CN104662018B - 取代的杂双环化合物、组合物及其医疗应用 - Google Patents
取代的杂双环化合物、组合物及其医疗应用 Download PDFInfo
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- CN104662018B CN104662018B CN201380019452.8A CN201380019452A CN104662018B CN 104662018 B CN104662018 B CN 104662018B CN 201380019452 A CN201380019452 A CN 201380019452A CN 104662018 B CN104662018 B CN 104662018B
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- phenyl
- pyrrolo
- methyl
- dihydro
- cyclopropyl
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- 125000002618 bicyclic heterocycle group Chemical group 0.000 title abstract description 6
- 239000000203 mixture Substances 0.000 title description 46
- 150000001875 compounds Chemical class 0.000 claims abstract description 145
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 26
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 25
- 201000010099 disease Diseases 0.000 claims abstract description 16
- -1 1-methyl-4-piperidinyl Chemical group 0.000 claims description 265
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 92
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 67
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
- 239000003814 drug Substances 0.000 claims description 30
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 26
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 25
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- 230000001404 mediated effect Effects 0.000 claims description 15
- 229940124597 therapeutic agent Drugs 0.000 claims description 15
- ISTPWRBDTGUHNF-UHFFFAOYSA-N C1OC=CC(C2=C1C=CC=C2)=O Chemical compound C1OC=CC(C2=C1C=CC=C2)=O ISTPWRBDTGUHNF-UHFFFAOYSA-N 0.000 claims description 12
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 claims description 12
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical compound C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 claims description 8
- NBJDSMIOWPVWRW-UHFFFAOYSA-N 2h-oxazepin-5-one Chemical compound O=C1C=CNOC=C1 NBJDSMIOWPVWRW-UHFFFAOYSA-N 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- ZFHWVNBXUFXNKH-UHFFFAOYSA-N 3-[4-[4-[3-(8-cyclopropyl-6-fluoro-5-oxo-2,3-dihydro-1,4-benzoxazepin-4-yl)-2-(hydroxymethyl)phenyl]-1h-pyrrolo[2,3-b]pyridin-2-yl]-3,6-dihydro-2h-pyridin-1-yl]-3-oxopropanenitrile Chemical compound OCC1=C(N2C(C3=C(F)C=C(C=C3OCC2)C2CC2)=O)C=CC=C1C(C=1C=2)=CC=NC=1NC=2C1=CCN(C(=O)CC#N)CC1 ZFHWVNBXUFXNKH-UHFFFAOYSA-N 0.000 claims description 6
- KIOUKGCNGFYNFJ-UHFFFAOYSA-N 8-cyclopropyl-4-[3-[6-[1-(3-hydroxypropyl)-3,6-dihydro-2h-pyridin-4-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]-2,3-dihydro-1,4-benzoxazepin-5-one Chemical compound CC1=C(N2C(C3=CC=C(C=C3OCC2)C2CC2)=O)C=CC=C1C(C=1C=2)=NC=NC=1NC=2C1=CCN(CCCO)CC1 KIOUKGCNGFYNFJ-UHFFFAOYSA-N 0.000 claims description 6
- LCCCCYKLSPXNSS-UHFFFAOYSA-N 4-[4-[3-(8-cyclopropyl-5-oxo-2,3-dihydro-1,4-benzoxazepin-4-yl)-2-(hydroxymethyl)phenyl]-1h-pyrrolo[2,3-b]pyridin-2-yl]-n,n-dimethyl-3,6-dihydro-2h-pyridine-1-carboxamide Chemical compound C1N(C(=O)N(C)C)CCC(C=2NC3=NC=CC(=C3C=2)C=2C(=C(N3C(C4=CC=C(C=C4OCC3)C3CC3)=O)C=CC=2)CO)=C1 LCCCCYKLSPXNSS-UHFFFAOYSA-N 0.000 claims description 5
- DGXUXVUZSZMKCN-UHFFFAOYSA-N 6-cyclopropyl-2-[2-(hydroxymethyl)-3-[6-[4-(4-methylpiperazin-1-yl)phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]isoquinolin-1-one Chemical compound C1CN(C)CCN1C1=CC=C(C=2NC3=NC=NC(=C3C=2)C=2C(=C(C=CC=2)N2C(C3=CC=C(C=C3C=C2)C2CC2)=O)CO)C=C1 DGXUXVUZSZMKCN-UHFFFAOYSA-N 0.000 claims description 5
- FERYHLCESDDAMA-UHFFFAOYSA-N 8-cyclopropyl-6-fluoro-4-[2-(hydroxymethyl)-3-[2-(1-methylsulfonyl-3,6-dihydro-2h-pyridin-4-yl)-1h-pyrrolo[2,3-b]pyridin-4-yl]phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one Chemical compound C1N(S(=O)(=O)C)CCC(C=2NC3=NC=CC(=C3C=2)C=2C(=C(N3C(C4=C(F)C=C(C=C4OCC3)C3CC3)=O)C=CC=2)CO)=C1 FERYHLCESDDAMA-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 4
- HPYIZQVYHGPMDT-UHFFFAOYSA-N 6-cyclopropyl-2-[2-(hydroxymethyl)-3-[6-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]phthalazin-1-one Chemical compound C1CN(C)CCN1CC1=CC=C(C=2NC3=NC=NC(=C3C=2)C=2C(=C(C=CC=2)N2C(C3=CC=C(C=C3C=N2)C2CC2)=O)CO)C=C1 HPYIZQVYHGPMDT-UHFFFAOYSA-N 0.000 claims description 3
- AGUFMXQPXHLMJU-UHFFFAOYSA-N 6-cyclopropyl-2-[2-methyl-3-[6-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]isoquinolin-1-one Chemical compound C1CN(C)CCN1CC1=CC=C(C=2NC3=NC=NC(=C3C=2)C=2C(=C(C=CC=2)N2C(C3=CC=C(C=C3C=C2)C2CC2)=O)C)C=C1 AGUFMXQPXHLMJU-UHFFFAOYSA-N 0.000 claims description 3
- GYNGMWFFLDXWPR-UHFFFAOYSA-N 6-cyclopropyl-2-[3-[6-[4-[(4-ethylpiperazin-1-yl)methyl]phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]-3,4-dihydroisoquinolin-1-one Chemical compound C1CN(CC)CCN1CC1=CC=C(C=2NC3=NC=NC(=C3C=2)C=2C(=C(N3C(C4=CC=C(C=C4CC3)C3CC3)=O)C=CC=2)C)C=C1 GYNGMWFFLDXWPR-UHFFFAOYSA-N 0.000 claims description 3
- WBXYMSISUFNGBW-UHFFFAOYSA-N 8-cyclopropyl-4-[2-(hydroxymethyl)-3-[6-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one Chemical compound C1CN(C)CCC1N1N=CC(C=2NC3=NC=NC(=C3C=2)C=2C(=C(N3C(C4=CC=C(C=C4OCC3)C3CC3)=O)C=CC=2)CO)=C1 WBXYMSISUFNGBW-UHFFFAOYSA-N 0.000 claims description 3
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 claims description 3
- VQCJSOWBHMDBSX-UHFFFAOYSA-N 1-[[4-[4-[3-(8-cyclopropyl-5-oxo-2,3-dihydro-1,4-benzoxazepin-4-yl)-2-methylphenyl]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]methyl]piperidine-3-carbonitrile Chemical compound CC1=C(N2C(C3=CC=C(C=C3OCC2)C2CC2)=O)C=CC=C1C(C=1C=2)=NC=NC=1NC=2C(C=C1)=CC=C1CN1CCCC(C#N)C1 VQCJSOWBHMDBSX-UHFFFAOYSA-N 0.000 claims description 2
- XAYMZZWAKGFQGF-UHFFFAOYSA-N 2-[1-[2-[2-methyl-3-[6-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]cyclopropyl]acetic acid Chemical compound C1CN(C)CCN1CC1=CC=C(C=2NC3=NC=NC(=C3C=2)C=2C(=C(N3C(C4=CC=C(C=C4CC3)C3(CC(O)=O)CC3)=O)C=CC=2)C)C=C1 XAYMZZWAKGFQGF-UHFFFAOYSA-N 0.000 claims description 2
- FOMRVUOZIFMBPA-UHFFFAOYSA-N 2-[1-[4-[2-methyl-3-[6-[4-(4-methylpiperazine-1-carbonyl)phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]cyclopropyl]acetic acid Chemical compound C1CN(C)CCN1C(=O)C1=CC=C(C=2NC3=NC=NC(=C3C=2)C=2C(=C(N3C(C4=CC=C(C=C4OCC3)C3(CC(O)=O)CC3)=O)C=CC=2)C)C=C1 FOMRVUOZIFMBPA-UHFFFAOYSA-N 0.000 claims description 2
- LFIKCDWAKCZYRR-UHFFFAOYSA-N 2-[1-[4-[2-methyl-3-[6-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]cyclopropyl]acetic acid Chemical compound C1CN(C)CCN1CC1=CC=C(C=2NC3=NC=NC(=C3C=2)C=2C(=C(N3C(C4=CC=C(C=C4OCC3)C3(CC(O)=O)CC3)=O)C=CC=2)C)C=C1 LFIKCDWAKCZYRR-UHFFFAOYSA-N 0.000 claims description 2
- PPSDFDFYVHJNDI-UHFFFAOYSA-N 2-[3-[2-amino-6-(1-methylpyrazol-4-yl)-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]-6-cyclopropylisoquinolin-1-one Chemical compound CC1=C(C=2C=3C=C(NC=3N=C(N)N=2)C2=CN(C)N=C2)C=CC=C1N(C(C1=CC=2)=O)C=CC1=CC=2C1CC1 PPSDFDFYVHJNDI-UHFFFAOYSA-N 0.000 claims description 2
- RAJIXYLIGUBDRN-UHFFFAOYSA-N 2-[3-[2-amino-6-(4-morpholin-4-ylphenyl)-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]-6-cyclopropylphthalazin-1-one Chemical compound CC1=C(C=2C=3C=C(NC=3N=C(N)N=2)C=2C=CC(=CC=2)N2CCOCC2)C=CC=C1N(C(C1=CC=2)=O)N=CC1=CC=2C1CC1 RAJIXYLIGUBDRN-UHFFFAOYSA-N 0.000 claims description 2
- CYQNIVZZCOPIFP-UHFFFAOYSA-N 2-[3-[2-amino-6-[1-(2-hydroxyethyl)pyrazol-4-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]-6-cyclopropylisoquinolin-1-one Chemical compound CC1=C(C=2C=3C=C(NC=3N=C(N)N=2)C2=CN(CCO)N=C2)C=CC=C1N(C(C1=CC=2)=O)C=CC1=CC=2C1CC1 CYQNIVZZCOPIFP-UHFFFAOYSA-N 0.000 claims description 2
- DPVMWQNXIWVHCY-UHFFFAOYSA-N 2-[3-[2-amino-6-[4-(4-methylpiperazin-1-yl)phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]-6-cyclopropylisoquinolin-1-one Chemical compound C1CN(C)CCN1C1=CC=C(C=2NC3=NC(N)=NC(=C3C=2)C=2C(=C(C=CC=2)N2C(C3=CC=C(C=C3C=C2)C2CC2)=O)C)C=C1 DPVMWQNXIWVHCY-UHFFFAOYSA-N 0.000 claims description 2
- KVJUDBVUVVSKML-UHFFFAOYSA-N 2-[3-[4-[4-[3-(8-cyclopropyl-5-oxo-2,3-dihydro-1,4-benzoxazepin-4-yl)-2-(hydroxymethyl)phenyl]-1h-pyrrolo[2,3-b]pyridin-2-yl]pyrazol-1-yl]azetidin-1-yl]acetonitrile Chemical compound OCC1=C(N2C(C3=CC=C(C=C3OCC2)C2CC2)=O)C=CC=C1C(C=1C=2)=CC=NC=1NC=2C(=C1)C=NN1C1CN(CC#N)C1 KVJUDBVUVVSKML-UHFFFAOYSA-N 0.000 claims description 2
- ZUONYPFBCPIUFC-UHFFFAOYSA-N 2-[3-[6-[4-[(3-aminopiperidin-1-yl)methyl]phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]-6-cyclopropylphthalazin-1-one Chemical compound CC1=C(C=2C=3C=C(NC=3N=CN=2)C=2C=CC(CN3CC(N)CCC3)=CC=2)C=CC=C1N(C(C1=CC=2)=O)N=CC1=CC=2C1CC1 ZUONYPFBCPIUFC-UHFFFAOYSA-N 0.000 claims description 2
- AGXLZPQEFDXWJX-UHFFFAOYSA-N 3-[2-[2-methyl-3-[6-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]butanoic acid Chemical compound C1CC2=CC(C(CC(O)=O)C)=CC=C2C(=O)N1C(C=1C)=CC=CC=1C(C=1C=2)=NC=NC=1NC=2C(C=C1)=CC=C1CN1CCN(C)CC1 AGXLZPQEFDXWJX-UHFFFAOYSA-N 0.000 claims description 2
- BTLVODBTUAVKFY-UHFFFAOYSA-N 4-[2-(hydroxymethyl)-3-[2-[1-(oxetan-3-yl)imidazol-4-yl]-1h-pyrrolo[2,3-b]pyridin-4-yl]phenyl]-8-(2-hydroxypropan-2-yl)-2,3-dihydro-1,4-benzoxazepin-5-one Chemical compound C=1C(C(C)(O)C)=CC=C(C2=O)C=1OCCN2C(C=1CO)=CC=CC=1C(C=1C=2)=CC=NC=1NC=2C(N=C1)=CN1C1COC1 BTLVODBTUAVKFY-UHFFFAOYSA-N 0.000 claims description 2
- SUTHKAABAMUNSC-UHFFFAOYSA-N 4-[3-(8-cyclopropyl-5-oxo-2,3-dihydro-1,4-benzoxazepin-4-yl)phenyl]-2-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-1h-pyrrolo[2,3-b]pyridine-5-carbonitrile Chemical compound C1CN(C)CCN1CC1=CC=C(C=2NC3=NC=C(C(C=4C=C(C=CC=4)N4C(C5=CC=C(C=C5OCC4)C4CC4)=O)=C3C=2)C#N)C=C1 SUTHKAABAMUNSC-UHFFFAOYSA-N 0.000 claims description 2
- RQQQMQJHUMCWPZ-UHFFFAOYSA-N 4-[3-[6-[4-(3-aminopiperidine-1-carbonyl)phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]-8-cyclopropyl-2,3-dihydro-1,4-benzoxazepin-5-one Chemical compound CC1=C(N2C(C3=CC=C(C=C3OCC2)C2CC2)=O)C=CC=C1C(C=1C=2)=NC=NC=1NC=2C(C=C1)=CC=C1C(=O)N1CCCC(N)C1 RQQQMQJHUMCWPZ-UHFFFAOYSA-N 0.000 claims description 2
- MMANYZOAPCAECE-UHFFFAOYSA-N 6-[4-[3-(8-cyclopropyl-5-oxo-2,3-dihydro-1,4-benzoxazepin-4-yl)-2-(hydroxymethyl)phenyl]-1h-pyrrolo[2,3-b]pyridin-2-yl]pyridine-3-carboxylic acid Chemical compound OCC1=C(N2C(C3=CC=C(C=C3OCC2)C2CC2)=O)C=CC=C1C(C=1C=2)=CC=NC=1NC=2C1=CC=C(C(O)=O)C=N1 MMANYZOAPCAECE-UHFFFAOYSA-N 0.000 claims description 2
- OUSWPFRFTICEGP-UHFFFAOYSA-N 6-cyclopropyl-2-[2-(hydroxymethyl)-3-[6-[4-(piperazin-1-ylmethyl)phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]phthalazin-1-one Chemical compound OCC1=C(C=2C=3C=C(NC=3N=CN=2)C=2C=CC(CN3CCNCC3)=CC=2)C=CC=C1N(C(C1=CC=2)=O)N=CC1=CC=2C1CC1 OUSWPFRFTICEGP-UHFFFAOYSA-N 0.000 claims description 2
- BMTPDXHJAOHZSZ-UHFFFAOYSA-N 6-cyclopropyl-2-[2-(hydroxymethyl)-3-[6-[5-(1-methylpiperidin-3-yl)pyridin-2-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]phthalazin-1-one Chemical compound C1N(C)CCCC1C1=CC=C(C=2NC3=NC=NC(=C3C=2)C=2C(=C(C=CC=2)N2C(C3=CC=C(C=C3C=N2)C2CC2)=O)CO)N=C1 BMTPDXHJAOHZSZ-UHFFFAOYSA-N 0.000 claims description 2
- ALAVAELDKJLQDT-UHFFFAOYSA-N 6-cyclopropyl-2-[2-(hydroxymethyl)-3-[6-[5-(1-methylpiperidin-4-yl)pyridin-2-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]phthalazin-1-one Chemical compound C1CN(C)CCC1C1=CC=C(C=2NC3=NC=NC(=C3C=2)C=2C(=C(C=CC=2)N2C(C3=CC=C(C=C3C=N2)C2CC2)=O)CO)N=C1 ALAVAELDKJLQDT-UHFFFAOYSA-N 0.000 claims description 2
- BBAXWVYIMPQAGX-UHFFFAOYSA-N 6-cyclopropyl-2-[2-methyl-3-[6-[4-(4-methylpiperazin-1-yl)phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]phthalazin-1-one Chemical compound C1CN(C)CCN1C1=CC=C(C=2NC3=NC=NC(=C3C=2)C=2C(=C(C=CC=2)N2C(C3=CC=C(C=C3C=N2)C2CC2)=O)C)C=C1 BBAXWVYIMPQAGX-UHFFFAOYSA-N 0.000 claims description 2
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- YWDSXLINLIOGJH-UHFFFAOYSA-N 8-cyclopropyl-4-[2-(hydroxymethyl)-3-[2-[1-(oxetan-3-yl)imidazol-4-yl]-1h-pyrrolo[2,3-b]pyridin-4-yl]phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one Chemical compound OCC1=C(N2C(C3=CC=C(C=C3OCC2)C2CC2)=O)C=CC=C1C(C=1C=2)=CC=NC=1NC=2C(N=C1)=CN1C1COC1 YWDSXLINLIOGJH-UHFFFAOYSA-N 0.000 claims description 2
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- OGHCQGHYJOXQNB-UHFFFAOYSA-N Cc1c(cccc1-c1ncnc2[nH]c(cc12)-c1ccc(CN2CCC(CC2)C#N)cc1)N1CCOc2cc(ccc2C1=O)C1CC1 Chemical compound Cc1c(cccc1-c1ncnc2[nH]c(cc12)-c1ccc(CN2CCC(CC2)C#N)cc1)N1CCOc2cc(ccc2C1=O)C1CC1 OGHCQGHYJOXQNB-UHFFFAOYSA-N 0.000 claims description 2
- NVVQQFMOLHAWHJ-UHFFFAOYSA-N Cc1c(cccc1-c1ncnc2[nH]c(cc12)-c1ccc(CN2CCN(CC2)C2CC2)cc1)N1CCc2cc(ccc2C1=O)C1CC1 Chemical compound Cc1c(cccc1-c1ncnc2[nH]c(cc12)-c1ccc(CN2CCN(CC2)C2CC2)cc1)N1CCc2cc(ccc2C1=O)C1CC1 NVVQQFMOLHAWHJ-UHFFFAOYSA-N 0.000 claims description 2
- SSZSUVBGFXMILW-UHFFFAOYSA-N Cc1c(cccc1-c1ncnc2[nH]c(cc12)-c1ccc(CN2CCN(CCO)CC2)cc1)N1CCOc2cc(ccc2C1=O)C1CC1 Chemical compound Cc1c(cccc1-c1ncnc2[nH]c(cc12)-c1ccc(CN2CCN(CCO)CC2)cc1)N1CCOc2cc(ccc2C1=O)C1CC1 SSZSUVBGFXMILW-UHFFFAOYSA-N 0.000 claims description 2
- GRFYLCOEBHYBCJ-UHFFFAOYSA-N Cc1c(cccc1-c1ncnc2[nH]c(cc12)-c1ccc(CN2CCNC(=O)C2)cc1)N1CCOc2cc(ccc2C1=O)C1CC1 Chemical compound Cc1c(cccc1-c1ncnc2[nH]c(cc12)-c1ccc(CN2CCNC(=O)C2)cc1)N1CCOc2cc(ccc2C1=O)C1CC1 GRFYLCOEBHYBCJ-UHFFFAOYSA-N 0.000 claims description 2
- HBPUZNNBVMCEJB-UHFFFAOYSA-N Cc1c(cccc1-n1ccc2cc(ccc2c1=O)C1CC1)-c1nc(N)nc2[nH]c(cc12)-c1ccc(cc1)N1CCNCC1 Chemical compound Cc1c(cccc1-n1ccc2cc(ccc2c1=O)C1CC1)-c1nc(N)nc2[nH]c(cc12)-c1ccc(cc1)N1CCNCC1 HBPUZNNBVMCEJB-UHFFFAOYSA-N 0.000 claims description 2
- FDTZPWXWOAISLS-UHFFFAOYSA-N Cc1c(cccc1-n1ccc2cc(ccc2c1=O)C1CC1)-c1nc(N)nc2[nH]c(cc12)-c1ccc(cc1)N1CCOCC1 Chemical compound Cc1c(cccc1-n1ccc2cc(ccc2c1=O)C1CC1)-c1nc(N)nc2[nH]c(cc12)-c1ccc(cc1)N1CCOCC1 FDTZPWXWOAISLS-UHFFFAOYSA-N 0.000 claims description 2
- DGSNLFZQWWYHFG-UHFFFAOYSA-N Cc1c(cccc1-n1ccc2cc(ccc2c1=O)C1CC1)-c1nc(N)nc2[nH]c(cc12)-c1cnn2CCOCc12 Chemical compound Cc1c(cccc1-n1ccc2cc(ccc2c1=O)C1CC1)-c1nc(N)nc2[nH]c(cc12)-c1cnn2CCOCc12 DGSNLFZQWWYHFG-UHFFFAOYSA-N 0.000 claims description 2
- RKUFRRDXWHOOPD-UHFFFAOYSA-N Cc1c(cccc1-n1ncc2cc(ccc2c1=O)C1CC1)-c1ncnc2[nH]c(cc12)-c1ccc(CN2CCC(N)CC2)cc1 Chemical compound Cc1c(cccc1-n1ncc2cc(ccc2c1=O)C1CC1)-c1ncnc2[nH]c(cc12)-c1ccc(CN2CCC(N)CC2)cc1 RKUFRRDXWHOOPD-UHFFFAOYSA-N 0.000 claims description 2
- WZAOQXVOQPWJNP-UHFFFAOYSA-N Cc1c(cccc1-n1ncc2cc(ccc2c1=O)C1CC1)-c1ncnc2[nH]c(cc12)-c1ccc(cc1)N1CCOCC1 Chemical compound Cc1c(cccc1-n1ncc2cc(ccc2c1=O)C1CC1)-c1ncnc2[nH]c(cc12)-c1ccc(cc1)N1CCOCC1 WZAOQXVOQPWJNP-UHFFFAOYSA-N 0.000 claims description 2
- ZDWHQYQWTDQRQV-UHFFFAOYSA-N OCCN1CCC(=CC1)c1cc2c(ccnc2[nH]1)-c1cccc(N2CCOc3cc(cc(F)c3C2=O)C2CC2)c1CO Chemical compound OCCN1CCC(=CC1)c1cc2c(ccnc2[nH]1)-c1cccc(N2CCOc3cc(cc(F)c3C2=O)C2CC2)c1CO ZDWHQYQWTDQRQV-UHFFFAOYSA-N 0.000 claims description 2
- XRERXROIIROHKW-UHFFFAOYSA-N OCc1c(cccc1-c1ncnc2[nH]c(cc12)-c1cnn(c1)C1CCCN(C1)C(=O)C=C)N1CCOc2cc(ccc2C1=O)C1CC1 Chemical compound OCc1c(cccc1-c1ncnc2[nH]c(cc12)-c1cnn(c1)C1CCCN(C1)C(=O)C=C)N1CCOc2cc(ccc2C1=O)C1CC1 XRERXROIIROHKW-UHFFFAOYSA-N 0.000 claims description 2
- XGWLVPCSDMWYMW-UHFFFAOYSA-N 4-[3-[2-[1-(azetidine-1-carbonyl)-3,6-dihydro-2h-pyridin-4-yl]-1h-pyrrolo[2,3-b]pyridin-4-yl]-2-(hydroxymethyl)phenyl]-8-cyclopropyl-6-fluoro-2,3-dihydro-1,4-benzoxazepin-5-one Chemical compound OCC1=C(N2C(C3=C(F)C=C(C=C3OCC2)C2CC2)=O)C=CC=C1C(C=1C=2)=CC=NC=1NC=2C(CC1)=CCN1C(=O)N1CCC1 XGWLVPCSDMWYMW-UHFFFAOYSA-N 0.000 claims 2
- AVRBYOCCZYHNTC-UHFFFAOYSA-N 6-cyclopropyl-2-[2-(hydroxymethyl)-3-[6-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]isoquinolin-1-one Chemical compound C1CN(C)CCC1N1N=CC(C=2NC3=NC=NC(=C3C=2)C=2C(=C(C=CC=2)N2C(C3=CC=C(C=C3C=C2)C2CC2)=O)CO)=C1 AVRBYOCCZYHNTC-UHFFFAOYSA-N 0.000 claims 2
- RPDYTAUMOYXWQZ-UHFFFAOYSA-N 6-cyclopropyl-2-[2-methyl-3-[6-[4-[(3-oxopiperazin-1-yl)methyl]phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]-3,4-dihydroisoquinolin-1-one Chemical compound CC1=C(N2C(C3=CC=C(C=C3CC2)C2CC2)=O)C=CC=C1C(C=1C=2)=NC=NC=1NC=2C(C=C1)=CC=C1CN1CCNC(=O)C1 RPDYTAUMOYXWQZ-UHFFFAOYSA-N 0.000 claims 2
- VTLUUVURCKBARU-UHFFFAOYSA-N 6-cyclopropyl-2-[3-[6-[1-(1-ethylpiperidin-4-yl)pyrazol-4-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-(hydroxymethyl)phenyl]phthalazin-1-one Chemical compound C1CN(CC)CCC1N1N=CC(C=2NC3=NC=NC(=C3C=2)C=2C(=C(C=CC=2)N2C(C3=CC=C(C=C3C=N2)C2CC2)=O)CO)=C1 VTLUUVURCKBARU-UHFFFAOYSA-N 0.000 claims 2
- PSIWUKBLYARZHY-UHFFFAOYSA-N 8-cyclopropyl-4-[2-(hydroxymethyl)-3-[6-[4-(morpholin-4-ylmethyl)phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one Chemical compound OCC1=C(N2C(C3=CC=C(C=C3OCC2)C2CC2)=O)C=CC=C1C(C=1C=2)=NC=NC=1NC=2C(C=C1)=CC=C1CN1CCOCC1 PSIWUKBLYARZHY-UHFFFAOYSA-N 0.000 claims 2
- CWSOXPFQRKXROZ-UHFFFAOYSA-N 8-cyclopropyl-4-[2-methyl-3-[6-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one Chemical compound C1CN(C)CCC1N1N=CC(C=2NC3=NC=NC(=C3C=2)C=2C(=C(N3C(C4=CC=C(C=C4OCC3)C3CC3)=O)C=CC=2)C)=C1 CWSOXPFQRKXROZ-UHFFFAOYSA-N 0.000 claims 2
- KPFGEXIFBOYDKD-UHFFFAOYSA-N 8-cyclopropyl-4-[3-[6-[4-(4-hydroxypiperidine-1-carbonyl)phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]-2,3-dihydro-1,4-benzoxazepin-5-one Chemical compound CC1=C(N2C(C3=CC=C(C=C3OCC2)C2CC2)=O)C=CC=C1C(C=1C=2)=NC=NC=1NC=2C(C=C1)=CC=C1C(=O)N1CCC(O)CC1 KPFGEXIFBOYDKD-UHFFFAOYSA-N 0.000 claims 2
- ADPALRGBEKOVCD-UHFFFAOYSA-N 8-cyclopropyl-4-[3-[6-[4-[(4-ethylpiperazin-1-yl)methyl]phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-(hydroxymethyl)phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one Chemical compound C1CN(CC)CCN1CC1=CC=C(C=2NC3=NC=NC(=C3C=2)C=2C(=C(N3C(C4=CC=C(C=C4OCC3)C3CC3)=O)C=CC=2)CO)C=C1 ADPALRGBEKOVCD-UHFFFAOYSA-N 0.000 claims 2
- RSTYPPMDIMAXGY-UHFFFAOYSA-N 8-cyclopropyl-6-fluoro-4-[2-(hydroxymethyl)-3-[2-[1-(2-hydroxypropanoyl)-3,6-dihydro-2h-pyridin-4-yl]-1h-pyrrolo[2,3-b]pyridin-4-yl]phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one Chemical compound C1N(C(=O)C(O)C)CCC(C=2NC3=NC=CC(=C3C=2)C=2C(=C(N3C(C4=C(F)C=C(C=C4OCC3)C3CC3)=O)C=CC=2)CO)=C1 RSTYPPMDIMAXGY-UHFFFAOYSA-N 0.000 claims 2
- JLFXUEOJPWWZJU-UHFFFAOYSA-N 8-cyclopropyl-6-fluoro-4-[2-(hydroxymethyl)-3-[2-[1-(oxetan-3-yl)-3,6-dihydro-2h-pyridin-4-yl]-1h-pyrrolo[2,3-b]pyridin-4-yl]phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one Chemical compound OCC1=C(N2C(C3=C(F)C=C(C=C3OCC2)C2CC2)=O)C=CC=C1C(C=1C=2)=CC=NC=1NC=2C(CC1)=CCN1C1COC1 JLFXUEOJPWWZJU-UHFFFAOYSA-N 0.000 claims 2
- GOUMBHDEBOZBRW-UHFFFAOYSA-N 8-cyclopropyl-6-fluoro-4-[2-(hydroxymethyl)-3-[2-[5-(4-hydroxy-4-methylpiperidine-1-carbonyl)pyridin-2-yl]-1h-pyrrolo[2,3-b]pyridin-4-yl]phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one Chemical compound C1CC(C)(O)CCN1C(=O)C1=CC=C(C=2NC3=NC=CC(=C3C=2)C=2C(=C(N3C(C4=C(F)C=C(C=C4OCC3)C3CC3)=O)C=CC=2)CO)N=C1 GOUMBHDEBOZBRW-UHFFFAOYSA-N 0.000 claims 2
- BWCWHSROUJFVPM-UHFFFAOYSA-N OCc1c(cccc1-c1ccnc2[nH]c(cc12)-c1ccc(CN2CCS(=O)(=O)CC2)cn1)N1CCOc2cc(ccc2C1=O)C1CC1 Chemical compound OCc1c(cccc1-c1ccnc2[nH]c(cc12)-c1ccc(CN2CCS(=O)(=O)CC2)cn1)N1CCOc2cc(ccc2C1=O)C1CC1 BWCWHSROUJFVPM-UHFFFAOYSA-N 0.000 claims 2
- WSIAJDFKKPGCQN-UHFFFAOYSA-N 1-[4-[4-[3-(8-cyclopropyl-5-oxo-2,3-dihydro-1,4-benzoxazepin-4-yl)-2-methylphenyl]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]benzoyl]piperidine-3-carboxylic acid Chemical compound CC1=C(N2C(C3=CC=C(C=C3OCC2)C2CC2)=O)C=CC=C1C(C=1C=2)=NC=NC=1NC=2C(C=C1)=CC=C1C(=O)N1CCCC(C(O)=O)C1 WSIAJDFKKPGCQN-UHFFFAOYSA-N 0.000 claims 1
- KUFGLJZVEAAWRL-UHFFFAOYSA-N 1-[4-[4-[3-(8-cyclopropyl-5-oxo-2,3-dihydro-1,4-benzoxazepin-4-yl)-2-methylphenyl]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]benzoyl]pyrrolidine-2-carboxylic acid Chemical compound CC1=C(N2C(C3=CC=C(C=C3OCC2)C2CC2)=O)C=CC=C1C(C=1C=2)=NC=NC=1NC=2C(C=C1)=CC=C1C(=O)N1CCCC1C(O)=O KUFGLJZVEAAWRL-UHFFFAOYSA-N 0.000 claims 1
- KTGWVDVOBBVFEC-UHFFFAOYSA-N 1-[[4-[4-[3-(6-cyclopropyl-1-oxo-3,4-dihydroisoquinolin-2-yl)-2-methylphenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]methyl]piperidine-4-carbonitrile Chemical compound C1(CC1)C=1C=C2CCN(C(C2=CC1)=O)C=1C(=C(C=CC1)C=1C2=C(N=CN1)NC(=C2)C2=CC=C(C=C2)CN2CCC(CC2)C#N)C KTGWVDVOBBVFEC-UHFFFAOYSA-N 0.000 claims 1
- YKEXCZOVYFVFOD-UHFFFAOYSA-N 1-[[4-[4-[3-(6-cyclopropyl-1-oxo-3,4-dihydroisoquinolin-2-yl)-2-methylphenyl]-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]methyl]piperidine-3-carbonitrile Chemical compound CC1=C(N2C(C3=CC=C(C=C3CC2)C2CC2)=O)C=CC=C1C(C=1C=2)=NC=NC=1NC=2C(C=C1)=CC=C1CN1CCCC(C#N)C1 YKEXCZOVYFVFOD-UHFFFAOYSA-N 0.000 claims 1
- KHLJRUPSKNTILL-UHFFFAOYSA-N 2-[3-[2-amino-6-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]-7-cyclopropyl-4,5-dihydro-3h-2-benzazepin-1-one Chemical compound C1CN(C)CCN1CC1=CC=C(C=2NC3=NC(N)=NC(=C3C=2)C=2C(=C(N3C(C4=CC=C(C=C4CCC3)C3CC3)=O)C=CC=2)C)C=C1 KHLJRUPSKNTILL-UHFFFAOYSA-N 0.000 claims 1
- UCCYGGYHJGKNIS-UHFFFAOYSA-N 4-[2-(hydroxymethyl)-3-[6-[1-(oxetan-3-yl)imidazol-4-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]-8-(2-hydroxypropan-2-yl)-2,3-dihydro-1,4-benzoxazepin-5-one Chemical compound C=1C(C(C)(O)C)=CC=C(C2=O)C=1OCCN2C(C=1CO)=CC=CC=1C(C=1C=2)=NC=NC=1NC=2C(N=C1)=CN1C1COC1 UCCYGGYHJGKNIS-UHFFFAOYSA-N 0.000 claims 1
- ZTJWSDZYUPIKRC-UHFFFAOYSA-N 4-[3-[2-amino-6-(6-morpholin-4-ylpyridin-3-yl)-7h-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methylphenyl]-8-cyclopropyl-2,3-dihydro-1,4-benzoxazepin-5-one Chemical compound CC1=C(N2C(C3=CC=C(C=C3OCC2)C2CC2)=O)C=CC=C1C(C=1C=2)=NC(N)=NC=1NC=2C(C=N1)=CC=C1N1CCOCC1 ZTJWSDZYUPIKRC-UHFFFAOYSA-N 0.000 claims 1
