TW202220999A - 作為造血前驅細胞激酶1(hpk1)抑制劑的吲唑及其使用方法 - Google Patents
作為造血前驅細胞激酶1(hpk1)抑制劑的吲唑及其使用方法 Download PDFInfo
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- TW202220999A TW202220999A TW110135855A TW110135855A TW202220999A TW 202220999 A TW202220999 A TW 202220999A TW 110135855 A TW110135855 A TW 110135855A TW 110135855 A TW110135855 A TW 110135855A TW 202220999 A TW202220999 A TW 202220999A
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- Prior art keywords
- fluoro
- imidazo
- indazol
- carboxamide
- fluorocyclopropane
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- 238000000034 method Methods 0.000 title claims abstract description 21
- 102100028199 Mitogen-activated protein kinase kinase kinase kinase 1 Human genes 0.000 title claims abstract description 4
- 239000003112 inhibitor Substances 0.000 title description 7
- 108010002838 hematopoietic progenitor kinase 1 Proteins 0.000 title description 2
- 101100177670 Caenorhabditis elegans hpk-1 gene Proteins 0.000 title 1
- 150000002473 indoazoles Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 101
- 150000003839 salts Chemical class 0.000 claims abstract description 50
- 101001059991 Homo sapiens Mitogen-activated protein kinase kinase kinase kinase 1 Proteins 0.000 claims abstract description 3
- -1 cyano, hydroxyl Chemical group 0.000 claims description 163
- 125000000217 alkyl group Chemical group 0.000 claims description 128
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 112
- 125000005843 halogen group Chemical group 0.000 claims description 83
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 59
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 40
- 125000001188 haloalkyl group Chemical group 0.000 claims description 40
- 125000000623 heterocyclic group Chemical group 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 36
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 34
- 125000001072 heteroaryl group Chemical group 0.000 claims description 32
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 28
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 27
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 27
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 26
- 239000000460 chlorine Substances 0.000 claims description 25
- 201000010099 disease Diseases 0.000 claims description 25
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 23
- 125000003342 alkenyl group Chemical group 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 17
- 235000019253 formic acid Nutrition 0.000 claims description 17
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 15
- 125000000304 alkynyl group Chemical group 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- 208000035475 disorder Diseases 0.000 claims description 15
- 239000011737 fluorine Substances 0.000 claims description 15
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 206010028980 Neoplasm Diseases 0.000 claims description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 13
- 150000002460 imidazoles Chemical class 0.000 claims description 13
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 12
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- 201000011510 cancer Diseases 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 8
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 claims description 8
- 125000002541 furyl group Chemical group 0.000 claims description 8
- 125000000262 haloalkenyl group Chemical group 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 7
- 201000009030 Carcinoma Diseases 0.000 claims description 6
- 208000008383 Wilms tumor Diseases 0.000 claims description 6
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 6
- 125000000532 dioxanyl group Chemical group 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 125000004372 methylthioethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 claims description 6
- 201000008968 osteosarcoma Diseases 0.000 claims description 6
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000006699 (C1-C3) hydroxyalkyl group Chemical group 0.000 claims description 5
- 208000023275 Autoimmune disease Diseases 0.000 claims description 5
- LGGDENKJIQHSQR-KOLCDFICSA-N CC(C)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F Chemical compound CC(C)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F LGGDENKJIQHSQR-KOLCDFICSA-N 0.000 claims description 5
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 5
- 125000005265 dialkylamine group Chemical group 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
- DJTAVUYZFGAHDI-PWSUYJOCSA-N (1S,2S)-2-fluoro-N-[6-[6-fluoro-5-methylsulfanyl-7-(propan-2-ylamino)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]cyclopropane-1-carboxamide Chemical compound CC(C)NC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(SC)=C1F DJTAVUYZFGAHDI-PWSUYJOCSA-N 0.000 claims description 4
- UHUBESIVQGZCHC-KOLCDFICSA-N (1S,2S)-2-fluoro-N-[6-[6-fluoro-7-propan-2-yl-5-(trifluoromethyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]cyclopropane-1-carboxamide Chemical compound CC(C)C(C(F)=C1C(F)(F)F)=C2NN=CC2=C1C(N=C1)=CN2C1=NC(NC([C@H](C1)[C@H]1F)=O)=C2 UHUBESIVQGZCHC-KOLCDFICSA-N 0.000 claims description 4
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 4
- HNQOENJOJKGMNL-YPMHNXCESA-N CC(C)=C(C)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F Chemical compound CC(C)=C(C)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F HNQOENJOJKGMNL-YPMHNXCESA-N 0.000 claims description 4
- 206010061218 Inflammation Diseases 0.000 claims description 4
- 206010027476 Metastases Diseases 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000005350 hydroxycycloalkyl group Chemical group 0.000 claims description 4
- 230000004054 inflammatory process Effects 0.000 claims description 4
- 230000009401 metastasis Effects 0.000 claims description 4
- 229910052698 phosphorus Inorganic materials 0.000 claims description 4
- WHXVADORTTUIIS-CMPLNLGQSA-N (1R,2R)-N-[6-[5-chloro-7-[cyclopropyl(methyl)amino]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C1CC1)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@@H](C2)[C@@H]2F)=O)=C3)C(Cl)=C1F WHXVADORTTUIIS-CMPLNLGQSA-N 0.000 claims description 3
- LGGDENKJIQHSQR-ONGXEEELSA-N (1R,2S)-N-[6-(5-chloro-6-fluoro-7-propan-2-yl-1H-indazol-4-yl)imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F LGGDENKJIQHSQR-ONGXEEELSA-N 0.000 claims description 3
- WHXVADORTTUIIS-JQWIXIFHSA-N (1R,2S)-N-[6-[5-chloro-7-[cyclopropyl(methyl)amino]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C1CC1)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F WHXVADORTTUIIS-JQWIXIFHSA-N 0.000 claims description 3
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- KTODKKZSKSFAMG-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(furan-2-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C2=C(C=NN3)C3=C(C3=CC=CO3)C(F)=C2Cl)N=C2)C2=N1 KTODKKZSKSFAMG-KOLCDFICSA-N 0.000 claims description 2
- DSMSFGHWRGFWJQ-KCJUWKMLSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(methylaminomethyl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CNCC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F DSMSFGHWRGFWJQ-KCJUWKMLSA-N 0.000 claims description 2
- ADTLLHXZZYRVEX-PPHWZAGGSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(oxolan-2-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C2=C(C=NN3)C3=C(C3OCCC3)C(F)=C2Cl)N=C2)C2=N1 ADTLLHXZZYRVEX-PPHWZAGGSA-N 0.000 claims description 2
- IGFIUDDUTIXHMH-YWTFCRFGSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(oxolan-3-yl)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C2=C(C=NN3)C3=C(C3COCC3)C(F)=C2Cl)N=C2)C2=N1 IGFIUDDUTIXHMH-YWTFCRFGSA-N 0.000 claims description 2
- ITLLPDKAFUALEK-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-(propylamino)-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCCNC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F ITLLPDKAFUALEK-KOLCDFICSA-N 0.000 claims description 2
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- PZQICGNFTCJPSE-FOGDFJRCSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(3R)-3-hydroxypyrrolidin-1-yl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O[C@H](CC1)CN1C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F PZQICGNFTCJPSE-FOGDFJRCSA-N 0.000 claims description 2
- PZQICGNFTCJPSE-UMNHJUIQSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(3S)-3-hydroxypyrrolidin-1-yl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O[C@@H](CC1)CN1C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F PZQICGNFTCJPSE-UMNHJUIQSA-N 0.000 claims description 2
- AXYUUFCBLSWTFK-RISCZKNCSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(4-methylimidazol-1-yl)methyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC1=CN(CC2=C3NN=CC3=C(C(N=C3)=CN4C3=NC(NC([C@H](C3)[C@H]3F)=O)=C4)C(Cl)=C2F)C=N1 AXYUUFCBLSWTFK-RISCZKNCSA-N 0.000 claims description 2
- LBNDFPKMBATLEQ-AKDQNTJRSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[(E)-prop-1-enyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound C/C=C/C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F LBNDFPKMBATLEQ-AKDQNTJRSA-N 0.000 claims description 2
- IQJUIUMBNZYNOA-AOUZGSJDSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[1-(4-methylimidazol-1-yl)ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)N1C=NC(C)=C1 IQJUIUMBNZYNOA-AOUZGSJDSA-N 0.000 claims description 2
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- RWBDIIYSDJZLQO-AOUZGSJDSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[1-(5-methylpyrazol-1-yl)ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)N1N=CC=C1C RWBDIIYSDJZLQO-AOUZGSJDSA-N 0.000 claims description 2
- XREYTABGTXMKAJ-SNZBGZMYSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[1-(methanesulfonamido)ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)NS(C)(=O)=O XREYTABGTXMKAJ-SNZBGZMYSA-N 0.000 claims description 2
- XEKOZEKLRINBIP-YWTFCRFGSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[1-(triazol-2-yl)ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)N1N=CC=N1 XEKOZEKLRINBIP-YWTFCRFGSA-N 0.000 claims description 2
- NNWGVHLYRWBOOJ-VWHDNNRLSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[1-[(2,2,2-trifluoroacetyl)amino]ethyl]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)NC(C(F)(F)F)=O NNWGVHLYRWBOOJ-VWHDNNRLSA-N 0.000 claims description 2
- SPUGTHIKXGYGNT-CZXHOFHRSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[[(1R,3S)-3-hydroxycyclopentyl]-methylamino]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN([C@H](CC1)C[C@H]1O)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F SPUGTHIKXGYGNT-CZXHOFHRSA-N 0.000 claims description 2
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- KQPNTIBMWVHEDR-KOLCDFICSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[methyl(1H-pyrazol-5-yl)amino]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CN(C1=CC=NN1)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F KQPNTIBMWVHEDR-KOLCDFICSA-N 0.000 claims description 2
- GELXMLGWJNUSKL-SCZZXKLOSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[methyl(methylcarbamoyl)amino]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CNC(N(C)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F)=O GELXMLGWJNUSKL-SCZZXKLOSA-N 0.000 claims description 2
- OGGZRWZTORSMPY-PWSUYJOCSA-N (1S,2S)-N-[6-[5-chloro-6-fluoro-7-[methyl(propan-2-yl)amino]-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C)N(C)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F OGGZRWZTORSMPY-PWSUYJOCSA-N 0.000 claims description 2
- IAPKMOREAFOZOM-WPLSFSDESA-N (1S,2S)-N-[6-[5-chloro-7-(1-cyclopropylethylamino)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CC(C1CC1)NC1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F IAPKMOREAFOZOM-WPLSFSDESA-N 0.000 claims description 2
- ZRRRAWZAIYRGGI-VRCHLBOPSA-N (1S,2S)-N-[6-[5-chloro-7-(1-ethoxy-2,2,2-trifluoroethyl)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CCOC(C(F)(F)F)C1=C2NN=CC2=C(C(N=C2)=CN3C2=NC(NC([C@H](C2)[C@H]2F)=O)=C3)C(Cl)=C1F ZRRRAWZAIYRGGI-VRCHLBOPSA-N 0.000 claims description 2
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- VHOMQEUAMIQYAM-PWSUYJOCSA-N (1S,2S)-N-[6-[5-chloro-7-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C(C(Cl)=C2F)=C(C=NN3)C3=C2N2CC(C3)(CC3(F)F)C2)N=C2)C2=N1 VHOMQEUAMIQYAM-PWSUYJOCSA-N 0.000 claims description 2
- URXREUDKCZZMMF-YPMHNXCESA-N (1S,2S)-N-[6-[5-chloro-7-(cyclopentylamino)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C(C(Cl)=C2F)=C(C=NN3)C3=C2NC2CCCC2)N=C2)C2=N1 URXREUDKCZZMMF-YPMHNXCESA-N 0.000 claims description 2
- PLTXDJYJERJABK-SVRRBLITSA-N (1S,2S)-N-[6-[5-chloro-7-(difluoromethyl)-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound O=C([C@H](C1)[C@H]1F)NC1=CN(C=C(C2=C(C=NN3)C3=C(C(F)F)C(F)=C2Cl)N=C2)C2=N1 PLTXDJYJERJABK-SVRRBLITSA-N 0.000 claims description 2
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- XGSKNJGZEJBOLY-WCUVEOEZSA-N (1S,2S)-N-[6-[5-chloro-7-[(3S,4S)-3,4-dimethoxypyrrolidin-1-yl]-6-fluoro-1H-indazol-4-yl]imidazo[1,2-a]pyrazin-2-yl]-2-fluorocyclopropane-1-carboxamide Chemical compound CO[C@@H](CN(C1)C2=C3NN=CC3=C(C(N=C3)=CN4C3=NC(NC([C@H](C3)[C@H]3F)=O)=C4)C(Cl)=C2F)[C@H]1OC XGSKNJGZEJBOLY-WCUVEOEZSA-N 0.000 claims description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
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Abstract
本發明提供式(I)化合物或其藥學上可接受的鹽、含有該化合物的組成物、使用該化合物治療與HPK1相關的各種疾病的方法以及製備這些化合物的方法。
Description
本發明係關於造血前驅細胞激酶1(HPK1)的抑制劑、含有該抑制劑的藥物組成物、使用該抑制劑治療與HPK1相關的各種疾病的方法以及製備這些化合物的方法。
免疫療法是一種利用人體自體免疫系統來幫助對抗癌症和其他疾病的治療方法。近年來,這種相對新的方法在治療多種腫瘤類型方面取得了顯著的臨床成功,尤其是在免疫檢查點抑制劑的治療和嵌合抗原T細胞療法方面。研究最多的檢查點抑制劑包含CTLA4、PD-1或PD-L1抑制劑,其透過克服腫瘤位點的免疫抑制機制而顯示出顯著的抗腫瘤活性。
造血前驅細胞激酶1(HPK1,MAP4K1)是一種絲胺酸/蘇胺酸激酶,為MAP4K的一員。HPK1在造血細胞譜系的亞群中顯著表達。HPK1是一種新發現的T淋巴細胞和樹突細胞活化中的關鍵負調節因子。最近已經證明,HPK1的激酶活性作為一種新的細胞內檢查點分子在抗癌免疫中的重要作用,以及與現有檢查點方案聯合治療的潛在優勢。HPK1抑制被預期具有雙重功能:1、延長T細胞活化;2、透過樹突細胞增強APC功能。這種雙重靶向可能協同作用並於腫瘤微環境中達成高效的免疫應答。因此,HPK1已被證實為抗癌免疫治療的新靶點。使用本發明的化合物治療的癌症的實例包含但不限於所有形式的上皮癌、黑色素瘤、母細胞瘤、肉瘤、淋巴瘤和白血病,包含但不限於膀胱癌、腦腫瘤、乳癌、子宮頸癌、結腸直腸癌、食道癌、子宮內膜癌、肝細胞癌、喉癌、肺癌、骨肉瘤、卵巢癌、胰臟癌、前列腺癌、腎癌和甲狀腺癌、急性淋巴細胞白血病、急性骨髓性白血病、室管膜瘤、尤文氏肉瘤、膠質母細胞瘤、髓母細胞瘤、神經母細胞瘤、骨肉瘤、橫紋肌肉瘤、橫紋肌樣癌和腎母細胞瘤(威爾姆氏瘤)。
用小分子抑制劑抑制HPK1具有治療癌症及其他疾病的潛力[Hernandez, S., et. al., (2018)
Cell Reports 25, 80-94]。
本發明提供了作為有效的HPK1抑制劑及T細胞與樹突細胞的雙重活化劑的新型吲唑化合物和藥學上可接受的鹽。
在另一種實施方式中,提供了一種藥物組成物,其含有藥學上可接受的載體或稀釋劑和式(I)的化合物或其藥學上可接受的鹽。
在又一種實施方式中,提供了治療患有與HPK1調節相關的疾病或病症的受試者的方法,包含:向受試者施用治療有效劑量的式(I)的化合物或其藥學上可接受的鹽。
下述描述本質上僅是示例性的,並不旨在限制本發明、應用或用途。
定義
為清楚起見,本文定義了本發明中使用的通用術語。
本說明書可交替使用術語「取代基」、「自由基」、「基團」、「部分」和「片段」。
如本文所用,術語「烯基」是指具有至少一個不飽和位點的直鏈或支鏈烴基,即碳-碳sp2雙鍵。在一種實施方式中,烯基具有2至12個碳原子。在一些實施方式中,烯基是C
2-C
10烯基或C
2-C
6烯基。烯基的實例包含但不限於乙烯或乙烯基(—CH═CH
2)、烯丙基(—CH
2CH═CH
2)、環戊烯基(—C
5H
7)和5-己烯基(—CH
2CH
2CH
2CH
2CH═CH
2)。
如本文所用,術語「烷氧基」是RO—,其中,R是烷基。烷氧基的非限制性實例包含甲氧基、乙氧基和丙氧基。
如本文所用,術語「烷氧基烷基」是指被烷氧基取代的烷基部分。烷氧基烷基的實例包含甲氧基甲基、甲氧基乙基、甲氧基丙基和乙氧基乙基。
如本文所用,術語「烷氧羰基」是ROC(O)—,其中,R是本文定義的烷基。在各種實施方式中,R是C
1-C
10烷基或C
1-C
6烷基。
如本文所用,術語「烷基」是指直鏈或支鏈烴基。在一種實施方式中,烷基具有1至12個碳原子。在一些實施方式中,烷基是C
1-C
10烷基或C
1-C
6烷基。烷基的實例包含但不限於甲基、乙基、丙基、異丙基、丁基、異丁基、三級丁基、戊基、己基、庚基、辛基、壬基和癸基。「低級烷基」是指具有1至4個碳原子的烷基。
如本文所用,如果使用術語「C
1-C
6」,則表示碳原子數為1至6。例如,C
1-C
6烷基是指碳原子數為1至6的任意整數的烷基。
如本文所用,術語「烷基胺基」是指被一個或多個烷基取代的胺基。「N-(烷基)胺基」是RNH-並且「N,N-(烷基)
2胺基」是R
2N—,其中,R基團是如本文所定義的相同或不同的烷基。在各種實施方式中,R是C
1-C
10烷基或C
1-C
6烷基。烷基胺基的實例包含甲胺基、乙胺基、丙胺基、丁胺基、二甲胺基、二乙胺基和甲乙胺基。
如本文所用,術語「烷基胺基烷基」是指被烷基胺基取代的烷基部分,其中,烷基胺基如本文所定義。烷基胺基烷基的實例包含甲基胺基甲基和乙基胺基甲基。
如本文所用,術語「炔基」是指具有至少一個不飽和位點的直鏈或支鏈碳鏈基團,即碳-碳sp三鍵。在一種實施方式中,炔基具有2至12個碳原子。在一些實施方式中,炔基是C
2-C
10炔基或C
2-C
6炔基。炔基的實例包含炔基(—C≡CH)和炔丙基(—CH
2C≡CH)。
如本文所用,術語「芳基」是指每個環中最多7個原子的任意單環或雙環碳環,其中,至少一個環是芳香環,或包含與5或6元環烷基融合的碳環芳香基的5至14個碳原子的芳香環體系。芳基的代表性實例包含但不限於苯基、甲苯基、二甲苯基、萘基、四氫萘基、蒽基、茀基、茚基、薁基和二氫茚基。碳環芳香基可以是未取代的或可選取代的。
如本文所用,術語「環烷基」是含有至少一個飽和的或部分不飽和的環結構並經由環碳連接的烴基。在各種實施方式中,它是指飽和的或部分不飽和的C
3-C
12環狀部分,其實例包含環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環庚基和環辛基。「環烷氧基」是RO—,其中,R是環烷基。
如本文所用,術語「鹵素」和「鹵基」是指氯(—Cl)、溴(—Br)、氟(—F)或碘(—I)。「鹵代烷氧基」是指被一個或多個鹵基取代的烷氧基,鹵代烷氧基的實例包含但不限於—OCF
3、—OCHF
2和—OCH
2F。「鹵代烷氧基烷基」是指被鹵代烷氧基取代的烷基部分,其中,鹵代烷氧基如本文所定義。鹵代烷氧基烷基的實例包含三氟甲氧基甲基、三氟乙氧基甲基和三氟甲氧基乙基。「鹵代烷基」是指被一個或多個鹵基取代的烷基部分。鹵代烷基的實例包含—CF
3和—CHF
2。
如本文所用,術語「雜烷基」是指鏈中具有2至14個碳(在一些實施方式中,2至10個碳)的直鏈或支鏈烷基,其中一個或多個已被雜原子替代,雜原子選自S、O、P和N。示例性的雜烷基包含烷基醚、二級和三級烷基胺、醯胺、烷基硫化物等。
如本文所用,術語「雜環基」包含下述定義的雜芳基,並且是指具有2至14個環碳原子並且除了環碳原子之外還有1至4個雜原子的飽和或部分不飽和的單環、雙環或三環基團,雜原子選自P、N、O和S。在各種實施方式中,雜環基團透過碳或透過雜原子連接到另一部分,並且可選地在碳或雜原子上被取代。雜環基的實例包含氮呾、苯並咪唑基、苯並呋喃基、苯並呋呫基、苯並吡唑基、苯並三唑基、苯並苯硫基、苯並噁唑基、咔唑基、咔啉基、㖕啉基、呋喃基、咪唑基、二氫吲哚基、吲哚基、吲哚嗪基、吲唑基、異苯並呋喃基、異吲哚基、異喹啉基、異噻唑基、異噁唑基、萘吡啶基、噁二唑基、噁唑基、噁唑啉、異噁唑啉、氧呾基、哌喃基、吡嗪基、吡唑基、嗒𠯤基、吡啶並吡啶基、嗒𠯤基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、喹㗁啉基、四氫哌喃基、四氫噻喃基、四氫異喹啉基、四唑基、四唑吡啶基、噻二唑基、噻唑基、噻吩基、三唑基、氮呾、1,4-二噁烷基、六氫氮呯基、哌嗪基、哌啶基、吡啶-2-酮基、吡咯烷基、嗎啉基、硫代嗎啉基、二氫苯並咪唑基、二氫苯並呋喃基、二氫苯並苯硫基、二氫苯並噁唑基、二氫呋喃基、二氫咪唑基、二氫吲哚基、二氫異噁唑基、二氫異噻唑基、二氫噁二唑基、二氫噁唑基、二氫吡嗪基、二氫吡唑基、二氫吡啶基、二氫嘧啶基、二氫吡咯基、二氫喹啉基、二氫四唑基、二氫噻二唑基、二氫噻唑基、二氫噻吩基、二氫三唑基、二氫氮呾、亞甲二氧基苯甲醯基、四氫呋喃基和四氫噻吩基,及其N-氧化物。「雜環氧基」是RO—,其中,R是雜環基。「雜環硫基」是RS—,其中,R是雜環基。
如本文所用,術語「3-或4-元雜環基」是指具有3或4個環原子的單環,其中,至少一個環原子是選自由N、O和S組成的組的雜原子。3-或4-元雜環基的非限制性實例包含氮丙啶基、2
H-氮丙啶基、環氧乙烷基、硫環丙烷基、氮呾、2,3-二氫吖唉基、吖唉基、1,3-二氮呾、氧呾基、2
H-氧唉基、硫呾基和2
H-硫唉基。
如本文所用,術語「雜芳基」是指在每個環中具有至多7個原子的單環、雙環或三環,其中,至少一個環是芳族的並且在該環中含有1至4個選自由N、O和S組成的組的雜原子。雜芳基的非限制性實例包含吡啶基、噻吩基、呋喃基、嘧啶基、咪唑基、哌喃基、吡唑基、噻唑基、噻二唑基、異噻唑基、噁唑基、異噁唑基、吡咯基、嗒𠯤基、吡嗪基、喹啉基、異喹啉基、苯並呋喃基、二苯並呋喃基、二苯並苯硫基、苯並噻吩基、吲哚基、苯並噻唑基、苯並噁唑基、苯並咪唑基、異吲哚基、苯並三唑基、嘌呤基、噻萘基和吡嗪基。雜芳基的連接可以透過芳香環發生,或者,如果雜芳基是雙環或三環並且其中一個環不是芳香環或不含雜原子,則透過非芳香環或不含雜原子的環連接。「雜芳基」還應理解為包含任意含氮雜芳基的N-氧化物衍生物。「雜芳氧基」是RO—,其中,R是雜芳基。
如本文所用,術語「羥基烷氧基」是指被羥基(-OH)取代的烷氧基,其中,烷氧基如本文所定義。羥基烷氧基的一個實例是羥基乙氧基。
如本文所用,術語「羥烷基」是指被至少一個羥基取代的直鏈或支鏈單價C
1-C
10烴基,並且羥烷基的實例包含但不限於羥甲基、羥乙基、羥丙基和羥丁基。
如本文所用,術語「藥學上可接受的」是指適用於藥物製備,且對於這種用途通常認為是安全的,被國家或州政府的監管機構正式批准用於這種用途,或被列入美國藥典或其他公認的用於動物尤其是人類的藥典。
如本文所用,術語「藥學上可接受的載體」是指稀釋劑、佐劑、賦形劑或載體,或藥學上可接受的並且與本發明的化合物一起施用的其他成分。
如本文所用,術語「藥學上可接受的鹽」是指可增強所期望的藥理活性的鹽。藥學上可接受的鹽的實例包含與無機或有機酸形成的酸加成鹽、金屬鹽和胺鹽。與無機酸形成的酸加成鹽的實例包含與鹽酸、氫溴酸、硫酸、硝酸和磷酸形成的鹽。與有機酸形成的酸加成鹽的實例,有機酸例如乙酸、丙酸、己酸、庚酸、環戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、蘋果酸、馬來酸、富馬酸、酒石酸、檸檬酸、苯甲酸、o-(4-羥基-苯甲醯基)-苯甲酸、肉桂酸、苦杏仁酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羥基乙磺酸、苯磺酸、對氯苯磺酸、2-萘磺酸、對甲苯磺酸、樟腦磺酸、4-甲基-雙環[2.2.2]oct-2-烯-1-羧酸、葡庚糖酸、4,4'-亞甲基雙(3-羥基-2-萘甲基)酸、3-苯基丙酸、三甲基乙酸、三級丁基乙酸、月桂基硫酸、葡萄糖酸、谷胺酸、羥基萘甲酸、水楊酸、硬脂酸和黏康酸。金屬鹽的實例包含與鈉、鉀、鈣、鎂、鋁、鐵和鋅離子形成的鹽。胺鹽的實例包含與胺和有機含氮鹼形成的鹽,其強度足以與羧酸形成鹽。
如本文所用,術語「取代的」是指任意上述基團(即,烷基、芳基、雜芳基、雜環或環烷基),其中,被取代部分的至少一個氫原子被取代基取代。在一種實施方式中,被取代基團的每個碳原子被不超過兩個取代基取代。在另一種實施方式中,被取代基團的每個碳原子被不超過一個取代基取代。在酮取代基的實例中,兩個氫原子被透過雙鍵連接到碳上的氧取代。除非特別定義,取代基包含鹵基、羥基、(低級)烷基、鹵代烷基、單或二烷基胺基、芳基、雜環、-NO
2、B(OH)
2、BPin、-NR
aR
b、-NR
aC(=O)R
b、-NR
aC(=O)NR
aR
b、-NR
aC(=O)OR
b、-NR
aSO
2R
b、-OR
a、-CN、-C(=O)R
a、-C(=O)OR
a、-C(=O)NR
aR
b、-OC(=O)R
a、-OC(=O)OR
a、-OC(=O)NR
aR
b、-NR
aSO
2R
b、-PO
3R
a、-PO(OR
a)(OR
b)
、-SO
2R
a、-S(O)R
a、-SO(N)R
a(例如,硫醯亞胺)、-(R
a)S=NR
b(例如,磺亞醯胺)和-SR
a,其中,R
a和R
b相同或不同,並且獨立地為-H、鹵基、胺基、烷基、鹵代烷基、芳基或雜環,或其中,R
a和R
b與它們所連接的氮原子一起形成雜環。基於所連接的原子,R
a和R
b可以是複數形式。
如本文所用,術語「治療有效劑量」是指當應用本發明的化合物時,其表示預期足以改善、減輕、穩定、逆轉、減緩或延遲病症進展或疾病狀態、或病症或疾病的症狀的劑量。在一種實施方式中,本發明的方法提供於化合物組合的施用。在這種情况下,「治療有效劑量」是本發明化合物在組合中足以引起預期生物效應的劑量。
如本文所用,本文所用的術語「治療(treatment)」或「治療(treating)」是指改善或逆轉疾病或病症的進展或嚴重性,或改善或逆轉這種疾病或病症的一種或多種症狀或副作用。如本文所用,「治療(treatment)」或「治療(treating)」還指抑制或阻斷疾病或病症的系統、條件或狀態的進展,如延遲、阻滯、約束、妨礙或阻礙。為了本發明的目的,「治療(treatment)」或「治療(treating)」進一步指獲得有益的或期望的臨床結果的方法,其中,「有益的或期望的臨床結果」包含但不限於部分或全部的症狀的減輕、病症或疾病程度的減少,穩定(即,不惡化)疾病或病症狀態,疾病或病症狀態的延遲或減緩,疾病或病症狀態的改善或緩和,以及疾病或病症的緩解。
化合物
本公開提供了式(I)的化合物:
式(I)
或其藥學上可接受的鹽、水合物或溶劑化物,其中:
X為O或S;
L為鍵、-O-、-S-或-NR
6-;
R
1為烷基、環烷基、芳基、雜芳基或雜環基,其中,R
1可選地被一個或多個獨立地選自R
7的取代基取代;
R
6為-H或C
1-6烷基;
R
7為C
1-6烷基、C
2-6烯基、C
2-6炔基、環烷基、芳基、雜芳基、雜環基、鹵基、側氧基、氰基、羥基、-C(O)R
9、-C(O)OR
9、-C(O)NR
10R
11、-OR
9、-OC(O)R
9、-OC(O)NR
10R
11、-SR
9、-S(O)R
9、-S(O)
2R
9、-S(O)(=NH)R
10、-S(O)
2NR
10R
11、-NR
10R
11、-N(R
6)NR
10R
11、-N(R
6)OR
9、-N(R
6)C(O)R
9、-N(R
6)C(O)OR
9、-N(R
6)C(O)NR
10R
11、-N(R
6)S(O)
2R
9、-N(R
6)S(O)
2NR
10R
11或-P(O)R
12R
13;
R
9為-H、C
1-6烷基、C
1-6鹵代烷基、C
2-6烯基、C
2-6炔基、環烷基、芳基、雜芳基或雜環基;
每個R
10和R
11獨立地為-H、C
1-6烷基、C
2-6烯基、C
2-6炔基、環烷基、芳基、雜芳基或雜環基,或R
10和R
11與它們所連接的氮原子一起形成可選被一個或多個基團取代的4至12元雜環基,基團選自由鹵基、羥基、烷基、烯基、炔基、鹵代烷基、羥烷基、-CN、-NO
2、-NR
10R
11、-NR
10C(=O)R
9、-NR
10C(=O)NR
10R
11、-NR
10C(=O)OR
9、-OR
9、-C(=O)R
9、-C(=O)OR
9、-C(=O)NR
10R
11、-OC(=O)R
9、-OC(=O)OR
9和-OC(=O)NR
10R
11組成的組;
每個R
12和R
13獨立地為C
1-6烷基、C
1-6烷氧基、C
3-8環烷基、芳基、雜芳基、雜環基,或R
12和R
13與它們所連接的磷原子一起形成可選被一個或多個基團取代的4至8元雜環基,基團選自由鹵基、羥基、烷基、烯基、炔基、鹵代烷基、羥烷基、-CN、-NO
2、-NR
10R
11、-NR
10C(=O)R
9、-NR
10C(=O)NR
10R
11、-NR
10C(=O)OR
9、-OR
9、-C(=O)R
9、-C(=O)OR
9、-C(=O)NR
10R
11、-OC(=O)R
9、-OC(=O)OR
9和-OC(=O)NR
10R
11組成的組;
Het選自由下述組成的組:
R
a、R
b和R
c各自獨立地為-H、-D、鹵基、-CF
3、-CF
2H、-CH
2F、-CN、-OR
9或-NR
10R
11;
R
2為-H、-D、-CD
3、C
1-6烷基、C
2-6烯基、C
2-6炔基、環烷基、芳基、雜芳基、雜環基、鹵基、羥基、-CD
2OH、-CN、-NO
2、鹵代烷基、三甲基矽基乙氧基甲基、-C(O)R
9、-C(O)OR
9、-C(O)NR
10R
11、-OR
9、-OC(O)R
9、-OC(O)NR
10R
11、-SR
9、-S(O)R
9、-S(O)
2R
9、-S(O)(=NH)R
10、-S(O)
2NR
10R
11、-NR
10R
11、-N(R
6)NR
10R
11、-N(R
6)OR
9、-N(R
6)C(O)R
9、-N(R
6)C(O)R
9、-N(R
6)C(O)OR
9、-N(R
6)C(O)NR
10R
11、-N(R
6)S(O)
2R
9、-N(R
6)S(O)
2NR
10R
11或-P(O)R
12R
13,其中,C
1-6烷基、C
2-6烯基、C
2-6炔基、環烷基、芳基、雜芳基或雜環基可選地被一個或多個基團取代,基團選自由鹵基、羥基、烷基、烯基、炔基、鹵代烷基、羥烷基、-CN、-NO
2、-NR
10R
11、-NR
10C(=O)R
9、-NR
10C(=O)NR
10R
11、-NR
10C(=O)OR
9、-OR
9、-C(=O)R
9、-C(=O)OR
9、-C(=O)NR
10R
11、-OC(=O)R
9、-OC(=O)OR
9和-OC(=O)NR
10R
11組成的組;
R
3為-H、-D、-CD
3、C
1-6烷基、C
2-6烯基、C
2-6炔基、環烷基、芳基、雜芳基、雜環基、鹵基、氰基、羥基、-CH
2OH、-CD
2OH、-OH、-CN、-NO
2、鹵代烷基、-C(O)R
9、-C(O)OR
9、-C(O)NR
10R
11、-OR
9、-OC(O)R
9、-OC(O)NR
10R
11、-SR
9、-S(O)R
9、-S(O)
2R
9、-S(O)(=NH)R
10、-S(O)
2NR
10R
11、-NR
10R
11、-N(R
6)NR
10R
11、-N(R
6)OR
9、-N(R
6)C(O)R
9、-N(R
6)C(O)OR
9、-N(R
6)C(O)NR
10R
11、-N(R
6)S(O)
2R
9、-N(R
6)S(O)
2NR
10R
11或-P(O)R
12R
13;
M為鍵、-O-、-S-或-NR
6-;
R
6為-H或C
1-6烷基;
R
4為-H、-D、C
1-6烷基、C
2-6烯基、C
2-6炔基、環烷基、芳基、雜芳基、雜環基、鹵基、氰基、羥基、-C(O)R
9、-C(O)OR
9、-C(O)NR
10R
11、- -S(O)
2R
9、-S(O)(=NH)R
10、-S(O)
2NR
10R
11或-P(O)R
12R
13,其中,C
1-6烷基、C
2-6烯基、C
2-6炔基、環烷基、芳基、雜芳基或雜環基可選地被一個或多個基團取代,基團選自由鹵基、羥基、烷基、烯基、炔基、鹵代烷基、羥烷基、-CN、-CD
3、-NO
2、-NR
10R
11、-NR
10C(=O)R
9、-NR
10C(=O)NR
10R
11、-NR
10C(=O)OR
9、-NR
10S(O)
2R
9、-OR
9、-C(=O)R
9、-C(=O)OR
9、-C(=O)NR
10R
11、-OC(=O)R
9、-OC(=O)OR
9和-OC(=O)NR
10R
11組成的組;並且
R
5為-H、-D、-CD
3、C
1-6烷基、C
2-6烯基、C
2-6炔基、環烷基、鹵基、羥基、-CH
2OH、-CD
2OH、-CN或鹵代烷基。
在一些實施方式中,L為鍵,並且R
1為環烷基,其可選地被一個或多個基團取代,基團選自由C
1-6烷基、C
2-6烯基、C
2-6炔基、環烷基、鹵基、氰基、羥基、-C(O)R
9、-C(O)OR
9、-C(O)NR
10R
11、-OR
9、-OC(O)R
9、-OC(O)NR
10R
11、-NR
10R
11、-N(R
6)NR
10R
11、-N(R
6)OR
9、-N(R
6)C(O)R
9、-N(R
6)C(O)OR
9和-N(R
6)C(O)NR
10R
11組成的組。
在一些實施方式中,R
2和R
3各自獨立地為-H、鹵基、烷硫基、鹵代烷基或烷基。
在一些實施方式中,M為鍵、-O-或-NR
6-;並且R
4為-H、-D、C
1-6烷基、C
2-6烯基、C
2-6炔基、環烷基、芳基、雜芳基、雜環基、鹵基、氰基、羥基、-C(O)R
9、-C(O)NR
10R
11、-S(O)
2R
9、-S(O)(=NH)R
10或-S(O)
2NR
10R
11,其中,C
1-6烷基、C
2-6烯基、C
2-6炔基、環烷基、芳基、雜芳基或雜環基可選地被一個或多個基團取代,基團選自由鹵基、羥基、烷基、烯基、炔基、鹵代烷基、羥烷基、-CN、-CD
3、-NR
10R
11、-NR
10S(O)
2R
9和-NR
10C(=O)R
9組成的組。
其中,R
1、R
2、R
3、R
4、R
5、R
a、R
b、M和L如上式(I)所定義。
在一些實施方式中,L為鍵;R
1為環丙基,其可選地被一個或多個基團取代,基團選自由鹵基、C
1-3烷基、C
1-3羥烷基和C
1-3鹵代烷基組成的組;R
2為-H、烷基、鹵基、鹵代烷基或烷硫基;R
3為-H、烷基或鹵基;M為鍵、-O-、-S-或-NR
6-;R
4為-H、鹵基、烷基、羥烷基、鹵代烷基、鹵代烯基、環烷基、氰基烷基、胺基羰基烷基、乙醯胺基乙基、丙醯胺基乙基、甲醯胺基乙基、環烷基烷基、環烷基(羥基)烷基、羥基環烷基、甲氧基環烷基、環烷基(甲氧基)甲基、烷氧基烷基、烯基、甲基磺醯胺基乙基、咪唑基乙基、二噁烷基、環丁基羰基胺基乙基、二氟乙醯胺基乙基、三氟乙醯胺基乙基、甲硫甲基、甲硫乙基、環丙基羰基胺基(氰基)甲基、氰基(二氟乙醯胺基)甲基、丙基-1,1,1,3,3,3-d6)胺基、四氫呋喃基、甲基咪唑基乙基、呋喃基、吡咯基、甲基吡咯基、異噁唑基、四唑基烷基、甲基吡唑基或甲基吡唑基甲基;並且R
5為–H、烷基或鹵基。非限制性的示例性的式(II)化合物包含表1的實施例1和2。
其中,R
1、R
2、R
3、R
4、R
5、R
a、R
b、M和L如上式(I)所定義。
在一些實施方式中,L為鍵;R
1為環丙基,其任選地被一個或多個基團取代,基團選自由鹵基、C
1-3烷基、C
1-3羥烷基和C
1-3鹵代烷基組成的組;R
2為-H、烷基、鹵基、鹵代烷基或烷硫基;R
3為-H、烷基或鹵基;M為鍵、-O-、-S-或-NR
6-;R
4為-H、鹵基、烷基、羥烷基、鹵代烷基、鹵代烯基、環烷基、氰基烷基、胺基羰基烷基、乙醯胺基乙基、丙醯胺基乙基、甲醯胺基乙基、環烷基烷基、環烷基(羥基)烷基、羥基環烷基、甲氧基環烷基、環烷基(甲氧基)甲基、烷氧基烷基、烯基、甲基磺醯胺基乙基、咪唑基乙基、二噁烷基、環丁基羰基胺基乙基、二氟乙醯胺基乙基、三氟乙醯胺基乙基、甲硫甲基、甲硫乙基、環丙基羰基胺基(氰基)甲基、氰基(二氟乙醯胺基)甲基、丙基-1,1,1,3,3,3-d6)胺基、四氫呋喃基、甲基咪唑基乙基、呋喃基、吡咯基、甲基吡咯基、異噁唑基、四唑基烷基、甲基吡唑基或甲基吡唑基甲基;並且R
5為–H、烷基或鹵基。非限制性的示例性的式(III)化合物包含表1的實施例3和23。
其中,R
1、R
2、R
3、R
4、R
5、R
a、R
b、M和L如上式(I)所定義。非限制性的示例性的式(IV)化合物包含表1的實施例24和307。
在一些實施方式中,L為鍵,並且R
1為環烷基,其可選地被一個或多個基團取代,基團選自由C
1-6烷基、C
2-6烯基、C
2-6炔基、環烷基、鹵基、氰基、羥基、-C(O)R
9、-C(O)OR
9、-C(O)NR
10R
11、-OR
9、-OC(O)R
9、-OC(O)NR
10R
11、-NR
10R
11、-N(R
6)NR
10R
11、-N(R
6)OR
9、-N(R
6)C(O)R
9、-N(R
6)C(O)OR
9和-N(R
6)C(O)NR
10R
11組成的組。
在一些實施方式中,L為鍵;R
1為環烷基,其可選被一個或多個基團取代,基團選自由鹵基、C
1-3烷基、C
1-3羥烷基和C
1-3鹵代烷基組成的組。在特定實施方式中,環烷基選自環丙基、環丁基和環戊基。
在一些實施方式中,L為鍵;R
1為環丙基,其可選地被一個或多個基團取代,基團選自由鹵基、C
1-C
3烷基、C
1-C
3羥烷基和C
1-C
3鹵代烷基組成的組;R
2為-H、烷基、鹵代烷基或鹵基;R
3為-H、烷基或鹵基;M為鍵、-O-或-NR
6-;R
4為-H、鹵基、烷基、單烷基胺基或二烷基胺基;R
5為-H、烷基或鹵基。在特定實施方式中,L為鍵;R
a為-H;R
b為-H;R
1為被氯、氟、C
1-C
3烷基、C
1-C
3羥烷基或C
1-C
3鹵代烷基取代的環丙基;R
2為-H、烷基、氯或氟;R
3為-H、烷基、氯或氟;M為鍵或-NH-;R
4為-H、氯、氟、甲基、乙基、丙基、異丙基、丁基、甲胺基或二甲胺基;並且R
5為-H或烷基。在特定實施方式中,L為鍵;R
a為-H;R
b為-H;R
1為被氯或氟取代的環丙基;R
2為-H、氯或氟;R
3為-H、氯或氟;M為鍵或-NH-;R
4為-H、氯、氟、甲基、乙基、丙基或異丙基;並且R
5為-H。具有這種取代基的非限制性示例性化合物包含表1的實施例61、64、84、85、86、155、156和157。
在一些實施方式中,L為鍵;R
1為環丙基,其可選地被一個或多個基團取代,基團選自由鹵基、C
1-C
3烷基、C
1-C
3羥烷基和C
1-C
3鹵代烷基組成的組;R
2為-H、烷基、鹵基、鹵代烷基或烷硫基;R
3為-H、烷基或鹵基;M為鍵、-O-、-S-或-NR
6-;R
4為-H、鹵基、烷基、羥烷基、鹵代烷基、鹵代烯基、環烷基、單烷基胺基或二烷基胺基;並且R
5為-H、烷基或鹵基。具有這種取代基的非限制性示例性化合物包含表1的實施例33、39、40、46、82、102、141、166、228和286。
在一些實施方式中,L為鍵;R
1為環丙基,其可選地被一個或多個基團取代,基團選自由鹵基、C
1-C
3烷基、C
1-C
3羥烷基和C
1-C
3鹵代烷基組成的組;R
2為-H、烷基、鹵基、鹵代烷基或烷硫基;R
3為-H、烷基或鹵基;M為鍵、-O-、-S-或-NR
6-;R
4為-H、鹵基、烷基、羥烷基、鹵代烷基、鹵代烯基、環烷基、氰基烷基、胺基羰基烷基、乙醯胺基乙基、丙醯胺基乙基、甲醯胺基乙基、環烷基烷基、環烷基(羥基)烷基、羥基環烷基、甲氧基環烷基、環烷基(甲氧基)甲基、烷氧基烷基、烯基、甲基磺醯胺基乙基、咪唑基乙基、二噁烷基、環丁基羰基胺基乙基、二氟乙醯胺基乙基、三氟乙醯胺基乙基、甲硫甲基、甲硫乙基、環丙基羰基胺基(氰基)甲基、氰基(二氟乙醯胺基)甲基、丙基-1,1,1,3,3,3-d6)胺基、四氫呋喃基、甲基咪唑基乙基、呋喃基、吡咯基、甲基吡咯基、異噁唑基、四唑基烷基、甲基吡唑基或甲基吡唑基甲基;並且R
5為–H、烷基或鹵基。具有這種取代基的非限制性示例性化合物包含表1的實施例26、27、34、38、41-44、50、58、62、63、66、68、73、77、79、80、83、87、88、90-92、94、96、101、105、107、110、113、116、118-120、128、130、131、133、134、136、141、153、160、162、166-168、170、173-176、179、181、183、186、188、190、191、194、208、210、213、215-219、221、223、226、228、232、235、237、248、250、252、257、261、262、264、266、268、269、272、273、284-290、295、300和302-305。
在一種實施方式中,提供了一種藥物組成物,其含有藥學上可接受的載體或稀釋劑和式(I)的化合物或其藥學上可接受的鹽。
使用該化合物的醫療用途和治療方法
本發明提供了治療患有與HPK1調節相關的疾病或病症的受試者的方法,包含:向需要其的受試者施用治療有效劑量的式(I)化合物或其藥學上可接受的鹽。在一些實施方式中,與HPK1的調節相關的疾病或病症為癌症、轉移、炎症或包含自體免疫疾病的免疫疾病。
在一些其他實施方式中,疾病為癌症、轉移、炎症或自體免疫疾病。在特定的實施方式中,癌症選自由上皮癌、黑色素瘤、母細胞瘤、肉瘤、淋巴瘤和白血病組成的組,包含但不限於膀胱癌、腦腫瘤、乳癌、子宮頸癌、結腸直腸癌、食道癌、子宮內膜癌、肝細胞癌、喉癌、肺癌、骨肉瘤、卵巢癌、胰臟癌、前列腺癌、腎癌和甲狀腺癌、急性淋巴細胞白血病、急性骨髓性白血病、室管膜瘤、尤文氏肉瘤、膠質母細胞瘤、髓母細胞瘤、神經母細胞瘤、骨肉瘤、橫紋肌肉瘤、橫紋肌樣癌和腎母細胞瘤(威爾姆氏瘤)。
在一些實施方式中,自身免疫疾病是炎症性腸病、愛迪生氏病、斑禿、僵直性脊柱炎、抗磷脂質症候群、溶血性貧血、自身免疫性肝炎、貝西氏症、柏格氏病、大疱性類天疱瘡、心肌病、乳糜瀉、慢性疲勞免疫功能障礙症候群(CFIDS)、慢性脫髓鞘多發性神經炎、Churg-Strauss症候群、瘢痕性類天疱瘡、冷凝集素病、第1型糖尿病、盤狀狼瘡、原發性混合性冷凝球蛋白血症、葛瑞夫茲氏病、格林-巴利症候群、橋本氏甲狀腺炎、甲狀腺功能減退症、自體免疫淋巴增生症候群(ALPS)、特發性肺纖維化、自發性血小板缺乏紫斑症(ITP)、幼年關節炎、扁平苔蘚、紅斑性狼瘡、梅尼爾氏症、混合性結締組織疾病、多發性硬化症、重症肌無力、尋常型天疱瘡、惡性貧血、多發性軟骨炎、自體免疫多腺症候群、風濕性多肌痛、多發性肌炎、皮肌炎、原發性無γ球蛋白血症、原發性膽汁性肝硬化、乾癬、乾癬性關節炎、雷諾氏現象、Reiter氏症候群、風濕熱、類風濕關節炎、類肉瘤病、硬皮病、修格蘭氏症候群、僵硬人症候群、高安氏動脈炎、巨大細胞動脈炎、潰瘍性結腸炎、葡萄膜炎、血管炎或血管炎肉芽腫。
在另一種實施方式中,提供了式(I)化合物或其藥學上可接受的鹽的用途,以製備藥物用於抑制需要抑制HPK1活性的受試者的HPK1活性。在一些實施方式中,該用途包含治療癌症或自體免疫疾病。
根據本發明的適合受治療的受試者包含哺乳動物受試者。根據本發明的哺乳動物包含但不限於人、犬、猫、牛、山羊、馬、綿羊、猪、嚙齒動物、兔類、靈長類等,並且包含子宮內的哺乳動物。受試者可以是任何性別,也可以處於任何發育階段。在一種實施方式中,根據本發明的適合受治療的受試者是人。
本發明的化合物通常以治療有效劑量施用。本發明的化合物可以透過任何合適的途徑,以適於這種途徑的藥物組成物的形式,並且以對預期治療有效的劑量施用。有效劑量通常在約0.01至約1000mg/kg體重/天的範圍內,理想約0.01至約500mg/kg/天,以單次或分次劑量。根據年齡、物種和所治療的疾病或狀況,低於該範圍下限的劑量水平可能是合適的。在其他情况下,可以使用更大的劑量而無有害的副作用。較大的劑量也可以分成幾個較小的劑量,用於全天給藥。確定合適劑量的方法在本發明所屬技術領域中是眾所周知的。例如可使用,Remington: The Science and Practice of Pharmacy, Mack Publishing Co., 20th ed., 2000。
藥物組成物、劑型和施用途徑
為了治療上述提及的疾病或狀況,本文所述的化合物或其藥學上可接受的鹽可以如下施用:
口服給藥
本發明的化合物可以口服給藥,包含透過吞咽,使得化合物進入胃腸道,或直接從口腔吸收到血流中(例如,口頰或舌下給藥)。適合口服給藥的組成物包含固體、液體、凝膠或粉末製劑,並具有諸如片劑、口含錠、膠囊、顆粒劑或粉末的劑型。用於口服給藥的組成物可配製成立即釋放或控制釋放,包含延遲釋放或緩釋,且可選地帶有腸溶衣。液體製劑可包含溶液、糖漿和懸浮液,可用於軟膠囊或硬膠囊。這種製劑可包含藥學上可接受的載體,例如水、乙醇、聚乙二醇、纖維素或油。製劑還可包含一種或多種乳化劑及/或懸浮劑。
在片劑劑型中,按劑型重量計,存在的藥物量可為重量的約0.05%至約95%,更通常為約2%至約50%。另外,片劑可含有崩散劑,按劑型重量計,含有約0.5%至約35%,更通常為劑型的約2%至約25%。崩散劑的實例包含但不限於乳糖、澱粉、甘醇酸澱粉鈉、交聯聚維酮、交聯羧甲基纖維素鈉、麥芽糊精或其混合物。
用於片劑的合適潤滑劑,按重量計,可為約0.1%至約5%,並且包含但不限於滑石、二氧化矽、硬脂酸、硬脂酸鈣、硬脂酸鋅或硬脂酸鎂、硬脂富馬酸鈉等。
用於片劑的合適黏合劑包含但不限於明膠、聚乙二醇、糖、樹膠、澱粉、聚乙烯吡咯烷酮、羥丙基纖維素、羥丙基甲基纖維素等。用於片劑的合適稀釋劑包含但不限於甘露醇、木糖醇、乳糖、右旋糖、蔗糖、山梨醇、微晶纖維素和澱粉。
用於片劑的合適增溶劑,按重量計,可為約0.1%至約3%,並且包含但不限於聚山梨醇酯、月桂基硫酸鈉、十二烷基硫酸鈉、碳酸丙烯酯、二甘醇單乙醚、異山梨醇二甲醚、聚乙二醇(天然或氫化)蓖麻油、HCOR
TM(Nikkol)、油基酯、Gelucire
TM、辛酸/辛酸單/雙甘油酯、山梨醇酐脂肪酸酯和Solutol HS
TM。
腸胃
外給藥
本發明的化合物可直接施用到血流、肌肉或內臟中。腸胃外給藥的合適方式包含靜脈內、肌肉內、皮下動脈內、腹膜內、鞘內、顱內等。腸胃外給藥的合適裝置包含注射器(包含針式和無針式注射器)和輸注方法。
用於腸胃外給藥的組成物可配製成立即釋放或控制釋放,包含延遲釋放或緩釋。大多數腸胃外製劑是含有賦形劑的水溶液,包含鹽、緩衝劑和等滲劑。腸胃外製劑也可以以脫水形式(例如,透過凍乾)或作為無菌非水溶液製備。這些製劑可以與合適的載體一起使用,例如無菌水。溶解度增強劑也可用於製備腸胃外溶液。
經皮給藥
本發明的化合物可局部給藥至皮膚或經皮給藥。用於這種局部給藥的製劑可包含乳液、溶液、乳膏、凝膠、水凝膠、軟膏、泡沫、植入物、貼片等。用於局部給藥製劑的藥學上可接受的載體可包含水、醇、礦物油、甘油、聚乙二醇等。局部或經皮給藥也可透過電穿孔、離子電滲療法、聲滲療法等進行。用於局部給藥的組成物可配製成立即釋放或控制釋放,包含延遲釋放或緩釋。
聯合療法
根據本發明的藥物組成物可含有一種或多種附加治療劑,例如,以增加療效或減少副作用。因此,在一些實施方式中,藥物組成物進一步含有一種或多種附加治療劑,附加治療劑選自用於治療或抑制由HPK1直接或間接介導的疾病的活性成分。這種活性成分的實例包含但不限於治療癌症、轉移、炎症或自身免疫發病機制的藥劑。在一些實施方式中,式(I)化合物與抗PD-1劑、抗PD-L1劑或抗CTLA4劑一起施用。
製備藥物組成物的參考文獻
製備用於治療或預防疾病或病症的藥物組成物的方法是本發明所屬技術領域中眾所周知的。例如,根據
Handbook of Pharmaceutical Excipients(7
thed.)、
Remington: The Science and Practice of Pharmacy(20
thed.)、
Encyclopedia of Pharmaceutical Technology(3
rded.)或
