CN114901653A - 可用作二酰基甘油酰基转移酶2抑制剂的新的酰胺衍生物及其用途 - Google Patents
可用作二酰基甘油酰基转移酶2抑制剂的新的酰胺衍生物及其用途 Download PDFInfo
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- CN114901653A CN114901653A CN202080089274.6A CN202080089274A CN114901653A CN 114901653 A CN114901653 A CN 114901653A CN 202080089274 A CN202080089274 A CN 202080089274A CN 114901653 A CN114901653 A CN 114901653A
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- Prior art keywords
- piperidin
- ethoxyphenoxy
- pyrazin
- amino
- acid
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- 102100027840 Acyl-CoA wax alcohol acyltransferase 1 Human genes 0.000 title claims description 7
- 101000698136 Homo sapiens Acyl-CoA wax alcohol acyltransferase 1 Proteins 0.000 title claims description 7
- 150000001408 amides Chemical class 0.000 title abstract description 11
- 239000003112 inhibitor Substances 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 92
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 239000004480 active ingredient Substances 0.000 claims abstract description 7
- -1 nitro, carboxy Chemical group 0.000 claims description 179
- 101000930020 Homo sapiens Diacylglycerol O-acyltransferase 2 Proteins 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 102100035762 Diacylglycerol O-acyltransferase 2 Human genes 0.000 claims description 28
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000004450 alkenylene group Chemical group 0.000 claims description 9
- 125000000732 arylene group Chemical group 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000004104 aryloxy group Chemical group 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 8
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 125000005549 heteroarylene group Chemical group 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000000979 2-amino-2-oxoethyl group Chemical group [H]C([*])([H])C(=O)N([H])[H] 0.000 claims description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
- 208000008589 Obesity Diseases 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 150000005840 aryl radicals Chemical class 0.000 claims description 6
- 125000005111 carboxyalkoxy group Chemical group 0.000 claims description 6
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 6
- 235000020824 obesity Nutrition 0.000 claims description 6
- 235000019260 propionic acid Nutrition 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- LBDVDXVYWNGDQQ-HSZRJFAPSA-N 2-[4-[1-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-2-methyl-1-oxopropan-2-yl]phenyl]-2-methylpropanoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)C(C)(C)C4=CC=C(C=C4)C(C)(C)C(=O)O LBDVDXVYWNGDQQ-HSZRJFAPSA-N 0.000 claims description 5
- YWFOGCSHZJPBKR-OAQYLSRUSA-N 2-[4-[2-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-2-oxoethyl]phenyl]acetic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)CC4=CC=C(C=C4)CC(=O)O YWFOGCSHZJPBKR-OAQYLSRUSA-N 0.000 claims description 5
- SABCYISHWVQMEY-JOCHJYFZSA-N 2-[4-[3-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-3-oxopropyl]phenyl]acetic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)CCC4=CC=C(C=C4)CC(=O)O SABCYISHWVQMEY-JOCHJYFZSA-N 0.000 claims description 5
- 208000004930 Fatty Liver Diseases 0.000 claims description 5
- 206010019708 Hepatic steatosis Diseases 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 208000010706 fatty liver disease Diseases 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 231100000240 steatosis hepatitis Toxicity 0.000 claims description 5
- ZKVHTDCCXOIGAX-HSZRJFAPSA-N 1-[4-[3-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-3-oxopropyl]phenyl]cyclopropane-1-carboxylic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)CCC4=CC=C(C=C4)C5(CC5)C(=O)O ZKVHTDCCXOIGAX-HSZRJFAPSA-N 0.000 claims description 4
- VZDQNUULDJYOEQ-GOSISDBHSA-N 2,6-dichloro-4-[3-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-3-oxopropyl]benzoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)CCC4=CC(=C(C(=C4)Cl)C(=O)O)Cl VZDQNUULDJYOEQ-GOSISDBHSA-N 0.000 claims description 4
- KTWOXYWYVRTCSR-JOCHJYFZSA-N 2-[4-[2-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyridin-2-yl]amino]-2-oxoethyl]phenyl]acetic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=CC=CC(=N3)NC(=O)CC4=CC=C(C=C4)CC(=O)O KTWOXYWYVRTCSR-JOCHJYFZSA-N 0.000 claims description 4
- YTOUVVPSJAKJSW-JOCHJYFZSA-N 2-[4-[2-oxo-2-[[6-[(3R)-3-(2-propan-2-yloxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]ethyl]phenyl]acetic acid Chemical compound CC(C)OC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)CC4=CC=C(C=C4)CC(=O)O YTOUVVPSJAKJSW-JOCHJYFZSA-N 0.000 claims description 4
- KEDSBWFBXXSAGP-HSZRJFAPSA-N 2-[4-[3-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-3-oxopropyl]phenyl]-2-methylpropanoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)CCC4=CC=C(C=C4)C(C)(C)C(=O)O KEDSBWFBXXSAGP-HSZRJFAPSA-N 0.000 claims description 4
- RHCNZNIXVHKCKR-LJQANCHMSA-N 2-chloro-4-[3-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-3-oxopropyl]benzoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)CCC4=CC(=C(C=C4)C(=O)O)Cl RHCNZNIXVHKCKR-LJQANCHMSA-N 0.000 claims description 4
- AUOVWWTXBVLAOT-HXUWFJFHSA-N 3-[2-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-2-oxoethyl]benzoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)CC4=CC(=CC=C4)C(=O)O AUOVWWTXBVLAOT-HXUWFJFHSA-N 0.000 claims description 4
- FMPCMTBHWZXIHW-JIKIWWBOSA-N 4-[(E)-3-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-2-methyl-3-oxoprop-1-enyl]benzoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)/C(=C/C4=CC=C(C=C4)C(=O)O)/C FMPCMTBHWZXIHW-JIKIWWBOSA-N 0.000 claims description 4
- GBXNPYSMCHZJNN-AVKWCDSFSA-N 4-[3-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-2-methyl-3-oxopropyl]benzoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)C(C)CC4=CC=C(C=C4)C(=O)O GBXNPYSMCHZJNN-AVKWCDSFSA-N 0.000 claims description 4
- DQOKRTMGIHLPSL-LJQANCHMSA-N 4-[3-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-3-oxopropyl]-2-fluorobenzoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)CCC4=CC(=C(C=C4)C(=O)O)F DQOKRTMGIHLPSL-LJQANCHMSA-N 0.000 claims description 4
- ITZNLFAIAGTZQR-OAQYLSRUSA-N 4-[3-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-3-oxopropyl]-2-methylbenzoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)CCC4=CC(=C(C=C4)C(=O)O)C ITZNLFAIAGTZQR-OAQYLSRUSA-N 0.000 claims description 4
- ZMRAGPLUDLUKBW-QYWNIODHSA-N 6-[3-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]carbamoyl]-3-methylpyrrolidin-1-yl]pyridine-3-carboxylic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)C4(CCN(C4)C5=NC=C(C=C5)C(=O)O)C ZMRAGPLUDLUKBW-QYWNIODHSA-N 0.000 claims description 4
- VKNIXWDYUUUILB-QGFLDLQWSA-N C1=CC(=CC=C1/C=C/C(=O)NC1=NC(N2C[C@@H](CCC2)OC2=C(C=CC=C2)OCC)=CN=C1)C(=O)O Chemical compound C1=CC(=CC=C1/C=C/C(=O)NC1=NC(N2C[C@@H](CCC2)OC2=C(C=CC=C2)OCC)=CN=C1)C(=O)O VKNIXWDYUUUILB-QGFLDLQWSA-N 0.000 claims description 4
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000006588 heterocycloalkylene group Chemical group 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- QYQRAGODWHBCST-GVYDCBATSA-N (1R)-2-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]carbamoyl]cyclopentane-1-carboxylic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)C4CCC[C@H]4C(=O)O QYQRAGODWHBCST-GVYDCBATSA-N 0.000 claims description 3
- RPMNMPHTUVJOLI-DENIHFKCSA-N (2R)-2-[4-[2-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-2-oxoethyl]phenoxy]propanoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)CC4=CC=C(C=C4)O[C@H](C)C(=O)O RPMNMPHTUVJOLI-DENIHFKCSA-N 0.000 claims description 3
- RPMNMPHTUVJOLI-SIKLNZKXSA-N (2S)-2-[4-[2-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-2-oxoethyl]phenoxy]propanoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)CC4=CC=C(C=C4)O[C@@H](C)C(=O)O RPMNMPHTUVJOLI-SIKLNZKXSA-N 0.000 claims description 3
- YRLGLQAGHWEOQS-LJQANCHMSA-N 1-[3,5-bis(trifluoromethyl)phenyl]-3-[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]urea Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)NC4=CC(=CC(=C4)C(F)(F)F)C(F)(F)F YRLGLQAGHWEOQS-LJQANCHMSA-N 0.000 claims description 3
- UZGIINHJJNKWQR-AREMUKBSSA-N 1-[4-[3-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-3-oxopropyl]phenyl]piperidine-4-carboxylic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)CCC4=CC=C(C=C4)N5CCC(CC5)C(=O)O UZGIINHJJNKWQR-AREMUKBSSA-N 0.000 claims description 3
- DVKVRCRJTNIWBV-MRXNPFEDSA-N 1-[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]-3,3-dimethylpyrrolidine-2,5-dione Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=CN=CC(=N3)N4C(=O)CC(C4=O)(C)C DVKVRCRJTNIWBV-MRXNPFEDSA-N 0.000 claims description 3
- IAZUUWHWWVKGKW-JOCHJYFZSA-N 2-[4-[2-[[2-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrimidin-4-yl]amino]-2-oxoethyl]phenoxy]-2-methylpropanoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC=CC(=N3)NC(=O)CC4=CC=C(C=C4)OC(C)(C)C(=O)O IAZUUWHWWVKGKW-JOCHJYFZSA-N 0.000 claims description 3
- BMQPXYWHKYSOHI-OAQYLSRUSA-N 2-[4-[2-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-2-oxoethoxy]phenyl]acetic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)COC4=CC=C(C=C4)CC(=O)O BMQPXYWHKYSOHI-OAQYLSRUSA-N 0.000 claims description 3
- MPYJNRXQOUVPMQ-AVKWCDSFSA-N 2-[4-[2-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-2-oxoethoxy]phenyl]propanoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)COC4=CC=C(C=C4)C(C)C(=O)O MPYJNRXQOUVPMQ-AVKWCDSFSA-N 0.000 claims description 3
- LCPRTSBCGJGZES-JOCHJYFZSA-N 2-[4-[2-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-2-oxoethyl]phenyl]-2-methylpropanoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)CC4=CC=C(C=C4)C(C)(C)C(=O)O LCPRTSBCGJGZES-JOCHJYFZSA-N 0.000 claims description 3
- SXOQTTHXAJMENB-HSZRJFAPSA-N 2-[4-[2-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyridin-2-yl]amino]-2-oxoethyl]phenyl]-2-methylpropanoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=CC=CC(=N3)NC(=O)CC4=CC=C(C=C4)C(C)(C)C(=O)O SXOQTTHXAJMENB-HSZRJFAPSA-N 0.000 claims description 3
- NZCLDOPFEJRQDJ-OAQYLSRUSA-N 2-[4-[2-[[6-[(3R)-3-(3-ethoxypyridin-2-yl)oxypiperidin-1-yl]pyrazin-2-yl]amino]-2-oxoethyl]phenoxy]-2-methylpropanoic acid Chemical compound CCOC1=C(N=CC=C1)O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)CC4=CC=C(C=C4)OC(C)(C)C(=O)O NZCLDOPFEJRQDJ-OAQYLSRUSA-N 0.000 claims description 3
- JVVOEPZDWLTYMF-HSZRJFAPSA-N 2-[4-[3-[[2-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrimidin-4-yl]amino]-3-oxopropyl]phenoxy]-2-methylpropanoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC=CC(=N3)NC(=O)CCC4=CC=C(C=C4)OC(C)(C)C(=O)O JVVOEPZDWLTYMF-HSZRJFAPSA-N 0.000 claims description 3
- DOTZXRYUJYYLQB-HSZRJFAPSA-N 2-[4-[3-[[2-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrimidin-4-yl]amino]-3-oxopropyl]phenyl]-2-methylpropanoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC=CC(=N3)NC(=O)CCC4=CC=C(C=C4)C(C)(C)C(=O)O DOTZXRYUJYYLQB-HSZRJFAPSA-N 0.000 claims description 3
- OXSLOOHNWKNNFI-RUZDIDTESA-N 2-[4-[3-[[6-[(3R)-3-(2-cyclobutyloxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-3-oxopropyl]phenyl]-2-methylpropanoic acid Chemical compound CC(C)(C1=CC=C(C=C1)CCC(=O)NC2=CN=CC(=N2)N3CCC[C@H](C3)OC4=CC=CC=C4OC5CCC5)C(=O)O OXSLOOHNWKNNFI-RUZDIDTESA-N 0.000 claims description 3
- RKDNZYQOSMKRCE-XMMPIXPASA-N 2-[4-[3-[[6-[(3R)-3-(2-cyclopropyloxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-3-oxopropyl]phenyl]-2-methylpropanoic acid Chemical compound CC(C)(C1=CC=C(C=C1)CCC(=O)NC2=CN=CC(=N2)N3CCC[C@H](C3)OC4=CC=CC=C4OC5CC5)C(=O)O RKDNZYQOSMKRCE-XMMPIXPASA-N 0.000 claims description 3
- PRIXSFZQHOCTOQ-XMMPIXPASA-N 2-[4-[3-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-2,2-dimethyl-3-oxopropyl]phenyl]-2-methylpropanoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)C(C)(C)CC4=CC=C(C=C4)C(C)(C)C(=O)O PRIXSFZQHOCTOQ-XMMPIXPASA-N 0.000 claims description 3
- JUEWACRCTFCLEI-XMMPIXPASA-N 2-[4-[3-[[6-[(3R)-3-(2-ethoxyphenoxy)piperidin-1-yl]pyridin-2-yl]amino]-3-oxopropyl]phenyl]-2-methylpropanoic acid Chemical compound CCOC1=CC=CC=C1O[C@@H]2CCCN(C2)C3=CC=CC(=N3)NC(=O)CCC4=CC=C(C=C4)C(C)(C)C(=O)O JUEWACRCTFCLEI-XMMPIXPASA-N 0.000 claims description 3
- XMXQCSWMOUNDFM-JOCHJYFZSA-N 2-[4-[3-[[6-[(3R)-3-(2-methoxyphenoxy)piperidin-1-yl]pyrazin-2-yl]amino]-3-oxopropyl]phenyl]-2-methylpropanoic acid Chemical compound CC(C)(C1=CC=C(C=C1)CCC(=O)NC2=CN=CC(=N2)N3CCC[C@H](C3)OC4=CC=CC=C4OC)C(=O)O XMXQCSWMOUNDFM-JOCHJYFZSA-N 0.000 claims description 3
- AHDLKTXOMVTFFN-JOCHJYFZSA-N 2-[4-[3-[[6-[(3R)-3-(3-ethoxypyridin-2-yl)oxypiperidin-1-yl]pyrazin-2-yl]amino]-3-oxopropyl]phenoxy]-2-methylpropanoic acid Chemical compound CCOC1=C(N=CC=C1)O[C@@H]2CCCN(C2)C3=NC(=CN=C3)NC(=O)CCC4=CC=C(C=C4)OC(C)(C)C(=O)O AHDLKTXOMVTFFN-JOCHJYFZSA-N 0.000 claims description 3
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
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- TVIVLENJTXGRAM-UHFFFAOYSA-N methyl 2-(4-aminophenyl)acetate Chemical compound COC(=O)CC1=CC=C(N)C=C1 TVIVLENJTXGRAM-UHFFFAOYSA-N 0.000 description 1
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- DCOVRTUBIOIEKW-UHFFFAOYSA-N methyl 2-(4-carbamoylphenoxy)-2-methylpropanoate Chemical compound CC(C)(C(=O)OC)OC1=CC=C(C=C1)C(=O)N DCOVRTUBIOIEKW-UHFFFAOYSA-N 0.000 description 1
- OUWFDISHMBDYON-UHFFFAOYSA-N methyl 2-(4-phenylmethoxyphenyl)acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1OCC1=CC=CC=C1 OUWFDISHMBDYON-UHFFFAOYSA-N 0.000 description 1
- COFYZYAHKARQQM-UHFFFAOYSA-N methyl 2-(6-chloropyridin-3-yl)-2-methylpropanoate Chemical compound COC(=O)C(C)(C)C1=CC=C(Cl)N=C1 COFYZYAHKARQQM-UHFFFAOYSA-N 0.000 description 1
- JBPDCHNIPFVAOK-UHFFFAOYSA-N methyl 2-[4-(2-amino-2-oxoethoxy)phenyl]propanoate Chemical compound CC(C1=CC=C(C=C1)OCC(=O)N)C(=O)OC JBPDCHNIPFVAOK-UHFFFAOYSA-N 0.000 description 1
- VJOKXLBQCKCWLV-UHFFFAOYSA-N methyl 2-chloropyrimidine-5-carboxylate Chemical compound COC(=O)C1=CN=C(Cl)N=C1 VJOKXLBQCKCWLV-UHFFFAOYSA-N 0.000 description 1
- KTOVFDQCJIOFNX-FMIVXFBMSA-N methyl 2-methyl-2-[4-[(E)-3-[(2-methylpropan-2-yl)oxy]-3-oxoprop-1-enyl]phenyl]propanoate Chemical compound CC(C)(C)OC(=O)/C=C/C1=CC=C(C=C1)C(C)(C)C(=O)OC KTOVFDQCJIOFNX-FMIVXFBMSA-N 0.000 description 1
- WVWZECQNFWFVFW-UHFFFAOYSA-N methyl 2-methylbenzoate Chemical compound COC(=O)C1=CC=CC=C1C WVWZECQNFWFVFW-UHFFFAOYSA-N 0.000 description 1
- RMEVCLVBXHVLHC-UHFFFAOYSA-N methyl 3-(2-chloro-2-oxoethyl)benzoate Chemical compound COC(=O)C1=CC=CC(CC(Cl)=O)=C1 RMEVCLVBXHVLHC-UHFFFAOYSA-N 0.000 description 1
- INXPCMKHDNRRKA-CMDGGOBGSA-N methyl 3-[(e)-3-[(2-methylpropan-2-yl)oxy]-3-oxoprop-1-enyl]benzoate Chemical compound COC(=O)C1=CC=CC(\C=C\C(=O)OC(C)(C)C)=C1 INXPCMKHDNRRKA-CMDGGOBGSA-N 0.000 description 1
- LWYLSHMAHBYNAX-UHFFFAOYSA-N methyl 3-[3-[(2-methylpropan-2-yl)oxy]-3-oxopropyl]benzoate Chemical compound COC(=O)C1=CC=CC(CCC(=O)OC(C)(C)C)=C1 LWYLSHMAHBYNAX-UHFFFAOYSA-N 0.000 description 1
- XVNXAGVGAFPVSF-UHFFFAOYSA-N methyl 3-[4-(1-amino-2-methyl-1-oxopropan-2-yl)phenyl]propanoate Chemical compound CC(C)(C1=CC=C(C=C1)CCC(=O)OC)C(=O)N XVNXAGVGAFPVSF-UHFFFAOYSA-N 0.000 description 1
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- KJRFTNVYOAGTHK-UHFFFAOYSA-N methyl 3-hydroxy-2,2-dimethylpropanoate Chemical compound COC(=O)C(C)(C)CO KJRFTNVYOAGTHK-UHFFFAOYSA-N 0.000 description 1
- KEQUVXVLIIKCRO-UHFFFAOYSA-N methyl 4-(2-chloro-2-oxoethyl)benzoate Chemical compound COC(=O)C1=CC=C(CC(Cl)=O)C=C1 KEQUVXVLIIKCRO-UHFFFAOYSA-N 0.000 description 1
- HGBWLXYIWPTIHQ-UHFFFAOYSA-N methyl 4-(3-amino-3-oxopropyl)-2,6-difluorobenzoate Chemical compound COC(=O)C1=C(C=C(C=C1F)CCC(=O)N)F HGBWLXYIWPTIHQ-UHFFFAOYSA-N 0.000 description 1
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- SZYVHPORSXBLNH-ZHACJKMWSA-N methyl 4-[(E)-2-methyl-3-[(2-methylpropan-2-yl)oxy]-3-oxoprop-1-enyl]benzoate Chemical compound COC(=O)C1=CC=C(\C=C(/C)C(=O)OC(C)(C)C)C=C1 SZYVHPORSXBLNH-ZHACJKMWSA-N 0.000 description 1
- JZXKQYKOCDKNPN-QPJJXVBHSA-N methyl 4-[(e)-3-amino-3-oxoprop-1-enyl]benzoate Chemical compound COC(=O)C1=CC=C(\C=C\C(N)=O)C=C1 JZXKQYKOCDKNPN-QPJJXVBHSA-N 0.000 description 1
- DFLUGSRDMHYEQD-UHFFFAOYSA-N methyl 4-[2-methyl-3-[(2-methylpropan-2-yl)oxy]-3-oxopropyl]benzoate Chemical compound COC(C1=CC=C(C=C1)CC(C)C(=O)OC(C)(C)C)=O DFLUGSRDMHYEQD-UHFFFAOYSA-N 0.000 description 1
- JBXJLZRTTCGLNR-UHFFFAOYSA-N methyl 4-bromo-2,6-difluorobenzoate Chemical compound COC(=O)C1=C(F)C=C(Br)C=C1F JBXJLZRTTCGLNR-UHFFFAOYSA-N 0.000 description 1
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- 229940124597 therapeutic agent Drugs 0.000 description 1
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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Abstract
本发明涉及一种由化学式(1)表示并表现出二酰基甘油酰基转移酶(DGAT)2抑制剂活性的酰胺衍生物化合物、包含所述化合物作为活性成分的药物组合物及其用途。
Description
技术领域
本发明涉及一种对二酰基甘油酰基转移酶2(DGAT2)显示出抑制活性的由式(1)表示的酰胺衍生物化合物、包含所述化合物作为活性成分的药物组合物及其用途。
背景技术
随着经济发展,生活水平的提高,方便食品的频繁食用以及以肉为主的饮食习惯的改变,导致体内热量的过度积累。现代人饮食生活的这些变化,也导致因缺乏运动而造成的热量消耗减少,导致代谢疾病例如肥胖症、高脂血症、糖尿病、心血管疾病、冠状动脉疾病的严重流行。具体而言,肥胖症是迅速增加的疾病之一,并且据报道是代谢疾病例如糖尿病的原因。通过控制参与作为肥胖的主要原因的甘油三酯的生物合成途径的酶的功能来开发用于代谢疾病的治疗剂,正在引起人们的关注。
中性脂肪例如甘油三酯(TG),作为体内的能量来源在储存功能中发挥非常重要的作用。然而,当中性脂肪在器官或组织中过度积累时,它们引起肥胖症、高甘油三酯血症、脂肪肝等,从而引起严重疾病例如糖尿病、动脉硬化、代谢异常和器官功能减退。二酰基甘油酰基转移酶是甘油三酯生物合成中的关键酶,存在于哺乳动物的各种不同组织中,是在作为甘油三酯合成的主要途径的磷酸甘油途径的最后一步中通过将脂肪酰基辅酶A与二酰基甘油的羟基结合来合成TG的一种酶。目前已知有两种亚型——DGAT1和DGAT2。尽管它们的生化功能相似,但区别在于DGAT1主要在小肠和脂肪组织中表达,而DGAT2主要在肝脏和脂肪组织中表达。另外,在基因家族方面,DGAT1属于ACAT家族,而DGAT2属于MGAT家族。因此,预计它们在TG生物合成中的作用也不同。
包括动物研究在内的几项研究显示,DGAT2主要对体内TG的生物合成有贡献。与几乎不合成TG并由于皮肤层异常而在出生后不久死亡的DGAT2敲除小鼠不同,DGAT1敲除小鼠显示出TG水平的略微下降,并且小鼠的生存没有问题(Stone SJ等,2000.Nat.Genet.25:87-90)。此外,作为通过在脂肪肝动物模型中使用反义寡核苷酸(ASO)降低DGAT1或DGAT2的表达水平的结果,只有当DGAT2的量减少时脂肪肝症状才会得到缓解,并且肝脏中葡萄糖的产生速率才会显著降低(Choi CS等,2007.Hepatology.45:1366-74)。
潜在的分子机制尚未被完全阐明,但据认为DGAT2的抑制导致多个参与脂质生产的蛋白质的编码基因的表达下调,所述蛋白质例如甾醇调节元件结合蛋白1c(SREBP1c)和硬脂酰辅酶A-去饱和酶1(SCD1)。同时,据认为氧化途径由诸如肉毒碱棕榈酰基转移酶1(CPT1)的基因的增加所诱导。这种变化反过来导致肝脏DAG和TAG脂质水平的降低,从而改善肝脏中的胰岛素响应性。此外,DGAT2的抑制抑制肝脏VLDL TAG分泌并降低循环胆固醇水平。最后,血浆载脂蛋白B(APOB)水平受到抑制,这据认为是由在新合成的APOB蛋白的脂化中TAG的供应减少所造成的。也就是说,当DGAT2被抑制时,显示出对血糖控制和血浆胆固醇谱两者的有益效应,这意味着DGAT2的抑制可应用于代谢障碍的治疗。
发明内容
技术问题
本发明的一个目的是提供一种对二酰基甘油酰基转移酶2(DGAT2)显示出抑制活性的由式(1)表示的新的酰胺衍生物化合物。
本发明的另一个目的是提供一种制备所述酰胺衍生物化合物的方法。
本发明的另一个目的是提供一种包含所述酰胺衍生物化合物作为活性成分,用于治疗与DGAT2相关的代谢疾病的药物组合物及其制备方法。
本发明的又一个目的是提供一种在受试者中治疗与DGAT2相关的代谢疾病的方法,其中通过使用与常规化合物相比具有改进的物理和化学性质的酰胺衍生物化合物作为活性成分,提高了在疾病动物模型中的功效并提高了在所述受试者中的功效和服用方便性。
技术解决方案
为了实现上述目的,本发明提供了一种下式(1)的化合物或其可药用盐或异构体:
[式(1)]
其中
A、B和E各自独立地是CH或N;
D是N、CH或C-卤代烷基;
R1是烷基、环烷基或卤代烷基;
R2是氢或烷基;
R3是-G-J-L;
其中G是-NH-或直接连键;
J是亚烷基、亚烯基、亚烷基-亚芳基、亚烷基-氨基-亚芳基、亚烷基-亚芳氧基-亚烷基、亚烷基-环烷基、亚烯基-环烷基、亚烷氧基-亚芳基、亚芳基、环烷基、芳基、芳基-烷基、亚杂环烷基、亚杂环烷基-亚芳基、亚杂环烷基-亚杂芳基或杂环烷基;
L是氢、卤素、氨基、硝基、羧基(-COOH)、氨基羰基烷基、羧基烷基、羧基烷氧基、羧基烷基-芳基、环烷基、芳基、芳氧基、杂环烷基或杂芳基;或者
R2和R3与它们所连接的氮原子一起可以形成杂环烷基;
其中所述烷基、亚烷基、亚烷基-亚芳基、烯基、亚烯基、环烷基、羧基烷基、羧基烷氧基、烷氧基烷基、氨基羰基、芳基、芳基-烷基、亚芳基、芳氧基、杂环烷基或杂芳基任选地被选自羟基、卤素、氧代、硝基、-COOH、-CH2COOH、烷基、烯基、烷氧基、卤代烷基、烷基磺酰基、烷基羰基、烷氧基羰基和杂芳基-烷基的一个或多个取代基取代;并且
所述亚杂环烷基、杂环烷基、亚杂芳基或杂芳基包括一个或多个选自N、O和S的杂原子。
根据本发明的式(1)的化合物可以形成可药用盐。可药用盐可以包括从下述酸形成的酸加成盐:无机酸例如盐酸、硫酸、硝酸、磷酸、氢溴酸和氢碘酸,有机酸例如酒石酸、甲酸、柠檬酸、乙酸、三氯乙酸、三氟乙酸、葡萄糖酸、苯甲酸、乳酸、延胡索酸、马来酸和水杨酸,或磺酸例如甲磺酸、乙磺酸、苯磺酸和对甲苯磺酸,所述酸形成包括可药用阴离子的无毒酸加成盐。此外,可药用羧酸盐包括与碱金属或碱土金属例如锂、钠、钾、钙和镁的盐,与氨基酸例如赖氨酸、精氨酸和胍的盐,有机盐例如二环己胺、N-甲基-D-葡萄糖胺、三(羟甲基)甲基胺、二乙醇胺、胆碱和三乙醇胺。根据本发明的式(1)的化合物可以通过常规方法转变成它们的盐。
同时,由于根据本发明的式(1)的化合物可以具有不对称碳中心和不对称轴或平面,因此它们可以作为E-或Z-异构体、R-或S-异构体、外消旋混合物或非对映异构体混合物和每种非对映异构体存在,这些都在本发明的范围之内。
在本文中,除非另有指明,否则术语“式(1)的化合物”用于指称所有式(1)的化合物,包括其可药用盐和异构体。
在本文中,使用下述为取代基定义的概念来定义式(1)的化合物。
术语“卤素”或“卤代”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“烷基”或“亚烷基”是指直链或支链烃,可以包含单键、双键或叁键,并且优选为C1-C10烷基或C1-C10亚烷基或C1-C7烷基或C1-C7亚烷基。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、乙炔基、乙烯基、三氟甲基等。
术语“烯基”或“亚烯基”是指具有至少一个碳-碳双键的直链或支链烃,并且优选为C2-C10烯基或C2-C10亚烯基或C2-C7烯基或C2-C7亚烯基。烯基的实例包括但不限于乙烯基、烯丙基、丁烯基、异丙烯基、异丁烯基等。
术语“环烷基”是指部分或完全饱和的单环或稠合环烃,并且优选为C3-C10-环烷基。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基等。
除非另有定义,否则术语“烷氧基”是指具有1至10个碳原子的烷氧基。
除非另有定义,否则术语“环烷氧基”是指具有3至10个碳原子的环烷氧基。
术语“芳基”或“亚芳基”是指芳香族烃,优选为C5-C12芳基或C5-C12亚芳基,更优选为C6-C10芳基或C6-C10亚芳基,并且包括但不限于苯基、萘基等。
术语“杂芳基”或“亚杂芳基”是指3至12元、更优选地5至12元的芳香族烃,其形成包括一个或多个选自N、O和S的杂原子作为环成员的单环或稠合环(其可以与苯环或C3-C8环烷基稠合)。杂芳基的实例包括但不限于吡啶基、嘧啶基、哒嗪基、吡嗪基、二唑基、异二唑基、四唑基、三唑基、吲哚基、吲唑基、异唑基、唑基、噻唑基、异噻唑基、呋喃基、苯并呋喃基、咪唑基、硫苯基、苯并噻唑、苯并咪唑、喹啉基、吲哚啉基、1,2,3,4-四氢异喹啉基、3,4-二氢异喹啉基、噻唑并吡啶基、2,3-二氢苯并呋喃、2,3-二氢噻吩、2,3-二氢吲哚、苯并[1,3]二英、色满、硫色满、1,2,3,4-四氢喹啉、4H-苯并[1,3]二英、2,3-二氢苯并[1,4]-二英、6,7-二氢-5H-环戊并[d]嘧啶等。
术语“杂环烷基”是指部分或完全饱和的烃,其形成包括一个或多个选自N、O和S的杂原子的单环或稠合环,并且优选为3至12元杂环烷基或5至12元杂环烷基。杂环烷基的实例包括但不限于吡咯烷基、哌啶基、吗啉基、咪唑啉基、哌嗪基、四氢呋喃、四氢硫呋喃等。
芳基-烷基、烷基-芳基和杂芳基-烷基是指由上述芳基和烷基或杂芳基和烷基的组合形成的基团。实例包括但不限于苯甲基、噻吩甲基、嘧啶甲基等。
根据本发明的一个实施方式,在上式(1)中
A、B和E各自独立地是CH或N;
D是N、CH或C-卤代-C1-C7烷基;
R1是C1-C7烷基、C3-C10环烷基或卤代-C1-C7烷基;
R2是氢或C1-C7烷基;
R3是-G-J-L;
其中G是-NH-或直接连键;
J是C1-C7亚烷基、C2-C7亚烯基、C1-C7亚烷基-C6-C10亚芳基、C1-C7亚烷基-氨基-C6-C10亚芳基、C1-C7亚烷基-C6-C10亚芳氧基-C1-C7亚烷基、C1-C7亚烷基-C3-C10环烷基、C2-C7亚烯基-C3-C10环烷基、C1-C7亚烷氧基-C6-C10亚芳基、C6-C10亚芳基、C3-C10环烷基、C6-C10芳基、C6-C10芳基-C1-C7烷基、5至12元亚杂环烷基、5至12元亚杂环烷基-C6-C10亚芳基、5至12元亚杂环烷基-5至12元亚杂芳基或5至12元杂环烷基;
L是氢、卤素、氨基、硝基、羧基(-COOH)、氨基羰基-C1-C7烷基、羧基-C1-C7烷基、羧基-C1-C7烷氧基、羧基-C1-C7烷基-C6-C10芳基、C3-C10环烷基、C6-C10芳基、C6-C10芳氧基、5至12元杂环烷基或5至12元杂芳基;或者
R2和R3与它们所连接的氮原子一起可以形成5至12元杂环烷基;
其中所述烷基、亚烷基、亚烷基-亚芳基、烯基、亚烯基、环烷基、羧基烷基、羧基烷氧基、烷氧基烷基、氨基羰基、芳基、芳基-烷基、亚芳基、芳氧基、杂环烷基或杂芳基任选地被选自羟基、卤素、氧代、硝基、-COOH、-CH2COOH、C1-C7烷基、C2-C7烯基、C1-C7烷氧基、卤代-C1-C7烷基、C1-C7烷基磺酰基、C1-C7烷基羰基、C1-C7烷氧基羰基和5至12元杂芳基-C1-C7烷基的1至4个取代基取代;并且
所述亚杂环烷基、杂环烷基、亚杂芳基或杂芳基包括1至5个选自N、O和S的杂原子。
根据本发明的代表性的式(1)的化合物包括但不限于下述化合物:
(R)-1-(3,5-双(三氟甲基)苯基)-3-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)脲;
((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)-L-苯丙氨酸;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)吗啉-4-甲酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)吡咯烷-1-甲酰胺;
1-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)吡咯烷-3-甲酸;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)苯甲酰胺;
(R)-4-氯-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)苯甲酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-3-甲氧基苯甲酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-4-甲氧基苯甲酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-4-硝基苯甲酰胺;
(R)-2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯甲酸;
(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯基)乙酸;
(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯基)-2-甲基丙酸;
(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯氧基)-2-甲基丙酸;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-1-(甲磺酰基)哌啶)-4-甲酰胺;