- AZHHQZQJTHKCKM-UHFFFAOYSA-N 4-[3-[6-(2-cyclohexyltriazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-(hydroxymethyl)phenyl]-8-cyclopropyl-2,3-dihydro-1,4-benzoxazepin-5-one Chemical compound C1(CCCCC1)N1N=CC(=N1)C1=CC2=C(N=CN=C2C=2C(=C(C=CC2)N2CCOC3=C(C2=O)C=CC(=C3)C3CC3)CO)N1 AZHHQZQJTHKCKM-UHFFFAOYSA-N 0.000 claims 1
- GOTAKOCZVHHKTK-UHFFFAOYSA-N 4-[4-[2-[1-(azetidine-1-carbonyl)-3,6-dihydro-2h-pyridin-4-yl]-1h-pyrrolo[2,3-b]pyridin-4-yl]-3-(hydroxymethyl)pyridin-2-yl]-8-cyclopropyl-6-fluoro-2,3-dihydro-1,4-benzoxazepin-5-one Chemical compound OCC1=C(N2C(C3=C(F)C=C(C=C3OCC2)C2CC2)=O)N=CC=C1C(C=1C=2)=CC=NC=1NC=2C(CC1)=CCN1C(=O)N1CCC1 GOTAKOCZVHHKTK-UHFFFAOYSA-N 0.000 claims 1
- LNWKIIHCZNTSSD-UHFFFAOYSA-N 4-[4-[3-(8-cyclopropyl-6-fluoro-5-oxo-2,3-dihydro-1,4-benzoxazepin-4-yl)-2-(hydroxymethyl)phenyl]-1h-pyrrolo[2,3-b]pyridin-2-yl]-n,n-dimethyl-3,6-dihydro-2h-pyridine-1-carboxamide Chemical compound C1N(C(=O)N(C)C)CCC(C=2NC3=NC=CC(=C3C=2)C=2C(=C(N3C(C4=C(F)C=C(C=C4OCC3)C3CC3)=O)C=CC=2)CO)=C1 LNWKIIHCZNTSSD-UHFFFAOYSA-N 0.000 claims 1
- JYAWNPMKKXUPKW-UHFFFAOYSA-N 4-[4-[3-(8-cyclopropyl-6-fluoro-5-oxo-2,3-dihydro-1,4-benzoxazepin-4-yl)-2-(hydroxymethyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-N,N-dimethyl-3,6-dihydro-2H-pyridine-1-carboxamide Chemical compound C1(CC1)C1=CC2=C(C(N(CCO2)C=2C(=C(C=CC2)C=2C3=C(N=CN2)NC(=C3)C=3CCN(CC3)C(=O)N(C)C)CO)=O)C(=C1)F JYAWNPMKKXUPKW-UHFFFAOYSA-N 0.000 claims 1
- FYOQAHJHDZHCGP-UHFFFAOYSA-N 6-cyclopropyl-2-[2-(hydroxymethyl)-3-[6-[1-(1-methylpiperidin-4-yl)-3,6-dihydro-2H-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]phthalazin-1-one Chemical compound CN1CCC(CC1)N1CCC(=CC1)c1cc2c(ncnc2[nH]1)-c1cccc(c1CO)-n1ncc2cc(ccc2c1=O)C1CC1 FYOQAHJHDZHCGP-UHFFFAOYSA-N 0.000 claims 1
- FQYPGROARQOJSH-DEOSSOPVSA-N 6-cyclopropyl-2-[2-(hydroxymethyl)-3-[6-[1-[(3s)-1-methylpiperidin-3-yl]pyrazol-4-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]phthalazin-1-one Chemical compound C1N(C)CCC[C@@H]1N1N=CC(C=2NC3=NC=NC(=C3C=2)C=2C(=C(C=CC=2)N2C(C3=CC=C(C=C3C=N2)C2CC2)=O)CO)=C1 FQYPGROARQOJSH-DEOSSOPVSA-N 0.000 claims 1
- MSMBHKRWMAYJOT-UHFFFAOYSA-N 6-cyclopropyl-2-[2-(hydroxymethyl)-3-[6-[4-(1-methylpiperidin-4-yl)phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]isoquinolin-1-one Chemical compound C1CN(C)CCC1C1=CC=C(C=2NC3=NC=NC(=C3C=2)C=2C(=C(C=CC=2)N2C(C3=CC=C(C=C3C=C2)C2CC2)=O)CO)C=C1 MSMBHKRWMAYJOT-UHFFFAOYSA-N 0.000 claims 1
- FSUIFAYOHAWZKP-UHFFFAOYSA-N 6-cyclopropyl-2-[2-(hydroxymethyl)-3-[6-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]isoquinolin-1-one Chemical compound C1CN(C)CCN1CC1=CC=C(C=2NC3=NC=NC(=C3C=2)C=2C(=C(C=CC=2)N2C(C3=CC=C(C=C3C=C2)C2CC2)=O)CO)C=C1 FSUIFAYOHAWZKP-UHFFFAOYSA-N 0.000 claims 1
- RXAXBBMDWTVTJY-UHFFFAOYSA-N 6-cyclopropyl-2-[2-(hydroxymethyl)-3-[6-[5-(1-methylazetidin-3-yl)oxypyridin-2-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]phthalazin-1-one Chemical compound C1N(C)CC1OC1=CC=C(C=2NC3=NC=NC(=C3C=2)C=2C(=C(C=CC=2)N2C(C3=CC=C(C=C3C=N2)C2CC2)=O)CO)N=C1 RXAXBBMDWTVTJY-UHFFFAOYSA-N 0.000 claims 1
- ATXZZUKDKJQZMJ-UHFFFAOYSA-N 6-cyclopropyl-2-[2-(hydroxymethyl)-3-[6-[5-(1-methylpiperidin-4-yl)oxypyridin-2-yl]-7h-pyrrolo[2,3-d]pyrimidin-4-yl]phenyl]phthalazin-1-one Chemical compound C1CN(C)CCC1OC1=CC=C(C=2NC3=NC=NC(=C3C=2)C=2C(=C(C=CC=2)N2C(C3=CC=C(C=C3C=N2)C2CC2)=O)CO)N=C1 ATXZZUKDKJQZMJ-UHFFFAOYSA-N 0.000 claims 1
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Abstract
本公开提供了式(I)的杂双环化合物、其互变异构体、多晶型物、立体异构体、前药、溶剂化物、水合物、N氧化物、共晶体、药学可接受的盐、含有它们的药物组合物,以及治疗由Bruton酪氨酸激酶(Btk)活性介导的病症和疾病的方法。本公开还涉及式(I)化合物的制备方法。
Description
技术领域
本公开涉及一类(I)的取代的杂双环式化合物、其互变异构体、多晶型物、立体异构体、前药、溶剂化物、水合物、N氧化物、共晶体、药学可接受的盐和含有它们的药物组合物。本公开还涉及式(I)化合物的制备方法。这些化合物用于治疗、防止、预防、管理或辅助治疗与Bruton酪氨酸激酶(Btk)抑制相关的所有医学病症,例如炎性和/或自身免疫疾患、细胞增殖、类风湿性关节炎、银屑病、银屑病关节炎、移植排斥、移植物抗宿主疾病、多发性硬化、炎性肠病、变应性疾病、哮喘、慢性阻塞性肺病(COPD)1型糖尿病、重症肌无力、造血功能障碍、B细胞恶性肿瘤、系统性红斑狼疮、非霍奇金淋巴瘤、慢性淋巴细胞性白血病、套细胞淋巴瘤或其他疾患。
背景
Bruton酪氨酸激酶(Btk)属于酪氨酸激酶,在酪氨酸残基的酚部分磷酸化蛋白的蛋白激酶子家族。它是非受体细胞质酪氨酸激酶以及B细胞发育、活化、信号传导和存活的关键调节剂(Schaeffer和Schwartzberg,Curr.Op.Imm.2000,282;Niiro和Clark,NatureRev.Immumol.2002,945;Di Paolo和Currie,Nat.Chem.Biol.2011,7)。Btk在所有造血细胞类型中表达,不包括血浆细胞、T淋巴细胞和天然杀伤细胞。在被上游B细胞抗原受体或Toll样受体-4活化之后,Btk诱导PLC-γ2磷酸化,其最终导致核因子κB(NFκB)和活化的T细胞依赖途径的核因子的活化。此外,Btk对于许多其他造血细胞信号传导是关键的;例如单核细胞/巨噬细胞中Fcγ介导的炎性细胞因子生成(例如TNF-α、IL1β和IL6)、肥大细胞中IgE介导的信号传导、B谱系淋巴细胞中Fas/APO-1凋亡信号传导的抑制等等(Jeffries等人,J.Biol.Chem.2003,26258;Horwood等人,J.Experimental Med.2003,1603)。
基于B细胞清除蛋白的治疗剂(例如,Rituxan,一种CD20抗体)用于治疗许多自身免疫和/或炎性疾病的用途提供了B细胞和体液免疫系统在自身免疫和/或炎性疾病的致病中作用的充分证据,这还提供了Btk在自身免疫和/或炎性疾病中作用的间接推理。
Btk参与各种自身免疫和/或炎性疾病的其他原理来自Btk缺陷小鼠模型;例如,已知Btk缺陷导致系统性红斑狼疮(SLE)的鼠临床前模型中疾病进展的显著减缓。BTK缺陷小鼠抵抗发展胶原蛋白诱导的关节炎(Jansson和Holmdahl Clin.Exp.Immumol.1993,459)。
Btk参与各种自身免疫和/或炎性疾病的药理验证来自两个不同类别的Btk抑制剂,例如(a)不可逆的Btk抑制剂(Pan等人,Chem.Med.Chem.2007,58),和(b)可逆的Btk抑制剂(Di Paolo,Nat.Chem.Biol.2010,41)。两个类型的抑制剂都证明了关节炎小鼠模型中的效力。PCI-32765(一种不可逆的Btk抑制剂)已经显示在慢性淋巴细胞性白血病(CLL)和小淋巴细胞淋巴瘤(SLL)中有前景的临床活性(Burger等人,Blood 2010,32&J Clin Oncol2011,6508)。因此,预期小分子Btk抑制剂用于治疗参与B细胞活化的疾病进展。
几个现有技术文献描述了小分子Btk抑制剂的发现(有关最近的综述,Lou等人.J.Med.Chem.2012)。例如,利用其丙烯酰胺官能团以共价修饰靶蛋白的基于氨基-吡唑并-嘧啶(WO2011046964A2)和咪唑并[1,5-a]喹喔啉(Kim等人,Bio-org.Med.Chem.Lett.,2011,6258)的化合物作为不可逆抑制剂公开。还有文献现有技术公开了可逆的Btk抑制剂,例如取代的氨基-嘧啶类似物(WO2010123870A1);基于咪唑并[1,2-f][1,2,4]三嗪核心的酰胺化合物(WO2010068810A2);各种杂环(例如,咪唑并[1,2-a]吡嗪、氨基嘧啶、2-吡啶酮等)酰胺衍生物(WO2010068788A1、WO2010068806A1);苯并[f][1,4]氧杂吖庚因类似物(WO2010122038A1);基于3,4-二氢-2H-异喹啉或2H-异喹啉-1-酮的类似物(WO2010100070A1、WO2013024078);苯基咪唑并吡嗪类似物(WO2010006970A1);3,5-二取代的吡啶-2-酮类似物(WO2007027729A1);氮杂吲唑化合物(WO2011019780A1);烟酰胺化合物(WO2010144647A1);咔唑羧酰胺类似物(WO2010080481A1)、吡咯并嘧啶衍生物(WO2013008095)。
尽管该领域的几个发现,市场上还没有可用的小分子Btk抑制剂。临床试验中最先进的化合物是Btk的不可逆抑制剂。此类不可逆的作用机理经常遭遇与蛋白的非特异性结合,包括脱靶,导致特别是长期使用时的安全性关注,例如脱靶相关的不良副作用、一般肝毒性和器官毒性、抗体介导的反应。因此,需要具有更安全的作用机理、例如可逆抑制机理的Btk抑制剂。这些化合物将在以下疾病领域具有医疗应用:炎症、自身免疫疾患和细胞增殖、类风湿性关节炎、银屑病、银屑病关节炎、移植排斥、移植物抗宿主疾病、多发性硬化、炎性肠病、变应性疾病和哮喘、1型糖尿病、重症肌无力、造血功能障碍、B细胞恶性肿瘤、系统性红斑狼疮。
概述
本公开提供了式(I)的杂双环化合物、其互变异构体、多晶型物、立体异构体、前药、溶剂化物、水合物、N氧化物、共晶体、药学可接受的盐、含有它们的药物组合物,以及治疗由Bruton酪氨酸激酶(Btk)活性介导的病症和疾病的方法。
其中,
环A和环C独立为不饱和或部分不饱和的、任选具有最多3个独立选自O、N或S的杂原子的5-7元环;
环B代表饱和、不饱和或部分不饱和的、任选具有最多3个独立选自O、N或S的杂原子的5-7元环;
每个X独立代表N或C(R1);
Y代表-C(O)或-S(O)p-;
J不存在或选自亚环烷基、亚环烯基、亚芳基、亚杂环基、亚杂芳基、亚螺环基、(C1-6)亚烷基、(C1-6)亚烯基或(C1-6)亚炔基;
K是键或者选自-(CRaRb)-、(C1-6)亚烷基、(C1-6)亚烯基和(C1-6)亚炔基,其中任选地,亚烷基、亚烯基或亚炔基的一个或多于一个亚甲基独立地被杂原子或诸如-O-、-S(O)p-、-N(R6)-、-C(O)-、-C(=NR’)-或-C(R’)=N-的基团替代,其中R’是H、烷基、氰基、羟基、羟基烷基、卤代烷基或全卤代烷基;
M选自氢、氰基、卤素、卤代烷基、全卤代烷基、烷基、烯基、炔基、氰基烷基、酰基、氰基烷基羰基、氰基烯基羰基、-(CRaRb)mOR6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、硫羰基、S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6、-SO3H、环烷基、环烯基、环烷基烷基、芳基、芳基烷基、杂环基、杂环基烷基、杂芳基、螺环基或杂芳基烷基;
J、K和M任选经一个或多个独立选自以下的取代基取代:氰基、硝基、酮基、氧代、卤素、卤代烷基、全卤代烷基、羟基氨基、-(CRaRb)mOR6、-(CRaRb)mC(O)R6、-OC(O)R6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、-NR6C(O)R6、硫羰基、-S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6、-SO3H、烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基;其中烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基任选地经一个或多个选自以下的取代基取代:羟基、烷基、烷氧基、烷氧基烷基、卤素、卤代烷基、全卤代烷基、氰基、氰基烷基、氨基、羧基、羧基烷基、-OC(O)R6、-(CRaRb)mC(O)NR7R8、-NR6C(O)R6、-SR6、-S(O)pR6、-S(O)2NR7R8或-NR6S(O)2R6;
U是键或选自亚环烷基、亚环烯基、亚芳基、亚杂环基、亚杂芳基、(C1-6)亚烷基、(C1-6)亚烯基和(C1-6)亚炔基,其中亚烷基、亚烯基或亚炔基的一个或多于一个亚甲基任选地地被杂原子或诸如-O-、-S(O)p-、-N(R6)-、-C(O)-、-C(=NR’)-或-C(R’)=N-的基团替代,其中R’是H、烷基、氰基、羟基、羟基烷基、卤代烷基或全卤代烷基;
T选自氢、氰基、卤素、卤代烷基、全卤代烷基、烷基、烯基、炔基、氰基烷基、酰基、氰基烷基羰基、氰基烯基羰基、-(CRaRb)mOR6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、硫羰基、S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6、-SO3H、环烷基、环烯基、环烷基烷基、环烷基氧基、环烷基氨基、芳基、芳基烷基、芳基氧基、芳基氨基、杂环基、杂环基烷基、杂环基氧基、杂环烷基氨基、杂芳基、杂芳基烷基、杂芳基氧基或杂芳基氨基;
U和T任选地经一个或多个独立选自以下的取代基取代:氰基、硝基、酮基、氧代、卤素、卤代烷基、全卤代烷基、羟基氨基、-(CRaRb)mOR6、-(CRaRb)mC(O)R6、-OC(O)R6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、-NR6C(O)R6、硫羰基、-S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6、-SO3H、烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基;
其中烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基任选地经一个或多个选自以下的取代基取代:羟基、烷基、烷氧基、烷氧基烷基、卤素、卤代烷基、全卤代烷基、氰基、氰基烷基、氨基、羧基、羧基烷基、-OC(O)R6、-(CRaRb)mC(O)NR7R8、-NR6C(O)R6、-SR6、-S(O)pR6、-S(O)2NR7R8或-NR6S(O)2R6;
R1、R2、R3、R4和R5独立选自氢、烷基、烯基、炔基、烷氧基、酰基、酰基氨基、酰基氧基、R6、-(CRaRb)mC(O)R6、-(CRaRb)mNR7R8、-(CRaRb)mO(CRaRb)nSi(R7)3、氨基羰基、烷氧基羰基氨基、烷基磺酰基氨基、氨基羰基氨基、羟基氨基、烷氧基氨基、叠氮基、氰基、卤素、羟基、羟基烷基、卤代烷基、全卤代烷基、硫羰基、羧基、烷基羧基、羧基烷基、羧基烷基氧基、烷基羧基烷基氧基-SO3H、、-S(O)pR6、-S(O)2NR7R8烷基硫代或硝基;或者当R1或R2或R3或R4或R5多于一个时,则任何2个R1或2个R2或2个R3或2个R4或2个R5独立地任选合在一起形成饱和或部分不饱和且任选具有选自O、N或S的额外杂原子的单环或双环系统;
R6选自氢、-(CRaRb)mOR6、卤素、卤代烷基、-(CRaRb)mC(O)R6、烷基、烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基或杂环基烷基;
其中烷基、烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基或杂环基烷基任选地经一个或多个选自以下的取代基取代:羟基、烷基、烷氧基、烷氧基烷基、卤素、卤代烷基、全卤代烷基、氰基、氰基烷基、氨基、羧基、羧基烷基、OR5、-OC(O)R6、-(CRaRb)mC(O)NR7R8、-NR6C(O)R6、-SR6、-S(O)pR6、-S(O)2NR7R8或-NR6S(O)2R6;
R7和R8独立选自氢、-(CRaRb)mOR6、卤代烷基、-(CRaRb)mC(O)R6、烷基、烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基或杂环基烷基,或
R7和R8合在一起形成饱和或部分不饱和且任选具有选自O、N或S的额外杂原子的单环或双环系统,所述环系统进一步任选地经1至4个独立选自以下的取代基取代:卤代、烷基、烯基、炔基、硝基、氰基、-(CRaRb)mOR6、-SR6、-(CRaRb)mNR7R8、氧代、烷基磺酰基、-(CRaRb)mCOOR6、-(CRaRb)mC(O)NR7R8、环烷基、环烷基烷基、芳基、芳基烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基;
Ra和Rb独立选自氢、-OR6、卤素、卤代烷基、全卤代烷基和烷基;或
Ra和Rb合在一起形成饱和或部分不饱和且任选具有选自O、N或S的额外杂原子的单环或双环系统;
m是0-6;
n是0-3;
p是0、1或2;并且
q是1或2。
详述
定义
在此处和本公开通篇中给出的结构式中,除非另有明确说明,否则下列术语具有所指出的含义。
本文使用的术语“任选地取代”意思是谈及的基团是未取代的或者被一个或多个指定的取代基取代。当谈及的基团被多于一个取代基取代时,所述取代基可以相同或不同。
术语“烷基”指单价团支链或直链饱和烃链,其具有1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个碳原子,优选1、2、3、4、5、6、7、8、9或10个碳原子,更优选1、2、3、4、5或6个碳原子。该术语由以下基团例证:例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正己基、正癸基、十四烷基,等等。
术语“亚烷基”指支链或直链饱和烃链的双价团,其具有1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个碳原子,优选1、2、3、4、5、6、7、8、9或10个碳原子,更优选1、2、3、4、5或6个碳原子。该术语由以下基团例证:例如亚甲基(-CH2-)、亚乙基(-CH2CH2-)、亚丙基异构体(例如-CH2CH2CH2-和-CH(CH3)CH2-)CH2-)等等。
术语“取代烷基”或“取代亚烷基”指:1)如上定义的烷基或亚烷基,其具有1、2、3、4或5个取代基,优选1、2或3个取代基,所述取代基选自烯基、炔基、烷氧基、环烷基、环烯基、酰基、酰氨基、酰氧基、氨基、单烷基氨基、二烷基氨基、芳氨基、杂芳氨基、氨基羰基、烷氧羰基氨基、叠氮基、氰基、卤素、羟基、羟基烷基、酮基、硫羰基、羧基、羧基烷基、-SO3H、芳基、芳氧基、杂芳基、氨基羰基氨基、杂芳氧基、杂环基、杂环氧基、羟氨基、烷氧氨基、硝基、-S(O)2NRaRa、-NRaS(O)2Ra和-S(O)pRb,其中每一个Ra独立地选自氢、烷基、环烷基、环烷基烷基、芳基、芳基烷基、杂芳基杂芳基烷基、杂环基和杂环基烷基;杂环氧基,其中Rb是氢、烷基、芳基、杂芳基或杂环基。除非另有定义的约束,所有的取代基可以任选地进一步被1、2或3个选自烷基、羧基、羧基烷基、氨基羰基、羟基、烷氧基、卤素、CF3、氨基、取代氨基、氰基或-S(O)pRc的取代基取代,其中Rc是烷基、芳基或杂芳基并且p是0、1或2;
或2)如上定义的烷基或亚烷基,其被1、2、3、4、5、6、7、8、9或10个原子中断,所述原子独立地选自氧、硫和NRd,其中Rd选自氢、烷基、环烷基、环烯基、芳基、杂芳基和杂环基、羰基烷基、羧基酯、羧基酰胺或磺酰基。所有的取代基可以任选地进一步被烷基、烷氧基、卤素、CF3、氨基、取代氨基、氰基或-S(O)pRc取代,其中Rc是烷基、芳基或杂芳基并且p是0、1或2;
或3)如上定义的烷基或亚烷基,其具有1、2、3、4或5个如上定义的取代基,并且被1、2、3、4、5、6、7、8、9或10个如上定义的原子中断。
术语“烯基”指支链或直链不饱和烃基的单价团,优选具有2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个碳原子,更优选具有2、3、4、5、6、7、8、9或10个碳原子并且甚至更优选具有2、3、4、5或6个碳原子,并且具有1、2、3、4、5或6个双键(乙烯基),优选1个双键。优选的烯基包括乙烯基(-CH=CH2)、1-丙烯或丙烯基(-CH2CH=CH2)、异丙烯(-C(CH3)=CH2)、双环[2.2.1]庚烯,等等。
术语“亚烯基”指支链或直链不饱和烃基的双价团,优选具有2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个碳原子,更优选具有2、3、4、5、6、7、8、9或10个碳原子并且甚至更优选具有2、3、4、5或6个碳原子,并且具有1、3、4、5或6个双键(乙烯基),优选1个双键。
术语“取代烯基”指如上定义的烯基,其具有1、2、3、4或5个取代基和优选1、2或3个取代基,所述取代基选自烯基、炔基、烷氧基、环烷基、环烯基、酰基、酰氨基、酰氧基、氨基、单烷基氨基、二烷基氨基、芳氨基、杂芳氨基、氨基羰基、烷氧羰基氨基、叠氮基、氰基、卤素、羟基、羟基烷基、酮基、硫羰基、羧基、羧基烷基、-SO3H、芳基、芳氧基、杂芳基、氨基羰基氨基、杂芳氧基、杂环基、杂环氧基、羟氨基、烷氧氨基、硝基、-S(O)2NRaRa、-NRaS(O)2Ra和-S(O)pRb,其中每一个Ra独立地选自氢、烷基、环烷基、环烷基烷基、芳基、芳基烷基、杂芳基杂芳基烷基、杂环基、杂环基烷基和杂环氧基,其中Rb是烷基、芳基、杂芳基或杂环基,并且p是0、1或2。除非另有定义的约束,所有的取代基可以任选地进一步被1、2或3个选自烷基、羧基、羧基烷基、氨基羰基、羟基、烷氧基、卤素、CF3、氨基、取代氨基、氰基或-S(O)pRc的取代基取代,其中Rc是烷基、芳基或杂芳基并且p是0、1或2。
术语“炔基”指不饱和烃的单价团,优选具有2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个碳原子,更优选具有2、3、4、5、6、7、8、9或10个碳原子并且甚至更优选具有2、3、4、5或6个碳原子,并且具有1、2、3、4、5或6个乙炔(三键)不饱和位点,优选为1个三键。优选的炔基包括乙炔基(-C≡CH)、丙炔基(或丙-1-炔-3-基,-CH2C≡CH)、高炔丙基(或丁-1-炔-4-基,-CH2CH2C≡CH)等等。
术语“亚炔基”指支链或直链不饱和烃基的双价团,优选具有2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个碳原子,更优选具有2、3、4、5、6、7、8、9或10个碳原子并且甚至更优选具有2、3、4、5或6个碳原子,并且具有1、3、4、5或6个乙炔(三键)不饱和位点,优选为1个三键。
术语“取代炔基”指如上定义的炔基,其具有1、2、3、4或5个取代基,且优选为1、2或3个取代基,所述取代基选自烷基、烯基、炔基、烷氧基、环烷基、环烯基、酰基、酰氨基、酰氧基、氨基、氨基羰基、烷氧羰基氨基、叠氮基、氰基、卤素、羟基、酮、硫羰基、羧基、羧基烷基、-SO3H、芳基、芳氧基、杂芳基、氨基羰基氨基、杂芳氧基、杂环基、杂环氧基、羟氨基、烷氧氨基、硝基、-S(O)2NRaRa、-NRaS(O)2Ra或-S(O)pRb,其中每一个Ra独立地选自氢、烷基、环烷基、环烷基烷基、芳基、芳基烷基、杂芳基杂芳基烷基、杂环基、杂环基烷基和杂环氧基,其中Rb是烷基、芳基、杂芳基或杂环基并且p是0、1或2。除非另有定义的约束,所有的取代基可以任选地进一步被1、2或3个选自烷基、羧基、羧基烷基、氨基羰基、羟基、烷氧基、卤素、CF3、氨基、取代氨基、氰基和-S(O)pRc的取代基取代,其中Rc是烷基、芳基或杂芳基并且p是0、1或2。
术语“环烷基”指从3至20个碳原子的碳环基团,所述碳环基团具有单环或多重稠环或螺环或桥接环,其可能是饱和或部分不饱和的。这样的环烷基包括例如,单环结构例如环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环辛基等等,或多重环结构例如金刚烷基、双环[2.2.1]庚烷、1,3,3-三甲基双环[2.2.1]庚-2-基、(2,3,3-三甲基双环[2.2.1]庚-2-基),或与芳基稠合的碳环基团例如茚满等等。
术语“亚环烷基”指二价的如上定义的环烷基。该术语由以下基团例证:例如1,4-亚环己基、1,3-亚环己基、1,2-亚环己基、1,4-环己烯基等等。
术语“取代环烷基”指具有1、2、3、4或5个取代基和优选1、2或3个取代基的环烷基,所述取代基选自烷基、烷氧基、环烷基、环烯基、酰基、酰氨基、酰氧基、氨基、氨基羰基、烷氧羰基氨基、叠氮基、氰基、卤素、羟基、氧代、硫羰基、芳基、芳氧基、杂芳基、氨基磺酰基、氨基羰基氨基、杂芳氧基、杂环基、杂环氧基、羟基氨基、烷氧氨基、硝基、-C(O)R和-S(O)pRb,其中R是氢、羟基、烷氧基、烷基和环烷基、杂环氧基,其中Rb是烷基、芳基、杂芳基或杂环基并且p是0、1或2。除非另有定义的约束,所有的取代基可以任选地进一步被1、2或3个选自烷基、羧基、羧基烷基、氨基羰基、羟基、烷氧基、卤素、CF3、氨基、取代氨基、氰基和S(O)pRc的取代基取代,其中Rc是烷基、芳基或杂芳基并且p是0、1或2。
“卤代”或“卤素”,单独或与任何其他术语结合意思是卤素,例如氯(Cl)、氟(F)、溴(Br)和碘(I)。
“卤代烷基”指具有1至6个碳原子的直链或支链卤代烷基。烷基可能部分或全部被卤代。卤代烷基的代表性例子包括但不限于氟甲基、氯甲基、溴甲基、二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、2-氟乙基、2-氯乙基、2-溴乙基、2,2,2-三氟乙基、3-氟丙基、3-氯丙基、3-溴丙基等等。
术语“烷氧基”指R″′-O-基团,其中R″′是任选地取代烷基或任选地取代环烷基,或任选地取代烯基或任选地取代炔基;或任选地取代环烯基,其中烷基、烯基、炔基、环烷基和环烯基如本文定义。烷氧基的代表性例子包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基、1,2-二甲基丁氧基、三氟甲氧基,等等。
术语“氨基羰基”指-C(O)NR′R′基团,其中每一个R'独立地为氢、烷基、芳基、杂芳基、杂环基或两个R'基团连接形成杂环基团(例如吗啉代)。除非另有定义的约束,所有的取代基可以任选地进一步被1-3个选自烷基、羧基、羧基烷基、氨基羰基、羟基、烷氧基、卤素、CF3、氨基、取代氨基、氰基和-S(O)pRc的取代基取代,其中Rc是烷基、芳基或杂芳基并且p是0、1或2。
术语“酰氨基”指-NR"C(O)R"基团,其中每一个R"独立地为氢、烷基、芳基、杂芳基或杂环基。除非另有定义的约束,所有的取代基可以任选地进一步被1-3个选自烷基、羧基、羧基烷基、氨基羰基、羟基、烷氧基、卤素、CF3、氨基、取代氨基、氰基和-S(O)pRc的取代基取代,其中Rc是烷基、芳基或杂芳基并且p是0、1或2。
术语“酰氧基”指-OC(O)-烷基、-OC(O)-环烷基、-OC(O)-芳基、-OC(O)-杂芳基和-OC(O)-杂环基基团。除非另有定义的约束,所有的取代基可以任选地进一步被烷基、羧基、羧基烷基、氨基羰基、羟基、烷氧基、卤素、CF3、氨基、取代氨基、氰基和-S(O)pRc的取代基取代,其中Rc是烷基、芳基或杂芳基并且p是0、1或2。
“烷氧烷基”指如上定义的烷基,其中至少一个烷基的氢原子被如上定义的烷氧基替代。烷氧烷基的代表性例子包括但不限于甲氧基甲基、甲氧基乙基、乙氧基甲基等等。
“芳氧基烷基”指-烷基-O-芳基基团。芳氧基烷基的代表性例子包括但不限于苯氧甲基、萘氧甲基、苯氧乙基、萘氧乙基等等。
“二烷基氨基”指氨基,两个相同或不同的具有1至6个碳原子的直链或支链烷基连接于其上。二烷基氨基的代表性例子包括但不限于二甲氨基、二乙基氨基、甲基乙基氨基、二丙基氨基、二丁基氨基等等。
“环烷基烷基”指被如上定义的环烷基取代的如上定义的烷基。环烷基烷基的代表性例子包括但不限于环丙基甲基、环丁基甲基、环戊基甲基、环己基甲基、1-环戊基乙基、1-环己基乙基、2-环戊基乙基、2-环己基乙基、环丁基丙基、环戊基丙基、环己基丁基等等。
“氨基烷基”指连接于本文定义的(C1-6)亚烷基的氨基。氨基烷基的代表性例子包括但不限于氨甲基、氨乙基、1-氨丙基、2-氨丙基,等等。氨基烷基的氨基部分可能被烷基一次或两次取代,从而分别得到烷基氨基烷基和二烷基氨基烷基。烷基氨基烷基的代表性例子包括但不限于甲基氨甲基、甲基氨乙基、甲基氨丙基、乙基氨乙基等等。二烷基氨基烷基的代表性例子包括但不限于二甲基氨甲基、二甲基氨乙基、二甲基氨丙基、N-甲基-N-乙基氨乙基等等。
术语“芳基”指6至20个碳原子的芳香碳环基团,其具有单环(例如,苯基)或多环(例如,二苯基),或多重稠合环(例如萘基或蒽基)。优选的芳基包括苯基、萘基等等。
术语“亚芳基”指如上定义的芳基的双价团。该术语由以下基团例证,例如1,4-亚苯基、1,3-亚苯基、1,2-亚苯基、1,4'-亚联苯基,等等。
除非另有约束,芳基或亚芳基可以任选地用1、2、3、4或5个取代基,优选1、2或3个取代基取代,所述取代基选自烷基、烷氧基、环烷基、环烯基、酰基、酰氨基、酰氧基、氨基、氨基羰基、烷氧羰基氨基、叠氮基、氰基、卤素、羟基、羧基、羧基烷基、-SO3H、芳基、芳氧基、杂芳基、氨基磺酰基、氨基羰基氨基、杂芳氧基、杂环基、杂环氧基、羟基氨基、烷氧氨基、硝基、-S(O)2NRaRa,-NRaS(O)2Ra和-S(O)pRb,其中每一个Ra独立地选自氢、烷基、环烷基、环烷基烷基、芳基、芳基烷基、杂芳基杂芳基烷基、杂环基和杂环基烷基;其中Rb是氢、烷基、芳基、杂环基或杂芳基并且p是0、1或2。除非另有定义的约束,所有的取代基可以任选地进一步被1、2或3个选自烷基、羧基、羧基烷基、氨基羰基、羟基、烷氧基、卤素、CF3、氨基、取代氨基、氰基和-S(O)pRc的取代基取代,其中Rc是氢、烷基、芳基或杂芳基并且p是0、1或2。
术语“芳基烷基”指共价连接于亚烷基的芳基,其中芳基和亚烷基如本文定义。
“任选地取代芳基烷基”指共价连接于任选地取代亚烷基的任选地取代芳基。这样的芳基烷基以苄基、苯乙基、萘甲基等等为例。
术语“芳氧基”指芳基-O-基团,其中芳基如上定义,并且包括也如上定义的任选地取代芳基。
术语“芳硫基”指-S-芳基基团,其中芳基如本文定义,包括也如上定义的任选地取代芳基。
术语“取代氨基”指-NR'R'基团,其中每一个R'独立地选自氢、烷基、环烷基、羧基烷基、烷氧基羰基、芳基、杂芳基和杂环基。除非另有定义的约束,所有的取代基可以任选地进一步被1、2或3个选自烷基、羧基、羧基烷基、氨基羰基、羟基、烷氧基、卤素、CF3、氨基、取代氨基、氰基和-S(O)pRc的取代基取代,其中Rc是烷基、芳基或杂芳基并且p是0、1或2。
术语“羧基烷基”指-亚烷基-C(O)OH基团。
术语“烷基羧基烷基”指-亚烷基-C(O)ORd基团,其中Rd是烷基、环烷基,其中烷基、环烷基如本文定义,并且可以任选地进一步被烷基、卤素、CF3、氨基、取代氨基、氰基或-S(O)pRc取代,其中Rc是烷基、芳基或杂芳基并且p是0、1或2。
术语“杂芳基”指芳香环基团,其具有1、2、3、4、5、6、7、8、9、10、11、12、13、14或15个碳原子和至少在一个环内的1、2、3或4个选自氧、氮和硫的杂原子,这样的杂芳基可以具有单环(例如,吡啶基或呋喃基)或多重稠环(例如吲嗪基、苯并噻唑基或苯并噻吩基)。杂芳基的例子包括但不限于[1,2,4]噁二唑、[1,3,4]噁二唑、[1,2,4]噻二唑、[1,3,4]噻二唑、吡咯、咪唑、吡唑、吡啶、吡嗪、嘧啶、哒嗪、吲嗪、异吲哚、吲哚、吲唑、嘌呤、喹嗪、异喹啉、喹啉、酞嗪、喹喔啉、喹唑啉、噌啉、蝶啶、咔唑、咔啉、菲啶、吖啶、菲咯啉、异噻唑、吩嗪、异噁唑、吩噁嗪、吩噻嗪、呋喃、噻吩、噁唑、噻唑、三唑、三嗪等等。
术语“杂亚芳基”指如上定义的杂芳基的双价团。
除非另有约束,杂芳基或杂亚芳基可以任选地被1、2、3、4或5个取代基,优选1、2或3个取代基取代,所述取代基选自烷基、烯基、炔基、烷氧基、环烷基、环烯基、酰基、酰氨基、酰氧基、氨基、氨基羰基、烷氧基羰基烷基、叠氮基、氰基、卤素、羟基、硫羰基、羧基、羧基烷基、-SO3H、芳基、芳氧基、杂芳基、氨基羰基氨基、杂芳氧基、杂环基、杂环氧基、羟基氨基、烷氧基氨基、硝基、-S(O)2NRaRa、-NRaS(O)2Ra和-S(O)pRb,其中每一个Ra独立地选自氢、烷基、环烷基、环烷基烷基、芳基、芳基烷基、杂芳基杂芳基烷基、杂环基和杂环基烷基;其中Rb是氢、烷基、芳基、杂环基或杂芳基,并且p是0、1或2。除非另有定义的约束,所有的取代基可以任选地进一步被1-3个选自烷基、羧基、羧基烷基、氨基羰基、羟基、烷氧基、卤素、CF3、氨基、取代氨基、氰基和-S(O)nRc的取代基取代,其中Rc是烷基、芳基或杂芳基并且n是0、1或2。
术语“杂芳基烷基”指与亚烷基共价连接的杂芳基,其中杂芳基和亚烷基如本文定义。
“任选地取代杂芳基烷基”指共价连接于任选地取代亚烷基的任选地取代杂芳基。这样的杂芳基烷基以3-吡啶基甲基、喹啉-8-基乙基、4-甲氧基噻唑-2-基丙基等等为例。
术语“杂环基”指饱和或部分不饱和基团,除非另外提及,其具有单环或多重稠环或螺环或桥接环,在环内具有1至40个碳原子和1至10个杂原子,优选1、2、3或4个杂原子,杂原子选自氮、硫、磷和/或氧。杂环基可以具有单环或多重稠环,并且包括四氢呋喃基、吗啉基、哌啶基、哌嗪基、二氢吡啶基、四氢喹啉基等等。除非另有对杂环取代基的定义的约束,这样的杂环基可以任选地用1、2、3、4或5个,且优选为1、2或3个取代基取代,所述取代基选自烷基、烯基、炔基、烷氧基、环烷基、环烯基、酰基、酰氨基、酰氧基、氨基、氨基羰基、烷氧基羰基氨基、叠氮基、氰基、卤素、羟基、氧代、-C(O)R(其中R是氢、羟基、烷氧基、烷基或环烷基)、硫羰基、羧基、羧基烷基、芳基、芳氧基、杂芳基、氨基磺酰基、氨基羰基氨基、杂芳氧基、杂环基、杂环氧基、羟基氨基、烷氧基氨基、硝基和-S(O)pRb,其中Rb是氢、烷基、芳基、杂环基或杂芳基并且p是0、1或2。除非另有定义的约束,所有的取代基可以任选地进一步被1-3个选自烷基、羧基、羧基烷基、氨基羰基、羟基、烷氧基、卤素、CF3、氨基、取代氨基、氰基和-S(O)nRc的取代基取代,其中Rc是烷基、芳基或杂芳基并且n是0、1或2。
术语“杂环基烷基”指共价连接于亚烷基的杂环基,其中杂环基和亚烷基如本文定义。
“任选地取代杂环基烷基”指共价连接于任选地取代亚烷基的任选地取代杂环基。
术语“杂芳氧基”指杂芳基-O-基团。
术语“巯基”指-SH基团。
术语“取代烷基硫代”指-S-取代烷基基团。
术语“杂芳硫代”指-S-杂芳基基团,其中杂芳基如上所定义,包括也如上定义的任选地取代杂芳基。
术语“亚砜”指-S(O)基团。
“取代亚砜”指-S(O)R基团,其中R是如本文定义的取代烷基、取代芳基或取代杂芳基。
术语“砜”指-S(O)2R基团。
术语“取代砜”指-S(O)2R基团,其中R是烷基、芳基或杂芳基。
本公开化合物可能具有以不只一种形式结晶的能力,即被称为同质多晶的特征,并且所用这样的多晶型形式(“多晶型物”)都包含于本公开的范围。同质多晶通常可以作为对温度或压力或二者的变化的反应而发生,并且还可以由结晶方法的变化而产生。多晶型物可以通过各种物理特征区分,并且通常使用化合物的X射线衍射图、溶解度行为和熔点来区分多晶型物。
本文描述的化合物可能含有一个或多个手性中心和/或双键,因此,可能以立体异构体的形式存在,例如双键异构体(即,几何异构体)、区域异构体、对映异构体或非对映异构体。因此,本文描述的化学结构包含示例的或经鉴别的化合物的所有可能的对映异构体和立体异构体,包括立体异构体纯形式(例如,几何异构体纯的、对映异构体纯的或非对映异构体纯的)和对映异构体的和立体异构体的混合物。可以使用本领域技术人员熟知的分离技术或手性合成技术,将对映异构体的和立体异构体的混合物拆分为它们的组分对映异构体或立体异构体。所述化合物还可能以数个互变异构的形式存在,包括烯醇形式、酮形式及其混合物。因此,本文描述的化学结构包含示例的或经鉴别的化合物所有可能的互变异构体形式。
化合物可能以非溶剂化和溶剂化的形式存在,包括水合形式和N-氧化物的形式。总体而言,化合物可能是水合化物、溶剂化物或N-氧化物。某些化合物可能以多种结晶或无定形形式存在。在本发明范围内还预期的是所述化合物的同类物、类似物、水解产物、代谢物和前体或前药。总体而言,除非另外指出,所有物理形式对于本文预期的用途是等效的,并且预期在本发明的范围内。
“前药”指药物分子的衍生物,例如,酯、碳酸酯、氨甲酸酯、脲、酰胺或磷酸酯,其需要在体内转化以释放活性药物。尽管不是必须,前药经常是药理学非活性的,直至被转换为母体药物。前药可以通过将引入部分(promoiety)(本文定义)典型地通过官能团与药物结合而获得。
“引入部分”指与药物结合的基团,典型地与药物的官能团通过在规定的应用条件下可以裂解的键结合。在药物和引入部分之间的键可以通过酶的或非酶的手段裂解。在应用条件下,例如在施用给患者之后,在药物和引入部分之间的键可以裂解释放母体药物。引入部分的裂解可以自发地进行,例如通过水解反应,或其可能通过以下催化或诱导:通过另一剂(例如通过酶)、通过光、通过酸、或通过物理的或环境参数的变化或暴露于物理或环境参数,例如温度、PH等的变化。所述剂可能对于应用条件而言是内源性的,例如存在于前药被施用的体循环内或胃的酸性条件下的酶,或者所述剂可能外源地提供。
“药学可接受盐”包括具有药学可接受酸或碱的盐。药学可接受的酸包括无机酸,例如盐酸、硫酸、磷酸、焦磷酸、氢溴酸、氢碘酸和硝酸,以及有机酸,例如柠檬酸、富马酸、马来酸、苹果酸、扁桃酸、抗坏血酸、草酸、琥珀酸、酒石酸、苯甲酸、乙酸、甲磺酸、乙磺酸、苯磺酸或对甲苯磺酸。药学可接受碱包括碱金属(例如,钠或钾)和碱土金属(例如,钙或镁)的氢氧化物以及有机碱,例如烷基胺、芳烷基胺和杂环胺。
根据本公开的其他优选的盐是季铵化合物,其中阴离子(M-)的等价物与N原子的正电荷相伴。M-可以是各种矿物酸的阴离子,例如氯离子、溴离子、碘离子、硫酸根、硝酸根、磷酸根,或有机酸的阴离子,例如醋酸根、马来酸根、富马酸根、柠檬酸根、草酸根、琥珀酸根、酒石酸根、苹果酸根、扁桃酸根、三氟乙酸根、甲磺酸根和对甲苯磺酸根。M-优选地为选自氯离子、溴离子、碘离子、硫酸根、硝酸根、乙酸根、马来酸根、草酸根、琥珀酸根或三氟乙酸根的阴离子。更优选地M-是氯离子、溴离子、三氟乙酸根或甲磺酸根。
“共结晶”指在室温(20至25摄氏度,优选20摄氏度)下包含两种或多种化合物的结晶材料,其中至少两种通过弱相互作用结合在一起,其中至少一种化合物是共晶体形成剂。弱相互作用被定义为既不是离子也不是共价的相互作用,并且包括例如:氢键、范德华力和相互作用。
“药物组合物”指一种或多种活性成分,和构成载体的一种或多种惰性成分,以及直接或间接源自任何两种或多种成分的组合、复合或聚集或者源自一种或多种成分的解离或者源自一种或多种成分的其他类型的反应或相互作用的任何产物。相应地,本公开的药物组合物涵盖包含本公开化合物和药学可接受载体的任何组合物。
“载体”指与治疗剂一起施用的稀释剂、佐剂、赋形剂或媒介物。此类药物载体可以是无菌液体,例如水和油,包括石油、动物、植物或合成来源的那些,包括但不限于花生油、豆油、矿物油、芝麻油等。当药物组合物口服施用时,水是优选的载体。当药物组合物静脉内施用时,盐水和右旋糖水溶液是优选载体。盐水溶液和右旋糖水溶液和甘油溶液优选作为液体载体供注射溶液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、稻米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙烯、乙二醇、水、乙醇等。如果需要,组合物还可以含有小量润湿剂或乳化剂、或pH缓冲剂。这些组合物可以采取溶液、悬液、乳液、片剂、丸剂、胶囊、粉剂、持续释放制剂等形式。组合物还可以配制为栓剂,使用传统粘合剂和载体,例如甘油三酯。口服制剂可以包括标准载体,例如药物级甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药物载体的实例描述于“Remington's Pharmaceutical Sciences”,E.W.Martin。此类组合物将含有治疗有效量的、优选纯化形式的治疗剂以及适量的载体,以提供适合施用给患者的形式。制剂应该适合施用方式。
“药物或药学活性剂”包括将引发例如研究人员或临床医生寻求的组织、系统、动物或人的生物学或医学响应的药物或药剂。
“组合的”或“组合中”或“组合”应该被理解为功能性共同施用,其中一些或所有化合物可以分开、以不同制剂、不同施用方式(例如,皮下、静脉内或口服)和不同施用时间来施用。此类组合的个体化合物可以分开的药物组合物顺序施用,以及以组合的药物组合物同时施用。
“治疗有效量”是式(I)化合物或两种或多种此类化合物的组合完全或部分抑制病症进展或至少部分缓解病症的一个或多个症状的量。治疗有效量还可以是预防上有效的量。治疗有效量将取决于患者大小和性别、待治疗病症、病症严重度和寻求的结果。对于给定患者,可以通过本领域技术人员已知的方法确定治疗有效量。
本公开提供了式(I)的杂双环化合物、其互变异构体、多晶型物、立体异构体、前药、溶剂化物、水合物、N氧化物、共晶体、药学可接受的盐、含有它们的药物组合物,以及治疗由Bruton酪氨酸激酶(Btk)活性介导的病症和疾病的方法,
其中,
环A和环C独立为不饱和或部分不饱和的、任选具有最多3个独立选自O、N或S的杂原子的5-7元环;
环B代表饱和、不饱和或部分不饱和的、任选具有最多3个独立选自O、N或S的杂原子的5-7元环;
每个X独立代表N或C(R1);
Y代表-C(O)或-S(O)p-;
J不存在或选自亚环烷基、亚环烯基、亚芳基、亚杂环基、亚杂芳基、亚螺环基、(C1-6)亚烷基、(C1-6)亚烯基或(C1-6)亚炔基;
K是键或选自-(CRaRb)-、(C1-6)亚烷基、(C1-6)亚烯基和(C1-6)亚炔基,其中任选地,亚烷基、亚烯基或亚炔基的一个或多于一个亚甲基独立地被杂原子或诸如-O-、-S(O)p-、-N(R6)-、-C(O)-、-C(=NR’)-或-C(R’)=N-的基团替代,其中R’是H、烷基、氰基、羟基、羟基烷基、卤代烷基或全卤代烷基;
M选自氢、氰基、卤素、卤代烷基、全卤代烷基、烷基、烯基、炔基、氰基烷基、酰基、氰基烷基羰基、氰基烯基羰基、-(CRaRb)mOR6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、硫羰基、S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6、-SO3H、环烷基、环烯基、环烷基烷基、芳基、芳基烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基;
J、K和M任选经一个或多个独立选自以下的取代基取代:氰基、硝基、酮基、氧代、卤素、卤代烷基、全卤代烷基、羟基氨基、-(CRaRb)mOR6、-(CRaRb)mC(O)R6、-OC(O)R6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、-NR6C(O)R6、硫羰基、-S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6、-SO3H、烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基;
其中烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基任选地经一个或多个选自以下的取代基取代:羟基、烷基、烷氧基、烷氧基烷基、卤素、卤代烷基、全卤代烷基、氰基、氰基烷基、氨基、羧基、羧基烷基、-OC(O)R6、-(CRaRb)mC(O)NR7R8、-NR6C(O)R6、-SR6、-S(O)pR6、-S(O)2NR7R8或-NR6S(O)2R6;
U是键或选自亚环烷基、亚环烯基、亚芳基、亚杂环基、亚杂芳基、(C1-6)亚烷基、(C1-6)亚烯基和(C1-6)亚炔基,其中亚烷基、亚烯基或亚炔基的一个或多于一个亚甲基任选地地被杂原子或诸如-O-、-S(O)p-、-N(R6)-、-C(O)-、-C(=NR’)-或-C(R’)=N-的基团替代,其中R’是H、烷基、氰基、羟基、羟基烷基、卤代烷基或全卤代烷基;
