毫摩尔),加完后,将反应混合物继续搅拌0.5小时,然后加入冰水和酒石酸钾钠淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色油状物(R)-8-溴-2-(4-甲氧基苄基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(5.84克,91%)。MS:386.1&388.1(M+H)
+。
步骤5:(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑的制备(中间体A1)
将(R)-8-溴-2-(4-甲氧基苄基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(0.5克,1.294毫摩尔)溶于TFA(10毫升)中。将反应混合物在80度搅拌反应3小时,然后浓缩反应混合物,并用乙酸乙酯稀释萃取。有机相用饱和碳酸氢钠溶液,饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到黄色油状物(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(0.344克,100%)。MS:266.1&268.1(M+H)
+。
制备例 中间体A2(S)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑的制备
中间体A2的合成参考中间体A1,通过使用(R)-1-氨基丙醇-2-醇代替(S)-1-氨基丙醇-2-醇制备得到中间体A2。MS:266.1&268.1(M+H)
+。
制备例 中间体A3(R)-7-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑的制备
中间体A3的合成参考中间体A1,通过使用7-溴-1H-吲唑-3-羧酸代替6-溴-1H-吲唑-3-羧酸制备得到中间体A3。MS:266.1&268.1(M+H)
+。
制备例 中间体A4(R)-9-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑的制备
中间体A4的合成参考中间体A1,通过使用5-溴-1H-吲唑-3-羧酸代替6-溴-1H-吲唑-3-羧酸制备得到中间体A4。MS:266.1&268.1(M+H)
+。
制备例 中间体A5 8-溴-4-乙基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑的制备
中间体A5的合成参考中间体A1,通过使用1-氨基丁醇代替(S)-1-氨基丙烷-2-醇制备得到中间体A5。MS:280.1&282.1(M+H)
+。
制备例 中间体A6(R)-4-(4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌嗪-1-羧酸叔丁酯的制备
将Pd
2(dba)
3(138毫克,0.15毫摩尔),碳酸铯(1469毫克,4.51毫摩尔),二环己基(2',6'-二异丙氧基-[1,1'-联苯]-2-基)膦(70.1毫克,0.15毫摩尔),哌嗪-1-羧酸叔丁酯(560毫克,3.01毫摩尔)和(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A1,400毫克,1.50毫摩尔)溶于DMF(20毫升)中。反应混合物在氮气的保护下缓慢升至100℃并搅拌16小时,然后反应混合液用水稀释并用乙酸乙酯萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固 体(R)-4-(4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌嗪-1-羧酸叔丁酯(100毫克,17.9%)。MS:372.1(M+H)
+。
制备例 中间体A7(R)-4-(4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌啶-1-羧酸叔丁酯的制备
步骤1:(R)-4-(4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的制备(中间体A7-2)
将(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A1,0.3克,1.13毫摩尔),碳酸钾(0.467克,3.38毫摩尔),PdCl
2(dppf)(0.082克,0.113毫摩尔)和4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(0.523克,1.69毫摩尔)溶于二氧六环(10毫升)和水(2毫升)中。反应混合物在氮气的保护下缓慢升至80℃并搅拌16小时,然后反应混合液用水稀释并用乙酸乙酯萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色油状物(R)-4-(4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(0.16克,38%)。MS:369.1(M+H)
+。
步骤2:(R)-4-(4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌啶-1-羧酸叔丁酯的制备(中间体A7)
将(R)-4-(4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(0.16克,0.434毫摩尔)溶于乙酸乙酯(5毫升)中,在搅拌条件下向反应混合物中加入钯碳(5.21毫克)。反应混合物在20度氢气压力下搅拌16小时,然后将混合物溶液过滤。将滤液真空浓缩,得到黄色油状物(R)-4-(4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌啶-1-羧酸叔丁酯(0.161克,100%)。MS:371.1(M+H)
+。
制备例 中间体A8 4-氟吡唑并[1,5-a]吡啶-7-腈的制备
步骤1:(E)-N-((甲磺酰基磺酰氧基)氧基)乙酰亚胺酸乙酯的制备(中间体A8-1)
将(1E)-N-羟基乙酰胺基乙酯(100克,969.7毫摩尔),DMAP(12克,98.2毫摩尔)和DIEA(155克,1.2摩尔)溶于无水二氯甲烷(30毫升)中,在0℃时搅拌缓慢加入3,4,5-三甲基苯磺酰氯(233克,1.07摩尔)。滴完后,将反应混合物缓慢升至室温并搅拌1小时,然后加入冰水淬灭反应,并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到白色固体(E)-N-((甲磺酰基磺酰氧基)氧基)乙酰亚胺酸乙酯(220克,72.3%)。MS:286.2(M+H)
+。
步骤2:O-(间甲磺酰基)羟胺的制备(中间体A8-2)
将(E)-N-((甲磺酰基磺酰基)氧基)乙酰亚胺酸乙酯(220克,771.0毫摩尔)溶于无水1,4-二氧六环(600毫升)中,在0℃时搅拌缓慢加入高氯酸(120毫升)。滴完后,将反应混合物在0℃搅拌1小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物用石油醚-乙酸乙酯重结晶得到白色固体O-(间甲磺酰基)羟胺(80克,42%)。MS:216.2(M+H)
+。
步骤3:1-氨基-2-溴-5-氟吡啶-1-鎓2,4,6-三甲基苯磺酸盐的制备(中间体A8-3)
将O-(甲磺酰基磺酰基)羟胺(90克,418毫摩尔)和2-溴-5-氟吡啶(73克,418毫摩尔)溶于无水二氯甲烷(1000毫升)中,并在10℃时搅拌18小时,然后浓缩反应液得到粗产物,并将粗产物在乙酸乙酯中重结晶,得到白色固体的1-氨基-2-溴-5-氟吡啶-1-鎓2,4,6-三甲基苯磺酸盐(80克,99%)。MS:191.0(M+H)
+。
步骤4:7-溴-4-氟吡唑并[1,5-a]吡啶-3-羧酸乙酯的制备(中间体A8-4)
将1-氨基-2-溴-5-氟吡啶-1-鎓2,4,6-三甲基苯磺酸盐(80克,416毫摩尔),碳酸钾(115克,833毫摩尔)和丙酸乙酯(49毫升,500毫摩尔)溶于DMF(1300毫升)中,将反应混合物在10℃时搅拌18小时。将反应混合物用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到白色固体7-溴-4-氟吡唑并[1,5-a]吡啶-3-羧酸乙酯(9.1克,7.6%)。MS:287.2(M+H)
+。
步骤5:7-溴-4-氟吡唑并[1,5-a]吡啶的制备(中间体A8-5)
将7-溴-4-氟吡唑并[1,5-a]吡啶-3-羧酸乙酯(4.0克,13.9毫摩尔)溶于乙酸(24毫升)和水(24毫升)中,在搅拌下加入浓盐酸(18毫升,216毫摩尔)。滴完后,将反应混合物缓慢升至100℃并搅拌18小时,然后加入水和饱和碳酸氢钠水溶液,调pH值到8,并用乙酸乙酯萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到白色固体7-溴-4-氟吡唑并[1,5-a]吡啶(1.95克,65.1%)。MS:214.9(M+H)
+。
步骤6:4-氟吡唑并[1,5-a]吡啶-7-腈的制备(中间体A8)
将7-溴-4-氟吡唑并[1,5-a]吡啶(1.95克,9.07毫摩尔),氰化锌(1.73克,14.7毫摩尔),锌粉(70.74毫克,1.09毫摩尔),XantPhos(866.67毫克)和醋酸钯(433.33毫克,2.25毫摩尔)溶于DMA(30毫升)中。反应混合物在氮气的保护下缓慢升至120℃并搅拌1小时,然后用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体4-氟吡唑并[1,5-a]吡啶-7-腈(1.13克,77.3%)。MS:162.3(M+H)
+,
1H NMR(400MHz,CDCl
3)δ8.13(d,J=2.3Hz,1H),7.33(dd,J=7.9,4.8Hz,1H),6.94–6.78(m,2H)。
制备例 中间体A9 3,4-二氟吡唑并[1,5-a]吡啶-7-腈的制备
步骤1:7-溴-4-氟吡唑并[1,5-a]吡啶-3-羧酸的制备(中间体A9-1)
将7-溴-4-氟-吡唑并[1,5-a]吡啶-3-羧酸乙酯(中间体A8-4,10.8克,37.6毫摩尔),氢氧化钠(4.5克,112.8毫摩尔)溶于乙醇(190毫升)和水(147毫升)的混合溶液中。将反应混合物缓慢升至60℃并搅拌2小时,然后浓缩反应液,残留物加入冰水,并用1N的盐酸调节pH值到5,析出灰色固体沉淀,然后过滤,干燥,得到灰色色固体7-溴-4-氟吡唑并[1,5-a]吡啶-3-羧酸(9.0克,92.7%)。MS:261.0(M+H)
+。
步骤2:7-溴-3,4-二氟吡唑并[1,5-a]吡啶的制备(中间体A9-2)
将7-溴-4-氟吡唑并[1,5-a]吡啶-3-羧酸(0.880克,3.4毫摩尔),SelectFluro(2.4克,6.77毫摩尔)和氟化钾(0.792克,13.6毫摩尔)溶于水(10毫升)和DCE(12毫升)中。反应混合物缓慢升至70℃并搅拌16小时,然后用水稀释并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到白色固体7-溴-3,4-二氟吡唑并[1,5-a]吡啶(0.38克,48.0%)。MS:233.0(M+H)
+。
步骤3:3,4-二氟吡唑并[1,5-a]吡啶-7-腈的制备(中间体A9)
将7-溴-3,4-二氟-吡唑并[1,5-a]吡啶(0.38克,1.63毫摩尔),氰化锌(383毫克,3.26毫摩尔),锌粉(21.2毫克,326.2微摩尔),XantPhos(130毫克)和醋酸钯(100毫克)溶于DMA(10毫升)中。反应混合物在氮气的保护下缓慢升至110℃并搅拌2小时,然后用水 稀释并用乙酸乙酯萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到白色固体3,4-二氟吡唑并[1,5-a]吡啶-7-腈(0.18克,47.4%)。MS:180.0(M+H)
+。
1H NMR(400MHz,CDCl
3)δ7.98(d,J=3.6Hz,1H),7.29(dd,J=8.0,4.8Hz,1H),6.84–6.77(m,1H)。
制备例 中间体A10(S)-4-(4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌啶-1-羧酸叔丁酯的制备
中间体A10的合成参考中间体A7,通过使用中间体A2代替中间体A1制备得到中间体A10。MS:370.1&372.1(M+H)
+。
制备例 中间体A11(R)-4-(4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-7-基)哌啶-1-羧酸叔丁酯的制备
中间体A11的合成参考中间体A7,通过使用中间体A3代替中间体A1制备得到中间体A11。MS:370.1&372.1(M+H)
+。
制备例 中间体A12(R)-8-溴-4,7-二甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑的制备
中间体A12的合成参考中间体A1,通过使用6-溴-7-甲基-1H-吲唑-3-羧酸代替6-溴-1H-吲唑-3-羧酸制备得到中间体A12。MS:280.1&282.1(M+H)
+。
制备例 中间体A13 5-氯-8-碘-[1,2,4]三唑并[1,5-a]吡啶的制备
步骤1:(6-氯吡啶-2-基)氨基羧酸叔丁酯的制备(中间体A13-1)
将6-氯吡啶-2-胺(10克,77.8毫摩尔)溶于无水四氢呋喃(100毫升)中,在-30℃时搅拌缓慢加入双(三甲基硅基)氨基钠(2M的THF溶液,77.8毫升)。滴完后,将反应混合物在-30℃继续搅拌30分钟后,向反应液中缓慢加入碳酸叔丁氧基羰基叔丁酯(18.8克,86.1毫摩尔)的四氢呋喃(100毫升)溶液。滴完后,将反应混合物缓慢升温到室温并继续搅拌3小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到白色固体叔丁基N-(6-氯-2-吡啶基)氨基甲酸酯(17克,95.5%)。MS:173.0(M+H-56)
+。
步骤2:(6-氯-3-碘吡啶-2-基)氨基羧酸叔丁酯的制备(中间体A13-2)
将(N-(6-氯-2-吡啶基)氨基羧酸叔丁酯(17克,74.3毫摩尔)溶于无水四氢呋喃(200毫升)中,在-78℃时搅拌缓慢加入丁基锂溶液(1.6M的THF溶液,92.9毫升),并继续搅拌30分钟,然后将碘(20.8克,81.8毫摩尔)的四氢呋喃(100毫升)溶液缓慢加到反应液中。滴完后,将反应混合物缓慢升至室温并搅拌3小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到白色固体6-氯-3-碘吡啶-2-基)氨基羧酸叔丁酯(16克,60.7%)。MS:298.8(M+H-56)
+。
步骤3:6-氯-3-碘吡啶-2-胺的制备(中间体A13-3)
将6-氯-3-碘吡啶-2-基)氨基羧酸叔丁酯(16克,45.1毫摩尔)溶于盐酸的甲醇溶液(30毫升)中,反应混合物在室温搅拌48小时,然后加入冰水稀释,并用乙酸乙酯稀释萃取。有机相用饱和碳酸钠水溶液,饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到白色固体6-氯-3-碘吡啶-2-胺(11.4克,99.3%)。MS:254.9(M+H)
+。
步骤4:(Z)-N'-(6-氯-3-碘吡啶-2-基)-N,N-二甲基甲酰胺的制备(中间体A13-4)
将6-氯-3-碘吡啶-2-胺(11.4克,44.8毫摩尔)溶于乙醇(150毫升)中,在0℃时搅拌缓慢加入1,1-二甲氧基-N,N-二甲基-甲胺(8.91克,74.8毫摩尔)。滴完后,将反应混合物缓慢升至90℃并搅拌18小时,然后浓缩得到粗产物(Z)-N'-(6-氯-3-碘吡啶-2-基)-N,N-二甲基甲酰胺(13.9克,100%)。MS:309.9(M+H)
+。
步骤5:(Z)-N'-(6-氯-3-碘吡啶-2-基)-N-羟基甲酰亚胺的制备(中间体A13-5)
将(Z)-N'-(6-氯-3-碘吡啶-2--2-基)-N,N-二甲基甲酰胺(13.9克,44.8毫摩尔)溶于甲醇(150毫升)中,在0℃时搅拌缓慢加入羟胺盐酸盐(4.67克,67.2毫摩尔)。滴完后,将反应混合物缓慢升至25℃并搅拌2小时,析出白色固体,过滤,干燥得到白色固体(Z)-N'-(6-氯-3-碘吡啶-2-基)-N-羟基甲酰亚胺(13.3克,100.0%)。MS:297.9(M+H)
+。
步骤6:5-氯-8-碘-[1,2,4]三唑并[1,5-a]吡啶的制备(中间体A13)
将(Z)-N'-(6-氯-3-碘吡啶-2--2-基)-N-羟基甲酰亚胺(14.5克,48.7毫摩尔)溶于多聚磷酸(66克,48.7毫摩尔)中。反应混合物在85℃搅拌6小时,然后反应液用冰水稀释并用乙酸乙酯萃取。有机相用饱和碳酸钠水溶液,饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩白色固体5-氯-8-碘-[1,2,4]三唑并[1,5-a]吡啶(10.2克,74.9%)。MS:279.9(M+H)
+。
1H NMR(400MHz,CDCl
3)δ8.46(s,1H),7.96(d,J=7.8Hz,1H),6.96(d,J=7.8Hz,1H)。
制备例 中间体A14:(R)-2-(4-苄基哌嗪-1-基)-6-(4-甲氧基苄基)-8-甲基-7,8-二氢吡啶[2',3':3,4]吡唑并[1,5-a]吡嗪-5(6H)-酮
步骤1:6-氯-3-碘-1H-吡唑并[3,4-b]吡啶的制备(中间体A14-1)
将碘(992毫克,3.91毫摩尔)和6-氯-1H-吡唑并[3,4-b]吡啶(300毫克,1.95毫摩尔)溶于DMF(20毫升)中。在20度氮气保护下搅拌加入氢氧化钾(329毫克,5.86毫摩尔),加完后,将反应混合物在50度继续搅拌1.5小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到6-氯-3-碘-1H-吡唑并[3,4-b]吡啶(500毫克,92%)。MS:280.1(M+H)
+。
步骤2:6-氯-3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶的制备(中间体 A14-2)
将3,4-二氢-2H-吡喃(4.79克,56.9毫摩尔),对甲苯磺酸(0.361克,1.90毫摩尔)和6-氯-3-碘-1H-吡唑并[3,4-b]吡啶(5.3克,18.96毫摩尔)的DCM(30毫升)溶液在20度搅拌反应16小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到6-氯-3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶(6.5克,94%)。MS:364.1(M+H)
+。
步骤3:6-氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-3-羧酸甲酯的制备(中间体A14-3)
将TEA(8.35克,83毫摩尔),六羰基钼(5.66克,21.45毫摩尔),xantphos(0.955克,1.65毫摩尔)和6-氯-3-碘-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶(6克,16.50毫摩尔)的DMSO(50毫升)和甲醇(50毫升)溶液在70度搅拌反应2小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到6-氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-3-羧酸甲酯(4克,82%)。MS:296.1(M+H)
+。
步骤4:6-氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-3-羧酸的制备(中间体A14-4)
将6-氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-3-羧酸甲酯(1.5克,5.07毫摩尔)和氢氧化锂(0.486克,20.29毫摩尔)的THF(20毫升),水(20毫升)和甲醇(20毫升)溶液在20度搅拌反应3小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到6-氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-3-羧酸甲酯(1.3克,91%)。MS:282.1(M+H)
+。
步骤5:6-氯-N-((S)-2-羟丙基)-N-(4-甲氧基苄基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺的制备(中间体A14-5)
中间体A14-5的合成参考中间体A1-4,通过使用中间体A14-4代替中间体A1-3制备得到中间体A14-5。MS:459.1(M+H)
+。
步骤6:(S)-6-氯-N-(2-羟丙基)-N-(4-甲氧基苄基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺的制备(中间体A14-6)
将6-氯-N-((S)-2-羟丙基)-N-(4-甲氧基苄基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(2.0克,4.36毫摩尔)溶于3M氯化氢1,4-二氧六环(20毫升)溶液在20度搅拌反应16小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到(S)-6-氯-N-(2-羟丙基)-N-(4-甲氧基苄基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(600毫克,36.7%)。MS:375.1(M+H)
+。
步骤7:(R)-2-氯-6-(4-甲氧基苄基)-8-甲基-7,8-二氢吡啶[2',3':3,4]吡唑[1,5-a]吡嗪-5(6H)-酮的制备(中间体A14-7)
中间体A14-7的合成参考中间体A1-5,通过使用中间体A14-6代替中间体A1-4制备得到中间体A14-7。MS:357.1(M+H)
+。
步骤8:(R)-2-(4-苄基哌嗪-1-基)-6-(4-甲氧基苄基)-8-甲基-7,8-二氢吡啶[2',3':3,4]吡唑[1,5-a]吡嗪-5(6H)-酮的制备(中间体A14)
中间体A14的合成参考中间体A6,通过使用中间体A14-7代替中间体A1和1-苄基哌嗪代替哌嗪-1-羧酸叔丁酯制备得到中间体A14。MS:497.1(M+H)
+。
制备例 中间体A15-a和中间体A15-b:(1S,4R)-8-溴-1,4-二甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑和(1R,4R)-8-溴-1,4-二甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑
步骤1:6-溴-N-甲氧基-N-甲基-1H-吲唑-3-甲酰胺的制备(中间体A15-1)
中间体A15-1的合成参考中间体A1-4,通过使用二甲基羟胺盐酸盐代替中间体A1-2制备得到中间体A15-1。MS:284&286(M+H)
+。
步骤2:1-(6-溴-1H-吲唑-3-基)乙烷-1-酮的制备(中间体A15-2)
将6-溴-N-甲氧基-N-甲基-1H-吲唑-3-甲酰胺(0.568克,2毫摩尔)溶于THF(10毫升)中。在0度搅拌下缓慢加入MeMgBr(10.00毫摩尔),加完后,将反应混合物在0度继续搅拌0.5小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到浅黄色油状物1-(6-溴-1H-吲唑-3-基)乙烷-1-酮(0.493克,100%)。MS:239&241(M+H)
+。
步骤3:(2S)-1-((1-(6-溴-1H-吲唑-3-基)乙基)氨基)丙醇的制备(中间体A15-3)
将1-(6-溴-1H-吲唑-3-基)乙烷-1-酮(0.170克,0.711毫摩尔),(S)-1-氨基丙烷-2-醇(0.270克,3.59毫摩尔)和四异丙氧基钛酸酯(0.303克,1.07毫摩尔)溶于THF(10毫升)中。在25度搅拌反应16小时,然后将NaBH
4(0.027克,0.711毫摩尔)加入到上述反应液中,加完后,将反应混合物在25度继续搅拌2小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗 产物,粗产物经硅胶柱层析纯化得到浅黄色油状物(2S)-1-((1-(6-溴-1H-吲唑-3-基)乙基)氨基)丙醇(0.2克,94%)。MS:298&300(M+H)
+。
步骤4:叔丁基(1-(6-溴-1H-吲唑-3-基)乙基)((S)-2-羟丙基)氨基甲酸酯的制备(中间体A15-4)
将(2S)-1-((1-(6-溴-1H-吲唑-3-基)乙基)氨基)丙醇(1.950克,6.54毫摩尔)和DIEA(1.69克,13.08毫摩尔)溶于DCM(40毫升)中。然后将二叔丁基二碳酸酯(1.50克,6.87毫摩尔)加入到上述反应液中,加完后,将反应混合物在25度继续搅拌2小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到浅黄色油状物叔丁基(1-(6-溴-1H-吲唑-3-基)乙基)((S)-2-羟丙基)氨基甲酸酯(2.3克,88%)。MS:398&400(M+H)
+。
步骤5:(2S)-1-((1-(6-溴-1H-吲唑-3-基)乙基)(叔丁氧羰基)氨基)丙-2-基甲磺酸酯的制备(中间体A15-5)
将叔丁基(1-(6-溴-1H-吲唑-3-基)乙基)((S)-2-羟丙基)氨基甲酸酯(2.28克,5.72毫摩尔)和DIEA(1.48克,11.45毫摩尔)溶于DCM(50毫升)中。然后将甲磺酰氯(0.722克,6.30毫摩尔)加入到上述反应液中,加完后,将反应混合物在20度继续搅拌2小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到浅黄色油状物(2S)-1-((1-(6-溴-1H-吲唑-3-基)乙基)(叔丁氧羰基)氨基)丙-2-基甲磺酸酯(1.95克,71.5%)。MS:476&478(M+H)
+。
步骤6:中间体A15-6a和中间体A15-6b的制备
将(2S)-1-((1-(6-溴-1H-吲唑-3-基)乙基)(叔丁氧羰基)氨基)丙-2-基甲磺酸酯(1.950克,4.09毫摩尔)溶于THF(40毫升)中。然后将NaH(98毫克,4.09毫摩尔)加入到上述反应液中,加完后,将反应混合物在20度继续搅拌2小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到浅黄色油状物中间体A15-6a(保留时间:2.410分钟,0.2518克,16%)和中间体A15-6b(保留时间:2.365分钟,0.477克,31%)。MS:380&382(M+H)
+。
步骤7:中间体A15-a和中间体A15-b的制备
中间体A15-a的合成参考中间体A1,通过使用中间体A15-6a代替中间体A1-6制备得到中间体A15-a。MS:280&282(M+H)
+。
中间体A15-b的合成参考中间体A1,通过使用中间体A15-6b代替中间体A1-6制备得到中间体A15-b。MS:280&282(M+H)
+。
制备例 中间体A5-a和中间体A5-b(R)-8-溴-4-乙基-1,2,3,4-四氢吡嗪[1,2-b]吲唑和(S)-8-溴-4-乙基-1,2,3,4-四氢吡嗪[1,2-b]吲唑的制备
将中间体A5经SFC手性拆分(柱型号:CHIRALPAK IA,3cm×25cm,5μm色谱柱,流动相:35%甲醇在二氧化碳中)得到均为白色固体的第一个组分峰中间体A5-a(保留时间为2.14分钟)和第二个组分峰中间体A5-b(保留时间为2.50分钟)。MS:280.1&282.1(M+H)
+。
制备例 中间体A16
7-氯-5-甲基-2,3,4,5-四氢-1H-吡咯[3,2-c:4,5-c']联吡啶
步骤1:7-氯-1,3,4,5-四氢-2H-吡咯[3,2-c:4,5-c']联吡啶-2-羧酸叔丁酯的制备(A16-1)
将4-氧哌啶-1-羧酸叔丁酯(3132毫克,15.72毫摩尔),正硅酸乙酯(1801毫克,8.65毫摩尔),2-氯-5-碘吡啶-4-胺(2000毫克,7.86毫摩尔),TsOH(299毫克,1.572毫摩尔),N-环己基-N-甲基环己胺(1996毫克,10.22毫摩尔)和Pd(Ph