(R)-1-乙酰基-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)哌啶)-4-甲酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-1-(异丙基磺酰基)哌啶-4-甲酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-1-(5-乙基嘧啶-2-基)哌啶-4-甲酰胺;
(R)-4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-4-氧代丁酸;
(1R)-2-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)环戊烷-1-甲酸;
(R)-4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)双环[2.2.2]辛烷-1-甲酸;
(R)-4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2,2-二甲基-4-氧代丁酸;
(R)-1-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-3,3-二甲基吡咯烷-2,5-二酮;
(R)-5-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2,2-二甲基-5-氧代戊酸;
(R)-5-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3,3-二甲基-5-氧代戊酸;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-2-(3-三氟甲基)苯基)乙酰胺;
(R)-2-(3,5-双(三氟甲基)苯基)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)乙酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-2-苯基乙酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-3-苯基丙酰胺;
(R)-2-(3-氯苯基)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)乙酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-2-甲基-2-苯基丙酰胺;
(R)-4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯甲酸;
(R)-3-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯甲酸;
(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)乙酸;
(R)-2-(4-(2-氨基-2-氧代乙基)苯基-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)乙酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-2-(4-羟基苯基)乙酰胺;
(R)-4-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯氧基)丁酸;
(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基-2-氧代乙基)苯氧基)-2-甲基丙酸;
(R)-2-(4-(1-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2-甲基丙酸;
(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯甲酸;
(R,E)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙-1-烯-1-基)苯甲酸;
(R,E)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-3-氧代丙-1-烯-1-基)苯甲酸;
4-(3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-3-氧代丙基)苯甲酸;
(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)-2-氟苯甲酸;
(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)-2-甲基苯甲酸;
(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)-2-甲氧基苯甲酸;
(R)-2-氯-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯甲酸;
(R)-3-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯甲酸;
(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)乙酸;
(R)-3-(4-(2-氨基-2-氧代乙基)苯基-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)丙烯酰胺;
(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸;
(R)-1-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)环丙烷-1-甲酸;
(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)-2,6-二氟苯甲酸;
(R)-2,6-二氯-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯甲酸;
(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)-2,6-二甲基苯甲酸;
(R)-1-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)哌啶-4-甲酸;
(R)-1-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基-2,6-二氟苯基)哌啶-4-甲酸;
(R)-2-(1-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基-2,6-二氟苯基)哌啶-4-基)乙酸;
(R)-4-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)苯甲酸;
(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯氧基)-2-甲基丙酸;
(R)-3-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)丙酸;
(R)-4-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯氧基)苯甲酸;
(R)-3-(4-(3-((6-(R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2-甲基丙酸;
(S)-3-(4-(3-((6-(R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2-甲基丙酸;
(R)-3-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶-2-基)氨基)-2-氧代乙基)苯基)乙酸;
(R)-2-(4-(3-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)脲基)苯基)乙酸;
(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶-2-基)氨基)-2-氧代乙基)苯基)-2-甲基丙酸;
(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2-甲基丙酸;
(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸;
(R)-3-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶-2-基)氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(2-((4-(3-(2-乙氧基苯氧基)哌啶-1-基)-6-(三氟甲基)嘧啶-2-基)氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(1-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)丙酸;
(R)-3-(4-((2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)烯丙基)氨基)苯基)丙酸;
(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)嘧啶-5-甲酸;
3-(3-((R)-3-((6-((R)-3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)苯基-2,2-二甲基丙酸;
(R)-3-(4-(1-((4-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(1-((4-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)嘧啶-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸;
(R)-2-(4-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)苯基)乙酸;
(R)-2-(4-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)苯基)-2-甲基丙酸;
(R)-2-(6-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)吡啶-3-基)-2-甲基丙酸;
(R)-2-(5-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)-2H-四唑-2-基)乙酸;
(R)-4-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)-4-氧代丁酸;
(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)乙酸;
3-(3-((R)-3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)苯基)-2,2-二甲基丙酸;
(R)-1-(4-(1-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)哌啶-4-甲酸;
6-(3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)吡咯烷-1-基)烟酸;
N-(6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-3-甲基吡咯烷-3-甲酰胺;
6-(3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)-3-甲基吡咯烷-1-基)烟酸;
(R)-2-(4-(2-((6-(3-(2-异丙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)乙酸;
(R)-2-(4-(3-((6-(3-(2-甲氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸;
(R)-2-甲基-2-(4-(3-氧代-3-((6-(3-(2-(三氟甲氧基)苯氧基)哌啶-1-基)吡嗪-2-基)氨基)丙基)苯基)丙酸;
(R)-2-(4-(3-((6-(3-(2-(2-氟乙氧基)苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸;
(R)-3-(4-(2-((6-(3-(2-(2-氟乙氧基)苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(2-((6-(3-(2-环丙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(2-((6-(3-(2-环丁氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-2-(4-(3-((6-(3-(2-环丙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸;
(R)-2-(4-(3-((6-(3-(2-环丁氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸;
(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基-2-氧代乙基)苯氧基)乙酸;
(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙氧基)苯基)乙酸;
2-(4-(2-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙氧基)苯基)丙酸;
(R)-3-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯氧基-2,2-二甲基丙酸;
(R)-2-(4-(2-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯氧基)丙酸;
(S)-2-(4-(2-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯氧基)丙酸;
(R)-2-(4-(2-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯氧基)-2-甲基丙酸;
(R)-2-(4-(2-((2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-4-基)氨基)-2-氧代乙基)苯氧基)-2-甲基丙酸;
(R)-2-(4-((4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯氧基)甲基)苯基)-2-甲基丙酸;
(R)-2-(4-(3-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯氧基)-2-甲基丙酸;
(R)-2-(4-(3-((2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-4-基)氨基)-3-氧代丙基)苯氧基)-2-甲基丙酸;
(R)-3-(4-(1-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸;
(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2,2-二甲基-3-氧代丙基)苯基)-2-甲基丙酸;
(R)-3-(4-(2-((2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-4-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(2-((4-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(2-((4-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)嘧啶-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(2-((2-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)嘧啶-4-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(2-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)双环[2.2.2]辛烷-1-甲酸;
(R)-4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)双环[2.2.2]辛烷-1-甲酸;
(R)-4-(3-((2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-4-基)氨基)-3-氧代丙基)双环[2.2.2]辛烷-1-甲酸;
(R)-4-(3-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)双环[2.2.2]辛烷-1-甲酸;
(R,E)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙-1-烯-1-基)双环[2.2.2]辛烷-1-甲酸;
(R)-2-(4-(3-((2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-4-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸;
(R)-2-(4-(3-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸;
(R)-3-(4-(1-((2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-4-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(1-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(1-((6-(3-(2-环丁氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸;
(R)-3-(3-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2,2-二甲基丙酸;
(R)-3-(3-(3-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2,2-二甲基丙酸;
(R)-3-(3'-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)-[1,1'-联苯]-3-基)-2,2-二甲基丙酸;和
(R)-3-(3'-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)-[1,1'-联苯]-4-基)-2,2-二甲基丙酸。
除非另有指明,否则本文中使用的术语和缩略语均保留它们的原始含义。
本发明还提供了一种制备式(1)的化合物的方法。在后文中,将在示例性反应的基础上解释所述制备式(1)的化合物的方法,以便说明本发明。然而,本领域技术人员可以在式(1)的结构的基础上通过各种不同方法制备式(1)的化合物,并且此类方法应该被解释为在本发明的范围之内。也就是说,式(1)的化合物可以通过本文描述的方法或通过组合现有技术中公开的各种不同方法来制备,这些方法应该被解释为在本发明的范围之内。因此,用于制备式(1)的化合物的方法不限于下述方法。
本发明的式(1)的化合物可以按照下述反应路线1的方法,通过将取代的酰胺基团例如式(4)的化合物直接引入到化合物(2)中,或通过将受保护的胺引入到化合物(2)中、除去保护基团、然后在制备的化合物(3)上进行酰胺化反应来制备。
[反应路线1]
化合物(2)可以按照下述反应路线2的方法从作为起始原料的3-羟基哌啶-1-甲酸叔丁酯制备。
[反应路线2]
此外,化合物(3)可以按照下述反应路线3的方法来制备。
[反应路线3]
反应路线1中式(4)的化合物中的酰胺衍生物可以通过用亚硫酰氯或草酰氯处理适合的酸,然后用氨水处理来获得。例如,可以按照下述反应路线4的方法制备4-(3-氨基-3-氧代丙基)苯甲酸甲酯。
[反应路线4]
在本说明书的制备方法中未具体描述的化合物是已知化合物或可以通过已知合成方法或类似方法从已知化合物容易地合成的化合物。
通过上述方法获得的式(1)的化合物,可以通过常规方法例如重结晶、离子电渗、硅胶柱层析或离子交换层析从反应产物分离或纯化。
正如上文解释的,根据本发明所述的化合物、用于制备它们的起始原料或中间体可以通过各种不同的方法制备,所述方法应该被解释为就式(1)的化合物的制备而言在本发明的范围之内。
根据本发明的式(1)的化合物对二酰基甘油酰基转移酶2(DGAT2)表现出抑制活性。因此,本发明提供了一种用于治疗与DGAT2相关的疾病的药物组合物,其包含式(1)的化合物或其可药用盐或异构体以及可药用载体。在体内转变成式(1)的化合物的各种不同类型的前体药物,也在本发明的范围之内。
可以通过本发明的药物组合物治疗的与DGAT2相关的示例性疾病包括但不限于选自脂肪肝、非酒精性脂肪性肝炎(NASH)、非酒精性脂肪性肝病(NAFLD)、糖尿病、肥胖症、高脂血症、动脉粥样硬化和高胆固醇血症的疾病。
在本发明中,除了本发明的活性成分之外,“药物组合物”还可以包含其他组分例如载体、稀释剂、赋形剂等。因此,如果需要,所述药物组合物可以包含可药用载体、稀释剂、赋形剂或其组合。所述药物组合物便于化合物在身体中的给药。给药所述化合物的各种不同方法包括但不限于口服、注射、气溶胶、肠胃外和局部给药。
在本文中,“载体”是指便于将化合物添加到细胞或组织中的化合物。例如,二甲基亚砜(DMSO)是一种常规载体,便于许多有机化合物在活细胞或组织中的给药。
在本文中,“稀释剂”是指不仅使生物活性形式稳定,而且在溶解化合物的溶剂中稀释的化合物。使用在缓冲液中溶解的盐作为本领域中的稀释剂。一种常用缓冲液是模拟体液中的盐形式的磷酸盐缓冲盐水。由于缓冲溶液可以在低浓度下控制所述溶液的pH,因此缓冲稀释剂几乎不改变化合物的生物活性。
在本文中,“可药用”是指不损害化合物的生物活性和物理性质的性质。
根据本发明的化合物可以被配制成各种不同的药物给药剂型。在本发明的药物组合物的制备中,将活性组分、具体来说是式(1)的化合物或其可药用盐或异构体,与考虑到待制备的剂型而选择的可药用载体混合。例如,如果需要,本发明的药物组合物可以被配制成注射剂、口服制剂等。
本发明的化合物可以使用已知的制药载体和赋形剂通过常规方法来配制,并插入到单元或多单元容器中。所述制剂可以是在油或水性溶剂中的溶液、悬液或乳液,并包含常规分散剂、悬浮剂或稳定剂。此外,所述化合物可以是例如干粉形式,其在使用前溶解在灭菌的无热原水中。本发明的化合物可以通过使用常规的栓剂基料例如可可脂或其他甘油酯配制成栓剂。用于口服给药的固体形式包括胶囊、片剂、丸剂、粉剂和颗粒剂。优选的是胶囊和片剂。片剂和丸剂优选被肠溶包衣。固体形式通过将本发明的化合物与选自惰性稀释剂例如蔗糖、乳糖或淀粉、润滑剂例如硬脂酸镁、崩解剂、粘合剂等的至少一种载体混合来制备。
如果需要,根据本发明的化合物或包含它们的药物组合物可以与其他药物例如其他代谢障碍治疗剂联合给药。
根据本发明的式(1)的化合物的剂量由医生根据患者的体重、年龄和疾病状况开出的处方确定。根据给药的频率和强度,成人的典型剂量在每天约0.3至500mg的范围内。成人肌肉内或静脉内给药的典型日剂量为每天约1至300mg,其可以在分单位剂量中给药。一些患者需要更高的每日剂量。
在本文中,术语“治疗”用于表示在表现出疾病症状的受试者中阻止、延迟或改善疾病的进展。
有利效果
根据本发明的式(1)的新的酰胺衍生物化合物对二酰基甘油酰基转移酶2(DGAT2)表现出出色的抑制活性,并因此可以有用地用于与DGAT2相关的代谢障碍的预防、缓解或治疗。此外,根据本发明的式(1)的新的酰胺衍生物化合物表现出提高的亲脂性和肝脏选择性,从而通过增加向肝脏的暴露来提高功效,并且由于在疾病动物模型和临床实践中半衰期相对长,因此预计具有服用方便的优点。
具体实施方式
在下文中,将通过制备例和实施例更详细地描述本发明。然而,这些实施例仅仅是说明性的,并且本发明的范围不限于此。
在下面的实施例中,M表示摩尔浓度,N表示当量浓度。此外,在反应路线、制备例和实施例中使用的缩略语和术语的描述如下:
DCM:二氯甲烷
DIPEA:二异丙基乙胺
DMF:N,N-二甲基甲酰胺
EA:乙酸乙酯
HCl:盐酸
TBAF:四丁基氟化铵
TEA:三乙胺
TFA:三氟乙酸
THF:四氢呋喃
制备例1:(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪
步骤1:(R)-3-(2-乙氧基苯氧基)哌啶-1-甲酸叔丁酯
将(S)-3-羟基哌啶-1-甲酸叔丁酯(30.0g,149mmol)、2-乙氧基苯酚(20.6g,149mmol)和三苯基膦(43.8g,167mmol)溶解在500mL甲苯中并在室温搅拌。将偶氮二甲酸二乙酯(30.4mL)在50ml甲苯中稀释,并缓慢地逐滴添加到反应混合物。在室温搅拌15小时后,将反应混合物过滤,用300mL二乙醚洗涤并用100mL 3N氢氧化钠溶液洗涤。将有机溶剂在硫酸镁上脱水并在减压下除去。通过硅胶柱进行纯化(乙酸乙酯:己烷=1:6),得到所需产物(得率:47%)。
m/z(M+NH4)+为C18H27NO4的计算值为344,实测值为344.2
1H NMR(300MHz,氯仿-D):δ6.89-6.95(m,4H),4.07(m,3H),3.9(bs,1H),3.66(bs,1H),3.16(m,2H),2.07(bs,1H),1.76-1.83(m,2H),1.45(m+s,3H)
步骤2:(R)-3-(2-乙氧基苯氧基)哌啶盐酸盐
将在步骤1中得到的(R)-3-(2-乙氧基苯氧基)哌啶-1-甲酸叔丁酯(10.0g,31.1mmol)溶解在100mL二氯甲烷中,并在室温下向其逐滴添加4M盐酸溶液。在室温搅拌4小时后,通过TLC实验确认反应结束,并在减压下除去有机溶剂。在用乙酸乙酯稀释后,将混合物用碳酸氢钠水溶液洗涤,并将有机溶剂在硫酸镁上脱水。将通过在减压下蒸馏得到的化合物不需进一步纯化即用于下一反应中。
m/z(M+H)+为C13H19NO2的计算值为221.3,实测值为222.1
步骤3:(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪
将在步骤2中得到的(R)-3-(2-乙氧基苯氧基)哌啶盐酸盐、2,6-二氯吡嗪(5.10g,34.2mmol)和三乙胺(13mL,93mmol)与100mL乙醇混合并在室温搅拌。在室温搅拌24小时后,通过TLC实验确认了反应结束。在减压下除去有机溶剂后,将混合物溶解在乙酸乙酯中并用盐水洗涤。将有机溶剂在硫酸镁上脱水并在减压下除去。通过硅胶柱进行纯化(乙酸乙酯:己烷=1:3),得到所需产物(得率:91%)。
m/z(M+Na)+为C17H20ClN3O2的计算值为Na 356.8,实测值为356.1
1H-NMR(500MHz,氯仿-D)δ7.93(s,1H),7.74(s,1H),7.04-6.93(m,2H),6.92-6.80(m,2H),4.35-4.24(m,1H),4.07-3.89(m,3H),3.82-3.68(m,1H),3.67-3.46(m,2H),2.09(q,J=4.3Hz,1H),2.02-1.97(m,1H),1.93(q,J=4.3Hz,1H),1.68-1.58(m,1H),1.38(t,J=7.0Hz,3H)
制备例2:(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺
步骤1:(R)-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基甲酸叔丁酯
将在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(1.41g,4.22mmol)、氨基甲酸叔丁酯(0.55g,4.65mmol)、碳酸铯(3.44g,10.56mmol)、4,5-双(二苯基膦)-9,9-二甲基黄嘌呤(220mg,0.38mmol)和三(二亚苯甲基丙酮)二钯(0)(232mg,0.25mmol)溶解在50mL 1,4-二氧杂环己烷中,在搅拌下通过氮气鼓泡除去溶解氧,然后在气密容器中阻断外部空气的流入。将反应混合物在110℃搅拌5小时,然后冷却至室温。在通过硅藻土垫过滤并在减压下除去有机溶剂后,将混合物溶解在乙酸乙酯中并用盐水洗涤。将有机溶剂在硫酸镁上脱水并在减压下除去。通过硅胶柱进行纯化(乙酸乙酯:己烷=3:1),得到所需产物(得率:89%)。
m/z(M+H)+为C22H30N4O4的计算值为:415.5,实测值为415.0
1H-NMR(500MHz,氯仿-D)δ8.40(s,1H),7.78(s,1H),6.96(t,J=7.0Hz,2H),6.91-6.77(m,2H),6.66(s,1H),4.48-4.15(m,1H),4.14-3.85(m,3H),3.84-3.69(m,1H),3.52-3.41(1H),3.40-3.23(m,1H),2.11(t,J=6.1Hz,1H),2.01-1.92(m,1H),1.88(q,J=4.3Hz,1H),1.57(dt,J=13.4,4.0Hz,1H),1.52(s,9H),1.37(t,J=7.0Hz,3H)
步骤2:(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺
将在步骤1中得到的(R)-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基甲酸叔丁酯溶解在10mL二氯甲烷中,并在搅拌下添加2mL三氟乙酸。在通过TLC确认反应完成后,在减压下除去有机溶剂。将反应混合物用乙酸乙酯稀释并用碳酸氢钠水溶液洗涤。将有机溶剂用硫酸镁脱水并在减压下除去,以得到粗产物,并且不需进一步纯化进行下一反应。
m/z(M+H)+为C17H22N4O2的计算值为315.3,实测值为315.0
1H NMR(300MHz,氯仿-D):δ7.49(s,1H),7.28(s,1H),7.27(d,1H),6.90-7.05(m,3H),3.80-4.25(m,7H),3.25(m,2H),2.18(m,1H),1.75-1.98(m,2H),1.91(m,1H),1.43(t,3H),1.27(m,1H)
制备例3:2-(4-氨甲酰基苯基)乙酸甲酯
步骤1:4-(2-甲氧基-2-氧代乙基)苯甲酸
在0℃下向150mL甲醇缓慢地逐滴添加0.34mL亚硫酰氯。然后溶解4-(羧甲基)苯甲酸(17.0g,94mmol)并在室温搅拌5.5小时。在通过TLC确认反应完成后,在减压下除去有机溶剂。将反应混合物用200mL二乙醚稀释,用碳酸氢钠水溶液(2×50mL)和水(30mL)洗涤,并将得到的水性溶液层在0℃下用浓盐酸酸化。将得到的固体过滤,用水洗涤并干燥,得到所需产物(得率:71%)。
步骤2:2-(4-氨甲酰基苯基)乙酸甲酯
将在步骤1中得到的4-(2-甲氧基-2-氧代乙基)苯甲酸(1.0g,5.15mmol)溶解在30mL二氯甲烷中,并在室温下缓慢地逐滴添加亚硫酰氯(0.8mL,10.3mmol)。室温搅拌4小时后,在减压下除去有机溶剂。将混合物溶解在5mL THF中,然后在0℃下缓慢地逐滴添加到25%氨水溶液。在搅拌1小时后,将得到的固体过滤,得到所需产物。
制备例4:2-(4-氨甲酰基苯基)-2-甲基丙酸甲酯
步骤1:4-(2-甲氧基-2-氧代乙基)苯甲酸2-(三甲基甲硅烷基)乙基酯
将在制备例3的步骤1中得到的4-(2-甲氧基-2-氧代乙基)苯甲酸(7.1g,36.6mmol)在氮气存在下溶解在12mL THF中,并顺序添加2-(三甲基甲硅烷基)乙-1-醇(6.5g,54.8mmol)和三苯基膦(24g,91mmol)。将偶氮二甲酸二异丙酯(16.35mL)溶解在30mLTHF中并缓慢地逐滴添加。将混合物在室温搅拌15小时。在通过TLC确认起始原料消失后,将混合物过滤并用100mL二乙醚洗涤。在用3N氢氧化钠溶液洗涤有机层后,将有机溶剂在硫酸镁上脱水并在减压下除去。通过硅胶柱进行纯化(乙酸乙酯:己烷=1:10),得到所需产物(得率:35%)。
步骤2:4-(1-甲氧基-2-甲基-1-氧代丙-2-基)苯甲酸2-(三甲基甲硅烷基)乙基酯
将在步骤1中得到的4-(2-甲氧基-2-氧代乙基)苯甲酸2-(三甲基甲硅烷基)乙基酯(3.81g,12.9mmol)溶解在50mL二甲基甲酰胺中,并在0℃下缓慢地逐滴添加氢化钠(60%,1.04g,25.9mmol)。在搅拌15分钟后,缓慢地逐滴添加碘代甲烷(1.62mL,25.9mmol),并在室温搅拌12小时。使用1N盐酸水溶液终止反应,将反应混合物用乙酸乙酯萃取(2×30mL)并用盐水洗涤(20mL)。将有机溶剂在硫酸镁上脱水并在减压下除去。通过硅胶柱进行纯化(乙酸乙酯:己烷=1:9),得到所需产物(得率:76%)。
步骤3:4-(1-甲氧基-2-甲基-1-氧代丙-2-基)苯甲酸
将在步骤2中得到的4-(1-甲氧基-2-甲基-1-氧代丙-2-基)苯甲酸2-(三甲基甲硅烷基)乙基酯(1.0g,3.10mmol)在氮气存在下溶解在10mL THF中,在0℃下添加1.0M TBAF(4.65mL,4.65mmol),并在室温搅拌12小时。在通过TLC确认起始原料消失后,将THF在减压下浓缩,用1N盐酸溶液和H2O一起(3mL)调整到pH 2,并通过过滤得到产生的固体。
步骤4:2-(4-氨甲酰基苯基)-2-甲基丙酸甲酯
使用在步骤3中得到的4-(1-甲氧基-2-甲基-1-氧代丙-2-基)苯甲酸,以与制备例3的步骤2相似的方式得到所需产物。
制备例5:2-(4-氨甲酰基苯氧基)-2-甲基丙酸乙酯
使用4-羟基苯甲酸苯甲酯(0.73g,3.20mmol)和2-溴-2-甲基丙酸乙酯(0.563mL,3.84mmol),顺序执行制备例7、制备例10的步骤2和制备例6的步骤3的方法,得到所需产物(得率:46%)。
1H-NMR(500MHz,氯仿-D):δ7.72(d,2H),6.85(d,2H),5.97(s,1H),5.75(s,1H),4.23(m,2H),1.63(s,6H),1.23(t,3H)
制备例6:2-(4-(2-氨基-2-氧代乙基)苯基)乙酸甲酯
步骤1:2,2'-(1,4-亚苯基)二乙酸二甲酯
在0℃下向甲醇(20mL)缓慢地逐滴添加乙酰氯(2.9mL,40.8mmol)。然后溶解1,4-亚苯基二乙酸(4.0g,20.6mmol),并将混合物在回流下搅拌5小时。在通过TLC确认反应完成后,将混合物冷却至室温,并在减压下除去有机溶剂。将反应产物用100mL乙酸乙酯稀释,用碳酸氢钠水溶液和盐水洗涤,将有机溶剂在硫酸镁上脱水并在减压下除去,得到所需产物。
1H-NMR(500MHz,氯仿-D)δ7.24(s,2H),3.68(s,3H),3.61(s,2H)
步骤2:2-(4-(2-甲氧基-2-氧代乙基)苯基)乙酸
将在步骤1中得到的2,2'-(1,4-亚苯基)二乙酸二甲酯(4.58g,20.6mmol)溶解在THF(30mL)和甲醇(10mL)中,缓慢地逐滴添加10mL 2N氢氧化钠并在室温搅拌3小时。在减压下除去有机溶剂,将反应混合物用水稀释并用2N盐酸溶液酸化。在用乙酸乙酯萃取后,将有机溶剂在硫酸镁上脱水并在减压下除去。通过重结晶得到所需产物(得率:30%)。
1H-NMR(500MHz,氯仿-D)δ7.25(d,J=4.9Hz,4H),3.68(s,3H),3.66-3.62(2H),3.61(s,2H)
步骤3:2-(4-氨甲酰基苯氧基)-2-甲基丙酸甲酯
将在步骤2中得到的2-(4-(2-甲氧基-2-氧代乙基)苯基)乙酸(1.0g,4.8mmol)溶解在30mL二氯甲烷中,在室温下缓慢地逐滴添加亚硫酰氯(0.7mL,9.6mmol)。在室温搅拌4小时后,在减压下除去有机溶剂,并将反应混合物溶解在5ml THF中,然后在0℃下缓慢地逐滴添加到25%氨水溶液。在搅拌1小时后,将得到的固体过滤,得到所需产物(得率:74%)。
1H-NMR(500MHz,DMSO-D6)δ7.42(s,1H),7.15(dd,J=12.2,7.9Hz,4H),6.83(s,1H),3.60(s,2H),3.57(d,J=4.3Hz,3H),3.30(s,2H)
制备例7:4-(4-(2-氨基-2-氧代乙基)苯氧基)丁酸乙酯
将2-(4-羟基苯基)乙酰胺(1.00g,6.62mmol)、4-溴丁酸乙酯(1.041mL,7.28mmol)和碳酸铯(4.31g,13.23mmol)溶解在DMF(22.05mL)中。将反应混合物在室温搅拌48小时。当反应完成时,向反应溶液添加水,然后用乙酸乙酯萃取。将有机层在减压下浓缩并通过硅胶柱进行纯化(乙酸乙酯:己烷=2:1),得到所需产物(得率:66%)。
1H-NMR(500MHz,氯仿-D):δ7.16(d,2H),6.85(d,2H),5.89(s,1H),5.45(s,1H),4.13(m,2H),3.97(t,2H),3.48(s,2H),2.51(m,2H),2.10(m,2H),1.25(t,3H)
制备例8:2-(4-(2-氨基-2-氧代乙基)苯氧基)-2-甲基丙酸乙酯
使用2-(4-羟基苯基)乙酰胺(2.0g,13.23mmol)和2-溴-2-甲基丙酸乙酯(3.88mL,26.5mmol),以与制备例7相似的方式得到所需产物(得率:26%)。
1H-NMR(500MHz,氯仿-D):δ7.11(d,2H),6.79(d,2H),6.03(s,1H),5.54(s,1H),4.22(m,2H),3.46(s,2H),1.56(s,6H),1.24(t,3H)
制备例9:2-(4-(1-氨基-2-甲基-1-氧代丙-2-基)苯基)-2-甲基丙酸甲酯
步骤1:2,2'-(1,4-亚苯基)双(2-甲基丙酸二甲酯)
将在制备例6的步骤1中得到的2,2'-(1,4-亚苯基)二乙酸二甲酯(3.0g,13.5mmol)溶解在50mL二甲基甲酰胺中,并缓慢地逐滴添加氢化钠(60%,2.16g,54mmol)。在搅拌15分钟后,缓慢地逐滴添加碘代甲烷(3.71mL,59.4mmol)并在室温搅拌12小时。使用1N盐酸水溶液终止反应,将得到的产物用乙酸乙酯萃取并用盐水洗涤,将有机溶剂用硫酸镁脱水并在减压下除去。通过硅胶柱进行纯化(乙酸乙酯:己烷=1:9),得到所需产物(得率:76%)。
1H-NMR(400MHz,氯仿-D)δ7.28(s,4H),3.66(s,6H),1.57(s,12H)
步骤2:2-(4-(1-氨基-2-甲基-1-氧代丙-2-基)苯基)-2-甲基丙酸甲酯
使用在步骤1中得到的2,2'-(1,4-亚苯基)双(2-甲基丙酸二甲酯),顺序执行制备例6的步骤2和3,得到标题化合物(得率:26%)。
1H-NMR(400MHz,氯仿-D)δ7.25-7.29(m,4H),5.31-5.38(brs,2H),3.66(s,3H),1.56(s,12H)
制备例10:4-(3-氨基-3-氧代丙基)苯甲酸甲酯
步骤1:(E)-4-(3-叔丁氧基)-3-氧代丙-1-烯-1-基)苯甲酸甲酯
将4-溴苯甲酸甲酯(16.4g,0.07mol)、丙烯酸叔丁酯(18g,0.14mol)和三乙胺(50mL,0.35mol)溶解在200mL二甲基甲酰胺中,通过用氮气鼓泡除去溶解氧,添加双(三苯基膦)二氯化钯(2.5g,3.58mmol)并在75℃搅拌12小时。在减压下除去有机溶剂,将反应混合物用乙酸乙酯稀释,用盐水洗涤并用硫酸镁脱水。在减压下除去有机溶剂。通过硅胶柱进行纯化(乙酸乙酯:己烷=1:3),得到所需产物(得率:79%)。
1H-NMR(500MHz,氯仿-D)δ7.56(d,J=15.9Hz,1H),7.46(d,J=8.7Hz,2H),7.28(d,J=7.9Hz,2H),6.34(d,J=15.9Hz,1H),3.70(s,3H),3.64(s,2H),1.53(s,9H)
步骤2:4-(3-(叔丁氧基)-3-氧代丙基)苯甲酸甲酯
将在步骤1中得到的(E)-4-(3-叔丁氧基)-3-氧代丙-1-烯-1-基)苯甲酸甲酯(5.0g,18mmol)溶解在50mL甲醇中,逐滴添加钯炭(0.5g),并使用氢气球进行还原反应。在确认反应完成后,将得到的产物通过硅藻土垫过滤,并在减压下除去有机溶剂,得到所需产物(得率:93%)。
1H-NMR(500MHz,氯仿-D)δ7.17(dd,J=18.3,7.9Hz,4H),3.68(s,3H),3.59(s,2H),2.88(t,J=7.9Hz,2H),2.52(t,J=7.6Hz,2H),1.41(s,9H)
步骤3:3-(4-(甲氧基羰基)苯基)丙酸
将在步骤2中得到的4-(3-(叔丁氧基)-3-氧代丙基)苯甲酸甲酯(4.67g,16.8mmol)溶解在100mL 20%三氟乙酸/二氯甲烷溶液中并在室温搅拌2小时。在确认反应完成后,在减压下除去有机溶剂,并通过重结晶得到所需产物(得率:100%)。
1H-NMR(500MHz,氯仿-D)δ9.58(s,2H),7.18(dd,J=19.0,7.9Hz,4H),3.70(s,3H),3.61(s,2H),2.95(t,J=7.6Hz,2H),2.69(t,J=7.9Hz,2H)
步骤4:4-(3-氨基-3-氧代丙基)苯甲酸甲酯
使用在步骤3中得到的3-(4-(甲氧基羰基)苯基)丙酸(2.08g,9.98mmol),以与制备例6的步骤3相似的方式通过酰胺化反应得到所需产物(得率:65%)。
1H-NMR(500MHz,氯仿-D)δ7.18(q,J=7.7Hz,4H),5.41(s,2H),3.66(d,J=15.9Hz,3H),3.59(s,2H),3.02-2.87(2H),2.51(t,J=7.6Hz,2H)
制备例11:(E)-4-(3-氨基-3-氧代丙-1-烯-1-基)苯甲酸甲酯
使用在制备例10的步骤1中得到的(E)-4-(3-叔丁氧基)-3-氧代丙-1-烯-1-基)苯甲酸甲酯(0.09g,0.44mmol),以与制备例10的步骤3和4相似的方式通过水解反应(得率:100%)和酰胺化反应(得率:76%)得到所需产物。
1H-NMR(400MHz,氯仿-D)δ8.05(d,J=8.4Hz,2H),7.68(d,J=15.6Hz,1H),7.58(d,J=8.4Hz,H),6.53(d,J=15.6Hz,1H),5.5(brds,2H),3.93(s,3H)
制备例12:(E)-4-(3-氨基-2-甲基-3-氧代丙-1-烯-1-基)苯甲酸甲酯
步骤1:(E)-4-(3-(叔丁氧基)-2-甲基-3-氧代丙-1-烯-1-基)苯甲酸甲酯
使用甲基丙烯酸叔丁酯(3.97g,27.9mmol)和4-溴苯甲酸甲酯(3.0g,13.95mmol),以与制备例10的步骤1相似的方式得到所需产物(得率:48%)。
1H-NMR(500MHz,甲醇-D3)δ8.04(d,J=6.7Hz,2H),7.95(d,J=7.3Hz,2H),7.58(s,1H),7.42(dd,J=20.5,13.1Hz,2H),7.25(dd,J=4.0,2.8Hz,6H),3.99-3.85(m,7H),3.63(s,2H),2.11-2.01(m,3H),1.47-1.36(9H)
步骤2:(E)-3-(4-(甲氧基羰基)苯基)-2-甲基丙烯酸
使用在步骤1中得到的(E)-4-(3-(叔丁氧基)-2-甲基-3-氧代丙-1-烯-1-基)苯甲酸甲酯(0.72g,2.59mmol),以与制备例10的步骤3相似的方式得到所需产物(得率:100%)。
1H-NMR(500MHz,氯仿-D)δ8.07(d,J=7.9Hz,2H),7.97(d,J=7.9Hz,2H),7.80(s,1H),7.47(d,J=7.9Hz,2H),7.28(d,J=7.9Hz,2H),7.25(s,5H),7.23(s,1H),6.41(s,1H),5.62(s,1H),3.93(s,3H),3.89(d,J=13.4Hz,3H),3.69(s,2H),2.17-2.07(m,3H)
步骤3:(E)-4-(3-氨基-2-甲基-3-氧代丙-1-烯-1-基)苯甲酸甲酯
使用在步骤2中得到的(E)-3-(4-(甲氧基羰基)苯基)-2-甲基丙烯酸(0.57g,2.59mmol),以与制备例10的步骤4相似的方式通过酰胺化反应得到所需产物(得率:92%)。
1H-NMR(500MHz,氯仿-D)δ8.10-8.02(2H),7.98(d,J=7.9Hz,2H),7.45(d,J=10.4Hz,1H),7.42-7.34(m,2H),7.29(d,J=7.9Hz,2H),5.81(s,1H),5.38-5.28(m,1H),3.93(s,3H),3.90(s,3H),3.72(s,2H),2.17(s,2H),2.12(d,J=1.2Hz,3H),2.03(d,J=10.4Hz,0H),1.26(t,J=7.0Hz,2H),0.88(t,J=7.0Hz,1H)
制备例13:4-(3-氨基-2-甲基-3-氧代丙基)苯甲酸甲酯
步骤1:4-(3-(叔丁氧基)-2-甲基-3-氧代丙基)苯甲酸甲酯
使用在制备例12的步骤1中得到的(E)-4-(3-(叔丁氧基)-2-甲基-3-氧代丙-1-烯-1-基)苯甲酸甲酯(1.12g,4.05mmol),以与制备例10的步骤2相似的方式通过还原反应得到所需产物(得率:96%)。
1H-NMR(500MHz,氯仿-D)δ7.98-7.91(m,2H),7.28-7.25(m,2H),7.24(s,1H),3.91(d,J=10.4Hz,3H),3.05-2.95(m,1H),2.72-2.59(m,2H),1.58(s,0H),1.43-1.32(m,10H),1.17(s,0H),1.17-1.10(3H)
步骤2:3-(4-(甲氧基羰基)苯基)-2-甲基丙酸
使用在步骤1中得到的4-(3-(叔丁氧基)-2-甲基-3-氧代丙基)苯甲酸甲酯(1.08g,3.90mmol),以与制备例10的步骤3相似的方式得到所需产物(得率:100%)。
1H-NMR(500MHz,氯仿-D)δ7.95(q,J=7.7Hz,2H),7.35-7.22(m,2H),3.99-3.85(m,3H),3.11(q,J=6.5Hz,1H),2.87-2.69(m,2H),2.34(d,J=15.3Hz,1H),1.32-1.13(m,3H)
步骤3:4-(3-氨基-2-甲基-3-氧代丙基)苯甲酸甲酯
使用在步骤2中得到的3-(4-(甲氧基羰基)苯基)-2-甲基丙酸(0.87g,3.90mmol),以与制备例10的步骤4相似的方式通过酰胺化反应得到所需产物(得率:92%)。
1H-NMR(500MHz,氯仿-D)δ8.10-8.02(2H),7.98(d,J=7.9Hz,2H),7.45(d,J=10.4Hz,1H),7.42-7.34(m,2H),7.29(d,J=7.9Hz,2H),5.81(s,1H),5.38-5.28(m,1H),3.93(s,3H),3.90(s,3H),3.72(s,2H),2.17(s,2H),2.12(d,J=1.2Hz,3H),2.03(d,J=10.4Hz,0H),1.26(t,J=7.0Hz,2H),0.88(t,J=7.0Hz,1H)
制备例14:4-(3-氨基-3-氧代丙基)-2-氟苯甲酸甲酯
步骤1:(E)-4-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)-2-氟苯甲酸甲酯
使用4-溴-2-氟苯甲酸甲酯(0.34g,1.46mmol)和丙烯酸叔丁酯(0.37g,2.92mmol),以与制备例10的步骤1相似的方式得到所需产物(得率:56%)。
1H-NMR(500MHz,氯仿-D)δ7.94(s,1H),7.51(d,J=15.9Hz,1H),7.32(d,J=7.9Hz,1H),7.26(t,J=5.8Hz,1H),6.43(d,J=15.9Hz,1H),3.93(s,3H),1.53(s,9H)
步骤2:4-(3-(叔丁氧基)-3-氧代丙基)-2-氟苯甲酸甲酯
使用在步骤1中得到的(E)-4-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)-2-氟苯甲酸甲酯(0.23g,0.82mmol),以与制备例10的步骤2相似的方式通过还原反应得到所需产物(得率:99%)。
1H-NMR(500MHz,氯仿-D):δ7.85(t,J=7.9Hz,1H),7.04(dd,J=7.9,1.2Hz,1H),6.98(dd,J=11.6,1.2Hz,1H),3.91(s,3H),2.93(t,J=7.6Hz,2H),2.55(t,J=7.3Hz,2H),1.41(s,9H)
步骤3:3-(3-氟-4-(甲氧基羰基)苯基)丙酸
使用在步骤2中得到的4-(3-(叔丁氧基)-3-氧代丙基)-2-氟苯甲酸甲酯(0.23g,0.82mmol),以与制备例10的步骤3相似的方式得到所需产物(得率:98%)。
1H-NMR(500MHz,氯仿-D):δ10.05(s,1H),7.87(t,J=7.9Hz,1H),7.12-7.04(m,1H),7.00(d,J=11.6Hz,1H),3.92(s,3H),2.99(t,J=7.6Hz,2H),2.72(t,J=7.6Hz,2H)
步骤4:4-(3-氨基-3-氧代丙基)-2-氟苯甲酸甲酯
使用在步骤3中得到的3-(3-氟-4-(甲氧基羰基)苯基)丙酸(0.18g,0.8mmol),以与制备例10的步骤4相似的方式得到所需产物(得率:95%)。
制备例15:4-(3-氨基-3-氧代丙基)-2-甲基苯甲酸甲酯
步骤1:(E)-4-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)-2-甲基苯甲酸甲酯
使用4-溴-2-甲基苯甲酸甲酯(1.0g,4.54mmol)和丙烯酸叔丁酯(1.15g,9.08mmol),以与制备例10的步骤1相似的方式得到所需产物(得率:100%)。
1H-NMR(500MHz,氯仿-D):δ7.90(d,J=7.9Hz,1H),7.54(d,J=15.9Hz,1H),7.42-7.31(2H),6.42(d,J=15.9Hz,1H),3.89(s,3H),2.60(s,3H),1.53(s,9H)
步骤2:4-(3-(叔丁氧基)-3-氧代丙基)-2-甲基苯甲酸甲酯
使用在步骤1中得到的(E)-4-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)-2-甲基苯甲酸甲酯(1.2g,4.34mmol),以与制备例10的步骤2相似的方式通过还原反应得到所需产物(得率:96%)。
1H-NMR(500MHz,氯仿-D):δ7.89-7.78(m,1H),7.06(d,J=6.1Hz,2H),3.86(s,3H),2.89(t,J=7.6Hz,2H),2.57(s,3H),2.52(d,J=7.9Hz,2H),1.41(s,9H)
步骤3:3-(4-甲氧基羰基)-3-甲基苯基)丙酸