T选自氢、氰基、卤素、卤代烷基、全卤代烷基、烷基、烯基、炔基、氰基烷基、酰基、氰基烷基羰基、氰基烯基羰基、-(CRaRb)mOR6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、硫羰基、S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6、-SO3H、环烷基、环烯基、环烷基烷基、环烷基氧基、环烷基氨基、芳基、芳基烷基、芳基氧基、芳基氨基、杂环基、杂环基烷基、杂环基氧基、杂环烷基氨基、杂芳基、杂芳基烷基、杂芳基氧基或杂芳基氨基;
U和T任选地经一个或多个独立选自以下的取代基取代:氰基、硝基、酮基、氧代、卤素、卤代烷基、全卤代烷基、羟基氨基、-(CRaRb)mOR6、-(CRaRb)mC(O)R6、-OC(O)R6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、-NR6C(O)R6、硫羰基、-S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6、-SO3H、烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基;
其中烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基任选地经一个或多个选自以下的取代基取代:羟基、烷基、烷氧基、烷氧基烷基、卤素、卤代烷基、全卤代烷基、氰基、氰基烷基、氨基、羧基、羧基烷基、-OC(O)R6、-(CRaRb)mC(O)NR7R8、-NR6C(O)R6、-SR6、-S(O)pR6、-S(O)2NR7R8或-NR6S(O)2R6;
R1、R2、R3、R4和R5独立选自氢、烷基、烯基、炔基、烷氧基、酰基、酰基氨基、酰基氧基、R6、-(CRaRb)mC(O)R6、-(CRaRb)mNR7R8、-(CRaRb)mO(CRaRb)nSi(R7)3、氨基羰基、烷氧基羰基氨基、烷基磺酰基氨基、氨基羰基氨基、羟基氨基、烷氧基氨基、叠氮基、氰基、卤素、羟基、羟基烷基、卤代烷基、全卤代烷基、硫羰基、羧基、烷基羧基、羧基烷基、羧基烷基氧基、烷基羧基烷基氧基-SO3H、、-S(O)pR6、-S(O)2NR7R8烷基硫代或硝基;或者当R1或R2或R3或R4或R5多于一个时,则任何2个R1或2个R2或2个R3或2个R4或2个R5独立地任选合在一起形成饱和或部分不饱和且任选具有选自O、N或S的额外杂原子的单环或双环系统;
R6选自氢、-(CRaRb)mOR6、卤素、卤代烷基、-(CRaRb)mC(O)R6、烷基、烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基和杂环基烷基;
其中烷基、烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基或杂环基烷基任选地经一个或多个选自以下的取代基取代:羟基、烷基、烷氧基、烷氧基烷基、卤素、卤代烷基、全卤代烷基、氰基、氰基烷基、氨基、羧基、羧基烷基、OR5、-OC(O)R6、-(CRaRb)mC(O)NR7R8、-NR6C(O)R6、-SR6、-S(O)pR6、-S(O)2NR7R8或-NR6S(O)2R6;
R7和R8独立选自氢、-(CRaRb)mOR6、卤代烷基、-(CRaRb)mC(O)R6、烷基、烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基或杂环基烷基,或
R7和R8合在一起形成饱和或部分不饱和且任选具有选自O、N或S的额外杂原子的单环或双环系统,所述环系统进一步任选地经1至4个独立选自以下的取代基取代:卤代、烷基、烯基、炔基、硝基、氰基、-(CRaRb)mOR6、-SR6、-(CRaRb)mNR7R8、氧代、烷基磺酰基、-(CRaRb)mCOOR6、-(CRaRb)mC(O)NR7R8、环烷基、环烷基烷基、芳基、芳基烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基;
Ra和Rb独立选自氢、-OR6、卤素、卤代烷基、全卤代烷基和烷基;或
Ra和Rb合在一起形成饱和或部分不饱和且任选具有选自O、N或S的额外杂原子的单环或双环系统;
m是0-6;
n是0-3;
p是0、1或2;并且
q是1或2。
根据另一实施方案,本公开涉及式(I)化合物或其互变异构体、多晶型物、立体异构体、前药、溶剂化物、共晶体或其药学可接受的盐,其中,
环A和环C独立为不饱和或部分不饱和的、任选具有最多3个独立选自O、N或S的杂原子的5-7元环;
环B代表不饱和的、任选具有最多3个独立选自O、N或S的杂原子的6元环;
每个X独立代表N或C(R1);
Y代表-C(O);
J不存在或选自亚环烷基、亚环烯基、亚芳基、亚杂环基、亚杂芳基、(C1-6)亚烷基、(C1-6)亚烯基或(C1-6)亚炔基;
K是键或(C1-6)亚烷基,其中其中任选地,亚烷基的一个或多于一个亚甲基独立地被杂原子或诸如-O-、-S(O)p-、-N(R6)-、-C(O)-、-C(=NR’)-或-C(R’)=N-的基团替代,其中R’是H、烷基、氰基、羟基、羟基烷基、卤代烷基或全卤代烷基;
M选自氢、氰基、卤素、卤代烷基、全卤代烷基、烷基、烯基、炔基、氰基烷基、酰基、氰基烷基羰基、氰基烯基羰基、-(CRaRb)mOR6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、硫羰基、S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6、-SO3H、环烷基、环烯基、环烷基烷基、芳基、芳基烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基;
J、K和M任选经一个或多个独立选自以下的取代基取代:氰基、硝基、酮基、氧代、卤素、卤代烷基、全卤代烷基、羟基氨基、-(CRaRb)mOR6、-(CRaRb)mC(O)R6、-OC(O)R6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、-NR6C(O)R6、硫羰基、-S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6、-SO3H、烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基;
其中烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基任选地经一个或多个选自以下的取代基取代:羟基、烷基、烷氧基、烷氧基烷基、卤素、卤代烷基、全卤代烷基、氰基、氰基烷基、氨基、羧基、羧基烷基、-OC(O)R6、-(CRaRb)mC(O)NR7R8、-NR6C(O)R6、-SR6、-S(O)pR6、-S(O)2NR7R8或-NR6S(O)2R6;
U是键或选自亚环烷基、亚环烯基、亚芳基、亚杂环基、亚杂芳基、(C1-6)亚烷基、(C1-6)亚烯基和(C1-6)亚炔基,其中亚烷基、亚烯基或亚炔基的一个或多于一个亚甲基任选地地被杂原子或诸如-O-、-S(O)p-、-N(R6)-、-C(O)-、-C(=NR’)-或-C(R’)=N-的基团替代,其中R’是H、烷基、氰基、羟基、羟基烷基、卤代烷基或全卤代烷基;
T选自氢、氰基、卤素、卤代烷基、全卤代烷基、烷基、烯基、炔基、氰基烷基、酰基、氰基烷基羰基、氰基烯基羰基、-(CRaRb)mOR6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、硫羰基、S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6或-SO3H;
R1、R2、R3、R4和R5独立选自氢、烷基、烯基、炔基、烷氧基、酰基、酰基氨基、酰基氧基、R6、-(CRaRb)mC(O)R6、-(CRaRb)mNR7R8、-(CRaRb)mO(CRaRb)nSi(R7)3、氨基羰基、烷氧基羰基氨基、烷基磺酰基氨基、氨基羰基氨基、羟基氨基、烷氧基氨基、叠氮基、氰基、卤素、羟基、羟基烷基、卤代烷基、全卤代烷基、硫羰基、羧基、烷基羧基、羧基烷基、羧基烷基氧基、烷基羧基烷基氧基-SO3H、、-S(O)pR6、-S(O)2NR7R8烷基硫代或硝基;或者当R1或R2或R3或R4或R5多于一个时,则任何2个R1或2个R2或2个R3或2个R4或2个R5独立地任选合在一起形成饱和或部分不饱和且任选具有选自O、N或S的额外杂原子的单环或双环系统;
R6选自氢、-(CRaRb)mOR6、卤素、卤代烷基、-(CRaRb)mC(O)R6、烷基、烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基或杂环基烷基;
其中烷基、烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基或杂环基烷基任选地经一个或多个选自以下的取代基取代:羟基、烷基、烷氧基、烷氧基烷基、卤素、卤代烷基、全卤代烷基、氰基、氰基烷基、氨基、羧基、羧基烷基、OR5、-OC(O)R6、-(CRaRb)mC(O)NR7R8、-NR6C(O)R6、-SR6、-S(O)pR6、-S(O)2NR7R8或-NR6S(O)2R6;
R7和R8独立选自氢、-(CRaRb)mOR6、卤代烷基、-(CRaRb)mC(O)R6、烷基、烯基、炔基、芳基、芳基烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基或杂环基烷基,或
R7和R8合在一起形成饱和或部分不饱和且任选具有选自O、N或S的额外杂原子的单环或双环系统,所述环系统进一步任选地经1至4个独立选自以下的取代基取代:卤代、烷基、烯基、炔基、硝基、氰基、-(CRaRb)mOR6、-SR6、-(CRaRb)mNR7R8、氧代、烷基磺酰基、-(CRaRb)mCOOR6、-(CRaRb)mC(O)NR7R8、环烷基、环烷基烷基、芳基、芳基烷基、杂环基、杂环基烷基、杂芳基或杂芳基烷基;
Ra和Rb独立选自氢、-OR6、卤素、卤代烷基、全卤代烷基和烷基;或
Ra和Rb合在一起形成饱和或部分不饱和且任选具有选自O、N或S的额外杂原子的单环或双环系统;
m是0-6;
n是0-3;
p是0、1或2;并且
q是1或2。
根据另一实施方案,本公开涉及式(I)化合物或其互变异构体、多晶型物、立体异构体、前药、溶剂化物、共晶体或其药学可接受的盐,其中,
环A代表不饱和的具有最多3个独立选自O、N或S的杂原子的5元环;
环B代表不饱和的、任选具有最多3个独立选自O、N或S的杂原子的6元环;
环C代表不饱和或部分不饱和的、任选具有最多3个独立选自O、N或S的杂原子的6-7元环;
每个X独立代表N或C(R1);
Y代表-C(O);
J不存在或选自亚芳基、亚杂环基、亚杂芳基、(C1-6)亚烷基、(C1-6)亚烯基或(C1-6)亚炔基;
K是键或(C1-6)亚烷基,其中任选地,亚烷基的一个或多于一个亚甲基独立地被杂原子或诸如-O-、-N(R6)-、-C(O)-的基团替代;
M选自氢、氰基、卤素、卤代烷基、全卤代烷基、烷基、烯基、炔基、氰基烷基、酰基、-(CRaRb)mOR6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、硫羰基、-S(O)pR6、-SO3H、环烷基、芳基、芳基烷基、杂环基或杂芳基;
J、K和M任选经一个或多个独立选自以下的取代基取代:氰基、硝基、酮基、氧代、卤素、卤代烷基、全卤代烷基、羟基氨基、-(CRaRb)mOR6、-(CRaRb)mC(O)R6、-OC(O)R6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、-NR6C(O)R6、硫羰基、-S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6、-SO3H、烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基;
其中烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基任选地经一个或多个选自以下的取代基取代:羟基、烷基、烷氧基、烷氧基烷基、卤素、卤代烷基、全卤代烷基、氰基、氰基烷基、氨基、羧基、羧基烷基、-OC(O)R6、-(CRaRb)mC(O)NR7R8、-NR6C(O)R6、-SR6、-S(O)pR6、-S(O)2NR7R8或-NR6S(O)2R6;
U是键或选自亚环烷基或(C1-6)亚烷基;
T选自氢、氰基、卤素、卤代烷基、全卤代烷基、烷基、烯基、炔基、氰基烷基、酰基、-(CRaRb)mOR6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、-S(O)pR6或-SO3H;
R1、R2、R3、R4和R5独立选自氢、烷基、烷氧基、酰基、酰基氨基、酰基氧基、-(CRaRb)mC(O)R6、-(CRaRb)mNR7R8、-(CRaRb)mO(CRaRb)nSi(R7)3、氨基羰基、烷氧基羰基氨基、羟基氨基、烷氧基氨基、叠氮基、氰基、卤素、羟基、羟基烷基、卤代烷基、全卤代烷基、硫羰基、羧基、烷基羧基、羧基烷基、羧基烷基氧基、烷基羧基烷基氧基-SO3H、烷基硫代、氨基磺酰基、烷基磺酰基或硝基;
R6选自氢、-(CRaRb)mOR6、卤素、卤代烷基、-(CRaRb)mC(O)R6、烷基或环烷基;
R7和R8独立选自氢、-(CRaRb)mOR6、卤代烷基、-(CRaRb)mC(O)R6、烷基或
R7和R8合在一起形成饱和或部分不饱和且任选具有选自O、N或S的额外杂原子的单环或双环系统;
Ra和Rb独立选自氢、-OR6、卤素、卤代烷基、全卤代烷基和烷基;或
Ra和Rb合在一起形成饱和或部分不饱和且任选具有选自O、N或S的额外杂原子的单环或双环系统;
m是0-6;
n是0-3;
p是0、1或2;并且
q是1或2。
根据另一实施方案,本公开涉及式(I)化合物或其互变异构体、多晶型物、立体异构体、前药、溶剂化物、共晶体或其药学可接受的盐,其中,
环A选自吡咯、咪唑、吡唑、噁唑、异噁唑、噻唑、异噻唑、三唑、噁二唑、噻二唑、二噻唑;
环B选自苯基、吡啶、哒嗪、嘧啶或吡嗪;
环C代表不饱和或部分不饱和的、任选具有最多3个独立选自O、N或S的杂原子的6-7元环;
每个X独立代表N或C(R1);
Y代表-C(O);
J不存在或选自亚芳基、亚杂环基、亚杂芳基、(C1-6)亚烷基、(C1-6)亚烯基或(C1-6)亚炔基;
K是键或(C1-6)亚烷基,其中任选地,亚烷基的一个或多于一个亚甲基独立地被杂原子或诸如-O-、-N(R6)-、-C(O)-的基团替代;
M选自氢、氰基、卤素、卤代烷基、全卤代烷基、烷基、烯基、炔基、氰基烷基、酰基、-(CRaRb)mOR6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、硫羰基、-S(O)pR6、-SO3H、环烷基、芳基、芳基烷基、杂环基或杂芳基;
J、K和M任选经一个或多个独立选自以下的取代基取代:氰基、硝基、酮基、氧代、卤素、卤代烷基、全卤代烷基、羟基氨基、-(CRaRb)mOR6、-(CRaRb)mC(O)R6、-OC(O)R6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、-NR6C(O)R6、硫羰基、-S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6、-SO3H、烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基;
其中烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基任选地经一个或多个选自以下的取代基取代:羟基、烷基、烷氧基、烷氧基烷基、卤素、卤代烷基、全卤代烷基、氰基、氰基烷基、氨基、羧基、羧基烷基、-OC(O)R6、-(CRaRb)mC(O)NR7R8、-NR6C(O)R6、-SR6、-S(O)pR6、-S(O)2NR7R8或-NR6S(O)2R6;
U是键或选自环丙烯、环丁烯、亚环己基或(C1-6)亚烷基;
T选自氢、氰基、卤素、卤代烷基、全卤代烷基烷基或-(CRaRb)mOR6;
R1、R2、R3、R4和R5独立选自氢、烷基、烷氧基、酰基、酰基氨基、酰基氧基、-(CRaRb)mC(O)R6、-(CRaRb)mNR7R8、-(CRaRb)mO(CRaRb)nSi(R7)3、氨基羰基、烷氧基羰基氨基、羟基氨基、烷氧基氨基、叠氮基、氰基、卤素、羟基、羟基烷基、卤代烷基、全卤代烷基、硫羰基、羧基、烷基羧基、羧基烷基、羧基烷基氧基、烷基羧基烷基氧基-SO3H、烷基硫代、氨基磺酰基、烷基磺酰基或硝基;
R6选自氢、-(CRaRb)mOR6、卤素、卤代烷基、-(CRaRb)mC(O)R6、烷基或环烷基;
R7和R8独立选自氢、-(CRaRb)mOR6、卤代烷基、-(CRaRb)mC(O)R6、烷基;
Ra和Rb独立选自氢、-OR6、卤素、卤代烷基、全卤代烷基和烷基;
m是0-6;
n是0-3;
p是0、1或2;并且
q是1或2。
根据另一实施方案,本公开涉及式(I)化合物或其互变异构体、多晶型物、立体异构体、前药、溶剂化物、共晶体或其药学可接受的盐,其中,
环A选自吡咯、咪唑或吡唑;
环B选自苯基、吡啶或嘧啶;
环C代表不饱和或部分不饱和的、任选具有1、2或3个独立选自O、N或S的杂原子的6-7元环;
每个X独立代表N或C(R1);
Y代表-C(O);
J不存在或选自亚芳基、亚杂环基、亚杂芳基、(C1-6)亚烷基或(C1-6)亚炔基;
K是键或(C1-6)亚烷基,其中任选地,亚烷基的一个或多于一个亚甲基独立地被杂原子或诸如-O-、-N(R6)-、-C(O)-的基团替代;
M选自氢、氰基、卤素、卤代烷基、全卤代烷基、烷基、氰基烷基、酰基、-(CRaRb)mOR6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-SO3H、芳基、杂环基或杂芳基;
J、K和M任选经一个或多个独立选自以下的取代基取代:氰基、硝基、酮基、氧代、卤素、卤代烷基、全卤代烷基、羟基氨基、-(CRaRb)mOR6、-(CRaRb)mC(O)R6、-OC(O)R6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、-NR6C(O)R6、硫羰基、-S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6、-SO3H、烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基;
其中烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基任选地经一个或多个选自以下的取代基取代:羟基、烷基、烷氧基、烷氧基烷基、卤素、卤代烷基、全卤代烷基、氰基、氰基烷基、氨基、羧基、羧基烷基、-OC(O)R6、-(CRaRb)mC(O)NR7R8、-NR6C(O)R6、-SR6、-S(O)pR6、-S(O)2NR7R8或-NR6S(O)2R6;
U是键或选自环丙烯、环丁烯、亚环己基或(C1-6)亚烷基;
T选自氢、氰基、卤素、羟基、卤代烷基、全卤代烷基烷基或-(CRaRb)mOR6;
R1、R2、R3、R4和R5独立选自氢、烷基、烷氧基、酰基、酰基氨基、酰基氧基、-(CRaRb)mC(O)R6、-(CRaRb)mNR7R8、-(CRaRb)mO(CRaRb)nSi(R7)3、叠氮基、氰基、卤素、羟基、羟基烷基、卤代烷基、全卤代烷基、硫羰基、羧基、烷基羧基、羧基烷基、羧基烷基氧基、烷基羧基烷基氧基-SO3H、烷基硫代、氨基磺酰基、烷基磺酰基或硝基;
R6选自氢、卤素、烷基、卤代烷基或环烷基;
R7和R8独立选自氢、卤代烷基或烷基;
Ra和Rb独立选自氢、-OR6、卤素、卤代烷基、全卤代烷基和烷基;
m是0-3;
n是0-3;
p是0、1或2;并且
q是1或2。
根据另一实施方案,本公开涉及式(I)化合物或其互变异构体、多晶型物、立体异构体、前药、溶剂化物、共晶体或其药学可接受的盐,其中,
环A选自吡咯、咪唑或吡唑;
环B选自苯基、吡啶或嘧啶;
环C代表不饱和或部分不饱和的、任选具有1、2或3个独立选自O、N或S的杂原子的6-7元环;
每个X独立代表N或C(R1);
Y代表-C(O);
J不存在或选自(C1-6)亚烷基、亚苯基、亚吡唑基、亚咪唑基、亚噻吩基、亚呋喃基、亚噻唑基、亚噁唑基、亚三唑基、亚吡啶基、亚哒嗪基、亚吡嗪基、亚二氢吡唑基、亚二氢咪唑基或亚四氢吡啶基;
K是键或(C1-6)亚烷基,其中任选地,亚烷基的一个或多于一个亚甲基独立地被杂原子或诸如-O-、-N(R6)-、-C(O)-的基团替代;
M选自氢、氰基、卤素、卤代烷基、全卤代烷基、烷基、氰基烷基、酰基、-(CRaRb)mOR6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、硫羰基、-S(O)pR6、-SO3H、环丙基、环丁基、环戊基、环己基、环庚基、苯基、氮杂环丁烷基、氧杂环丁烷基、吡咯烷基、二氢咪唑基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、噻嗪基二氧化物、四氢吡喃基、四氢吡啶基、吡咯基、咪唑基、呋喃基、噻唑基、噁唑基、吡喃基、吡啶基或嘧啶基;
J、K和M任选经一个或多个独立选自以下的取代基取代:氰基、硝基、酮基、氧代、卤素、卤代烷基、全卤代烷基、羟基氨基、-(CRaRb)mOR6、-(CRaRb)mC(O)R6、-OC(O)R6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、-NR6C(O)R6、硫羰基、-S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6、-SO3H、烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基;
其中烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基任选地经一个或多个选自以下的取代基取代:羟基、烷基、烷氧基、烷氧基烷基、卤素、卤代烷基、全卤代烷基、氰基、氰基烷基、氨基、羧基、羧基烷基、-OC(O)R6、-(CRaRb)mC(O)NR7R8、-NR6C(O)R6、-SR6、-S(O)pR6、-S(O)2NR7R8或-NR6S(O)2R6;
U是键或选自环丙烯、环丁烯、亚环己基或(C1-6)亚烷基;
T选自氢、氰基、卤素、羟基、卤代烷基、全卤代烷基烷基或-(CRaRb)mOR6;
R1、R2、R3、R4和R5独立选自氢、烷基、烷氧基、酰基、酰基氨基、酰基氧基、-(CRaRb)mC(O)R6、-(CRaRb)mNR7R8、-(CRaRb)mO(CRaRb)nSi(R7)3、叠氮基、氰基、卤素、羟基、羟基烷基、卤代烷基、全卤代烷基、硫羰基、羧基、烷基羧基、羧基烷基、羧基烷基氧基、烷基羧基烷基氧基-SO3H、烷基硫代、氨基磺酰基、烷基磺酰基或硝基;
R6选自氢、卤素、烷基、卤代烷基或环烷基;
R7和R8独立选自氢、卤代烷基或烷基;
Ra和Rb独立选自氢、-OR6、卤素、卤代烷基、全卤代烷基和烷基;
m是0-3;
n是0-3;
p是0、1或2;并且
q是1或2。
根据另一实施方案,本公开涉及式(Ia)化合物或其互变异构体、多晶型物、立体异构体、前药、溶剂化物、共晶体或其药学可接受的盐,
其中,
环A选自吡咯、咪唑、吡唑、噁唑、异噁唑、噻唑、异噻唑、三唑、噁二唑、噻二唑、二噻唑;
环B选自苯基、吡啶、哒嗪、嘧啶或吡嗪;
每个X独立代表N或C(R1);
J不存在或选自(C1-6)亚烷基、亚苯基、亚吡唑基、亚咪唑基、亚噻吩基、亚呋喃基、亚噻唑基、亚噁唑基、亚三唑基、亚吡啶基、亚哒嗪基、亚吡嗪基、亚二氢吡唑基、亚二氢咪唑基或亚四氢吡啶基;
K是键或(C1-6)亚烷基,其中任选地,亚烷基的一个或多于一个亚甲基独立地被杂原子或诸如-O-、-N(R6)-、-C(O)-的基团替代;
M选自氢、氰基、卤素、卤代烷基、全卤代烷基、烷基、氰基烷基、酰基、-(CRaRb)mOR6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、硫羰基、-S(O)pR6、-SO3H、环丙基、环己基、苯基、氮杂环丁烷基、氧杂环丁烷基、吡咯烷基、二氢咪唑基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、噻嗪基二氧化物、四氢吡喃基、四氢吡啶基、吡咯基、咪唑基、呋喃基、噻唑基、噁唑基、吡喃基、吡啶基或嘧啶基;
J、K和M任选经一个或多个独立选自以下的取代基取代:氰基、硝基、酮基、氧代、卤素、卤代烷基、全卤代烷基、羟基氨基、-(CRaRb)mOR6、-(CRaRb)mC(O)R6、-OC(O)R6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、-NR6C(O)R6、硫羰基、-S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6、-SO3H、烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基;
其中烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基任选地经一个或多个选自以下的取代基取代:羟基、烷基、烷氧基、烷氧基烷基、卤素、卤代烷基、全卤代烷基、氰基、氰基烷基、氨基、羧基、羧基烷基、-OC(O)R6、-(CRaRb)mC(O)NR7R8、-NR6C(O)R6、-SR6、-S(O)pR6、-S(O)2NR7R8或-NR6S(O)2R6;
U是键或选自环丙烯、环丁烯、亚环己基或(C1-6)亚烷基;
T选自氢、氰基、卤素、卤代烷基、全卤代烷基或烷基-(CRaRb)mOR6;
R1、R2、R3、R4和R5独立选自氢、烷基、烷氧基、酰基、酰基氨基、酰基氧基、-(CRaRb)mNR7R8、-(CRaRb)mO(CRaRb)nSi(R7)3、叠氮基、氰基、卤素、羟基、羟基烷基、卤代烷基、全卤代烷基、羧基、烷基羧基、羧基烷基、羧基烷基氧基、-SO3H、烷基硫代、烷基磺酰基或硝基;
R6选自氢、-(CRaRb)mOR6、卤素、卤代烷基、-(CRaRb)mC(O)R6或烷基、环烷基;
R7和R8独立选自氢、-(CRaRb)mOR6、卤代烷基、-(CRaRb)mC(O)R6、烷基;
Ra和Rb独立选自氢、-OR6、卤素、卤代烷基、全卤代烷基和烷基;
m是0-3;
n是0-3;
p是0、1或2;并且
q是1或2。
根据另一实施方案,本公开涉及式(Ib)化合物或其互变异构体、多晶型物、立体异构体、前药、溶剂化物、共晶体或其药学可接受的盐,
----代表单键或双键;
环A选自吡咯、咪唑、吡唑、噁唑、异噁唑、噻唑、异噻唑、三唑、噁二唑、噻二唑、二噻唑;
环B选自苯基、吡啶、哒嗪、嘧啶或吡嗪;
每个X独立代表N或C(R1);
J不存在或选自亚芳基、亚杂环基、亚杂芳基、(C1-6)亚烷基、亚苯基、亚吡唑基、亚咪唑基、亚噻吩基、亚呋喃基、亚噻唑基、亚噁唑基、亚三唑基、亚吡啶基、亚哒嗪基、亚吡嗪基、亚二氢吡唑基、亚二氢咪唑基或亚四氢吡啶基;
K是键或(C1-6)亚烷基,其中任选地,亚烷基的一个或多于一个亚甲基独立地被杂原子或诸如-O-、-N(R6)-、-C(O)-的基团替代;
M选自氢、氰基、卤素、卤代烷基、全卤代烷基、烷基、氰基烷基、酰基、-(CRaRb)mOR6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8,、-S(O)pR6、-SO3H、环丙基、环己基、苯基、氮杂环丁烷基、氧杂环丁烷基、吡咯烷基、二氢咪唑基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、噻嗪基二氧化物、四氢吡喃基、四氢吡啶基、吡咯基、咪唑基、呋喃基、噻唑基、噁唑基、吡喃基、吡啶基或嘧啶基;
J、K和M任选经一个或多个独立选自以下的取代基取代:氰基、硝基、酮基、氧代、卤素、卤代烷基、全卤代烷基、羟基氨基、-(CRaRb)mOR6、-(CRaRb)mC(O)R6、-OC(O)R6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、-NR6C(O)R6、硫羰基、-S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6、-SO3H、烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基;
其中烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基任选地经一个或多个选自以下的取代基取代:羟基、烷基、烷氧基、烷氧基烷基、卤素、卤代烷基、全卤代烷基、氰基、氰基烷基、氨基、羧基、羧基烷基、-OC(O)R6、-(CRaRb)mC(O)NR7R8、-NR6C(O)R6、-SR6、-S(O)pR6、-S(O)2NR7R8或-NR6S(O)2R6;
U是键或选自环丙烯、环丁烯、亚环己基或(C1-6)亚烷基;
T选自氢、氰基、卤素、卤代烷基、全卤代烷基烷基或-(CRaRb)mOR6;
R1、R2、R3、R4和R5独立选自氢、烷基、烷氧基、酰基、酰基氨基、酰基氧基、-(CRaRb)mNR7R8、-(CRaRb)mO(CRaRb)nSi(R7)3、叠氮基、氰基、卤素、羟基、羟基烷基、卤代烷基、全卤代烷基、羧基、烷基羧基、羧基烷基、羧基烷基氧基、-SO3H、烷基硫代、烷基磺酰基或硝基;
R6选自氢、-(CRaRb)mOR6、卤素、卤代烷基、-(CRaRb)mC(O)R6或烷基、环烷基;
R7和R8独立选自氢、-(CRaRb)mOR6、卤代烷基、-(CRaRb)mC(O)R6、烷基;
Ra和Rb独立选自氢、-OR6、卤素、卤代烷基、全卤代烷基和烷基;
m是0-3;
n是0-3;
p是0、1或2;并且
q是1或2。
根据另一实施方案,本公开涉及式(Ia)化合物或其互变异构体、多晶型物、立体异构体、前药、溶剂化物、共晶体或其药学可接受的盐,
其中,
环A选自吡咯、咪唑、吡唑、噁唑、异噁唑、噻唑、异噻唑、三唑、噁二唑、噻二唑、二噻唑;
环B选自苯基、吡啶、哒嗪、嘧啶或吡嗪;
每个X独立代表N或C(R1);
J不存在或选自(C1-6)亚烷基、亚苯基、亚吡唑基、亚咪唑基、亚噻吩基、亚呋喃基、亚噻唑基、亚噁唑基、亚三唑基、亚吡啶基、亚哒嗪基、亚吡嗪基、亚二氢吡唑基、亚二氢咪唑基或亚四氢吡啶基;
K是键或(C1-6)亚烷基,其中任选地,亚烷基的一个或多于一个亚甲基独立地被杂原子或诸如-O-、-N(R6)-、-C(O)-的基团替代;
M选自氢、氰基、卤素、卤代烷基、全卤代烷基、烷基、氰基烷基、酰基、-(CRaRb)mOR6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、硫羰基、-S(O)pR6、-SO3H、环丙基、环己基、苯基、氮杂环丁烷基、氧杂环丁烷基、吡咯烷基、二氢咪唑基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、噻嗪基二氧化物、四氢吡喃基、四氢吡啶基、吡咯基、咪唑基、呋喃基、噻唑基、噁唑基、吡喃基、吡啶基或嘧啶基;
J、K和M任选经一个或多个独立选自以下的取代基取代:氰基、硝基、酮基、氧代、卤素、卤代烷基、全卤代烷基、羟基氨基、-(CRaRb)mOR6、-(CRaRb)mC(O)R6、-OC(O)R6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、-NR6C(O)R6、硫羰基、-S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6、-SO3H、烷基、烯基或炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基;
其中烷基、烯基或炔基任选地经一个或多个选自以下的取代基取代:羟基、烷基、烷氧基、烷氧基烷基、卤素、卤代烷基、全卤代烷基、氰基、氰基烷基、氨基、羧基、羧基烷基、-OC(O)R6、-(CRaRb)mC(O)NR7R8、-NR6C(O)R6、-SR6、-S(O)pR6、-S(O)2NR7R8或-NR6S(O)2R6;
U是键或选自环丙烯、环丁烯、亚环己基或(C1-6)亚烷基;
T选自氢、氰基、卤素、卤代烷基、全卤代烷基或烷基-(CRaRb)mOR6;
R1、R2、R3、R4和R5独立选自氢、烷基、烷氧基、酰基、酰基氨基、酰基氧基、-(CRaRb)mNR7R8、-(CRaRb)mO(CRaRb)nSi(R7)3、叠氮基、氰基、卤素、羟基、羟基烷基、卤代烷基、全卤代烷基、羧基、烷基羧基、羧基烷基、羧基烷基氧基、-SO3H、烷基硫代、烷基磺酰基或硝基;
R6选自氢、-(CRaRb)mOR6、卤素、卤代烷基、-(CRaRb)mC(O)R6或烷基、环烷基;
R7和R8独立选自氢、-(CRaRb)mOR6、卤代烷基、-(CRaRb)mC(O)R6、烷基;
Ra和Rb独立选自氢、-OR6、卤素、卤代烷基、全卤代烷基和烷基;
m是0-3;
n是0-3;
p是0、1或2;并且
q是1或2。
根据另一实施方案,本公开涉及式(Ib)化合物或其互变异构体、多晶型物、立体异构体、前药、溶剂化物、共晶体或其药学可接受的盐,
----代表单键或双键;
环A选自吡咯、咪唑、吡唑、噁唑、异噁唑、噻唑、异噻唑、三唑、噁二唑、噻二唑、二噻唑;
环B选自苯基、吡啶、哒嗪、嘧啶或吡嗪;
每个X独立代表N或C(R1);
J不存在或选自亚芳基、亚杂环基、亚杂芳基、(C1-6)亚烷基、亚苯基、亚吡唑基、亚咪唑基、亚噻吩基、亚呋喃基、亚噻唑基、亚噁唑基、亚三唑基、亚吡啶基、亚哒嗪基、亚吡嗪基、亚二氢吡唑基、亚二氢咪唑基或亚四氢吡啶基;
K是键或(C1-6)亚烷基,其中任选地,亚烷基的一个或多于一个亚甲基独立地被杂原子或诸如-O-、-N(R6)-、-C(O)-的基团替代;
M选自氢、氰基、卤素、卤代烷基、全卤代烷基、烷基、氰基烷基、酰基、-(CRaRb)mOR6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8,、-S(O)pR6、-SO3H、环丙基、环己基、苯基、氮杂环丁烷基、氧杂环丁烷基、吡咯烷基、二氢咪唑基、四氢呋喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、噻嗪基二氧化物、四氢吡喃基、四氢吡啶基、吡咯基、咪唑基、呋喃基、噻唑基、噁唑基、吡喃基、吡啶基或嘧啶基;
J、K和M任选经一个或多个独立选自以下的取代基取代:氰基、硝基、酮基、氧代、卤素、卤代烷基、全卤代烷基、羟基氨基、-(CRaRb)mOR6、-(CRaRb)mC(O)R6、-OC(O)R6、-SR6、-(CRaRb)mCOOR6、-(CRaRb)mNR7R8、-(CRaRb)mC(O)NR7R8、-(CRaRb)mNR6C(O)NR7R8、-NR6C(O)R6、硫羰基、-S(O)2NR7R8、-NR6S(O)2R6、-S(O)pR6、-SO3H、烷基、烯基或炔基、环烷基、环烯基、环烷基烷基、芳基、杂环基或杂芳基
其中烷基、烯基或炔基任选地经一个或多个选自以下的取代基取代:羟基、烷基、烷氧基、烷氧基烷基、卤素、卤代烷基、全卤代烷基、氰基、氰基烷基、氨基、羧基、羧基烷基、-OC(O)R6、-(CRaRb)mC(O)NR7R8、-NR6C(O)R6、-SR6、-S(O)pR6、-S(O)2NR7R8或-NR6S(O)2R6;
U是键或选自环丙烯、环丁烯、亚环己基或(C1-6)亚烷基;
T选自氢、氰基、卤素、卤代烷基、全卤代烷基烷基或-(CRaRb)mOR6;
R1、R2、R3、R4和R5独立选自氢、烷基、烷氧基、酰基、酰基氨基、酰基氧基、-(CRaRb)mNR7R8、-(CRaRb)mO(CRaRb)nSi(R7)3、叠氮基、氰基、卤素、羟基、羟基烷基、卤代烷基、全卤代烷基、羧基、烷基羧基、羧基烷基、羧基烷基氧基、-SO3H、烷基硫代、烷基磺酰基或硝基;
R6选自氢、-(CRaRb)mOR6、卤素、卤代烷基、-(CRaRb)mC(O)R6或烷基、环烷基;
R7和R8独立选自氢、-(CRaRb)mOR6、卤代烷基、-(CRaRb)mC(O)R6、烷基;
Ra和Rb独立选自氢、-OR6、卤素、卤代烷基、全卤代烷基和烷基;
m是0-3;
n是0-3;
p是0、1或2;并且
q是1或2。
本发明还涉及式(I)化合物或其药学可接受的盐的制备方法。
式(I)化合物可以如以下方案所述制备:
方案1:式(I)化合物的制备
如方案1所示,式(I)化合物可以使用Suzuki偶联从式(II)和(III)的中间体制备,其中PG是H或选自甲苯磺酰基、SEM、MEM等的保护基,并且LG1是选自卤素、三氟甲磺酸酯等的离去基团。保护基(PG)的脱保护还得到式(I)化合物。
方案1中使用的式(II)和(III)的中间体可以如以下方案2和3所示制备:
方案2:式(II)化合物的制备
如方案2所示,通式(II)的中间体可以使用Suzuki偶联反应从通式(IV)和(V)的中间体的反应来制备,其中PG是H或选自甲苯磺酰基、SEM、MEM等的保护基,并且LG1和LG2是选自卤素、三氟甲磺酸酯等的离去基团。
方案3:式(III)化合物的制备
如方案3所示,通式(III)的中间体可以从通式(VI)和(VII)的中间体制备,使用N-芳基化或Buchwald偶联条件以提供通式(VIII)的中间体,其可以被转化为通式(III)的硼酸酯。
方案4:其中K是-CH2-的式(I)化合物的制备
可选地,如方案4所示,式(I)化合物还可以通过还原性胺化而从式(IX)的中间体制备,其中PG是H或选自甲苯磺酰基、SEM、MEM等的保护基。保护基(PG)的脱保护还得到式(I)化合物。
方案5:其中K是-CO的式(I)化合物的制备
可选地,如方案5所示,式(I)化合物还可以使用酰胺偶联反应条件从相应的通式(X)的中间体制备,其中PG是H或选自甲苯磺酰基、SEM、MEM等的保护基。保护基(PG)的脱保护还得到式(I)化合物。
方案6:式(IX)和(X)化合物的制备
如方案6所示,通式(IX)和(X)的中间体可以经由Suzuki偶联反应条件从通式(XI)和(III)的中间体制备,其中PG是H或选自甲苯磺酰基、SEM、MEM的保护基;Q1是-CR(O)(化合物IX)或-CO2R(化合物IXA);R是H或低级烷基,LG1是选自卤素、三氟甲磺酸酯等的离去基团。
方案7:式(II)化合物的制备
如方案7所示,通式(II)的中间体还可以使用Stille偶联反应从通式(IV)和(Va)的中间体反应制备,其中PG是H或选自甲苯磺酰基、苯磺酰基、SEM、MEM等的保护基,并且LG1和LG2是选自卤素、三氟甲磺酸酯等的离去基团。
Suzuki偶联:Suzuki偶联是钯(0)复合物、例如四(三苯基膦)钯催化的芳基-或乙烯基-硼酸与芳基-或乙烯基-卤化物的有机反应[Chemical Reviews 95(7):2457-2483]。
Stille偶联:Stille偶联是芳基-或乙烯基锡烷和芳基-或杂芳基-或乙烯基卤化物(或拟卤化物)之间C-C键形成反应,其利用各种Pd(0)复合物作为催化剂,例如四(三苯基膦)钯[J.Org.Chem.,2009,74,5599-5602]。
N-芳基化反应:N-芳基化是用于碳-氮键形成的有机化学中使用的化学反应,其可以包括Ullmann偶联条件或Buchwald-Hartwig胺化反应条件。这可以是钯催化的胺或酰胺与芳基卤化物在配体如Xantphos存在下的交联,或者是Cu(I)催化的胺或酰胺与芳基卤化物在配体如反式-N,N′-二甲基环己烷-1,2-二胺存在下的交联。该反应中使用的钯催化剂可以包括PdCl2[P(o-甲苯基)3]2、Pd(PPh3)4[Chem.Sci.2:27-50;Pure Appl.Chem,71(8):1416-1423;J.Am.Chem.Soc.2001,123(31),7727-7729]。
还原性胺化:还原性胺化是涉及羰基经由中间体亚胺转化为胺的反应形式。羰基最常见的是酮或醛。该反应使用比酮更大的对质子化亚胺反应性并且在适度酸性条件下稳定的还原剂进行。这些包括氰基硼氢化钠(NaBH3CN)和三乙酰氧基硼氢化钠(NaBH(OCOCH3)3。[Organic Reactions,1,59,2002]
酰胺偶联:酰胺偶联可以使用任何适合的酰胺偶联试剂在有机非亲核基存在下进行,所述酰胺偶联试剂例如草酰氯、亚硫酰氯、BOP-Cl、DCC、HOBt、HOAt、HATU、EDCI、氯甲酸烷基酯等,所述有机非亲核基例如三乙胺、二-异丙基乙胺、吡啶、N-甲基吡咯烷、N,N-二甲基氨基吡啶、DBU、DABCO、其他受阻的胺和吡啶。酰胺偶联反应可以在溶剂存在下在范围从-5至150的温度下进行,所述溶剂例如二氯甲烷、二氯乙烷、DMF、二甲基乙酰胺、THF、乙腈或其混合物可以使用。反应可以任选地在催化量的DMF存在下进行。酰胺偶联还可以通过在不存在溶剂或存在高沸点溶剂如甲苯、二甲苯、DMSO下加热酯和胺来进行。酰胺偶联可以在三烷基铝存在下进行(Chem.Commun.,2008,1100-1102)。
在上述过程的任何一个中只要需要或必要,式(I)化合物的任何一个可以转化为药学可接受的盐或反之亦然,或者将一种盐形式转化成另一种药学可接受的盐形式。
根据本发明的另一个实施方案提供了包含式(I)化合物的共晶体,其中含有能够用作氢键供体和/或受体的基团的式(I)化合物能够与适当共晶体形成剂形成共晶体。这些共晶体可以通过已知的共晶体形成程序而从式(I)化合物制备。此类程序包括式I化合物与共晶体形成剂在结晶条件下在溶液中研磨、加热、共升华、共熔或接触,并分离由此形成的共晶体。
根据本发明的另一实施方案提供了包含作为活性成分的式(I)化合物或其药学可接受的盐以及药学可接受的载体的药物组合物,任选与一种或多种其他药物组合物组合。
本发明另一实施方案提供了用作药剂的式(I)化合物或其药学可接受的盐。
本发明另一实施方案提供了用于治疗由BtK介导的疾患或疾病的式(I)化合物或其药学可接受的盐。
根据另一实施方案,组合物可以通过混合一种或多种本文描述的化合物或其药学可接受的盐或互变异构体与药学可接受的载体或类似物来制备,以治疗或减轻许多Btk相关病症。本公开的药物组合物可以通过本领域公知的方法生产,例如常规制粒、混合、溶解、包囊、冻干、乳化或研磨过程等。组合物可以是例如颗粒、粉末、片剂、胶囊糖浆、栓剂、注射剂、乳剂、酏剂、混悬剂或溶液剂等形式。本发明组合物可以被配制用于各种施用途径,例如通过口服施用、经粘膜施用、直肠施用、局部施用或皮下施用以及鞘内、静脉内、肌肉内、腹膜内、鼻内、眼内或室内注射。本发明化合物还可以局部而非全身方式施用,例如作为持续释放制剂的注射。
除了上述那些代表性剂型,药学可接受的赋形剂和载体是本领域技术人员公知的,并且因此包括在本发明内。此类赋形剂和载体描述于例如“Remington’sPharmaceutical Sciences”Mack Pub.Co.,New Jersey(1991)。
本发明制剂可以被设计为短效、快速释放、长效和持续释放。因此,药物制剂还可以被配制用于控释或缓释。
本公开药物组合物还可以包括例如胶束或脂质体或一些其他包囊形式,或者可以延迟释放形式施用以提供延长的贮存和/或递送效果。因此,药物制剂可以被压成小球或圆筒,并作为贮库注射剂或作为植入剂例如支架而在肌肉内或皮下植入。此类植入物可以采用已知的材料,例如硅酮和生物可降解聚合物。
根据施用方法,药物组合物可以含有例如约0.1%重量至约90%或更多重量的活性材料。当组合物包含剂量单位时,每个单位可以含有例如约0.1至500mg或更多活性成分。根据施用途径和频率,用作成人治疗的剂量范围可以是例如约0.1至1000mg每天。
可以根据以下条件来调节具体剂量:BTK相关病症,受试者年龄、体重、一般健康状况、性别和饮食,剂量间隔,施用途径,排泄率,和药物组合。含有有效量的上述剂型的任何一个都完全在常规实验范围内,并且因此完全在本发明范围内。一般而言,总日剂量可以通常范围从约1mg/kg/日至约500mg/kg/日,以单次或分开剂量。通常,人类剂量可以范围从约5mg至约100mg每日,以单次或多次剂量。
治疗有效剂量或量可以根据施用途径和剂型而改变。一些本发明的组合物是表现出高治疗指数的制剂。治疗指数是毒性效应和治疗效应的剂量比,其可以表示为LD50和ED50之比。LD50是半数致死剂量,而ED50是实现50%希望响应的最低有效剂量。LD50和ED50可以通过动物细胞培养物或实验模型中标准的药学程序来确定。
另一方面,本发明提供了包含本发明化合物和药学可接受的载体的药物组合物。药物组合物可以被配制用于特定的施用途径,例如口服施用、胃肠外施用和直肠施用等。
本发明化合物可用于治疗选自以下的适应症:自身免疫疾患,炎性疾病,变应性疾病,气道疾病例如哮喘和慢性阻塞性肺病(COPD),移植排斥;其中抗体生成、抗原呈递、细胞因子生成或淋巴器官发生是异常或不希望的疾病;包括类风湿性关节炎、全身性发作幼年特发性关节炎(SOJIA)、痛风、寻常天疱疮、特发性血小板减少性紫癜、系统性红斑狼疮、多发性硬化、重症肌无力、Sjogren综合征、自身免疫性溶血性贫血、抗中性粒细细胞质抗体(ANCA)相关的血管炎、冷球蛋白血症、血栓性血小板减少性紫癜、慢性自身免疫性荨麻疹、过敏症(特应性皮炎、接触性皮炎、过敏性皮炎)、粥样硬化、1型糖尿病、2型糖尿病、炎性肠病、溃疡性结肠炎、morbus Crohn病、胰腺炎、肾小球肾炎、Goodpasture综合征、Hashimoto甲状腺炎、Grave病、抗体介导的移植排斥(AMR)、移植物抗宿主疾病、B细胞介导的超急性、急性和慢性移植排斥;血栓栓塞性疾患、心肌梗死、心绞痛、中风、缺血性疾患、肺栓塞;造血起源的癌症,包括但不限于多发性骨髓瘤;白血病;急性髓细胞性白血病;慢性髓细胞性白血病;淋巴细胞性白血病;髓细胞性白血病;非霍奇金淋巴瘤;淋巴瘤;真性红细胞增多症;慢性淋巴细胞性白血病;套细胞淋巴瘤、特发性血小板增多症;骨髓纤维化与髓样化生;和Waldenstroem疾病。
在另一实施方案,本发明提供了治疗通过调节Btk而治疗的疾病的方法-包括施用治疗可接受量的式(I)化合物或其盐。在另一实施方案中,所述疾病选自前述列表。
本发明化合物可以与一种或多种其他治疗剂同时或之前或之后施用。本发明化合物可以通过相同或不同的施用途径单独施用,或者在相同药物组合物中与其他剂一起施用。
根据另一实施方案,本发明式(I)化合物可单独使用或者与一种或多种其他治疗剂组合使用,所述治疗剂选自BTK抑制剂,例如Ibrutinib、AVL-292、ONO-4059;基于B细胞清除蛋白的治疗剂,例如Rituxan,一种CD20抗体;钙调磷酸酶抑制剂,例如环孢菌素A或FK506;mTOR抑制剂,例如雷帕霉素、40-O-(2-羟基乙基)-雷帕霉素、CCI779、ABT578、AP23573、AP23464、AP23675、AP23841、TAFA-93、biolimus-7或biolimus-9;具有免疫抑制性质的子囊霉素,例如ABT-281、ASM981;皮质类固醇,例如可的松、地塞米松、甲基强的松龙、强的松龙、强的松;环磷酰胺;咪唑硫嘌呤;氨甲喋呤;来氟米特;特立氟胺;咪唑立宾;依那西普;英利昔单抗;化疗剂,例如帕利他赛、吉西他滨、顺铂、多柔比星、5-氟尿嘧啶、伊马替尼、达沙替尼、舒尼替尼、吉非替尼、索拉替尼、厄洛替尼、喜树碱、托泊替康、道诺霉素、依托泊苷、泰素、长春碱、硼替佐米、卡非佐米;霉酚酸或盐;麦考酚酸莫酯;15-脱氧精胍菌素或其免疫抑制性同系物、类似物或衍生物;NSAID,例如布洛芬、氟吡洛芬、萘普生、双氯芬酸、米索前列醇、舒林酸、噁丙嗪、二氟尼柳、吡罗昔康、吲哚美辛、依托度酸、非诺洛芬、酮基布洛芬、萘丁美酮钠、柳氮磺吡啶、托美丁钠、羟基氯喹、塞来考昔、伐地考昔、芦米考昔、依托考昔;JAK激酶抑制剂,例如Tofacitinib、LY-3009104、VX-509、GLPG-0634、ASP-015K、N-苄基-3,4-二羟基-亚苄基-氰基乙酰胺α-氰基-(3,4-二羟基)-]N-苄基肉桂酰胺(Tyrphostin AG 490)、灵菌红素25-C(PNU156804)、[4-(4'-羟基苯基)-氨基-6,7-二甲氧基喹唑啉](WHI-P131)、[4-(3'-溴-4'-羟基l苯基)-氨基-6,7-二甲氧基喹唑啉](WHI-P154)、[4-(3',5'-二溴-4'-羟基l苯基)-氨基-6,7-二甲氧基喹唑啉]WHI-P97、KRX-211,3-{(3R,4R)-4-甲基-3-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-哌啶-1-基}-3-氧-丙腈,以游离形式或者以药学可接受的盐形式,例如单柠檬酸盐(还称为CP-690,550);SYK抑制剂,例如福他替尼;1-磷酸鞘氨醇受体调节剂,例如FTY720(芬戈莫德);免疫抑制性单克隆抗体,例如对白细胞受体如MHC、CD2、CD3、CD4、CD7、CD8、CD25、CD28、CD40、CD45、CD52、CD58、CD80、CD86或其配体的单克隆抗体;其他免疫调节化合物,例如具有CTLA4或其突变体的细胞外域的至少一部分,例如与非CTLA4蛋白序列结合的CTLA4或其突变体的至少细胞外部分的重组结合分子,例如CTLA4lg(例如,命名为ATCC 68629)或其突变体,例如LEA29Y;黏附分子抑制剂,例如LFA-1拮抗剂、ICAM-1或-3拮抗剂、VCAM-4拮抗剂或VLA-4拮抗剂;或抗感染剂。式(I)化合物的其他组合配偶体可以选自PI3K抑制剂(例如,泛或α、β、γ、δ选择性)、TNF抑制剂、ILIγ抑制剂、IL17抑制剂、和IL6或IL受体的抑制剂。