3P)
4(272毫克,0.236毫摩尔)溶于吡啶(15毫升)中。反应混合物在氮气的保护下缓慢升至160℃并搅拌40分钟,然后反应混合液用水稀释并用乙酸乙酯萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到7-氯-1,3,4,5-四氢-2H-吡咯[3,2-c:4,5-c']联吡啶-2-羧酸叔丁酯(990毫克,41.3%)。MS:308.0&310.0(M+H)
+
步骤2:7-氯-5-甲基-1,3,4,5-四氢-2H-吡咯[3,2-c:4,5-c']联吡啶-2-羧酸叔丁酯的制备(A16-2)
将7-氯-1,3,4,5-四氢-2H-吡咯[3,2-c:4,5-c']联吡啶-2-羧酸叔丁酯(990毫克,3.22毫摩尔)溶于THF(20毫升)中。反应混合物在0度氮气的保护下缓慢加入NaH(618毫克,25.7毫摩尔),并在0度继续搅拌30分钟,然后将碘甲烷(3.65克,25.7毫摩尔)加入到反应液中,并在试问搅拌反应16小时。然后反应混合液用水稀释并用乙酸乙酯萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到7-氯-5-甲基-1,3,4,5-四氢-2H-吡咯[3,2-c:4,5-c']联吡啶-2-羧酸叔丁酯(0.3克,29%)。MS:322.0&324.0(M+H)
+
步骤3:7-氯-5-甲基-2,3,4,5-四氢-1H-吡咯[3,2-c:4,5-c']联吡啶的制备(A16)
中间体A16的合成参考中间体A1,通过使用中间体A16-2代替中间体A1-6制备得到中间体A16。MS:222&224(M+H)
+
制备例 中间体A17a和中间体A17b
(R)-8-溴-4-(三氟甲基)-1,2,3,4-四氢吡嗪[1,2-b]吲唑和(S)-8-溴-4-(三氟甲基)-1,2,3,4-四氢吡嗪[1,2-b]吲唑的制备
中间体A17的合成参考中间体A1,通过使用中间体A17代替(S)-1-氨基丙烷-2-醇制备得到中间体A17。MS:320.1&322.1(M+H)
+。
将中间体A17经SFC手性拆分(柱型号:CHIRALPAK AD,3cm×25cm,5μm色谱柱,流动相:15%甲醇在二氧化碳中)得到均为白色固体的第一个组分峰中间体A17-a(保留时间为1.67分钟)和第二个组分峰中间体A17-b(保留时间为1.93分钟)。
制备例 中间体A18
3-((R)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲哚唑-8-基)哌啶-1-羧酸叔丁酯的制备
中间体A18的合成参考中间体A7,通过使用中间体A18-1代替中间体A7-1制备得到中间体A18。MS:371.1(M+H)
+。
制备例 中间体A19
3-((R)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)吡咯烷-1-羧酸叔丁酯的制备
中间体A19的合成参考中间体A7,通过使用中间体A19-1代替中间体A7-1制备得到中间体A19。MS:357.1(M+H)
+。
制备例 中间体A20
(R)-8-溴-10-氟-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑的制备
中间体A20的合成参考中间体A22,通过使用中间体A20-1代替中间体A22-1制备得到中间体A20。MS:284.1&286.1(M+H)
+。
制备例 中间体A21
(R)-4-(10-氟-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲哚唑-8-基)哌啶-1-羧酸叔丁酯的制备
中间体A21的合成参考中间体A7,通过使用中间体A20代替中间体A1制备得到中间体A21。MS:389.1(M+H)
+。
制备例 中间体A22
(R)-8-溴-9-氟-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑的制备
步骤1:6-溴-5-氟-1H-吲唑-3-甲醛的制备(中间体A22-1)
在0度搅拌下,将NaNO
2(32.2克,467毫摩尔)的水溶液(50毫升)缓慢滴加到6-溴-5-氟-1H-吲哚(10克,46.7毫摩尔)的THF(100毫升)溶液中,反应混合物并在0度搅拌反应10分钟;然后将3mol/L的盐酸溶液(39毫升)缓慢地滴加到上述反应液中,加完后,将反应混合物在15度搅拌反应16小时。然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体6-溴-5-氟-1H-吲唑-3-甲醛(4.1克,37%)。MS:243.1&245.1(M+H)
+
步骤2:(S)-1-(((6-溴-5-氟-1H-吲唑-3-基)甲基)(4-甲氧基苄基)氨基)丙烷-2-醇的制备(中间体A22-2)
在0度搅拌下,将三乙酰氧基硼氢化钠(10.46克,49.4毫摩尔)缓慢加到(S)-1-((4-甲氧基苄基)氨基)丙烷-2-醇(9.64克,49.4毫摩尔)和6-溴-5-氟-1H-吲唑-3-甲醛(8.0克,32.9毫摩尔)的DCE(150毫升)溶液中,将反应混合物在25度搅拌反应16小时。然后加入碳酸钠的冰水溶液淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色油状物(S)-1-(((6-溴-5-氟-1H-吲唑-3-基)甲基)(4-甲氧基苄基)氨基)丙烷-2-醇(7.6克,54%)。MS:422.1&424.1(M+1)
+
步骤3:(R)-8-溴-9-氟-2-(4-甲氧基苄基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑的制备(中间体A22-3)
在20度搅拌下,将双(2-甲氧基乙基)二氮烯-1,2-二甲酸酯(20.80克,89毫摩尔)缓慢加到(S)-1-(((6-溴-5-氟-1H-吲唑-3-基)甲基)(4-甲氧基苄基)氨基)丙烷-2-醇(7.50克,17.76毫摩尔)和三丁基膦(19.97克,89毫摩尔)的THF(150毫升)溶液中,并将反应混合物在20度搅拌反应16小时。然后加入碳酸钠的冰水溶液淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色油状物(R)-8-溴-9-氟-2-(4-甲氧基苄基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑(2.5克,40%)。MS:404.1&406.1(M+H)
+
步骤4:(R)-8-溴-9-氟-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑的制备(中间体A22)
中间体A22的合成参考中间体A1,通过使用中间体A22-3代替中间体A1-6制备得到中间体A22。MS:284.1&286.1(M+H)
+。
制备例 中间体A23
(R)-4-(9-氟-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲哚唑-8-基)哌啶-1-羧酸叔丁酯的制备
中间体A23的合成参考中间体A7,通过使用中间体A22代替中间体A1制备得到中间体A23。MS:389.1(M+H)
+。
制备例 中间体A24
(R)-8-溴-9-氯-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑的制备
中间体A24的合成参考中间体A22,通过使用6-溴-5-氯-1H-吲哚代替6-溴-5-氟-1H-吲哚制备得到中间体A24。MS:300.5&302.5(M+H)
+。
制备例 中间体A25
(R)-4-(9-氯-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲哚唑-8-基)哌啶-1-羧酸叔丁酯的制备
中间体A25的合成参考中间体A23,通过使用中间体A24代替中间体A22制备得到中间体A25。MS:405.1(M+H)
+。
制备例 中间体A26
4-(1,2,3,4-四氢咪唑[1,2-a:5,4-c']联吡啶-7-基)哌啶-1-羧酸叔丁酯的制备
步骤1:7-溴-3,4-二氢咪唑[1,2-a:5,4-c']联吡啶-2(1H)-羧酸叔丁酯的制备(中间体A26-1)
将3-溴-4-氧哌啶-1-羧酸叔丁酯(8.04克,28.9毫摩尔)和4-溴吡啶-2-胺(5克,28.9毫 摩尔)的异丙醇(100毫升)和AcOH(30毫升)混合溶液在130度搅拌反应16小时。然后加入碳酸钠的冰水溶液淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体7-溴-3,4-二氢咪唑[1,2-a:5,4-c']联吡啶-2(1H)-羧酸叔丁酯(7克,68%)。MS:352.1&354.1(M+H)
+
步骤2:7-溴-1,2,3,4-四氢咪唑[1,2-a:5,4-c']联吡啶的制备(中间体A26-2)
将7-溴-3,4-二氢咪唑[1,2-a:5,4-c']联吡啶-2(1H)-羧酸叔丁酯(3.0克,8.52毫摩尔)的DCM(20毫升)和TFA(10毫升)混合溶液在20度搅拌反应2小时。然后浓缩得到粗产物,并用乙酸乙酯稀释萃取。有机相用饱和碳酸钠水溶液,饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到黄色固体7-溴-1,2,3,4-四氢咪唑[1,2-a:5,4-c']联吡啶(2.1克,94%)。MS:252.1&254.1(M+H)
+
步骤3:4-(1,2,3,4-四氢咪唑[1,2-a:5,4-c']联吡啶-7-基)哌啶-1-羧酸叔丁酯的制备(中间体A26)
中间体A26的合成参考中间体A23,通过使用中间体A26-2代替中间体A22制备得到中间体A26。MS:357.1(M+H)
+。
制备例 中间体A27
(R)-2-氯-8-甲基-5,6,7,8-四氢吡啶[2',3':3,4]吡唑[1,5-a]吡嗪的制备
中间体A27的合成参考中间体A22,通过使用中间体A27-1代替中间体A22-1制备得到中间体A27。MS:223.1(M+H)
+。
制备例 中间体A28
(R)-4-(8-甲基-5,6,7,8-四氢吡啶[2',3':3,4]吡唑并[1,5-a]吡嗪-2-基)哌啶-1-羧酸叔丁酯的制备
中间体A28的合成参考中间体A23,通过使用中间体A27代替中间体A22制备得到中间体A28。MS:372.1(M+H)
+。
制备例 中间体A29
(R)-3-氯-7-甲基-7,8,9,10-四氢吡啶[4',3':3,4]吡唑[1,5-a]吡嗪的制备
中间体A29的合成参考中间体A22,通过使用中间体A29-1代替中间体A22-1制备得到中间体A29。MS:223.1(M+H)
+。
制备例 中间体I-48-3a,中间体I-48-3b,中间体I-48-3c&中间体I-48-3d
(3R,4S)-4-((R)-2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)-3-氟哌啶-1-羧酸叔丁酯和(3S,4R)-4-((R)-2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)-3-氟哌啶-1-羧酸叔丁酯和(3S,4S)-4-((R)-2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)-3-氟吡啶-1-羧酸叔丁酯和3R,4R)-4-((R)-2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)-3-氟哌啶-1-羧酸叔丁酯
将中间体I-48-3经SFC手性拆分(柱型号:CHIRALPAK IF,2cm×25cm,5μm色谱柱,流动相:20%乙醇在二氧化碳中)得到均为白色固体的第一个组分峰中间体I-48-3a(保留时间为1.318分钟)和第二个组分峰中间体I-48-3c(保留时间为1.578分钟)和第三个组分峰中间体I-48-3b(保留时间为1.770分钟)和第四个组分峰中间体I-48-3d(保留时间为2.48分钟)。MS:548.1(M+H)
+。
制备例 中间体A30
(R)-3-(4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)氮杂环丁烷-1-羧酸叔丁酯的制备
步骤1:中间体A30-1的制备
将中间体A1(2克,7.51毫摩尔),乙酸钾(2.213克,22.54毫摩尔),联硼酸频那醇酯(2.86克,11.27毫摩尔)和PdCl
2(dppf)(0.385克,0.526毫摩尔)的DMF(60毫升)反应混合溶液在90度反应3小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体中间体A30-1(700毫克,30%),MS:314.1(M+H)
+。
步骤2:(R)-3-(4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)氮杂环丁烷-1-羧酸叔丁酯的制备(中间体A30)
在20度搅拌下,将碘化镍(0.051克,0.163毫摩尔)和二(三甲基硅基)酰胺钾(0.974克,4.88毫摩尔)缓慢加入到中间体A30-1(0.51克,1.628毫摩尔),3-碘代氮杂环丁胺-1-羧酸叔丁酯(1.152克,4.07毫摩尔)和(1R,2R)-2-氨基环己烷-1-醇盐酸盐(0.025克,0.163毫摩尔)的异丙醇(10毫升)溶液中,并将反应混合溶液在100度反应1小时,然后加入冰 水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体中间体A30(110毫克,20%),MS:343.1(M+H)
+。
制备例 中间体A31
4-(1,2,3,4-四氢吡唑[1,5-a:4,3-c']联吡啶-8-基)哌啶-1-羧酸叔丁酯的制备
步骤1:中间体A31-1的制备
将2,5-二溴吡啶(10克,42.2毫摩尔),丁-3-炔-1-醇(2.96克,42.2毫摩尔),Et
3N(8.54克,84毫摩尔),CuI(0.804克,4.22毫摩尔)和Pd(PPh
3)
2Cl
2(1.482克,2.111毫摩尔)的THF(100毫升)反应混合溶液在20度反应5小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体中间体A31-1(7克,73.4%),MS:226.1&228.1(M+H)
+。
步骤2:中间体A31-2的制备
将中间体A31-1(3.00克,13.27毫摩尔)溶于DCM(100毫升)中,在0度搅拌下加入2,4,6-三甲基苯磺酰羟胺(14.28克,66.4毫摩尔),并将反应混合溶液在20度反应3小时,然后加入冰水淬灭反应,并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到黄色油状物中间体A31-2(3.2克,54.6%)。
步骤3:中间体A31-3的制备
将中间体A31-2(3.20克,7.25毫摩尔)溶于DMF(40毫升)中,在20度搅拌下加入K
2CO
3(3.01克,21.75毫摩尔),并将反应混合溶液在20度反应2小时,然后加入冰水淬灭反应,并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体中间体A31-3(1.54克,88%),MS:241.1&243.1(M+H)
+。
步骤4:中间体A31-4的制备
将中间体A31-3(1.540克,6.39毫摩尔),异吲哚-1,3-二酮(1.128克,7.67毫摩尔)和三苯基膦(2.011克,7.67毫摩尔)溶于THF(30毫升)中,在0度搅拌下加入二异丙基(E)-二氮烯-1,2-二甲酸酯(1.550克,7.67毫摩尔),并将反应混合溶液在20度反应12小时,然后加入冰水淬灭反应,并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤,无水干燥硫 酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体中间体A31-4(1.54克,88%),MS:370.1&372.1(M+H)
+。
步骤5:中间体A31-5的制备
将中间体A31-4(0.290克,0.783毫摩尔)溶于乙醇(10毫升)中,在0度搅拌下加入水合肼(0.245克,3.92毫摩尔),并将反应混合溶液在20度反应12小时,然后加入冰水淬灭反应,并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到白色固体中间体A31-5(71克,38%),MS:240.1&242.1(M+H)
+。
步骤6:中间体A31-6的制备
将中间体A31-5(71毫克,0.296毫摩尔)溶于乙酸(3毫升)中,在0度搅拌下加入多聚甲醛(18毫克,0.591毫摩尔),并将反应混合溶液在25度反应2小时,然后加入冰水淬灭反应,并用饱和碳酸氢钠溶液调节pH值到8,并乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得黄色固体中间体A31-6(77毫克,94%),MS:252.1&254.1(M+H)
+。
步骤7:中间体A31的制备
中间体A31的合成参考中间体A23,通过使用中间体A31-6代替中间体A22制备得到中间体A31。MS:357.1(M+H)
+。
制备例 中间体A32
步骤1:中间体A32-1的制备
将中间体A1(10克,37.6毫摩尔)和TEA(9.51克,94毫摩尔)溶于DCM(100毫升)中,在0度搅拌下加入Boc
2O(8.20克,37.6毫摩尔),并将反应混合溶液在20度反应12小时,然后加入冰水淬灭反应,并用二氯甲烷稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色油状物中间体A32-1(4.8克,35%),MS:366.1&368.1(M+H)
+。
步骤2:中间体A32-2的制备
将中间体A32-1(4.8克,13.11毫摩尔),Pd(OAc)
2(0.294克,1.311毫摩尔),Xantphos(0.758克,1.311毫摩尔),TEA(7.96克,79毫摩尔)和六羰基钼(10.38克,39.3毫摩尔)的乙醇(100毫升)溶液在100度反应12小时,然后过滤,浓缩得到粗产物,粗产物经硅胶柱 层析纯化得到黄色固体中间体A32-2(2.5克,53%),MS:360.1(M+H)
+。
步骤3:中间体A32-3的制备
中间体A32-3的合成参考中间体A1-6,通过使用中间体A32-2代替中间体A1-5制备得到黄色油状物中间体A32-3。MS:318.2(M+H)
+。
步骤4:中间体A32-4的制备
将中间体A32-3(2.2克,6.93毫摩尔)和二氧化锰(6.03克,69.3毫摩尔)的DCM(30毫升)溶液在40度反应12小时,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色油状物中间体A32-4(1.6克,73%),MS:316.1(M+H)
+。
步骤5:中间体A32-5的制备
在0度搅拌下,将NaH(0.285克,7.13毫摩尔)缓慢加入到二甲基甲硫碘(1.57克,7.13毫摩尔)的THF(50毫升)和DMSO(10.0毫升)混合反应液中,并在0度搅拌反应1小时,然后将中间体A32-4(1.5克,4.76毫摩尔)在0度加入到上述反应液中,并将反应混合液在20度搅拌反应3小时。然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体中间体A32-5(0.54克,35%),MS:330.1(M+H)
+。
步骤6:中间体A32-6的制备
将中间体A32-5(510毫克,1.548毫摩尔)和2-(苄基氨基)乙烷-1-醇(2.34克,15.5毫摩尔)的THF(5毫升)溶液在100度搅拌反应12小时,然后浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色油状物中间体A32-6(0.37克,49%),MS:481.1(M+H)
+。
步骤7:中间体A32-7的制备
在0度搅拌下,将NaH(62.4毫克,1.561毫摩尔)缓慢加入到中间体A32-6(300毫克,0.624毫摩尔)的THF(20毫升)溶液中,并在0度搅拌反应1小时,然后将1-对甲苯磺酰-1H-咪唑(153毫克,0.687毫摩尔)在0度加入到上述反应液中,并将反应混合液在20度搅拌反应2小时。然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色油状物中间体A32-7(170毫克,59%),MS:463.1(M+H)
+。
步骤8:中间体A32的制备
中间体A32的合成参考化合物I-1,通过使用中间体A32-7代替中间体I-1-2制备得到黄色固体中间体A32。MS:363.1(M+1)
+
制备例 中间体A33(R)-8-溴-7-氟-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑的制备
步骤1:中间体A33-1的制备
将4-溴-2,3-二氟苯甲醛(24.0克,109毫摩尔),碳酸钾(18.01克,130毫摩尔),甲氧基胺盐酸盐(9.98克,119毫摩尔)的1,2-二甲氧基乙烷(240毫升)反应混合溶液在40度反应3小时,然后冷却反应液并过滤,滤液浓缩得到50毫升溶液。将50毫升溶液溶于1,2-二甲氧基乙烷(200毫升)和水合肼(50毫升)中,并将反应混合溶液在90度反应24小时,然后冷却反应液并浓缩到20毫升,然后加入冰水,析出固体,过滤,滤饼水洗干燥得到白色固体中间体A33-1(21克,90%),MS:215.1&217.1(M+H)
+。
步骤2:中间体A33-4的制备
中间体A33-4的合成参考中间体A14-4,通过使用中间体A33-1代替6-氯-1H-吡唑[3,4-b]吡啶制备得到A33-4。MS:259.1&261.1(M+H)
+。
步骤3:中间体A33的制备
中间体A33的合成参考中间体A1,通过使用中间体A33-4代替6-溴-1H-吲唑-3-羧酸制备得到中间体A33。MS:284.1&286.1(M+H)
+。
制备例 中间体A34
(R)-4-(7-氟-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲哚唑-8-基)哌啶-1-羧酸叔丁酯的制备
中间体A34的合成参考中间体A7,通过使用中间体A33代替中间体A1制备得到中间体A34。MS:389.1(M+H)
+。
制备例 中间体A35(R)-8-溴-4,9-二甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑的制备
中间体A35的合成参考中间体A33,通过使用6-溴-5-甲基-1H-吲唑代替中间体A33-1制备得到中间体A35。MS:280.1&282.1(M+H)
+。
制备例 中间体A36
(R)-4-(4,9-二甲基-1,2,3,4-四氢吡嗪[1,2-b]吲哚唑-8-基)哌啶-1-羧酸叔丁酯的制备
中间体A36的合成参考中间体A7,通过使用中间体A35代替中间体A1制备得到中间体A36。MS:385.1(M+H)
+。
制备例 中间体A37
(R)-1-苄基-4-(4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-4-甲腈
步骤1:中间体A37-1的制备
将中间体A32-1(1克,2.73毫摩尔),Xantphos(0.316克,0.546毫摩尔),2-(三甲基硅基)乙腈(0.371克,3.28毫摩尔),氟化锌(0.169克,1.638毫摩尔)和Pd
2(dba)
3(0.250克,0.273毫摩尔)的DMF(15毫升)反应混合液在105℃搅拌反应16小时,然后用水稀释并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体中间体A37-1(0.3克,33%)。MS:327.0(M+H)
+。
步骤2:中间体A37-2的制备
将中间体A37-1(250毫克,0.766毫摩尔),N-苄基-2-氯-N-(2-氯乙基)乙烷-1-胺(206毫克,0.766毫摩尔),四(正丁基)铵硫酸盐(26.0毫克,0.077毫摩尔)和氢氧化钠(245毫克,3.06毫摩尔)的甲苯(15毫升)反应混合液在85℃搅拌反应3小时,然后用水稀释并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体中间体A37-2(60毫克,16%)。MS:486.0(M+H)
+。
步骤3:中间体A37的制备
中间体A37的合成参考化合物I-1,通过使用中间体A37-2代替中间体I-1-2制备得到黄色固体中间体A37。MS:386.1(M+1)
+。
制备例 中间体A38
(R)-1-苄基-4-(9-氟-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-4-甲腈
中间体A38的合成参考中间体A37,通过使用中间体A22代替中间体A1制备得到黄色固体中间体A38。MS:404.1(M+1)
+。
制备例 中间体A39
(S)-4-苄基-2-((R)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)吗啉
步骤1:中间体A39-1的制备
将中间体A32-1(3克,8.19毫摩尔),PdCl
2(dppf)(0.6克,0.819毫摩尔),K
3PO
4(5.22克,24.57毫摩尔),乙烯基硼酸频哪醇酯(2.52克,16.38毫摩尔)的1,4-二氧六环(60毫升)和水(10毫升)的反应混合液在90℃搅拌反应12小时,然后用水稀释并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体中间体A39-1(2.6克,99%)。MS:314.0(M+H)
+。
步骤2:中间体A39-2的制备
将中间体A39-1(5.7克,18.19毫摩尔)的叔丁醇(80毫升)溶液在0度搅拌下缓慢加入到AD-mix-alfa(19克)的叔丁醇(200毫升)和水(280毫升)混合溶液中,将反应混合液在0℃搅拌反应16小时,然后用Na
2SO
3(20毫升)水溶液稀释并用乙酸乙酯稀释萃取。有机相分别用饱和碳酸氢钠溶液,盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到白色固体中间体A39-2(1.2克,19%收率;ee%91.8%)。MS:348.0(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ7.61(d,J=8.6Hz,1H),7.46(s,1H),7.01(d,J=8.7Hz,1H),5.24(d,J=4.2Hz,1H),5.01(d,J=17.2Hz,1H),4.87(s,1H),4.68(t,J=5.8Hz,1H),4.60(t,J=6.3Hz,2H),3.91(dd,J=13.9,4.0Hz,1H),3.80(s,1H),3.44(t,J=5.9Hz,2H),1.49(d,J=6.5Hz,3H),1.46(s,9H).
步骤3:中间体A39-3的制备
在0度搅拌条件下,将1,1,1-三甲氧基乙烷(1.45克,12.09毫摩尔)缓慢加入到中间体A39-2(1.4克,4.03毫摩尔)的二氯甲烷(12毫升)溶液中,然后将三甲基氯硅烷(1.13克,12.09毫摩尔)缓慢加入到上述反应混合液中。将反应混合液在20℃搅拌反应1小时,然后浓缩得到白色固体,将白色固体和碳酸钾(1.11克,8.06毫摩尔)的甲醇(10毫升)溶液在室温搅拌反应1小时。然后过滤,并用乙酸乙酯稀释萃取,有机相分别用饱和碳酸氢钠溶液,盐水洗涤,无水干燥硫酸钠干燥,过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到无色油状物中间体A39-3(1.02克,77%收率;ee%90.8%)。
1H NMR(400MHz,DMSO-d
6)δ7.69(d,J=8.7Hz,1H),7.57(s,1H),6.82(d,J=8.7Hz,1H),5.01(d,J=17.4Hz,1H),4.88(s,1H),4.63(d,J=6.7Hz,1H),4.00(t,J=3.4Hz,1H),3.92(dd,J=13.8,4.0Hz,1H),3.80(s,1H),3.13(t,J=4.6Hz,1H),2.90(dd,J=5.4,2.6Hz,1H),1.50(d,J=6.6Hz,3H),1.45(s,9H).