使用在步骤2中得到的4-(3-(叔丁氧基)-3-氧代丙基)-2-甲基苯甲酸甲酯(1.16g,4.17mmol),以与制备例10的步骤3相似的方式得到所需产物(得率:92%)。
1H-NMR(500MHz,氯仿-D):δ10.96(s,1H),7.85(d,J=8.6Hz,1H),7.08(s,2H),3.88(s,3H),2.95(t,J=7.6Hz,2H),2.70(t,J=7.6Hz,2H),2.57(s,3H)
步骤4:4-(3-氨基-3-氧代丙基)-2-甲基苯甲酸甲酯
使用在步骤3中得到的3-(4-甲氧基羰基)-3-甲基苯基)丙酸(0.9g,4.04mmol),以与制备例10的步骤4相似的方式通过酰胺化反应得到所需产物(得率:90%)。
1H-NMR(500MHz,氯仿-D):δ7.84(t,J=4.3Hz,1H),7.08(d,J=5.5Hz,2H),5.37(d,J=22.0Hz,2H),3.86(s,3H),2.96(t,J=7.6Hz,2H),2.56(s,3H),2.52(t,J=7.6Hz,2H)
制备例16:4-(3-氨基-3-氧代丙基)-2-甲氧基苯甲酸甲酯
使用4-溴-2-甲氧基苯甲酸甲酯(0.98g,4.00mmol),以与制备例10相似的方式得到所需产物(得率:39%)。
制备例17:4-(3-氨基-3-氧代丙基)-2-氯苯甲酸甲酯
步骤1:(E)-4-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)-2-氯苯甲酸甲酯
使用4-溴-2-氯苯甲酸甲酯(2.0g,8.73mmol)和丙烯酸叔丁酯(2.24g,17.5mmol),以与制备例10的步骤1相似的方式得到所需产物(得率:85%)。
1H-NMR(400MHz,氯仿-D)δ7.84(d,J=8Hz,1H),7.58(d,J=1.2Hz,1H),7.54(d,J=13.6Hz,1H),7.42(d,J=8Hz,1H),6.43(d,J=16Hz,1H),3.94(s,3H),1.54(s,9H)
步骤2:4-(3-(叔丁氧基)-3-氧代丙基)-2-氯苯甲酸甲酯
使用在步骤1中得到的(E)-4-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)-2-氯苯甲酸甲酯(0.28g,0.93mmol),以与制备例10的步骤2相似的方式通过还原反应得到所需产物(得率:89%)。
1H-NMR(400MHz,氯仿-D)δ7.78(d,J=8H,1H),7.30(s,1H),7.15(d,J=8Hz,1H),3.92(s,3H),2.92(t,J=8Hz,2H),2.55(t,J=8Hz,2H),1.42(s,9H)
步骤3:3-(3-氯-4-(甲氧基羰基)苯基)丙酸
使用在步骤2中得到的4-(3-(叔丁氧基)-3-氧代丙基)-2-氯苯甲酸甲酯(0.25g,0.83mmol),以与制备例10的步骤3相似的方式得到所需产物(得率:100%)。
1H-NMR(400MHz,氯仿-D)δ7.79(s,J=8Hz,1H),7.32(d,J=4Hz,1H),7.17(dd,J=8Hz,4Hz,1H),3.92(s,3H),2.97(t,J=8Hz,2H),2.70(t,J=8Hz,2H)
步骤4:4-(3-氨基-3-氧代丙基)-2-氯苯甲酸甲酯
使用在步骤3中得到的3-(3-氯-4-(甲氧基羰基)苯基)丙酸(0.20g,0.83mmol),以与制备例10的步骤4相似的方式通过酰胺化反应得到所需产物(得率:89%)。
1H-NMR(400MHz,氯仿-D)δ7.78(d,J=8Hz,1H),7.32(s,1H),7.17(d,J=8Hz,1H),3.92(s,3H),2.99(t,J=8Hz,2H),2.53(t,J=8Hz,2H)
制备例18:3-(3-氨基-3-氧代丙基)苯甲酸甲酯
步骤1:(E)-3-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)苯甲酸甲酯
将3-甲酰基苯甲酸甲酯(0.60g,3.65mmol)和(叔丁氧基羰基亚甲基)三苯基磷烷(2.06g,5.48mmol)溶解在二氯甲烷(18.27mL)中并在室温搅拌16小时。将反应溶液在减压下浓缩并通过硅胶柱进行纯化(乙酸乙酯:己烷=1:4),得到所需产物(得率:94%)。
步骤2:3-(3-(叔丁氧基)-3-氧代丙基)苯甲酸甲酯
使用在步骤1中得到的(E)-3-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)苯甲酸甲酯(0.90g,3.43mmol),以与制备例10的步骤2相似的方式得到所需产物(得率:99%)。
步骤3:3-(3-氨基-3-氧代丙基)苯甲酸甲酯
使用在步骤2中得到的3-(3-(叔丁氧基)-3-氧代丙基)苯甲酸甲酯(0.90g,3.40mmol),顺序执行制备例10的步骤3和4的方法,得到所需产物(得率:78%)
制备例19:2-(4-(3-氨基-3-氧代丙基)苯基)乙酸甲酯
步骤1:(E)-4-(3-叔丁氧基)-3-氧代丙-1-烯-1-基)苯甲酸甲酯
使用2-(4-溴苯基)乙酸甲酯(16.4g,70.0mmol)和丙烯酸叔丁酯(18.0g,140.0mmol),以与制备例10的步骤1相似的方式得到所需产物(得率:79%)。
1H-NMR(500MHz,氯仿-D)δ7.56(d,J=15.9Hz,1H),7.46(d,J=8.7Hz,2H),7.28(d,J=7.9Hz,2H),6.34(d,J=15.9Hz,1H),3.70(s,3H),3.64(s,2H),1.53(s,9H)
步骤2:4-(3-(叔丁氧基)-3-氧代丙基)苯甲酸甲酯
使用在步骤1中得到的(E)-4-(3-叔丁氧基)-3-氧代丙-1-烯-1-基)苯甲酸甲酯(5.0g,18.0mmol),以与制备例10的步骤2相似的方式通过还原反应得到所需产物(得率:93%)。
1H-NMR(500MHz,氯仿-D)δ7.17(dd,J=18.3,7.9Hz,4H),3.68(s,3H),3.59(s,2H),2.88(t,J=7.9Hz,2H),2.52(t,J=7.6Hz,2H),1.41(s,9H)
步骤3:3-(4-(2-甲氧基-2-氧代乙基)苯基)丙酸
使用在步骤2中得到的4-(3-(叔丁氧基)-3-氧代丙基)苯甲酸甲酯(4.67g,16.8mmol),以与制备例10的步骤3相似的方式得到所需产物(得率:100%)。
1H-NMR(500MHz,氯仿-D)δ9.58(s,2H),7.18(dd,J=19.0,7.9Hz,4H),3.70(s,3H),3.61(s,2H),2.95(t,J=7.6Hz,2H),2.69(t,J=7.9Hz,2H)
步骤4:2-(4-(3-氨基-3-氧代丙基)苯基)乙酸甲酯
使用在步骤3中得到的3-(4-(2-甲氧基-2-氧代乙基)苯基)丙酸(3.73g,16.8mmol),以与制备例10的步骤4相似的方式通过酰胺化反应得到所需产物(得率:65%)。
1H-NMR(500MHz,氯仿-D)δ7.18(q,J=7.7Hz,4H),5.41(s,2H),3.66(d,J=15.9Hz,3H),3.59(s,2H),3.02-2.87(2H),2.51(t,J=7.6Hz,2H)
步骤1:(E)-3-(4-(1-甲氧基-2-甲基-1-氧代丙-2-基)苯基)丙烯酸叔丁酯
使用2-(4-溴苯基)-2-甲基丙酸甲酯(1.0g,3.89mmol)和丙烯酸叔丁酯(0.98g,7.8mmol),以与制备例10的步骤1相似的方式得到所需产物(得率:79%)。
1H-NMR(500MHz,氯仿-D):δ7.56(dd,J=15.9,4.3Hz,1H),7.51-7.42(2H),7.41-7.31(m,2H),6.34(dd,J=15.9,4.9Hz,1H),3.66(d,J=4.9Hz,3H),1.58(d,J=4.9Hz,6H),1.53(d,J=4.9Hz,9H)
步骤2:2-(4-(3-(叔丁氧基)-3-氧代丙基)苯基)-2-甲基丙酸甲酯
使用在步骤1中得到的(E)-3-(4-(1-甲氧基-2-甲基-1-氧代丙-2-基)苯基)丙烯酸叔丁酯(0.93g,3.06mmol),以与制备例10的步骤2相似的方式通过还原反应得到所需产物(得率:96%)。
1H-NMR(500MHz,氯仿-D):δ7.23(s,2H),7.15(d,J=7.9Hz,2H),3.63(s,3H),2.87(t,J=7.9Hz,2H),2.52(t,J=7.9Hz,2H),1.55(s,6H),1.40(s,9H)
步骤3:3-(4-(1-甲氧基-2-甲基-1-氧代丙-2-基)苯基)丙酸
使用在步骤2中得到的2-(4-(3-(叔丁氧基)-3-氧代丙基)苯基)-2-甲基丙酸甲酯(0.90g,2.92mmol),以与制备例10的步骤3相似的方式得到所需产物(得率:96%)。
1H-NMR(500MHz,氯仿-D):δ7.26(d,J=7.3Hz,2H),7.16(d,J=7.9Hz,2H),3.66(s,3H),3.03-2.84(2H),2.82-2.55(2H),1.56(s,6H)
步骤4:2-(4-(3-氨基-3-氧代丙基)苯基)-2-甲基丙酸甲酯
使用在步骤3中得到的3-(4-(1-甲氧基-2-甲基-1-氧代丙-2-基)苯基)丙酸(0.7g,2.8mmol),以与制备例10的步骤4相似的方式通过酰胺化反应得到所需产物(得率:99%)。
1H-NMR(500MHz,氯仿-D):δ7.25(dd,J=6.4,2.1Hz,2H),7.17(d,J=7.9Hz,2H),5.36(s,2H),3.64(s,3H),3.00-2.90(2H),2.52(t,J=7.6Hz,2H),1.56(d,J=4.3Hz,6H)
制备例21:1-(4-(3-氨基-3-氧代丙基)苯基)环丙烷-1-甲酸甲酯
步骤1:(E)-1-(4-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)苯基)环丙烷-1-甲酸甲
酯
使用1-(4-溴苯基)环丙烷-1-甲酸甲酯(1.0g,3.92mmol)和丙烯酸叔丁酯(0.99g,7.84mmol),以与制备例10的步骤1相似的方式得到所需产物(得率:78%)。
1H-NMR(500MHz,氯仿-D):δ7.56(d,J=15.9Hz,1H),7.44(d,J=7.9Hz,2H),7.33(d,J=7.9Hz,2H),6.34(d,J=15.9Hz,1H),3.62(s,3H),1.62(t,J=3.4Hz,2H),1.52(s,9H),1.19(t,J=3.4Hz,2H)
步骤2:1-(4-(3-(叔丁氧基)-3-氧代丙基)苯基)环丙烷-1-甲酸甲酯
使用在步骤1中得到的(E)-1-(4-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)苯基)环丙烷-1-甲酸甲酯(0.93g,3.08mmol),以与制备例10的步骤2相似的方式通过还原反应得到所需产物(得率:96%)。
1H-NMR(500MHz,氯仿-D):δ7.24(d,J=8.6Hz,2H),7.13(d,J=7.9Hz,2H),3.61(s,3H),2.89(t,J=7.9Hz,2H),2.53(t,J=7.9Hz,2H),1.57(q,J=3.7Hz,2H),1.40(d,J=4.9Hz,9H),1.16(q,J=3.7Hz,2H)
步骤3:3-(4-(1-(甲氧基羰基)环丙基)苯基)丙酸
使用在步骤2中得到的1-(4-(3-(叔丁氧基)-3-氧代丙基)苯基)环丙烷-1-甲酸甲酯(0.90g,2.96mmol),以与制备例10的步骤3相似的方式得到所需产物(得率:97%)。
1H-NMR(500MHz,氯仿-D):δ8.61(s,1H),7.26(d,J=8.6Hz,2H),7.15(d,J=7.9Hz,2H),3.64(s,3H),2.95(t,J=7.3Hz,2H),2.74(s,2H),1.61(q,J=3.5Hz,2H),1.20(q,J=3.5Hz,2H)
步骤4:1-(4-(3-氨基-3-氧代丙基)苯基)环丙烷-1-甲酸甲酯
使用在步骤3中得到的3-(4-(1-(甲氧基羰基)环丙基)苯基)丙酸(0.7g,2.82mmol),以与制备例10的步骤4相似的方式通过酰胺化反应得到所需产物(得率:95%)。
1H-NMR(500MHz,氯仿-D):δ7.28-7.24(m,2H),7.15(d,J=8.6Hz,2H),5.41(s,2H),3.61(t,J=2.4Hz,3H),2.95(t,J=7.6Hz,2H),2.52(t,J=7.6Hz,2H),1.58(q,J=3.7Hz,2H),1.16(q,J=3.5Hz,2H)
制备例22:4-(3-氨基-3-氧代丙基)-2,6-二氟苯甲酸甲酯
使用4-溴-2,6-二氟苯甲酸甲酯(1.0g,3.98mmol),以与制备例10相似的方式得到所需产物(得率:39%)。
1H-NMR(400MHz,氯仿-D):δ6.81(d,J=9.1Hz,2H),5.35(s,2H),3.92(s,3H),3.02-2.92(t,2H),2.51(t,J=7.5Hz,2H)
制备例23:4-(3-氨基-3-氧代丙基)2,6-二氯苯甲酸2-(三甲基甲硅烷基)乙基酯
步骤1:4-溴-2,6-二氯苯甲酸2-(三甲基甲硅烷基)乙基酯
在将4-溴-2,6-二氯苯甲酸(300mg,1.112mmol)在氮气存在下溶解在8mL THF中之后,在0℃下顺序添加2-(三甲基甲硅烷基)乙-1-醇(0.250mL,1.667mmol)、偶氮二甲酸二异丙酯(0.530mL,2.56mmol)和三苯基膦(729mg,2.78mmol),并在室温搅拌2小时。在通过TLC确认起始原料消失后,将反应用水终止,然后用乙酸乙酯萃取(30mL×3)。将萃取溶剂在硫酸镁上脱水,并在减压下除去有机溶剂。通过硅胶柱进行纯化(乙酸乙酯:己烷=1:10),得到所需产物(得率:47%)。
1H NMR(300MHz,氯仿-D):δ7.52(s,2H),4.52-4.46(m,2H),1.20-1.14(m,2H),0.10(s,9H)
步骤2:(E)-4-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)-2,6-二氯苯甲酸2-(三甲基
甲硅烷基)乙基酯
使用在步骤1中得到的4-溴-2,6-二氯苯甲酸2-(三甲基甲硅烷基)乙基酯(205mg,0.554mmol),以与制备例10的步骤1相似的方式得到所需产物。
1H NMR(300MHz,氯仿-D):δ7.45(s,2H),7.44(d,J=15.9Hz,1H),6.41(d,J=15.9Hz,1H),4.53-4.47(m,2H),1.55(s,9H)1.21-1.15(m,2H),0.10(s,9H)
步骤3:4-(3-(叔丁氧基)-3-氧代丙基)-2,6-二氯苯甲酸2-(三甲基甲硅烷基)乙
基酯
使用在步骤2中得到的(E)-4-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)-2,6-二氯苯甲酸2-(三甲基甲硅烷基)乙基酯(150mg,0.453mmol),以与制备例10的步骤2相似的方式通过还原反应得到所需产物。
1H NMR(300MHz,氯仿-D):δ7.19(s,2H),3.98(s,3H),2.87(t,J=7.5Hz,2H),2.54(t,J=7.5Hz,2H),1.44(s,9H)
步骤4:3-(3,5-二氯-4-((2-(三甲基甲硅烷基)乙基)羰基)苯基)丙酸
使用在步骤3中得到的4-(3-(叔丁氧基)-3-氧代丙基)-2,6-二氯苯甲酸2-(三甲基甲硅烷基)乙基酯(141mg,0.423mmol),以与制备例10的步骤3相似的方式得到所需产物。
步骤5:4-(3-氨基-3-氧代丙基)2,6-二氯苯甲酸2-(三甲基甲硅烷基)乙基酯
使用在步骤4中得到的3-(3,5-二氯-4-((2-(三甲基甲硅烷基)乙基)羰基)苯基)丙酸,以与制备例10的步骤4相似的方式通过酰胺化反应得到所需产物。
制备例24:4-(3-氨基-3-氧代丙基)-2,6-二甲基苯甲酸2-(三甲基甲硅烷基)乙基酯
步骤1:4-溴-2,6-二甲基苯甲酸2-(三甲基甲硅烷基)乙基酯
使用4-溴-2,6-二甲基苯甲酸(2.0g,8.73mmol),以与制备例23的步骤1相似的方式得到所需产物(得率:69%)。
1H-NMR(500MHz,氯仿-D):δ7.19(s,2H),4.40(t,J=8.9Hz,2H),2.29(s,6H),1.11(t,J=8.9Hz,2H),0.07(d,J=3.1Hz,9H)
步骤2:(E)-4-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯甲酸2-(三甲
基甲硅烷基)乙基酯
使用在步骤1中得到的4-溴-2,6-二甲基苯甲酸2-(三甲基甲硅烷基)乙基酯(1.99g,6.04mmol),以与制备例10的步骤1相似的方式得到所需产物(得率:50%)。
1H-NMR(500MHz,氯仿-D):δ7.49(d,J=15.9Hz,1H),7.17-7.10(2H),6.35(d,J=15.9Hz,1H),4.41(t,J=8.9Hz,2H),2.30(s,6H),1.52(s,9H),1.16-1.07(m,2H),0.07(d,J=2.4Hz,9H)
步骤3:4-(3-(叔丁氧基)-3-氧代丙基)-2,6-二甲基苯甲酸2-(三甲基甲硅烷基)
乙基酯
使用在步骤2中得到的(E)-4-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)-2,6-二甲基苯甲酸2-(三甲基甲硅烷基)乙基酯(1.13g,3.0mmol),以与制备例10的步骤2相似的方式通过还原反应得到所需产物(得率:69%)。
1H-NMR(500MHz,氯仿-D):δ6.85(s,2H),4.39(t,J=8.9Hz,2H),2.81(d,J=7.9Hz,2H),2.49(t,J=7.9Hz,2H),2.29(s,6H),1.45-1.39(9H),1.16-1.07(m,2H),0.06(s,9H)
步骤4:3-(3,5-二甲基-4-((2-(三甲基甲硅烷基)乙基)羰基)苯基)丙酸
使用在步骤3中得到的4-(3-(叔丁氧基)-3-氧代丙基)-2,6-二甲基苯甲酸2-(三甲基甲硅烷基)乙基酯(0.78g,2.06mmol),以与制备例10的步骤3相似的方式得到所需产物(得率:60%)。
步骤5:4-(3-氨基-3-氧代丙基)-2,6-二甲基苯甲酸2-(三甲基甲硅烷基)乙基酯
使用在步骤4中得到的3-(3,5-二甲基-4-((2-(三甲基甲硅烷基)乙基)羰基)苯基)丙酸,以与制备例10的步骤4相似的方式通过酰胺化反应得到所需产物(得率:88%)。
制备例25:1-(4-(3-氨基-3-氧代丙基)苯基)哌啶-4-甲酸乙酯
步骤1:1-(4-甲酰基苯基)哌啶-4-甲酸乙酯
将4-氟苯甲醛(0.864mL 8.06mmol)、哌啶-4-甲酸乙酯(1.490mL,9.67mmol)和碳酸钾(5.57g,40.3mmol)溶解在DMF(16.11mL)中。将温度升高到100℃并搅拌16小时。当反应完成时,向反应溶液添加水,然后用乙酸乙酯萃取。将有机层在减压下浓缩并通过硅胶柱进行纯化(乙酸乙酯:己烷=1:4),得到所需产物(得率:81%)。
1H-NMR(500MHz,氯仿-D):δδ9.72(d,J=3.1Hz,1H),7.70(m,2H),6.97-6.78(m,2H),4.12(m,2H),3.91-3.72(m,2H),3.10-2.88(m,2H),2.61-2.43(m,1H),2.08-1.89(m,2H),1.87-1.69(m,2H),1.23(m,3H)
步骤2:(E)-1-(4-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)苯基)哌啶-4-甲酸乙酯
将在步骤1中得到的1-(4-甲酰基苯基)哌啶-4-甲酸乙酯(0.52g,1.990mmol)和(叔丁氧基羰基亚甲基)三苯基磷烷(0.974g,2.59mmol)溶解在二氯甲烷(9.95mL)中并在室温搅拌16小时。将反应溶液在减压下浓缩并通过硅胶柱进行纯化(乙酸乙酯:己烷=1:4),得到所需产物(得率:84%)。
1H-NMR(500MHz,氯仿-D):δ7.50(d,J=15.9Hz,1H),7.39(d,J=8.6Hz,2H),6.86(d,J=8.6Hz,2H),6.19(d,J=15.9Hz,1H),4.15(q,J=7.1Hz,2H),3.74(m,2H),2.98-2.80(m,2H),2.55-2.37(m,1H),2.11-1.94(m,2H),1.94-1.74(m,2H),1.51(s,9H),1.26(t,J=7.0Hz,3H)
步骤3:1-(4-(3-(叔丁氧基)-3-氧代丙基)苯基)哌啶-4-甲酸乙酯
使用在步骤2中得到的(E)-1-(4-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)苯基)哌啶-4-甲酸乙酯(0.60g,1.669mmol),以与制备例10的步骤2相似的方式通过还原反应得到所需产物(得率:99%)。
步骤4:1-(4-(3-氨基-3-氧代丙基)苯基)哌啶-4-甲酸乙酯
使用在步骤3中得到的1-(4-(3-(叔丁氧基)-3-氧代丙基)苯基)哌啶-4-甲酸乙酯(0.60g,1.660mmol),顺序执行制备例10的步骤3和4的方法,得到所需产物(得率:69%)。
制备例26:1-(4-氨甲酰基-2,6-二氟苯基)哌啶-4-甲酸乙酯
使用3,4,5-三氟苯甲酸叔丁酯(0.50g,2.15mmol)和哌啶-4-甲酸乙酯(0.398mL,2.58mmol),顺序执行制备例25的步骤1和制备例10的步骤3和4,得到所需产物(得率:58%)。
1H-NMR(400MHz,氯仿-D):δ7.33(m,2H),5.78(s,2H),4.19(m,2H),3.42(d,2H),3.17(t,2H),2.50(m,1H),2.00-1.82(m,4H),1.29(t,3H)
制备例27:2-(1-(4-氨甲酰基-2,6-二氟苯基)哌啶-4-基)乙酸乙酯
使用3,4,5-三氟苯甲酸叔丁酯(0.50g,2.15mmol)和2-(哌啶-4-基)乙酸乙酯(0.44g,2.58mmol),以与制备例26相似的方式得到所需产物(得率:59%)。
1H-NMR(400MHz,氯仿-D):δ7.27(m,2H),5.67(s,2H),4.18(m,2H),3.38(d,2H),3.17(t,2H),2.30(d,2H),1.97(m,1H),1.79(d,2H),1.45(m,2H),1.29(t,3H)
制备例28:2-(4-(3-氨基-3-氧代丙基)苯氧基)-2-甲基丙酸乙酯
使用4-羟基苯甲醛(1.0g,8.19mmol)和2-溴-2-甲基丙酸乙酯(2.404mL,16.38mmol),以与制备例25相似的方式得到所需产物(得率:29%)。
1H-NMR(500MHz,氯仿-D):δ7.07(d,2H),6.77(d,2H),5.29(s,2H),4.25(m,2H),2.91(t,2H),2.50(t,2H),1.59(s,6H),1.26(t,3H)
制备例29:3-(4-(3-氨基-3-氧代丙基)苯基)丙酸乙酯
使用4-溴苯甲醛(0.5g,2.70mmol)和(乙氧基羰基亚甲基)三苯基磷烷(1.224g,3.51mmol),顺序执行制备例18的步骤1和制备例10,得到所需产物(得率:66%)。
1H-NMR(500MHz,氯仿-D):δ7.14(m,4H),5.36(s,2H),4.12(m,2H),2.93(m,4H),2.60(t,2H),2.52(t,2H),1.25(t,3H)
制备例30:4-(4-氨甲酰基苯氧基)苯甲酸乙酯
使用4-氟苯甲酸苯甲酯(0.5g,2.172mmol)和4-羟基苯甲酸乙酯(0.361g,2.172mmol),顺序执行制备例25的步骤1、制备例10的步骤2和制备例6的步骤3的方法,得到所需产物(得率:11%)。
1H-NMR(500MHz,氯仿-D):δ8.06(d,2H),7.84(d,2H),7.08(m,4H),6.03(s,1H),5.63(s,1H),4.38(m,2H),1.40(t,3H)
制备例31:(R)-3-(4-(2-氨基-2-氧代乙基)苯基)-2-甲基丙酸甲酯
将(S)-4-苯甲基-3-丙酰基唑烷-2-酮(1.363g,5.84mmol)溶解在无水四氢呋喃中,将温度降低至-78℃,并将混合物搅拌15分钟。缓慢地逐滴添加双(三甲基甲硅烷基)酰胺钠(3.38mL,6.43mmol,1.0M,在THF中)。在将反应溶液在相同温度下搅拌1小时后,逐滴添加2-(4-(溴甲基)苯基)乙酸叔丁酯(2g,7.01mmol)。在相同温度下搅拌6小时后,将温度升高至室温。添加饱和氯化铵水溶液以终止反应,并将混合物用乙酸乙酯萃取。将有机层在减压下浓缩并通过硅胶柱进行纯化(乙酸乙酯:己烷=1:2),得到所需产物(得率:94%)。
1H-NMR(500MHz,氯仿-D):δ7.17(d,J=7.9Hz,2H),7.10(d,J=7.9Hz,2H),3.63(s,3H),3.48(s,2H),3.00(q,J=6.7Hz,1H),2.77-2.67(m,1H),2.66-2.58(m,1H),1.42(s,9H),1.13(d,J=7.3Hz,3H)
步骤2:(R)-3-(4-(2-(叔丁氧基)-2-氧代乙基)苯基)-2-甲基丙酸甲酯
将在步骤1中得到的2-(4-((R)-3-((S)-4-苯甲基-2-氧代唑烷-3-基)-2-甲基-3-氧代丙基)苯基)乙酸叔丁酯(2.4g,5.49mmol)溶解在四氢呋喃(21mL)和水(7mL)中,在室温下顺序添加过氧化氢(3.36mL,54.9mmol)和氢氧化锂(0.921g,21.94mmol)。将反应溶液在室温搅拌3小时,并用1N盐酸终止反应。将得到的产物用乙酸乙酯萃取并在减压下浓缩。将粗品化合物溶解在二乙醚(28mL)中,并将温度降低至0℃。逐滴添加重氮甲烷(0.5M,在二乙醚中),直至溶液的颜色变成黄色。将反应溶液在减压下浓缩并通过硅胶柱进行纯化(乙酸乙酯:己烷=1:4),得到所需产物(得率:31%)。
步骤3:(R)-3-(4-(2-氨基-2-氧代乙基)苯基)-2-甲基丙酸甲酯
使用在步骤2中得到的(R)-3-(4-(2-(叔丁氧基)-2-氧代乙基)苯基)-2-甲基丙酸甲酯(0.5g,1.71mmol),顺序执行制备例10的步骤3和4的方法,得到所需产物(得率:87%)。
1H-NMR(400MHz,氯仿-D):δ7.16(m,4H),5.35(s,2H),3.62(s,3H),3.54(s,2H),3.00(m,1H),2.68(m,2H),1.14(d,J=6.9Hz,3H)
制备例32:(S)-3-(4-(2-氨基-2-氧代乙基)苯基)-2-甲基丙酸甲酯
使用(R)-4-苯甲基-3-丙酰基唑烷-2-酮(0.744g,3.19mmol)和2-(4-(溴甲基)苯基)乙酸叔丁酯(1.00g,3.51mmol),以与制备例31相似的方式得到所需产物(得率:25%)。
1H-NMR(400MHz,氯仿-D):δ7.16(m,4H),5.38(s,2H),3.62(s,3H),3.54(s,2H),3.00(m,1H),2.68(m,2H),1.13(t,J=7.5Hz,3H)
制备例33:3-(4-(2-氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸甲酯
步骤1:2-(4-(3-甲氧基-2,2-二甲基-3-氧代丙基)苯基)乙酸
向无水四氢呋喃(20mL)添加二异丙基胺(1.867mL,13.10mmol),并在-78℃下缓慢地逐滴添加2.5M正丁基锂(5.24mL,13.10mmol)。将反应溶液在相同温度下搅拌20分钟。在将温度升高至室温并搅拌10分钟后,将温度再次降低至-78℃并搅拌10分钟。将反应溶液逐滴添加到溶解在无水四氢呋喃(20mL)中的异丁酸甲酯(1.501mL,13.10mmol)。将反应溶液在-78℃搅拌1小时,并缓慢地逐滴添加到溶解在无水四氢呋喃(20mL)中的2-(4-(溴甲基)苯基)乙酸(1g,4.37mmol)。将温度升高至室温,并将反应溶液搅拌20分钟。通过向反应溶液添加1N盐酸水溶液(10mL)终止反应,然后用二乙醚萃取。将有机层在减压下浓缩并通过硅胶柱进行纯化(甲醇:二氯甲烷=1:9),得到所需产物(得率:82%)。
1H-NMR(500MHz,氯仿-D):δ7.17(d,J=7.9Hz,2H),7.06(d,J=7.9Hz,2H),3.65(s,3H),3.61(s,2H),2.83(s,2H),1.17(s,6H)
步骤2:3-(4-(2-氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸甲酯
使用在步骤1中得到的2-(4-(3-甲氧基-2,2-二甲基-3-氧代丙基)苯基)乙酸(0.90g,3.60mmol),以与制备例6的步骤3相似的方式得到所需产物(得率:87%)。
1H-NMR(500MHz,氯仿-D):δ7.17(d,2H),7.09(d,2H),5.36(s,2H),3.66(s,3H),3.55(s,2H),2.84(s,2H),1.17(s,6H)
制备例34:4-(4-氨甲酰基哌啶-1-基)苯甲酸乙酯
使用4-氟苯甲酸乙酯(0.524mL,3.57mmol)和哌啶-4-甲酸苯甲酯盐酸盐(1.10g,4.28mmol),顺序执行制备例25的步骤1、制备例10的步骤2和制备例6的步骤3的方法,得到所需产物(得率:26%)。
1H-NMR(400MHz,氯仿-D):δ7.97(d,2H),6.92(d,2H),5.51(s,1H),5.41(s,1H),4.40(m,2H),3.96(d,2H),2.98(m,2H),2.46(m,1H),2.05(m,2H),1.94(m,2H),1.43(t,3H)
制备例35:1-(5-乙基嘧啶-2-基)哌啶-4-甲酰胺
步骤1:1-(5-乙基嘧啶-2-基)哌啶-4-甲酸乙酯
将哌啶-4-甲酸乙酯(0.980mL,6.36mmol)、碳酸铯(2.176g,6.68mmol)和2-氯-5-乙基嘧啶(0.796mL,6.55mmol)溶解在DMF(6.36mL)中,并在100℃搅拌4小时。当反应完成时,向反应溶液添加水,然后用乙酸乙酯萃取。将有机层在减压下浓缩并通过硅胶柱进行纯化(乙酸乙酯:己烷=1:4),得到所需产物(得率:96%)。
1H-NMR(500MHz,氯仿-D):δ8.16(s,2H),4.61(m,2H),4.14(q,J=7.1Hz,2H),3.09-2.91(m,2H),2.62-2.51(m,1H),2.45(q,J=7.5Hz,2H),1.96(m,2H),1.80-1.63(m,2H),1.25(t,J=7.3Hz,3H),1.18(t,J=7.6Hz,3H)
步骤2:1-(5-乙基嘧啶-2-基)哌啶-4-甲酰胺
使用在步骤1中得到的1-(5-乙基嘧啶-2-基)哌啶-4-甲酸乙酯(0.56g,2.127mmol),顺序执行制备例6的步骤2和3的方法,得到所需产物(得率:14%)。
1H-NMR(500MHz,氯仿-D):δ8.16(s,2H),5.49(s,2H),4.76(m,2H),2.94(m,2H),2.48(m,3H),1.96(m,2H),1.70(m,2H),1.19(t,3H)
制备例36:2-(4-(2-氨基-2-氧代乙基)苯基)2-甲基丙酸甲酯
步骤1:2-(4-(溴甲基)苯基)-2-甲基丙酸甲酯
将2-甲基-2-(对甲苯基)丙酸甲酯溶解在DCE(55.3mL)中,添加N-溴琥珀酰亚胺(4.63g,26.0mmol)和偶氮二异丁腈(0.085g,0.520mmol)。将反应混合物在80℃搅拌2小时30分钟。在减压下除去溶剂,用EA稀释,用盐水洗涤,并将有机溶剂在硫酸镁上脱水。通过硅胶柱进行纯化,得到所需产物(得率:56.7%)。
1H-NMR(400MHz,氯仿-D)δ7.37-7.27(m,4H),4.47(s,2H),3.65(d,J=4.6Hz,3H),1.56(d,J=3.2Hz,6H)
步骤2:2-(4-氰基甲基)苯基)-2-甲基丙酸甲酯
将在步骤1中得到的2-(4-(溴甲基)苯基)-2-甲基丙酸甲酯(100mg,0.369mmol)溶解在DMF(5mL)中,添加氰化钾(36.0mg,0.553mmol)并在室温搅拌16小时。在通过添加水终止反应后,将得到的产物用二乙醚稀释,用盐水洗涤,并将有机溶剂用硫酸镁脱水。通过硅胶柱进行纯化,得到所需产物(得率:52.4%)。
1H-NMR(400MHz,氯仿-D)δ7.34(d,J=8.7Hz,2H),7.28(d,J=8.2Hz,2H),3.71(s,2H),3.64(s,3H),1.54(d,J=15.6Hz,6H)
步骤3:2-(4-(2-甲氧基-2-氧代乙基)苯基)-2-甲基丙酸甲酯
将在步骤2中得到的2-(4-氰基甲基)苯基)-2-甲基丙酸甲酯(1.46g,6.72mmol)溶解在甲醇(8.4mL)中,并向其添加4N HCl溶液(8.40mL,33.6mmol)。将反应混合物在100℃搅拌16小时。在减压下除去溶剂后,将得到的产物用乙酸乙酯稀释并用盐水洗涤,并将有机溶剂在硫酸镁上脱水。通过硅胶柱得到所需产物(得率:32.1%)。
1H-NMR(400MHz,氯仿-D)δ7.28(d,J=8.2Hz,2H),7.23(d,J=8.2Hz,2H),3.68(s,3H),3.64(s,3H),3.59(s,2H),1.57(s,6H)
步骤4:2-(4-(1-甲氧基-2-甲基-1-氧代丙烷-2-基)苯基)乙酸
将在步骤3中得到的2-(4-(2-甲氧基-2-氧代乙基)苯基)-2-甲基丙酸甲酯(27mg,0.108mmol)溶解在THF(1mL)和甲醇(1mL)中,并向其添加溶解在水(0.5mL)中的氢氧化锂(2.58mg,0.108mmol)。将反应混合物在室温搅拌3小时。在减压下除去溶剂后,将得到的产物用EA稀释并用盐水洗涤,并将有机溶剂在硫酸镁上脱水。通过硅胶柱进行纯化,得到所需产物(得率:100%)。
1H-NMR(400MHz,氯仿-D)δ7.36-7.19(m,7H),3.75-3.57(m,6H),1.69-1.50(m,6H)
步骤5:2-(4-(2-氨基-2-氧代乙基)苯基)-2-甲基丙酸甲酯
使用在步骤4中得到的2-(4-(1-甲氧基-2-甲基-1-氧代丙烷-2-基)苯基)乙酸(26mg,0.110mmol),以与制备例6的步骤3相似的方式得到所需产物(得率:77%)。
1H-NMR(400MHz,氯仿-D)δ7.31(d,J=8.2Hz,2H),7.22(d,J=8.2Hz,2H),5.47(d,J=59.9Hz,1H),3.64(s,3H),3.55(s,2H),1.56(t,J=14.6Hz,6H)
制备例37:3-(4-(1-氨基-2-甲基-1-氧代丙-2-基)苯基)丙酸甲酯
将2-(4-溴苯基)-2-甲基丙酸(1.00g,4.11mmol)溶解在DCM(21mL)中,添加草酰氯(0.94g,7.40mmol),并添加5滴DMF。将反应混合物在室温搅拌30分钟,并在减压下除去溶剂。将浓缩物溶解在THF(21mL)中,将温度降低至0℃,并向其添加叔丁醇钾(0.55g,4.94mmol)。在室温搅拌12小时后,添加水,然后用乙酸乙酯萃取。在用水和盐水洗涤后,将有机层在硫酸镁上脱水并在减压下浓缩。通过柱层析进行纯化,给出2-(4-溴苯基)-2-甲基丙酸叔丁酯。然后顺序执行与制备例10相似的方法,得到所需产物(得率:31%)。
1H-NMR(400MHz,氯仿-D):δ7.37-7.29(m,2H),7.18(d,J=8.2Hz,2H),5.97(s,1H),5.24(s,1H),3.67(d,J=1.4Hz,3H),2.94(t,J=7.5Hz,2H),2.63(t,J=7.8Hz,2H),1.66-1.44(m,6H)
制备例38:3-(4-(3-氨甲酰基氮杂环丁烷-1-基)苯基)丙酸乙酯
步骤1:1-(4-甲酰基苯基)氮杂环丁烷-3-甲酸苯甲酯
向DMF(7.3mL)添加1-(4-甲酰基苯基)氮杂环丁烷-3-甲酸(1.50g,7.31mmol)、碳酸钾(1.11g,8.04mmol)和苄基溴(1.25g,7.31mmol),并在室温搅拌12小时。向反应混合物添加水,然后用乙酸乙酯萃取。在用水和盐水洗涤后,将有机层在硫酸镁上脱水并在减压下浓缩。通过柱层析进行纯化,得到所需产物(得率:56%)。
1H NMR(400MHz,氯仿-D):δ9.74(s,1H),7.72(d,J=8.7Hz,2H),7.45-7.29(m,5H),6.42(d,J=8.7Hz,2H),5.20(s,2H),4.26-4.13(m,4H),3.70-3.59(m,1H)
步骤2:1-(4-(3-乙氧基-3-氧代丙基)苯基)氮杂环丁烷-3-甲酸
使用在步骤1中得到的1-(4-甲酰基苯基)氮杂环丁烷-3-甲酸苯甲酯(1.20g,4.06mmol),顺序执行制备例25的步骤2和3的方法,得到标题化合物(得率:52%)。
1H NMR(400MHz,氯仿-D):δ7.07(d,J=8.2Hz,2H),6.43(d,J=8.2Hz,2H),4.18-3.97(m,6H),3.59(dd,J=14.4,6.2Hz,1H),2.86(t,J=7.8Hz,2H),2.56(t,J=7.8Hz,2H),1.30-1.16(m,3H)
步骤3:3-(4-(3-(氯羰基)氮杂环丁烯-1-基)苯基)丙酸乙酯
在将步骤中得到的1-(4-(3-乙氧基-3-氧代丙基)苯基)氮杂环丁烷-3-甲酸(590mg,2.13mmol)溶解在二氯甲烷中之后,将温度降低至0℃。向其逐滴添加草酰氯(0.37mL,4.26mmol),并将温度逐渐升高至室温。在反应完成后,将得到的产物在减压下浓缩并不需进一步纯化即用于下一反应中(得率:99%)。
m/z(M+H)+为C15H19ClNO3的计算值为296,实测值为296
步骤4:3-(4-(3-氨甲酰基氮杂环丁烷-1-基)苯基)丙酸乙酯
使用在步骤3中得到的3-(4-(3-(氯羰基)氮杂环丁烯-1-基)苯基)丙酸乙酯(629mg,2.127mmol),以与制备例6的步骤3相似的方式得到所需产物(得率:4%)。
1H-NMR(400MHz,氯仿-D)δ7.08-6.90(m,2H),6.57(dd,J=23.8,15.6Hz,2H),6.09(s,NH),5.59(s,NH),4.10(q,J=7.0Hz,3H),3.87-3.54(m,2H),3.50-3.32(m,2H),3.02-2.86(m,1H),2.82(t,J=7.8Hz,2H),2.72-2.43(m,2H),1.22(t,J=7.1Hz,3H)
制备例39:2-(4-氨甲酰基哌啶-1-基)嘧啶-5-甲酸甲酯
步骤1:1-(5-(甲氧基羰基)嘧啶-2-基)哌啶-4-甲酸
将哌啶-4-甲酸(50mg,0.387mmol)和2-氯嘧啶-5-甲酸甲酯(80mg,0.465mmol)溶解在DMF中,添加TEA(108μL,0.774mmol)并在80℃搅拌。在搅拌1小时后,通过TLC确认反应终止。在通过萃取过程除去DMF并中和以得到有机层后,使用硫酸镁除去水,将得到的材料在减压下蒸馏并通过柱层析进行纯化(二氯甲烷:甲醇=10:1),得到1-(5-(甲氧基羰基)嘧啶-2-基)哌啶-4-甲酸(40mg,0.151mmol,得率:39%)。
1H-NMR(400MHz,甲醇-D4)δ8.77(d,J=2.3Hz,2H),4.71(d,J=13.7Hz,2H),3.83(d,J=2.3Hz,3H),3.22-3.04(m,2H),2.61(s,1H),2.09-1.88(m,2H),1.75-1.49(m,2H)
步骤2:2-(4-氨甲酰基哌啶-1-基)嘧啶-5-甲酸甲酯
使用在步骤1中得到的1-(5-(甲氧基羰基)嘧啶-2-基)哌啶-4-甲酸(42.8mg,0.151mmol),以与制备例6的步骤3相似的方式得到所需产物(得率:88%)。
1H-NMR(400MHz,氯仿-D)δ8.80(s,2H),8.41(s,1H),4.81-4.70(m,2H),4.68(s,1H),3.86-3.75(m,3H),3.24-3.13(m,1H),2.65(tt,J=10.7,3.9Hz,1H),2.12-1.84(m,5H),1.86-1.61(m,3H)
制备例40:2-(4-(4-氨甲酰基哌啶-1-基)苯基)乙酸叔丁酯
使用2-(4-溴苯基)乙酸叔丁酯(0.3g,1.106mmol)和哌啶-4-甲酸乙酯(0.209g,1.328mmol),顺序执行与制备例2的步骤1和制备例6的步骤2和3相似的方法,得到所需产物(3步得率:20.1%)。
1H-NMR(400MHz,氯仿-D)δ7.13(d,J=8.7Hz,2H),6.90-6.83(2H),5.60(d,J=16.9Hz,2H),3.68(d,J=12.3Hz,2H),3.42(s,2H),2.70(td,J=12.1,2.4Hz,2H),2.32-2.20(m,1H),1.96(d,J=11.0Hz,2H),1.84(qd,J=12.2,3.7Hz,2H),1.43(d,J=10.5Hz,9H)
制备例41:2-(4-(4-氨甲酰基哌啶-1-基)苯基)-2-甲基丙酸甲酯
使用2-(4-溴苯基)-2-甲基丙酸甲酯(0.20g,0.78mmol)和哌啶-4-甲酸叔丁酯(0.17g,0.93mmol),顺序执行制备例2和制备例6的步骤3的方法,得到所需产物(得率:64%)。
1H-NMR(400MHz,氯仿-D):δ7.23-7.13(m,2H),6.91-6.80(m,2H),5.54(s,2H),3.70(d,J=12.3Hz,2H),3.63(d,J=7.8Hz,3H),2.72(td,J=12.1,2.3Hz,2H),2.27(qd,J=7.8,4.0Hz,1H),1.97(d,J=10.5Hz,2H),1.84(qd,J=12.2,3.9Hz,2H),1.54(d,J=7.3Hz,6H)
制备例42:2-(6-(4-氨甲酰基哌啶-1-基)吡啶-3-基)-2-甲基丙酸甲酯
使用2-(6-氯吡啶-3-基)-2-甲基丙酸甲酯(2.05g,9.59mmol)和哌啶-4-甲酸叔丁酯(2.13g,11.51mmol),以与制备例41相似的方式得到所需产物(得率:12%)。
1H-NMR(400MHz,氯仿-D):δ8.15(t,J=2.1Hz,1H),7.44(dt,J=9.0,2.4Hz,1H),6.61(dd,J=8.9,1.6Hz,1H),5.58(s,2H),4.30(d,J=12.8Hz,2H),3.62(d,J=2.3Hz,3H),2.95-2.76(m,2H),2.45-2.28(m,1H),2.00-1.88(2H),1.80-1.63(m,2H),1.53(d,J=1.8Hz,6H)
制备例43:2-(5-(4-氨甲酰基哌啶-1-基)-2H-四唑-2-基)乙酸乙酯
步骤1:哌啶-1,4-二甲酸4-苯甲基1-(叔丁基)酯
将1-(叔丁氧基羰基)哌啶-4-甲酸(4.37g,19.06mmol)溶解在丙酮中,向其添加苄基溴(2.72mL,22.87mmol)和碳酸钾(6.32g,45.7mmol)。连接回流冷凝器,并将反应混合物加热2小时。在反应完成后,将得到的产物冷却至室温并添加水。分离有机层并在硫酸镁上脱水。将在减压下通过蒸馏得到的材料通过柱层析进行纯化(己烷:乙酸乙酯),得到哌啶-1,4-二甲酸4-苯甲基1-(叔丁基)酯(6.09g,19.07mmol,得率:99%)。
1H-NMR(400MHz,氯仿-D)δ7.45-7.27(m,6H),5.12(s,2H),4.07-3.91(2H),2.91-2.71(2H),2.56-2.39(m,1H),1.88(d,J=10.5Hz,2H),1.71-1.56(m,2H),1.44(t,J=15.1Hz,9H)
步骤2:哌啶-4-甲酸苯甲酯
使用在步骤1中得到的哌啶-1,4-二甲酸4-苯甲基1-(叔丁基)酯(6.09g,19.07mmol),以与制备例2的步骤2相似的方式得到所需产物(得率:48%)。
1H-NMR(400MHz,甲醇-D4)δ7.40-7.20(m,5H),5.09(s,2H),2.98(td,J=8.5,4.1Hz,2H),2.58(td,J=12.1,2.7Hz,2H),2.50(qd,J=7.5,3.5Hz,1H),1.86(dd,J=13.7,3.2Hz,2H),1.70-1.47(m,2H)
步骤3:1-氰基哌啶-4-甲酸苯甲基酯
将在步骤2中得到的哌啶-4-甲酸苯甲基酯(1.9934g,9.09mmol)溶解在乙腈中,添加DIPEA(4.76mL,27.3mmol)和溴化氰(0.573mL,10.91mmol),并在室温搅拌2小时。在反应完成后添加水。分离有机层并在硫酸镁上脱水,将在减压下通过蒸馏得到的材料通过柱层析进行纯化(己烷:乙酸乙酯),得到1-氰基哌啶-4-甲酸苯甲基酯(2.1838g,8.94mmol,得率:98%)。
1H-NMR(400MHz,氯仿-D)δ7.45-7.27(m,5H),5.20-5.05(2H),3.41(td,J=8.5,4.3Hz,2H),3.15-2.95(m,2H),2.57-2.37(m,1H),1.98(dd,J=14.2,3.7Hz,2H),1.92-1.73(2H)
步骤4:1-(2H-四唑-5-基)哌啶-4-甲酸苯甲基酯
将在步骤3中得到的1-氰基哌啶-4-甲酸苯甲基酯(2.1838g,8.94mmol)溶解在DMF中,添加氯化铵(0.717g,13.41mmol)和叠氮化钠(0.872g,13.41mmol),并在100℃反应6小时。在反应完成后添加水。分离有机层并在硫酸镁上脱水,将在减压下通过蒸馏得到的材料通过柱层析进行纯化(己烷:乙酸乙酯),得到1-(2H-四唑-5-基)哌啶-4-甲酸苯甲基酯(2.57g,8.94mmol,得率:99%)。
1H-NMR(400MHz,甲醇-D4)δ7.95(s,1H),7.31(dt,J=12.3,4.3Hz,5H),5.12(s,2H),3.78(dt,J=13.3,3.9Hz,2H),3.32(s,1H),3.21-3.05(m,2H),2.97(s,2H),2.83(s,2H),2.76-2.56(m,1H),2.00(dd,J=13.5,3.4Hz,2H),1.74(ddd,J=24.6,11.3,4.0Hz,2H)
步骤5:1-(2-(2-乙氧基-2-氧代乙基)-2H-四唑-5-基)哌啶-4-甲酸苯甲基酯
将在步骤4中得到的1-(2H-四唑-5-基)哌啶-4-甲酸苯甲基酯(1.465g,5.10mmol)溶解在DMF中,添加碳酸钾(1.409g,10.20mmol)和2-溴乙酸乙酯(1.277g,7.65mmol),并在室温搅拌12小时。在反应完成后添加水。分离有机层并在硫酸镁上脱水,将在减压下通过蒸馏得到的材料通过柱层析进行纯化(己烷:乙酸乙酯),得到1-(2-(2-乙氧基-2)-氧代乙基)-2H-四唑-5-基)哌啶-4-甲酸苯甲基酯(1.8039g,4.83mmol,得率:95%)。
1H-NMR(400MHz,氯仿-D)δ7.44-7.27(m,5H),5.17(s,2H),5.13(s,2H),4.31-4.19(m,2H),4.03(td,J=8.5,4.6Hz,2H),3.13-2.93(m,2H),2.55(tt,J=11.1,3.8Hz,1H),1.99(d,J=1.8Hz,2H),1.81(ddd,J=24.8,11.1,4.2Hz,2H),1.32-1.26(m,3H)
步骤6:1-(2-(2-乙氧基-2-氧代乙基)-2H-四唑-5-基)哌啶-4-甲酸
使用在步骤5中得到的1-(2-(2-乙氧基-2-氧代乙基)-2H-四唑-5-基)哌啶-4-甲酸苯甲基酯(1.8039g,4.83mmol),以与制备例10的步骤2相似的方式得到所需产物(得率:79%)。
1H-NMR(400MHz,甲醇-D4)δ5.35(s,2H),4.23(q,J=7.2Hz,2H),3.96(dt,J=13.0,3.5Hz,2H),3.14-2.93(m,2H),2.61-2.42(m,1H),1.96(dd,J=13.7,3.2Hz,2H),1.71(ddd,J=24.7,11.4,4.1Hz,2H),1.34-1.21(m,3H)
步骤7:2-(5-(4-氨甲酰基哌啶-1-基)-2H-四唑-2-基)乙酸乙酯
使用在步骤6中得到的1-(2-(2-乙氧基-2-氧代乙基)-2H-四唑-5-基)哌啶-4-甲酸(1.085g,4.83mmol),以与制备例6的步骤3相似的方式得到所需产物(得率:13%)。
1H-NMR(400MHz,甲醇-D4)δ5.35(s,2H),4.32-4.16(2H),4.05(d,J=12.8Hz,2H),3.32(d,J=6.9Hz,1H),2.96(td,J=12.6,2.7Hz,2H),2.50-2.34(2H),1.84(d,J=12.3Hz,2H),1.74(td,J=12.1,4.4Hz,2H),1.26(t,J=7.3Hz,3H)
制备例44:2-(4-氨甲酰基哌啶-1-基)乙酸乙酯
使用哌啶-4-甲酰胺(300mg,2.341mmol)和2-溴乙酸乙酯(311μL,2.81mmol),以与制备例43的步骤3相似的方式得到所需产物(得率:36%)。
1H-NMR(MeOD)δ4.19(q,J=7.1Hz,2H),3.24(s,2H),3.00(d,J=11.3Hz,2H),2.35-2.16(m,3H),1.88-1.72(m,4H),1.28(t,J=7.0Hz,3H)
制备例45:1-(4-(1-氨基-2-甲基-1-氧代丙-2-基)苯基)哌啶-4-甲酸乙酯
使用哌啶-4-甲酸乙酯(0.13g,0.80mmol)和2-(4-溴苯基)-2-甲基丙酸叔丁酯(0.2g,0.67mmol),以与制备例41相似的方式得到所需产物(得率:72%)。
1H-NMR(400MHz,氯仿-D):δ7.27-7.15(m,2H),6.95-6.75(m,2H),5.88(s,1H),5.24(s,1H),4.19-4.06(2H),3.60(dt,J=12.3,3.4Hz,2H),2.83-2.66(m,2H),2.46-2.32(m,1H),1.98(dd,J=13.3,2.7Hz,2H),1.92-1.74(m,2H),1.51(s,6H),1.24(t,J=7.1Hz,3H)
制备例46:6-(3-氨甲酰基吡咯烷-1-基)烟酸甲酯
步骤1:吡咯烷-1,3-二甲酸3-苯甲基1-(叔丁基)酯
将1-(叔丁氧基羰基)吡咯烷-3-甲酸(1.22g,5.67mmol)溶解在DMF中,向其添加苄基溴(0.808mL,6.80mmol)和碳酸铯(2.216g,6.80mmol)并在室温搅拌12小时。在反应完成后添加水,分离有机层并在硫酸镁上脱水。将在减压下通过蒸馏得到的材料通过柱层析进行纯化(己烷:乙酸乙酯),得到吡咯烷-1,3-二甲酸3-苯甲基1-(叔丁基)酯(1.7g,5.57mmol,得率:98%)。
1H-NMR(400MHz,氯仿-D)δ7.34(s,5H),5.12(d,J=11.0Hz,2H),3.57(s,2H),3.33(s,1H),3.08(s,1H),2.12(s,2H),1.43(d,J=11.0Hz,9H)
步骤2:吡咯烷-3-甲酸苯甲基酯
使用在步骤1中得到的吡咯烷-1,3-二甲酸3-苯甲基1-(叔丁基)酯(1.7g,5.57mmol),以与制备例2的步骤2相似的方式得到所需产物(得率:99%)。
1H-NMR(400MHz,氯仿-D)δ7.44-7.26(m,14H),7.10(dd,J=7.5,1.6Hz,6H),5.12(s,2H),4.11(q,J=7.2Hz,3H),4.00(td,J=8.5,4.6Hz,2H),3.07-2.87(m,2H),2.61-2.42(m,1H),1.97(dd,J=13.5,3.9Hz,2H),1.90-1.67(m,2H)