Sustained and Controlled Release Drug Delivery Systems(1978),可選擇藥學上可接受的賦形劑、載體、添加劑等,接著與本發明的化合物混合用於製成藥物組成物。
本發明提供透過抑制HPK1活性而具有多種藥理作用的化合物、具有該化合物作為有效藥劑的藥物組成物、該化合物的醫療用途,特別是用於治療由HPK1調節的疾病或病症,以及治療或預防方法,包含向需要這種治療或預防的受試者施用該化合物。本發明的化合物及其藥學上可接受的鹽具有良好的安全性和對HPK1的高選擇性,因此表現出其作為藥物的優異性質。
化合物製備
下述製備實施例說明可用於製備式(I)化合物的中間化合物的製備。本文所述的新型中間化合物以及用於製備中間化合物的合成方法代表了本發明的實施方式。
步驟1)3-溴-4-氯-5-氟-2-甲基苯胺
向3-溴-5-氟-2-甲基苯胺(50g,245mmol,1eq)的AcOH(100mL)溶液中加入N-氯琥珀醯亞胺(36g,270mmol,1.1eq)。將混合物在25℃下攪拌16小時。在真空下濃縮混合物並用二氯甲烷(200mL*2)萃取殘餘物。將合併的有機層用飽和NaHCO
3200 mL洗滌,經Na
2SO
4乾燥,過濾並在減壓下濃縮以得到殘餘物。獲得呈黑色油狀的粗產物(66g,粗品)。
步驟2)4-溴-5-氯-6-氟-1H-吲唑
向3-溴-4-氯-5-氟-2-甲基苯胺(25.8g,108mmol,1eq)的AcOH(1.96L,0.05M)、H
2O(0.065L,1.5M)溶液中加入亞硝酸鈉(8.96g,130mmol,1.2eq)。將混合物在25℃下攪拌16小時。在真空下濃縮混合物並用二氯甲烷(1L*2)萃取殘餘物。將合併的有機層用飽和NaHCO
3(1L)洗滌,經Na
2SO
4乾燥,過濾並在減壓下濃縮以得到殘餘物。獲得呈棕色固體的粗產物(23.6g,粗品)。
步驟3)4-溴-5-氯-6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑
向4-溴-5-氯-6-氟-1H-吲唑(1.98g,7.97mmol,1eq)的THP(40mL)溶液中加入3,4-二氫-2H-哌喃(2.18ml,23.9mmol,3eq)和對甲苯磺酸單水合物(300mg,1.59mmol,0.2eq)。將反應混合物在70℃下攪拌14小時。用乙酸乙酯萃取反應混合物並經MgSO
4乾燥。有機殘餘物透過管柱層析法(矽膠,己烷:乙酸乙酯=1:0至4:1)純化。獲得4-溴-5-氯-6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑(1.51g,4.54mmol,57%產率)。
1H NMR (400MHz, DMSO-d
6) δ 8.16 (s, 1H), 8.00 (dd, J = 9.3, 1.1 Hz, 1H), 5.85 (dd, J = 9.6, 2.5 Hz, 1H), 3.87 (d, J = 12.6 Hz, 1H), 3.79-3.72 (m, 1H), 2.38-2.30 (m, 1H), 2.04-1.94 (m, 2H), 1.77-1.55 (m, 3H)。
步驟1)4-溴-5-氯-6-氟-7-碘-1H-吲唑
向4-溴-5-氯-6-氟-1H-吲唑(2g,8.02mmol)的硫酸(1.7mL)溶液中分批加入N-碘琥珀醯亞胺(2.7g,12.03mmol)。將混合物在0℃下攪拌3小時。反應完成後,將混合物倒入冰水中,並用固體NaOH驟冷,接著用二氯甲烷萃取。在真空下濃縮合併的有機殘餘物。(2.99g,粗品)。
1H NMR (400MHz, DMSO-d
6) δ 13.91 (s, 1H), 8.27 (d, J = 1.6 Hz, 1H)。
步驟2)4-溴-5-氯-6-氟-7-碘-2-(四氫-2H-哌喃-2-基)-2H-吲唑
向4-溴-5-氯-6-氟-7-碘-1H-吲唑(2.99g,7.97mmol,1eq)的THP(40mL)溶液中加入3,4-二氫-2H-哌喃(2.18ml,23.9mmol,3eq)和對甲苯磺酸單水合物(300mg,1.59mmol,0.2eq)。將反應混合物在60℃下攪拌16小時。用乙酸乙酯萃取反應混合物並經MgSO
4乾燥。將有機殘餘物透過管柱層析法(矽膠,己烷:乙酸乙酯=1:0至4:1)純化。獲得4-溴-5-氯-6-氟-7-碘-2-(四氫-2H-哌喃-2-基)-2H-吲唑(1.64g,7.97mmol,60.7%產率)。
1H NMR (400MHz, DMSO-d
6) δ 8.84 (s, 1H), 5.80 (dd, J = 9.9, 2.7 Hz, 1H), 5.66 (s, 1H), 4.02 (t, J = 6.6 Hz, 1H), 3.85-3.70 (m, 1H), 2.33-2.21 (m, 1H), 2.08-1.91 (m, 2H), 1.79-1.45 (m, 4H)。
步驟1)4-溴-5-氯-6-氟-7-硝基-1H-吲唑
向在0℃下攪拌的HNO
3(12.63g,200.43mmol,9.02mL,5eq)的H
2SO
4(50mL)混合物中緩慢加入4-溴-5-氯-6-氟-1H-吲唑(10g,40.09mmol,1eq)。加入後將混合物在0℃下攪拌2小時。TLC(石油醚:乙酸乙酯=3:1)顯示所有反應物都被消耗,並出現了一個主要的新點。將混合物倒入冰水中,用乙酸乙酯(50mL*3)萃取,合併的有機相經Na
2SO
4乾燥,過濾並濃縮濾液獲得呈黃色固體的4-溴-5-氯-6-氟-7-硝基-1H-吲唑(12g,粗品)。
步驟2)4-溴-5-氯-6-氟-7-硝基-2-(四氫-2H-哌喃-2-基)-2H-吲唑
向4-溴-5-氯-6-氟-7-硝基-1H-吲唑(2.34g,7.97mmol,1eq)的THF(40mL)溶液中加入3,4-二氫-2H-哌喃(2.18ml,23.9mmol,3eq)和對甲苯磺酸單水合物(300mg,1.59mmol,0.2eq)。將反應混合物在60℃下攪拌14小時。用乙酸乙酯萃取反應混合物並經MgSO
4乾燥。有機殘餘物透過管柱層析法(矽膠,己烷:乙酸乙酯=1:0至4:1)純化。獲得4-溴-5-氯-6-氟-7-硝基-2-(四氫-2H-哌喃-2-基)-2H-吲唑(1.65g,4.35mmol,54.7%產率)。
步驟3)4-溴-5-氯-6-氟-2-(四氫-2H-哌喃-2-基)-2H-吲唑-7-胺
向4-溴-5-氯-6-氟-7-硝基-2-(四氫-2H-哌喃-2-基)-2H-吲唑(600mg,1.58mmol,1eq)的EtOH(5mL)和H
2O(5mL)的溶液中加入NH
4Cl(508.66mg,9.51mmol,6eq)和Fe(531.04mg,9.51mmol,6eq),接著將反應混合物在80℃下攪拌1小時。過濾反應混合物,用乙酸乙酯(20mL)稀釋濾液,用水(20mL*2)洗滌混合物,接著有機層經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。透過prep-TLC(SiO
2,石油醚/乙酸乙酯=1:1)純化殘餘物。獲得呈黃色油狀的4-溴-5-氯-6-氟-2-(四氫-2H-哌喃-2-基)-2H-吲唑-7-胺(390mg,1.12mmol,70.59%產率)。
1H NMR (400MHz, DMSO-d
6) δ 8.41 (s, 1H), 5.85 (br s, 2H), 5.71 (br d, J=8.0 Hz, 1H), 4.00 (br d, J=11.3 Hz, 1H), 3.77 - 3.59 (m, 1H), 2.29 - 2.17 (m, 1H), 2.10 - 1.91 (m, 2H), 1.78 - 1.54 (m, 3H)。
步驟1)4-溴-5-氯-6-氟-7-硝基-1H-吲唑
在-15℃下向中間物1A(900mg,3.61mmol,1eq)的H
2SO
4(10mL)(98%純度)溶液中逐滴加入HNO
3(419.69mg,4.33mmol,299.78uL,1.2eq)(65%純度),接著將反應混合物在0℃下攪拌2小時。將反應混合物緩慢倒入冰水(20mL)中,接著用飽和NaOH水溶液將混合物的pH值調節至pH=7,接著用乙酸乙酯(30mL*2)萃取混合物,合併的有機層經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。獲得呈黃色固體的4-溴-5-氯-6-氟-7-硝基-1H-吲唑(900mg,粗品)。
1H NMR (400MHz, DMSO-d
6) δ 14.36 (br s, 1H), 8.37 (br s, 1H)。
步驟2)4-溴-5-氯-6-氟-7-硝基-1-(四氫-2H-哌喃-2-基)-1H-吲唑
向4-溴-5-氯-6-氟-7-硝基-1H-吲唑(900mg,3.06mmol,1eq)(粗品)的DCM(10mL)溶液中加入TsOH.H
2O(58.14mg,305.64umol,0.1eq)和DHP(771.27mg,9.17mmol,838.34uL,3eq),接著將反應混合物在20℃下攪拌2小時。用二氯甲烷(20mL)稀釋反應混合物,並用NaHCO
3(15mL*2)的飽和水溶液洗滌混合物,有機層經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。殘餘物透過管柱層析法純化(SiO
2,石油醚/乙酸乙酯=40/1至25:1,4-溴-5-氯-6-氟-7-硝基-1-(四氫-2H-哌喃-2-基)-1H-吲唑在石油醚/乙酸乙酯=40/1時出現,4-溴-5-氯-6-氟-7-硝基-2-(四氫-2H-哌喃-2-基)-2H-吲唑在石油醚/乙酸乙酯=25/1時出現)。獲得呈棕色固體的4-溴-5-氯-6-氟-7-硝基-1-(四氫-2H-哌喃-2-基)-1H-吲唑(200mg,528.29umol,17.28%產率)。獲得呈黃色固體的4-溴-5-氯-6-氟-7-硝基-2-(四氫-2H-哌喃-2-基)-2H-吲唑(600mg,1.58mmol,51.85%產率)。
4-溴-5-氯-6-氟-7-硝基-1-(四氫-2H-哌喃-2-基)-1H-吲唑
1H NMR (400MHz, DMSO-d
6) δ 8.43 (s, 1H), 5.50 (dd, J=2.8, 7.8 Hz, 1H), 3.45 - 3.38 (m, 2H), 2.35 - 2.27 (m, 1H), 2.23 - 2.14 (m, 1H), 1.92 (td, J=4.6, 13.6 Hz, 1H), 1.68 (ddt, J=4.0, 10.1, 13.9 Hz, 1H), 1.59 - 1.36 (m, 2H)。
4-溴-5-氯-6-氟-7-硝基-2-(四氫-2H-哌喃-2-基)-2H-吲唑
1H NMR (400MHz, DMSO-d
6) δ 8.99 (s, 1H), 5.86 (dd, J=2.7, 9.7 Hz, 1H), 4.08 - 3.96 (m, 1H), 3.81 - 3.68 (m, 1H), 2.28 - 2.14 (m, 1H), 2.14 - 2.02 (m, 1H), 2.02 - 1.89 (m, 1H), 1.78 - 1.67 (m, 1H), 1.64 - 1.56 (m, 2H)。
步驟3)4-溴-5-氯-6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑-7-胺
向4-溴-5-氯-6-氟-7-硝基-1-(四氫-2H-哌喃-2-基)-1H-吲唑(200mg,528.29umol,1eq)的EtOH(5mL)和H
2O(5mL)的溶液中加入NH
4Cl(169.55mg,3.17mmol,6eq)和Fe(177.03mg,3.17mmol,6eq),接著將反應混合物在80℃下攪拌2小時。過濾反應混合物,並將濾液濃縮以除去EtOH,接著用乙酸乙酯(20mL)稀釋混合物,用水(20mL*2)洗滌混合物,接著有機層經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。獲得呈黃色固體的4-溴-5-氯-6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑-7-胺(140mg,粗品)。
步驟4)4-溴-5-氯-6-氟-N,N-二甲基-1-(四氫-2H-哌喃-2-基)-1H-吲唑-7-胺
於N
2中在0℃下向4-溴-5-氯-6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑-7-胺(120mg,344.24umol,1eq)的THF(5mL)溶液中分批加入NaH(34.42mg,860.59umol,60%純度,2.5eq),接著將混合物於N
2中在0℃下攪拌30分鐘,接著逐滴加入MeI(293.16mg,2.06mmol,128.58uL,6eq),並將反應混合物在20℃下於N
2中攪拌12小時。將反應混合物倒入NH
4Cl的飽和水溶液(20mL)中,接著用乙酸乙酯(20mL*2)萃取混合物,合併的有機層經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。透過prep-TLC(SiO
2,石油醚/乙酸乙酯=5:1)純化殘餘物。獲得呈黃色油狀的中間物1E(30mg,78.06umol,22.68%產率,98%純度)。
向中間物1B(100mg,0.218mmol,1eq)的2-甲基-2-丁醇(1.09mL)溶液中加入Xantphos Pd G3(21mg,21.8μmol,0.1eq)和Cs
2CO
3(142mg,0.436mmol,2.0eq)。將混合物脫氣並用N
2氣沖3次,接著加入丙-2-胺(0.19mL,2.18mmol,10eq)。將混合物在密封管中於90℃下攪拌3小時。用H
2O(40mL)稀釋反應混合物,接著用DCM(50mL*3)萃取混合物。合併的有機層經Na
2SO
4乾燥,過濾並在真空下濃縮濾液以得到殘餘物。透過矽膠層析法純化殘餘物(產物在己烷/乙酸乙酯=10/1時出現)以提供呈米色固體的中間物1E(47mg,0.120mmol,55%產率)。
1H NMR (400 MHz, DMSO-d
6) δ 8.43 (s, 1H), 5.74 (dd, J = 9.6, 2.5 Hz, 1H), 5.29 (dd, J = 9.9, 3.3 Hz, 1H), 4.63-4.57 (m, 1H), 3.99 (d, J = 11.0 Hz, 1H), 3.74-3.68 (m, 1H), 2.23-2.17 (m, 1H), 2.05-1.95 (m, 2H), 1.74-1.57 (m, 3H), 1.23-1.18 (m, 6H)。
向中間物1E(600mg,1.54mmol,1.0eq)的甲醇(7.7mL)溶液中加入甲醛(0.572mL,7.68mmol,5.0eq)和乙酸(88μL,1.54mmol,1.0eq)。混合物在室溫下攪拌10分鐘。加入氰基硼氫化鈉(290mg,4.61mmol,3.0eq),接著將混合物在室溫下攪拌16小時。用H
2O驟冷反應混合物並用乙酸乙酯(150mL*3)萃取。合併的有機層經Na
2SO
4乾燥,過濾並在真空下濃縮濾液以得到殘餘物。透過矽膠層析法純化殘餘物(產物在己烷/乙酸乙酯=100/4時出現)以提供呈棕色油狀的中間物1F(292mg,0.722mmol,47%產率)。
1H NMR (400 MHz, DMSO-d
6) δ 8.51 (s, 1H), 5.75 (dd, J = 9.3, 2.7 Hz, 1H), 4.14-4.05 (m, 1H), 4.00-3.93 (m, 1H), 3.78-3.67 (m, 1H), 2.92 (d, J = 4.4 Hz, 3H), 2.23-2.20 (m, 1H), 2.05-1.95 (m, 2H), 1.75-1.60 (m, 3H), 1.17 (d, J = 6.6 Hz, 6H)。
步驟1)4-溴-5-氯-6-氟-1H-吲唑-7-胺
向4-溴-5-氯-6-氟-7-硝基-1H-吲唑(12g,40.75mmol,1eq)的EtOH(100mL)和H
2O(40mL)的溶液中加入Fe(6.83g,122.26mmol,3eq)和NH
4Cl(6.54g,122.26mmol,3eq)。將反應混合物加熱至80℃並反應2小時。透過矽藻土濾餅過濾反應混合物,濃縮濾液以得到粗產物。透過管柱層析法(SiO
2,石油醚/乙酸乙酯=20/1至3/1)純化殘餘物。獲得呈黃色固體的4-溴-5-氯-6-氟-1H-吲唑-7-胺(5g,18.90mmol,46.39%產率)。
步驟2)N-(4-溴-5-氯-6-氟-1H-吲唑-7-基)乙醯胺
向4-溴-5-氯-6-氟-1H-吲唑-7-胺(3g,11.34mmol,1eq)的AcOH(30mL)溶液中加入Ac
2O(1.39g,13.61mmol,1.27mL,1.2eq),將反應混合物加熱至80℃並反應3小時。在真空下除去溶劑。殘餘物透過管柱層析法(SiO
2,石油醚/乙酸乙酯=50/1至4/1)純化以獲得呈黃色固體的N-(4-溴-5-氯-6-氟-1H-吲唑-7-基)乙醯胺(3g,9.79mmol,86.29%產率)。
步驟3)4-溴-5-氯-N-乙基-6-氟-1H-吲唑-7-胺
在0℃下於N
2中向LAH(520.00mg,13.70mmol,1.5eq)的THF(50mL)溶液中逐滴加入N-(4-溴-5-氯-6-氟-1H-吲唑-7-基)乙醯胺(2.8g,9.13mmol,1eq)的THF(100mL)溶液,加入後,使反應混合物升溫至25℃,並反應16小時。將混合物倒入水(500mL)中,用乙酸乙酯(100mL*2)萃取,合併的有機相經Na
2SO
4乾燥,過濾並濃縮濾液以得到粗品。殘餘物透過管柱層析法(SiO
2,石油醚/乙酸乙酯=50/1至2/1)純化以獲得呈黃色固體的4-溴-5-氯-N-乙基-6-氟-1H-吲唑-7-胺(1g,3.42mmol,37.42%產率)。
步驟4)4-溴-5-氯-N-乙基-6-氟-N-甲基-1H-吲唑-7-胺
向4-溴-5-氯-N-乙基-6-氟-1H-吲唑-7-胺(1.4g,4.79mmol,1eq)和 HCHO(718.48mg,23.93mmol,659.16uL,5eq)的MeOH(50mL)溶液中加入NaBH3CN(902.21mg,14.36mmol,3eq)和AcOH(287.38mg,4.79mmol,273.70uL,1eq)。將反應混合物在25℃下攪拌16小時。在真空下除去溶劑。殘餘物透過管柱層析法(SiO
2,石油醚/乙酸乙酯=50/1至5/1)純化以獲得呈白色固體的4-溴-5-氯-N-乙基-6-氟-N-甲基-1H-吲唑-7-胺(1.4g,4.57mmol,95.42%產率)。
在-78℃下向4-溴-5-氯-6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑(0.5g,1.50mmol,1eq)的THF(10mL)溶液中逐滴加入LDA(2M,1.87mL,2.5eq)。加入後,將混合物在該溫度下攪拌2.5小時,接著在-78℃下逐滴加入MeI(319.12mg,2.25mmol,139.97uL,1.5eq)。並將所得混合物在20℃下攪拌16小時。將混合物倒入飽和的NH
4Cl中並用EA 20mL萃取。濃縮有機層。透過管柱層析法(SiO
2,石油醚/乙酸乙酯=20/1至10/1)純化殘餘物。我們得到期望的產物,獲得呈白色固體的4-溴-5-氯-6-氟-7-甲基-1-(四氫-2H-哌喃-2-基)-1H-吲唑 (0.38g,1.09mmol,72.93%產率)。
步驟1)4-溴-6-氟-7-硝基-1H-吲唑
在0℃下向4-溴-6-氟-1H-吲唑(10g,46.51mmol,1eq)的H
2SO
4(80mL)(98%純度)溶液中分批加入KNO
3(4.70g,46.51mmol,1eq),接著在0℃下將混合物攪拌1小時。接著將反應混合物倒入冰水(200mL)中,並用乙酸乙酯(100mL*2)萃取混合物,合併的有機層用飽和NaHCO
3水溶液(100mL*2)和鹽水(100mL)洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。殘餘物經矽膠層析法純化(200-300篩孔矽膠,石油醚/乙酸乙酯=15/1至1/1,產物4-溴-6-氟-7-硝基-1H-吲唑在石油醚/乙酸乙酯=8/1時出現),以得到呈黃色固體的 4-溴-6-氟-7-硝基-1H-吲唑 (2.7g,10.38mmol,22.32%產率)和粗產物。透過MPLC(石油醚/乙酸乙酯)純化粗產物,以得到呈黃色固體的4-溴-6-氟-7-硝基-1H-吲唑(3.57g,13.73mmol,29.52%產率)。
步驟2)4-溴-6-氟-5-碘-7-硝基-1H-吲唑
在25℃下向4-溴-6-氟-7-硝基-1H-吲唑(2.7g,10.38mmol,1eq)的H
2SO
4(30mL)溶液中加入 NIS(7.01g,31.15mmol,3eq)。將反應混合物在50℃下攪拌16小時。用冰水(50mL)驟冷反應混合物。接著用乙酸乙酯(50mL*3)萃取混合物。合併的有機層用Na
2SO
3水溶液(20mL*2)、NaHCO
3水溶液(20mL*2)和鹽水(20mL)洗滌,經硫酸鈉乾燥,過濾並在真空下濃縮濾液以得到呈黃色固體的4-溴-6-氟-5-碘-7-硝基-1H-吲唑(3.4g,8.81mmol,84.85%產率)。
1H NMR (400 MHz, DMSO-d
6) δ 14.28 (br s, 1H), 8.30 (s, 1H)。
步驟3)4-溴-6-氟-5-碘-1H-吲唑-7-胺
向4-溴-6-氟-5-碘-7-硝基-1H-吲唑(3.4g,8.81mmol,1eq)的EtOH(50mL)和H
2O(25mL)溶液中加入NH
4Cl(2.83g,52.86mmol,6eq),接著在60℃下分批加入Fe(2.95g,52.86mmol,6eq)。將混合物在80℃下攪拌1小時。反應混合物趁熱透過矽藻土過濾。接著在真空下濃縮濾液以除去EtOH。用乙酸乙酯(50mL*2)萃取所得水相。合併的有機層用鹽水(50mL)洗滌,經硫酸鈉乾燥,過濾並在真空下濃縮濾液,以得到殘餘物。殘餘物經矽膠層析法純化(MPLC,石油醚/乙酸乙酯=5/1至2/1,產物在石油醚/乙酸乙酯=2/1時出現),以得到呈灰色固體的4-溴-6-氟-5-碘-1H-吲唑-7-胺(2.2g,6.18mmol,70.16%產率)。
1H NMR (400 MHz, DMSO-d
6) δ 13.09 (br s, 1H), 7.86 (d, J = 1.7 Hz, 1H), 5.62 (s, 2H)。
步驟4)4-溴-6-氟-5-碘-N,N-二甲基-1H-吲唑-7-胺
向4-溴-6-氟-5-碘-1H-吲唑-7-胺(2.2g,6.18mmol,1eq)的MeOH(50mL)溶液中加入 AcOH(1.11g,18.54mmol,1.06mL,3eq)、HCHO(5.02g,61.81mmol,4.60mL,10eq),接著在40℃下分批加入NaBH
3CN(3.88g,61.81mmol,10eq)。氣體釋放且溫度升高。懸浮液在25℃下攪拌16小時。將反應混合物倒入水(50mL)中,接著將混合物濃縮以除去MeOH,用乙酸乙酯(50mL*2)萃取混合物,並將合併的有機層用鹽水(50mL)洗滌,經硫酸鈉乾燥,過濾並減壓濃縮以得到殘餘物。殘餘物經矽膠層析法純化(200-300篩孔矽膠,石油醚/乙酸乙酯=15/1至8/1,產物在石油醚/乙酸乙酯=8/1時出現),以得到呈灰白色固體的4-溴-6-氟-5-碘-N,N-二甲基-1H-吲唑-7-胺(2.05g,5.34mmol,86.37%產率)。
步驟5) 4-溴-6-氟-N,N-二甲基-5-(甲硫基)-1H-吲唑-7-胺
向配備磁力攪拌棒的100mL瓶中依次加入4-溴-6-氟-5-碘-N,N-二甲基-1H-吲唑-7-胺 (1.2g,3.13mmol,1eq)、NaSMe(328.56mg,4.69mmol,1.5eq)、Xantphos(361.65mg,625.02umol,0.2eq)、K
2CO
3(1.30g,9.38mmol,3eq)、二噁烷(20mL)和Pd
2(dba)
3(286.17mg,312.51umol,0.1eq)。將瓶子抽真空並用氮氣回填。接著將混合物於氮氣環境中在90℃下攪拌16小時。殘餘物經矽膠層析法純化(200-300篩孔矽膠,石油醚/乙酸乙酯=20/1至8/1,產物在石油醚/乙酸乙酯=10/1時出現),以得到呈橙色固體的4-溴-6-氟-N,N-二甲基-5-(甲硫基)-1H-吲唑-7-胺(540mg,1.78mmol,56.81%產率)。
1H NMR (400 MHz, DMSO-d
6) δ 13.59 (br s, 1H), 8.00 (d, J = 1.6 Hz, 1H), 2.91 (d, J = 2.4 Hz, 6H), 2.39 (s, 3H)。
向4-溴-6-氟-5-碘-N,N-二甲基-1H-吲唑-7-胺(1.0g,2.61mmol,1eq)和2,2-二氟-2-(氟磺醯基)乙酸甲酯(1.00g,5.22mmol,664.45uL,2eq)的DMF(10mL) 溶液中加入CuI(994.63mg,5.22mmol,2eq)。將混合物於N
2環境中在100℃下攪拌6小時。過濾反應混合物,並用水50mL稀釋濾液及用乙酸乙酯(50mL*2)萃取。合併的有機層用鹽水(50mL*3)洗滌,經無水Na
2SO
4乾燥,過濾並減壓濃縮濾液以得到殘餘物。透過矽膠管柱層析法(石油醚:乙酸乙酯=1:0至10:1)純化殘餘物。獲得呈黃色固體的4-溴-6-氟-N,N-二甲基-5-(三氟甲基)-1H-吲唑-7-胺 (502mg,1.54mmol,58.91%產率)。
步驟1)4-溴-5-乙基-6-氟-2-三苯甲基-2H-吲唑
於N
2環境中在-78℃下向二異丙胺(132.75mg,1.31mmol,185.41uL,1.2eq)的THF(5mL)溶液中緩慢加入正丁基鋰(2.5M,481.04uL,1.1eq)0.5小時。接著將4-溴-6-氟-2-三苯甲基-2H-吲唑(500mg,1.09mmol,1eq)的THF(2mL)溶液逐滴加入到溶液中。將混合物在-78℃下攪拌0.5小時後,將EtI(204.62mg,1.31mmol,104.93uL,1.2eq)的THF(2mL)溶液加入混合物中,並將溶液加熱至15℃並在N
2環境下攪拌2小時。透過在15℃下加入3mL飽和NH
4Cl水溶液來驟冷反應混合物,用20mL的水稀釋並用乙酸乙酯(30mL*2)萃取。合併的有機層用鹽水(30mL*2)洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮濾液以得到殘餘物。獲得呈黃色固體的4-溴-5-乙基-6-氟-2-三苯甲基-2H-吲唑(500mg,粗品)。
步驟2)4-溴-5-乙基-6-氟-1H-吲唑
向4-溴-5-乙基-6-氟-2-三苯甲基-2H-吲唑(500mg,1.03mmol,1eq)的DCM(6mL)溶液中加入TFA(3.08g,27.01mmol,2.00mL,26.22eq)。將混合物在15℃下攪拌4小時。用飽和NaHCO
3水溶液將反應混合物的pH值調節至7,並將混合物用二氯甲烷(30mL*2)萃取。合併的有機層用鹽水(30mL*2)洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮濾液以得到殘餘物。殘餘物透過prep-HPLC(柱:Phenomenex luna C18 150*40mm*15um;流動相:[水(0.1%TFA)-ACN];B%:40%-70%,10分鐘)純化。將分液減壓濃縮以除去ACN,用飽和NaHCO
3水溶液將水溶液的pH值調節至7。用乙酸乙酯(10mL*2)萃取水溶液。合併的有機層用鹽水(10mL*2)洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮濾液以得到產物。獲得呈黃色固體的4-溴-5-乙基-6-氟-1H-吲唑(70mg,287.98umol,27.96%產率) 。
1H NMR (400MHz, DMSO-d
6) δ 13.39 (br s, 1H), 8.01 - 7.98 (m, 1H), 7.41 (d, J=9.9 Hz, 1H), 2.83 (dq, J=2.4, 7.5 Hz, 2H), 1.14 (t, J=7.5 Hz, 3H)。
步驟1)6-氟-5-硝基-1H-吲唑
在-15℃下向6-氟-1H-吲唑(4.4g,32.32mmol,1
eq)的H
2SO
4(30mL)溶液中逐滴加入HNO
3(2.44g,38.79mmol,1.75mL,1.2
eq),將反應混合物在0℃下攪拌2小時。將反應混合物緩慢倒入冰水(100mL)中,接著用乙酸乙酯(100mL*2)萃取混合物,合併的有機層經Na
2SO
4乾燥,過濾並減壓濃縮,獲得呈黃色固體的6-氟-5-硝基-1H-吲唑(5.4g,粗品)。
步驟2)6-氟-5-硝基-1-(四氫-2H-哌喃-2-基)-1H-吲唑
向6-氟-5-硝基-1H-吲唑(4.9g,27.05mmol,1
eq)(粗品)的DCM(50mL)混合物中加入DHP(6.83g,81.16mmol,7.42mL,3
eq)和TsOH.H
2O (514.60mg,2.71mmol,0.1
eq),並將反應混合物在15℃下攪拌1小時。將反應混合物倒入NaHCO
3的飽和溶液(100mL)中,接著用二氯甲烷(50mL*2)萃取混合物,合併的有機層經Na
2SO
4乾燥,過濾並減壓濃縮至得到殘餘物。殘餘物透過管柱層析法(SiO
2,石油醚/乙酸乙酯=20/1至15:1)純化,獲得呈黃色固體的6-氟-5-硝基-1-(四氫-2H-哌喃-2-基)-1H-吲唑(3g,11.31mmol,41.81%產率)。
1H NMR (400MHz, DMSO-d
6) δ 8.78 (d,
J=7.3 Hz, 1H), 8.41 (s, 1H), 7.97 (d,
J=12.1 Hz, 1H), 5.90 (dd,
J=2.1, 9.7 Hz, 1H), 3.94 - 3.85 (m, 1H), 3.82 - 3.72 (m, 1H), 2.43 - 2.28 (m, 1H), 2.10 - 1.93 (m, 2H), 1.82 - 1.34 (m, 3H)。
步驟3)6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑-5-胺
在N
2環境下,向6-氟-5-硝基-1-(四氫-2H-哌喃-2-基)-1H-吲唑(2.9g,10.93mmol,1eq)的MeOH(30mL)溶液中加入濕的Pd/C(300mg,10%純度)。將懸浮液脫氣並用H
2氣沖3次。將混合物於H
2(15 Psi)中在15℃下攪拌4小時。過濾反應混合物,並減壓濃縮濾液以得到殘餘物。透過管柱層析法(SiO
2,石油醚/乙酸乙酯=15/1至8:1)純化殘餘物。獲得呈磚紅色固體的6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑-5-胺 (1.5g,5.87mmol,53.65%產率,92%純度)。
1H NMR (400MHz, DMSO-d
6) δ 7.82 (s, 1H), 7.43 (d,
J=11.6 Hz, 1H), 6.98 (d,
J=8.6 Hz, 1H), 5.66 (dd,
J=2.3, 9.7 Hz, 1H), 4.91 (s, 2H), 3.85 (br d,
J=12.1 Hz, 1H), 3.77 - 3.62 (m, 1H), 2.42 - 2.27 (m, 1H), 2.07 - 1.96 (m, 1H), 1.95 - 1.86 (m, 1H), 1.76 - 1.63 (m, 1H), 1.59 - 1.51 (m, 2H); LCMS (電灑) m/z 236.1 (M+H)+。
步驟4)4-溴-6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑-5-胺
在0℃下向6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑-5-胺(1.45g,5.67mmol,1eq)的MeCN(10 mL)溶液中分批加入NBS(1.21g,6.80mmol,1.2eq)。並將混合物在0℃下攪拌2小時。濃縮反應混合物以得到殘餘物。接著將殘餘物溶解在乙酸乙酯(30mL)中,混合物用鹽水(15mL*2)洗滌,有機層經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。透過管柱層析法(SiO
2,石油醚/乙酸乙酯=20/1)純化殘餘物。獲得呈棕色固體的4-溴-6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑-5-胺(1.3g,4.14mmol,72.98%產率)。
1H NMR (400MHz, DMSO-d
6) δ 7.80 (s, 1H), 7.60 (d,
J=10.6 Hz, 1H), 5.71 (dd,
J=2.5, 9.6 Hz, 1H), 5.15 (s, 2H), 3.88 - 3.82 (m, 1H), 3.76 - 3.68 (m, 1H), 2.36 - 2.27 (m, 1H), 2.02 (br dd,
J=4.6, 8.5 Hz, 1H), 1.96 - 1.90 (m, 1H), 1.76 - 1.65 (m, 1H), 1.60 - 1.52 (m, 2H)
。
步驟1)4-溴-5-氯-6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑-7-甲醛
於N
2中,在-78℃下,向中間物1A(3g,8.99mmol,1eq)的THF(60mL)混合物中逐滴加入LDA(2M,17.99mL,4eq)。將混合物在-78℃下攪拌1小時。接著,在-78℃下逐滴加入HCO
2Et(3.17g,35.97mmol,3.52mL,4eq)的THF(8mL)溶液,接著將混合物在-78℃下攪拌2小時。在-78℃下,透過加入飽和NH
4Cl溶液(20mL)來驟冷反應混合物,接著用EA(30mL*3)萃取。合併的有機層用鹽水(30mL*2)洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。透過管柱層析法(SiO
2,石油醚/乙酸乙酯=30/1至20/1)純化殘餘物。獲得呈灰白色固體的4-溴-5-氯-6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑-7-甲醛(2.78g,7.69mmol,85.49%產率)。
1H NMR (400 MHz, DMSO-d
6) δ 10.40 (s, 1H), 8.35 (s, 1H), 6.09 (dd, J = 2.6, 8.9 Hz, 1H), 3.71 - 3.63 (m, 1H), 3.63 - 3.52 (m, 1H), 2.42 - 2.30 (m, 1H), 2.21 - 2.10 (m, 1H), 2.07 - 1.95 (m, 1H), 1.77 - 1.63 (m, 2H), 1.60 - 1.40 (m, 2H); LCMS (電灑) m/z 278.9 (M+H)+。
步驟2)1-(4-溴-5-氯-6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑-7-基)丁-3-烯-1-醇
於N
2中,在0℃下,向4-溴-5-氯-6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑-7-甲醛(2.2g,6.08mmol,1eq)的THF(60mL)混合物中逐滴加入烯丙基溴化鎂(1M,9.13mL,1.5eq)。在0℃下攪拌混合物2小時。在0℃下透過加入飽和NH
4Cl溶液(20mL)來驟冷反應混合物,接著用EA(30mL*3)萃取。合併的有機層用鹽水(30mL*2)洗滌,經無水Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。透過管柱層析法(SiO
2,石油醚/乙酸乙酯=10/1至5/1)純化殘餘物。獲得呈無色油狀的1-(4-溴-5-氯-6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑-7-基)丁-3-烯-1-醇(2g,4.95mmol,81.43%產率)。
1H NMR (400 MHz, DMSO-d
6) δ 8.25 - 8.21 (m, 1H), 8.20 - 8.18 (m, 1H), 6.61 (br d, J = 9.0 Hz, 1H), 6.23 (d, J = 4.0 Hz, 1H), 6.18 (br d, J = 8.3 Hz, 1H), 5.95 (d, J = 5.0 Hz, 1H), 5.90 - 5.75 (m, 2H), 5.36 (dt, J = 4.3, 7.5 Hz, 1H), 5.30 (td, J = 5.9, 7.9 Hz, 1H), 5.10 - 4.97 (m, 4H), 3.97 (br d, J = 11.5 Hz, 1H), 3.89 (br d, J = 11.3 Hz, 1H), 3.69 - 3.55 (m, 2H), 2.87 - 2.74 (m, 2H), 2.70 - 2.55 (m, 4H), 2.06 (br d, J = 10.8 Hz, 3H), 1.96 - 1.87 (m, 1H), 0.90 - 0.78 (m, 1H); LCMS (電灑) m/z 302.9 (M+H)+。
步驟3)4-溴-7-(3-溴環戊基)-5-氯-6-氟-1H-吲唑
於N
2中,在-20℃下,向1-(4-溴-5-氯-6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑-7-基)丁-3-烯-1-醇(2g,4.95mmol,1eq)的DCM(20mL)混合物中逐滴加入Br
2(1.19g,7.43mmol,383.11uL,1.5eq)的DCM(2mL)混合物。混合物在-10℃下攪拌3小時。透過加入Na
2SO
3溶液(30mL)驟冷混合物,接著用DCM(30mL)稀釋。有機層用Na
2SO
3溶液(30mL*2)洗滌,經無水Na
2SO
4乾燥,過濾並濃縮以獲得殘餘物。將殘餘物溶解在MeOH(15mL)中,接著加入K
2CO
3(2.05g,14.86mmol,3eq)並將所得混合物在20℃下攪拌16小時。加入水(20mL)驟冷反應,用EA(30mL*3)萃取,經Na
2SO
4乾燥,過濾並濃縮以獲得殘餘物。透過管柱層析法(SiO
2,石油醚/乙酸乙酯=10/1至3:1)純化殘餘物。透過反相HPLC(0.1% FA條件)純化粗產物。獲得呈白色固體的4-溴-7-(3-溴環戊基)-5-氯-6-氟-1H-吲唑 (300mg,752.91umol,15.20%產率)。
1H NMR (400 MHz, DMSO-d
6) δ 13.44 - 13.37 (m, 2H), 8.14 - 8.11 (m, 2H), 5.71 - 5.67 (m, 1H), 5.44 (dt, J = 1.2, 7.5 Hz, 1H), 4.97 (s, 1H), 4.83 - 4.76 (m, 2H), 4.47 (dd, J = 3.7, 10.1 Hz, 1H), 4.22 (dd, J = 5.5, 10.1 Hz, 1H), 4.15 (dd, J = 2.3, 10.6 Hz, 1H), 3.20 - 3.13 (m, 1H), 2.69 - 2.64 (m, 1H), 2.34 - 2.27 (m, 2H); LCMS (電灑) m/z 398.8 (M+H)+。
步驟4)3-(4-溴-5-氯-6-氟-1H-吲唑-7-基)乙酸環戊酯
於N
2中,在20℃下,向4-溴-7-(3-溴環戊基)-5-氯-6-氟-1H-吲唑(100mg,250.97μmol,1eq)的DMSO(2mL)混合物中加入一份KOAc(73.89mg,752.91μmol,3eq)。接著將混合物加熱至70℃並攪拌3小時。加入水(15mL)驟冷反應,接著用EA(20mL*3)萃取,合併的有機層用鹽水(20mL*2)洗滌,經Na
2SO
4乾燥,過濾並濃縮以得到殘餘物。3-(4-溴-5-氯-6-氟-1H-吲唑-7-基)乙酸環戊酯(100mg,粗品,棕色油狀)不經進一步純化直接用於下一步。
LCMS(電灑)m/z 378.8 (M+H)+。
步驟5)3-(4-溴-5-氯-6-氟-1H-吲唑-7-基)環戊烷-1-醇
於N
2中,在20℃下,向3-(4-溴-5-氯-6-氟-1H-吲唑-7-基)乙酸環戊酯(80mg,211.87umol,1eq)的MeOH(4mL)和H
2O(0.8mL)混合物中加入一份K
2CO
3(442.15mg,3.20mmol,15.1eq)。在20℃下攪拌混合物2小時。在20℃下透過加入水(15mL)來驟冷反應混合物,接著用乙酸乙酯(20mL*3)萃取。合併的有機層用鹽水(20mL*1)洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。透過管柱層析法(SiO
2,石油醚/乙酸乙酯=3/1至1/2)純化殘餘物。獲得呈白色固體的3-(4-溴-5-氯-6-氟-1H-吲唑-7-基)環戊烷-1-醇(50mg,149.01umol,70.33%產率)。
LCMS(電灑)m/z 336.9 (M+H)+。
步驟1)5-氟-2-碘-4-(三氟甲基)苯胺
在15℃下向3-氟-4-(三氟甲基)苯胺(4g,22.33mmol,1eq)的MeCN(40mL)溶液中加入 NIS(5.53g,24.57mmol,1.1eq),接著將反應混合物在15℃下攪拌15小時。用H
2O (100mL)稀釋反應混合物,並用EtOAc(100mL*3)萃取。合併的有機層經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。獲得呈棕色油狀的5-氟-2-碘-4-(三氟甲基)苯胺(5.6g,粗品)。
LCMS(電灑)m/z 305.9 (M+H)+。
步驟2)5-氟-2-甲基-4-(三氟甲基)苯胺
在15℃下,向5-氟-2-碘-4-(三氟甲基)苯胺(6.0g,19.67mmol,1eq)和2,4,6-三甲基-1,3,5,2,4,6-三氧雜三硼雜環己烷(8.82g,29.51mmol,9.82mL,42%純度,1.5eq)的DME (60 mL)溶液中加入Pd(PPh
3)
4(1.14g,983.57umol,0.05eq)和K
2CO
3(8.16g,59.01mmol,3eq),接著將反應混合物在100℃下攪拌60小時。減壓濃縮反應混合物以提供殘餘物。透過管柱層析法(SiO
2,石油醚/乙酸乙酯=5/1至3/1,石油醚/乙酸乙酯=2:1,Rf=0.3)純化殘餘物。獲得呈黃色油狀的5-氟-2-甲基-4-(三氟甲基)苯胺(1.6g,4.06mmol,20.64%產率,49%純度)。
LCMS(電灑)m/z 194.1.9 (M+H)+。
步驟3)6-氟-5-(三氟甲基)-1H-吲唑
在0℃下向5-氟-2-甲基-4-(三氟甲基)苯胺(1g,5.18mmol,1eq)的AcOH(15mL)溶液中加入NaNO
2(357.25mg,5.18mmol,1eq)和H
2O(3mL),接著將反應混合物在15℃下攪拌2小時。透過在20℃下加入H
2O(60mL)驟冷反應,並用EtOAc(50mL*3)萃取所得混合物。合併的有機層用H
2O(50mL*3)洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。透過管柱(SiO2,石油醚/乙酸乙酯=10/1至5/1,石油醚/乙酸乙酯=3:1,Rf=0.5)純化殘餘物。獲得呈黃色固體的6-氟-5-(三氟甲基)-1H-吲唑(500mg,2.45mmol,47.31%產率)。
LCMS(電灑)m/z 205.2 (M+H)+。
步驟4)6-氟-7-硝基-5-(三氟甲基)-1H-吲唑
在0℃下向6-氟-5-(三氟甲基)-1H-吲唑(500mg,2.45mmol,1eq)的H
2SO
4(5mL,95%純度)溶液中加入KNO
3(249mg,2.46mmol,1.01eq),接著將反應混合物在15℃下攪拌15小時。用水(100mL)稀釋反應混合物並用乙酸乙酯(50mL*2)萃取。合併的有機層用飽和碳酸氫鈉溶液處理至pH=7,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。獲得呈黃色固體的6-氟-7-硝基-5-(三氟甲基)-1H-吲唑(500mg)。
LCMS(電灑)m/z 250.2 (M+H)+。
步驟5)6-氟-7-硝基-2-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-2H-吲唑
在0℃下,向6-氟-7-硝基-5-(三氟甲基)-1H-吲唑(500mg,2.01mmol,1eq)的THF(10mL)溶液中加入PPTS (50.44mg,200.71umol,0.1eq)和DHP(844.13mg,10.04mmol,917.53uL,5eq),接著在60℃下將反應混合物攪拌15小時。用溶劑H
2O(50mL)稀釋反應混合物,並用EtOAc(50mL*3)萃取。合併的有機層用H
2O(50mL*3)洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。獲得呈黃色油狀的6-氟-7-硝基-2-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-2H-吲唑(1g,粗品)。
步驟6)6-氟-2-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-2H-吲唑-7-胺
在0℃下,向6-氟-7-硝基-2-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-2H-吲唑(800mg,2.40mmol,1eq)和H
2O(2mL)的EtOH(10mL)溶液中加入NH
4Cl(642.08mg,12.00mmol,5eq)和Fe(268.13mg,4.80mmol,2eq),接著將反應混合物在60℃下攪拌1小時。用H
2O(20mL)稀釋反應混合物,並用EtOAc(20mL*3)萃取。合併的有機層用H
2O(30mL*2)洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。透過管柱層析法(SiO
2,石油醚/乙酸乙酯=10/1至5/1,石油醚:乙酸乙酯=3:1,Rf=0.3)純化殘餘物。獲得呈黃色固體的6-氟-2-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-2H-吲唑-7-胺(500mg,1.65mmol,68.68%產率)。
LCMS(電灑)m/z 220.2 (M+H)+。
步驟7)4-溴-6-氟-2-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-2H-吲唑-7-胺
在20℃下向6-氟-2-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-2H-吲唑-7-胺(200mg,659.51umol,1eq)的DMF(1mL)溶液中加入NBS(129.12mg,725.46umol,1.1eq),接著將反應混合物在20℃下攪拌2小時。用H
2O(10mL)稀釋反應混合物,並用EtOAc(10mL*3)萃取。合併的有機層用H
2O(10mL*2)洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。獲得呈黃色固體的4-溴-6-氟-2-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-2H-吲唑-7-胺(120mg,粗品)。
LCMS(電灑)m/z 297.9 (M+H)+。
步驟8) 4-溴-6-氟-N-異丙基-5-(三氟甲基)-1H-吲唑-7-胺
在20℃下向4-溴-6-氟-2-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-2H-吲唑-7-胺(100mg,335.53umol,1eq)的MeOH(1mL)溶液中加入AcOH(40.30mg,671.06umol,38.38uL,2eq)和丙酮(97.44mg,1.68mmol,123.34uL,5eq),接著加入NaBH
3CN(105.42mg,1.68mmol,5eq)並將反應混合物在20℃下攪拌2小時。接著,將丙酮(97.44mg,1.68mmol,123.34uL,5eq)、NaBH
3CN(105.43mg,1.68mmol,5eq)和AcOH(60.45mg,1.01mmol,57.57uL,3eq)加入到混合物中,並在20℃下攪拌反應混合物20小時。用H
2O(10mL)稀釋反應混合物,並用EtOAc(10mL*3)萃取。合併的有機層用H
2O(10mL*2)洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。透過prep-TLC(石油醚/乙酸乙酯=3:1,Rf=0.4)純化殘餘物。獲得呈白色固體的4-溴-6-氟-N-異丙基-5-(三氟甲基)-1H-吲唑-7-胺(60mg,165.83umol,49.42%產率,94%純度)。
LCMS(電灑)m/z 340.1 (M+H)+。
步驟9)4-溴-6-氟-N-異丙基-2-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-2H-吲唑-7-胺
在0℃下,向4-溴-6-氟-N-異丙基-5-(三氟甲基)-1H-吲唑-7-胺(50mg,147.01umol,1eq)的THF(1mL)溶液中加入PPTS(3.69mg,14.70umol,0.1eq)和DHP(61.83mg,735.05umol,67.21uL,5eq),接著在60℃下將反應混合物攪拌2小時。用H
2O(50mL)稀釋反應混合物,並用EtOAc(50mL*3)萃取。合併的有機層用H
2O(50mL*3)洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。透過prep-TLC(石油醚:乙酸乙酯=5:1,Rf=0.6)純化殘餘物。獲得呈黃色油狀的4-溴-6-氟-N-異丙基-2-(四氫-2H-哌喃-2-基)-5-(三氟甲基)-2H-吲唑-7-胺(50mg,117.86umol,80.17%產率)。
LCMS(電灑)m/z 424.1 (M+H)+。
步驟1)3-溴-5-氟-2-甲基苯胺
向1-溴-5-氟-2-甲基-3-硝基苯(23g,98.28mmol,1
eq)的EtOH(80mL)和H
2O(80mL)的混合物中加入Fe(27.44g,491.41mmol,5
eq)和NH
4Cl(26.29g,491.41mmol,5
eq)。將混合物在100℃下攪拌3小時。過濾混合物並減壓濃縮濾液以除去EtOH。所得混合物用DCM(50mL*3)萃取。合併的有機相用鹽水(50mL*2)洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物以得到呈黃色液體的3-溴-5-氟-2-甲基苯胺(20.6g,粗品)。
1H NMR (400MHz, DMSO-d
6) δ 6.59 (br d, J=8.4 Hz, 1H), 6.42 (br d, J=11.2 Hz, 1H), 5.51 (br s, 2H), 2.09 (s, 3H)。
步驟2)3-溴-5-氟-4-碘-2-甲基苯胺
在0℃下,向3-溴-5-氟-2-甲基苯胺(18g,88.22mmol,1eq)(粗品)的CH
3CN(150mL)混合物中分批加入NIS(19.85g,88.22mmol,1eq)。將混合物在30℃下攪拌3小時。3小時後,LCMS顯示出化合物2殘留,亦檢測到所需的質量。接著將混合物在30℃下再另外攪拌12小時。LCMS顯示沒有化合物2殘留並且檢測到所需質量的一個主峰。用飽和Na
2SO
3(200mL)驟冷混合物並用EtOAc(50mL*3)萃取所得混合物。合併的有機相用鹽水(50mL*2)洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。殘餘物透過矽膠層析法(1000篩孔矽膠,石油醚/乙酸乙酯=50/1、30/1;TLC(石油醚:乙酸乙酯=10:1;Rf=0.28))純化,以得到呈棕色固體的3-溴-5-氟-4-碘-2-甲基苯胺(22g,66.68mmol,75.58%產率)。
1H NMR (400MHz, DMSO-d
6) δ 6.55 (d, J=10.5 Hz, 1H), 5.67 (s, 2H), 2.25 (d, J=0.8 Hz, 3H)。
步驟3)4-溴-6-氟-5-碘-1H-吲唑
在0℃下,向3-溴-5-氟-4-碘-2-甲基苯胺(22g,66.68mmol,1eq)的CH
3COOH(200mL)混合物中加入溶解於水(40mL)的NaNO
2(5.52g,80.02mmol,1.2eq)。將混合物在30℃下攪拌16小時。將混合物倒入飽和NaHCO
3(1000mL)中並用EtOAc(200mL*3)萃取所得混合物。合併的有機相用鹽水(100mL*2)洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。殘餘物經矽膠層析法(1000篩孔矽膠,石油醚/乙酸乙酯=15/1、5/1)純化,以得到呈棕色固體的4-溴-6-氟-5-碘-1H-吲唑(7.5g,22.00mmol,32.99%產率)。
1H NMR (400MHz, DMSO-d
6) δ 13.58 (br s, 1H), 8.00 (s, 1H), 7.51 (d, J=8.1 Hz, 1H), 3.32 (s, 1H)。
步驟4)4-溴-6-氟-5-碘-1-(四氫-2H-哌喃-2-基)-1H-吲唑
向4-溴-6-氟-5-碘-1H-吲唑(7.5g,22.00mmol,1eq)和4-甲基苯磺酸水合物(418.47mg,2.20mmol,0.1eq)的DCM(100mL)混合物中緩慢加入DHP(5.55g,66.00mmol,6.03mL,3eq)。將混合物在30℃下攪拌1小時。混合物用飽和NaHCO
3(30mL*3)和鹽水(30mL*3)洗滌。有機相經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。殘餘物經矽膠層析法(1000篩孔矽膠,石油醚/乙酸乙酯=100/1、50/1)純化,以得到呈黃色固體的4-溴-6-氟-5-碘-1-(四氫-2H-哌喃-2-基)-1H-吲唑(7.4g,17.41mmol,79.14%產率)。
1H NMR (400MHz, DMSO-d
6) δ 8.06 (s, 1H), 7.80 (dd, J=0.7, 8.4 Hz, 1H), 5.83 (dd, J=2.4, 9.6 Hz, 1H), 3.88 - 3.85 (m, 1H), 3.80 - 3.70 (m, 2H), 2.40 - 2.27 (m, 1H), 2.07 - 1.94 (m, 2H), 1.81 - 1.63 (m, 2H), 1.62 - 1.53 (m, 2H)。
步驟5)4-溴-5-環丙基-6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑
於N
2中,向4-溴-6-氟-5-碘-1-(四氫-2H-哌喃-2-基)-1H-吲唑(1.5g,3.53mmol,1eq) 和環丙基硼酸(303.14mg,3.53mmol,1eq)的二噁烷(10 mL)和H
2O(2.5mL)的混合物中加入Na
2CO
3(748.10mg,7.06mmol,2eq)和Pd(dppf)Cl
2(258.23mg,352.91μmol,0.1eq)。將混合物在80℃下攪拌16小時。減壓濃縮混合物以得到殘餘物。殘餘物透過prep-TLC(石油醚:乙酸乙酯=20:1)純化以得到呈無色油狀的4-溴-5-環丙基-6-氟-1-(四氫-2H-哌喃-2-基)-1H-吲唑(0.21g,619.10umol,17.54%產率)。
1H NMR (400MHz, CDCl
3) δ 7.98 (d, J=0.6 Hz, 1H), 7.20 (d, J=10.4 Hz, 1H), 5.61 (dd, J=2.8, 9.1 Hz, 1H), 4.03 - 3.94 (m, 1H), 3.76-3.69 (m, 1H), 2.55 - 2.42 (m, 1H), 2.19 - 2.06 (m, 2H), 1.91-1.86 (m, 1H), 1.81 - 1.64 (m, 3H), 1.12 - 1.05 (m, 2H), 0.87 - 0.81 (m, 2H)。
步驟1)4-溴-6-氟-5-(丙-1-烯-2-基)-1-(四氫-2H-哌喃-2-基)-1H-吲唑
於N
2中,向4-溴-6-氟-5-碘-1-(四氫-2H-哌喃-2-基)-1H-吲唑(1.5g,3.53mmol,1
eq)和三氟(異丙烯基)硼氫化鉀(626.67mg,4.23mmol,1.2
eq)的二噁烷(10mL)和H
2O(2mL)的混合物中加入Pd(dppf)Cl
2(258.23mg,352.91umol,0.1
eq)和Na
2CO
3(748.10mg,7.06mmol,2
eq)。將混合物在80℃下攪拌16小時。減壓濃縮混合物以得到殘餘物。殘餘物透過矽膠層析法(1000篩孔矽膠,石油醚/乙酸乙酯=100/1、50/1;TLC(石油醚:乙酸乙酯=10:1;Rf=0.61))純化以得到0.9g的黃色的油。這種油透過prep-TLC(石油醚:乙酸乙酯=20:1)純化以得到呈黃色油狀的4-溴-6-氟-5-(丙-1-烯-2-基)-1-(四氫-2H-哌喃-2-基)-1H-吲唑(0.55g,1.62mmol,45.94%產率)。
1H NMR (400MHz, CDCl
3) δ 8.00 (d,
J=0.6 Hz, 1H), 7.28 (d,
J=0.9 Hz, 0.5H), 7.26 (d,
J=0.7 Hz, 0.5H), 5.64 (dd,
J=2.8, 9.0 Hz, 1H), 5.46 (t,
J=1.6 Hz, 1H), 5.01 (s, 1H), 4.05 - 3.97 (m, 1H), 3.80 - 3.69 (m, 1H), 2.57 - 2.42 (m, 1H), 2.19 - 2.09 (m, 2H), 2.07 (s, 3H), 1.81 - 1.66 (m, 4H)。
步驟2)4-溴-6-氟-5-異丙基-1-(四氫-2H-哌喃-2-基)-1H-吲唑
於N
2中,向4-溴-6-氟-5-(丙-1-烯-2-基)-1-(四氫-2H-哌喃-2-基)-1H-吲唑(0.4g,1.18mmol,1
eq)的MeOH(10mL)溶液中加入PtO
2。將懸浮液在真空下脫氣並用H
2氣沖數次。將混合物在H
2(15Psi)下在30℃下攪拌2.5小時。過濾混合物並減壓濃縮濾液以得到殘餘物。殘餘物透過矽膠層析法(300-400篩孔矽膠,石油醚/乙酸乙酯=50/1)純化以得到呈無色油狀的4-溴-6-氟-5-異丙基-1-(四氫-2H-哌喃-2-基)-1H-吲唑(0.3g,879.20umol,74.56%產率)。
步驟3)4-溴-6-氟-5-異丙基-1H-吲唑
向4-溴-6-氟-5-異丙基-1-(四氫-2H-哌喃-2-基)-1H-吲唑(0.3g,879.20umol,1eq) 的DCM(1mL)溶液中加入TFA(2.30g,20.14mmol,1.49mL,22.91eq)。將混合物在 30℃下攪拌0.5小時。減壓濃縮混合物以得到殘餘物。殘餘物用DCM(10mL)稀釋並用TEA將所得混合物調節pH至約8。減壓濃縮混合物以得到殘餘物。殘餘物經矽膠層析法(300-400篩孔矽膠,石油醚/乙酸乙酯=30/1、5/1)純化以得到呈無色油狀的4-溴-6-氟-5-異丙基-1H-吲唑(0.2g,777.90umol,88.48%產率)。
1H NMR (400MHz, CDCl
3) δ 8.04 (s, 1H), 7.11 (d, J=11.2 Hz, 1H), 3.75 - 3.63 (m, 1H), 1.38 (dd, J=1.7, 7.1 Hz, 6H)。
步驟1)2-溴-4-氟-3-甲氧基-1-甲基苯
向2-溴-6-氟-3-甲苯酚(4.8g,23.41mmol,1
eq)的丙酮(50mL)溶液中加入K
2CO
3(6.47g,46.82mmol,2
eq)和碘甲烷(9.97g,70.24mmol,4.37mL,3
eq),並將混合物在25℃下攪拌1小時。濃縮反應混合物以得到殘餘物。將殘餘物溶於乙酸乙酯(50mL)中,並過濾混合物,再濃縮濾液以得到呈黃色油狀的殘餘物(4.6g,21.00mmol,89.70%產率)。
1H NMR (400MHz, CHLOROFORM-d) δ 7.05 - 6.85 (m, 2H), 3.95 (d,
J=1.2 Hz, 3H), 2.38 (s, 3H)。
步驟2)3-溴-1-氟-2-甲氧基-4-甲基-5-硝基苯
在0℃下向2-溴-4-氟-3-甲氧基-1-甲基苯(4.4g,20.09mmol,1
eq)的H
2SO
4(40mL)(98%)溶液中分批加入KNO
3(2.23g,22.10mmol,1.1
eq),並將混合物在25℃下攪拌1小時。將反應混合物緩慢倒入冰水(200mL)中,接著用乙酸乙酯(200mL*2)萃取混合物,合併的有機層經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。獲得呈棕色油狀的3-溴-1-氟-2-甲氧基-4-甲基-5-硝基苯(4.6g,粗品)。
1H NMR (400MHz, CHLOROFORM-d) δ 7.70 (d,
J=10.9 Hz, 1H), 4.08 (d,
J=2.7 Hz, 3H), 2.61 (d,
J=1.1 Hz, 3H)。
步驟3)3-溴-5-氟-4-甲氧基-2-甲基苯胺
向3-溴-1-氟-2-甲氧基-4-甲基-5-硝基苯(4.6g,17.42mmol,1
eq)的EtOH(30mL)和H
2O(30mL)的溶液中加入Fe(5.84g,104.53mmol,6
eq)和NH
4Cl(5.59g,104.53mmol,6
eq),並將混合物在80℃下攪拌2小時。過濾反應混合物,並將濾液濃縮以除去EtOH,接著用EA(50mL)稀釋混合物,並用水(20mL*2)洗滌混合物,接著有機層經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。獲得呈棕色油狀的3-溴-5-氟-4-甲氧基-2-甲基苯胺(3.5g,粗品)。
1H NMR (400MHz, CHLOROFORM-d) δ 6.44 (d,
J=11.9 Hz, 1H), 3.83 (s, 3H), 3.76 - 3.48 (m, 2H), 2.24 (d,
J=1.0 Hz, 3H)。
步驟4)4-溴-6-氟-5-甲氧基-1H-吲唑
在0℃下向3-溴-5-氟-4-甲氧基-2-甲基苯胺(3.5g,14.95mmol,1
eq)(粗品)的AcOH (20mL)混合物中逐滴加入NaNO
2(1.24g,17.94mmol,1.2
eq)的H
2O(4mL)溶液,接著將混合物在25℃下攪拌12小時。將反應混合物用冰水(100mL)稀釋,並透過使用KOH將混合物調節至pH7,接著用EA(100mL*2)萃取混合物,合併的有機層用鹽水(50mL*2)洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。透過管柱層析法(SiO
2,石油醚/乙酸乙酯=20/1至15:1)純化殘餘物。獲得呈棕色固體的4-溴-6-氟-5-甲氧基-1H-吲唑(600mg,2.45mmol,16.37%產率)。
1H NMR (400MHz, DMSO-d
6) δ 13.44 (br s, 1H), 8.00 (s, 1H), 7.52 (br d,
J=10.4 Hz, 1H), 3.84 (s, 3H)。
式(I) 化合物的合成使用合成方法A至F製備下述化合物。下文描述了本發明的一些化合物的說明性合成實例,並且其他化合物可以透過與下文所述方法類似的方法用不同的起始或反應材料製備。
合成方法A
步驟1) 5-胺基-1-(3-甲氧基-3-側氧丙-1-烯-1-基)-1H-吡唑-3-羧酸甲酯
向
化合物 1(9.1g,64.48mmol,1eq)的EtOH(700mL)溶液中加入丙炔酸甲酯(27.11g,322.40mmol,26.84mL,5eq)。將混合物在90℃下攪拌16小時。減壓濃縮反應混合物直至所有固體沉澱出來,過濾並減壓濃縮以得到粗產物。獲得呈黃色固體的
化合物 2(7.8g,粗品)。
1H NMR (400 MHz, DMSO-
d 6)
δ8.09 (d, J = 14.8 Hz, 1H), 7.05 (s, 1H), 6.68 (br s, 2H), 6.63 (d, J = 14.8 Hz, 1H), 3.88 (s, 3H), 3.76 (s, 3H)。
步驟2) 5-側氧-4,5-二氫吡唑並[1,5-a]嘧啶-2-羧酸乙酯
向
化合物 2(3.9g,17.32mmol,1eq)的EtOH(15mL)中加入EtONa(1.77g,25.98mmol,1.5eq)。 將混合物在90℃下攪拌16小時。減壓濃縮反應混合物以得到殘餘物。用200mL的水稀釋殘餘物並用乙酸乙酯(200mL*2)萃取。過濾水層,並將所得濾餅減壓濃縮,以得到呈黃色固體的