步骤4:中间体A39的制备
中间体A39的合成参考中间体A32,通过使用中间体A39-3代替中间体A32-5制备得到黄色固体中间体A39。MS:363.1(M+1)
+
制备例 中间体A40
(R)-4-苄基-2-((R)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)吗啉
中间体A40的合成参考中间体A39,通过使用AD-mix-beta代替AD-mix-alfa制备得到黄色固体中间体A40。MS:363.1(M+1)
+
实施例1
化合物I-1:(R)-5-(4-甲基-8-(哌嗪-1-基)-3,4-二氢吡嗪并[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
步骤1:(R)-5-(8-溴-4-甲基-3,4-二氢吡嗪并[1,2-b]吲唑-2(1H)-基)喹啉-8-腈的制备(中间体I-1-1)
将Pd
2(dba)
3(0.017克,0.019毫摩尔),叔丁醇钠(0.054克,0.564毫摩尔),BINAP(0.023克,0.038毫摩尔),5-溴-8-氰基喹啉(中间体D1,0.219克,0.939毫摩尔)和(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A1,50毫克,0.188毫摩尔)溶于甲苯(5毫升)中。反应混合物在氮气的保护下缓慢升至80℃并搅拌1.5小时,然后反应混合液用水稀释并用乙酸乙酯萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体(R)-5-(8-溴-4-甲基-3,4-二氢吡嗪并[1,2-b]吲唑-2(1H)-基)喹啉-8-腈(40毫克,51%)。MS:418&420(M+H)
+。
步骤2:(R)-4-(2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌嗪-1-羧酸叔丁酯的制备(中间体I-1-2)
将Pd
2(dba)
3(0.022克,0.024毫摩尔),碳酸铯(0.234克,0.717毫摩尔),BINAP(0.015克,0.024毫摩尔),哌嗪-1-羧酸叔丁酯(0.089克,0.478毫摩尔)和(R)-5-(8-溴-4-甲基-3,4-二氢吡嗪并[1,2-b]吲唑-2(1H)-基)喹啉-8-腈的制备(中间体I-1-1,0.1克,0.239毫摩尔)溶于甲苯(5毫升)中。反应混合物在氮气的保护下缓慢升至80℃并搅拌16小时,然后反应混合液用水稀释并用乙酸乙酯萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色油状物(R)-4-(2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌嗪-1-羧酸叔丁酯(60毫克,48%)。MS:524(M+H)
+。
步骤3:(R)-5-(4-甲基-8-(哌嗪-1-基)-3,4-二氢吡嗪并[1,2-b]吲唑-2(1H)-基)喹啉-8-腈的制备
将(R)-4-(2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌嗪-1-羧酸叔丁酯(60毫克,0.115毫摩尔)溶于二氯甲烷(5毫升)中,在15℃时搅拌缓慢加入TFA(2毫升)。滴完后,将反应混合物在25℃搅拌1小时,然后将反应混合液浓缩蒸干,并用二氯甲烷稀释萃取。有机相用饱和碳酸氢钠溶液,饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经pre-HPLC纯化得到白色固体(R)-5-(4-甲基-8-(哌嗪-1-基)-3,4-二氢吡嗪并[1,2-b]吲唑-2(1H)-基)喹啉-8-腈(5.89毫克, 12%)。MS:424(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.08(d,J=4.2Hz,1H),8.76–8.63(m,2H),8.33(d,J=8.0Hz,1H),7.71(dd,J=8.5,4.2Hz,1H),7.61(d,J=9.0Hz,1H),7.41(d,J=8.1Hz,1H),6.94(d,J=9.5Hz,2H),4.89(q,J=8.9,7.7Hz,1H),4.82(s,2H),4.01–3.89(m,1H),3.41–3.17(m,9H),1.63(d,J=6.4Hz,3H)。
实施例2
化合物I-2:(R)-5-(4-甲基-8-(1,2,3,6-四氢吡啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
步骤1:(R)-4-(2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的制备(中间体I-2-1)
将(R)-5-(8-溴-4-甲基-3,4-二氢吡嗪并[1,2-b]吲唑-2(1H)-基)喹啉-8-腈(中间体I-1-1,0.18克,0.430毫摩尔),碳酸钾(0.178克,1.29毫摩尔),PdCl
2(dppf)(0.031克,0.043毫摩尔)和4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(0.200克,0.645毫摩尔)溶于二氧六环(10毫升)和水(2毫升)中。反应混合物在氮气的保护下缓慢升至80℃并搅拌16小时,然后反应混合液用水稀释并用乙酸乙酯萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色油状物(R)-4-(2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(0.316克,71%)。MS:521(M+H)
+。
步骤2:(R)-5-(4-甲基-8-(1,2,3,6-四氢吡啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)喹啉-8-腈的制备
化合物I-2的合成参考化合物I-1,通过使用(R)-4-(2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(中间体I-2-1)代替(R)-4-(2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌嗪-1-羧酸叔丁酯(中间体I-1-2)制备得到黄色固体化合物I-2。
化合物I-2(2.4毫克),MS:421.1(M+H)
+。
实施例3
化合物I-3:(R)-2-(1,6-二甲基-1H-吡唑[3,4-b]吡啶-4-基)-4-甲基-8-(哌嗪-1-基)-1,2,3,4-四氢吡嗪[1,2-b]吲唑
化合物I-3的合成参考化合物I-1,通过使用4-溴-1,6-二甲基-1H-吡唑啉[3,4-b]吡啶(中间体D3)代替5-溴-8-氰基喹啉(中间体D1)制备得到白色固体化合物I-3。
化合物I-3(6.2毫克),MS:417.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.72(br,1H),8.58(s,1H),7.79(d,J=9.1Hz,1H),6.98(d,J=9.3Hz,1H),6.90(d,J=1.9Hz,1H),6.78(s,1H),5.32(s,2H),4.80(s,1H),4.35–4.28(m,1H),4.22–4.08(m,1H),4.00(s,3H),3.42–3.21(m,8H),2.56(s,3H),1.62(d,J=6.5Hz,3H)。
实施例4
化合物I-4:(S)-2-(1,6-二甲基-1H-吡唑[3,4-b]吡啶-4-基)-4-甲基-8-(哌嗪-1-基)-1,2,3,4-四氢吡嗪[1,2-b]吲唑
化合物I-4的合成参考化合物I-1,通过使用(S)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A2)代替(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A1)和4-溴-1,6-二甲基-1H-吡唑啉[3,4-b]吡啶(中间体D3)代替5-溴-8-氰基喹啉(中间体D1)制备得到白色固体化合物I-4。
化合物I-4(9.3毫克),MS:417.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.72(br,1H),8.58(s,1H),7.79(d,J=9.1Hz,1H),6.98(d,J=9.3Hz,1H),6.90(d,J=1.9Hz,1H),6.78(s,1H),5.32(s,2H),4.80(s,1H),4.35–4.28(m,1H),4.22–4.08(m,1H),4.00(s,3H),3.42–3.21(m,8H),2.56(s,3H),1.62(d,J=6.5Hz,3H)。
实施例5
化合物I-5:(S)-5-(4-甲基-8-(哌嗪-1-基)-3,4-二氢吡嗪并[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
化合物I-5的合成参考化合物I-1,通过使用(S)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A2)代替(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A1)制备得到白色固体化合物I-5。
化合物I-5(19.3毫克),MS:424.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.09(d,J=4.2Hz,1H),8.74(br,1H),8.67(d,J=8.6Hz,1H),8.33(d,J=8.0Hz,1H),7.71(dd,J=8.5,4.2Hz,1H),7.61(d,J=9.0Hz,1H),7.41(d,J=8.1Hz,1H),6.94(d,J=9.0Hz,2H),4.89(s,1H),4.82(s,2H),4.02–3.83(m,1H),3.37–3.23(m,9H),1.63(d,J=6.4Hz,3H)。
实施例6
化合物I-6:(R)-5-(4-甲基-8-(哌啶-4-基)-3,4-二氢吡嗪并[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
化合物I-6的合成参考化合物I-1,通过使用(R)-4-(4-甲基-1,2,3,4-四氢吡嗪酮[1,2-b]吲哚-8-基)哌啶-1-羧酸叔丁酯(中间体A7)代替(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A1)制备得到白色固体化合物I-6。
化合物I-6(28.3毫克),MS:423.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.08(d,J=4.2Hz,1H),8.76–8.63(m,2H),8.33(d,J=8.0Hz,1H),7.71(dd,J=8.5,4.2Hz,1H),7.61(d,J=9.0Hz,1H),7.41(d,J=8.1Hz,1H),6.94(d,J=9.5Hz,2H),4.89(q,J=8.9,7.7Hz,1H),4.82(s,2H),4.01–3.89(m,1H),3.41–3.17(m,5H),2.26–2.19(m,1H),2.06–1.84(m,4H),1.63(d,J=6.4Hz,3H)。
实施例7
化合物I-7:(R)-2-(1,6-二甲基-1H-吡唑[3,4-b]吡啶-4-基)-4-甲基-8-(哌啶-4-基)-1,2,3,4-四氢吡嗪[1,2-b]吲唑
化合物I-7的合成参考化合物I-1,通过使用(R)-4-(4-甲基-1,2,3,4-四氢吡嗪酮[1,2-b]吲哚-8-基)哌啶-1-羧酸叔丁酯(中间体A7)代替(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A1)和4-溴-1,6-二甲基-1H-吡唑啉[3,4-b]吡啶(中间体D3)代替5-溴-8-氰基喹啉(中间体D1)制备得到白色固体化合物I-7。
化合物I-7(46毫克),MS:416.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.72(br,1H),8.58(s,1H),7.79(d,J=9.1Hz,1H),6.98(d,J=9.3Hz,1H),6.90(d,J=1.9Hz,1H),6.78(s,1H),5.32(s,2H),4.80(s,1H),4.35–4.28(m,1H),4.22–4.08(m,1H),4.00(s,3H),3.42–3.21(m,4H),2.56(s,3H),2.29–2.19(m,1H),2.08–1.71(m,4H),1.62(d,J=6.5Hz,3H)。
实施例8
化合物I-8:(R)-3-氟-4-(4-甲基-8-(哌嗪-1-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
步骤1:(R)-4-(8-溴-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈的制备(中间体I-8-1)
将(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A1,0.08克,0.301毫摩尔),3,4-二氟吡唑[1,5-a]吡啶-7-腈(中间体A9,0.108克,0.601毫摩尔)和DIEA(0.117克,0.902毫摩尔)溶于DMSO(5毫升)中。反应混合物在氮气的保护下缓慢升至120℃并搅拌1小时,然后反应混合液用水稀释并用乙酸乙酯萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体(R)-4-(8-溴-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈(67毫克,52%)。MS:426.1(M+H)
+。
步骤2:(R)-3-氟-4-(4-甲基-8-(哌嗪-1-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-8的合成参考化合物I-1,通过使用(R)-4-(8-溴-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈(中间体I-8-1)代替(R)-4-(2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌嗪-1-羧酸叔丁酯(中间体I-1-2)制备得到白色固体化合物I-8。
化合物I-8(11毫克),MS:431.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.31–8.29(m,1H),7.81–7.71(m,1H),7.61–7.51(m,1H),6.81–6.71(m,2H),6.69–6.59(m,1H),4.87(q,J=8.9,7.7Hz,1H),4.81(s,2H),4.11–3.87(m,1H),3.41–3.18(m,9H),1.63(d,J=6.4Hz,3H)。
实施例9
化合物I-9:(S)-5-(4-甲基-8-(哌啶-4-基)-3,4-二氢吡嗪并[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
化合物I-9的合成参考化合物I-1,通过使用(S)-4-(4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌啶-1-羧酸叔丁酯(中间体A10)代替(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A1)制备得到白色固体化合物I-9。
化合物I-9(19.3毫克),MS:423.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.08(d,J=4.2Hz,1H),8.76–8.63(m,2H),8.33(d,J=8.0Hz,1H),7.71(dd,J=8.5,4.2Hz,1H),7.61(d,J=9.0Hz,1H),7.41(d,J=8.1Hz,1H),6.94(d,J=9.5Hz,2H),4.89(q,J =8.9,7.7Hz,1H),4.82(s,2H),4.01–3.89(m,1H),3.41–3.17(m,5H),2.26–2.19(m,1H),2.06–1.84(m,4H),1.63(d,J=6.4Hz,3H)。
实施例10
化合物I-10:(S)-2-(1,6-二甲基-1H-吡唑[3,4-b]吡啶-4-基)-4-甲基-8-(哌啶-4-基)-1,2,3,4-四氢吡嗪[1,2-b]吲唑
化合物I-10的合成参考化合物I-1,通过使用(S)-4-(4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌啶-1-羧酸叔丁酯(中间体A10)代替(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A1)和4-溴-1,6-二甲基-1H-吡唑啉[3,4-b]吡啶(中间体D3)代替5-溴-8-氰基喹啉(中间体D1)制备得到白色固体化合物I-10。
化合物I-10(21.1毫克),MS:416.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.72(br,1H),8.58(s,1H),7.79(d,J=9.1Hz,1H),6.98(d,J=9.3Hz,1H),6.90(d,J=1.9Hz,1H),6.78(s,1H),5.32(s,2H),4.80(s,1H),4.35–4.28(m,1H),4.22–4.08(m,1H),4.00(s,3H),3.42–3.21(m,4H),2.56(s,3H),2.29–2.19(m,1H),2.08–1.71(m,4H),1.62(d,J=6.5Hz,3H)。
实施例11
化合物I-11:(R)-5-(4-甲基-7-(哌嗪-1-基)-3,4-二氢吡嗪并[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
化合物I-11的合成参考化合物I-1,通过使用(R)-7-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A3)代替(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A1)制备得到白色固体化合物I-11。
化合物I-11(12毫克),MS:424.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.06(d,J=4.2Hz,1H),8.75(br,1H),8.68(d,J=8.6Hz,1H),8.35(d,J=8.0Hz,1H),7.71–7.63(m,1H),7.41(d,J=8.1Hz,1H),7.31–7.23(m,1H),6.94–6.83(m,1H),6.64–6.53(m,1H),4.89(m,1H),4.82(s,2H),4.02–3.83(m,1H),3.37–3.23(m,9H),1.63(d,J=6.4Hz,3H)。
实施例12
化合物I-12:(R)-5-(4-甲基-7-(哌啶-4-基)-3,4-二氢吡嗪并[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
化合物I-12的合成参考化合物I-1,通过使用(R)-4-(4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-7-基)哌啶-1-羧酸叔丁酯(中间体A11)代替(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A1)制备得到白色固体化合物I-12。
化合物I-12(10毫克),MS:423.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.07(d,J=4.3Hz,1H),8.77(br,1H),8.69(d,J=8.5Hz,1H),8.37(d,J=8.0Hz,1H),7.77–7.63(m,1H),7.45(d,J=8.1Hz,1H),7.31–7.24(m,1H),6.94–6.8(m,1H),6.6–6.53(m,1H),4.88(m,1H),4.82(s,2H),4.02–3.83(m,1H),3.39–3.25(m,5H),2.26–2.19(m,1H),2.06–1.84(m,4H),1.64(d,J=6.4Hz,3H)。
实施例13
化合物I-13:(R)-4-甲基-2-(8-甲基-[1,2,4]三唑并[1,5-a]吡啶-6-基)-8-(哌嗪-1-基)-1,2,3,4-四氢吡嗪[1,2-b]吲唑
化合物I-13的合成参考化合物I-1,通过使用6-溴-8-甲基-[1,2,4]三唑[1,5-a]吡啶(中间体D2)代替5-溴-8-氰基喹啉(中间体D1)制备得到白色固体化合物I-13。
化合物I-13(20毫克),MS:403.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.71(br,2H),8.42–8.33(m,1H),7.85(m,1H),7.61–6.99(m,1H),6.84–6.78(m,1H),4.89–4.82(m,3H),4.02–3.83(m,1H),3.37–3.23(m,9H),2.62(s,3H),1.62(d,J=6.2Hz,3H)。
实施例14
化合物I-14:(R)-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲哚唑-8-羧酸
将(R)-5-(8-溴-4-甲基-3,4-二氢吡嗪并[1,2-b]吲唑-2(1H)-基)喹啉-8-腈(中间体I-1-1,0.05克,0.120毫摩尔),Pd(OAc)
2(2.68毫克,0.012毫摩尔),Mo(CO)
6(63毫克)和DIEA(0.031克,0.239毫摩尔)溶于乙醇(1.5毫升)和DMSO(1.5毫升)中。在20度搅拌下缓慢加入Xantphos(6.92毫克,0.012毫摩尔),加完后,将反应混合物在140度微波反应15分钟,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到浅黄色固体(R)-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-羧酸乙酯(中间体I-14-1,20毫克,41%),MS:412.1(M+H)
+和黄色固体(R)-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲哚唑-8-羧酸(化合物I-14,1.5毫克,3.3%),MS:384.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.05(d,J=4.2Hz,1H),8.76–8.63(m,2H),8.33(d,J=8.0Hz,1H),7.71(dd,J=8.5,4.2Hz,1H),7.61(d,J=9.0Hz,1H),7.41(d,J=8.1Hz,1H),6.94(d,J=9.5Hz,1H),4.89(q,J=8.9,7.7Hz,1H),4.82(s,2H),4.01–3.89(m,1H),3.41–3.17(m,1H),1.61(d,J=6.4Hz,3H)。
实施例15
化合物I-15:(R)-5-(4-甲基-8-(哌嗪-1-羰基)-3,4-二氢吡嗪[1,2-b]吲哚唑-2(1H)-基)喹啉-8-腈
步骤1:(R)-4-(2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-羰基)哌嗪-1-羧酸叔丁酯的制备(中间体I-15-1)
将(R)-5-(8-溴-4-甲基-3,4-二氢吡嗪并[1,2-b]吲唑-2(1H)-基)喹啉-8-腈(中间体I-1-1,0.05克,0.120毫摩尔),哌嗪-1-羧酸叔丁酯(0.045克,0.239毫摩尔),Pd(OAc)
2(2.68毫克,0.012毫摩尔),Mo(CO)
6(63毫克)和DIEA(0.031克,0.239毫摩尔)溶于乙醇(2毫升)和DMSO(2毫升)中。在20度搅拌下缓慢加入Xantphos(6.92毫克,0.012毫摩尔),加完后,将反应混合物在140度微波反应15分钟,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体(R)-4-(2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-羰基)哌嗪-1-羧酸叔丁酯(20毫克,30%),MS:552.1(M+H)
+。
步骤2:(R)-5-(4-甲基-8-(哌嗪-1-羰基)-3,4-二氢吡嗪[1,2-b]吲哚唑-2(1H)-基)喹啉-8-腈
化合物I-15的合成参考化合物I-1,通过使用(R)-4-(2-(8-氰基喹啉-5-基)-4-甲基- 1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-羰基)哌嗪-1-羧酸叔丁酯(中间体I-15-1)代替(R)-4-(2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌嗪-1-羧酸叔丁酯(中间体I-1-2)制备得到白色固体化合物I-15。
化合物I-15(13.4毫克),MS:452.1(M+H)
+。
实施例16
化合物I-16:(R)-5-(4-甲基-8-(哌啶-4-基氨基)-3,4-二氢吡嗪并[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
化合物I-16的合成参考化合物I-1,通过使用4-氨基哌啶-1-羧酸叔丁酯代替哌嗪-1-羧酸叔丁酯制备得到白色固体化合物I-16。
化合物I-16(13.4毫克),MS:438.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.08(d,J=4.1Hz,1H),8.65(d,J=8.6Hz,1H),8.50(s,1H),8.32(d,J=8.0Hz,2H),7.70(dd,J=8.6,4.2Hz,1H),7.41(t,J=8.4Hz,2H),6.63–6.37(m,2H),4.79(m,3H),4.11–3.53(m,5H),3.49–3.21(m,2H),3.06(m,2H),2.12(m,2H),1.61(d,J=6.4Hz,3H)。
实施例17
化合物I-17:5-(4-乙基-8-(哌嗪-1-基)-3,4-二氢吡嗪并[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
化合物I-17的合成参考化合物I-1,通过使用8-溴-4-乙基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A5)代替(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A1)制备得到白色固体化合物I-17。
化合物I-17(10毫克),MS:438.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.08(d,J=4.1Hz,1H),8.80–8.54(m,2H),8.34(d,J=8.0Hz,1H),7.71(dd,J=8.7,4.2Hz,1H),7.60(d,J=9.0Hz,1H),7.44(d,J=8.2Hz,1H),6.93(d,J=8.8Hz,2H),4.79(m,2H),4.15–3.78(m,2H),3.54(m,1H),3.42–3.14(m,8H),2.29(m,1H),2.00(m,1H),0.94(t,J=7.5Hz,3H)。
实施例18
化合物I-18:(R)-5-(8-(羟甲基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
化合物I-18的合成参考中间体A1-6,通过使用(R)-2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-羧酸乙酯(中间体I-14-1)代替(R)-8-溴-2-(4-甲氧基苄基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-1(2H)-酮(中间体A1-5)制备得到白色固体化合物I-18。
化合物I-18(8毫克),MS:370.1(M+H)
+。
实施例19
化合物I-19:(R)-5-(8-溴-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-[1,2,4]三唑[1,5-a]吡啶-8-腈
步骤1:(R)-8-溴-2-(8-碘代-[1,2,4]三唑并[1,5-a]吡啶-5-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑的制备(中间体I-19-1)
中间体I-19-1的合成参考中间体I-8-1,通过使用5-氯-8-碘-[1,2,4]三唑并[1,5-a]吡啶(中间体A13)代替3,4-二氟吡唑[1,5-a]吡啶-7-腈(中间体A9)制备得到中间体I-19-1。MS:509.1&511.1(M+H)
+。
步骤2:(R)-5-(8-溴-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-[1,2,4]三唑[1,5-a]吡啶-8-腈的制备
将(R)-8-溴-2-(8-碘代-[1,2,4]三唑并[1,5-a]吡啶-5-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑(0.02克,0.039毫摩尔),氰化锌(9.22毫克,0.079毫摩尔),Pd(Ph
3P)
4(4.54毫克,3.93微摩尔)溶于DMF(4毫升)中。反应混合物在氮气的保护下缓慢升至70℃并搅拌16小时,然后用水稀释并用乙酸乙酯萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经Pre-HPLC制备得到白色固体(R)-5-(8-溴-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-[1,2,4]三唑[1,5-a]吡啶-8-腈(4毫克,25%)。MS:418&420(M+H)
+。
实施例20
化合物I-20:5-((R)-8-((3R,4S)-3-氨基-4-氟吡咯烷-1-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
化合物I-20的合成参考化合物I-1,通过使用((3R,4S)-4-氟吡咯烷-3-基)氨基甲酸叔丁酯代替哌嗪-1-羧酸叔丁酯制备得到白色固体化合物I-20。
化合物I-20(16毫克),MS:442.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.08(d,J=4.1Hz,1H),8.67(d,J=8.6Hz,1H),8.56(br,2H),8.32(d,J=8.0Hz,1H),7.71(dd,J=8.6,4.2Hz,1H),7.60(d,J=9.1Hz,1H),7.41(d,J=8.1Hz,1H),6.71–6.58(m,1H),6.47(s,1H),4.84(m,3H),4.03–3.63(m,6H),3.52–3.30(m,2H),1.62(d,J=6.4Hz,3H)。
实施例21
化合物I-21:(R)-5-(4-甲基-8-(5-氧杂-2,8-二氮螺环[3.5]壬-2-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
化合物I-21的合成参考化合物I-1,通过使用5-氧代-2,8-二氮螺环[3.5]壬烷-8-羧酸叔丁酯代替哌嗪-1-羧酸叔丁酯制备得到白色固体化合物I-21。
化合物I-21(26毫克),MS:466.1(M+H)
+。
1H NMR(400MHz,DMSO-d6)δ9.08(br,2H),8.66(d,J=8.6Hz,1H),8.32(d,J=8.0Hz,1H),7.70(dd,J=8.6,4.2Hz,1H),7.58(d,J=8.9Hz,1H),7.41(d,J=8.1Hz,1H),6.45(d,J=8.9Hz,1H),6.39(s,1H),4.83(m,3H),4.02(m,3H),3.84(s,2H),3.71(s,2H),3.44(d,J=5.9Hz,3H),3.13(s,2H),1.62(d,J=6.3Hz,3H)。
实施例22
化合物I-22:(R)-5-(8-(3-氨基-3-甲基氮杂环丁烷-1-基)-4-甲基-3,4-二氢吡嗪并[1,2-b]吲哚唑-2(1H)-基)喹啉-8-腈
化合物I-22的合成参考化合物I-1,通过使用(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯代替哌嗪-1-羧酸叔丁酯制备得到白色固体化合物I-22。
化合物I-22(21毫克),MS:424.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.08(d,J=4.1Hz,1H),8.66(d,J=8.6Hz,1H),8.44(br,1H),8.32(d,J=8.0Hz,1H),7.71(dd,J=8.7,4.2Hz,1H),7.58(d,J=8.8Hz,1H),7.40(d,J=8.0Hz,1H),6.52–6.41(m,2H),4.84(m,3H),3.91–3.76(m,5H),3.45(m,1H),1.62(d,J=6.4Hz,3H),1.58(s,3H)。
实施例23
化合物I-23:(R)-5-(4-甲基-8-(5-氧杂-2,8-二氮螺环[3.5]壬-8-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
化合物I-23的合成参考化合物I-1,通过使用(5-氧代-2,8-二氮螺环[3.5]壬烷-2-羧酸叔丁酯代替哌嗪-1-羧酸叔丁酯制备得到白色固体化合物I-23。
化合物I-23(15毫克),MS:466.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.08(d,J=4.1Hz,1H),8.67(d,J=8.6Hz,1H),8.32(d,J=8.0Hz,1H),7.71(dd,J=8.6,4.2Hz,1H),7.60(d,J=9.1Hz,1H),7.41(d,J=8.0Hz,1H),7.06–6.97(m,1H),6.86(s,1H),4.86(m,3H),4.01(m,1H),3.75–3.66(m,6H),3.56–3.36(m,5H),1.63(d,J=6.4Hz,3H)。
实施例24
化合物I-24:(R)-5-(4,7-二甲基-8-(哌嗪-1-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
化合物I-24的合成参考化合物I-1,通过使用(R)-8-溴-4,7-二甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑(中间体A12)代替(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A1)制备得到白色固体化合物I-24。
化合物I-24(22毫克),MS:438.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.08(d,J=4.1Hz,1H),8.76–8.61(m,2H),8.32(d,J=8.0Hz,1H),7.71(dd,J=8.5,4.2Hz,1H),7.55(d,J=8.8Hz,1H),7.42(d,J=8.2Hz,1H),6.94(d,J=9.1Hz,1H),4.93(m,1H),4.83(m,2H),4.03(m,1H),3.58–3.42(m,5H),3.35–3.25(m,4H),3.07(s,3H),1.66(d,J=6.4Hz,3H)。
实施例25