步骤3:6-(3-((苯甲氧基)羰基)吡咯烷-1-基)烟酸甲酯
使用在步骤2中得到的吡咯烷-3-甲酸苯甲基酯(1.277g,6.22mmol),以与制备例2的步骤1相似的方式得到所需产物(得率:46%)。
1H-NMR(氯仿-D)δ8.82(d,J=2.4Hz,1H),8.02(dd,J=9.0,2.3Hz,1H),7.44-7.30(m,5H),6.35(d,J=8.8Hz,1H),5.18(dd,J=16.0,12.4Hz,2H),3.88(s,3H),3.87-3.75(2H),3.76-3.63(1H),3.63-3.48(1H),3.29(t,J=7.3Hz,1H),2.43-2.28(m,2H)
步骤4:1-(5-(甲氧基羰基)吡啶-2-基)吡咯烷-3-甲酸
使用在步骤3中得到的6-(3-((苯甲氧基)羰基)吡咯烷-1-基)烟酸甲酯(524mg,1.539mmol),以与制备例10的步骤2相似的方式得到所需产物(得率:99%)。
1H-NMR(MeOD)δ8.68(d,J=2.1Hz,1H),8.03(dd,J=9.0,2.3Hz,1H),6.55(d,J=9.2Hz,1H),3.87(s,3H),3.77(t,J=5.0Hz,3H),3.71-3.51(m,3H),3.28(t,J=7.2Hz,1H),2.42-2.25(m,2H)
步骤5:6-(3-氨甲酰基吡咯烷-1-基)烟酸甲酯
将在步骤4中得到的1-(5-(甲氧基羰基)吡啶-2-基)吡咯烷-3-甲酸(423mg,1.690mmol)溶解在DMF中,将温度降低至0℃,并向其添加氯化铵(380mg,7.10mmol)、DIPEA(886μL,5.07mmol)和1-羟基苯并三唑(337mg,2.197mmol)。在向反应溶液缓慢添加1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(389mg,2.028mmol)后,将反应温度升高至室温并搅拌12小时。在反应完成后添加水,分离有机层并在硫酸镁上脱水。将在减压下通过蒸馏得到的材料通过柱层析进行纯化(己烷:乙酸乙酯),得到6-(3-氨甲酰基吡咯烷-1-基)烟酸甲酯(213mg,0.854mmol,得率:51%)。
1H-NMR(400MHz,甲醇-D4)δ8.66-8.61(1H),8.02-7.96(1H),6.54-6.46(1H),3.85-3.80(4H),3.79-3.71(1H),3.69-3.56(2H),3.55-3.42(1H),3.23-3.06(1H),2.37-2.07(3H)
制备例47:3-氨甲酰基-3-甲基吡咯烷-1-甲酸叔丁酯
步骤1:(R)-吡咯烷-1,3-二甲酸3-苯甲基1-(叔丁基)酯
使用(R)-1-(叔丁氧基羰基)吡咯烷-3-甲酸(518mg,2.407mmol),以与制备例43的步骤1相似的方式得到所需产物(得率:93%)。
1H-NMR(400MHz,氯仿-D)δ7.44-7.26(m,5H),5.13(s,2H),3.66-3.39(m,2H),3.33(s,1H),3.07(d,J=7.3Hz,1H),2.13(t,J=7.1Hz,2H),1.50-1.33(9H)
步骤2:3-甲基吡咯烷-1,3-二甲酸3-苯甲基1-(叔丁基)酯
将在步骤1中得到的(R)-吡咯烷-1,3-二甲酸3-苯甲基1-(叔丁基)酯(684mg,2.240mmol)溶解在无水THF中,并向其添加碘代甲烷(0.42mL,6.72mmol)。将反应溶液降低至-78℃,然后缓慢地逐滴添加双(三甲基甲硅烷基)酰胺锂(6.72mL,6.72mmol)。在TLC确认后,使用氢氧化铵水溶液终止反应,分离有机层并在硫酸镁上脱水。将在减压下通过蒸馏得到的材料通过柱层析进行纯化(己烷:乙酸乙酯),得到3-甲基吡咯烷-1,3-二甲酸3-苯甲基1-(叔丁基)酯(594mg,2.240mmol,得率:83%)。
1H-NMR(400MHz,氯仿-D)δ7.33(dd,J=13.3,5.5Hz,5H),5.13(s,2H),3.78(dd,J=16.0,11.0Hz,1H),3.40(td,J=13.6,6.7Hz,2H),3.19(dd,J=33.6,11.2Hz,1H),2.32(q,J=5.9Hz,1H),1.86-1.66(m,1H),1.43(s,9H),1.29(d,J=36.1Hz,3H)
步骤3:1-(叔丁氧基羰基)-3-甲基吡咯烷-3-甲酸
使用在步骤2中得到的3-甲基吡咯烷-1,3-二甲酸3-苯甲基1-(叔丁基)酯(80mg,0.250mmol),以与制备例10的步骤2相似的方式得到所需产物(得率:99%)。
1H-NMR(400MHz,甲醇-D4)δ3.75(d,J=11.0Hz,1H),3.47-3.31(m,2H),3.09(d,J=11.0Hz,1H),2.38-2.21(m,1H),1.77(dd,J=12.8,5.5Hz,1H),1.43(s,9H),1.30(s,3H)
步骤4:3-氨甲酰基-3-甲基吡咯烷-1-甲酸叔丁酯
使用在步骤3中得到的1-(叔丁氧基羰基)-3-甲基吡咯烷-3-甲酸(60mg,0.262mmol),以与制备例46的步骤5相似的方式得到所需产物(得率:62%)。
1H-NMR(氯仿-D)δ5.87-5.28(2H),3.81-3.61(m,1H),3.50(d,J=36.0Hz,2H),3.23(s,1H),2.28(s,1H),1.79(dd,J=12.5,7.0Hz,1H),1.46(d,J=12.5Hz,10H),1.36(d,J=13.7Hz,3H)
制备例48:6-(3-氨甲酰基-3-甲基吡咯烷-1-基)烟酸甲酯
步骤1:3-甲基吡咯烷-3-甲酸苯甲基酯
使用在制备例47的步骤2中得到的3-甲基吡咯烷-1,3-二甲酸3-苯甲基1-(叔丁基)酯(510mg,1.597mmol),以与制备例2的步骤2相似的方式得到所需产物(得率:99%)。
1H-NMR(400MHz,甲醇-D4)δ7.44-7.25(m,5H),5.28-5.11(m,2H),3.76(d,J=11.9Hz,1H),3.40(ddd,J=12.6,7.5,4.3Hz,1H),3.27-3.17(m,1H),3.05(d,J=11.9Hz,1H),2.53-2.34(m,1H),2.07-1.87(m,1H),1.41(s,3H)
步骤2:6-(3-((苯甲氧基)羰基)-3-甲基吡咯烷-1-基)烟酸甲酯
使用在步骤1中得到的3-甲基吡咯烷-3-甲酸苯甲基酯(357mg,1.628mmol)和6-氯烟酸甲酯(307mg,1.791mmol),以与制备例2的步骤1相似的方式得到所需产物(得率:23%)。
1H-NMR(400MHz,氯仿-D)δ8.78(d,J=2.3Hz,1H),7.98(dd,J=9.1,2.3Hz,1H),7.39-7.26(m,6H),6.29(d,J=8.7Hz,1H),5.14(d,J=1.4Hz,2H),4.13-4.00(1H),3.85(s,3H),3.58(s,2H),3.48-3.30(1H),2.52(t,J=6.2Hz,1H),1.96(dd,J=7.1,5.7Hz,1H),1.43(s,3H)
步骤3:1-(5-(甲氧基羰基)吡啶-2-基)-3-甲基吡咯烷-3-甲酸
使用在步骤2中得到的6-(3-((苯甲氧基)羰基)-3-甲基吡咯烷-1-基)烟酸甲酯(130mg,0.367mmol),以与制备例10的步骤2相似的方式得到所需产物(得率:99%)。
1H-NMR(MeOD)δ8.67(d,J=2.1Hz,1H),8.01(dd,J=9.2,2.1Hz,1H),6.52(d,J=9.2Hz,1H),4.09-3.98(1H),3.87(d,J=4.6Hz,3H),3.70-3.55(m,2H),3.35(s,1H),2.52(t,J=6.3Hz,1H),2.03-1.88(m,1H),1.41(s,3H)
步骤4:6-(3-氨甲酰基-3-甲基吡咯烷-1-基)烟酸甲酯
使用在步骤3中得到的1-(5-(甲氧基羰基)吡啶-2-基)-3-甲基吡咯烷-3-甲酸(97mg,0.367mmol),以与制备例46的步骤5相似的方式得到所需产物(得率:59%)。
1H-NMR(MeOD)δ8.68(d,J=2.1Hz,1H),8.03(dd,J=9.0,2.3Hz,1H),6.53(d,J=9.2Hz,1H),3.96(d,J=10.7Hz,1H),3.88(d,J=7.9Hz,3H),3.69-3.56(m,2H),2.87-2.81(2H),2.76(t,J=7.5Hz,1H),2.56-2.40(m,1H),2.10-1.94(1H),1.46(d,J=22.3Hz,3H)
制备例49:2-(4-(2-氨基-2-氧代乙基)苯氧基)乙酸叔丁酯
使用2-(4-羟基苯基)乙酰胺(1.00g,6.62mmol)和2-溴乙酸叔丁酯(1.36g,6.95mmol),以与制备例38的步骤1相似的方式得到所需产物(得率:85%)。
1H-NMR(400MHz,氯仿-D):δ7.22-7.14(m,2H),6.87(dt,J=9.5,2.4Hz,2H),5.34(s,2H),4.50(s,2H),3.52(s,2H),1.48(s,9H)
制备例50:2-(4-(2-氨基-2-氧代乙氧基)苯基)乙酸甲酯
使用2-(4-羟基苯基)乙酸甲酯(1.00g,6.02mmol)和2-溴乙酸叔丁酯(1.29g,6.62mmol),顺序执行制备例38的步骤1、制备例2的步骤2和制备例6的步骤3,得到所需产物(得率:52%)。
1H-NMR(400MHz,氯仿-D):δ7.25-7.19(m,2H),6.89(dt,J=9.3,2.5Hz,2H),6.53(s,1H),5.68(s,1H),4.49(s,2H),3.69(s,3H),3.58(s,2H)
制备例51:2-(4-(2-氨基-2-氧代乙氧基)苯基)丙酸甲酯
使用2-(4-(苯甲氧基)苯基)乙酸甲酯(3.10g,12.10mmol)和碘代甲烷(6.87g,48.4mmol),顺序执行制备例4的步骤2、制备例10的步骤2和制备例50的方法,得到所需产物(得率:63%)。
1H-NMR(400MHz,氯仿-D):δ7.22(d,J=8.2Hz,2H),6.86(d,J=8.7Hz,2H),6.52(d,J=43.9Hz,2H),4.45(s,2H),3.74-3.57(m,4H),1.45(d,J=7.3Hz,3H)
制备例52:3-(4-(2-氨基-2-氧代乙基)苯氧基)-2,2-二甲基丙酸甲酯
使用3-羟基-2,2-二甲基丙酸甲酯(0.80g,6.02mmol)和2-(4-羟基苯基)乙酸甲酯(1.00g,6.02mmol),顺序执行制备例4的步骤1和制备例6的步骤2和3的方法,得到所需产物(得率:34%)。
1H-NMR(400MHz,氯仿-D):δ7.13(d,J=8.2Hz,2H),6.84(d,J=8.7Hz,2H),6.02(s,1H),5.52(s,1H),3.91(s,2H),3.66(s,3H),3.46(s,2H),1.28(s,6H)
制备例53:(R)-2-(4-(2-氨基-2-氧代乙基)苯氧基)丙酸乙酯
使用2-(4-羟基苯基)乙酸苯甲基酯(0.80g,3.30mmol)和(S)-2-羟基丙酸乙酯(0.43g,3.63mmol),顺序执行制备例4的步骤1和制备例10的步骤2和4的方法,得到所需产物(得率:33%)。
1H-NMR(400MHz,氯仿-D):δ7.15(d,J=8.2Hz,2H),6.83(d,J=8.7Hz,2H),5.87(s,1H),5.60(s,1H),4.70(q,J=6.9Hz,1H),4.20(q,J=7.2Hz,2H),3.49(s,2H),1.59(d,J=6.9Hz,3H),1.24(t,J=7.1Hz,3H)
制备例54:(S)-2-(4-(2-氨基-2-氧代乙基)苯氧基)丙酸甲酯
使用(R)-2-羟基丙酸甲酯(1.081mL,11.35mmol)和2-(4-羟基苯基)乙酸苯甲基酯(2.5g,10.32mmol),顺序执行制备例4的步骤1和制备例10的步骤2和4的方法,得到所需产物(3步得率:11.3%)。
1H-NMR(500MHz,氯仿-D)δ7.25-7.16(m,2H),6.88(dt,J=9.4,2.5Hz,2H),5.41(d,J=28.4Hz,2H),4.77(q,J=6.7Hz,1H),3.79(s,3H),3.54(s,2H),1.43-1.04(m,3H)
制备例55:2-(4-(2-氨基-2-氧代乙基)苯氧基)-2-甲基丙酸乙酯
使用2-(4-羟基苯基)乙酸苯甲基酯(0.80g,3.30mmol)和2-溴-2-甲基丙酸乙酯(1.29g,6.60mmol),顺序执行制备例38的步骤1和制备例10的步骤2和4的方法,得到所需产物(得率:55%)。
1H-NMR(400MHz,氯仿-D):δ7.13(d,J=8.2Hz,2H),6.81(d,J=8.7Hz,2H),5.88-5.29(m,2H),4.22(q,J=7.2Hz,2H),3.51(s,2H),1.58(s,6H),1.24(t,J=7.1Hz,3H)
制备例56:2-(4-((4-(2-氨基-2-氧代乙基)苯氧基)甲基)苯基)-2-甲基丙酸甲酯
使用2-(4-羟基苯基)乙酸甲酯(1.50g,9.03mmol)和2-(4-(溴甲基)苯基)-2-甲基丙酸甲酯(2.69g,9.93mmol),顺序执行制备例38的步骤1和制备例6的步骤2和3的方法,得到所需产物(得率:52%)。
1H-NMR(400MHz,氯仿-D):δ7.43-7.28(m,4H),7.18(dt,J=9.3,2.5Hz,2H),6.95(dt,J=9.3,2.5Hz,2H),5.53(s,2H),5.02(s,2H),3.64(s,3H),3.53(s,2H),1.57(s,6H)
制备例57:(R)-2-氯-6-(3-(2-环丁氧基苯氧基)哌啶-1-基)吡嗪
使用2-(苯甲氧基)苯酚(2.00g,9.99mmol)和溴代环丁烷(2.70g,19.98mmol),以与制备例73相似的方式得到所需产物(得率:29%)。
1H-NMR(400MHz,氯仿-D):δ7.92(s,1H),7.74(s,1H),7.02-6.90(m,2H),6.89-6.81(m,1H),6.74(dd,J=8.0,1.6Hz,1H),4.62-4.52(m,1H),4.28(td,J=7.2,3.5Hz,1H),4.03(dd,J=13.3,3.2Hz,1H),3.81-3.68(m,1H),3.68-3.50(m,2H),2.48-2.32(m,2H),2.23-1.75(m,6H),1.73-1.52(m,2H)
制备例58:2-(4-(3-氨基-2,2-二甲基-3-氧代丙基)苯基)-2-甲基丙酸甲酯
步骤1:3-(4-(1-甲氧基-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸叔丁酯
使用2-(4-(溴甲基)苯基)-2-甲基丙酸甲酯(5.40g,19.91mmol)和异丁酸叔丁酯(3.45g,23.90mmol),以与制备例33的步骤1相似的方式得到所需产物(得率:78%)。
1H-NMR(400MHz,氯仿-D:)δ7.20(d,J=8.2Hz,2H),7.09(d,J=8.2Hz,2H),3.63(s,3H),2.78(s,2H),1.54(s,6H),1.41(s,9H),1.11(s,6H)
步骤2:2-(4-(3-氨基-2,2-二甲基-3-氧代丙基)苯基)-2-甲基丙酸甲酯
使用在步骤1中得到的3-(4-(1-甲氧基-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸叔丁酯(0.50g,1.50mmol),顺序执行制备例10的步骤3和4的方法,得到所需产物(得率:72%)。
1H-NMR(400MHz,氯仿-D):δ7.19(d,J=7.8Hz,2H),7.08(d,J=8.2Hz,2H),5.81(d,J=49.4Hz,2H),3.61(d,J=1.4Hz,3H),2.79(s,2H),1.52(s,6H),1.15(d,J=1.4Hz,6H)
制备例59:3-(4-(1-氨基-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸叔丁酯
使用在制备例58的步骤1中得到的3-(4-(1-甲氧基-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸叔丁酯(0.50g,1.50mmol),顺序执行制备例6的步骤2和3的方法,得到所需产物(得率:76%)。
1H-NMR(400MHz,氯仿-D):δ7.25(d,J=8.2Hz,2H),7.11(d,J=8.2Hz,2H),5.85(s,1H),5.31(s,1H),2.78(s,2H),1.53(s,6H),1.41(s,9H),1.10(s,6H)
制备例60:(E)-4-(3-氨基-3-氧代丙-1-烯-1-基)双环[2.2.2]辛烷-1-甲酸苯甲基酯
步骤1:4-(羟基甲基)双环[2.2.2]辛烷-1-甲酸苯甲基酯
使用4-(羟基甲基)双环[2.2.2]辛烷-1-甲酸(8.50g,46.1mmol)和苄基溴(11.84g,69.2mmol),以与制备例38的步骤1相似的方式得到所需产物(得率:66%)。
1H-NMR(400MHz,氯仿-D):δ7.42-7.27(m,5H),5.08(s,2H),3.27(s,2H),1.88-1.76(m,6H),1.49-1.37(m,6H)
步骤2:4-甲酰基双环[2.2.2]辛烷-1-甲酸苯甲基酯
将草酰氯(1.02g,8.02mmol)溶解在DCM(25mL)中,并将温度降低至-78℃。进一步添加DMSO(1.25g,16.04mmol),并在5分钟后,将在步骤1中得到的4-(羟基甲基)双环[2.2.2]辛烷-1-甲酸苯甲基酯(2.00g,7.29mmol)溶解在DCM(10mL)中并添加。在继续搅拌15分钟后,添加三乙胺(3.69g,36.4mmol),并将温度升高至室温。在添加水后,将反应混合物用DCM萃取。将有机层在硫酸镁上脱水,过滤,在减压下浓缩,并将得到的产物不需进一步纯化即用于下一反应中。
1H-NMR(400MHz,氯仿-D):δ9.44(s,1H),7.39-7.27(m,5H),5.09(s,2H),1.91-1.82(m,6H),1.72-1.62(m,6H)
步骤3:(E)-4-(3-氨基-3-氧代丙-1-烯-1-基)双环[2.2.2]辛烷-1-甲酸苯甲基酯
使用在步骤2中得到的4-甲酰基双环[2.2.2]辛烷-1-甲酸苯甲基酯(1.00g,3.67mmol),以与制备例18相似的方式得到所需产物(得率:68%)。
1H-NMR(400MHz,氯仿-D):δ7.39-7.27(m,5H),6.76(d,J=15.6Hz,1H),5.65(d,J=15.6Hz,1H),5.33(s,2H),5.09(s,2H),1.91-1.81(m,6H),1.59-1.55(m,6H)
制备例61:4-(2-氨基-2-氧代乙基)双环[2.2.2]辛烷-1-甲酸甲酯
使用2-(4-(甲氧基羰基)双环[2.2.2]辛-1-基)乙酸(0.90g,3.98mmol),以与制备例6的步骤3相似的方式得到所需产物(得率:84%)。
1H-NMR(400MHz,氯仿-D):δ5.51(s,2H),3.62(s,3H),2.01(s,2H),1.91-1.70(m,6H),1.62-1.47(m,6H)
制备例62:3-(3-(3-氨基-3-氧代丙基)苯基)-2,2-二甲基丙酸叔丁酯
使用1-溴-3-(溴甲基)苯(5.00g,20.01mmol)和异丁酸叔丁酯(3.46g,24.01mmol),顺序执行制备例33的步骤1、制备例10的步骤1和制备例6的步骤2和步骤3的方法,得到所需产物(得率:31%)。
1H-NMR(400MHz,氯仿-D:)δ7.17(t,J=7.8Hz,1H),7.04(d,J=7.8Hz,1H),6.99(d,J=5.5Hz,2H),5.30(s,2H),2.92(t,J=7.8Hz,2H),2.78(s,2H),2.50(t,J=7.5Hz,2H),1.43(s,9H),1.10(s,6H)
制备例63:3-(4-(2-氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸叔丁酯
使用2-(4-(溴甲基)苯基)乙酸(14.0g,61.1mmol)和异丁酸叔丁酯(26.4g,183mmol),以与制备例33相似的方式得到所需产物(得率:42%)。
1H-NMR(400MHz,氯仿-D:)δ7.19-7.11(m,4H),5.38(d,J=23.8Hz,2H),3.54(s,2H),2.80(s,2H),1.46-1.37(9H),1.11(s,6H)
制备例64:(R)-3-(3-(3-氨甲酰基哌啶-1-基)苯基)-2,2-二甲基丙酸叔丁酯
使用1-溴-3-(溴甲基)苯(5.00g,20.01mmol)和异丁酸叔丁酯(3.46g,24.01mmol),顺序执行制备例33的步骤1、制备例2的步骤1和制备例6的步骤2和3的方法,得到所需产物(得率:16%)。
1H-NMR(400MHz,氯仿-D:)δ7.18-7.09(m,1H),6.82(d,J=8.2Hz,1H),6.79-6.66(m,3H),5.80(s,1H),3.30-3.23(m,2H),3.16-3.08(m,2H),2.77(dd,J=16.0,13.3Hz,2H),2.59(s,1H),1.92-1.77(m,3H),1.77-1.64(m,1H),1.45-1.35(m,9H),1.15-1.06(m,6H)
制备例65:(E)-2-(4-(3-氨基-3-氧代丙-1-烯-1-基)苯基)-2-甲基丙酸苯甲基酯
使用2-(4-溴苯基)-2-甲基丙酸(5.00g,20.57mmol)和苄基溴(4.22g,24.68mmol),顺序执行制备例43的步骤1和制备例10的步骤1、3和4的方法,得到所需产物(得率:60%)。
1H-NMR(400MHz,氯仿-D):δ7.66-7.59(m,1H),7.54-7.40(m,2H),7.40-7.25(m,5H),7.19-7.10(m,2H),6.47-6.40(m,1H),5.61(s,2H),5.09(s,2H),1.59(s,6H)
制备例66:(R)-2-氯-4-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)嘧啶
使用在制备例70的步骤3中得到的(R)-3-乙氧基-2-(哌啶-3-基氧基)吡啶盐酸盐(5.90g,22.80mmol)和2,4-二氯嘧啶(3.74g,25.08mmol),以与制备例1的步骤3相似的方式得到所需产物(得率:26%)。
1H-NMR(400MHz,氯仿-D):δ7.91(d,J=6.4Hz,1H),7.70(dd,J=4.8,1.6Hz,1H),7.03(dd,J=7.8,1.4Hz,1H),6.82(q,J=4.1Hz,1H),6.32(d,J=5.9Hz,1H),5.19(s,1H),4.05-3.59(m,6H),2.25-1.90(m,3H),1.76-1.57(m,1H),1.31(t,J=6.9Hz,3H)
制备例67:3-(4-(2-((2-氯嘧啶-4-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸叔丁酯
使用在制备例63中得到的3-(4-(2-氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸叔丁酯(0.50g,1.50mmol)和2,4-二氯嘧啶(0.20g,1.34mmol),以与制备例2的步骤1相似的方式得到所需产物(得率:28%)。
1H-NMR(400MHz,氯仿-D):δ8.46(d,J=5.5Hz,1H),8.11(d,J=5.5Hz,1H),8.01(s,1H),7.17(s,4H),3.72(s,2H),3.70-3.65(m,1H),2.82(s,2H),1.42(s,9H),1.12(s,6H)
制备例68:(R)-4-氯-2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶
使用在制备例1的步骤1中得到的(R)-3-(2-乙氧基苯氧基)哌啶-1-甲酸叔丁酯(15.0g,46.7mmol)和2,4-二氯嘧啶(13.9g,93mmol),以与制备例1的步骤2和3相似的方式得到所需产物(得率:19%)。
m/z(M+H)+为C17H21ClN3O2的计算值为334,实测值为334
制备例69:(R)-2-氯-4-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶
使用在制备例1的步骤1中得到的(R)-3-(2-乙氧基苯氧基)哌啶-1-甲酸叔丁酯(15.0g,46.7mmol)和2,4-二氯嘧啶(13.9g,93mmol),以与制备例1的步骤2和3相似的方式得到所需产物(得率:72%)。
m/z(M+H)+为C17H21ClN3O2的计算值为334,实测值为334
制备例70:(R)-2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪
步骤1:2-氯-3-乙氧基吡啶
向77mL DMF添加2-氯-3-羟基吡啶(10.0g,77mmol)、碘代乙烷(14.45g,93mmol)和碳酸钾(21.34g,154mmol),并在室温搅拌48小时。将反应混合物过滤,添加水,然后用乙酸乙酯萃取。在用水和盐水洗涤后,将有机层在硫酸镁上脱水并在减压下浓缩。通过柱层析进行纯化,得到所需产物(得率:99%)。
1H NMR(400MHz,氯仿-D):δ7.96(t,J=3.0Hz,1H),7.17(d,J=3.2Hz,2H),4.10(q,J=7.0Hz,2H),1.48(t,J=7.1Hz,3H)
步骤2:(R)-3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯
向96mL无水DMF添加氢化钠(3.38g,84mmol),并进一步添加(R)-3-羟基哌啶-1-甲酸叔丁酯(17.00g,84mmol)。将温度升高至60℃,并将反应混合物搅拌1小时。向其添加在步骤1中得到的2-氯-3-乙氧基吡啶(12.1g,77mmol),然后搅拌24小时。向反应混合物添加水,然后用乙酸乙酯萃取。在用水和盐水洗涤后,将有机层在硫酸镁上脱水并在减压下浓缩。通过柱层析进行纯化,得到所需产物(得率:75%)。
1H NMR(400MHz,氯仿-D):δ7.68(td,J=3.2,1.7Hz,1H),7.03(dt,J=7.8,1.4Hz,1H),6.82-6.72(m,1H),5.06(s,1H),4.03(q,J=7.0Hz,2H),3.55(d,J=100.2Hz,4H),2.16-1.96(m,1H),1.96-1.70(m,2H),1.68-1.50(m,1H),1.50-1.27(m,12H)
步骤3:(R)-3-乙氧基-2-(哌啶-3-基氧基)吡啶盐酸盐
使用在步骤2中得到的(R)-3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-甲酸叔丁酯(31.5g,98mmol),以与制备例1的步骤2相似的方式得到标题化合物。
步骤4:(R)-2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪
使用在步骤3中得到的(R)-3-乙氧基-2-(哌啶-3-基氧基)吡啶盐酸盐(30g,116mmol)和2,6-二氯吡嗪(19g,128mmol),以与制备例1的步骤3相似的方式得到标题化合物(得率:80%)。
1H NMR(400MHz,氯仿-D):δ7.96(d,J=11.0Hz,1H),7.74-7.66(m,2H),7.04(dd,J=7.8,1.4Hz,1H),6.83(dd,J=7.8,5.0Hz,1H),5.24(td,J=7.0,3.4Hz,1H),4.05-3.83(m,3H),3.83-3.70(m,2H),3.67-3.53(m,1H),2.22-2.09(m,1H),2.07-1.93(m,2H),1.75-1.60(m,1H),1.35-1.27(t,J=7.1Hz,3H)
制备例71:(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶
使用在制备例1的步骤2中得到的(R)-3-(2-乙氧基苯氧基)哌啶盐酸盐(10g,45.2mmol)和2,6-二氯吡啶(11.37g,77mmol),以与制备例1的步骤3相似的方式得到所需产物(得率:41%)。
1H-NMR(400MHz,氯仿-D)δ7.44-7.29(m,1H),7.17-7.05(m,1H),6.94-6.86(m,3H),6.73-6.49(m,1H),6.49-6.32(m,1H),4.30-4.17(m,2H),4.04-3.96(m,2H),3.95-3.78(m,1H),3.35-3.18(m,2H),2.22-2.07(m,1H),1.97-1.75(m,2H),1.64-1.52(m,1H),1.40(q,J=6.9Hz,3H)
制备例72:(R)-2-氯-4-(3-(2-乙氧基苯氧基)哌啶-1-基)-6-(三氟甲基)嘧啶
使用在制备例1的步骤2中得到的(R)-3-(2-乙氧基苯氧基)哌啶盐酸盐(0.23g,0.89mmol)和2,4-二氯-6-(三氟甲基)嘧啶(0.21g,0.98mmol),以与制备例1的步骤3相似的方式得到标题化合物(得率:86%)。
1H NMR(400MHz,氯仿-D):δ7.14-6.31(m,5H),4.79-3.18(m,7H),2.04(s,3H),1.60(s,1H),1.30(dt,J=29.7,6.7Hz,3H)
制备例73:(R)-2-氯-6-(3-(2-异丙氧基苯氧基)哌啶-1-基)吡嗪
步骤1:1-(苯甲氧基)-2-异丙氧基苯
将2-(苯甲氧基)苯酚(1.15g,5.74mmol)、2-溴丙烷(1.413g,11.49mmol)和碳酸钾(3.17g,22.97mmol)溶解在19mL DMF中并在45℃搅拌15小时。在通过TLC确认反应完成后,在减压下除去有机溶剂。在用乙酸乙酯(2×30mL)萃取后,将得到的产物用盐水(20mL)洗涤,将有机溶剂在硫酸镁上脱水并在减压下除去。通过硅胶柱进行纯化(乙酸乙酯:己烷=1:30),得到所需产物(得率:93%)。
m/z(M+H)+为C16H18O2的计算值为242,实测值为243
步骤2:2-异丙氧基苯酚
将在步骤1中得到的1-(苯甲氧基)-2-异丙氧基苯(1.3g,5.36mmol)溶解在40mL甲醇中,并逐滴添加钯炭(0.143g,1.341mmol),然后使用氢气球进行去保护反应。在确认反应完成后,将得到的产物用硅藻土垫过滤,并在减压下除去有机溶剂,得到所需产物(得率:99%)。
1H-NMR(500MHz,氯仿-D)δ7.02-6.75(m,4H),5.69(d,J=19.0Hz,1H),4.63-4.52(m,1H),1.46-1.32(m,6H)
步骤3:(R)-3-(2-异丙氧基苯氧基)哌啶-1-甲酸叔丁酯
使用在步骤2中得到的2-异丙氧基苯酚(0.81g,5.32mmol)和(S)-3-羟基哌啶-1-甲酸叔丁酯(1.07g,5.32mmol),以与制备例1的步骤1相似的方式得到所需产物(得率:13.6%)。
1H-NMR(500MHz,氯仿-D)δ7.01-6.81(m,4H),4.45(td,J=12.2,6.1Hz,1H),4.11(q,J=7.3Hz,2H),3.62(s,1H),3.27(s,1H),3.16(s,1H),2.03(d,J=7.9Hz,2H),1.83(s,1H),1.74(d,J=6.7Hz,1H),1.42(s,9H),1.32(q,J=2.9Hz,6H)
步骤4:(R)-3-(2-异丙氧基苯氧基)哌啶
使用在步骤3中得到的(R)-3-(2-异丙氧基苯氧基)哌啶-1-甲酸叔丁酯(0.27g,0.805mmol),以与制备例1的步骤2相似的方式得到所需产物。
m/z(M+H)+为C16H18O2的计算值为235.3,实测值为236.2
步骤5:(R)-2-氯-6-(3-(2-异丙氧基苯氧基)哌啶-1-基)吡嗪
使用在步骤4中得到的(R)-3-(2-异丙氧基苯氧基)哌啶(0.189g,0.803mmol),以与制备例1的步骤3相似的方式得到所需产物(得率:25%)。
1H-NMR(500MHz,氯仿-D)δ7.93(s,1H),7.74(s,1H),7.01-6.85(m,4H),4.44(td,J=12.2,6.1Hz,1H),4.32-4.22(m,1H),4.02(dd,J=13.4,3.1Hz,1H),3.74(qd,J=6.5,3.8Hz,1H),3.64-3.47(m,2H),2.12-2.05(m,1H),2.03-1.85(m,2H),1.61(qd,J=8.7,4.3Hz,1H),1.32-1.18(m,6H)
制备例74:(R)-2-氯-6-(3-(2-甲氧基苯氧基)哌啶-1-基)吡嗪
使用(S)-3-羟基哌啶-1-甲酸叔丁酯(2.00g,9.94mmol)和2-甲氧基苯酚(1.23g,9.94mmol),以与制备例1相似的方式得到所需产物(3步得率:32%)。
1H-NMR(400MHz,氯仿-D)δ7.95(s,1H),7.77(s,1H),7.13-6.82(m,4H),4.31(td,J=7.8,4.1Hz,1H),4.25-4.15(m,1H),3.97-3.64(m,4H),3.57-3.33(m,2H),2.14(d,J=5.0Hz,1H),2.03-1.82(m,2H),1.73-1.59(m,1H)
制备例75:(R)-2-氯-6-(3-(2-(三氟甲氧基)苯氧基)哌啶-1-基)吡嗪
使用(S)-3-羟基哌啶-1-甲酸叔丁酯(2.00g,9.94mmol)和2-(三氟甲氧基)苯酚(1.77g,9.94mmol),以与制备例1相似的方式得到所需产物(得率:8%)。
1H-NMR(400MHz,氯仿-D)δ7.98(s,1H),7.79(s,1H),7.45-7.28(1H),7.25-7.07(m,2H),6.98(t,J=7.5Hz,1H),4.39(d,J=3.7Hz,1H),4.18(d,J=13.3Hz,1H),3.93-3.70(m,1H),3.67-3.39(2H),2.15(d,J=18.3Hz,1H),2.02-1.82(m,2H),1.79-1.60(m,1H)
制备例76:(R)-2-氯-6-(3-(2-(2-氟乙氧基)苯氧基)哌啶-1-基)吡嗪
步骤1:1-(苯甲氧基)-2-(2-氟乙氧基)苯
将2-氟乙-1-醇(1.10mL,18.7mmol)、2-(苯甲氧基)苯酚(3.26mL,18.7mmol)和三苯基膦(5.50g,21.0mmol)溶解在50mL甲苯中并在室温搅拌。向反应混合物缓慢地逐滴添加在44mL甲苯中稀释的偶氮二甲酸二乙酯(3.82mL)。在室温搅拌15小时后,将混合物过滤,用二乙醚洗涤,用1N氢氧化钠溶液洗涤,在硫酸镁上脱水并在减压下除去有机溶剂。通过硅胶柱进行纯化(乙酸乙酯:己烷=1:20),得到所需产物(得率:76%)。
1H-NMR(400MHz,氯仿-D)δ7.53-7.27(m,5H),7.05-6.84(m,4H),5.14(s,2H),4.75(dt,J=47.4,4.2Hz,2H),4.29(dt,J=27.7,4.3Hz,2H)
步骤2:2-(2-氟乙氧基)苯酚
将在步骤1中得到的1-(苯甲氧基)-2-(2-氟乙氧基)苯(1.50g,6.09mmol)和钯炭(0.65g,0.61mmol)溶解在122mL甲醇中,并在吹入氢气的同时在室温搅拌。在搅拌15小时后,将得到的产物过滤,并在减压下除去有机溶剂(得率:96%)。
1H-NMR(400MHz,氯仿-D)δ7.04-6.75(m,4H),5.76-5.61(1H),4.90-4.63(m,2H),4.40-4.18(2H)
步骤3:(R)-2-氯-6-(3-(2-(2-氟乙氧基)苯氧基)哌啶-1-基)吡嗪
使用(S)-3-羟基哌啶-1-甲酸叔丁酯(1.17g,5.83mmol)和在步骤2中得到的2-(2-氟乙氧基)苯酚(0.91g,5.8mmol),以与制备例1相似的方式得到所需产物(得率:24%)。
1H-NMR(400MHz,氯仿-D)δ7.95(s,1H),7.75(s,1H),7.11-6.85(m,4H),4.71(dt,J=47.6,4.1Hz,2H),4.41-4.28(m,1H),4.28-4.14(m,2H),4.03(dd,J=13.5,3.0Hz,1H),3.83-3.47(m,3H),2.18-2.05(m,1H),2.04-1.84(m,2H),1.72-1.58(m,1H)
制备例77:(R)-2-氯-6-(3-(2-环丙氧基苯氧基)哌啶-1-基)吡嗪
使用2-(苯甲氧基)苯酚(2.00g,9.99mmol)和环丙基溴(3.63g,30.0mmol),以与制备例73相似的方式得到所需产物(得率:8.1%)。
1H-NMR(400MHz,氯仿-D):δ7.92(s,1H),7.74(s,1H),7.24-7.18(m,1H),7.04-6.94(m,2H),6.93-6.85(m,1H),4.23(td,J=7.5,3.7Hz,1H),4.09-4.01(m,1H),3.83-3.67(m,2H),3.59-3.44(m,2H),2.15-2.04(m,1H),2.02-1.84(m,2H),1.67-1.51(m,1H),0.74(d,J=4.6Hz,4H)
制备例78:3-(3′-(氯羰基)-[1,1′-联苯]-3-基)-2,2-二甲基丙酸叔丁酯
步骤1:2,2-二甲基-3-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊烷-2-基)苯基)丙
酸叔丁酯
将在制备例64中得到的中间体3-(3-溴苯基)-2,2-二甲基丙酸叔丁酯(0.870g,2.78mmol)、双(频哪醇基)二硼(0.846g,3.33mmol)和乙酸钾(0.818g,8.33mmol)溶解在1,4-二氧杂环己烷(13.89mL)中,并添加[1,1'-双(二苯基膦)二茂铁]二氯化钯-二氯甲烷加成物(0.113g,0.139mmol)。将反应混合物在100℃回流搅拌16小时。将得到的产物通过硅藻土垫过滤,并在减压下除去有机溶剂。通过硅胶柱进行纯化,得到所需产物(得率:32.4%)。
1H-NMR(400MHz,氯仿-D):δ7.69-7.54(2H),7.23(d,J=1.4Hz,2H),2.82(s,2H),1.55(d,J=1.4Hz,2H),1.43(s,9H),1.31(s,12H),1.12(s,6H)
步骤2:3′-(3-(叔丁氧基)-2,2-二甲基-3-氧代丙基)-[1,1′-联苯]-3-甲酸乙酯
将在步骤1中得到的2,2-二甲基-3-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼戊烷-2-基)苯基)丙酸叔丁酯(0.173g,0.480mmol)、3-溴苯甲酸乙酯(0.100g,0.437mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯-二氯甲烷加成物(0.018g,0.022mmol)溶解在1,4-二氧杂环己烷(4.37mL)中,逐滴添加2M碳酸钠溶液(0.655mL,1.310mmol),然后在90℃搅拌5小时。在冷却至室温后,将得到的产物通过硅藻土垫过滤,用二氯甲烷洗涤,在硫酸镁上脱水,并在减压下除去有机溶剂。通过硅胶柱进行纯化,得到所需产物(得率:68.6%)。
1H-NMR(400MHz,氯仿-D):δ8.24(t,J=1.6Hz,1H),8.00(dt,J=7.8,1.4Hz,1H),7.74(dt,J=7.8,1.4Hz,1H),7.47(q,J=7.5Hz,2H),7.39(s,1H),7.34(t,J=7.8Hz,1H),7.17(d,J=7.8Hz,1H),4.40(q,J=7.2Hz,2H),2.90(s,2H),1.43-1.37(m,12H),1.15(s,6H)
步骤3:3′-(3-(叔丁氧基)-2,2-二甲基-3-氧代丙基)-[1,1′-联苯]-3-甲酸
使用在步骤2中得到的3′-(3-(叔丁氧基)-2,2-二甲基-3-氧代丙基)-[1,1′-联苯]-3-甲酸乙酯(0.1145g,0.299mmol)和1N氢氧化钠进行水解反应,得到所需产物(得率:32.1%)。
1H-NMR(400MHz,氯仿-D):δ8.33(s,1H),8.09(d,J=7.8Hz,1H),7.81(d,J=7.8Hz,1H),7.53(t,J=7.8Hz,1H),7.48(d,J=7.8Hz,1H),7.42(s,1H),7.35(t,J=7.8Hz,1H),7.19(d,J=7.8Hz,1H),2.91(s,2H),1.42(s,9H),1.18(d,J=6.4Hz,6H)
步骤4:3-(3′-(氯羰基)-[1,1′-联苯]-3-基)-2,2-二甲基丙酸叔丁酯
使用在步骤3中得到的3'-(3-(叔丁氧基)-2,2-二甲基-3-氧代丙基)-[1,1'-联苯]-3-甲酸(0.0341g,0.096mmol),以与制备例10的步骤4相似的方式通过酰胺化反应得到所需产物(得率:99%)。
1H-NMR(400MHz,氯仿-D):δ8.08-7.93(m,1H),7.75(dt,J=7.8,1.4Hz,1H),7.73-7.68(m,1H),7.48(t,J=7.8Hz,1H),7.44(dd,J=7.8,1.4Hz,1H),7.37(d,J=6.4Hz,1H),7.33(t,J=7.8Hz,1H),7.16(d,J=7.8Hz,1H),6.07(d,J=135.4Hz,2H),2.89(s,2H),1.50-1.36(m,9H),1.15(s,6H)
制备例79:3-(3'-(氯羰基)-[1,1'-联苯]-4-基)-2,2-二甲基丙酸叔丁酯
步骤1:3-(4-溴苯基)-2,2-二甲基丙酸叔丁酯
使用1-溴-4-(溴甲基)苯(2.311g,9.25mmol)和异丁酸叔丁酯(2.0g,13.87mmol),以与制备例33的步骤1相似的方式得到所需产物(得率:79%)。
1H-NMR(400MHz,氯仿-D):δ7.36(d,J=8.2Hz,2H),7.02(d,J=8.2Hz,2H),2.76(s,2H),1.41(d,J=0.9Hz,9H),1.10(s,6H)
步骤2:3-(3′-(氯羰基)-[1,1′-联苯]-4-基)-2,2-二甲基丙酸叔丁酯
使用在步骤1中得到的3-(4-溴苯基)-2,2-二甲基丙酸叔丁酯(2.27g,7.265mmol),以与制备例78相似的方式得到所需产物(得率:26.3%)。
1H-NMR(400MHz,氯仿-D):δ8.04(t,J=1.6Hz,1H),7.82-7.61(2H),7.46(t,J=8.7Hz,3H),7.21(d,J=8.2Hz,2H),6.68-6.16(m,2H),2.84(s,2H),1.43(s,9H),1.15-1.10(6H)
实施例1:(R)-1-(3,5-双(三氟甲基)苯基)-3-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)脲
向30mL二氯甲烷添加在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺(0.49g,1.57mmol)、氰酸3,5-双(三氟甲基)苯基酯(0.44g,1.73mmol)和二异丙基乙胺(0.55mL,3.14mmol),并在室温搅拌6小时。在通过TLC确认反应完成后,将得到的产物用二氯甲烷稀释,用碳酸氢钠水溶液和盐水洗涤,将有机溶剂在硫酸镁上脱水并在减压下除去。通过硅胶柱进行纯化(乙酸乙酯:己烷=1:1),得到所需产物(得率:31%)。
1H NMR(300MHz,氯仿-D):δ11.40(s,1H),8.48(s,1H),7.99(s,2H),7.82(s,1H),7.55(s,1H),7.53(s,1H),6.69-6.89(m,4H),4.46(m,1H),3.95(m,3H),3.78(m,2H),3.65(m,1H),2.07-2.17(m,3H),1.73(m,1H),1.30(t,3H)
实施例2:((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)-L-苯丙氨酸
步骤1:((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)-L-苯丙
氨酸甲酯
将(S)-2-氨基-3-苯基丙酸甲酯(32.5mg,0.1mmol)与1mL二氯甲烷混合并在0℃搅拌。在向该溶液添加1mL饱和碳酸氢钠水溶液后,添加三光气(56.6mg,0.191mmol),然后添加在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺(50mg,0.159mmol)。在分离有机层后,将溶剂转变成THF,并将反应混合物在70℃搅拌12小时。在减压下除去有机溶剂后,通过硅胶柱纯化得到的产物(丙酮:二氯甲烷=1:3),得到所需酯产物(得率:18%)。
m/z(M+Na)+为C28H33N5O5Na的计算值为542.6,实测值为542.3
1H NMR(300MHz,氯仿-D):δ9.07(d,1H),7.74(s,1H),7.68(s,1H),7.44(s,1H),7.25(m,3H),7.09-7.11(2H,m),6.87-6.96(m,4H),5.04(m,1H),4.26(m,1H),3.98-4.03(m,2H),3.73(m,1H),3.71(s,3H),3.45-3.50(m,2H),3.17(d,2H),2.98(t,1H),2.07(m,1H),1.80(m,2H),1.58(bs,1H),1.48(m,1H),1.40(t,3H),1.26(m,1H)
步骤2:((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)-L-苯丙
氨酸
将在步骤1中得到的酯化合物(15mg,0.029mmol)溶解在0.3mL THF和0.3mL水中。在添加氢氧化锂(3mg,0.1mmol)后,将反应混合物在40℃搅拌12小时。在冷却至室温后,使用1N盐酸溶液将反应混合物滴定至pH 4.5,用乙酸乙酯稀释。在除去水层后,将得到的产物在硫酸镁上干燥,并在减压下除去有机溶剂,得到所需产物。
1H NMR(300MHz,氯仿-D):δ9.21(s,1H),8.99(s,1H),7.68(s,1H),7.45(s,1H),7.14(m,5H),6.90(m,4H),5.02(m,1H),4.17(m,1H),4.05(m,2H),3.90(d,1H),3.68(m,1H),3.47(m,1H),3.30(m,1H),3.20(m,3H),2.96(m,1H),2.05(m,3H),1.73(m,2H),1.25-1.42(m,5H)
实施例3:(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)吗啉-4-甲酰胺
使用在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺和吗啉,以与实施例2的步骤1相似的方式得到所需产物。
1H NMR(300MHz,氯仿-D):δ8.54(s,1H),7.82(s,1H),6.86-6.99(m,4H),6.57(s,1H),4.31(m,1H),4.00(m,3H),3.75(m,5H),3.57(m,1H),3.50(m,4H),3.39(m,1H),2.13(m,1H),1.93-1.96(m,2H),1.60-1.63(m,2H),1.39(t,3H),1.26(m,1H)
实施例4:(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)吡咯烷-1-甲酰胺
使用在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺和吡咯烷,以与实施例2的步骤1相似的方式得到所需产物。
1H NMR(300MHz,氯仿-D):δ8.63(s,1H),7.78(s,1H),6.87-6.98(m,4H),6.45(s,1H),4.29(m,1H),3.96-4.10(m,3H),3.77(m,1H),3.48(m,5H),3.34(m,1H),2.13(m,1H),1.89-1.99(m,7H),1.61(m,1H),1.39(t,3H)
实施例5:1-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)吡咯烷-3-甲酸
使用在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺和吡咯烷-3-甲酸甲酯,以与实施例2相似的方式得到所需产物。
1H NMR(300MHz,甲醇-D):δ8.27(s,1H),7.69(s,1H),7.00(d,1H),6.93(bs,3H),4.47(bs,1H),3.92(m,2H),3.71(m,2H),3.68(m,3H),3.57(m,4H),3.21(m,1H),2.25(m,2H),2.03(m,5H),2.61(bs,2H),1.28(m,10H),0.92(m 2H)
实施例6:(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)苯甲酰胺
将在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺(0.15g,0.5mmol)和三乙胺(0.35mL,2.5mmol)在0℃下溶解在10mL二氯甲烷中,并缓慢地逐滴添加苯甲酰氯(0.07mL,0.5mmol)。在0℃搅拌2小时后,通过TLC确认反应完成,并将得到的产物用盐水洗涤。将有机溶剂在硫酸镁上脱水并在减压下除去。通过硅胶柱进行纯化(乙酸乙酯:己烷=3:1),得到所需产物(得率:38%)。
1H NMR(300MHz,氯仿-D):δ8.86(s,1H),8.09(m,4H),7.61(m,1H),7.50(m,2H),6.98(m,1H),6.89(m,3H),4.36(m,1H),3.92-4.03(m,3H),3.74(m,1H),3.66(m,1H),3.49(m,1H),2.11(m,1H),2.01(m,1H),1.94(m,1H),1.62(m,1H),1.36(t,3H)
实施例7:(R)-4-氯-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)苯甲酰胺
使用在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺(0.09g,0.25mmol)和4-氯苯甲酰氯(0.04g,0.25mmol),以与实施例6相似的方式得到所需产物(得率:19%)。
1H NMR(300MHz,氯仿-D):δ8.83(s,1H),7.95(s,1H),7.82(m,3H),7.45 9m,2H),6.97(m,1H),6.88(m,3H),4.36(m,1H),3.90-4.35(m,3H),3.72(m,2H),3.52(m,1H),2.12(m,1H),2.01(m,1H),1.96(m,1H),1.63(m,1H),1.37(t,3H)
实施例8:(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-3-甲氧基苯甲酰胺