在一个实施方案中,本发明提供了治疗或预防受试者(例如哺乳动物,即,人或非人哺乳动物)中BTK相关病症的方法,包括给受试者施用有效量的一种或多种本文描述的化合物。可以治疗的适当的非人类受试者包括家养或野生动物,伴侣动物例如狗、猫等;家畜,包括马、牛和其他反刍动物、猪、家禽、兔等;灵长类动物,例如猴,例如猕猴,包括恒河猴和食蟹猴、狨猴、塔玛琳猴等,猿,包括黑猩猩和猩猩;和啮齿类动物,例如大鼠、小鼠、沙鼠、豚鼠等。
在一个实施方案中,本发明提供了包含式(I)化合物和至少一种其他治疗剂的产品,作为供同时、分开或顺序用于疗法的组合制品。在一个实施方案中,所述疗法是BtK激酶介导的疾病或病症的治疗。以组合制品提供的产品包括,包含在相同药物组合物中的式(I)化合物和其他治疗剂的组合物,或者包含分开形式(例如,药盒的形式)的式(I)化合物和其他治疗剂的组合物。
在一个实施方案中,本发明提供了包含式(I)化合物和另一治疗剂的药物组合物。任选地,药物组合物可以包含上述药学可接受的赋形剂。
本发明还提供了用于治疗由Btk介导的疾病或病症的方法的式(I)化合物,其中式(I)化合物被制备用于与另一治疗剂一起施用。本发明还提供了用于治疗由Btk介导的疾病或病症的方法的另一治疗剂,其中其他治疗剂被制备用于与式(I)化合物一起施用。本发明还提供了用于治疗由Btk介导的疾病或病症的方法的式(I)化合物,其中式(I)化合物与另一治疗剂一起施用。本发明还提供了用于治疗由Btk介导的疾病或病症的方法的另一治疗剂,其中其他治疗剂与式(I)化合物一起施用。
实施例
本发明进一步通过以下实施例阐明,实施例决不应该被解释为进一步的限制。本领域技术人员将容易领会描述的具体方法和结果仅仅是实例说明性的。中间体以及最终化合物的结构通过质子的核磁共振光谱(1H NMR)和LCMS确证。
中间体IV-1至IV-5的合成:
如下表(表-1)中提及的参考文献中描述的,合成以下中间体。
表-1
中间体VII-1:8-环丙基-3,4-二氢-2H-1,4-苯并氧杂吖庚因-5-酮
步骤-I:4-氯-2-羟基-苯甲酸甲酯(VII-1-I):向4-氯代水杨酸(75g,435.6mmol)在无水DMF(871mL)中的溶液顺序添加Cs2CO3(70.7g,217.8mmol)和MeI(27.5mL,439.9mmol)。反应混合物在室温搅拌过夜。向反应混合物添加冰冷水(3L),并过滤沉淀的固体并干燥以提供VII-1-I(75g,92%产率)。
步骤-II:2-[2-(叔丁氧基羰基氨基)乙氧基]-4-氯-苯甲酸甲酯(VII-1-II):向VII-1-I(126.8g,679.6mmol)在无水DMF(1L)中的溶液添加无水K2CO3(187.5g,1.36mol)并在室温搅拌30min。最后,向其添加N-(2-溴代乙基)氨基甲磺酸叔丁酯(228.4g,1.02mol)在THF(360mL)中的溶液,并在65℃搅拌反应混合物16h。然后通过硅藻土过滤反应混合物并减压浓缩滤液。向残余物添加二乙醚(1.5L)并用水(1L);盐水(1L)洗涤,经无水Na2SO4干燥,过滤并减压浓缩以提供粗中间体VII-1-II(242g);其没有进一步纯化而使用。
步骤-III:8-氯-3,4-二氢-2H-1,4-苯并氧杂吖庚因-5-酮(VII-1-III)
在0℃下向粗VII-1-II(242g)在CH2Cl2(500mL)中的溶液添加TFA(250mL,3.68mol),并在室温下搅拌反应混合物16h。减压去除溶剂并干燥残余物。向其添加甲苯(500mL)和Et3N(512mL,3.68mol),并使反应混合物回流16h。最后,减压去除溶剂并向残余物添加冰冷水(500mL)。过滤沉淀的固体并干燥。其然后在二乙醚(200mL)中搅拌并过滤以提供VII-1-III(40g,两个步骤产率29%)。LCMS:m/z 198(M+1)+。
步骤-IV:8-环丙基-3,4-二氢-2H-1,4-苯并氧杂吖庚因-5-酮(VII-1):将氩经VII-1-III(10g,50.7mmol)、环丙基硼酸(13.1g,152mmol)、无水K3PO4(32g,152.3mmol)和三环己基膦(5.7g,20.3mmol)在甲苯:水(150mL+20mL)中的混悬液吹扫30min,随后添加Pd(OAc)2(2.3g,10.1mmol)。然后在110℃下搅拌反应混合物16h。反应完成之后,反应混合物经硅藻土过滤并用EtOAc(50mL×3)洗涤残余物。合并的有机层在减压下浓缩并通过硅胶柱色谱(己烷中25%丙酮)纯化残余物以提供INT VII-1(8g,77%产率)。LCMS;m/z:204(M+1)+。1H NMR(CDCl3,400MHz)δ0.73-0.77(m,2H);0.99-1.04(m,2H);1.86-1.90(m,1H);3.50(q,J=4.8Hz,2H);4.37(两个d,J=4.4Hz,2H);6.80(d,J=1.6Hz,1H);6.81(dd,J1=1.2Hz,J2=8.8Hz,1H);7.35(bs,1H);7.89(d,J=8.8Hz,1H)。
如下表(表-2)中提及的参考文献中描述的,合成以下中间体VII-2至VII-4。
表-2
中间体VII-5:8-环丙基-6-氟-3,4-二氢-2H-1,4-苯并氧杂吖庚因-5-酮
步骤-I:4-氯-2,6-二氟-苯甲酸甲酯(VII-5-I):如上针对VII-1-1的合成描述的合成中间体VII-5-I;使用4-氯-2,6-二氟苯甲酸(产率:93%)。
步骤-II:2-[2-(叔丁氧基羰基氨基)乙氧基]-4-氯-6-氟-苯甲酸甲酯(VII-5-II):将VII-5-I(5g,24.2mmol)和N-(2-羟基乙基)氨基甲磺酸叔丁酯(4.7g,29.0mmol)在无水THF(50mL)中的溶液冷却至-40℃,并经30min向其分部分添加NaH(用己烷洗涤)(0.76g,31.5mmol)。经1h加热反应混合物至-20℃并使用饱和NH4Cl溶液(100mL)猝灭。使用EtOAc(50mL)进行提取;用盐水(100mL)洗涤合并的有机层,经无水Na2SO4干燥,过滤并减压浓缩。通过硅胶柱色谱(己烷中12%EA)纯化残余物以提供VII-5-II(5.2g,61%产率)。LCMS;m/z:348(M+1)+。
步骤-III:8-氯-6-氟-3,4-二氢-2H-1,4-苯并氧杂吖庚因-5-酮(VII-5-III):向VII-5-II(4.8g,13.8mmol)在MeOH(50mL)中的溶液添加NaOH水溶液(30mL H2O中2.8g,69.2mmol)并在60℃下搅拌反应混合物1h。减压去除MeOH并向反应混合物添加10%柠檬酸溶液以使之成酸性(pH<4)。使用EtOAc(50mL×3)进行提取;合并的有机层用水(100mL)、盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。然后残余物在二氧己环(50mL)中的1MHCl中室温搅拌3h。最后,减压去除二氧己环;用乙醚(30mL×2)洗涤残余物并干燥。然后将获得的固体溶解于DMF(30mL),向其顺序添加N-甲基吗啉(4.2mL;38.7mmol)和HATU(7.4g,19.4mmol)。室温下搅拌反应混合物16h。最后,向反应混合物添加冰冷水,得到的固体经过滤并干燥以提供VII-5-III(1.8g,60%产率)。LCMS;m/z:216(M+1)+。
步骤-IV:8-环丙基-6-氟-3,4-二氢-2H-1,4-苯并氧杂吖庚因-5-酮(VII-5):
如针对VII-1的合成所描述的合成了中间体VII-5;使用中间体VII-5-III(产率:80%)。LCMS;m/z:222(M+1)+。1H NMR(CDCl3,400MHz)δ0.65-0.68(m,2H);1.01-1.04(m,2H);1.81-1.86(m,1H);3.40(q,J=5.6Hz,2H);4.27(t,J=5.6Hz,2H);6.57(s,1H);6.62(d,J=11.2Hz,1H);7.28(bs,1H)。
可选地,还可以如下所述使用4-溴-2,6-二氟苯甲酸合成中间体VII-5。
步骤-I:4-溴-2,6-二氟-苯甲酸甲酯(VII-5-I-a):如针对VII-5-I合成所描述的。
步骤-II:4-溴-2-[2-(叔丁氧基羰基氨基)乙氧基]-6-氟-苯甲酸甲酯(VII-5-II-a):如针对VII-5-II合成所描述的。
步骤-III:8-溴-6-氟-3,4-二氢-2H-1,4-苯并氧杂吖庚因-5-酮(VII-5-III-a):如针对VII-5-III-a合成所描述的。
步骤-IV:8-环丙基-6-氟-3,4-二氢-2H-1,4-苯并氧杂吖庚因-5-酮(VII-5):如上所述(VII-5-III至VII-5)。
VII-5的可选合成:
步骤-I:4-溴-2,6-二氟-苯甲酸叔丁酯(VII-5-IV):在-78℃下经15min时段向二异丙基胺(17.9mL,0.12mol)在无水THF中的溶液逐滴添加n-BuLi(45.5mL,0.11mol,己烷中2.5M),得到的溶液在-78℃下搅拌30min。向其逐滴添加THF(30mL)中的1-溴-3,5-二氟苯(20.0g,0.10mol),搅拌1h。最后,向其添加Boc-酸酐(26.0mL,0.11mol)并使反应混合物经2h时段缓慢回到室温。在反应完成之后,用水(100mL)稀释,并使用二乙醚(300×2)进行提取。合并的有机层用水(250mL)、盐水(250mL)洗涤,并经无水Na2SO4干燥,过滤并减压浓缩以提供为棕色液体的粗VII-5-IV(26g),其没有任何纯化而用于下一步骤。1H NMR(DMSO-d6,400MHz)δ1.42(s,9H),7.63(d,J=8.0Hz,2H)。
步骤-II:4-溴-2-[2-(叔丁氧基羰基氨基)乙氧基]-6-氟-苯甲酸叔丁酯(VII-5-V):将VII-5-IV(26g,88.7mmol)和N-(2-羟基乙基)氨基甲磺酸叔丁酯(15.7g,97.6mmol)在无水THF(400mL)中的溶液冷却至-10℃;并经30min向其分部分添加NaH(油中60%混悬液)(5.3g,133mmol)。搅拌反应混合物1h并使用饱和NH4Cl溶液(300mL)猝灭。使用EtOAc(300mL×2)进行提取;合并的有机层用盐水(350mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩以提供为棕色粘稠油的希望产物VII-5-V(32g),其没有任何纯化而用于下一步骤。LCMS:m/z:278[M-(2×BOC)]+(67%纯)。1H NMR(CDCl3,400MHz)δ1.44(s,9H);1.56(s,9H);3.51(q,J=5.4Hz,2H);4.07(t,J=5.3Hz,2H);5.07(bs,1H);6.84(bs,1H);6.93(dd,J1=1.4Hz,J2=8.1Hz,1H)。
步骤-III:2-(2-氨基乙氧基)-4-溴-6-氟-苯甲酸(盐酸盐)(VII-5-VI):向化合物VII-5-V(32g)在无水CH2Cl2(400mL)中的溶液添加4M HCl在二氧己环(55mL)中的溶液;室温搅拌反应混合物16h。最后,减压去除溶剂;残余物用二乙醚(50mL×2)洗涤并干燥以提供为白色固体的希望化合物VII-5-VI(17g)。LCMS:m/z:278(M+1)+。1H NMR(DMSO-d6,400MHz)δ3.10-3.16(m,2H);4.33(t,J=6.0Hz,2H);7.30-7.35(芳香族,2H);8.11(bs,3H);13.60(bs,1H)。
步骤-IV:8-溴-6-氟-3,4-二氢-2H-1,4-苯并氧杂吖庚因-5-酮(VII-5-III-a):如VII-5-III合成的步骤-III中所述,使中间体VII-5-VI经历分子内酰胺偶联环化反应条件;以提供VII-5-III-a。
步骤-V:如针对VII-5合成的步骤-IV中所描述(从VII-5-III)。
中间体VII-6:8-环丙基-3,4-二氢-2H-吡啶并[2,3-f][1,4]氧杂吖庚因-5-酮
步骤-I:N-[2-[(5-溴-2-氰基-3-吡啶基)氧基]乙基]氨基甲酸叔丁酯(VII-6-I):向5-溴-3-氟吡啶甲腈(7.5g,37.7mmol)和N-(2-羟基乙基)氨基甲酸叔丁酯(7.3g,45.2mmol)在无水DMF(50mL)中的溶液添加无水K2CO3(10.0g,75.4mmol),并在100℃搅拌反应混合物7h。然后向其添加冰冷水(100mL),得到的固体经过滤并干燥以提供VII-6-I(7.1g,55%产率)。LCMS;m/z:342(M+1)+。
步骤-II:5-溴-3-[2-(叔丁氧基羰基氨基)乙氧基]吡啶-2-羧酸(VII-6-II):向VII-6-I(5g,20.7mmol)在EtOH(100mL)中的溶液添加NaOH水溶液(40mL水中4.1g,103.7mmol)并使反应混合物回流16h。然后减压去除EtOH,使用10%柠檬酸溶液酸化残余物。使用EtOAc(50mL×2)进行提取;合并的有机层用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩以提供VII-6-II(3.6g,68%产率)。LCMS;m/z:362(M+1)+。
步骤-III:8-溴-3,4-二氢-2H-吡啶并[2,3-f][1,4]氧杂吖庚因-5-酮(VII-6-III):在0℃下向VII-6-II(3.6g,9.9mmol)在MeOH(60mL)中的溶液吹扫HCl气体3h。然后回流反应混合物16h。减压去除溶剂并干燥残余物。然后在1,4-二氧己环(50mL)和TEA(13.8mL,99mmol)中回流16h。最后,减压去除溶剂和并使残余物经受硅胶柱色谱(EtOAc)以提供VII-6-III(1g,41%产率)。LCMS;m/z:243(M+1)+;245(M+3)+。
步骤-IV:8-环丙基-3,4-二氢-2H-吡啶并[2,3-f][1,4]氧杂吖庚因-5-酮(VII-6):使用中间体VII-6-III,如针对VII-1合成所述合成中间体VII-6(产率:80%)。LCMS;m/z:205(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.79-0.85(m,2H);1.02-1.07(m,2H);1.96-2.01(m,1H);3.29-3.33(m,2H);4.23(t,J=5.2Hz,2H);7.10(s,1H);8.24(s,1H);8.41(bs,1H)。
中间体VIII-1:4-(3-溴-2-甲基-苯基)-8-环丙基-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮
步骤-I:将氩经VII-1(9g,44.33mmol)、2,6-二溴甲苯(16.6g,66.5mmol)、N,N-二甲基环己烷-1,2-二胺(2.52g,17.7mmol)和K3PO4(18.8g,88.66mmol)在二氧己环中的溶液吹扫30min,然后添加碘化亚铜(3.37g,3.37mmol)。然后在100℃下加热得到的反应混合物16h。反应完成之后(通过TLC监测),滤掉固体,并使用EtOAc(150mL)稀释滤液。有机层用水(100mL)、盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。如此获得的粗产物通过硅胶柱色谱纯化(使用己烷中20%EtOAc)以提供标题化合物VIII-1(7g,44%);LCMS:m/z 372(M+1)+。1H NMR(CDCl3,400MHz)δ0.74-0.78(m,2H);1.02-1.06(m,2H);1.80-1.93(m,1H);2.36(s,3H);3.80-3.82(m,2H);4.42-4.44(m,2H);6.75(s,1H);6.90(d,J=8.0Hz,1H);7.11-7.19(芳香族,2H);7.55(d,J=8.0Hz,1H);7.76(d,J=8.0Hz,1H)。
使用如针对VIII-1合成描述的相似程序从其相应中间体还合成了以下三个中间体。
表-3
中间体VIII-5:[2-溴-6-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)苯基]甲基乙酸酯
步骤-I:2-溴-6-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)苯甲醛(VIII-5-I):向8-环丙基-3,4-二氢-2H-1,4-苯并氧杂吖庚因-5-酮(VII-1)(2.0g,9.85mmol)在1,4-二氧己环(10ml)中的搅拌溶液添加2,6-二溴苯甲醛(5.14g,19.7mmol)、xanthphos(0.171g,0.29mmol)和碳酸铯(4.50g,13.79mmol,1.4当量)。使用氩吹扫反应混合物45分钟,然后添加Pd(dba)2(0.113g,1.97mmol)。在100℃搅拌得到的反应混合物18h。冷却反应混合物至室温并通过硅藻土过滤,并用乙酸乙酯(20mL×2)洗涤。合并的有机层用水(50mL);盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩以提供粗产物,其使用硅胶柱色谱(己烷中20-25%乙酸乙酯)进一步纯化以提供标题化合物VIII-5-I(1.60g,43%)。LCMS:m/z 386.0(M+1)+。
步骤-II:4-[3-溴-2-(羟基甲基)苯基]-8-环丙基-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(VIII-5-II):在20℃下向VIII-5-I(1.6g,4.14mmol)在THF(12mL)中的搅拌溶液添加超级氢化物(THF中1M溶液,8.3mL,8.29mmol)。15min之后,使用饱和NH4Cl溶液(30mL)猝灭反应混合物并使用EtOAc(30mL×2)萃取。合并的有机层用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并减压蒸发以提供粗产物,其使用硅胶柱色谱(己烷中25-30%EtOAc)进一步纯化以提供标题化合物VIII-5-II(1.35g,85%)。LCMS:m/z 388(M+1)+。
步骤-III:[2-溴-6-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)苯基]甲基乙酸酯(VIII-5):室温下向VIII-5-II(1.30g,3.35mmol)在CH2Cl2(15mL)中的搅拌溶液添加TEA(1.0mL,5.02mmol)、乙酸酐(0.62mL,6.71mmol)和DMAP(50mg,0.35mmol)。搅拌2h之后,减压蒸发挥发物,使用硅胶柱色谱(己烷中15-25%乙酸乙酯)纯化残余物以提供标题化合物VIII-5(1.37g,95%)。LCMS:m/z 430(M+1)+。1H NMR(CDCl3,400MHz)δ0.74-0.78(m,2H);1.02-1.07(m,2H);1.86-1.93(m,1H);2.05(s,3H);3.73-3.79(m,1H);3.87-3.94(m,1H);4.40-4.50(m,2H);5.11(d,J=12.0Hz,1H);5.33(d,J=12.0Hz,1H);6.74(d,J=1.6Hz,1H);6.89(dd,J1=1.6Hz,J2=8.4Hz,1H);7.24-7.28(芳香族,1H);7.32(t,J=8.0Hz,1H);7.63(td,J1=1.2Hz,J2=8.0Hz,1H);7.75(d,J=8.0Hz,1H)。
中间体VIII-6:[2-溴-6-(6-环丙基-1-氧-2-异喹啉基)苯基]甲基乙酸酯
步骤-I:2-溴-6-(6-环丙基-1-氧-2-异喹啉基)苯甲醛(VIII-6-I)
使用VII-3和2,6-二溴苯甲醛,如针对VIII-1合成所描述的合成中间体VIII-6-I。
步骤-II和III:使用VIII-6-I,如针对VIII-5(步骤-II和步骤-III)合成所描述的合成中间体VIII-6。LCMS:m/z 412(M+1)+。1H NMR(CDCl3,400MHz)δ0.83-0.87(m,2H);1.08-1.13(m,2H);1.95(s,3H);2.00-2.07(m,1H);4.97(d,J=12.4Hz,1H);5.22(d,J=12.4Hz,1H);6.49(d,J=7.2Hz,1H);7.00(d,J=7.2Hz,1H);7.19-7.22(芳香族,2H);7.29(s,1H);7.36(t,J=8.0Hz,1H);7.72(d,J=8.0Hz,1H);8.29(d,J=8.4Hz,1H)。
从VII-4开始,使用如针对VIII-6合成所描述的相似反应顺序和程序还合成了中间体VIII-7。
表-4
中间体VIII-8:4-[3-溴-2-[[叔丁基(二甲基)甲硅烷基]氧基甲基]苯基]-8-环丙基-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮
步骤-I:中间体VIII-5-II(3.1g,7.98mmol)溶解于无水CH2Cl2(50mL),在0℃下向其顺序添加咪唑(1.36g,19.96mmol)和TBDMSCl(1.56g,10.4mmol)。2h之后,减压去除溶剂并使残余物经受硅胶柱色谱(己烷中10%EA)以提供希望化合物VIII-8(4g,定量产量)。LCMS:m/z;502.1(M+1)+。
使用如针对中间体VIII-5合成所描述的相似反应顺序和程序合成以下两种中间体。
表-5
中间体III-1的合成:8-环丙基-4-[2-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮
步骤-I:使用氩吹扫VIII-1(7g,18.81mmol)、双频哪醇基二硼(5.7g,22.58mmol)和乙酸钾(5.54g,56.45mmol)在DMSO(100mL)中的溶液30分钟,然后添加Pd(dppf)Cl2(0.41g,0.56mmol)。在80℃加热得到的反应混合物16h。反应完成之后(通过TLC监测),过滤固体并用EtOAc(50mL×2)洗涤残余物。合并的有机层用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。通过硅胶柱色谱(己烷中50%EtOAc)纯化如此获得的粗产物以提供标题化合物III-1(8g,前药连同脱溴的起始材料的混合物);LCMS:m/z 420.2(M+1)+。1H NMR(CDCl3;400MHz)0.74-0.78(m,2H);1.00-1.04(m,2H);1.26(s,12H);1.85-1.95(m,1H);2.48(s,3H);3.68-3.88(m,2H);4.43(t,J=5.1Hz,2H);6.74(s,1H);6.89(d,J=8.0Hz,1H);7.23-7.29(芳香族,2H);7.76-7.79(芳香族,2H)。
使用如针对III-1所述相似的程序合成以下中间体。
表-6
中间体II-1:4-[[4-[4-氯-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]苯基]甲基]哌嗪-1-羧酸叔丁酯
步骤-I:4-[(4-溴代苯基)甲基]哌嗪-1-羧酸叔丁酯(V-1-I):向4-溴代苄基溴化物(5g,20mmol)和N-Boc哌嗪(4.47g,24mmol)在DMF(25mL)中的混合物添加K2CO3(5.52g,40mmol)并在室温搅拌反应混合物16h。反应完成之后(通过TLC监测),将反应混合物倒入水(100mL)并用乙酸乙酯(30mL×3)萃取。合并的有机层用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩以提供粗产物V-1-I。该化合物没有纯化而用于下一步骤。
步骤-II:4-[[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基]甲基]哌嗪-1-羧酸叔丁酯(V-1)
使用氩吹扫V-1-I(7.5g,21.1mmol)、双频哪醇基二硼(8g,31.7mmol)和KOAc(4.1g,42.2mmol)在DMSO(50mL)中的混合物30min并添加PdCl2(dppf)(0.77g,1.06mmol)。在90℃加热得到的反应混合物16h。反应完成之后(通过TLC监测),添加水(100mL)至反应混合物并使用EtOAc(50mL×3)进行萃取。合并的有机层用水(100mL);盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。通过硅胶柱色谱(CH2Cl2中2-20%MeOH)纯化粗产物以提供标题化合物V-1(7g,82%)。LCMS:m/z403.3(M+1)+。
步骤-III:4-[[4-[4-氯-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]苯基]甲基]哌嗪-1-羧酸叔丁酯(II-1):将IV-I(0.5g,1.15mmol)和V-1(0.32g,0.8mmol)的混合物溶解于二氧己环:水(4:1,12mL)并向其添加K2CO3(0.31g,2.3mmol)。使用氩吹扫反应混合物30分钟,随后添加PdCl2(dppf)(0.09g,0.11mmol)。在100℃加热得到的反应混合物16h。反应完成之后(通过TLC监测),其用水(30mL)和EtOAc(50mL)洗涤。分离有机层,用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。通过硅胶柱色谱(己烷中15%EtOAc)纯化粗产物以提供标题化合物II-I(0.435g,65%);LCMS:m/z 582.2(M+1)+。
使用如针对II-1合成描述的相似反应顺序和程序从其相应的起始材料合成以下中间体。
表-7
中间体II-5:4-[4-(4-氯-7H-吡咯并[2,3-d]嘧啶-6-基)苯基]哌嗪-1-羧酸叔丁酯
4-[4-[4-氯-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]苯基]哌嗪-1-羧酸叔丁酯(中间体II-5)的合成:使氩经IV-1(1.5g,3.46mmol)、4-[4-(4,4,5,5-四甲基-[1,3,2]二氧杂硼烷-2-基)-苯基]-哌嗪-1-羧酸叔丁酯V-2(如WO2003/041649所述制备)(1.34g,3.46mmol)和粉末K2CO3(0.954g,6.92mmol)在二氧己环(24mL)和水(6mL)混合物中的溶液吹扫15分钟。向该混合物添加PdCl2(dppf)(0.282g,0.346mmol),然后在90℃搅拌8h。减压去除溶剂并通过硅胶柱色谱(己烷中30%EtOAc)纯化得到的残余物以提供标题化合物II-5(0.55g,30%);LCMS:m/z 568.1(M+1)+。
中间体II-6:4-[4-[4-氯-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]吡唑-1-基]哌啶-1-羧酸叔丁酯:
步骤-I:4-(4-碘代吡唑-1-基)哌啶-1-羧酸叔丁酯(Va-1-I):在0℃下向4-碘代吡唑(5g,25.7mmol)在无水DMF(30mL)中的溶液分部分添加NaH(60%混悬液,1.13g,28.4mmol);其被搅拌1h。最后,向反应混合物添加4-甲磺酰基哌啶-1-羧酸叔丁酯(CAS:141699-59-4)(6.5g,32.7mmol),并使其在100℃搅拌16h。其然后被冷却并使用饱和NH4Cl溶液(100mL)猝灭。使用EtOAc(50mL×2)进行萃取;合并的有机层用水(100mL);盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩以提供粗产物,其通过硅胶柱色谱(己烷中20%EtOAc)进一步纯化以提供标题化合物Va-1-I(4g,41%)。LCMS:m/z 378.1(M+1)+。
步骤-II:4-(4-三丁基甲锡烷基吡唑-1-基)哌啶-1-羧酸叔丁酯(Va-1):在-78℃下向Va-1-I(1.5g,3.97mmol)在无水THF(15mL)中的溶液添加n-BuLi(THF中1.6M,5mL,7.96mmol),并搅拌1h。最后,在-78℃下向反应混合物添加n-Bu3SnCl(2.2mL,7.96mmol)并使反应混合物经2h温至室温。向反应混合物添加饱和NH4Cl溶液(30mL),并使用EtOAc(30mL×2)进行萃取。合并的有机层用水(50mL);盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩以提供粗产物,其通过硅胶柱色谱(使用己烷中10%EtOAc)进一步纯化以提供标题化合物Va-1(0.5g,23%)。LCMS:m/z 541.3(M+1)+。
步骤-III:4-[4-[4-氯-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]吡唑-1-基]哌啶-1-羧酸叔丁酯(II-6):使氩经IV-1(0.25g,0.56mmol)和Va-1(0.47g,0.86mmol)在DMF(2.5mL)中的溶液吹扫15min。最后,向其添加PdCl2(PPh3)2(0.02mg,0.03mmol)并在100℃搅拌反应混合物3h。然后向其添加水(25mL),使用EtOAc(15mL×2)进行萃取。合并的有机层用水(30mL);盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩以提供粗产物,其通过硅胶柱色谱(使用己烷中30%EtOAc)进一步纯化以提供标题化合物II-6(0.17g,23%)。LCMS:m/z 557.1(M+1)+。1H NMR(DMSO-d6;400MHz)δ1.42(s,9H);1.75-1.90(m,2H);2.02-2.10(m,2H);2.34(s,3H);2.95(bs,2H);4.02-4.08(m,2H);4.44-4.49(m,1H);6.88(s,1H);7.38(d,J=8.0Hz,2H);7.71(d,J=8.4Hz,2H);7.77(s,1H);8.21(s,1H);8.80(s,1H)。
使用如针对II-6所述的相似反应顺序和程序合成以下中间体。
表-8
中间体II-12:4-[4-[4-氯-1-(p-甲苯基磺酰基)吡咯并[2,3-b]吡啶-2-基]苯基]-3,6-二氢-2H-吡啶-1-羧酸叔丁酯
步骤-I:使氩经IV-2(0.84g,1.95mmol)、V-3(0.75g,1.95mmol)(如WO2009114180所述合成)和K2CO3(0.53g,3.9mmol)在二氧己环-水(15mL+4mL)中的溶液吹扫30min。最后,向反应混合物添加PdCl2(dppf)-DCM(0.158g,0.19mmol)并再次吹扫氩5min。然后使其在100℃搅拌3h。然后减压去除溶剂并使粗产物经受硅胶柱色谱(己烷中50%EtOAc)以提供II-12(0.96g,87%产率)。LCMS:m/z;564.1(M+1)+。1H NMR(CDCl3;400MHz)δ1.53(s,9H);2.35(s,3H);2.55-2.65(m,2H);3.60-3.70(m,2H);4.10-4.20(m,2H);6.18(bs,1H);6.61(s,1H);7.17-7.21(芳香族,3H);7.48(d,J=8.0Hz,2H);7.53(d,J=8.0Hz,2H);7.76(d,J=8.0Hz,2H);8.35(d,J=4.8Hz,1H)。
中间体II-13:4-[4-[4-氯-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]苯基]哌啶-1-羧酸叔丁酯
步骤-I:4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基]哌啶-1-羧酸叔丁酯(V-4):向V-3(1.4g,3.64mmol)在EtOAc(15mL)中的溶液添加Pd/C(0.14g),并在H2气氛(气球压力)下搅拌反应混合物16h。最后,滤掉催化剂并减压浓缩滤液以提供V-4(1.3g,91%产率)。LCMS:m/z;332.1[(M-tert-Bu)+1]+。
步骤-II:4-[4-[4-氯-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]苯基]哌啶-1-羧酸叔丁酯(II-13):使用中间体V-4和IV-1,如针对II-12合成所述合成标题化合物。LCMS:m/z;567.3(M+1)+。1H NMR(CDCl3;400MHz)δ1.24(s,9H);1.64-1.74(m,2H);1.88-1.96(m,3H);2.34(s,3H);2.72-2.92(m,2H);4.20-4.40(m,2H);6.58(s,1H);7.25(d,J=8.4Hz,2H);7.31(d,J=8.0Hz,2H);7.45(d,J=8.0Hz,2H);7.81(d,J=8.4Hz,2H);8.82(s,1H)。
中间体II-14:2-[4-[4-氯-1-(p-甲苯基磺酰基)吡咯并[2,3-b]吡啶-2-基]苯基]吗啉-4-羧酸叔丁酯
步骤-I:6-(4-溴代苯基)吗啉-3-酮(V-5-II):向V-5-I(CAS:41147-82-4)(4.5g,20.0mmol)在CH2Cl2(100mL)中的溶液添加NaOH水溶液(1g,100mL,25.0mmol)并将其冷却至0℃。向其添加氯代乙酰氯(2.5mL,31.0mmol)并在室温下搅拌反应混合物16h。最后,分离有机层并用1N HCl(50mL)、饱和NaHCO3溶液(50mL)、盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。将获得的残余物溶解于EtOH(50mL),向其室温下滴加EtOH(25mL)中的KOH(2.0g,35mmol)。使其搅拌16h,然后浓缩。向残余物添加水,并使用CH2Cl2(50ml×2)进行提取。合并的有机层用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。将残余物在二乙醚(30mL)中搅拌并过滤以提供V-5-II(1.7g,62%纯)。LCMS:m/z;256(M+1)+。
步骤-II:2-(4-溴代苯基)吗啉-4-羧酸叔丁酯(V-5-III):向V-5-II(1.7g,6.6mmol)在无水THF(10mL)中的溶液添加THF(37.8mL,39mmol)中的1M BH3并使反应混合物回流16h。然后使用浓HCl(10mL)猝灭并回流1h。减压去除溶剂并向残余物添加1N NaOH溶液(50mL)。使用EtOAc(25mL×2)进行萃取。合并的有机层用水(30mL);盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩以提供粗产物,其溶解于CH2Cl2(20mL)。向其添加TEA(1.9mL,14.0mmol)和(Boc)2O(1.9g,8.6mmol)。搅拌反应混合物16h之后,减压去除溶剂并使用硅胶柱色谱纯化残余物以提供V-5-III(1.5g,两步产率19%)。LCMS:m/z;286[(M-tert-Bu)+1]+。
步骤-III:2-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基]吗啉-4-羧酸叔丁酯(V-5):如针对II-1合成的步骤-II所述合成该中间体(58%产率)。LCMS:m/z;334[(M-tert-Bu)+1]+。
步骤-IV:2-[4-[4-氯-1-(p-甲苯基磺酰基)吡咯并[2,3-b]吡啶-2-基]苯基]吗啉-4-羧酸叔丁酯(II-14):如针对II-12合成所述(使用V-5和IV-2,35%产率)。LCMS:m/z;568.2(M+1)+。
中间体II-15:3-[[5-[4-氯-1-(p-甲苯基磺酰基)吡咯并[2,3-b]吡啶-2-基]-2-吡啶基]氧基]氮杂环丁烷-1-羧酸叔丁酯
步骤-I:3-[(5-溴-2-吡啶基)氧基]氮杂环丁烷-1-羧酸叔丁酯(Va-2-I):1-Boc-3-羟基氮杂环丁烷(4.0g,23mmol)溶解于DMF(30mL)并冷却至0℃。向其添加NaH(60%混悬液,0.83g,34mmol)并搅拌15min。最后,向其添加5-溴-2-碘代吡啶(6.5g,23mmol)在DMF(20mL)中的溶液,并在70℃搅拌反应混合物5h。然后使其冷却至室温并使用EtOAc(200mL)稀释。有机层用水(150mL×2)、盐水(150mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。获得的残余物通过硅胶柱色谱(己烷中10%EtOAc)纯化以提供Va-2-I(4.5g,59%产率)。LCMS:m/z;329.
步骤-II和步骤-III:3-[(5-溴-2-吡啶基)氧基]氮杂环丁烷-1-羧酸酯(Va-2)和3-[[5-[4-氯-1-(p-甲苯基磺酰基)吡咯并[2,3-b]吡啶-2-基]-2-吡啶基]氧基]氮杂环丁烷-1-羧酸叔丁酯(II-15):按照如针对中间体II-6合成的步骤-II和III中描述的相似程序合成II-15。LCMS:m/z;555.3(M+1)+。1H NMR(CDCl3;400MHz)δ1.47(s,9H);2.35(s,3H);4.03-4.07(m,2H);4.36-4.40(m,2H);5.38-5.45(m,1H);6.61(s,1H);6.89(d,J=8.4Hz,1H);7.20(d,J=8.4Hz,2H);7.23(d,J=5.2Hz,1H);7.73(d,J=8.4Hz,2H);7.85(dd,J1=2.4Hz,J2=8.4Hz,1H);8.21(d,J=2.0Hz,1H);8.37(d,J=5.6Hz,1H)。
中间体II-16:4-[5-[4-氯-1-(p-甲苯基磺酰基)吡咯并[2,3-b]吡啶-2-基]-2-吡啶基]哌嗪-1-羧酸叔丁酯:使用针对中间体II-6合成描述的程序合成该中间体[从Va-3-1(CAS:153747-97-8)和IV-2开始]。
LCMS:m/z;568.3(M+1)+。1H NMR(CDCl3;400MHz)δ1.53(s,9H);2.33(s,3H);3.56-3.62(m,4H);3.66-3.70(m,4H);6.56(s,1H);6.74(d,J=8.8Hz,1H);7.17(d,J=8.4Hz,2H);7.20(d,J=5.2Hz,1H);7.72(d,J=8.4Hz,2H);7.77(dd,J1=2.0Hz,J2=8.8Hz,1H);8.28(d,J=2.0Hz,1H);8.34(d,J=5.6Hz,1H)。
中间体II-17:4-氯-2-[4-(4-氟-1-甲基-4-哌啶基)苯基]-1-(p-甲苯基磺酰基)吡咯并[2,3-b]吡啶
步骤-I和步骤-II:4-[4-[4-氯-1-(p-甲苯基磺酰基)吡咯并[2,3-b]吡啶-2-基]苯基]-4-氟-哌啶-1-羧酸叔丁酯(II-17-I):使用V-6和IV-2,按照针对II-12合成的程序合成中间体II-17-I。从V-6-I合成中间体V-6(如WO2009151598中所述合成)。LCMS:m/z;584.2(M+1)+。
步骤-III:4-氯-2-[4-(4-氟-1-甲基-4-哌啶基)苯基]-1-(p-甲苯基磺酰基)吡咯并[2,3-b]吡啶(II-17):室温下向II-17-I(1.2g,2.05mmol)在二氧己环(4mL)中的溶液添加4M HCl的二氧己环溶液(10mL),并搅拌反应混合物16h。减压去除溶剂,并用二乙醚(10mL×2)洗涤残余物。然后向残余物添加饱和NaHCO3溶液(30mL),过滤得到的固体并干燥以提供相应的Boc-和甲苯磺酰基-脱保护的中间体(0.6g,1.82mmol),其溶解于MeOH(3mL)。向其添加甲醛(37%,0.7mL,21.8mmol)并使反应混合物回流1h。最后,在0℃下向反应混合物添加NaBH3CN(0.17g,2.73mmol)并搅拌2h。减压去除溶剂并将残余物溶解于EtOAc(50mL)。有机层用水(30mL)、盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。使用硅胶柱色谱(CH2Cl2中5%MeOH)纯化残余物以提供希望的中间体II-17(0.32g,两步产率45%)。LCMS:m/z;344.1(M+1)+。1H NMR(DMSO-d6;400MHz)δ1.20-1.30(m,2H);1.88-1.94(m,2H);2.05-2.20(m,2H);2.26(s,3H);2.70-2.76(m,2H);7.02(s,1H);7.21(d,J=4.8Hz,1H);7.53(d,J=8.0Hz,2H);8.01(d,J=8.4Hz,2H);8.18(d,J=4.8Hz,1H);12.55(bs,1H)。
使用如针对II-17合成描述的相似反应顺序和程序还合成了以下中间体II-18。
表-9
中间体II-19:4-[4-[4-氯-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]苯氧基]哌啶-1-羧酸叔丁酯
步骤-I:4-(4-溴苯氧基)哌啶-1-羧酸叔丁酯(V-7-I):如WO2010048149所述合成V-7-I。LCMS:m/z;356(M+1)+。
步骤-II:4-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯氧基]哌啶-1-羧酸叔丁酯(V-7):如WO2008078091所述合成V-7。LCMS:m/z;404.2(M+1)+。
步骤-III:4-[4-[4-氯-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]苯氧基]哌啶-1-羧酸叔丁酯(II-19):使用中间体V-7和IV-1,按照如针对II-12合成所述相似程序合成II-19。LCMS:m/z;583.3(M+1)+。1H NMR(CDCl3;400MHz)δ1.24(s,9H);1.76-2.10(m,4H);2.38(s,3H);3.36-3.42(m,2H);3.70-3.77(m,2H);4.56-4.60(m,1H);6.54(s,1H);6.99(d,J=8.4Hz,2H);7.24(d,J=8.4Hz,2H);7.42(d,J=8.4Hz,2H);7.79(d,J=8.4Hz,2H);8.81(s,1H)。
使用如针对II-19合成描述的相似反应顺序和程序还合成了以下中间体II-20。
表-10
中间体II-21:[4-[4-氯-1-(2-三甲基甲硅烷基乙氧基甲基)吡咯并[2,3-b]吡啶-2-基]苯基]-(4-羟基-4-甲基-1-哌啶基)甲酮
步骤-I:4-[4-氯-1-(2-三甲基甲硅烷基乙氧基甲基)吡咯并[2,3-b]吡啶-2-基]苯甲酸乙酯(II-21-I):向IV-5(4g,12.24mmol)和4-溴苯甲酸乙酯(2.0mL,12.24mmol)在1,4-二氧己环(40mL)中的溶液添加K2CO3(6.7g,48.96mmol)在水(10mL)中的溶液;向其中吹扫氩30min。最后,向其添加Pd(PPh3)4(1.4g,1.22mmol)并继续吹扫另外10min。然后在90℃搅拌反应混合物12h。其然后冷却至室温并使用EtOAc(100mL)稀释。有机层用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。最后使用硅胶柱色谱(己烷中10%EtOAc)纯化残余物以提供II-21-I(3.8g,72%产率)。LCMS:m/z;431(M+1)+。
步骤-II:[4-[4-氯-1-(2-三甲基甲硅烷基乙氧基甲基)吡咯并[2,3-b]吡啶-2-基]苯基]-(4-羟基-4-甲基-1-哌啶基)甲酮(II-21):向II-21-I(2.0g,4.64mmol)在THF(20mL)中的溶液添加NaOH水溶液(0.93g,23.2mmol,8mL)并在室温下搅拌反应混合物16h。其然后使用10%柠檬酸溶液酸化并使用EtOAc(30mL×2)进行萃取。合并的有机层用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩以提供相应的酸中间体(1.3g,3.22mmol),其溶解于DMF(15mL)。向此添加4-甲基哌啶-4-醇(CAS:3970-68-1)(0.97g,6.45mmol)、二异丙基乙胺(2.1mL,12.88mmol)和HATU(1.83g,4.83mmol);并在室温搅拌反应混合物16h。其然后使用EtOAc(100mL)洗脱,并用水(100mL×2)、盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。最后使用硅胶柱色谱(己烷中20%丙酮)纯化残余物以提供II-21(0.7g,30%产率)。LCMS:m/z;500.2(M+1)+。1H NMR(CDCl3,400MHz)δ0.16(s,9H);1.01(t,J=8.4Hz,2H);1.36(s,3H);1.72-1.75(m,4H);3.41-3.59(m,4H);3.79(t,J=8.4Hz,2H);4.40(bs,1H);5.69(s,2H);6.76(s,1H);7.19(d,J=5.6Hz,1H);7.56(d,J=8.0Hz,2H);7.90(d,J=8.0Hz,2H);8.26(d,J=5.6Hz,1H)。
使用针对II-21合成描述的相似程序合成以下中间体。
表-11
中间体II-23:4-[4-氯-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]-3,6-二氢-2H-吡啶-1-羧酸叔丁酯
步骤-I:向IV-1(3gm,6.92mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-3,6-二氢-2H-吡啶-1-羧酸叔丁酯(根据W02010005783A1中提到的程序制备)(1.49gm,4.84mmol)在二氧己环(60mL)中的混合物添加K2CO3(1.9gm,13.84mmol)在水(12mL)中的溶液;使用氩吹扫得到的反应混合物20分钟。向得到的溶液添加Pd(PPh3)4(0.078g,0.06mmol)并在90-95℃加热4小时的时段。将反应混合物倒入冰冷水(100mL)并用EtOAc(3×100mL)萃取。合并的有机层用盐水溶液(150mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩以提供粗产物,其通过硅胶柱色谱(己烷中20%EtOAc)纯化以提供标题化合物II-23(1g,31.8%);LCMS:m/z 489.1(M+1)+。
按照针对II-23描述的相似程序还合成了以下中间体II-24。
表-12
中间体XI-1:4-[4-氯-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]苯甲醛
步骤-I:将氩经IV-1(8.4g,19.39mmol)、4-甲酰基苯基硼酸(2.76g,18.42mmol)和Na2CO3(5.13g,48.47mmol)在乙腈-水(194mL+48mL)中的溶液吹扫30min。最后,向反应混合物添加PdCl2(PPh3)2(1.90g,2.71mmol)并继续吹扫另外10min。使反应混合物在100℃搅拌2h。其然后通过硅藻土垫过滤,残余物用CH2Cl2(300mL×2)洗涤。合并的有机层用盐水(150mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。最后使用EtOH(50mL)结晶残余物以提供希望的中间体XI-1(6.0g,75%产率)。LCMS:m/z;412.1(M+1)+。1H NMR(DMSO-d6;400MHz)δ2.36(s,3H);7.11(s,1H);7.44(d,J=8.1Hz,2H);7.80-7.84(芳香族,4H);8.05(d,J=7.6Hz,2H);8.88(s,1H);10.13(s,1H)。