化合物I-25:(R)-2-(4-(2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌嗪-1-基)乙酰胺
将(R)-5-(4-甲基-8-(哌嗪-1-基)-3,4-二氢吡嗪[1,2-b]吲哚-2(1H)-基)喹啉-8-腈(化合物I-1,40毫克,0.094毫摩尔),2-溴乙酰胺(18.37毫克,0.133毫摩尔)和TEA(28.7毫克,0.283毫摩尔)溶于乙腈(3毫升)中,将反应混合物在25℃搅拌1小时,然后将反应混合液浓缩蒸干,并用二氯甲烷稀释萃取。有机相用饱和碳酸氢钠溶液,饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经pre-HPLC纯化得到黄色固体(R)-2-(4-(2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌嗪-1-基)乙酰胺(7.3毫克,16.08%)。MS:481.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.08(d,J=4.1Hz,1H),8.67(d,J=8.6Hz,1H),8.33(d,J=8.0Hz,1H),7.97(s,1H),7.77–7.67(m,2H),7.61(d,J=9.2Hz,1H),7.41(d,J=8.1Hz,1H),6.93(d,J=8.1Hz,2H),4.86(m,3H),4.01(m,2H),3.85–2.97(m,10H),1.63(d,J=6.4Hz,3H)。
实施例26
化合物I-26:5-((R)-8-((3R,4R)-3-氨基-4-甲氧基吡咯烷-1-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
化合物I-26的合成参考化合物I-1,通过使用((3R,4R)-4-甲氧基吡咯烷-3-基)氨基甲酸叔丁酯代替哌嗪-1-羧酸叔丁酯制备得到白色固体化合物I-26。
化合物I-26(11毫克),MS:454.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.08(d,J=4.1Hz,1H),8.67(d,J=8.6Hz,1H),8.32(d,J=8.0Hz,1H),8.24(br,2H),7.71(dd,J=8.6,4.2Hz,1H),7.59(d,J=9.0Hz,1H),7.40(d,J=8.1Hz,1H),6.69(d,J=9.1Hz,1H),6.49(s,1H),4.84(m,3H),4.12–3.96(m,2H),3.95–3.25(m,9H),1.62(d,J=6.3Hz,3H)。
实施例27
化合物I-27:(R)-1-甲基-4-(4-甲基-8-(哌嗪-1-基)-3,4-二氢吡嗪并[1,2-b]吲哚唑-2(1H)-基)-1,8-萘啶-2(1H)-酮
化合物I-27的合成参考化合物I-12,通过使用(R)-4-(4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌嗪-1-羧酸叔丁酯(中间体A6)代替(R)-4-(4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-7-基)哌啶-1-羧酸叔丁酯(中间体A11)和4-溴-1-甲基-1,8-萘啶-2(1H)-酮(中间体D4)代替5-溴-8-氰基喹啉(中间体D1)制备得到白色固体化合物I-27。
化合物I-27(5毫克),MS:430.1(M+H)
+。
实施例28
化合物I-28:(R)-5-(4-甲基-9-(哌嗪-1-基)-3,4-二氢吡嗪并[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
化合物I-28的合成参考化合物I-1,通过使用(R)-9-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A4)代替(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A1)制备得到白色固体化合物I-28。
化合物I-28(32毫克),MS:424.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.09(dd,J=4.3,1.7Hz,1H),8.76(br,1H),8.67(d,J=8.8Hz,1H),8.34(d,J=8.0Hz,1H),7.71(dd,J=8.6,4.2Hz,1H),7.54(d,J=9.3Hz,1H),7.42(d,J=8.1Hz,1H),7.17(dd,J=9.3,2.2Hz,1H),7.07(d,J=2.1Hz,1H),4.93(s,1H),4.81(d,J=5.0Hz,2H),4.03-3.98(m,1H),3.87-3.76(m,8H),3.54-3.46(m,1H),1.64(d,J=6.3Hz,3H)。
实施例29
化合物I-29:(R)-2-(4-(2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲哚唑-8-基)哌啶-1-基)乙酰胺
化合物I-29的合成参考化合物I-25,通过使用化合物I-6代替化合物I-1制备得到白色固体化合物I-29。
化合物I-29(5毫克),MS:480.1(M+H)
+。
实施例30
化合物I-30:(R)-2-(8-碘代-[1,2,4]三唑并[1,5-a]吡啶-5-基)-4-甲基-8-(哌啶-4-基)-1,2,3,4-四氢吡嗪[1,2-b]吲唑
步骤1:(R)-4-(2-(8-碘代-[1,2,4]三唑并[1,5-a]吡啶-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌啶-1-羧酸叔丁酯的制备(中间体I-30-1)
中间体I-30-1的合成参考中间体I-19-1,通过使用(R)-4-(4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌啶-1-羧酸叔丁酯(中间体A7)代替(R)-8-溴-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑(中间体A1)制备得到中间体I-30-1。MS:614.1(M+H)
+。
步骤2:(R)-2-(8-碘代-[1,2,4]三唑并[1,5-a]吡啶-5-基)-4-甲基-8-(哌啶-4-基)-1,2,3,4-四氢吡嗪[1,2-b]吲唑的制备
化合物I-30的合成参考化合物I-1,通过使用(R)-4-(2-(8-碘代-[1,2,4]三唑并[1,5-a]吡啶-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌啶-1-羧酸叔丁酯(中间体I-30-1)代替(R)-4-(2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌嗪-1-羧酸叔丁酯(中间体I-1-2)制备得到黄色固体化合物I-30。
化合物I-30(6.4毫克),MS:514.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.55 (m,2H),8.10(d,J=8.0Hz,1H),7.69(d,J=8.6Hz,1H),7.38(s,1H),6.94(d,J=8.6Hz,1H),6.61(d,J=8.1Hz,1H),5.26–4.91(m,2H),4.79(d,J=5.4Hz,1H),4.45–4.25(m,1H),4.15–3.92(m,1H),3.14–2.84(m,5H),2.00(m,2H),1.84(m,2H),1.67(d,J=6.5Hz,3H)。
实施例31
化合物I-31:(R)-4-(4-甲基-8-(哌嗪-1-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-31的合成参考化合物I-8,通过使用4-氟吡唑并[1,5-a]吡啶-7-腈(中间体A8)代替3,4-二氟吡唑[1,5-a]吡啶-7-腈(中间体A9)制备得到黄色固体化合物I-31。
化合物I-31(11.4毫克),MS:413.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.66(br,1H),8.18(d,J=2.3Hz,1H),7.76(d,J=8.1Hz,1H),7.65(d,J=9.0Hz,1H),7.13(d,J=2.5Hz,1H),6.95(d,J=9.4Hz,1H),6.90(s,1H),6.78(d,J=8.3Hz,1H),5.10–4.89(m,2H),4.81(m,1H),4.21(m,1H),3.80(m,1H),3.27(m,8H),1.66(d,J=6.4Hz,3H)。
实施例32
化合物I-32:(R)-5-(4-甲基-8-(哌啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-[1,2,4]三唑并[1,5-a]吡啶-8-腈
步骤1:(R)-4-(2-(8-氰基-[1,2,4]三唑并[1,5-a]吡啶-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌啶-1-羧酸叔丁酯的制备(中间体I-32-1)
中间体I-32-1的合成参考中间体A9,通过使用(R)-4-(2-(8-碘代-[1,2,4]三唑并[1,5-a]吡啶-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌啶-1-羧酸叔丁酯(中间体I-30-1)代替7-溴-3,4-二氟吡唑并[1,5-a]吡啶(中间体A9-2)制备得到化合物I-32-1。MS:513.1(M+H)
+。
步骤2:(R)-5-(4-甲基-8-(哌啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-[1,2,4]三唑并[1,5-a]吡啶-8-腈的制备
化合物I-32的合成参考化合物I-1,通过使用(R)-4-(2-(8-氰基-[1,2,4]三唑并[1,5-a]吡啶-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌啶-1-羧酸叔丁酯(中间体I- 32-1)代替(R)-4-(2-(8-氰基喹啉-5-基)-4-甲基-1,2,3,4-四氢吡嗪并[1,2-b]吲唑-8-基)哌嗪-1-羧酸叔丁酯(中间体I-1-2)制备得到黄色固体化合物I-32。
化合物I-32(16.4毫克),MS:413.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.69(s,1H),8.29(d,J=8.3Hz,1H),7.70(d,J=8.7Hz,1H),7.38(s,1H),6.96(d,J=8.7Hz,1H),6.87(d,J=8.4Hz,1H),5.46–5.13(m,2H),4.96–4.80(m,1H),4.58(dd,J=13.3,3.9Hz,1H),4.26(dd,J=13.6,7.1Hz,1H),3.57–2.83(m,5H),1.99(d,J=13.7Hz,2H),1.83(q,J=13.1Hz,2H),1.68(d,J=6.6Hz,3H)。
实施例33
化合物I-33:(R)-3-氟-4-(8-甲基-5-氧代-2-(哌嗪-1-基)-7,8-二氢吡啶[2',3':3,4]吡唑并[1,5-a]吡嗪-6(5H)-基)吡唑并[1,5-a]吡啶-7-腈
步骤1:(R)-2-(4-苄基哌嗪-1-基)-8-甲基-7,8-二氢吡啶[2',3':3,4]吡唑并[1,5-a]吡嗪-5(6H)-酮的制备(中间体I-33-1)
将(R)-2-(4-苄基哌嗪-1-基)-6-(4-甲氧基苄基)-8-甲基-7,8-二氢吡啶[2',3':3,4]吡唑并[1,5-a]吡嗪-5(6H)-酮(中间体A14,100毫克,0.201毫摩尔),苯甲醚(9.9克,92毫摩尔)和三氟化硼乙醚(1120毫克,7.89毫摩尔)的甲苯(10毫升)溶液在120度搅拌反应16小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到(R)-2-(4-苄基哌嗪-1-基)-8-甲基-7,8-二氢吡啶[2',3':3,4]吡唑并[1,5-a]吡嗪-5(6H)-酮(70毫克,92%),MS:377.1(M+H)
+。
步骤2:(R)-4-(2-(4-苄基哌嗪-1-基)-8-甲基-5-氧代-7,8-二氢吡啶[2',3':3,4]吡唑并[1,5-a]吡嗪-6(5H)-基)-3-氟吡唑并[1,5-a]吡啶-7-腈的制备(中间体I-33-2)
中间体I-33-2的合成参考中间体I-8-1,通过使用中间体I-33-1代替中间体A1制备得到中间体I-33-2。MS:536.1(M+H)
+。
步骤3:(R)-3-氟-4-(8-甲基-5-氧代-2-(哌嗪-1-基)-7,8-二氢吡啶[2',3':3,4]吡唑并[1,5-a]吡嗪-6(5H)-基)吡唑并[1,5-a]吡啶-7-腈的制备(化合物I-33)
将氯乙基氯甲酸酯(70.7毫克,0.495毫摩尔)和(R)-4-(2-(4-苄基哌嗪-1-基)-8-甲基-5-氧代-7,8-二氢吡啶[2',3':3,4]吡唑并[1,5-a]吡嗪-6(5H)-基)-3-氟吡唑并[1,5-a]吡啶-7- 腈(53毫克,0.099毫摩尔)的1,2-二氯乙烷(5毫升)溶液在80度搅拌反应16小时,然后加入甲醇(5毫升)并继续回流2小时。将反应混合物浓缩得到粗产物,粗产物经pre-
HPLC制备纯化得到白色固体(R)-3-氟-4-(8-甲基-5-氧代-2-(哌嗪-1-基)-7,8-二氢吡啶[2',3':3,4]吡唑并[1,5-a]吡嗪-6(5H)-基)吡唑并[1,5-a]吡啶-7-腈(9毫克)。MS:446.1(M+H)
+。
实施例34
化合物I-34a和化合物I-34b:5-((1S,4R)-1,4-二甲基-8-(哌嗪-1-基)-3,4-二氢吡嗪并[1,2-b]吲哚唑-2(1H)-基)喹啉-8-腈和5-((1R,4R)-1,4-二甲基-8-(哌嗪-1-基)-3,4-二氢吡嗪并[1,2-b]吲哚唑-2(1H)-基)喹啉-8-腈
化合物I-34a的合成参考化合物I-1,通过使用中间体A15-a代替中间体A1制备得到白色固体化合物I-34a。
化合物I-34a(3.3毫克),MS:438.1(M+H)
+。
化合物I-34b的合成参考化合物I-1,通过使用中间体A15-b代替中间体A1制备得到白色固体化合物I-34b。
化合物I-34b(2.6毫克),MS:438.1(M+H)
+。
实施例36
化合物I-36:3-氟-4-(5-甲基-7-(哌啶-4-基)-1,3,4,5-四氢-2H-吡咯[3,2-c:4,5-c']联吡啶-2-基)吡唑[1,5-a]吡啶-7-腈
步骤1:4-(7-氯-5-甲基-1,3,4,5-四氢-2H-吡咯[3,2-c:4,5-c']联吡啶-2-基)-3-氟吡唑[1,5-a]吡啶-7-腈(I-36-1)
中间体I-36-1的合成参考中间体I-8-1,通过使用中间体A16代替中间体A1制备得到中间体I-36-1。MS:381.1(M+H)
+
步骤2:4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-5-甲基-2,3,4,5-四氢-1H-吡咯
[3,2-c:4,5-c']联吡啶-7-基)哌啶-1-羧酸叔丁酯(I-36-3)
中间体I-36-3的合成参考中间体A7,通过使用中间体I-36-1代替中间体A1制备得到中间体I-36-3。MS:530.1(M+H)
+
步骤3:3-氟-4-(5-甲基-7-(哌啶-4-基)-1,3,4,5-四氢-2H-吡咯[3,2-c:4,5-c']联吡啶-2-基)吡唑[1,5-a]吡啶-7-腈(I-36)
化合物I-36的合成参考化合物I-1,通过使用中间体I-36-3代替中间体I-1-2制备得到化合物I-36。MS:430.2(M+H)
+
实施例37
化合物I-37:(R)-3-氟-4-(4-甲基-8-(1,2,3,6-四氢吡啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-37的合成参考化合物I-2,通过使用中间体I-8-1代替中间体I-1-1制备得到化合物I-37。MS:428.2(M+H)
+
实施例38
化合物I-38:(R)-3-氟-4-(4-甲基-8-(哌啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-38的合成参考化合物I-31,通过使用中间体A9代替中间体A8和中间体A7代替中间体A1制备得到化合物I-38。MS:430.2(M+H)
+
实施例39
化合物I-39:(R)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四 氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)乙酰胺
化合物I-39的合成参考化合物I-25,通过使用化合物I-38代替化合物I-1制备得到化合物I-39。MS:487.2(M+H)
+
实施例40
化合物I-40:(R)-3-氟-4-(7-甲基-3-(哌嗪-1-基)-7,8-二氢吡啶[4',3':3,4]吡唑[1,5-a]吡嗪-9(10H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-40的合成参考化合物I-8,通过使用中间体A29代替中间体A1制备得到白色固体化合物I-40。MS:432.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.97(s,1H),8.86(s,2H),8.31(s,1H),7.74(d,J=7.8Hz,1H),6.87–6.61(m,2H),5.05(d,J=16.6Hz,1H),4.91(d,J=16.4Hz,1H),4.71(s,1H),4.16–4.05(m,1H),3.81(s,1H),3.63(s,4H),3.22(s,4H),1.59(d,J=6.4Hz,3H).
实施例41
化合物I-41:(R)-4-(8-(1-(二甲基甘氨酸)哌啶-4-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-41的合成参考化合物I-39,通过使用二甲基甘氨酸酰氯代替2-溴乙酰胺制备得到化合物I-41。MS:515.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.49(s,1H),8.32(d,J=3.5Hz,1H),7.75(d,J=8.0Hz,1H),7.67(d,J=8.6Hz,1H),7.39(s,1H),6.97(d,J=8.6Hz,1H),6.75(d,J=8.1Hz,1H),4.96(d,J=16.0Hz,1H),4.84 (d,J=16.0Hz,1H),4.79–4.69(m,1H),4.53(d,J=12.7Hz,1H),4.40–4.21(m,2H),4.16–4.07(m,1H),3.75–3.65(m,1H),3.60–3.54(m,1H),,3.19(t,J=12.9Hz,1H),2.98–2.87(m,1H),2.86–2.78(m,7H),1.95–1.86(m,2H),1.76–1.66(m,1H),1.62(d,J=6.4Hz,3H),1.58–1.49(m,1H).
实施例42
化合物I-42:(R)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)-N,N-二甲基乙酰胺
化合物I-42的合成参考化合物I-39,通过使用2-溴-N,N-二甲基乙酰胺代替2-溴乙酰胺制备得到化合物I-42。MS:515.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.49(s,1H),8.32(d,J=3.5Hz,1H),7.75(d,J=8.0Hz,1H),7.70(d,J=8.7Hz,1H),7.41(s,1H),6.98(d,J=8.9Hz,1H),6.75(d,J=8.1Hz,1H),4.97(d,J=16.0Hz,1H),4.85(d,J=16.1Hz,1H),4.75(s,1H),4.45–4.25(m,2H),4.18–4.07(m,1H),3.63–3.52(m,3H),3.20–3.09(m,2H),2.98–2.89(m,7H),2.05(s,3H),1.62(d,J=6.4Hz,3H).
实施例43
化合物I-43:(R)-3-氟-4-(8-甲基-2-(哌啶-4-基)-7,8-二氢吡啶[2',3':3,4]吡唑[1,5-a]吡嗪-6(5H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-43的合成参考化合物I-38,通过使用中间体A28代替中间体A7制备得到化合物I-38。MS:431.2(M+H)
+
实施例44
化合物I-44:4-((R)-8-((3R,5S)-3-氨基-5-(三氟甲基)哌啶-1-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-44的合成参考化合物I-1,通过使用中间体I-8-1代替中间体I-1-1,((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯代替哌嗪-1-羧酸叔丁酯制备得到白色固体化合物I-44。MS:513.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.31(d,J=3.3Hz,1H),8.07–7.98(m,3H),7.75(d,J=8.0Hz,1H),7.63(d,J=9.1Hz,1H),
6.99–6.85(m,2H),6.74(d,J=8.1Hz,1H),4.93(d,J=16.0Hz,1H),4.80(d,J=16.0Hz,1H),4.75–4.59(m,1H),4.18–4.06(m,1H),3.98–3.82(m,1H),3.60–3.42(m,1H),3.24–3.21(m,3H),2.79–2.62(m,3H),2.34–2.22(m,1H),1.59(d,J=6.5Hz,3H).
实施例45
化合物I-45:4-((R)-8-((3R,5S)-3-氨基-5-氟吡啶-1-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-45的合成参考化合物I-44,通过使用((3R,5S)-5-氟哌啶-3-基)氨基甲酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-45。MS:463.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.31(d,J=3.2Hz,1H),7.95(s,3H),7.75(d,J=8.1Hz,1H),7.64(d,J=8.8Hz,1H),6.97–6.89(m,2H),6.73(d,J=8.4Hz,1H),5.15–4.57(m,1H),3.62–3.49(m,1H),3.46-3.38(m,3H),3.24–3.17(m,4H),2.66(br s,1H),2.31(br s,1H),1.60(d,J=6.4Hz,3H).
实施例46
化合物I-46:4-((R)-8-((R)-5-氨基-3,3-二氟哌啶-1-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-46的合成参考化合物I-44,通过使用(R)-(5,5-二氟哌啶-3-基)氨基甲酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-46。MS:481.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.31(d,J=3.6Hz,1H),8.07(s,3H),7.75(d,J=7.9Hz,1H),7.64(d,J=9.1Hz,1H),6.99(s,1H),6.92(d,J=9.9Hz,1H),6.77–6.69(m,1H),5.00–4.76(m,2H),4.69(s,1H),4.17–4.03(m,1H),3.80–3.52(m,5H),3.22–3.16(m,3H),1.60(d,J=6.4Hz,3H).
实施例47
化合物I-47:(R)-3-氟-4-(4-甲基-8-(5-氧-2,8-二氮螺环[3.5]壬-2-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-甲酰胺
化合物I-47的合成参考化合物I-44,通过使用5-氧代-2,8-二氮螺环[3.5]壬烷-8-羧酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-47。MS:491.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.34(s,1H),9.07(s,2H),8.31(d,J=3.3Hz,1H),8.24(s,1H),7.71(d,J=7.9Hz,1H),7.59(d,J=8.9Hz,1H),6.88(d,J=8.0Hz,1H),6.46(d,J=9.0Hz,1H),6.38(s,1H),4.84(d,J=15.7Hz,1H),4.77–4.60(m,2H),4.09–3.95(m,3H),3.84(s,2H),3.71(dd,J=8.4,2.4Hz,2H),3.45-3.41(m,3H),3.12(s,2H),1.59(d,J=6.4Hz,3H).
实施例48
化合物I-48:3-氟-4-((4R)-8-(3-氟吡啶-4-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
步骤1:3-羟基-4-((R)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲哚唑-8-基)哌啶-1-羧酸叔丁酯的制备(中间体I-48-1)
将中间体I-48-1(1.75克,4.75毫摩尔)溶于THF(20毫升)中,在0度搅拌下将硼烷(23.75毫摩尔)加入到上述反应液中,反应混合物在氮气的保护下在20℃继续搅拌3小时。然后在0度搅拌下将氢氧化钠(14.25毫摩尔)缓慢地加入到盛有上述反应液的广口瓶中,并将H
2O
2(2.69克,23.75毫摩尔)缓慢加入到上述混合液中,反应混合物在在20℃继续搅拌16小时。反应混合液用水稀释并用乙酸乙酯萃取。有机相用饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色油状物中间体I-48-1(560毫克,30%)。MS:387.2(M+H)
+。
步骤2:4-((R)-2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)-3-羟基哌啶-1-羧酸叔丁酯的制备(中间体I-48-2)
中间体I-48-2的合成参考化合物I-8-1,通过使用中间体I-48-1代替中间体A1制备得到中间体I-48-2。MS:546.2(M+H)
+。
步骤3:4-((R)-2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)-3-氟哌啶-1-羧酸叔丁酯酯的制备(中间体I-48-3)
在0度搅拌条件下,将DAST(0.591克,3.67毫摩尔)缓慢加入到中间体I-48-2(0.5克,0.916毫摩尔)的DCM(2毫升)溶液中。将反应混合液在20度搅拌反应1小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体中间体I-48-3(300毫克,59.8%),MS:548.1(M+H)
+。
步骤4:3-氟-4-((4R)-8-(3-氟吡啶-4-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈的制备(化合物I-48)
化合物I-48的合成参考化合物I-1,通过使用中间体I-48-3代替中间体I-1-2制备得到黄色固体化合物I-48。MS:448.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.09(s,1H),8.76(s,1H),8.32(d,J=3.5Hz,1H),7.81–7.71(m,2H),7.48(s,1H),6.96(d,J=8.3Hz,1H),6.76(d,J=8.1Hz,1H),5.11–4.69(m,3H),4.20–4.08(m,1H),3.74–3.44(m,2H),3.20–2.98(m,4H),2.13–1.88(m,2H),1.63(d,J=6.4Hz,3H).
实施例49
化合物I-49:(R)-3-氟-4-(4-甲基-8-(5-氧-2,8-二氮螺环[3.5]壬-2-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-49的合成参考化合物I-44,通过使用5-氧代-2,8-二氮螺环[3.5]壬烷-8-羧酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-49。MS:473.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.06(s,2H),8.31(d,J=3.5Hz,1H),7.75(d,J=8.0Hz,1H),7.58(d,J=8.9Hz,1H),6.73(d,J=8.1Hz, 1H),6.46(d,J=9.0,1H),6.37(s,1H),4.91(d,J=15.9Hz,1H),4.78(d,J=15.9Hz,1H),4.67(s,1H),4.14–4.05(m,1H),4.05–3.97(m,2H),3.84(s,2H),3.76–3.67(m,2H),3.58–3.49(m,3H),3.12(s,2H),1.59(d,J=6.4Hz,3H).
实施例50
化合物I-50:2-(4-((R)-2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)-3-氟吡啶-1-基)乙酰胺
化合物I-50的合成参考化合物I-25,通过使用化合物I-48代替化合物I-1制备得到白色固体化合物I-50。MS:505.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.31(d,J=3.5Hz,1H),7.90(d,J=26.4Hz,1H),7.80–7.64(m,3H),7.50(s,1H),6.99(d,J=9.0Hz,1H),6.75(d,J=8.1Hz,1H),5.32–4.65(m,4H),4.28–3.66(m,5H),3.63–3.52(m,2H),3.04(s,2H),2.20–1.97(m,2H),1.62(d,J=6.4Hz,3H).
实施例51
化合物I-51:(S)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)乙酰胺
化合物I-51的合成参考化合物I-39,通过使用中间体A10代替中间体A7制备得到白色固体化合物I-51。MS:487.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.31(d,J=3.5Hz,1H),7.97(s,1H),7.78–7.66(m,3H),7.39(s,1H),6.95(d,J=8.7Hz,1H),6.75(d,J=8.1Hz,1H),4.96(d,J=16.0Hz,1H),4.84(d,J=16.0Hz,1H), 4.74(s,1H),4.12(d,J=14.1Hz,1H),3.92(s,2H),3.62–3.53(m,3H),3.17(s,3H),2.86(s,1H),2.02(s,4H),1.62(d,J=6.5Hz,3H).
实施例52
化合物I-52:(S)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)-N,N-二甲基乙酰胺
化合物I-52的合成参考化合物I-51,通过使用2-溴-N,N-二甲基乙酰胺代替2-溴乙酰胺制备得到白色固体化合物I-52。MS:515.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.31(d,J=3.4Hz,1H),7.72(dd,J=22.1,8.3Hz,2H),7.40(s,1H),6.97(d,J=8.8Hz,1H),6.75(d,J=8.2Hz,1H),5.04–4.79(m,2H),4.74(s,1H),4.28(d,J=4.6Hz,2H),4.12(d,J=13.6Hz,1H),3.58(d,J=12.4Hz,3H),3.41(d,J=6.5Hz,2H),3.31–3.04(m,2H),2.93(d,J=11.9Hz,5H),2.04(s,4H),1.62(d,J=6.4Hz,3H).
实施例53
化合物I-53:(S)-4-(8-(1-(二甲基甘氨酸)哌啶-4-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-53的合成参考化合物I-51,通过使用二甲基甘氨酸酰氯代替2-溴乙酰胺制备得到白色固体化合物I-53。MS:515.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.31(d,J=3.5Hz,1H),7.70(dd,J=33.3,8.3Hz,2H),7.38(s,1H),6.97(d,J=8.7Hz,1H),6.75(d,J=8.1Hz,1H),5.02–4.80(m,2H),4.73(s,1H),4.52(d,J=12.7Hz,1H),4.43–4.18(m,2H),4.17–4.02(m,1H),3.77–3.49(m,2H),3.18(t,J=12.9Hz,1H),2.90(t,J=12.0Hz,1H),2.81(dd,J=7.2,4.8Hz,7H),1.89(d,J=12.8Hz,2H),1.74–1.65(m,1H),1.61(d,J=6.5Hz,3H),1.54(d,J=12.0Hz,1H).
实施例54
化合物I-54:(R)-3-氟-4-(4-甲基-8-(1-(2-(甲磺酰基)乙基)哌啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-54的合成参考化合物I-39,通过使用1-氯-2-(甲磺酰)乙烷代替2-溴乙酰胺制备得到白色固体化合物I-54。MS:536.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.31(d,J=3.4Hz,1H),7.72(dd,J=22.8,8.2Hz,2H),6.96(d,J=8.7Hz,1H),6.75(d,J=8.2Hz,1H),4.97(d,J=15.9Hz,1H),4.84(d,J=16.1Hz,1H),4.74(s,1H),4.12(d,J=12.0Hz,1H),3.75–3.52(m,7H),3.41(d,J=3.9Hz,2H),3.13(s,3H),2.11(d,J=14.3Hz,2H),1.88(s,3H),1.62(d,J=6.6Hz,3H).
实施例55
化合物I-55:(R)-3-氟-4-(4-甲基-8-(1-(2-吗啉-2-氧乙基)哌啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-55的合成参考化合物I-39,通过使用2-氯-1-吗啉酮代替2-溴乙酰胺制备得到白色固体化合物I-55。MS:557.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.32(d,J=3.4Hz,1H),7.73(dd,J=21.5,8.4Hz,2H),7.41(s,1H),6.98(d,J=8.7Hz,1H),6.75(d,J=8.1Hz,1H),4.95(s,1H),4.87(s,1H),4.33(s,1H),3.60(t,J=8.9Hz,7H),3.49(d,J=21.0Hz,2H),3.27(s,9H),2.06(s,3H),1.62(d,J=6.5Hz,3H).