向5mL二氧杂环己烷添加在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.05g,0.15mmol)、3-甲氧基苯甲酰胺(0.03g,0.17mmol)、三(二亚苯甲基丙酮)二钯(0)(8.2mg,0.009mmol)、4,5-双(二苯基膦)-9,9-二甲基黄嘌呤(7.7mg,0.01mmol)和碳酸铯(0.12g,0.38mmol),并在回流下搅拌4小时。在反应完成后,将得到的产物冷却至室温,用乙酸乙酯稀释,并用碳酸氢钠水溶液和盐水洗涤。将有机溶剂在硫酸镁上脱水并在减压下除去。通过硅胶柱进行纯化(乙酸乙酯:己烷=3:1),得到所需产物(得率:52%)。
1H-NMR(500MHz,氯仿-D):δ8.85(s,1H),7.92(s,1H),7.90(s,1H),7.47(m,1H),7.41(m,2H),7.12(m,1H),6.99(m,1H),6.92-6.84(m,3H),4.34(m,1H),4.03-3.91(m,3H),3.89(s,3H),3.75(m,1H),3.67(m,1H),3.48(m,1H),2.13(m,1H),2.02(m,1H),1.94(m,1H),1.62(m,1H),1.36(t,3H)
实施例9:(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-4-甲氧基苯甲酰胺
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.05g,0.15mmol)和4-甲氧基苯甲酰胺(0.03g,0.17mmol),以与实施例8相似的方式得到所需产物(得率:54%)。
1H-NMR(500MHz,氯仿-D):δ8.84(s,1H),7.91(s,1H),7.84(m,3H),6.99(m,3H),6.92-6.83(m,3H),4.34(m,1H),4.03-3.90(m,3H),3.88(s,3H),3.75(m,1H),3.66(m,1H),3.45(m,1H),2.12(m,1H),2.04(m,1H),1.93(m,1H),1.61(m,1H),1.37(t,3H)
实施例10:(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-4-硝基苯甲酰胺
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.05g,0.15mmol)和4-硝基苯甲酰胺(0.03g,0.17mmol),以与实施例8相似的方式得到所需产物(得率:55%)。
1H-NMR(500MHz,氯仿-D):δ8.81(s,1H),8.37(d,2H),8.06(d,2H),7.97(s,1H),7.88(s,1H),6.95(m,1H),6.87(m,3H),4.37(m,1H),4.02-3.88(m,3H),3.79(m,1H),3.70(m,1H),3.56(m,1H),2.12(m,1H),2.05(m,1H),1.97(m,1H),1.62(m,1H),1.36(t,3H)
实施例11:(R)-2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯甲酸
使用在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺和邻苯二甲酸酐,以与实施例6相似的方式得到所需产物。
1H NMR(300MHz,氯仿-D):δ8.71(s,1H),8.03(s,1H),7.92(m,2H),7.56(m,3H),6.95(m,1H),6.84(s,3H),4.31(bs,1H),3.95(m,3H),3.78(m,1H),3.64(m,3H),3.40(bs,1H),1.94-2.25(m,4H),1.50(m,1H),1.27-1.42(m,5H),0.90(m,2H)
实施例12:(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯基)乙酸
步骤1:(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯
基)乙酸甲酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.864g,2.59mmol)和在制备例3中得到的2-(4-氨甲酰基苯基)乙酸甲酯(0.6g,3.11mmol),以与实施例8相似的方式得到所需产物(得率:37%)。
1H-NMR(400MHz,氯仿-D)δ8.85(s,1H),7.92(s,1H),7.89(s,1H),7.85(d,2H),7.43(d,2H),6.99-6.85(m,4H),4.34(m,1H),4.13-4.10(m,3H),4.01-3.94(m,3H),3.68-3.65(m,4H),3.47(m,1H),2.13(m,1H),1.95(m,2H),1.61(m,1H),1.38-1.35(t,3H)
步骤2:(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯
基)乙酸
使用在步骤1中得到的酯化合物,在1N氢氧化锂水溶液中,以与实施例2的步骤2相似的方式得到所需产物(得率:50%)。
1H-NMR(400MHz,氯仿-D)δ8.83(s,1H),7.95(s,1H),7.92(s,1H),7.86(d,2H),7.44(d,2H),6.96(m,1H),6.92-6.83(m,3H),4.35-4.34(m,1H),4.02-3.89(m,3H),3.75(s,2H),3.72-3.68(m,2H),3.51-3.46(m,1H),2.1(m,1H),2.02-1.93(m,2H),1.62-1.59(m,1H),1.37-1.33(t,3H)
实施例13:(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯基)-2-甲基丙酸
步骤1:(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯
基)-2-甲基丙酸甲酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪和在制备例4中得到的2-(4-氨甲酰基苯基)-2-甲基丙酸甲酯,以与实施例8相似的方式得到所需产物(得率:82%)。
1H-NMR(400MHz,氯仿-D)δ8.85(s,1H),7.92(s,1H),7.88(s,1H),7.85(d,J=8Hz,2H),7.47(d,J=8Hz,2H),6.97-6.87(m,4H),4.38(m,1H),3.98-3.96(m,3H),3.79-3.48(m,3H),3.68(s,3H),2.15-1.95(m,3H),1.63(s,6H),1.63(m,1H),1.37(t,J=8Hz,3H)
步骤2:(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯
基)-2-甲基丙酸
使用在步骤1中得到的酯化合物,在2N氢氧化钠水溶液中,以与实施例2的步骤2相似的方式得到所需产物(得率:70%)。
1H-NMR(400MHz,氯仿-D)δ8.82(s,1H),7.93(s,1H),7.92(s,1H),7.85(d,J=8Hz,2H),7.54(d,J=8.4Hz,2H),6.97-6.83(m,4H),4.34(m,1H),3.99-3.90(m,3H),3.70-3.65(m,2H),3.47(m,1H),2.09(m,1H),2.04-1.92(m,2H),1.65(s,6H),1.65(m,1H),1.35(t,J=6.8Hz,3H)
实施例14:(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯氧基)-2-甲基丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例5中得到的2-(4-氨甲酰基苯氧基)-2-甲基丙酸乙酯(0.08g,0.30mmol),以与实施例34相似的方式得到所需产物(得率:43%)。
1H-NMR(400MHz,氯仿-D):δ8.72(s,1H),8.04(s,1H),7.86(s,1H),7.76(d,2H),6.93-6.79(m,6H),4.31(m,1H),4.13-3.88(m,3H),3.68(m,2H),3.48(m,1H),2.07(m,1H),1.97(m,2H),1.67(s,6H),1.57(m,1H),1.33(t,3H)
实施例15:(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-1-(甲磺酰基)哌啶)-4-甲酰胺
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.05g,0.15mmol)和1-(甲磺酰基)哌啶-4-甲酰胺(0.03g,0.17mmol),以与实施例8相似的方式得到所需产物(得率:46%)。
1H-NMR(500MHz,氯仿-D):δ8.65(s,1H),7.88(s,1H),7.35(s,1H),6.96(m,2H),6.87(m,2H),4.30(m,1H),4.03-3.89(m,3H),3.80(m,2H),3.69(m,1H),3.62(m,1H),3.45(m,1H),2.88(m,2H),2.80(s,3H),2.40(m,1H),2.12(m,1H),2.07-1.87(m,6H),1.59(m,1H),1.35(t,3H)
实施例16:(R)-1-乙酰基-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)哌啶)-4-甲酰胺
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.05g,0.15mmol)和1-乙酰基哌啶-4-甲酰胺(0.03g,0.17mmol),以与实施例8相似的方式得到所需产物(得率:43%)。
1H-NMR(500MHz,氯仿-D):δ8.66(s,1H),7.88(s,1H),7.33(s,1H),6.94(m,2H),6.88(m,2H),4.65(m,1H),4.31(m,1H),4.03-3.88(m,4H),3.71(m,1H),3.62(m,1H),3.44(m,1H),3.15(m,1H),2.71(m,1H),2.48(m,1H),2.11(m,4H),2.05-1.88(m,4H),1.85-1.65(m,2H),1.60(m,1H),1.36(t,3H)
实施例17:(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-1-(异丙基磺酰基)哌啶-4-甲酰胺
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.05g,0.15mmol)和1-(异丙基磺酰基)哌啶-4-甲酰胺(0.04g,0.17mmol),以与实施例8相似的方式得到所需产物(得率:53%)。
1H-NMR(500MHz,氯仿-D):δ8.65(s,1H),7.88(s,1H),7.28(s,1H),6.94(m,2H),6.88(m,2H),4.31(m,1H),4.03-3.90(m,3H),3.87(m,2H),3.70(m,1H),3.62(m,1H),3.44(m,1H),3.18(m,1H),3.00(m,2H),2.41(m,1H),2.12(m,1H),2.00(m,2H),1.95-1.82(m,3H),1.60(m,2H),1.35(m,9H)
实施例18:(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-1-(5-乙基嘧啶-2-基)哌啶-4-甲酰胺
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.05g,0.15mmol)和在制备例35中得到的1-(5-乙基嘧啶-2-基)哌啶-4-甲酰胺(0.04g,0.17mmol),以与实施例8相似的方式得到所需产物(得率:54%)。
1H-NMR(500MHz,氯仿-D):δ8.67(s,1H),8.17(s,2H),7.86(s,1H),7.33(s,1H),6.94(m,2H),6.87(m,2H),4.80(m,2H),4.30(m,1H),4.03-3.90(m,3H),3.73(m,1H),3.60(m,1H),3.43(m,1H),2.94(m,2H),2.55-2.42(m,3H),2.13(m,1H),1.99(m,3H),1.93(m,1H),1.80(m,2H),1.59(m,1H),1.35(t,3H),1.20(t,3H)
实施例19:(R)-4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-4-氧代丁酸
使用在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺和琥珀酸酐,以与实施例6相似的方式得到所需产物。
1H NMR(300MHz,氯仿-D):δ8.63(s,1H),7.88(s,1H),7.51(s,1H),7.30(s,1H),6.88-7.00(m,4H),4.34(m,1H),4.12(m,1H),3.96(m,3H),3.70(m,2H),3.69(m,1H),2.78(d,2H),2.68(d,2H),2.15(d,2H),1.96-2.10(m,3H),1.61(m,1H),1.44(t,3H),0.89(m,1H)
实施例20:(1R)-2-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)环戊烷-1-甲酸
使用在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺,以与实施例6相似的方式得到所需产物。
1H NMR(300MHz,甲醇-D):δ8.26(s,1H),7.69(s,1H),6.89-7.02(m,5H),4.48(m,2H),3.79-3.96(m,8H),3.53-3.65(m,6H),3.22(q,2H),2.30(m,2H),2.09(m,10H),1.61(bs,3H),1.35(m,12H),0.89(m,1H)
实施例21:(R)-4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)双环[2.2.2]辛烷-1-甲酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.05g,0.15mmol)和4-氨甲酰基双环[2.2.2]辛烷-1-甲酸甲酯(0.04g,0.17mmol),以与实施例34相似的方式得到所需产物(得率:34%)。
1H-NMR(500MHz,氯仿-D):δ8.68(s,1H),7.87(s,1H),7.35(s,1H),6.96(m,2H),6.88(m,2H),4.29(m,1H),4.07-3.93(m,3H),3.75(m,1H),3.57(m,1H),3.41(m,1H),2.15(m,1H),2.04-1.86(m,14H),1.59(m,1H),1.37(t,3H)
实施例22:(R)-4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2,2-二甲基-4-氧代丁酸
使用在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺和3,3-二甲基琥珀酸酐,以与实施例6相似的方式得到所需产物(得率:51%)。
1H NMR(300MHz,氯仿-D):δ8.64(s,1H),7.87(s,1H),7.85(s,1H),6.86-6.98(m,4H),4.3(m,1H),3.94-4.03(m,3H),3.7(m,1H),3.57(dd,1H),3.35(m,1H),2.68(s,2H),2.04(m,H),1.93(m,2H),1.5(m,1H),1.33(m+6H s,10H)
实施例23:(R)-1-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-3,3-二甲基吡咯烷-2,5-二酮
在制备实施例22的过程中产生副产物,并在分离和纯化过程中得到所需产物。
1H NMR(300MHz,氯仿-D):δ8.11(s,1H),7.77(s,1H),6.87-7.01(m,4H),4.30(m,1H),4.15(dd,1H),4.03(q,2H),3.85(m,1H),3.50(m,2H),2.10(m,1H),1.97(m,2H),1.60(m,1H),1.45(s,6H),1.38(t,3H),1.27(m,2H),0.90(m,1H)
实施例24:(R)-5-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2,2-二甲基-5-氧代戊酸
使用在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺和3,3-二甲基戊二酸酐,以与实施例6相似的方式得到所需产物。
1H NMR(300MHz,氯仿-D):δ8.68(s,1H),7.89(s,1H),7.66(s,1H),6.87-6.98(m,4H),4.20(m,1H),3.95(m,3H),3.70(m,1H),3.58(dd,1H),3.40(m,1H),2.44(m,2H),1.99-2.16(m,6H),1.39(t,3H),0.90(m,2H)
实施例25:(R)-5-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3,3-二甲基-5-氧代戊酸
使用在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺和4,4-二甲基戊二酸酐,以与实施例6相似的方式得到所需产物。
1H NMR(300MHz,氯仿-D):δ8.68(s,1H),8.13(s,1H),7.92(s,1H),6.87-7.00(m,4H),4.31(m,1H),4.00(m,3H),3.72(m,1H),3.62(dd,1H),3.45(m,1H),2.45(s,2H),2.00(m,3H),1.60(m,2H),1.38(t,3H),1.28(s,2H),1.20(s,3H),1.92(s,3H),0.90(m,2H)
实施例26:(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-2-(3-三氟甲基)苯基)乙酰胺
使用在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺和2-(3-三氟甲基)苯基乙酰氯,以与实施例6相似的方式得到所需产物(得率:54%)。
1H NMR(300MHz,氯仿-D):δ8.65(s,1H),7.83(s,1H),7.55(m,4H),7.38(s,1H),6.85-6.96(m,4H),4.28(m,1H),3.94(m,3H),3.77(s,2H),3.65(m,2H),3.42(m,1H),1.93-2.11(m,3H),1.56(m,1H),1.94(t,3H)
实施例27:(R)-2-(3,5-双(三氟甲基)苯基)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)乙酰胺
使用在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺和3,5-双(三氟甲基)苯基乙酰氯,以与实施例6相似的方式得到所需产物(得率:38%)。
1H NMR(300MHz,氯仿-D):δ8.64(s,1H),7.92(s,1H),7.84(s,1H),7.82(s,2H),7.50(s,1H),6.68-7.00(m,4H),4.35(m,1H),3.95(m,3H),3.84(s,2H),3.70(m,2H),3.50(m,1H),1.97-2.13(m,3H),1.61(m,1H),1.61(t,3H)
实施例28:(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-2-苯基乙酰胺
使用在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺(0.17g,0.50mmol)和苯基乙酰氯(0.078g,0.50mmol),以与实施例6相似的方式得到所需产物(得率:23%)。
1H NMR(400MHz,氯仿-D):δ8.69(s,1H),7.78(s,1H),7.29-7.41(m,5H),6.97(m,2H),6.85(m,2H),4.27(m,1H),3.91-4.00(m,3H),3.72(s,2H),3.68(m,1H),3.52(m,1H),3.37(m,1H),2.09(m,1H),1.96(m,1H),1.86(m,1H),1.56(m,1H),1.34(t,3H)
实施例29:(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-3-苯基丙酰胺
使用在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺(0.17g,0.50mmol)和3-苯基丙酰氯(0.08g,0.50mmol),以与实施例6相似的方式得到所需产物(得率:46%)。
1H-NMR(500MHz,氯仿-D):δ8.67(s,1H),7.86(s,1H),7.30(t,J=7.6Hz,2H),7.22(dd,J=17.1,7.3Hz,3H),7.12(s,1H),6.98-6.90(m,2H),6.88-6.70(m,2H),4.35-4.27(m,1H),4.02-3.85(m,3H),3.72-3.59(2H),3.46-3.38(m,1H),3.09-3.01(m,2H),2.66(t,J=7.6Hz,2H),2.09(d,J=12.2Hz,1H),2.02-1.87(m,2H),1.57(q,J=4.3Hz,1H),1.33(t,J=7.0Hz,3H)
实施例30:(R)-2-(3-氯苯基)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)乙酰胺
使用在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺(0.17g,0.50mmol)和3-氯苯基乙酰氯(0.08g,0.50mmol),以与实施例6相似的方式得到所需产物(得率:30%)。
1H NMR(400MHz,氯仿-D):δ8.66(s,1H),7.86(s,1H),7.29-7.33(m,3H),7.21(m,1H),6.97(m,2H),6.86(m,2H),4.29(m,1H),3.90-4.00(m,3H),3.72(m,3H),3.59(m,1H),3.41(m,1H),2.09(m,1H),1.96(m,1H),1.86(m,1H),1.56(m,1H),1.36(t,3H)
实施例31:(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-2-甲基-2-苯基丙酰胺
使用在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺(0.17g,0.50mmol)和2-甲基-2-苯基丙酰氯(0.08g,0.50mmol),以与实施例6相似的方式得到所需产物(得率:30%)。
1H NMR(400MHz,氯仿-D):δ8.75(s,1H),7.82(s,1H),7.33-7.43(m,4H),7.31(m,1H),7.02(s,1H),6.79-6.93(m,4H),4.23(m,1H),3.91-4.00(m,3H),3.69(m,1H),3.41(m,1H),3.27(m,1H),2.08(m,1H),1.91(m,1H),1.85(m,1H),1.66(s,6H),1.55(m,1H),1.34(t,3H)
实施例32:(R)-4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯甲酸
步骤1:(R)-4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧
代乙基)苯甲酸甲酯
使用在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺(0.40g,1.27mmol)和4-(2-氯-2-氧代乙基)苯甲酸甲酯(0.74g,3.82mmol),以与实施例6相似的方式得到所需酯化合物(得率:51%)。
1H-NMR(500MHz,氯仿-D):δ8.65(s,1H),8.05(d,J=8.6Hz,2H),7.86(s,1H),7.40(d,J=8.6Hz,2H),7.22(s,1H),6.93(q,J=7.9Hz,2H),6.83(q,J=7.1Hz,2H),4.34-4.19(m,1H),4.04-3.85(m,6H),3.76(s,2H),3.71-3.64(m,1H),3.57(q,J=6.9Hz,1H),3.45-3.33(m,1H),2.09(td,J=7.9,4.1Hz,1H),2.03-1.94(m,1H),1.92-1.80(m,1H),1.56(q,J=4.3Hz,1H),1.33(t,J=7.0Hz,3H)
步骤2:(R)-4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧
代乙基)苯甲酸
使用2N氢氧化钠,通过步骤1中得到的酯化合物(0.32g,0.65mmol)的水解得到所需产物(得率:16%)。
1H-NMR(500MHz,氯仿-D):δ8.67(s,1H),8.09(d,J=7.9Hz,2H),7.89(s,1H),7.52(s,1H),7.41(d,J=7.9Hz,2H),6.92(q,J=7.7Hz,2H),6.86-6.65(m,2H),4.42-4.13(m,1H),4.11-3.86(m,3H),3.78(s,2H),3.70-3.55(m,2H),3.44-3.36(m,1H),2.33-2.02(m,1H),1.96(td,J=6.7,3.7Hz,1H),1.89(q,J=4.1Hz,1H),1.65-1.48(m,1H),1.31(t,J=7.0Hz,3H)
实施例33:(R)-3-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯甲酸
步骤1:(R)-3-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧
代乙基)苯甲酸甲酯
使用在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺(0.40g,1.27mmol)和3-(2-氯-2-氧代乙基)苯甲酸甲酯(0.74g,3.82mmol),以与实施例6相似的方式得到所需酯化合物(得率:20%)。
1H-NMR(500MHz,氯仿-D):δ8.66(s,1H),8.00(d,J=6.7Hz,2H),7.86(s,1H),7.55(d,J=7.3Hz,1H),7.47(t,J=7.9Hz,1H),7.21(s,1H),6.94(q,J=7.9Hz,2H),6.87-6.77(m,2H),4.34-4.24(m,1H),4.05-3.84(m,6H),3.76(s,2H),3.73-3.64(m,1H),3.58(q,J=6.7Hz,1H),3.39(td,J=8.9,4.1Hz,1H),2.19-2.05(m,1H),1.98(q,J=3.3Hz,1H),1.90(q,J=4.1Hz,1H),1.68-1.58(1H),1.33(t,J=6.7Hz,3H)
步骤2:(R)-3-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧
代乙基)苯甲酸
使用2N氢氧化钠,通过步骤1中得到的酯化合物(0.12g,0.25mmol)的水解,以与实施例32的步骤2相似的方式得到所需产物(得率:26%)。
1H-NMR(500MHz,氯仿-D):δ8.68(s,1H),8.06(s,1H),8.02(d,J=7.3Hz,1H),7.87(s,1H),7.81(s,1H),7.56(d,J=7.3Hz,1H),7.47-7.41(m,1H),6.95-6.85(m,2H),6.84-6.71(m,2H),4.35-4.21(m,1H),3.98-3.84(m,3H),3.77(s,2H),3.67-3.54(m,2H),3.43-3.35(m,1H),2.05(q,J=4.1Hz,1H),1.94(td,J=6.7,3.3Hz,1H),1.90-1.80(m,1H),1.64-1.47(m,1H),1.30(t,J=7.0Hz,3H)
实施例34:(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)乙酸
步骤1:(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-
氧代乙基)苯基)乙酸甲酯
向50mL二氧杂环己烷添加在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.98g,2.93mmol)和在制备例6中得到的2-(4-(2-氨基-2-氧代乙基)苯基)乙酸甲酯(0.61g,2.93mmol)、三(二亚苯甲基丙酮)二钯(0)(0.16g,0.18mmol)、4,5-双(二苯基膦)-9,9-二甲基黄嘌呤(0.15g,0.26mmol)和碳酸铯(2.39g,7.33mmol),并在回流下搅拌4小时。在反应完成后,将得到的产物冷却至室温,用乙酸乙酯稀释,并用碳酸氢钠水溶液和盐水洗涤。将有机溶剂在硫酸镁上脱水并在减压下除去。通过硅胶柱进行纯化(乙酸乙酯:己烷=3:1),得到所需产物(得率:68%)。
1H-NMR(500MHz,氯仿-D)δ8.67(s,1H),7.85(s,1H),7.32-7.28(m,4H),7.24(s,1H),6.97-6.89(m,2H),6.88-6.77(m,2H),4.31-4.24(m,1H),4.03-3.89(m,3H),3.69(m,3H),3.67(d,J=7.9Hz,3H),3.63(s,2H),3.54(q,J=6.9Hz,1H),3.41-3.33(m,1H),2.08(q,J=4.1Hz,1H),2.00-1.93(m,1H),1.88(q,J=4.1Hz,1H),1.55(t,J=4.6Hz,1H),1.34(t,J=7.0Hz,3H)
步骤2:(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-
氧代乙基)苯基)乙酸
将步骤1中得到的酯(1.0g,1.98mmol)溶解在THF-甲醇(40mL,3:1)中,并缓慢地逐滴添加2N氢氧化钠溶液(10mL,19.8mmol)。在室温搅拌4小时后,将得到的产物用水稀释,用2N盐酸溶液中和,并用乙酸乙酯萃取。将有机溶剂在硫酸镁上脱水并在减压下除去。通过硅胶柱进行纯化(丙酮:二氯甲烷=1:1),得到所需产物(得率:29%)。
1H-NMR(500MHz,氯仿-D):δ8.62(s,1H),7.84(s,1H),7.42(s,1H),7.36-7.17(m,4H),6.95-6.87(m,2H),6.87-6.78(m,2H),4.30-4.21(m,1H),4.00-3.86(m,3H),3.67(s,2H),3.63(t,J=14.7Hz,3H),3.51(td,J=14.4,7.4Hz,1H),3.39-3.29(m,1H),2.06(q,J=3.5Hz,1H),1.93(td,J=6.7,3.1Hz,1H),1.85(q,J=4.1Hz,1H),1.53(q,J=4.5Hz,1H),1.31(t,J=7.0Hz,3H)
实施例35:(R)-2-(4-(2-氨基-2-氧代乙基)苯基-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)乙酰胺
将在实施例34中得到的(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)乙酸(0.27g,0.55mmol)溶解在二氯甲烷(10mL)中,并在室温下缓慢地逐滴添加亚硫酰氯(0.08mL,1.1mmol)。在室温搅拌4小时后,在减压下除去有机溶剂,将得到的产物用THF稀释,并在0℃下缓慢地逐滴添加到25%氨水溶液。将得到的固体过滤并干燥,得到所需产物(得率:82%)。
1H-NMR(500MHz,氯仿-D):δ8.66(s,1H),7.92-7.77(1H),7.36-7.27(m,5H),6.99-6.90(m,2H),6.89-6.80(m,2H),5.39(s,2H),4.31-4.24(m,1H),4.03-3.89(3H),3.70(s,2H),3.69-3.65(m,1H),3.58(s,2H),3.56-3.50(1H),3.41-3.33(1H),2.13-2.06(m,1H),1.96(td,J=6.7,3.5Hz,1H),1.88(q,J=4.1Hz,1H),1.59-1.51(m,1H),1.35(t,J=6.7Hz,3H)
实施例36:(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-2-(4-羟基苯基)乙酰胺
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.25g,0.75mmol)和2-(4-羟基苯基)乙酰胺(0.11g,0.75mmol),以与实施例34相似的方式得到所需产物(得率:54%)。
1H-NMR(500MHz,氯仿-D):δ8.69(s,1H),7.82(s,1H),7.31(m,1H),7.14(d,2H),6.98(m,2H),6.84(m,4H),4.27(m,1H),3.95(m,3H),3.63(m,3H),3.55(m,1H),3.37(m,1H),2.04(m,1H),1.98-1.83(m,2H),1.55(m,1H),1.34(t,3H)
实施例37:(R)-4-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯氧基)丁酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.05g,0.15mmol)和在制备例7中得到的4-(4-(2-氨基-2-氧代乙基)苯氧基)丁酸乙酯(0.04g,0.17mmol),以与实施例34相似的方式得到所需产物(得率:44%)。
1H-NMR(500MHz,氯仿-D):δ8.67(s,1H),7.85(s,1H),7.29(s,1H),7.22(d,2H),6.97-6.80(m,6H),4.26(m,1H),4.02(t,2H),3.94(m,3H),3.67(m,3H),3.52(m,1H),3.37(m,1H),2.57(t,2H),2.13(m,3H),1.98-1.83(m,2H),1.56(m,1H),1.35(t,3H)
实施例38:(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基-2-氧代乙基)苯氧基)-2-甲基丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.30g,0.90mmol)和在制备例8中得到的2-(4-(2-氨基-2-氧代乙基)苯氧基)-2-甲基丙酸乙酯(0.24g,0.90mmol),以与实施例34相似的方式得到所需产物(得率:52%)。
1H-NMR(400MHz,氯仿-D):δ8.62(s,1H),7.85(s,1H),7.50(s,1H),7.17(d,2H),6.96-6.82(m,6H),4.29(m,1H),4.01-3.89(m,3H),3.62(m,3H),3.55(m,1H),3.37(m,1H),2.07(m,1H),1.93(m,1H),1.88(m,1H),1.58(m,7H),1.34(t,3H)
实施例39:(R)-2-(4-(1-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2-甲基丙酸
步骤1:(R)-2-(4-(1-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-
甲基-1-氧代丙-2-基)苯基)-2-甲基丙酸甲酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪和在制备例9中得到的2-(4-(1-氨基-2-甲基-1-氧代丙-2-基)苯基)-2-甲基丙酸甲酯,以与实施例34的步骤1相似的方式得到所需产物(得率45%)。
1H-NMR(500MHz,氯仿-D):δ8.73(s,1H),7.81(d,J=4.3Hz,1H),7.41-7.27(m,4H),7.06(s,1H),6.98-6.86(m,2H),6.85-6.69(m,2H),4.33-4.16(m,1H),4.04-3.85(m,3H),3.66(td,J=9.0,3.7Hz,1H),3.61(d,J=4.9Hz,3H),3.43(dd,J=13.1,7.6Hz,1H),3.37-3.21(m,1H),2.13-2.04(m,1H),1.98-1.78(m,2H),1.62(s,6H),1.58-1.44(m,7H),1.32(t,J=7.0Hz,3H)
步骤2:(R)-2-(4-(1-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-
甲基-1-氧代丙-2-基)苯基)-2-甲基丙酸
将在步骤1中得到的酯化合物以与实施例34的步骤2相似的方式水解,得到所需产物(得率:48%)。
1H-NMR(400MHz,氯仿-D):δ8.69(s,1H),7.83(s,1H),7.44-7.26(m,4H),7.06(s,1H),6.94-6.88(m,2H),6.83-6.77(m,2H),4.23-4.21(m,1H),4.13-3.91(m,3H),3.63(m,1H),3.46(m,1H),3.28(m,1H),2.05(m,1H),1.98-1.78(m,2H),1.64(s,3H),1.59(s,3H),1.58-1.44(m,1H),1.32(t,J=7.0Hz,3H)
实施例40:(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯甲酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.51g,1.53mmol)和在制备例10中得到的4-(3-氨基-3-氧代丙基)苯甲酸甲酯(0.32g,1.53mmol),以与实施例34相似的方式得到所需产物(得率:62%)。
1H-NMR(400MHz,氯仿-D):δ8.67(s,1H),8.02(d,2H),7.89(s,1H),7.33(m,3H),6.93(m,2H),6.84(m,2H),4.31(m,1H),4.00-3.86(m,3H),3.64(m,2H),3.43(m,1H),3.12(t,2H),2.71(t,2H),2.11(m,1H),1.98(m,1H),1.90(m,1H),1.58(m,1H),1.34(t,3H)
实施例41:(R,E)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙-1-烯-1-基)苯甲酸
步骤1:(R,E)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-
氧代丙-1-烯-1-基)苯甲酸甲酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.09g,0.28mmol)和在制备例11中得到的(E)-4-(3-氨基-3-氧代丙-1-烯-1-基)苯甲酸甲酯(0.07g,0.33mmol),以与实施例34的步骤1相似的方式得到所需产物(得率:63%)。
1H-NMR(500MHz,氯仿-D)δ8.82(s,1H),8.08-7.94(3H),7.88(d,J=4.3Hz,1H),7.81-7.69(m,1H),7.54(t,J=4.0Hz,2H),7.26(d,J=4.9Hz,0H),7.01-6.90(2H),6.88-6.78(m,2H),6.66(d,J=15.3Hz,1H),4.36-4.18(m,1H),4.10(qd,J=7.0,4.7Hz,3H),4.05-3.94(m,3H),3.93-3.84(m,4H),3.83-3.64(m,1H),3.55(dt,J=12.8,3.7Hz,1H),3.37(td,J=8.9,3.9Hz,1H),2.19-2.07(m,1H),2.03(d,J=4.3Hz,5H),1.94(s,2H),1.90-1.78(m,1H),1.63-1.48(m,1H),1.41-1.30(m,3H),1.28-1.10(m,6H)
步骤2:(R,E)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-
氧代丙-1-烯-1-基)苯甲酸
将步骤1中得到的酯化合物(0.07g,0.14mmol)以与实施例34的步骤2相似的方式水解,得到所需产物(得率:64%)。
1H-NMR(500MHz,氯仿-D)δ8.80(s,1H),8.12(d,J=7.9Hz,2H),7.93(s,1H),7.80(d,J=15.1Hz,1H),7.64(d,J=7.8Hz,2H),7.48(d,J=18.3Hz,1H),6.96(t,J=7.6Hz,2H),6.88(dd,J=14.2,8.1Hz,2H),6.62(d,J=15.9Hz,1H),4.35(s,1H),4.08-3.85(m,3H),3.79-3.62(m,2H),3.49(s,1H),2.15(d,J=26.9Hz,2H),2.01(s,1H),1.94(d,J=7.9Hz,1H),1.58(d,J=38.5Hz,2H),1.44-1.33(m,4H),1.23(dd,J=38.5,15.9Hz,3H),0.96-0.75(m,2H)
实施例42:(R,E)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-3-氧代丙-1-烯-1-基)苯甲酸
步骤1:(R,E)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-
甲基-3-氧代丙-1-烯-1-基)苯甲酸甲酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.66g,1.99mmol)和在制备例12中得到的(E)-4-(3-氨基-2-甲基-3-氧代丙-1-烯-1-基)苯甲酸甲酯(0.52g,2.39mmol),以与实施例34的步骤1相似的方式得到所需产物(得率:67%)。
1H-NMR(500MHz,氯仿-D)δ8.81-8.77(1H),8.08(d,J=7.9Hz,2H),7.92(d,J=4.3Hz,1H),7.67(s,1H),7.51-7.42(m,3H),7.00-6.95(m,1H),6.95-6.90(1H),6.87(d,J=7.9Hz,2H),4.37-4.29(m,1H),4.06-3.96(m,2H),3.94(s,3H),3.81-3.71(1H),3.66(q,J=6.7Hz,1H),3.52-3.42(m,1H),2.21(d,J=1.8Hz,3H),2.19-2.08(m,1H),2.03-1.87(m,2H),1.61(qd,J=8.9,4.7Hz,1H),1.36(q,J=6.5Hz,3H)
步骤2:(R,E)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-
甲基-3-氧代丙-1-烯-1-基)苯甲酸
将步骤1中得到的酯化合物(0.69g,1.34mmol)以与实施例34的步骤2相似的方式水解,得到所需产物(得率:41%)。
1H-NMR(500MHz,氯仿-D)δ8.79(s,1H),8.13(s,2H),7.93(s,1H),7.69(s,1H),7.48(s,3H),7.02-6.67(m,5H),4.33(s,1H),4.00(d,J=9.2Hz,3H),3.81-3.59(2H),2.21(s,3H),2.13(s,1H),2.03(s,1H),1.96-1.87(1H),1.65(d,J=31.2Hz,7H),1.36(s,5H),1.30-1.16(1H)
实施例43:4-(3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-3-氧代丙基)苯甲酸
步骤1:4-(3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲
基-3-氧代丙基)苯甲酸甲酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.95g,2.83mmol)和在制备例13中得到的4-(3-氨基-2-甲基-3-氧代丙基)苯甲酸甲酯(0.75g,3.40mmol),以与实施例34的步骤1相似的方式得到所需产物(得率:92%)。
1H-NMR(500MHz,氯仿-D)δ8.81-8.77(1H),8.08(d,J=7.9Hz,2H),7.92(d,J=4.3Hz,1H),7.67(s,1H),7.51-7.42(m,3H),7.00-6.95(m,1H),6.95-6.90(1H),6.87(d,J=7.9Hz,2H),4.37-4.29(m,1H),4.06-3.96(m,2H),3.94(s,3H),3.81-3.71(1H),3.66(q,J=6.7Hz,1H),3.52-3.42(m,1H),2.21(d,J=1.8Hz,3H),2.19-2.08(m,1H),2.03-1.87(m,2H),1.61(qd,J=8.9,4.7Hz,1H),1.36(q,J=6.5Hz,3H)
步骤2:4-(3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲
基-3-氧代丙基)苯甲酸
将步骤1中得到的酯化合物(1.35g,2.60mmol)以与实施例34的步骤2相似的方式水解,得到所需产物(得率:39%)。
1H-NMR(500MHz,氯仿-D)δ8.67(d,J=3.4Hz,1H),7.98(dd,J=12.5,8.1Hz,2H),7.86(s,1H),7.30(d,J=10.7Hz,2H),7.18(s,0H),7.04(s,0H),6.98-6.89(m,2H),6.85(d,J=7.8Hz,2H),6.79(d,J=8.3Hz,0H),4.29(s,1H),4.05-3.86(m,3H),3.67(s,1H),3.61-3.51(m,1H),3.44-3.29(m,1H),3.21-3.08(m,1H),2.88-2.75(m,1H),2.64(t,J=6.3Hz,1H),2.13(d,J=35.2Hz,1H),1.96(s,1H),1.91-1.76(m,1H),1.64-1.49(m,1H),1.34(q,J=6.3Hz,3H),1.29(d,J=6.8Hz,3H)
实施例44:(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)-2-氟苯甲酸
步骤1:(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧
代丙基)-2-氟苯甲酸甲酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.39g,1.15mmol)和在制备例14中得到的4-(3-氨基-3-氧代丙基)-2-氟苯甲酸甲酯(0.26g,1.15mmol),以与实施例34的步骤1相似的方式得到所需产物(得率:68%)。
1H-NMR(500MHz,氯仿-D):δ8.65(s,1H),7.87(t,J=7.6Hz,2H),7.24-7.15(1H),7.08(d,J=7.9Hz,1H),7.02(d,J=12.2Hz,1H),6.93(t,J=7.3Hz,2H),6.84(q,J=7.9Hz,2H),4.40-4.24(m,1H),3.96(dd,J=15.0,8.3Hz,2H),3.91(s,3H),3.88(d,J=2.4Hz,1H),3.67(t,J=3.1Hz,1H),3.62(t,J=6.4Hz,1H),3.44(t,J=4.6Hz,1H),3.08(t,J=7.6Hz,2H),2.68(t,J=7.3Hz,2H),2.15-2.06(m,1H),1.97(t,J=3.4Hz,1H),1.91(q,J=4.1Hz,1H),1.57(q,J=4.3Hz,1H),1.33(t,J=7.0Hz,3H)
步骤2:(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧
代丙基)-2-氟苯甲酸
将步骤1中得到的酯化合物(0.41g,0.79mmol)以与实施例34的步骤2相似的方式水解,得到所需产物(得率:50%)。
1H-NMR(500MHz,氯仿-D):δ8.65(s,1H),7.93(d,J=7.3Hz,1H),7.89(s,1H),7.44-7.30(1H),7.09(d,J=7.9Hz,1H),7.03(d,J=11.9Hz,1H),6.92(t,J=7.3Hz,2H),6.84(q,J=7.1Hz,2H),4.31(d,J=3.1Hz,1H),4.05-3.82(m,3H),3.71-3.57(m,2H),3.55-3.37(m,1H),3.09(t,J=7.4Hz,2H),2.77-2.53(2H),2.09(d,J=4.3Hz,1H),1.98(s,1H),1.90(d,J=8.6Hz,1H),1.57(q,J=4.3Hz,1H),1.33(t,J=7.0Hz,3H)
实施例45:(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)-2-甲基苯甲酸
步骤1:(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧
代丙基)-2-甲基苯甲酸甲酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.35g,1.05mmol)和在制备例15中得到的4-(3-氨基-3-氧代丙基)-2-甲基苯甲酸甲酯(0.23g,1.05mmol),以与实施例34的步骤1相似的方式得到所需产物(得率:63%)。
1H-NMR(500MHz,氯仿-D):δ8.66(s,1H),7.85(d,J=7.3Hz,2H),7.23(s,1H),7.10(d,J=6.1Hz,2H),7.03-6.90(m,2H),6.89-6.73(m,2H),4.45-4.24(m,1H),4.09-3.80(m,6H),3.80-3.57(2H),3.42(dd,J=8.9,3.4Hz,1H),3.03(t,J=7.9Hz,2H),2.66(t,J=7.6Hz,2H),2.57(s,3H),2.09(d,J=4.9Hz,1H),1.97(td,J=6.7,3.7Hz,1H),1.91(q,J=4.1Hz,1H),1.57(t,J=4.3Hz,1H),1.44-1.29(m,3H)