化合物 3(5.4g,粗品)。
1H NMR (400 MHz, DMSO-d
6)
δ12.62 (br s, 1H), 7.99 (d, J = 7.5 Hz, 1H), 6.58 (s, 1H), 5.82 (d, J = 7.5 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H)。
步驟3) 5-氯吡唑並[1,5-a]嘧啶-2-羧酸乙酯
在N
2環境下,向
化合物 3(1g,4.83mmol,1eq)的MeCN (5mL) 溶液中加入N,N-二甲基苯胺 (1.17g,9.65mmol,1.22mL,2eq)、氯化苄基(三乙基)銨(5.50g,24.13mmol,5eq)和POCl
3(7.40g,48.27mmol,4.49mL,10eq)。在N
2環境下,將反應混合物在100℃下攪拌16小時。減壓濃縮反應混合物。殘餘物用水(100mL)驟冷並用飽和碳酸氫鈉溶液處理至pH=7。接著用乙酸乙酯(100mL*2)萃取混合物。合併的有機層用100mL鹽水洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。殘餘物透過管柱層析法(矽膠,石油醚:乙酸乙酯=1:0至1:1)純化。獲得呈黃色固體的
化合物 4(900mg,3.99mmol,82.64%產率)。
1H NMR (400 MHz, DMSO-
d 6)
δ8.63 (d, J = 4.5 Hz, 1H), 7.61 (d, J = 4.5 Hz, 1H), 7.36 (s, 1H), 4.40 (d, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H)。
步驟4) 5-(5-甲基-1H-吲唑-4-基)吡唑並[1,5-a]嘧啶-2-羧酸乙酯
在N
2環境下,向化合物4(900mg,3.99mmol,1eq)、(5-甲基-1H-吲唑-4-基)硼酸(701.95mg,3.99mmol,1eq)和Na
2CO
3(845.55mg,7.98mmol,2eq)的二噁烷(5mL)和H
2O(1mL)的混合物中加入Pd(dppf)Cl
2(145.93mg,199.44umol,0.05eq)。在N
2環境下,將混合物在80℃下攪拌16小時。用100mL的水稀釋反應混合物並用乙酸乙酯(50mL*2)萃取。合併的有機層用50mL鹽水洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。殘餘物透過管柱層析法(矽膠,石油醚:乙酸乙酯=1:0至0:1)純化。獲得呈黃色固體的
化合物 5(450mg,1.40mmol,35.10%產率)。
1H NMR (400 MHz, DMSO-
d 6)
δ13.28 (s, 1H), 8.81 - 8.78 (m, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.66 (s, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 4.1 Hz, 1H), 7.31 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.14 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H)。
步驟5) 5-(5-甲基-1H-吲唑-4-基)吡唑並[1,5-a]嘧啶-2-羧酸
向
化合物 5(450mg,1.40mmol,1eq)的THF(5mL)和H
2O(5mL)溶液中加入LiOH•H
2O (117.53mg,2.80mmol,2eq)。將混合物在45℃下攪拌2小時。用100mL的水稀釋反應混合物並用乙酸乙酯(100mL*2)萃取。合併的水層用HCl(1M)處理至pH4,攪拌直至所有固體沉澱出來,過濾並減壓濃縮以得到殘餘物。獲得呈黃色固體的
化合物 6(330mg,粗品)。
1H NMR (400 MHz, DMSO-
d 6)
δ13.51 - 13.06 (m, 1H), 8.77 (d, J = 4.2 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.66 (d, J = 0.9 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.31 (d, J = 4.2 Hz, 1H), 7.24 (s, 1H), 2.14 (s, 3H)。
步驟6) 5-(5-甲基-1H-吲唑-4-基)吡唑並[1,5-a]嘧啶-2-胺
在N
2環境下,向
化合物 6(230mg,784.23umol,1eq)的甲苯(2mL)溶液中加入TEA(87.29mg,862.66umol,120.07uL,1.1eq)和DPPA(237.40mg,862.66umol,186.93uL,1.1eq)。將混合物在110℃下攪拌16小時。在N
2環境下,將H
2O(1.00g,55.51mmol,1mL,70.78eq)加入到混合物中。在N
2環境下,將混合物在110℃下攪拌3小時。用50mL的水稀釋反應混合物並用乙酸乙酯(50mL*2)萃取。合併的有機層用50mL鹽水洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。殘餘物透過prep-TLC(石油醚:乙酸乙酯=0:1)純化。獲得呈黃色固體的
化合物 7(70mg,264.87umol,33.77%產率)。
1H NMR (400 MHz, DMSO-
d 6)
δ13.19 (s, 1H), 8.32 (d, J = 4.3 Hz, 1H), 7.63 - 7.59 (m, 2H), 7.35 (d, J = 8.6 Hz, 1H), 6.71 (d, J = 4.4 Hz, 1H), 5.79 (s, 1H), 5.71 - 5.63 (m, 2H), 2.15 (s, 3H)。
步驟 7) (1S,2S)-2-氟-N-(5-(5-甲基-1H-吲唑-4-基)吡唑並[1,5-a]嘧啶-2-基)環丙烷-1-甲醯胺
於N
2環境中,在0℃下,向化合物7(70mg,264.87umol,1eq)、(1S,2S)-2-氟環丙烷甲酸 (33.08mg,317.84umol,1.2eq)和3-甲基吡啶(123.33mg,1.32mmol,128.95uL,5eq)的MeCN(2mL)溶液中加入MsCl(45.51mg,397.30umol,30.75uL,1.5eq)。在N
2環境下,將混合物在25℃下攪拌16小時。將反應混合物逐滴加入到20mL水中並用乙酸乙酯(20mL*2)萃取。合併的有機層用鹽水20mL洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。殘餘物透過prep-TLC(石油醚:乙酸乙酯=0:1)純化。接著殘餘物透過prep-HPLC(管柱:Phenomenex luna C18 150*25mm*10um;流動相:[水(0.1%TFA)-ACN];B%:%-%,10分鐘)純化並凍乾。獲得呈黃色固體的
實施例 1(4.3mg,12.27umol,4.63%產率,100%純度)。
1H NMR (400 MHz, METHANOL-
d 4)
δ8.57 (d, J = 4.3 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.13 (s, 1H), 7.04 (d, J = 4.3 Hz, 1H), 4.75 - 4.61 (m, 1H), 2.26 (s, 3H), 1.98 - 1.90 (m, 1H), 1.83 - 1.72 (m, 1H), 1.19 - 1.11 (m, 1H)。
合成方法B
步驟 1) N-(6-氯嗒𠯤-3-基)-4-甲基苯磺醯胺
向
化合物 8(25g,192.98mmol,1eq)的吡啶(300mL)溶液中加入TsCl(40.47g,212.28mmol,1.1eq),接著將混合物在90℃下於N
2中攪拌6小時。將水(100mL)倒入混合物中,並用乙酸乙酯(50mL*3)萃取混合物,接著有機相用無水硫酸鈉(Na
2SO
4)乾燥,過濾並在真空下濃縮以獲得呈灰色固體的
化合物 9(56.5g,粗品)。
1H NMR (400 MHz, DMSO-
d 6)
δ8.67 - 8.59 (m, 1H), 7.82 - 7.77 (m, 2H), 7.61 - 7.54 (m, 1H), 7.52 - 7.46 (m, 1H), 7.38 (d, J = 8.3 Hz, 2H), 2.35 (s, 3H)。
步驟2)(E)-2-(3-氯-6-(甲苯磺醯亞胺基)嗒𠯤-1(6H)-基)乙醯胺
向
化合物 9(53g,186.79mmol,1eq)的DMF(300mL)溶液中加入DIPEA(26.56g,205.47mmol,35.79mL,1.1eq)和2-溴乙醯胺(28.35g,205.47mmol,1.1eq),接著將混合物在25℃下攪拌20小時。向混合物中加入水(1000mL)並過濾混合物,收集濾餅並真空濃縮以得到呈棕色固體的
化合物 10(40g,117.38mmol,62.84%產率)。
1H NMR (400 MHz, DMSO-
d 6)
δ8.00 (d, J = 9.8 Hz, 1H), 7.79 (d, J = 9.8 Hz, 1H), 7.70 (br d, J = 7.1 Hz, 3H), 7.38 (br s, 1H), 7.32 (br d, J = 7.8 Hz, 2H), 4.88 - 4.77 (m, 2H), 2.40 - 2.30 (m, 3H)。
步驟 3) N-(6-氯咪唑並[1,2-b]嗒𠯤-2-基)-2,2,2-三氟乙醯胺
向
化合物 10(35g,102.70mmol,1eq)的DCE(250mL)溶液中加入TFAA(258.85g,1.23mol,171.43mL,12eq),接著將混合物在60℃下攪拌3小時。 向混合物中加入水 (1000 mL),接著向混合物中加入足量的NaHCO
3以調節pH值為8,接著將混合物過濾並收集濾餅,接著用水(500 mL)和乙酸乙酯(500mL)萃取,接著有機相用Na
2SO
4乾燥並真空濃縮以獲得呈白色固體的
化合物 11(21g,79.37mmol,77.28%產率)。
1H NMR (400 MHz, DMSO-
d 6)
δ12.88 - 12.57 (m, 1H), 8.41 (s, 1H), 8.19 (d, J = 9.4 Hz, 1H), 7.43 (d, J = 9.4 Hz, 1H)。
步驟 4) 6-氯咪唑並[1,2-b]嗒𠯤-2-胺
向
化合物 11(21g,79.37mmol,1eq)的MeOH(200mL)和H
2O(200mL)的溶液中加入K
2CO
3(54.85g,396.84mmol,5eq),接著將混合物在75℃下攪拌3小時。 將水(100mL)倒入混合物中,並用乙酸乙酯(50mL*3)萃取混合物,接著有機相用Na
2SO
4乾燥,過濾並在真空下濃縮以獲得
化合物 60(13.5g,粗品)。
1H NMR (400 MHz, DMSO-
d 6) δ 7.68 (d, J = 9.2 Hz, 1H), 7.36 (s, 1H), 7.03 (d, J = 9.2 Hz, 1H), 5.65 (s, 2H)。
步驟 5) (1S,2S)-N-(6-氯咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺
向
化合物 12(2g,11.86mmol,1eq)、(1S,2S)-2-氟環丙烷甲酸(1.56g,14.24mmol,1.2eq)的DCM(50mL)溶液中加入EDCI(3.41g,17.80mmol,1.5eq),接著將混合物在25℃下攪拌16小時。真空濃縮混合物以得到殘餘物。 接著將水(100mL)倒入混合物中,並用乙酸乙酯(50mL*3)萃取混合物,接著有機相用Na
2SO
4乾燥,過濾並在真空下濃縮以得到呈白色固體的
化合物 13(3.8g,粗品)。
1H NMR (400 MHz, DMSO-
d 6) δ 11.37 - 11.22 (m, 1H), 8.32 - 8.23 (m, 1H), 8.07 (d, J = 9.4 Hz, 1H), 7.72 - 7.64 (m, 1H), 5.07 - 4.80 (m, 1H), 2.21 - 2.12 (m, 1H), 1.73 - 1.61 (m, 1H), 1.13 - 1.05 (m, 1H)。
步驟 6) (1S,2S)-2-氟-N-(6-(5-甲基-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)環丙烷-1-甲醯胺。 2 TFA
向
化合物 13(170mg,667.59umol,1eq)、Na
2CO
3(141.51mg,1.34mmol,2eq)的二噁烷(6mL)和H
2O(2mL)的溶液中加入(5-甲基-1H-吲唑-4-基)硼酸(117.48mg,667.59umol,1eq)和Pd(dppf)Cl
2(48.85mg,66.76umol,0.1eq),接著將混合物在90℃下於N
2中攪拌16小時。反應混合物透過prep-HPLC(管柱:Phenomenex luna C18 150*25mm*10um;流動相:[水(0.1%TFA)-ACN];B%: 19%-49%,10分鐘)純化以獲得呈淡黃色固體的
實施例 3(56.8mg,93.88umol,14.06%產率,95.6%純度,2TFA)。
1H NMR (400 MHz, DMSO-
d 6)
δ11.27 (s, 1H), 8.31 (s, 1H), 8.10 (d, J = 9.3 Hz, 1H), 7.84 (d, J = 0.9 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.9, 16.1 Hz, 2H), 5.08 - 4.82 (m, 1H), 2.38 (s, 3H), 2.23 - 2.14 (m, 1H), 1.77 - 1.62 (m, 1H), 1.23 - 1.12 (m, 1H)。
合成方法C
步驟 1) (1S,2S)-N-(6-溴咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷甲醯胺
向(1S,2S)-2-氟環丙烷甲酸(537.41mg,5.16mmol,1.1eq)和
化合物 14(1g,4.69mmol,1eq)的NMP(20mL)的溶液中加入T
3P(2.99g,9.39mmol,2.79mL,2eq)和DIPEA(1.42g,11.03mmol,1.92mL,2.35eq)。將反應混合物在25℃下攪拌16小時。加入水(15mL),並用EtOAc(10mL*2)萃取水相。合併的有機相用飽和鹽水(10mL*2)洗滌,並真空濃縮。粗產物透過反向急速層析法(MeCN/H
2O.0.05%TFA)純化,以得到呈淡黃色固體的
化合物 15(750mg,2.51mmol,53.42%產率)。
1H NMR (400 MHz, DMSO-
d 6)
δ11.39 (s, 1H), 8.93 (d, J = 1.2 Hz, 1H), 8.75 (s, 1H), 8.29 (s, 1H), 5.17 - 4.76 (m, 1H), 2.23 - 2.11 (m, 1H), 1.67 (tdd, J = 3.3, 6.9, 19.9 Hz, 1H), 1.25 - 1.13 (m, 1H)。
步驟2) (1S,2S)-2-氟-N-(6-(5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙甲醯胺。2 TFA
在N
2下,向(5-甲基-1H-吲唑-4-基)硼酸(58.84mg,334.34umol,1eq)的二噁烷/H
2O (3mL)的溶液中加入Pd(dppf)Cl
2(12.23mg,16.72umol,0.05eq)、
化合物 15(100mg,334.34umol,1eq)和Na
2CO
3(70.87mg,668.67umol,2eq)。將混合物在90℃下攪拌3小時。加入水(10mL)並用EtOAc(10mL*2)萃取水相。合併的有機相用飽和鹽水(10mL*2)洗滌並真空濃縮。粗產物透過prep-HPLC(管柱:Phenomenex luna C18 150*25mm*10um;流動相:[水(0.1%TFA)-ACN];B%:13%-43%,10分鐘)純化以得到呈淡黃色固體的
實施例 24(38.2mg,62.74umol,18.77%產率,95%純度,2TFA)。
1H NMR (400 MHz, DMSO-
d 6)
δ11.48 - 11.28 (m, 1H), 9.06 (s, 1H), 8.83 (d, J = 1.3 Hz, 1H), 8.36 (s, 1H), 7.91 (d, J = 0.9 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 5.15 - 4.79 (m, 1H), 2.43 - 2.35 (m, 3H), 2.26 - 2.14 (m, 1H), 1.78 - 1.62 (m, 1H), 1.37 - 1.06 (m, 1H)。
合成方法D
步驟1) (1S,2S)-2-氟-N-(6-(三丁基錫烷基)咪唑並[1,2-a]吡嗪-2-基)環丙烷甲醯胺。
在N
2下,向三丁基(三丁基錫烷基)錫烷(1.16g,2.01mmol,1.00mL,3eq)和
化合物 16(200mg,668.67umol,1eq)的二噁烷(3mL)的溶液中加入Pd(PPh
3)
4(38.63mg,33.43umol,0.05eq)和TBAI(246.99mg,668.67umol,1eq)。將反應混合物在110℃下攪拌32小時。過濾反應並濃縮濾液以得到產物。粗產物透過prep-TLC(石油醚:乙酸乙酯=1:1)純化以得到呈白色固體的
化合物 17(130mg,255.28umol,38.18%產率)。
步驟 2) (1S,2S)-N-(6-(5-乙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷甲醯胺。 2 TFA
在N
2下,向4-溴-5-乙基-6-氟-1H-吲唑(40mg,164.56umol,1eq)和
化合物 17(92.18mg,181.01umol,1.1eq)的EtOH(2mL)溶液中加入Ad
2n-BuP-Pd-G3 (11.98mg,16.46umol,0.1eq)。將反應混合物在90℃下攪拌16小時。真空濃縮反應混合物。粗產物透過prep-HPLC(管柱:Phenomenex Luna C18 150*25mm*10um;流動相:[水(0.1%TFA)-ACN];B%:24%-54%,10分鐘)純化以得到呈白色固體的
實施例 25(10mg,16.22umol,9.86%產率,99%純度,2TFA)。
1H NMR (400 MHz METHANOL-
d 4)
δ8.99 (s, 1H), 8.71 (s, 1H), 8.42 (s, 1H), 7.83 (s, 1H), 7.36 (d, J=10.4 Hz, 1H), 5.00 - 4.97 (m, 1H), 2.76 - 2.72 (m, 2H), 2.16 - 2.15 (m, 1H), 1.86 - 1.79 (m, 1H), 1.26 - 1.24 (m, 1H), 1.19 - 1.16 (m, 3H)。
合成方法E
向
化合物 17(456mg,0.896mmol,1.3eq)和
中間物 1E(269mg,0.689mmol)的EtOH (3.44mL)溶液中加入Ad
2nBuP-Pd-G3(50mg,0.0689mmol,0.1eq)。將混合物脫氣並用N
2氣沖3次,接著於N
2環境中在90℃下攪拌16小時。真空濃縮反應混合物。粗產物透過矽膠層析法純化(產物在乙酸乙酯時出現)以提供呈黃色固體的
實施例 61(86mg,0.162mmol,24%產率)。
合成方法F
步驟1)4-溴-5-氯-6-氟-7-(丙-1-烯-2-基)-2-(四氫-2H-哌喃-2-基)-2H-吲唑
在N
2環境下,向
中間物 1B(2g,4.35mmol,1eq)、4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧硼戊環(877.73mg,5.22mmol,1.2eq)的二噁烷(0.4mL)和H
2O(0.1mL)的溶液中加入Na
2CO
3(922.69mg,8.71mmol,2eq)和Pd(dppf)Cl
2(159.25mg,217.64μmol,0.05eq)。在N
2環境下,將混合物在80℃下攪拌16小時。用100mL的水稀釋反應混合物並用乙酸乙酯(100mL*2)萃取。合併的有機層用100mL鹽水洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。透過管柱層析法(矽膠,石油醚:乙酸乙酯=1:0至20:1)純化殘餘物。獲得呈黃色油狀的
化合物 18(870mg,2.33mmol,53.49%產率)。
步驟2)4-溴-5-氯-6-氟-7-異丙基-1H-吲唑
在N
2下,向
化合物 18(400mg,1.07mmol,1eq)的MeOH(0.5mL)溶液中加入PtO
2(40.00mg,176.15umol,1.65e-1eq)。將懸浮液在真空下脫氣並用H
2氣沖數次。將混合物於H
2(15psi)中在25℃下攪拌1小時。過濾反應混合物並減壓濃縮以得到殘餘物。透過管柱層析法(矽膠,石油醚:乙酸乙酯=1:0至4:1)純化殘餘物。
獲得呈黃色固體的
化合物 19(240mg,823.19umol,76.90%產率)。
1H NMR (400 MHz, DMSO-
d 6)
δ13.73 (br s, 1H), 8.09 (s, 1H), 3.59 - 3.49 (m, 1H), 1.39 (d, J = 6.9 Hz, 6H)。
步驟3)(1S,2S)-N-(6-(5-氯-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺
在N
2環境下,向
化合物 19(70mg,240.10umol,1eq)、
化合物 17(134.50mg,264.11umol,1.1eq)的EtOH(1mL)溶液中加入Ad
2nBuP-Pd-G3(17.49mg,24.01umol,0.1eq)。在N
2環境下,將混合物在80℃下攪拌12小時。加入5mL飽和KF水溶液以驟冷反應混合物。將混合物溶解於水(20mL)中並用乙酸乙酯(20mL*2)萃取。合併的有機層用20mL鹽水洗滌,經Na
2SO
4乾燥,過濾並減壓濃縮以得到殘餘物。殘餘物透過prep-HPLC(管柱:Unisil 3-100 C18 Ultra 150*50mm*3 um;流動相:[水(0.225%FA)-ACN];B%:40%-60%,10分鐘)純化並凍乾。獲得呈白色固體的
實施例 64(15mg,34.12umol,14.21%產率,98%純度)。
1H NMR (400 MHz, DMSO-
d 6)
δ13.52 (br s, 1H), 11.40 (s, 1H), 9.14 - 8.87 (m, 2H), 8.38 (s, 1H), 8.04 (br s, 1H), 5.17 - 4.75 (m, 1H), 3.66 - 3.59 (m, 1H), 2.19 (td, J = 7.0, 13.6 Hz, 1H), 1.75 - 1.62 (m, 1H), 1.45 (br d, J = 7.0 Hz, 6H), 1.20 (tdd, J = 6.3, 8.9, 12.3 Hz, 1H); LCMS (電灑) m/z 431.2 (M+H+)。
下表1顯示了實施例的化合物以及用於製備該化合物的一般合成方法和特徵數據。
表1. 實施例的化合物
Ex # | 結構/名稱 | 1H NMR / MS (M+1) | 方法 |
1 | (1S,2S)-2-氟-N-(5-(5-甲基-1H-吲唑-4-基)吡唑並[1,5-a]嘧啶-2-基)環丙烷-1-甲醯胺 | 1H NMR (400 MHz, METHANOL-d 4) δ 8.57 (d, J = 4.3 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.13 (s, 1H), 7.04 (d, J = 4.3 Hz, 1H), 4.75 - 4.61 (m, 1H), 2.26 (s, 3H), 1.98 - 1.90 (m, 1H), 1.83 - 1.72 (m, 1H), 1.19 - 1.11 (m, 1H); LCMS (電灑) m/z 351.2 (M+H)+。 | A |
2 | (1S,2S)-N-(5-(5-乙基-6,7-二氟-1H-吲唑-4-基)吡唑並[1,5-a]嘧啶-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, METHANOL-d 4) δ 8.89 (d, J=7.0 Hz, 1H), 7.93 (d, J=3.1 Hz, 1H), 7.10 (d, J=7.1 Hz, 1H), 7.05 (s, 1H), 4.96 (dt, J=3.8, 6.2 Hz, 1H), 4.80 (dt, J=3.8, 6.3 Hz, 1H), 2.88 - 2.80 (m, 2H), 2.15 - 2.07 (m, 1H), 2.03 (s, 1H), 1.88 - 1.76 (m, 1H), 1.28 - 1.19 (m, 4H); LCMS(電灑) m/z 401.2 (M +H+)。 | A |
3 | (1S,2S)-2-氟-N-(6-(5-甲基-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)環丙烷-1-甲醯胺。2 TFA | 1H NMR (400 MHz, DMSO-d 6) δ 11.27 (s, 1H), 8.31 (s, 1H), 8.10 (d, J = 9.3 Hz, 1H), 7.84 (d, J = 0.9 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.9, 16.1 Hz, 2H), 5.08 - 4.82 (m, 1H), 2.38 (s, 3H), 2.23 - 2.14 (m, 1H), 1.77 - 1.62 (m, 1H), 1.23 - 1.12 (m, 1H); LCMS (電灑) m/z 351.1 (M+H)+。 | B |
4 | (1S,2S)-N-(6-(5-乙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺。2 TFA | 1H NMR (400 MHz, DMSO-d 6) δ 11.31 (s, 1H), 8.32 (s, 1H), 8.13 (d, J=9.2 Hz, 1H), 7.82 (s, 1H), 7.50 (d, J = 10.4 Hz, 1H), 7.39 (d, J = 9.1 Hz, 1H), 5.24 - 4.78 (m, 1H), 2.67 - 2.62 (m, 2H), 2.25 - 2.14 (m, 1H), 1.77 - 1.60 (m, 1H), 1.25 - 1.18 (m, 1H), 1.14 (br t, J = 7.3 Hz, 3H); LCMS (電灑) m/z 383.1 (M+H)+。 | B |
5 | (1S,2S)-2-氟-N-(6-(6-氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 11.31 (s, 1H), 8.34 (s, 1H), 8.14 (d, J = 9.8 Hz, 1H), 7.88 (d, J = 0.9 Hz, 1H), 7.50 (d, J = 9.9 Hz, 1H), 7.42 (d, J = 9.3 Hz, 1H), 5.13 - 4.83 (m, 1H), 2.27 (d, J = 2.6 Hz, 3H), 2.23 - 2.16 (m, 1H), 1.78 - 1.61 (m, 1H), 1.28 - 1.12 (m, 1H); LCMS (電灑) m/z 369.1 (M+H)+。 | B |
6 | (1S,2S)-N-(6-(5-乙基-6,7-二氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.95 (br s, 1H), 11.32 (s, 1H), 8.32 (s, 1H), 8.14 (d, J=9.3 Hz, 1H), 7.95 (br s, 1H), 7.38 (d, J=9.2 Hz, 1H), 5.07 - 4.85 (m, 1H), 2.71 - 2.66 (m, 2H), 2.19 (quin, J=6.9 Hz, 1H), 1.75 - 1.62 (m, 1H), 1.25 - 1.19 (m, 1H), 1.16 (t, J=7.5 Hz, 3H); LCMS(電灑) m/z 401.1 (M +H+)。 | B |
7 | (1S,2S)-N-(6-(7-(二甲胺基)-5-乙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.27 (br s, 1H), 11.29 (s, 1H), 8.29 (s, 1H), 8.10 (d, J = 9.3 Hz, 1H), 7.79 (br t, J = 4.4 Hz, 1H), 7.35 (d, J = 9.3 Hz, 1H), 5.08 - 4.83 (m, 1H), 2.99 (br d, J = 1.5 Hz, 6H), 2.61 (br d, J = 5.7 Hz, 2H), 2.22 - 2.15 (m, 1H), 1.73 - 1.62 (m, 1H), 1.24 - 1.18 (m, 1H), 1.15 (t, J = 7.4 Hz, 3H)); LCMS(電灑) m/z 426.3 (M+H+)。 | B |
8 | (1S,2S)-N-(6-(6,7-二氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.90 (s, 1H), 11.30 (s, 1H), 8.33 (s, 1H), 8.13 (d, J=9.3 Hz, 1H), 8.03 (br s, 1H), 7.40 (d, J=9.2 Hz, 1H), 5.07 - 4.86 (m, 1H), 2.32 (d, J=2.9 Hz, 3H), 2.22 - 2.15 (m, 1H), 1.74 - 1.64 (m, 1H), 1.20 (br dd, J=9.2, 12.3 Hz, 1H)); LCMS(電灑) m/z 387.2 (M +H+)。 | B |
9 | (1S,2S)-2-氟-N-(6-(6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.46 (br s, 1H), 11.29 (s, 1H), 8.23 (s, 1H), 8.12 - 8.10 (m, 1H), 7.92 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 9.3 Hz, 1H), 5.05 - 4.84 (m, 1H), 2.31 (s, 3H), 2.19 (br s, 1H), 1.75 - 1.64 (m, 1H), 1.22 - 1.15 (m, 1H); LCMS(電灑) m/z 400.9 (M+H+)。 | B |
10 | (1S,2S)-N-(6-(5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺。1 TFA | 1H NMR (400 MHz, DMSO-d 6) δ 11.33 (s, 1H), 8.36 (s, 1H), 8.18 (d, J = 9.3 Hz, 1H), 8.03 (s, 1H), 7.79 (dd, J = 1.0, 9.2 Hz, 1H), 7.52 (d, J = 9.4 Hz, 1H), 5.09 - 4.84 (m, 1H), 2.24 - 2.15 (m, 1H), 1.74 - 1.63 (m, 1H), 1.25 - 1.17 (m, 1H)); LCMS(電灑) m/z 389.3 (M+H+)。 | B |
11 | (1S,2S)-N-(6-(5-胺基-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 11.43 - 11.12 (m, 1H), 8.39 - 8.34 (m, 1H), 8.04 (s, 1H), 7.87 (s, 1H), 7.56 (d, J = 9.4 Hz, 1H), 7.46 - 7.40 (m, 1H), 5.55 - 5.47 (m, 2H), 5.10 - 4.76 (m, 1H), 2.24 (br d, J = 8.9 Hz, 1H), 1.76 - 1.60 (m, 1H), 1.28 - 1.12 (m, 1H); LCMS(電灑) m/z 370.2(M +H+)。 | B |
12 | (1S,2S)-N-(6-(5-乙基-7-(乙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.24 (s, 1H), 11.30 (s, 1H), 8.30 (s, 1H), 8.11 (d, J=9.3 Hz, 1H), 7.78 (s, 1H), 7.37 (d, J=9.3 Hz, 1H), 5.11 - 4.82 (m, 1H), 3.24 (br d, J=6.8 Hz, 2H), 2.96 (d, J=2.0 Hz, 3H), 2.62 (br d, J=7.5 Hz, 2H), 2.23 - 2.13 (m, 1H), 1.72 - 1.57 (m, 1H), 1.23 (br s, 1H), 1.14 (t, J=7.4 Hz, 3H), 1.07 (t, J=7.0 Hz, 3H); LCMS(電灑) m/z 440.2 (M+H+)。 | B |
13 | (1S,2S)-N-(6-(7-乙氧基-5-乙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.58 (br s, 1 H) 11.31 (s, 1 H) 8.31 (s, 1 H) 8.11 (d, J=9.29 Hz, 1 H) 7.85 (s, 1 H) 7.37 (d, J=9.29 Hz, 1 H) 4.84 - 5.06 (m, 1 H) 4.31 - 4.41 (m, 2 H) 2.60 - 2.69 (m, 2 H) 2.18 (dt, J=13.83, 6.82 Hz, 1 H) 1.62 - 1.73 (m, 1 H) 1.40 (t, J=6.96 Hz, 3 H) 1.18 - 1.24 (m, 1 H) 1.15 (t, J=7.34 Hz, 3 H); LCMS(電灑) m/z 427.1 (M+H+)。 | B |
14 | (1S,2S)-N-(6-(5-氯-7-乙氧基-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺。 | 1H NMR (400 MHz, METHANOL-d 4) δ 8.44 - 8.39 (s, 1H), 8.03 - 7.93 (m, 2H), 7.55 - 7.45 (d, 1H), 4.80 - 4.57 (m, 1H), 4.50 - 4.42 (m, 2H), 4.51 - 4.41 (m, 2H), 2.17 - 2.07 (m, 1H), 1.83 - 1.71 (m, 1H), 1.51 - 1.44 (t, 3H), 1.23 - 1.15 (m, 1H); LCMS(電灑) m/z 433.2 (M+H+)。 | B |
15 | (1S,2S)-N-(6-(5-氯-7-(乙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 11.36 - 11.29 (s, 1H), 8.39 - 8.31 (s, 1H), 8.19 - 8.09 (d, 1H), 8.03 - 7.98 (s, 1H), 7.54 - 7.46 (d, 1H), 5.13 - 4.86 (dm, 1H), 3.06 - 2.98 (s, 3H), 2.24 - 2.16 (m, 1H), 1.77 - 1.62 (m, 1H), 1.23 - 1.16 (m, 1H), 1.13 - 1.08 (t, 3H); LCMS(電灑) m/z 433.2 (M+H+)。 | B |
16 | (1S,2S)-N-(6-(7-(二甲胺基)-6-氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.17 (s, 1H), 11.36 - 11.21 (m, 1H), 8.33 - 8.28 (m, 1H), 8.12 (s, 1H), 7.84 (s, 1H), 7.40 - 7.34 (m, 1H), 5.10 - 4.84 (m, 1H), 2.98 (d, J = 1.7 Hz, 6H), 2.24 (d, J = 3.4 Hz, 3H), 2.22 - 2.13 (m, 1H), 1.77 - 1.60 (m, 1H), 1.29 - 1.12 (m, 1H); LCMS(電灑) m/z 412.1(M +H+)。 | B |
17 | (1S,2S)-N-(6-(7-乙氧基-6-氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.54 (br s, 1H), 11.30 (s, 1H), 8.32 (s, 1H), 8.11 (d, J = 9.3 Hz, 1H), 7.89 (s, 1H), 7.39 (d, J= 9.3 Hz, 1H), 5.07 - 4.85 (m, 1H), 4.34 (br d, J = 7.0 Hz, 2H), 2.27 (d, J = 2.9 Hz, 3H), 2.18 (br s, 1H), 1.74 - 1.62 (m, 1H),1.39 (t, J = 7.0 Hz, 3H), 1.26 - 1.16 (m, 1H); LCMS(電灑) m/z 418.1 (M+H+)。 | B |
18 | (1S,2S)-N-(6-(7-(二甲胺基)-6-氟-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.79 (br s, 1H),11.32 (s, 1H), 8.29 (s, 1H), 8.12 (d, J = 9.3 Hz, 1H), 7.90 (s, 1H), 7.36 (d, J = 9.3 Hz, 1H), 5.09 - 4.78 (m, 1H), 3.04 (br s, 6H),2.23 - 2.09 (m, 1H), 1.75 - 1.60 (m, 1H), 1.27 - 1.12 (m, 1H); LCMS(電灑) m/z 466.1(M+H+)。 | B |
19 | (1S,2S)-N-(6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺。 | 1H NMR (400 MHz, DMSO-d 6) δ 13.94 - 13.79 (m, 1H), 11.39 - 11.28 (m, 1H), 8.36 (s, 1H), 8.17 (d, J = 9.3 Hz, 1H), 8.14 - 8.08 (m, 1H), 7.55 - 7.49 (m, 1H), 5.08 - 4.85 (m, 1H), 2.60 (s, 3H), 2.25 - 2.14 (m, 1H), 1.76 - 1.62 (m, 1H), 1.28 - 1.14 (m, 1H); LCMS(電灑) m/z 435.1(M +H+)。 | B |
20 | (1S,2S)-N-(6-(6,7-二氟-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 14.18 (s, 1H), 11.28 (s, 1H), 8.32 (s, 1H), 8.12 - 8.08 (m, 2H), 7.45 - 7.43 (m, 1H), 5.06 - 4.85 (m, 1H), 2.35 (s, 3H), 2.19 - 2.17 (m, 1H), 1.72 - 1.65 (m, 1H), 1.23 - 1.17 (m, 1H); LCMS(電灑) m/z 419.0 (M +H+)。 | B |
21 | (1S,2S)-N-(6-(5-氯-7-(二甲胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺。 | 1H NMR (400 MHz, DMSO-d 6) δ 13.53 (br s, 1H), 11.31 (s, 1H), 8.33 (s, 1H), 8.13 (br d, J = 9.4 Hz, 1H), 7.98 (br s, 1H), 7.47 (d, J = 9.3 Hz, 1H), 5.07 - 4.84 (m, 1H), 3.03 (br s, 6H), 2.23 - 2.14 (m, 1H), 1.74 - 1.62 (m, 1H), 1.25 - 1.14 (m, 1H); LCMS(電灑) m/z 432.1 (M +H+)。 | B |
22 | (1S,2S)-N-(6-(5-氯-6,7-二氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺。 | 1H NMR (400 MHz, DMSO-d 6) δ 14.27 (br s, 1H), 11.33 (s, 1H), 8.36 (s, 1H), 8.19 (s, 1H), 8.18 - 8.15 (m, 1H), 7.50 (d, J = 9.3 Hz, 1H), 5.07 - 4.85 (m, 1H), 2.24 - 2.15 (m, 1H), 1.76 - 1.61 (m, 1H), 1.25 - 1.14 (m, 1H); LCMS(電灑) m/z 406.8 (M+H+)。 | B |
23 | (1S,2S)-N-(6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺。 | 1H NMR (400 MHz, DMSO-d 6) δ 13.84 (br s, 1H), 11.34 (s, 1H), 8.36 (s, 1H), 8.17 (d, J = 9.2 Hz, 1H), 8.09 (s, 1H), 7.53 (d, J = 9.2 Hz, 1H), 5.05 - 4.86 (m, 1H), 2.59 (s, 3H), 2.24 - 2.15 (m, 1H), 1.71 - 1.61 (m, 1H), 1.20 - 1.17 (m, 1H); LCMS(電灑) m/z 435.0 (M+H+)。 | B |
24 | (1S,2S)-2-氟-N-(6-(5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺。2 TFA | 1H NMR (400 MHz, DMSO-d 6) δ 11.48 - 11.28 (m, 1H), 9.06 (s, 1H), 8.83 (d, J = 1.3 Hz, 1H), 8.36 (s, 1H), 7.91 (d, J = 0.9 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 5.15 - 4.79 (m, 1H), 2.43 - 2.35 (m, 3H), 2.26 - 2.14 (m, 1H), 1.78 - 1.62 (m, 1H), 1.37 - 1.06 (m, 1H); LCMS (電灑) m/z 351.1 (M+H)+。 | C |
25 | (1S,2S)-N-(6-(5-乙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。2 TFA | 1H NMR (400 MHz, METHANOL-d 4) δ 8.99 (s, 1H), 8.71 (s, 1H), 8.42 (s, 1H), 7.83 (s, 1H), 7.36 (d, J=10.4 Hz, 1H), 5.00 - 4.97 (m, 1H), 2.76 - 2.72 (m, 2H), 2.16 - 2.15 (m, 1H), 1.86 - 1.79 (m, 1H), 1.26 - 1.24 (m, 1H), 1.19 - 1.16 (m, 3H); LCMS (電灑) m/z 383.1 (M+H)+。 | D |
26 | (1S,2S)-N-(6-(7-(二甲胺基)-5-乙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.15 (br s, 1H), 11.35 (s, 1H), 9.01 (d, J = 0.6 Hz, 1H), 8.76 (d, J = 1.3 Hz, 1H), 8.35 (s, 1H), 7.83 (s, 1H), 5.08 - 4.84 (m, 1H), 2.97 (br d, J = 1.1 Hz, 6H), 2.64 (br dd, J = 2.0, 7.4 Hz, 2H), 2.23 - 2.15 (m, 1H), 1.74 - 1.63 (m, 1H), 1.24 - 1.17 (m, 1H), 1.12 (t, J = 7.3 Hz, 3H) ; LCMS (電灑) m/z 426.4 (M+H)+。 | D |
27 | (1S,2S)-2-氟-N-(6-(6-氟-5,7-雙(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺。2 HCl | 1H NMR (400 MHz, DMSO-d 6) δ 11.39 (s, 1H), 9.04 (s, 1H), 8.89 (d, J = 1.5 Hz, 1H), 8.38 (s, 1H), 8.03 (s, 1H), 5.10 - 4.78 (m, 1H), 2.56 (s, 3H), 2.31 - 2.27 (m, 3H), 2.26 - 2.14 (m, 1H), 1.74 - 1.63 (m, 1H), 1.25 - 1.17 (m, 1H); LCMS (電灑) m/z 447.1 (M+H)+。 | D |
28 | (1S,2S)-2-氟-N-(6-(6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺。2 TFA | 1H NMR (400 MHz, DMSO-d 6) δ 11.37 (s, 1H), 9.04 - 9.01 (m, 1H), 8.87 (d, J = 1.4 Hz, 1H), 8.36 (s, 1H), 7.94 (d, J = 0.9 Hz, 1H), 7.54 (dd, J = 0.8, 9.4 Hz, 1H), 5.12 - 4.82 (m, 1H), 2.26 (s, 3H), 2.22 - 2.13 (m, 1H), 1.75 - 1.61 (m, 1H), 1.19 (tdd, J = 6.3, 9.0, 12.4 Hz, 1H); LCMS (電灑) m/z 401.1 (M+H)+。 | D |
29 | (1S,2S)-N-(6-(5-乙基-6,7-二氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。 | 1H NMR (400 MHz, DMSO-d 6) δ 13.86 (br s, 1H), 11.38 (s, 1H), 9.03 (d, J=0.6 Hz, 1H), 8.82 (d, J=1.4 Hz, 1H), 8.36 (s, 1H), 8.02 (br s, 1H), 5.09 - 4.83 (m, 1H), 2.72 (br d, J=9.0 Hz, 2H), 2.18 (br d, J=7.1 Hz, 1H), 1.76 - 1.62 (m, 1H), 1.22 (br d, J=9.0 Hz, 1H), 1.15 (t, J=7.4 Hz, 3H); LCMS (電灑) m/z 401.2 (M+H)+。 | D |
30 | (1S,2S)-2-氟-N-(6-(6-氟-5-甲基-7-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺。1 TFA | 1H NMR (400 MHz, DMSO-d 6) δ 11.47 (s, 1H), 9.13 (s, 1H), 8.92 (d, J = 1.2 Hz, 1H), 8.42 (s, 1H), 7.97 (d, J = 1.0 Hz, 1H), 7.44 (d, J = 10.0 Hz, 1H), 5.06 - 4.88 (m, 1H), 2.29 (d, J = 2.6 Hz, 3H), 2.25 - 2.14 (m, 1H), 1.77 - 1.63 (m, 1H), 1.29 - 1.16 (m, 1H); LCMS (電灑) m/z 369.3 (M+H)+。 | D |
31 | (1S,2S)-2-氟-N-(6-(6-氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺。 | 1H NMR (400 MHz, DMSO-d 6) δ 13.42 (br s, 1H), 11.37 (s, 1H), 9.05 (s, 1H), 8.87 (d, J = 1.3 Hz, 1H), 8.35 (s, 1H), 8.02 (s, 1H), 5.09 - 4.80 (m, 1H), 2.52 (br s, 3H), 2.29 (d, J = 3.0 Hz, 3H), 2.19 (br dd, J = 5.9, 7.8 Hz, 1H), 1.76 - 1.62 (m, 1H), 1.24 - 1.17 (m, 1H); LCMS (電灑) m/z 415.3 (M+H)+。 | D |
32 | (1S,2S)-N-(6-(5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。1 TFA | 1H NMR (400 MHz, DMSO-d 6) 13.59 (s, 1H), 11.41 (s, 1H), 9.08 (s, 1H), 9.03 (s, 1H), 8.39 (s, 1H), 8.10 - 8.06 (m, 1H), 7.74 - 7.70 (m, 1H), 5.06 - 4.87 (m, 1H), 2.23 - 2.18 (m, 1H), 1.24 - 1.20 (m, 1H); LCMS(電灑) m/z 389.1 (M +H+)。 | D |
33 | (1S,2S)-N-(6-(5-氯-7-(二甲胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。 | 1H NMR (400 MHz, DMSO-d 6) δ 13.62 - 13.27 (m, 1H), 11.39 (s, 1H), 9.05 (s, 1H), 8.93 (d, J = 1.3 Hz, 1H), 8.38 (s, 1H), 8.00 (br s, 1H), 5.12 - 4.80 (m, 1H), 3.01 (br s, 6H), 2.25 - 2.13 (m, 1H), 1.77 - 1.61 (m, 1H), 1.27 - 1.14 (m, 1H); LCMS(電灑) m/z 432.3 (M +H+)。 | D |
34 | (1S,2S)-N-(6-(5-氯-7-乙氧基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。 | 1H NMR (400 MHz, DMSO-d 6) δ 13.90 - 13.65 (m, 1H), 11.39 (s, 1H), 9.05 (s, 1H), 8.97 (d, J = 1.3 Hz, 1H), 8.38 (s, 1H), 8.06 (s, 1H), 5.06 - 4.86 (m, 1H), 4.44 - 4.39 (m, 2H), 2.22 - 2.15 (m, 1H), 1.74 - 1.64 (m, 1H), 1.41 (t, J = 7.0 Hz, 3H), 1.25 - 1.18 (m, 1H); LCMS(電灑) m/z 433.2 (M +H+)。 | D |
35 | (1S,2S)-N-(6-(6,7-二氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.87 - 13.72 (m, 1H), 11.45 - 11.28 (m, 1H), 9.04 (s, 1H), 8.91 - 8.78 (m, 1H), 8.45 - 8.32 (m, 1H), 8.11 - 7.90 (m, 1H), 5.10 - 4.82 (m, 1H), 2.71 - 2.57 (m, 1H), 2.33 (br d, J = 2.9 Hz, 3H), 2.24 - 2.14 (m, 1H), 1.75 - 1.64 (m, 1H), 1.26 - 1.16 (m, 1H); LCMS(電灑) m/z 387.0 (M +H+)。 | D |
36 | (1S,2S)-N-(6-(6,7-二氟-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 14.30 - 13.89 (m, 1H), 11.43 - 11.32 (m, 1H), 9.07 - 9.00 (m, 1H), 8.88 (d, J = 1.4 Hz, 1H), 8.43 - 8.36 (m, 1H), 8.10 (d, J = 3.1 Hz, 1H), 5.10 - 4.82 (m, 1H), 2.32 (s, 3H), 2.24 - 2.14 (m, 1H), 1.73 - 1.62 (m, 1H), 1.29 - 1.15 (m, 1H); LCMS(電灑) m/z 419.1 (M +H+)。 | D |
37 | (1S,2S)-N-(6-(5-乙基-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 12.05 - 11.89 (m, 1H), 9.95 - 9.84 (m, 1H), 9.49 (s, 1H), 8.97 (d, J = 1.5 Hz, 1H), 8.82 (s, 1H), 8.43 (s, 1H), 5.56 - 5.25 (m, 1H), 3.32 (dq, J = 2.3, 7.4 Hz, 2H), 3.08 (s, 3H), 2.41 - 2.30 (m, 2H), 1.81 - 1.70 (m, 5H); LCMS(電灑) m/z 428.12 (M +H+)。 | D |
38 | (1S,2S)-N-(6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.76 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.02 (d, J = 1.5 Hz, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 5.08 - 4.86 (m, 1H), 2.59 (s, 3H), 2.21 - 2.17 (m, 1H), 1.74 - 1.64 (m, 1H), 1.24 - 1.18 (m, 1H; LCMS(電灑) m/z 435 (M+H+)。 | D |
39 | (1S,2S)-N-(6-(7-(二甲胺基)-6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.41 - 13.32 (m, 1H), 11.36 (s, 1H), 9.01 (d, J = 0.8 Hz, 1H), 8.80 (d, J = 1.4 Hz, 1H), 8.36 (s, 1H), 7.95 - 7.86 (m, 1H), 5.07 - 4.85 (m, 1H), 2.99 (d, J = 1.5 Hz, 6H), 2.28 (s, 3H), 2.22 - 2.14 (m, 1H), 1.73 - 1.63 (m, 1H), 1.23 - 1.17 (m, 1H); LCMS(電灑) m/z 444 (M+H+)。 | D |
40 | (1S,2S)-N-(6-(7-(二甲胺基)-6-氟-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 11.39 (s, 1H), 8.98 (s, 1H), 8.81 (d, J = 1.4 Hz, 1H), 8.33 (s, 1H), 7.98 (s, 1H), 5.21 - 4.77 (m, 1H), 3.03 (d, J = 2.4 Hz, 6H), 2.24 - 2.13 (m, 1H), 1.76 - 1.60 (m, 1H), 1.20 (tdd, J = 6.1, 9.1, 12.4 Hz, 1H); LCMS(電灑) m/z 466.1 (M+H+)。 | D |
41 | (1S,2S)-N-(6-(5-氯-7-(乙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.53 - 13.35 (m, 1H), 11.42 - 11.37 (m, 1H), 9.09 - 9.04 (m, 1H), 8.99 - 8.94 (m, 1H), 8.41 - 8.36 (m, 1H), 8.07 - 7.97 (m, 1H), 5.10 - 4.85 (m, 1H), 3.30 (br d, J = 7.0 Hz, 2H), 3.03 - 2.97 (m, 3H), 2.24 - 2.14 (m, 1H), 1.76 - 1.62 (m, 1H), 1.19 (s, 1H), 1.12 - 1.07 (m, 3H); LCMS(電灑) m/z 446.1 (M +H+)。 | D |
42 | (1S,2S)-N-(6-(7-(乙基(甲基)胺基)-6-氟-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.80 - 13.59 (m, 1H), 11.39 (s, 1H), 8.98 (s, 1H), 8.84 (d, J = 1.3 Hz, 1H), 8.33 (s, 1H), 8.00 (br s, 1H), 5.07 - 4.84 (m, 1H), 3.29 (br d, J = 7.3 Hz, 2H), 3.00 (d, J = 1.7 Hz, 3H), 2.24 - 2.14 (m, 1H), 1.75 - 1.64 (m, 1H), 1.24 - 1.17 (m, 1H), 1.09 (t, J = 7.1 Hz, 3H); LCMS(電灑) m/z 480.3 (M +H+)。 | D |
43 | (1S,2S)-N-(6-(5-乙基-7-(乙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.12 (s, 1H), 11.35 (s, 1H), 9.07 - 8.96 (m, 1H), 8.78 (d, J = 1.4 Hz, 1H), 8.39 - 8.28 (m, 1H), 7.83 (s, 1H), 5.10 - 4.81 (m, 1H), 3.21 (br s, 2H), 2.94 (d, J = 1.5 Hz, 3H), 2.64 (br d, J = 2.0 Hz, 1H), 2.21 - 2.16 (m, 1H), 1.73 - 1.64 (m, 1H), 1.20 - 1.17 (m, 1H), 1.12 (t, J = 7.5 Hz, 3H), 1.06 (t, J = 7.0 Hz, 3H); LCMS(電灑) m/z 440.1 (M +H+)。 | D |
44 | (1S,2S)-N-(6-(7-乙氧基-5-乙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.44 (br s, 1H), 11.36 (s, 1H), 9.02 (s, 1H), 8.79 (d, J = 1.4 Hz, 1H), 8.35 (s, 1H), 7.89 (s, 1H), 5.07 - 4.85 (m, 1H), 4.33 (q, J = 6.4 Hz, 2H), 2.70 - 2.63 (m, 2H), 2.19 (td, J = 6.9, 13.6 Hz, 1H), 1.74 - 1.63 (m, 1H), 1.39 (t, J = 7.0 Hz, 3H), 1.24 - 1.17 (m, 1H), 1.13 (t, J = 7.4 Hz, 3H); LCMS(電灑) m/z 427.0 (M+H+)。 | D |
45 | (1S,2S)-N-(6-(7-(乙基(甲基)胺基)-6-氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.11 (s, 1H), 11.36 (s, 1H), 9.03 (d, J = 0.6 Hz, 1H), 8.80 (d, J = 1.2 Hz, 1H), 8.33 (s, 1H), 7.90 (s, 1H), 5.11 - 4.82 (m, 1H), 3.26 - 3.17 (m, 2H), 2.94 (d, J = 1.6 Hz, 3H), 2.25 (d, J = 3.2 Hz, 3H), 2.22 - 2.15 (m, 1H), 1.77 - 1.61 (m, 1H), 1.25 - 1.14 (m, 1H), 1.06 (t, J = 7.1 Hz, 3H); LCMS(電灑) m/z 425.18 (M +H+)。 | D |
46 | (1S,2S)-N-(6-(7-(二甲胺基)-6-氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.53 - 12.84 (m, 1H), 11.37 (s, 1H), 9.04 (s, 1H), 8.79 (d, J = 1.3 Hz, 1H), 8.35 (s, 1H), 7.91 (s, 1H), 5.14 - 4.78 (m, 2H), 2.97 (d, J = 2.2 Hz, 6H), 2.25 (d, J = 3.3 Hz, 3H), 2.20 - 2.16 (m, 1H), 1.76 - 1.62 (m, 1H), 1.25 - 1.15 (m, 1H); LCMS(電灑) m/z 412.2 (M +H+)。 | D |
47 | (1S,2S)-N-(6-(7-乙氧基-6-氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.20 - 13.68 (m, 1 H) 11.26 - 11.47 (m, 1 H) 9.03 (s, 1 H) 8.81 (d, J=1.25 Hz, 1 H) 8.34 (s, 1 H) 7.96 (s, 1 H) 4.84 - 5.09 (m, 1 H) 4.33 (q, J=7.00 Hz, 2 H) 2.28 (d, J=3.00 Hz, 3 H) 2.14 - 2.23 (m, 1 H) 1.62 - 1.75 (m, 1 H) 1.39 (t, J=7.00 Hz, 3 H) 1.20 (ddt, J=12.37, 9.05, 6.24, 6.24 Hz, 1 H); LCMS(電灑) m/z 413.1 (M+H+)。 | D |
48 | (1S,2S)-2-氟-N-(6-(6-氟-5-甲基-7-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺。 | 1H NMR (400 MHz, DMSO-d 6) δ 13.62 (br s, 1H), 11.42 (s, 1H), 9.08 (s, 1H), 8.94 (d, J=1.2 Hz, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 5.09 - 4.83 (m, 1H), 2.32 (d, J=2.9 Hz, 3H), 2.24 - 2.15 (m, 1H), 1.76 - 1.63 (m, 1H), 1.26 - 1.15 (m, 1H); LCMS(電灑) m/z 437.2 (M+H+)。 | D |