中间体XI-2:4-[1-(苯磺酰基)-4-氯-吡咯并[2,3-b]吡啶-2-基]苯甲醛
步骤-I:与针对XI-1合成所述相同。没有任何进一步纯化而原样使用粗产物(通过LCMS,76%)。LCMS:m/z;396.9(M+1)+。
中间体XI-3:6-[4-氯-1-(2-三甲基甲硅烷基乙氧基甲基)吡咯并[2,3-b]吡啶-2-基]吡啶-3-甲醛
步骤-I:使氩经IV-5(1.05g,3.22mmol)、6-溴-3-吡啶甲醛(CAS:149806-06-4)(0.5g,2.7mmol)和KF(0.47g,8.06mmol)在乙腈:水(7mL+3.5mL)中的溶液吹扫30min。最后,向反应混合物添加Pd(PPh3)4(0.93g,0.81mmol)并继续吹扫另外10min。其然后在90℃搅拌4h。冷却反应混合物之后,其使用EtOAc(60mL)稀释,并用水(50mL×2)、盐水(50mL)洗涤有机层,经无水Na2SO4干燥,过滤并减压浓缩。然后使用硅胶柱色谱(己烷中12%EtOAc)纯化残余物以提供XI-3(0.56g,53%产率)。LCMS:m/z;388.1(M+1)+。1H NMR(CDCl3;400MHz)δ-0.16(s,9H);0.82(t,J=8.4Hz,2H);3.52(t,J=8.4Hz,2H);6.29(s,2H);7.18(d,J=5.2Hz,1H);7.19(s,1H);8.08(d,J=8.4Hz,1H);8.26(dd,J1=2.4Hz,J2=8.4Hz,1H);8.31(d,J=5.2Hz,1H);9.15(d,J=1.2Hz,1H);10.15(s,1H)。
使用针对XI-1合成描述的相似程序合成以下两个中间体。
表-13
中间体XI-6:5-[4-氯-1-(p-甲苯基磺酰基)吡咯并[2,3-b]吡啶-2-基]吡啶-2-甲醛
步骤-I:叔丁基-二甲基-[(5-三丁基甲锡烷基-2-吡啶基)甲氧基]硅烷(Va-4):使用二乙醚作为溶剂和Va-4-I(根据WO2011092140合成)作为起始材料,按照II-6合成的步骤-II中描述的程序合成Va-4。LCMS:m/z;514.3(M+1)+。
步骤-II:[5-[4-氯-1-(p-甲苯基磺酰基)吡咯并[2,3-b]吡啶-2-基]-2-吡啶基]甲醇(XI-6-I):使用Va-4和IV-2中间体,如II-6合成的步骤-III中所述合成该中间体。LCMS:m/z;414.1(M+1)+。
步骤-III:5-[4-氯-1-(p-甲苯基磺酰基)吡咯并[2,3-b]吡啶-2-基]吡啶-2-甲醛(XI-6):在0℃下向XI-6-I(0.9g,2.17mmol)在无水CH2Cl2(15mL)中的溶液添加戴斯-马丁过碘烷(1.84g,4.35mmol)并搅拌反应混合物30min。其然后使用CH2Cl2(50mL)稀释,并用10%硫代硫酸钠(30mL)、饱和NaHCO3溶液(50mL)和盐水(50mL)洗涤。经无水Na2SO4干燥之后减压去除溶剂。通过硅胶柱色谱纯化残余物(己烷中10%EtOAc)以提供希望的中间体XI-6(0.64g,71%产率)。LCMS:m/z 412.1(M+1)+。1H NMR(CDCl3;400MHz)δ2.35(s,3H);6.78(s,1H);7.23(d,J=8.4Hz,2H);7.28(s,1H);7.80(d,J=8.4Hz,2H);8.41-8.44(芳香族,2H);8.42(d,J=5.2Hz,1H);8.94(s,1H);10.18(s,1H)。
中间体XI-7:4-(4-氯-7H-吡咯并[2,3-d]嘧啶-6-基)苯甲酸甲酯
步骤-I:2-氨基-5-(4-甲氧基羰基苯基)-1H-吡咯-3-羧酸乙酯(XI-7-I):向乙醇(210mL)分部分添加Na金属(1.96g,85.3mmol)并搅拌30分钟以获得澄清溶液。向此添加3-氨基-3-亚胺基-丙酸乙酯盐酸盐(CAS:57508-48-2,14.25g,85.6mmol)并在室温搅拌额外30分钟。最后,向反应混合物添加4-(2-溴乙酰基)苯甲酸甲酯(11g,42.8mmol)并在室温搅拌16-20h。反应完成之后(如通过TLC和LCMS指示),通过硅藻土过滤反应混合物并用MeOH(50mL×2)洗涤残余物。减压浓缩合并的滤液并使用硅胶柱色谱(己烷中40%EtOAc)纯化残余物以提供XI-7-I(7g,56.7%产率)。LCMS;m/z:289.1(M+1)+。
步骤-II:4-(4-羟基-7H-吡咯并[2,3-d]嘧啶-6-基)苯甲酸甲酯(XI-7-II):向甲酰胺(10mL)、甲酸(4mL)和DMF(2mL)的混合物添加XI-7-I(7.5g,26mmol)并在150℃搅拌得到的反应混合物16-20h。反应完成之后(通过TLC监测和LCMS),使反应混合物冷却至0℃并向其添加2-丙醇(35mL)。搅拌15min之后,过滤残余物并用二乙醚(10mL)洗涤以提供XI-7-II(6g,85.6%产率)。LCMS;m/z:270(M+1)+。
步骤-III:4-(4-氯-7H-吡咯并[2,3-d]嘧啶-6-基)苯甲酸甲酯(XI-7):使XI-7-II(6g,22.3mmol)在过量POCl3(100mL)中的混悬液回流16-20h。反应完成之后(通过TLC监测),减压去除POCl3。向残余物缓慢添加饱和NaHCO3(100mL)溶液并搅拌30分钟。过滤固体并悬浮于最小量的MeOH(10mL)。搅拌30min之后,过滤并干燥以提供XI-7(5.8g,90%产率)。LCMS;m/z:288(M+1)+。1H NMR(CDCl3;400MHz)δ3.86(s,3H);7.28(s,1H);8.04(d,J=8.0Hz,2H);8.16(d,J=8.4Hz,2H);8.61(s,1H);13.18(s,1H)。
按照如制备XI-7所描述的相似的反应顺序和程序合成以下中间体(II-25和II-26)。
表-14
中间体XI-8:4-[4-氯-2-(2,2-二甲基丙酰基氨基)-7H-吡咯并[2,3-d]嘧啶-6-基]苯甲酸甲酯
步骤-I:4-(2-氨基-4-羟基-7H-吡咯并[2,3-d]嘧啶-6-基)苯甲酸甲酯(XI-8-I):在100℃下搅拌2,6-二氨基-4-羟基嘧啶(CAS:56-06-4,1g,7.93mmol)和乙酸钠(0.85g,10.32mmol)在水(180mL)中的溶液30分钟。将4-(2-溴乙酰基)苯甲酸甲酯(2.24g,8.72mmol)悬浮于MeOH(25mL)并缓慢添加至上述溶液。然后在100℃搅拌反应混合物16-20h,然后冷却至室温。过滤残余物并干燥。然后将其在CH2Cl2(10mL)中搅拌并过滤以提供XI-8-I(1.07g,47.5%)。LCMS:m/z 285(M+1)+。
步骤-II:4-[2-(2,2-二甲基丙酰基氨基)-4-羟基-7H-吡咯并[2,3-d]嘧啶-6-基]苯甲酸甲酯(XI-8-II):使XI-8-I(2g,7.04mmol)在三甲基乙酸酐(5mL)中的混悬液回流3-5h。反应完成之后(通过TLC监测),使反应混合物冷却至室温并向其添加己烷(10mL)。过滤残余物并用二乙醚(5mL)洗涤以提供XI-8-II(1.9g,73.3%)。LCMS:m/z:369.1(M+1)+。
步骤-III:4-[4-氯-2-(2,2-二甲基丙酰基氨基)-7H-吡咯并[2,3-d]嘧啶-6-基]苯甲酸甲酯(XI-8):使XI-8-II(1.9g,5.16mmol)在POCl3(2mL)中的混悬液回流3-5h。反应完成之后(通过TLC监测),减压去除POCl3并向残余物添加饱和NaHCO3溶液(50mL)。获得的固体经过滤并干燥。然后将其在MeOH(5mL)中搅拌15min,过滤并干燥以提供XI-8(1g,50%)。LCMS:m/z 387.1(M+1)+。
按照如制备XI-8所用的相似的反应顺序和程序制备以下中间体。
表-15
中间体XI-10:4-(2-氨基-4-氯-7H-吡咯并[2,3-d]嘧啶-6-基)苄腈
步骤-I:4-(2-氨基-4-羟基-7H-吡咯并[2,3-d]嘧啶-6-基)苄腈(XI-10-I):将2,6-二氨基嘧啶-4-醇(1g,7.93mmol)和NaOAc(0.846g,10.31mmol)在水(180mL)中的混合物加热至100℃持续20分钟。向此添加4-(2-溴乙酰基)苄腈(2.2gm,8.73mmol)[根据J.Med.Chem,2011,54(12),4042-4056中提到的程序制备]在MeOH(25mL)中的混悬液,并在100℃加热过夜。反应完成之后,使反应混合物冷却至0℃。滤掉得到的固体产物并减压干燥以提供标题化合物XI-10-I(1.2g,100%)。LCMS:m/z 252(M+1)+。
步骤-II:4-(2-氨基-4-氯-7H-吡咯并[2,3-d]嘧啶-6-基)苄腈(XI-10):使XI-10-I(0.5g,1.99mmol)在POCl3(10mL)中的混悬液回流16h。反应完成之后,减压去除过量POCl3。冷却反应混合物至0℃并使用饱和NaHCO3水溶液的缓慢添加来中和。产物用EtOAc(20mL×2)萃取。有机层用盐水溶液(50mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩以获得粗产物,其通过硅胶柱色谱(己烷中40%丙酮)纯化以提供标题化合物XI-10(0.18g,33%)。LCMS:m/z 270(M+1)+。1H NMR(DMSO-d6;400MHz)δ6.78(bs,2H);7.05(s,1H);7.88(d,J=8.3Hz,2H);8.05(d,J=8.3Hz,2H);12.17(bs,1H)。
实施例A-1:8-环丙基-4-[2-甲基-3-[6-[4-(哌嗪-1-基甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮的合成
步骤-I:4-[[4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]苯基]甲基]哌嗪-1-羧酸叔丁酯(A-1-I):向中间体II-1(0.4g,0.68mmol)和III-1(0.57g,1.37mmol)在二氧己环(20mL)中的溶液添加Na2CO3水溶液(0.18g,1.71mmol,4mL)。使用氩吹扫得到的反应混合物30分钟,然后向其添加Pd(PPh3)4(0.08g,0.068mmol)。然后在100℃加热反应混合物6小时。反应完成之后(通过TLC监测),用水(30mL)稀释反应混合物。使用EtOAc(20mL×2)进行萃取。合并的有机层用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。粗产物通过硅胶柱色谱(己烷中60%EtOAc)纯化以提供标题化合物A-1-I(0.45g,79%);LCMS:m/z 839.1(M+1)+。
步骤-II:4-[[4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苯基]甲基]哌嗪-1-羧酸叔丁酯(A1-II):向中间体A-1-I(0.45g,0.53mmol)在THF、甲醇和水(3:1:1)混合物(5mL)中的溶液添加LiOH.H2O(0.067g,1.60mmol)并在室温搅拌反应混合物1h。反应完成之后,添加水(30mL)并使用EtOAc(20mL×2)进行萃取。合并的有机层用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。粗产物(A-1-II)没有任何纯化而使用。LCMS:m/z 685.1(M+1)+。
步骤-III:8-环丙基-4-[2-甲基-3-[6-[4-(哌嗪-1-基甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(实施例A-1):室温下搅拌中间体A-1-II(0.3g,0.437mmol)和4M HCl在二氧己环(5mL)中的混合物1h。反应完成之后(通过TLC监测),减压蒸发溶剂并向其添加饱和NaHCO3溶液(30mL)。过滤沉淀的固体并通过制备型TLC(CH2Cl2中10%甲醇)纯化以提供为黄色固体的标题化合物A-1(0.045g,18%);LCMS:m/z 585.4(M+1)+。1H NMR(400MHz,DMSO-d6)δ0.74-0.77(m,2H);0.98-1.06(m,2H);1.93-2.00(m,1H);2.15(s,3H);2.30-2.40(m,4H);2.73-2.80(m,4H);3.48(s,2H);3.89-3.99(m,2H);4.45-4.48(m,2H);6.82(s,2H);6.91(d,J=8.0Hz,1H);7.39(d,J=8.1Hz,2H);7.43-7.47(芳香族,2H);7.52-7.54(芳香族,1H);7.62(d,J=8.1Hz,1H);7.93(d,J=8.1Hz,2H);8.84(s,1H);12.80(s,1H)。
如针对A-1合成描述的相似的反应顺序和程序合成以下化合物。
表-16
实施例B-1:8-环丙基-4-[2-(羟基甲基)-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮的合成
步骤-I:4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]苯甲醛(B-1-I):按照如A-1-I合成所述相似程序,使用中间体XI-1和III-5制备中间体B-1-I。LCMS:m/z 685.3(M+1)+。
步骤-II:8-环丙基-4-[2-(羟基甲基)-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(B-1-II):25℃下向中间体B-1-I(0.08g,0.10mmol)在1,2-二氯乙烷(2mL)中的搅拌溶液添加N-甲基哌嗪(0.016g,0.15mmol)、乙酸(2滴)和活化的分子筛(0.1g)。室温下搅拌反应混合物15分钟,然后在相同温度下向其添加氰基硼氢化钠(0.01g,0.16mmol)。搅拌反应混合物1h,然后使其蒸发至干并用乙酸乙酯(30mL)稀释。有机层用水(30mL)、盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩以提供粗产物B-1-II(0.120g),其没有任何纯化而用于下一步骤。LCMS:m/z 769.1(M+1)+。
步骤-III:8-环丙基-4-[2-(羟基甲基)-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(B-1):向中间体B-1-II(0.12g,0.15mmol)在1,4-二氧己环(4mL)中的搅拌溶液添加氢氧化锂(0.032g,0.78mmol)。室温搅拌18h之后,减压蒸发挥发物。得到残余物溶解于EtOAc(50mL),并用水(50mL)、盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。通过制备型HPLC纯化残余物以提供标题化合物B-1(0.006g,6%)。LCMS:m/z 615.3(M+1)+。1H NMR(DMSO-d6,400MHz;)δ0.74-0.78(m,2H);1.00-1.04(m,2H);1.94-2.00(m,1H);2.17(s,3H);2.24-2.44(m,8H);3.50(s,2H);3.84-4.02(m,2H);4.36-4.44(m,2H);4.47-4.61(m,2H);5.37-5.41(m,1H);6.83(s,1H);6.91(d,J=8.1Hz,1H);7.04(s,1H);7.41(d,J=8.1Hz,2H);7.50(d,J=7.8Hz,1H);7.63(d,J=8.3Hz,2H);7.78(d,J=7.6Hz,1H);7.96(d,J=8.1Hz,2H);8.82(s,1H);12.82(bs,1H)。
使用如针对B-1合成描述的相似的反应顺序和程序合成以下化合物。
表-17
实施例C-1:6-环丙基-2-[2-(羟基甲基)-3-[6-[4-(4-甲基哌嗪-1-基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]异喹啉-1-酮的合成
步骤-I:4-[4-[4-[2-(乙酰氧基甲基)-3-(6-环丙基-1-氧-2-异喹啉基)苯基]-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]苯基]哌嗪-1-羧酸叔丁酯(C-1-I):按照B-1-I合成所述的相似程序,使用中间体II-5和III-6合成中间体C-1-I。LCMS:m/z 865.3(M+1)+。
步骤-II:[2-(6-环丙基-1-氧-2-异喹啉基)-6-[6-[4-(4-甲基哌嗪-1-基)苯基]-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-4-基]苯基]甲基乙酸酯(C-1-II):中间体C-1-I(0.5g,0.57mmol)在CH2Cl2(10mL)中的溶液在室温下用TFA(4mL)处理,然后搅拌30分钟。减压去除溶剂并向其添加饱和NaHCO3溶液(30mL)。使用CH2Cl2(30mL×2)进行提取。合并的有机层用水(30mL)、盐水(30mL)连续洗涤,经无水Na2SO4干燥,过滤并减压浓缩以提供相应的Boc-脱保护中间体(0.1g,0.13mmol),其溶解于MeOH(4mL)。向其添加甲醛水溶液(37%溶液,0.11mL,1.43mmol)和冰乙酸(1滴);然后在80℃搅拌反应混合物1h。使混合物缓慢冷却至0℃并用CH2Cl2(1mL)、随后氰基硼氢化钠(0.11g,1.76mmol)处理。继续搅拌额外1h。在证实反应完成之后(通过TLC),减压去除溶剂。将残余物溶解于CH2Cl2(50mL)并用水(15mL)和盐水(10mL)连续洗涤。有机层经无水Na2SO4干燥,过滤并浓缩以提供标题化合物C-1-II(0.115g,100%)。LCMS:m/z 779.4(M+1)+。
步骤-III:6-环丙基-2-[2-(羟基甲基)-3-[6-[4-(4-甲基哌嗪-1-基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]异喹啉-1-酮(实施例C-1)
室温下向中间体C-1-II(0.1g,0.128mmol)在THF(6mL)和H2O(2mL)的混合物中的溶液添加LiOH.H2O(0.027g,0.64mmol)并在该温度下搅拌混合物3天。证实反应完成之后,减压去除溶剂并使用制备型TLC板纯化残余物(硅胶,8%MeOH:CH2Cl2)以提供标题化合物C-1(0.027g,38.5%)。LCMS:m/z 583.3(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.82-0.88(m,2H);1.06-1.13(m,2H);2.06-2.16(m,1H);2.24(s,3H);2.42-2.50(m,4H);3.11-3.30(m,4H);4.14(dd,J1=8.2Hz,J2=11.8Hz,1H);4.33(dd,J1=4.3Hz,J2=12.0Hz,1H);5.32-5.35(m,1H);6.67(d,J=7.6Hz,1H);6.90(bs,1H);7.03(d,J=8.8Hz,2H);7.27(d,J=7.4Hz,1H);7.40(d,J=7.3Hz,1H);7.44(bs,1H);7.52(d,J=7.6Hz,1H);7.66(t,J=7.7Hz,1H);7.84-7.92(芳香族,3H);8.12(d,J=8.4Hz,1H);8.80(s,1H);12.68(s,1H)。
使用如针对C-1合成描述的相似的反应顺序和程序合成以下实施例。
表-18
实施例D-1:8-环丙基-4-[2-(羟基甲基)-3-[6-[1-(1-甲基-4-哌啶基)吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮
步骤-I:4-[4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]吡唑-1-基]哌啶-1-羧酸叔丁酯(D-1-I):按照如B-1-I合成所述相似程序,使用中间体II-6和III-5制备中间体D-1-I。LCMS:m/z 830.4(M+1)+。
步骤-II:8-环丙基-4-[2-(羟基甲基)-3-[6-[1-(1-甲基-4-哌啶基)吡唑-4-基]-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(D-1-II):按照如C-1-II合成(步骤-II,实施例C-1)所述相似程序,从中间体D-1-I合成中间体D-1-II。LCMS:m/z;744.3(M+1)+。
步骤-III:8-环丙基-4-[2-(羟基甲基)-3-[6-[1-(1-甲基-4-哌啶基)吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(D-1):使用如C-1合成(步骤-III)所述相似程序合成实施例D-1。LCMS:m/z 590.1(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.72-0.78(m,2H);0.98-1.04(m,2H);1.90-2.00(m,3H);2.03-2.09(m,4H);2.22(s,3H);2.80-2.90(m,2H);3.82-4.00(m,2H);4.10-4.20(m,1H);4.33-4.39(m,2H);4.42-4.58(m,2H);5.42-5.45(m,1H);6.75(s,1H);6.82(s,1H);6.91(d,J=7.8Hz,1H);6.48(d,J=7.9Hz,1H);7.58-7.63(芳香族,2H);7.73(d,J=7.6Hz,1H);8.09(s,1H);8.42(s,1H);8.78(s,1H);12.64(s,1H)。
使用如针对D-1合成描述的相似的反应顺序和程序合成以下实施例。
表-19
实施例E-1:8-环丙基-4-[2-(羟基甲基)-3-[2-[3-甲基-1-(1-甲基氮杂环丁烷-3-基)吡唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮的合成
步骤-I:4-氯-2-[3-甲基-1-(1-甲基氮杂环丁烷-3-基)吡唑-4-基]-1-(p-甲苯基磺酰基)吡咯并[2,3-b]吡啶(E-1-I):使用如针对D-1-II合成(步骤-II)所述的相似程序合成中间体E-1-I。LCMS:m/z;456.1(M+1)+。
步骤-II:8-环丙基-4-[2-(羟基甲基)-3-[2-[3-甲基-1-(1-甲基氮杂环丁烷-3-基)吡唑-4-基]-1-(p-甲苯基磺酰基)吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(E-1-II):使用如针对B-1-I合成所述的相似程序合成中间体E-1-II。LCMS:m/z;729.3(M+1)+。
步骤-III:8-环丙基-4-[2-(羟基甲基)-3-[2-[3-甲基-1-(1-甲基氮杂环丁烷-3-基)吡唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮:使用如针对C-1合成所述的相似程序从E-1-II制备实施例E-1。LCMS:m/z 575.3(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.73-0.77(m,2H);1.00-1.04(m,2H);1.95-1.98(m,1H);2.33(s,3H);2.34(s,3H);3.22-3.24(m,2H);3.70(t,J=7.3Hz,2H);3.90-3.96(m,2H);4.20-4.26(m,1H);4.32-4.40(m,1H);4.52-4.60(m,2H);4.76-4.84(m,1H);4.86-4.91(m,1H);6.25(s,1H);6.81(d,J=1.5Hz,1H);6.89(dd,J1=1.5Hz,J2=8.3Hz,1H);7.17(bs,1H);7.41(d,J=7.8Hz,1H);7.47(d,J=6.8Hz,1H);7.52-7.56(m,1H);7.66(d,J=8.1Hz,1H);8.21(d,J=4.9Hz,1H);8.34(s,1H);11.98(s,1H)。
实施例F-1:8-环丙基-4-[2-(羟基甲基)-3-[2-[1-(氧杂环丁烷-3-基)吡唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮
步骤-I:4-氯-2-[1-(氧杂环丁烷-3-基)吡唑-4-基]-1H-吡咯并[2,3-b]吡啶(F-1-I):使用如针对C-1合成的步骤-III所述的相似程序合成中间体F-1-I。LCMS:m/z 275.2(M+1)+。
步骤-II:8-环丙基-4-[2-(羟基甲基)-3-[2-[1-(氧杂环丁烷-3-基)吡唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(F-1):使用如针对B-1合成的步骤-I所述的相似程序制备实施例F-1。LCMS:m/z 548.1(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.71-0.75(m,2H);0.97-1.01(m,2H);1.90-1.98(m,1H);3.82-3.92(m,2H);4.16-4.24(m,1H);4.26-4.36(m,1H);4.47-4.54(m,2H);4.70-4.80(m,1H);4.86(t,J=6.8Hz,2H);4.92(t,J=6.8Hz,2H);5.54-5.60(m,1H);6.40(d,J=2.4Hz,1H);6.78(s,1H);6.86(d,J=8.3Hz,1H);7.14(d,J=3.9Hz,1H);7.38(d,J=7.8Hz,1H);7.43(d,J=7.3Hz,1H);7.50-7.54(m,1H);7.63(d,J=7.8Hz,1H);8.11(s,1H);8.17(d,J=4.9Hz,1H);8.40(s,1H);12.03(s,1H)。
使用如针对F-1合成描述的相似的反应顺序和程序合成以下实施例。
表-20
实施例G-1:8-环丙基-4-[2-(羟基甲基)-3-[6-[4-[(1-甲基-4-哌啶基)氧基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮的合成
步骤-I:4-[4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]苯氧基]哌啶-1-羧酸叔丁酯(G-1-I):按照如B-1合成的步骤-I所述相似程序合成中间体G-1-I。LCMS:m/z;856(M+1)+。
步骤-II:8-环丙基-4-[2-(羟基甲基)-3-[6-[4-[(1-甲基-4-哌啶基)氧基]苯基]-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(G-1-II):按照如D-1-II合成的步骤-II所述相似程序合成中间体G-1-II。LCMS:m/z;770.1(M+1)+。
步骤-III:8-环丙基-4-[2-(羟基甲基)-3-[6-[4-[(1-甲基-4-哌啶基)氧基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(G-1):使用如C-1合成的步骤-II所述相似程序制备实施例G-1。LCMS:m/z 616.1(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.75-0.77(m,2H);1.00-1.04(m,2H);1.64-1.70(m,2H);1.94-1.99(m,2H);2.23(s,3H);2.26-2.35(m,2H);2.61-2.72(m,2H);3.84-4.02(m,2H);4.04-4.14(m,1H);4.34-4.43(m,2H);4.47-4.50(m,2H);4.56-4.62(m,1H);5.45(两个d,J=4.9Hz,1H);6.83(s,1H);6.89(dd,J1=1.7Hz,J2=6.5Hz,1H);6.92(d,J=1.4Hz,1H);7.07(d,J=8.8Hz,2H);7.49(d,J=8.0Hz,1H);7.59-7.63(芳香族,2H);7.78(dd,J1=1.0Hz,J2=7.6Hz,1H);7.93(d,J=8.8Hz,2H);8.83(s,1H);12.76(s,1H)。
如G-1合成所述还合成了实施例G-2。
表-21
实施例H-1:6-环丙基-2-[3-[6-[4-[1-(2-羟基乙基)-4-哌啶基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]异喹啉-1-酮的合成
步骤-I:4-[4-[4-[3-(6-环丙基-1-氧-2-异喹啉基)-2-甲基-苯基]-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]苯基]哌啶-1-羧酸叔丁酯(H-1-I):按照如B-1合成的步骤-I所述相似程序合成了中间体H-1-I。LCMS:m/z;806.4(M+1)+。
步骤-II:2-[3-[6-[4-[1-[2-[叔丁基(二甲基)甲硅烷基]氧基乙基]-4-哌啶基]苯基]-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-异喹啉-1-酮(H-1-II):将中间体H-1-I(0.64g,0.795mmol)溶解于二氧己环(3mL),向其添加乙醚(6mL)中的2M HCl,并在室温搅拌反应混合物2h。减压去除溶剂并向残余物添加饱和NaHCO3溶液(30mL)。使用EtOAc(30mL×2)进行提取;合并的有机层用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。将获得的残余物(0.25g)溶解于DMF(2mL);向其添加无水K2CO3(0.073g,0.53mmol)和2-溴乙氧基-叔丁基-二甲基-硅烷(0.1g,0.42mmol)。室温搅拌反应混合物16h。向其添加冰冷水(30mL)并过滤沉淀的固体。最后使用硅胶柱色谱以提供H-1-II纯化该固体(0.26g,两步产率38%)。LCMS:m/z;864.5(M+1)+。
步骤-III:6-环丙基-2-[3-[6-[4-[1-(2-羟基乙基)-4-哌啶基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]异喹啉-1-酮:将中间体H-1-II(0.26g,0.30mmol)溶解于THF(2mL)并向其添加1N HCl(2mL)。搅拌反应混合物2h,然后减压去除挥发物。获得的残余物溶解于THF-H2O(5mL+5mL),向其添加LiOH-H2O(0.1g,2.46mmol)并在室温下搅拌反应混合物16h。其然后使用EtOAc(30mL)稀释并用盐水(30mL)洗涤。减压去除有机层,获得残余物使用制备型HPLC纯化来纯化以提供标题化合物H-1(0.014g,8%产率)。LCMS:m/z 596.2(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.80-0.86(m,2H);1.08-1.10(m,2H);1.66-1.74(m,4H);1.87-1.96(m,4H);2.00-2.18(m,4H);2.38-2.44(m,2H);2.98(d,J=10.3Hz,2H);3.51(t,J=6.4Hz,2H);6.68(d,J=7.3Hz,1H);6.85(s,1H);7.27(d,J=7.6Hz,1H);7.35(d,J=8.1Hz,2H);7.41-7.52(芳香族,3H);7.56(t,J=7.6Hz,1H);7.66(d,J=7.4Hz,1H);7.91(d,J=8.1Hz,2H);8.13(d,J=8.4Hz,1H);8.84(s,1H)。
实施例I-1:8-环丙基-4-[2-(羟基甲基)-3-[2-[5-[(4-甲基哌嗪-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮的合成
步骤-I:6-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1-(2-三甲基甲硅烷基乙氧基甲基)吡咯并[2,3-b]吡啶-2-基]吡啶-3-甲醛(I-1-I):使用如针对B-1合成的步骤-I所述的相似程序合成中间体中间体I-1-I。LCMS:m/z;661.4(M+1)+。
步骤-II:8-环丙基-4-[2-(羟基甲基)-3-[2-[5-[(4-甲基哌嗪-1-基)甲基]-2-吡啶基]-1-(2-三甲基甲硅烷基乙氧基甲基)吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(I-1-II):使用如针对B-1合成的步骤-II所述的相似程序合成中间体中间体I-1-II。LCMS:m/z;745.3(M+1)+。
步骤-III:8-环丙基-4-[2-(羟基甲基)-3-[2-[5-[(4-甲基哌嗪-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(I-1):中间体I-1-II(0.45g,0.60mmol)溶解于二氧己环(5mL)中的1M HCl,向其添加4M HCl水溶液(20mL)并在室温搅拌反应混合物48h。最后,减压去除溶剂并向残余物添加饱和NaHCO3溶液(30mL)。使用EtOAc(30mL×2)进行提取;合并的有机层用水(50mL)、盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。使用制备型HPLC纯化来纯化残余物以提供标题化合物I-1(0.155g,33%产率)。LCMS:m/z 615.2(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.73-0.77(m,2H);1.00-1.04(m,2H);1.94-1.99(m,1H);2.19(s,3H);2.30-2.45(m,8H);3.52(s,2H);3.86-3.96(m,2H);4.20-4.28(m,1H);4.30-4.40(m,1H);4.52-4.58(m,2H);4.72-4.82(m,1H);6.81(s,1H);6.87-6.90(芳香族,2H);7.22(bs,1H);7.43-7.48(芳香族,2H);7.55-7.59(m,1H);7.66(d,J=8.2Hz,1H);7.76(d,J=8.1Hz,1H);8.01(d,J=8.2Hz,1H);8.32(d,J=4.6Hz,1H);8.53(s,1H);12.36(bs,1H)。
使用如针对I-1合成描述的相似的反应顺序和程序合成以下化合物。
表-22
实施例I-12:8-环丙基-4-[3-[2-[5-[(4-乙基哌嗪-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮的合成
步骤-I:6-[4-[3-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1-(2-三甲基甲硅烷基乙氧基甲基)吡咯并[2,3-b]吡啶-2-基]吡啶-3-甲醛(I-12-I)的合成:向XI-3(1.5g,3.87mmol)和III-9(通过HPLC,60%纯)(2.8g,5.64mmol)在1,4-二氧己环(60mL)中的溶液添加Na2CO3(2g,18.9mmol)在水(15mL)中的溶液。使氩经该溶液吹扫20min。最后,向其添加Pd(PPh3)4(0.223g,0.19mmol)并继续吹扫另外20min。然后在90-100℃搅拌反应混合物16h。然后减压去除二氧己环,并使用EtOAc(150mL)稀释残余物。有机层用盐水(100mL)洗涤;经无水Na2SO4干燥,过滤并减压浓缩。使用硅胶柱色谱纯化残余物以提供I-12-I(1.2g,46%产率)。LCMS:679(M+1)+
步骤-II:8-环丙基-4-[3-[2-[5-[(4-乙基哌嗪-1-基)甲基]-2-吡啶基]-1-(2-三甲基甲硅烷基乙氧基甲基)吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(I-12-II)的合成:向I-12-I(2g,2.95mmol)在CH2Cl2(40mL)中的溶液添加N-Et-哌嗪(4.5mL,35mmol)、HOAc(1mL)和4A°分子筛。搅拌1h之后,向其添加NaBH3CN(0.186g,2.95mmol)并搅拌反应混合物2-3h。在SM完全消耗之后(通过TLC指示),向其添加饱和NaHCO3溶液。使用CH2Cl2(50mL×2)进行提取;合并的有机层用盐水(70mL)洗涤;经无水Na2SO4干燥,过滤并减压浓缩。使用硅胶柱色谱(CH2Cl2中4-10%MeOH)纯化残余物以提供希望的中间体I-12-II(1.7g,74%产率)。LCMS:777.3(M+1)+。
步骤-III:8-环丙基-4-[3-[2-[5-[(4-乙基哌嗪-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(I-12):向I-12-II(1.8g,2.32mmol)在CH2Cl2(15mL)中的溶液添加TFA(7mL,过量)并在室温搅拌反应混合物3-4h。在反应完成之后,减压去除溶剂并向残余物添加饱和NaHCO3溶液(50mL)。使用CH2Cl2(50mL×3)进行提取;合并的有机层用盐水(70mL)洗涤;经无水Na2SO4干燥,过滤并减压浓缩。使残余物经受硅胶柱色谱,随后使用乙腈(20mL)结晶以提供希望化合物I-12(1.4g,93%产率)。LCMS:m/z 647.2(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.77-0.78(m,2H);0.94-1.03(m,5H);1.96-2.02(m,1H);2.28-2.33(m,6H);3.52(bs,2H);3.76-3.85(m,2H);3.93-3.99(m,2H);4.20-4.26(m,2H);4.31-4.41(m,2H);4.46-4.52(m,2H);4.82(bs,1H);6.76(s,1H);6.82-6.84(芳香族,1H);6.88(s,1H);7.20(bs,1H);7.42-7.48(芳香族,2H);7.59-7.61(芳香族,1H);7.74(d,J=6.8Hz,1H);8.01(d,J=8.0Hz,1H);8.31(d,J=4.8Hz,1H);8.51(s,1H);12.36(s,1H)
使用如针对I-12合成所述的相似反应顺序和程序合成以下化合物。
表-23
实施例I-17:8-环丙基-6-氟-4-[5-氟-2-(羟基甲基)-3-[2-[5-[[4-(氧杂环丁烷-3-基)哌嗪-1-基]甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮的合成
步骤-I:6-[4-[3-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-5-氟-2-(羟基甲基)苯基]-1-(2-三甲基甲硅烷基乙氧基甲基)吡咯并[2,3-b]吡啶-2-基]吡啶-3-甲醛(I-17-I)的合成:向XI-13(20g,51.67mmol)和III-12(通过LCMS,80%纯)(37.1g,57.74mmol)在1,4-二氧己环(400mL)中的溶液添加Na2CO3(5.9g,155mmol)在水(80mL)中的溶液。使氩经该溶液吹扫20min。最后,向其添加Pd(PPh3)4(5.9g,5.16mmol)并继续吹扫另外20min。然后在100℃(油浴温度)搅拌反应混合物9h。在反应完成之后,减压去除二氧己环并使用水(250mL)稀释残余物。使用EtOAc(200mL×3)进行提取;合并的有机层用盐水(300mL)洗涤;经无水Na2SO4干燥,过滤并减压浓缩。使用硅胶柱色谱纯化残余物以提供I-17-I(28g,78%产率)。LCMS:m/z 697(M+1)+。(60%纯,其含有杂质TPPO)。
步骤-II:8-环丙基-6-氟-4-[5-氟-2-(羟基甲基)-3-[2-[5-[[4-(氧杂环丁烷-3-基)哌嗪-1-基]甲基]-2-吡啶基]-1-(2-三甲基甲硅烷基乙氧基甲基)吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(I-17-II)的合成:向I-17-I(OH和OAc的混合物,~25%OAc)(3.7g,5.3mmol)在CH2Cl2(40mL)中的溶液添加1-(氧杂环丁烷-3-基)哌嗪(7.5g,53mmol)(CAS:1254115-23-5)、HOAc(5滴)和4A°分子筛(~500mg)。搅拌2h之后,向其添加三乙酰氧基硼氢化钠(2.2g,10.6mmol),搅拌反应混合物16h。起始材料完全消耗之后(通过TLC指示),向其添加饱和NaHCO3溶液(60mL)并使用CH2Cl2(50mL×2)进行提取。合并的有机层用水(100mL)、盐水(100mL)洗涤;经无水Na2SO4干燥,过滤并减压浓缩。使用硅胶柱色谱(CH2Cl2中2-3%MeOH)纯化残余物以提供希望的中间体I-17-II。分离的产率:3.3g(OH和OAc的混合物);LCMS:m/z 823(M+1)+。
步骤-III:向I-17-II(4.1g,4.98mmol)在CH2Cl2(40mL)中的溶液添加TFA(20mL,过量)并在室温搅拌反应混合物2h。在反应完成之后,减压去除溶剂并向残余物添加饱和NaHCO3溶液(50mL)(pH:~8)。使用CH2Cl2(70mL×3)进行提取;合并的有机层用盐水(100mL)洗涤;经无水Na2SO4干燥,过滤并减压浓缩。获得的残余物溶解于THF(50mL),向其添加LiOH-H2O水溶液(1g,24.9mmol,10mL水),并在室温搅拌6-8h(以转化Oac至OH)。然后使用水(30mL)稀释并使用EtOAc(50mL×3)进行提取。合并的有机层用盐水(100mL)洗涤;经无水Na2SO4干燥,过滤并减压浓缩。获得的残余物经受硅胶柱色谱(CH2Cl2中4-5%MeOH);随后使用乙腈(20mL)结晶残余物以提供最终产物I-17(1.3g,37%产率)。LCMS:m/z 693.3(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.77-0.82(m,2H);1.00-1.10(m,2H);1.95-2.05(m,1H);2.30-2.50(m,8H);3.34-3.41(m,1H);3.53(s,2H);3.80-4.00(m,2H);4.15-4.30(m,1H);4.30-4.40(m,2H);4.40(t,J=6.0Hz,2H);4.51(t,J=6.0Hz,2H);4.50-4.60(m,1H);4.79(bs,1H);6.77(s,1H);6.84(d,J=11.2Hz,1H);6.93(d,J=2.0Hz,1H);7.22(d,J=3.6Hz,1H);7.34(dd,J1=2.8Hz,J2=9.2Hz,1H);7.40(dd,J1=3.2Hz,J2=9.2Hz,1H);7.76(dd,J1=2.0Hz,J2=8.4Hz,1H);8.04(d,J=8.0Hz,1H);8.34(d,J=4.8Hz,1H);8.53(s,1H);12.38(s,1H)
合成I-17的可选路线:
步骤-I:6-[4-[3-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-5-氟-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]吡啶-3-甲醛(I-17-III)的合成:向I-17-I(通过LCMS,60%,TPPO为杂质)(20g,28.7mmol)在无水CH2Cl2(200mL)中的溶液添加TFA(220mL,过量)并在室温搅拌3-4h。在反应完成之后,减压去除溶剂(<40℃)并向残余物添加饱和NaHCO3溶液(~300mL)(pH:~8)。使用CH2Cl2(200mL×3)进行提取;合并的有机层用盐水(300mL)洗涤;经无水Na2SO4干燥,过滤并减压浓缩。使用硅胶柱色谱(CH2Cl2中2%MeOH)纯化残余物以提供I-17-III(8.5g,52%产率)。LCMS:567(M+1)+。
步骤-II:向I-17-III(8.5g,15mmol)在CH2Cl2(250mL)中的溶液添加1-(氧杂环丁烷-3-基)哌嗪(10.7g,75mmol)、HOAc(0.84g,15mmol)和4A°分子筛(~2g)。搅拌2h之后,向其添加三乙酰氧基硼氢化钠(6.36g,30mmol)并搅拌反应混合物3h。在起始材料完全消耗之后(通过TLC指示),向其添加饱和NaHCO3溶液(100mL)并使用CH2Cl2(100mL×3)进行提取。合并的有机层用水(150mL)、盐水(150mL)洗涤;经无水Na2SO4干燥,过滤并减压浓缩。使用硅胶柱色谱(CH2Cl2中2-5%MeOH)纯化残余物以提供希望化合物I-17(9.1g,87%产率)。
使用如针对I-17合成所述的相似反应顺序和程序合成以下化合物。
表-24
实施例J-1:8-环丙基-4-[3-[2-[4-(4-氟-1-甲基-4-哌啶基)苯基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮的合成
步骤-I:8-环丙基-4-[3-[2-[4-(4-氟-1-甲基-4-哌啶基)苯基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(J-1)的合成:使用如针对B-1合成的步骤-I所述的相似程序制备实施例J-1。LCMS:m/z 617.2(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.72-0.77(m,2H);0.96-1.02(m,2H);1.87-2.00(m,6H);2.06-2.27(m,4H);2.66-2.76(m,2H);3.88-4.00(m,2H);4.20-4.28(m,1H);4.30-4.38(m,1H);4.50-4.60(m,2H);4.72-4.84(m,1H);6.70(s,1H);6.81(s,1H);6.88(d,J=8.3Hz,1H);7.20(bs,1H);7.43(d,J=7.9Hz,1H);7.49(d,J=7.5Hz,3H);7.54-7.58(芳香族,1H);7.66(d,J=8.4Hz,1H);7.93(d,J=8.0Hz,2H);8.28(d,J=4.4Hz,1H);12.33(s,1H)。
使用如针对J-1合成所述的相似反应顺序和程序还合成了以下实施例J-2。
表-25
实施例K-1:8-环丙基-4-[2-甲基-3-[6-[4-(4-甲基哌嗪-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮
步骤-I:4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苯甲酸甲酯(K-1-I):按照如B-1合成的步骤-I中所述的相似程序从中间体XI-7和III-1制备中间体K-1-I。LCMS:m/z 545.3(M+1)+。
步骤-II:4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苯甲酸(K-1-II):向中间体K-1-I(2g,3.67mmol)在MeOH(20mL)中的溶液添加氢氧化钠水溶液(0.44g,11.02mmol,10mL)并加热得到的反应混合物回流6-8h。反应完成之后(通过TLC监测),真空蒸发溶剂,然后用10%柠檬酸水溶液酸化残余物。过滤如此获得的固体并真空干燥以提供标题化合物K-1-II(1.9g,98%)。LCMS:m/z 531.3(M+1)+。
步骤-III:8-环丙基-4-[2-甲基-3-[6-[4-(4-甲基哌嗪-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮:向中间体K-1-II(0.1g,0.188mmol)、N-甲基哌嗪(0.09g,0.943mmol)和苯并三唑-1-基-氧基三吡咯烷基鏻六氟磷酸盐(0.15g,0.283mmol)在DMF(3mL)中的混合物添加N,N-二异丙基乙胺(0.12g,0.943mmol)。然后在室温搅拌得到的反应混合物过夜。反应完成之后(通过TLC监测),将反应混合物倒入冰冷水(15mL)。得到的沉淀经过滤并真空干燥。通过制备型TLC(CH2Cl2中7%MeOH)纯化如此获得的粗固体以提供标题化合物K-1(0.055g,48%)。LCMS:m/z 613.1(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.73-0.78(m,2H);0.81-0.87(m,2H);0.99-1.03(m,2H);1.94-2.02(m,1H);2.16(s,3H);2.19(s,3H);2.21-2.41(m,4H);3.62(bs,2H);3.88-3.94(m,2H);4.44-4.50(m,2H);6.82(d,J=1.4Hz,1H);6.92(dd,J1=1.2Hz,J2=8.0Hz,1H);6.95(d,J=1.5Hz,1H);7.44-7.50(芳香族,4H),7.55(dd,J1=2.0Hz,J2=6.6Hz,1H);7.63(d,J=8.1Hz,1H);8.05(d,J=8.3Hz,2H);8.87(s,1H);12.85(s,1H)。
使用如K-1合成所用的相似反应顺序和程序合成以下化合物。
表-26
实施例L-1:8-环丙基-4-[2-(羟基甲基)-3-[2-[5-(4-羟基-4-甲基-哌啶-1-羰基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮的合成
步骤-I:8-环丙基-4-[2-(羟基甲基)-3-[2-[5-(4-羟基-4-甲基-哌啶-1-羰基)-2-吡啶基]-1-(2-三甲基甲硅烷基乙氧基甲基)吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(L-1-I):按照如B-1合成的步骤-I中所述的相似程序使用中间体II-22a和III-8-a合成中间体L-1-I。LCMS:m/z;774.3(M+1)+。
步骤-II:8-环丙基-4-[2-(羟基甲基)-3-[2-[5-(4-羟基-4-甲基-哌啶-1-羰基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(L-1):中间体L-1-I(0.16g,0.206mmol)溶解于CH2Cl2(10mL)并冷却至0℃。向其添加TFA(2mL,过量)并搅拌6h。在反应完成之后,减压去除溶剂并向残余物添加饱和NaHCO3溶液(30mL)。使用EtOAc(20mL×2)进行萃取;合并的有机层用水(30mL)、盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。使用硅胶柱色谱(CH2Cl2中3%MeOH)纯化获得的残余物以提供标题化合物L-1(0.05g,37%产率)。LCMS:m/z 644.5(M+1)+。1H NMR(DMSO-d6,400MHz,)δ0.74-0.77(m,2H);0.99-1.04(m,2H);1.16(s,3H);1.44-1.56(m,4H);1.95-1.99(m,1H);3.37-3.42(m,2H);3.90-3.95(m,2H);4.08-4.12(m,1H);4.22-4.28(m,1H);4.32-4.38(m,1H);4.45(s,1H);4.52-4.58(m,2H);4.80(bs,1H);6.81(s,1H);6.89(dd,J1=1.3Hz,J2=7.9Hz,1H);7.01(d,J=1.8Hz,1H);7.24(d,J=3.9Hz,1H);7.43-7.48(芳香族,2H);7.55-7.59(芳香族,1H);7.66(d,J=8.4Hz,1H);7.89(dd,J1=1.8Hz,J2=8.0Hz,1H);8.11(d,J=7.9Hz,1H);8.36(d,J=4.9Hz,1H);8.63(d,J=1.3Hz,1H);12.47(s,1H)。
使用如针对L-1合成所述的相似反应顺序和程序合成以下化合物。
表-27
实施例M-1:8-环丙基-4-[2-甲基-3-(6-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮
步骤-I:按照如B-1合成的步骤-I中所述的相似程序使用中间体II-25和III-1合成实施例M-1。LCMS:m/z 487.2(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.70-0.80(m,2H);0.95-1.05(m,2H);1.91-2.04(m,1H);2.16(s,3H);3.83-4.00(m,2H);4.38-4.55(m,2H);6.79-6.88(芳香族,2H);6.91(d,J=7.9Hz,1H);7.34-7.58(芳香族,6H);7.63(d,J=7.6Hz,1H);7.99(d,J=7.1Hz,2H);8.85(s,1H);12.77(s,1H)。
使用如针对实施例M-1合成所述的相似反应顺序和程序合成以下实施例。
表-28
实施例N-1:4-[3-[2-氨基-6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-8-环丙基-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮的合成
步骤-I:N-[4-氯-6-[4-(羟基甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-2-基]-2,2-二甲基-丙酰胺(N-1-I):XI-8(2.2g,5.69mmol)在无水THF中的溶液冷却至-78℃并滴加DIBAL(甲苯中1M溶液)(28.4mL,28.45mmol)。得到的反应混合物在-78℃搅拌1小时并经2-3小时的时段缓慢温至0℃。然后通过缓慢添加饱和NH4Cl溶液(50mL)、随后添加1NHCl(10mL)来猝灭反应。使用EtOAc(30mL×3)进行提取。合并的有机层用盐水(60mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩以获得粗产物,其使用二乙醚结晶以提供标题化合物N-1-I(1.1g,55%)。LCMS:m/z;359(M+1)+。
步骤-II:N-[4-氯-6-[4-(氯甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-2-基]-2,2-二甲基-丙酰胺(N-1-II):0℃下向中间体N-1-I(1.1gm,3.06mmol)在甲苯(30mL)中的溶液添加亚硫酰氯(4.4mL,61.31mmol),得到的反应混合物在室温搅拌1小时。反应完成之后,减压浓缩至干。残余物冷却至0℃并使用饱和NaHCO3溶液中和。得到的沉淀经过滤,用己烷洗涤并真空干燥以提供中间体N-1-II(1.1g,95%)。LCMS:m/z 377(M+1)+。
步骤-III:N-[4-氯-6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-2-基]-2,2-二甲基-丙酰胺(N-1-III):向中间体N-1-II(1.1g,2.91mmol)和粉末化K2CO3(0.603g,4.37mmol)在无水DMF中的混合物添加N-甲基哌嗪(0.48mL,4.37mmol);在室温N2气氛下搅拌反应混合物过夜。反应混合物倒入冰冷水(50mL)并滤掉得到的沉淀。用NaCl水溶液饱和滤液并用EtOAc(50mL)萃取。有机层用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并浓缩以获得粗产物,其通过硅胶柱色谱纯化以提供标题产物N-1-III(0.470g,39%)。LCMS:m/z 441(M+1)+。
步骤-IV:N-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-2-基]-2,2-二甲基-丙酰胺(N-1-IV):向中间体N-1-III(0.3g,0.68mmol)和III-1(0.34g,0.81mmol)在二氧己环(20mL)中的混合物添加Na2CO3(0.18g,1.70mmol)在水(4mL)中的溶液;室温下使用氩吹扫得到的反应混合物20分钟。向得到的溶液添加Pd(PPh3)4(0.078g,0.06mmol)并在95℃加热10h。反应完成之后(通过TLC监测),减压浓缩以提供粗产物,其通过硅胶柱色谱(CH2Cl2中1%三乙胺和2%MeOH)洗脱纯化以提供标题化合物N-1-IV(0.1g,21%)。LCMS:m/z 698(M+1)+。
步骤-V:4-[3-[2-氨基-6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-8-环丙基-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(实施例N-1):向中间体N-1-IV(0.1g,0.14mmol)在MeOH(5mL)中的溶液添加水(2.5mL)中的氢氧化钠(0.057g,1.43mmol);并加热至80℃过夜。反应完成之后(通过TLC监测),减压浓缩反应混合物以提供粗产物,其通过制备型TLC(CH2Cl2中10%MeOH)纯化以提供作为黄色固体的标题化合物N-1(0.022g,27%)。LCMS:m/z 614.4(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.68-0.74(m,2H);0.96-1.01(m,2H);1.90-1.99(m,1H);2.11(bs,6H);2.24-2.38(m,6H);2.60-2.66(m,2H);3.41(bs,2H);3.81-3.88(m,2H);4.36-4.48(m,2H);6.22(bs,2H);6.45(d,J=1.9Hz,1H);6.78(s,1H);6.88(d,J=8.2Hz,1H);7.26(d,J=8.0Hz,2H);7.31-7.42(芳香族,3H);7.59(d,J=8.2Hz,1H);7.72(d,J=8.2Hz,2H);11.7(s,1H)。
按照如针对N-1合成描述的相似的程序顺序合成以下实施例。
表-29
实施例O-1:4-[3-[2-氨基-6-[4-(吗啉-4-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-8-环丙基-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮
步骤-I:4-[2-氨基-4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苄腈(O-1-I):按照针对N-1-IV合成(实施例N-1)描述的相似程序使用中间体XI-10和III-1合成中间体O-1-I。LCMS:m/z 527(M+1)+。
步骤-II:4-[2-氨基-4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苯甲酸(O-1-II):向中间体O-1-I(0.15g,0.28mmol)在甲醇(3mL)中的搅拌混悬液添加NaOH(0.113g,2.84mmol)在水(1mL)中的溶液,并使得到的反应混合物回流过夜。减压去除溶剂并使用10%柠檬酸水溶液酸化反应混合物。得到的沉淀经过滤,用水洗涤并真空干燥以提供目标化合物O-1-II(0.12g,77%)。LCMS:m/z 546(M+1)+。
步骤-III:4-[3-[2-氨基-6-[4-(吗啉-4-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-8-环丙基-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(O-1):向中间体O-1-II(0.12g,0.22mmol)和吗啉(0.09mL,1.1mmol)在无水DMF(1mL)中的溶液添加苯并三唑-1-基-氧基三吡咯烷基鏻六氟磷酸盐(0.17g,0.33mmol);并在室温搅拌反应混合物过夜。然后将反应混合物缓慢倒入冰冷水(10mL)并过滤得到的固体沉淀。其溶解于CH2Cl2(30mL),经无水Na2SO4干燥,过滤并减压浓缩以提供标题化合物O-1(0.015g,11%)。LCMS:m/z 615.3(M++1)。1H NMR(DMSO-d6,400MHz)δ0.70-0.78(m,2H);0.98-1.11(m,2H);1.92-2.02(m,1H);2.08(s,3H);2.12-2.30(m,4H);3.50-3.68(m,4H);3.82-3.95(m,2H);4.40-4.50(m,2H);6.31(bs,2H);6.61(s,1H);6.82(s,1H);6.91(d,J=7.8Hz,1H);7.35-7.48(芳香族,5H);7.62(d,J=8.0Hz,1H);7.88(d,J=7.8Hz,2H);11.86(s,1H)。
实施例P-1:8-环丙基-4-[3-[6-[1-(3-羟基丙基)-3,6-二氢-2H-吡啶-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮的合成
步骤-I:4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]-3,6-二氢-2H-吡啶-1-羧酸叔丁酯(P-1-I):按照如B-1合成的步骤-I中所述的相似程序,使用中间体II-23和III-1合成中间体P-1-I。LCMS:m/z;746.3(M+1)+。
步骤-II:4-[3-[6-[1-[3-[叔丁基(二甲基)甲硅烷基]氧基丙基]-3,6-二氢-2H-吡啶-4-基]-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-8-环丙基-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(P-1-II):按照如H-1-II合成(实施例H-1)的步骤-II中所述的相似程序从中间体P-1-I合成中间体P-1-II。LCMS:m/z;704.4(M-TBS)+。
步骤-III:8-环丙基-4-[3-[6-[1-(3-羟基丙基)-3,6-二氢-2H-吡啶-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(P-1):使用如实施例H-1合成的步骤-III中所述的相似程序合成实施例P-1。LCMS:m/z 550.3(M+1)+。1H NMR(DMSO-d6,400MHz):δ0.70-0.78(m,2H);0.96-1.02(m,2H);1.56-1.66(m,2H);1.90-2.00(m,1H);2.09(s,3H);2.38-3.47(m,4H);2.54-2.63(m,2H);3.06-3.14(m,2H);3.42(t,J=6.2Hz,2H);3.84-3.91(m,2H);4.36-4.46(m,2H);6.26(s,1H);6.54(s,1H);6.79(s,1H);6.89(d,J=8.0Hz,1H);7.40-7.46(芳香族,3H);7.59(d,J=8.1Hz,1H);8.77(s,1H);12.30(bs,1H)。
使用如针对P-1合成描述的相似程序合成以下实施例。
表-30
实施例P-3:8-环丙基-4-[3-[6-[1-(3-羟基丙基)-4-哌啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮的合成
步骤-I:向P-1(0.085g,0.15mmol)在MeOH(15mL)中的溶液添加10%Pd/C(10mg)并在H2气氛下搅拌得到的反应混合物16h。反应完成之后(通过TLC监测),通过硅藻土过滤反应混合物并用CH2Cl2中过量10%MeOH洗涤。减压浓缩滤液并使用二乙醚洗涤残余物以提供标题产物P-3(0.018g,21%)。LCMS:m/z;552.3(M++1)。1H NMR(DMSO-d6,400MHz)δ0.70-0.80(m,2H);0.98-1.08(m,2H);1.58-1.82(m,6H);1.93-2.08(m,2H);2.10(s,3H);2.72-2.78(m,2H);2.90-3.20(m,2H);3.44(t,J=6.2Hz,3H);3.85-3.95(m,3H);4.40-4.51(m,2H);6.08(s,1H);6.82(s,1H);6.92(d,J=8.1Hz,1H);7.38-7.50(芳香族,3H);7.62(d,J=8.0Hz,1H);8.76(s,1H);12.20(bs,1H)。
实施例P-4:8-环丙基-4-[2-甲基-3-[6-(1,2,3,6-四氢吡啶-5-基)-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮的合成
步骤-I 5-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7-(p-甲苯基磺酰基)吡咯并[2,3-d]嘧啶-6-基]-3,6-二氢-2H-吡啶-1-羧酸叔丁酯(P-4-I):按照如P-1合成的步骤-I中所述的相似程序,使用中间体II-24和III-1合成中间体P-4-I。LCMS:m/z;746(M+1)+。
步骤-II:8-环丙基-4-[2-甲基-3-[6-(1,2,3,6-四氢吡啶-5-基)-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(P-4):使用如针对P-1合成的Boc-脱保护(步骤-II中)和甲苯磺酰基-脱保护(步骤-III中)所述的相似程序,合成实施例P-4。LCMS:m/z;492.3(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.73-0.78(m,2H);0.98-1.06(m,2H);1.95-2.10(m,1H);2.11(s,3H);2.20-2.30(m,2H);2.85-2.92(m,2H);3.60-3.65(m,2H);3.85-3.95(m,2H);4.40-4.52(m,2H);6.25(s,1H);6.65-6.70(芳香族,1H);6.82(d,J=1.4Hz,1H);6.91(d,J=8.1Hz,1H);7.40-7.50(芳香族,3H);7.62(d,J=7.9Hz,1H);8.79(s,1H);12.35(s,1H)。
实施例P-5:4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺
步骤-I:4-[4-氯-1-(p-甲苯基磺酰基)吡咯并[2,3-b]吡啶-2-基]-3,6-二氢-2H-吡啶-1-羧酸叔丁酯(P-5-I):按照如中间体II-23合成所述的程序合成中间体P-5-I。LCMS:m/z;488.3(M+1)+。
步骤-II:4-[4-氯-1-(p-甲苯基磺酰基)吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺(P-5-II):中间体P-5-I(2g,6.94mmol)溶解于CH2Cl2(20mL),在0℃向其添加三氟乙酸(10mL,过量)并在室温搅拌反应混合物2h。减压去除溶剂并向其添加饱和NaHCO3溶液(50mL)。使用EtOAc(30mL×2)进行提取;用水(60mL)、盐水(60mL)洗涤合并的有机层,经无水Na2SO4干燥,过滤并减压浓缩以提供相应的Boc-脱保护的中间体(1.6g)。其(0.5g,1.28mmol)溶解于CH2Cl2(10mL)并冷却至0℃。向其顺序添加吡啶(1.0mL,12.8mmol)和4-硝基苯基氯甲酸酯(1.29g,6.44mmol)。在减压去除溶剂之前,室温搅拌反应混合物3h。向获得的残余物添加DMF(10mL)并冷却至0℃。向该反应混合物添加TEA(1.6mL,12.8mmol)和二甲基胺盐酸盐(0.525g,6.44mmol)并在室温搅拌16h。其然后使用水(30mL)稀释并使用EtOAc(20mL×3)进行提取。合并的有机层用盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。使用硅胶柱色谱(己烷中25%丙酮)纯化残余物以提供标题化合物P-5-II(0.25g,53%产率)。LCMS:m/z;459.2(M+1)+。
步骤-III:4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1-(p-甲苯基磺酰基)吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺(P-5-III):按照如B-1-I合成的步骤-II中所述的相似程序,使用中间体P-5-II和III-5合成中间体P-5-III。LCMS:m/z;732.4(M+1)+。
步骤-IV:4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺(P-5):中间体P-5-III(0.15g,0.19mmol)溶解于丙酮(5mL);向其添加NaOH水溶液(0.038g,0.96mmol,2mL)并在70℃搅拌反应混合物16h。最后,减压去除丙酮并向残余物添加水。使用EtOAc(10mL×3)进行提取。合并的有机层用盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。使用制备型TLC(CH2Cl2中5%MeOH)纯化残余物以提供标题化合物P-5(0.02g,17%产率)。LCMS:m/z;578.1(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.76-0.80(m,2H);1.04-1.09(m,2H);1.89-1.97(m,1H);2.56-2.68(m,2H);2.87(bs,6H);3.44-3.52(m,2H);3.92-3.98(m,2H);4.02-4.08(m,2H),4.24-4.34(m,1H);4.50-4.60(m,3H);6.28(s,1H);6.32(s,1H);6.78(s,1H);6.92(d,J=8.0Hz,1H);7.36(d,J=8.8Hz,1H);7.48-7.58(芳香族,3H);7.82(d,J=8.0Hz,1H);8.31(d,J=4.7Hz,1H);10.97(bs,1H)。
实施例P-6:4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)苯基]-2-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-1H-吡咯并[2,3-b]吡啶-5-腈
按照如实施例B-1合成所述的相似反应顺序和程序从中间体XI-11和III-13开始合成实施例P-6。LCMS:m/z;609.2(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.73-0.79(m,2H);0.99-1.06(m,2H);1.91-2.02(m,1H);2.16(s,3H);2.25-2.45(m,8H);3.49(s,2H);4.00-4.08(m,2H),4.48-4.55(m,2H);6.81(s,1H);6.92(d,J=7.9Hz,1H);7.09(s,1H);7.40(d,J=7.3Hz,2H);7.61-7.71(芳香族,4H);7.82(s,1H);7.94(d,J=7.0Hz,2H);8.70(d,J=1.7Hz,1H);12.93(bs,1H)。
实施例P-7:6-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]吡啶-3-羧酸
按照上述反应顺序并使用针对L-1合成描述的相似程序合成实施例P-7。在碱水解条件下进行酯水解。LCMS:m/z;547.1(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.74-0.78(m,2H);0.99-1.04(m,2H);1.93-2.00(m,1H);3.88-3.98(m,2H);4.20-4.30(m,1H);4.32-4.38(m,1H);4.52-4.60(m,2H);4.70-4.82(m,1H);6.81(s,1H);6.87-6.90(芳香族,2H);7.20(bs,1H);7.44(d,J=7.8Hz,2H);7.48(d,J=7.3Hz,1H);7.55-7.59(芳香族,1H);7.67(d,J=8.3Hz,1H);7.93(d,J=7.8Hz,1H);8.12(dd,J1=1.9Hz,J2=7.8Hz,1H);8.31(d,J=4.9Hz,1H);12.38(bs,1H)。
实施例P-8:8-环丙基-4-[3-[2-[4-(1,2-二羟基乙基)苯基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮
步骤-I:按照针对G-1合成(步骤-I和步骤-III)描述的程序合成中间体P-8-I。P-8-I(0.05g,0.095mmol)溶解于THF-水(4mL+1mL),向其顺序添加N-甲基吗啉-N-氧化物(0.017g,0.142mmol)和OsO4(0.003g,0.0095mmol)。反应混合物在室温搅拌16h,然后使用EtOAc(30mL)稀释。有机层用水(30mL)、盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。使用制备型TLC(CH2Cl2中5%MeOH)纯化获得的残余物以提供标题化合物P-8(0.01g,18%产率)。LCMS:m/z;562.2(M+1)+。1H NMR(CD3OD,400MHz)δ0.74-0.80(m,2H);1.02-1.10(m,2H);1.92-2.00(m,1H);3.54-3.68(m,3H);3.96-4.06(m,2H);4.50-4.56(m,1H);4.58-4.64(m,2H);4.70-4.74(m,1H);6.69(s,1H);6.82(s,1H);6.94(d,J=8.0Hz,1H);7.22(d,J=4.8Hz,1H);7.46(d,J=7.9Hz,2H);7.51(d,J=7.5Hz,2H);7.58-7.62(芳香族,1H);7.70(d,J=8.0Hz,1H);7.82(d,J=8.0Hz,2H);8.24(d,J=3.9Hz,1H)。
实施例P-9:8-环丙基-4-[2-(羟基甲基)-3-[2-[1-(1-异丙基氮杂环丁烷-3-基)咪唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮
步骤-I:按照针对D-1合成描述的相似的反应顺序和程序合成中间体P-9-I。LCMS:m/z;801.4(M+1)+。按照针对D-1合成(步骤-II和III)描述的相似程序使用中间体P-9-I合成实施例P-9(丙酮用于还原性胺化步骤)。LCMS:m/z 589.2(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.74-0.77(m,2H);0.91(d,J=6.3Hz,6H);0.99-1.04(m,2H);1.93-2.00(m,1H);3.22(t,J=6.8Hz,2H);3.63-3.70(m,2H);3.86-3.96(m,2H);4.20-4.38(m,2H);4.52-4.58(m,2H);4.74-4.80(m,1H);4.82-4.88(m,1H);6.41(d,J=1.5Hz,1H);6.81(d,J=1.5Hz,1H);6.88(d,J=7.8Hz,1H);7.15(d,J=3.9Hz,1H);7.41(d,J=7.8Hz,1H);7.44(d,J=7.3Hz,1H);7.53-7.57(m,1H);7.67(d,J=7.8Hz,1H);7.85(s,1H);8.05(s,1H);8.19(d,J=4.9Hz,1H);12.00(bs,1H)。
实施例P-10:4-[4-[2-(羟基甲基)-3-[8-(1-羟基-1-甲基-乙基)-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基]苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺
步骤-I:向中间体P-10-I(0.18g,0.59mmol)和中间体P-10-II(0.34g,0.59mmol)在1-丙醇(8mL)中的溶液添加Na2CO3水溶液(0.06g,1.18mmol,0.6mL)并使氩经该溶液吹扫15min。最后,向其添加PdCl2(PPh3)2(0.033g,0.047mmol)并继续氩吹扫另外10min。最后,反应混合物在90℃搅拌16h。在反应完成之后,减压去除溶剂并首先使用硅胶柱色谱、然后使用制备型TLC(CH2Cl2中5%MeOH)纯化残余物以提供标题化合物P-10(60mg,17%产率)。LCMS:m/z;596.2(M+1)+。1H NMR(DMSO-d6,400MHz)δ1.40(s,6H);2.73(s,6H);3.20-3.40(m,4H);3.80-3.96(m,4H);4.10-4.35(m,2H);4.50-4.60(m,2H);4.70-4.80(m,1H);5.25(s,1H);6.21(s,1H);6.49(s,1H);7.10-7.18(芳香族,2H);7.24(dd,J1=1.5Hz,J2=8.3Hz,1H);7.38-7.46(芳香族,2H);7.50-7.54(芳香族,1H);7.70(d,J=8.3Hz,1H);8.22(d,J=4.9Hz,1H);11.91(bs,1H)。
可以使用以下的反应顺序和条件合成中间体P-10-II
按照如针对中间体III-8-a合成所述的相似反应顺序和条件合成中间体P-10-II,使用P-10-IIb作为起始材料。
使用如针对P-10合成所述的相似的反应顺序和条件,还合成了以下化合物。
表-31
实施例P-27:3-[4-[4-[3-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-3,6-二氢-2H-吡啶-1-基]-3-氧-丙腈
步骤-I:4-[4-[3-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-3,6-二氢-2H-吡啶-1-羧酸叔丁酯(P-27-II):按照针对P-10合成描述的程序,使用P-27-I和III-9合成中间体P-27-II。LCMS:m/z625.4(M+1)+。
步骤-II:8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-(1,2,3,6-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(P-27-III):0℃下向P-27-II(0.3g)在无水CH2Cl2(6mL)中的搅拌溶液添加TFA(0.3mL)并在相同温度下搅拌反应混合物2h。在反应完成之后,减压去除溶剂,并使用EtOAc(30mL)稀释残余物。有机层用饱和NaHCO3溶液(30mL×2)、水(30mL)、盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。没有任何进一步纯化而使用获得的残余物。LCMS:m/z 525.1(M+1)+。
步骤-III:3-[4-[4-[3-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-3,6-二氢-2H-吡啶-1-基]-3-氧-丙腈(P-27):向P-27-III(0.25g,0.48mmol)、氰基乙酸(0.08g,0.95mmol)和DIPEA(0.42mL,2.38mmol)在DMF(2mL)中的搅拌溶液添加HATU(0.27g,0.71mmol)并在室温下搅拌反应混合物16h。在反应完成之后,其使用水(30mL)稀释并使用EtOAc(30mL×2)进行提取。合并的有机层用水(50mL)、盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。使用硅胶柱色谱(CH2Cl2中5%MeOH作为洗脱剂)纯化获得的残余物以提供希望化合物P-27。LCMS:m/z592.1(M+1)+。1H NMR(DMSO-d6,,400MHz)δ0.74-0.84(m,2H);1.00-1.08(m,2H);1.20-1.28(m,2H);1.96-2.06(m,1H);2.56-2.60(m,1H);3.30-3.36(m,1H);3.62-3.68(m,1H);3.76-3.86(m,1H);3.92-4.02(m,1H);4.06-4.26(m,4H);4.34-4.42(m,2H);4.46-4.56(m,1H);4.76-4.86(m,1H);6.24(d,J=12.7Hz,1H);6.48-6.55(芳香族,1H);6.77(s,1H);6.84(d,J=11.3Hz,1H);7.16(bs,1H);7.41-7.57(芳香族,3H);8.26(d,J=4.9Hz,1H);11.98(d,J=7.6Hz,1H)。
使用如针对P-27合成所述的相似的反应顺序和条件,还合成了以下化合物。
表-32
实施例P-31:2-[4-[4-[3-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-3,6-二氢-2H-吡啶-1-基]乙酰胺
步骤-I:向P-27-III(0.05g,0.095mmol)和TEA(0.026mL)在无水CH2Cl2(3mL)中的搅拌溶液添加2-溴乙酰胺(0.017g,0.123mmol);并在室温搅拌反应混合物16h。在反应完成之后,使用CH2Cl2(30mL)稀释并用水(30mL);盐水(30mL)洗涤;经无水Na2SO4干燥,过滤并减压浓缩。使用硅胶柱色谱(CH2Cl2中5%MeOH)纯化获得的残余物以提供希望化合物P-31。LCMS:m/z;582.2(M+1)+。1H NMR(CD3OD,400MHz)δ0.78-0.84(m,2H);1.06-1.12(m,2H);1.94-2.04(m,1H);2.56-2.66(m,2H);2.78-2.86(m,2H);3.17(s,2H);3.30-3.40(m,2H);3.86-3.96(m,1H);3.98-4.10(m,1H);4.44-4.64(m,4H);6.28(s,1H);6.39(bs,1H);6.74(s,1H);6.79(d,J=11.0Hz,1H);7.17(d,J=4.8Hz,1H);7.44-7.50(芳香族,2H);7.56-7.62(芳香族,1H);8.21(d,J=4.8Hz,1H)。
实施例P-32:4-[4-[2-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-3-(羟基甲基)-4-吡啶基]-1H-吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺
使用如针对P-25和P-14合成所述的相似的反应顺序和条件,合成了该实施例。
LCMS:m/z 597.1(M+1)+。1H NMR(400MHz;CDCl3):δ0.76-0.80(m,2H);1.07-1.12(m,2H);1.88-1.95(m,1H);2.58-2.64(m,2H);2.87(s,6H);3.47(t,J=5.3Hz,2H);4.02-4.20(m,5H);4.46-4.54(m,3H);6.27(bs,1H);6.37(s,1H);6.66(s,1H);6.69(d,J=11.0Hz,1H);7.40-7.46(芳香族,2H);8.30-8.34(芳香族,1H);8.61(d,J=4.3Hz,1H);11.22(bs,1H)。
实施例Q-1:8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[5-(2-吗啉代乙氧基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮的合成
步骤-I:2-溴-5-(2-溴乙氧基)吡啶(Q-1-I):6-溴-3-羟基吡啶(2g,11.56mmol)溶解于无水DMF(20mL);向其添加1,2-二溴乙烷(10g,57.82mmol)并在室温下搅拌反应混合物16h。在反应完成之后,向其添加水(100mL)并使用EtOAc(30mL×3)进行提取。合并的有机层用水(100mL)、盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。使用硅胶柱色谱纯化残余物以提供Q-1-I(2.7g,86%产率)。LCMS:m/z;280.0(M+1)+。
步骤-II:4-[2-[(6-溴-3-吡啶基)氧基]乙基]吗啉(Q-1-II):向Q-1-I(1.2g,4.3mmol)在无水DMF(10mL)中的溶液添加吗啉(1.1g,12.8mmol)并在室温下搅拌反应混合物16h。在反应完成之后,向其添加水(100mL)并使用EtOAc(30mL×3)进行提取。合并的有机层用水(100mL)、盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。使用硅胶柱色谱(CH2Cl2中2%MeOH作为洗脱剂)纯化残余物以提供Q-1-II(2.7g,定量产量)。LCMS:m/z;287.1(M+1)+。
步骤-III:2-[[4-氯-2-[5-(2-吗啉代乙氧基)-2-吡啶基]吡咯并[2,3-b]吡啶-1-基]甲氧基]乙基-三甲基-硅烷(Q-1-III):按照如针对XI-3合成描述的相似程序,使用中间体Q-1-II和IV-5合成本中间体(58%产率)。LCMS:m/z;489.3(M+1)+。
步骤-IV:8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[5-(2-吗啉代乙氧基)-2-吡啶基]-1-(2-三甲基甲硅烷基乙氧基甲基)吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(Q-1-IV):按照如针对I-1合成(步骤-I)描述的程序,使用中间体Q-1-III和III-9合成本中间体。LCMS:m/z;780.4(M+1)+。
步骤-V:8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[5-(2-吗啉代乙氧基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(Q-1):L-1如针对L-1合成(步骤-II)描述的。
LCMS:m/z;650.3(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.76-0.82(m,2H);1.01-1.09(m,2H);1.95-2.05(m,1H);2.40-2.50(m,4H),2.71(t,J=6.0Hz,2H);3.58(t,J=4.4Hz,4H);3.78-3.88(m,1H);3.90-4.00(m,1H);4.22(t,J=6.0Hz,2H);4.25-4.30(m,1H);4.35-4.45(m,2H);4.48-4.58(m,1H);4.80(bs,1H);6.76-6.80(芳香族,2H);6.84(d,J=11.2Hz,1H);7.19(d,J=4.0Hz,1H);7.42-7.54(芳香族,3H);7.54-7.60(芳香族,1H);8.00(d,J=8.8Hz,1H);8.29(d,J=5.2Hz,1H);8.34(d,J=2.8Hz,1H);12.20(bs,1H)。
使用与针对Q-1合成描述的相似的反应顺序和条件,还合成了以下实施例。
表-33
实施例R-1:4-[3-[2-[1-(1-乙酰基氮杂环丁烷-3-基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-8-环丙基-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮的合成
步骤-I:4-氯-1-(p-甲苯基磺酰基)-2-(1,2,3,6-四氢吡啶-4-基)吡咯并[2,3-b]吡啶(R-1-I):0℃下向P-5-I(2.4g)在CH2Cl2(20mL)中的溶液添加三氟乙酸(5mL)并在室温搅拌反应混合物3h。在反应完成之后,减压去除溶剂并向残留物添加饱和NaHCO3溶液(60mL)。使用EtOAc(50mL×3)进行提取;合并的有机层用水(100mL);盐水(100mL)洗涤;经无水Na2SO4干燥,过滤并减压浓缩。获得的残余物(1.9g,定量)没有任何纯化而使用。LCMS:m/z;388.2(M+1)+。
步骤-II:3-[4-[4-氯-1-(p-甲苯基磺酰基)吡咯并[2,3-b]吡啶-2-基]-3,6-二氢-2H-吡啶-1-基]氮杂环丁烷-1-羧酸叔丁酯(R-1-II):R-1-I(2g,5.16mmol)、1-Boc-3-氮杂环丁酮(2.65g,15.5mmol)和ZnCl2(2.1g,15.5mmol)在MeOH(60mL)中的溶液搅拌30min。向其分部分添加NaBH3CN(0.98g,15.5mmol),并搅拌反应混合物4h。在反应完成之后,减压去除MeOH并向残余物添加饱和NH4Cl溶液(60mL)。使用EtOAc(50mL×3)进行提取;合并的有机层用水(100mL);盐水(100mL)洗涤;经无水Na2SO4干燥,过滤并减压浓缩。获得的残余物在己烷(60mL)中搅拌并过滤以提供希望的R-1-II(2.6g,89%)。LCMS:m/z;543.1(M+1)+。
步骤-III:3-[4-(4-氯-1H-吡咯并[2,3-b]吡啶-2-基)-3,6-二氢-2H-吡啶-1-基]氮杂环丁烷-1-羧酸叔丁酯(R-1-III):按照如P-5合成(步骤-IV)中描述的相似程序。LCMS:389.1(M+1)+。
步骤-IV:4-[3-[2-[1-(氮杂环丁烷-3-基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-8-环丙基-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(R-1-IV):按照P-10合成中描述的反应条件进行Suzuki偶联,使用中间体R-1-III和III-9。然后用TFA处理Boc-脱保护的化合物(步骤-I,如在R-1-I的步骤-I中所描述的)以提供希望的中间体R-1-IV(2步产率17%)。LCMS:m/z;580.1(M+1)+。
步骤-V:0℃下向R-1-IV(0.25g,0.43mmol)和吡啶(0.17g,2.15mmol)在CH2Cl2(6mL)中的溶液添加乙酰氯(0.068g,0.86mmol)并搅拌反应混合物30min。向其添加饱和NaHCO3溶液(20mL)并使用CH2Cl2(20mL×2)进行提取。合并的有机层用水(50mL);盐水(50mL)洗涤;经无水Na2SO4干燥,过滤并减压浓缩。获得的残余物在MeOH中搅拌,向其添加K2CO3(0.29g,2.15mmol)。搅拌16h之后,然后滤掉K2CO3并减压浓缩MeOH。使获得的残余物首先经受硅胶柱色谱,然后经受制备型HPLC纯化以提供希望化合物R-1(35mg,13%产率)。LCMS:m/z 622.3(M+1)+。1H NMR(DMSO-d6,,400MHz)δ0.75-0.82(m,2H);0.98-1.04(m,2H);1.73(s,3H);1.94-2.02(m,1H);2.40-2.50(m,4H);3.07(bs,2H);3.18-3.25(m,1H);3.66-3.72(m,1H);3.75-4.05(m,4H);4.08-4.25(m,2H);4.30-4.40(m,2H);4.45-4.55(m,1H);4.70-4.85(m,1H);6.16(s,1H);6.49(bs,1H);6.75(s,1H);6.82(d,J=11.2Hz,1H);7.10-7.16(芳香族,1H);7.38-7.46(芳香族,2H);7.50-7.58(芳香族,1H);8.22(d,J=4.8Hz1H);11.82(bs,1H)。
实施例R-2:8-环丙基-4-[3-[2-[1-(1-乙基氮杂环丁烷-3-基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮的合成
步骤-I:向R-1-IV(0.4g,0.69mmol)在CH2Cl2-MeOH(5mL+5mL)中的溶液添加HOAc(2滴)并使其冷却至0℃。向其添加NaB(OAc)3H(0.56g,2.64mmol),随后滴加乙醛(0.4mL,过量)。室温下搅拌反应混合物1h,然后减压去除溶剂。然后向其添加饱和NaHCO3溶液(30mL)并使用CH2Cl2(20mL×3)进行提取。合并的有机层用水(50mL);盐水(50mL)洗涤;经无水Na2SO4干燥,过滤并减压浓缩。使用硅胶柱色谱、随后通过从乙腈结晶来纯化残余物以提供希望化合物R-2(0.12g,28%产率)。LCMS:m/z 608.3(M+1)+。1H NMR(DMSO-d6,,400MHz)δ0.76-0.82(m,2H);0.87(t,J=7.2Hz,3H);1.00-1.09(m,2H);1.96-2.04(m,1H);2.38-2.50(m,6H);2.81(bs,2H);2.95-3.04(m,3H);3.40-3.48(m,2H);3.78-3.84(m,1H);3.90-4.00(m,1H);4.18-4.30(m,1H);4.35-4.44(m,2H);4.48-4.56(m,1H);4.70-4.90(m,1H);6.16(s,1H);6.49(bs,1H);6.77(s,1H);6.83(d,J=11.2Hz,1H);7.10-7.16(芳香族,1H);7.38-7.46(芳香族,2H);7.52-7.58(芳香族,1H);8.23(d,J=4.9Hz,1H);11.82(bs,1H)。
使用针对R-2合成描述的相似的反应顺序和条件,还合成了以下实施例。
表-34
实施例R-5:8-环丙基-4-[3-[2-[1-(1-乙基氮杂环丁烷-3-羰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮的合成
步骤-I:3-[4-(4-氯-1H-吡咯并[2,3-b]吡啶-2-基)-3,6-二氢-2H-吡啶-1-羰基]氮杂环丁烷-1-羧酸叔丁酯(R-5-II):使用P-27合成(步骤-III)中描述的条件,使用R-5-I和N-Boc-氮杂环丁烷-3-羧酸合成了本中间体。LCMS:m/z;417.1(M+1)+。
步骤-II:4-[3-[2-[1-(氮杂环丁烷-3-羰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-8-环丙基-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮(R-5-III):按照R-1-IV合成(步骤-IV)中描述的条件,使用R-5-II和III-9合成了该特定中间体(Suzuki偶联,随后使用TFA的Boc-脱保护)。LCMS:m/z;608.1(M+1)+。
步骤-III:如针对R-2合成描述的进行该特定的转化。LCMS:m/z;636.2(M+1)+。1HNMR(DMSO-d6,,400MHz)δ0.76-0.90(m,5H);1.00-1.08(m,2H);1.96-2.02(m,1H);2.30-2.45(m,4H);3.08-3.16(m,2H);3.44-3.52(m,4H);3.62-3.66(m,1H);3.78-3.86(m,1H);3.90-4.06(m,2H);4.12-4.28(m,2H);4.34-4.44(m,2H);4.48-4.58(m,1H);4.75-4.85(m,1H);6.18-6.26(芳香族,1H);6.46-6.56(芳香族,1H);6.77(s,1H);6.83(d,J=11.3Hz,1H);7.12-7.18(芳香族,1H);7.40-7.46(芳香族,2H);7.52-7.58(芳香族,1H);8.25(d,J=4.9Hz,1H);11.92(bs,1H)。
实施例S-1:8-环丙基-4-[2-(羟基甲基)-3-[6-[1-(1-丙-2-烯酰基-3-哌啶基)吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮
步骤-I:中间体S-1-I(按照D-1合成的步骤-I和步骤-III中描述的程序合成,使用中间体II-7&III-5)(0.43g,0.64mmol)在室温下在CH2Cl2(5mL)和三氟乙酸(1mL)的混合物中搅拌1h。在反应完成之后,减压去除溶剂并使用EtOAc(30mL)稀释残余物。有机层用饱和NaHCO3溶液(30mL)、盐水(30mL)洗涤,经无水Na2SO4干燥,过滤并减压浓缩。获得的残余物(0.3g,0.52mmol)溶解于CH2Cl2(5mL)并冷却至0℃。向其添加吡啶(0.05mL,0.57mmol)和丙烯酰氯(0.05mL,0.625mmol)并搅拌反应混合物30min。其使用CH2Cl2(30mL)稀释并使用饱和NaHCO3溶液(30mL);盐水(30mL)洗涤;经无水Na2SO4干燥,过滤并减压浓缩。获得的残余物使用制备型HPLC纯化以提供标题化合物S-1(10mg)。LCMS:m/z;630.2(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.72-0.78(m,2H);0.98-1.08(m,2H);1.50-1.60(m,2H);1.80-2.26(m,4H);2.94-3.20(m,2H);3.80-4.10(m,2H);4.20-4.70(m,5H);5.40-5.48(m,1H);5.64-5.76(m,1H);6.04-6.18(芳香族,1H);6.77-6.92(芳香族,5H);7.49(d,J=7.5Hz,1H);7.58-7.63(芳香族,2H);7.74(d,J=7.3Hz,1H);8.14(s,1H);8.45(s,1H);8.79(s,1H);12.68(s,1H)。
实施例S-2:2-[3-[4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]吡唑-1-基]氮杂环丁烷-1-基]乙腈
步骤-I:实施例S-2按照D-1合成的步骤-I中描述的相似程序合成,使用中间体S-2-I和III-5。LCMS:m/z;586.2(M+1)+。1H NMR(DMSO-d6,400MHz)δ0.73-0.77(m,2H);1.20-1.28(m,2H);1.94-2.00(m,1H);3.58-3.66(m,2H);3.76-3.80(m,4H);3.88-3.96(m,2H);4.16-4.38(m,2H);4.52-4.58(m,2H);4.72-4.82(m,1H);5.02-5.10(m,1H);6.41(d,J=1.8Hz,1H);6.81(d,J=1.3Hz,1H);6.88(dd,J1=1.4Hz,J2=8.2Hz,1H);7.16(d,J=3.8Hz,1H);7.41(d,J=7.7Hz,1H);7.45(d,J=7.1Hz,1H);7.52-7.57(芳香族,1H);7.66(d,J=8.0Hz,1H);8.08(s,1H);8.19(d,J=3.8Hz,1H);8.42(s,1H);12.09(s,1H)。
实施例S-3:8-环丙基-4-[2-(羟基甲基)-3-[2-[5-(4-甲基哌嗪-1-基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮
实施例S-3按照针对实施例C-1合成描述的相似反应顺序和条件合成。LCMS:m/z;601.3(M+1)+。1H NMR(CDCl3,400MHz)δ0.76-0.80(m,2H);1.01-1.09(m,2H);1.91-1.95(m,1H);2.39(s,3H);2.58-2.48(m,4H),3.31-3.43(m,4H);3.91-3.99(m,3H);4.41(bs,1H);4.51-46.1(m,3H);6.66(s,1H);6.78(d,J=1.6Hz,1H);6.91-6.93(芳香族,1H);7.10-7.21(芳香族,2H);7.35-7.38(芳香族,1H);7.52-7.63(芳香族,3H);7.82(d,J=8.4Hz,1H);8.30(s,1H);8.37(s,1H);10.01(s,1H)。
还可以按照以上描述的一般合成来合成以下列表的实例,但不限于这些:
6-氟-4-[5-氟-2-(羟基甲基)-3-[2-[5-[[4-(氧杂环丁烷-3-基)哌嗪-1-基]甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-8-(1-羟基-1-甲基-乙基)-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-4-[5-氟-2-(羟基甲基)-3-[2-[5-[[4-(2,2,2-三氟乙基)哌嗪-1-基]甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-8-(1-羟基-1-甲基-乙基)-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[3-[2-[5-[[4-(2,2-二氟乙基)哌嗪-1-基]甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-5-氟-2-(羟基甲基)苯基]-6-氟-8-(1-羟基-1-甲基-乙基)-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[3-[2-[5-[[4-(2,2-二氟乙基)哌嗪-1-基]甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-5-氟-2-(羟基甲基)苯基]-6-氟-8-(1-氟代环丙基)-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-8-(1-氟代环丙基)-4-[5-氟-2-(羟基甲基)-3-[2-[5-[[4-(2,2,2-三氟乙基)哌嗪-1-基]甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-8-(1-氟代环丙基)-4-[5-氟-2-(羟基甲基)-3-[2-[5-[[4-(氧杂环丁烷-3-基)哌嗪-1-基]甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[5-氟-2-(羟基甲基)-3-[6-[5-[[4-(氧杂环丁烷-3-基)哌嗪-1-基]甲基]-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[6-[5-[[4-(氧杂环丁烷-3-基)哌嗪-1-基]甲基]-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[5-氟-2-(羟基甲基)-3-[6-[5-[[4-(2,2,2-三氟乙基)哌嗪-1-基]甲基]-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[6-[5-[[4-(2,2,2-三氟乙基)哌嗪-1-基]甲基]-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[5-[[4-(2,2-二氟乙基)哌嗪-1-基]甲基]-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]-5-氟-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[5-[[4-(2,2-二氟乙基)哌嗪-1-基]甲基]-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[6-[5-[(3-羟基-3-甲基-氮杂环丁烷-1-基)甲基]-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[5-氟-2-(羟基甲基)-3-[6-[5-[(3-羟基-3-甲基-氮杂环丁烷-1-基)甲基]-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[5-氟-2-(羟基甲基)-3-[2-[5-[(3-羟基-3-甲基-氮杂环丁烷-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[5-[(3-羟基-3-甲基-氮杂环丁烷-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[5-[(4-羟基-4-甲基-1-哌啶基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[5-氟-2-(羟基甲基)-3-[2-[5-[(4-羟基-4-甲基-1-哌啶基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[5-氟-2-(羟基甲基)-3-[6-[5-[(4-羟基-4-甲基-1-哌啶基)甲基]-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[6-[5-[(4-羟基-4-甲基-1-哌啶基)甲基]-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[6-[5-(吗啉代甲基)-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[5-氟-2-(羟基甲基)-3-[6-[5-(吗啉代甲基)-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[5-氟-2-(羟基甲基)-3-[2-[5-(吗啉代甲基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[5-(吗啉代甲基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[5-[[3,5-二甲基-4-(2,2,2-三氟乙基)哌嗪-1-基]甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-5-氟-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[5-[[3,5-二甲基-4-(氧杂环丁烷-3-基)哌嗪-1-基]甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-5-氟-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[5-[[4-(2,2-二氟乙基)-3,5-二甲基-哌嗪-1-基]甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-5-氟-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[5-[[4-(2,2-二氟乙基)-3-甲基-哌嗪-1-基]甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-5-氟-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[5-氟-2-(羟基甲基)-3-[2-[5-[[3-甲基-4-(2,2,2-三氟乙基)哌嗪-1-基]甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[5-氟-2-(羟基甲基)-3-[2-[5-[[3-甲基-4-(氧杂环丁烷-3-基)哌嗪-1-基]甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[5-氟-2-(羟基甲基)-3-[2-[5-[1-甲基-1-[4-(氧杂环丁烷-3-基)哌嗪-1-基]乙基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[5-氟-2-(羟基甲基)-3-[2-[5-[1-甲基-1-[4-(2,2,2-三氟乙基)哌嗪-1-基]乙基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[5-[1-[4-(2,2-二氟乙基)哌嗪-1-基]-1-甲基-乙基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-5-氟-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[5-[[4-(2,2-二氟乙基)哌嗪-1-基]甲基]-4-氟-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-5-氟-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[5-氟-3-[2-[4-氟-5-[[4-(2,2,2-三氟乙基)哌嗪-1-基]甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[5-氟-3-[2-[4-氟-5-[[4-(氧杂环丁烷-3-基)哌嗪-1-基]甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[5-氟-2-(羟基甲基)-3-[2-[5-[[4-(氧杂环丁烷-3-基甲基)哌嗪-1-基]甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[5-[[4-(氧杂环丁烷-3-基甲基)哌嗪-1-基]甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[5-氟-2-(羟基甲基)-3-[6-[5-[[4-(氧杂环丁烷-3-基甲基)哌嗪-1-基]甲基]-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
1-[4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苯甲酰基]哌啶-4-腈;
4-[3-[6-[4-(4-氨基哌啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-8-环丙基-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[3-[6-[4-(3-氨基哌啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-8-环丙基-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[4-(3-氧代哌嗪-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[4-(4-甲基-3-氧-哌嗪-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[4-[(4-甲基-3-氧-哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[4-[(3-氧代哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
1-[[4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苯基]甲基]哌啶-4-腈;
1-[[4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苯基]甲基]哌啶-3-腈;
6-环丙基-2-[3-[6-[4-[(4-乙基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-3,4-二氢异喹啉-1-酮;
6-环丙基-2-[3-[6-[4-[(4-环丙基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-3,4-二氢异喹啉-1-酮;
6-环丙基-2-[2-甲基-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]异喹啉-1-酮;
6-环丙基-2-[2-甲基-3-[6-[4-[(4-甲基-3-氧-哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]异喹啉-1-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[4-[(4-甲基-3-氧-哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]异喹啉-1-酮;
6-环丙基-2-[3-[6-[4-[(4-环丙基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]异喹啉-1-酮;
6-环丙基-2-[3-[6-[4-[(4-乙基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]异喹啉-1-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[4-(哌嗪-1-基甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
2-[3-[6-[4-[(4-氨基-1-哌啶基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-酞嗪-1-酮;
2-[3-[6-[4-[(3-氨基-1-哌啶基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-酞嗪-1-酮;
6-环丙基-2-[2-甲基-3-[6-[4-(4-甲基哌嗪-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
6-环丙基-2-[2-甲基-3-[6-(4-吗啉代苯基)-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
6-环丙基-2-[2-甲基-3-[6-[4-(4-甲基哌嗪-1-基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
6-环丙基-2-[3-[6-[4-(1,4-二甲基哌嗪-2-基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]酞嗪-1-酮;
2-[3-[2-氨基-6-[4-(4-甲基哌嗪-1-基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-酞嗪-1-酮;
2-[3-[2-氨基-6-(4-吗啉代苯基)-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-酞嗪-1-酮;
2-[3-[2-氨基-6-(4-吗啉代苯基)-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-异喹啉-1-酮;
2-[3-[2-氨基-6-(4-哌嗪-1-基苯基)-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-异喹啉-1-酮;
2-[3-[2-氨基-6-[4-(4-甲基哌嗪-1-基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-异喹啉-1-酮;
2-[3-[2-氨基-6-(1-甲基吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-异喹啉-1-酮;
2-[3-[2-氨基-6-[1-(2-羟基乙基)吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-异喹啉-1-酮;
2-[3-[2-氨基-6-(5-甲基-6,7-二氢-4H-吡唑并[1,5-a]吡嗪-3-基)-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-异喹啉-1-酮;
2-[3-[2-氨基-6-(6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪-3-基)-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-异喹啉-1-酮;
3-[2-[2-甲基-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-1-氧-3,4-二氢异喹啉-6-基]丁酸;
2-[1-[2-[2-甲基-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-1-氧-3,4-二氢异喹啉-6-基]环丙基]乙酸;
2-[2-甲基-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-6-[1-(1,2,5-噁二唑-3-基)环丙基]-3,4-二氢异喹啉-1-酮;
2-[2-甲基-3-[6-(4-吗啉代苯基)-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-6-[1-(1,2,5-噁二唑-3-基)环丙基]-3,4-二氢异喹啉-1-酮;
2-[1-[4-[2-甲基-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-8-基]环丙基]乙酸;
2-[1-[4-[2-甲基-3-[6-[4-(4-甲基哌嗪-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-8-基]环丙基]乙酸;
8-环丙基-4-[2-甲基-3-[6-[5-甲基-1-[(1-甲基-2-氧-4-哌啶基)甲基]咪唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
2-环丙基-6-[2-甲基-3-[6-(6-吗啉代-3-吡啶基)-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-7,8-二氢嘧啶并[5,4-f][1,4]氧杂吖庚因-5-酮;
2-环丙基-6-[2-甲基-3-[6-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-7,8-二氢嘧啶并[5,4-f][1,4]氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[4-[(3-甲基-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[4-[[4-(2-羟基乙基)哌嗪-1-基]甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[3-[6-[4-(3-氮杂双环[3.3.2]癸烷-3-基甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-8-环丙基-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[5-(5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
7-环丙基-2-甲基-3-[2-甲基-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]喹唑啉-4-酮;
7-环丙基-2-甲基-3-[2-甲基-3-[6-[4-(4-甲基哌嗪-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]喹唑啉-4-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[1-[(3R)-1-甲基-3-哌啶基]吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
6-环丙基-2-[3-[6-[1-[(3R)-1-乙基-3-哌啶基]吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]酞嗪-1-酮;
6-环丙基-2-[3-[6-[5-[(1-乙基-4-哌啶基)氧基]-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]酞嗪-1-酮;
6-环丙基-2-[3-[6-[5-(1-乙基氮杂环丁烷-3-基)氧基-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]酞嗪-1-酮;
6-环丙基-2-[3-[6-[1-(1-乙基-4-哌啶基)-3,6-二氢-2H-吡啶-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]酞嗪-1-酮;
8-环丙基-4-[3-[6-[1-(1-乙基-4-哌啶基)-3,6-二氢-2H-吡啶-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[5-(1-甲基-4-哌啶基)-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[5-(1-甲基-3-哌啶基)-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[5-(1-甲基-3-哌啶基)-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[5-(1-甲基-4-哌啶基)-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
8-环丙基-6-氟-4-[3-[2-[1-(2-羟基乙基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-(1-甲基磺酰基-3,6-二氢-2H-吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[3-[6-[1-(3-羟基氮杂环丁烷-1-羰基)-3,6-二氢-2H-吡啶-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[4-[3-[8-(1-氟代环丙基)-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基]-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺;
4-[4-[3-[8-(1-羟基环丙基)-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基]-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺;
4-[4-[3-(8-环丙基-6-氟-5-氧-2,3-二氢吡啶并[3,2-f][1,4]氧杂吖庚因-4-基)-5-氟-2-(羟基甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺;
8-(1-羟基-1-甲基-乙基)-4-[2-(羟基甲基)-3-[2-[5-(4-羟基-4-甲基-哌啶-1-羰基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[5-(4-羟基-4-甲基-哌啶-1-羰基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢吡啶并[3,2-f][1,4]氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[5-(4-羟基-4-甲基-哌啶-1-羰基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1H-1,4-苯并二吖庚因-5-酮;
8-环丙基-4-[3-[2-[5-[(2,4-二甲基哌嗪-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[5-[(2,4-二甲基哌嗪-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-5-氟-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[5-[1-(3,4-二甲基哌嗪-1-基)乙基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-5-氟-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-8-(1-羟基环丙基)-4-[2-(羟基甲基)-3-[2-[5-(4-甲基哌嗪-1-基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-8-(1-羟基-1-甲基-乙基)-4-[2-(羟基甲基)-3-[2-[5-(4-甲基哌嗪-1-基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[1-(氧杂环丁烷-3-基)咪唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[1-(氧杂环丁烷-3-基)咪唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-(1-羟基-1-甲基-乙基)-4-[2-(羟基甲基)-3-[2-[1-(氧杂环丁烷-3-基)咪唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[1-(氧杂环丁烷-3-基)咪唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[6-[1-(氧杂环丁烷-3-基)咪唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-8-(1-羟基-1-甲基-乙基)-4-[2-(羟基甲基)-3-[6-[1-(氧杂环丁烷-3-基)咪唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-(1-四氢吡喃-4-基咪唑-4-基)-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-8-(1-羟基-1-甲基-乙基)-4-[2-(羟基甲基)-3-[2-[1-(3-羟基-3-甲基-氮杂环丁烷-1-羰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[1-(3,3,3-三氟代丙酰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-8-(1-羟基-1-甲基-乙基)-4-[2-(羟基甲基)-3-[2-[1-(3,3,3-三氟代丙酰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[4-[2-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-3-(羟基甲基)-4-吡啶基]-1H-吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺;
4-[4-[5-氟-3-[6-氟-8-(1-羟基-1-甲基-乙基)-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基]-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺;
4-[3-[2-[1-(氮杂环丁烷-1-羰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]-5-氟-2-(羟基甲基)苯基]-8-环丙基-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
3-[4-[4-[5-氟-3-[6-氟-8-(1-羟基-1-甲基-乙基)-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基]-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-3,6-二氢-2H-吡啶-1-基]-3-氧-丙腈;
3-[4-[4-[3-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-5-氟-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-3,6-二氢-2H-吡啶-1-基]-3-氧-丙腈。
生物活性
重组人Bruton酪氨酸激酶(Btk)抑制测定。
对于A2e腺苷警体的放射件配体结合
将全长人BTK(hBTK,Genbank#NM_000061.2)克隆入pFastBac-HTB载体(Invitrogen,目录号10359-016)。使用Bac-to-Bac(R)杆状病毒表达系统(Invitrogen,目录号10359-016)在Sf9细胞中表达具有N’-末端6XHis标签的hBTK基因,并通过Ni-NTA方法纯化重组蛋白。hBTK的洗脱缓冲液由50mM Hepes pH 8.0、300mM NaCl、10%甘油、1mM二硫苏糖醇和200mM咪唑组成。
使用来自Cis Bio的通用酪氨酸激酶测定试剂盒(KinEASE-TKTM#62TK0PEB)进行抑制测定。该测定是基于铕穴状化合物标记的抗磷酸酪氨酸抗体和链霉亲和素标记的荧光团XL-665之间荧光共振能量转移(FRET)的原理。在未抑制的激酶反应中,生物素化的肽底物(Tk-生物素)在中间体酪氨酸位点磷酸化,其被最终用作FRET供体的抗磷酸酪氨酸抗体捕获。链霉亲和素标记的XL-665强力结合Tk-生物素底物并用作FRET受体。得到的FRET信号在665nm测量。该特定荧光(665nm)与游离抗体赋予的背景荧光(620nm)的比例与激酶活性成正比。药物介入、例如本公开的Btk抑制剂对激酶活性的抑制将导致减少的FRET信号。
使用终体积10μl反应缓冲液中20ng/ml rhBtk进行Btk抑制测定,所述反应缓冲液含有77μM ATP和1μM TK-生物素底物,50mM HEPES pH 7.0,5mM MgCl2,1mM DTT,0.01%Tween 20和50nM一定范围浓度的抑制剂。以ATP的KM(77μM)以及Tk-生物素底物的KM(1μM)进行激酶反应。90min之后,通过添加在含有EDTA的检测缓冲液中62.5nM浓度的SA-XL665来停止反应。最后向反应添加5μl TK抗体-穴状化合物,并孵育板另外60min。使用Flexstation(Molecular Devices)读取荧光,以340nm激发并以620nm(对于穴状化合物)和665nm(对于FRET)发射。计算每孔的2次发射的比例并表示如下:
特定信号=比例(样品)-比例(阴性)
比例=(665nm/620nm)X 104
平均比例=∑比例/3(三次重复)
对于每个数据点,基于未抑制的反应来计算%抑制,其被认为是相对于无活性或底物对照的100%活性。然后使用四参数逻辑方程拟合剂量响应数据,使用Graph-padPrism 5软件以确定抑制常数50(IC50)。
如果重组人Btk(hBtk)酶抑制的IC50低于10μM和更特别低于1.0μM,则认为本公开的化合物是活性的。
通过在小鼠脾细胞中的CD69表达测量B细胞活化的抑制:
为了测试BTK抑制剂在抑制B细胞受体(BCR)介导的B细胞活化中的作用,我们开发了基于流式细胞术的测定以分析来自小鼠的总脾细胞中B细胞群中CD69表达。解剖C57/BL6小鼠脾并通过用注射器柱塞研磨组织、随后RBC裂解(0.85%氯化铵)并在PBS中几次洗涤来分离脾细胞。最后,在含有10%FBS的RPMI培养基中培养细胞。
在100%DMSO(200X)中从2mM开始半对数稀释测试化合物。将1X105脾细胞与1uL稀释的测试化合物在200uL培养基中在U底96孔板(Greiner)中在37℃、5%CO2下孵育30min。对照孔接收1uL 100%DMSO而无任何化合物。细胞用3ug/mL山羊抗鼠IgM(Sigma,目录号M8644)刺激并孵育18-20h。刺激之后,细胞在含有1%FBS的冷PBS中洗涤并用抗CD69-PE(eBioscience,目录号12-0691-83)和抗CD19-PeCy5(eBioscience,目录号15-0193-83)的1:100稀释液在冰上染色1h。然后,细胞用含有1%FBS的PBS洗涤三次,并通过GuavaEasycyte Mini流式细胞仪系统(Millipore)分析。使用Weasel软件(WEHI,Melbourne)分析流式细胞术数据。首先使用CD19标志物门控B细胞。然后分析CD69表达为CD69+ve细胞在CD19内的百分比。使用下式计算每个数据点的百分比活性:
使用S形剂量响应来拟合百分比活性,使用Graph-pad Prism 5软件中的可变斜率逻辑方程来确定抑制常数50(IC50)。
如果IC50值低于10μM,则认为本公开的化合物在B细胞特异性功能测定(CD69表达的抑制)中是活性的。
以下表1中给出了本公开代表性化合物的数据:
表1:hBTK和小鼠脾细胞IC50值:
尽管参考其某些优选的实施方案非常详细地描述了主题,但其他具体实施方案也是可能的。因此,本公开的精神和范围不应限于其中包含的优选的实施方案的描述。
Claims (4)
1.一种化合物,及其药学可接受的盐,所述化合物选自:
8-环丙基-4-[2-甲基-3-[6-[4-(哌嗪-1-基甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-环丙基-2-[2-甲基-3-[6-[4-(哌嗪-1-基甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-3,4-二氢异喹啉-1-酮;
6-环丙基-2-[2-甲基-3-[6-[3-(哌嗪-1-基甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-3,4-二氢异喹啉-1-酮;
8-环丙基-4-[2-甲基-3-[6-[3-(哌嗪-1-基甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[4-(吗啉代甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-环丙基-2-[2-甲基-3-[6-[4-(吗啉代甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-3,4-二氢异喹啉-1-酮;
8-环丙基-4-[2-甲基-3-[6-[3-(吗啉代甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-环丙基-2-[2-甲基-3-[6-[3-(吗啉代甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-3,4-二氢异喹啉-1-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-环丙基-2-[2-甲基-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-3,4-二氢异喹啉-1-酮;
6-环丙基-2-[3-[6-[4-[(4-乙基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-3,4-二氢异喹啉-1-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[4-(吗啉代甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[4-[(4-羟基-4-甲基-1-哌啶基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[4-[(4-乙基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]异喹啉-1-酮;
6-环丙基-2-[2-甲基-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]异喹啉-1-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
6-环丙基-2-[2-甲基-3-[6-[4-[(3-氧代哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-3,4-二氢异喹啉-1-酮;
6-环丙基-2-[3-[6-[4-[(4-羟基-4-甲基-1-哌啶基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-3,4-二氢异喹啉-1-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
1-[[4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苯基]甲基]哌啶-4-腈;
8-环丙基-4-[2-甲基-3-[2-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[4-[(4-乙基哌嗪-1-基)甲基]苯基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[4-[(3-羟基-3-甲基-氮杂环丁烷-1-基)甲基]苯基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[2-氟-4-[(4-甲基哌嗪-1-基)甲基]苯基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[3-氟-4-[(4-甲基哌嗪-1-基)甲基]苯基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-甲基-苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[6-[(4-甲基哌嗪-1-基)甲基]-3-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[6-[(4-乙基哌嗪-1-基)甲基]-3-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-环丙基-2-[3-[6-[4-[(4-羟基-1-哌啶基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-3,4-二氢异喹啉-1-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[4-(4-甲基哌嗪-1-基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]异喹啉-1-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[4-(4-甲基哌嗪-1-基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[4-(4-甲基哌嗪-1-基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[4-(1-甲基-3,6-二氢-2H-吡啶-4-基)苯基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[4-(4-甲基吗啉-2-基)苯基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[1-(1-甲基-4-哌啶基)吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[1-(1-甲基-4-哌啶基)吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[1-(1-甲基-4-哌啶基)吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]异喹啉-1-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[4-(1-甲基-4-哌啶基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]异喹啉-1-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[1-(1-甲基-4-哌啶基)吡唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[1-(1-甲基-3-哌啶基)吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[1-(1-甲基氮杂环丁烷-3-基)吡唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[1-(1-异丙基氮杂环丁烷-3-基)吡唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-环丙基-2-[2-(羟基甲基)-3-[2-[1-(1-甲基-4-哌啶基)吡唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]酞嗪-1-酮;
8-环丙基-4-[3-[2-[1-(1-乙基氮杂环丁烷-3-基)吡唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[6-(1-异丙基氮杂环丁烷-3-基)氧基-3-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-环丙基-2-[3-[6-[1-(1-乙基-4-哌啶基)吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]酞嗪-1-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[3-甲基-1-(1-甲基氮杂环丁烷-3-基)吡唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[1-(氧杂环丁烷-3-基)吡唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-(1-四氢吡喃-4-基吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[4-[(1-甲基-4-哌啶基)氧基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[4-(1-甲基氮杂环丁烷-3-基)氧基苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-环丙基-2-[3-[6-[4-[1-(2-羟基乙基)-4-哌啶基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]异喹啉-1-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[5-[(4-甲基哌嗪-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[5-[(4-甲基哌嗪-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[5-[(4-甲基哌嗪-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢吡啶并[2,3-f][1,4]氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[5-[(4-乙基哌嗪-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[5-[(4-环丙基哌嗪-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[5-[(4-甲基磺酰基哌嗪-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[5-[(4-异丙基哌嗪-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[5-[(1,1-二氧-1,4-噻嗪烷-4-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[5-[[4-(2,2,2-三氟乙基)哌嗪-1-基]甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[5-[(4-环丙基磺酰基哌嗪-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[5-[(1,1-二氧-1,4-噻嗪烷-4-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[[6-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-3-吡啶基]甲基]-N,N-二甲基-哌嗪-1-羧酰胺;
8-环丙基-4-[3-[2-[5-[(4-乙基哌嗪-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[4-(4-氟-1-甲基-4-哌啶基)苯基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[4-(3-氟-1-甲基-3-哌啶基)苯基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[4-(4-甲基哌嗪-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[4-(4-羟基哌啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[4-(3-羟基哌啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[4-(4-羟基-4-甲基-哌啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[4-(哌啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[4-(哌嗪-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]-N-(2,2,2-三氟乙基)苯甲酰胺;
8-环丙基-4-[3-[6-[4-(3-羟基氮杂环丁烷-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[4-(吡咯烷-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[4-(4-甲氧基哌啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[4-(3-甲氧基氮杂环丁烷-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
1-[4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苯甲酰基]吡咯烷-2-羧酸;
1-[4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苯甲酰基]哌啶-3-羧酸;
1-[4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苯甲酰基]哌啶-4-羧酸;
6-环丙基-2-[2-甲基-3-[6-[4-(吗啉-4-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-3,4-二氢异喹啉-1-酮;
6-环丙基-2-[3-[6-[4-(4-羟基哌啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-3,4-二氢异喹啉-1-酮;
6-环丙基-2-[3-[6-[4-(3-羟基氮杂环丁烷-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-3,4-二氢异喹啉-1-酮;
6-环丙基-2-[2-甲基-3-[6-[4-(4-甲基哌嗪-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-3,4-二氢异喹啉-1-酮;
6-环丙基-2-[2-甲基-3-[6-[4-(哌嗪-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-3,4-二氢异喹啉-1-酮;
6-环丙基-2-[3-[6-[4-(4-羟基哌啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]酞嗪-1-酮;
8-环丙基-4-[3-[6-[4-(4-羟基哌啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]吡啶-3-羧酰胺;
8-环丙基-4-[2-(羟基甲基)-3-[2-[5-(4-羟基-4-甲基-哌啶-1-羰基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[4-(4-羟基-4-甲基-哌啶-1-羰基)苯基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[5-(4-羟基-4-甲基-哌啶-1-羰基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
7-环丙基-2-[2-甲基-3-(6-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)苯基]-4,5-二氢-3H-2-苯并吖庚因-1-酮;
6-环丙基-2-[2-甲基-3-(6-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)苯基]-3,4-二氢异喹啉-1-酮;
8-环丙基-4-[2-甲基-3-[6-(4-吗啉代苯基)-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
2-[3-[2-氨基-6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-7-环丙基-4,5-二氢-3H-2-苯并吖庚因-1-酮;
4-[3-[2-氨基-6-(6-吗啉代-3-吡啶基)-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-8-环丙基-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[3-[2-氨基-6-[4-(吗啉-4-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-8-环丙基-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[1-(3-羟基丙基)-3,6-二氢-2H-吡啶-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
7-环丙基-2-[3-[6-[1-(2-羟基乙基)-3,6-二氢-2H-吡啶-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-4,5-二氢-3H-2-苯并吖庚因-1-酮;
8-环丙基-4-[3-[6-[1-(3-羟基丙基)-4-哌啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-2,3-二氢-1、4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-(1,2,3,6-四氢吡啶-5-基)-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺;
4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)苯基]-2-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-1H-吡咯并[2,3-b]吡啶-5-腈;
6-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]吡啶-3-羧酸;
8-环丙基-4-[3-[2-[4-(1,2-二羟基乙基)苯基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[1-(1-异丙基氮杂环丁烷-3-基)咪唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[4-[2-(羟基甲基)-3-[8-(1-羟基-1-甲基-乙基)-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基]苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-(1-甲基磺酰基-3,6-二氢-2H-吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[1-(氧杂环丁烷-3-基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
3-[4-[4-[3-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-3,6-二氢-2H-吡啶-1-基]-3-氧-丙腈;
4-[3-[2-[1-(氮杂环丁烷-1-羰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-8-环丙基-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[1-(1-丙-2-烯酰基-3哌啶基)吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
2-[3-[4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]吡唑-1-基]氮杂环丁烷-1-基]乙腈;
1-[4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苯基]哌啶-4-腈;
1-[4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苯基]哌啶-3-腈;
4-[3-[6-[4-(4-氨基哌啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-8-环丙基-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[3-[6-[4-(3-氨基哌啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-8-环丙基-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[4-(3-氧代哌嗪-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[4-(4-甲基-3-氧-哌嗪-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[4-[(4-甲基-3-氧-哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[4-[(3-氧代哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
1-[[4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苯基]甲基]哌啶-4-腈;
1-[[4-[4-[3-(8-环丙基-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苯基]甲基]哌啶-3-腈;
8-环丙基-4-[3-[6-[4-[(4-环丙基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[4-[(4-乙基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-环丙基-2-[3-[6-[4-[(4-乙基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-3,4-二氢异喹啉-1-酮;
6-环丙基-2-[3-[6-[4-[(4-环丙基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-3,4-二氢异喹啉-1-酮;
1-[[4-[4-[3-(6-环丙基-1-氧-3,4-二氢异喹啉-2-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苯基]甲基]哌啶-4-腈;
1-[[4-[4-[3-(6-环丙基-1-氧-3,4-二氢异喹啉-2-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苯基]甲基]哌啶-3-腈;
6-环丙基-2-[2-甲基-3-[6-[4-[(3-氧代哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-3,4-二氢异喹啉-1-酮;
6-环丙基-2-[2-甲基-3-[6-[4-[(4-甲基-3-氧-哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-3,4-二氢异喹啉-1-酮;
6-环丙基-2-[2-甲基-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]异喹啉-1-酮;
6-环丙基-2-[2-甲基-3-[6-[4-[(4-甲基-3-氧-哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]异喹啉-1-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[4-[(4-甲基-3-氧-哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]异喹啉-1-酮;
6-环丙基-2-[3-[6-[4-[(4-环丙基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]异喹啉-1-酮;
6-环丙基-2-[3-[6-[4-[(4-乙基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]异喹啉-1-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[4-(哌嗪-1-基甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
6-环丙基-2-[2-甲基-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
2-[3-[6-[4-[(4-氨基-1-哌啶基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-酞嗪-1-酮;
2-[3-[6-[4-[(3-氨基-1-哌啶基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-酞嗪-1-酮;
6-环丙基-2-[2-甲基-3-[6-[4-(4-甲基哌嗪-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
6-环丙基-2-[2-甲基-3-[6-(4-吗啉代苯基)-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
6-环丙基-2-[2-甲基-3-[6-[4-(4-甲基哌嗪-1-基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
6-环丙基-2-[3-[6-[4-(1,4-二甲基哌嗪-2-基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]酞嗪-1-酮;
2-[3-[2-氨基-6-[4-(4-甲基哌嗪-1-基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-酞嗪-1-酮;
2-[3-[2-氨基-6-(4-吗啉代苯基)-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-酞嗪-1-酮;
2-[3-[2-氨基-6-(4-吗啉代苯基)-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-异喹啉-1-酮;
2-[3-[2-氨基-6-(4-哌嗪-1-基苯基)-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-异喹啉-1-酮;
2-[3-[2-氨基-6-[4-(4-甲基哌嗪-1-基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-异喹啉-1-酮;
2-[3-[2-氨基-6-(1-甲基吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-异喹啉-1-酮;
2-[3-[2-氨基-6-[1-(2-羟基乙基)吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-异喹啉-1-酮;
2-[3-[2-氨基-6-(5-甲基-6,7-二氢-4H-吡唑并[1,5-a]吡嗪-3-基)-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-异喹啉-1-酮;
2-[3-[2-氨基-6-(6,7-二氢-4H-吡唑并[5,1-c][1,4]噁嗪-3-基)-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-6-环丙基-异喹啉-1-酮;
3-[2-[2-甲基-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-1-氧-3,4-二氢异喹啉-6-基]丁酸;
2-[1-[2-[2-甲基-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-1-氧-3,4-二氢异喹啉-6-基]环丙基]乙酸;
2-[2-甲基-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-6-[1-(1,2,5-噁二唑-3-基)环丙基]-3,4-二氢异喹啉-1-酮;
2-[2-甲基-3-[6-(4-吗啉代苯基)-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-6-[1-(1,2,5-噁二唑-3-基)环丙基]-3,4-二氢异喹啉-1-酮;
2-[1-[4-[2-甲基-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-8-基]环丙基]乙酸;
2-[1-[4-[2-甲基-3-[6-[4-(4-甲基哌嗪-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-8-基]环丙基]乙酸;
8-环丙基-4-[2-甲基-3-[6-[5-甲基-1-[(1-甲基-2-氧-4-哌啶基)甲基]咪唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[6-(4-羟基-4-甲基-1-哌啶基)-3-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
2-环丙基-6-[2-甲基-3-[6-(6-吗啉代-3-吡啶基)-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-7,8-二氢嘧啶并[5,4-f][1,4]氧杂吖庚因-5-酮;
2-环丙基-6-[2-甲基-3-[6-[6-(4-甲基哌嗪-1-基)-3-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-7,8-二氢嘧啶并[5,4-f][1,4]氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[4-[(3-甲基-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[3-[6-(2-环己基三唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]-8-环丙基-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[4-[[4-(2-羟基乙基)哌嗪-1-基]甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[3-[6-[4-(3-氮杂双环[3.3.2]癸烷-3-基甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-甲基-苯基]-8-环丙基-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-甲基-3-[6-[5-(5-甲基-2,5-二氮杂双环[2.2.1]庚烷-2-基)-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
7-环丙基-2-甲基-3-[2-甲基-3-[6-[4-[(4-甲基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]喹唑啉-4-酮;
7-环丙基-2-甲基-3-[2-甲基-3-[6-[4-(4-甲基哌嗪-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]喹唑啉-4-酮;
1-[[4-[4-[3-(7-环丙基-2-甲基-4-氧-喹唑啉-3-基)-2-甲基-苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]苯基]甲基]哌啶-3-羧酰胺;
6-环丙基-2-[2-(羟基甲基)-3-[6-[1-(1-甲基-4-哌啶基)吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]异喹啉-1-酮;
8-环丙基-4-[2-甲基-3-[6-[1-(1-甲基-4-哌啶基)吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[1-(1-甲基-4-哌啶基)吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[4-(吗啉代甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[4-[(4-羟基-4-甲基-1-哌啶基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[4-[(4-乙基哌嗪-1-基)甲基]苯基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[1-[(3R)-1-甲基-3-哌啶基]吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[1-[(3S)-1-甲基-3-哌啶基]吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[1-[(3S)-1-乙基-3-哌啶基]吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[1-[(3R)-1-乙基-3-哌啶基]吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[1-(1-乙基-4-哌啶基)吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[5-[(1-甲基-4-哌啶基)氧基]-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[5-[(1-乙基-4-哌啶基)氧基]-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[5-(1-甲基氮杂环丁烷-3-基)氧基-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[5-(1-乙基氮杂环丁烷-3-基)氧基-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[1-(1-甲基-4-哌啶基)吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
6-环丙基-2-[3-[6-[1-(1-乙基-4-哌啶基)吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]酞嗪-1-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[1-[(3R)-1-甲基-3-哌啶基]吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
6-环丙基-2-[3-[6-[1-[(3R)-1-乙基-3-哌啶基]吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]酞嗪-1-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[1-[(3S)-1-甲基-3-哌啶基]吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
6-环丙基-2-[3-[6-[1-[(3S)-1-乙基-3-哌啶基]吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]酞嗪-1-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[5-[(1-甲基-4-哌啶基)氧基]-2吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
6-环丙基-2-[3-[6-[5-[(1-乙基-4-哌啶基)氧基]-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]酞嗪-1-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[5-(1-甲基氮杂环丁烷-3-基)氧基-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
6-环丙基-2-[3-[6-[5-(1-乙基氮杂环丁烷-3-基)氧基-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]酞嗪-1-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[1-(1-甲基-4-哌啶基基)-3,6-二氢-2H-吡啶-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮;
6-环丙基-2-[3-[6-[1-(1-乙基-4-哌啶基)-3,6-二氢-2H-吡啶-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]酞嗪-1-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[1-(1-甲基-4-哌啶基)-3,6-二氢-2H-吡啶-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[6-[1-(1-乙基-4-哌啶基)-3,6-二氢-2H-吡啶-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[5-(1-甲基-4-哌啶基)-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[5-(1-甲基-3-哌啶基)-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-环丙基-2-[2-(羟基甲基)-3-[6-[5-(1-甲基-3-哌啶基)-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮和
6-环丙基-2-[2-(羟基甲基)-3-[6-[5-(1-甲基-4-哌啶基)-2-吡啶基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]酞嗪-1-酮.
4-[4-[3-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺;
8-环丙基-6-氟-4-[3-[2-[1-(2-羟基乙基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[1-(2-羟基丙酰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-(1-甲基磺酰基-3,6-二氢-2H-吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[4-[3-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺;
8-环丙基-6-氟-4-[3-[6-[1-(3-羟基氮杂环丁烷-1-羰基)-3,6-二氢-2H-吡啶-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[4-[3-[8-(1-氟环丙基)-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基]-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺;
4-[4-[3-[8-(1-羟基环丙基)-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基]-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺;
4-[4-[3-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-5-氟-2-(羟基甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺;
4-[4-[3-(8-环丙基-6-氟-5-氧-2,3-二氢吡啶并[3,2-f][1,4]氧杂吖庚因-4-基)-5-氟-2-(羟基甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-6-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[5-(4-羟基-4-甲基-哌啶-1-羰基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-(1-羟基-1-甲基-乙基)-4-[2-(羟基甲基)-3-[2-[5-(4-羟基-4-甲基-哌啶-1-羰基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[5-(4-羟基-4-甲基-哌啶-1-羰基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢吡啶并[3,2-f][1,4]氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[5-(4-羟基-4-甲基-哌啶-1-羰基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1H-1,4-苯并二氮吖庚因-5-酮;
8-环丙基-4-[3-[2-[5-[(2,4-二甲基哌嗪-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[5-[(2,4-二甲基哌嗪-1-基)甲基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-5-氟-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[3-[2-[5-[1-(3,4-二甲基哌嗪-1-基)乙基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-5-氟-2-(羟基甲基)苯基]-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[5-(4-甲基哌嗪-1-基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[3-[2-[5-[4-(2-羟基乙基)哌嗪-1-基]-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-8-(1-羟基环丙基)-4-[2-(羟基甲基)-3-[2-[5-(4-甲基哌嗪-1-基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-8-(1-羟基-1-甲基-乙基)-4-[2-(羟基甲基)-3-[2-[5-(4-甲基哌嗪-1-基)-2-吡啶基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[6-[1-(氧杂环丁烷-3-基)咪唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-4-[2-(羟基甲基)-3-[2-[1-(氧杂环丁烷-3-基)咪唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-(1-羟基-1-甲基-乙基)-4-[2-(羟基甲基)-3-[2-[1-(氧杂环丁烷-3-基)咪唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-(1-羟基-1-甲基-乙基)-4-[2-(羟基甲基)-3-[6-[1-(氧杂环丁烷-3-基)咪唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[1-(氧杂环丁烷-3-基)咪唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[6-[1-(氧杂环丁烷-3-基)咪唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-8-(1-羟基-1-甲基-乙基)-4-[2-(羟基甲基)-3-[6-[1-(氧杂环丁烷-3-基)咪唑-4-基]-7H-吡咯并[2,3-d]嘧啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-8-(1-羟基-1-甲基-乙基)-4-[2-(羟基甲基)-3-[2-[1-(氧杂环丁烷-3-基)咪唑-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-(1-四氢吡喃-4-基咪唑-4-基)-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-8-(1-羟基-1-甲基乙基)-4-[2-(羟基甲基)-3-[2-(1-四氢吡喃-4-基咪唑--4-基)-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[1-(氧杂环丁烷-3-基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-8-(1-羟基-1-甲基-乙基)-4-[2-(羟基甲基)-3-[2-[1-(氧杂环丁烷-3-基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-(1-四氢吡喃-4-基-3,6-二氢-2H-吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-8-(1-羟基-1-甲基-乙基)-4-[2-(羟基甲基)-3-[2-(1-四氢吡喃-4-基-3,6-二氢-2H-吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[1-(3-羟基-3-甲基-氮杂环丁烷-1-羰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-8-(1-羟基-1-甲基-乙基)-4-[2-(羟基甲基)-3-[2-[1-(3-羟基-3-甲基-氮杂环丁烷-1-羰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[3-[2-[1-(氮杂环丁烷-1-羰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-8-环丙基-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
3-[4-[4-[3-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-3,6-二氢-2H-吡啶-1-基]-3-氧-丙腈;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[1-(2-羟基丙酰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-(1-甲基磺酰基-3,6-二氢-2H-吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[2-(羟基甲基)-3-[2-[1-(3,3,3-三氟代丙酰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[3-[2-[1-(氮杂环丁烷-1-羰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]-2-(羟基甲基)苯基]-6-氟-8-(1-羟基-1-甲基-乙基)-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
3-[4-[4-[3-[6-氟-8-(1-羟基-1-甲基-乙基)-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基]-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-3,6-二氢-2H-吡啶-1-基]-3-氧-丙腈;
6-氟-8-(1-羟基-1-甲基-乙基)-4-[2-(羟基甲基)-3-[2-[1-(2-羟基丙酰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-8-(1-羟基-1-甲基-乙基)-4-[2-(羟基甲基)-3-[2-[1-(3,3,3-三氟代丙酰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-8-(1-羟基-1-甲基-乙基)-4-[2-(羟基甲基)-3-[2-(1-甲基磺酰基-3,6-二氢-2H-吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-8-(1-羟基-1-甲基-乙基)-4-[3-(羟基甲基)-4-[2-(1-甲基磺酰基-3,6-二氢-2H-吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-4-基]-2-吡啶基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
8-环丙基-6-氟-4-[3-(羟基甲基)-4-[2-(1-甲基磺酰基-3,6-二氢-2H-吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-4-基]-2-吡啶基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
3-[4-[4-[2-[6-氟-8-(1-羟基-1-甲基-乙基)-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基]-3-(羟基甲基)-4-吡啶基]-1H-吡咯并[2,3-b]吡啶-2-基]-3,6-二氢-2H-吡啶-1-基]-3-氧-丙腈;
3-[4-[4-[2-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-3-(羟基甲基)-4-吡啶基]-1H-吡咯并[2,3-b]吡啶-2-基]-3,6-二氢-2H-吡啶-1-基]-3-氧-丙腈;
4-[4-[2-[1-(氮杂环丁烷-1-羰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]-3-(羟基甲基)-2-吡啶基]-6-氟-8-(1-羟基-1-甲基-乙基)-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[4-[2-[1-(氮杂环丁烷-1-羰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]-3-(羟基甲基)-2-吡啶基]-8-环丙基-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[4-[2-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-3-(羟基甲基)-4-吡啶基]-1H-吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺;
4-[4-[2-[6-氟-8-(1-羟基-1-甲基-乙基)-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基]-3-(羟基甲基)-4-吡啶基]-1H-吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺;
4-[4-[5-氟-3-[6-氟-8-(1-羟基-1-甲基-乙基)-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基]-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺;
4-[4-[3-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-5-氟-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-N,N-二甲基-3,6-二氢-2H-吡啶-1-羧酰胺;
4-[3-[2-[1-(氮杂环丁烷-1-羰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]-5-氟-2-(羟基甲基)苯基]-8-环丙基-6-氟-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
4-[3-[2-[1-(氮杂环丁烷-1-羰基)-3,6-二氢-2H-吡啶-4-基]-1H-吡咯并[2,3-b]吡啶-4-基]-5-氟-2-(羟基甲基)苯基]-6-氟-8-(1-羟基-1-甲基-乙基)-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
3-[4-[4-[5-氟-3-[6-氟-8-(1-羟基-1-甲基-乙基)-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基]-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-3,6-二氢-2H-吡啶-1-基]-3-氧-丙腈;
3-[4-[4-[3-(8-环丙基-6-氟-5-氧-2,3-二氢-1,4-苯并氧杂吖庚因-4-基)-5-氟-2-(羟基甲基)苯基]-1H-吡咯并[2,3-b]吡啶-2-基]-3,6-二氢-2H-吡啶-1-基]-3-氧-丙腈;
8-环丙基-6-氟-4-[5-氟-2-(羟基甲基)-3-[2-(1-甲基磺酰基-3,6-二氢-2H-吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮;
6-氟-4-[5-氟-2-(羟基甲基)-3-[2-(1-甲基磺酰基-3,6-二氢-2H-吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-4-基]苯基]-8-(1-羟基-1-甲基-乙基)-2,3-二氢-1,4-苯并氧杂吖庚因-5-酮。
2.一种药物组合物,包含至少一种权利要求1的化合物和一种或多种药学可接受的赋形剂。
3.一种药物组合物,包含至少一种权利要求1的化合物和一种或多种药学可接受的赋形剂,与一种或多种额外治疗剂组合。
4.根据权利要求1的化合物或其药学可接受的盐在生产用于治疗由BtK介导的疾患或疾病的药剂中的用途。
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JP6182593B2 (ja) | 2017-08-16 |
CA2869954C (en) | 2023-01-03 |
JP2015514749A (ja) | 2015-05-21 |
US20150064196A1 (en) | 2015-03-05 |
EP2838898B1 (en) | 2017-01-18 |
WO2013157022A1 (en) | 2013-10-24 |
US9233983B2 (en) | 2016-01-12 |
IN2012CH01573A (zh) | 2015-07-10 |
AU2013250726A1 (en) | 2014-10-09 |
AU2013250726B2 (en) | 2017-01-05 |
ZA201407341B (en) | 2015-06-24 |
EP2838898A1 (en) | 2015-02-25 |
CA2869954A1 (en) | 2013-10-24 |
IL235146A (en) | 2017-07-31 |
CN104662018A (zh) | 2015-05-27 |
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