实施例56
化合物I-56:(R)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)-2-甲基丙烷酰胺
化合物I-56的合成参考化合物I-39,通过使用2-溴-2-甲基丙烷酰胺代替2-溴乙酰胺制备得到白色固体化合物I-56。MS:515.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.31(s,1H),7.90(d,J=16.1Hz,2H),7.73(dd,J=16.9,8.1Hz,2H),7.39(s,1H),6.95(s,1H),6.75(d,J=8.0Hz,1H),4.97(d,J=16.1Hz,1H),4.87(s,1H),4.75(s,2H),4.13(d,J=14.3Hz,1H),3.89(s,1H),3.60–3.44(m,1H),3.26(d,J=21.1Hz,3H),2.95(s,2H),2.11–1.88(m,2H),1.68–1.49(m,9H).
实施例57
化合物I-57:4-((R)-8-(1-((S)-4,4-二氟吡咯烷-2-羰基)哌啶-4-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
步骤1:(S)-2-(4-((R)-2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-羰基)-4,4-二氟吡咯烷-1-羧酸叔丁酯的制备(I-57-1)
将(S)-1-(叔丁氧羰基)-4,4-二氟吡咯烷-2-羧酸(0.014克,0.056毫摩尔),HATU(0.021克,0.056毫摩尔),DIEA(0.018克,0.140毫摩尔),中间体I-38(0.02克,0.047毫摩尔)溶于DMF(3毫升)中。将反应混合物在20度搅拌反应12小时,然后加入冰水淬灭反应,并用乙酸乙酯稀释萃取。有机相用饱和盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经硅胶柱层析纯化得到黄色固体(S)-2-(4-((R)-2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-羰基)-4,4-二氟吡咯烷-1-羧酸叔丁酯(20毫克),MS:663.1(M+H)
+。
步骤2:4-((R)-8-(1-((S)-4,4-二氟吡咯烷-2-羰基)哌啶-4-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈的制备(I-57)
化合物I-57的合成参考化合物I-1,通过使用I-57-1代替I-1-2制备得到白色固体化合物I-57。MS:563.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.31(d,J=3.5Hz,1H),7.75(d,J=8.0Hz,1H),7.66(dd,J=8.6,3.6Hz,1H),7.42(d,J=26.0Hz,1H),6.99(dd,J=16.5,8.6Hz,1H),6.75(d,J=8.1Hz,1H),5.11–4.92(m,2H),4.84(d,J=16.0Hz,1H),4.73(s,1H),4.51(s,1H),4.17–4.08(m,1H),3.84(d,J=15.4Hz,2H),3.81–3.66(m,2H),3.62–3.54(m,3H),3.22(t,J=13.0Hz,1H),3.08(t,J=12.1Hz,1H),2.84(t,J=12.3Hz,5H),1.88(d,J=14.7Hz,5H),1.66(d,J=28.6Hz,3H),1.61(s,3H).
实施例58
化合物I-58:3-氟-4-((R)-8-(1-((2S,4S)-4-氟吡咯烷-2-羰基)哌啶-4-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-58的合成参考化合物I-57,通过使用(2S,4S)-1-(叔丁氧羰基)-4-氟吡咯烷-2-羧酸代替(S)-1-(叔丁氧羰基)-4,4-二氟吡咯烷-2-羧酸制备得到白色固体化合物I-58。MS:545.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.89(s,1H),8.31(d,J=3.5Hz,1H),7.75(d,J=7.8Hz,1H),7.66(d,J=8.8Hz,1H),7.42(d,J=22.0Hz,1H),7.00(dd,J=14.5,8.7Hz,1H),6.75(d,J=8.1Hz,1H),5.50(d,J=7.2Hz,1H),5.37(dd,J=8.7,4.5Hz,1H),4.96(d,J=16.1Hz,1H),4.84(d,J=15.9Hz,2H),4.74(q,J=7.6,7.1Hz,2H),4.52(d,J=12.1Hz,1H),4.12(dd,J=14.0,4.2Hz,1H),3.90–3.61(m,2H),3.23(t,J=12.5Hz,2H),2.87(dt,J=25.7,12.4Hz,3H),2.26(q,J=23.8,23.0Hz,1H),1.90(d,J=12.4Hz,3H),1.76–1.57(m,4H).
实施例59
化合物I-59:2-(4-((R)-2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)-3-氟吡啶-1-基)-N,N-二甲基乙酰胺
化合物I-59的合成参考化合物I-50,通过使用2-溴-N,N-二甲基乙酰胺代替2-溴乙酰胺制备得到白色固体化合物I-59。MS:533.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ10.05(s,1H),8.32(d,J=3.5Hz,1H),7.85–7.68(m,2H),7.00(s,1H),6.76(d,J=8.1Hz,1H),5.20(s,1H),4.99(d,J=16.1Hz,1H),4.86(d,J=16.1Hz,1H),4.76(s,1H),4.36(s,2H),4.14(d,J=12.9Hz,1H),3.82(s,1H),3.31–3.03(m,4H),2.94(d,J=12.8Hz,6H),2.11(s,2H),1.63(d,J=6.4Hz,3H).
实施例60
化合物I-60:(R)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)-N-甲基乙酰胺
化合物I-60的合成参考化合物I-39,通过使用2-溴-N-甲基乙酰胺代替2-溴乙酰胺制备得到化合物I-60。MS:501.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.48(d,J=4.9Hz,1H),8.31(d,J=3.5Hz,1H),7.72(dd,J=21.0,8.3Hz,2H),7.39(s,1H),6.96(d,J=8.7Hz,1H),6.75(d,J=8.1Hz,1H),4.97(d,J=16.0Hz,1H),4.84(d,J=16.0Hz,1H),4.75(s,1H),4.13(d,J=14.0Hz,1H),3.91(s,2H),3.57(dd,J=14.6,9.5Hz,3H),3.17(s,2H),2.87(s,1H),2.69(d,J=4.6Hz,3H),2.03(s,4H),1.62(d,J=6.5Hz,3H).
实施例61
化合物I-61:(R)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-乙基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)乙酰胺
步骤1:中间体I-61-1的制备
中间体I-61-1的合成参考中间体A7,通过使用中间体A5-a代替中间体A1制备得到中间体I-61-1。MS:385.1(M+H)
+。
步骤2:(R)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-乙基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)乙酰胺的制备(I-61)
化合物I-61的合成参考化合物I-51,通过使用中间体I-61-1代替中间体A10制备得到白色固体化合物I-61。MS:501.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.32(d,J=3.5Hz,1H),7.98(s,1H),7.80–7.67(m,4H),7.39(s,1H),6.96(d,J=8.7 Hz,1H),6.77(d,J=8.1Hz,1H),4.98-4.94(m,1H),4.84-4.80(d,1H),4.62–4.58(m,1H),4.21–4.14(m,1H),3.93(s,2H),3.34(s,1H),3.18(s,2H),2.87(s,1H),2.40–2.33(m,1H),2.08–1.88(m,6H),0.95(t,J=7.5Hz,3H).
实施例62
化合物I-62:(R)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-乙基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)-N,N-二甲基乙酰
化合物I-62的合成参考化合物I-61,通过使用2-溴-N,N-二甲基乙酰胺代替2-溴乙酰胺制备得到白色固体化合物I-62。MS:529.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.34–8.29(m,1H),7.76(d,J=8.0Hz,1H),7.70(d,J=8.6Hz,1H),7.40(s,1H),6.98(d,J=8.7Hz,1H),6.77(d,J=8.1Hz,1H),4.94(s,1H),4.85-4.81(m,1H),4.68–4.55(m,1H),4.29(d,J=4.4Hz,2H),4.19-4.16(m,1H),3.38-3.34(m,2H),3.15–3.12(m,2H),2.95–2.92(m,6H),2.89(d,J=4.6Hz,1H),2.38(s,1H),2.09-2.05(m,4H),1.95–1.88(m,2H),0.95(t,J=7.5Hz,3H).
实施例63
化合物I-63:(S)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-乙基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)乙酰胺
化合物I-63的合成参考化合物I-61,通过使用中间体A5-b代替中间体A5-a制备得到白色固体化合物I-63。MS:501.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.59(s,1H),8.32(d,J=3.5Hz,1H),7.98(s,1H),7.76(d,J=8.0Hz,1H),7.73–7.68(m,2H),7.39(s,1H),6.96(d,J=8.7Hz,1H),6.77(d,J=8.1Hz,1H),4.96(d,J=16.0Hz,1H),4.82(d,J=16.0Hz,1H),4.58-4.63(m,1H),4.15-4.20(m,1H),3.93(s,2H),3.18(d,J=10.9Hz,2H),2.85-2.90(m,1H),2.35-2.41(m,1H),2.03(s,5H),1.86-1.95(m,2H),0.95(t,J=7.5Hz,3H).
实施例64
化合物I-64:(S)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-乙基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)-N,N-二甲基乙酰
化合物I-64的合成参考化合物I-63,通过使用2-溴-N,N-二甲基乙酰胺代替2-溴乙酰胺制备得到白色固体化合物I-64。MS:529.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.50(s,1H),8.32(d,J=3.5Hz,1H),7.77(d,J=8.0Hz,1H),7.71(d,J=8.6Hz,1H),7.41(s,1H),6.98(d,J=8.6Hz,1H),6.77(d,J=8.1Hz,1H),4.97(d,J=16.0Hz,1H),4.83(d,J=15.9Hz,1H),4.62(d,J=7.9Hz,1H),4.29(d,J=4.5Hz,2H),4.22–4.15(m,1H),3.34(s,1H),3.13(d,J=10.9Hz,2H),2.96(s,3H),2.92(s,3H),2.88(dd,J=10.4,4.7Hz,1H),2.37(d,J=10.9Hz,1H),2.06(s,4H),1.93(dd,J=15.0,8.4Hz,2H),0.96(t,J=7.5Hz,3H).
实施例65
化合物I-65:(R)-4-(8-(1-(2-(氮杂环丁-1-基)-2-氧乙基)哌啶-4-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-65的合成参考化合物I-39,通过使用1-(氮杂环丁烷-1-基)-2-溴甲烷-1-酮代替2-溴乙酰胺制备得到白色固体化合物I-65。MS:527.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.32(d,J=3.5Hz,1H),7.73(dd,J=21.6,8.3Hz,2H),7.40(s,1H),6.97(d,J=8.7Hz,1H),6.76(d,J=8.1Hz,1H),4.97(d,J=16.0Hz,1H),4.85(d, J=16.1Hz,1H),4.75(s,1H),4.22–4.09(m,3H),4.02–3.93(m,4H),3.57(dd,J=13.2,8.8Hz,3H),3.14(s,2H),2.87(s,1H),2.34–2.24(m,3H),2.04(s,3H),1.63(d,J=6.4Hz,3H).
实施例66
化合物I-66:3-氟-4-((R)-4-甲基-8-(1-(甲基-L-脯氨酰)哌啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-66的合成参考化合物I-57-1,通过使用甲基-L-脯氨酸代替(S)-1-(叔丁氧羰基)-4,4-二氟吡咯烷-2-羧酸制备得到白色固体化合物I-66。MS:541.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.32(d,J=3.6Hz,1H),7.76(d,J=8.0Hz,1H),7.67(dd,J=8.6,4.1Hz,1H),7.42(d,J=6.7Hz,1H),7.00(dd,J=8.8,4.4Hz,1H),6.76(d,J=8.1Hz,1H),4.97(d,J=16.0Hz,1H),4.84(d,J=16.0Hz,1H),4.74(s,1H),4.54(d,J=11.9Hz,2H),4.13(d,J=11.8Hz,1H),3.80(d,J=13.4Hz,1H),3.60(s,2H),3.30–3.21(m,1H),3.17–2.86(m,3H),2.82(dd,J=14.8,4.6Hz,4H),2.55(s,1H),2.09(s,1H),1.91(s,5H),1.62(d,J=6.4Hz,3H).
实施例67
化合物I-67:(R)-3-氟-4-(4-甲基-8-(1-(氧杂环丁-3-基)哌啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
将化合物I-38(60毫克,0.115毫摩尔)溶于甲醇(5毫升)中,在40℃时搅拌缓慢加入氧杂环丁酮(17毫克,0.233毫摩尔),NaBH
3CN(14.63毫克,0.233毫摩尔)和醋酸(6.99毫克,0.116毫摩尔)。然后将反应混合物在40℃搅拌反应12小时,将反应混合液用二氯甲烷稀释萃取,有机相依次用饱和碳酸氢钠溶液,饱和食盐水洗涤,无水干燥硫酸钠干燥,然后过滤,浓缩得到粗产物,粗产物经pre-HPLC纯化得到白色固体化合物I-67。MS:486.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.32(d,J=3.5Hz,1H),7.76(d,J=8.0Hz,1H),7.71(d,J=8.6Hz,1H),7.40(s,1H),6.97(d,J=8.7Hz,1H),6.76(d,J=8.0Hz,1H),4.99-4.92(m,1H),4.87-4.81(m,1H),4.79-4.72(m,5H),4.41(s,1H),4.15-4.11(m,1H),3.58(s,1H),3.52(s,1H),2.96(s,3H),2.12-2.09(m, 2H),1.98-1.91(m,3H),1.63(d,J=6.4Hz,3H).
实施例68
化合物I-68:3-氟-4-(8-(哌啶-4-基)-3,4-二氢吡唑[1,5-a:4,3-c']联吡啶-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-68的合成参考化合物I-39,通过使用中间体A31代替中间体A7制备得到白色固体化合物I-68。MS:416.1(M+H)
+。
实施例69
化合物I-69:3-氟-4-((R)-8-(1-((2S,4S)-4-氟吡咯烷-2-羰基)哌啶-4-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-69的合成参考化合物I-57,通过使用(叔丁氧羰基)-L-脯氨酸代替(S)-1-(叔丁氧羰基)-4,4-二氟吡咯烷-2-羧酸制备得到白色固体化合物I-69。MS:527.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.50(s,1H),8.32(d,J=3.5Hz,1H),7.75(d,J=8.0Hz,1H),7.66(dd,J=8.7,3.1Hz,1H),7.41(d,J=16.2Hz,1H),6.99(t,J=9.5Hz,1H),6.75(d,J=8.1Hz,1H),4.96(d,J=16.0Hz,1H),4.84(d,J=16.0Hz,1H),4.74(s,1H),4.57(dd,J=39.6,21.0Hz,2H),4.12(d,J=11.8Hz,1H),3.95(d,J=13.0Hz,1H),3.56(dd,J=13.8,8.7Hz,1H),3.42(s,1H),3.32–3.20(m,1H),3.18(s,2H),2.91(t,J=12.0Hz,1H),2.82(t,J=12.7Hz,1H),2.41(dd,J=13.6,7.6Hz,1H),1.91(p,J=7.8,7.1Hz,5H),1.83–1.67(m,1H),1.62(d,J=6.4Hz,4H).
实施例70
化合物I-70:(R)-3-氟-4-(4-甲基-8-(1-(3-吗啉丙酰基)哌啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-70的合成参考化合物I-39,通过使用3-吗啉丙酰氯代替2-溴乙酰胺制备得到白色固体化合物I-70。MS:571.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.31(d,J=3.4Hz,1H),7.75(d,J=8.0Hz,1H),7.66(d,J=8.6Hz,1H),7.38(s,1H),6.97(d,J=8.6Hz,1H),6.75(d,J=8.1Hz,1H),4.94(s,1H),4.86-4.82(m,1H),4.74-4.72(m,1H),4.56(d,J=12.8Hz,1H),4.14-4.11(m,1H),4.00-3.96(m,2H),3.71-3.64(m,2H),3.59-3.57(m,1H),3.50-3.47(m,2H),3.39-3.35(m,2H),3.16–3.14(m,4H),2.92–2.88(m,3H),2.72-2.67(m,1H),1.91–1.85(m,2H),1.70-1.67(m,1H),1.62(d,J=6.5Hz,3H),1.55–1.43(m,1H).
实施例71
化合物I-71:(R)-3-氟-4-(4-甲基-8-(1-(2-(吡咯烷-1-基)乙酰基)哌啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-71的合成参考化合物I-39,通过使用2-(吡咯烷-1-基)乙酰氯代替2-溴乙酰胺制备得到白色固体化合物I-71。MS:541.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.79(s,1H),8.33(d,J=3.5Hz,1H),7.76(d,J=8.0Hz,1H),7.68(d,J=8.6Hz,1H),7.40(s,1H),6.98(d,J=8.4Hz,1H),6.76(d,J=8.1Hz,1H),4.97(d,J=16.0Hz,1H),4.85(d,J=16.1Hz,1H),4.75(s,1H),4.54(d,J=12.9Hz,1H),4.41(qd,J=16.3,5.3Hz,2H),4.18–4.10(m,1H),3.73(d,J=13.4Hz,1H),3.63–3.52(m,3H),3.20(t,J=13.1Hz,1H),3.08(p,J=6.3Hz,2H),2.91(s,1H),2.80(t,J=12.6Hz,1H),2.00(d,J=7.2Hz,2H),1.96–1.87(m,4H),1.70(s,1H),1.63(d,J=6.4Hz,3H),1.55(d,J=12.5Hz,1H).
实施例72
化合物I-72:(R)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-(三氟甲基)-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)乙酰胺
化合物I-72的合成参考化合物I-61,通过使用中间体A17-a代替中间体A5-a制备得到白色固体化合物I-72。MS:541.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.62(s,1H),8.33(d,J=3.5Hz,1H),8.00(s,1H),7.79–7.76(m,2H),7.73(s,1H),7.45(s,1H),7.03(d,J=8.8Hz,1H),6.84(d,J=8.0Hz,1H),5.87–5.80(m,1H),5.15(d,J=16.6Hz,1H),4.84(d,J=16.6Hz,1H),4.22(d,J=5.0Hz,2H),3.59(d,J=11.6Hz,2H),3.20(s,2H),2.90(s,1H),2.05(s,4H).
实施例73
化合物I-73:(R)-3-氟-4-(4-甲基-8-(1-(2-吗啉乙酰基)哌啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-73的合成参考化合物I-39,通过使用2-吗啉乙酰氯代替2-溴乙酰胺制备得到白色固体化合物I-73。MS:557.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ10.08(s,1H),8.32(d,J=3.5Hz,1H),7.76(d,J=7.9Hz,1H),7.68(d,J=8.6Hz,1H),7.40(s,1H),6.98(d,J=8.7Hz,1H),6.76(d,J=8.1Hz,1H),4.97(d,J=16.0Hz,1H),4.85(d,J=16.0Hz,1H),4.81–4.69(m,1H),4.55(d,J=12.9Hz,1H),4.41(q,J=16.4Hz,3H),4.13(dd,J=14.0,4.3Hz,1H),3.96(s,2H),3.87–3.70(m,3H),3.57(dd,J=13.8,8.6Hz,1H),3.44(s,2H),3.30–3.16(m,2H),2.92(t,J=12.1Hz,1H),2.81(t,J=12.4Hz,1H),1.92(d,J=12.8Hz,2H),1.79–1.67(m,1H),1.63(d,J=6.4Hz,3H),1.59–1.47(m,1H).
实施例74
化合物I-74:(S)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-(三氟甲基)-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)乙酰胺
化合物I-74的合成参考化合物I-61,通过使用中间体A17-b代替中间体A5-a制备得到白色固体化合物I-74。MS:541.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.61(s,1H),8.34(d,J=3.5Hz,1H),8.00(s,1H),7.81–7.71(m,3H),7.45(s,1H),7.03(d,J=8.7Hz,1H),6.84(d,J=8.0Hz,1H),5.90–5.74(m,2H),5.15(d,J=16.6Hz,1H),4.84(d,J=16.6Hz,1H),4.22(d,J=5.0Hz,2H),3.94(s,2H),3.59(d,J=11.7Hz,2H),3.28–3.12(m,2H),2.97–2.81(m,1H),2.15–1.97(m,4H).
实施例75
化合物I-75:(R)-3-氟-4-(4-甲基-8-(1-(四氢-2H-吡喃-4-基)哌啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-75的合成参考化合物I-67,通过使用四氢-4H-吡喃-4-酮代替氧杂环丁酮制备得到白色固体化合物I-75。MS:514.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.33(d,J=3.5Hz,1H),7.77(d,J=8.0Hz,1H),7.71(d,J=8.8Hz,1H),7.41(s,1H),6.97(d,J=8.7Hz,1H),6.78-6.75(m,1H),5.00-4.96(m,1H),4.88-4.84(m,1H),4.79-4.72(s,1H),4.16-4.13(m,1H),4.02–3.99(m,3H),3.64-3.55(m,3H),3.48(s, 1H),3.41-3.32(m,2H),3.17-3.11(m,2H),2.95-2.92(m,1H),2.14-2.11(m,2H),2.02-1.94(m,4H),1.75-1.69(m,1H),1.64(d,J=6.4Hz,3H).
实施例76
化合物I-76:3-氟-4-((4R)-4-甲基-8-(哌啶-3-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-76的合成参考化合物I-38,通过使用中间体A18代替中间体A8制备得到化合物I-76。MS:430.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.81(s,2H),8.50(s,2H),8.33(d,J=3.5Hz,1H),7.74(dd,J=15.2,8.3Hz,2H),7.49(s,1H),7.01(d,J=8.6Hz,1H),6.76(d,J=8.1Hz,1H),4.98(d,J=16.0Hz,1H),4.86(d,J=16.0Hz,1H),4.77(s,1H),4.14(dd,J=13.8,4.1Hz,1H),3.58(dd,J=13.8,8.6Hz,1H),3.44(s,1H),3.32(s,2H),3.15–3.06(m,1H),3.04–2.91(m,2H),1.93(d,J=9.6Hz,2H),1.77(t,J=10.3Hz,2H),1.63(d,J=6.4Hz,3H).
实施例77
化合物I-77:2-(3-((R)-2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)-N,N-二甲基乙酰胺
化合物I-77的合成参考化合物I-41,通过使用化合物I-76代替化合物I-38制备得到白色固体化合物I-77。MS:515.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.70(s,1H),8.32(d,J=3.4Hz,1H),7.75(t,J=8.0Hz,2H),7.47(s,1H),6.96(d,J=8.7Hz,1H),6.76(d,J=8.1Hz,1H),4.98(d,J=16.1Hz,1H),4.86(d,J=16.0Hz,1H),4.78(dd,J=8.0,3.4Hz,1H),4.26(s,2H),4.17–4.11(m,1H),3.53-3.61(m,3H),3.46(s,1H),3.23(d,J=10.7Hz,2H),2.92(d,J=10.2Hz,6H),1.97(d,J=10.9Hz,2H),1.77–1.70(m,1H),1.63(d,J=6.4Hz,3H).
实施例78
化合物I-78:(R)-3-氟-4-(4-甲基-8-(1-(2-氧代-2-(吡咯烷-1-基)乙基)哌啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-78的合成参考化合物I-39,通过使用2-溴-1-(吡咯烷-1-基)乙烷-1-酮代替2-溴乙酰胺制备得到白色固体化合物I-78。MS:541.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.33(d,J=3.6Hz,1H),7.74(dd,J=20.1,8.3Hz,2H),7.42(s,1H),6.99(d,J=8.8Hz,1H),6.77(d,J=8.1Hz,1H),4.98(d,J=16.0Hz,1H),4.86(d,J=16.0Hz,1H),4.76(s,1H),4.16(d,J=30.3Hz,3H),3.58(d,J=16.5Hz,3H),3.53–3.38(m,3H),3.38–3.23(m,2H),3.17(s,3H),2.90(s,2H),2.06(s,5H),1.97–1.91(m,2H),1.84(q,J=6.7Hz,2H),1.64(d,J=6.4Hz,3H).
实施例79
化合物I-79:(R)-4-(8-(1-(2-(3,3-二氟氮杂环丁烷-1-基)-2-氧乙基哌啶-4-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-79的合成参考化合物I-39,通过使用2-溴-1-(3,3-二氟氮杂环丁烷-1-基)乙烷-1-酮代替2-溴乙酰胺制备得到白色固体化合物I-79。MS:563.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.33(d,J=3.6Hz,1H),7.74(dd,J=20.4,8.3Hz,2H),7.42(s,1H),6.98(d,J=8.7Hz,1H),6.77(d,J=8.1Hz,1H),4.98(d,J=15.9Hz,1H),4.86(d,J=16.1Hz,1H),4.58(dt,J=90.6,12.2Hz,5H),4.12(s,2H),3.63–3.53(m,2H),3.26(d,J=72.5Hz,3H),2.98–2.86(m,3H),2.09–2.03(m,5H),1.64(d,J=6.4Hz,3H).
实施例80
化合物I-80:3-氟-4-((4R)-4-甲基-8-(吡咯烷-3-基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-80的合成参考化合物I-38,通过使用中间体A19代替中间体A8制备得到化合物I-80。MS:416.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.33(d,J=3.5Hz,1H),7.78–7.73(m,2H),7.56(s,1H),7.04(dd,J=8.7,1.4Hz,1H),6.76(d,J=8.1Hz,1H),5.01-4.97(m,1H),4.88-4.84(m,1H),4.79-4.74(m,1H),4.17-4.12(m,1H),3.68-3.61(m,1H),3.59-3.52(m,3H),3.44(s,1H),3.30-3.27(m,1H),3.21–3.11(m,1H),2.44–2.34(m,1H),2.04-1.99(m,1H),1.64(d,J=6.4Hz,3H).
实施例81
化合物I-81:(R)-3-氟-4-(10-氟-4-甲基-8-(哌啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-81的合成参考化合物I-39,通过使用中间体A21代替中间体A7制备得到白色固体化合物I-81。MS:448.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.67(s,1H),8.43(s,1H),7.72(d,J=8.0Hz,1H),7.25(s,1H),6.79(d,J=8.1Hz,1H),6.71(d,J=11.9Hz,1H),4.97(s,2H),4.79(s,1H),4.14(dd,J=14.4,4.2Hz,1H),3.60(dd,J=13.8,8.5Hz,2H),3.40(d,J=12.5Hz,2H),3.04(t,J=12.1Hz,2H),2.02(d,J=13.7Hz,2H),1.82(q,J=13.0Hz,2H),1.63(d,J=6.5Hz,3H).
实施例82
化合物I-82:4-((4R)-8-(3-氨基-4-氟吡咯烷-1-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-82的合成参考化合物I-44,通过使用(4-氟吡咯烷-3-基)氨基甲酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-82。MS:449.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.55(d,J=4.8Hz,3H),8.32(d,J=3.5Hz,1H),7.76(d,J=8.0Hz,1H),7.62(d,J=9.0Hz,1H),6.72(dd,J=22.2,8.7Hz,2H),6.46(s,1H),5.47(d,J=54.0Hz,1H),4.93(d,J=16.0Hz,1H),4.80(d,J=15.9Hz,1H),4.67(s,1H),4.20–4.07(m,2H),3.82–3.65(m,3H),3.39(t,J=9.1Hz,1H),1.61(d,J=6.4Hz,3H).