49 | (1S,2S)-N-(6-(5-溴-6,7-二氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。 | 1H NMR (400MHz, METHANOL-d 4) δ 9.04 - 8.94 (m, 1H), 8.82 (d, J=1.5 Hz, 1H), 8.44 - 8.36 (m, 1H), 8.01 (br s, 1H), 5.00 - 4.95 (m, 1H), 2.17 - 2.11 (m, 1H), 1.89 - 1.76 (m, 1H), 1.30 - 1.21 (m, 1H); LCMS(電灑) m/z 451.0 (M +H+)。 | D |
50 | (1S,2S)-N-(6-(7-(乙基(甲基)胺基)-6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.34 (br s, 1H), 8.04 (d, J = 1.3 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.68 (s, 1H), 7.49 (dd, J = 1.7, 8.3 Hz, 1H), 5.16 - 4.94 (m, 1H), 3.23 (q, J = 7.1 Hz, 2H), 2.95 (d, J = 2.0 Hz, 3H), 2.28 - 2.22 (m, 1H), 2.20 (s, 3H), 1.82 - 1.68 (m, 1H), 1.31 (tdd, J = 6.2, 8.9, 12.6 Hz, 1H), 1.07 (t, J = 7.1 Hz, 3H)); LCMS(電灑) m/z 474 (M+H+)。 | D |
51 | (1S,2S)-N-(6-(5-氯-6,7-二氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。 | 1H NMR (400 MHz, DMSO-d 6) δ 14.33 - 13.89 (m, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.01 (d, J=1.4 Hz, 1H), 8.39 (s, 1H), 8.20 (br s, 1H), 5.09 - 4.85 (m, 1H), 2.19 (td, J=7.0, 14.2 Hz, 1H), 1.76 - 1.63 (m, 1H), 1.25 - 1.17 (m, 1H)); LCMS(電灑) m/z 407.2 (M +H+)。 | D |
52 | (1S,2S)-N-(6-(5-溴-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。1 TFA | 1H NMR (400 MHz, DMSO-d 6) δ 13.41 (s, 1H), 11.43 - 11.36 (m, 1H), 9.11 - 9.05 (m, 1H), 8.97 (d, J = 1.5 Hz, 1H), 8.38 (s, 1H), 7.99 (s, 1H), 7.69 - 7.65 (m, 1H), 5.21 - 4.77 (m, 1H), 2.25 - 2.13 (m, 1H), 1.74 - 1.63 (m, 1H), 1.25 - 1.18 (m, 1H)); LCMS(電灑) m/z 435.0 (M +H+)。 | D |
53 | (1S,2S)-2-氟-N-(6-(6-氟-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺。 | 1H NMR (400 MHz, DMSO-d 6) δ 13.71 (br s, 1H), 11.40 (s, 1H), 9.01 (s, 1H), 8.91 (d, J=1.3 Hz, 1H), 8.35 (s, 1H), 8.08 (s, 1H), 7.77 (d, J=11.4 Hz, 1H), 5.18 - 4.81 (m, 1H), 2.25 - 2.15 (m, 1H), 1.78 - 1.54 (m, 1H), 1.28 - 1.09 (m, 1H)); LCMS(電灑) m/z 423.1 (M+H+)。 | D |
54 | (1S,2S)-N-(6-(5-氯-6-氟-7-(吡咯烷-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.15 (s, 1H), 11.37 (s, 1H), 9.03 (s, 1H), 8.89 (S, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 5.08-4.84 (m, 1H), 3.99-3.88 (m, 1H), 3.79-3.62 (m, 4H), 2.27-2.12 (m, 1H), 2.04-1.86 (m, 5H), 1.78-1.60 (m, 1H), 1.30-1.18 (m, 1H); LCMS (電灑) m/z 458.1 (M+H)+。 | D |
55 | (1S,2S)-N-(6-(5-氯-6-氟-7-(哌啶-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.36 (s, 1H), 11.41 (s, 1H), 9.05 (d, J = 4.9 Hz, 1H), 8.95 (d, J = 1.1 Hz, 1H), 8.37 (d, J = 4.4 Hz, 1H), 8.01 (s, 1H), 5.14-4.81 (m, 1H), 3.30-3.08 (m, 4H), 2.26-2.10 (m, 1H), 1.79 - 1.71 (m, 4H), 1.71-1.55 (m, 3H), 1.26-1.15 (m, 1H); LCMS (電灑) m/z 472.1 (M+H)+。 | D |
56 | (1S,2S)-N-(6-(5-氯-6-氟-7-((3-羥丙基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.14 (s, 1H), 11.38 (s, 1H), 9.02 (s, 1H), 8.89 (s, 1H), 8.35 (s, 1H), 7.94 (s, 1H), 5.64 (s, 1H), 5.11-4.80 (m, 1H), 4.68 (s, 1H), 3.63 - 3.48 (m, 4H), 2.25-2.10 (m, 1H), 1.78-1.63 (m, 3H), 1.32-1.10 (m, 1H); LCMS (電灑) m/z 462.1 (M+H)+。 | D |
57 | (1S,2S)-N-(6-(7-(氮呾-1-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。 | 1H NMR (400 MHz, DMSO-d 6) δ 13.03 (s, 1H), 11.38 (s, 1H), 9.02 (s, 1H), 8.88 (s, 1H), 8.36 (s, 1H), 7.97 (s, 1H), 5.11-4.82 (m, 1H), 4.49 - 4.34 (s, 4H), 2.36 (q, J = 7.3 Hz, 2H), 2.25-2.13 (m, 1H), 1.76 - 1.63 (m, 1H), 1.22-1.13 (m, 1H); LCMS (電灑) m/z 444.1 (M+H)+。 | D |
58 | (1S,2S)-N-(6-(5-氯-7-(環丙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.49 (s, 1H), 11.41 (s, 1H), 9.05 (s, 1H), 8.96 (s, 1H), 8.36 (s, 1H), 8.00 (s, 1H), 5.03 - 4.83 (m, 1H), 3.01 (br, 4H), 2.17-2.14 (m, 1H), 1.69 - 1.62 (m, 1H), 1.19 - 1.14 (m, 1H) 0.64-0.59 (m, 2H), 0.48-0.45 (m, 2H); LCMS (電灑) m/z 458.1 (M+H)+。 | D |
59 | (1S,2S)-N-(6-(5-氯-6-氟-7-(甲胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.50 (s, 1H), 11.38 (s, 1H), 9.01 (s, 1H), 8.87 (s, 1H), 8.34 (s, 1H), 7.92 (s, 1H), 5.03 - 4.83 (m, 1H), 3.15 (t, J = 4.6 Hz, 3H), 2.17-2.14 (m, 1H), 1.69 - 1.62 (m, 1H), 1.19 - 1.14 (m, 1H); LCMS (電灑) m/z 418.1 (M+H)+。 | D |
60 | (1S,2S)-N-(6-(5-氯-6-氟-7-硫代嗎啉-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.43 (s, 1H), 11.41 (s, 1H), 9.06 (s, 1H), 8.96 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 8.03 (d, J = 1.6 Hz, 1H), 5.08 - 4.85 (m, 1H), 3.52 - 3.44 (s, 4H), 2.91 - 2.86 (m, 4H), 2.26-2.12 (m, 1H), 1.78-1.60 (m, 1H), 1.31-1.12 (m, 1H); LCMS (電灑) m/z 490.1 (M+H)+。 | D |
61 | (1S,2S)-N-(6-(5-氯-6-氟-7-(異丙胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.18 (s, 1H), 11.37 (s, 1H), 9.03 (s, 1H), 8.91 (d, J = 1.6 Hz, 1H), 8.35 (s, 1H), 7.97 (s, 1H), 5.21 (d, J = 10.0 Hz, 1H), 5.06 - 4.86 (m, 1H), 4.05 (m, 1H), 2.20 - 2.15 (m, 1H), 1.72 - 1.65 (m, 1H), 1.28 – 1.16 (m, 7H) ; LCMS (電灑) m/z 446.10 (M+H)+。 | E |
62 | (1S,2S)-N-(6-(5-氯-6-氟-7-(異丙基(甲基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.38 (s, 1H), 11.41 (s, 1H), 9.06 (s, 1H), 8.97 (d, J = 1.2 Hz, 1H), 8.37 (s, 1H), 8.01 (s, 1H), 5.06 – 4.86 (m, 1H), 3.56 (m, 1H), 2.90 (d, J = 2.8 Hz, 3H), 2.20 – 2.17 (m, 1H), 1.72 – 1.65 (m, 1H), 1.23 – 1.13 (m, 7H) ; LCMS (電灑) m/z 460.10 (M+H)+。 | E |
63 | (1S,2S)-N-(6-(5-氯-6-氟-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.46 (br s, 1H), 11.41 (s, 1H), 9.08 (dd, J = 0.7, 1.3 Hz, 1H), 9.00 (d, J = 1.5 Hz, 1H), 8.39 (s, 1H), 8.07 (s, 1H), 5.64 (s, 1H), 5.39 (s, 1H), 5.13 - 4.78 (m, 1H), 2.22 (s, 3H), 2.21 - 2.13 (m, 1H), 1.76 - 1.62 (m, 1H), 1.21 (tdd, J = 6.2, 9.0, 12.5 Hz, 1H); LCMS (電灑) m/z 429.2 (M+H+)。 | D |
64 | (1S,2S)-N-(6-(5-氯-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.52 (br s, 1H), 11.40 (s, 1H), 9.14 - 8.87 (m, 2H), 8.38 (s, 1H), 8.04 (br s, 1H), 5.17 - 4.75 (m, 1H), 3.66 - 3.59 (m, 1H), 2.19 (td, J = 7.0, 13.6 Hz, 1H), 1.75 - 1.62 (m, 1H), 1.45 (br d, J = 7.0 Hz, 6H), 1.20 (tdd, J = 6.3, 8.9, 12.3 Hz, 1H); LCMS (電灑) m/z 431.2 (M+H+)。 | F |
65 | (1S,2S)-N-(6-(5-氯-7-((1-氰乙基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.16 (s, 1H), 11.19 (s, 1H), 9.01 (s, 1H), 8.91 (s, 1H), 8.35 (s, 1H), 8.02 (s, 1H), 6.03 (s, 1H), 5.16-4.77 (m, 2H), 2.32-2.11 (m, 1H), 1.81-1.64 (m, 4H), 1.24-1.09 (m, 1H); LCMS (電灑) m/z 457.10 (M+H)+。 | D |
66 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1H-吡咯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.61 (s, 1H), 11.29 (s, 1H), 9.08 (s, 1H), 9.02 (d, J = 1.1 Hz, 1H), 8.42 (s, 1H), 8.16 (s, 1H), 7.23 (s, 2H), 6.42 (s, 2H), 5.12-4.79 (m, 1H), 2.28-2.14 (m, 1H), 1.79-1.63 (m, 1H), 1.32-1.19 (m, 1H); LCMS (電灑) m/z 454.10 (M+H)+。 | D |
67 | (1S,2S)-N-(6-(7-胺基-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 12.89 (s, 1H), 11.32 (s, 1H), 8.98 (s, 1H), 8.85 (d, J = 1.6 Hz, 1H), 8.31 (s, 1H), 7.89 (d, J = 1.6 Hz, 1H), 5.79 (s, 2H), 5.06-4.78 (m, 1H), 2.20-2.09 (m, 1H), 1.73-1.56 (m, 1H), 1.18-1.13 (m, 1H); LCMS (電灑) m/z 404.05 (M+H)+。 | D |
68 | (1S,2S)-N-(6-(5-氯-7-((氰甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.18 (s, 1H), 11.25 (s, 1H), 9.02 (s, 1H), 8.92 (s, 1H), 8.35 (s, 1H), 8.02 (s, 1H), 6.66-6.18 (m, 1H), 5.08-4.48 (m, 3H), 2.27-2.14 (m, 1H), 1.79-1.61 (m, 1H), 1.20-1.09 (m, 1H); LCMS (電灑) m/z 443.10 (M+H)+。 | D |
69 | (1S,2S)-N-(6-(7-((2H-四唑-2-基)甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。 | 1H NMR (400 MHz, DMSO-d 6) δ 13.93 (s, 1H), 11.42 (s, 1H), 9.09 (s, 1H), 9.06 (d, J = 1.1 Hz, 1H), 9.00 (s, 1H), 8.39 (s, 1H), 8.17 (s, 1H), 6.37 (s, 2H), 5.07-4.86 (m, 1H), 2.22-2.15 (m, 1H), 1.73-1.63 (m, 1H), 1.25-1.16 (m, 1H); LCMS (電灑) m/z 471.10 (M+H)+。 | D |
70 | (1S,2S)-N-(6-(5-氯-6-氟-7-(2-羥基丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。1甲酸 | 1H NMR (400 MHz, DMSO-d 6) δ 12.87 (br s, 1H), 11.39 (s, 1H), 9.06 (s, 1H), 8.97 (s, 1H), 8.38 (s, 1H), 7.97 (s, 1H), 6.05 (br s, 1H), 5.13 - 4.82 (m, 1H), 2.19 (br s, 1H), 1.70 (s, 6H), 1.63 (br s, 1H), 1.21 (br s, 1H); LCMS (電灑) m/z 447.0 (M+H)+。 | D |
71 | (1S,2S)-N-(6-(5-氯-6-氟-7-乙烯基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.96 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.03 (d, J = 1.4 Hz, 1H), 8.39 (s, 1H), 8.15 (br s, 1H), 7.11 (dd, J = 11.8, 17.9 Hz, 1H), 6.39 - 6.22 (m, 1H), 5.84 (d, J = 11.9 Hz, 1H), 5.12 - 4.80 (m, 1H), 2.26 - 2.12 (m, 1H), 1.77 - 1.60 (m, 1H), 1.21 (tdd, J = 6.3, 9.1, 12.4 Hz, 1H); LCMS (電灑) m/z 415.1 (M+H)+。 | D |
72 | (1S,2S)-N-(6-(7-乙醯基-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.68 (br s, 1H), 11.42 (s, 1H), 9.10 (s, 2H), 8.49 - 8.37 (m, 1H), 8.17 (s, 1H), 5.09 - 4.84 (m, 1H), 2.77 (d, J=6.2 Hz, 3H), 2.25 - 2.12 (m, 1H), 1.74 - 1.62 (m, 1H), 1.27 - 1.21 (m, 1H); LCMS (電灑) m/z 431.1 (M+H)+。 | D |
73 | (1S,2S)-N-(6-(5-氯-7-環丙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.74 (s, 1H), 11.39 (s, 1H), 9.06 (s, 1H), 8.96 (d, J = 1.4 Hz, 1H), 8.38 (s, 1H), 8.04 (br s, 1H), 5.18 - 4.72 (m, 1H), 2.25 - 2.11 (m, 2H), 1.76 - 1.62 (m, 1H), 1.25 - 1.19 (m, 1H), 1.18 - 1.10 (m, 2H), 1.06 - 0.92 (m, 2H); LCMS (電灑) m/z 429.3 (M+H)+。 | D |
74 | (1S,2S)-N-(6-(5-氯-7-(2-乙氧基丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。 | 1H NMR (400 MHz, DMSO-d 6) δ 12.93 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.00 (d, J=1.3 Hz, 1H), 8.39 (s, 1H), 8.01 (s, 1H), 5.11 - 4.84 (m, 1H), 3.29 - 3.03 (m, 2H), 2.20 (td, J=7.0, 13.7 Hz, 1H), 1.75 (br d, J=3.3 Hz, 6H), 1.68 (br dd, J=3.8, 7.1 Hz, 1H), 1.25 - 1.18 (m, 1H), 1.14 (t, J=7.0 Hz, 3H); LCMS (電灑) m/z 475.1 (M+H)+。 | D |
75 | (1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲氧基丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 12.98 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 8.99 (d, J=1.3 Hz, 1H), 8.38 (s, 1H), 8.00 (s, 1H), 5.13 - 4.81 (m, 1H), 3.18 (s, 3H), 2.19 (td, J=7.0, 13.7 Hz, 1H), 1.72 (br d, J=2.4 Hz, 6H), 1.69 - 1.60 (m, 1H), 1.24 - 1.18 (m, 1H); LCMS (電灑) m/z 461.0 (M+H)+。 | D |
76 | (1S,2S)-N-(6-(7-(三級丁基胺基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.36 (s, 1H), 11.41 (s, 1H), 9.05 (s, 1H), 8.98 (d, J = 1.1 Hz, 1H), 8.36 (s, 1H), 7.98 (s, 1H), 5.07-4.86 (m, 1H), 4.49 (s, 1H), 2.21-2.15 (m, 1H), 1.72-1.63 (m, 1H), 1.28-1.18 (m, 10H); LCMS (電灑) m/z 460.10 (M+H)+。 | D |
77 | (1S,2S)-N-(6-(5-氯-7-(環丙胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 12.98 (s, 1H), 11.36 (s, 1H), 9.02 (s, 1H), 8.89 (d, J = 1.1 Hz, 1H), 8.35 (s, 1H), 7.94 (s, 1H), 6.15 (s, 1H), 5.06-4.86 (m, 1H), 3.17-3.13 (m, 1H), 2.22-2.15 (m, 1H), 1.73-1.63 (m, 1H), 1.23-1.16 (m, 2H), 0.85-0.80 (m, 2H), 0.64-0.61 (m, 2H); LCMS (電灑) m/z 444.10 (M+H)+。 | D |
78 | (1S,2S)-N-(6-(5-氯-6-氟-7-(3-氟吡咯烷-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.17 (s, 1H), 11.24 (s, 1H), 9.01 (s, 1H), 8.87 (s, 1H), 8.39 (s, 1H), 8.01 (brs, 1H), 5.63-5.34 (m, 1H), 5.09-4.74 (m, 1H), 4.51-3.46 (m, 4H), 2.38-2.03 (m, 3H), 1.85-1.59 (m, 1H), 1.31-1.09 (m, 1H); LCMS (電灑) m/z 476.10 (M+H)+。 | D |
79 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲基-1H-吡咯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.41 (s, 1H), 11.43 (s, 1H), 9.10 (s, 1H), 9.06 (d, J = 1.1 Hz, 1H), 8.41 (s, 1H), 8.11 (d, J = 0.8 Hz, 1H), 7.09 (t, J = 1.9 Hz, 1H), 6.40 (q, J = 1.8 Hz, 1H), 6.27 (t, J = 3.0 Hz, 1H), 5.08-4.87 (m, 1H), 3.55 (d, J = 1.1 Hz, 3H), 2.23-2.16 (m, 1H), 1.74-1.64 (m, 1H), 1.25-1.17 (m, 1H); LCMS (電灑) m/z 469.1 (M+H)+。 | D |
80 | (1S,2S)-N-(6-(7-(1-(2H-四唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.74 (s, 1H), 11.43 (s, 1H), 9.09 (s, 1H), 9.04 (d, J = 1.1 Hz, 2H), 8.39 (s, 1H), 8.16 (s, 1H), 6.79 (q, J = 7.1 Hz, 1H), 5.07-4.86 (m, 1H), 2.28 (d, J = 6.6 Hz, 3H), 2.22-2.15 (m, 1H), 1.72-1.65 (m, 1H), 1.23-1.18 (m, 2H); LCMS (電灑) m/z 485.10 (M+H)+。 | D |
81 | (1S,2S)-N-(6-(5-氯-6-氟-7-(丙-1-炔-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 14.11 - 13.58 (m, 1H), 11.41 (s, 1H), 9.12 - 8.97 (m, 2H), 8.47 (s, 1H), 8.39 (s, 1H), 8.12 (s, 1H), 5.13 - 4.80 (m, 1H), 2.26 (s, 3H), 2.22 - 2.16 (m, 1H), 1.74 - 1.63 (m, 1H), 1.24 - 1.16 (m, 1H); LCMS (電灑) m/z 427.3 (M+H)+。 | D |
82 | (1S,2S)-2-氟-N-(6-(6-氟-7-異丙基-5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.19 (s, 1H), 11.37 (s, 1H), 9.04 (d, J = 0.8 Hz, 1H), 8.82 (d, J = 1.4 Hz, 1H), 8.34 (s, 1H), 7.93 (s, 1H), 5.09 - 4.86 (m, 1H), 3.64 - 3.54 (m, 1H), 2.26 (d, J = 3.0 Hz, 3H), 2.21 - 2.15 (m, 1H), 1.77 - 1.63 (m, 1H), 1.44 (d, J = 7.0 Hz, 6H), 1.27 - 1.16 (m, 1H); LCMS (電灑) m/z 411.2 (M+H)+。 | D |
83 | (1S,2S)-2-氟-N-(6-(6-氟-5-甲基-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.13 (s, 1H), 11.38 (s, 1H), 9.05 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 7.96 (s, 1H), 5.56 (s, 1H), 5.32 (s, 1H), 5.07 - 4.85 (m, 1H), 2.27 (d, J = 2.9 Hz, 3H), 2.23 - 2.17 (m, 4H), 1.77 - 1.62 (m, 1H), 1.25 - 1.16 (m, 1H); LCMS (電灑) m/z 409.2 (M+H)+。 | D |
84 | (1R,2S)-N-(6-(5-氯-6-氟-7-(異丙胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.39 (s, 1H), 11.47 (s, 1H), 9.03 (s, 1H), 8.90 (d, J=1.2 Hz, 1H), 8.30 (s, 1H), 8.06 - 7.77 (m, 1H), 5.31 - 5.14 (m, 1H), 5.07 - 4.77 (m, 1H), 4.05 (br s, 1H), 1.67 - 1.48 (m, 1H), 1.33 - 1.26 (m, 1H), 1.23 (d, J=6.2 Hz, 6H), 1.22 - 1.18 (m, 1H); LCMS (電灑) m/z 446.2 (M+H)+。 | D |
85 | (1S,2R)-N-(6-(5-氯-6-氟-7-(異丙胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.21 (br s, 1H), 11.47 (s, 1H), 9.03 (s, 1H), 8.90 (d, J=1.3 Hz, 1H), 8.35 - 8.22 (m, 1H), 8.07 - 7.89 (m, 1H), 5.29 - 5.18 (m, 1H), 5.04 - 4.77 (m, 1H), 4.04 (br s, 1H), 1.65 - 1.48 (m, 1H), 1.33 - 1.26 (m, 1H), 1.26 - 1.19 (m, 7H); LCMS (電灑) m/z 446.1 (M+H)+。 | D |
86 | (1R,2R)-N-(6-(5-氯-6-氟-7-(異丙胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.20 (br s, 1H), 11.36 (s, 1H), 9.02 (s, 1H), 8.90 (d, J=1.3 Hz, 1H), 8.35 (s, 1H), 7.96 (br s, 1H), 5.27 - 5.15 (m, 1H), 5.08 - 4.78 (m, 1H), 4.22 - 3.84 (m, 1H), 2.18 (td, J=7.0, 13.9 Hz, 1H), 1.78 - 1.59 (m, 1H), 1.23 (d, J=6.3 Hz, 6H), 1.22 - 1.16 (m, 1H); LCMS (電灑) m/z 446.1 (M+H)+。 | D |
87 | (1S,2S)-N-(6-(5-氯-6-氟-7-丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.62 (br s, 1H), 11.39 (s, 1H), 9.08 - 9.04 (m, 1H), 8.99 (d, J = 1.5 Hz, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 8.03 (s, 1H), 5.09 - 4.83 (m, 1H), 2.98 (br t, J = 7.4 Hz, 2H), 2.24 - 2.14 (m, 1H), 1.75 - 1.65 (m, 3H), 1.20 (tdd, J = 6.3, 9.0, 12.4 Hz, 1H), 0.97 (t, J = 7.3 Hz, 3H); LCMS (電灑) m/z 431.3 (M+H)+。 | D |
88 | (1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲基-1H-吡咯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.95 (s, 1H), 11.42 (s, 1H), 9.10 (s, 1H), 9.08 (d, J = 1.5 Hz, 1H), 8.42 (s, 1H), 8.20 (s, 1H), 6.97 (s, 1H), 6.27 (t, J = 3.1 Hz, 1H), 6.13 (d, J = 1.1 Hz, 1H), 5.12 - 4.84 (m, 1H), 2.24 - 2.16 (m, 1H), 2.06 (s, 3H), 1.77 - 1.64 (m, 1H), 1.26 - 1.16 (m, 1H); LCMS (電灑) m/z 468.2 (M+H)+。 | D |
89 | 1-(5-氯-6-氟-4-(2-((1S,2S)-2-氟環丙烷-1-甲醯胺基)咪唑並[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)-N,N-二甲基-1H-吡咯-3-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 14.15 (s, 1H), 11.42 (s, 1H), 9.10 (s, 1H), 9.05 (s, 1H), 8.43 (s, 1H), 8.32-8.24 (m, 1H), 7.66 (s, 1H), 7.29 (s, 1H), 6.69-6.64 (m, 1H), 5.12 - 4.80 (m, 1H), 3.23-2.89 (m, 6H), 2.20 (dt, J=13.8, 6.8 Hz, 1H),1.78 -1.62 (m, 1H), 1.29 - 1.14 (m, 1H); LCMS (電灑) m/z 525.1 (M+H)+。 | D |
90 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-羥基丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.57 (s, 1H), 11.41 (s, 1H), 9.08 (s, 1H), 8.98 (d, J = 1.1 Hz, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 5.08 - 4.86 (m, 2H), 3.88 - 3.75 (m, 2H), 3.65 - 3.56 (m, 1H), 2.20 (td, J = 7.0, 13.8 Hz, 1H), 1.76 - 1.64 (m, 1H), 1.40 (d, J = 7.1 Hz, 3H), 1.21 (tdd, J = 6.3, 9.0, 12.4 Hz, 1H); LCMS (電灑) m/z 447.3 (M+H)+。 | D |
91 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲氧基丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.54 (s, 1H), 11.41 (s, 1H), 9.08 (d, J = 0.6 Hz, 1H), 9.00 (d, J = 1.5 Hz, 1H), 8.39 (s, 1H), 8.05 (br s, 1H), 5.09 - 4.85 (m, 1H), 3.85 - 3.75 (m, 2H), 3.73 - 3.66 (m, 1H), 3.25 (s, 3H), 2.25 - 2.16 (m, 1H), 1.76 - 1.64 (m, 1H), 1.41 (br d, J = 6.4 Hz, 3H), 1.21 (tdd, J = 6.3, 9.1, 12.4 Hz, 1H); LCMS (電灑) m/z 461.3 (M+H)+。 | D |
92 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-氟丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.72 (s, 1H), 11.39 (s, 1H), 9.07 (d, J = 0.6 Hz, 1H), 9.01 (d, J = 1.4 Hz, 1H), 8.38 (s, 1H), 8.05 (s, 1H), 5.13 - 4.84 (m, 2H), 3.38 - 3.35 (m, 2H), 2.23 - 2.14 (m, 1H), 1.74 - 1.63 (m, 1H), 1.46 - 1.37 (m, 3H), 1.24 - 1.15 (m, 1H); LCMS (電灑) m/z 449.4 (M+H)+。 | D |
93 | (1S,2S)-N-(6-(5-氯-6-氟-7-(異丁胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.21 (br s, 1H), 11.37 (s, 1H), 9.02 (s, 1H), 8.89 (s, 1H), 8.46 (s, 1H), 8.35 (s, 1H), 7.96 (br s, 1H), 5.74 (br s, 1H), 5.09 - 4.83 (m, 1H), 2.18 (td, J = 7.1, 13.7 Hz, 1H), 1.94 - 1.77 (m, 1H), 1.77 - 1.60 (m, 1H), 1.32 - 1.11 (m, 1H), 0.94 (d, J = 6.6 Hz, 6H); LCMS (電灑) m/z 460.2 (M+H)+。 | D |
94 | (1S,2S)-N-(6-(5-氯-6-氟-7-(丙胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.16 (br s, 1H), 11.37 (s, 1H), 9.02 (s, 1H), 8.89 (s, 1H), 8.35 (s, 1H), 7.95 (br s, 1H), 5.65 (br s, 1H), 5.07 - 4.85 (m, 1H), 3.53 - 3.42 (m, 2H), 2.18 (td, J = 6.9, 13.9 Hz, 1H), 1.75 - 1.64 (m, 1H), 1.63 - 1.56 (m, 2H), 1.24 - 1.15 (m, 1H), 0.95 (t, J = 7.4 Hz, 3H); LCMS (電灑) m/z 446.2 (M+H)+。 | D |
95 | (1S,2S)-N-(6-(5-氯-6-氟-7-((E)-丙-1-烯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.77 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.01 (d, J = 1.5 Hz, 1H), 8.42 - 8.34 (m, 1H), 8.09 (br s, 1H), 7.04 - 6.44 (m, 2H), 5.24 - 4.63 (m, 1H), 2.25 - 2.14 (m, 1H), 2.03 (br d, J = 4.5 Hz, 3H), 1.76 - 1.63 (m, 1H), 1.21 (tdd, J = 6.2, 9.1, 12.4 Hz, 1H); LCMS (電灑) m/z 429.3 (M+H)+。 | D |
96 | (1S,2S)-N-(6-(5-氯-7-(乙胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ13.41 (s, 1H), 11.37 (s, 1H), 9.02 (d, J = 0.6 Hz, 1H), 8.89 (d, J = 1.3 Hz, 1H), 8.49 - 8.44 (m, 1H), 8.35 (s, 1H), 8.02 - 7.92 (m, 1H), 5.80 - 5.58 (m, 1H), 5.08 - 4.84 (m, 1H), 3.65 - 3.53 (m, 2H), 2.26 - 2.13 (m, 1H), 1.79 (s, 1H), 1.25 - 1.20 (m, 3H), 1.20 (s, 1H); LCMS (電灑) m/z 432.2 (M+H)+。 | D |
97 | (3R,4S)-4-甲基四氫呋喃-3-基 (6-(5-氯-7-(二甲胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-yl)胺基甲酸酯 | 1H NMR (400 MHz, DMSO-d 6) δ 13.47 (s, 1 H) 10.74 (s, 1 H) 9.01 (s, 1 H) 8.92 (s, 1 H) 8.18 (s, 1 H) 8.00 (br s, 1 H) 4.87 - 4.92 (m, 1 H) 3.91 - 4.04 (m, 2 H) 3.78 (br d, J=9.76 Hz, 1 H) 3.02 (s, 6 H) 1.07 (d, J=7.13 Hz, 3 H); LCMS (電灑) m/z 474.1 (M+H)+。 | D |
98 | (1S,2S)-N-(6-(5-氯-7-(2-(二甲胺基)-2-側氧乙基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.45 (s, 1H), 11.39 (s, 1H), 9.08 (s, 1H), 9.02 (d, J=1.5 Hz, 1H), 8.40 (s, 1H), 8.03 (s, 1H), 5.07 - 4.86 (m, 1H), 4.12 (s, 2H), 3.20 (s, 3H), 2.90 (s, 3H), 2.23 - 2.17 (m, 1H), 1.74 - 1.65 (m, 1H), 1.24 - 1.17 (m, 1H); LCMS (電灑) m/z 474.2 (M+H)+。 | D |
99 | (1S,2S)-N-(6-(5-氯-7-((2-(二甲胺基)-2-側氧乙基)硫基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。1甲酸 | 1H NMR (400 MHz, DMSO-d 6) δ 13.80 (s, 1H), 11.43 (s, 1H), 9.08 (s, 1H), 9.03 (d, J=1.3 Hz, 1H), 8.47 (s, 1H), 8.40 (s, 1H), 8.12 (s, 1H), 5.20 - 4.75 (m, 1H), 4.05 (s, 2H), 3.02 (s, 3H), 2.81 (s, 3H), 2.26 - 2.08 (m, 1H), 1.76 - 1.61 (m, 1H), 1.29 - 1.15 (m, 2H); LCMS (電灑) m/z 506.0 (M+H)+。 | D |
100 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-氟乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.47 (s, 1H), 11.47 - 11.38 (m, 1H), 9.07 (s, 1H), 9.03 - 8.98 (m, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 5.08 - 5.05 (m, 1H), 5.04 - 4.84 (m, 1H), 3.24 (s, 3H), 2.19 (td, J = 7.0, 13.8 Hz, 1H), 1.76 - 1.63 (m, 1H), 1.59 (d, J = 6.6 Hz, 3H), 1.25 - 1.17 (m, 1H); LCMS (電灑) m/z 447.1 (M+H)+。 | D |
101 | (1S,2S)-N-(6-(5-氯-6-氟-7-(3,3,3-三氟丙-1-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.83 (s, 1H), 11.42 (s, 1H), 9.11 - 9.03 (m, 2H), 8.48 (s, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 6.65 (s, 1H), 6.34 (s, 1H), 5.11 - 4.84 (m, 1H), 2.25 - 2.14 (m, 1H), 1.78 - 1.62 (m, 1H), 1.27 - 1.13 (m, 1H); LCMS (電灑) m/z 483.0 (M+H)+。 | D |
102 | (1S,2S)-2-氟-N-(6-(6-氟-7-(異丙胺基)-5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.06 (s, 1H), 11.34 (s, 1H), 9.01 (s, 1H), 8.76 (d, J = 1.1 Hz, 1H), 8.48 (s, 1H), 8.32 (s, 1H), 7.88 (br s, 1H), 5.08 - 4.85 (m, 1H), 4.77 (br d, J = 8.8 Hz, 1H), 4.07 - 3.91 (m, 1H), 2.27 (d, J = 3.3 Hz, 3H), 2.23 - 2.15 (m, 1H), 1.75 - 1.63 (m, 1H), 1.25 - 1.24 (m, 1H), 1.21-1.20 (m, 7H); LCMS (電灑) m/z 426.1 (M+H)+。 | D |
103 | (1S,2S)-N-(6-(5-氯-6-氟-7-((甲胺基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 11.41 (s, 1H), 9.07 (s, 1H), 9.00 (dd, J = 8.2, 1.1 Hz, 1H), 8.39 (s, 1H), 8.05-8.03 (m, 1H), 5.07-4.86 (m, 1H), 4.17-4.02 (m, 2H), 2.37-2.15 (m, 4H), 1.74-1.64 (m, 1H), 1.27-1.20 (m, 1H); LCMS (電灑) m/z 432.10 (M+H)+。 | D |
104 | (1S,2S)-N-(6-(5-氯-7-((二甲胺基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.44 (s, 1H), 11.41 (d, J = 11.5 Hz, 1H), 9.08 (s, 1H), 9.02 (d, J = 1.6 Hz, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 5.07-4.86 (m, 1H), 3.79 (d, J = 24.2 Hz, 2H), 2.27-2.15 (m, 8H), 1.69 (dtd, J = 23.3, 6.9, 3.8 Hz, 1H), 1.25-1.09 (m, 1H); LCMS (電灑) m/z 446.10 (M+H)+。 | D |
105 | (1S,2S)-N-(6-(5-乙基-6-氟-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.14 (s, 1H), 11.39 (s, 1H), 9.04 (s, 1H), 8.82 (d, J = 1.1 Hz, 1H), 8.36 (s, 1H), 7.94-7.85 (m, 1H), 5.57 (s, 1H), 5.32 (s, 1H), 5.10-4.83 (m, 1H), 2.77-2.60 (m, 2H), 2.28-2.11 (m, 4H), 1.82-1.58 (m, 1H), 1.22-1.16 (m, 1H), 1.13 (t, J = 7.6 Hz, 3H); LCMS (電灑) m/z 423.15 (M+H)+。 | D |
106 | (1S,2S)-N-(6-(5-乙基-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.20 (s, 1H), 11.38 (s, 1H), 9.03 (d, J = 1.1 Hz, 1H), 8.80 (s, 1H), 8.35 (s, 1H), 7.87 (d, J = 6.0 Hz, 1H), 5.09-4.84 (m, 1H), 3.67-3.53 (m, 1H), 2.74-2.59 (m, 2H), 2.25-2.13 (m, 1H), 1.78-1.61 (m, 1H), 1.44 (d, J = 7.1 Hz, 6H), 1.22-1.15 (m, 1H), 1.15-1.06 (m, 3H); LCMS (電灑) m/z 425.20 (M+H)+。 | D |
107 | (1S,2S)-N-(6-(5-乙基-6-氟-7-(異丙胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 12.93 (s, 1H), 11.35 (s, 1H), 8.99 (s, 1H), 8.73 (d, J = 1.6 Hz, 1H), 8.33 (s, 1H), 7.80 (d, J = 1.1 Hz, 1H), 5.12-4.83 (m, 1H), 4.74 (dd, J = 9.9, 2.2 Hz, 1H), 4.10-3.90 (m, 1H), 2.72-2.60 (m, 2H), 2.24-2.14 (m, 1H), 1.75-1.61 (m, 1H), 1.32-1.16 (m, 7H), 1.13 (t, J = 7.1 Hz, 3H); LCMS (電灑) m/z 440.20 (M+H)+。 | D |
108 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲基-1H-吡咯-3-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.31 (s, 1H), 11.42 (s, 1H), 9.08 (s, 1H), 9.01 (d, J = 1.6 Hz, 1H), 8.39 (s, 1H), 8.07 (s, 1H), 7.48 (s, 1H), 7.01-6.96 (m, 1H), 6.65 (d, J = 2.2 Hz, 1H), 5.07-4.86 (m, 1H), 3.76 (s, 3H), 2.23-2.16 (m, 1H), 1.74-1.64 (m, 1H), 1.25-1.16 (m, 1H); LCMS (電灑) m/z 469.1 (M+H)+。 | D |
109 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1H-吡咯-3-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.31 (s, 1H), 11.45 (s, 1H), 11.41 (s, 1H), 9.08 (s, 1H), 9.01 (d, J = 1.1 Hz, 1H), 8.39 (s, 1H), 8.07 (d, J = 1.1 Hz, 1H), 7.50 (s, 1H), 7.02 (q, J = 2.4 Hz, 1H), 6.69 (s, 1H), 5.07-4.86 (m, 1H), 2.23-2.16 (m, 1H), 1.69 (dtd, J = 23.5, 6.9, 3.7 Hz, 1H), 1.25-1.16 (m, 1H); LCMS (電灑) m/z 455.1 (M+H)+。 | D |
110 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲基-1H-吡唑-5-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.54 (s, 1H), 11.44 (s, 1H), 9.12 (s, 1H), 9.09 (d, J = 1.6 Hz, 1H), 8.43 (d, J = 7.7 Hz, 1H), 8.18 (d, J = 1.1 Hz, 1H), 7.71-7.68 (m, 1H), 6.67 (d, J = 1.9 Hz, 1H), 5.08-4.88 (m, 1H), 3.77 (t, J = 11.0 Hz, 3H), 2.24-2.17 (m, 1H), 1.70 (dtd, J = 23.4, 6.8, 3.8 Hz, 1H), 1.26-1.18 (m, 2H); LCMS (電灑) m/z 470.1 (M+H)+。 | D |
111 | (1S,2S)-N-(6-(5-氯-6-氟-7-((1-羥基-2-甲基丙烷-2-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.82 (s, 1H), 11.39 (s, 1H), 9.04 (s, 1H), 8.96 (d, J = 1.3 Hz, 1H), 8.48 (br s, 1H), 8.36 (s, 1H), 7.98 (s, 1H), 5.54 - 4.80 (m, 2H), 4.61 (br s, 1H), 3.44 - 3.40 (m, 3H), 2.27 - 2.08 (m, 1H), 1.75 - 1.62 (m, 1H), 1.23 (s, 1H), 1.19 (s, 6H); LCMS (電灑) m/z 476.2 (M+H)+。 | D |
112 | (1S,2S)-N-(6-(5-氯-6-氟-7-三甲基乙醯-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.79 (s, 1H), 11.42 (s, 1H), 9.12 - 9.05 (m, 2H), 8.41 (s, 1H), 8.18 (s, 1H), 5.10 - 4.85 (m, 2H), 2.23 - 2.16 (m, 1H), 1.75 - 1.64 (m, 1H), 1.30 (d, J = 1.1 Hz, 9H), 1.25 (br s, 1H); LCMS (電灑) m/z 473.3 (M+H)+。 | D |
113 | (1S,2S)-N-(6-(5-氯-7-環丙氧基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.63 (s, 1 H) 11.40 (s, 1 H) 9.04 - 9.10 (m, 1 H) 8.98 (s, 1 H) 8.38 (s, 1 H) 8.07 (br s, 1 H) 4.81 - 5.12 (m, 1 H) 4.55 (m, 1 H) 2.15 - 2.25 (m, 1 H) 1.63 - 1.77 (m, 1 H) 1.15 - 1.28 (m, 1 H) 0.86 - 0.96 (m, 2 H) 0.69 - 0.78 (m, 2 H); LCMS (電灑) m/z 445.0 (M+H)+。 | D |
114 | 4-甲基四氫呋喃-3-基 (6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)胺基甲酸酯 | 1H NMR (400 MHz, DMSO-d 6) δ 13.98 (s, 1H), 10.95 - 10.53 (m, 1H), 9.03 (s, 1H), 9.00 (d, J = 1.3 Hz, 1H), 8.50 (s, 1H), 8.19 (br s, 1H), 8.12 (s, 1H), 4.92 - 4.81 (m, 1H), 4.04 - 3.91 (m, 2H), 3.81 - 3.71 (m, 1H), 2.59 (s, 3H), 1.23 (br s, 1H), 1.07 (d, J = 7.1 Hz, 3H); LCMS (電灑) m/z 477.3 (M+H)+。 | D |
115 | (1S,2S)-N-(6-(5-氯-6-氟-7-((2-羥乙基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.50 (s, 1H), 11.35 (s, 1H), 9.02 (d, J = 0.6 Hz, 1H), 8.88 (d, J = 1.3 Hz, 1H), 8.49 (s, 1H), 8.35 (s, 1H), 8.01 - 7.88 (m, 1H), 8.09 - 7.79 (m, 1H), 5.67 (br d, J = 2.6 Hz, 1H), 5.07 - 4.83 (m, 2H), 3.66 - 3.53 (m, 4H), 2.24 - 2.10 (m, 1H), 1.76 - 1.59 (m, 1H), 1.20 (tdd, J = 6.3, 9.0, 12.4 Hz, 1H), 1.05 (t, J = 7.0 Hz, 1H); LCMS (電灑) m/z 448.3 (M+H)+。 | D |
116 | (1S,2S)-N-(6-(5-氯-7-(環丁胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.12 (s, 1H), 11.35 (s, 1H), 9.02 (s, 1H), 8.88 (d, J = 1.1 Hz, 1H), 8.35 (s, 1H), 7.94 (br s, 1H), 5.79 (br d, J = 6.4 Hz, 1H), 5.10 - 4.80 (m, 1H), 4.35 (br d, J = 5.3 Hz, 1H), 2.36 - 2.30 (m, 2H), 2.22 - 2.15 (m, 1H), 2.06 - 2.01 (m, 1H), 2.06 - 1.99 (m, 1H), 1.71 (td, J = 3.2, 6.8 Hz, 2H), 1.68 - 1.63 (m, 1H), 1.25 - 1.15 (m, 2H); LCMS (電灑) m/z 458.1 (M+H)+。 | D |
117 | (1S,2S)-N-(6-(5-氯-7-(環戊胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.53 (s, 1H), 11.36 (s, 1H), 9.02 (s, 1H), 8.89 (d, J = 1.2 Hz, 1H), 8.47 (s, 1H), 8.35 (s, 1H), 7.96 (br s, 1H), 5.52 - 5.39 (m, 1H), 5.11 - 4.82 (m, 1H), 4.43 - 4.23 (m, 1H), 2.23 - 2.15 (m, 1H), 1.94 (br d, J = 5.4 Hz, 2H), 1.82 - 1.69 (m, 3H), 1.63 - 1.55 (m, 4H), 1.25 - 1.16 (m, 1H); LCMS (電灑) m/z 472.1 (M+H)+。 | D |
118 | (1S,2S)-N-(6-(5-氯-6-氟-7-((2-甲氧基乙基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.31 (s, 1H), 11.36 (s, 1H), 9.02 (s, 1H), 8.89 (d, J = 1.3 Hz, 1H), 8.35 (s, 1H), 8.08 - 7.86 (m, 1H), 5.67 (br s, 1H), 5.15 - 4.76 (m, 1H), 3.74 - 3.61 (m, 2H), 3.58 - 3.49 (m, 2H), 3.29 (s, 3H), 2.25 - 2.11 (m, 1H), 1.80 - 1.54 (m, 1H), 1.26 - 1.12 (m, 1H); LCMS (電灑) m/z 426.0 (M+H)+。 | D |
119 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1,1,1-三氟丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。1甲酸 | 1H NMR (400 MHz, DMSO-d 6) δ 13.94 (s, 1H), 11.42 (s, 1H), 9.11 - 9.01 (m, 2H), 8.47 (s, 1H), 8.38 (s, 1H), 8.13 (s, 1H), 5.12 - 4.82 (m, 1H), 4.60 - 4.46 (m, 1H), 2.25 - 2.15 (m, 1H), 1.75 (br d, J = 6.7 Hz, 3H), 1.66 (dt, J = 3.8, 6.7 Hz, 1H), 1.29 - 1.13 (m, 1H); LCMS (電灑) m/z 485.0 (M+H)+。 | D |
120 | (1S,2S)-N-(6-(5-氯-6-氟-7-((1-羥基丙烷-2-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。1甲酸 | 1H NMR (400MHz, DMSO-d 6) δ 13.65 (s, 1H), 11.38 (s, 1H), 9.03 (s, 1H), 8.90 (s, 1H), 8.44 (s, 1H), 8.36 (s, 1H), 7.98 (s, 1H), 7.23 (s, 1H), 6.96-6.84 (m, 1H), 5.31 (d, J=7.9 Hz, 1H), 5.14-5.00 (m, 1H), 4.98-4.82 (m, 1H), 4.14-3.85 (m, 1H), 2.25-2.14 (m, 1H), 2.08 (s, 2H), 1.79-1.57 (m, 1H), 1.30-1.12 (m, 5H); LCMS (電灑) m/z 462.0 (M+H)+。 | D |
121 | (1S,2S)-N-(6-(5-氯-6-氟-7-((1-甲氧基丙烷-2-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.20 (s, 1H), 11.36 (s, 1H), 9.02 (s, 1H), 8.90 (s, 1H), 8.35 (s, 1H), 7.95 (s, 1H), 5.32-5.20 (m, 1H), 5.05 (dd, J=6.2, 3.7 Hz, 1H), 4.95-4.81 (m, 1H), 4.42-4.29 (m, 1H), 4.16-3.99 (m, 1H), 3.27 (m, 3H), 2.24-2.12 (m, 1H), 1.77-1.61 (m, 1H), 1.29-1.13 (m, 1H), 1.05 (t, J=7.0 Hz, 1H); LCMS (電灑) m/z 476.1 (M+H)+。 | D |
122 | (1S,2R,3S)-N-(6-(5-氯-7-(二甲胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-甲基-3-(1-甲基-1H-吡唑-4-基)環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.80 (s, 1H), 11.27 (s, 1H), 9.04 (s, 1H), 8.93 (d, J=1.3 Hz, 1H), 8.37 (s, 1H), 8.00 (s, 1H), 7.54 (s, 1H), 7.29 (s, 1H), 3.80 (s, 3H), 3.02 (d, J=2.3 Hz, 6H), 2.37-2.30 (m, 1H), 2.02 (t, J=4.7 Hz, 1H), 1.62 (ddd, J=9.1, 6.1, 4.8 Hz, 1H), 0.97 (d, J=6.2 Hz, 3H); LCMS (電灑) m/z 508.1 (M+H)+。 | D |
123 | (1S,2S,3S)-N-(6-(5-氯-7-(二甲胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-甲基-3-(1-甲基-1H-吡唑-4-基)環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 11.27 (s, 1H), 9.04 (d, J=0.6 Hz, 1H), 8.92 (d, J=1.4 Hz, 1H), 8.41 (s, 1H), 8.00 (s, 1H), 7.53 (s, 1H), 7.26 (s, 1H), 3.76 (s, 3H), 3.01 (d, J=2.4 Hz, 7H), 2.23-2.16 (m, 1H), 2.12 (dd, J=8.9, 4.8 Hz, 1H), 1.60 (dt, J=8.9, 6.3 Hz, 1H), 1.25 (d, J=6.1 Hz, 3H); LCMS (電灑) m/z 508.1 (M+H)+。 | D |
124 | (1S,2S)-N-(6-(5-氯-6-氟-7-(2-氟丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.19 (br s, 1H), 11.40 (s, 1H), 9.08 (s, 1H), 8.99 (s, 1H), 8.39 (s, 1H), 8.06 (s, 1H), 5.12 - 4.84 (m, 1H), 2.28 - 2.15 (m, 1H), 1.96 - 1.86 (m, 6H), 1.74 - 1.64 (m, 1H), 1.26 - 1.16 (m, 1H); LCMS (電灑) m/z 449.2 (M+H)+。 | D |