步骤2:(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧
代丙基)-2-甲基苯甲酸
将步骤1中得到的酯化合物(0.33g,0.64mmol)以与实施例34的步骤2相似的方式水解,得到所需产物(得率:22%)。
1H-NMR(400MHz,氯仿-D):δ8.66(s,1H),7.98(d,J=8.8Hz,1H),7.87(s,1H),7.14(s,3H),6.95-6.91(m,2H),6.88-6.83(m,2H),4.31(m,1H),3.98-3.92(m,3H),3.65(2H),3.45(m,1H),3.06(m,2H),2.68(m,2H),2.61(s,3H),2.09(m,1H),1.97(m,1H),1.91(m,1H),1.57(m,1H),1.35(t,3H)
实施例46:(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)-2-甲氧基苯甲酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例16中得到的4-(3-氨基-3-氧代丙基)-2-甲氧基苯甲酸甲酯(0.07g,0.30mmol),以与实施例34相似的方式得到所需产物(得率:38%)。
1H-NMR(400MHz,氯仿-D):δ8.65(s,1H),8.09(d,1H),7.88(s,1H),7.38(s,1H),7.02-6.83(m,6H),4.31(m,1H),4.05-3.89(m,6H),3.63(m,2H),3.44(m,1H),3.12(t,2H),2.73(t,2H),2.08(m,1H),1.94(m,2H),1.58(m,1H),1.35(t,3H)
实施例47:(R)-2-氯-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯甲酸
步骤1:(R)-2-氯-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-
3-氧代丙基)苯甲酸甲酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪和在制备例17中得到的4-(3-氨基)-3-氧代丙基)-2-氯苯甲酸甲酯,以与实施例34的步骤1相似的方式得到所需产物(得率:42%)。
1H-NMR(400MHz,氯仿-D)δ8.65(s,1H),7.87(s,1H),7.78(d,J=8Hz,1H),7.36-7.33(m,2H),7.18(d,J=8Hz,1H),7.36-7.33(m,2H),7.18(d,J=8Hz,1H),6.95-6.91(m,2H),6.87-6.82(m,2H),4.31-4.30(m,1H),3.99-3.92(m,3H),3.91(s,3H),3.66-3.61(m,2H),3.42(m,1H),3.05(t,J=7.4Hz,2H),2.67(t,J=7.4Hz,2H),2.09-2.07(m,1H),1.96-1.89(m,2H),1.58(m,1H),1.33(t,J=7Hz,3H)
步骤2:(R)-2-氯-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-
3-氧代丙基)苯甲酸
将步骤1中得到的酯化合物以与实施例34的步骤2相似的方式水解,得到所需产物(得率:18%)。
1H-NMR(400MHz,氯仿-D)δ8.64(s,1H),7.88(s,1H),7.79(m,1H),7.64(m,1H),7.11(m,1H),6.91-6.89(m,2H),6.85-6.81(m,2H),4.29(m,1H),3.98-3.88(m,3H),3.62(m,2H),3.40(m,1H),3.00(m,2H),2.66(m,2H),2.04(m,1H),1.94(m,1H),1.88(m,1H),1.56(m,1H),1.31(t,J=6Hz,3H)
实施例48:(R)-3-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯甲酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例18中得到的3-(3-氨基-3-氧代丙基)苯甲酸甲酯(0.06g,0.30mmol),以与实施例34相似的方式得到所需产物(得率:35%)。
1H-NMR(400MHz,氯仿-D):δ8.69(s,1H),8.01(s,1H),7.98(d,1H),7.90(s,1H),7.60(s,1H),7.49(d,1H),7.45(t,1H),7.02-6.80(m,4H),4.32(m,1H),4.02-3.85(m,3H),3.67(m,2H),3.46(m,1H),3.14(t,2H),2.74(t,2H),2.12-1.92(m,3H),1.60(m,1H),1.37(t,3H)
实施例49:(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)乙酸
步骤1:(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-
氧代丙基)苯基)乙酸甲酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(1.00g,3.00mmol)和在制备例19中得到的2-(4-(3-氨基-3-氧代丙基)苯基)乙酸甲酯(0.66g,3.00mmol),以与实施例34的步骤1相似的方式得到所需产物(得率:80%)。
1H-NMR(500MHz,氯仿-D):δ8.67(s,1H),7.90-7.81(1H),7.35(d,J=7.3Hz,1H),7.18(td,J=8.9,2.6Hz,4H),6.96-6.88(m,2H),6.86-6.75(m,2H),4.37-4.24(m,1H),4.00-3.86(m,3H),3.69(t,J=2.4Hz,1H),3.66(s,3H),3.61(t,J=6.7Hz,1H),3.58(s,2H),3.40(td,J=8.7,3.9Hz,1H),3.09-2.94(m,2H),2.64(t,J=7.6Hz,2H),2.08(q,J=4.1Hz,1H),1.96(td,J=6.7,3.1Hz,1H),1.92-1.83(m,1H),1.56(q,J=4.5Hz,1H),1.32(t,J=6.7Hz,3H)
步骤2:(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-
氧代丙基)苯基)乙酸
将步骤1中得到的酯化合物(1.24g,2.39mmol)以与实施例34的步骤2相似的方式水解,得到所需产物(得率:57%)。
1H-NMR(500MHz,氯仿-D):δ8.64(s,1H),7.94-7.77(1H),7.40(s,1H),7.19(dd,J=19.9,8.3Hz,4H),6.95-6.88(m,2H),6.87-6.73(2H),4.35-4.26(m,1H),4.04-3.84(m,3H),3.69-3.60(m,2H),3.59(s,2H),3.41(t,J=4.6Hz,1H),3.00(t,J=7.3Hz,2H),2.63(t,J=7.6Hz,2H),2.07(q,J=4.1Hz,1H),1.96(q,J=3.3Hz,1H),1.89(q,J=4.1Hz,1H),1.55(q,J=4.3Hz,1H),1.31(t,J=6.7Hz,3H)
实施例50:(R)-3-(4-(2-氨基-2-氧代乙基)苯基-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)丙酰胺
使用在实施例49中得到的(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)乙酸(0.21g,0.42mmol),以与实施例35相似的方式得到所需产物(得率:62%)。
1H-NMR(500MHz,氯仿-D):δ8.66(s,1H),7.86(s,1H),7.21(q,J=7.5Hz,5H),6.98-6.90(m,2H),6.89-6.80(m,2H),5.38(s,2H),4.35-4.25(m,1H),4.02-3.87(m,3H),3.68(qd,J=6.5,4.0Hz,1H),3.61(q,J=6.9Hz,1H),3.54(s,2H),3.46-3.37(1H),3.03(t,J=7.6Hz,2H),2.66(t,J=7.6Hz,2H),2.15-2.05(m,1H),2.04-1.94(m,1H),1.94-1.83(m,1H),1.57(q,J=4.5Hz,1H),1.34(t,J=7.0Hz,3H)
实施例51:(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸
步骤1:(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-
氧代丙基)苯基)-2-甲基丙酸甲酯
使用在制备例1中制备的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.48g,1.44mmol)和在制备例20中得到的2-(4-(3-氨基-3-氧代丙基)苯基)-2-甲基丙酸甲酯(0.36g,1.44mmol),以与实施例34的步骤1相似的方式得到所需产物(得率:91%)。
1H-NMR(500MHz,氯仿-D):δ8.68(s,1H),7.86(s,1H),7.27(d,J=7.9Hz,2H),7.20(d,J=8.6Hz,2H),7.16(s,1H),6.93(qd,J=7.3,1.5Hz,2H),6.85(td,J=7.6,1.4Hz,1H),6.80(d,J=7.9Hz,1H),4.45-4.24(m,1H),4.06-3.80(m,3H),3.78-3.65(m,2H),3.64-3.57(3H),3.45(q,J=3.9Hz,1H),3.15-2.93(2H),2.65(t,J=7.6Hz,2H),2.21-2.07(1H),1.99(td,J=6.7,3.1Hz,1H),1.92(q,J=4.1Hz,1H),1.59(t,J=4.0Hz,1H),1.55(s,6H),1.33(t,J=7.0Hz,3H)
步骤2:(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-
氧代丙基)苯基)-2-甲基丙酸
将步骤1中得到的酯化合物(0.72g,1.32mmol)以与实施例34的步骤2相似的方式水解,得到所需产物(得率:14%)。
1H-NMR(500MHz,氯仿-D):δ8.66(s,1H),7.86(s,1H),7.33(d,J=8.6Hz,2H),7.19(d,J=7.9Hz,3H),6.98-6.89(m,2H),6.88-6.76(m,2H),4.29(q,J=3.7Hz,1H),4.08-3.81(m,3H),3.65(d,J=2.4Hz,1H),3.60(q,J=6.7Hz,1H),3.40(s,1H),3.01(t,J=7.3Hz,2H),2.65(t,J=4.0Hz,2H),2.08(q,J=4.1Hz,1H),1.96(q,J=3.5Hz,1H),1.89(q,J=4.3Hz,1H),1.57(s,7H),1.32(t,J=7.0Hz,3H)
实施例52:(R)-1-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)环丙烷-1-甲酸
步骤1:(R)-1-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-
氧代丙基)苯基)环丙烷-1-甲酸甲酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.48g,1.44mmol)和在制备例21中得到的1-(4-(3-氨基-3-氧代丙基)苯基)环丙烷-1-甲酸甲酯(0.36g,1.44mmol),以与实施例34的步骤1相似的方式得到所需产物(得率:76%)。
1H-NMR(500MHz,氯仿-D):δ8.68(s,1H),7.86(s,1H),7.35-7.24(m,2H),7.21-7.10(m,3H),6.98-6.89(m,2H),6.86(dd,J=7.6,1.5Hz,1H),6.81(dd,J=7.6,1.5Hz,1H),4.37-4.26(m,1H),4.06-3.83(m,3H),3.72-3.62(m,2H),3.60(s,3H),3.48-3.38(m,1H),3.03(td,J=7.6,3.3Hz,2H),2.66(t,J=7.3Hz,2H),2.15-2.06(m,1H),2.02-1.95(m,1H),1.92(q,J=4.1Hz,1H),1.60-1.51(m,3H),1.33(t,J=7.0Hz,3H),1.15(q,J=3.5Hz,2H)
步骤2:(R)-1-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-
氧代丙基)苯基)环丙烷-1-甲酸
将步骤1中得到的酯化合物(0.6g,1.10mmol)以与实施例34的步骤2相似的方式水解,得到所需产物(得率:34%)。
1H-NMR(500MHz,氯仿-D):δ8.66(s,1H),7.86(s,1H),7.36-7.27(3H),7.17(d,J=7.9Hz,2H),6.92(t,J=7.0Hz,2H),6.84(q,J=7.9Hz,2H),4.30(q,J=3.5Hz,1H),4.07-3.82(m,3H),3.76-3.55(m,2H),3.42(t,J=4.6Hz,1H),3.01(t,J=7.6Hz,2H),2.64(t,J=7.6Hz,2H),2.08(q,J=4.1Hz,1H),2.04-1.94(m,1H),1.90(q,J=4.1Hz,1H),1.63(q,J=3.3Hz,2H),1.56(q,J=4.3Hz,1H),1.33(t,J=7.0Hz,3H),1.21(q,J=3.3Hz,2H)
实施例53:(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)-2,6-二氟苯甲酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例22中得到的4-(3-氨基-3-氧代丙基)苯基)-2,6-二氟苯甲酸甲酯(0.07g,0.30mmol),以与实施例34相似的方式得到所需产物(得率:34%)。
1H-NMR(400MHz,氯仿-D):δ8.61(s,1H),7.90(s,1H),7.44(s,1H),7.05-6.80(m,6H),4.33(m,1H),4.06-3.85(m,3H),3.68(m,2H),3.47(m,1H),3.04(t,2H),2.67(t,2H),2.15-1.84(m,3H),1.60(m,1H),1.34(t,3H)
实施例54:(R)-2,6-二氯-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯甲酸
步骤1:(R)-2,6-二氯-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨
基)-3-氧代丙基)苯甲酸2-(三甲基甲硅烷基)乙基酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪和在制备例23中得到的4-(3-氨基-3-氧代丙基)2,6-二氯苯甲酸2-(三甲基甲硅烷基)乙基酯,以与实施例8相似的方式得到所需产物(得率:76%)。
1H NMR(300MHz,氯仿-D):δ8.65(s,1H),7.89(s,1H),7.32(s,1H),7.22(s,2H),6.97-6.84(m,4H),4.50-4.44(m,2H),4.41-4.33(m,1H),3.98-3.89(m,1H),3.98-3.89(m,2H),3.73-3.66(m,2H),3.51-3.38(m,1H),3.04-2.66(m,4H),2.13-2.06(m,4H),1.34(t,J=7.2Hz,3H),1.19-1.13(m,2H),0.09(s,9H)
步骤2:(R)-2,6-二氯-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨
基)-3-氧代丙基)苯甲酸
将步骤1中得到的酯化合物在氮气存在下溶解在1mL THF中,在0℃下添加1.0M四丁基氟化铵(0.063mL,0.063mmol),然后在室温搅拌12小时。在通过TLC确认起始原料消失后,将THF在减压下浓缩,使用1N盐酸溶液与3mL水一起调整到pH 2。将得到的固体过滤,得到标题化合物。
1H NMR(300MHz,氯仿-D):δ8.58(s,1H),7.88(s,1H),7.47(s,1H),7.18(s,2H),6.96-6.86(m,4H),4.41-4.35(m,1H),4.00-3.88(m,1H),4.00-3.88(m,2H),3.73-3.69(m,2H),3.67-3.54(m,1H),3.01-2.66(m,4H),2.14-1.42(m,4H),1.00(t,J=7.2Hz,3H)
实施例55:(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)-2,6-二甲基苯甲酸
步骤1:(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧
代丙基)-2,6-二甲基苯甲酸2-(三甲基甲硅烷基)乙基酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.35g,1.05mmol)和在制备例24中得到的4-(3-氨基-3-氧代丙基)-2,6-二甲基苯甲酸2-(三甲基甲硅烷基)乙基酯(0.34g,1.05mmol),以与实施例8相似的方式得到所需产物(得率:45%)。
1H NMR(400MHz,氯仿-D):δ8.67(s,1H),7.87(s,1H),7.13(s,1H),6.81-6.96(m,6H),4.37-4.41(m,2H),4.31(m,1H),3.94(m,2H),3.66-3.75(m,2H),3.45(m,1H),2.99(m,2H),2.63(m,2H),2.30(s,6H),2.15(m,1H),2.02(m,1H),1.85(m,1H),1.34(t,3H),1.12(m,2H)
步骤2:(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧
代丙基)-2,6-二甲基苯甲酸
使用步骤1中得到的酯化合物(0.29g,0.47mmol),以与实施例54的步骤2相似的方式得到所需产物(得率:48%)。
1H NMR(400MHz,氯仿-D):δ8.63(s,1H),7.86(s,1H),7.19(s,1H),6.82-6.95(m,6H),4.31(m,1H),3.91-3.78(m,3H),3.65(m,2H),3.43(m,1H),2.97(m,2H),2.64(m,2H),2.38(s,6H),2.08(m,1H),1.92(m,1H),1.89(m,1H),1.59(m,1H),1.34(t,3H)
实施例56:(R)-1-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)哌啶-4-甲酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例25中得到的1-(4-(3-氨基-3-氧代丙基)苯基)哌啶-4-甲酸乙酯(0.09g,0.30mmol),以与实施例34相似的方式得到所需产物(得率:44%)。
1H-NMR(400MHz,氯仿-D):δ8.67(s,1H),7.87(s,1H),7.14(s,1H),7.14(d,2H),6.95-6.82(m,6H),4.31(m,1H),4.15-3.89(m,3H),3.70-3.58(m,4H),3.46(m,1H),2.98(t,2H),2.76(t,2H),2.65(t,2H),2.47(m,1H),2.17-1.91(m,7H),1.59(m,1H),1.36(t,3H)
实施例57:(R)-1-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基-2,6-二氟苯基)哌啶-4-甲酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例26中得到的1-(4-氨甲酰基-2,6-二氟苯基)哌啶-4-甲酸乙酯(0.09g,0.30mmol),以与实施例34相似的方式得到所需产物(得率:38%)。
1H-NMR(400MHz,氯仿-D):δ8.77(s,1H),7.94(s,1H),7.80(s,1H),7.39(d,2H),6.98-6.84(m,4H),4.36(m,1H),4.04-3.91(m,3H),3.80-3.68(m,2H),3.53(m,1H),3.49(m,2H),3.21(t,2H),2.57(m,1H),2.11-1.88(m,7H),1.63(m,1H),1.36(t,3H)
实施例58:(R)-2-(1-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基-2,6-二氟苯基)哌啶-4-基)乙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例27中得到的2-(1-(4-氨甲酰基-2,6-二氟苯基)哌啶-4-基)乙酸乙酯(0.10g,0.30mmol),以与实施例34相似的方式得到所需产物(得率:36%)。
1H-NMR(400MHz,氯仿-D):δ8.77(s,1H),7.93(s,1H),7.81(s,1H),7.40(d,2H),6.98-6.83(m,4H),4.36(m,1H),4.04-3.90(m,3H),3.78-3.68(m,2H),3.52(m,1H),3.49(m,2H),3.17(t,2H),2.36(m,2H),2.21(m,1H),1.99(m,3H),1.85(m,2H),1.62(m,1H),1.45(m,2H),1.36(t,3H)
实施例59:(R)-4-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)苯甲酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例34中得到的4-(4-氨甲酰基哌啶-1-基)苯甲酸乙酯(0.08g,0.30mmol),以与实施例34相似的方式得到所需产物(得率:34%)。
1H-NMR(400MHz,氯仿-D):δ8.69(s,1H),7.98-7.90(m,3H),7.54(s,1H),7.02-6.86(m,6H),4.32(m,1H),4.13-3.87(m,5H),3.69(m,1H),3.63(m,1H),3.43(m,1H),2.94(m,2H),2.50(m,1H),2.09-1.92(m,7H),1.60(m,1H),1.39(t,3H)
实施例60:(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯氧基)-2-甲基丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例28中得到的2-(4-(3-氨基-3-氧代丙基)苯氧基)-2-甲基丙酸乙酯(0.08g,0.30mmol),以与实施例34相似的方式得到所需产物(得率:32%)。
1H-NMR(400MHz,氯仿-D):δ8.62(s,1H),7.85(s,1H),7.36(s,1H),7.09(d,2H),6.95-6.80(m,6H),4.30(m,1H),4.00-3.87(m,3H),3.63(m,2H),3.42(m,1H),2.98(t,2H),2.2.64(t,2H),2.08(m,1H),1.96(m,1H),1.90(m,1H),1.56(m,7H),1.33(t,3H)
实施例61:(R)-3-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例29中得到的3-(4-(3-氨基-3-氧代丙基)苯基)丙酸乙酯(0.08g,0.30mmol),以与实施例34相似的方式得到所需产物(得率:34%)。
1H-NMR(400MHz,氯仿-D):δ8.65(s,1H),7.85(s,1H),7.43(s,1H),7.15(m,4H),6.93(m,2H),6.82(m,2H),4.30(m,1H),3.94(m,3H),3.64(m,2H),3.43(m,1H),2.99(t,2H),2.92(t,2H),2.64(m,4H),2.08(m,1H),1.96(m,1H),1.90(m,1H),1.57(m,1H),1.33(t,3H)
实施例62:(R)-4-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯氧基)苯甲酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例30中得到的4-(4-氨甲酰基苯氧基)苯甲酸乙酯(0.09g,0.30mmol),以与实施例34相似的方式得到所需产物(得率:40%)。
1H-NMR(400MHz,氯仿-D):δ8.84(s,1H),8.14(d,2H),7.93(m,4H),7.16(d,2H),7.10(d,2H),6.97(m,1H),6.88(m,3H),4.36(m,1H),4.00(m,3H),3.73(m,2H),3.52(m,1H),2.12(m,1H),2.04(m,1H),1.95(m,1H),1.62(m,1H),1.45(t,3H)
实施例63:(R)-3-(4-(3-((6-(R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2-甲基丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例31中得到的(R)-3-(4-(2-氨基-2-氧代乙基)苯基)-2-甲基丙烯酸甲酯(0.07g,0.30mmol),以与实施例34相似的方式得到所需产物(得率:56%)。
1H-NMR(400MHz,氯仿-D):δ8.64(s,1H),7.83(s,1H),7.49(s,1H),7.21(m,4H),6.89(m,2H),6.83(m,2H),4.25(m,1H),3.95(m,3H),3.66(m,3H),3.50(m,1H),3.33(m,1H),3.02(m,1H),2.74(m,2H),2.04(m,1H),1.92(m,1H),1.85(m,1H),1.54(m,1H),1.32(t,3H),1.17(d,3H)
实施例64:(S)-3-(4-(3-((6-(R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2-甲基丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例32中得到的(S)-3-(4-(2-氨基-2-氧代乙基)苯基)-2-甲基丙烯酸甲酯(0.07g,0.30mmol),以与实施例34相似的方式得到所需产物(得率:48%)。
1H-NMR(400MHz,氯仿-D):δ8.64(s,1H),7.83(s,1H),7.52(s,1H),7.22(m,4H),6.89(m,2H),6.83(m,2H),4.25(m,1H),3.94(m,3H),3.66(m,3H),3.53(m,1H),3.35(m,1H),3.04(m,1H),2.73(m,2H),2.06(m,1H),1.92(m,1H),1.86(m,1H),1.53(m,1H),1.32(t,3H),1.16(d,3H)
实施例65:(R)-3-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例33中得到的3-(4-(2-氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸甲酯(0.08g,0.30mmol),以与实施例34相似的方式得到所需产物(得率:47%)。
1H-NMR(400MHz,氯仿-D):δ8.62(s,1H),7.85(s,1H),7.36(s,1H),7.09(d,2H),6.91(m,2H),6.85(m,4H),4.30(m,1H),3.92(m,3H),3.63(m,2H),3.42(m,1H),2.98(t,2H),2.64(t,2H),2.08(m,1H),1.96(m,1H),1.90(m,1H),1.56(m,7H),1.33(t,3H)
实施例66:(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶-2-基)氨基)-2-氧代乙基)苯基)乙酸
步骤1:(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶-2-基)氨基)-2-
氧代乙基)苯基)乙酸甲酯
使用在制备例71中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶和在制备例6中得到的2-(4-(2-氨基-2-氧代乙基)苯基)乙酸甲酯,以与实施例8相似的方式得到所需产物(得率:74.2%)。
1H-NMR(400MHz,氯仿-D)δ7.78(d,J=27.0Hz,1H),7.52-7.36(m,2H),7.30-7.19(4H),6.99-6.90(m,2H),6.89-6.78(m,2H),6.40-6.28(m,1H),4.28-4.18(m,1H),4.18-4.07(1H),4.05-3.91(m,2H),3.86-3.74(m,1H),3.65(d,J=8.2Hz,3H),3.64-3.60(m,2H),3.59(s,2H),3.31-3.19(1H),3.15-3.02(m,1H),2.20-2.05(m,1H),1.86(qd,J=8.6,4.5Hz,1H),1.81-1.69(m,1H),1.60-1.46(m,1H),1.41-1.31(m,3H)
步骤2:(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶-2-基)氨基)-2-
氧代乙基)苯基)乙酸
使用5N氢氧化钠水溶液,通过步骤1中得到的酯化合物的水解得到所需产物(得率:61.7%)。
1H-NMR(400MHz,氯仿-D)δ7.64(s,1H),7.47-7.37(m,2H),7.27(s,4H),7.00-6.91(m,2H),6.91-6.78(m,2H),6.34(t,J=4.6Hz,1H),4.30-4.12(m,2H),4.08-3.95(m,2H),3.83-3.72(1H),3.66(s,2H),3.63-3.56(2H),3.15(dd,J=12.8,8.2Hz,1H),3.10-2.97(m,1H),2.22-2.08(m,1H),1.86(q,J=4.4Hz,1H),1.79-1.65(m,1H),1.61-1.48(m,1H),1.42-1.31(m,3H)
实施例67:(R)-2-(4-(3-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)脲基)苯基)乙酸
步骤1:(R)-2-(4-(3-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)脲基)苯
基)乙酸甲酯
将2-(4-氨基苯基)乙酸甲酯(0.2g,1.211mmol)溶解在DCM(18mL)中,并在0℃下添加三光气(0.119g,0.400mmol)和TEA(0.338mL,2.421mmol)。在搅拌3小时后,在减压下除去溶剂。将得到的化合物和在制备例2中得到的(R)-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-胺(190mg,0.606mmol)与THF(20mL)混合,并向其添加DIPEA(0.317mL,1.817mmol)。通过添加水将反应终止,并用乙酸乙酯萃取。将有机溶剂在硫酸镁上脱水并在减压下除去。通过硅胶柱进行纯化,得到所需产物(得率:29.2%)。
1H-NMR(400MHz,氯仿-D)δ10.86(s,1H),9.15-9.09(1H),7.74(d,J=12.3Hz,1H),7.61(s,1H),7.51-7.41(m,2H),7.15(t,J=9.1Hz,2H),7.03-6.72(m,4H),4.44-4.36(m,1H),4.06-3.85(m,3H),3.73(q,J=6.7Hz,1H),3.68(s,3H),3.67-3.63(m,1H),3.56(s,2H),3.54(s,1H),2.16-2.01(m,2H),2.01-1.86(m,1H),1.74-1.60(m,1H),1.31(q,J=7.3Hz,3H)
步骤2:(R)-2-(4-(3-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)脲基)苯
基)乙酸
使用在步骤1中得到的(R)-2-(4-(3-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)脲基)苯基)乙酸甲酯(11mg,0.022mmol),以与制备例34的步骤2相似的方式得到所需产物(得率:15.9%)。
1H-NMR(400MHz,甲醇-D4)δ7.83(s,1H),7.70(s,1H),7.68-7.64(1H),7.35(d,J=8.7Hz,2H),7.15(d,J=8.7Hz,2H),6.90-6.78(m,2H),6.75-6.68(m,1H),4.51(d,J=2.7Hz,1H),4.00-3.90(1H),3.90-3.72(m,4H),3.60-3.53(1H),3.51(s,2H),2.11-2.00(m,2H),1.95(s,1H),1.25-1.14(m,3H),0.79-0.68(m,1H)
实施例68:(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶-2-基)氨基)-2-氧代乙基)苯基)-2-甲基丙酸
使用在制备例71中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶(0.120g,0.361mmol)和在制备例36中得到的2-(4-(2-氨基-2-氧代乙基)苯基)2-甲基丙酸甲酯(0.102g,0.433mmol),以与实施例34相似的方式得到所需产物(2步得率:37.2%)。
1H-NMR(400MHz,氯仿-D)δ8.23(s,1H),7.54-7.39(m,2H),7.36(d,J=7.8Hz,2H),7.31-7.25(m,2H),7.02-6.90(m,2H),6.90-6.76(m,2H),6.40-6.26(m,1H),4.31-4.16(m,1H),4.10-4.04(m,1H),4.04-3.90(m,2H),3.83-3.70(m,1H),3.66(d,J=11.9Hz,2H),3.19(dd,J=12.6,8.5Hz,1H),3.11-2.98(m,1H),2.20-2.06(m,1H),1.85(q,J=4.4Hz,1H),1.79-1.65(m,1H),1.63-1.54(m,6H),1.54-1.44(m,1H),1.42-1.30(m,3H)
实施例69:(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2-甲基丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.118g,0.354mmol)和在制备例36中得到的2-(4-(2-氨基-2-氧代乙基)苯基)2-甲基丙酸甲酯(0.1g,0.425mmol),以与实施例34相似的方式得到所需产物(2步得率:20.1%)。
1H-NMR(400MHz,氯仿-D)δ8.62(s,1H),7.82(d,J=16.0Hz,1H),7.55-7.43(1H),7.43-7.33(m,2H),7.26(dd,J=23.8,15.1Hz,2H),6.91(ddd,J=14.8,6.5,1.7Hz,2H),6.86-6.75(m,2H),4.31-4.20(m,1H),4.02-3.84(m,3H),3.68(d,J=14.2Hz,2H),3.62(q,J=4.3Hz,1H),3.52(q,J=6.9Hz,1H),3.41-3.28(m,1H),2.11-2.04(m,1H),1.99-1.78(m,2H),1.61(t,J=15.3Hz,6H),1.56-1.46(m,1H),1.31(q,J=7.2Hz,3H)
实施例70:(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸
使用在制备例71中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶(0.50g,1.50mmol)和在制备例20中得到的2-(4-(3-氨基-3-氧代丙基)苯基-2-甲基丙酸甲酯(0.38g,1.50mmol),以与实施例34相似的方式得到所需产物(得率:26%)。
1H-NMR(400MHz,氯仿-D):δ7.84(s,1H),7.46(d,J=4.6Hz,2H),7.32(d,J=8.2Hz,2H),7.17(d,J=8.2Hz,2H),6.83-6.99(m,4H),6.36(t,J=4.3Hz,1H),4.25(td,J=8.2,4.0Hz,1H),4.08-4.13(m,1H),3.96-4.04(m,2H),3.79(td,J=8.7,4.1Hz,1H),3.28(dd,J=12.8,8.2Hz,1H),3.10-3.16(m,1H),2.99(t,J=7.8Hz,2H),2.61(t,J=7.5Hz,2H),2.15(dd,J=12.6,4.3Hz,1H),1.89(q,J=4.4Hz,1H),1.74-1.83(m,1H),1.53-1.61(m,7H),1.37(t,J=7.1Hz,3H)
实施例71:(R)-3-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶-2-基)氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸
使用在制备例71中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶(0.15g,0.45mmol)和在制备例33中得到的3-(4-(2-氨基-2-氧代乙基)苯基)-2,2-二甲基丙烯酸甲酯(0.11g,0.45mmol),以与实施例34相似的方式得到所需产物(得率:50%)。
1H-NMR(400MHz,氯仿-D):δ7.87(s,1H),7.51-7.38(m,2H),7.18(dd,J=22.9,8.2Hz,4H),7.02-6.78(m,4H),6.34(d,J=8.7Hz,1H),4.27-4.17(m,1H),4.16-4.04(m,1H),4.04-3.92(m,2H),3.79(td,J=8.7,4.3Hz,1H),3.65(s,2H),3.21(dd,J=12.8,8.7Hz,1H),3.12-3.02(m,1H),2.87(s,2H),2.18-2.07(m,1H),1.92-1.69(m,2H),1.61-1.46(m,1H),1.37(t,J=6.9Hz,3H),1.19(s,6H)
实施例72:(R)-3-(4-(2-((4-(3-(2-乙氧基苯氧基)哌啶-1-基)-6-(三氟甲基)嘧啶-2-基)氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸
向使用在制备例72中得到的(R)-2-氯-4-(3-(2-乙氧基苯氧基)哌啶-1-基)-6-(三氟甲基)嘧啶(0.18g,0.45mmol)和在制备例63中得到的3-(4-(2-氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸叔丁酯(0.13g,0.45mmol)以与实施例8相似的方式得到的(R)-3-(4-(2-((4-(3-(2-乙氧基苯氧基)哌啶-1-基)-6-(三氟甲基)嘧啶-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸叔丁酯,缓慢添加DCM(0.30mL)和TFA(0.45mL),并在室温搅拌1小时。通过添加1N HCl将反应混合物中和,用乙酸乙酯萃取并用水和盐水洗涤。将混合的溶液在硫酸镁上脱水,并在减压下除去溶剂。通过柱层析进行纯化,得到标题化合物(得率:59%)。
1H-NMR(400MHz,甲醇-D4):δ7.24-7.04(m,4H),6.97-6.07(m,5H),4.46(s,1H),4.12-3.49(m,5H),3.49-3.31(m,1H),3.28(s,2H),2.81(d,J=9.6Hz,2H),1.96(d,J=2.3Hz,3H),1.54(s,1H),1.17(t,J=7.1Hz,3H),1.09(d,J=15.1Hz,6H)
实施例73:(R)-3-(4-(1-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.15g,0.45mmol)和在制备例37中得到的3-(4-(1-氨基-2-甲基-1-氧代丙-2-基)苯基)丙酸甲酯(0.11g,0.45mmol),以与实施例34相似的方式得到所需产物(得率:63%)。
1H-NMR(400MHz,氯仿-D):δ8.71(s,1H),7.83(s,1H),7.33(d,J=8.2Hz,2H),7.24(d,J=8.2Hz,2H),7.07(s,1H),6.96-6.73(m,4H),4.27-4.17(m,1H),4.03-3.86(m,3H),3.73-3.59(m,1H),3.42(dd,J=13.0,7.5Hz,1H),3.36-3.23(m,1H),2.97(t,J=7.8Hz,2H),2.66(t,J=7.8Hz,2H),2.08(m,1H),1.97-1.74(m,2H),1.63(s,6H),1.54(m,1H),1.33(t,J=6.9Hz,3H)
实施例74:(R)-3-(4-((2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)烯丙基)氨基)苯基)丙酸
步骤1:(R)-3-(4-((2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰
基)烯丙基)氨基)苯基)丙酸乙酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(20.13mg,0.060mmol)和在制备例38中得到的3-(4-(3-氨甲酰基氮杂环丁烷-1-基)苯基)丙酸乙酯(20mg,0.072mmol),以与实施例8相似的方式得到所需产物(得率:37%)。
1H-NMR(400MHz,氯仿-D)δ8.78-8.63(m,1H),8.42(s,1H),7.94-7.78(m,1H),7.01(dd,J=8.7,2.7Hz,2H),6.91(td,J=7.8,2.4Hz,2H),6.86-6.72(m,2H),6.62(dd,J=8.2,2.7Hz,2H),6.01(d,J=2.7Hz,1H),5.72(s,1H),4.28(q,J=3.5Hz,1H),4.11(td,J=7.1,2.9Hz,5H),4.03-3.81(m,4H),3.81-3.63(m,1H),3.63-3.48(m,1H),3.50-3.29(m,1H),2.92-2.72(m,2H),2.54(td,J=7.8,2.7Hz,2H),2.19-2.02(m,1H),2.02-1.78(m,2H),1.47-1.29(m,3H),1.29-1.09(m,3H)
步骤2:(R)-3-(4-((2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰
基)烯丙基)氨基)苯基)丙酸
使用1N氢氧化锂水溶液将步骤1中得到的酯化合物水解,得到标题化合物(得率:51%)。
1H-NMR(400MHz,氯仿-D)δ8.70(s,1H),8.42(s,1H),7.86(s,1H),7.02(d,J=8.2Hz,2H),6.91(t,J=7.5Hz,2H),6.83(d,J=6.4Hz,2H),6.62(d,J=8.2Hz,2H),6.01(s,1H),5.72(s,1H),4.28(d,J=3.7Hz,1H),4.10(d,J=12.3Hz,2H),4.02-3.80(m,4H),3.77-3.63(m,1H),3.58(q,J=6.9Hz,1H),3.52-3.29(m,1H),3.00-2.74(m,2H),2.60(t,J=7.5Hz,2H),2.18-2.02(m,1H),2.01-1.77(m,2H),1.57(td,J=8.6,4.1Hz,2H),1.33(t,J=7.1Hz,2H),0.84(q,J=6.6Hz,3H)
实施例75:(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)嘧啶-5-甲酸
步骤1:(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌
啶-1-基)嘧啶-5-甲酸甲酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(20.13mg,0.060mmol)和在制备例39中得到的2-(4-氨甲酰基哌啶-1-基)嘧啶-5-甲酸甲酯(95mg,0.359mmol),以与实施例8相似的方式得到所需产物(得率:61%)。
1H-NMR(400MHz,氯仿-D)δ8.84(d,J=9.1Hz,2H),8.66(s,1H),7.87(s,1H),7.03-6.78(m,5H),4.94(d,J=14.2Hz,2H),4.39-4.22(1H),4.04-3.89(m,4H),3.87(s,3H),3.77-3.66(m,1H),3.60(q,J=6.9Hz,1H),3.51-3.33(m,1H),3.19-2.98(m,2H),2.64-2.47(m,1H),2.15-2.07(m,1H),2.02-1.88(m,2H),1.83(t,J=12.3Hz,2H),1.67-1.56(m,1H),1.35(t,J=6.9Hz,3H)
步骤2:(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌
啶-1-基)嘧啶-5-甲酸
以与实施例2的步骤2相似的方式将在步骤1中得到的酯化合物水解,得到标题化合物(得率:69%)。
1H-NMR(400MHz,氯仿-D)δ8.84(d,J=9.1Hz,2H),8.66(s,1H),7.87(s,1H),7.03-6.78(m,5H),4.94(d,J=14.2Hz,2H),4.39-4.22(1H),4.04-3.89(m,4H),3.87(s,3H),3.77-3.66(m,1H),3.60(q,J=6.9Hz,1H),3.51-3.33(m,1H),3.19-2.98(m,2H),2.64-2.47(m,1H),2.15-2.07(m,1H),2.02-1.88(m,2H),1.83(t,J=12.3Hz,2H),1.67-1.56(m,1H),1.35(t,J=6.9Hz,3H)
实施例76:3-(3-((R)-3-((6-((R)-3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)苯基-2,2-二甲基丙酸
使用在制备例70中得到的(R)-2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例64中得到的(R)-3-(3-(3-氨甲酰基哌啶-1-基)苯基)-2,2-二甲基丙酸叔丁酯(0.11g,0.30mmol),以与实施例72相似的方式得到所需产物(得率:28%)。
1H-NMR(400MHz,甲醇-D4):δ8.44(s,1H),7.75(d,J=4.1Hz,1H),7.66-7.58(m,1H),7.18-7.05(m,2H),6.94-6.75(m,3H),6.70(d,J=7.3Hz,1H),5.16(q,J=2.7Hz,1H),4.14-3.93(m,1H),3.94-3.70(m,4H),3.65-3.50(m,2H),3.49-3.40(m,1H),3.05-2.94(m,1H),2.90-2.69(m,4H),2.18-1.90(m,4H),1.90-1.65(m,3H),1.60(d,J=9.1Hz,1H),1.24-1.16(m,3H),1.12(d,J=2.3Hz,6H)
实施例77:(R)-3-(4-(1-((4-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸
使用在制备例69中得到的(R)-2-氯-4-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶(0.10g,0.30mmol)和在制备例59中得到的3-(4-(1-氨基-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸叔丁酯(0.096g,0.30mmol),以与实施例72相似的方式得到所需产物(得率:66%)。
1H-NMR(400MHz,氯仿-D):δ11.51(s,1H),8.34(s,1H),7.89-7.76(m,1H),7.29(d,J=7.3Hz,2H),7.10(d,J=7.3Hz,2H),7.01-6.87(m,2H),6.87-6.74(m,2H),6.07(d,J=5.9Hz,1H),4.24(s,1H),4.02-3.42(m,6H),2.75(s,2H),2.12-1.80(m,3H),1.67-1.45(m,7H),1.32(td,J=6.9,1.4Hz,3H),1.10(s,6H)
实施例78:(R)-3-(4-(1-((4-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)嘧啶-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸
使用在制备例66中得到的(R)-2-氯-4-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)嘧啶(0.10g,0.30mmol)和在制备例59中得到的3-(4-(1-氨基-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸叔丁酯(0.095g,0.30mmol),以与实施例72相似的方式得到所需产物(得率:71%)。