实施例84
化合物I-84:2-(3-((R)-2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)吡咯烷-1-基)-N,N-二甲基乙酰胺
化合物I-84的合成参考化合物I-39,通过使用化合物I-80代替化合物I-38和2-溴-N,N-二甲基乙酰胺代替2-溴乙酰胺制备得到化合物I-84。MS:501.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.33(d,J=3.5Hz,1H),7.78-7.73(m,2H),7.64–7.51(m,1H),7.08-7.03(m,1H),6.76(d,J=8.0Hz,1H),4..01-4.97(m,1H),4.89-4.85(m,1H),4.79-4.72(m,1H),4.50-4.42(m,2H),4.17–4.10(m,1H),3.96-3.92(m,1H),3.78-3.71(m,1H),3.61-3.56(m,2H),3.44-3.40(m,1H),3.28-3.25(m,1H),2.95-2.90(m,6H),2.43-2.40(m,1H),2.17-2.10(m,1H),1.64(d,J=6.4Hz,3H).
实施例85
化合物I-85:2-(3-((R)-2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)吡咯烷-1-基)乙酰胺
化合物I-85的合成参考化合物I-39,通过使用化合物I-80代替化合物I-38制备得到白色固体化合物I-85。MS:473.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.33(d,J=3.5Hz,1H),7.95(s,1H),7.78-7.74(m,2H),7.65(s,1H),7.58-7.54(m,1H),7.07(d,J=8.8Hz,1H),6.76(d,J=8.1Hz,1H),5.01-4.97(m,1H),4.88-4.84(m,1H),4.79-4.74(m,1H),4.17-4.12(m,1H),4.12(s,2H),3.92(s,1H),3.77(s,2H),3.61-5.52(m,2H),3.27(s,1H),2.51-2.42(m,1H),1.63(d,J=6.4Hz,3H),1.26(t,J=6.2Hz,1H).
实施例86
化合物I-86:(R)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-10-氟-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)-N,N-二甲基乙酰胺
化合物I-86的合成参考化合物I-39,通过使用化合物I-81代替化合物I-38和2-溴-N,N-二甲基乙酰胺代替2-溴乙酰胺制备得到化合物I-86。MS:533.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.33(d,J=3.5Hz,1H),7.73(d,J=7.9Hz,1H),7.28(s,1H),6.80(d,J=8.1Hz,1H),6.75(d,J=12.0Hz,1H),4.98(s,2H),4.79(s,1H),4.45–4.28(m,2H),4.21–4.10(m,1H),3.60(dd,J=13.7,9.1Hz,3H),3.14(d,J=10.0Hz,2H),2.96(s,3H),2.93(s,3H),2.06(s,4H),1.64(d,J=6.4Hz,3H),1.25(q,J=5.5,4.8Hz,1H).
实施例87
化合物I-87:(R)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-10-氟-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)乙酰胺
化合物I-87的合成参考化合物I-39,通过使用化合物I-81代替化合物I-38制备得到白色固体化合物I-87。MS:505.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.33(d,J=3.4Hz,1H),7.99(s,1H),7.72(d,J=7.4Hz,2H),7.26(s,1H),6.83–6.72(m,1H),4.98(s,2H),4.79(s,1H),4.53(d,J=52.2Hz,1H),4.18(dd,J=24.6,13.2Hz,2H),3.94(s,1H),3.60(dd,J=14.6,9.6Hz,3H),3.18(s,1H),2.89(s,0H),2.19(s,1H),2.05(d,J=9.2Hz,4H),1.64(d,J=6.4Hz,3H).
实施例88
化合物I-88:(R)-3-氟-4-(9-氟-4-甲基-8-(哌啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-88的合成参考化合物I-39,通过使用中间体A23代替中间体A7制备得到白色固体化合物I-88。MS:448.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.79–8.68(m,1H),8.54–8.39(m,1H),8.33(d,J=3.5Hz,1H),7.77(d,J=8.0Hz,1H),7.58–7.47(m,2H),6.72(d,J=8.1Hz,1H),4.95(d,J=16.0Hz,1H),4.85–4.79(m,1H),4.78–4.69(m,1H),4.17–4.11(m,1H),3.58(dd,J=13.8,8.7Hz,1H),3.41(d,J=12.4Hz,2H),3.21–3.02(m,6H),2.01(d,J=13.6Hz,2H),1.96–1.79(m,3H),1.63(d,J=6.4Hz,3H).
实施例89
化合物I-89:(R)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-9-氟-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)乙酰胺
化合物I-89的合成参考化合物I-39,通过使用化合物I-88代替化合物I-38制备得到白色固体化合物I-89。MS:505.5(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.70(s,1H),8.33(d,J=3.5Hz,1H),8.00(s,1H),7.77(d,J=7.9Hz,1H),7.73(s,1H),7.51(dd,J=11.5,8.8Hz,2H),6.72(d,J=8.1Hz,1H),4.96(d,J=16.1Hz,1H),4.82(d,J=16.0Hz,1H),4.76(dd,J=7.9,4.4Hz,1H),4.18–4.10(m,1H),3.93(s,2H),3.58(dd,J=13.5,8.9Hz,3H),3.34–3.18(m,2H),3.17–3.06(m,1H),2.15–2.00(m,4H),1.63(d,J=6.4Hz,3H).
实施例90
化合物I-90:4-((R)-8-((3S,4R)-3-氨基-4-氟吡咯烷-1-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-90的合成参考化合物I-44,通过使用((3S,4R)-4-氟吡咯烷-3-基)氨基甲酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-90。MS:449.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.57(s,3H),8.32(d,J=3.4Hz,1H),7.76(d,J=8.1Hz,1H),7.62(d,J=8.9Hz,1H),6.72(dd,J=22.4,8.6Hz,2H),6.46(s,1H),5.47(d,J=54.3Hz,1H),4.93(d,J=16.0Hz,1H),4.80(d,J=16.0Hz,1H),4.67(s,1H),4.11(d,J=11.5Hz,2H),3.75(d,J=9.9Hz,1H),3.54(dd,J=13.7,8.9Hz,1H),3.39(t,J=9.1Hz,1H),1.61(d,J=6.4Hz,3H).
实施例91
化合物I-91:3-氟-4-(7-(哌啶-4-基)-3,4-二氢咪唑[1,2-a:5,4-c']联吡啶-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-91的合成参考化合物I-39,通过使用中间体A26代替中间体A7制备得到白色固体化合物I-91。MS:416.5(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.81(s,1H),8.70(d,J=7.0Hz,1H),8.59(s,1H),8.32(d,J=3.4Hz,1H),7.90–7.69(m,2H),7.42(d,J=7.1Hz,1H),6.74(d,J=8.1Hz,1H),4.74(s,2H),3.79(d,J=4.9Hz,2H),3.45(d,J=12.5Hz,2H),3.14–3.01(m,5H),2.07(d,J=13.5Hz,2H),1.94–1.76(m,2H).
实施例92
化合物I-92:3-氟-4-((4R)-8-(4-氟吡咯烷-3-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-92的合成参考化合物I-48,通过使用中间体A19-2代替中间体A7-2制备得到黄色固体化合物I-92。MS:434.1(M+H)
+。
实施例93
化合物I-93:(R)-4-(8-(azetidin-3-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-93的合成参考化合物I-39,通过使用中间体A30代替中间体A7制备得到白色固体化合物I-93。MS:402.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.97(s,1H),8.64(s,1H),8.33(d,J=3.5Hz,1H),7.78(dd,J=8.3,4.4Hz,2H),7.64(s,1H),7.08(d,J=8.7Hz,1H),6.76(d,J=8.1Hz,1H),5.00(d,J=16.0Hz,1H),4.87(d,J= 16.0Hz,1H),4.78(s,1H),4.36–4.27(m,2H),4.14(d,J=11.4Hz,3H),3.64–3.53(m,2H),1.64(d,J=6.4Hz,3H).
实施例94
化合物I-94:4-((R)-8-((3R,4S)-3-氨基-4-(三氟甲基)吡咯烷-1-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-94的合成参考化合物I-44,通过使用((3R,4S)-4-(三氟甲基)吡咯烷-3-基)氨基甲酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-94。MS:499.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.50(s,3H),8.32(d,J=3.5Hz,1H),7.76(d,J=8.0Hz,1H),7.63(d,J=9.1Hz,1H),6.74-6.80(m,2H),6.59(s,1H),4.94(d,J=16.0Hz,1H),4.81(d,J=15.9Hz,1H),4.71–4.65(m,1H),4.22(s,1H),4.11(d,J=13.0Hz,1H),3.90(t,J=9.4Hz,1H),3.69-3.65(m,1H),3.57-3.51(m,2H),3.47–3.41(m,2H),1.61(d,J=6.4Hz,3H).
实施例95
化合物I-95:4-((R)-8-((3R,4R)-3-氨基-4-甲氧基吡咯烷-1-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-95的合成参考化合物I-44,通过使用((3R,4R)-4-甲氧基吡咯烷-3-基)氨基甲酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-95。MS:461.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.32(d,J=3.5Hz,1H),8.29(s,2H),7.76(d,J=8.0Hz,1H),7.60(d,J=9.0Hz,1H),6.76-6.70(m,2H),6.53–6.42(m,1H),4.95-4.91(m,1H),4.82-4.78(d,J=15.9Hz,1H),4.68-4.52(m,1H),4.13-4.07(m,2H),3.90(s,1H),3.83-3.79(d,J=5.6Hz,1H),3.64-3.60(m,1H),3.56-3.50(m,1H),3.40(s,1H),3.37(s,3H),3.33–3.28(m,1H),1.61(d,J=6.4Hz,3H).
实施例96
化合物I-96:4-((R)-8-((3R,4R)-4-氨基-3-氟吡啶-1-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-96的合成参考化合物I-44,通过使用((3R,4R)-3-氟哌啶-4-基)氨基甲酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-96。MS:463.2(M+H)
+。
实施例97
化合物I-97:4-((R)-8-((3R,4S)-3-氨基-4-氟吡咯烷-1-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-97的合成参考化合物I-44,通过使用((3R,4S)-4-氟吡咯烷-3-基)氨基甲酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-97。MS:449.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.54(s,3H),8.32(d,J=3.5Hz,1H),7.77(d,J=8.0Hz,1H),7.62(d,J=8.9Hz,1H),6.72(dd,J=22.7,8.8Hz,2H),6.47(s,1H),5.47(d,J=54.6Hz,1H),4.94(d,J=16.0Hz,1H),4.80(d,J=16.0Hz,1H),4.67(s,1H),4.20–4.07(m,2H),3.76(s,2H),3.54(dd,J=13.6,8.9Hz,1H),3.39(t,J=9.0Hz,1H),1.61(d,J=6.4Hz,3H).
实施例98
化合物I-98:(R)-3-氟-4-(4-甲基-8-(2,6-二氮螺环[3.3]庚烷-2-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-98的合成参考化合物I-44,通过使用2,6-二氮螺环[3.3]庚烷-2-羧酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-98。MS:443.2(M+H)
+
实施例99
化合物I-99:4-((R)-8-((3S,5R)-3,5-二甲基哌嗪-1-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-99的合成参考化合物I-44,通过使用(2S,6R)-2,6-二甲基哌嗪-1-羧酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-99。MS:459.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.09(d,J=10.7Hz,1H),8.41(d,J=11.5Hz,1H),8.33(d,J=3.4Hz,1H),7.77(d,J=8.0Hz,1H),7.62(d,J=9.1Hz,1H),7.03–6.91(m,2H),6.74(d,J=8.1Hz,1H),4.94(d,J=16.0Hz,1H),4.80(d,J=16.0Hz,1H),4.69(s,2H),4.11(d,J=12.6Hz,1H),3.87(d,J=12.8Hz,2H),3.54(dd,J=13.8,8.8Hz,1H),2.62(t,J=12.5Hz,2H),1.61(d,J=6.4Hz,3H),1.28(d,J=6.4Hz,7H).
实施例100
化合物I-100:(R)-3-氟-4-(10-氟-4-甲基-8-(5-氧杂-2,8-二氮螺环[3.5]壬烷-2-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-100的合成参考化合物I-8,通过使用中间体A20代替中间体A1和5-氧代-2,8-二氮螺环[3.5]壬烷-8-羧酸叔丁酯代替哌嗪-1-羧酸叔丁酯制备得到白色固体化合物I-100。MS:491.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.10(s,2H),8.32(d,J=3.4Hz,1H),7.72(d,J=8.0Hz,1H),6.77(d,J=8.1Hz,1H),6.31–6.18(m,2H),4.91(s,2H),4.68(s,1H),4.15–4.06(m,1H),4.00(d,J=8.4Hz,2H),3.84(s,2H),3.84(d,J=9.9Hz,1H),3.73(d,J=8.5Hz,2H),3.55(dd,J=13.8,8.8Hz,1H),3.13(s,2H),1.59(d,J=6.4Hz,3H),1.23(s,1H).
实施例101
化合物I-101:4-((R)-8-((2S,5R)-2,5-二甲基哌嗪-1-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-101的合成参考化合物I-44,通过使用(2R,5S)-2,5-二甲基哌嗪-1-羧酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-101。MS:459.2(M+H)
+。
实施例102
化合物I-102:4-((R)-8-((S)-7-氨基-5-氮杂螺[2.4]庚烷-5-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-102的合成参考化合物I-44,通过使用(S)-(5-氮杂螺环[2.4]庚烷-7-基)氨基甲酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-102。MS:457.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.31(d,J=3.5Hz,1H),8.15(d,J=5.4Hz,3H),7.75(d,J=8.0Hz,1H),7.61(d,J=9.0Hz,1H),6.72(dd,J=20.8,8.6Hz,2H),6.42(s,1H),4.93(d,J=16.0Hz,1H),4.80(d,J=16.0Hz,1H),4.67(s,1H),4.10(dd,J=14.0,4.1Hz,1H),3.62–3.47(m,3H),3.06(d,J=9.4Hz,1H),1.61(d,J=6.4Hz,3H),1.09(dt,J=9.9,5.0Hz,1H),0.94–0.69(m,3H).
实施例103
化合物I-103:4-((4R)-8-(3,8-二氮杂环[3.2.1]辛烷-3-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-103的合成参考化合物I-44,通过使用3,8-二氮杂环[3.2.1]辛烷-8-羧酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-103。MS:457.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.87(s,2H),8.32(d,J=3.5Hz,1H),7.76(d,J=8.0Hz,1H),7.61(d,J=9.2Hz,1H),6.98(d,J=9.3Hz,1H),6.80(s,1H),6.74(d,J=8.1Hz,1H),4.94(d,J=16.0Hz,1H),4.80(d,J=16.0Hz,1H),4.68(s,1H),4.13(d,J=25.2Hz,3H),3.65(d,J=12.4Hz,2H),3.04(d,J=12.4Hz,2H),2.04–1.96(m,4H),1.60(d,J=6.4Hz,3H).
实施例104
化合物I-104:4-((R)-8-((3R,4S)-4-氨基-3-氟吡啶-1-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-104的合成参考化合物I-44,通过使用((3R,4S)-3-氟哌啶-4-基)氨基甲酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-104。MS:463.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.32(d,J=3.5Hz,1H),8.25(s,3H),7.76(d,J=8.0Hz,1H),7.58(d,J=9.1Hz,1H),6.93(d,J=9.2Hz,1H),6.84(s,1H),6.74(d,J=8.1Hz,1H),5.07(s,1H),4.93(d,J=15.5Hz,2H),4.80(d,J=16.0Hz,1H),4.67(s,1H),4.14–3.98(m,2H),3.78(d,J=12.7Hz,1H),3.09–2.96(m,1H),2.82(t,J=11.9Hz,1H),2.01–1.86(m,2H),1.60(d,J=6.4Hz,3H).
实施例105
化合物I-105:4-((4R)-8-(3,8-二氮杂环[3.2.1]辛烷-8-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-105的合成参考化合物I-44,通过使用3,8-二氮杂环[3.2.1]辛烷-3-羧酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-105。MS:457.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.92(s,1H),8.72-8.69(m,1H),8.32(d,J=3.4Hz,1H),7.77(d,J=8.0Hz,1H),7.64(d,J=9.2Hz,1H),6.92-6.90(m,3H),6.76(d,J=8.1Hz,1H),4.96-4.92(m,1H),4.82-4.78(m,1H),4.68(s,1H),4.46(s,2H),4.14–4.06(m,1H),3.56-3.50(m,1H),3.18-3.12(m,2H),3.05–3.03(m,1H),2.11(s,2H),2.04-2.00(m,3H),1.61(d,J=6.4Hz,3H).
实施例106
化合物I-106:(R)-3-氟-4-(9-氟-4-甲基-8-(5-氧杂-2,8-二氮螺环[3.5]壬烷-2-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-106的合成参考化合物I-44,通过使用中间体A22代替中间体A1和5-氧代-2,8-二氮螺环[3.5]壬烷-8-羧酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-106。MS:491.5(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.17(s,2H),8.32(d,J=3.5Hz,1H),7.76(d,J=8.0Hz,1H),7.43(d,J=12.6Hz,1H),6.70(d,J=8.1Hz,1H),6.58(d,J=8.0Hz,1H),4.89(d,J=16.0Hz,1H),4.75(d,J=15.9Hz,1H),4.72–4.61(m,1H),4.18–4.00(m,3H),3.90–3.75(m,4H),3.53(dd,J=13.7,8.8Hz,1H),3.46(s,2H),3.13(s,2H),1.59(d,J=6.4Hz,3H).
实施例107
化合物I-107:(R)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-9-氟-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)-N,N-二甲基乙酰胺
化合物I-107的合成参考化合物I-86,通过使用化合物I-88代替化合物I-81制备得到化合物I-107。MS:533.6(M+H)
+。
实施例108
化合物I-108:3-氟-4-((R)-4-甲基-8-((R)-3-甲基哌嗪-1-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-108的合成参考化合物I-44,通过使用(R)-2-甲基哌嗪-1-羧酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-108。MS:445.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.06(d,J=10.8Hz,1H),8.65(d,J=11.3Hz,1H),8.33(d,J=3.4Hz,1H),7.77(d,J=8.1Hz,1H),7.63(d,J=9.1Hz,1H),7.02–6.91(m,2H),6.76(d,J=8.1Hz,1H),4.95(d,J=16.0Hz,1H),4.82(d,J=16.0Hz,1H),4.70(s,1H),4.12(d,J=12.9Hz,1H),3.74(d,J=13.0Hz,1H),3.56(dd,J=13.7,8.7Hz,1H),3.43(d,J=12.5Hz,2H),3.20(d,J=12.2Hz,1H),2.95(t,J=12.0Hz,1H),2.73(t,J=11.7Hz,1H),1.62(d,J=6.4Hz,3H),1.30(d,J=6.4Hz,3H).
实施例109
化合物I-109:(R)-4-(8-(3-氨基-3-甲基氮杂环丁烷-1-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-109的合成参考化合物I-44,通过使用(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-109。MS:431.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.46(s,3H),8.33(d,J=3.5Hz,1H),7.77(d,J=8.0Hz,1H),7.61(d,J=8.8Hz,1H),6.75(d,J=8.2Hz,1H),6.52(d,J=9.1Hz,1H),6.45(s,1H),4.93(d,J=16.0Hz,1H),4.80(d,J=15.9Hz,1H),4.68(s,1H),4.12(d,J=12.7Hz,1H),3.94(d,J=8.2Hz,2H),3.85(d,J=8.1Hz,2H),1.61(d,J=7.2Hz,6H).
实施例110
化合物I-110:4-((R)-8-((3S,4R)-3-氨基-4-甲氧基吡咯烷-1-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-110的合成参考化合物I-44,通过使用((3S,4R)-4-甲氧基吡咯烷-3-基)氨基甲酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-110。MS:461.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.33(s,1H),8.24(s,3H),7.77(d,J=8.0Hz,1H),7.61(d,J=9.0Hz,1H),6.75(d,J=8.1Hz,1H),6.69(d,J=9.1Hz,1H),6.43(s,1H),4.93(d,J=16.0Hz,1H),4.80(d,J=16.0Hz,1H),4.67(s,1H),4.20(s,2H),4.16–3.96(m,5H),3.68–3.49(m,4H),3.40–3.34(m,1H),1.61(d,J=6.3Hz,3H).
实施例111
化合物I-111:3-氟-4-((4R)-8-(六氢吡咯[3,4-c]吡咯-2(1H)-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-111的合成参考化合物I-44,通过使用六氢吡咯[3,4-c]吡咯-2(1H)-羧酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-111。MS:457.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.91(s,2H),8.33(d,J=3.5Hz,1H),7.77(d,J=7.9Hz,1H),7.59(d,J=9.0Hz,1H),6.84–6.72(m,2H), 6.54(s,1H),4.93(d,J=16.0Hz,1H),4.81(d,J=16.0Hz,1H),4.68(s,1H),3.50(s,2H),3.41(d,J=10.2Hz,2H),3.33(s,2H),3.13(s,4H),1.61(d,J=6.3Hz,3H).
实施例112
化合物I-112:3-氟-4-((4R)-8-(4-氟吡啶-3-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-112的合成参考化合物I-48,通过使用中间体A18-2代替中间体A7-2制备得到白色固体化合物I-112。MS:448.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.28(s,0H),8.79(s,1H),8.34(d,J=3.5Hz,1H),7.89–7.70(m,3H),7.19(d,J=8.8Hz,1H),7.07(d,J=9.1Hz,0H),6.78(d,J=8.1Hz,1H),5.03(d,J=16.2Hz,1H),4.90(d,J=16.0Hz,1H),4.81(s,1H),4.17(d,J=14.0Hz,2H),3.59(d,J=16.5Hz,3H),3.31(s,1H),3.11(s,1H),2.42–1.82(m,3H),1.66(d,J=6.4Hz,4H).
实施例113
化合物I-113:(R)-4-甲基-2-(8-甲基-[1,2,4]三唑基[1,5-a]吡啶-5-基)-8-(哌啶-4-基)-1,2,3,4-四氢吡嗪[1,2-b]吲唑
化合物I-113的合成参考化合物I-38,通过使用5-溴-8-甲基-[1,2,4]三唑并[1,5-a]吡啶代替中间体A9制备得到化合物I-113。MS:402.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.69(s,1H),8.53(s,1H),8.44(s,1H),7.72(d,J=8.6Hz,1H),7.39(s,1H),7.12–6.91(m,3H),5.13(d,J=16.1Hz,1H),4.92(d,J=16.2Hz,1H),4.83–4.72(m,1H),4.43(dd,J=13.6,2.9Hz,1H),4.12(dd,J=12.9,6.6Hz,1H),3.42(d,J=12.2Hz,2H),3.14–2.99(m,2H),2.98–2.88(m,1H),2.66(s,3H),2.01(d,J=13.5Hz,2H),1.88(t,J=14.8Hz,2H),1.69(d,J=6.4Hz,3H).
实施例114
化合物I-114:(R)-2-(4-甲基-2-(8-甲基-[1,2,4]三唑基[1,5-a]吡啶-5-基)-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)乙酰胺
化合物I-114的合成参考化合物I-39,通过使用化合物I-113代替化合物I-38制备得到化合物I-114。MS:459.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.65(s,1H),8.52(s,1H),8.02(s,1H),7.73(d,J=8.6Hz,2H),7.40(s,1H),7.16–6.92(m,3H),5.13(d,J=16.1Hz,1H),4.92(d,J=16.0Hz,1H),4.78(d,J=7.1Hz,1H),4.43(d,J=12.1Hz,1H),4.12(dd,J=13.4,6.5Hz,1H),3.95(s,3H),3.60(d,J=11.6Hz,2H),2.96–2.78(m,1H),2.66(s,3H),2.20–1.90(m,5H),1.69(d,J=6.4Hz,3H).
实施例115
化合物I-115:(R)-N,N-二甲基-2-(4-(4-甲基-2-(8-甲基-[1,2,4]三唑基[1,5-a]吡啶-5-基)-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)乙酰胺
化合物I-115的合成参考化合物I-114,通过使用2-溴-N,N-二甲基乙酰胺代替2-溴乙酰胺制备得到白色固体化合物I-115。MS:487.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.54(s,1H),8.53(s,1H),7.73(d,J=8.7Hz,1H),7.40(d,J=10.1Hz,1H),7.09–6.94(m,3H),5.13(d,J=16.0Hz,1H),4.92(d,J=16.0Hz,1H),4.78(s,1H),4.43(d,J=11.5Hz,1H),4.31(s,1H),4.13(s,1H),3.67–3.40(m,6H),3.15(s,2H),2.96(d,J=12.8Hz,6H),2.67(s,3H),2.17–1.98(m,4H),1.69(d,J=6.1Hz,3H).
实施例116
化合物I-116:(R)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)-N-(3,3-二氟环丁基)乙酰胺
化合物I-116的合成参考化合物I-39,通过使用2-氯-N-(3,3-二氟环丁基)乙酰胺代替2-溴乙酰胺制备得到白色固体化合物I-116。MS:577.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.06(d,J=6.4Hz,1H),8.31(d,J=3.6Hz,1H),7.72(dd,J=22.2,8.3Hz,2H),7.39(s,1H),6.95(d,J=8.7Hz,1H),6.75(d,J=8.1Hz,1H),4.96(d,J=15.8Hz,1H),4.84(d,J=16.0Hz,1H),4.74(s,1H),4.11(s,3H),3.94(s,2H),3.55(d,J=11.5Hz,2H),3.44(s,2H),2.86(s,2H),2.62–2.52(m,2H),2.02(s,5H),1.62(d,J=6.4Hz,3H).
实施例117
化合物I-117:(R)-4-(8-(3-(二甲氨基)氮杂环丁烷-1-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-117的合成参考化合物I-44,通过使用N,N-二甲基氮杂环丁胺盐酸盐代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-117。MS:445.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.30(d,J=3.6Hz,1H),7.74(d,J=8.0Hz,1H),7.53(d,J=8.8Hz,1H),6.72(d,J=8.0Hz,1H),6.43(dd,J=8.8,2.0Hz,1H),6.27(s,1H),4.89(d,J=16.0Hz,1H),4.76(d,J=16.0Hz,1H),4.63(s,1H),4.07(d,J=12.8Hz,1H),3.92(t,J=7.2Hz,2H),3.51(dt,J=12.4,7.2Hz,3H),3.15(q,J=6.0Hz,1H),2.09(s,6H),1.57(d,J=6.4Hz,3H).