125 | (1S,2S)-N-(6-(5-氯-7-(環戊-1-烯-1-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.37 (s, 1H), 11.42 (s, 1H), 9.08 (s, 1H), 9.01 (d, J = 1.1 Hz, 1H), 8.39 (s, 1H), 8.08 (d, J = 1.1 Hz, 1H), 6.42 (t, J = 1.9 Hz, 1H), 5.07-4.86 (m, 1H), 3.01-2.85 (m, 2H), 2.67-2.59 (m, 2H), 2.33-2.16 (m, 1H), 2.09-1.91 (m, 2H), 1.69 (dtd, J = 23.4, 3.6 Hz, 1H), 1.31-1.16 (m, 1H); LCMS (電灑) m/z 455.10 (M+H)+。 | D |
126 | (1S,2S)-N-(6-(7-((1H-咪唑-1-基)甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.97 (s, 1H), 11.42 (s, 1H), 9.07 (s, 1H), 9.02 (d, J = 1.1 Hz, 1H), 8.38 (s, 1H), 8.15 (s, 1H), 7.86 (s, 1H), 7.22 (s, 1H), 6.89 (t, 1H), 5.62 (s, 2H), 5.07-4.86 (m, 1H), 2.22-2.15 (m, 1H), 1.72-1.63 (m, 1H), 1.22-1.16 (m, 1H); LCMS (電灑) m/z 469.10 (M+H)+。 | D |
127 | (1S,2S)-N-(6-(5-氯-6-氟-7-(嗎啉胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 12.73 (s, 1H), 11.39 (s, 1H), 9.03 (s, 1H), 8.94-8.86 (m, 1H), 8.37 (d, J = 7.7 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.32 (d, J = 2.7 Hz, 1H), 5.13-4.81 (m, 1H), 3.95-3.72 (m, 4H), 2.97-2.78 (m, 4H), 2.24-2.13 (m, 1H), 1.75-1.62 (m, 1H), 1.27-1.18 (m, 1H); LCMS (電灑) m/z 489.10 (M+H)+。 | D |
128 | (1S,2S)-N-(6-(5-氯-6-氟-7-異丙氧基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 14.26 (s, 1H), 11.39 (s, 1H), 9.05 (s, 1H), 8.98 (d, J = 1.4 Hz, 1H), 8.37 (s, 1H), 8.06 (s, 1H), 5.09 - 4.83 (m, 1H), 4.75 (br s, 1H), 4.68 - 4.66 (m, 1H), 2.24 - 2.13 (m, 1H), 2.07 (s, 1H), 1.79 - 1.59 (m, 1H), 1.37 (d, J = 6.1 Hz, 6H), 1.26 - 1.12 (m, 1H); LCMS (電灑) m/z 447.0 (M+H)+。 | D |
129 | (1S,2S)-N-(6-(7-(2-胺基-2-側氧乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.55 (s, 1H), 11.39 (s, 1H), 9.08 (s, 1H), 9.00 (d, J=1.4 Hz, 1H), 8.40 (s, 1H), 8.04 (s, 1H), 7.66 (br s, 1H), 7.15 (br s, 1H), 5.07 - 4.84 (m, 1H), 3.89 (s, 2H), 2.24 - 2.15 (m, 1H), 1.78 - 1.63 (m, 1H), 1.24 - 1.17 (m, 1H); LCMS (電灑) m/z 446.2 (M+H)+。 | D |
130 | (1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲基丙-1-烯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.41 (s, 1H), 11.41 (s, 1H), 9.08 (d, J = 0.6 Hz, 1H), 9.03 (d, J = 1.5 Hz, 1H), 8.39 (s, 1H), 8.06 (s, 1H), 6.31 (d, J = 1.1 Hz, 1H), 5.12 - 4.80 (m, 1H), 2.24 - 2.15 (m, 1H), 2.04 (s, 3H), 1.74 - 1.65 (m, 4H), 1.26 - 1.17 (m, 2H); LCMS (電灑) m/z 443.2 (M+H)+。 | D |
131 | (1S,2S)-N-(6-(5-氯-7-((2,2-二氟乙基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 14.09 (s, 1H), 11.36 (s, 1H), 9.02 (s, 1H), 8.90 (d, J = 1.2 Hz, 1H), 8.45 (br s, 1H), 8.35 (s, 1H), 8.05 (br s, 1H), 6.44 - 6.00 (m, 2H), 5.10 - 4.80 (m, 1H), 4.12 - 3.79 (m, 2H), 2.23 - 2.14 (m, 1H), 2.07 (s, 1H), 1.75 - 1.62 (m, 1H), 1.26 - 1.14 (m, 1H); LCMS (電灑) m/z 468.3 (M+H)+。 | D |
132 | (1S,2S)-N-(6-(7-(2-溴-2-氟環丙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 14.08 (s, 1H), 11.44 - 11.37 (m, 1H), 9.34 (s, 1H), 9.07 (s, 1H), 9.05 - 9.00 (m, 1H), 8.73 (s, 1H), 8.45 (s, 1H), 8.41 - 8.36 (m, 1H), 8.13 (s, 1H), 7.59 (d, J = 12.1 Hz, 1H), 5.16 - 4.71 (m, 1H), 2.27 - 2.04 (m, 3H), 1.77 - 1.60 (m, 1H), 1.29 - 1.13 (m, 2H); LCMS (電灑) m/z 527.3 (M+H)+。 | D |
133 | (1S,2S)-N-(6-(7-(烯丙基胺基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.01 (s, 1 H) 11.24 - 11.49 (m, 1 H) 8.97 - 9.11 (m, 1 H) 8.90 (s, 1 H) 8.29 - 8.43 (m, 1 H) 7.90 - 8.06 (m, 1 H) 5.88 - 6.08 (m, 2 H) 5.21 (br d, J=16.94 Hz, 1 H) 5.07 - 5.14 (m, 1 H) 4.85 - 5.07 (m, 1 H) 4.02 - 4.28 (m, 2 H) 2.11 - 2.26 (m, 1 H) 1.54 - 1.79 (m, 1 H) 1.13 - 1.25 (m, 1 H); LCMS (電灑) m/z 444.0 (M+H)+。 | D |
134 | (1S,2S)-N-(6-(5-氯-7-環戊基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.48 (s, 1H), 11.39 (s, 1H), 9.07 (s, 1H), 8.99 (dd, J = 13.5, 1.4 Hz, 1H), 8.45-8.38 (m, 1H), 8.07-8.03 (m, 1H), 5.07-4.86 (m, 1H), 3.62 (t, J = 8.2 Hz, 1H), 2.23-2.16 (m, 1H), 2.07-1.91 (m, 6H), 1.73-1.64 (m, 3H), 1.25-1.16 (m, 1H); LCMS (電灑) m/z 455.10 (M+H)+。 | D |
135 | (1S,2S)-N-(6-(5-氯-6-氟-7-((4-甲基哌嗪-1-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H MR (400MHz, DMSO-d 6) δ 12.54 (s, 1H), 11.38 (s, 1H), 9.02 (s, 1H), 8.89 (d, J = 1.6 Hz, 1H), 8.35 (s, 1H), 7.94 (d, J = 1.6 Hz, 1H), 7.20 (s, 1H), 5.09-4.83 (m, 1H), 2.88 (m, 4H), 2.57 (m, 4H), 2.29-2.11 (m, 4H), 1.76-1.60 (m, 1H), 1.21-1.18 (m, 1H); LCMS (電灑) m/z 502.20 (M+H)+。 | D |
136 | (1S,2S)-N-(6-(5-氯-6-氟-7-((2-氟乙基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.49 (s, 1H), 11.36 (s, 1H), 9.02 (d, J = 0.6 Hz, 1H), 8.90 (d, J = 1.4 Hz, 1H), 8.35 (s, 1H), 8.01 (br d, J = 2.5 Hz, 1H), 5.93 (br s, 1H), 5.10 - 4.80 (m, 1H), 4.68 (t, J = 4.8 Hz, 1H), 4.56 (t, J = 4.9 Hz, 1H), 4.01 - 3.66 (m, 2H), 2.25 - 2.13 (m, 1H), 1.75 - 1.61 (m, 1H), 1.20 (tdd, J = 6.3, 9.1, 12.4 Hz, 1H); LCMS (電灑) m/z 450.3 (M+H)+。 | D |
137 | (1S,2S)-N-(6-(5-氯-7-((1,3-二羥基-2-甲基丙烷-2-基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.98 (s, 1H), 11.38 (s, 1H), 9.11 - 9.02 (m, 1H), 8.96 (d, J = 1.5 Hz, 1H), 8.36 (s, 1H), 8.00 (br s, 1H), 5.28 - 4.82 (m, 3H), 4.51 (br s, 1H), 3.56 - 3.45 (m, 4H), 2.19 (td, J = 7.0, 13.9 Hz, 1H), 1.74 - 1.62 (m, 1H), 1.30 - 1.11 (m, 2H), 1.06 (br s, 3H); LCMS (電灑) m/z 492.2 (M+H)+。 | D |
138 | (1S,2S)-2-氟-N-(6-(6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ13.34 (br s, 1H), 11.36 (s, 1H), 9.28 (d, J=1.3 Hz, 1H), 9.05 (s, 1H), 8.66 (s, 1H), 8.38 (s, 1H), 7.51 (d, J=12.7 Hz, 1H), 5.08 - 4.85 (m, 1H), 3.64 - 3.53 (m, 1H), 2.19 (td, J=6.9, 13.8 Hz, 1H), 1.77 - 1.63 (m, 1H), 1.43 (d, J=7.0 Hz, 6H), 1.23 - 1.14 (m, 1H); LCMS (電灑) m/z 397.2 (M+H)+。 | D |
139 | (1S,2S)-N-(6-(5-氯-6-氟-7-((1-甲基-1H-吡唑-5-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.19 (br s, 1H), 11.39 (s, 1H), 9.06 (s, 1H), 8.99 (d, J=1.1 Hz, 1H), 8.49 (s, 1H), 8.38 (s, 1H), 8.28 (br s, 1H), 8.04 (br s, 1H), 7.24 (d, J=1.9 Hz, 1H), 5.45 (br s, 1H), 5.10 - 4.83 (m, 1H), 3.79 (s, 3H), 2.19 (td, J=6.9, 13.8 Hz, 1H), 1.77 - 1.61 (m, 1H), 1.21 (tdd, J=6.2, 9.0, 12.3 Hz, 1H); LCMS (電灑) m/z 484.1 (M+H)+。 | D |
140 | (1S,2S)-N-(6-(5-氯-6-氟-7-((4-羥基丁烷-2-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.30 (s, 1H), 11.35 (s, 1H), 9.02 (s, 1H), 8.90 (s, 1H), 8.35 (s, 1H), 7.95 (s, 1H), 5.26 - 5.18 (m, 1H), 5.10-5.00 (m, 1H), 4.90-4.84 (m, 1H), 4.78-4.71 (m, 1H), 4.04-3.94 (m, 1H), 3.66-3.54 (m, 3H), 2.23-2.15 (m, 2H), 1.85-1.75 (m, 1H), 1.73-1.63 (m, 3H), 1.22 (d, J=6.2 Hz, 4H); LCMS (電灑) m/z 476.1 (M+H)+。 | D |
141 | (1S,2S)-2-氟-N-(6-(6-氟-7-異丙基-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺。2甲酸 | 1H NMR (400 MHz, DMSO-d 6) δ 13.33 - 13.64 (m, 1H), 11.33 - 11.43 (m, 1H), 9.00 - 9.07 (m, 1H), 8.81 - 8.89 (m, 1H), 8.43 - 8.43 (m, 1H), 8.40 - 8.46 (m, 3H), 8.34 - 8.38 (m, 1H), 7.91 - 8.00 (m, 1H), 5.13-4.97 (m, 1H), 4.91- 4.84 (m, 1H), 2.28 - 2.25 (m, 3H), 2.23 - 2.14 (m, 1H) 1.77 - 1.62 (m, 1H), 1.50 - 1.41 (m, 6H), 1.12 - 1.00 (m, 1H); LCMS (電灑) m/z 443.1 (M+H)+。 | D |
142 | (1S,2R,3S)-N-(6-(5-氯-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-甲基-3-(1-甲基-1H-吡唑-4-基)環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.80 (s, 1H), 11.28 (s, 1 H), 9.06 (s, 1 H), 8.97 (d, J=1.3 Hz, 1H), 8.37 (s, 1H), 8.04 (s, 1H), 7.54 (s, 1H), 7.29 (s, 1H), 3.80 (s, 3H), 2.33 (dd, J=5.3, 3.8 Hz, 1H), 2.02 (t, J=4.7 Hz, 1H), 1.72-1.57 (m, 2H), 1.45 (d, J=6.9 Hz, 7H), 0.97 (d, J=6.2 Hz, 3H); LCMS (電灑) m/z 507.1 (M+H)+。 | D |
143 | (1S,2S,3S)-N-(6-(5-氯-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-甲基-3-(1-甲基-1H-吡唑-4-基)環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.74 (s, 1H), 11.26 (s, 1H), 9.05 (s, 1H), 8.95 (d, J=1.3 Hz, 1H), 8.40 (s, 1H), 8.04 (s, 1H), 7.53 (s, 1H), 7.26 (s, 1H), 3.76 (s, 3H), 3.67-3.62 (m, 1H), 2.23 - 2.16 (m, 1 H), 2.13 (dd, J=8.9, 4.7 Hz, 1H), 1.60 (dt, J=8.9, 6.2 Hz, 1H), 1.45 (d, J=7.0 Hz, 6H), 1.30 - 1.21 (m, 3H); LCMS (電灑) m/z 507.1 (M+H)+。 | D |
144 | (1S,2S)-N-(6-(7-((1H-吡咯-1-基)甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.86 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.02 (d, J = 1.6 Hz, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 6.93 (t, 2H), 6.00 (t, J = 2.2 Hz, 2H), 5.51 (s, 2H), 5.05-4.88 (m, 1H), 2.21-2.21 (m, 1H), 1.72-1.66 (m, 1H), 1.18-1.18 (m, 1H); LCMS (電灑) m/z 468.10 (M+H)+。 | D |
145 | (1S,2S)-N-(6-(7-((1H-吡唑-1-基)甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.79 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.02 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.43 (s, 1H), 6.26 (t, J = 1.9 Hz, 1H), 5.75 (s, 2H), 5.05-4.86 (m, 1H), 2.21-2.15 (m, 1H), 1.74-1.65 (m, 1H), 1.21-1.16 (m, 1H); LCMS (電灑) m/z 469.10 (M+H)+。 | D |
146 | (1S,2S)-N-(6-(5-氯-6-氟-7-(2,2,2-三氟-1-羥乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.31 (s, 1H), 11.37 (s, 1H), 9.07-8.99 (m, 2H), 8.34 (s, 1H), 8.04 (s, 1H), 7.60 (d, J = 5.5 Hz, 1H), 5.75 (q, J = 6.6 Hz, 1H), 5.03-4.82 (m, 1H), 2.19-2.12 (m, 1H), 1.70-1.62 (m, 1H), 1.18-1.13 (m, 1H); LCMS (電灑) m/z 488.1 (M+H)+。 | D |
147 | (1S,2S)-N-(6-(5-氯-6-氟-7-(吡咯烷-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.87 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.01 (d, J = 1.1 Hz, 1H), 8.38 (s, 1H), 8.12 (s, 1H), 6.83 (t, J = 2.5 Hz, 1H), 6.64 (s, 1H), 5.81 (t, 1H), 5.41 (s, 2H), 5.06-4.86 (m, 1H), 2.22-2.15 (m, 1H), 1.94 (s, 3H), 1.74-1.64 (m, 1H), 1.25-1.16 (m, 1H); LCMS (電灑) m/z 482.10 (M+H)+。 | D |
148 | (1S,2S)-N-(6-(5-氯-6-氟-7-(3-羥基吡咯烷-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.12 (s, 1H), 11.35 (s, 1H), 9.02 (s, 1H), 8.88 (s, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 5.11-4.80 (m, 2H), 4.50-4.32 (m, 1H), 4.23-3.88 (m, 2H), 3.81-3.61 (m, 1H), 3.53-3.40 (m, 1H), 2.26-2.13 (m, 1H), 2.13-1.95 (m, 1H), 1.95-1.82 (m, 1H), 1.78-1.58 (m, 1H), 1.22-1.11 (m, 1H); LCMS (電灑) m/z 474.10 (M+H)+。 | D |
149 | (1S,2S)-N-(6-(5-氯-6-氟-7-((R)-3-羥基吡咯烷-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.12 (s, 1H), 11.36 (s, 1H), 9.03 (s, 1H), 8.87 (d, J = 11.5 Hz, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 5.12-4.82 (m, 2H), 4.50-4.34 (m, 1H), 4.22-3.88 (m, 2H), 3.82-3.63 (m, 1H), 3.53-3.38 (m, 1H), 2.26-2.12 (m, 1H), 2.12-1.96 (m, 1H), 1.95-1.82 (m, 1H), 1.77-1.60 (m, 1H), 1.28-1.13 (m, 1H); LCMS (電灑) m/z 474.10 (M+H)+。 | D |
150 | (1S,2S)-N-(6-(5-氯-6-氟-7-(3-側氧環戊-1-烯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.58 (s, 1H), 11.41 (s, 1H), 9.10-9.06 (m, 2H), 8.41 (d, J = 6.0 Hz, 1H), 8.19 (d, J = 1.1 Hz, 1H), 6.79 (s, 1H), 5.07-4.86 (m, 1H), 3.40-3.36 (m, 1H), 3.29-3.27 (m, 2H), 2.58-2.56 (m, 2H), 2.23-2.16 (m, 1H), 1.75-1.64 (m, 1H), 1.25-1.17 (m, 1H); LCMS (電灑) m/z 469.10 (M+H)+。 | D |
151 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲氧基乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.47 (s, 1H), 11.47 - 11.38 (m, 1H), 9.07 (s, 1H), 9.03 - 8.98 (m, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 5.08 - 5.05 (m, 1H), 5.04 - 4.84 (m, 1H), 3.24 (s, 3H), 2.19 (td, J = 7.0, 13.8 Hz, 1H), 1.76 - 1.63 (m, 1H), 1.59 (d, J = 6.6 Hz, 3H), 1.25 - 1.17 (m, 1H); LCMS (電灑) m/z 447.1 (M+H)+。 | D |
152 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(N-甲基乙醯胺基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.44 (s, 1H), 11.40 (s, 1H), 9.36 - 9.30 (m, 1H), 9.07 (s, 1H), 8.99 (s, 1H), 8.69 (br s, 1H), 8.38 (s, 1H), 8.25 - 8.16 (m, 1H), 8.08 (s, 1H), 7.60 - 7.51 (m, 1H), 6.17 - 5.99 (m, 1H), 5.80 - 5.68 (m, 1H), 5.11 - 4.84 (m, 1H), 3.03 (s, 2H), 2.96 (s, 1H), 2.78 (br s, 1H), 2.21 - 2.17 (m, 1H), 2.04 (s, 3H), 1.86 - 1.72 (m, 1H), 1.68 (br d, J = 7.3 Hz, 3H), 1.24 - 1.16 (m, 1H); LCMS (電灑) m/z 488.1 (M+H)+。 | D |
153 | (1S,2S)-N-(6-(5-氯-7-(環丙基(羥基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.26 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.00 (d, J=1.3 Hz, 1H), 8.38 (s, 1H), 8.01 (s, 1H), 5.88 (d, J=1.5 Hz, 1H),5.08-5.01 (m, 1H), 4.92-4.84 (m, 1H), 4.62 (d, J=6.0 Hz, 1H), 2.25-2.12 (m, 1H), 1.78 - 1.60 (m, 1H), 1.52-1.39 (m, 1H), 1.35-1.13 (m, 3H), 0.65-0.52 (m, 2H), 0.48-0.28 (m, 2H); LCMS (電灑) m/z 459.1 (M+H)+。 | D |
154 | (1S,2S)-N-(6-(7-((1H-吡唑-5-基)胺基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.26 (br s, 1H), 12.14 (br s, 1H), 11.37 (s, 1H), 9.05 (s, 1H), 8.96 (d, J=1.5 Hz, 1H), 8.44 (br s, 1H), 8.38 (s, 1H), 8.00 (s, 1H), 7.63 (s, 1H), 5.90 (s, 1H), 5.08 - 4.84 (m, 1H), 2.19 (td, J=6.9, 13.8 Hz, 1H), 1.75 - 1.63 (m, 1H), 1.25 - 1.16 (m, 1H); LCMS (電灑) m/z 470.1 (M+H)+。 | D |
155 | (1R,2R)-N-(6-(5-氯-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.51 (br s, 1H), 11.39 (s, 1H), 9.06 (s, 1H), 8.97 (d, J=1.4 Hz, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 5.08 - 4.85 (m, 1H), 3.69 - 3.56 (m, 1H), 2.19 (td, J=7.0, 13.9 Hz, 1H), 1.75 - 1.63 (m, 1H), 1.46 (d, J=7.0 Hz, 6H), 1.26 - 1.16 (m, 1H); LCMS (電灑) m/z 431.1 (M+H)+。 | D |
156 | (1S,2R)-N-(6-(5-氯-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.52 (br s, 1H), 11.51 (br s, 1H), 9.08 (s, 1H), 8.98 (d, J=1.3 Hz, 1H), 8.34 (s, 1H), 8.04 (s, 1H), 5.06 - 4.82 (m, 1H), 3.63 (td, J=7.0, 14.0 Hz, 1H), 1.64 - 1.51 (m, 1H), 1.46 (d, J=7.0 Hz, 6H), 1.28 (td, J=6.4, 13.1 Hz, 1H); LCMS (電灑) m/z 431.2 (M+H)+。 | D |
157 | (1R,2S)-N-(6-(5-氯-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.52 (br s, 1H), 11.50 (s, 1H), 9.07 (d, J=0.6 Hz, 1H), 8.97 (d, J=1.3 Hz, 1H), 8.33 (s, 1H), 8.04 (br s, 1H), 5.05 - 4.82 (m, 1H), 3.63 (td, J=7.0, 14.2 Hz, 1H), 1.65 - 1.51 (m, 1H), 1.45 (d, J=7.1 Hz, 6H), 1.34 - 1.21 (m, 1H); LCMS (電灑) m/z 431.2 (M+H)+。 | D |
158 | (1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(1H-吡唑-5-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.47 (br s, 1H), 11.88 (br s, 1H), 11.40 (s, 1H), 9.08 (s, 1H), 9.02 (d, J=1.2 Hz, 1H), 8.40 (s, 1H), 8.07 (s, 1H), 7.52 (s, 1H), 5.51 (s, 1H), 5.09 - 4.85 (m, 1H), 3.38 (s, 3H), 2.20 (td, J=6.9, 14.0 Hz, 1H), 1.76 - 1.63 (m, 1H), 1.27 - 1.15 (m, 1H); LCMS (電灑) m/z 484.1 (M+H)+。 | D |
159 | (1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(1-((2-(三甲基矽基)乙氧基)甲基)-1H-吡唑-5-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.55 (br s, 1H), 11.40 (s, 1H), 9.08 (d, J=0.6 Hz, 1H), 9.01 (d, J=1.5 Hz, 1H), 8.40 (s, 1H), 8.08 (s, 1H), 7.68 (d, J=2.4 Hz, 1H), 5.59 (d, J=2.3 Hz, 1H), 5.21 (s, 2H), 5.08 - 4.86 (m, 1H), 3.55 - 3.47 (m, 2H), 3.37 (br s, 3H), 2.19 (td, J=6.9, 13.9 Hz, 1H), 1.76 - 1.63 (m, 1H), 1.26 - 1.16 (m, 1H), 0.85 - 0.80 (m, 2H), -0.03 (s, 9H); LCMS (電灑) m/z 614.2 (M+H)+。 | D |
160 | (1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(1-甲基-1H-吡唑-5-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.76 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.01 (d, J=1.3 Hz, 1H), 8.39 (s, 1H), 8.13 (d, J=1.2 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 6.07 (d, J=2.0 Hz, 1H), 5.07 - 4.85 (m, 1H), 3.32 (br s, 3H), 3.28 (s, 3H), 2.19 (td, J=7.0, 13.9 Hz, 1H), 1.76 - 1.62 (m, 1H), 1.21 (tdd, J=6.2, 9.0, 12.4 Hz, 1H); LCMS (電灑) m/z 498.2 (M+H)+。 | D |
161 | (1S,2S)-N-(6-(5-氯-6-氟-7-異丁醯-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.78 (s, 1H), 11.43 (s, 1H), 9.10 (s, 2H), 8.43 (s, 1H), 8.18 (s, 1H), 5.14 - 4.79 (m, 1H), 3.62 - 3.53 (m, 1H), 2.20 (td, J = 6.9, 13.8 Hz, 1H), 1.79 - 1.67 (m, 1H), 1.24 (d, J = 6.6 Hz, 7H); LCMS (電灑) m/z 459.3 (M+H)+。 | D |
162 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-羥基-2-甲基丙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.18 (br s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.01 (d, J = 1.5 Hz, 1H), 8.39 (s, 1H), 8.00 (s, 1H), 5.87 (br d, J = 3.1 Hz, 1H), 5.10 - 4.83 (m, 2H), 2.24 - 2.14 (m, 2H), 1.75 - 1.63 (m, 1H), 1.21 (tdd, J = 6.1, 9.0, 12.3 Hz, 1H), 1.08 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 6.7 Hz, 3H); LCMS (電灑) m/z 461.4 (M+H)+。 | D |
163 | (1S,2S)-N-(6-(5-氯-6-氟-7-(((1S,3R)-3-羥基環戊基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.21 (s, 1H), 11.35 (s, 1H), 9.02 (s, 1H), 8.89 (d, J = 1.1 Hz, 1H), 8.34 (d, J = 6.0 Hz, 1H), 7.95 (s, 1H), 5.56-5.39 (m, 1H), 5.09-4.84 (m, 1H), 4.84-4.73 (m, 1H), 4.48-4.13 (m, 2H), 2.26-2.11 (m, 2H), 2.03-1.87 (m, 1H), 1.81-1.53 (m, 5H), 1.22-1.13 (m, 1H); LCMS (電灑) m/z 488.10 (M+H)。 | D |
164 | (1S,2S)-N-(6-(5-氯-6-氟-7-((2-甲基-1H-咪唑-1-基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.92 (s, 1H), 11.41 (d, J = 7.4 Hz, 1H), 9.08 (d, J = 7.1 Hz, 1H), 9.04-9.02 (m, 1H), 8.39 (d, J = 7.1 Hz, 1H), 8.18 (d, J = 6.6 Hz, 1H), 7.03 (d, J = 7.1 Hz, 1H), 6.73-6.71 (m, 1H), 5.53 (d, J = 7.1 Hz, 2H), 5.06-4.88 (m, 1H), 2.39 (d, J = 7.7 Hz, 3H), 2.22-2.17 (m, 1H), 1.72-1.67 (m, 1H), 1.19-1.19 (m, 1H); LCMS (電灑) m/z 483.10 (M+H)+。 | D |
165 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-羥基環戊基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 12.91 (s, 1H), 11.39 (s, 1H), 9.07 (d, J = 1.6 Hz, 1H), 8.97 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 7.98 (d, J = 1.1 Hz, 1H), 5.76 (d, J = 5.5 Hz, 1H), 5.07-4.86 (m, 1H), 2.20 (d, J = 17.6 Hz, 6H), 1.95 (dd, J = 18.7, 13.2 Hz, 3H), 1.83 (d, J = 6.6 Hz, 2H), 1.74-1.64 (m, 1H), 1.25-1.19 (m, 1H); LCMS (電灑) m/z 473.10 (M+H)+。 | D |
166 | (1S,2S)-2-氟-N-(6-(6-氟-7-異丙基-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺。 | 1H NMR (400 MHz, DMSO-d 6) δ 13.39 (s, 1 H) 11.32 - 11.50 (m, 1 H) 8.96 - 9.04 (m, 1 H) 8.81 - 8.91 (m, 1 H) 8.27 - 8.40 (m, 1 H) 7.95 - 8.11 (m, 1 H) 5.11 – 4.83 (m, 1 H) 3.59 - 3.74 (m, 1 H) 2.14 - 2.26 (m, 1 H) 1.63 - 1.77 (m, 1 H) 1.40 - 1.52 (m, 6 H) 1.13 - 1.26 (m, 1 H); LCMS (電灑) m/z 465.1 (M+H)+。 | D |
167 | (1S,2S)-N-(6-(5-氯-7-(1,1-二氟丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 11.40 (s, 1H), 9.07 (s, 1H), 9.02 (d, J = 1.5 Hz, 1H), 9.04 - 8.99 (m, 1H), 8.39 (s, 1H), 8.12 (s, 1H), 6.70 - 6.31 (m, 1H), 5.12 - 4.82 (m, 1H), 4.10 - 3.89 (m, 1H), 2.25 - 2.15 (m, 2H), 1.78 - 1.62 (m, 1H), 1.56 (d, J = 7.2 Hz, 3H), 1.29 - 1.13 (m, 2H); LCMS (電灑) m/z 467.0 (M+H)+。 | D |
168 | (1S,2S)-N-(6-(5-氯-6-氟-7-異丁基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.60 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.01 (d, J = 1.3 Hz, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 5.06 - 4.86 (m, 1H), 2.89 (br d, J = 7.2 Hz, 2H), 2.23 - 2.17 (m, 1H), 2.09 - 2.03 (m, 1H), 1.74 - 1.66 (m, 1H), 1.26 - 1.18 (m, 1H), 0.97 (d, J = 6.5 Hz, 6H); LCMS (電灑) m/z 445.4 (M+H)+。 | D |
169 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲氧基-2-甲基丙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.35 (s, 1H), 11.40 (br s, 1H), 9.07 (s, 1H), 9.03 (d, J = 1.3 Hz, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 5.07 - 4.85 (m, 1H), 4.55 (d, J = 7.9 Hz, 1H), 3.21 (s, 3H), 2.27 (br dd, J = 7.0, 13.5 Hz, 1H), 2.22 - 2.16 (m, 1H), 1.74 - 1.63 (m, 1H), 1.24 - 1.16 (m, 1H), 1.10 (d, J = 6.6 Hz, 3H), 0.79 (d, J = 6.7 Hz, 3H); LCMS (電灑) m/z 475.4 (M+H)+。 | D |
170 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-氟-2-甲基丙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。1甲酸 | 1H NMR (400 MHz, DMSO-d 6) δ 13.60 (s, 1H), 11.42 (s, 1H), 9.09 (d, J = 0.6 Hz, 1H), 9.05 (d, J = 1.5 Hz, 1H), 8.46 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 5.92 - 5.76 (m, 1H), 5.58 (br d, J = 8.2 Hz, 1H), 5.10 - 4.85 (m, 1H), 2.21 (br dd, J = 2.1, 6.8 Hz, 1H), 1.64 - 1.60 (m, 1H), 1.56 - 1.47 (m, 1H), 1.18 (br d, J = 6.5 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H); LCMS (電灑) m/z 463.4 (M+H)+。 | D |
171 | (1S,2S)-N-(6-(5-氯-6-氟-7-((4-甲氧基丁烷-2-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.10 (s, 1H), 11.35 (s, 1H), 9.02 (s, 1H), 8.90 (s, 1H), 8.35 (s, 1H), 7.98 –7.92 (m, 1H), 5.29 – 4.84,(m, 2H), 3.47 (t, J=6.17 Hz, 2H), 3.21 (s, 4H), 2.23-2.14 (m, 2H), 1.22 (d, J=6.2 Hz, 4H), 1.16 (d, J=6.9 Hz, 2H); LCMS (電灑) m/z 443.1 (M+H)+。 | D |
172 | (1S,2S)-N-(6-(5-氯-6-氟-7-((3-氟環丁基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ13.70 (s, 1H), 11.35 (s, 1H), 9.02 (s, 1H), 8.89 (s, 1H), 8.35 (s, 1H), 7.96 (br s, 1H), 5.46 - 5.20 (m, 1H), 5.11 - 4.82 (m, 1H), 4.75 - 4.44 (m, 1H), 2.70 - 2.64 (m, 1H), 2.35 - 2.30 (m, 1H), 2.26 - 2.10 (m, 2H), 1.74 - 1.60 (m, 1H), 1.20 (br dd, J = 9.0, 12.2 Hz, 2H); LCMS (電灑) m/z 476.2 (M+H)+。 | D |
173 | (1S,2S)-N-(6-(5-氯-7-(環丙基(甲氧基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.40 (s, 1H), 11.44 (s, 1H), 9.08 (s, 1H), 9.03 (s, 1H), 8.38 (s, 1H), 8.05 (s, 1H), 5.10 – 4.82 (m, 1 H), 4.26 (d, J=8.6 Hz, 1H), 3.26 (s, 3H), 2.19 (dt, J=13.2, 6.6 Hz, 1H), 1.79 - 1.62 (m, 1H), 1.35-1.11 (m, 2H), 0.77-0.53 (m, 2H), 0.51-0.21 (m, 2H); LCMS (電灑) m/z 473.0 (M+H)+。 | D |
174 | (1S,2S)-N-(6-(7-((E)-丁-2-烯-2-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.40 (s, 1H), 11.41 (s, 1H), 9.08 (s, 1H), 9.03 (s, 1H), 8.39 (s, 1H), 8.06 (s, 1H), 6.95 – 5.97 (m, 1H), 5.07– 4.86 (m, 1H), 2.18 - 2.21 (m, 1H), 2.14 (m, 3H), 1.63 - 1.73 (m, 1H), 1.47 (m, 3H), 1.23 (m, 1H); LCMS (電灑) m/z 443.1 (M+H)+。 | D |
175 | (1S,2S)-N-(6-(7-(丁-3-烯-2-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.52 (s, 1H), 11.41 (s, 1H), 9.07 (s, 1H), 9.00 (s, 1H), 8.39 (s, 1H), 8.06 (s, 1H), 6.20 - 6.28 (m, 1H), 5.19 (d, J= 8 Hz, 1H), 5.12 (d, J= 8 Hz, 1H), 4.87 – 5.07(m, 1H), 4.20 - 4.24 (m, 1 H), 2.16 - 2.23 (m, 1 H), 1.53 - 1.74 (m, 1 H), 1.56 (d, J= 6.8 Hz, 3 H), 0.84 - 0.88 (m, 1 H); LCMS (電灑) m/z 443.1 (M+H)+。 | D |
176 | (1S,2S)-N-(6-(7-(二級丁基胺基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.03 - 13.28 (m, 1H), 11.26 - 11.42 (m, 1H), 8.99 - 9.07 (m, 1H), 8.86 - 8.95 (m, 1H), 8.32 - 8.39 (m, 1H), 7.89 - 8.04 (m, 1H), 5.25 - 4.85 (m, 1H), 3.73 - 3.99 (m, 1H), 2.14 - 2.24 (m, 1H), 1.59 - 1.74 (m, 2H), 1.45 - 1.56 (m, 1H), 1.16 - 1.25 (m, 4H) 0.91 - 0.98 (m, 3H); LCMS (電灑) m/z 460.2 (M+H)+。 | D |
177 | (1S,2S)-N-(6-(5-氯-6-氟-7-((2-甲基-1H-吡咯-1-基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.65 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.03 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 8.12 (s, 1H), 6.68 (s, 1H), 5.87 (t, J = 3.0 Hz, 1H), 5.77 (s, 1H), 5.44 (s, 2H), 5.05-4.88 (m, 1H), 2.23-2.17 (m, 4H), 1.71-1.66 (m, 1H), 1.17-1.15 (m, 1H); LCMS (電灑) m/z 482.10 (M+H)+。 | D |
178 | (1S,2S)-N-(6-(5-氯-6-氟-7-((4-甲基-1H-咪唑-1-基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.92 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.01 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 8.14 (s, 1H), 7.72 (s, 1H), 6.87 (s, 1H), 5.53 (s, 2H), 5.07-4.86 (m, 1H), 2.22-2.15 (m, 1H), 2.02 (s, 3H), 1.74-1.64 (m, 1H), 1.22-1.16 (m, 1H); LCMS (電灑) m/z 483.10 (M+H)+。 | D |
179 | (1S,2S)-N-(6-(5-氯-6-氟-7-((4-甲基-1H-吡唑-1-基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.79 (s, 1H), 11.40 (s, 1H), 9.07 (d, J = 1.6 Hz, 1H), 9.02 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 8.10 (s, 1H), 7.65 (s, 1H), 7.22 (s, 1H), 5.64 (s, 2H), 5.07-4.86 (m, 1H), 2.23-2.15 (m, 1H), 1.98 (s, 3H), 1.74-1.64 (m, 1H), 1.25-1.16 (m, 1H) ); LCMS (電灑) m/z 483.10 (M+H)+。 | D |
180 | (1S,2S)-N-(6-(5-氯-6-氟-7-((S)-3-羥基吡咯烷-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.12 (s, 1H), 11.36 (s, 1H), 9.02 (s, 1H), 8.88 (s, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 5.11-4.82 (m, 2H), 4.51-4.33 (m, 1H), 4.22-3.89 (m, 2H), 3.70 (s, 1H), 3.54-3.41 (m, 1H), 2.26-2.14 (m, 1H), 2.11-1.95 (m, 1H), 1.95-1.81 (m, 1H), 1.77-1.62 (m, 1H), 1.25-1.18 (m, 1H); LCMS (電灑) m/z 474.10 (M+H)+。 | D |
181 | (1S,2S)-N-(6-(5-氯-6-氟-7-(2-羥基環戊基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.47 (s, 1H), 11.37 (d, J = 13.2 Hz, 1H), 9.07 (s, 1H), 8.97 (d, J = 1.6 Hz, 1H), 8.39 (d, J = 4.4 Hz, 1H), 8.02 (d, J = 1.1 Hz, 1H), 7.53 (d, J = 12.6 Hz, 0H), 5.07-4.86 (m, 2H), 4.53-4.42 (m, 1H), 3.48 (dd, J = 18.7, 8.2 Hz, 1H), 2.33-2.01 (m, 4H), 1.99-1.61 (m, 6H), 1.25-1.16 (m, 1H); LCMS (電灑) m/z 473.10 (M+H)+。 | D |
182 | (1S,2S)-N-(6-(5-氯-6-氟-7-((四氫呋喃-3-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.12 (s, 1H), 11.32 (s, 1H), 8.98 (d, J = 8.2 Hz, 1H), 8.85 (d, J = 10.4 Hz, 1H), 8.31 (d, J = 6.6 Hz, 1H), 7.92 (s, 1H), 5.60 (d, J = 8.2 Hz, 1H), 5.01-4.82 (m, 1H), 4.53 (s, 1H), 3.93-3.81 (m, 2H), 3.75-3.67 (m, 2H), 2.24-2.11 (m, 2H), 1.88 (d, J = 9.3 Hz, 1H), 1.67-1.61 (m, 1H), 1.19-1.12 (m, 1H); LCMS (電灑) m/z 475.1 (M+H)+。 | D |
183 | (1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲氧基環戊基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.58 (s, 1H), 11.38 (d, J = 13.2 Hz, 1H), 9.07 (s, 1H), 8.99 (t, J = 1.9 Hz, 1H), 8.38 (s, 1H), 8.04 (d, J = 1.1 Hz, 1H), 5.07-4.86 (m, 1H), 4.20 (q, J = 5.9 Hz, 1H), 3.61 (q, J = 8.2 Hz, 1H), 3.15-3.10 (m, 3H), 2.23-2.08 (m, 4H), 1.97-1.64 (m, 6H), 1.27-1.16 (m, 2H); LCMS (電灑) m/z 486.90 (M+H)+。 | D |
184 | (1S,2S)-N-(6-(5-氯-6-氟-7-(((1S,3S)-3-羥基環戊基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.12 (s, 1H), 11.35 (s, 1H), 9.02 (s, 1H), 8.90 (s, 1H), 8.34 (s, 1H), 7.94 (s, 1H), 5.34 (d, J = 7.7 Hz, 1H), 5.09-4.82 (m, 1H), 4.55 (d, J = 3.3 Hz, 1H), 4.50-4.38 (m, 1H), 4.35-4.21 (m, 1H), 2.26-2.08 (m, 2H), 2.04-1.87 (m, 2H), 1.81-1.62 (m, 2H), 1.59-1.44 (m, 2H), 1.22-1.11 (m, 1H); LCMS (電灑) m/z 488.10 (M+H)+。 | D |
185 | (1S,2S)-N-(6-(5-氯-7-(1-(二甲胺基)-1-側氧丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.24 (br s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.00 (s, 1H), 8.38 (s, 1H), 8.08 (br s, 1H), 5.09 - 4.84 (m, 1H), 4.61 (q, J=7.0 Hz, 1H), 2.87 (d, J=3.2 Hz, 6H), 2.24 - 2.12 (m, 1H), 1.77 - 1.62 (m, 1H), 1.50 (d, J=7.0 Hz, 3H), 1.27 - 1.15 (m, 1H); LCMS (電灑) m/z 488.1 (M+H)+。 | D |
186 | (1S,2S)-N-(6-(7-((R)-1-(2H-四唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ14.04 - 13.53 (m, 1H), 11.40 (s, 1H), 9.08 (s, 1H), 9.06 - 8.96 (m, 2H), 8.39 (s, 1H), 8.18 (br s, 1H), 6.79 (q, J = 6.9 Hz, 1H), 5.11 - 4.77 (m, 1H), 2.28 (br d, J = 6.9 Hz, 3H), 2.22 - 2.16 (m, 1H), 1.77 - 1.63 (m, 1H), 1.22 - 1.15 (m, 1H); LCMS (電灑) m/z 485.1 (M+H)+。 | D |
187 | (1S,2S)-N-(6-(7-((S)-1-(2H-四唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.72 (s, 1H), 11.40 (s, 1H), 9.08 (s, 1H), 9.03 (s, 2H), 8.39 (s, 1H), 8.15 (s, 1H), 6.79 (br d, J = 7.0 Hz, 1H), 5.08 - 4.81 (m, 1H), 2.28 (br d, J = 7.0 Hz, 3H), 2.22 - 2.16 (m, 1H), 1.73 - 1.64 (m, 1H), 1.23 - 1.17 (m, 1H); LCMS (電灑) m/z 485.1 (M+H)+。 | D |
188 | (1S,2S)-N-(6-(5-氯-7-(1-氰乙基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 14.11 - 13.66 (m, 1H), 11.41 (s, 1H), 9.08 (s, 1H), 9.03 (s, 1H), 8.52 (br s, 1H), 8.40 (s, 1H), 8.18 (s, 1H), 5.11 - 4.79 (m, 2H), 2.20 (br s, 1H), 1.75 (br d, J = 7.1 Hz, 3H), 1.67 (br s, 1H), 1.27 - 1.16 (m, 1H); LCMS (電灑) m/z 442.3 (M+H)+。 | D |
189 | (1S,2S)-N-(6-(7-((R)-1-(1H-四唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.97 - 13.60 (m, 1H), 11.40 (s, 1H), 9.76 (s, 1H), 9.08 (s, 1H), 9.02 (d, J = 1.1 Hz, 1H), 8.39 (s, 1H), 8.20 (br s, 1H), 6.60 (q, J = 7.0 Hz, 1H), 5.08 - 4.83 (m, 1H), 2.24 - 2.13 (m, 4H), 1.74 - 1.63 (m, 1H), 1.23 - 1.16 (m, 1H); LCMS (電灑) m/z 485.4 (M+H)+。 | D |
190 | (1S,2S)-N-(6-(7-((S)-1-(1H-四唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 14.15 - 13.21 (m, 1H), 11.40 (s, 1H), 11.33 (s, 1H), 9.76 (s, 1H), 9.38 (s, 1H), 9.08 (s, 1H), 9.02 (s, 1H), 8.98 (s, 1H), 8.45 (s, 1H), 8.39 (s, 1H), 8.20 (br s, 1H), 7.77 (s, 1H), 6.59 (q, J = 7.0 Hz, 1H), 5.08 - 4.83 (m, 1H), 2.19 - 2.14 (m, 1H), 1.74 - 1.63 (m, 1H), 1.19 (br d, J = 8.5 Hz, 1H); LCMS (電灑) m/z 485.4 (M+H)+。 | D |
191 | (1S,2S)-N-(6-(7-(1-胺基-1-側氧丙烷-2-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.29 (br s, 1H), 11.39 (s, 1H), 9.07 (s, 1H), 8.98 (s, 1H), 8.40 (s, 1H), 8.05 (br s, 1H), 7.48 (br s, 1H), 7.16 (br s, 1H), 5.11 - 4.78 (m, 1H), 4.25 (br d, J=7.4 Hz, 1H), 2.19 (br s, 1H), 1.78 - 1.62 (m, 1H), 1.55 (br d, J=7.0 Hz, 3H), 1.20 (br s, 1H); LCMS (電灑) m/z 460.0 (M+H)+。 | D |
192 | (1S,2S)-N-(6-(5-氯-6-氟-7-((1-氟丙烷-2-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。1甲酸 | 1H NMR (400MHz, DMSO-d 6) δ 13.68 ( s, 1H), 11.52 (s, 1H), 9.07 (s, 1H), 8.96 (s, 1H), 8.51 (s, 1H), 8.39 (s, 1H), 6.08 ( s, 1H), 5.33-4.68 (m, 1H), 4.13-3.96 (m, 1H), 2.23-2.14 (m, 1H), 1.77 - 1.60 (m, 1H), 1.42-1.28 (m, 1H), 1.26-1.10 (m, 1H); LCMS (電灑) m/z 464.1 (M+H)+。 | D |
193 | (1S,2S)-N-(6-(5-氯-6-氟-7-(呋喃-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.70 (br s, 1H), 11.41 (s, 1H), 9.09 (s, 1H), 9.06 (s, 1H), 8.40 (s, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 7.18 (br s, 1H), 6.82 (dd, J = 1.7, 3.2 Hz, 1H), 5.10 - 4.82 (m, 1H), 2.20 (td, J = 6.8, 13.7 Hz, 1H), 1.76 - 1.63 (m, 1H), 1.21 (tdd, J = 6.2, 8.9, 12.3 Hz, 1H); LCMS (電灑) m/z 455.0 (M+H)+。 | D |
194 | (1S,2S)-N-(6-(5-氯-6-氟-7-(異噁唑-4-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.60 (br s, 1H), 11.41 (s, 1H), 9.70 (s, 1H), 9.29 (s, 1H), 9.09 (s, 1H), 9.06 (d, J = 0.9 Hz, 1H), 8.41 (s, 1H), 8.28 (br s, 1H), 5.08 - 4.85 (m, 1H), 2.25 - 2.12 (m, 1H), 1.75 - 1.62 (m, 1H), 1.25 - 1.17 (m, 1H); LCMS (電灑) m/z 455.9 (M+H)+。 | D |
195 | (1S,2S)-N-(6-(5-氯-6-氟-7-(((1R,3S)-3-羥基環戊基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.21 (s, 1H), 11.35 (s, 1H), 9.02 (s, 1H), 8.89 (d, J = 0.8 Hz, 1H), 8.35 (s, 1H), 7.95 (s, 1H), 5.46 (d, J = 6.6 Hz, 1H), 5.11-4.83 (m, 1H), 4.77 (d, J = 2.7 Hz, 1H), 4.29 (s, 1H), 4.19 (s, 1H), 2.28-2.09 (m, 2H), 2.04-1.87 (m, 1H), 1.83-1.51 (m, 6H), 1.22-1.11 (m, 1H); LCMS (電灑) m/z 488.70 (M+H)+。 | D |