1H-NMR(400MHz,氯仿-D):δ11.71-10.30(bs,1H),7.80(d,J=5.5Hz,1H),7.73-7.61(m,1H),7.28(d,J=7.8Hz,2H),7.11(d,J=8.2Hz,2H),6.96(d,J=7.8Hz,1H),6.82-6.69(m,1H),6.10(d,J=6.4Hz,1H),5.13-5.03(m,1H),4.01-3.48(m,6H),2.76(dd,J=17.2,13.5Hz,2H),2.14-2.02(m,1H),1.99-1.86(m,2H),1.59(s,7H),1.33-1.17(m,3H),1.11(s,6H)
实施例79:(R)-2-(4-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)苯基)乙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.032g,0.097mmol)和在制备例40中得到的2-(4-(4-氨甲酰基哌啶-1-基)苯基)乙酸叔丁酯(0.031g,0.097mmol),以与实施例72相似的方式得到所需产物(2步得率:9.0%)。
1H-NMR(400MHz,氯仿-D)δ8.68(s,1H),7.87(s,1H),7.46(s,1H),7.17(d,J=8.7Hz,2H),6.99-6.81(m,6H),4.35-4.25(m,1H),4.03-3.88(m,3H),3.78-3.67(m,3H),3.60(q,J=6.6Hz,1H),3.55(s,2H),3.46-3.37(1H),2.82-2.66(2H),2.43-2.29(m,1H),2.19-2.06(1H),2.02-1.82(m,6H),1.58(td,J=8.8,4.4Hz,1H),1.35(t,J=7.1Hz,3H)
实施例80:(R)-2-(4-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)苯基)-2-甲基丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.12g,0.36mmol)和在制备例41中得到的2-(4-(4-氨甲酰基哌啶-1-基)苯基)-2-甲基丙酸甲酯(0.11g,0.36mmol),以与实施例34相似的方式得到所需产物(得率:26%)。
1H-NMR(400MHz,氯仿-D):δ8.68(s,1H),7.87(s,1H),7.40(s,1H),7.32-7.26(m,2H),6.99-6.81(m,6H),4.35-4.25(m,1H),4.04-3.88(m,3H),3.79-3.66(m,3H),3.59(q,J=6.9Hz,1H),3.47-3.36(m,1H),2.75(t,J=11.4Hz,2H),2.37(t,J=11.2Hz,1H),2.18-2.06(m,1H),2.02-1.83(m,6H),1.65-1.48(m,7H),1.35(t,J=7.1Hz,3H)
实施例81:(R)-2-(6-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)吡啶-3-基)-2-甲基丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.080g,0.24mmol)和在制备例42中得到的2-(6-(4-氨甲酰基哌啶-1-基)吡啶-3-基)-2-甲基丙酸甲酯(0.073g,0.24mmol),以与实施例34相似的方式得到所需产物(得率:34%)。
1H-NMR(400MHz,氯仿-D):δ8.65(s,1H),8.23(d,J=2.3Hz,1H),7.86(s,1H),7.57-7.41(m,2H),6.98-6.89(m,2H),6.89-6.78(m,2H),6.65(d,J=9.1Hz,1H),4.31(d,J=11.9Hz,3H),4.03-3.87(m,3H),3.69(d,J=13.7Hz,1H),3.59(q,J=6.9Hz,1H),3.41(t,J=9.6Hz,1H),2.88(t,J=12.6Hz,2H),2.46(t,J=10.7Hz,1H),2.16-2.04(1H),2.02-1.73(m,6H),1.64-1.48(7H),1.34(dd,J=7.5,6.6Hz,3H)
实施例82:(R)-2-(5-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)-2H-四唑-2-基)乙酸
步骤1:(R)-2-(5-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰
基)哌啶-1-基)-2H-四唑-2-基)乙酸乙酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(167mg,0.499mmol)和在制备例43中得到的2-(5-(4-氨甲酰基哌啶-1-基)-2H-四唑-2-基)乙酸乙酯(141mg,0.499mmol),以与实施例8相似的方式得到所需产物(得率:17%)。
1H-NMR(400MHz,氯仿-D)δ8.66(s,1H),7.87(s,1H),7.35-7.27(1H),7.05-6.90(m,2H),6.90-6.77(2H),5.19(s,2H),4.31(t,J=3.7Hz,1H),4.29-4.23(2H),4.19(d,J=14.2Hz,2H),4.11(q,J=7.0Hz,2H),4.06-3.84(4H),3.81-3.66(m,1H),3.60(dd,J=13.5,7.5Hz,1H),3.42(t,J=9.6Hz,1H),3.02(t,J=11.9Hz,2H),2.43(d,J=11.0Hz,1H),2.20-2.05(m,2H),2.02-1.79(m,7H),1.60(q,J=4.6Hz,1H),1.36(q,J=6.9Hz,5H),1.28(t,J=7.1Hz,3H),1.23(d,J=7.3Hz,3H)
步骤2:(R)-2-(5-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰
基)哌啶-1-基)-2H-四唑-2-基)乙酸
以与实施例2的步骤2相似的方式将步骤1中得到的酯化合物水解,得到标题化合物(得率:33%)。
1H-NMR(400MHz,甲醇-D4)δ8.45(s,1H),7.73(s,1H),7.04-6.76(m,4H),4.99(s,2H),4.42(s,1H),4.07(q,J=7.2Hz,3H),4.00-3.86(m,1H),3.86-3.80(m,3H),3.80-3.68(m,1H),3.62-3.50(m,1H),3.32(s,1H),3.08-2.86(m,2H),2.62(t,J=11.4Hz,1H),2.13-2.00(m,2H),1.97-1.68(m,6H),1.57(s,1H),1.25(t,J=6.4Hz,3H)
实施例83:(R)-4-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)-4-氧代丁酸
步骤1:(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)哌啶-4-甲酰胺
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.50g,1.50mmol)和4-氨甲酰基哌啶-1-甲酸叔丁酯(0.41g,1.80mmol),以与实施例72相似的方式得到所需产物(得率:45%)。
步骤2:(R)-4-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌
啶-1-基)-4-氧代丁酸
向DCM(2mL)中的在步骤1中得到的(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)哌啶-4-甲酰胺(0.095g,0.22mmol)缓慢添加DIPEA(0.078mL,0.45mmol)和琥珀酸酐(0.034g,0.34mmol),并在室温搅拌30分钟。将反应混合物用2N HCl和盐水洗涤并在硫酸镁上脱水。在减压下除去溶剂并通过柱层析进行纯化,得到标题化合物(得率:55%)。
1H-NMR(400MHz,氯仿-D):δ8.65(s,1H),7.89(s,1H),7.53(s,1H),7.01-6.80(m,4H),4.58(d,J=11.4Hz,1H),4.31(q,J=3.5Hz,1H),4.07-3.87(m,4H),3.71(d,J=13.7Hz,1H),3.60(q,J=6.7Hz,1H),3.43(t,J=9.6Hz,1H),3.23-3.07(1H),2.88-2.61(m,5H),2.51(d,J=10.5Hz,1H),2.20-2.05(m,1H),2.05-1.66(m,6H),1.66-1.48(m,1H),1.36(t,J=6.9Hz,3H)
实施例84:(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)乙酸
步骤1:(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)
哌啶-1-基)乙酸乙酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(232mg,0.696mmol)和在制备例44中得到的2-(4-氨甲酰基哌啶-1-基)乙酸乙酯(179mg,0.835mmol),以与实施例8相似的方式得到所需产物(得率:91%)。
1H-NMR(氯仿-D)δ8.70(s,1H),7.89(s,1H),7.33(s,1H),7.04-6.92(m,2H),6.92-6.83(m,2H),4.39-4.27(m,1H),4.21(q,J=7.2Hz,2H),4.09-3.90(m,4H),3.79-3.69(m,1H),3.61(dd,J=13.4,7.3Hz,1H),3.49-3.36(m,1H),3.27(s,2H),3.04(dd,J=10.4,2.7Hz,2H),2.42-2.30(m,2H),2.30-2.21(m,1H),2.21-2.10(m,1H),2.05-1.85(m,7H),1.68-1.55(m,1H),1.36-1.21(m,6H)
步骤2:(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌
啶-1-基)乙酸
以与实施例2的步骤2相似的方式将步骤1中得到的酯化合物水解,得到标题化合物(得率:41%)。
1H-NMR(MeOD)δ8.50(s,1H),7.85(s,1H),7.02-6.82(m,5H),4.52(s,1H),4.12(s,2H),4.08-3.92(m,3H),3.92-3.84(m,1H),3.81(dd,J=13.7,2.4Hz,1H),3.79-3.70(1H),3.56(s,1H),2.17(s,3H),2.10-1.93(m,2H),1.62(d,J=3.1Hz,1H),1.28(t,J=7.0Hz,3H)
实施例85:3-(3-((R)-3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)苯基)-2,2-二甲基丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例64中得到的(R)-3-(3-(3-氨甲酰基哌啶-1-基)苯基)-2,2-二甲基丙酸叔丁酯(0.11g,0.30mmol),以与实施例72相似的方式得到所需产物(得率:61%)。
1H-NMR(400MHz,氯仿-D):δ9.33(s,1H),8.67(s,1H),7.91-7.79(m,1H),7.15(t,J=7.8Hz,1H),7.00-6.75(m,6H),6.65(d,J=7.3Hz,1H),4.34-4.21(m,1H),4.04-3.86(m,3H),3.78-3.57(m,2H),3.51(dd,J=12.8,7.3Hz,2H),3.42-3.29(m,1H),3.22(dd,J=13.3,8.7Hz,1H),3.17-3.03(m,1H),3.03-2.91(m,1H),2.68(d,J=13.3Hz,2H),2.16-2.04(m,1H),2.01-1.80(m,4H),1.78-1.65(m,2H),1.65-1.49(m,1H),1.35(td,J=7.0,3.5Hz,3H),1.25(s,3H),1.09(s,3H)
实施例86:(R)-1-(4-(1-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)哌啶-4-甲酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.12g,0.36mmol)和在制备例45中得到的1-(4-(1-氨基-2-甲基-1-氧代丙-2-基)苯基)哌啶-4-甲酸乙酯(0.11g,0.36mmol),以与实施例34相似的方式得到所需产物(得率:38%)。
1H-NMR(400MHz,氯仿-D):δ8.72(s,1H),7.81(s,1H),7.27(d,J=8.7Hz,2H),7.09(s,1H),6.97-6.73(m,6H),4.26-4.15(m,1H),4.03-3.87(m,3H),3.72-3.59(m,3H),3.39(dd,J=13.3,7.8Hz,1H),3.33-3.19(m,1H),2.87-2.73(m,2H),2.53-2.41(m,1H),2.07(d,J=3.7Hz,3H),1.97-1.74(m,4H),1.66-1.46(m,7H),1.33(t,J=7.1Hz,3H)
实施例87:6-(3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)吡咯烷-1-基)烟酸
步骤1:6-(3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)吡
咯烷-1-基)烟酸甲酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(34.8mg,0.104mmol)和在制备例46中得到的6-(3-氨甲酰基吡咯烷-1-基)烟酸甲酯(26mg,0.104mmol),以与实施例8相似的方式得到所需产物(得率:31%)。
1H-NMR(氯仿-D)δ8.83(d,J=2.4Hz,1H),8.68(s,1H),8.05(d,J=8.8Hz,1H),7.92(s,1H),7.40(d,J=3.7Hz,1H),6.94(dd,J=39.5,8.7Hz,5H),6.39(dd,J=8.8,3.1Hz,1H),4.35(q,J=3.6Hz,1H),4.02(q,J=7.2Hz,1H),3.99-3.91(m,3H),3.89(s,4H),3.88-3.77(m,2H),3.71(s,2H),3.60(d,J=8.8Hz,1H),3.49(s,1H),3.29-3.13(1H),2.49-2.35(m,2H),2.13(s,1H),2.06-1.89(2H),1.61(s,11H),1.38(t,J=7.0Hz,3H)
步骤2:6-(3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)吡
咯烷-1-基)烟酸
以与实施例2的步骤2相似的方式将步骤1中得到的酯化合物水解,得到标题化合物(得率:59%)。
1H-NMR(MeOD)δ8.71(s,1H),8.51(s,1H),8.06(d,J=9.2Hz,1H),8.00(s,1H),7.85-7.74(1H),7.00(d,J=7.6Hz,1H),6.98-6.83(m,3H),6.57(d,J=8.8Hz,1H),4.48(s,1H),4.03-3.90(m,1H),3.90-3.86(m,3H),3.84(d,J=14.3Hz,2H),3.80-3.68(m,2H),3.68-3.52(m,2H),3.48-3.35(1H),2.45-2.28(2H),2.13-2.02(2H),1.96(d,J=9.2Hz,1H),1.63(s,1H),1.29(td,J=7.0,1.5Hz,3H)
实施例88:N-(6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-3-甲基吡咯烷-3-甲酰胺
步骤1:3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)-3-甲
基吡咯烷-1-甲酸叔丁酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(59.5mg,0.178mmol)和在制备例47中得到的3-氨甲酰基-3-甲基吡咯烷-1-甲酸叔丁酯(26mg,0.104mmol),以与实施例8相似的方式得到所需产物(得率:99%)。
1H-NMR(氯仿-D)δ8.71(s,1H),7.91(s,1H),7.41(s,1H),7.04-6.83(m,4H),4.33(q,J=3.7Hz,1H),4.10-3.91(m,3H),3.87-3.70(m,2H),3.69-3.24(m,5H),2.52-2.24(1H),2.13(d,J=8.2Hz,1H),2.02(s,1H),1.99-1.81(m,2H),1.62(qd,J=8.8,4.3Hz,4H),1.49(s,10H),1.46(s,3H),1.39(t,J=7.0Hz,3H)
步骤2:N-(6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-3-甲基吡咯烷-
3-甲酰胺
将步骤1中得到的酯化合物溶解在DCM中,向其添加三氟乙酸(0.31mL,4.04mmol),然后在室温搅拌2小时。在反应完成后,将得到的产物在减压下蒸馏以除去过量有机溶剂,然后用1N氢氧化钠水溶液中和。在用有机溶剂萃取后,将得到的产物在硫酸镁上脱水并通过柱层析进行纯化(己烷:乙酸乙酯),得到所需化合物(得率:99%)。
1H-NMR(400MHz,甲醇-D4)δ8.45(s,1H),7.78(s,1H),7.03-6.76(m,4H),4.51-4.34(m,1H),3.97-3.71(m,6H),3.64-3.50(m,1H),3.50-3.37(m,1H),3.03(dd,J=11.9,1.4Hz,1H),2.62-2.43(m,1H),2.17-1.99(m,3H),1.99-1.83(m,2H),1.66-1.55(m,1H),1.53(s,3H),1.33-1.22(m,4H)
实施例89:6-(3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)-3-甲基吡咯烷-1-基)烟酸
步骤1:6-(3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)-
3-甲基吡咯烷-1-基)烟酸甲酯
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(138mg,0.414mmol)和在制备例48中得到的6-(3-氨甲酰基-3-甲基吡咯烷-1-基)烟酸甲酯(99mg,0.376mmol),以与实施例8相似的方式得到所需产物(得率:33%)。
1H-NMR(400MHz,甲醇-D4)δ8.64(d,J=2.3Hz,1H),8.42(s,1H),8.06-7.91(1H),7.78-7.67(1H),7.02-6.75(m,5H),6.50(d,J=9.1Hz,1H),4.42(s,1H),4.01-3.84(m,3H),3.82(s,4H),3.81-3.71(m,3H),3.70-3.37(m,5H),2.55(t,J=6.4Hz,1H),2.17-1.99(m,3H),1.98-1.83(m,2H),1.64-1.51(m,1H),1.51-1.41(3H),1.25-1.21(3H)
步骤2:6-(3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)- 3-甲基吡咯烷-1-基)烟酸
以与实施例2的步骤2相似的方式将步骤1中得到的酯化合物水解,得到标题化合物(得率:14%)。
1H-NMR(400MHz,甲醇-D4)δ8.66(d,J=2.3Hz,1H),8.42(s,1H),8.01(dd,J=9.1,2.3Hz,1H),7.74(d,J=3.2Hz,1H),6.95(d,J=7.3Hz,1H),6.92-6.77(m,3H),6.51(d,J=9.1Hz,1H),4.43(s,1H),4.16-3.97(m,2H),3.97-3.86(m,2H),3.86-3.70(m,3H),3.70-3.49(m,3H),3.46(d,J=11.0Hz,1H),2.56(t,J=6.4Hz,1H),2.18-2.04(1H),2.04-1.87(m,6H),1.54(d,J=23.3Hz,1H),1.49(s,3H),1.34-1.24(m,2H),1.21(dd,J=7.3,6.4Hz,3H)
实施例90:(R)-2-(4-(2-((6-(3-(2-异丙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)乙酸
步骤1:(R)-2-(4-(2-((6-(3-(2-异丙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-
2-氧代乙基)苯基)乙酸甲酯
使用在制备例73中得到的(R)-2-氯-6-(3-(2-异丙氧基苯氧基)哌啶-1-基)吡嗪(70mg,0.201mmol)和在制备例6中得到的2-(4-(2-氨基-2-氧代乙基)苯基)乙酸甲酯(50mg,0.241mmol),以与实施例8相似的方式得到所需产物(得率:77%)。
m/z(M+H)+为C29H34N4O5的计算值为518.6,实测值为519.3
步骤2:(R)-2-(4-(2-((6-(3-(2-异丙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-
2-氧代乙基)苯基)乙酸
使用5N氢氧化钠水溶液以与实施例2的步骤2相似的方式将步骤1中得到的酯化合物水解,得到所需产物(得率:64%)。
1H NMR(500MHz,氯仿-D)δ8.67(s,1H),7.93(s,1H),7.74(s,1H),7.33-7.21(m,3H),7.01-6.85(m,4H),4.4(td,1H),4.25(m,1H),4.02(dd,1H),3.71(qd,3H),3.65(m,2H),3.39(m,1H),3.31(m,1H),2.12-2.05(m,1H),2.03-1.85(m,2H),1.61(qd,J=8.7,4.3Hz,1H),1.32-1.18(m,6H)
实施例91:(R)-2-(4-(3-((6-(3-(2-甲氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸
使用在制备例74中得到的(R)-2-氯-6-(3-(2-甲氧基苯氧基)哌啶-1-基)吡嗪(0.13g,0.40mmol)和在制备例20中得到的2-(4-(3-氨基-3-氧代丙基)苯基-2-甲基丙酸甲酯(0.10g,0.40mmol),以与实施例34相似的方式得到所需产物(2步得率:12%)。
1H-NMR(400MHz,氯仿-D)δ8.68(s,1H),7.88(s,1H),7.32(t,J=8.7Hz,2H),7.26-7.09(m,3H),7.01-6.76(m,4H),4.40-4.21(m,1H),4.05(d,J=13.3Hz,1H),3.89-3.58(m,4H),3.57-3.39(m,1H),3.39-3.21(m,1H),3.02(t,J=7.3Hz,2H),2.77-2.56(2H),2.16-2.06(m,1H),2.03-1.78(m,2H),1.72-1.46(m,7H)
实施例92:(R)-2-甲基-2-(4-(3-氧代-3-((6-(3-(2-(三氟甲氧基)苯氧基)哌啶-1-基)吡嗪-2-基)氨基)丙基)苯基)丙酸
使用在制备例75中得到的(R)-2-氯-6-(3-(2-(三氟甲氧基)苯氧基)哌啶-1-基)吡嗪(0.15g,0.40mmol)和在制备例20中得到的2-(4-(3-氨基-3-氧代丙基)苯基-2-甲基丙酸甲酯(0.10g,0.40mmol),以与实施例34相似的方式得到所需产物(2步得率:10%)。
1H-NMR(400MHz,氯仿-D)δ8.68(s,1H),7.88(s,1H),7.43(s,1H),7.33(d,J=8.2Hz,2H),7.25-7.10(m,4H),7.10-6.86(m,2H),4.44-4.26(m,1H),4.07(dd,J=13.3,2.7Hz,1H),3.83-3.58(m,1H),3.48(dd,J=13.3,7.8Hz,1H),3.41-3.25(m,1H),2.97(dt,J=32.6,7.9Hz,2H),2.66(t,J=7.5Hz,2H),2.23-2.05(m,1H),2.02-1.76(m,2H),1.76-1.37(m,7H)
实施例93:(R)-2-(4-(3-((6-(3-(2-(2-氟乙氧基)苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸
使用在制备例76中得到的(R)-2-氯-6-(3-(2-(2-氟乙氧基)苯氧基)哌啶-1-基)吡嗪(0.14g,0.40mmol)和在制备例20中得到的2-(4-(3-氨基-3-氧代丙基)苯基-2-甲基丙酸甲酯(0.10g,0.40mmol),以与实施例34相似的方式得到所需产物(2步得率:12%)。
1H-NMR(400MHz,氯仿-D)δ8.66(s,1H),7.86(s,1H),7.33(d,J=8.2Hz,3H),7.18(dd,J=14.6,8.2Hz,2H),7.04-6.77(m,4H),4.64(dt,J=47.6,4.1Hz,2H),4.38-4.23(m,1H),4.23-4.00(m,2H),3.96(dd,J=13.3,2.7Hz,1H),3.68-3.53(m,2H),3.53-3.34(m,1H),3.02(t,J=7.5Hz,2H),2.65(t,J=7.5Hz,2H),2.13-2.05(m,1H),2.04-1.79(m,2H),1.68-1.46(m,7H)
实施例94:(R)-3-(4-(2-((6-(3-(2-(2-氟乙氧基)苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸
使用在制备例76中得到的(R)-2-氯-6-(3-(2-(2-氟乙氧基)苯氧基)哌啶-1-基)吡嗪(0.080g,0.23mmol)和在制备例33中得到的3-(4-(2-氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸甲酯(0.057g,0.23mmol),以与实施例34相似的方式得到所需产物(得率:39%)。
1H-NMR(400MHz,氯仿-D):δ8.65(s,1H),7.83(s,1H),7.56(s,1H),7.23-7.08(m,4H),6.99-6.82(m,4H),4.69(t,J=4.1Hz,1H),4.58(t,J=4.1Hz,1H),4.30-4.21(m,1H),4.20-3.99(m,2H),3.94(dd,J=13.0,3.0Hz,1H),3.66(s,2H),3.64-3.57(m,1H),3.52(q,J=6.9Hz,1H),3.42-3.30(m,1H),2.91-2.81(m,2H),2.12-2.05(m,1H),1.99-1.78(m,2H),1.53(qd,J=8.6,4.5Hz,1H),1.22-1.13(s,6H)
实施例95:(R)-3-(4-(2-((6-(3-(2-环丙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸
使用在制备例77中得到的(R)-2-氯-6-(3-(2-环丙氧基苯氧基)哌啶-1-基)吡嗪(0.14g,0.41mmol)和在制备例63中得到的3-(4-(2-氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸叔丁酯(0.12g,0.41mmol),以与实施例72相似的方式得到所需产物(得率:34%)。
1H-NMR(400MHz,氯仿-D):δ8.66(s,1H),7.87-7.79(m,1H),7.60(s,1H),7.24-7.10(m,5H),7.01-6.78(m,3H),4.23-4.14(m,1H),4.01-3.92(m,1H),3.73-3.60(m,4H),3.45-3.34(m,1H),3.32-3.20(m,1H),2.87(t,J=14.0Hz,2H),2.11-1.99(m,1H),1.96-1.72(m,2H),1.61-1.44(m,1H),1.21-1.12(m,6H),0.75-0.63(m,4H)
实施例96:(R)-3-(4-(2-((6-(3-(2-环丁氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸
使用在制备例57中得到的(R)-2-氯-6-(3-(2-环丁氧基苯氧基)哌啶-1-基)吡嗪(0.14g,0.39mmol)和在制备例63中得到的3-(4-(2-氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸叔丁酯(0.11g,0.39mmol),以与实施例72相似的方式得到所需产物(得率:59%)。
1H-NMR(400MHz,氯仿-D):δ8.66(s,1H),7.86(d,J=20.1Hz,1H),7.65-7.47(m,1H),7.18(q,J=8.1Hz,4H),6.97-6.84(m,2H),6.84-6.74(m,1H),6.71(d,J=7.8Hz,1H),4.53(td,J=14.6,7.6Hz,1H),4.29-4.18(m,1H),3.93(dd,J=13.3,3.2Hz,1H),3.73-3.58(m,3H),3.48(dd,J=13.0,7.5Hz,1H),3.39-3.27(m,1H),2.87(t,J=14.2Hz,2H),2.42-2.27(m,2H),2.17-2.04(m,3H),1.98-1.70(m,3H),1.68-1.44(m,2H),1.21-1.11(m,6H)
实施例97:(R)-2-(4-(3-((6-(3-(2-环丙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸
向使用在制备例77中得到的(R)-2-氯-6-(3-(2-环丙氧基苯氧基)哌啶-1-基)吡嗪(0.14g,0.41mmol)和在制备例65中得到的(E)-2-(4-(3-氨基-3-氧代丙-1-烯-1-基)苯基)-2-甲基丙酸苯甲基酯(0.13g,0.41mmol)以与实施例8相似的方式得到的(R,E)-2-(4-(3-((6-(3-(2-环丙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙-1-烯-1-基)苯基)-2-甲基丙酸苯甲基酯添加甲醇(1.82mL)和钯/碳(12mg),并在装填氢气的同时在室温搅拌4小时。使用硅藻土将反应混合物过滤并在减压下除去溶剂。通过柱层析进行纯化,得到标题化合物(得率:59%)。
1H-NMR(400MHz,氯仿-D):δ8.64(s,1H),7.88-7.81(m,1H),7.56-7.39(m,1H),7.32(d,J=8.2Hz,2H),7.22-7.12(m,3H),7.00-6.79(m,3H),4.22(s,1H),4.00-3.90(m,1H),3.73-3.60(m,2H),3.49(ddd,J=13.0,7.5,2.7Hz,1H),3.40-3.27(m,1H),3.00(t,J=7.3Hz,2H),2.65(t,J=7.5Hz,2H),2.12-2.04(m,1H),1.98-1.76(m,2H),1.63-1.46(m,7H),0.75-0.62(m,4H)
实施例98:(R)-2-(4-(3-((6-(3-(2-环丁氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸
使用在制备例57中得到的(R)-2-氯-6-(3-(2-环丁氧基苯氧基)哌啶-1-基)吡嗪(0.14g,0.39mmol)和在制备例65中得到的(E)-2-(4-(3-氨基-3-氧代丙-1-烯-1-基)苯基)-2-甲基丙酸苯甲基酯(0.13g,0.39mmol),以与实施例97相似的方式得到所需产物(得率53%)。
1H-NMR(400MHz,氯仿-D):δ8.64(s,1H),7.88-7.81(m,1H),7.46(d,J=32.5Hz,1H),7.32(d,J=8.2Hz,2H),7.20-7.12(m,2H),6.94-6.78(m,3H),6.69(dd,J=7.8,1.4Hz,1H),4.55-4.45(m,1H),4.32-4.22(m,1H),3.92(dd,J=13.3,3.2Hz,1H),3.71-3.52(m,2H),3.45-3.33(m,1H),3.05-2.94(m,2H),2.70-2.58(m,2H),2.44-2.27(m,2H),2.17-2.04(m,3H),2.01-1.70(m,3H),1.69-1.47(m,8H)
实施例99:(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基-2-氧代乙基)苯氧基)乙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例49中得到的2-(4-(2-氨基-2-氧代乙基)苯氧基)乙酸叔丁酯(0.079g,0.30mmol),以与实施例72相似的方式得到所需产物(得率:72%)。
1H-NMR(400MHz,甲醇-D4):δ8.42(s,1H),7.71(s,1H),7.23(d,J=8.2Hz,2H),6.97-6.78(m,6H),4.58(s,2H),4.40(s,1H),4.00-3.66(m,4H),3.62(d,J=7.8Hz,3H),3.58-3.46(m,1H),2.08-1.78(m,3H),1.63-1.48(m,1H),1.21(t,J=7.1Hz,3H)
实施例100:(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙氧基)苯基)乙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.15g,0.45mmol)和在制备例50中得到的2-(4-(2-氨基-2-氧代乙氧基)苯基)乙酸甲酯(0.10g,0.45mmol),以与实施例34相似的方式得到所需产物(得率:35%)。
1H-NMR(400MHz,氯仿-D):δ8.71(s,1H),8.37(s,1H),7.93(s,1H),7.28(m,2H),7.04-6.88(4H),6.88-6.78(m,2H),4.59(s,2H),4.35-4.25(m,1H),4.08-3.85(m,3H),3.73(m,1H),3.65-3.54(m,3H),3.49-3.39(m,1H),2.17-2.06(m,1H),2.03-1.85(m,2H),1.59(m,1H),1.34(q,J=7.3Hz,3H)
实施例101:2-(4-(2-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙氧基)苯基)丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.70g,2.1mmol)和在制备例51中得到的2-(4-(2-氨基-2-氧代乙氧基)苯基)丙酸甲酯(0.50g,2.1mmol),以与实施例34相似的方式得到所需产物(得率:26%)。
1H-NMR(400MHz,氯仿-D):δ8.69(s,1H),8.36(s,1H),7.91(s,1H),7.42-7.26(m,2H),7.04-6.75(m,6H),4.57(s,2H),4.36-4.22(m,1H),4.09-3.83(m,3H),3.71(q,J=7.2Hz,2H),3.66-3.53(m,1H),3.52-3.35(m,1H),2.29-1.76(m,3H),1.67-1.52(m,1H),1.49(d,J=6.9Hz,3H),1.39-1.26(m,3H)
实施例102:(R)-3-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯氧基-2,2-二甲基丙酸
使用在制备例1中制备的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.12g,0.36mmol)和在制备例52中得到的3-(4-(2-氨基-2-氧代乙基)苯氧基)-2,2-二甲基丙酸甲酯(0.095g,0.36mmol),以与实施例34相似的方式得到所需产物(得率:38%)。
1H-NMR(400MHz,氯仿-D):δ8.65(s,1H),7.84(s,1H),7.38-7.27(1H),7.19(d,J=8.7Hz,2H),6.99-6.76(m,6H),4.29-4.20(m,1H),4.01-3.86(m,5H),3.71-3.59(m,3H),3.51(dd,J=13.0,7.5Hz,1H),3.40-3.28(m,1H),2.13-2.04(m,1H),2.00-1.80(m,2H),1.61-1.47(m,1H),1.32(t,J=6.6Hz,9H)
实施例103:(R)-2-(4-(2-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯氧基)丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.18g,0.54mmol)和在制备例53中得到的(R)-2-(4-(2-氨基-2-氧代乙基)苯氧基)丙酸乙酯(0.14g,0.54mmol),以与实施例34相似的方式得到所需产物(得率:24%)。
1H-NMR(400MHz,甲醇-D4):δ8.42(s,1H),7.71(s,1H),7.21(d,J=8.7Hz,2H),6.99-6.77(m,6H),4.69(q,J=6.7Hz,1H),4.39(dd,J=8.5,3.4Hz,1H),3.95-3.70(m,5H),3.60(s,2H),3.56-3.45(m,1H),2.07-1.82(m,3H),1.53(d,J=6.9Hz,4H),1.21(t,J=7.1Hz,3H)
实施例104:(S)-2-(4-(2-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯氧基)丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.354g,1.061mmol)和在制备例54中得到的(S)-2-(4-(2-氨基-2-氧代乙基)苯氧基)丙酸甲酯(0.277g,1.168mmol),以与实施例34相似的方式得到所需产物(2步得率:3.7%)。
1H-NMR(氯仿-D)δ8.61(s,1H),7.85(s,1H),7.42(d,J=8.2Hz,1H),7.25-7.15(2H),7.01-6.88(m,4H),6.88-6.77(m,2H),4.78(q,J=6.8Hz,1H),4.28(td,J=7.2,3.8Hz,1H),4.01-3.82(m,3H),3.72-3.49(m,4H),3.46-3.31(m,1H),2.09-2.05(m,1H),1.96(td,J=6.7,3.4Hz,1H),1.91-1.80(m,1H),1.68(d,J=6.7Hz,3H),1.61-1.47(1H),1.37-1.29(3H)
实施例105:(R)-2-(4-(2-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯氧基)-2-甲基丙酸
使用在制备例70中得到的(R)-2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪(0.060g,0.18mmol)和在制备例55中得到的2-(4-(2-氨基-2-氧代乙基)苯氧基)-2-甲基丙酸乙酯(0.048g,0.18mmol),以与实施例34相似的方式得到所需产物(得率:29%)。
1H-NMR(400MHz,氯仿-D):δ8.56(s,1H),7.85(s,1H),7.70-7.66(m,1H),7.35(d,J=13.3Hz,1H),7.21-7.11(m,2H),6.98-6.87(m,3H),6.79-6.75(m,1H),5.15-5.05(m,1H),3.93-3.71(m,4H),3.61(d,J=11.0Hz,3H),3.50-3.39(m,1H),2.14-2.04(m,1H),1.92(t,J=5.0Hz,2H),1.60(s,7H),1.25(t,J=7.0Hz,3H)
实施例106:(R)-2-(4-(2-((2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-4-基)氨基)-2-氧代乙基)苯氧基)-2-甲基丙酸
使用在制备例68中得到的(R)-4-氯-2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶(0.060g,0.18mmol)和在制备例55中得到的2-(4-(2-氨基-2-氧代乙基)苯氧基)-2-甲基丙酸乙酯(0.048g,0.18mmol),以与实施例34相似的方式得到所需产物(得率:29%)。
1H-NMR(400MHz,氯仿-D):δ8.18(d,J=5.5Hz,1H),7.68(s,1H),7.34-7.21(m,1H),7.11(d,J=6.4Hz,2H),7.04-6.77(m,6H),4.41-4.13(m,2H),4.09-3.85(m,3H),3.58(s,2H),3.55-3.44(m,1H),3.44-3.30(m,1H),2.12-1.99(m,1H),1.95-1.74(m,2H),1.67-1.40(m,7H),1.35(t,J=7.2Hz,3H)
实施例107:(R)-2-(4-((4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯氧基)甲基)苯基)-2-甲基丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.18g,0.54mmol)和在制备例56中得到的2-(4-((4-(2-氨基-2-氧代乙基)苯氧基)甲基)苯基)-2-甲基丙酸甲酯(0.18g,0.54mmol),以与实施例34相似的方式得到所需产物(得率:39%)。
1H-NMR(400MHz,甲醇-D4):δ8.42(s,1H),7.71(s,1H),7.41-7.30(m,4H),7.21(d,J=8.7Hz,2H),7.18-7.11(m,1H),6.95-6.76(m,5H),5.01(s,2H),4.43-4.34(m,1H),4.01-3.68(m,5H),3.60(s,2H),3.55-3.49(m,1H),2.08-1.80(m,3H),1.58-1.45(m,7H),1.24-1.15(m,3H)
实施例108:(R)-2-(4-(3-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯氧基)-2-甲基丙酸
使用在制备例70中得到的(R)-2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪(0.050g,0.15mmol)和在制备例28中得到的2-(4-(3-氨基-3-氧代丙基)苯氧基)-2-甲基丙酸乙酯(0.042g,0.15mmol),以与实施例34相似的方式得到所需产物(得率:34%)。
1H-NMR(400MHz,氯仿-D):δ8.57(s,1H),7.85(s,1H),7.69(dd,J=5.0,1.4Hz,1H),7.18(d,J=5.5Hz,1H),7.08(d,J=8.2Hz,2H),6.86(t,J=8.5Hz,3H),6.74(dd,J=7.8,5.0Hz,1H),5.19-5.08(m,1H),3.91-3.71(m,4H),3.66-3.44(m,2H),3.04-2.86(m,2H),2.58(dd,J=7.3,5.5Hz,2H),2.08(dd,J=9.6,3.7Hz,1H),2.02-1.87(m,2H),1.68-1.47(m,7H),1.24(t,J=7.1,3H)
实施例109:(R)-2-(4-(3-((2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-4-基)氨基)-3-氧代丙基)苯氧基)-2-甲基丙酸
使用在制备例68中得到的(R)-4-氯-2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶(0.050g,0.15mmol)和在制备例28中得到的2-(4-(3-氨基-3-氧代丙基)苯氧基)-2-甲基丙酸乙酯(0.042g,0.15mmol),以与实施例34相似的方式得到所需产物(得率:34%)。
1H-NMR(400MHz,氯仿-D):δ8.19(d,J=5.9Hz,1H),7.61-7.48(m,1H),7.30-7.20(m,1H),7.11-6.74(m,8H),4.32-4.09(m,2H),4.07-3.86(m,3H),3.68-3.52(m,1H),3.53-3.19(m,1H),2.92(t,J=7.3Hz,2H),2.59(t,J=7.3Hz,2H),2.18-2.04(m,1H),1.98-1.75(m,2H),1.52(s,7H),1.35(t,J=7.1,3H)
实施例110:(R)-3-(4-(1-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.50g,1.50mmol)和在制备例59中得到的3-(4-(1-氨基-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸叔丁酯(0.48g,1.50mmol),以与实施例72相似的方式得到所需产物(得率:49%)。
1H-NMR(400MHz,氯仿-D):δ8.68(d,J=10.5Hz,1H),7.80(s,1H),7.29(d,J=8.2Hz,2H),7.18(d,J=8.2Hz,2H),7.04(s,1H),6.95-6.72(m,4H),4.21(t,J=3.0Hz,1H),4.01-3.77(m,3H),3.58(td,J=9.7,3.7Hz,1H),3.47(dd,J=13.0,7.5Hz,1H),3.38-3.26(m,1H),2.87(s,2H),2.08-1.96(m,1H),1.96-1.74(m,2H),1.63(t,J=6.4Hz,6H),1.56-1.41(m,1H),1.30(t,J=7.1Hz,3H),1.16(s,6H)
实施例111:(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2,2-二甲基-3-氧代丙基)苯基)-2-甲基丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.50g,1.50mmol)和在制备例58中得到的2-(4-(3-氨基-2,2-二甲基-3-氧代丙基)苯基)-2-甲基丙酸甲酯(0.48g,1.50mmol),以与实施例34相似的方式得到所需产物(得率:54%)。
1H-NMR(400MHz,氯仿-D):δ8.70(s,1H),7.86(s,1H),7.36-7.22(m,3H),7.09(d,J=8.7Hz,2H),6.97-6.71(m,4H),4.33-4.23(m,1H),4.00-3.82(m,3H),3.70-3.55(m,2H),3.43(t,J=9.1Hz,1H),2.88(dd,J=24.2,13.3Hz,2H),2.12-1.80(m,3H),1.59-1.47(m,7H),1.35-1.21(m,9H)
实施例112:(R)-3-(4-(2-((2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-4-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸
使用在制备例68中得到的(R)-4-氯-2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶(1.35g,4.04mmol)和在制备例63中得到的3-(4-(2-氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸叔丁酯(1.07g,3.67mmol),以与实施例72相似的方式得到所需产物(得率:67%)。
1H-NMR(400MHz,甲醇-D4):δ8.09(d,J=5.5Hz,1H),7.29-7.16(m,3H),7.13(d,J=8.2Hz,2H),7.04-6.74(m,4H),4.39-4.22(m,1H),4.12(dd,J=13.5,3.4Hz,1H),4.00-3.81(m,3H),3.75(q,J=6.7Hz,1H),3.69-3.55(m,3H),2.82(s,2H),2.11-2.00(m,1H),1.96-1.76(m,2H),1.61-1.42(m,1H),1.32-1.23(m,3H),1.12(s,6H)
实施例113:(R)-3-(4-(2-((4-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸
使用在制备例69中得到的(R)-2-氯-4-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶(0.18g,0.54mmol)和在制备例63中得到的3-(4-(2-氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸叔丁酯(0.16g,0.54mmol),以与实施例72相似的方式得到所需产物(得率:59%)。
1H-NMR(400MHz,甲醇-D4):δ7.77(d,J=64.5Hz,1H),7.22(d,J=7.3Hz,2H),7.15(d,J=7.8Hz,2H),6.99-6.44(m,5H),4.64(s,1H),4.33-3.31(m,8H),2.83(s,2H),2.10-1.85(m,3H),1.65(s,1H),1.30-1.14(m,3H),1.12(s,6H)
实施例114:(R)-3-(4-(2-((4-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)嘧啶-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸
使用在制备例66中得到的(R)-2-氯-4-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)嘧啶(0.18g,0.54mmol)和在制备例63中得到的3-(4-(2-氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸叔丁酯(0.16g,0.54mmol),以与实施例72相似的方式得到所需产物(得率:42%)。
1H-NMR(400MHz,甲醇-D4):δ8.06-7.51(m,2H),7.29-7.07(m,5H),7.02-6.46(m,2H),5.35(d,J=44.8Hz,1H),4.65-3.49(m,8H),2.83(s,2H),2.06(s,3H),1.71(s,1H),1.14(t,J=6.6Hz,9H)
实施例115:(R)-3-(4-(2-((2-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)嘧啶-4-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸
使用在制备例70的步骤3中得到的(R)-3-乙氧基-2-(哌啶-3-基氧基)吡啶盐酸盐(0.40g,1.55mmol)和在制备例67中得到的3-(4-(2-((2-氯嘧啶-4-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸叔丁酯(0.62g,1.55mmol),顺序执行实施例1的步骤3和实施例88的步骤2的方法,得到所需产物(得率:63%)。
1H-NMR(400MHz,氯仿-D):δ8.15(d,J=5.5Hz,1H),7.74(dd,J=5.0,1.4Hz,1H),7.49(s,1H),7.28-7.00(m,5H),6.96(dd,J=7.5,1.6Hz,1H),6.82-6.69(m,1H),5.09(s,1H),4.01-3.47(m,8H),2.99-2.70(m,2H),2.12-1.83(m,3H),1.64-1.56(m,1H),1.33-1.09(m,9H)
实施例116:(R)-3-(4-(2-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸
使用在制备例70中得到的(R)-2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪(1.50g,4.48mmol)和在制备例63中得到的3-(4-(2-氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸叔丁酯(1.31g,4.48mmol),以与实施例72相似的方式得到所需产物(得率:52%)。
1H-NMR(400MHz,氯仿-D):δ8.60(s,1H),7.86(s,1H),7.77-7.70(m,1H),7.30(s,1H),7.18(s,4H),6.96(dd,J=7.8,1.4Hz,1H),6.78(dd,J=7.5,5.3Hz,1H),5.11(td,J=6.4,3.2Hz,1H),3.97-3.77(m,3H),3.72(d,J=12.3Hz,1H),3.64(s,2H),3.61-3.42(m,2H),2.99-2.89(m,1H),2.82(d,J=13.3Hz,1H),2.13-1.87(m,3H),1.69-1.53(m,1H),1.27(t,J=7.1Hz,3H),1.20(d,J=12.8Hz,6H)
实施例117:(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)双环[2.2.2]辛烷-1-甲酸
使用在制备例1中得到的的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.20g,0.60mmol)和在制备例60中得到的(E)-4-(3-氨基-3-氧代丙-1-烯-1-基)双环[2.2.2]辛烷-1-甲酸苯甲基酯(0.19g,0.60mmol),以与实施例97相似的方式得到所需产物(得率:45%)。
1H-NMR(400MHz,氯仿-D):δ8.64(s,1H),7.86(s,1H),7.28(s,1H),6.99-6.82(m,4H),4.36-4.24(m,1H),4.05-3.87(m,3H),3.77-3.65(m,1H),3.60(q,J=6.9Hz,1H),3.47-3.35(m,1H),2.27(t,J=8.5Hz,2H),2.17-2.05(m,1H),2.01-1.85(m,2H),1.81(t,J=7.8Hz,6H),1.68-1.50(m,3H),1.42(t,J=7.8Hz,6H),1.36(t,J=7.0,3H)
实施例118:(R)-4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)双环[2.2.2]辛烷-1-甲酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.50g,1.50mmol)和在制备例61中得到的4-(2-氨基-2-氧代乙基)双环[2.2.2]辛烷-1-甲酸甲酯(0.48g,1.50mmol),以与实施例34相似的方式得到所需产物(得率:47%)。
1H-NMR(400MHz,氯仿-D):δ8.67(d,J=7.3Hz,1H),7.86(s,1H),7.14(s,1H),7.00-6.92(m,2H),6.89-6.83(m,2H),4.33-4.24(m,1H),4.05-3.91(m,3H),3.79-3.68(m,1H),3.63(s,2H),3.55(dd,J=13.3,7.8Hz,1H),3.44-3.34(m,1H),2.16-2.07(m,1H),2.02-1.92(m,1H),1.92-1.85(m,1H),1.85-1.75(m,6H),1.67-1.56(m,7H),1.36(td,J=6.9,2.7Hz,3H)
实施例119:(R)-4-(3-((2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-4-基)氨基)-3-氧代丙基)双环[2.2.2]辛烷-1-甲酸
使用在制备例68中得到的(R)-4-氯-2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶(0.20g,0.60mmol)和在制备例60中得到的(E)-4-(3-氨基-3-氧代丙-1-烯-1-基)双环[2.2.2]辛烷-1-甲酸苯甲基酯(0.19g,0.60mmol),以与实施例97相似的方式得到所需产物(得率:24%)。
1H-NMR(400MHz,氯仿-D):δ8.20(d,J=5.5Hz,1H),7.66(s,1H),7.26(s,1H),7.01-6.81(m,4H),4.36-4.20(m,2H),4.06-3.88(m,3H),3.58(dd,J=12.8,7.8Hz,1H),3.50-3.39(m,1H),2.29-2.17(m,2H),2.11(q,J=4.9Hz,1H),1.97-1.82(m,2H),1.82-1.72(m,6H),1.60-1.47(m,3H),1.46-1.30(m,9H)
实施例120:(R)-4-(3-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)双环[2.2.2]辛烷-1-甲酸
使用在制备例70中得到的(R)-2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪(0.20g,0.60mmol)和在制备例60中得到的(E)-4-(3-氨基-3-氧代丙-1-烯-1-基)双环[2.2.2]辛烷-1-甲酸苯甲基酯(0.19g,0.60mmol),以与实施例97相似的方式得到所需产物(得率:41%)。
1H-NMR(400MHz,氯仿-D):δ8.60(s,1H),7.88(s,1H),7.71(q,J=2.3Hz,1H),7.21(s,1H),7.03-6.94(m,1H),6.79(dd,J=7.5,4.8Hz,1H),5.23-5.12(m,1H),4.00-3.76(m,4H),3.75-3.69(m,1H),3.56-3.44(m,1H),2.24(t,J=8.2Hz,2H),2.15(qd,J=9.2,4.5Hz,1H),2.02-1.90(m,2H),1.87-1.73(m,6H),1.70-1.59(m,1H),1.58-1.49(m,2H),1.45-1.39(m,6H),1.31(t,J=6.8Hz,3H)
实施例121:(R,E)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙-1-烯-1-基)双环[2.2.2]辛烷-1-甲酸
标题化合物在实施例117的制备过程中作为副产物获得。
1H-NMR(400MHz,氯仿-D):8.72(s,1H),7.88(d,J=7.8Hz,1H),6.99-6.90(m,3H),6.90-6.81(m,3H),5.74(d,J=15.6Hz,1H),4.37-4.27(m,1H),4.03-3.86(m,3H),3.75-3.67(m,1H),3.63(q,J=6.9Hz,1H),3.49-3.38(m,1H),2.16-2.05(m,1H),2.02-1.77(m,7H),1.70-1.53(m,8H),1.34(t,J=7.0,3H)
实施例122:(R)-2-(4-(3-((2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-4-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸
使用在制备例68中得到的(R)-4-氯-2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶(0.20g,0.60mmol)和在制备例65中得到的(E)-2-(4-(3-氨基-3-氧代丙-1-烯-1-基)苯基)-2-甲基丙酸苯甲基酯(0.19g,0.60mmol),以与实施例97相似的方式得到所需产物(得率:28%)。
1H-NMR(400MHz,氯仿-D):δ8.23-8.17(m,1H),7.69(d,J=11.4Hz,1H),7.35-7.26(m,3H),7.15(d,J=8.2Hz,2H),6.99-6.77(m,4H),4.30-4.18(m,2H),4.03-3.85(m,3H),3.59(dd,J=13.7,8.2Hz,1H),3.52-3.41(m,1H),2.96(t,J=7.5Hz,2H),2.61(t,J=7.8Hz,2H),2.14-2.04(m,1H),1.95-1.79(m,2H),1.60-1.44(m,7H),1.32(t,J=6.9Hz,3H)
实施例123:(R)-2-(4-(3-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸
使用在制备例70中得到的(R)-2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪(0.20g,0.60mmol)和在制备例65中得到的(E)-2-(4-(3-氨基-3-氧代丙-1-烯-1-基)苯基)-2-甲基丙酸苯甲基酯(0.19g,0.60mmol),以与实施例97相似的方式得到所需产物(得率:47%)。
1H-NMR(400MHz,氯仿-D):δ8.60(s,1H),7.86(s,1H),7.69(dd,J=5.0,1.4Hz,1H),7.32(d,J=8.2Hz,2H),7.24-7.13(m,3H),6.84(dd,J=8.0,1.6Hz,1H),6.73(dd,J=7.8,5.0Hz,1H),5.19-5.08(m,1H),3.95-3.70(m,4H),3.66-3.55(m,1H),3.55-3.44(m,1H),3.07-2.89(m,2H),2.60(dt,J=20.4,7.3Hz,2H),2.15-2.04(m,1H),2.01-1.87(m,2H),1.68-1.50(m,7H),1.24(t,J=7.1Hz,3H)
实施例124:(R)-3-(4-(1-((2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-4-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸
使用在制备例68中得到的(R)-4-氯-2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶(0.10g,0.30mmol)和在制备例59中得到的3-(4-(1-氨基-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸叔丁酯(0.096g,0.30mmol),以与实施例72相似的方式得到所需产物(得率:60%)。
1H-NMR(400MHz,氯仿-D):δ8.18(d,J=5.9Hz,1H),7.36-7.26(m,3H),7.22-7.07(m,3H),6.97-6.75(m,4H),4.29(d,J=12.8Hz,1H),4.21-4.11(m,1H),4.06-3.88(m,3H),3.40(d,J=5.0Hz,2H),2.87(dd,J=22.4,13.3Hz,2H),2.12-2.04(m,1H),1.91-1.72(m,2H),1.61(s,6H),1.47(dd,J=9.4,3.9Hz,1H),1.32(t,J=6.9Hz,3H),1.18(d,J=3.7Hz,6H)
实施例125:(R)-3-(4-(1-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸
使用在制备例70中得到的(R)-2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例59中得到的3-(4-(1-氨基-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸叔丁酯(0.095g,0.30mmol),以与实施例72相似的方式得到所需产物(得率:77%)。
1H-NMR(400MHz,氯仿-D):δ8.61(s,1H),7.82(s,1H),7.75-7.67(m,1H),7.28(d,J=8.7Hz,2H),7.23-7.11(m,2H),6.95(dd,J=8.0,1.1Hz,1H),6.87(s,1H),6.78(dd,J=7.8,5.0Hz,1H),5.14-5.02(m,1H),3.95-3.65(m,4H),3.59-3.37(m,2H),3.00-2.75(m,2H),2.05(t,J=4.1Hz,1H),2.00-1.84(m,2H),1.59(dd,J=18.3,2.7Hz,7H),1.34-1.25(m,3H),1.23-1.12(m,6H)
实施例126:(R)-3-(4-(1-((6-(3-(2-环丁氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸
使用在制备例57中得到的(R)-2-氯-6-(3-(2-环丁氧基苯氧基)哌啶-1-基)吡嗪(0.080g,0.22mmol)和在制备例59中得到的3-(4-(1-氨基-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸叔丁酯(0.071g,0.22mmol),以与实施例72相似的方式得到所需产物(得率:62%)。
1H-NMR(400MHz,氯仿-D):δ8.69(s,1H),7.80(s,1H),7.29(d,J=8.2Hz,2H),7.18(d,J=8.2Hz,2H),7.04(s,1H),6.91-6.81(m,2H),6.81-6.72(m,1H),6.72-6.63(m,1H),4.58-4.43(m,1H),4.25-4.14(m,1H),3.90(dd,J=13.3,2.7Hz,1H),3.67-3.54(m,1H),3.43(dd,J=13.0,7.5Hz,1H),3.36-3.20(m,1H),2.87(dd,J=15.1,13.3Hz,2H),2.42-2.26(m,2H),2.16-2.03(m,3H),1.97-1.68(m,3H),1.67-1.40(m,8H),1.20-1.09(m,6H)
实施例127:(R)-3-(3-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2,2-二甲基丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例62中得到的3-(3-(3-氨基-3-氧代丙基)苯基)-2,2-二甲基丙酸叔丁酯(0.091g,0.30mmol),以与实施例72相似的方式得到所需产物(得率:61%)。
1H-NMR(400MHz,氯仿-D):δ8.64(s,1H),7.84(s,1H),7.66(s,1H),7.15(t,J=8.0Hz,1H),7.03(d,J=6.9Hz,2H),6.98(d,J=7.3Hz,1H),6.94-6.87(m,2H),6.87-6.76(m,2H),4.27(td,J=7.2,3.5Hz,1H),4.00-3.83(m,3H),3.69-3.51(m,2H),3.45-3.32(m,1H),2.95(t,J=7.5Hz,2H),2.83(s,2H),2.59(t,J=7.8Hz,2H),2.10-2.00(m,1H),2.00-1.80(m,2H),1.53(td,J=8.5,4.3Hz,1H),1.31(t,J=7.1Hz,3H),1.16(s,6H)
实施例128:(R)-3-(3-(3-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2,2-二甲基丙酸
使用在制备例70中得到的(R)-2-氯-6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪(0.10g,0.30mmol)和在制备例62中得到的3-(3-(3-氨基-3-氧代丙基)苯基)-2,2-二甲基丙酸叔丁酯(0.091g,0.30mmol),以与实施例72相似的方式得到所需产物(得率:58%)。
1H-NMR(400MHz,氯仿-D):δ8.58(s,1H),7.86(s,1H),7.73(dd,J=5.0,1.4Hz,2H),7.15(t,J=7.5Hz,1H),7.04(d,J=9.1Hz,2H),7.00-6.90(m,2H),6.80(dd,J=7.8,5.0Hz,1H),5.20-5.11(m,1H),3.97-3.72(m,4H),3.71-3.60(m,1H),3.56-3.42(m,1H),2.96(t,J=7.1Hz,2H),2.82(dd,J=19.2,13.3Hz,2H),2.62(t,J=7.3Hz,2H),2.19-2.07(m,1H),2.02-1.90(m,2H),1.71-1.55(m,1H),1.28(t,J=7.1Hz,3H),1.17(s,3H),1.14(s,3H)
实施例129:(R)-3-(3'-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)-[1,1'-联苯]-3-基)-2,2-二甲基丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.029g,0.086mmol)和在制备例79中得到的3-(3′-(氯羰基)-[1,1′-联苯]-3-基)-2,2-二甲基丙酸叔丁酯(0.034g,0.095mmol),以与实施例72相似的方式得到所需产物(得率:55%)。
1H-NMR(400MHz,氯仿-D):δ8.80(s,1H),8.09-7.93(m,2H),7.86(s,1H),7.77(dd,J=30.2,8.2Hz,2H),7.59-7.41(m,3H),7.35(t,J=7.5Hz,1H),7.22-7.11(1H),7.01-6.87(m,1H),6.87-6.70(m,3H),4.31(td,J=7.1,3.5Hz,1H),4.03-3.79(m,3H),3.77-3.56(m,2H),3.52-3.32(m,1H),2.96(s,2H),2.17-2.04(m,1H),2.01-1.79(m,2H),1.56(qd,J=8.5,4.2Hz,1H),1.32(t,J=7.1Hz,3H),1.24-1.06(m,6H)
实施例130:(R)-3-(3'-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)-[1,1'-联苯]-4-基)-2,2-二甲基丙酸
使用在制备例1中得到的(R)-2-氯-6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪(0.052g,0.154mmol)和在制备例80中得到的3-(3'-(氯羰基)-[1,1'-联苯]-4-基)-2,2-二甲基丙酸叔丁酯(0.060g,0.170mmol),以与实施例72相似的方式得到所需产物(得率:69%)。
1H-NMR(400MHz,氯仿-D):δ8.86(s,1H),8.08(d,J=12.3Hz,2H),7.93(s,1H),7.78(dd,J=22.0,7.8Hz,2H),7.62-7.43(m,3H),7.29(d,J=8.2Hz,2H),7.03-6.89(m,1H),6.88-6.72(3H),4.41-4.23(m,1H),4.04-3.80(m,3H),3.69(q,J=6.7Hz,2H),3.57-3.37(m,1H),2.97(d,J=8.7Hz,2H),2.18-2.05(m,1H),2.03-1.81(m,2H),1.58(qd,J=8.4,4.5Hz,1H),1.33(t,J=7.1Hz,3H),1.26(s,6H)
实验例:对DGAT2酶活性的抑制作用的测量
通过对根据本发明的式(1)的化合物进行下述实验,研究了对DGAT2酶活性的抑制作用。
1.DGAT2表达载体的制备
为了制备作为DGAT2表达载体的pBacPAK9-DGAT2,将通过聚合酶链反应(PCR)扩增的人类DGAT2基因克隆到pBacPAK9(clonctech)载体的EcoR1和Xho1位点中。在PCR中使用的引物的核苷酸序列是正向引物5'CTATAAATACGGATCCCGGGAATTCATGGACTACAAGGACGACGATGACAAGCTTAAGACCCTCATAGCCGCC和反向引物5'
TAAGCGGCCGCCCTGCAGGCCTCGAGTCAGTTCACCTCCAGGAC。反应溶液的组成是含有50ngcDNA克隆(OriGene),200μM dATP、dCTP、dTTP、dGTP,200nM每种引物,1单位的Tag DNA聚合酶(Toyobo),1x PCR缓冲液,并将终体积调整到20μl。反应条件是在95℃变性5分钟,然后是30次的94℃20秒、60℃20秒和72℃90秒,然后在72℃继续反应7分钟。
2.DGAT2表达和膜蛋白的制备
使用BacPack杆状病毒表达系统(Clontech),在作为昆虫细胞的Sf-21细胞中表达重组人类DGAT2蛋白。简要的制造过程如下。首先,使用Bacfectin将pBacPAK9-DGAT2表达载体与BacPAK6病毒DNA(Bsu36I消化物)转染到sf21细胞中,以制备表达重组DGAT2的杆状病毒。将由此制备的杆状病毒以10MOI(感染复数)感染Sf-21细胞,并在72小时后收集感染的昆虫细胞并分离膜蛋白。为了分离膜蛋白,将细胞沉积物溶解在含有250mM蔗糖、10mM Tris(pH 7.4)和1mM乙二胺四乙酸(EDTA)的蔗糖溶液中,然后使用杜恩斯匀浆器匀浆,通过以600×g离心15分钟获取上清液,将其以100,000×g离心1小时以舍弃上清液,并将剩余的沉积物重悬浮在20mM HEPES缓冲液(pH 7.4)中。将所述制备的过表达DGAT2的膜蛋白以100μl分装并储存在-80℃下直至使用。使用BCA蛋白质测定试剂盒(Thermo Scientific)对蛋白质浓度定量。
3.对DGAT2酶活性的抑制作用的测量
体外DGAT2分析使用基于SPA(闪烁接近测定法)原理的磷脂快闪板(PerkinElmer)进行。首先,将从3nM至10μM(终浓度,1%DMSO)的连续5倍稀释的DGAT2抑制化合物混合在含有2μg DGAT2膜蛋白和20mM HEPES、20mM MgCl2、1mg/mL BSA、50μM 1,2 sn-油酰基甘油(Sigma)的缓冲溶液中,置于96孔快闪板(FlashPlate)中并在37℃反应20分钟,然后添加1μM[14C]油酰基辅酶A(PerkinElmer,NEC651050UC)以使终体积为100μL,然后在37℃反应15分钟。在酶反应完成后,添加100μL异丙醇,将板用薄膜密封,并将板在摇板器中缓慢摇动。第二天,在Topcounter(Packard)中测量放大的闪烁信号(cpm),以测量作为反应产物的[14C]标记的三酰基甘油(TG)的产生程度。将未用化合物处理时的测量值用作阳性对照,并将化合物处理组的测量值计算为相对%,以度量化合物对TG产生的抑制作用。IC50值是将TG产生抑制50%的化合物浓度,通过使用PRISM(Graphpad Inc.)用非线性回归曲线处理根据化合物浓度的响应值来确定。
作为测量式(1)的化合物对DGAT2酶作用的抑制作用的结果,各个实施例化合物的具体IC50值如下面的表1中所示。
[表1]
Claims (5)
1.一种下式(1)的化合物或其可药用盐或异构体:
[式(1)]
其中
A、B和E各自独立地是CH或N;
D是N、CH或C-卤代烷基;
R1是烷基、环烷基或卤代烷基;
R2是氢或烷基;
R3是-G-J-L;
其中G是-NH-或直接连键;
J是亚烷基、亚烯基、亚烷基-亚芳基、亚烷基-氨基-亚芳基、亚烷基-亚芳氧基-亚烷基、亚烷基-环烷基、亚烯基-环烷基、亚烷氧基-亚芳基、亚芳基、环烷基、芳基、芳基-烷基、亚杂环烷基、亚杂环烷基-亚芳基、亚杂环烷基-亚杂芳基或杂环烷基;
L是氢、卤素、氨基、硝基、羧基(-COOH)、氨基羰基烷基、羧基烷基、羧基烷氧基、羧基烷基-芳基、环烷基、芳基、芳氧基、杂环烷基或杂芳基;或者
R2和R3与它们所连接的氮原子一起可以形成杂环烷基;
其中所述烷基、亚烷基、亚烷基-亚芳基、烯基、亚烯基、环烷基、羧基烷基、羧基烷氧基、烷氧基烷基、氨基羰基、芳基、芳基-烷基、亚芳基、芳氧基、杂环烷基或杂芳基任选地被选自羟基、卤素、氧代、硝基、-COOH、-CH2COOH、烷基、烯基、烷氧基、卤代烷基、烷基磺酰基、烷基羰基、烷氧基羰基和杂芳基-烷基的一个或多个取代基取代;并且
所述亚杂环烷基、杂环烷基、亚杂芳基或杂芳基包括一个或多个选自N、O和S的杂原子。
2.根据权利要求1所述的化合物或其可药用盐或异构体,其中
A、B和E各自独立地是CH或N;
D是N、CH或C-卤代-C1-C7烷基;
R1是C1-C7烷基、C3-C10环烷基或卤代-C1-C7烷基;
R2是氢或C1-C7烷基;
R3是-G-J-L;
其中G是-NH-或直接连键;
J是C1-C7亚烷基、C2-C7亚烯基、C1-C7亚烷基-C6-C10亚芳基、C1-C7亚烷基-氨基-C6-C10亚芳基、C1-C7亚烷基-C6-C10亚芳氧基-C1-C7亚烷基、C1-C7亚烷基-C3-C10环烷基、C2-C7亚烯基-C3-C10环烷基、C1-C7亚烷氧基-C6-C10亚芳基、C6-C10亚芳基、C3-C10环烷基、C6-C10芳基、C6-C10芳基-C1-C7烷基、5至12元亚杂环烷基、5至12元亚杂环烷基-C6-C10亚芳基、5至12元亚杂环烷基-5至12元亚杂芳基或5至12元杂环烷基;
L是氢、卤素、氨基、硝基、羧基(-COOH)、氨基羰基-C1-C7烷基、羧基-C1-C7烷基、羧基-C1-C7烷氧基、羧基-C1-C7烷基-C6-C10芳基、C3-C10环烷基、C6-C10芳基、C6-C10芳氧基、5至12元杂环烷基或5至12元杂芳基;或者
R2和R3与它们所连接的氮原子一起可以形成5至12元杂环烷基;
其中所述烷基、亚烷基、亚烷基-亚芳基、烯基、亚烯基、环烷基、羧基烷基、羧基烷氧基、烷氧基烷基、氨基羰基、芳基、芳基-烷基、亚芳基、芳氧基、杂环烷基或杂芳基任选地被选自羟基、卤素、氧代、硝基、-COOH、-CH2COOH、C1-C7烷基、C2-C7烯基、C1-C7烷氧基、卤代-C1-C7烷基、C1-C7烷基磺酰基、C1-C7烷基羰基、C1-C7烷氧基羰基和5至12元杂芳基-C1-C7烷基的1至4个取代基取代;并且
所述亚杂环烷基、杂环烷基、亚杂芳基或杂芳基包括1至5个选自N、O和S的杂原子。
3.根据权利要求1所述的化合物或其可药用盐或异构体,其中所述化合物选自:
(R)-1-(3,5-双(三氟甲基)苯基)-3-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)脲;
((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)-L-苯丙氨酸;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)吗啉-4-甲酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)吡咯烷-1-甲酰胺;
1-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)吡咯烷-3-甲酸;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)苯甲酰胺;
(R)-4-氯-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)苯甲酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-3-甲氧基苯甲酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-4-甲氧基苯甲酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-4-硝基苯甲酰胺;
(R)-2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯甲酸;
(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯基)乙酸;
(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯基)-2-甲基丙酸;
(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯氧基)-2-甲基丙酸;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-1-(甲磺酰基)哌啶)-4-甲酰胺;
(R)-1-乙酰基-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)哌啶)-4-甲酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-1-(异丙基磺酰基)哌啶-4-甲酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-1-(5-乙基嘧啶-2-基)哌啶-4-甲酰胺;
(R)-4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-4-氧代丁酸;
(1R)-2-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)环戊烷-1-甲酸;
(R)-4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)双环[2.2.2]辛烷-1-甲酸;
(R)-4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2,2-二甲基-4-氧代丁酸;
(R)-1-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-3,3-二甲基吡咯烷-2,5-二酮;
(R)-5-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2,2-二甲基-5-氧代戊酸;
(R)-5-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3,3-二甲基-5-氧代戊酸;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-2-(3-三氟甲基)苯基)乙酰胺;
(R)-2-(3,5-双(三氟甲基)苯基)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)乙酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-2-苯基乙酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-3-苯基丙酰胺;
(R)-2-(3-氯苯基)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)乙酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-2-甲基-2-苯基丙酰胺;
(R)-4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯甲酸;
(R)-3-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯甲酸;
(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)乙酸;
(R)-2-(4-(2-氨基-2-氧代乙基)苯基-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)乙酰胺;
(R)-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-2-(4-羟基苯基)乙酰胺;
(R)-4-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯氧基)丁酸;
(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基-2-氧代乙基)苯氧基)-2-甲基丙酸;
(R)-2-(4-(1-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2-甲基丙酸;
(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯甲酸;
(R,E)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙-1-烯-1-基)苯甲酸;
(R,E)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-3-氧代丙-1-烯-1-基)苯甲酸;
4-(3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-3-氧代丙基)苯甲酸;
(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)-2-氟苯甲酸;
(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)-2-甲基苯甲酸;
(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)-2-甲氧基苯甲酸;
(R)-2-氯-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯甲酸;
(R)-3-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯甲酸;
(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)乙酸;
(R)-3-(4-(2-氨基-2-氧代乙基)苯基-N-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)丙烯酰胺;
(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸;
(R)-1-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)环丙烷-1-甲酸;
(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)-2,6-二氟苯甲酸;
(R)-2,6-二氯-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯甲酸;
(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)-2,6-二甲基苯甲酸;
(R)-1-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)哌啶-4-甲酸;
(R)-1-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基-2,6-二氟苯基)哌啶-4-甲酸;
(R)-2-(1-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基-2,6-二氟苯基)哌啶-4-基)乙酸;
(R)-4-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)苯甲酸;
(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯氧基)-2-甲基丙酸;
(R)-3-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)丙酸;
(R)-4-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)苯氧基)苯甲酸;
(R)-3-(4-(3-((6-(R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2-甲基丙酸;
(S)-3-(4-(3-((6-(R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2-甲基丙酸;
(R)-3-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶-2-基)氨基)-2-氧代乙基)苯基)乙酸;
(R)-2-(4-(3-(6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)脲基)苯基)乙酸;
(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶-2-基)氨基)-2-氧代乙基)苯基)-2-甲基丙酸;
(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2-甲基丙酸;
(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸;
(R)-3-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡啶-2-基)氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(2-((4-(3-(2-乙氧基苯氧基)哌啶-1-基)-6-(三氟甲基)嘧啶-2-基)氨基-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(1-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)丙酸;
(R)-3-(4-((2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)烯丙基)氨基)苯基)丙酸;
(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)嘧啶-5-甲酸;
3-(3-((R)-3-((6-((R)-3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)苯基-2,2-二甲基丙酸;
(R)-3-(4-(1-((4-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(1-((4-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)嘧啶-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸;
(R)-2-(4-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)苯基)乙酸;
(R)-2-(4-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)苯基)-2-甲基丙酸;
(R)-2-(6-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)吡啶-3-基)-2-甲基丙酸;
(R)-2-(5-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)-2H-四唑-2-基)乙酸;
(R)-4-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)-4-氧代丁酸;
(R)-2-(4-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)乙酸;
3-(3-((R)-3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)哌啶-1-基)苯基)-2,2-二甲基丙酸;
(R)-1-(4-(1-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)哌啶-4-甲酸;
6-(3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)吡咯烷-1-基)烟酸;
N-(6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)-3-甲基吡咯烷-3-甲酰胺;
6-(3-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)-3-甲基吡咯烷-1-基)烟酸;
(R)-2-(4-(2-((6-(3-(2-异丙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)乙酸;
(R)-2-(4-(3-((6-(3-(2-甲氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸;
(R)-2-甲基-2-(4-(3-氧代-3-((6-(3-(2-(三氟甲氧基)苯氧基)哌啶-1-基)吡嗪-2-基)氨基)丙基)苯基)丙酸;
(R)-2-(4-(3-((6-(3-(2-(2-氟乙氧基)苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸;
(R)-3-(4-(2-((6-(3-(2-(2-氟乙氧基)苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(2-((6-(3-(2-环丙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(2-((6-(3-(2-环丁氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-2-(4-(3-((6-(3-(2-环丙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸;
(R)-2-(4-(3-((6-(3-(2-环丁氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸;
(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基-2-氧代乙基)苯氧基)乙酸;
(R)-2-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙氧基)苯基)乙酸;
2-(4-(2-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙氧基)苯基)丙酸;
(R)-3-(4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯氧基-2,2-二甲基丙酸;
(R)-2-(4-(2-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯氧基)丙酸;
(S)-2-(4-(2-((6-((R)-3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯氧基)丙酸;
(R)-2-(4-(2-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯氧基)-2-甲基丙酸;
(R)-2-(4-(2-((2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-4-基)氨基)-2-氧代乙基)苯氧基)-2-甲基丙酸;
(R)-2-(4-((4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯氧基)甲基)苯基)-2-甲基丙酸;
(R)-2-(4-(3-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯氧基)-2-甲基丙酸;
(R)-2-(4-(3-((2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-4-基)氨基)-3-氧代丙基)苯氧基)-2-甲基丙酸;
(R)-3-(4-(1-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸;
(R)-2-(4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2,2-二甲基-3-氧代丙基)苯基)-2-甲基丙酸;
(R)-3-(4-(2-((2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-4-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(2-((4-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(2-((4-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)嘧啶-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(2-((2-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)嘧啶-4-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(2-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)苯基)-2,2-二甲基丙酸;
(R)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)双环[2.2.2]辛烷-1-甲酸;
(R)-4-(2-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-氧代乙基)双环[2.2.2]辛烷-1-甲酸;
(R)-4-(3-((2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-4-基)氨基)-3-氧代丙基)双环[2.2.2]辛烷-1-甲酸;
(R)-4-(3-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)双环[2.2.2]辛烷-1-甲酸;
(R,E)-4-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙-1-烯-1-基)双环[2.2.2]辛烷-1-甲酸;
(R)-2-(4-(3-((2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-4-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸;
(R)-2-(4-(3-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2-甲基丙酸;
(R)-3-(4-(1-((2-(3-(2-乙氧基苯氧基)哌啶-1-基)嘧啶-4-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(1-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸;
(R)-3-(4-(1-((6-(3-(2-环丁氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-2-甲基-1-氧代丙-2-基)苯基)-2,2-二甲基丙酸;
(R)-3-(3-(3-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2,2-二甲基丙酸;
(R)-3-(3-(3-((6-(3-((3-乙氧基吡啶-2-基)氧基)哌啶-1-基)吡嗪-2-基)氨基)-3-氧代丙基)苯基)-2,2-二甲基丙酸;
(R)-3-(3'-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)-[1,1'-联苯]-3-基)-2,2-二甲基丙酸;和
(R)-3-(3'-((6-(3-(2-乙氧基苯氧基)哌啶-1-基)吡嗪-2-基)氨甲酰基)-[1,1'-联苯]-4-基)-2,2-二甲基丙酸。
4.一种用于治疗与二酰基甘油酰基转移酶2(DGAT2)相关的疾病的药物组合物,其包含权利要求1至3任一项中所定义的式(1)的化合物或其可药用盐或异构体作为活性成分,以及可药用载体。
5.根据权利要求4所述的药物组合物,其中所述与DGAT2相关的疾病选自脂肪肝、非酒精性脂肪性肝炎(NASH)、非酒精性脂肪性肝病(NAFLD)、糖尿病、肥胖症、高脂血症、动脉粥样硬化和高胆固醇血症。
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