实施例118
化合物I-118:3-氟-4-((R)-8-((3S,4S)-3-氟吡啶-4-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-118的合成参考化合物I-1,通过使用中间体I-48-3c代替中间体I-1-2制备得到黄色固体化合物I-118。MS:448.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.31(d,J=3.5Hz,1H),7.71(dd,J=24.0,8.3Hz,2H),7.50(s,1H),7.00(d,J=8.6Hz, 1H),6.75(d,J=8.1Hz,1H),5.03–4.80(m,3H),4.74(s,1H),4.12(d,J=12.0Hz,1H),3.57(dd,J=13.8,8.6Hz,1H),3.17(s,1H),3.08(s,2H),2.87(d,J=10.3Hz,1H),2.75(q,J=11.4Hz,2H),2.14(s,1H),1.62(d,J=6.4Hz,4H).
实施例119
化合物I-119:3-氟-4-((R)-8-((3R,4R)-3-氟吡啶-4-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-119的合成参考化合物I-1,通过使用中间体I-48-3d代替中间体I-1-2制备得到黄色固体化合物I-119。MS:448.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.31(d,J=3.6Hz,1H),8.14(s,0H),7.71(dd,J=22.2,8.3Hz,2H),7.51(s,1H),7.01(d,J=8.5Hz,1H),6.75(d,J=8.1Hz,1H),4.97(d,J=16.0Hz,1H),4.85(d,J=16.0Hz,1H),4.75(s,1H),4.12(d,J=11.3Hz,1H),3.57(dd,J=13.8,8.6Hz,1H),3.17(s,1H),2.90(d,J=10.6Hz,1H),2.85–2.60(m,2H),2.47(s,2H),2.16(s,1H),1.67(s,1H),1.62(d,J=6.5Hz,3H).
实施例120a
化合物I-120a:3-氟-4-((R)-8-((3R,4S)-3-氟吡啶-4-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-120a的合成参考化合物I-1,通过使用中间体I-48-3a代替中间体I-1-2制备得到黄色固体化合物I-120a。MS:448.1(M+H)
+。
实施例120b
化合物I-120b:3-氟-4-((R)-8-((3S,4R)-3-氟吡啶-4-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-120b的合成参考化合物I-1,通过使用中间体I-48-3b代替中间体I-1-2制备得到黄色固体化合物I-120b。MS:448.1(M+H)
+。
实施例121
化合物I-121:4-((R)-8-((3R,4R)-4-氨基-3-氟吡啶-1-基)-9-氟-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-121的合成参考化合物I-96,通过使用中间体I-106-1代替中间体I-8-1制备得到白色固体化合物I-121。MS:481.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.37(s,3H),8.31(d,J=3.5Hz,1H),7.76(d,J=8.0Hz,1H),7.50(d,J=12.4Hz,1H),7.17(d,J=7.6Hz,1H),6.70(d,J=8.1Hz,1H),4.95–4.66(m,4H),4.18–4.04(m,1H),3.78–3.68(m,1H),3.54(dd,J=13.8,8.7Hz,2H),3.38(d,J=12.4Hz,1H),2.89–2.83(m,1H),2.80–2.70(m,1H),2.17–2.06(m,1H),1.75(dd,J=12.4,4.0Hz,1H),1.60(d,J=6.4Hz,3H).
实施例122
化合物I-122:(R)-4-(9-氯-4-甲基-8-(5-氧-2,8-二氮螺环[3.5]壬烷-2-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-122的合成参考化合物I-106,通过使用中间体A24代替中间体A22制备得到白色固体化合物I-122。MS:507.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.32(d,J=3.5Hz,1H),7.84–7.73(m,2H),6.75–6.66(m,2H),4.94(d,J=16.2Hz,1H),4.78(d,J=16.3Hz,1H),4.69(s,1H),4.20–4.07(m,3H),3.81(t,J=4.7Hz,4H),3.55(dd,J=13.8,8.7Hz,1H),3.39(d,J=7.7Hz,2H),3.07(s,2H),1.59(d,J=6.4Hz,3H),1.23(s,1H).
实施例123
化合物I-123:(R)-4-(8-(3-氨基-3-甲基氮杂环丁烷-1-基)-9-氯-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-123的合成参考化合物I-109,通过使用中间体I-122-1代替中间体I-8-1制备得到白色固体化合物I-123。MS:465.2(M+H)
+。
实施例124
化合物I-124:4-((R)-8-((3S,4R)-3-氨基-4-甲氧基吡咯烷-1-基)-9-氯-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-124的合成参考化合物I-110,通过使用中间体I-122-1代替中间体I-8-1制备得到白色固体化合物I-124。MS:495.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.32(d,J=3.6Hz,1H),8.14(s,3H),7.88(s,1H),7.77(d,J=8.0Hz,1H),7.07(s,1H),6.71(d,J=8.0Hz,1H),4.96(d,J=16.0Hz,1H),4.80(d,J=16.0Hz,1H),4.70(s,1H),4.12(dd,J=10.2,6.4Hz,2H),3.97(d,J=6.0Hz,1H),3.62–3.44(m,5H),3.39(s,3H),3.31(s,1H),1.60(d,J=6.4Hz,3H).
实施例125
化合物I-125:4-((R)-8-((3S,4R)-3-氨基-4-甲氧基吡咯烷-1-基)-9-氟-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-125的合成参考化合物I-110,通过使用中间体I-106-1代替中间体I-8-1制备得到白色固体化合物I-125。MS:479.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.32(d,J=3.6Hz,1H),8.17(s,2H),7.76(d,J=8.0Hz,1H),7.45(d,J=13.7Hz,1H),6.71(dd,J=10.2,8.0Hz,2H),4.89(d,J=16.0Hz,1H),4.75(d,J=15.9Hz,1H),4.66(s,1H),4.17–4.07(m,2H),3.99(s,2H),3.61–3.51(m,3H),3.51–3.44(m,1H),3.39(s,3H),1.59(d,J=6.4Hz,3H).
实施例126
化合物I-126:(R)-4-(8-(3-(二甲氨基)氮杂环丁烷-1-基)-9-氟-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-126的合成参考化合物I-117,通过使用中间体I-106-1代替中间体I-8-1制备得到白色固体化合物I-126。MS:463.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.32(d,J=3.6Hz,1H),7.76(d,J=8.0Hz,1H),7.46(d,J=12.5Hz,1H),6.70(d,J=8.0Hz,1H),6.61(d,J=8.0Hz,1H),4.89(d,J=16.0Hz,1H),4.75(d,J=16.0Hz,1H),4.67(s,1H),4.19(s,2H),4.05(d,J=6.4Hz,3H),3.60–3.51(m,1H),3.47(d,J=21.6Hz,1H),1.59(d,J=6.4Hz,3H).
实施例127
化合物I-127:(R)-4-(8-(3-氨基-3-甲基氮杂环丁烷-1-基)-9-氟-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-127的合成参考化合物I-123,通过使用中间体I-106-1代替中间体I-122-1制备得到白色固体化合物I-127。MS:449.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.45(s,3H),8.32(d,J=3.6Hz,1H),7.76(d,J=8.0Hz,1H),7.44(d,J=12.6Hz,1H),6.70(d,J=8.1Hz,1H),6.64(d,J=8.0Hz,1H),4.89(d,J=15.9Hz,1H),4.74(d,J=15.9Hz,1H),4.71–4.61(m,2H),4.10(d,J=12.1Hz,1H),4.00(d,J=8.6Hz,2H),3.91(d,J=8.4Hz,2H),3.52(dd,J=13.7,8.8Hz,1H),1.59(d,J=6.0Hz,6H).
实施例128
化合物I-128:(R)-3-氟-4-(4-甲基-8-(2-氧代哌嗪-1-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-90的合成参考化合物I-44,通过使用碘化亚铜代替Pd
2(dba)
3,(1R,2R)-N1,N2-二甲基环己烷-1,2-二胺代替BINAP和3-氧代哌嗪-1-羧酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-128。MS:445.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.27(s,3H),8.33(d,J=3.5Hz,1H),7.78(t,J=7.9Hz,2H),7.53(s,1H),7.02–6.94(m,1H),6.76(d,J=8.2Hz,1H),5.01(d,J=16.2Hz,1H),4.88(d,J=16.1Hz,1H),4.78(s,1H),4.15(d,J=13.5Hz,1H),3.90(d,J=13.3Hz,4H),3.66–3.54(m,3H),1.64(d,J=6.4Hz,3H).
实施例129
化合物I-129:4-((4R)-8-(4-苄基吗啉-2-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-129的合成参考中间体I-106-1,通过使用中间体A32代替中间体A22制备得到白色固体化合物I-129。MS:522.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.32(d,J=3.5Hz,1H),7.77(dd,J=8.4,6.8Hz,2H),7.59(d,J=3.7Hz,1H),7.55–7.43(m,5H),7.03(d,J=8.7Hz,1H),6.76(d,J=8.1Hz,1H),5.00(d,J=16.0Hz,1H),4.91–4.73(m,3H),4.38(s,2H),4.24–4.09(m,2H),3.58(dd,J=13.8,8.7Hz,1H),3.47(d,J=12.4Hz,1H),3.34(d,J=12.3Hz,1H),3.21(s,2H),1.63(dd,J=6.4,1.9Hz,3H),1.22(s,1H).
实施例130
化合物I-130:3-氟-4-((4R)-4-甲基-8-(吗啉-2-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
将化合物I-129(78毫克,0.150毫摩尔)和1-氯乙基氯甲酸酯(107毫克,0.748毫摩尔)的DCE(5毫升)溶液85度搅拌反应3小时,然后浓缩得到粗产物,将产物溶于甲醇(5毫升)中,并将反应混合溶液在70度反应1小时。然后浓缩得到粗产物,粗产物经Pre-HPLC制备纯化得到黄固体化合物I-130(17.43毫克,26%),MS:432.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.47(s,2H),8.32(d,J=3.5Hz,1H),7.76(d,J=8.4Hz,2H),7.60(s,1H),7.06(dd,J=8.5,2.4Hz,1H),6.75(d,J=8.0Hz,1H),4.99(d,J=16.1Hz,1H),4.91–4.80(m,2H),4.78(s,1H),4.18–4.09(m,2H),3.95(t,J=12.3Hz,1H),3.58(dd,J=13.7,8.6Hz,2H),3.26(d,J=12.6Hz,1H),3.09(dd,J=30.5,11.1Hz,1H),1.63(d,J=6.4Hz,3H),1.22(s,1H).
化合物I-130a:3-氟-4-((R)-4-甲基-8-((S)-吗啉-2-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-130a的合成参考化合物I-130,通过使用中间体A39代替中间体A32制备得到黄色固体化合物I-130a,ee%:90.0%。MS:432.2(M+1)
+.
1H NMR(400MHz,DMSO-d
6)δ8.32(d,J=3.6Hz,1H),7.74(dd,J=10.8,8.5Hz,2H),7.56(s,1H),7.05(d,J=8.7Hz,1H),6.76(d,J=8.1Hz,1H),5.04–4.73(m,3H),4.66(d,J=10.3Hz,1H),4.09(dd,J=37.4,12.5Hz,2H),3.80(t,J=11.3Hz,1H),3.57(d,J=10.7Hz,1H),3.08–2.94(m,3H),2.85(t,J=11.5Hz,1H),1.63(d,J=6.4Hz,3H).
化合物I-130b:3-氟-4-((R)-4-甲基-8-((R)-吗啉-2-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-130b的合成参考化合物I-130,通过使用中间体A40代替中间体A32制备得到黄色固体化合物I-130b,ee%:98.1%。MS:432.2(M+1)
+.1H NMR(400MHz,DMSO-d
6)δ9.24(s,1H),8.32(s,1H),7.76(d,J=8.1Hz,2H),7.60(s,1H),7.06(d,J=8.5Hz,1H),6.79–6.72(m,1H),4.99(d,J=16.2Hz,1H),4.91–4.73(m,3H),4.13(d,J=13.1Hz,2H),3.94(d,J=12.8Hz,1H),3.60(d,J=13.6Hz,2H),3.27-3.21(m,1H),3.08(dt,J=25.8,12.1Hz,2H),1.63(d,J=6.4Hz,3H)
..
实施例131
化合物I-131:(R)-2-(4-(2-(7-氰基-3-氟吡唑基[1,5-a]吡啶-4-基)-9-氟-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)-2-甲基丙烷酰胺
化合物I-131的合成参考化合物I-107,通过使用2-溴-2-甲基丙烷酰胺代替2-溴-N,N-二甲基乙酰胺制备得到化合物I-131。MS:533.6(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.30–9.15(m,1H),8.33(d,J=3.6Hz,1H),7.93(d,J=14.6Hz,2H),7.77(d,J=8.0Hz,1H),7.56–7.45(m,2H),6.72(d,J=8.1Hz,1H),4.95(d,J=16.0Hz,1H),4.81(d,J=16.0Hz,1H),4.79–4.69(m,2H),4.18–4.09(m,2H),3.58(dd,J=13.8,8.8Hz,1H),3.38(d,J=10.8Hz,2H),3.30–3.09(m,4H),2.23–1.96(m,4H),1.64–1.60(m,3H),1.54(s,6H).
实施例132
化合物I-132:(R)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-9-氟-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)-N-甲基乙酰胺
化合物I-132的合成参考化合物I-131,通过使用2-溴-N-甲基乙酰胺代替2-溴-N,N-二甲基乙酰胺制备得到化合物I-132。MS:519.6(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.86(s,1H),8.58(d,J=4.7Hz,1H),8.31(d,J=3.5Hz,1H),7.75(d,J=7.9Hz,1H),7.60–7.42(m,2H),6.71(d,J=8.1Hz,1H),4.94(d,J=16.0Hz,1H),4.80(d,J=16.1Hz,1H),4.77–4.67(m,2H),4.12(dd,J=14.1,4.3Hz,1H),3.93(s,1H),3.64–3.50(m,3H),3.16–3.05(m,1H),2.76–2.61(m,4H),2.16–1.94(m,4H),1.62(d,J=6.4Hz,3H),1.25(t,J=6.4Hz,1H).
实施例133
化合物I-133:4-((4R)-8-(3,8-二氮杂环[3.2.1]辛烷-3-基)-9-氟-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-133的合成参考化合物I-103,通过使用中间体I-106-1代替中间体I-8-1制备得到白色固体化合物I-133。MS:475.2(M+H)
+。
实施例134
化合物I-134:4-((4R)-8-(3,6-二氮杂环[3.1.1]庚烷-6-基)-7-氟-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-134的合成参考化合物I-8,通过使用中间体A33代替中间体A1和3,6-二氮杂二环[3.1.1]庚烷-3-甲酸叔丁酯代替哌嗪-1-羧酸叔丁酯制备得到白色固体化合物I-134。MS:461.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.33(s,1H),8.61(s,1H),8.33(d,J=3.5Hz,1H),7.78(d,J=8.0Hz,1H),7.52(d,J=8.8Hz,1H),6.76(d,J=8.1Hz,1H),6.63(dd,J=8.9,7.0Hz,1H),4.95(d,J=16.2Hz,1H),4.83(d,J=16.2Hz,1H),4.74(d,J=10.6Hz,1H),4.43(d,J=5.7Hz,2H),4.17–4.07(m,1H),3.57(dd,J=13.7,8.3Hz,1H),3.53–3.41(m,2H),3.39–3.27(m,2H),2.91–2.84(m,2H),1.98(d,J=9.4Hz,1H),1.61(d,J=6.4Hz,3H).
实施例135
化合物I-135:3-氟-4-((4R)-7-氟-8-(六氢吡咯[3,4-c]吡咯-2(1H)-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-135的合成参考化合物I-134,通过使用六氢吡咯并[3,4-c]吡咯-2(1H)- 甲酸叔丁酯代替3,6-二氮杂二环[3.1.1]庚烷-3-甲酸叔丁酯制备得到白色固体化合物I-135。MS:475.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.79(s,2H),8.32(d,J=3.6Hz,1H),7.76(d,J=8.0Hz,1H),7.44(d,J=8.9Hz,1H),6.85(t,J=8.1Hz,1H),6.74(d,J=8.1Hz,1H),4.94(d,J=16.2Hz,1H),4.82(d,J=16.1Hz,1H),4.72(s,1H),4.11(d,J=13.3Hz,1H),3.43(d,J=14.6Hz,4H),3.34(s,3H),3.05(s,5H),1.62(d,J=6.4Hz,3H).
实施例136
化合物I-136:(R)-4-(8-(3-氨基-3-甲基氮杂环丁烷-1-基)-7-氟-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-136的合成参考化合物I-134,通过使用(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯代替3,6-二氮杂二环[3.1.1]庚烷-3-甲酸叔丁酯制备得到白色固体化合物I-136。MS:449.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.39(s,3H),8.32(d,J=3.6Hz,1H),7.77(d,J=8.0Hz,1H),7.45(d,J=8.8Hz,1H),6.74(d,J=8.1Hz,1H),6.56(t,J=8.1Hz,1H),4.94(d,J=15.5Hz,1H),4.81(d,J=16.1Hz,1H),4.71(s,1H),4.14–4.03(m,3H),3.98(d,J=7.8Hz,2H),3.55(dd,J=13.7,8.7Hz,1H),1.64–1.55(m,6H).
实施例137
化合物I-137:4-((4R)-8-(3,8-二氮杂双环[3.2.1]辛烷-8-基)-7-氟-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-137的合成参考化合物I-134,通过使用3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯代替3,6-二氮杂二环[3.1.1]庚烷-3-甲酸叔丁酯制备得到白色固体化合物I-137。MS:475.2(M+H)
+。
实施例138
化合物I-138:(R)-3-氟-4-(7-氟-4-甲基-8-(5-氧-2,8-二氮螺环[3.5]壬-2-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-138的合成参考化合物I-134,通过使用5-氧代-2,8-二氮螺环[3.5]壬烷-8-羧酸叔丁酯代替3,6-二氮杂二环[3.1.1]庚烷-3-甲酸叔丁酯制备得到白色固体化合物I-138。MS:491.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.11(s,2H),8.31(d,J=3.5Hz,1H),7.75(d,J=8.0Hz,1H),7.43(d,J=8.8Hz,1H),6.73(d,J=8.1Hz,1H),6.51(dd,J=8.9,7.4Hz,1H),4.93(d,J=16.2Hz,1H),4.80(d,J=16.1Hz,1H),4.70(s,1H),4.13(dd,J=24.3,9.5Hz,3H),3.84(t,J=8.6Hz,4H),3.54(dd,J=13.8,8.6Hz,1H),3.45(s,2H),3.12(s,2H),1.61(d,J=6.4Hz,3H).
实施例139
化合物I-139:4-((4R)-8-(3,8-二氮杂环[3.2.1]辛烷-3-基)-7-氟-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-139的合成参考化合物I-134,通过使用3,8-二氮杂二环[3.2.1]辛烷-8-甲酸叔丁酯代替3,6-二氮杂二环[3.1.1]庚烷-3-甲酸叔丁酯制备得到白色固体化合物I-139。MS:475.2(M+H)
+。
实施例140
化合物I-140:(R)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-7-氟-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)-N,N-二甲基乙酰胺
化合物I-140的合成参考化合物I-39,通过使用中间体I-142代替中间体I-38和2-溴-N,N-二甲基乙酰胺代替2-溴乙酰胺制备得到白色固体化合物I-140。MS:533.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.58(s,1H),8.32(d,J=3.5Hz,1H),7.76(d,J=8.0Hz,1H),7.57(d,J=8.5Hz,1H),6.95(dd,J=8.6,5.7Hz,1H),6.75(d,J=8.0Hz,1H),4.98(d,J=16.2Hz,1H),4.86(d,J=16.1Hz,1H),4.83–4.73(m,1H),4.33–4.23(m,2H),4.13(d,J=11.7Hz,1H),3.66–3.48(m,4H),3.44–3.16(m,2H),2.94(d,J=12.8Hz,6H),2.21(d,J=13.6Hz,2H),1.92(d,J=13.8Hz,2H),1.64(d,J=6.4Hz,3H).
实施例141
化合物I-141:4-((4R)-8-(3,6-二氮杂环[3.1.1]庚烷-3-基)-7-氟-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-141的合成参考化合物I-134,通过使用3,6-二氮杂二环[3.1.1]庚烷-6-甲酸叔丁酯代替3,6-二氮杂二环[3.1.1]庚烷-3-甲酸叔丁酯制备得到白色固体化合物I-141。MS:461.2(M+H)
+。
实施例142
化合物I-142:(R)-3-氟-4-(7-氟-4-甲基-8-(哌啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-142的合成参考化合物I-38,通过使用中间体A34代替中间体A7制备得到白色固体化合物I-142。MS:449.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.78(s,1H),8.54(s,1H),8.31(d,J=3.6Hz,1H),7.75(dd,J=8.2,3.4Hz,1H),7.56(d,J=8.6Hz,1H),6.92(dd,J=8.7,5.7Hz,1H),6.82–6.65(m,1H),4.98(d,J=16.2Hz,1H),4.86(d,J=16.1Hz,1H),4.78(s,1H),4.18–4.07(m,1H),3.58(dd,J=13.8,8.7Hz,1H),3.40(d,J=12.5Hz,2H),3.37–3.25(m,1H),3.23–2.98(m,2H),2.05–1.83(m,4H),1.64(d,J=6.4Hz,3H).
实施例143
化合物I-143:(R)-4-(8-(3-氨基-3-甲基氮杂环丁烷-1-基)-4,9-二甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-143的合成参考化合物I-134,通过使用中间体A35代替中间体A33和(3-甲基氮杂环丁烷-3-基)氨基甲酸叔丁酯代替3,6-二氮杂二环[3.1.1]庚烷-3-甲酸叔丁酯制备得到白色固体化合物I-143。MS:445.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.58(s,1H),8.32(d,J=3.5Hz,1H),7.76(d,J=8.0Hz,1H),7.57(d,J=8.5Hz,1H),6.95(dd,J=8.6,5.7Hz,1H),6.75(d,J=8.0Hz,1H),4.98(d,J=16.2Hz,1H),4.86(d,J=16.1Hz,1H),4.77(d,J=9.3Hz,1H),4.29(d,J=4.2Hz,1H),4.18–4.10(m,1H),3.62–3.56(m,2H),2.94(d,J=12.8Hz,5H),2.21(d,J=13.6Hz,2H),1.92(d,J=13.8Hz,2H),1.64(d,J=6.4Hz,3H).
实施例144
化合物I-144:(R)-4-(4,9-二甲基-8-(哌啶-4-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-144的合成参考化合物I-38,通过使用中间体A36代替中间体A7制备得到白色固体化合物I-144。MS:444.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.36(s,1H),8.63(s,1H),8.33(d,J=3.5Hz,1H),7.78(d,J=8.0Hz,1H),7.52(d,J=8.8Hz,1H),6.76(d,J=8.1Hz,1H),6.63(dd,J=8.9,7.0Hz,1H),4.95(d,J=16.2Hz,1H),4.83(d,J=16.2Hz,1H),4.73(s,1H),4.43(d,J=5.7Hz,3H),4.15–4.08(m,2H),3.57(dd,J=13.7,8.3Hz,1H),3.51–3.41(m,3H),3.32(dd,J=13.4,6.3Hz,3H),2.87(d,J=7.3Hz,1H),1.98(d,J=9.4Hz,1H),1.61(d,J=6.4Hz,3H).
实施例145
化合物I-145:(R)-2-(4-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4,9-二甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)哌啶-1-基)-N,N-二甲基乙酰胺
化合物I-145的合成参考化合物I-140,通过使用化合物I-144代替化合物I-142制备得到白色固体化合物I-145。MS:529.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.31(d,J=3.4Hz,1H),7.74(d,J=7.8Hz,1H),7.50(d,J=3.2Hz,1H),7.36(d,J=10.6Hz,1H),6.74(dd,J=8.1,3.7Hz,1H),4.93(d,J=16.0Hz,1H),4.81(d,J=16.0Hz,1H),4.72(s,1H),4.29(d,J=4.4Hz,1H),4.12(d,J=12.7Hz,1H),3.67–3.50(m,3H),3.40(d,J=14.1Hz,1H),3.27–2.81(m,8H),2.39(s,3H),2.15–1.75(m,4H),1.61(dd,J=6.6,2.2Hz,2H),1.25(t,J=6.4Hz,3H).
实施例146
化合物I-146:(R)-3-氟-4-(9-氟-4-甲基-8-(哌嗪-1-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-146的合成参考化合物I-8,通过使用中间体I-106-1代替中间体I-8-1制备得到白色固体化合物I-146。MS:449.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.30(d,J=3.5Hz,1H),7.74(d,J=7.9Hz,1H),7.46(d,J=12.6Hz,1H),7.07(d,J=7.4Hz,1H),6.70(d,J=8.0Hz,1H),4.92-4.88(m,1H),4.81–4.63(m,2H),4.10(d,J=12.4Hz,1H),3.56-3.50(m,5H),3.02(s,5H),1.59(d,J=6.4Hz,3H).
实施例147
化合物I-147:4-((R)-8-((S)-3-氨基吡咯烷-1-基)-9-氟-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-147的合成参考化合物I-146,通过使用(S)-吡咯烷-3-基氨基甲酸叔丁酯代替哌嗪-1-羧酸叔丁酯制备得到白色固体化合物I-147。MS:449.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.32(d,J=3.5Hz,1H),8.04(s,3H),7.77(d,J=8.0Hz,1H),7.45(d,J=13.8Hz,1H),6.79(d,J=7.8Hz,1H),6.70(d,J=8.1Hz,1H),4.90(d,J=15.9Hz,1H),4.75(d,J=15.5Hz,1H),4.66(s,1H),4.11(d,J=13.4Hz,1H),3.93(d,J=7.6Hz,1H),3.61–3.48(m,3H),3.40(d,J=11.0Hz,1H),3.29(d,J=7.6Hz,1H),2.36–2.26(m,1H),1.99(d,J=5.4Hz,1H),1.59(d,J=6.4Hz,3H).