196 | (1S,2S)-N-(6-(5-氯-6-氟-7-(3-羥基環戊-1-烯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.32 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.02 (d, J = 1.6 Hz, 1H), 8.39 (s, 1H), 8.09 (s, 1H), 6.37 (s, 1H), 4.99 (d, J = 52.2 Hz, 2H), 2.92-3.09 (1H), 2.67 (s, 1H), 2.33 (s, 1H), 2.19 (d, J = 4.9 Hz, 1H), 1.72 (s, 3H), 1.35-1.18 (m, 4H); LCMS (電灑) m/z 471.1 (M+H)+。 | D |
197 | (1S,2S)-N-(6-(5-氯-6-氟-7-((3-甲基-1H-吡唑-1-基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.61-13.94 (1H), 11.39 (s, 1H), 9.07 (s, 1H), 9.02 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 8.10 (s, 1H), 7.84 (d, J = 2.2 Hz, 1H), 6.02 (d, J = 1.6 Hz, 1H), 5.65 (s, 2H), 5.06-4.86 (m, 1H), 2.22-2.15 (m, 1H), 2.09 (d, J = 3.3 Hz, 3H), 1.72-1.64 (m, 1H), 1.25-1.16 (m, 1H); LCMS (電灑) m/z 483.70 (M+H)+。 | D |
198 | (1S,2S)-N-(6-(5-氯-6-氟-7-(2,2,2-三氟-1-甲氧基乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.46 (s, 1H), 11.42 (s, 1H), 9.08-9.06 (m, 2H), 8.40 (d, J = 11.0 Hz, 1H), 8.14 (d, J = 20.9 Hz, 1H), 5.82-5.75 (m, 1H), 5.07-4.86 (m, 1H), 3.50 (s, 3H), 2.23-2.16 (m, 1H), 1.74-1.64 (m, 1H), 1.21-1.16 (m, 1H); LCMS (電灑) m/z 501.7 (M+H)+。 | D |
199 | (1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(四氫呋喃-3-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.51 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 8.98 (d, J = 1.6 Hz, 1H), 8.39 (s, 1H), 8.03 (d, J = 1.1 Hz, 1H), 5.07-4.87 (m, 1H), 4.12 (t, J = 5.5 Hz, 1H), 3.92-3.80 (m, 2H), 3.75-3.65 (m, 2H), 2.90-2.86 (m, 3H), 2.23-2.16 (m, 1H), 2.06 (td, J = 13.1, 7.3 Hz, 1H), 1.91 (td, J = 12.6, 7.1 Hz, 1H), 1.75-1.65 (m, 1H), 1.23-1.17 (m, 1H); LCMS (電灑) m/z 488.7 (M+H)+。 | D |
200 | (1S,2S)-N-(6-(7-(1-(2H-1,2,3-三唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.63 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.02 (d, J = 1.1 Hz, 1H), 8.38 (s, 1H), 8.11 (s, 1H), 7.84 (s, 2H), 6.50 (q, J = 7.1 Hz, 1H), 5.07-4.86 (m, 1H), 2.23-2.14 (m, 4H), 1.74-1.65 (m, 1H), 1.22-1.16 (m, 1H); LCMS (電灑) m/z 484.70 (M+H)+。 | D |
201 | (1S,2S)-N-(6-(7-(1-(1H-1,2,4-三唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.61 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.01 (d, J = 1.1 Hz, 1H), 8.86 (s, 1H), 8.38 (s, 1H), 8.11 (s, 1H), 7.98 (s, 1H), 6.29 (q, J = 7.0 Hz, 1H), 5.06-4.86 (m, 1H), 2.22-2.09 (m, 4H), 1.74-1.65 (m, 1H), 1.22-1.16 (m, 1H); LCMS (電灑) m/z 484.70 (M+H)+。 | D |
202 | (1S,2S)-N-(6-(5-氯-7-((3S,4S)-3,4-二羥基吡咯烷-1-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.02 (s, 1H), 11.24 (s, 1H), 9.00 (s, 1H), 8.85 (s, 1H), 8.35 (s, 1H), 7.93 (s, 1H), 5.11-4.84 (m, 3H), 4.17 (d, J = 9.9 Hz, 2H), 4.08 (s, 2H), 3.49 (d, J = 8.8 Hz, 1H), 3.41 (t, J = 2.7 Hz, 1H), 2.19 (q, J = 7.1 Hz, 1H), 1.70 (ddd, J = 23.4, 10.7, 6.9 Hz, 1H), 1.25-1.16 (m, 1H); LCMS (電灑) m/z 490.10 (M+H)+。 | D |
203 | (1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲氧基吡咯烷-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.10 (s, 1H), 11.24 (s, 1H), 9.01 (s, 1H), 8.87 (s, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 5.12-4.79 (m, 1H), 4.37-3.78 (m, 4H), 3.78-3.51 (m, 1H), 3.31 (s, 3H), 2.27-2.14 (m, 1H), 2.13-1.97 (m, 2H), 1.70 (m, 1nH, 1.24-1.14 (m, 1H); LCMS (電灑) m/z 488.70 (M+H)+。 | D |
204 | (1S,2S)-N-(6-(5-氯-6-氟-7-((R)-3-甲氧基吡咯烷-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.09 (s, 1H), 11.24 (s, 1H), 9.00 (s, 1H), 8.86 (s, 1H), 8.35 (s, 1H), 7.94 (s, 1H), 5.05-4.82 (m, 1H), 4.42-3.75 (m, 4H), 3.74-3.52 (m, 1H), 3.31 (s, 3H), 2.27-1.99 (m, 3H), 1.79-1.63 (m, 1H), 1.24-1.14 (m, 1H); LCMS (電灑) m/z 488.70 (M+H)+。 | D |
205 | (1S,2S)-N-(6-(5-氯-6-氟-7-((S)-3-甲氧基吡咯烷-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.09 (s, 1H), 11.24 (s, 1H), 9.01 (s, 1H), 8.86 (s, 1H), 8.36 (s, 1H), 7.94 (s, 1H), 5.05-4.83 (m, 1H), 4.37-3.80 (m, 4H), 3.76-3.50 (m, 1H), 3.31 (s, 3H), 2.27-1.99 (m, 3H), 1.76-1.64 (m, 1H), 1.23-1.08 (m, 1H); LCMS (電灑) m/z 488.70 (M+H)+。 | D |
206 | (1S,2S)-N-(6-(5-氯-7-((1-環丙基乙基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.17 (s, 1H), 11.36 (s, 1H), 9.10 - 8.97 (m, 1H), 8.91 (s, 1H), 8.35 (s, 1H), 7.95 (s, 1H), 5.33 (br d, J = 7.9 Hz, 1H), 5.10 - 4.81 (m, 1H), 2.56 - 2.52 (m, 3H), 2.26 - 2.12 (m, 1H), 1.76 - 1.55 (m, 1H), 1.27 (d, J = 6.4 Hz, 3H), 1.23 (br s, 1H), 1.21 - 1.15 (m, 1H), 1.05 - 0.92 (m, 1H), 0.49 - 0.33 (m, 2H), 0.24 (dt, J = 4.8, 9.7 Hz, 2H); LCMS (電灑) m/z 472.1 (M+H)+。 | D |
207 | (1S,2S)-N-(6-(5-氯-7-((3,3-二氟環丁基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.83 - 12.67 (m, 1H), 11.36 (s, 1H), 9.02 (s, 1H), 8.90 (d, J = 1.2 Hz, 1H), 8.36 (s, 1H), 8.03 (br s, 1H), 6.16 (br s, 1H), 5.08 - 4.85 (m, 1H), 4.66 - 4.14 (m, 1H), 3.31 - 3.25 (m, 1H), 3.01 (br s, 2H), 2.83 - 2.70 (m, 2H), 2.23 - 2.14 (m, 1H), 1.75 - 1.61 (m, 1H), 1.23 (br s, 2H), 1.21 - 1.15 (m, 1H); LCMS (電灑) m/z 494.1 (M+H)+。 | D |
208 | (1R,2S)-N-(6-(5-氯-7-(環丙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ13.60 - 13.15 (m, 1H), 11.51 (br s, 1H), 9.07 (s, 1H), 8.96 (s, 1H), 8.33 (s, 1H), 8.00 (br s, 1H), 5.09 - 4.81 (m, 1H), 3.02 (br s, 4H), 2.61 - 2.59 (m, 1H), 1.68 - 1.50 (m, 1H), 1.38 - 1.21 (m, 1H), 0.70 - 0.56 (m, 2H), 0.48 (br s, 2H); LCMS (電灑) m/z 458.1 (M+H)+。 | D |
209 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-羥基丙-2-炔-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.38 (br s, 1H), 11.41 (s, 1H), 9.09 (s, 1H), 9.03 (d, J = 1.3 Hz, 1H), 8.40 (s, 1H), 8.07 (s, 1H), 6.59 (br d, J = 4.3 Hz, 1H), 6.03 (br d, J = 1.8 Hz, 1H), 5.11 - 4.84 (m, 1H), 3.60 (d, J = 2.0 Hz, 1H), 2.27 - 2.16 (m, 1H), 1.78 - 1.63 (m, 1H), 1.22 - 1.15 (m, 1H); LCMS (電灑) m/z 443.1 (M+H)+。 | D |
210 | (1S,2S)-N-(6-(7-(1-乙醯胺基乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ13.44 (s, 1H), 11.41 (s, 1H), 9.08 (s, 1H), 8.99 (d, J = 1.2 Hz, 1H), 8.45 (br d, J = 7.0 Hz, 1H), 8.38 (s, 1H), 8.05 (s, 1H), 5.50 - 5.43 (m, 1H), 5.11 - 4.84 (m, 1H), 2.23 - 2.16 (m, 1H), 1.86 (s, 3H), 1.74 - 1.64 (m, 1H), 1.57 (br d, J = 7.2 Hz, 3H), 1.23 - 1.17 (m, 1H); LCMS (電灑) m/z 474.1 (M+H)+。 | D |
211 | (1S,2S)-N-(6-(5-氯-7-(2-氰基丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.84-13.64 (m, 1H), 11.41 (s, 1H), 9.19 (d, J = 1.3 Hz, 1H), 9.08 (s, 1H), 9.01 (d, J = 1.3 Hz, 1H), 8.73 (d, J = 1.3 Hz, 1H), 8.46 (s, 1H), 8.39 (s, 1H), 8.25 (m, 1H), 5.08 - 4.86 (m, 1H), 4.43-4.29 (m, 1H), 2.24 - 2.15 (m, 1H), 2.06 (s, 1H), 1.75 - 1.63 (m, 1H), 1.25 - 1.15 (m, 1H); LCMS (電灑) m/z 456.0 (M+H)+。 | D |
212 | (1S,2S)-N-(6-(5-氯-6-氟-7-(5-甲基呋喃-2-基)-2H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.66-13.56 (m, 1H), 11.42 (s, 1H), 9.08 (s, 1H), 9.06 (s, 1H), 8.40 (s, 1H), 8.16 (s, 1H), 7.05 (s, 1H), 6.44 (s, 1H), 45.05-4.88 (m, 1H), 4.1 (d, J = 4.8 Hz, 2H), 3.39 (d, J=4.4 Hz, 3H), 2.21-2.19 (m, 1H), 1.75-1.66 (m, 1H), 1.23-1.16 (m, 1H); LCMS (電灑) m/z 469.0 (M+H)+。 | D |
213 | (1S,2S)-2-氟-N-(6-(6-氟-5-(甲硫基)-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.24-13.41 (m, 1H), 11.29-11.47 (m, 1H), 9.01-9.07 (m, 1H), 8.84-8.91 (m, 1H), 8.33-8.43 (m, 1H), 7.90-8.03 (m, 1H), 5.55-5.67 (m, 1H), 5.31-5.42 (m, 1H), 5.00-5.08 (m, 1H), 4.83-4.93 (m, 1H), 2.26-2.31 (m, 3H), 2.14-2.25 (m, 4H), 1.62-1.76 (m, 1H), 1.13-1.27 (m, 1H); LCMS (電灑) m/z 441.1 (M+H)+。 | D |
214 | (1S,2S)-N-(6-(7-((E)-丁-1,3-二烯-1-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.95-13.52 (m, 1H), 11.49-11.31 (m, 1H), 9.07 (d, J=0.6 Hz, 1H), 9.02 (d, J=1.4 Hz, 1H), 8.42-8.37 (m, 1H), 8.17-8.12 (m, 1H), 7.59-7.40 (m, 1H), 7.04 (d, J=15.8 Hz, 1H), 6.76-6.59 (m, 1H), 5.58 (d, J=16.7 Hz, 1H), 5.38 (d, J=10.2 Hz, 1H), 5.11-4.83 (m, 1H), 2.28-2.10 (m, 1H), 1.80-1.58 (m, 1H), 1.30-1.10 (m, 1H); LCMS (電灑) m/z 441.1 (M+H)+。 | D |
215 | (1S,2S)-N-(6-(5-氯-6-氟-7-((S)-1,1,1-三氟丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.65 (s, 1H), 11.41 (s, 1H), 9.08 (s, 1H), 9.04 (d, J=1.3 Hz, 1H), 8.39 (s, 1H), 8.12 (s, 1H), 4.96 (m, 1H), 4.50 (m, 1H), 2.19 (m, 1H), 1.75 (br d, J=6.6 Hz, 3H), 1.66 (m, 1H), 1.21 (m, 1H); LCMS (電灑) m/z 485.0 (M+H)+。 | D |
216 | (1S,2S)-N-(6-(5-氯-6-氟-7-((R)-1,1,1-三氟丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.65 (s, 1H), 11.41 (s, 1H), 9.08 (s, 1H), 9.04 (d, J=1.3 Hz, 1H), 8.39 (s, 1H), 8.12 (s, 1H), 4.96 (m, 1H), 4.50 (m, 1H), 2.19 (m, 1H), 1.75 (br d, J=6.6 Hz, 3H), 1.66 (m, 1H), 1.21 (m, 1H); LCMS (電灑) m/z 485.0 (M+H)+。 | D |
217 | (1S,2S)-N-(6-(5-氯-7-((環丙基甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.19 (br s, 1H), 11.36 (s, 1H), 9.03 (s, 1H), 8.90 (s, 1H), 8.36 (s, 1H), 7.96 (br s, 1H), 5.76 - 5.58 (m, 1H), 5.13 - 4.81 (m, 1H), 3.36 (br d, J = 5.5 Hz, 2H), 2.19 (td, J = 6.9, 13.8 Hz, 1H), 1.76 - 1.61 (m, 1H), 1.23 - 1.15 (m, 1H), 1.07 (br d, J = 9.9 Hz, 1H), 0.48 (br d, J = 7.4 Hz, 2H), 0.33 - 0.23 (m, 2H); LCMS (電灑) m/z 458.1 (M+H)+。 | D |
218 | (1S,2S)-N-(6-(5-氯-6-氟-7-((R)-1-甲氧基丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.51 (br s, 1H), 11.39 (s, 1H), 9.07 (s, 1H), 8.99 (s, 1H), 8.38 (s, 1H), 8.04 (br s, 1H), 5.09 - 4.85 (m, 1H), 3.79 (br s, 2H), 3.71 - 3.62 (m, 1H), 3.25 (s, 3H), 2.23 - 2.15 (m, 1H), 1.75 - 1.63 (m, 1H), 1.41 (br d, J = 6.0 Hz, 3H), 1.26 - 1.20 (m, 1H); LCMS (電灑) m/z 461.2 (M+H)+。 | D |
219 | (1S,2S)-N-(6-(5-氯-6-氟-7-((S)-1-甲氧基丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.52 (br s, 1H), 11.39 (s, 1H), 9.07 (s, 1H), 8.99 (s, 1H), 8.38 (s, 1H), 8.04 (br s, 1H), 5.09 - 4.84 (m, 1H), 3.79 (br s, 2H), 3.68 (br s, 1H), 3.25 (s, 3H), 2.25 - 2.14 (m, 1H), 1.76 - 1.62 (m, 1H), 1.41 (br d, J = 5.9 Hz, 3H), 1.26 - 1.20 (m, 2H); LCMS (電灑) m/z 461.1 (M+H)+。 | D |
220 | (1S,2S)-N-(6-(5-氯-7-(1-乙氧基-2,2,2-三氟乙基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.38 (s, 1H), 11.42 (s, 1H), 9.09-9.07 (m, 2H), 8.39 (s, 1H), 8.12 (d, J = 1.6 Hz, 1H), 5.83 (q, J = 7.0 Hz, 1H), 5.08-4.87 (m, 1H), 3.80-3.60 (m, 2H), 2.24-2.17 (m, 1H), 1.75-1.65 (m, 1H), 1.25-1.18 (m, 4H); LCMS (電灑) m/z 515.7 (M+H)+。 | D |
221 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1,2,2,2-四氟乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.74 (s, 1H), 11.42 (s, 1H), 9.09 (d, J = 1.1 Hz, 2H), 8.40 (s, 1H), 8.19 (s, 1H), 7.12-7.00 (m, 1H), 5.07-4.86 (m, 1H), 2.23-2.16 (m, 1H), 1.69 (dtd, J = 23.4, 6.9, 3.6 Hz, 1H), 1.25-1.17 (m, 1H); LCMS (電灑) m/z 489.8 (M+H)+。 | D |
222 | (1S,2S)-N-(6-(5-氯-7-((3S,4S)-3,4-二甲氧基吡咯烷-1-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.11 (s, 1H), 11.24 (s, 1H), 9.01 (s, 1H), 8.86 (s, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 4.94 (dd, J = 66.2, 4.1 Hz, 1H), 4.08-3.99 (m, 5H), 3.60 (d, J = 9.9 Hz, 1H), 3.37 (s, 7H), 2.20 (d, J = 6.6 Hz, 1H), 1.73-1.65 (m, 1H), 1.22-1.10 (m, 1H); LCMS (電灑) m/z 518.9 (M+H)+。 | D |
223 | (1S,2S)-N-(6-(5-氯-6-氟-7-(呋喃-3-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 11.41 (s, 1H), 9.09 (s, 1H), 9.04 (s, 1H), 8.49 (s, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.18 ( d, J = 1.2 Hz, 1H), 5.14 - 4.83 (m, 1H), 2.23 - 2.17 (m, 1H), 1.77 - 1.64 (m, 1H), 1.24 - 1.18 (m, 1H); LCMS (電灑) m/z 455.1 (M+H)+。 | D |
224 | (1S,2S)-N-(6-(5-氯-6-氟-7-(丙-1,2-二烯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.66 - 13.30 (m, 1H), 11.41 (s, 1H), 9.08 (s, 1H), 9.03 (d, J = 1.2 Hz, 1H), 8.49 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 6.78 (t, J = 6.7 Hz, 1H), 5.51 (d, J = 7.0 Hz, 2H), 5.17 - 4.68 (m, 1H), 2.25 - 2.14 (m, 1H), 1.77 - 1.62 (m, 1H), 1.24 - 1.17 (m, 1H); LCMS (電灑) m/z 427.1 (M+H)+。 | D |
225 | (1S,2R)-N-(6-(5-氯-7-(環丙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.35 (br s, 1H), 11.50 (s, 1H), 9.07 (d, J = 0.6 Hz, 1H), 8.96 (d, J = 1.5 Hz, 1H), 8.33 (s, 1H), 8.00 (s, 1H), 5.06 - 4.79 (m, 1H), 3.06 - 2.99 (m, 4H), 2.60 - 2.53 (m, 2H), 1.66 - 1.50 (m, 1H), 1.29 (qd, J = 6.6, 13.2 Hz, 1H), 0.68 - 0.59 (m, 2H), 0.53 - 0.41 (m, 2H); LCMS (電灑) m/z 458.1 (M+H)+。 | D |
226 | (1R,2R)-N-(6-(5-氯-7-(環丙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.34 - 13.32 (m, 1H), 11.38 (s, 1H), 9.05 (d, J = 0.4 Hz, 1H), 8.95 (d, J = 1.6 Hz, 1H), 8.36 (s, 1H), 7.99 (s, 1H), 5.06 - 4.86 (m, 1H), 3.01 (m, 4H), 2.20 - 2.17 (m, 1H), 1.73 - 1.64 (m, 1H), 1.20 - 1.16 (m, 1H), 0.65 - 0.61 (m, 2H), 0.49 - 0.45 (m, 2H); LCMS (電灑) m/z 458.1 (M+H)+。 | D |
227 | (1S,2S)-N-(6-(5-氯-6-氟-7-(羥基(四氫-2H-哌喃-3-基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.28 (br s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.00 (d, J = 1.3 Hz, 1H), 8.38 (s, 1H), 8.02 (s, 1H), 5.88 (br d, J = 3.5 Hz, 1H), 5.08 - 4.85 (m, 2H), 4.16 (br dd, J = 3.4, 10.6 Hz, 1H), 3.74 (br d, J = 11.5 Hz, 1H), 3.42 (t, J = 10.0 Hz, 1H), 3.30 (s, 1H), 2.23 - 2.17 (m, 2H), 1.76 - 1.63 (m, 1H), 1.56 - 1.49 (m, 1H), 1.38 - 1.29 (m, 2H), 1.23 - 1.17 (m, 2H); LCMS (電灑) m/z 503.4 (M+H)+。 | D |
228 | (1S,2S)-2-氟-N-(6-(6-氟-7-(異丙胺基)-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.02-13.21 (m, 1H), 11.30-11.40 (m, 1H), 8.95-9.06 (m, 1H), 8.75-8.82 (m, 1H), 8.29-8.41 (m, 1H), 7.81-7.95 (m, 1H), 5.01-5.08 (m, 1H), 4.84-4.95 (m, 2H), 3.92-4.13 (m, 1H), 2.24-2.30 (m, 3H), 2.12-2.23 (m, 2H), 1.61-1.76 (m, 1H), 1.20-1.27 (m, 1H), 1.16-1.20 (m, 1H); LCMS (電灑) m/z 458.1 (M+H)+。 | D |
229 | (1S,2S)-N-(6-(5-氯-7-(5,6-二氫-1,4-戴奧辛-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.28 (br s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.01 (d, J = 1.3 Hz, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 6.94 (s, 1H), 5.12 - 4.82 (m, 1H), 4.36 (dd, J = 2.8, 4.8 Hz, 2H), 4.27 - 4.22 (m, 2H), 2.24 - 2.15 (m, 1H), 1.76 - 1.58 (m, 1H), 1.26 - 1.14 (m, 1H); LCMS (電灑) m/z 473.1 (M+H)+。 | D |
230 | (1S,2S)-N-(6-(7-(1-(1H-吡唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.51 (s, 1H), 11.39 (s, 1H), 9.07 (s, 1H), 9.00 (d, J = 1.1 Hz, 1H), 8.38 (s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.48 (s, 1H), 6.30 (s, 1H), 6.25 (q, J = 6.8 Hz, 1H), 5.06-4.86 (m, 1H), 2.21-2.15 (m, 1H), 2.09 (d, J = 7.1 Hz, 3H), 1.72-1.65 (m, 1H), 1.21-1.16 (m, 1H); LCMS (電灑) m/z 483.85 (M+H)+。 | D |
231 | (1S,2S)-N-(6-(5-氯-6-氟-7-(((1R,3S)-3-羥基環戊基)(甲基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.41 (s, 1H), 11.39 (s, 1H), 9.05 (s, 1H), 8.97 (d, J = 1.1 Hz, 1H), 8.37 (s, 1H), 8.00 (d, J = 1.1 Hz, 1H), 5.10-4.82 (m, 1H), 4.57 (d, J = 3.8 Hz, 1H), 4.48-4.39 (m, 1H), 4.16-4.04 (m, 1H), 3.70 (t, J = 7.1 Hz, 1H), 2.89 (d, J = 1.1 Hz, 3H), 2.28-2.14 (m, 1H), 2.14-2.03 (m, 1H), 1.78-1.63 (m, 4H), 1.61-1.39 (m, 2H), 1.33-1.20 (m, 1H); LCMS (電灑) m/z 502.90 (M+H)+。 | D |
232 | (1S,2S)-2-氟-N-(6-(6-氟-7-(丙-1-烯-2-基)-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.52-13.91 (m, 1H), 11.38-11.44 (m, 1H), 8.99 (s, 1H), 8.87-8.93 (m, 1H), 8.32-8.38 (m, 1H), 8.06-8.12 (m, 1H), 5.64-5.71 (m, 1H), 5.38-5.44 (m, 1H), 5.00-5.09 (m, 1H), 4.85-4.92 (m, 1H), 2.15-2.27 (m, 5H), 1.63-1.76 (m, 1H), 1.15-1.27 (m, 1H); LCMS (電灑) m/z 463.2 (M+H)+。 | D |
233 | (1S,2S)-N-(6-(5-氯-6-氟-7-(5-甲基呋喃-3-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.99 - 13.14 (m, 1H), 11.40 (s, 1H), 9.26 - 8.79 (m, 2H), 8.40 (s, 1H), 8.29 (s, 1H), 8.17 (s, 1H), 6.78 (br s, 1H), 5.13 - 4.68 (m, 1H), 2.40 (s, 3H), 2.22 - 2.15 (m, 1H), 1.74 - 1.64 (m, 1H), 1.22 - 1.15 (m, 1H); LCMS (電灑) m/z 469.1 (M+H)+。 | D |
234 | (1S,2S)-N-(6-(5-氯-6-氟-7-(3-羥基丙-1-炔-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 14.48 - 13.25 (m, 1H), 11.41 (s, 1H), 9.08 (s, 1H), 9.06 (d, J = 1.5 Hz, 1H), 8.40 (s, 1H), 8.16 (s, 1H), 5.55 (br d, J = 1.8 Hz, 1H), 5.13 - 4.77 (m, 1H), 4.50 (s, 2H), 2.89 (s, 1H), 2.73 (s, 1H), 2.28 - 2.06 (m, 1H), 1.84 - 1.55 (m, 1H), 1.21 (tdd, J = 6.3, 9.0, 12.4 Hz, 1H); LCMS (電灑) m/z 443.0 (M+H)+。 | D |
235 | (1S,2S)-N-(6-(5-氯-6-氟-7-(丙-2-炔-1-基胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。1甲酸 | 1H NMR (400MHz, DMSO-d 6) δ 13.83 - 13.38 (m, 1H), 11.37 (s, 1H), 9.03 (s, 1H), 8.93 (s, 1H), 8.48 (s, 1H), 8.35 (s, 1H), 8.01 (br s, 1H), 6.29 (br dd, J = 1.3, 3.0 Hz, 1H), 5.13 - 4.80 (m, 1H), 4.30 (br s, 2H), 3.09 (s, 1H), 2.19 (td, J = 7.0, 13.7 Hz, 1H), 1.78 - 1.60 (m, 1H), 1.20 (tdd, J = 6.1, 9.1, 12.5 Hz, 1H); LCMS (電灑) m/z 442.1 (M+H)+。 | D |
236 | (1S,2S)-N-(6-(5-氯-6-氟-7-(四氫呋喃-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.09 (m, 1H), 11.41 (s, 1H), 9.08 (s, 1H), 9.01 (d, J=1.3 Hz, 1H), 8.40 (s, 1H), 8.06 (s, 1H), 5.39 - 5.30 (m, 1H), 5.10-4.83 (m, 1H), 4.32 (q, J=7.3 Hz, 1H), 3.91-3.79 (m, 1H), 2.46-2.38 (m, 1H), 2.26-2.16 (m, 1H), 2.16-2.00 (m, 3H), 1.99-1.82 (m, 1H), 1.77 - 1.61 (m, 1H), 1.28-1.14 (m, 1H); LCMS (電灑) m/z 459.1 (M+H)+。 | D |
237 | (1S,2S)-N-(6-(5-氯-7-((1,1-二氟丙烷-2-基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.83-13.06 (m, 1H), 11.36 (s, 1H), 9.03 (d, J=0.6 Hz, 1H), 8.91 (d, J=1.3 Hz, 1H), 8.36 (s, 1H), 8.06 (s, 1H), 8.05 (br d, J=1.2 Hz, 1H), 6.32-5.92 (m, 1H), 5.75-5.54 (m, 1H), 5.11-4.81 (m, 1H), 4.74-4.15 (m, 1H), 2.25-2.12 (m, 1H), 1.78-1.60 (m, 1H), 1.33 (d, J=6.6 Hz, 3H), 1.20 (ddt, J=12.33, 9.00, 6.15, 6.15 Hz, 1H); LCMS (電灑) m/z 459.1 (M+H)+。 | D |
238 | (1S,2S)-N-(6-(5-氯-6-氟-7-(4-羥基四氫呋喃-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 11.40 (s, 1H), 9.39 (d, J = 1.2 Hz, 1H), 9.07 (s, 1H), 8.995 - 8.992 (m, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 5.59 (dd, J = 5.7, 10.6 Hz, 1H), 5.18 - 5.17 (m, 1H), 5.08 - 4.85 (m, 1H), 4.55 (br s, 1H), 4.47 (dd, J = 4.6, 9.1 Hz, 1H), 3.73 - 3.70 (m, 1H), 2.28 - 2.23 (m, 1H), 2.21 - 2.16 (m, 1H), 2.12 - 2.05 (m, 1H), 1.74 - 1.64 (m, 1H), 1.22 – 1.16(m, 1H); LCMS (電灑) m/z 475.1 (M+H)+。 | D |
239 | (1S,2S)-N-(6-(5-氯-7-(3,3-二甲基氮呾-1-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 12.97 (s, 1H), 11.35 (s, 1H), 9.02 (s, 1H), 8.87 (d, J = 6.0 Hz, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 5.06-4.85 (m, 1H), 4.14 (d, J = 11.5 Hz, 4H), 2.22-2.15 (m, 1H), 1.72-1.65 (m, 1H), 1.32 (d, J = 12.1 Hz, 6H), 1.24-1.16 (m, 1H); LCMS (電灑) m/z 472.10 (M+H)+。 | D |
240 | (1S,2S)-N-(6-(5-氯-7-((3-氯-2,2-二甲基丙基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.28 (s, 1H), 11.36 (s, 1H), 9.02 (d, J = 9.3 Hz, 1H), 8.91-8.88 (m, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 5.25 (d, J = 6.0 Hz, 1H), 5.07-4.86 (m, 1H), 3.64 (d, J = 17.6 Hz, 2H), 3.49-3.39 (m, 2H), 2.23-2.16 (m, 1H), 1.73-1.66 (m, 1H), 1.24-1.16 (m, 1H), 1.05 (t, J = 12.9 Hz, 6H); LCMS (電灑) m/z 472.10 (M+H)+。 | D |
241 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(4-甲基-1H-吡唑-1-基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.53 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.00 (d, J = 1.6 Hz, 1H), 8.39 (s, 1H), 8.10 (s, 1H), 7.79 (s, 1H), 7.28 (s, 1H), 6.16 (q, J = 7.0 Hz, 1H), 5.07-4.86 (m, 1H), 2.21-2.16 (m, 1H), 2.06-2.00 (m, 6H), 1.73-1.66 (m, 1H), 1.22-1.18 (m, 1H); LCMS (電灑) m/z 497.90 (M+H)+。 | D |
242 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(5-甲基-1H-吡唑-1-基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.05 (s, 1H), 11.39 (s, 1H), 9.06 (s, 1H), 9.00 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 8.09 (s, 1H), 7.48 (s, 1H), 6.22 (q, 1H), 6.09 (s, 1H), 5.05-4.86 (m, 1H), 2.29 (s, 3H), 2.21-2.17 (m, 1H), 2.03 (d, J = 7.1 Hz, 3H), 1.72-1.66 (m, 1H), 1.14-1.22 (m, 1H) ); LCMS (電灑) m/z 497.90 (M+H)+。 | D |
243 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(3-甲基-1H-吡唑-1-基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.56 (s, 1H), 11.39 (s, 1H), 9.07 (s, 1H), 9.00 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 8.10 (s, 1H), 7.91 (d, J = 2.2 Hz, 1H), 6.14 (q, J = 7.0 Hz, 1H), 6.06 (d, J = 2.7 Hz, 1H), 5.07-4.86 (m, 1H), 2.23-2.15 (m, 1H), 2.12 (s, 3H), 2.04 (d, J = 7.7 Hz, 3H), 1.72-1.64 (m, 1H), 1.22-1.16 (m, 1H) ); LCMS (電灑) m/z 497.90 (M+H)+。 | D |
244 | (1S,2S)-N-(6-(5-氯-7-(3,3-二氟氮呾-1-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.10 (s, 1H), 11.25 (s, 1H), 9.01 (s, 1H), 8.87 (s, 1H), 8.32 (d, J = 36.8 Hz, 1H), 8.01 (s, 1H), 5.05-4.82 (m, 5H), 2.23-2.16 (m, 1H), 1.75-1.65 (m, 1H), 1.24-1.16 (m, 1H); LCMS (電灑) m/z 480.10 (M+H)+。 | D |
245 | (1S,2S)-N-(6-(5-氯-7-(氰甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400MHz, DMSO-d 6) δ 13.78 (s, 1H), 11.40 (s, 1H), 9.08 (s, 1H), 9.05 (d, J = 1.6 Hz, 1H), 8.40 (s, 1H), 8.18-8.10 (1H), 5.09-4.83 (m, 1H), 4.47-4.32 (m, 2H), 2.25-2.14 (m, 1H), 1.75-1.62 (m, 1H), 1.26-1.15 (m, 1H); LCMS (電灑) m/z 428.80 (M+H)+。 | D |
246 | (1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲氧基丙-1-炔-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.98 (br s, 1H), 11.41 (s, 1H), 9.08 (s, 1H), 9.06 (d, J = 1.3 Hz, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 5.12 - 4.77 (m, 1H), 4.52 (s, 2H), 3.43 (s, 3H), 2.27 - 2.11 (m, 1H), 1.79 - 1.61 (m, 1H), 1.35 - 1.13 (m, 1H); LCMS (電灑) m/z 457.1 (M+H)+。 | D |
247 | (1S,2S)-N-(6-(5-氯-7-(2,5-二氫呋喃-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。1甲酸 | 1H NMR (400 MHz, DMSO-d 6) δ 13.33-13.04 (m, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.00 (d, J = 1.3 Hz, 1H), 8.49 (s, 1H), 8.39 (s, 1H), 8.07 (s, 1H), 6.40 (br d, J=2.0 Hz, 1H), 6.33-6.21 (m, 1H), 6.09 (br d, J=6.48 Hz, 1H), 5.15 - 4.99 (m, 1H), 4.88 (td, J=6.14, 3.6 Hz, 1H), 4.80-4.68 (m, 1H), 2.27 - 2.13 (m, 1H), 1.79 - 1.59 (m, 1H), 1.31 - 1.12 (m, 1H); LCMS (電灑) m/z 457.1 (M+H)+。 | D |
248 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-丙醯胺基乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.48 (br d, J = 5.4 Hz, 1H), 11.39 (s, 1H), 9.07 (s, 1H), 8.98 (d, J = 1.5 Hz, 1H), 8.40 - 8.33 (m, 2H), 8.05 (s, 1H), 5.46 (s, 1H), 5.09 - 4.85 (m, 1H), 2.22 - 2.10 (m, 3H), 1.76 - 1.63 (m, 1H), 1.56 (d, J = 7.1 Hz, 3H), 1.26 - 1.16 (m, 1H), 0.94 (t, J = 7.6 Hz, 3H); LCMS (電灑) m/z 488.1 (M+H)+。 | D |
249 | (1R,2S)-N-(6-(5-氯-6-氟-7-(3-羥基丙醯胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.34 (m, 1H), 11.52 (s, 1H), 10.33 (s, 1H), 9.08 (s, 1H), 9.03 (d, J = 1.4 Hz, 1H), 8.34 (s, 1H), 8.04 (s, 1H), 4.92 (m, 1H), 4.76 (br d, J=7.8 Hz, 1H), 3.79 (br t, J=6.30 Hz, 2H), 2.65 (br t, J=6.6 Hz, 3H), 1.57 (m, 1H), 1.29 (dq, J=13.16, 6.62 Hz, 1H); LCMS (電灑) m/z 476.1 (M+H)+。 | D |
250 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲醯胺基乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.78 - 13.27 (m, 1H), 11.39 (s, 1H), 9.07 (s, 1H), 8.99 (s, 1H), 8.68 (br d, J = 7.1 Hz, 1H), 8.38 (s, 1H), 8.06 (br s, 2H), 5.56 (br t, J = 7.2 Hz, 1H), 5.12 - 4.79 (m, 1H), 2.25 - 2.12 (m, 1H), 1.73 - 1.63 (m, 1H), 1.58 (d, J = 7.1 Hz, 3H), 1.20 (ddd, J = 2.9, 6.3, 9.5 Hz, 1H); LCMS (電灑) m/z 460.1 (M+H)+。 | D |
251 | (1S,2S)-N-(6-(5-氯-6-氟-7-((E)-4-羥基丁-1-烯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 11.41 (s, 1H), 9.08 (d, J=0.6 Hz, 1H), 9.02 (d, J=1.3 Hz, 1H), 8.43 (s, 1H), 8.40-8.36 (m, 1H), 8.28 (s, 1H), 8.18-8.09 (m, 1H), 6.94-6.73 (m, 1H), 5.11-4.83 (m, 1H), 4.76-4.65 (m, 1H), 4.35 (t, J=6.5 Hz, 1H), 3.68-3.60 (m, 1H), 2.76-2.69 (m, 1H), 2.26-2.15 (m, 1H), 2.06-1.9 (m, 1H), 2.06-1.91 (m, 1H), 1.80-1.59 (m, 1H), 1.33-1.14 (m, 1H); LCMS (電灑) m/z 487.1 (M+H)+。 | D |
252 | (1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁-1-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 或(1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁-2-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.49 - 13.39 (m, 1H), 13.38-13.27 (m, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.02 (t, J=1.6 Hz, 1H), 8.43 (s, 1H), 8.38 (d, J=2.0 Hz, 1H), 8.05 (d, J=6.9 Hz, 1H), 5.57 (s, 1H), 5.28 (s, 1H), 5.10 - 4.82 (m, 1H), 2.80 (dt, J=13.2, 6.6 Hz, 1H), 2.25-2.15 (m, 1H), 2.01 (s, 2H), 1.92 (s, 2H), 1.76-1.63 (m, 1 H), 1.52 (s, 2H), 1.27-1.16 (m, 2H), 1.11 (d, J=6.7 Hz, 4H), 0.84 (t, J=7.4 Hz, 1H); LCMS (電灑) m/z 457.2 (M+H)+。 | D |
253 | (1S,2S)-N-(6-(5-氯-6-氟-7-(3-(三甲基矽基)丙-2-炔-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。1甲酸 | 1H NMR (400 MHz, DMSO-d 6) δ 11.41 (s, 1H), 9.05 (br d, J = 18.0 Hz, 2H), 8.46 (s, 1H), 8.39 (s, 1H), 8.09 (s, 1H), 5.19 - 4.71 (m, 1H), 4.16 - 3.92 (m, 2H), 2.26 - 2.12 (m, 1H), 1.77 - 1.57 (m, 1H), 1.21 - 1.10 (m, 1H), 0.11 (s, 9H); LCMS (電灑) m/z 499.2 (M+H)+。 | D |
254 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-羥基-3-(三甲基矽基)丙-2-炔-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。1甲酸 | 1H NMR (400 MHz, DMSO-d 6) δ 13.98 - 12.92 (m, 1H), 11.41 (s, 1H), 9.05 (br d, J = 18.2 Hz, 2H), 8.45 (s, 1H), 8.39 (s, 1H), 8.06 (s, 1H), 6.04 (s, 1H), 5.15 - 4.74 (m, 1H), 2.28 - 2.12 (m, 1H), 1.78 - 1.60 (m, 1H), 1.24 - 1.13 (m, 2H), 0.13 (s, 9H); LCMS (電灑) m/z 515.3 (M+H)+。 | D |
255 | (1S,2S)-N-(6-(5-氯-6-氟-7-((3-羥基丁烷-2-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 12.98-13.58 (m, 1H), 11.30-11.43 (m, 1H), 9.01-9.06 (m, 1H), 8.87-8.93 (m, 1H), 8.33-8.38 (m, 1H), 7.92-8.10 (m, 1H), 5.09-5.23 (m, 1H), 5.00-5.08 (m, 1H), 4.79-4.92 (m, 1H), 3.71-4.06 (m, 2H), 2.14-2.23 (m, 1H), 1.63-1.75 (m, 1H), 1.11-1.24 (m, 8H); LCMS (電灑) m/z 476.2 (M+H)+。 | D |
256 | (1S,2S)-N-(6-(5-氯-7-(5,5-二甲基四氫呋喃-3-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.64-13.48 (m, 1H), 11.49-11.34 (m, 1H), 9.10-9.03 (m, 1H), 8.98 (d, J=1.3 Hz, 1H), 8.43-8.35 (m, 1H), 8.11-8.02 (m, 1H), 5.11-4.81 (m, 1H), 4.21-4.12 (m, 2H), 4.10-3.98 (m, 1H), 2.28-2.15 (m, 3H), 1.77-1.63 (m, 1H), 1.40 (s, 3H), 1.32 (s, 3H), 1.22-1.17 (m, 1H); LCMS (電灑) m/z 487.1 (M+H)+。 | D |
257 | (1S,2S)-N-(6-(7-(1-(1H-咪唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.81 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.00 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.31 (s, 1H), 6.91 (s, 1H), 6.15 (q, J = 7.3 Hz, 1H), 5.04-4.87 (m, 1H), 2.23-2.15 (m, 1H), 2.09 (d, J = 7.1 Hz, 3H), 1.72-1.65 (m, 1H), 1.18-1.18 (m, 1H); LCMS (電灑) m/z 483.90 (M+H)+。 | D |
258 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(2-甲基-1H-咪唑-1-基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.73 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.01 (s, 1H), 8.37 (s, 1H), 8.16 (s, 1H), 7.51 (s, 1H), 6.79 (s, 1H), 6.07-6.05 (m, 1H), 5.05-4.87 (m, 1H), 2.18 (s, 3H), 2.01 (d, 3H), 1.72-1.66 (m, 1H), 1.18-1.16 (m, 1H); LCMS (電灑) m/z 497.90 (M+H)+。 | D |
259 | (1S,2S)-N-(6-(5-氯-6-氟-7-((E)-3-(三乙基矽基)丙-1-烯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.60 (br s, 1H), 11.39 (s, 1H), 9.07 (s, 1H), 8.99 (s, 1H), 8.39 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 6.86 - 6.73 (m, 1H), 6.67 - 6.60 (m, 1H), 5.17 - 4.77 (m, 1H), 2.26 - 2.12 (m, 1H), 1.92 (br d, J = 8.3 Hz, 2H), 1.80 - 1.60 (m, 1H), 1.30 - 1.13 (m, 1H), 1.06 - 0.91 (m, 9H), 0.61 (q, J = 7.9 Hz, 6H); LCMS (電灑) m/z 543.3 (M+H)+。 | D |
260 | (1S,2S)-N-(6-(5-氯-7-((1,1-二氟丙烷-2-基)(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.42 (s, 1H), 11.40 (s, 1H), 9.06 (d, J=0.7 Hz, 1H), 8.97 (d, J=1.3 Hz, 1H), 8.39 (s, 1H), 8.04 (d, J=1.2 Hz, 1H), 6.46 - 6.06 (m, 1H), 5.12 - 4.82 (m, 1H), 3.77-3.53 (m, 1H), 3.02 (d, J = 1.2 Hz, 3H), 2.25-2.14 (m, 1H), 1.77-1.62 (m, 1H), 1.34 (br d, J=6.8 Hz, 3H), 1.26 - 1.15 (m, 2H); LCMS (電灑) m/z 496.2 (M+H)+。 | D |
261 | (1S,2S)-N-(6-(7-(二級丁基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.51 (br d, J=1.5 Hz, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.00 (d, J=1.3 Hz, 1H), 8.38 (s, 1H), 8.05 (s, 1H), 5.11 - 4.85 (m, 1H), 3.42 (s, 1H), 2.27-2.15 (m, 1H), 1.86 (td, J=13.7, 6.4 Hz, 2H), 1.77-1.64 (m, 1H), 1.45 (br d, J=7.0 Hz, 3H), 1.35-1.16 (m, 1H), 1.10 - 1.02 (m, 1H), 0.85 (q, J=7.5 Hz, 4H); LCMS (電灑) m/z 445.3 (M+H)+。 | D |
262 | (1S,2S)-N-(6-(5-氯-7-(1,4-二噁烷-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.31 (br s, 1H), 11.41 (s, 1H), 9.07 (s, 1H), 9.00 (d, J = 1.4 Hz, 1H), 8.39 (s, 1H), 8.06 (s, 1H), 5.25 (dd, J = 2.7, 10.3 Hz, 1H), 5.09 - 4.85 (m, 1H), 4.01 (d, J = 9.4 Hz, 1H), 3.95 - 3.84 (m, 3H), 3.79 (d, J = 9.0 Hz, 1H), 3.72 - 3.64 (m, 1H), 2.26 - 2.09 (m, 1H), 1.78 - 1.62 (m, 1H), 1.28 - 1.13 (m, 1H); LCMS (電灑) m/z 475.1 (M+H)+。 | D |
263 | (1S,2S)-N-(6-(5-氯-6-氟-7-(四氫-2H-哌喃-3-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.82-13.50(m, 1H), 11.44-11.34 (m, 1H), 9.06 (s, 1H), 8.97 (d, J=1.3 Hz, 1H), 8.45 (s, 1H), 8.38 (s, 1H), 8.06 (s, 1H), 5.13-4.83 (m, 1H), 3.99-3.87 (m, 1H), 3.61-3.52 (m, 1H), 2.25-2.14 (m, 1H), 2.04-1.95 (m, 1H), 1.82-1.72 (m, 2H), 1.71-1.62 (m, 1H), 1.29-1.13 (m, 1H); LCMS (電灑) m/z 473.1 (M+H)+。 | D |
264 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(4-甲基-1H-咪唑-1-基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.75 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.00 (s, 1H), 8.38 (s, 1H), 8.15 (s, 1H), 7.77 (s, 1H), 6.96 (s, 1H), 6.06-6.04 (m, 1H), 5.05-4.88 (m, 1H), 2.19-2.19 (m, 1H), 2.05 (d, J = 8.2 Hz, 6H), 1.72-1.66 (m, 1H), 1.21-1.21 (m, 1H); LCMS (電灑) m/z 497.90 (M+H)+。 | D |
265 | (1S,2S)-N-(6-(5-氯-7-(氰氟甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.94 (s, 1H), 11.42 (s, 1H), 9.10 (s, 2H), 8.42 (s, 1H), 8.24 (s, 1H), 7.37 (d, J = 43.4 Hz, 1H), 5.06-4.86 (m, 1H), 2.21-2.16 (m, 1H), 1.73-1.66 (m, 1H), 1.30-1.21 (m, 1H); LCMS (電灑) m/z 446.85 (M+H)+。 | D |
266 | (1S,2S)-N-(6-(7-(乙醯胺基(氰基)甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.79 (S, 1H), 11.41 (s, 1H), 9.30 (s, 1H), 9.07 (d, J = 18.1 Hz, 2H), 8.41 (s, 1H), 8.21 (s, 1H), 6.56 (s, 1H), 5.07-4.81 (m, 1H), 2.19 (s, 1H), 1.95 (s, 3H), 1.72 (s, 1H), 1.21-1.12 (m, 1H); LCMS (電灑) m/z 485.85 (M+H)+。 | D |
267 | (1S,2S)-N-(6-(5-氯-7-(6,6-二氟-2-氮雜螺[3.3]庚烷-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 1H-NMR (400 MHz, DMSO-D6) δ 12.96 (s, 1H), 11.24 (s, 1H), 8.99 (d, J = 8.8 Hz, 1H), 8.87 (d, J = 12.6 Hz, 1H), 8.35 (s, 1H), 7.95 (s, 1H), 5.04-4.85 (m, 1H), 4.53 (d, J = 11.0 Hz, 4H), 2.90 (t, J = 12.6 Hz, 4H), 2.19 (t, J = 7.1 Hz, 1H), 1.73-1.66 (m, 1H), 1.22-1.17 (m, 1H); LCMS (電灑) m/z 519.8 (M+H)+。 | D |
268 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(甲基磺醯胺基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 1H-NMR (400 MHz, DMSO-D6) δ 13.43 (s, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 9.01 (d, J = 1.1 Hz, 1H), 8.38 (s, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.68 (d, J = 6.6 Hz, 1H), 5.21 (t, J = 6.6 Hz, 1H), 5.07-4.86 (m, 1H), 2.86 (s, 3H), 2.23-2.16 (m, 1H), 1.74-1.60 (m, 4H), 1.21-1.16 (m, 1H); LCMS (電灑) m/z 475.9 (M+H)+。 | D |
269 | (1S,2S)-N-(6-(5-氯-7-(1,1-二氟丙-1-烯-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.77 (s, 1H), 11.42 (s, 1H), 9.08 (d, J = 1.6 Hz, 1H), 9.03 (d, J = 1.6 Hz, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 5.07-4.86 (m, 1H), 2.23-2.16 (m, 1H), 2.05 (t, J = 3.0 Hz, 3H), 1.74-1.65 (m, 1H), 1.22-1.16 (m, 1H); LCMS (電灑) m/z 465.90 (M+H)+。 | D |
270 | (1S,2S)-N-(6-(5-氯-7-((1S,2R)-1,2-二羥基丙基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.05 (s, 1H), 11.39 (s, 1H), 9.07 (s, 1H), 8.99 (d, J = 1.1 Hz, 1H), 8.38 (s, 1H), 7.99 (s, 1H), 5.89 (s, 1H), 5.07-5.00 (m, 2H), 4.88 (td, J = 6.3, 3.8 Hz, 0H), 4.80 (s, 1H), 4.09-4.01 (m, 1H), 2.23-2.16 (m, 1H), 1.77-1.64 (m, 1H), 1.25-1.16 (m, 1H), 1.04 (d, J = 6.6 Hz, 3H); LCMS (電灑) m/z 463.10 (M+H)+。 | D |
271 | (1S,2S)-N-(6-(5-氯-6-氟-7-(丙-2-炔-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.70 (s, 1H), 11.41 (s, 1H), 9.08 (s, 1H), 9.03 (d, J = 1.5 Hz, 1H), 8.40 (s, 1H), 8.09 (s, 1H), 5.11 - 4.82 (m, 1H), 3.98 (d, J = 1.8 Hz, 2H), 3.05 (s, 1H), 2.26 - 2.16 (m, 1H), 1.82 - 1.64 (m, 1H), 1.30 - 1.13 (m, 1H); LCMS (電灑) m/z 427.2 (M+H)+。 | D |
272 | (1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。2甲酸 | 1H NMR (400 MHz, DMSO-d 6) δ 13.58-13.46(m, 1H), 11.46-11.37 (m, 1H), 9.07 (s, 1H), 9.01 (s, 1H), 8.46 (s, 2H), 8.38 (s, 1H), 8.05 (s, 1H), 5.13 - 4.82 (m, 1H), 3.13-3.04 (m, 1H), 2.20 (dd, J=7.1, 5.4 Hz, 2H), 2.08(s, 3H), 1.77-1.63 (m, 1H), 1.47-1.39 (m, 3H), 1.24 (t, J=7.2 Hz, 1H), 1.11(d, J=6.5 Hz, 3H), 0.78-0.68 (m, 3H); LCMS (電灑) m/z 459.3 (M+H)+。 | D |
273 | (1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁-2-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。1甲酸 | 1H NMR (400 MHz, DMSO-d 6) δ 13.39-13.30(m, 1H), 11.42 (s, 1H), 9.08 (s, 1H), 9.03 (d, J=1.0 Hz, 1H), 8.47 (s, 2H), 8.39 (s, 1H), 8.05 (s, 1H), 5.12 - 4.83 (m, 1H), 2.20 (dd, J=7.6, 6.1 Hz, 1H), 2.08(s, 9H), 2.02 (s, 3H), 1.93 (s, 3H), 1.79-1.63 (m, 1H), 1.52 (s, 3H), 1.32-1.25 (m, 1H); LCMS (電灑) m/z 457.2 (M+H)+。 | D |
274 | (1S,2S)-N-(6-(7-(乙醯胺基甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.33 (s, 1H), 11.37 (d, J = 9.9 Hz, 1H), 9.06 (s, 1H), 8.98 (d, J = 1.6 Hz, 1H), 8.45 (t, J = 5.5 Hz, 1H), 8.41-8.38 (m, 1H), 8.05 (d, J = 1.6 Hz, 1H), 5.06-4.85 (m, 1H), 4.61 (dd, J = 17.9, 5.2 Hz, 2H), 2.32-2.15 (m, 1H), 2.01-1.80 (m, 3H), 1.68 (dtd, J = 23.2, 6.9, 3.8 Hz, 1H), 1.27-1.15 (m, 1H); LCMS (電灑) m/z 425.90 (M+H)+。 | D |
275 | (1S,2S)-N-(6-(5-氯-6-氟-7-甲醯基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.94 (s, 1H), 11.43 (s, 1H), 10.49 (s, 1H), 9.13 (d, J = 1.6 Hz, 1H), 9.11 (s, 1H), 8.43 (s, 1H), 8.22 (d, J = 1.6 Hz, 1H), 5.07-4.87 (m, 1H), 2.22-2.16 (m, 1H), 1.75-1.66 (m, 1H), 1.25-1.18 (m, 1H); LCMS (電灑) m/z 417.85 (M+H)+。 | D |
276 | 5-氯-6-氟-4-(2-((1S,2S)-2-氟環丙烷-1-甲醯胺基)咪唑並[1,2-a]吡嗪-6-基)-1H-吲唑-7-羧酸乙酯 | 1H NMR (400 MHz, DMSO-d 6) δ 13.54 (s, 1H), 11.42 (s, 1H), 9.10 (s, 2H), 8.42 (s, 1H), 8.20 (d, J = 1.1 Hz, 1H), 5.07-4.86 (m, 1H), 4.51 (q, J = 7.0 Hz, 2H), 2.21-2.16 (m, 1H), 1.75-1.64 (m, 1H), 1.41 (t, J = 6.9 Hz, 3H), 1.22-1.17 (m, 1H); LCMS (電灑) m/z 461.80 (M+H)+。 | D |
277 | (1S,2S)-N-(6-(5-氯-6-氟-7-(((2R,3R)-3-甲氧基丁烷-2-基)(甲基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。2甲酸 | 1H NMR (400 MHz, DMSO-d 6) δ 13.11-13.51 (m, 1H), 11.31-11.43 (m, 1H), 9.02-9.06 (m, 1H), 8.91-8.96 (m, 1H), 8.40-8.47 (m, 2H), 8.31-8.38 (m, 1H), 7.97-8.08 (m, 1H), 4.98-5.12 (m, 1H), 4.83-4.92 (m, 1H), 3.48-3.49 (m, 1H), 3.47-3.54 (m, 8H), 3.24-3.26 (m, 3H), 2.96-3.05 (m, 4H), 2.11-2.24 (m, 1H), 1.62-1.78 (m, 2H), 1.47-1.58 (m, 2H), 1.27 (br d, J = 6.6 Hz, 3H), 1.06-1.13 (m, 3H); LCMS (電灑) m/z 504.2 (M+H)+。 | D |
278 | (1S,2S)-N-(6-(5-氯-6-氟-7-(((2R,3S)-3-甲氧基丁烷-2-基)(甲基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。2甲酸 | 1H NMR (400 MHz, DMSO-d 6) δ 13.11-13.50 (m, 1H), 11.31-11.43 (m, 1H), 9.02-9.06 (m, 1H), 8.91-8.96 (m, 1H), 8.40-8.47 (m, 2H), 8.31-8.38 (m, 1H), 7.97-8.08 (m, 1H), 4.98-5.12 (m, 1H), 4.83-4.92 (m, 1H), 3.48-3.49 (m, 1H), 3.47-3.54 (m, 8H), 3.24-3.26 (m, 3H), 2.96-3.05 (m, 4H), 2.11-2.24 (m, 1H), 1.62-1.78 (m, 2H), 1.47-1.58 (m, 2H), 1.28 (br d, J = 6.6 Hz, 3H), 1.05-1.12 (m, 3H); LCMS (電灑) m/z 504.2 (M+H)+。 | D |
279 | (1S,2S)-N-(6-(5-氯-7-(1-((1-氰環丙基)胺基)乙基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.28-13.03 (m, 1H), 11.52-11.34 (m, 1H), 9.07 (s, 1H), 9.03-8.98 (m, 1H), 8.46 (s, 1H), 8.39 (s, 1H), 8.08-8.01 (m, 1H), 5.10-4.84 (m, 1H), 4.81-4.70 (m, 1H), 4.04 (d, J=3.3 Hz, 1H), 2.24-2.15 (m, 1H), 1.75-1.63 (m, 1H), 1.52 (d, J = 6.7 Hz, 3H), 1.29-1.23 (m, 1H), 1.22-1.14 (m, 1H), 0.97 (ddd, J=9.9, 7.6, 4.6 Hz, 1H), 0.66-0.56 (m, 1H); LCMS (電灑) m/z 497.2 (M+H)+。 | D |
280 | 2-(5-氯-6-氟-4-(2-((1S,2S)-2-氟環丙烷-1-甲醯胺基)咪唑並[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)乙酸乙酯 | 1H NMR (400 MHz, DMSO-d 6) δ 13.67 (s, 1H), 11.42 (s, 1H), 9.07 (s, 1H), 9.02 (d, J = 1.1 Hz, 1H), 8.39 (s, 1H), 8.07 (s, 1H), 5.05-4.86 (m, 1H), 4.36 (t, J = 6.3 Hz, 2H), 3.38 (d, J = 3.8 Hz, 2H), 2.18 (q, J = 7.0 Hz, 1H), 1.94 (s, 3H), 1.69 (dd, J = 23.6, 3.8 Hz, 1H), 1.19 (d, J = 8.8 Hz, 1H); LCMS (電灑) m/z 475.10 (M+H)+。 | D |
281 | (9H-茀-9-基)甲基 (5-氯-6-氟-4-(2-((1S,2S)-2-氟環丙烷-1-甲醯胺基)咪唑並[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)胺基甲酸酯 | 1H NMR (400 MHz, DMSO-d 6) δ 13.35-13.57 (m, 1H), 11.43 (s, 1H), 9.80-10.03 (m, 1H), 9.09 (s, 1H), 9.05 (s, 1H), 8.40 (s, 1H), 8.07 (s, 1H), 7.89 (d, J = 30.2 Hz, 4H), 7.44-7.34 (m, 4H), 4.83-5.13 (m, 1H), 4.21-4.66 (m, 3H), 2.14-2.27 (m, 1H), 1.71-1.71 (m, 1H), 1.14-1.21 (m, 1H); LCMS (電灑) m/z 627.80 (M+H)+。 | D |
282 | (1S,2S)-N-(6-(5-氯-7-(二氟甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.84 (s, 1H), 11.45 (d, J = 4.4 Hz, 1H), 9.14-9.08 (m, 2H), 8.42 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 7.65 (t, J = 53.3 Hz, 1H), 5.08-4.87 (m, 1H), 2.22-2.16 (m, 1H), 1.74-1.64 (m, 1H), 1.21-1.17 (m, 1H); LCMS (電灑) m/z 439.80 (M+H)+。 | D |
283 | (1S,2S)-N-(6-(5-氯-7-(氰基(羥基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。1 HCl | 1H NMR (400 MHz, DMSO-d 6) δ 11.43 (s, 1H), 9.10 (d, J = 2.0 Hz, 1H), 9.06 (d, J = 1.6 Hz, 1H), 8.40 (d, J = 5.5 Hz, 1H), 8.16 (s, 1H), 6.37 (s, 1H), 5.17-4.87 (m, 1H), 2.23-2.16 (m, 1H), 1.74-1.64 (m, 1H), 1.24-1.17 (m, 1H); LCMS (電灑) m/z 444.00 (M+H)+。 | D |
284 | N-(1-(5-氯-6-氟-4-(2-((1S,2S)-2-氟環丙烷-1-甲醯胺基)咪唑並[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)乙基)環丁烷甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ13.78 - 13.32 (m, 1H), 11.40 (s, 1H), 9.07 (s, 1H), 8.99 (d, J = 1.0 Hz, 1H), 8.50 (s, 1H), 8.37 (s, 1H), 8.33 (br d, J = 6.8 Hz, 1H), 8.04 (s, 1H), 5.45 (br t, J = 7.0 Hz, 1H), 5.10 - 4.81 (m, 1H), 3.08 (br t, J = 8.1 Hz, 1H), 2.24 - 2.17 (m, 1H), 2.15 - 2.01 (m, 2H), 1.98 - 1.91 (m, 2H), 1.90 - 1.82 (m, 1H), 1.76 - 1.63 (m, 2H), 1.56 (br d, J = 7.2 Hz, 3H), 1.25 - 1.16 (m, 1H); LCMS (電灑) m/z 514.2 (M+H)+。 | D |
285 | (1S,2S)-N-(6-(5-氯-6-氟-7-(2-氟環丙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.95-13.62 (1H), 11.41 (s, 1H), 9.06 (s, 1H), 8.96 (d, J = 1.2 Hz, 1H), 8.39 (s, 1H), 8.08 (s, 1H), 5.46-5.22 (m, 1H), 5.08-4.85 (m, 1H), 2.82-2.69 (m, 1H), 2.25-2.13 (m, 1H), 1.80-1.72 (m, 1H), 1.71-1.62 (m, 1H), 1.48-1.36 (m, 1H), 1.22-1.15 (m, 1H); LCMS (電灑) m/z 447.1 (M+H)+。 | D |
286 | (1S,2S)-2-氟-N-(6-(6-氟-7-(異丙胺基)-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺。2甲酸 | 1H NMR (400 MHz, DMSO-d 6) δ 13.02-13.21 (m, 1H), 11.30-11.40 (m, 1H), 8.95-9.06 (m, 1H), 8.75-8.82 (m, 1H), 8.29-8.41 (m, 1H), 7.81-7.95 (m, 1H), 5.01-5.08 (m, 1H), 4.84-4.95 (m, 2H), 3.92-4.13 (m, 1H), 2.24-2.30 (m, 3H), 2.12-2.23 (m, 2H), 1.61-1.76 (m, 1H), 1.20-1.27 (m, 1H), 1.16-1.20 (m, 1H); LCMS (電灑) m/z 564.3 (M+H)+。 | D |
287 | (1S,2S)-N-(6-(5-氯-6-氟-7-(四氫呋喃-3-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.43-13.59 (m, 1H), 13.34 (br d, J = 1.2 Hz, 1H), 11.35-11.48 (m, 1H), 9.28-9.33 (m, 1H), 9.28-9.33 (m, 1H), 9.04-9.10 (m, 1H), 8.97-9.02 (m, 1H), 8.63-8.72 (m, 1H), 8.63-8.65 (m, 1H), 8.36-8.42 (m, 1H), 8.00-8.11 (m, 1H), 7.53-7.60 (m, 1H), 5.00-5.11 (m, 1H), 4.82-4.94 (m, 1H), 4.06-4.16 (m, 2H), 3.96-4.04 (m, 1H), 3.82-3.96 (m, 2H), 2.35-2.44 (m, 1H), 2.11-2.30 (m, 2H), 1.62-1.75 (m, 1H), 1.15-1.29 (m, 1H); LCMS (電灑) m/z 458.8 (M+H)+。 | D |
288 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(2,2,2-三氟乙醯胺基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.66 (m, 1H), 11.40 (s, 1H), 10.13 (m, 1H), 9.07 (s, 1H), 9.01 (d, J = 1.3 Hz, 1H), 8.38 (s, 1H), 8.10 (s, 1H), 5.56 (q, J=7.2 Hz, 1H), 4.96 (m, 1H), 2.19 (m, 1H), 1.70 (m, 4H), 1.21 (ddt, J=12.3, 9.0, 6.2, 6.2 Hz, 1H); LCMS (電灑) m/z 528.1 (M+H)+。 | D |
289 | (1S,2S)-N-(6-(5-氯-6-氟-7-((甲硫基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.65 (s, 1H), 11.42 (s, 1H), 9.08 (s, 1H), 9.03 (d, J = 1.6 Hz, 1H), 8.39 (s, 1H), 8.07 (d, J = 1.1 Hz, 1H), 5.07-4.86 (m, 1H), 4.11 (s, 2H), 2.23-2.15 (m, 1H), 2.10-2.03 (m, 3H), 1.69 (dtd, J = 23.3, 6.9, 3.8 Hz, 1H), 1.25-1.16 (m, 1H); LCMS (電灑) m/z 450.00 (M+H)+。 | D |
290 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(甲硫基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.53 (s, 1H), 11.42 (s, 1H), 9.08 (s, 1H), 9.02 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 5.76 (s, 0H), 5.07-4.86 (m, 1H), 4.65 (q, J = 7.1 Hz, 1H), 2.23-2.16 (m, 1H), 1.97 (d, J = 11.0 Hz, 3H), 1.78 (d, J = 7.1 Hz, 3H), 1.69 (dtd, J = 23.4, 6.9, 3.6 Hz, 1H), 1.25-1.16 (m, 1H); LCMS (電灑) m/z 464.10 (M+H)+。 | D |
291 | (1S,2S)-N-(6-(5-氯-6-氟-7-((甲基亞磺醯基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.67 (s, 1H), 11.41 (d, J = 9.9 Hz, 1H), 9.09-9.05 (m, 2H), 8.39 (d, J = 3.3 Hz, 1H), 8.10 (d, J = 1.6 Hz, 1H), 5.07-4.87 (m, 1H), 4.56-4.44 (m, 2H), 2.74-2.67 (m, 3H), 2.23-2.16 (m, 1H), 1.69 (dtd, J = 23.5, 6.9, 3.7 Hz, 1H), 1.25-1.15 (m, 1H); LCMS (電灑) m/z 466.00 (M+H)+。 | D |
292 | (1S,2S)-N-(6-(5-氯-6-氟-7-((甲基磺醯基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.67 (s, 1H), 11.43 (s, 1H), 9.09-9.06 (m, 2H), 8.40 (s, 1H), 8.12 (s, 1H), 5.07-4.87 (m, 3H), 3.13 (d, J = 14.3 Hz, 3H), 2.23-2.16 (m, 1H), 1.69 (dtd, J = 23.1, 6.9, 3.8 Hz, 1H), 1.25-1.17 (m, 1H); LCMS (電灑) m/z 482.00 (M+H)+。 | D |
293 | (1S,2S)-N-(6-(5-氯-7-(1,3-二甲基脲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.67 (s, 1H), 11.42 (s, 1H), 9.09 (s, 1H), 8.99 (d, J = 1.6 Hz, 1H), 8.44 (s, 1H), 8.10 (s, 1H), 6.46 (s, 1H), 5.07-4.87 (m, 1H), 3.21 (s, 3H), 2.58 (d, J = 4.4 Hz, 3H), 2.23-2.16 (m, 1H), 1.72-1.66 (m, 1H), 1.25-1.15 (m, 1H); LCMS (電灑) m/z m/z 475.10 (M+H)+。 | D |
294 | (1S,2S)-N-(6-(5-氯-7-((1S,2R)-1,2-二甲氧基丙基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.28 (s, 1H), 11.42 (s, 1H), 9.07 (s, 1H), 9.03 (d, J = 1.1 Hz, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 5.07-4.87 (m, 2H), 3.90 (t, J = 6.3 Hz, 1H), 3.37 (s, 3H), 3.25 (s, 3H), 2.23-2.15 (m, 1H), 1.69 (dtd, J = 23.3, 7.1, 3.6 Hz, 1H), 1.25-1.15 (m, 1H), 0.96-0.91 (m, 3H); LCMS (電灑) m/z 491.1 (M+H)+。 | D |
295 | (1S,2S)-N-(6-(5-氯-7-(1-(2,2-二氟乙醯胺基)乙基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.96 - 12.70 (m, 1H), 11.39 (br s, 1H), 9.07 (s, 1H), 8.99 (br d, J = 1.3 Hz, 1H), 8.38 (s, 1H), 8.09 (s, 1H), 6.49 - 6.10 (m, 1H), 5.56 (br d, J = 7.2 Hz, 1H), 5.10 - 4.83 (m, 1H), 2.28 - 2.13 (m, 1H), 1.71 (br s, 1H), 1.66 (br d, J = 7.2 Hz, 3H), 1.26 - 1.16 (m, 1H); LCMS (電灑) m/z 510.2 (M+H)+。 | D |
296 | (1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲基-1H-咪唑-5-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.18 (s, 1H), 12.55-12.26 (m, 1H), 11.41 (s, 1H), 9.09 (s, 1H), 9.05 (d, J = 1.3 Hz, 1H), 8.40 (s, 1H), 8.08 (s, 1H), 7.70 (d, J = 3.7 Hz, 1H), 5.10 - 4.84 (m, 1H), 2.49 (s, 3H), 2.27-2.16 (m, 1H), 1.78-1.64 (m, 1H), 1.26-1.16 (m, 1H); LCMS (電灑) m/z 468.9 (M+H)+。 | D |
297 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(甲基磺醯基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.34-13.85 (0H), 11.42 (s, 1H), 9.09 (s, 1H), 9.03 (d, J = 1.6 Hz, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 5.18 (q, J = 7.3 Hz, 1H), 5.07-4.86 (m, 1H), 3.06 (s, 3H), 2.23-2.16 (m, 1H), 1.99-1.96 (m, 3H), 1.74-1.64 (m, 2H), 1.22-1.15 (m, 1H); LCMS (電灑) m/z 496.00 (M+H)+。 | D |
298 | (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(甲基亞磺醯基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.57-13.99 (1H), 11.43 (s, 1H), 9.10 (d, J = 11.5 Hz, 1H), 9.02 (d, J = 1.6 Hz, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 5.08-4.87 (m, 1H), 4.65 (q, J = 7.1 Hz, 1H), 2.49 (s, 3H), 2.23-2.16 (m, 1H), 1.84-1.83 (m, 3H), 1.75-1.64 (m, 2H), 1.23-1.16 (m, 1H); LCMS (電灑) m/z 480.05 (M+H)+。 | D |
299 | (1S,2S)-N-(6-(5-氯-7-(1-(乙基胺基)-1-側氧丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.24 (s, 1H), 11.38 (d, J = 24.2 Hz, 1H), 9.07 (s, 1H), 8.99-8.89 (m, 1H), 8.43 (d, J = 24.2 Hz, 1H), 8.04 (dd, J = 6.0, 4.9 Hz, 2H), 5.07-4.86 (m, 1H), 4.25 (q, J = 7.1 Hz, 1H), 3.14-3.08 (m, 2H), 2.33-2.15 (m, 1H), 1.77-1.65 (m, 1H), 1.64-1.49 (m, 3H), 1.35-1.16 (m, 1H), 1.01 (t, J = 7.1 Hz, 3H), 0.86 (q, J = 7.5 Hz, 1H); LCMS (電灑) m/z 488.1 (M+H)+。 | D |
300 | (1S,2S)-N-(6-(5-氯-7-(氰基(2,2,2-三氟乙醯胺基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.72 (s, 1H), 11.43 (d, J = 8.2 Hz, 1H), 10.96 (s, 1H), 9.13-9.05 (m, 2H), 8.40 (d, J = 10.4 Hz, 1H), 8.20 (d, J = 11.5 Hz, 1H), 6.63 (s, 1H), 5.06-4.86 (m, 1H), 2.32-2.15 (m, 1H), 1.73-1.65 (m, 1H), 1.24-1.16 (m, 1H); LCMS (電灑) m/z 539.1 (M+H)+。 | D |
301 | 2-(5-氯-6-氟-4-(2-((1S,2S)-2-氟環丙烷-1-甲醯胺基)咪唑並[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)-3-(環丁胺基)-3-側氧丙酸甲酯 | 1H NMR (400 MHz, DMSO-d 6) δ 13.54 (s, 1H), 11.38 (s, 1H), 9.02 (dd, J = 19.2, 1.6 Hz, 2H), 8.62 (d, J = 5.5 Hz, 1H), 8.35 (s, 1H), 8.06 (s, 1H), 6.19 (d, J = 7.1 Hz, 1H), 4.93 (ddd, J = 66.0, 9.9, 6.0 Hz, 1H), 3.64 (d, J = 12.1 Hz, 4H), 2.29-1.62 (m, 11H), 1.34-1.13 (m, 1H); LCMS (電灑) m/z 558.1 (M+H)+。 | D |
302 | (1S,2S)-N-((5-氯-6-氟-4-(2-((1S,2S)-2-氟環丙烷-1-甲醯胺基)咪唑並[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)(氰基)甲基)-2-氟環丙烷-1-甲醯胺。 | 1H NMR (400 MHz, DMSO-d 6) δ 13.76 (s, 1H), 11.43 (s, 1H), 9.62-9.58 (m, 1H), 9.10-9.06 (m, 2H), 8.41 (s, 1H), 8.18 (d, J = 13.7 Hz, 1H), 6.62 (t, J = 5.8 Hz, 1H), 5.07-4.77 (m, 2H), 2.23-2.16 (m, 1H), 1.93-1.86 (m, 1H), 1.73-1.55 (m, 2H), 1.27-1.15 (m, 3H); LCMS (電灑) m/z 529.1 (M+H)+。 | D |
303 | (1S,2S)-N-(6-(5-氯-7-(氰基(環丙甲醯胺基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.25 (s, 1H), 11.43 (s, 1H), 9.54 (d, J = 4.9 Hz, 1H), 9.10-9.06 (m, 2H), 8.42 (s, 1H), 8.05-8.31 (1H), 6.58 (d, J = 4.9 Hz, 1H), 4.97 (d, J = 69.8 Hz, 1H), 2.20 (d, J = 7.1 Hz, 1H), 1.94 (d, J = 30.8 Hz, 1H), 1.71 (d, J = 5.5 Hz, 1H), 1.34 (s, 7H); LCMS (電灑) m/z 511.1 (M+H)+。 | D |
304 | (1S,2S)-N-(6-(5-氯-7-(氰基(2,2-二氟乙醯胺基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.72 (s, 1H), 11.43 (s, 1H), 10.37-10.32 (m, 1H), 9.10-9.06 (m, 2H), 8.41 (t, J = 5.5 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 6.65 (d, J = 4.9 Hz, 1H), 6.50-6.23 (m, 1H), 5.07-4.87 (m, 1H), 2.19 (q, J = 7.0 Hz, 1H), 1.72-1.66 (m, 1H), 1.24-1.17 (m, 1H); LCMS (電灑) m/z 521.1 (M+H)+。 | D |
305 | (1S,2S)-N-(6-(5-氯-6-氟-7-((丙烷-2-基-1,1,1,3,3-d6)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.16 (s, 1H), 11.36 (s, 1H), 9.01 (s, 1H), 8.90 (s, 1H), 8.34 (s, 1H), 7.94 (s, 1H), 5.28-5.18 (m, 1H), 5.06-4.85 (m, 1H), 4.00 (d, J = 9.3 Hz, 1H), 2.21-2.14 (m, 1H), 1.67 (dtd, J = 23.3, 6.8, 3.7 Hz, 1H), 1.23-1.15 (m, 1H); LCMS (電灑) m/z 452.9 (M+H)+。 | D |
306 | (1S,2S)-N-(6-(7-乙氧基-6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 13.68 (s, 1H), 11.39 (s, 1H), 9.02 (s, 1H), 8.84 (d, J = 1.4 Hz, 1H), 8.36 (s, 1H), 7.97 (s, 1H), 5.05-4.89 (m, 1H), 4.36 (q, J = 7.0 Hz, 2H), 2.29 (s, 3H), 2.20-2.16 (m, 1H), 1.72-1.66 (m, 1H), 1.40 (t, J = 7.1 Hz, 3H), 1.20 (s, 1H) ; LCMS (電灑) m/z 445.10 (M+H)+。 | D |
307 | (1S,2S)-N-(6-(5-乙氧基-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ13.48 (s, 1H), 11.40 (s, 1H), 9.13 (d, J = 1.6 Hz, 1H), 9.08 (s, 1H), 8.44 (s, 1H), 8.31 (s, 1H), 5.07-4.86 (m, 1H), 3.96 (q, J = 7.0 Hz, 2H), 2.55 (s, 3H), 2.22-2.15 (m, 1H), 1.72-1.65 (m, 1H), 1.21-1.16 (m, 4H) ; LCMS (電灑) m/z 445.10 (M+H)+。 | D |
化合物的評定
HPK1激酶檢測
透過Promega的ADP-Glo™激酶檢測來測量HPK1激酶活性。 在該檢測中,將5ng的重組人類HPK1(signalchem)與5μL的化合物(0.5% DMSO)、5μL的MBP (0.5μg/μl)和5μL的ATP(25μM)緩衝液(40mM Tris,7.5;20mM MgCl
2;0.1mg/ml BSA;50μM DTT。)一起培養。於檢測開始,將反應混合物在96孔盤中於30℃下培養40分鐘。培養後,加入25uL ADP-Glo試劑,並在室溫下培養作用40分鐘以停止反應並降解殘餘的ATP。接著透過在每孔中加入50uL的檢測試劑將ADP產物轉化為ATP。在室溫下培養30分鐘後,用Molecular device I3X讀盤儀檢測冷光。使用GraphPad Prism 7軟體和SigmaPlot13.0中執行的軟體程序,從抑制劑濃度範圍中選定的一系列抑制百分比值計算出IC
50值。
表2顯示了本發明化合物的IC
50值,其中+表示為>1000nM,++為501-1000nM,+++為101-500nM,++++為<100nM。
表2. 針對HPK1數據的體外活性
實施例 | HPK1 IC 50(nM) | 實施例 | HPK1 IC 50(nM) | 實施例 | HPK1 IC 50(nM) |
1 | + | 45 | ++++ | 89 | ++++ |
2 | ++++ | 46 | ++++ | 90 | ++++ |
3 | +++ | 47 | ++++ | 91 | ++++ |
4 | ++++ | 48 | ++++ | 92 | ++++ |
5 | ++++ | 49 | ++++ | 93 | ++++ |
6 | ++++ | 50 | ++++ | 94 | ++++ |
7 | ++++ | 51 | ++++ | 95 | ++++ |
8 | +++ | 52 | ++++ | 96 | ++++ |
9 | ++++ | 53 | ++++ | 97 | ++++ |
10 | ++++ | 54 | ++++ | 98 | +++ |
11 | + | 55 | ++++ | 99 | +++ |
12 | ++++ | 56 | ++++ | 100 | ++++ |
13 | ++++ | 57 | ++++ | 101 | ++++ |
14 | ++++ | 58 | ++++ | 102 | ++++ |
15 | ++++ | 59 | +++ | 103 | +++ |
16 | ++++ | 60 | ++++ | 104 | +++ |
17 | ++++ | 61 | ++++ | 105 | ++++ |
18 | ++++ | 62 | ++++ | 106 | ++++ |
19 | ++++ | 63 | ++++ | 107 | ++++ |
20 | ++++ | 64 | ++++ | 108 | ++++ |
21 | ++++ | 65 | ++++ | 109 | ++++ |
22 | +++ | 66 | ++++ | 110 | ++++ |
23 | ++++ | 67 | ++++ | 111 | +++ |
24 | + | 68 | ++++ | 112 | +++ |
25 | ++++ | 69 | ++++ | 113 | ++++ |
26 | ++++ | 70 | ++++ | 114 | ++++ |
27 | ++++ | 71 | ++++ | 115 | ++++ |
28 | ++++ | 72 | +++ | 116 | ++++ |
29 | ++++ | 73 | ++++ | 117 | ++++ |
30 | ++++ | 74 | +++ | 118 | ++++ |
31 | +++ | 75 | ++++ | 119 | ++++ |
32 | ++++ | 76 | ++++ | 120 | ++++ |
33 | ++++ | 77 | ++++ | 121 | ++++ |
34 | ++++ | 78 | ++++ | 122 | ++++ |
35 | +++ | 79 | ++++ | 123 | ++++ |
36 | ++++ | 80 | ++++ | 124 | ++++ |
37 | ++++ | 81 | ++++ | 125 | ++++ |
38 | ++++ | 82 | ++++ | 126 | ++++ |
39 | ++++ | 83 | ++++ | 127 | +++ |
40 | ++++ | 84 | ++++ | 128 | ++++ |
41 | ++++ | 85 | ++++ | 129 | +++ |
42 | ++++ | 86 | ++++ | 130 | ++++ |
43 | ++++ | 87 | ++++ | 131 | ++++ |
44 | ++++ | 88 | ++++ | 132 | ++++ |
133 | ++++ | 179 | ++++ | 225 | ++++ |
134 | ++++ | 180 | ++++ | 226 | ++++ |
135 | + | 181 | ++++ | 227 | +++ |
136 | ++++ | 182 | ++++ | 228 | ++++ |
137 | + | 183 | ++++ | 229 | ++++ |
138 | +++ | 184 | +++ | 230 | ++++ |
139 | ++++ | 185 | ++++ | 231 | ++++ |
140 | ++++ | 186 | ++++ | 232 | ++++ |
141 | ++++ | 187 | ++++ | 233 | ++++ |
142 | ++++ | 188 | ++++ | 234 | ++++ |
143 | ++++ | 189 | +++ | 235 | ++++ |
144 | ++++ | 190 | ++++ | 236 | ++++ |
145 | ++++ | 191 | ++++ | 237 | ++++ |
146 | ++++ | 192 | ++++ | 238 | +++ |
147 | ++++ | 193 | ++++ | 239 | +++ |
148 | ++++ | 194 | ++++ | 240 | +++ |
149 | +++ | 195 | ++++ | 241 | ++++ |
150 | ++++ | 196 | ++++ | 242 | ++++ |
151 | ++++ | 197 | ++++ | 243 | ++++ |
152 | +++ | 198 | ++++ | 244 | ++++ |
153 | ++++ | 199 | ++++ | 245 | ++++ |
154 | +++ | 200 | ++++ | 246 | ++++ |
155 | ++++ | 201 | ++++ | 247 | ++++ |
156 | ++++ | 202 | +++ | 248 | ++++ |
157 | ++++ | 203 | +++ | 249 | +++ |
158 | ++++ | 204 | +++ | 250 | ++++ |
159 | +++ | 205 | +++ | 251 | ++++ |
160 | ++++ | 206 | ++++ | 252 | ++++ |
161 | +++ | 207 | ++++ | 253 | ++++ |
162 | ++++ | 208 | ++++ | 254 | ++++ |
163 | +++ | 209 | ++++ | 255 | ++++ |
164 | +++ | 210 | ++++ | 256 | ++++ |
165 | ++++ | 211 | ++++ | 257 | ++++ |
166 | ++++ | 212 | ++++ | 258 | ++++ |
167 | ++++ | 213 | ++++ | 259 | +++ |
168 | ++++ | 214 | ++++ | 260 | ++++ |
169 | ++++ | 215 | ++++ | 261 | ++++ |
170 | ++++ | 216 | ++++ | 262 | ++++ |
171 | ++++ | 217 | ++++ | 263 | ++++ |
172 | ++++ | 218 | ++++ | 264 | ++++ |
173 | ++++ | 219 | ++++ | 265 | ++++ |
174 | ++++ | 220 | ++++ | 266 | ++++ |
175 | ++++ | 221 | ++++ | 267 | +++ |
176 | ++++ | 222 | ++++ | 268 | ++++ |
177 | ++++ | 223 | ++++ | 269 | ++++ |
178 | +++ | 224 | ++++ | 270 | +++ |
271 | ++++ | 306 | ++++ | ||
272 | ++++ | 307 | ++++ | ||
273 | ++++ | ||||
274 | ++++ | ||||
275 | +++ | ||||
276 | +++ | ||||
277 | +++ | ||||
278 | + | ||||
279 | ++++ | ||||
280 | ++++ | ||||
281 | + | ||||
282 | ++++ | ||||
283 | +++ | ||||
284 | ++++ | ||||
285 | ++++ | ||||
286 | ++++ | ||||
287 | ++++ | ||||
288 | ++++ | ||||
289 | ++++ | ||||
290 | ++++ | ||||
291 | +++ | ||||
292 | +++ | ||||
293 | ++++ | ||||
294 | +++ | ||||
295 | ++++ | ||||
296 | ++++ | ||||
297 | ++++ | ||||
298 | ++++ | ||||
299 | ++++ | ||||
300 | ++++ | ||||
301 | ++++ | ||||
302 | ++++ | ||||
303 | ++++ | ||||
304 | ++++ | ||||
305 | ++++ |
人類周邊泛T
細胞的IFNγ
和IL-2
分析
人類周邊血泛T細胞購自STEMCELL
TMTechnologies Inc.。將人類周邊血泛T細胞解凍並懸浮在DMEM培養基(10%FBS和1%青黴素/鏈黴素)中。 將8 X 10
4T細胞接種在96孔盤中,並與不同濃度的化合物和100nM前列腺素E2培養1小時。用Dynabeads人類T-活化劑CD3/CD28(Life Technologies)以1:3的細胞:珠比例刺激T細胞。按照製造商的建議,使用MSD V-PLEX人類細胞激素試劑組在刺激後24小時測量細胞激素分泌。用MESO Quickplex SQ120(Mesoscale Discovery)分析數據。
在表3中,值+表示為>1000nM,++為200-1,000nM,+++為<200nM,和–為未測定。
表3. 本發明化合物在人類周邊血泛T細胞中的IFNγ和IL-2分泌
實施例 | IFNγ (EC 50) | IL-2 (EC 50) |
4 | +++ | ++ |
7 | ++ | ++ |
13 | ++ | ++ |
26 | +++ | ++ |
27 | +++ | - |
33 | +++ | ++ |
34 | +++ | ++ |
38 | ++ | ++ |
38 | +++ | ++ |
40 | +++ | ++ |
41 | +++ | ++ |
42 | +++ | ++ |
44 | +++ | ++ |
58 | +++ | ++ |
61 | +++ | ++ |
62 | +++ | ++ |
64 | +++ | +++ |
本申請要求2020年9月28日提交的美國臨時專利申請號63/084,059的權益和優先權。在本段落中指明的該申請的全部公開內容透過引用併入本文。
Claims (29)
- 一種化合物或其藥學上可接受的鹽、水合物或溶劑化物式,其特徵係該化合物如式(I)所示: 式(I), 其中: X為O或S; L為鍵、-O-、-S-或-NR 6-; R 1為烷基、環烷基、芳基、雜芳基或雜環基,其中,R 1可選地被一個或多個獨立地選自R 7的取代基取代; R 6為-H或C 1-6烷基; R 7為C 1-6烷基、C 2-6烯基、C 2-6炔基、環烷基、芳基、雜芳基、雜環基、鹵基、側氧基、氰基、羥基、-C(O)R 9、-C(O)OR 9、-C(O)NR 10R 11、-OR 9、-OC(O)R 9、-OC(O)NR 10R 11、-SR 9、-S(O)R 9、-S(O) 2R 9、-S(O)(=NH)R 10、-S(O) 2NR 10R 11、-NR 10R 11、-N(R 6)NR 10R 11、-N(R 6)OR 9、-N(R 6)C(O)R 9、-N(R 6)C(O)OR 9、-N(R 6)C(O)NR 10R 11、-N(R6)S(O) 2R 9、-N(R 6)S(O) 2NR 10R 11或-P(O)R 12R 13; R 9為-H、C 1-6烷基、C 1-6鹵代烷基、C 2-6烯基、C 2-6炔基、環烷基、芳基、雜芳基或雜環基; 每個R 10和R 11獨立地為-H、C 1-6烷基、C 2-6烯基、C 2-6炔基、環烷基、芳基、雜芳基或雜環基,或R 10和R 11與它們所連接的氮原子一起形成可選被一個或多個基團取代的4至12元雜環基,基團選自由鹵基、羥基、烷基、烯基、炔基、鹵代烷基、羥烷基、-CN、-NO 2、-NR 10R 11、-NR 10C(=O)R 9、-NR 10C(=O)NR 10R 11、-NR 10C(=O)OR 9、-OR 9、-C(=O)R 9、-C(=O)OR 9、-C(=O)NR 10R 11、-OC(=O)R 9、-OC(=O)OR 9和-OC(=O)NR 10R 11組成之群組; 每個R 12和R 13獨立地為C 1-6烷基、C 1-6烷氧基、C 3-8環烷基、芳基、雜芳基、雜環基,或R 12和R 13與它們所連接的磷原子一起形成可選被一個或多個基團取代的4至8元雜環基,基團選自由鹵基、羥基、烷基、烯基、炔基、鹵代烷基、羥烷基、-CN、-NO 2、-NR 10R 11、-NR 10C(=O)R 9、-NR 10C(=O)NR 10R 11、-NR 10C(=O)OR 9、-OR 9、-C(=O)R 9、-C(=O)OR 9、-C(=O)NR 10R 11、-OC(=O)R 9、-OC(=O)OR 9和-OC(=O)NR 10R 11組成之群組; Het選自下述基團: R a、R b和R c各自獨立地為-H、-D、鹵基、-CF 3、-CF 2H、-CH 2F、-CN、-OR 9或-NR 10R 11; R 2為-H、-D、-CD 3、C 1-6烷基、C 2-6烯基、C 2-6炔基、環烷基、芳基、雜芳基、雜環基、鹵基、羥基、-CD 2OH、-CN、-NO 2、鹵代烷基、三甲基矽基乙氧基甲基、-C(O)R 9、-C(O)OR 9、-C(O)NR 10R 11、-OR 9、-OC(O)R 9、-OC(O)N R 10R 11、-SR 9、-S(O)R 9、-S(O) 2R 9、-S(O)(=NH)R 10、-S(O) 2NR 10R 11、-NR 10R 11、-N(R 6)NR 10R 11、-N(R 6)OR 9、-N(R 6)C(O)R 9、-N(R 6)C(O)R 9、-N(R 6)C(O)OR 9、-N(R 6)C(O)NR 10R 11、-N(R 6)S(O) 2R 9、-N(R 6)S(O) 2NR 10R 11或-P(O)R 12R 13,其中,C 1-6烷基、C 2-6烯基、C 2-6炔基、環烷基、芳基、雜芳基或雜環基可選地被一個或多個基團取代,基團選自由鹵基、羥基、烷基、烯基、炔基、鹵代烷基、羥烷基、-CN、-NO 2、-NR 10R 11、-NR 10C(=O)R 9、-NR 10C(=O)NR 10R 11、-NR 10C(=O)OR 9、-OR 9、-C(=O)R 9、-C(=O)OR 9、-C(=O)NR 10R 11、-OC(=O)R 9、-OC(=O)OR 9和-OC(=O)NR 10R 11組成之群組; R 3為-H、-D、-CD 3、C 1-6烷基、C 2-6烯基、C 2-6炔基、環烷基、芳基、雜芳基、雜環基、鹵基、氰基、羥基、-CH 2OH、-CD 2OH、-OH、-CN、-NO 2、鹵代烷基、-C(O)R 9、-C(O)OR 9、-C(O)NR 10R 11、-OR 9、-OC(O)R 9、-OC(O)NR 10R 11、-SR 9、-S(O)R 9、-S(O) 2R 9、-S(O)(=NH)R 10、-S(O) 2NR 10R 11、-NR 10R 11、-N(R 6)NR 10R 11、-N(R 6)OR 9、-N(R 6)C(O)R 9、-N(R 6)C(O)OR 9、-N(R 6)C(O)NR 10R 11、-N(R 6)S(O) 2R 9、-N(R 6)S(O) 2NR 10R 11或-P(O)R 12R 13; M為鍵、-O-、-S-或-NR 6-; R 6為-H或C 1-6烷基; R 4為-H、-D、C 1-6烷基、C 2-6烯基、C 2-6炔基、環烷基、芳基、雜芳基、雜環基、鹵基、氰基、羥基、-C(O)R 9、-C(O)OR 9、-C(O)NR 10R 11、- -S(O) 2R 9、-S(O)(=NH)R 10、-S(O) 2NR 10R 11或-P(O)R 12R 13,其中,C 1-6烷基、C 2-6烯基、C 2-6炔基、環烷基、芳基、雜芳基或雜環基可選地被一個或多個基團取代,基團選自由鹵基、羥基、烷基、烯基、炔基、鹵代烷基、羥烷基、-CN、-CD 3、-NO 2、-NR 10R 11、-NR 10C(=O)R 9、-NR 10C(=O)NR 10R 11、-NR 10C(=O)OR 9、-NR 10S(O) 2R 9、-OR 9、-C(=O)R 9、-C(=O)OR 9、-C(=O)NR 10R 11、-OC(=O)R 9、-OC(=O)OR 9和-OC(=O)NR 10R 11組成之群組;且 R 5為-H、-D、-CD 3、C 1-6烷基、C 2-6烯基、C 2-6炔基、環烷基、鹵基、羥基、-CH 2OH、-CD 2OH、-CN或鹵代烷基。
- 如請求項1所述之化合物或其藥學上可接受的鹽,其中,L為鍵,並且R 1為環烷基,其可選地被一個或多個基團取代,基團選自由C 1-6烷基、C 2-6烯基、C 2-6炔基、環烷基、鹵基、氰基、羥基、-C(O)R 9、 -C(O)OR 9、-C(O)NR 10R 11、-OR 9、-OC(O)R 9、-OC(O)NR 10R 11、-NR 10R 11、-N(R 6)NR 10R 11、-N(R 6)OR 9、-N(R 6)C(O)R 9、-N(R 6)C(O)OR 9和-N(R 6)C(O)NR 10R 11組成之群組。
- 如請求項1所述之化合物或其藥學上可接受的鹽,其中,R 2和R 3各自獨立地為-H、鹵基、烷硫基、鹵代烷基或烷基。
- 如請求項1所述之化合物或其藥學上可接受的鹽,其中,M為鍵、-O-或-NR 6-;並且R 4為-H、-D、C 1-6烷基、C 2-6烯基、C 2-6炔基、環烷基、芳基、雜芳基、雜環基、鹵基、氰基、羥基、-C(O)R 9、-C(O)NR 10R 11、-S(O) 2R 9、-S(O)(=NH)R 10或-S(O) 2NR 10R 11,其中,C 1-6烷基、C 2-6烯基、C 2-6炔基、環烷基、芳基、雜芳基或雜環基可選地被一個或多個基團取代,基團選自由鹵基、羥基、烷基、烯基、炔基、鹵代烷基、羥烷基、-CN、-CD 3、-NR 10R 11、-NR 10S(O) 2R 9和-NR 10C(=O)R 9組成之群組。
- 如請求項5所述之化合物或其藥學上可接受的鹽,其中,L為鍵;R 1為環丙基,其可選地被一個或多個基團取代,基團選自由鹵基、C 1-3烷基、C 1-3羥烷基和C 1-3鹵代烷基組成之群組;R 2為-H、烷基、鹵基、鹵代烷基或烷硫基;R 3為-H、烷基或鹵基;M為鍵、-O-、-S-或-NR 6-;R 4為-H、鹵基、烷基、羥烷基、鹵代烷基、鹵烯基、環烷基、氰基烷基、胺基羰基烷基、乙醯胺基乙基、丙醯胺基乙基、甲醯胺基乙基、環烷基烷基、環烷基(羥基)烷基、羥基環烷基、甲氧基環烷基、環烷基(甲氧基)甲基、烷氧基烷基、烯基、甲基磺醯胺基乙基、咪唑基乙基、二噁烷基、環丁基羰基胺基乙基、二氟乙醯胺基乙基、三氟乙醯胺基乙基、甲硫甲基、甲硫乙基、環丙基羰基胺基(氰基)甲基、氰基(二氟乙醯胺基)甲基、丙基-1,1,1,3,3,3-d6)胺基、四氫呋喃基、甲基咪唑基乙基、呋喃基、吡咯基、甲基吡咯基、異噁唑基、四唑基烷基、甲基吡唑基或甲基吡唑基甲基;並且R 5為–H、烷基或鹵基。
- 如請求項5所述之化合物或其藥學上可接受的鹽,其為 (1S,2S)-2-氟-N-(5-(5-甲基-1H-吲唑-4-基)吡唑並[1,5-a]嘧啶-2-基)環丙烷-1-甲醯胺;或 (1S,2S)-N-(5-(5-乙基-6,7-二氟-1H-吲唑-4-基)吡唑並[1,5-a]嘧啶-2-基)-2-氟環丙烷-1-甲醯胺。
- 如請求項8所述之化合物或其藥學上可接受的鹽,其中,L為鍵,並且R 1為環烷基,其可選地被一個或多個基團取代,基團選自由C 1-6烷基、C 2-6烯基、C 2-6炔基、環烷基、鹵基、氰基、羥基、-C(O)R 9、-C(O)OR 9、-C(O)NR 10R 11、-OR 9、-OC(O)R 9、-OC(O)NR 10R 11、-NR 10R 11、-N(R 6)NR 10R 11、-N(R 6)OR 9、-N(R 6)C(O)R 9、-N(R 6)C(O)OR 9和-N(R 6)C(O)NR 10R 11組成之群組。
- 如請求項8所述之化合物或其藥學上可接受的鹽,其中,R 1為環丙基,其可選地被一個或多個基團取代,基團選自由鹵基、C 1-3烷基、C 1-3羥烷基和C 1-3鹵代烷基組成之群組;R 2為-H、烷基、鹵基、鹵代烷基或烷硫基;R 3為-H、烷基或鹵基;M為鍵、-O-、-S-或-NR 6-;R 4為-H、鹵基、烷基、羥烷基、鹵代烷基、鹵烯基、環烷基、氰基烷基、胺基羰基烷基、乙醯胺基乙基、丙醯胺基乙基、甲醯胺基乙基、環烷基烷基、環烷基(羥基)烷基、羥基環烷基、甲氧基環烷基、環烷基(甲氧基)甲基、烷氧基烷基、烯基、甲基磺醯胺基乙基、咪唑基乙基、二噁烷基、環丁基羰基胺基乙基、二氟乙醯胺基乙基、三氟乙醯胺基乙基、甲硫甲基、甲硫乙基、環丙基羰基胺基(氰基)甲基、氰基(二氟乙醯胺基)甲基、丙基-1,1,1,3,3,3-d6)胺基、四氫呋喃基、甲基咪唑基乙基、呋喃基、吡咯基、甲基吡咯基、異噁唑基、四唑基烷基、甲基吡唑基或甲基吡唑基甲基;並且R 5為–H、烷基或鹵基。
- 如請求項8所述之化合物或其藥學上可接受的鹽,其選自由下述組成之群組: (1S,2S)-2-氟-N-(6-(5-甲基-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-乙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-乙基-6,7-二氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(二甲胺基)-5-乙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(6,7-二氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-胺基-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-乙基-7-(乙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-乙氧基-5-乙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-乙氧基-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(乙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(二甲胺基)-6-氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-乙氧基-6-氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(二甲胺基)-6-氟-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(6,7-二氟-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(二甲胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6,7-二氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺;和 (1S,2S)-N-(6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺。
- 如請求項8所述之化合物或其藥學上可接受的鹽,其選自由下述組成之群組: (1S,2S)-N-(6-(5-乙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(二甲胺基)-5-乙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-乙基-7-(乙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-乙氧基-5-乙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(二甲胺基)-6-氟-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺;和 (1S,2S)-N-(6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-b]嗒𠯤-2-基)-2-氟環丙烷-1-甲醯胺。
- 如請求項13所述之化合物或其藥學上可接受的鹽,其中,L為鍵,並且R 1為環烷基,其可選地被一個或多個基團取代,基團選自由C 1-6烷基、C 2-6烯基、C 2-6炔基、環烷基、鹵基、氰基、羥基、-C(O)R 9、-C(O)OR 9、-C(O)NR 10R 11、-OR 9、-OC(O)R 9、-OC(O)NR 10R 11、-NR 10R 11、-N(R 6)NR 10R 11、-N(R 6)OR 9、-N(R 6)C(O)R 9、-N(R 6)C(O)OR 9和-N(R 6)C(O)NR 10R 11組成之群組。
- 如請求項13所述之化合物或其藥學上可接受的鹽,其中,L為鍵;R 1為環烷基,其可選地被一個或多個基團取代,基團選自由鹵基、C 1-3烷基、C 1-3羥烷基和C 1-3鹵代烷基組成之群組。
- 如請求項13所述之化合物或其藥學上可接受的鹽,其選自由下述組成之群組: (1S,2S)-2-氟-N-(6-(5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-乙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(二甲胺基)-5-乙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-5,7-雙(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-乙基-6,7-二氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-5-甲基-7-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(二甲胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-乙氧基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(6,7-二氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(6,7-二氟-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-乙基-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(二甲胺基)-6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(二甲胺基)-6-氟-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(乙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(乙基(甲基)胺基)-6-氟-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-乙基-7-(乙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-乙氧基-5-乙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(乙基(甲基)胺基)-6-氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(二甲胺基)-6-氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-乙氧基-6-氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-5-甲基-7-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-溴-6,7-二氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(乙基(甲基)胺基)-6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6,7-二氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-溴-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(吡咯烷-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(哌啶-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((3-羥丙基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(氮呾-1-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(環丙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(甲胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-硫代嗎啉基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(異丙胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(異丙基(甲基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((1-氰乙基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1H-吡咯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-胺基-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((氰甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-((2H-四唑-2-基)甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(2-羥基丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-乙烯基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-乙醯基-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-環丙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(2-乙氧基丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲氧基丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(三級丁基胺基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(環丙胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(3-氟吡咯烷-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲基-1H-吡咯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(1-(2H-四唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(丙-1-炔-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-7-異丙基-5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-5-甲基-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1R,2S)-N-(6-(5-氯-6-氟-7-(異丙胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2R)-N-(6-(5-氯-6-氟-7-(異丙胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1R,2R)-N-(6-(5-氯-6-氟-7-(異丙胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲基-1H-吡咯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; 1-(5-氯-6-氟-4-(2-((1S,2S)-2-氟環丙烷-1-甲醯胺基)咪唑並[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)-N,N-二甲基-1H-吡咯-3-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-羥基丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲氧基丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-氟丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(異丁胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(丙胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((E)-丙-1-烯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(乙胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (3R,4S)-4-甲基四氫呋喃-3-基 (6-(5-氯-7-(二甲胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)胺基甲酸酯; (1S,2S)-N-(6-(5-氯-7-(2-(二甲胺基)-2-側氧乙基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((2-(二甲胺基)-2-側氧乙基)硫基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-氟乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(3,3,3-三氟丙-1-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-7-(異丙胺基)-5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((甲胺基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((二甲胺基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-乙基-6-氟-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-乙基-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-乙基-6-氟-7-(異丙胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲基-1H-吡咯-3-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1H-吡咯-3-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲基-1H-吡唑-5-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((1-羥基-2-甲基丙烷-2-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-三甲基乙醯-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-環丙氧基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; 4-甲基四氫呋喃-3-基 (6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)胺基甲酸酯; (1S,2S)-N-(6-(5-氯-6-氟-7-((2-羥乙基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(環丁胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(環戊胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((2-甲氧基乙基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1,1,1-三氟丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((1-羥基丙烷-2-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((1-甲氧基丙烷-2-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2R,3S)-N-(6-(5-氯-7-(二甲胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-甲基-3-(1-甲基-1H-吡唑-4-基)環丙烷-1-甲醯胺; (1S,2S,3S)-N-(6-(5-氯-7-(二甲胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-甲基-3-(1-甲基-1H-吡唑-4-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(2-氟丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(環戊-1-烯-1-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-((1H-咪唑-1-基)甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(嗎啉胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-異丙氧基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(2-胺基-2-側氧乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲基丙-1-烯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((2,2-二氟乙基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(2-溴-2-氟環丙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(烯丙基胺基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-環戊基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((4-甲基哌嗪-1-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((2-氟乙基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((1,3-二羥基-2-甲基丙烷-2-基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((1-甲基-1H-吡唑-5-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((4-羥基丁烷-2-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-7-異丙基-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2R,3S)-N-(6-(5-氯-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-甲基-3-(1-甲基-1H-吡唑-4-基)環丙烷-1-甲醯胺; (1S,2S,3S)-N-(6-(5-氯-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-甲基-3-(1-甲基-1H-吡唑-4-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-((1H-吡咯-1-基)甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-((1H-吡唑-1-基)甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(2,2,2-三氟-1-羥乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(吡咯烷-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(3-羥基吡咯烷-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((R)-3-羥基吡咯烷-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(3-側氧環戊-1-烯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲氧基乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(N-甲基乙醯胺基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(環丙基(羥基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-((1H-吡唑-5-基)胺基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1R,2R)-N-(6-(5-氯-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2R)-N-(6-(5-氯-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1R,2S)-N-(6-(5-氯-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(1H-吡唑-5-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(1-((2-(三甲基矽基)乙氧基)甲基)-1H-吡唑-5-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(1-甲基-1H-吡唑-5-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-異丁醯-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-羥基-2-甲基丙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(((1S,3R)-3-羥基環戊基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((2-甲基-1H-咪唑-1-基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-羥基環戊基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-7-異丙基-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(1,1-二氟丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-異丁基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲氧基-2-甲基丙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-氟-2-甲基丙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((4-甲氧基丁烷-2-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((3-氟環丁基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(環丙基(甲氧基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-((E)-丁-2-烯-2-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(丁-3-烯-2-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(二級丁基胺基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((2-甲基-1H-吡咯-1-基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((4-甲基-1H-咪唑-1-基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((4-甲基-1H-吡唑-1-基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((S)-3-羥基吡咯烷-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(2-羥基環戊基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((四氫呋喃-3-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲氧基環戊基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(((1S,3S)-3-羥基環戊基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(1-(二甲胺基)-1-側氧丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-((R)-1-(2H-四唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-((S)-1-(2H-四唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(1-氰乙基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-((R)-1-(1H-四唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-((S)-1-(1H-四唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(1-胺基-1-側氧丙烷-2-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((1-氟丙烷-2-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(呋喃-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(異噁唑-4-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(((1R,3S)-3-羥基環戊基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(3-羥基環戊-1-烯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((3-甲基-1H-吡唑-1-基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(2,2,2-三氟-1-甲氧基乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(四氫呋喃-3-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(1-(2H-1,2,3-三唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(1-(1H-1,2,4-三唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((3S,4S)-3,4-二羥基吡咯烷-1-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲氧基吡咯烷-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((R)-3-甲氧基吡咯烷-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((S)-3-甲氧基吡咯烷-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((1-環丙基乙基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((3,3-二氟環丁基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1R,2S)-N-(6-(5-氯-7-(環丙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-羥基丙-2-炔-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(1-乙醯胺基乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(2-氰基丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(5-甲基呋喃-2-基)-2H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-5-(甲硫基)-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-((E)-丁-1,3-二烯-1-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((S)-1,1,1-三氟丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((R)-1,1,1-三氟丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((環丙基甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((R)-1-甲氧基丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((S)-1-甲氧基丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(1-乙氧基-2,2,2-三氟乙基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1,2,2,2-四氟乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((3S,4S)-3,4-二甲氧基吡咯烷-1-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(呋喃-3-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(丙-1,2-二烯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2R)-N-(6-(5-氯-7-(環丙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1R,2R)-N-(6-(5-氯-7-(環丙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(羥基(四氫-2H-哌喃-3-基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-7-(異丙胺基)-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(5,6-二氫-1,4-戴奧辛-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(1-(1H-吡唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(((1R,3S)-3-羥基環戊基)(甲基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-7-(丙-1-烯-2-基)-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(5-甲基呋喃-3-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(3-羥基丙-1-炔-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(丙-2-炔-1-基胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(四氫呋喃-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((1,1-二氟丙烷-2-基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(4-羥基四氫呋喃-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(3,3-二甲基氮呾-1-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((3-氯-2,2-二甲基丙基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(4-甲基-1H-吡唑-1-基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(5-甲基-1H-吡唑-1-基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(3-甲基-1H-吡唑-1-基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(3,3-二氟氮呾-1-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(氰甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲氧基丙-1-炔-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(2,5-二氫呋喃-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-丙醯胺基乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1R,2S)-N-(6-(5-氯-6-氟-7-(3-羥基丙醯胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲醯胺基乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((E)-4-羥基丁-1-烯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁-1-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁-2-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(3-(三甲基矽基)丙-2-炔-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。1甲酸; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-羥基-3-(三甲基矽基)丙-2-炔-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((3-羥基丁烷-2-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(5,5-二甲基四氫呋喃-3-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(1-(1H-咪唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(2-甲基-1H-咪唑-1-基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((E)-3-(三乙基矽基)丙-1-烯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((1,1-二氟丙烷-2-基)(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(二級丁基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(1,4-二噁烷-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(四氫-2H-哌喃-3-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(4-甲基-1H-咪唑-1-基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(氰氟甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(乙醯胺基(氰基)甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(6,6-二氟-2-氮雜螺[3.3]庚烷-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(甲基磺醯胺基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(1,1-二氟丙-1-烯-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((1S,2R)-1,2-二羥基丙基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(丙-2-炔-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁-2-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(乙醯胺基甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-甲醯基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; 5-氯-6-氟-4-(2-((1S,2S)-2-氟環丙烷-1-甲醯胺基)咪唑並[1,2-a]吡嗪-6-基)-1H-吲唑-7-羧酸乙酯; (1S,2S)-N-(6-(5-氯-6-氟-7-(((2R,3R)-3-甲氧基丁烷-2-基)(甲基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(((2R,3S)-3-甲氧基丁烷-2-基)(甲基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(1-((1-氰環丙基)胺基)乙基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; 2-(5-氯-6-氟-4-(2-((1S,2S)-2-氟環丙烷-1-甲醯胺基)咪唑並[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)乙酸乙酯; (9H-茀-9-基)甲基(5-氯-6-氟-4-(2-((1S,2S)-2-氟環丙烷-1-甲醯胺基)咪唑並[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)胺基甲酸酯; (1S,2S)-N-(6-(5-氯-7-(二氟甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(氰基(羥基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; N-(1-(5-氯-6-氟-4-(2-((1S,2S)-2-氟環丙烷-1-甲醯胺基)咪唑並[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)乙基)環丁烷甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(2-氟環丙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-7-(異丙胺基)-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(四氫呋喃-3-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(2,2,2-三氟乙醯胺基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((甲硫基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(甲硫基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((甲基亞磺醯基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((甲基磺醯基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(1,3-二甲基脲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((1S,2R)-1,2-二甲氧基丙基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(1-(2,2-二氟乙醯胺基)乙基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲基-1H-咪唑-5-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(甲基磺醯基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(甲基亞磺醯基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(1-(乙基胺基)-1-側氧丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(氰基(2,2,2-三氟乙醯胺基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; 2-(5-氯-6-氟-4-(2-((1S,2S)-2-氟環丙烷-1-甲醯胺基)咪唑並[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)-3-(環丁胺基)-3-側氧丙酸甲酯; (1S,2S)-N-((5-氯-6-氟-4-(2-((1S,2S)-2-氟環丙烷-1-甲醯胺基)咪唑並[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)(氰基)甲基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(氰基(環丙甲醯胺基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(氰基(2,2-二氟乙醯胺基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((丙烷-2-基-1,1,1,3,3,3-d6)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-乙氧基-6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺;和 (1S,2S)-N-(6-(5-乙氧基-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。
- 如請求項13所述之化合物或其藥學上可接受的鹽,其中,L為鍵;R 1為環丙基,其可選地被一個或多個基團取代,基團選自由鹵基、C 1-C 3烷基、C 1-C 3羥烷基和C 1-C 3鹵代烷基組成之群組;R 2為-H、烷基、鹵代烷基或鹵基;R 3為-H、烷基或鹵基;M為鍵、-O-或-NR 6-;R 4為-H、鹵基、烷基、單烷基胺基或二烷基胺基;並且R 5為-H、烷基或鹵基。
- 如請求項13所述之化合物或其藥學上可接受的鹽,其中,L為鍵;R a為-H;R b為-H;R 1為被氯、氟、C 1-C 3烷基、C 1-C 3羥烷基或C 1-C 3鹵代烷基取代的環丙基;R 2為-H、烷基、氯或氟;R 3為-H、烷基、氯或氟;M為鍵或-NH-;R 4為-H、氯、氟、甲基、乙基、丙基、異丙基、丁基、甲胺基或二甲胺基;並且R 5為-H或烷基。
- 如請求項13所述之化合物或其藥學上可接受的鹽,其中,L為鍵;R a為-H;R b為-H;R 1為被氯或氟取代的環丙基;R 2為-H、氯或氟;R 3為-H、氯或氟;M為鍵或-NH-;R 4為-H、氯、氟、甲基、乙基、丙基或異丙基;並且R 5為-H。
- 如請求項17所述之化合物或其藥學上可接受的鹽,其選自由下述組成之群組: (1S,2S)-N-(6-(5-氯-6-氟-7-(異丙胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1R,2S)-N-(6-(5-氯-6-氟-7-(異丙胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2R)-N-(6-(5-氯-6-氟-7-(異丙胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1R,2R)-N-(6-(5-氯-6-氟-7-(異丙胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1R,2R)-N-(6-(5-氯-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2R)-N-(6-(5-氯-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺;和 (1R,2S)-N-(6-(5-氯-6-氟-7-異丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。
- 如請求項13所述之化合物或其藥學上可接受的鹽,其中,L為鍵;R 1為環丙基,其可選地被一個或多個基團取代,基團選自由鹵基、C 1-C 3烷基、C 1-C 3羥烷基和C 1-C 3鹵代烷基組成之群組;R 2為-H、烷基、鹵基、鹵代烷基或烷硫基;R 3為-H、烷基或鹵基;M為鍵、-O-、-S-或-NR 6-;R 4為-H、鹵基、烷基、羥烷基、鹵代烷基、鹵烯基、環烷基、單烷基胺基或二烷基胺基;並且R 5為-H、烷基或鹵基。
- 如請求項21所述之化合物或其藥學上可接受的鹽,其選自由下述組成之群組: (1S,2S)-N-(6-(5-氯-7-(二甲胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(二甲胺基)-6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(二甲胺基)-6-氟-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(二甲胺基)-6-氟-5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-7-(異丙胺基)-5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-7-(異丙胺基)-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-7-(異丙胺基)-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-7-異丙基-5-甲基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-7-異丙基-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺;和 (1S,2S)-2-氟-N-(6-(6-氟-7-異丙基-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺。
- 如請求項13所述之化合物或其藥學上可接受的鹽,其中,R 1為環丙基,其可選地被一個或多個基團取代,基團選自由鹵基、C 1-C 3烷基、C 1-C 3羥烷基和C 1-C 3鹵代烷基組成之群組;R 2為-H、烷基、鹵基、鹵代烷基或烷硫基;R 3為-H、烷基或鹵基;M為鍵、-O-、-S-或-NR 6-;R 4為-H、鹵基、烷基、羥烷基、鹵代烷基、鹵烯基、環烷基、氰基烷基、胺基羰基烷基、乙醯胺基乙基、丙醯胺基乙基、甲醯胺基乙基、環烷基烷基、環烷基(羥基)烷基、羥基環烷基、甲氧基環烷基、環烷基(甲氧基)甲基、烷氧基烷基、烯基、甲基磺醯胺基乙基、咪唑基乙基、二噁烷基、環丁基羰基胺基乙基、二氟乙醯胺基乙基、三氟乙醯胺基乙基、甲硫甲基、甲硫乙基、環丙基羰基胺基(氰基)甲基、氰基(二氟乙醯胺基)甲基、丙基-1,1,1,3,3,3-d6)胺基、四氫呋喃基、甲基咪唑基乙基、呋喃基、吡咯基、甲基吡咯基、異噁唑基、四唑基烷基、甲基吡唑基或甲基吡唑基甲基;並且R 5為–H、烷基或鹵基。
- 如請求項23所述之化合物或其藥學上可接受的鹽,其選自由下述組成之群組: (1S,2S)-N-(6-(7-(二甲胺基)-5-乙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-5,7-雙(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-乙氧基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(乙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(乙基(甲基)胺基)-6-氟-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-乙基-7-(乙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-乙氧基-5-乙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(乙基(甲基)胺基)-6-氟-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(環丙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(異丙基(甲基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1H-吡咯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((氰甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-環丙基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(環丙胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲基-1H-吡咯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(1-(2H-四唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-5-甲基-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-丙基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲基-1H-吡咯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-羥基丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲氧基丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-氟丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(丙胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(乙胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(3,3,3-三氟丙-1-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-乙基-6-氟-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-乙基-6-氟-7-(異丙胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲基-1H-吡唑-5-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-環丙氧基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(環丁胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((2-甲氧基乙基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1,1,1-三氟丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((1-羥基丙烷-2-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-異丙氧基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲基丙-1-烯-1-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((2,2-二氟乙基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(烯丙基胺基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-環戊基-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((2-氟乙基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-7-異丙基-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(環丙基(羥基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(甲基(1-甲基-1H-吡唑-5-基)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-羥基-2-甲基丙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-7-異丙基-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(1,1-二氟丙烷-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-異丁基-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-氟-2-甲基丙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(環丙基(甲氧基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-((E)-丁-2-烯-2-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(丁-3-烯-2-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(二級丁基胺基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((4-甲基-1H-吡唑-1-基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(2-羥基環戊基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(2-甲氧基環戊基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-((R)-1-(2H-四唑-2-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(1-氰乙基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-((S)-1-(1H-四唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(1-胺基-1-側氧丙烷-2-基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(異噁唑-4-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1R,2S)-N-(6-(5-氯-7-(環丙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(1-乙醯胺基乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-5-(甲硫基)-7-(丙-1-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((S)-1,1,1-三氟丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((R)-1,1,1-三氟丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((環丙基甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((R)-1-甲氧基丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((S)-1-甲氧基丙烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1,2,2,2-四氟乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(呋喃-3-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1R,2R)-N-(6-(5-氯-7-(環丙基(甲基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-7-(異丙胺基)-5-(甲硫基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-7-(丙-1-烯-2-基)-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(丙-2-炔-1-基胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-((1,1-二氟丙烷-2-基)胺基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-丙醯胺基乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-甲醯胺基乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁-1-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁-2-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(1-(1H-咪唑-1-基)乙基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(二級丁基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(1,4-二噁烷-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(4-甲基-1H-咪唑-1-基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(7-(乙醯胺基(氰基)甲基)-5-氯-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(甲基磺醯胺基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(1,1-二氟丙-1-烯-2-基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁烷-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(3-甲基丁-2-烯-2-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; N-(1-(5-氯-6-氟-4-(2-((1S,2S)-2-氟環丙烷-1-甲醯胺基)咪唑並[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)乙基)環丁烷甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(2-氟環丙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-2-氟-N-(6-(6-氟-7-(異丙胺基)-5-(三氟甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(四氫呋喃-3-基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(2,2,2-三氟乙醯胺基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-((甲硫基)甲基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-6-氟-7-(1-(甲硫基)乙基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(1-(2,2-二氟乙醯胺基)乙基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(氰基(2,2,2-三氟乙醯胺基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-((5-氯-6-氟-4-(2-((1S,2S)-2-氟環丙烷-1-甲醯胺基)咪唑並[1,2-a]吡嗪-6-基)-1H-吲唑-7-基)(氰基)甲基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(氰基(環丙甲醯胺基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺; (1S,2S)-N-(6-(5-氯-7-(氰基(2,2-二氟乙醯胺基)甲基)-6-氟-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺;和 (1S,2S)-N-(6-(5-氯-6-氟-7-((丙烷-2-基-1,1,1,3,3,3-d6)胺基)-1H-吲唑-4-基)咪唑並[1,2-a]吡嗪-2-基)-2-氟環丙烷-1-甲醯胺。
- 一種藥物組成物,該藥物組成物含有藥學上可接受的載體或稀釋劑和請求項1所述之化合物或其藥學上可接受的鹽。
- 一種治療患有與HPK1調節相關的疾病或病症的受試者的方法,該方法包含: 向需要其的受試者施用治療有效劑量的如請求項1所述之化合物或其藥學上可接受的鹽。
- 如請求項26所述之方法,其中,該疾病為癌症,其中,請求項1所述之化合物與抗PD-1劑、抗PD-L1劑或抗CTLA4劑一併施用。
- 如請求項26所述之方法,其中,該疾病為癌症、轉移、炎症或自體免疫疾病。
- 如請求項28所述之方法,其中,該癌症選自由上皮癌、黑色素瘤、母細胞瘤、肉瘤、淋巴瘤和白血病組成之群組,包含但不限於膀胱癌、腦腫瘤、乳癌、子宮頸癌、結腸直腸癌、食道癌、子宮內膜癌、肝細胞癌、喉癌、肺癌、骨肉瘤、卵巢癌、胰臟癌、前列腺癌、腎癌和甲狀腺癌、急性淋巴細胞白血病、急性骨髓性白血病、室管膜瘤、尤文氏肉瘤、膠質母細胞瘤、髓母細胞瘤、神經母細胞瘤、骨肉瘤、橫紋肌肉瘤、橫紋肌樣癌和腎母細胞瘤(威爾姆氏瘤)。
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