实施例148
化合物I-148:4-((R)-8-((S)-7-氨基-5-氮杂螺[2.4]庚烷-5-基)-9-氟-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-148的合成参考化合物I-146,通过使用(5-氮杂螺环[2.4]庚烷-7-基)氨基甲酸叔丁酯代替哌嗪-1-羧酸叔丁酯制备得到白色固体化合物I-148。MS:475.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.30(d,J=3.5Hz,1H),8.10(s,3H),7.74(d,J=8.0Hz,1H),7.45(d,J=13.8Hz,1H),6.72(dd,J=21.1,7.9Hz,2H),4.89(d,J=15.9Hz,1H),4.74(d,J=15.9Hz,1H),4.66(s,1H),4.10(d,J=13.5Hz,1H),3.87–3.75(m,2H),3.53(d,J=13.1Hz,4H),3.03(d,J=9.7Hz,1H),1.59(d,J=6.4Hz,3H),1.04(dt,J=9.5,4.8Hz,1H),0.91–0.69(m,2H).
实施例149
化合物I-149:
(R)-4-(8-(4-氰基哌啶-4-基)-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-149的合成参考化合物I-130,通过使用中间体A37代替中间体A32制备得到白色固体化合物I-149。MS:455.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.82(s,1H),8.65(s,1H),8.32(d,J=3.5Hz,1H),7.88(d,J=8.8Hz,1H),7.79–7.69(m,2H),7.20(d,J=8.7Hz,1H),6.76(d,J=8.0Hz,1H),5.01(d,J=16.1Hz,1H),4.88 (d,J=16.1Hz,1H),4.79(s,1H),4.14(d,J=13.6Hz,1H),3.57(dd,J=28.3,12.0Hz,4H),3.16(d,J=10.8Hz,3H),2.26(t,J=13.8Hz,2H),1.64(d,J=6.5Hz,3H).
实施例150
化合物I-150:(R)-3-氟-4-(4-甲基-8-(4,7-二氮螺环[2.5]辛烷-7-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-150的合成参考化合物I-44,通过使用4,7-二氮螺环[2.5]辛烷-4-羧酸叔丁酯代替((3R,5S)-5-(三氟甲基)哌啶-3-基)氨基甲酸叔丁酯制备得到白色固体化合物I-150。MS:457.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.08(s,2H),8.32(d,J=3.6Hz,1H),7.77(d,J=8.0Hz,1H),7.61(d,J=9.2Hz,1H),7.00–6.87(m,2H),6.74(d,J=8.0Hz,1H),4.94(d,J=16.0Hz,1H),4.80(d,J=16.0Hz,1H),4.69(s,1H),4.11(d,J=13.6Hz,2H),3.54(dd,J=13.6,8.8Hz,1H),3.40(s,4H),3.28(s,2H),1.60(d,J=6.4Hz,3H),1.04(s,2H),0.96(s,2H).
实施例151
化合物I-151:(R)-2-(7-(2-(7-氰基-3-氟吡唑[1,5-a]吡啶-4-基)-4-甲基-1,2,3,4-四氢吡嗪[1,2-b]吲唑-8-基)-4,7-二氮螺环[2.5]辛烷-4-基)-N,N-二甲基乙酰胺
化合物I-151的合成参考化合物I-86,通过使用化合物I-150代替化合物I-81制备得到化合物I-151。MS:542.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.32(d,J=3.5Hz,1H),7.76(d,J=8.0Hz,1H),7.61(d,J=9.1Hz,1H),6.97(dd,J=9.0,2.1Hz,1H),6.89(d,J=1.9Hz,1H),6.74(d,J=8.1Hz,1H),4.93(d,J=16.0Hz,1H),4.80(d,J=16.0Hz,1H),4.69(s,1H),4.10(t,J=8.2Hz,1H),3.70–3.48(m,3H),3.25-3.11(m,7H),3.00(s,3H),2.92(s,3H),1.60(d,J=6.4Hz,3H),1.24(dd,J=11.3,5.2Hz,1H),0.93(s,2H).
实施例152
化合物I-152:(R)-4-(8-(3,3-二甲基哌嗪-1-基)-9-氟-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-152的合成参考化合物I-146,通过使用2,2-二甲基哌嗪-1-羧酸叔丁酯代替哌嗪-1-羧酸叔丁酯制备得到白色固体化合物I-152。MS:477.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.84(s,2H),8.32(d,J=3.6Hz,1H),7.77(d,J=8.0Hz,1H),7.53(d,J=12.4Hz,1H),7.20(d,J=7.6Hz,1H),6.71(d,J=8.1Hz,1H),4.93(d,J=16.0Hz,1H),4.80(s,1H),4.71(s,1H),4.16–4.08(m,1H),3.35(s,3H),3.22(d,J=5.2Hz,2H),3.00(s,2H),1.61(d,J=6.4Hz,3H),1.42(s,6H).
实施例153
化合物I-153:(R)-3-氟-4-(9-氟-4-甲基-8-(4,7-二氮螺环[2.5]辛烷-7-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)吡唑[1,5-a]吡啶-7-腈
化合物I-153的合成参考化合物I-146,通过使用4,7-二氮螺环[2.5]辛烷-4-羧酸叔丁酯代替哌嗪-1-羧酸叔丁酯制备得到白色固体化合物I-153。MS:475.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.13(s,2H),8.32(d,J=3.5Hz,1H),7.77(d,J=8.0Hz,1H),7.52(d,J=12.6Hz,1H),7.19(d,J=7.6Hz,1H),6.71(d,J=8.1Hz,1H),5.08–4.75(m,2H),4.71(s,1H),4.12(d,J=12.8Hz,1H),3.55(dd,J=13.8,8.8Hz,1H),3.31(d,J=6.1Hz,4H),3.14(s,2H),1.61(d,J=6.4Hz,3H),1.22–0.79(m,4H).
实施例154
化合物I-154:(R)-5-(8-(3,3-二甲基哌嗪-1-基)-9-氟-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
化合物I-154的合成参考化合物I-1,通过中间体A22代替中间体A1,2,2-二甲基哌嗪-1-羧酸叔丁酯代替哌嗪-1-羧酸叔丁酯制备得到白色固体化合物I-154。MS:470.2(M+H)
+。
实施例155
化合物I-155:(R)-5-(9-氟-4-甲基-8-(4,7-二氮螺环[2.5]辛烷-7-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
化合物I-155的合成参考化合物I-154,通过4,7-二氮螺环[2.5]辛烷-4-羧酸叔丁酯代替2,2-二甲基哌嗪-1-羧酸叔丁酯制备得到白色固体化合物I-155。MS:468.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.17–9.06(m,3H),8.66(dd,J=8.6,1.7Hz,1H),8.34(d,J=8.0Hz,1H),7.72(dd,J=8.6,4.2Hz,1H),7.51(d,J=12.6Hz,1H),7.39(d,J=8.1Hz,1H),7.20(d,J=7.6Hz,1H),4.98–4.86(m,1H),4.87–4.73(m,2H),4.03(d,J=9.7Hz,1H),3.53–3.46(m,2H),3.34(dd,J=14.2,4.2Hz,2H),3.14(s,2H),1.63(d,J=6.4Hz,3H),1.08(s,2H),0.93(s,2H).
实施例156
化合物I-156:(R)-5-(9-氟-4-甲基-8-(哌嗪-1-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
化合物I-156的合成参考化合物I-154,通过哌嗪-1-羧酸叔丁酯代替2,2-二甲基哌嗪-1-羧酸叔丁酯制备得到白色固体化合物I-155。MS:442.2(M+H)
+。
实施例157
化合物I-157:(R)-4-(8-(4-氰基哌啶-4-基)-9-氟-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-3-氟吡唑[1,5-a]吡啶-7-腈
化合物I-157的合成参考化合物I-130,通过使用中间体A38代替中间体A32制备得到白色固体化合物I-157。MS:473.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.93(s,2H),8.33(d,J=3.5Hz,1H),7.82–7.71(m,3H),6.73(d,J=8.0Hz,1H),5.00(d,J=16.1Hz,1H),4.90–4.76(m,2H),4.15(d,J=13.6Hz,1H),3.59(dd,J=30.1,11.2Hz,3H),3.19(d,J=11.9Hz,2H),2.60(d,J=14.0Hz,2H),2.30(t,J=13.3Hz,2H),1.64(d,J=6.4Hz,3H).
实施例158
化合物I-158:(R)-5-(8-(4-氰基哌啶-4-基)-9-氟-4-甲基-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)喹啉-8-腈
化合物I-158的合成参考化合物I-157,通过使用5-溴-8-氰基喹啉代替中间体A9制备得到白色固体化合物I-158。MS:466.1(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.09(d,J=4.5Hz,2H),8.71–8.64(m,1H),8.34(d,J=8.0Hz,1H),7.80(d,J=6.8Hz,1H),7.76–7.68(m,2H),7.41(d,J=8.1Hz,1H),5.01(s,1H),4.95–4.76(m,2H),4.12–3.99(m,1H),3.19(q,J=10.0,6.5Hz,4H),2.60(d,J=13.9Hz,3H),2.34(t,J=13.4 Hz,2H),1.67(d,J=6.4Hz,3H).
实施例159
化合物I-159:(R)-5-(9-氟-4-甲基-8-(哌嗪-1-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-1,2,4]三唑[1,5-a]吡啶-8-腈
化合物I-159的合成参考化合物I-1,通过中间体A22代替中间体A1,5-氯-[1,2,4]三唑并[1,5-a]吡啶-8-甲腈代替中间体D1制备得到白色固体化合物I-159。MS:432.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.78(s,2H),8.70(d,J=1.3Hz,1H),8.30(d,J=8.3Hz,1H),7.53(d,J=12.5Hz,1H),7.19(d,J=7.6Hz,1H),6.82(d,J=8.4Hz,1H),5.33(d,J=16.2Hz,1H),5.15(d,J=16.2Hz,1H),4.83(d,J=6.2Hz,1H),4.65–4.56(m,1H),4.24(dd,J=13.6,7.3Hz,1H),3.26(d,J=29.6Hz,8H),1.66(d,J=6.4Hz,3H).
实施例160
化合物I-160:(R)-8-(9-氟-4-甲基-8-(哌嗪-1-基)-3,4-二氢吡嗪[1,2-b]吲唑-2(1H)-基)-1,2,4]三唑[1,5-a]吡啶-5-腈
化合物I-160的合成参考化合物I-1,通过中间体A22代替中间体A1,8-氯-[1,2,4]三唑并[1,5-a]吡啶-5-甲腈代替中间体D1制备得到白色固体化合物I-160。MS:432.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ8.75(s,2H),8.68(s,1H),7.99(d,J=8.4Hz,1H),7.53(d,J=12.5Hz,1H),7.19(d,J=7.6Hz,1H),7.05(d,J=8.5Hz,1H),5.36(d,J=16.7Hz,1H),5.18(d,J=16.8Hz,1H),4.84–4.73(m,2H),4.67(dd,J=13.5,6.5Hz,1H),3.26(d,J=27.1Hz,8H),1.62(d,J=6.3Hz,3H).
实施例162
化合物I-162:(R)-3-氟-4-(7-甲基-3-(哌啶-4-基)-7,8-二氢吡啶[4',3':3,4]吡唑[1,5-a]吡嗪-9(10H)-基)吡唑[1,5-a]吡啶-7-腈
中间体I-162-1的合成参考中间体A7,通过使用中间体A29代替中间体A1制备得到白色固体中间体I-162-1。MS:371.2(M+H)
+。
化合物I-162的合成参考化合物I-51,通过使用中间体I-162-1代替中间体A10制备得到白色固体化合物I-162。MS:431.2(M+H)
+。
1H NMR(400MHz,DMSO-d
6)δ9.52(s,1H),8.82(s,1H),8.53(d,J=9.9Hz,1H),8.35(d,J=3.5Hz,1H),7.78(d,J=8.0Hz,1H),7.69(s,1H),6.76(d,J=8.1Hz,1H),5.22(d,J=17.1Hz,1H),5.06(d,J=17.1Hz,1H),4.89(s,1H),4.19(dd,J=14.3,4.3Hz,1H),3.69(dd,J=14.1,8.5Hz,1H),3.44(d,J=12.4Hz,2H),3.18(d,J=12.2Hz,1H),3.14–2.99(m,2H),2.15(d,J=13.7Hz,2H),2.03–1.86(m,2H),1.66(d,J=6.5Hz,3H).
效果实施例1细胞水平药效评价
采用稳定表达人源TLR7或者TLR8的HEK-Blue
TM细胞评价本发明化合物对TLR7或者TLR8的抑制活性,使用其对在IFN-β最小启动子融合到5个NF-κB和ap-1结合位点的控制下的SEAP报告基因的诱导能力来检测,具体如下:
将HEK-Blue
TM hTLR7(Invivogen,每孔80000个细胞)或者HEK-Blue
TM hTLR8(Invivogen,每孔60000个细胞)加入到96孔细胞培养板,随后加入待测化合物,待测化合物在培养基中的最终浓度范围为:0.001~36μM,孵育15分钟。然后加入TLR7配体(Gardiquimod,购自MedChemExpress,在细胞培养基中化合物的最终浓度为:10μM)或者TLR8配体(Resiquimod,购自MedChemExpress,在细胞培养基中化合物的最终浓度为:10μM),孵育20小时。根据制造商的说明书,用HEK-Blue检测试剂Quanti-blue(Invivogen)来检测细胞培养基中的SEAP水平。利用GraphPad Prism计算药物半数抑制浓度IC
50。
表1:本发明化合物在HEK-Blue hTLR7/8/细胞中的活性
M5049化合物的合成参考专利WO2017106607(A1)
结果显示,本发明化合物在细胞水平上具有优异的TLR7和/或TLR8抑制活性。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (12)
- 一种如下式I所示的化合物,其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物:其中,U选自下组:C或N;J选自下组:C或N;W为N、CR x或NR y;其中,所述的R x选自下组:H,卤素,C 1-6烷基,C 1-6烷氧基,卤代C 1-6烷基,或C 3-7环烷基;R y选自下组:H、C 1-6烷基,卤代C 1-6烷基,或C 3-7环烷基;R 1选自下组:取代或未取代的5元并6元杂芳基、取代或未取代的6元并6元杂芳基;R 2、R 3、R 4、R 5、R 6、R 7各自独立地选自下组:H、C 1-6烷氧基、卤代C 1-6烷基、C 1-6烷基、卤素、氰基、C 3-7环烷基,或R 2、R 3、R 4、R 5、R 6、R 7中位于相同碳原子上的两个共同构成=O;或R 2和R 3与它们相连的碳原子、R 4和R 5与它们相连的碳原子、R 6和R 7与它们相连的碳原子共同形成取代或未取代的3-至6-元环烷基、或取代或未取代的3-至6-元杂环基;L选自下组:化学键、C=O、O、S、N(La)、C 3-9环烷基、C 3-9杂环烷基或C 1-6烷基;其中,所述的La选自下组:H、C 3-9环烷基、C 3-9杂环烷基、C 1-6烷基;R 8选自下组:H、卤素、OH、NH 2、氰基、C(O)NH 2、取代或未取代的3-至9-元碳环基(饱和、不饱和的单环、螺环、并环或桥环)、或取代或未取代的3-至9-元杂环基(饱和、不饱和的单环、螺环、并环或桥环);X、Y、Z和V各自独立地选自下组:N或C(R 15);所述的L-R 8位于X、Y、Z和V中任一原子上,且当L-R 8位于X、Y、Z或V时,对应原子为C(R 15),且此时R 15被L-R 8替代;R 15选自下组:H、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、C 3-7环烷基或卤素;其中,所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、羟基、羧基、苄基、氧代(=O)、-(CH 2) nN(R 8-1R 8-2)、-(CH 2) nC(O)N(R 8-1R 8-2)、C(CH 3) 2N(R 8- 1R 8-2)、-(CH 2) nC(O)OH、(CH 2) nSO 2R 8-1、-(CH 2) nC(O)R 8-3、-C(O)(CH 2) nR 8-3、氨基、C 1- 6烷基NHS(O) 2-、C 1-6烷基NHC(O)-、-C(O)(CH 2) nN(R 8-1R 8-2)、-SO 2(CH 2) nN(R 8-1R 8-2)、(CH 2) nSO 2N(R 8-1R 8-2)、硝基、氰基、未取代或卤代的C 1-C 6烷基、C 2-C 10烯基、C 1-C 6烷氧基、C 1-C 6烷基-胺基、C 6-C 10芳基、五元或六元杂芳基、-O-(C 6-C 10芳基)、-O-(五元或六元杂芳基)、取代或未取代的C 3-7杂环烷基;其中所述的R 8-1、R 8-2选自下组:氢、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环烷基、或R 8-1和R 8-2与它们相连接的N共同形成“杂原子为N、或者N和O,杂原子数为1个或2个的4-6元杂环烷基”,所述的环烷基和杂环烷基可以被一个或多个卤素取代;其中所述的R 8-3选自下组:氢、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、或4-6元杂环烷基,所述的环烷基和杂环烷基可以被一个或多个卤素或C 1-6烷基取代;n为0、1、2、3、4、5或6。
- 如权利要求1所述的式I化合物,其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物,其特征在于,所述的R 1选自下组:其中,A 1、A 2、A 3、A 4、A 5、A 6、B 1、B 2、B 3、B 4各自独立地选自下组:CR、N、NR 14;A 7、A 8各自独立地选自下组:C、N;所述的R 14选自下组:H、C 1-6烷基、卤素取代的C 1-6烷基、C 3-7环烷基;各个R各自独立地选自下组:H、卤素、氰基、C 1-6烷基、C 1-6烷氧基、C 3-7环烷基、(CH 2) nC(O)NH 2、Ra取代的C 1-6烷基、或Rb取代的C 1-6烷氧基;其中,所述的Ra和Rb各自独立地选自下组:OH、卤素、氰基、C 1-3烷基或C 1-3烷氧基;n为0、1、2或3。
- 如权利要求5所述的化合物,其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物,其特征在于,所述的式I化合物中,R 2、R 3各自独立地选自下组:C 1-6烷氧基、卤代C 1-6烷基、C 1-6烷基、氰基、C 3-7环烷基;R 6和R 7各自独立地为H或甲基;或所述的R 6和R 7共同构成C=O。
- 如权利要求1-4任一所述的化合物,其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物,其特征在于,L选自下组:化学键、C=O;R 8选自下组:取代或未取代的3-至9-元碳环基(饱和、不饱和的单环、螺环、并环或桥环)、或取代或未取代的3-至9-元杂环基(饱和、不饱和的单环、螺环、并环或桥 环);其中,所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、羟基、羧基、苄基、氧代(=O)、-(CH 2) nN(R 8-1R 8-2)、-(CH 2) nC(O)N(R 8-1R 8-2)、C(CH 3) 2N(R 8-1R 8-2)、-(CH 2) nC(O)OH、(CH 2) nSO 2R 8-1、-(CH 2) nC(O)R 8-3、-C(O)(CH 2) nR 8- 3、C 1-6烷基NHS(O) 2-、C 1-6烷基NHC(O)-、-C(O)(CH 2) nN(R 8-1R 8-2)、-SO 2(CH 2) nN(R 8-1R 8- 2)、(CH 2) nSO 2N(R 8-1R 8-2)、氰基、未取代或卤代的C 1-C 6烷基、取代或未取代的C 3-7杂环烷基;其中所述的R 8-1、R 8-2选自下组:氢、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、4-6元杂环烷基、或R 8-1和R 8-2与它们相连接的N共同形成“杂原子为N、或者N和O,杂原子数为1个或2个的4-6元杂环烷基”,所述的环烷基和杂环烷基可以被一个或多个卤素取代;其中所述的R 8-3选自下组:氢、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 3-6环烷基、或4-6元杂环烷基,所述的环烷基和杂环烷基可以被一个或多个卤素或C 1-6烷基取代;n为0、1或2。
- 一种药物组合物,其特征在于,所述的药物组合物包括:如权利要求1所述的式I化合物、其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物中的一种或多种,以及一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
- 如权利要求1所述的式I化合物,其可药用的盐、外消旋体、R-异构体、S-异构体或它们的混合物的用途,其特征在于,用于制备治疗或预防自身免疫性疾病或者慢性炎性疾病的药物组合物。
- 如权利要求11所述的用途,其特征在于,所述的疾病选自下组:干燥综合征,系统性红斑狼疮,多发性硬化症,类风湿性关节炎、系统性硬化症、牛皮癣、系统性红斑狼疮、狼疮肾炎。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110968833 | 2021-08-23 | ||
CN202110968833.7 | 2021-08-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023025109A1 true WO2023025109A1 (zh) | 2023-03-02 |
Family
ID=85321529
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/114038 WO2023025109A1 (zh) | 2021-08-23 | 2022-08-22 | 一类Toll样受体抑制剂及其制备和应用 |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2023025109A1 (zh) |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007096743A1 (en) * | 2006-02-23 | 2007-08-30 | Pfizer Products Inc. | Substituted quinazolines as pde10 inhibitors |
CN101939324A (zh) * | 2008-02-25 | 2011-01-05 | 霍夫曼-拉罗奇有限公司 | 吡咯并吡嗪激酶抑制剂 |
WO2016090296A1 (en) * | 2014-12-05 | 2016-06-09 | Subramaniam Ananthan | Heterocyclic compounds as biogenic amine transport modulators |
CN108290855A (zh) * | 2015-07-01 | 2018-07-17 | 西北大学 | 被取代的喹唑啉化合物及其调节葡糖脑苷脂酶活性的用途 |
WO2020177952A1 (en) * | 2019-03-01 | 2020-09-10 | Ac Immune Sa | Novel compounds for the treatment, alleviation or prevention of disorders associated with tau aggregates |
CN111757882A (zh) * | 2018-01-05 | 2020-10-09 | Ac免疫有限公司 | 用于治疗、减轻或预防与Tau聚集体相关的病症如阿尔茨海默病的1,3,4,5-四氢-2H-吡啶并[4,3-b]吲哚衍生物 |
CN112204028A (zh) * | 2018-06-05 | 2021-01-08 | 豪夫迈·罗氏有限公司 | 用于治疗自身免疫性疾病的四氢-1H-吡嗪并[2,1-a]异吲哚基喹啉化合物 |
WO2021099285A1 (en) * | 2019-11-19 | 2021-05-27 | F. Hoffmann-La Roche Ag | Triazatricycle compounds for the treatment of autoimmune disease |
-
2022
- 2022-08-22 WO PCT/CN2022/114038 patent/WO2023025109A1/zh unknown
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007096743A1 (en) * | 2006-02-23 | 2007-08-30 | Pfizer Products Inc. | Substituted quinazolines as pde10 inhibitors |
CN101939324A (zh) * | 2008-02-25 | 2011-01-05 | 霍夫曼-拉罗奇有限公司 | 吡咯并吡嗪激酶抑制剂 |
WO2016090296A1 (en) * | 2014-12-05 | 2016-06-09 | Subramaniam Ananthan | Heterocyclic compounds as biogenic amine transport modulators |
CN108290855A (zh) * | 2015-07-01 | 2018-07-17 | 西北大学 | 被取代的喹唑啉化合物及其调节葡糖脑苷脂酶活性的用途 |
CN111757882A (zh) * | 2018-01-05 | 2020-10-09 | Ac免疫有限公司 | 用于治疗、减轻或预防与Tau聚集体相关的病症如阿尔茨海默病的1,3,4,5-四氢-2H-吡啶并[4,3-b]吲哚衍生物 |
CN112204028A (zh) * | 2018-06-05 | 2021-01-08 | 豪夫迈·罗氏有限公司 | 用于治疗自身免疫性疾病的四氢-1H-吡嗪并[2,1-a]异吲哚基喹啉化合物 |
WO2020177952A1 (en) * | 2019-03-01 | 2020-09-10 | Ac Immune Sa | Novel compounds for the treatment, alleviation or prevention of disorders associated with tau aggregates |
WO2021099285A1 (en) * | 2019-11-19 | 2021-05-27 | F. Hoffmann-La Roche Ag | Triazatricycle compounds for the treatment of autoimmune disease |
Non-Patent Citations (1)
Title |
---|
DATABASE REGISTRY ANONYMOUS : "1H-Pyrido[4,3-b]indole, 7-fluoro-2,3,4,5-tetrahydro-2-[2-(4-morpholinyl)- 1,7-naphthyridin-6-yl]-(CA INDEX NAME) ", XP093039724, retrieved from STN * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR102447084B1 (ko) | Trk 키나제 억제제로서의 거대 고리 화합물 및 그의 용도 | |
JP6298114B2 (ja) | 新規な三環式化合物 | |
TWI675833B (zh) | 布魯頓氏(bruton’s)酪胺酸激酶之聯芳基抑制劑 | |
CA2932425E (en) | Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides | |
US8551981B2 (en) | Furo[3,2-d]pyrimidine compounds | |
US8518945B2 (en) | Pyrrolopyrazine kinase inhibitors | |
IL265159A (en) | Compounds and preparations as endosomal toll-like receptor inhibitors | |
EP2247592B1 (en) | Pyrrolopyrazine kinase inhibitors | |
BR112020010322A2 (pt) | composto da fórmula i; composto da fórmula ia; composto da fórmula ib; processo de preparação de compostos da fórmula i; composição farmacêutica; método para o tratamento e/ou prevenção de várias doenças; uso dos compostos; método para o tratamento de câncer; e método para o tratamento e/ou prevenção de uma afecção mediada por prmt5 ou um distúrbio proliferativo ou câncer | |
WO2015158283A1 (en) | Heterocyclic kinase inhibitors | |
JP2011529920A (ja) | ピリミジン化合物、組成物及び使用方法 | |
WO2011156698A2 (en) | NOVEL PYRAZOLO[3,4-d]PYRIMIDINE COMPOUNDS | |
KR20120102724A (ko) | 신규한 트리사이클릭 화합물 | |
WO2013043826A1 (en) | Tricyclic compounds useful as protein kinase inhibitors | |
CN112566915B (zh) | 噻二唑irak4抑制剂 | |
TW202321242A (zh) | 雜環化合物及使用方法 | |
WO2016192630A1 (zh) | 一类具有激酶抑制活性的化合物、制备方法和用途 | |
WO2016168638A1 (en) | Indazolones as modulators of tnf signaling | |
US20150031674A1 (en) | Serine/threonine kinase inhibitors | |
WO2023104165A1 (zh) | 作为TLR7/8激动剂的吡啶[4,3-d]嘧啶类化合物 | |
WO2023025109A1 (zh) | 一类Toll样受体抑制剂及其制备和应用 | |
US20190382406A1 (en) | Atg7 inhibitors and the uses thereof | |
CN117964643A (zh) | 一种吡咯[2,3-b]并吡啶衍生物及其制备方法和用途 | |
TW202330536A (zh) | 雜環類化合物、藥物組成物及其應用 | |
ES2370973T3 (es) | Inhibidores de quinasa de pirrolopirazina. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22860455 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |