CN112105357A - 药用6,5杂双环衍生物 - Google Patents
药用6,5杂双环衍生物 Download PDFInfo
- Publication number
- CN112105357A CN112105357A CN201980013102.8A CN201980013102A CN112105357A CN 112105357 A CN112105357 A CN 112105357A CN 201980013102 A CN201980013102 A CN 201980013102A CN 112105357 A CN112105357 A CN 112105357A
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- CN
- China
- Prior art keywords
- piperazin
- pyrrolo
- pyridine
- pyridin
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 125000002618 bicyclic heterocycle group Chemical group 0.000 title claims abstract description 14
- 101710196623 Stimulator of interferon genes protein Proteins 0.000 claims abstract description 31
- 230000004913 activation Effects 0.000 claims abstract description 9
- 230000004968 inflammatory condition Effects 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- -1 difluoromethoxy, trifluoromethoxy, trifluoroethoxy Chemical group 0.000 claims description 274
- 150000001875 compounds Chemical class 0.000 claims description 122
- 239000000203 mixture Substances 0.000 claims description 111
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 69
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 44
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 44
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 39
- 229910052757 nitrogen Inorganic materials 0.000 claims description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 claims description 35
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 35
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 33
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 29
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 24
- 125000005124 aminocycloalkyl group Chemical group 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 229910052720 vanadium Inorganic materials 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 22
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 20
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims description 20
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 20
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 18
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 229910052727 yttrium Inorganic materials 0.000 claims description 18
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 16
- 229910052770 Uranium Inorganic materials 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000003386 piperidinyl group Chemical group 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 12
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 10
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 10
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 10
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 10
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 8
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 8
- 150000004885 piperazines Chemical class 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 7
- 125000004193 piperazinyl group Chemical group 0.000 claims description 7
- AKZGTNXSPPSGAC-UHFFFAOYSA-N 2-ethyl-1-azabicyclo[3.2.0]heptane Chemical compound C(C)C1N2CCC2CC1 AKZGTNXSPPSGAC-UHFFFAOYSA-N 0.000 claims description 6
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 6
- 125000004981 cycloalkylmethyl group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- QTFQKNJSUFOWNV-UHFFFAOYSA-N 1-[4-[4-[3-(1-methylpyrazol-4-yl)-1-piperidin-4-ylpyrrolo[2,3-b]pyridin-6-yl]piperazin-1-yl]phenyl]ethanone Chemical compound CN1N=CC(=C1)C1=CN(C2=NC(=CC=C21)N1CCN(CC1)C1=CC=C(C=C1)C(C)=O)C1CCNCC1 QTFQKNJSUFOWNV-UHFFFAOYSA-N 0.000 claims description 5
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- DULUKFZXVRNOKU-UHFFFAOYSA-N 6-[4-(4-acetylphenyl)piperazin-1-yl]-1-(5-azaspiro[3.4]octan-2-yl)pyrrolo[2,3-b]pyridine-3-carbonitrile Chemical compound C(C)(=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2C#N)C1CC2(C1)NCCC2 DULUKFZXVRNOKU-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- OJJKHYWYYULZGV-UHFFFAOYSA-N 1-[4-[4-[1-(1-methylpyrazol-4-yl)-3-piperidin-4-ylpyrrolo[3,2-b]pyridin-5-yl]piperazin-1-yl]phenyl]ethanone Chemical compound CN1N=CC(=C1)N1C=C(C2=NC(=CC=C21)N1CCN(CC1)C1=CC=C(C=C1)C(C)=O)C1CCNCC1 OJJKHYWYYULZGV-UHFFFAOYSA-N 0.000 claims description 4
- JKNXMPSMAZUQMJ-UHFFFAOYSA-N 1-ethyl-2-methylpyrrolidine Chemical compound CCN1CCCC1C JKNXMPSMAZUQMJ-UHFFFAOYSA-N 0.000 claims description 4
- VRZDRLWKTKGDKZ-UHFFFAOYSA-N 5-[4-(4-acetylphenyl)piperazin-1-yl]-1-(1-methylpyrazol-4-yl)-3-piperidin-4-ylbenzimidazol-2-one Chemical compound C(C)(=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC2=C(N(C(N2C2CCNCC2)=O)C=2C=NN(C=2)C)C=C1 VRZDRLWKTKGDKZ-UHFFFAOYSA-N 0.000 claims description 4
- TYSUHBKKLGUYOM-NRFANRHFSA-N 6-[(2S)-2-methyl-4-(2-methylphenyl)piperazin-1-yl]-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound C[C@@H]1N(CCN(C1)C1=C(C=CC=C1)C)C1=CC=C2C(=N1)N(C=C2)CCN1CCCC1 TYSUHBKKLGUYOM-NRFANRHFSA-N 0.000 claims description 4
- ZXFJTWKRIGHILK-UHFFFAOYSA-N 6-[4-(4-acetylphenyl)piperazin-1-yl]-1-piperidin-4-ylpyrrolo[2,3-b]pyridine-3-carbonitrile Chemical compound C(C)(=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2C#N)C1CCNCC1 ZXFJTWKRIGHILK-UHFFFAOYSA-N 0.000 claims description 4
- NESYXCSYIBWZRD-UHFFFAOYSA-N 6-piperazin-1-yl-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound N1(CCNCC1)C1=CC=C2C(=N1)N(C=C2)CCN1CCCC1 NESYXCSYIBWZRD-UHFFFAOYSA-N 0.000 claims description 4
- LIRIUFOISYXSBL-ZHRYYDEUSA-N CNC1CC(C1)N1C=C(C=2C1=NC(=CC=2)N1CCN(CC1)[C@@H]1CC[C@H](CC1)S(=O)(=O)C)C#N Chemical compound CNC1CC(C1)N1C=C(C=2C1=NC(=CC=2)N1CCN(CC1)[C@@H]1CC[C@H](CC1)S(=O)(=O)C)C#N LIRIUFOISYXSBL-ZHRYYDEUSA-N 0.000 claims description 4
- 125000005157 alkyl carboxy group Chemical group 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 150000003053 piperidines Chemical class 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 229940066769 systemic antihistamines substituted alkylamines Drugs 0.000 claims description 4
- 229910052721 tungsten Inorganic materials 0.000 claims description 4
- WERVLLXLWODAKP-UHFFFAOYSA-N 1-(2-pyrrolidin-1-ylethyl)-6-(4-thiophen-3-ylpiperazin-1-yl)pyrrolo[2,3-b]pyridine Chemical compound N1(CCCC1)CCN1C=CC=2C1=NC(=CC=2)N1CCN(CC1)C1=CSC=C1 WERVLLXLWODAKP-UHFFFAOYSA-N 0.000 claims description 3
- ZMTIEYZYRTYBLC-UHFFFAOYSA-N 1-[4-[4-[1-(1-methylpyrazol-4-yl)-3-piperazin-1-ylpyrrolo[3,2-b]pyridin-5-yl]piperazin-1-yl]phenyl]ethanone Chemical compound CN1N=CC(=C1)N1C=C(C2=NC(=CC=C21)N1CCN(CC1)C1=CC=C(C=C1)C(C)=O)N1CCNCC1 ZMTIEYZYRTYBLC-UHFFFAOYSA-N 0.000 claims description 3
- SIQGNAFWKOJWKO-UHFFFAOYSA-N 1-[4-[4-[5-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydropyrido[4,3-b]indol-8-yl]piperazin-1-yl]phenyl]ethanone Chemical compound CN1N=CC(=C1)N1C2=C(C=3C=C(C=CC1=3)N1CCN(CC1)C1=CC=C(C=C1)C(C)=O)CNCC2 SIQGNAFWKOJWKO-UHFFFAOYSA-N 0.000 claims description 3
- DOWHAQDBQSYRII-UHFFFAOYSA-N 1-methyl-5-[4-(4-methylsulfonylphenyl)piperazin-1-yl]-3-(1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2,3-c]pyridine Chemical compound CN1C=C(C=2C1=CN=C(C=2)N1CCN(CC1)C1=CC=C(C=C1)S(=O)(=O)C)C=1CCNCC=1 DOWHAQDBQSYRII-UHFFFAOYSA-N 0.000 claims description 3
- YALVUBGLEGMUEG-UHFFFAOYSA-N 1-methyl-5-[4-(4-methylsulfonylphenyl)piperazin-1-yl]spiro[2H-indole-3,4'-piperidine] Chemical compound CN1CC2(CCNCC2)C2=CC(=CC=C12)N1CCN(CC1)C1=CC=C(C=C1)S(=O)(=O)C YALVUBGLEGMUEG-UHFFFAOYSA-N 0.000 claims description 3
- MUCWDACENIACBH-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine-3-carbonitrile Chemical compound C1=CC=C2C(C#N)=CNC2=N1 MUCWDACENIACBH-UHFFFAOYSA-N 0.000 claims description 3
- UAOJEEXCZGKPCR-UHFFFAOYSA-N 2-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)-7-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-d]pyrimidine Chemical compound N=1C=CN2C=1C=CC=C2N1CCN(CC1)C=1N=CC2=C(N=1)N(C=C2)CCN1CCCC1 UAOJEEXCZGKPCR-UHFFFAOYSA-N 0.000 claims description 3
- RLRCLUCRYMCWET-UHFFFAOYSA-N 2-[4-[1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridin-6-yl]piperazin-1-yl]pyridine-3-carbonitrile Chemical compound C1(=CC=C2C(=N1)N(C=C2)CCN1CCCC1)N1CCN(C2=C(C=CC=N2)C#N)CC1 RLRCLUCRYMCWET-UHFFFAOYSA-N 0.000 claims description 3
- KFGPIQZCLNVUHP-UHFFFAOYSA-N 2-[6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)pyrrolo[2,3-b]pyridin-1-yl]ethanamine Chemical compound N=1C=CN2C=1C=CC=C2N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN KFGPIQZCLNVUHP-UHFFFAOYSA-N 0.000 claims description 3
- WAVSGJYDJAVUSC-UHFFFAOYSA-N 3-[4-(4-methylsulfonylphenyl)piperazin-1-yl]-5-piperazin-1-yl-1,2-benzoxazole Chemical compound CS(=O)(=O)C1=CC=C(C=C1)N1CCN(CC1)C1=NOC2=C1C=C(C=C2)N1CCNCC1 WAVSGJYDJAVUSC-UHFFFAOYSA-N 0.000 claims description 3
- QCVLMBYZCCTXRB-UHFFFAOYSA-N 3-methyl-6-[4-(4-methylsulfonylphenyl)piperazin-1-yl]-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound CC1=CN(C2=NC(=CC=C21)N1CCN(CC1)C1=CC=C(C=C1)S(=O)(=O)C)CCN1CCCC1 QCVLMBYZCCTXRB-UHFFFAOYSA-N 0.000 claims description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- WSADAXCOJWKCIW-UHFFFAOYSA-N 5-[4-(4-acetylphenyl)piperazin-1-yl]-1-(oxetan-3-yl)-3-piperidin-4-ylimidazo[4,5-b]pyridin-2-one Chemical compound C(C)(=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C(N2C1COC1)=O)C1CCNCC1 WSADAXCOJWKCIW-UHFFFAOYSA-N 0.000 claims description 3
- CSKHAITZOFAVQQ-UHFFFAOYSA-N 5-[4-(4-acetylphenyl)piperazin-1-yl]-3-(4-methylpiperidin-4-yl)-1-(oxetan-3-yl)imidazo[4,5-b]pyridin-2-one Chemical compound C(C)(=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C(N2C1COC1)=O)C1(CCNCC1)C CSKHAITZOFAVQQ-UHFFFAOYSA-N 0.000 claims description 3
- YSVACTKGKRPFDT-UHFFFAOYSA-N 5-[4-(4-methylsulfonylphenyl)piperazin-1-yl]-1-(2-pyrrolidin-1-ylethyl)imidazo[4,5-b]pyridine Chemical compound CS(=O)(=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C2C(=N1)N=CN2CCN1CCCC1 YSVACTKGKRPFDT-UHFFFAOYSA-N 0.000 claims description 3
- FICLXCZQHOLAIX-UHFFFAOYSA-N 5-[4-(4-methylsulfonylphenyl)piperazin-1-yl]-3-(2-pyrrolidin-1-ylethyl)imidazo[4,5-b]pyridine Chemical compound CS(=O)(=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C=N2)CCN1CCCC1 FICLXCZQHOLAIX-UHFFFAOYSA-N 0.000 claims description 3
- QQBOCFVTGNCPQJ-UHFFFAOYSA-N 5-[4-(4-methylsulfonylphenyl)piperazin-1-yl]-3-piperazin-1-yl-1,2-benzoxazole Chemical compound CS(=O)(=O)C1=CC=C(C=C1)N1CCN(CC1)C=1C=CC2=C(C(=NO2)N2CCNCC2)C=1 QQBOCFVTGNCPQJ-UHFFFAOYSA-N 0.000 claims description 3
- YBDRIUVWLVAIRS-UHFFFAOYSA-N 6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)-1-(2-piperazin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound N1(CCNCC1)CCN1C=CC=2C1=NC(=CC=2)N1CCN(CC1)C1=CC=CC=2N1C=CN=2 YBDRIUVWLVAIRS-UHFFFAOYSA-N 0.000 claims description 3
- HFOGCHVKHHWKEW-UHFFFAOYSA-N 6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)-1-(2-pyrrolidin-1-ylethyl)pyrrolo[3,2-c]pyridine Chemical compound C1=C2C(=CC(=N1)N1CCN(CC1)C=1N3C=CN=C3C=CC=1)N(C=C2)CCN1CCCC1 HFOGCHVKHHWKEW-UHFFFAOYSA-N 0.000 claims description 3
- RYPVZZVCINWNLB-UHFFFAOYSA-N 6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)-1-(2-pyrrolidin-3-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound C1=C(N2CCN(CC2)C=2N3C=CN=C3C=CC=2)N=C2C(C=CN2CCC2CCNC2)=C1 RYPVZZVCINWNLB-UHFFFAOYSA-N 0.000 claims description 3
- UWUOADPRIWIWHC-UHFFFAOYSA-N 6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)-1-[2-(2-methylimidazol-1-yl)ethyl]pyrrolo[2,3-b]pyridine Chemical compound CC=1N(C=CN=1)CCN1C=CC=2C1=NC(=CC=2)N1CCN(CC1)C1=CC=CC=2N1C=CN=2 UWUOADPRIWIWHC-UHFFFAOYSA-N 0.000 claims description 3
- FPCHNEAMERNJBM-UHFFFAOYSA-N 6-(4-imidazo[1,2-a]pyridin-6-ylpiperazin-1-yl)-1-(2-pyrrolidin-1-ylethyl)pyrrolo[3,2-c]pyridine Chemical compound N1(CCCC1)CCN1C=CC=2C=NC(=CC=21)N1CCN(CC1)C=1C=CC=2N(C=1)C=CN=2 FPCHNEAMERNJBM-UHFFFAOYSA-N 0.000 claims description 3
- IZVAOLYBTILNME-UHFFFAOYSA-N 6-[4-(2-methylphenyl)piperazin-1-yl]-1-(2-pyrrolidin-1-ylethyl)pyrrolo[3,2-c]pyridine Chemical compound N1=CC2=C(C=C1N1CCN(C3=CC=CC=C3C)CC1)N(C=C2)CCN1CCCC1 IZVAOLYBTILNME-UHFFFAOYSA-N 0.000 claims description 3
- AOMSYPAEPBQEIP-UHFFFAOYSA-N 6-[4-(3-methoxypyridin-2-yl)piperazin-1-yl]-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound COC=1C(=NC=CC=1)N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CCCC1 AOMSYPAEPBQEIP-UHFFFAOYSA-N 0.000 claims description 3
- CVRHMWVXTISNQQ-UHFFFAOYSA-N 6-[4-(4-acetyl-2-methylphenyl)piperazin-1-yl]-1-[3-(methylamino)cyclobutyl]pyrrolo[2,3-b]pyridine-3-carbonitrile Chemical compound C(C)(=O)C1=CC(=C(C=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2C#N)C1CC(C1)NC)C CVRHMWVXTISNQQ-UHFFFAOYSA-N 0.000 claims description 3
- UUIYVQLLYPSOJK-UHFFFAOYSA-N 6-[4-(4-acetylphenyl)phenyl]-1-[3-(methylamino)cyclobutyl]pyrrolo[2,3-b]pyridine-3-carbonitrile Chemical compound C(C)(=O)C1=CC=C(C=C1)C1=CC=C(C=C1)C1=CC=C2C(=N1)N(C=C2C#N)C1CC(C1)NC UUIYVQLLYPSOJK-UHFFFAOYSA-N 0.000 claims description 3
- JPGALXHZQSZPHD-UHFFFAOYSA-N 6-[4-(4-methylsulfonylphenyl)piperazin-1-yl]-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine-3-carbonitrile Chemical compound CS(=O)(=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2C#N)CCN1CCCC1 JPGALXHZQSZPHD-UHFFFAOYSA-N 0.000 claims description 3
- PBLQGJDKDXBCCK-UHFFFAOYSA-N 6-[4-(4-methylsulfonylphenyl)piperazin-1-yl]-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine-4-carbonitrile Chemical compound CS(=O)(=O)C1=CC=C(C=C1)N1CCN(CC1)C=1C=C(C2=C(N=1)N(C=C2)CCN1CCCC1)C#N PBLQGJDKDXBCCK-UHFFFAOYSA-N 0.000 claims description 3
- OBEMHLMINVRHLF-UHFFFAOYSA-N 6-[4-(4-methylsulfonylphenyl)piperazin-1-yl]-2-(2-pyrrolidin-1-ylethyl)pyrazolo[3,4-b]pyridine Chemical compound CS(=O)(=O)C1=CC=C(C=C1)N1CCN(CC1)C=1C=CC=2C(N=1)=NN(C=2)CCN1CCCC1 OBEMHLMINVRHLF-UHFFFAOYSA-N 0.000 claims description 3
- QWEKIPWMBRQQAO-UHFFFAOYSA-N 6-[4-[1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridin-6-yl]piperazin-1-yl]pyridine-2-carbonitrile Chemical compound C1(=CC=C2C(=N1)N(C=C2)CCN1CCCC1)N1CCN(CC1)C1=NC(=CC=C1)C#N QWEKIPWMBRQQAO-UHFFFAOYSA-N 0.000 claims description 3
- ABVNNLJYBNFWSL-UHFFFAOYSA-N 6-[4-[4-(1,1-dimethoxyethyl)phenyl]piperazin-1-yl]-5-fluoro-1-[3-(methylamino)cyclobutyl]pyrrolo[2,3-b]pyridine-3-carbonitrile Chemical compound COC(C)(OC)C1=CC=C(C=C1)N1CCN(CC1)C1=C(C=C2C(=N1)N(C=C2C#N)C1CC(C1)NC)F ABVNNLJYBNFWSL-UHFFFAOYSA-N 0.000 claims description 3
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- ZLCABRIABGGRRK-UHFFFAOYSA-N 1-[2-[3-(4,4-difluoropiperidin-1-yl)azetidin-1-yl]ethyl]-6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)pyrrolo[2,3-b]pyridine Chemical compound FC1(CCN(CC1)C1CN(C1)CCN1C=CC=2C1=NC(=CC=2)N1CCN(CC1)C1=CC=CC=2N1C=CN=2)F ZLCABRIABGGRRK-UHFFFAOYSA-N 0.000 claims description 2
- HDFAAJJLYCKLKV-UHFFFAOYSA-N 1-[2-[6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)pyrrolo[2,3-b]pyridin-1-yl]ethyl]-3-phenylazetidin-3-ol Chemical compound N=1C=CN2C=1C=CC=C2N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CC(C1)(O)C1=CC=CC=C1 HDFAAJJLYCKLKV-UHFFFAOYSA-N 0.000 claims description 2
- YBKCRLRILJLONK-UHFFFAOYSA-N 1-[2-[6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)pyrrolo[2,3-b]pyridin-1-yl]ethyl]-N,N-dimethylpyrrolidin-3-amine Chemical compound N=1C=CN2C=1C=CC=C2N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CC(CC1)N(C)C YBKCRLRILJLONK-UHFFFAOYSA-N 0.000 claims description 2
- OUDSRZIECBGYIT-UHFFFAOYSA-N 1-[2-[6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)pyrrolo[2,3-b]pyridin-1-yl]ethyl]pyrrolidin-2-one Chemical compound N=1C=CN2C=1C=CC=C2N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1C(CCC1)=O OUDSRZIECBGYIT-UHFFFAOYSA-N 0.000 claims description 2
- KXEYYEWYIGRWNZ-UHFFFAOYSA-N 1-[3-(methylamino)cyclobutyl]-6-[4-[4-(2,2,2-trifluoroacetyl)phenyl]piperazin-1-yl]pyrrolo[2,3-b]pyridine-3-carbonitrile Chemical compound CNC1CC(C1)N1C=C(C=2C1=NC(=CC=2)N1CCN(CC1)C1=CC=C(C=C1)C(C(F)(F)F)=O)C#N KXEYYEWYIGRWNZ-UHFFFAOYSA-N 0.000 claims description 2
- AUKPDQZCWLFSQZ-UHFFFAOYSA-N 1-[4-[1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridin-6-yl]piperazin-1-yl]isoquinoline Chemical compound N1(CCCC1)CCN1C=CC=2C1=NC(=CC=2)N1CCN(CC1)C1=NC=CC2=CC=CC=C12 AUKPDQZCWLFSQZ-UHFFFAOYSA-N 0.000 claims description 2
- IISHOCGBCROFLB-UHFFFAOYSA-N 1-[4-[4-[3-(2-methylpyridin-3-yl)-1-piperidin-4-ylpyrrolo[2,3-b]pyridin-6-yl]piperazin-1-yl]phenyl]ethanone Chemical compound CC1=NC=CC=C1C1=CN(C2=NC(=CC=C21)N1CCN(CC1)C1=CC=C(C=C1)C(C)=O)C1CCNCC1 IISHOCGBCROFLB-UHFFFAOYSA-N 0.000 claims description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- BRXIULDSMQZRKH-UHFFFAOYSA-N 2-[2-[6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)pyrrolo[2,3-b]pyridin-1-yl]ethyl]-3,4-dihydro-1H-isoquinoline Chemical compound N=1C=CN2C=1C=CC=C2N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CC2=CC=CC=C2CC1 BRXIULDSMQZRKH-UHFFFAOYSA-N 0.000 claims description 2
- XWDQABXXBIXYTI-UHFFFAOYSA-N 2-[4-[1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridin-6-yl]piperazin-1-yl]quinoline Chemical compound N1(CCCC1)CCN1C=CC=2C1=NC(=CC=2)N1CCN(CC1)C1=NC2=CC=CC=C2C=C1 XWDQABXXBIXYTI-UHFFFAOYSA-N 0.000 claims description 2
- UTHVAJDDNAWOIY-UHFFFAOYSA-N 2-[6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)pyrrolo[2,3-b]pyridin-1-yl]-N,N-dimethylethanamine Chemical compound N=1C=CN2C=1C=CC=C2N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN(C)C UTHVAJDDNAWOIY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- VPIWKZGOIJUDMM-UHFFFAOYSA-N 3-[4-[1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridin-6-yl]piperazin-1-yl]benzonitrile Chemical compound N1(CCCC1)CCN1C=CC=2C1=NC(=CC=2)N1CCN(CC1)C=1C=C(C#N)C=CC=1 VPIWKZGOIJUDMM-UHFFFAOYSA-N 0.000 claims description 2
- ASWXDBZNZPXVEO-UHFFFAOYSA-N 4-[4-[1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridin-6-yl]piperazin-1-yl]benzonitrile Chemical compound N1(CCCC1)CCN1C=CC=2C1=NC(=CC=2)N1CCN(CC1)C1=CC=C(C#N)C=C1 ASWXDBZNZPXVEO-UHFFFAOYSA-N 0.000 claims description 2
- BUWWQFWNVSZCDI-UHFFFAOYSA-N 4-[4-[1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridin-6-yl]piperazin-1-yl]phenol Chemical compound N1(CCCC1)CCN1C=CC=2C1=NC(=CC=2)N1CCN(CC1)C1=CC=C(C=C1)O BUWWQFWNVSZCDI-UHFFFAOYSA-N 0.000 claims description 2
- GPUNPIZKBAISKV-UHFFFAOYSA-N 4-phenyl-1-[1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridin-6-yl]piperidin-4-ol Chemical compound C1(=CC=CC=C1)C1(CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CCCC1)O GPUNPIZKBAISKV-UHFFFAOYSA-N 0.000 claims description 2
- KEWXCIZMMYPJFB-UHFFFAOYSA-N 4-phenyl-1-[1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridin-6-yl]piperidine-4-carbonitrile Chemical compound C1(=CC=CC=C1)C1(CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CCCC1)C#N KEWXCIZMMYPJFB-UHFFFAOYSA-N 0.000 claims description 2
- FWYAEXHJHSDVSS-UHFFFAOYSA-N 5-[4-(4-acetylphenyl)piperazin-1-yl]-1-(1-methylpyrazol-3-yl)-3-piperidin-4-ylimidazo[4,5-b]pyridin-2-one Chemical compound C(C)(=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C(N2C1=NN(C=C1)C)=O)C1CCNCC1 FWYAEXHJHSDVSS-UHFFFAOYSA-N 0.000 claims description 2
- SYEFZYUVHKXYFN-UHFFFAOYSA-N 5-[4-(4-acetylphenyl)piperazin-1-yl]-1-(1-methylpyrazol-4-yl)-3-piperidin-4-ylimidazo[4,5-b]pyridin-2-one Chemical compound C(C)(=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C(N2C=1C=NN(C=1)C)=O)C1CCNCC1 SYEFZYUVHKXYFN-UHFFFAOYSA-N 0.000 claims description 2
- XPCZGNDRCCTLDG-UHFFFAOYSA-N 5-[4-(4-acetylphenyl)piperazin-1-yl]-3-(4-methylpiperidin-4-yl)-1-(1-methylpyrazol-4-yl)imidazo[4,5-b]pyridin-2-one Chemical compound C(C)(=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C(N2C=1C=NN(C=1)C)=O)C1(CCNCC1)C XPCZGNDRCCTLDG-UHFFFAOYSA-N 0.000 claims description 2
- IYTRZJBLDURSRN-UHFFFAOYSA-N 5-[4-(4-acetylphenyl)piperazin-1-yl]-3-[3-(methylamino)cyclobutyl]-1-(1-methylpyrazol-4-yl)imidazo[4,5-b]pyridin-2-one Chemical compound C(C)(=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C(N2C=1C=NN(C=1)C)=O)C1CC(C1)NC IYTRZJBLDURSRN-UHFFFAOYSA-N 0.000 claims description 2
- RKAUYTJBBZGBIS-UHFFFAOYSA-N 5-[4-(4-methylsulfonylphenyl)piperazin-1-yl]-3-piperazin-1-ylthieno[3,2-b]pyridine Chemical compound CS(=O)(=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C2C(=N1)C(=CS2)N1CCNCC1 RKAUYTJBBZGBIS-UHFFFAOYSA-N 0.000 claims description 2
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
- CRQFCJSSUKUEKZ-UHFFFAOYSA-N 6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)-1-(2-piperidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound N1(CCCCC1)CCN1C=CC=2C1=NC(=CC=2)N1CCN(CC1)C1=CC=CC=2N1C=CN=2 CRQFCJSSUKUEKZ-UHFFFAOYSA-N 0.000 claims description 2
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- MWUABDQBGBTCQG-UHFFFAOYSA-N 6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)-1-[2-(2-phenylazetidin-1-yl)ethyl]pyrrolo[2,3-b]pyridine Chemical compound C1(=CC=CC=C1)C1N(CC1)CCN1C=CC=2C1=NC(=CC=2)N1CCN(CC1)C1=CC=CC=2N1C=CN=2 MWUABDQBGBTCQG-UHFFFAOYSA-N 0.000 claims description 2
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- GNDDYDAGRTZCCQ-UHFFFAOYSA-N 6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)-1-[2-(3-phenoxypyrrolidin-1-yl)ethyl]pyrrolo[2,3-b]pyridine Chemical compound O(C1=CC=CC=C1)C1CN(CC1)CCN1C=CC=2C1=NC(=CC=2)N1CCN(CC1)C1=CC=CC=2N1C=CN=2 GNDDYDAGRTZCCQ-UHFFFAOYSA-N 0.000 claims description 2
- BUYVZGMDFUCTKW-UHFFFAOYSA-N 6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)-1-[2-(3-pyrrolidin-1-ylazetidin-1-yl)ethyl]pyrrolo[2,3-b]pyridine Chemical compound N1(CCCC1)C1CN(C1)CCN1C=CC=2C1=NC(=CC=2)N1CCN(CC1)C1=CC=CC=2N1C=CN=2 BUYVZGMDFUCTKW-UHFFFAOYSA-N 0.000 claims description 2
- FOJKIBKTZTTWIZ-UHFFFAOYSA-N 6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)-1-[2-(oxolan-3-yl)ethyl]pyrrolo[2,3-b]pyridine Chemical compound N=1C=CN2C=1C=CC=C2N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCC1COCC1 FOJKIBKTZTTWIZ-UHFFFAOYSA-N 0.000 claims description 2
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- FEEDISIKQNEIPO-UHFFFAOYSA-N 6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)-1-[2-[3-(1-methylimidazol-2-yl)pyrrolidin-1-yl]ethyl]pyrrolo[2,3-b]pyridine Chemical compound CN1C(=NC=C1)C1CN(CC1)CCN1C=CC=2C1=NC(=CC=2)N1CCN(CC1)C1=CC=CC=2N1C=CN=2 FEEDISIKQNEIPO-UHFFFAOYSA-N 0.000 claims description 2
- ZFTGFYBNODTAGY-UHFFFAOYSA-N 6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)-1-[2-[4-(2-methylpyrazol-3-yl)piperidin-1-yl]ethyl]pyrrolo[2,3-b]pyridine Chemical compound N=1C=CN2C=1C=CC=C2N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CCC(CC1)C=1N(N=CC=1)C ZFTGFYBNODTAGY-UHFFFAOYSA-N 0.000 claims description 2
- AJJAJBXRFHOIKO-UHFFFAOYSA-N 6-(4-imidazo[1,2-a]pyridin-5-ylpiperazin-1-yl)-1-[2-[4-(oxetan-3-yl)piperidin-1-yl]ethyl]pyrrolo[2,3-b]pyridine Chemical compound N=1C=CN2C=1C=CC=C2N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CCC(CC1)C1COC1 AJJAJBXRFHOIKO-UHFFFAOYSA-N 0.000 claims description 2
- UUBHYQKQQSERRH-UHFFFAOYSA-N 6-(4-imidazo[1,2-a]pyridin-6-ylpiperazin-1-yl)-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound N1(CCCC1)CCN1C=CC=2C1=NC(=CC=2)N1CCN(CC1)C=1C=CC=2N(C=1)C=CN=2 UUBHYQKQQSERRH-UHFFFAOYSA-N 0.000 claims description 2
- RYYXRGXUGKTSTM-UHFFFAOYSA-N 6-(4-methylpiperazin-1-yl)-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound CN1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CCCC1 RYYXRGXUGKTSTM-UHFFFAOYSA-N 0.000 claims description 2
- CZZBNBBNIBKPLV-UHFFFAOYSA-N 6-(4-phenylpiperazin-1-yl)-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound C1(=CC=CC=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CCCC1 CZZBNBBNIBKPLV-UHFFFAOYSA-N 0.000 claims description 2
- HFXRKGORTUYIEP-UHFFFAOYSA-N 6-(4-phenylpiperidin-1-yl)-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound C1(=CC=CC=C1)C1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CCCC1 HFXRKGORTUYIEP-UHFFFAOYSA-N 0.000 claims description 2
- YASYFGZKMCSZCS-UHFFFAOYSA-N 6-(4-pyridin-2-ylpiperazin-1-yl)-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound N1=C(C=CC=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CCCC1 YASYFGZKMCSZCS-UHFFFAOYSA-N 0.000 claims description 2
- KYOBTRKHROBWDW-UHFFFAOYSA-N 6-(4-pyridin-3-ylpiperazin-1-yl)-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound N1=CC(=CC=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CCCC1 KYOBTRKHROBWDW-UHFFFAOYSA-N 0.000 claims description 2
- MOGATEPQZDNFJS-UHFFFAOYSA-N 6-(4-pyridin-4-ylpiperazin-1-yl)-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound N1=CC=C(C=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CCCC1 MOGATEPQZDNFJS-UHFFFAOYSA-N 0.000 claims description 2
- TYSUHBKKLGUYOM-OAQYLSRUSA-N 6-[(2R)-2-methyl-4-(2-methylphenyl)piperazin-1-yl]-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound C[C@H]1N(CCN(C1)C1=C(C=CC=C1)C)C1=CC=C2C(=N1)N(C=C2)CCN1CCCC1 TYSUHBKKLGUYOM-OAQYLSRUSA-N 0.000 claims description 2
- GWLIRJGQTVTEGB-NRFANRHFSA-N 6-[(3S)-3-methyl-4-(2-methylphenyl)piperazin-1-yl]-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound C[C@H]1CN(CCN1C1=C(C=CC=C1)C)C1=CC=C2C(=N1)N(C=C2)CCN1CCCC1 GWLIRJGQTVTEGB-NRFANRHFSA-N 0.000 claims description 2
- DSHFIECIHFYQFX-UHFFFAOYSA-N 6-[4-(2-methoxyphenyl)piperazin-1-yl]-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound COC1=C(C=CC=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CCCC1 DSHFIECIHFYQFX-UHFFFAOYSA-N 0.000 claims description 2
- UAXOMYKRXHTQML-UHFFFAOYSA-N 6-[4-(2-methylphenyl)piperazin-1-yl]-1-[2-(3-pyridin-2-ylpyrrolidin-1-yl)ethyl]pyrrolo[2,3-b]pyridine Chemical compound CC1=C(C=CC=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CC(CC1)C1=NC=CC=C1 UAXOMYKRXHTQML-UHFFFAOYSA-N 0.000 claims description 2
- GMMYXZLIURSLHN-UHFFFAOYSA-N 6-[4-(2-methylphenyl)piperazin-1-yl]-1-[2-(4-methylpiperazin-1-yl)ethyl]pyrrolo[2,3-b]pyridine Chemical compound CC1=C(C=CC=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CCN(CC1)C GMMYXZLIURSLHN-UHFFFAOYSA-N 0.000 claims description 2
- JHYYDNRORIDJPJ-OAQYLSRUSA-N 6-[4-(2-methylphenyl)piperazin-1-yl]-1-[2-[(2R)-2-methylpyrrolidin-1-yl]ethyl]pyrrolo[2,3-b]pyridine Chemical compound CC1=C(C=CC=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1[C@@H](CCC1)C JHYYDNRORIDJPJ-OAQYLSRUSA-N 0.000 claims description 2
- ALBOQTZAIUZTSM-UHFFFAOYSA-N 6-[4-(2-methylsulfonylphenyl)piperazin-1-yl]-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound CS(=O)(=O)C1=C(C=CC=C1)N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CCCC1 ALBOQTZAIUZTSM-UHFFFAOYSA-N 0.000 claims description 2
- OXEZYAPECVRFJD-UHFFFAOYSA-N 6-[4-(3-chlorophenyl)piperazin-1-yl]-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound ClC=1C=C(C=CC=1)N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CCCC1 OXEZYAPECVRFJD-UHFFFAOYSA-N 0.000 claims description 2
- QEJSVCUNIWXPED-UHFFFAOYSA-N 6-[4-(3-methoxyphenyl)piperazin-1-yl]-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound COC=1C=C(C=CC=1)N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CCCC1 QEJSVCUNIWXPED-UHFFFAOYSA-N 0.000 claims description 2
- JRNCXJWUHIBQQV-UHFFFAOYSA-N 6-[4-(3-methylphenyl)piperazin-1-yl]-1-(2-pyrrolidin-1-ylethyl)pyrrolo[2,3-b]pyridine Chemical compound CC=1C=C(C=CC=1)N1CCN(CC1)C1=CC=C2C(=N1)N(C=C2)CCN1CCCC1 JRNCXJWUHIBQQV-UHFFFAOYSA-N 0.000 claims description 2
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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Abstract
本发明涉及6,5杂双环衍生物,制备它们的方法,含有它们的药物组合物和它们用于治疗受STING激活驱动的炎性病况比如但不限制于SLE和地图样萎缩的用途。
Description
发明领域
本发明涉及6,5杂双环衍生物,制备它们的方法,含有它们的药物组合物和它们用于治疗受STING激活驱动的炎性病况比如但不限制于SLE和地图样萎缩的用途。
6,5杂双环衍生物可以用作STING(干扰素基因刺激蛋白)拮抗剂,其抑制STING途径。
背景技术
身体对组织损伤的应答是产生炎性反应。通常该反应是自限性的并且能够除去受损组织,抗击任何传染性微生物和恢复组织的正常功能。该先天免疫应答使用模式识别受体(PRRs),其可以分为识别特定微生物产物的那些(病原物有关的分子模式;PAMPs)和识别宿主分子的那些(损伤相关的分子模式;DAMPs)。响应PAMPs的价值是清楚的,但响应DAMPs同样重要,原因在于其放大炎性反应和使得在感染有机会压倒宿主之前就得到早期控制。
来自病毒和细菌的DNA和自身DNA(细胞核或线粒体)分别能够充当PAMPs和DAMPs(Paludan SR&Bowie AG(2013).Immune sensing of DNA.Immunity,38:870-880)。许多DNAPRRs已被识别,包括细胞质室中的环状GMP AMP合成酶(cGAS)。cGAS显得几乎不显示微生物DNA或自身DNA之间的区分,但是激活程度取决于DNA的长度、其结构和其是否是氧化的(Andreeva L et al(2017).cGAS Senses Long and HMGB/TFAM-bound U-Turn DNA byForming Protein-DNA Ladders.Nature 549:394-398)。在并无感染或组织损伤的情况下cGAS是沉默的,部分是因为自身DNA隔离在细胞核和线粒体中,和部分是因为DNA酶的活性,其负责自细胞和细胞器的低生理学水平的DNA渗漏。
在cGAS结合DNA的情况下其发生构象变化和获得酶活性,它使用ATP和GTP作为底物并且产生环状二核苷酸2’,3’-cGAMP产物。2’,3’-cGAMP连接作为二聚体存在于内质网上的衔接蛋白STING。STING的构象变化触发一系列事件,包括易位至反式Golgi网络,募集tank结合激酶TBK1,和底物IRF3、IKK和STAT 6的磷酸化导致I型干扰素应答,促炎细胞因子和趋化因子(Li,Y(2017).Regulating STING in health and disease.Journal ofInflammation 14:11)。激活也例如通过炎症体(inflammasome)激活关联细胞死亡途径(Gaidt MM et al(2017).The DNA Inflammasome in Human Myeloid Cells IsInitiated by a STING-Cell Death Program Upstream of NLRP3.Cell 171:1110-1124)。
存在人工刺激cGAS STING途径可以有价值的情况。例如,强化宿主对感染的免疫应答或增强对肿瘤细胞的免疫学应答。出于这些意图正开发STING激动剂(Mullard A(2018).Can innate immune system targets turn up the heat on'cold'tumours?NatRev Drug Discov.17:3-5)。
反过来同理。原因是,虽然cGAS STING途径的激活是对组织损伤和感染的重要应答,但是该途径过度激活所诱导的炎性变化可以是有害的。产生蛋白质组成型激活的人类STING突变导致SAVI(STING相关的婴儿血管病变)(Liu,Y(2014).Activated STING in aVascular and Pulmonary Syndrome.The New England Journal of Medicine,371:507-518),受其影响的儿童患皮疹、皮肤溃疡和间质性肺病(严重SLE中能够发现的全部症状)。在SLE中,外周血液单核细胞中2’,3’-cGAMP的度量与具有较高疾病得分的患者相关(An Jet al(2017).Expression of Cyclic GMP-AMP Synthase in Patients With SystemicLupus Erythematosus.Arthritis Rheumatol.69:800-807),这指出cGAS STING途径在患更严重SLE的患者活跃并且意味着STING抑制剂的治疗潜力。
存在其它病况,其中DNA传感途径和尤其是cGAS STING途径可以导致病理学变化并且其中STING抑制剂可以具有效用。在全身性炎性反应综合征(SIRS)中和在重症护理患者中观察到的广泛组织损伤与类似脓毒症的症状有关,其可以解释为组织损伤衍生的DNA与先天免疫受体的广泛连接(Boyapati,RK et al.(2017).Advances in theunderstanding of mitochondrial DNA as a pathogenic factor in inflammatorydiseases.F1000Research 6:169)。在修复过程受限的组织比如心脏和脑中,对组织损伤的炎性反应能够有助于组织损伤。实验证据表明cGAS STING途径在心肌梗死中的损害作用(King,KR et al(2017).IRF3 and type I interferons fuel a fatal response tomyocardial infarction.Nat.Med.23:1481-1487)和cGAS和STING在CNS细胞中的表达(Jeffries AM&Marriott I(2017).Human microglia and astrocytes express cGAS-STING viral sensing components.Neurosci Lett.658:53-56)意味着相似机理可能在卒中情况下活跃。
尽管炎性反应是宿主防御所必需,但是存在这样的情况:对传染性微生物的宿主应答的活力本身就是问题。例如,N5N1感染(禽流感)的高死亡率是由渗出物在肺中的局部蓄积引起的,所述渗出物即来自受患者自身免疫应答侵袭的受损细胞(Short KR et al(2016).Influenza virus damages the alveolar barrier by disrupting epithelialcell tight junctions.Eur Respir J.47:954-66)。在这种情况下,可能需要限制先天免疫应答的程度从而抑制剂(可以包括STING抑制剂)能在这些情况下有使用价值。
受到关注的又一领域涉及组织变性。许多疾病与线粒体应激有关并且这已与线粒体DNA释放入细胞质能够激活cGAS STING途径建立联系。该机理导致视网膜色素上皮细胞死亡和在地图样萎缩中致盲(Kerur N et al(2018).cGAS drives noncanonical-inflammasome activation in age-related macular degeneration.Nat.Med.24:50-61)。该机理还可以在其它神经变性疾病比如帕金森病、肌萎缩性侧索硬化、阿尔茨海默氏病和外周变性病症比如骨关节炎中的软骨细胞死亡、胰岛细胞损失等中活跃。
从而,明确需要开发STING拮抗剂来探寻其在一系列存在高度未满足的医学需求的人类病况中的治疗潜力。
发明概要
本发明涉及6,5杂双环衍生物,制备它们的方法,含有它们的药物组合物和它们在治疗受STING激活驱动的炎性病况比如但不限制于SLE和地图样萎缩中的用途。
本发明的又一方面是新化合物,其展示功能上拮抗STING激活的能力。
本发明的其它各方面将通过详细描述而变得明显。
发明详述
在一个方面,本发明涉及通式I化合物,或其药学上可接受的酸加成盐,外消旋混合物或其相应的对映体和/或旋光异构体,
其中
-作为含有选自O、N、S的至少一个杂原子和C原子的6,5杂双环的中央核A能够任选由下述取代:卤素,氰基,C1-6烷基,三氟甲基,二氟甲基,(C2-6)烯基,羟基,(C1-6)烷氧基,二氟甲氧基,三氟甲氧基,三氟乙氧基,(C1-6)烷硫基,(C1-6)烷基磺酰基,氨基,(C1-6)烷基氨基,二(C1-6)烷基氨基,(C1-6)烷氧基(C1-6)烷基-氨基,N-[(C1-6)烷基]-N-[羟基(C1-6)烷基]氨基,(C2-6)烷基羰基氨基,(C2-6)烷氧羰基氨基,(C1-6)烷基磺酰基氨基,甲酰基,(C2-6)烷基羰基,羧基,(C2-6)烷氧羰基,氨基羰基,(C1-6)烷基氨基羰基,二(C1-6)烷基氨基羰基,氨基磺酰基,(C1-6)烷基氨基磺酰基或二(C1-6)烷基氨基磺酰基;(C3-7)杂环烷基或(C3-7)螺杂环烷基,所述基团中任一种可以任选由一个或多个取代基取代;
-R1代表任选经取代的烷基胺或环烷基胺,包括稠合环烷基胺和螺环烷基胺,包括(C1-3)氨基烷基,(C3-7)氨基环烷基,(C1-3)烷基咪唑,(C1-3)烷基异吲哚啉,(C1-3)烷基哌嗪,(C1-3)烷基哌啶,(C1-3)烷基咪唑并哌嗪,(C1-3)烷基(C4-7)氨基环烷基,(C1-3)烷基(C4-7)氨基二环烷基;和
-R2代表芳基,杂芳基,杂双环,(C4-7)氨基环烷基,环烷基,杂环烷基,(C6-8)二氨基环烷基,吗啉代,(C4-7)环烷基甲基,哌嗪基,哌啶基;R2任选用包括下述的基团取代:羟基,(C1-6)烷基,乙酰基,卤素,氰基,C1-6烷基,三氟甲基,二氟甲基,(C2-6)烯基,羟基,(C1-6)烷氧基,二氟甲氧基,三氟甲氧基,三氟乙氧基,(C1-6)烷硫基,(C1-6)烷基磺酰基,氨基,(C1-6)烷基氨基,二(C1-6)烷基氨基,(C1-6)烷氧基(C1-6)烷基-氨基,N-[(C1-6)烷基]-N-[羟基(C1-6)烷基]氨基,(C2-6)烷基羰基氨基,(C2-6)烷氧羰基氨基,(C1-6)烷基磺酰基氨基,甲酰基,(C2-6)烷基羰基,羧基,(C2-6)烷氧羰基,氨基羰基,(C1-6)烷基氨基羰基,二(C1-6)烷基氨基羰基,氨基磺酰基,(C1-6)烷基氨基磺酰基或二(C1-6)烷基氨基磺酰基;(C3-7)杂环烷基或(C3-7)螺杂环烷基,所述基团中任一种可以任选由一个或多个取代基取代。
-中央核A的实例选自
优选地,中央核A选自
根据本发明的又一实施方式,中央核A选自:
其中
L、U、V、W是C或N;
X、T是C、N或O;
Y是C、N或S;
-R1代表(C4-7)环烷基;(4-9-元)-杂环烷基;稠合环烷基胺;稠合杂环烷基胺;螺环烷基胺;螺杂环烷基胺;(C1-3)氨基烷基;(C3-7)氨基环烷基;(C1-3)烷基咪唑;(C1-3)烷基异吲哚啉;(C1-3)烷基哌嗪;(C1-3)烷基哌啶;(C1-3)烷基咪唑并哌嗪;(C1-3)烷基(C4-7)氨基环烷基;(C1-3)烷基(C4-7)氨基二环烷基;用一个或多个基团取代的(C1-3)烷基,所述基团选自(C4-7)环烷基,(4-9-元)-杂环烷基,稠合环烷基胺,稠合杂环烷基胺,螺环烷基胺,螺杂环烷基胺,(C1-C3)氨基烷基,(C3-C7)氨基环烷基,(C1-C3)烷基咪唑,(C1-C3)烷基异吲哚啉,(C1-C3)烷基哌嗪,(C1-C3)烷基哌啶,(C1-C3)烷基咪唑并哌嗪,(C1-C3)烷基(C4-C7)氨基环烷基,(C1-C3)烷基(C4-C7)氨基二环烷基;
R1任选用下述取代:卤素,羟基,(C1-C3)烷基,(C1-C3)烷基羧基,(C1-C3)烷基氨基,(C5-C6)杂芳基,其任选用下述取代:(C1-C3)烷基,卤素,(C3-C7)氨基环烷基,其用下述取代:卤素,芳基,芳基(C1-C3)烷基,芳基(C1-C3)烷基(C1-C3)二烷基胺,芳氧基;
-R2代表H;卤素;芳基;杂芳基;杂双环;(C4-C7)氨基环烷基;环烷基;杂环烷基;(C6-C8)二氨基环烷基;吗啉代;(C4-C7)环烷基甲基;哌嗪基;哌啶基;
R2任选用包括下述的基团取代:芳基;杂芳基;羟基;(C1-C6)烷基;乙酰基;卤素;氰基;(C1-C6)烷基;三氟甲基;二氟甲基;(C2-C6)烯基;羟基;(C1-C6)烷氧基;二氟甲氧基;三氟甲氧基;三氟乙氧基;(C1-C6)烷硫基;(C1-6)烷基磺酰基;氨基;(C1-C6)烷基氨基;二(C1-6)烷基氨基;(C1-C6)烷氧基(C1-6)烷基-氨基;N-[(C1-6)烷基]-N-[羟基(C1-C6)烷基]氨基;(C2-C6)烷基羰基氨基;(C2-C6)烷氧羰基氨基;(C1-C6)烷基磺酰基氨基;甲酰基;(C2-C6)烷基羰基;羧基;(C2-C6)烷氧羰基:氨基羰基:(C1-C6)烷基氨基羰基;二(C1-C6)烷基氨基羰基;氨基磺酰基,(C1-6)烷基氨基磺酰基或二(C1-6)烷基氨基磺酰基;(C3-7)杂环烷基或(C3-7)螺杂环烷基;所述基团中任一种可以任选由一个或多个取代基取代,所述取代基选自羟基,卤素,氨基,甲基氨基,二甲基氨基,(C1-3)烷基,(C1-3)烷氧基,磺酰基,(C1-3)羰基,(C1-4)烷基羧基,氰基,氧代,(C1-6)烷基(C5-10)杂芳基(C1-3)羰基,磺酰基,甲磺酰基,吡啶基;
-R3相互独立地选自H;卤素;氰基;(C4-7)杂环烷基,其任选用下述取代:(甲磺酰基)芳基,乙酰基,(C1-C3)烷基羰基;
-R4选自H;卤素;二氟甲基;三氟甲基;苯基;氰基;(C1-3)烷基;氨基(C1-3)烷基;(C4-C7)杂环烷基;(C4-C7)杂芳基,其中所述杂芳基任选用(C1-C3)烷基取代;(C4-C7)杂芳基-(C1-C3)烷基,其中所述杂芳基任选用(C1-C3)烷基取代;(C4-C7)杂芳基,其任选用下述取代:(C1-C3)烷基,氨基-羰基,(C1-C3)-烷基氨基-羰基;(C1-C3)-烷氧羰基;(C1-C3)烷基-磺酰基;(C4-C7)杂烷基-羰基;(C1-C3)烷基氨基-羰基;二(C1-C3)烷基氨基-羰基;
R5选自H;氧代;(C1-C3)烷基;(C4-C7)杂环烷基-(C1-C3)烷基;甲氧羰基;
其中
在T是O,X是N的情况下,则L、U、V、W是C;
在W和T是N的情况下,则X、Y、V、U、L是C;
在W和Y是N的情况下,则L、T、X、V、U是C;
在W、T、X是N的情况下,则Y、V、U、L是C;
在W、T、Y是N的情况下,L、X、V、U是C;
在V、W、T是N的情况下,L、X、Y、U是C;
在U、T是N的情况下,则L、X、Y、V、W是C;
在L、T、X是N的情况下,则Y、V、U是C;
在W是N,Y是N或S的情况下,则T、X、V、U、L是C;
在T是N和W、X、Y、V、U是C的情况下,则R4形成6-元碳环;和R1、R3是甲基,R2、R5是H;
在Y是N和L、U、V、W,T是C的情况下,则R1和R5一起形成6-元杂环,R3、R4是氢。
根据又一实施方式,中央核A选自下述:
其中
X是O、C或N,其中C任选用氧代部分取代,
Y是C、S或N,
A是C或N,任选用下述取代:1-C(1-4)-4-芳基-哌嗪或1-C(1-4)-4-杂芳基-哌嗪或1-(4-C(1-4)-芳基)哌嗪或1-(4-C(1-4)-杂芳基)哌嗪或1-C(1-4)-4-芳基-哌啶或1-C(1-4)-4-杂芳基-哌啶或1-(4-C(1-4)-芳基)哌啶或1-(4-C(1-4)-杂芳基)哌啶,其中芳基、杂芳基、哌嗪或哌啶基团上有任选取代;
R1选自H,乙基-氮杂二环[3.2.0]庚烷;或2-取代的-5-氮杂螺[3.4]辛烷;或任选用一个或多个(C1-3)烷基取代的乙基-2-吡咯烷,或(C4-7)环烷基胺,包括3-取代的-N-甲基-环丁烷胺和哌啶;
R2选自1-C(1-4)-4-芳基-哌嗪或1-C(1-4)-4-杂芳基-哌嗪或1-(4-C(1-4)-芳基)哌嗪或1-(4-C(1-4)-杂芳基)哌嗪或1-C(1-4)-4-芳基-哌啶或1-C(1-4)-4-杂芳基-哌啶或1-(4-C(1-4)-芳基)哌啶或1-(4-C(1-4)-杂芳基)哌啶,其中芳基、杂芳基、哌嗪或哌啶基团上有任选取代;
R3、R4相互独立地选自H,卤素,氰基,C1-6烷基,三氟甲基,二氟甲基,(C2-6)烯基,羟基,(C1-6)烷氧基,二氟甲氧基,三氟甲氧基,三氟乙氧基,(C1-6)烷硫基,(C1-6)烷基磺酰基,氨基,(C1-6)烷基氨基,二(C1-6)烷基氨基,(C1-6)烷氧基(C1-6)烷基-氨基,N-[(C1-6)烷基]-N-[羟基(C1-6)烷基]氨基,(C2-6)烷基羰基氨基,(C2-6)烷氧羰基氨基,(C1-6)烷基磺酰基氨基,甲酰基,(C2-6)烷基羰基,羧基,(C2-6)烷氧羰基,氨基羰基,(C1-6)烷基氨基羰基,二(C1-6)烷基氨基羰基,氨基磺酰基,(C1-6)烷基氨基磺酰基或二(C1-6)烷基氨基磺酰基;(C3-7)杂环烷基或(C3-7)螺杂环烷基;
R5选自H,2-(吡咯烷-1-基)乙基。
根据又一实施方式,核心A选自下述:
其中R1、R2、R3、R4和R5如本文定义。
在特定的实施方式中,中央核A是
通常,R1是乙基-氮杂二环[3.2.0]庚烷;或2-取代的-5-氮杂螺[3.4]辛烷;或乙基-2-甲基-吡咯烷或(C4-7)环烷基胺,包括3-取代的-N-甲基-环丁烷胺和哌啶。
优选地,R1是3-取代的-N-甲基-环丁烷胺。
在又一优选的实施方式中,R1是2-取代的-5-氮杂螺[3.4]辛烷。
在又一优选的实施方式中,R1是(C4-7)环烷基胺,包括3-取代的-N-甲基-环丁烷胺和哌啶。
通常,R2是1-取代的-4-芳基-哌嗪或1-取代的-4-杂芳基-哌嗪或1-(4-取代的-芳基)哌嗪或1-(4-取代的-杂芳基)哌嗪或1-取代的-4-芳基-哌啶或1-取代的4-杂芳基-哌啶或1-(4-取代的-芳基)哌啶或1-(4-取代的-杂芳基)哌啶,其中芳基、杂芳基、哌嗪或哌啶基团上有任选取代。
优选地,R2是1-取代的-4-芳基-哌嗪或1-取代的-4-杂芳基-哌嗪,1-取代的-4-芳基-哌啶或1-取代的-4-杂芳基-哌啶。
在又一特定实施方式中,式I化合物是那些,其中
-中央核A是
-R1是乙基-氮杂二环[3.2.0]庚烷;或2-取代的-5-氮杂螺[3.4]辛烷;或乙基-2-甲基-吡咯烷或(C4-7)环烷基胺,包括3-取代的-N-甲基-环丁烷胺和哌啶;
-R2是1-取代的-4-芳基-哌嗪或1-取代的-4-杂芳基-哌嗪或1-(4-取代的-芳基)哌嗪或1-(4-取代的-杂芳基)哌嗪或1-取代的-4-芳基-哌啶或1-取代的4-杂芳基-哌啶或1-(4-取代的-芳基)哌啶或1-(4-取代的-杂芳基)哌啶,其中芳基、杂芳基、哌嗪或哌啶基团上有任选取代。
在又一实施方式中,式I化合物是那些,其中
-中央核心A是
在又一优选特定实施方式中,式I化合物是那些,其中
-中央核A是
-R1是2-取代的-5-氮杂螺[3.4]辛烷或3-取代的-N-甲基-环丁烷胺或4-取代的哌啶;
-R2是1-取代的-4-芳基-哌嗪或1-取代的-4-杂芳基-哌嗪,1-取代的-4-芳基-哌啶或1-取代的-4-杂芳基-哌啶。
根据又一实施方式,本发明化合物是那些,其中核心A如前文所定义和
R1选自:
2-(吡咯烷-1-基)乙基,
1-(甲基)吡咯烷-3-基,
3-(甲基氨基)-环丁-1-基,
哌啶-3-基,
2-[(4-甲基)哌嗪-1-基]乙基,
N-(异丙基)-乙-2-基,
2-[(N,N-二甲基)氨基]吡咯烷-3-基,
2-(2-甲基甲氧基-吡咯烷-1-基)乙基,
3-甲氧基-吡咯烷-1-基-乙基,
2-(氮杂二环[3.1.0]己-2-基)乙基,
2-(八氢-1H-吡咯并[2,3-c]吡啶-1-基)乙基,
2-[(6-甲基)-八氢-1H-吡咯并[3,4-b]吡啶-1-基]乙基,
2-(5-甲基六氢吡咯并[3,4-b]吡咯-1(2H)-基)乙基,
2-(3-甲氧基氮杂环丁烷-1-基)乙基,
2-[(2R)-2-甲基吡咯烷-1-基]乙基,
2-[3-(吡啶-2-基)吡咯烷-1-基]乙基,
2-[3-(N,N-二甲基氨基)-吡咯烷-1-基]乙基,
2-(6-氮杂二环[3.2.0]庚-6-基)乙基,
2-氨基[N-苄基-N-甲基]乙基,
2-(3-苯氧基吡咯烷-1-基)乙基,
2-(2-苯基氮杂环丁烷-1-基)乙基,
2-[(氟苯基)氮杂环丁烷-1-基]乙基,
2-(3-苯氧基氮杂环丁烷-1-基)乙基,
2-[(3-羟基,3-苯基)氮杂环丁烷-1-基]乙基,
3-(甲基氨基)环丁-1-基,
2-[1-(甲基)吡咯烷-3-基]乙基,
3-二甲基氨基-环丁-1-基,
(3S)-1-(甲基)吡咯烷-3-基,
(3R)-1-(甲基)吡咯烷-3-基,
顺式-N-苄基-N-甲基-氨基-环丁-3-基,
反式-N-苄基-N-甲基-氨基-环丁-3-基,
2-(1-苄基吡咯烷-3-基)乙基,
(3S)-1-苄基吡咯烷-3-基,
(3R)-1-苄基吡咯烷-3-基,
2-(N,N,二甲基氨基)-乙基,
2-(1-氧杂-6-氮杂螺[3.4]辛-6-基)乙基,
2-(2-氧杂-7-氮杂螺[3.5]壬-7-基)乙基
2-(吡咯烷-3-基)乙基
反式-(3-甲基氨基)-丁-1-基,
3-哌嗪-1-基,
2-(氧杂环戊烷-3-基)乙基,
2-[(叔丁基-乙酸酯)吡咯烷-3-基]-乙基,
2-(吡咯烷-2-酮-1-基)乙基,
(3R)-吡咯烷-3-基,
(3S)-吡咯烷-3-基,
2-(5-氮杂螺[3.4]辛-5-基)乙基,
哌啶-4-基,
(3R,4R)-3-氟哌啶-4-基,
1-(甲基)哌啶-4-基,
反式-3-氨基-环丁-1-基,
反式-N-甲基-3氨基-环丁-1-基,
2-氮杂螺[3.3]庚烷-6-基
顺式-1-(N-甲基氨基)环己-4-基
反式-1-(N-甲基氨基)环己-4-基
奎宁环-3-基,
1-甲基-哌啶-3-基,
1-甲基-哌啶-4-基,
3-(N,N-二甲基氨基-甲酰胺)氮杂环丁烷-1-基,
2-(3-咪唑-1-基吡咯烷-1-基)乙基,
3-(甲烷磺酰氨基)氮杂环丁烷-1-基,
2-(3-氟-3-甲基-吡咯烷-1-基)乙基,
2-[4-(2-甲基吡唑-3-基)-哌啶-1-基]乙基,
2-[4-(氧杂环丁烷-3-基)-哌啶-1-基]乙基,
2-(3,4-二氢-1H-异醌醇-1-基)乙基,
N-甲基氨基环丁-3-基,
5-氮杂螺[3.4]辛烷-2-基,
1,2,3,6-四氢吡啶-4-基
4-(甲基)哌啶-4-基,
哌啶-4-基,
哌嗪-3-基;
R2选自:
H,
氯,
(3S)-3-甲基-4-(2-甲基苯基)哌嗪-1-基,
(2S)-2-甲基-4-(2-甲基苯基)哌嗪-1-基,
4-[2-(甲磺酰基)苯基]哌嗪-1-基,
(2R)-2-甲基-4-(2-甲基苯基)哌嗪-1-基,
4-苯基哌嗪-1-基,
4-[4-(甲磺酰基)苯基]哌嗪-1-基,
4-[3-(甲磺酰基)苯基]哌嗪-1-基,
4-(乙基苯甲酸酯)哌嗪-1-基,
4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基,
4-(吡啶-2-基)哌嗪-1-基,
4-(吡啶-3-基)哌嗪-1-基,
4-(吡啶-4-基)哌嗪-1-基,
吡咯烷-1-基,
4-[4-(甲磺酰基)苯基]哌嗪-1-基,
4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基,
4-(4-乙酰基苯基)哌嗪-1-基,
4-(6-氰基吡啶-2-基)哌嗪-1-基,
4-(乙酰基苯基)哌嗪-1-基,
4-(甲磺酰基)苯基]哌嗪-1-基,
4-羟基-4-苯基-哌啶-1-基,
4-苯基哌啶-1-基
4-苯基-4-氰基-哌啶-1-基,
4-(3-甲氧基苯基)哌嗪-1-基,
4-(3-氯苯基)哌嗪-1-基,
4-(3-苄腈)哌嗪-1-基,
4-(噻吩-2-基)哌嗪-1-基,
4-(3-甲基苯基)哌嗪-1-基,
4-(4-甲基吡啶-3-基)哌嗪-1-基,
4-(4-甲氧基苯基)哌嗪-1-基,
4-(2-甲氧基苯基)哌嗪-1-基,
4-(4-苄腈)哌嗪-1-基,
4-(4-氯苯基)哌嗪-1-基,
4-(4-甲基苯基)哌嗪-1-基,
4-(3-甲基吡啶-4-基)哌嗪-1-基,
4-异醌醇-1-基-哌嗪-1-基,
咪唑并[1,2-a]吡啶-6-基,
咪唑并[1,2-a]吡啶-5-基,
4-(3-甲基吡啶-2-基)哌嗪-1-基,
4-(5-甲基吡啶-2-基)哌嗪-1-基,
4-(1-乙酰基)哌嗪-1-基,
4-[(1-甲基哌啶-3-基)-1-乙酰基]哌嗪-1-基,
4-[(1-甲基哌啶-2-基)-1-乙酰基]哌嗪-1-基,
4-(2-甲基苯基)哌嗪-1-基,
4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基,
4-[4-(甲磺酰基)苯基]哌嗪-1-基,
4-甲基哌嗪-1-基,
4-(1-氧代乙基
4-(苯基乙酮),
哌嗪-1-基,
4-(3-噻吩基)哌嗪-1-基,
4-(6-乙酰基-3-吡啶基)哌嗪-1-基,
4-(1-甲基-2-氧代-4-吡啶基)哌嗪-1-基,
4-(4-甲酰基苯基)哌嗪-1-基,
4-(4-羟基苯基)哌嗪-1-基,
4-(4-氧代色满-7-基)哌嗪-1-基,
4-[4-[(R)-甲基亚磺酰基]苯基]哌嗪-1-基,
4-(2-甲基-4-甲磺酰基苯基)哌嗪-1-基,
4-(2-甲基-1-氧代-3H-异吲哚-5-基)哌嗪-1-基,
5-(甲基-乙酰基)-吡啶-3-基-哌嗪-1-基,
4-(甲基-乙酰基)-哌嗪-5-基-哌嗪-1-基,
4-(N,N-二甲基苄基酰胺)哌嗪-1-基,
4-[4-(2-氧代吡咯烷-1-基)苯基]哌嗪-1-基,
4-(5-甲磺酰基吡啶-2-基)哌嗪-1-基,
4-(3-甲磺酰基苯基)哌嗪-1-基,
4-(4-吡啶-2-基苯基)哌嗪-1-基,
4-(4-乙酰基-吡啶-2-基苯基)哌嗪-1-基,
4-[4-(1-甲基咪唑-2-基)苯基]哌嗪-1-基,
(3S)-4-(4-乙酰基苯基)-3-甲基哌嗪-1-基,
(2R)-4-(4-乙酰基苯基)-2-甲基哌嗪-1-y,
(2S)-4-(4-乙酰基苯基)-2-甲基哌嗪-1-y,
(3R)-4-(4-乙酰基苯基)-3-甲基哌嗪-1-基,
(2S)-4-(4-乙酰基苯基)-2-甲基哌嗪-1-基,
4-(4-甲磺酰基苯基)哌嗪-1-基,
4-(4-乙酰基-3-羟基-苯基)哌嗪-1-基,
4-(4-乙酰基-3-氟-苯基)哌嗪-1-基,
4-(2-乙酰基-5-氟-苯基)哌嗪-1-基,
4-(4-乙酰基-嘧啶-2-基)哌嗪-1-基,
4-[(N,N-二甲基氨基羰基)吡啶-6-基]哌嗪-1-基,
4-[4-(2-甲基丙酰基)苯基]哌嗪-1-基,
4-(1-氧代四氢萘-6-基)哌嗪-1-基,
4-[4-(1,4-二氧代丁-1-基)苯基]-哌嗪-1-基,
4-[4-(叔丁基乙酰基)苯基]-哌嗪-1-基,
4-[4-(1,4-二氧代ehyl)苯基]-哌嗪-1-基,
4-[4-(3-(甲基)1,4-二氧代丁-1-基)苯基]-哌嗪-1-基,
4-(1-氧代茚满-5-基)哌嗪-1-基,
4-(5-乙酰基吡啶-2-基)哌嗪-1-基,
4-(5-乙酰基嘧啶-2-基)哌嗪-1-基,
4-(5-乙酰基吡嗪-2-基)哌嗪-1-基,
4-(6-乙酰基哒嗪-3-基)哌嗪-1-基,
4-(4-甲磺酰基环己基)哌嗪-1-基,
4-(1-甲磺酰基-4-哌啶基)哌嗪-1-基,
4-乙基哌嗪-1-基,
4-[4-(2,2,2-三氟乙酰基)苯基]哌嗪-1-基,
4-(邻-甲苯基)哌嗪-1-基,
4-(咪唑并[1,2-a]吡啶-5-基)-哌嗪-1-基
4-(环戊烷-羰基)哌嗪-1-基,
4-[2-(吡啶基)-乙酰基]哌嗪-1-基,
4-[(氮杂环丁烷基)-羰基]哌嗪-1-基,
4-[(苯基)-羰基]哌嗪-1-基
4-[(吡啶基)-羰基]哌嗪-1-基,
4-[(哌啶基)-羰基]哌嗪-1-基,
4-(3-甲氧基-2-吡啶基)哌嗪-1-基,
6-(4-乙酰基苯基)-3-吡啶基,
4-(4-甲磺酰基苯基)苯基,
4-[4-[(E)-N-甲氧基-C-甲基-亚氨代甲酰]苯基]哌嗪-1-基甲基羰基哌嗪-1-基,
4-[4-(1,1-二甲氧基乙基)苯基]哌嗪-1-基,
4-(4-乙酰基苯基)苯基,
4-(4-乙酰基-2-甲基苯基)哌嗪-1-基,
4-[4-(甲氧羰基)苯基]哌嗪-1-基,
4-[4-(氮杂环丁烷-1-羰基)苯基]哌嗪-1-基;
R3选自:
H,
氯,
氟,
4-[(4-甲磺酰基苯基)]哌嗪-1-基
哌嗪-1-基,
氰基,
4-乙酰基哌嗪-1-基;
R4选自:
H,
甲基,
溴,
三氟甲基,
氰基,
2-(吡咯烷-1-基)乙基,
1-甲基吡唑-4-基,
4-(4-甲磺酰基苯基)哌嗪-1-基
3-哌嗪-1-基,
苯基,
二甲基氨基羰基,
甲氧羰基,
甲基磺酰基,
2-甲基吡啶-3-基
1-甲基吡唑-3-基,
1-甲基吡唑-4-基,
2-甲基嘧啶-5-基,
吗啉代-羰基,
甲基氨基羰基,
4-哌啶基
1-甲基吡唑-5-基
1H-吡唑-5-基
吡啶-3-基,
氧杂环丁烷-3-基;
R5选自:
H,
氧代,
甲基,
2-(吡咯烷-1-基)乙基,
甲氧羰基。
本发明具体化合物是那些,其显著地选自:
6-[(3S)-3-甲基-4-(2-甲基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[(2S)-2-甲基-4-(2-甲基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-{4-[2-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[(2R)-2-甲基-4-(2-甲基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-(4-苯基哌嗪-1-基)-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-{4-[3-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
4-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)苯甲酸乙酯;
5-(4-{1-[2-(哌啶-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
N,N-二乙基-2-{6-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}乙胺;
6-[4-(吡啶-2-基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(吡啶-3-基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(吡啶-4-基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-(吡咯烷-1-基)-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
1-(1-甲基吡咯烷-3-基)-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶;
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[3,2-c]吡啶;
顺式-N-甲基-3-(6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)环丁烷胺;
反式-N-甲基-3-(6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)环丁烷胺;
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[(3R)-吡咯烷-3-基]-1H-吡咯并[2,3-b]吡啶;
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[(3S)-吡咯烷-3-基]-1H-吡咯并[2,3-b]吡啶;
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-(哌啶-4-基)-1H-吡咯并[3,2-c]吡啶;
顺式-3-{6-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}-N-甲基环丁烷胺;
反式-3-{6-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}-N-甲基环丁烷胺;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[反式-3-(甲基氨基)环丁基]-1H-吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[顺式-3-(甲基氨基)环丁基]-1H-吡咯并[2,3-b]吡啶-3-腈;
6-[4-(6-氰基吡啶-2-基)哌嗪-1-基]-1-[反式-3-(甲基氨基)环丁基]-1H-吡咯并[2,3-b]吡啶-3-腈;
6-[4-(6-氰基吡啶-2-基)哌嗪-1-基]-1-[顺式-3-(甲基氨基)环丁基]-1H-吡咯并[2,3-b]吡啶-3-腈;
1-[4-(4-{5-氟-1-[反式-3-(甲基氨基)环丁基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)苯基]乙烯酮;
反式-3-(5-氟-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)-N-甲基环丁烷胺;
1-(4-苯基-1-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌啶-4-基)乙烯酮;
4-苯基-1-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌啶-4-醇;
6-(4-苯基哌啶-1-基)-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
4-苯基-1-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌啶-4-腈;
6-[4-(3-甲氧基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(3-氯苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
3-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)苄腈;
1-[2-(吡咯烷-1-基)乙基]-6-[4-(噻吩-2-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(3-甲基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(4-甲基吡啶-3-基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(4-甲氧基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(2-甲氧基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
4-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)苄腈;
6-[4-(4-氯苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(4-甲基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(3-甲基吡啶-4-基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
2-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)喹啉;
1-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)异喹啉;
6-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
5-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
6-[4-(3-甲基吡啶-2-基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(5-甲基吡啶-2-基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
1-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)乙烯酮;
(1-甲基哌啶-3-基)(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)甲酮;
(1-甲基哌啶-2-基)(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)甲酮;
6-[4-(2-甲基苯基)哌嗪-1-基]-1-[2-(4-甲基哌嗪-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
N-(2-{6-[4-(2-甲基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}乙基)丙-2-胺;
N,N-二甲基-1-(2-{6-[4-(2-甲基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}乙基)吡咯烷-3-胺;
1-{2-[2-(甲氧基甲基)吡咯烷-1-基]乙基}-6-[4-(2-甲基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶;
1-[2-(3-甲氧基吡咯烷-1-基)乙基]-6-[4-(2-甲基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶;
1-[2-(2-氮杂二环[3.1.0]己-2-基)乙基]-6-[4-(2-甲基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶
6-甲基-1-(2-{6-[4-(2-甲基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}乙基)八氢-1H-吡咯并[2,3-c]吡啶;
6-甲基-1-(2-{6-[4-(2-甲基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}乙基)八氢-1H-吡咯并[3,4-b]吡啶;
1-[2-(5-甲基六氢吡咯并[3,4-b]吡咯-1(2H)-基)乙基]-6-[4-(2-甲基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶;
1-[2-(3-甲氧基氮杂环丁烷-1-基)乙基]-6-[4-(2-甲基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(2-甲基苯基)哌嗪-1-基]-1-{2-[(2R)-2-甲基吡咯烷-1-基]乙基}-1H-吡咯并[2,3-b]吡啶;
6-[4-(2-甲基苯基)哌嗪-1-基]-1-{2-[3-(吡啶-2-基)吡咯烷-1-基]乙基}-1H-吡咯并[2,3-b]吡啶;
1-(2-{6-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}乙基)-N,N-二甲基吡咯烷-3-胺;
5-(4-{1-[2-(6-氮杂二环[3.2.0]庚-6-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
5-[4-(1-{2-[3-(1-甲基-1H-咪唑-2-基)吡咯烷-1-基]乙基}-1H-吡咯并[2,3-b]吡啶-6-基)哌嗪-1-基]咪唑并[1,2-a]吡啶;
5-[4-(1-{2-[2-(1-甲基-1H-吡唑-4-基)吡咯烷-1-基]乙基}-1H-吡咯并[2,3-b]吡啶-6-基)哌嗪-1-基]咪唑并[1,2-a]吡啶;
5-[4-(1-{2-[3-(4,4-二氟哌啶-1-基)氮杂环丁烷-1-基]乙基}-1H-吡咯并[2,3-b]吡啶-6-基)哌嗪-1-基]咪唑并[1,2-a]吡啶;
5-[4-(1-{2-[3-(吡咯烷-1-基)氮杂环丁烷-1-基]乙基}-1H-吡咯并[2,3-b]吡啶-6-基)哌嗪-1-基]咪唑并[1,2-a]吡啶;
5-(4-{1-[2-(2-氧杂-7-氮杂螺[3.5]壬-7-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
5-(4-{1-[2-(5-氮杂螺[3.4]辛-5-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
5-(4-{1-[2-(6-氮杂螺[3.5]壬-6-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
N-苄基-2-{6-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}-N-甲基乙胺;
5-(4-{1-[2-(3-苯氧基吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
5-(4-{1-[2-(2-苯基氮杂环丁烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
5-[4-(1-{2-[3-(2-氟苯基)氮杂环丁烷-1-基]乙基}-1H-吡咯并[2,3-b]吡啶-6-基)哌嗪-1-基]咪唑并[1,2-a]吡啶;
5-(4-{1-[2-(3-苯氧基氮杂环丁烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
1-(2-{6-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}乙基)-3-苯基氮杂环丁烷-3-醇;
反式-N-甲基-3-[3-(1-甲基-1H-吡唑-4-基)-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基]环丁烷胺;
反式-N-甲基-3-[3-(1-甲基-1H-吡唑-5-基)-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基]环丁烷胺;
反式-N-甲基-3-[6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-3-(1H-吡唑-5-基)-1H-吡咯并[2,3-b]吡啶-1-基]环丁烷胺;
反式-N-甲基-3-[3-(1-甲基-1H-吡唑-3-基)-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基]环丁烷胺;
5-(4-{1-[2-(1-甲基吡咯烷-3-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
顺式-N,N-二甲基-3-(6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)环丁烷胺;
反式-N,N-二甲基-3-(6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)环丁烷胺;
1-[(3S)-1-甲基吡咯烷-3-基]-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶;
1-[(3R)-1-甲基吡咯烷-3-基]-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶;
顺式-N-苄基-N-甲基-3-(6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)环丁烷胺;
反式-N-苄基-N-甲基-3-(6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)环丁烷胺;
5-(4-{1-[2-(1-苄基吡咯烷-3-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
1-[(3S)-1-苄基吡咯烷-3-基]-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶;
1-[(3R)-1-苄基吡咯烷-3-基]-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶;
6-(4-甲基哌嗪-1-基)-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
2-{6-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}-N,N-二甲基乙胺;
5-(4-{1-[2-(1-氧杂-6-氮杂螺[3.4]辛-6-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-3-腈;
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-4-腈;
3-甲基-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
反式-3-(3-溴-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)-N-甲基环丁烷胺;
6-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)吡啶-2-腈;
2-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)吡啶-3-腈;
6-[4-(2-甲基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[3,2-c]吡啶;
顺式-3-(4-氯-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)-N-甲基环丁烷胺;
顺式-N-甲基-3-[6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-3-(三氟甲基)-1H-吡咯并[2,3-b]吡啶-1-基]环丁烷胺;
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡唑并[3,4-b]吡啶;
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-2-[2-(吡咯烷-1-基)乙基]-2H-吡唑并[3,4-b]吡啶;
5-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[3,2-c]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
2-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-7-[2-(吡咯烷-1-基)乙基]-7H-吡咯并[2,3-d]嘧啶;
6-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[3,2-c]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
5-(4-{1-[2-(哌嗪-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
5-(4-{1-[2-(2-甲基-1H-咪唑-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
5-(4-{1-[2-(吡咯烷-3-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
2-{6-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}乙胺;
4-[4-[1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯酚;
6-[4-[1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]吡啶-3-腈;
5-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-3-[2-(吡咯烷-1-基)乙基]-3H-咪唑并[4,5-b]吡啶;
5-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-咪唑并[4,5-b]吡啶;
1-(4-{1-[反式-3-(甲基氨基)环丁基]-1H-吡咯并[2,3-b]吡啶-6-基}苯基)乙烯酮;
6-哌嗪-1-基-1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶;
反式-N-甲基-3-[6-[4-(3-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环丁烷-1-胺;
5-[4-(4-甲磺酰基苯基)哌嗪-1-基]-3-哌嗪-1-基-噻吩并[3,2-b]吡啶;
1-(2-吡咯烷-1-基乙基)-6-[4-(3-噻吩基)哌嗪-1-基]吡咯并[2,3-b]吡啶;
顺式-N,N-二甲基-1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-甲酰胺;
顺式-1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-羧酸甲酯;
反式-6-[4-(6-乙酰基-3-吡啶基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(1-甲基-2-氧代-4-吡啶基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-(4-甲酰基苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
顺式-N-甲基-3-[3-甲磺酰基-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环丁烷胺;
反式-N-甲基-3-[7-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-c]吡啶-1-基]环丁烷胺;
反式-6-[4-(4-羟基苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(4-氧代色满-7-基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-[4-[(R)-甲基亚磺酰基]苯基]哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(2-甲基-4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(2-甲基-1-氧代-3H-异吲哚-5-基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-5-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]吡啶-3-羧酸甲酯;
反式-2-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]吡啶-4-羧酸甲酯;
反式-5-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]吡嗪-2-羧酸甲酯;
反式-4-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]-N,N-二甲基苯甲酰胺;
反式-1-[3-(甲基氨基)环丁基]-6-[4-[4-(2-氧代吡咯烷-1-基)苯基]哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(5-甲磺酰基吡啶-2-基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)-1-[2-(氧杂环戊烷-3-基)乙基]吡咯并[2,3-b]吡啶;
3-[2-[6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)吡咯并[2,3-b]吡啶-1-基]乙基]吡咯烷-1-羧酸叔丁酯;
1-[2-[6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)吡咯并[2,3-b]吡啶-1-基]乙基]吡咯烷-2-酮;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(3-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(4-吡啶-2-基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-N-甲基-3-[6-[4-(4-吡啶-2-基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环丁烷-1-胺;
反式-1-[3-(甲基氨基)环丁基]-6-[4-[4-(1-甲基咪唑-2-基)苯基]哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[(3R)-吡咯烷-3-基]吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[(3S)-吡咯烷-3-基]吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-哌啶-4-基吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-哌啶-4-基吡咯并[3,2-c]吡啶-3-腈;
6-[4-(4-甲磺酰基苯基)哌嗪-1-基]-1-[(3S)-吡咯烷-3-基]吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[rel-(3R,4R)-3-氟哌啶-4-基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[(3S)-4-(4-乙酰基苯基)-3-甲基哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[(3R)-4-(4-乙酰基苯基)-3-甲基哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[(2R)-4-(4-乙酰基苯基)-2-甲基哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[(2S)-4-(4-乙酰基苯基)-2-甲基哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
顺式-1-[4-[4-[1-[3-(甲基氨基)环丁基]-3-(1-甲基吡唑-4-基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮;
反式-1-[4-[4-[1-[3-(甲基氨基)环丁基]-3-(1-甲基吡唑-4-基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮;
反式-N-甲基-3-[3-(1-甲基吡唑-4-基)-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环丁烷-1-胺;
1-[4-[4-[3-(2-甲基吡啶-3-基)-1-哌啶-4-基吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮;
1-[4-[4-[3-(1-甲基吡唑-3-基)-1-哌啶-4-基吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮;
1-[4-[4-[3-(2-甲基嘧啶-5-基)-1-哌啶-4-基吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮;
1-[4-[4-[1-[3-(甲基氨基)环丁基]-3-(1-甲基吡唑-4-基)吡咯并[3,2-c]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮;
反式-6-[4-(4-乙酰基-3-羟基-苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-(4-乙酰基-3-氟-苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-(2-乙酰基-5-氟-苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-2-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]嘧啶-4-甲酰胺;
反式-6-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]-N,N-二甲基吡啶-2-甲酰胺;
反式-6-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]-N-甲基哒嗪-3-甲酰胺;
反式-6-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]-N,N-二甲基吡啶-3-甲酰胺;
反式-1-[3-(甲基氨基)环丁基]-6-[4-[4-(2-甲基丙酰基)苯基]哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(1-氧代四氢萘-6-基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-4-[4-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]-4-氧代-丁酸;
反式-6-[4-[4-(2,2-二甲基丙酰基)苯基]哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-4-[4-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]-2-甲基-4-氧代-丁酸;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(1-氧代茚满-5-基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-(5-乙酰基吡啶-2-基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-(5-乙酰基嘧啶-2-基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-(5-乙酰基吡嗪-2-基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-(6-乙酰基哒嗪-3-基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
顺式-[1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-基]-吗啉代-甲酮;
顺式-N-甲基-1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-甲酰胺;
反式-3-[6-氯-4-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]-N-甲基-环丁烷胺;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基环己基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基环己基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(1-甲磺酰基-4-哌啶基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-(1-乙酰基-4-哌啶基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-(4-乙基哌嗪-1-基)-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(1-甲基哌啶-4-基)吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[(3S)-1-甲基吡咯烷-3-基]吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[(3R)-1-甲基吡咯烷-3-基]吡咯并[2,3-b]吡啶-3-腈;
1-[(3S)-1-甲基吡咯烷-3-基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[3-(二甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-[4-(2,2,2-三氟乙酰基)苯基]哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-2-甲基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-3-[5-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环丁烷胺;
反式-N-甲基-3-[3-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡嗪-5-基]环丁烷胺;
反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-2-羧酸甲酯;
反式-1-[4-[4-[2-甲基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮;
反式-5-[4-(4-乙酰基苯基)哌嗪-1-基]-3-[3-(甲基氨基)环丁基]-1-(1-甲基吡唑-4-基)咪唑并[4,5-b]吡啶-2-酮;
5-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(1-甲基吡唑-4-基)-3-(4-哌啶基)咪唑并[4,5-b]吡啶-2-酮;
1-(1-甲基吡唑-4-基)-5-[4-(4-甲磺酰基苯基)哌嗪-1-基]-3-(4-哌啶基)咪唑并[4,5-b]吡啶-2-酮;
5-[4-(4-乙酰基苯基)哌嗪-1-基]-3-(4-甲基-4-哌啶基)-1-(1-甲基吡唑-4-基)咪唑并[4,5-b]吡啶-2-酮;
反式-5-[4-(4-乙酰基苯基)哌嗪-1-基]-3-[3-(甲基氨基)环丁基]-1-苯基-咪唑并[4,5-b]吡啶-2-酮;
5-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(1-甲基吡唑-3-基)-3-(4-哌啶基)咪唑并[4,5-b]吡啶-2-酮;
6-[4-(4-甲磺酰基苯基)哌嗪-1-基]-1-(4-哌啶基)吡咯并[2,3-b]吡啶;
(1R,3R)-3-[6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环戊烷胺;
1-(2-氮杂螺[3.3]庚烷-6-基)-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶;
(1R,3S)-3-[6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环戊烷胺;
顺式-N-甲基-4-[6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环己烷胺;
反式-N-甲基-4-[6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环己烷胺;
6-[4-(4-甲磺酰基苯基)哌嗪-1-基]-1-奎宁环-3-基-吡咯并[2,3-b]吡啶;
1-(1-甲基-3-哌啶基)-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶;
1-(1-甲基-4-哌啶基)-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶;
N,N-二甲基-1-[2-[6-[4-(邻-甲苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]乙基]氮杂环丁烷-3-甲酰胺;
1-[2-(3-咪唑-1-基吡咯烷-1-基)乙基]-6-[4-(邻-甲苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶;
N-[1-[2-[6-[4-(邻-甲苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]乙基]氮杂环丁烷-3-基]甲烷磺酰胺;
1-[2-(3-氟-3-甲基-吡咯烷-1-基)乙基]-6-[4-(邻-甲苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶;
6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)-1-[2-[4-(2-甲基吡唑-3-基)-1-哌啶基]乙基]吡咯并[2,3-b]吡啶;
6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)-1-[2-[4-(氧杂环丁烷-3-基)-1-哌啶基]乙基]吡咯并[2,3-b]吡啶;
2-[2-[6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)吡咯并[2,3-b]吡啶-1-基]乙基]-3,4-二氢-1H-异喹啉;
环戊基-[4-[1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]甲酮;
2-(2-吡啶基)-1-[4-[1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]乙烯酮;
环丁基-[4-[1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]甲酮;
苯基-[4-[1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]甲酮;
4-吡啶基-[4-[1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]甲酮;
4-哌啶基-[4-[1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]甲酮;
6-[4-(3-甲氧基-2-吡啶基)哌嗪-1-基]-1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶;
反式-N-甲基-3-[5-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环丁烷胺;
3-[4-(4-甲磺酰基苯基)哌嗪-1-基]-5-哌嗪-1-基-1,2-苯并噁唑;
5-[4-(4-甲磺酰基苯基)哌嗪-1-基]-3-哌嗪-1-基-1,2-苯并噁唑;
反式-6-[6-(4-乙酰基苯基)-3-吡啶基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基苯基)苯基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-[4-[(E)-N-甲氧基-C-甲基-亚氨代甲酰]苯基]哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
1-甲基-5-[4-(4-甲磺酰基苯基)哌嗪-1-基]螺[吲哚啉-3,4'-哌啶];
N-甲基-3-[6-[4-(4-甲磺酰基苯基)哌嗪-1-基]-2,3-二氢吡咯并[2,3-b]吡啶-1-基]环丁烷胺;
反式-1-[4-[1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-4-基]哌嗪-1-基]乙烯酮;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(5-氮杂螺[3.4]辛烷-2-基)吡咯并[2,3-b]吡啶-3-腈;
反式-1-(5-氮杂螺[3.4]辛烷-2-基)-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[4-[3-溴-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]乙烯酮;
5-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(1-甲基吡唑-4-基)-3-(4-哌啶基)苯并咪唑-2-酮;
5-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(氧杂环丁烷-3-基)-3-(4-哌啶基)咪唑并[4,5-b]吡啶-2-酮;
反式-1-[4-[4-[3-溴-2-甲基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮;
反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-2-羧酸甲酯;
反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-5-氟-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
6-[4-[4-(1,1-二甲氧基乙基)苯基]哌嗪-1-基]-5-氟-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
1-甲基-5-[4-(4-甲磺酰基苯基)哌嗪-1-基]-3-(1,2,3,6-四氢吡啶-4-基)吡咯并[2,3-c]吡啶;
反式-1-[4-[4-[1-[3-(甲基氨基)环丁基]-3-(3-吡啶基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮三氟乙酸盐;
7-[4-(4-甲磺酰基苯基)哌嗪-1-基]-2-哌啶-4-基吡唑并[3,4-c]吡啶;
7-[4-(4-甲磺酰基苯基)哌嗪-1-基]-1-(4-哌啶基)吡唑并[3,4-c]吡啶
6-[4-(4-乙酰基哌嗪-1-基)苯基]-1-[反式-3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
1-[4-[4-[5-(1-甲基吡唑-4-基)-1,2,3,4-四氢吡啶并[4,3-b]吲哚-8-基]哌嗪-1-基]苯基]乙酮;
反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-3-溴-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-2-羧酸甲酯;
5-[4-(4-乙酰基苯基)哌嗪-1-基]-3-(4-甲基-4-哌啶基)-1-(氧杂环丁烷-3-基)咪唑并[4,5-b]吡啶-2-酮;
反式-5-[4-(4-乙酰基苯基)哌嗪-1-基]-3-[3-(甲基氨基)环丁基]-1-(氧杂环丁烷-3-基)咪唑并[4,5-b]吡啶-2-酮;
6-[4-(4-乙酰基苯基)苯基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基-2-甲基苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-4-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯甲酸甲酯;
6-[4-[4-(氮杂环丁烷-1-羰基)苯基]哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
1-[4-[4-[3-(1-甲基吡唑-4-基)-1-哌啶-4-基吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙酮;
1-[4-[4-[1-(1-甲基吡唑-4-基)-3-哌嗪-1-基-吡咯并[3,2-b]吡啶-5-基]哌嗪-1-基]苯基]乙酮;
1-[4-[4-[1-(1-甲基吡唑-4-基)-3-哌啶-4-基吡咯并[3,2-b]吡啶-5-基]哌嗪-1-基]苯基]乙酮。
本发明的具体化合物是那些,其显著地选自:
1-[4-[4-[3-(1-甲基吡唑-4-基)-1-(4-哌啶基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙酮,
1-[4-[4-[3-(2-甲基-3-吡啶基)-1-(4-哌啶基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙酮,
6-[(2S)-2-甲基-4-(2-甲基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶,
1-[4-[4-[1-(1-甲基吡唑-4-基)-3-(4-哌啶基)吡咯并[3,2-b]吡啶-5-基]哌嗪-1-基]苯基]乙酮,
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(5-氮杂螺[3.4]辛烷-2-基)吡咯并[2,3-b]吡啶-3-腈,
1-[3-(甲基氨基)环丁基]-6-[4-[4-(2,2,2-三氟乙酰基)苯基]哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈,
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(4-哌啶基)吡咯并[2,3-b]吡啶-3-腈,6-[4-(4-乙酰基-3-羟基-苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈,
6-[4-(4-乙酰基-3-氟-苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈,
6-[(-4-(4-乙酰基苯基)-2-甲基-哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈,
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈,
5-[4-(4-乙酰基苯基)哌嗪-1-基]-3-[3-(甲基氨基)环丁基]-1-(1-甲基吡唑-4-基)咪唑并[4,5-b]吡啶-2-酮,
6-[4-(4-乙酰基苯基)-3-甲基-哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈,
6-[4-(4-乙酰基苯基)哌嗪-1-基]-2-甲基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈,
6-[4-(5-乙酰基-2-吡啶基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈。
下述段落提供构成本发明化合物的各种化学部分的定义,并且期望适用于通篇说明书和权利要求,除非另有明确定义提供更宽的定义。
如本文所用,术语"C1-C6烷基"是指饱和脂族烃基团,包括1-6个碳原子的直链或支化的碳链。"烷基"的实例是甲基,乙基,正丙基和异丙基。
术语"C1-C6烷氧基"是指基团-O-R',其中R'是如前文所定义的C1-C6烷基。
术语"卤素"是指氟,氯,溴或碘。
术语"被卤素或羟基或C1-C6烷氧基取代的C1-C6烷基"是指如前文所定义的烷基,其中至少一个氢原子用卤素原子、羟基或C1-C6烷氧基替换。
术语"被卤素或羟基或C1-C6烷氧基取代的C1-C6烷氧基"是指如前文所定义的烷氧基,其中至少一个氢原子用卤素原子、羟基或C1-C6烷氧基替换。
术语"杂环基"是指含有1-3个选自N、O或S的杂原子的饱和环,例如吗啉基,哌嗪基,哌啶基或吡咯烷基或氮杂环丁烷基。
术语杂芳基是指含有1至3个选自N、O、S的杂原子的不饱和芳族环,例如吡咯基,咪唑基,嘧啶基。
术语"药学上可接受的盐"或"药学上可接受的酸加成盐"根据本发明涵盖式I化合物能够形成的治疗活性的、非毒性的酸或碱盐形式。
游离形式为碱的式I化合物的酸加成盐形式能够用适当的酸处理游离碱来获得,所述酸是比如无机酸,例如氢卤酸比如盐酸或氢溴酸,硫酸,硝酸,磷酸等;或是有机酸,比如乙酸,三氟乙酸,草酸,羟基乙酸,丙酸,乳酸,丙酮酸,丙二酸,琥珀酸,马来酸,富马酸,苹果酸,酒石酸,柠檬酸,甲磺酸,乙磺酸,苯磺酸,对-甲苯磺酸,环己氨磺酸,水杨酸,对-氨基水杨酸,双羟萘酸等。
本发明也涉及式I化合物的全部立体异构形式比如对映体形式和非对映体形式或其混合物(包括立体异构体的全部可能混合物)。
关于本发明,一种或多种化合物的描述期望涵盖该化合物的各种可能异构形式及其混合物,除非特别描述了特定异构形式。
一些式I化合物还可以以互变异构体形式存在。尽管在上文式中并未明确指出所述形式,但仍期望包括在本发明范围内。
应当理解,在式(I)中或在下文所描述的式中存在的每个单独原子可以事实上以它的天然存在的同位素中的任一种形式存在,最丰富的同位素是优选的。因而,作为实例,在式(I)中或在下文所描述的式中存在的每个单独氢原子可以作为1H、2H(氘)或3H(氚)原子存在,优选1H。类似地,作为实例,在式(I)中或在下文所描述的式中存在的每个单独碳原子可以作为12C、13C或14C原子存在,优选12C。
本发明的又一实施方式涉及药物组合物,其包含可检测量的式I化合物或其药学上可接受的盐和与之组合的药学上可接受的稀释剂或载体。
在又一实施方式中,本发明涉及上文所列的化合物用作药物。
在特定实施方式中,本发明涉及上文所列的化合物用作治疗受STING驱动的炎性病况比如SLE(系统性红斑狼疮)和地图样萎缩的药物。
本发明涉及化合物用于治疗受STING激活驱动的炎性病况。
在又一实施方式中,本发明涉及含有上文所列的化合物以及药学上可接受的赋形剂的药物组合物。
在又一实施方式中,本发明涉及合成其中间体,酸加成盐,外消旋混合物或其相应的对映体和/或旋光异构体。
在又一实施方式中,本发明涉及合成通式II的中间体
其中R4代表(C1-6)烷基,(C1-6)烷氧基或氧代和R3代表任选经取代的芳基或杂芳基。
在又一实施方式中,本发明涉及合成通式III的中间体
其中
-X代表卤素(Br、Cl、I),其适于与式(II)中间体交联或与芳基或杂芳基取代硼酸衍生物交联;和
-R1代表任选经取代的烷基胺或环烷基胺,包括(C1-3)氨基烷基,(C3-7)氨基环烷基,(C1-3)烷基咪唑,(C1-3)烷基异吲哚啉,(C1-3)烷基哌嗪,(C1-3)烷基哌啶,(C1-3)烷基咪唑并哌嗪,(C1-3)烷基(C4-7)氨基环烷基,(C1-3)烷基(C4-7)氨基二环烷基。
在又一实施方式中,本发明涉及合成通式IV的中间体
其中R5能够是X或R2。
在又一实施方式中,本发明涉及合成通式V中间体
其中
-R4代表(C1-6)烷基,(C1-6)烷氧基或氧代;和
-R1代表任选经取代的烷基胺或环烷基胺,包括(C1-3)氨基烷基,(C3-7)氨基环烷基,(C1-3)烷基咪唑,(C1-3)烷基异吲哚啉,(C1-3)烷基哌嗪,(C1-3)烷基哌啶,(C1-3)烷基咪唑并哌嗪,(C1-3)烷基(C4-7)氨基环烷基,(C1-3)烷基(C4-7)氨基二环烷基。
在又一实施方式中,本发明涉及合成通式VI中间体
其中
-R6代表烷基或环烷基取代基,其携带适于被胺替代的官能团例如4-甲基苯磺酸酯基;和
-R2代表芳基,杂芳基,杂双环,(C4-7)氨基环烷基,环烷基,杂环烷基,(C6-8)二氨基环烷基,吗啉代,(C4-7)环烷基甲基,哌嗪基,哌啶基。R2任选用包括下述的基团取代:羟基,(C1-6)烷基,乙酰基,卤素,氰基,C1-6烷基,三氟甲基,二氟甲基,(C2-6)烯基,羟基,(C1-6)烷氧基,二氟甲氧基,三氟甲氧基,三氟乙氧基,(C1-6)烷硫基,(C1-6)烷基磺酰基,氨基,(C1-6)烷基氨基,二(C1-6)烷基氨基,(C1-6)烷氧基(C1-6)烷基-氨基,N-[(C1-6)烷基]-N-[羟基(C1-6)烷基]氨基,(C2-6)烷基羰基氨基,(C2-6)烷氧羰基氨基,(C1-6)烷基磺酰基氨基,甲酰基,(C2-6)烷基羰基,羧基,(C2-6)烷氧羰基,氨基羰基,(C1-6)烷基氨基羰基,二(C1-6)烷基氨基羰基,氨基磺酰基,(C1-6)烷基氨基磺酰基或二(C1-6)烷基氨基磺酰基;(C3-7)杂环烷基或(C3-7)螺杂环烷基,所述基团中任一种可以任选由一个或多个取代基取代。
在又一实施方式中,本发明涉及合成通式VII中间体
其中
-R7代表伯胺或仲胺;和
-R2代表芳基,杂芳基,杂双环,(C4-7)氨基环烷基,环烷基,杂环烷基,(C6-8)二氨基环烷基,吗啉代,(C4-7)环烷基甲基,哌嗪基,哌啶基。R2任选用包括下述的基团取代:羟基,(C1-6)烷基,乙酰基,卤素,氰基,C1-6烷基,三氟甲基,二氟甲基,(C2-6)烯基,羟基,(C1-6)烷氧基,二氟甲氧基,三氟甲氧基,三氟乙氧基,(C1-6)烷硫基,(C1-6)烷基磺酰基,氨基,(C1-6)烷基氨基,二(C1-6)烷基氨基,(C1-6)烷氧基(C1-6)烷基-氨基,N-[(C1-6)烷基]-N-[羟基(C1-6)烷基]氨基,(C2-6)烷基羰基氨基,(C2-6)烷氧羰基氨基,(C1-6)烷基磺酰基氨基,甲酰基,(C2-6)烷基羰基,羧基,(C2-6)烷氧羰基,氨基羰基,(C1-6)烷基氨基羰基,二(C1-6)烷基氨基羰基,氨基磺酰基,(C1-6)烷基氨基磺酰基或二(C1-6)烷基氨基磺酰基;(C3-7)杂环烷基或(C3-7)螺杂环烷基,所述基团中任一种可以任选由一个或多个取代基取代。
合成方法
根据本发明的式I化合物能够与合成有机化学领域的技术人员理解的常规方法类似地制备。
根据一种实施方式,一些通式I化合物可以制备如下:在Buchwald交联条件下将中间体(II)与中间体(III)反应,使用适宜的过渡金属催化剂和碱。通式(I)化合物还可以制备如下:在Suzuki交联条件下将中间体(III)与适当的芳基或杂芳基取代硼酸或取代硼酸酯反应。另选地,一些通式(I)化合物可以制备如下:将中间体(IV)与适宜的R1基团反应,所述基团携带用于直接烷基化的卤素(Cl、Br、I)或用于Mitsunobu偶联的醇。在该情况下,如果R5是中间体(IV)中的卤素,则还需要与携带胺、取代硼酸或取代硼酸酯的适宜R2基团进行Buchwald或Suzuki交联来产生式(I)化合物。
通式(I)化合物还可以通过与适宜的芳基卤或杂芳基卤Buchwald交联制备自中间体(V)。
通式(I)化合物还可以通过在适当偶联条件下与适宜的酸、酰氯或异氰酸酯反应形成酰胺键或形成脲而制备自中间体(V)。
另选地,通式(I)化合物还可以通过用胺替代R6取代基上的离去基团制备自中间体(VI)。
通式(I)化合物还可以通过还原胺化制备自中间体(VII),其牵涉与醛或酮缩合随后还原所得亚胺。
实施例
下述实施例说明可以如何合成式I和II涵盖的化合物。它们仅是出于示例性意图提供的并且不期望或不应该解释为以任何方式限制本发明。本领域技术人员将理解能够对下述实施例进行常规变化和修饰而不超出本发明的主旨或范围。
牵涉空气或水分敏感试剂的全部反应在氮气氛下用干燥溶剂和玻璃仪器进行,除非另有指出。
缩写
BOC:叔丁基氧基羰基
DCM:二氯甲烷 EtOAc:乙酸乙酯
DMF:N,N-二甲基甲酰胺 MeOH:甲醇
DMSO:二甲亚砜 EtOH:乙醇
Et2O:二乙醚 MeCN:乙腈
THF:四氢呋喃 DIPEA:N,N-二异丙基乙胺
H2O:水 LDA:二异丙基氨基锂
NH3:氨 Pd(OAc)2:乙酸钯(II)
MgSO4:硫酸镁 Na2SO4:硫酸钠
K2CO3:碳酸钾 NBS:N-溴代琥珀酰亚胺
NIS:N-碘琥珀酰亚胺 DBU:1,8-二氮杂二环[5.4.0]十一烷-7-烯
eq.:当量 SM:原料
TFA:三氟乙酸 DME:1,2-二甲氧基乙烷
pTSA:对-甲苯磺酸 TBAF:氟化四正丁基铵
min.:分 h:小时
rt:室温 RT:保留时间
br:宽 M:摩尔浓度
N:当量浓度 ES+:电喷雾正离子化
SCX:固相阳离子交换 N2:氮
HPLC:高效液相色谱
LCMS:液相色谱法质谱
盐水:饱和氯化钠水溶液
PdCl2(dppf)-DCM:[1,1′-二(二苯基膦基)二茂铁]二氯化钯(II)
Pd-Ruphos G3:(2-二环己基膦基-2′,6′-二异丙氧基-1,1′-联苯)[2-(2′-氨基-1,1′-联苯)]钯(II)甲磺酸盐
BINAP:(2,2'-二(二苯基膦基)-1,1'-联萘)
Pd2dba3:三(二亚苄基丙酮)二钯(0)
HATU:1-[二(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐
FCC:快速柱色谱法
CMBP:(氰基亚甲基)三甲基正膦
CDI:1,1′-碳酰二咪唑
命名
化合物命名借助ACD-Console版本14.03和/或Biovia Draw 2016。
分析条件
牵涉空气或水分敏感试剂的全部反应在氮气氛下用干燥溶剂和玻璃仪器进行,除非另有指出。
除非另有说明,分析LCMS数据是用下述方法获得。
描述的全部LCMS保留时间(RT)值按分钟计。
方法1:
pH 10
梯度:
时间(mins) | A% | B% |
0.00 | 95.00 | 5.00 |
4.00 | 5.00 | 95.00 |
5.00 | 5.00 | 95.00 |
5.10 | 95.00 | 5.00 |
流速:1mL/min
溶剂A:10mM甲酸铵/水+0.1%氨溶液
溶剂B:乙腈+5%水+0.1%氨溶液
柱:XBridge C18,2.1x 20mm,2.5μm
方法2:
pH 10
梯度:
时间(mins) | A% | B% |
0.00 | 95.00 | 5.00 |
1.50 | 5.00 | 95.00 |
2.25 | 5.00 | 95.00 |
2.50 | 95.00 | 5.00 |
流速:1mL/min
溶剂A:10mM甲酸铵/水+0.1%氨溶液
溶剂B:乙腈+5%水+0.1%氨溶液
柱:XBridge C18,2.1x 20mm,2.5μm
方法3:
pH 3
梯度:
时间(mins) | A% | B% |
0.00 | 98.00 | 2.00 |
0.3 | 98.00 | 2.00 |
3.00 | 5.00 | 95.00 |
4.00 | 5.00 | 95.00 |
4.10 | 98.00 | 2.00 |
5.10 | 98.00 | 2.00 |
流速:0.8mL/min
溶剂A:水+乙腈+甲酸(95/5/750μl/L)
溶剂B:水+乙腈+甲酸(5/95/500μl/L)
柱:Acquity UPLC HSS T3 C18柱(1.8μm,2.1x 50mm)
方法4:
pH 10
梯度:
时间(mins) | A% | B% |
0.0 | 95 | 5 |
0.1 | 95 | 5 |
2.6 | 5 | 95 |
2.75 | 5 | 95 |
2.8 | 95 | 5 |
3.0 | 95 | 5 |
流速:1mL/min
溶剂A=10mM甲酸铵+0.1%氨溶液(pH10)
溶剂B=MeCN+5%H2O+0.1%氨溶液(pH10)
柱:Waters XBridge BEH C18 XP 2.5μm 2.1x 50mm
方法5:
pH 3
梯度:
时间(mins) | A% | B% |
0.0 | 94 | 6 |
1.5 | 5 | 95 |
2.25 | 5 | 95 |
2.5 | 94 | 6 |
流速:1mL/min
溶剂A=10mM甲酸铵/水+0.1%甲酸
溶剂B=MeCN+5%H2O+0.1%甲酸
柱:X-Bridge C18 Waters 2.1x 20mm,2.5μM柱
方法6:
pH 10
梯度:
时间(mins) | A% | B% |
0.0 | 94 | 6 |
1.5 | 5 | 95 |
2.25 | 5 | 95 |
2.5 | 94 | 6 |
流速:1mL/min
溶剂A=10mM甲酸铵/水+0.1%氨溶液
溶剂B=MeCN+5%H2O+0.1%甲酸
柱:X-Bridge C18 Waters 2.1x 20mm,2.5μM柱
方法7:
梯度:
时间(mins) | A% | B% |
0.0 | 100 | 0 |
2.0 | 2 | 98 |
3.0 | 2 | 98 |
3.2 | 100 | 0 |
4.0 | 100 | 0 |
流速:1.2mL/min
溶剂A=5mM碳酸氢铵溶液
溶剂B=MeCN
柱:Waters XBridge BEH C18 2.5μm 3.0x 50mm
方法8:
梯度:
时间(mins) | A% | B% |
0.0 | 100 | 0 |
2.0 | 2 | 98 |
3.0 | 2 | 98 |
3.2 | 100 | 0 |
4.0 | 100 | 0 |
流速:1.2mL/min
溶剂A=0.05%甲酸:水/MeCN(95:5)
溶剂B=0.05%甲酸/MeCN
柱:Waters X-Select CSH 2.5μm 3.0x 50mm
方法9:
pH 10
梯度:
时间(mins) | A% | B% |
0.0 | 95 | 5 |
4.0 | 5 | 95 |
5.0 | 5 | 95 |
5.1 | 95 | 5 |
6.5 | 95 | 5 |
流速:1mL/min
溶剂A=5mM甲酸铵+0.1%氨溶液
溶剂B=MeCN+5%溶剂A+0.1%氨溶液
柱:Waters XBridge BEH C18 2.5μm 2.1x 50mm
方法10:
pH 3
梯度
时间(mins) | A% | B% |
0.0 | 95 | 5 |
1.2 | 0 | 100 |
1.30 | 0 | 100 |
1.31 | 95 | 5 |
流速:1.2mL/min
溶剂A=水+0.1%甲酸
溶剂B=MeCN+0.1%甲酸
柱:Kinetex Core-Shell C18,2.1x 50mm,5μm柱
方法11:
pH 3
梯度
流速:0.6mL/min
溶剂A=水+0.1%甲酸
溶剂B=MeCN+0.1%甲酸
柱:Phenomenex Kinetix-XB C18,2.1x 100mm,1.7μm柱
方法12:
pH 3
梯度
时间(mins) | A% | B% |
0.0 | 95 | 5 |
1.83 | 0 | 100 |
2.25 | 0 | 100 |
2.26 | 95 | 5 |
流速:1.2ml/min
溶剂A=水+0.1%甲酸
溶剂B=MeCN+0.1%甲酸
柱:Kinetex Core-Shell C8,2.1x 50mm,5μm柱
方法13:
pH 3
梯度
时间(mins) | A% | B% |
0.0 | 95 | 5 |
5.00 | 0 | 100 |
5.40 | 0 | 100 |
5.42 | 95 | 5 |
7.00 | 95 | 5 |
流速:0.6ml/min
溶剂A=水+0.1%甲酸
溶剂B=:MeCN+0.1%甲酸
柱:Waters Atlantis dC18,2.1x 100mm,3μm柱
一般程序1
将1-BOC-哌嗪(1当量),叔丁醇钠(1.5-3当量),芳基卤(1.2当量)和Pd-Ruphos G3(0.1当量)的混合物溶于预先脱气的1,4-二噁烷(0.15-0.3M)中。然后将反应混合物在100℃加热直至完成。将反应混合物冷却至环境温度,然后进行水性后处理或过滤通过C盐。干燥溶剂(用MgSO4、Na2SO4或分相器)和随后减压除去。残余物通过快速二氧化硅色谱法纯化以提供产品或直接用于后续步骤。然后将产品溶于DCM(4-5mL)和(在0℃或在室温下)加入TFA(0.5-1ml)。在环境温度搅拌反应混合物直至完成(LCMS监测)。然后,将反应过滤通过SCX柱,首先用甲醇然后用氨(2-7M)/甲醇洗脱。减压浓缩氨的甲醇溶液,提供所希望的产品。
一般程序2
将适当的杂环(1当量)溶于DMF和THF的混合物(1:1或1:1.5)。将溶液冷却至0℃和仔细地分批加入氢化钠(1.2或2.2当量)。在大约5分钟之后,分批加入烷基卤(1.2当量)。在0℃或在室温搅拌反应混合物15分钟至1小时,然后在80℃加热30分钟至6小时的时间段。将反应混合物冷却至0℃和用水淬灭和用EtOAc处理,分离有机层。干燥有机溶剂(用MgSO4、Na2SO4或分相器)和随后减压除去。残余物通过快速二氧化硅柱色谱法或反相柱色谱法纯化,提供产品。
一般程序3
将杂芳基卤或芳基卤(1当量-1.5当量)和仲胺(一般为4-取代的哌嗪)(1当量)溶于预先脱气的无水二噁烷(0.1-0.2M),加入叔丁醇钠(3当量),随后RuPhos Pd G3(0.1当量)。将反应混合物脱气和在80-100℃在密封管中搅拌1-16小时。过滤小规模反应(0.05mmol),用DMF(0.6mL)稀释和通过反相柱色谱法直接纯化,产生所希望的产品。将较大规模反应(>0.05mmol)冷却至室温,过滤通过C盐垫和/或进行水性后处理。干燥溶剂和真空浓缩和残余物通过FCC或通过SCX柱随后反相柱色谱法纯化。
一般程序4
将6-溴-1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶(100mg,0.3mmol),叔丁醇钠(3当量,98mg,1mmol),Pd-Ruphos G3(0.1当量,0.03mmol)和相应哌啶(1.2当量,0.34mmol)溶于脱气的1,4-二噁烷(0.05M,7mL)中。在100℃搅拌反应混合物过夜。然后将反应冷却至环境温度和过滤通过C盐柱,减压浓缩,溶于DMSO和进行反相柱色谱法。
一般程序5
将胺(1.0-1.5当量),叔丁醇钠(1.4当量),芳基卤(1.0当量)和BINAP(0.15当量)的混合物溶于1,4-二噁烷(0.2M),将混合物排空和反填充N2三次以使溶剂脱气。然后加入Pd2dba3(0.05当量),将反应混合物在80-100℃加热直至完成。将反应混合物冷却至室温然后进行水性后处理或过滤通过C盐。干燥溶剂(用MgSO4、Na2SO4或分相器)和随后减压除去。残余物通过快速二氧化硅色谱法纯化提供产品或直接用于后续步骤。
一般程序6
将适当的羧酸(0.05mmol,1当量)加入中间体7(15mg,0.05mmol,1当量)和2,4,6-三丙基-1,3,5,2,4,6-三氧杂三磷杂环己烷-2,4,6-三氧化物(38mg,0.06mmol,1.2当量)的DCM(0.5mL)溶液。在室温搅拌反应混合物过夜。过滤反应混合物和用DMF(0.45mL)稀释和通过反相柱色谱法纯化,产生所希望的产品。
一般程序7
在100℃在6-12小时期间内搅拌1,4-二噁烷中的适当的胺(1.4当量),碳酸钾(6当量)和中间体17(1.0当量)。过滤小规模反应(0.05mmol)和通过制备型HPLC纯化,产生所希望的产品。将较大规模反应(>0.08mmol)通过SCX柱,首先用MeOH洗涤然后用大约2M的NH3/MeOH洗脱。减压浓缩氨的甲醇溶液,粗制残余物通过反相HPLC纯化,产生所希望的产品。
一般程序8
将适当的胺(1.5当量)和中间体15(20mg,0.03mmol,1当量)在乙腈和三乙胺(0.02mL,0.14mmol,4当量)中的混合物在80℃搅拌过夜。过滤反应混合物和通过HPLC纯化,产生所希望的产品。
一般程序9
将醇(1.5当量)和杂环(1当量)的混合物溶于甲苯(0.25M)。然后加入氰基亚甲基三丁基正膦(1.5当量),将反应混合物在90-110℃加热3-12小时。将粗制反应混合物加载于二氧化硅柱和用乙酸乙酯/己烷梯度洗脱,提供所希望的产品。
一般程序10
将相应芳基溴(1当量),取代硼酸(1.5当量)和K2CO3(2当量)溶于1,4-二噁烷(0.1M)。加入H2O(1M),将混合物脱气,随后加入PdCl2(dppf)-DCM(0.01当量)和在90℃加热直至原料消耗。将反应混合物冷却至环境温度和加入EtOAc和H2O。分层和有机层在Na2SO4上干燥。减压除去溶剂,残余物通过快速二氧化硅柱色谱法纯化,用己烷至EtOAc作为洗脱液,提供所希望的产品。
一般程序11
将中间体23(70mg,0.11mmol),取代硼酸酯(2当量,0.22mmol),K2CO3(2当量,0.22mmol)和PdCl2(dppf)-DCM复合物(0.1当量,0.01mmol)溶于1,4-二噁烷(0.1M,1mL)。加入H2O(0.1mL),将混合物脱气1分钟。混合物在100℃搅拌过夜。然后将混合物冷却至环境温度和加入DCM(3mL)和H2O(2mL),分层。将TFA(1mL)加入DCM层,在室温下搅拌反应混合物2小时。反应混合物过滤通过SCX柱,用MeOH和DCM冲洗,产品用NH3(7N,在MeOH中)洗脱。减压除去挥发物,残余物通过反相HPLC纯化,提供所希望的产品。
一般程序12
将胺(1当量)溶于四氢呋喃和乙醇(2ml)的1:1混合物或DCM(2ml)或DMF(0.13M)。然后加入羰基化合物(1-10当量),随后乙酸(1-10当量)和三乙酰氧基硼氢化钠(3-4当量)。在室温下搅拌反应混合物直至完成。然后减压浓缩反应混合物,溶于DCM和用氢氧化钠水溶液(2M)洗涤。分开有机溶剂,干燥(Na2SO4)和减压浓缩。另选地,将反应混合物稀释于EtOAc,有机相用水、盐水洗涤,在Na2SO4上干燥和减压浓缩至干。残余物任选地通过反相柱色谱法纯化,提供所希望的产品,是游离碱或甲酸盐。
一般程序13
根据方法A或方法B处理Boc-保护的胺(1当量):
方法A:将胺溶于DCM(4-5mL)和加入TFA(0.5-1mL或20当量)。搅拌反应混合物直至完成。反应稀释于DCM中,用2M Na2CO3水溶液洗涤。有机相然后在Na2SO4上干燥和减压浓缩至干。另选地,纯化粗制反应混合物:过滤通过SCX柱,首先用甲醇洗涤然后用大约2M氨/甲醇洗脱。减压浓缩氨的甲醇溶液,提供所希望的产品。该产品任选进一步通过制备型HPLC纯化。
方法B:在室温下将4N HCl(10-50当量)/二噁烷加入Boc-保护的胺(1当量)的DCM溶液。在室温下搅拌反应混合物1-16小时。浓缩反应混合物至干,将所希望的产品作为HCl盐原样用于后续步骤,或者通过制备型HPLC纯化提供所希望的产品,是甲酸盐或游离碱。
一般程序14
加或不加碳酸钾(1.4当量),将胺(1当量)和相应卤素-取代的杂环(1当量)的DMSO溶液加热(80-140℃)直至反应完成。混合物用EtOAc稀释,用盐水(5次)洗涤,干燥(Na2SO4)和真空浓缩。产品任选进一步通过柱色谱法或经由与适当溶剂研磨而纯化。
一般程序15
在0℃向硝基芳烃的MeOH溶液加入锌(6当量)和甲酸铵(5当量)。在加入完成之后,将所得反应混合物在室温搅拌。在原料完全消耗之后(~15分钟),减压蒸发甲醇,然后将残余物溶于乙酸乙酯和过滤通过C盐。C盐用乙酸乙酯洗涤。收集的滤液用水洗涤(x 2),在硫酸钠上干燥和减压蒸发。粗制物质任选通过柱色谱法纯化。
一般程序16
在室温下在密封管中向搅拌的二胺的甲苯溶液加入CDI(2当量)。让反应混合物在100℃搅拌16小时。反应混合物用水稀释和用乙酸乙酯(x 2)萃取。有机层用盐水洗涤,干燥(Na2SO4)和减压浓缩。粗制化合物任选通过柱色谱法纯化。
一般程序17
在室温向搅拌的芳基咪唑-2-酮的MeCN溶液加入芳基碘(1.5当量),K2CO3(3当量)和N,N′-二甲基乙二胺(5当量)。混合物用氩气脱气15分钟。然后加入CuI(1.5当量),将反应混合物脱气15分钟。反应在100℃搅拌16h。冷却至rt之后,混合物用水稀释和用乙酸乙酯(x3)萃取。有机层用盐水洗涤,干燥(Na2SO4)和减压浓缩。粗制产品任选通过柱色谱法纯化。
一般程序18
将羧酸(1当量),胺(1.5当量)和HATU(1.3当量mmol)溶于N,N-二甲基甲酰胺和N,N-二异丙基乙胺。混合物然后在室温在N2下搅拌1小时。混合物用EtOAc、水和盐水稀释,然后分层,水层进一步用EtOAc萃取。经合并的有机物用盐水洗涤,干燥(Na2SO4)和真空浓缩。残余物任选通过柱色谱法纯化。
一般程序19
在氮下将1-取代的-{6-溴-1H-吡咯并[2,3-b]吡啶(1当量)溶于无水DMF(0.5M)和无水MeCN(0.5M)和冷却至0℃。加入氯磺酰异氰酸酯(1.15当量),在0℃在氮下搅拌反应混合物10分钟。让反应混合物温热至室温,在室温搅拌30分钟。将反应冷却至0℃,滴加1MNaOH水溶液直至水相pH=10。反应悬浮液用EtOAc萃取,经合并的有机相用盐水洗涤和在Na2SO4上干燥。粗制产品通过FCC(Biotage Isolera,SNAP Ultra,10-100%EtOAc:庚烷梯度洗脱)纯化,提供所希望的3-氰基产品。
一般程序20
在室温将NIS或NBS(1当量)加入1-取代的-{6-卤代-1H-吡咯并[2,3-b]吡啶(1当量)的无水DMF(0.05M)溶液。在氮下搅拌反应混合物20分钟。加水,反应混合物用EtOAc萃取。有机相依次用水、盐水洗涤,在Na2SO4上干燥,减压浓缩至干,提供所希望的3-卤化的产品。
一般程序21
将芳基卤(1当量),芳基取代硼酸(1当量)和2M碳酸钠(3当量)在二噁烷(0.12M)中的混合物用N2鼓泡脱气10分钟,然后加入四(三苯基膦)钯(0)(0.05-0.1当量),反应在80-100℃通过CEM微波200W加热30分钟或热源加热1-16小时。反应混合物稀释于EtOAc和依次用水和盐水洗涤。水相用EtOAc萃取,经合并的有机相在Na2SO4上干燥和减压浓缩至干。残余物通过FCC(Biotage isolera,SNAP Ultra,10-100%EtOAc:庚烷梯度洗脱)纯化,提供所希望的产品。
中间体1
1-(邻-甲苯基)哌嗪
1-(邻-甲苯基)哌嗪按照一般程序1制备:使用1-BOC-哌嗪(6g,32mmol)和2-溴甲苯(5mL,41mmol),提供中间体1(7.2g,82%收率)
LCMS(方法2,ES+)1.56分钟,177m/z(M+H)+。
中间体2
(3S)-3-甲基-1-(邻-甲苯基)哌嗪
(3S)-3-甲基-1-(邻-甲苯基)哌嗪按照一般程序1制备:使用2-溴甲苯(170mg,1mmol)和(S)-4-N-Boc-2-甲基哌嗪(240mg,1.2当量,1.2mmol),提供中间体2(110mg,47%收率)。
LCMS(方法2,ES+)1.1分钟,191m/z(M+H)+。
中间体3
(3R)-3-甲基-1-(邻-甲苯基)哌嗪
(3R)-3-甲基-1-(邻-甲苯基)哌嗪按照一般程序1制备:使用2-溴甲苯(170mg,1mmol)和(R)-4-N-Boc-2-甲基哌嗪(240mg,1.2当量,1.2mmol),提供中间体3(122mg,52%收率)。
LCMS(方法2,ES+)1.1分钟,191m/z(M+H)+。
中间体4
(2S)-2-甲基-1-(邻-甲苯基)哌嗪
(2S)-2-甲基-1-(邻-甲苯基)哌嗪按照一般程序1制备:使用2-溴甲苯(170mg,1mmol)和(S)-1-N-Boc-2-甲基哌嗪(240mg,1.2当量,1.2mmol),提供中间体4(180mg,77%收率)。
LCMS(方法2,ES+)1.08分钟,191m/z(M+H)+。
中间体5
5-哌嗪-1-基咪唑并[1,2-a]吡啶
5-哌嗪-1-基咪唑并[1,2-a]吡啶按照一般程序1制备:使用5-溴咪唑并[1,2-A]吡啶(5g,25mmol)和1-boc-哌嗪(4.7g,25mmol),提供中间体5(1.1g,55%收率)。
LCMS(方法2,ES+)0.35分钟,203m/z(M+H)+。
中间体6
6-溴-1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶
6-溴-1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶按照一般程序2制备:使用6-溴-1H-吡咯并[2,3-b]吡啶(10g,50mmol)和1-(2-氯乙基)吡咯烷盐酸盐(11g,63.4mmol)。将反应加热至80℃持续2小时。残余物通过快速二氧化硅柱色谱法用己烷至1:1己烷:EtOAc梯度洗脱纯化,提供中间体6(12g,82%收率)。
LCMS(方法2,ES+)1.30分钟,295&297m/z(M+H)+。
中间体7
6-哌嗪-1-基-1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶
中间体6(7g,23.8mmol)根据一般程序1随后一般程序13处理,提供中间体7(4.5g,67%收率)。
LCMS(方法2,ES+)1.02分钟,300m/z(M+H)+。
中间体8
(6-溴吡咯并[2,3-b]吡啶-1-基)-三异丙基-硅烷
将6-溴-1H-吡咯并[2,3-b]吡啶(4g,20.3mmol)溶于1,4-二噁烷(100mL),加入DIPEA(11mL,63.1mmol)、随后三异丙基甲硅烷基三氟甲磺酸酯(6.5mL,24mmol)。然后在室温搅拌反应混合物30分钟,随后在80℃加热过夜。加入三异丙基甲硅烷基三氟甲磺酸酯(1.2当量,24.4mmol),在80℃搅拌额外的3小时。将反应冷却至环境温度和加入NH4Cl水溶液和EtOAc。分层,水相用EtOAc萃取。经合并的有机层在MgSO4上干燥和减压除去溶剂。残余物通过快速色谱法用己烷至己烷:EtOAc1:1混合物梯度洗脱纯化,产生中间体8(5.2g,72%收率)。
LCMS(方法2,ES+)1.96分钟,353&355m/z(M+H)+。
中间体9
(6-氯吡咯并[3,2-c]吡啶-1-基)-三异丙基-硅烷
将6-氯-5-氮杂吲哚(1g,6.42mmol)部分悬浮于1,4-二噁烷(30mL)。然后加入DIPEA(3.5mL,20mmol)、随后三异丙基甲硅烷基三氟甲磺酸酯(2.5mL,9.3mmol)。在室温下搅拌反应混合物5小时30分钟然后进行水性后处理。干燥有机溶剂(Na2SO4)和减压浓缩,提供残余物,将其通过快速二氧化硅柱色谱法纯化,提供标题化合物(1.68g,84%)。
中间体10
6-溴-1-[2-(1-哌啶基)乙基]吡咯并[2,3-b]吡啶
6-溴-1-[2-(1-哌啶基)乙基]吡咯并[2,3-b]吡啶按照一般程序2制备:使用6-溴-1H-吡咯并[2,3-b]吡啶(400mg,2mmol)和1-(2-溴乙基)哌啶氢溴酸盐(1.2当量,2.39mmol)。产品通过快速二氧化硅柱色谱法用己烷至己烷:EtOAc 1:1梯度洗脱纯化,提供中间体10(420mg,69%收率)。
LCMS(方法2,ES+)1.45分钟,308&310m/z(M+H)+。
中间体11
2-(6-溴吡咯并[2,3-b]吡啶-1-基)-N,N-二乙基-乙胺
2-(6-溴吡咯并[2,3-b]吡啶-1-基)-N,N-二乙基-乙胺按照一般程序2制备:使用6-溴-1H-吡咯并[2,3-b]吡啶(400mg,2mmol)和2-溴-N,N-二乙胺氢溴酸盐(1.2当量,2.4mmol)。粗制产品通过快速二氧化硅柱色谱法用己烷至EtOAc梯度洗脱纯化,提供中间体11(360mg,61%收率)。
LCMS(方法2,ES+)1.42分钟,296&298m/z(M+H)+。
中间体12
[6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)吡咯并[2,3-b]吡啶-1-基]-三异丙基-硅烷
[6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)吡咯并[2,3-b]吡啶-1-基]-三异丙基-硅烷按照一般程序3制备:使用中间体8(1.2当量,13mmol)和中间体5(2.2g,11mmol)。残余物通过快速二氧化硅柱色谱法用己烷至EtOAc梯度洗脱纯化,产生中间体12(3.2g,61%收率)。
LCMS(方法2,ES+)1.90分钟,475m/z(M+H)+。
中间体13
5-[4-(1H-吡咯并[2,3-b]吡啶-6-基)哌嗪-1-基]咪唑并[1,2-a]吡啶
将中间体12(3.15g,6.64mmol)溶于THF(0.25M,26mL)和加入TBAF(8mL,1.2当量,7.96mmol,1mmol/mL)。在环境温度搅拌反应混合物3小时然后加入H2O和Et2O。分层和水相用Et2O萃取。减压除去溶剂,将残余物再溶于MeOH和过滤通过SCX柱和用MeOH洗涤然后用NH3(7N,在MeOH中)洗脱,提供中间体13(1.0g,44%)。
LCMS(方法2,ES+)1.13分钟,319m/z(M+H)+。
中间体14
叔丁基-[2-[6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)吡咯并[2,3-b]吡啶-1-基]乙氧基]-二甲基-硅烷
将中间体13(2g,6.3mmol)溶于THF(0.25M)和DMF(0.25M)的混合物和在0℃冷却,随后分批加入氢化钠(1.5当量,400mg,9.95mmol)。在环境温度搅拌混合物30分钟,随后加入(2-溴乙氧基)-叔丁基二甲基硅烷(1.2当量,8mmol)。将混合物温热至60℃和搅拌直至反应完成。反应混合物用H2O淬灭和加入EtOAc。分层和水相用EtOAc萃取。经合并的有机层在Na2SO4上干燥,减压除去溶剂。残余物通过柱色谱法纯化,从EtOAc至1:1MeOH:EtOAc梯度洗脱,提供中间体14,是白色固体(1g,44%收率)。
LCMS(方法2,ES+)1.78分钟,477m/z(M+H)+。
中间体15
2-[6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)吡咯并[2,3-b]吡啶-1-基]乙基4-甲基苯磺酸酯
将中间体14(1g,2.098mmol)溶于THF(0.25M,102.3mmol)和加入TBAF(3.1mL,3.15mmol,1mmol/mL)。在环境温度搅拌反应混合物3小时,然后加入H2O和Et2O。分层和水相用Et2O萃取。经合并的有机层在Na2SO4上干燥。减压除去溶剂,残余物溶于MeOH和过滤通过SCX柱和用MeOH洗涤然后用NH3(7N)/MeOH洗脱。所得残余物溶于DCM(0.25M)和加入三乙胺(1.5当量,3mmol)。将溶液冷却至0℃,加入对甲苯磺酰氯(1.2当量,2mmol),反应混合物在环境温度下搅拌过夜。反应混合物用H2O和DCM淬灭,分层。减压除去溶剂,残余物通过快速二氧化硅柱色谱法用己烷至EtOAc然后至20%MeOH/EtOAc梯度洗脱纯化,提供中间体15(900mg,69%收率)
LCMS(方法2,ES+)1.50分钟,517m/z(M+H)+。
中间体16
三异丙基-[6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]硅烷
三异丙基-[6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]硅烷按照一般程序3制备:使用中间体8(5g,14.2mmol)和1-[4-(甲磺酰基)苯基]哌嗪(1.2当量,17mmol)。残余物通过快速柱色谱法用己烷至EtOAc然后直至30%MeOH/EtOAc梯度洗脱纯化,提供中间体16(5.3g,73%收率)。
LCMS(方法2,ES+)1.98分钟,513m/z(M+H)+
中间体17
2-[6-[4-(邻-甲苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]乙基4-甲基苯磺酸酯
将中间体21(0.3g,0.89mmol)溶于二氯甲烷(5mL)和加入三乙胺(0.2mL,1mmol)、随后对-甲苯磺酰氯(171mg,0.88mmol)。在2小时之后,加入第二份三乙胺(0.2mL,1mmol)、随后第二份中间体21(0.3g,0.89mmol)/二氯甲烷(5mL)和第二份对甲苯磺酰氯(171mg,0.88mmol)。反应混合物然后在rt下搅拌过夜和进行水性后处理。干燥有机溶剂(Na2SO4)和减压浓缩。粗制残余物然后通过快速二氧化硅柱色谱法纯化,提供标题化合物(0.51g,quant。)
LCMS(方法2,ES+)1.63分钟,491m/z(M+H)+。
中间体18
6-[4-(4-甲磺酰基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶
在环境温度将中间体16(3g,5.9mmol)溶于THF(0.5M)和加入TBAF(8.8mL,1.5当量,8.8mmol,1mmol/mL)。搅拌混合物1小时然后加入H2O和Et2O。分层,水相用Et2O萃取。减压除去溶剂,残余物通过快速色谱法从己烷至EtOAc然后至1:1EtOAc:MeOH混合物梯度洗脱纯化,产生中间体18(950mg,46%收率)。
LCMS(方法2,ES+)1.20分钟,357m/z(M+H)+。
中间体19
3-溴-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶
将中间体16(730mg,1.4mmol)溶于DCM(30mL)和冷却至0℃。在20分钟内分批加入N-溴代琥珀酰亚胺(165mg,0.92mmol)。反应在该温度搅拌额外的10分钟,随后用饱和NaHCO3淬灭,分层。水相然后用DCM萃取。减压除去溶剂,残余物直接溶于THF(10mL)。加入TBAF(1.6mL,1.2当量,1.6mmol,1mmol/mL),混合物在环境温度搅拌20分钟粗制反应混合物用饱和NH4Cl水溶液淬灭和加入EtOAc。分层。水相然后用EtOAc萃取。合并经合并的有机层,在Na2SO4上干燥和减压除去溶剂。残余物通过色谱法从DCM至30%MeOH/DCM梯度洗脱纯化,产生中间体19(500mg,32%收率)。
LCMS(方法2,ES+)1.34分钟,434&436m/z(M+H)+。
中间体20
2-(6-溴吡咯并[2,3-b]吡啶-1-基)乙氧基-叔丁基-二甲基-硅烷
2-(6-溴吡咯并[2,3-b]吡啶-1-基)乙氧基-叔丁基-二甲基-硅烷按照一般程序2制备:使用6-溴-1H-吡咯并[2,3-b]吡啶(2g,9.9mmol)和(2-溴乙氧基)-叔丁基二甲基硅烷(2.7mL,12mmol),提供中间体20(3.13g,88%收率)。
LCMS(方法2,ES+)1.78分钟,355&357m/z(M+H)+。
中间体21
2-[6-[4-(邻-甲苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]乙醇
使用一般程序3、中间体1(1.2g,6.8mmol)、中间体20(2.7g,7.6mmol),提供叔丁基-二甲基-[2-[6-[4-(邻-甲苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]乙氧基]硅烷,然后将其溶于THF(20mL)。然后加入TBAF(14mL,14mmol)和在室温下搅拌反应混合物5天。减压浓缩反应混合物和加载于SCX柱,首先用甲醇洗涤然后用2M(大约)氨/甲醇洗脱。减压浓缩氨的甲醇溶液,残余物通过快速二氧化硅柱色谱法纯化,提供标题化合物(1.37g,60%收率)。
LCMS(方法2,ES+)1.47分钟,337m/z(M+H)+。
中间体22
6-[4-(邻-甲苯基)哌嗪-1-基]-1H-吡咯并[3,2-c]吡啶
用一般程序3、中间体9(455mg,1.47mmol)和中间体1(236mg,1.33mmol),提供三异丙基-[6-[4-(邻-甲苯基)哌嗪-1-基]吡咯并[3,2-c]吡啶-1-基]硅烷,将其溶于THF(5mL)。然后加入TBAF(4mL,4mmol),在室温搅拌反应混合物过夜。反应混合物进行水性后处理和有机层干燥(Na2SO4)处理和减压浓缩。所得残余物通过SCX柱首先用甲醇洗涤然后用大约2M氨/甲醇洗脱。减压浓缩溶液,提供标题化合物(46mg,12%两步收率)。
LCMS(方法2,ES+)1.31分钟,293m/z(M+H)+。
中间体23
反式-N-[3-[3-溴-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环丁基]-N-甲基-氨基甲酸叔丁酯
中间体19(500mg,1.15mmol)和顺式-N-(3-羟基环丁基)-N-甲基-氨基甲酸叔丁酯(1.5当量,1.7mmol)按照一般程序9反应和通过快速柱色谱法从己烷至70%EtOAc/己烷洗脱纯化,提供中间体23(410mg,78%收率)。
LCMS(方法2,ES+)1.73分钟,618&620m/z(M+H)+。
中间体24
顺式-N-[3-(6-溴-4-氯-吡咯并[2,3-b]吡啶-1-基)环丁基]-N-甲基-氨基甲酸叔丁酯
6-溴-4-氯-1H-吡咯并[2,3-b]吡啶(250mg,1.08mmol,100质量%)和反式-N-(3-羟基环丁基)-N-甲基-氨基甲酸叔丁酯(1.5当量,1.62mmol)按照一般程序9反应,产生中间体24(430mg,96%收率)。
LCMS(方法2,ES+)1.84分钟,414&416m/z(M+H)+。
中间体25
顺式-N-[3-[6-溴-3-(三氟甲基)吡咯并[2,3-b]吡啶-1-基]环丁基]-N-甲基-氨基甲酸叔丁酯
6-溴-3-(三氟甲基)-1H-吡咯并[2,3-b]吡啶(100mg,0.38mmol)和反式-N-(3-羟基环丁基)-N-甲基-氨基甲酸叔丁酯(1.5当量,0.6mmol)按照一般程序9反应,产生中间体25(160mg,86%收率)。
LCMS(方法2,ES+)1.84分钟,448&450m/z(M+H)+。
中间体26
反式-N-甲基-N-[3-[6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环丁基]氨基甲酸叔丁酯
6-[4-(4-甲磺酰基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶(中间体18,650mg,1.8mmol)和顺式-N-(3-羟基环丁基)-N-甲基-氨基甲酸叔丁酯(1.5当量,2.7mmol)按照一般程序9反应。浓缩反应混合物,残余物通过快速色谱法从己烷至EtOAc梯度洗脱直接纯化,提供中间体26(610mg,62%收率)。
LCMS(方法2,ES+)1.61分钟,640m/z(M+H)+。
中间体27
6-氯-1-(2-吡咯烷-1-基乙基)吡咯并[3,2-c]吡啶
6-氯-5-氮杂吲哚(750mg,4.8mmol)和1-(2-氯乙基)吡咯烷盐酸盐(1g,5.76mmol)用一般程序2反应,提供标题化合物(860mg,71%)。
LCMS(方法2,ES+)1.06分钟,250m/z(M+H)+。
中间体28
6-哌嗪-1-基-1-(2-吡咯烷-1-基乙基)吡咯并[3,2-c]吡啶
用一般程序1和中间体27(250mg,1.00mmol)获得标题化合物(250mg,83%)。
LCMS(方法2,ES+)0.94分钟,300m/z(M+H)+。
中间体29-32
中间体29-32能够用一般程序2合成自可商购的6-溴-1H-吡咯并[2,3-b]吡啶和适当的烷基卤。中间体29-32通过LCMS方法2分析。
中间体33
N-[2-[6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)吡咯并[2,3-b]吡啶-1-基]乙基]氨基甲酸叔丁酯
一般程序3,用中间体30(384mg,1.13mmol)和中间体5(240mg,1.18mmol)提供标题化合物(252mg,48%)。
LCMS(方法2,ES+)1.41分钟,462m/z(M+H)+。
中间体34-42
中间体34-42根据一般程序9合成自下文列表的适当杂环和醇。
中间体33过滤通过SCX柱纯化,首先用甲醇洗涤然后用大约2M氨/甲醇洗脱。减压浓缩氨的甲醇溶液,提供所希望的产品。
中间体34-42LCMS方法2分析。
中间体43
6-哌嗪-1-基吡啶-2-腈
中间体43用一般程序1制备自6-溴-2-吡啶腈(500mg,2.7mmol)和哌嗪-1-羧酸叔丁酯(610mg,3.2mmol),随后进行一般程序13,在反相色谱法后提供标题化合物(120mg,23%)
LCMS(方法2,ES+)0.51分钟,189m/z(M+H)+。
中间体44
4-(5-氯噻吩并[3,2-b]吡啶-3-基)哌嗪-1-羧酸叔丁酯
一般程序5,用3-溴-5-氯噻吩并[3,2-B]吡啶(200mg,0.79mmol)和1-boc-哌嗪(180mg,0.95mmol)在80℃提供标题化合物(24mg,9%)。
LCMS(方法2,ES+)1.53分钟,354&356m/z(M+H)+。
中间体45
6-溴-1H-吡咯并[2,3-b]吡啶-3-羧酸甲酯
将6-溴-1H-吡咯并[2,3-b]吡啶(1g,5.1mmol)溶于DCM(40mL)和在室温分批加入AlCl3(3.5当量,17.8mmol)。搅拌混合物30分钟,随后分批加入三氯乙酰氯(1当量,5.1mmol)。在室温搅拌混合物2小时。加入H2O和DCM,分层。减压除去溶剂。固体溶于MeOH(20mL),加入KOH(200mg,3.6mmol)。混合物在60℃搅拌3小时直至原料完全消耗。然后将反应冷却至室温,加入EtOAc和HCl(2M)水溶液。分层和有机层在Na2SO4上干燥。减压除去挥发物,残余物通过快速色谱法用己烷至EtOAc、然后10%MeOH/EtOAc梯度洗脱纯化,产生中间体45(420mg,24%收率)。
LCMS(方法2,ES+)1.01分钟,255&257m/z。
中间体46
顺式-6-溴-1-[3-[叔丁氧羰基(甲基)氨基]环丁基]吡咯并[2,3-b]吡啶-3-羧酸甲酯
将中间体45(400mg,1.6mmol)与反式-N-(反式-3-羟基环丁基)-N-甲基氨基甲酸叔丁酯(1.5当量,2.3mmol)按照一般程序9反应。产品通过快速柱色谱法从己烷至70%EtOAc/己烷梯度洗脱纯化,产生中间体46(550mg,80%收率)。
LCMS(方法2,ES+)1.66分钟,438&440m/z(M+H)+。
中间体47
顺式-1-[3-[叔丁氧羰基(甲基)氨基]环丁基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-羧酸甲酯
在60℃将中间体46(315mg,0.7mmol)和1-[4-甲磺酰基)苯基]哌嗪按照一般程序3反应。将混合物冷却至室温和加入H2O和EtOAc。分层,水相用EtOAc萃取。经合并的有机层在Na2SO4上干燥和减压除去挥发物。残余物通过快速柱色谱法用己烷至EtOAc然后EtOAc至30%的MeOH/EtOAc梯度洗脱纯化,提供中间体47(140mg,19%收率)和中间体48。
LCMS(方法2,ES+)1.54分钟,598m/z(M+H)+。
中间体48
顺式-6-溴-1-[3-[叔丁氧羰基(甲基)氨基]环丁基]吡咯并[2,3-b]吡啶-3-羧酸
中间体48(180mg,34%收率)作为合成中间体47的副产物获得。
LCMS(方法2,ES+)1.14分钟,424&426m/z
中间体49
反式-N-[3-(3-氰基-6-哌嗪-1-基-吡咯并[2,3-b]吡啶-1-基)环丁基]-N-甲基-氨基甲酸叔丁酯
将中间体50(3.4g,9.3mmol)和哌嗪(4.0g,46.0mmol)的溶液溶于二甲亚砜(15mL)、2-丙醇(5mL)和乙醇(3mL)的混合物。混合物在120℃加热过夜。冷却至rt之后,反应混合物用二乙醚(200mL)和50%饱和碳酸氢盐溶液(200mL)稀释。有机层用水(100mL)和盐水(200mL)洗涤,干燥(Na2SO4)和减压浓缩,提供油状物,其放置后固化,提供产品,是黄色固体(3.4g,89%)。
LCMS(方法2,ES+)1.23分钟,411m/z(M+H)+
中间体50
反式-N-[3-(6-氯-3-氰基-吡咯并[2,3-b]吡啶-1-基)环丁基]-N-甲基-氨基甲酸叔丁酯
6-氯-1H-吡咯并[2,3-b]吡啶-3-腈(2.0g,10.7mmol)和顺式-N-(3-羟基环丁基)-N-甲基-氨基甲酸叔丁酯(2.6g,13.0mmol)用于一般程序9,提供产品(3.4g,9.3mmol,86%)。
LCMS(方法2,ES+)1.46分钟,305&307m/z(M-tBu+H)+
中间体51
反式-1-[3-[叔丁氧羰基(甲基)氨基]环丁基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-羧酸
一般程序3用中间体46和1-[4-(甲磺酰基)苯基]哌嗪提供产品,15%收率。
LCMS(方法2,ES+)1.19分钟,584m/z(M+H)+
中间体52
6-溴-3-甲磺酰基-1H-吡咯并[2,3-b]吡啶
将6-溴-1H-吡咯并[2,3-b]吡啶(1g,5.1mmol,1当量)溶于THF(0.05M,100mL),在-10℃冷却,随后加入叔丁醇钾(626mg,1.1当量,5.6mmol)。在该温度搅拌反应混合物30分钟,随后加入三乙基硼烷(5.6mL,1.1当量,5.6mmol,1mol/L)。反应在该温度搅拌额外的30分钟然后,在-10℃滴加甲烷磺酰氯(0.45mL,1.2当量,5.8mmol),在室温下搅拌过周末。反应通过加入NH4Cl饱和水溶液和EtOAc猝灭。分层,水相用EtOAc再次萃取。经合并的有机层在Na2SO4上干燥。减压除去挥发物,残余物从己烷至1:1己烷:EtOAc纯化,提供中间体52,是白色固体(180mg,13%收率)。
LCMS(方法2,ES+)0.86分钟,275&277m/z(M+H)+
中间体53
顺式-N-[3-(6-溴-3-甲磺酰基-吡咯并[2,3-b]吡啶-1-基)环丁基]-N-甲基-氨基甲酸叔丁酯
中间体52(180mg,0.7mmol)与反式-N-(反式-3-羟基环丁基)-N-氨基甲酸叔丁酯(208mg,1.5当量,1mmol)按照一般程序9反应,提供中间体53,是淡黄色油状物(220mg,69%收率)。
LCMS(方法2,ES+)1.50分钟,458&460m/z(M+H)+。
中间体54
顺式-N-[3-(7-溴吡咯并[2,3-c]吡啶-1-基)环丁基]-N-甲基-氨基甲酸叔丁酯
7-溴-1H-吡咯并[2,3-c]吡啶(200mg,1mmol)和反式-N-(反式-3-羟基环丁基)-N-甲基氨基甲酸叔丁酯(306mg,1.5当量,1.45mmol)按照一般程序9反应,提供中间体54,是黄色浆液(330mg,90%收率)。
LCMS(方法2,ES+)1.45分钟,380&382m/z(M+H)+。
中间体55
4-(1-三异丙基甲硅烷基吡咯并[2,3-b]吡啶-6-基)哌嗪-1-羧酸叔丁酯
将中间体8(8.5g,24mmol),1-boc-哌嗪(1.8当量,43mmol),叔丁醇钠(3当量,72mmol)和(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯)[2-(2'-氨基-1,1'-联苯)]钯(II)甲磺酸盐(0.1当量,2.4mmol)溶于脱气的1,4-二噁烷(0.5M)。混合物加热至80℃过夜然后冷却至环境温度。加入EtOAc和H2O,分层。水相然后进一步用EtOAc萃取。经合并的有机层在Na2SO4上干燥和减压除去溶剂。残余物通过柱色谱法从DCM至20%MeOH/DCM纯化,提供中间体55,是淡黄色固体(11g,94%收率)。
LCMS(方法2,ES+)2.12分钟,459m/z(M+H)+。
中间体56
4-(3-溴-1-三异丙基甲硅烷基-吡咯并[2,3-b]吡啶-6-基)哌嗪-1-羧酸叔丁酯
将中间体55(4g,8.7mmol)溶于DCM(30mL),冷却至0℃。在30分钟内分批加入NBS(1.1g,0.75当量)。在冷却浴存在下搅拌反应混合物额外10分钟,随后用饱和碳酸氢盐(20mL)淬灭和用DCM(20mL)稀释。水层用DCM萃取,经合并的有机层在Na2SO4上干燥和减压浓缩。残余物从己烷至EtOAc纯化,提供浆液(4.1g,87%收率)。
LCMS(方法2,ES+)2.27分钟,537&539m/z(M+H)+。
中间体57
(3-溴-6-哌嗪-1-基-吡咯并[2,3-b]吡啶-1-基)-三异丙基-硅烷
中间体56(800mg,1.5mmol)按照一般程序13反应,提供中间体57(420mg,65%收率)。
LCMS(方法2,ES+)1.63分钟,437&439m/z(M+H)+。
中间体58
1-[4-(3-溴-1-三异丙基甲硅烷基-吡咯并[2,3-b]吡啶-6-基)哌嗪-1-基]乙烯酮
将中间体57(300mg,0.7mmol)和乙酸(1.5当量,1mmol)与一般程序6类似地反应。加入H2O,分层。水相用DCM再次洗涤。减压干燥经合并的有机层,残余物通过快速色谱法从己烷至EtOAc纯化,提供中间体58,是白色固体(220mg,67%收率)
LCMS(方法2,ES+)1.88分钟,479&481m/z(M+H)+。
中间体59
反式-N-[3-[6-(4-乙酰基哌嗪-1-基)-3-溴-吡咯并[2,3-b]吡啶-1-基]环丁基]-N-甲基-氨基甲酸叔丁酯
将中间体58(200mg,0.42mmol)溶于THF(0.1M)和加入TBAF(1.3当量,0.5mmol,1mmol/mL,在THF中)。混合物在环境温度搅拌30分钟直至原料消耗。将EtOAc和H2O加入反应混合物和分层。有机相在Na2SO4上干燥和减压除去溶剂。残余物然后与N-(3-羟基环丁基)-N-甲基-氨基甲酸叔丁酯按照一般程序9反应,提供中间体59,是褐色固体(100mg,47%两步收率)。
LCMS(方法2,ES+)1.54分钟,506&508m/z(M+H)+。
中间体60
反式-N-[3-(6-氯-3-氰基-2-甲基-吡咯并[2,3-b]吡啶-1-基)环丁基]-N-甲基-氨基甲酸叔丁酯
将6-氯-2-甲基-1H-吡咯并[2,3-b]吡啶与顺式-N-(3-羟基环丁基)-N-甲基-氨基甲酸叔丁酯用一般程序9反应。所得反式-N-[3-(6-氯-2-甲基-吡咯并[2,3-b]吡啶-1-基)环丁基]-N-甲基-氨基甲酸叔丁酯溶于1:1MeCN/DMF,冷却至0℃,然后加入氯磺酰基异氰酸酯(5当量)。混合物在40℃搅拌2小时。冷却至rt之后,混合物用水稀释,用EtOAc(2x)萃取,用盐水洗涤,干燥(Na2SO4)和真空浓缩。残余物然后通过柱色谱法纯化(10%EtOAc/己烷),提供产品(35%,2步)。
LCMS(方法7,ES+)2.34分钟,319&321m/z(M-tBu+H)+
中间体61
反式-N-(3-氨基环丁基)-N-甲基-氨基甲酸叔丁酯
在0℃向搅拌的顺式-N-(3-羟基环丁基)-N-甲基-氨基甲酸叔丁酯(3.00g,14.9mmol)的DCM(50mL)溶液加入三乙胺(5.02mL,44.7mmol)和甲烷磺酰氯(1.50mL,19.4mmol),在0℃保持30分钟。在加入完成之后,所得反应混合物在室温搅拌1小时。在原料完全消耗之后,反应混合物用冰冷水(100mL)猝灭。水层用DCM(100mL x 2)萃取。收集的有机层在硫酸钠上干燥和减压蒸发,提供粗制的顺式-[3-[叔丁氧羰基(甲基)氨基]环丁基]甲磺酸酯(粗制重量:4.2g)。
在0℃向搅拌的顺式-[3-[叔丁氧羰基(甲基)氨基]环丁基]甲磺酸酯(4.20g,14.2mmol)的DMF(30mL)溶液加入NaN3(4.61g,70.9mmol)。在加入完成之后,所得反应混合物在70℃搅拌16小时。在原料完全消耗之后,反应混合物用冰冷水(100mL)猝灭和用乙酸乙酯(100mL x 2)萃取。有机层用饱和碳酸氢钠溶液(100mL)和盐水(100mL)洗涤,收集有机层和在硫酸钠上干燥,然后过滤和减压蒸发,获得粗制的反式-N-(3-叠氮基环丁基)-N-甲基-氨基甲酸叔丁酯(粗制重量:4.3g)
向搅拌的反式-N-(3-叠氮基环丁基)-N-甲基-氨基甲酸叔丁酯(4.30g,17.6mmol)的氨甲醇溶液(30mL)加入20%钯/碳(1g)。在氢气氛下在室温下搅拌反应混合物36小时。在原料完全消耗之后,在C盐上过滤反应混合物和用甲醇(100mL)洗涤。减压浓缩滤液,通过柱色谱法纯化(15%甲醇/DCM),获得产品(2.0g,9.57mmol,64%,3步)。
LCMS(方法7,ES+)1.36分钟,201m/z(M+H)+
中间体62
反式-N-[3-(5-氯-2-氧代-1H-咪唑并[4,5-b]吡啶-3-基)环丁基]-N-甲基-氨基甲酸叔丁酯
在室温向搅拌的2,6-二氯-3-硝基-吡啶(1.00g,5.18mmol)的乙醇(20mL)溶液加入中间体61(1.30g,6.22mmol)、随后碳酸钠(1.63g,15.5mmol)。在室温搅拌混合物16小时,然后用水(50mL)稀释和用EtOAc(50mL x 2)萃取。收集的有机层用盐水(50mL)洗涤,干燥(Na2SO4)和减压浓缩。粗制化合物通过柱色谱法(1:1EtOAc/己烷)纯化,提供反式-N-[3-[(6-氯-3-硝基-2-吡啶基)氨基]环丁基]-N-甲基-氨基甲酸叔丁酯(1.30g,3.61mmol,70%)。
对反式-N-[3-[(6-氯-3-硝基-2-吡啶基)氨基]环丁基]-N-甲基-氨基甲酸叔丁酯(1.30g,3.61mmol)进行一般程序15,随后一般程序16,提供产品反式-N-[3-(5-氯-2-氧代-1H-咪唑并[4,5-b]吡啶-3-基)环丁基]-N-甲基-氨基甲酸叔丁酯(0.65g,1.84mmol,51%,两步)。
LCMS(方法8,ES+)1.87分钟,297&299m/z(M-tBu+H)+
中间体63
4-(5-氯-2-氧代-1H-咪唑并[4,5-b]吡啶-3-基)哌啶-1-羧酸叔丁酯
在室温向搅拌的2,6-二氯-3-硝基-吡啶(5.00g,25.9mmol)的乙醇(50mL)溶液加入4-氨基哌啶-1-羧酸叔丁酯(7.78g,38.9mmol)、随后碳酸钠(8.16g,77.7mmol)。在室温搅拌混合物16小时然后用乙酸乙酯(300mL)稀释和用水(300mL x 2)洗涤。分开有机层,用盐水洗涤(500mL),在硫酸钠上干燥和减压浓缩。粗制化合物通过柱色谱法纯化(70%EtOAc/己烷),提供4-[(6-氯-3-硝基-2-吡啶基)氨基]哌啶-1-羧酸叔丁酯(6.50g,18.2mmol,70%)。
对4-[(6-氯-3-硝基-2-吡啶基)氨基]哌啶-1-羧酸叔丁酯(4.0g,11.2mmol)进行一般程序15,随后一般程序16,提供产品4-(5-氯-2-氧代-1H-咪唑并[4,5-b]吡啶-3-基)哌啶-1-羧酸叔丁酯(1.0g,2.71mmol,24%,两步)。
LCMS(方法7,ES+)1.85分钟,297&299[55%]m/z(M-tBu+H)+,253&255[100%]m/z(M-tBuCO2+H)+
中间体64
4-(5-氯-2-氧代-1H-咪唑并[4,5-b]吡啶-3-基)-4-甲基-哌啶-1-羧酸叔丁酯
在室温在氩下将碳酸钠(3.26g,31.1mmol)和4-氨基-4-甲基-哌啶-1-羧酸叔丁酯(2.67g,12.4mmol)加入搅拌的2,6-二氯-3-硝基-吡啶(2g,10.4mmol)的乙醇(35mL)溶液。所得反应混合物在70℃加热24小时。反应混合物用乙酸乙酯稀释(100mL)和用水洗涤(100mL X 2)。分开有机层,用盐水洗涤(100mL),在硫酸钠上干燥和减压浓缩。粗制物质通过柱色谱法用50%乙酸乙酯/己烷纯化,提供4-[(6-氯-3-硝基-2-吡啶基)氨基]-4-甲基-哌啶-1-羧酸叔丁酯(2.50g,5.76mmol,56%)。
对4-[(6-氯-3-硝基-2-吡啶基)氨基]-4-甲基-哌啶-1-羧酸叔丁酯(2.50g,5.76mmol)进行一般程序15、然后一般程序16,提供4-(5-氯-2-氧代-1H-咪唑并[4,5-b]吡啶-3-基)-4-甲基-哌啶-1-羧酸叔丁酯(0.70g,1.84mmol,32%,两步)。
LCMS(方法7,ES+)2.07分钟,311&313m/z(M-tBu+H)+
中间体65
反式-N-[3-[6-[4-(4-乙酰基苯基)哌嗪-1-基]-3-溴-吡咯并[2,3-b]吡啶-1-基]环丁基]-N-甲基-氨基甲酸叔丁酯
将3-溴-6-氯-7-氮杂吲哚(4.0g,16.8mmol)和顺式-N-(3-羟基环丁基)-N-甲基-氨基甲酸叔丁酯(4.1g,20.1mmol)根据一般程序9反应,提供反式-N-[3-(3-溴-6-氯-吡咯并[2,3-b]吡啶-1-基)环丁基]-N-甲基-氨基甲酸叔丁酯(7.6g,定量)。
将N-[3-(3-溴-6-氯-吡咯并[2,3-b]吡啶-1-基)环丁基]-N-甲基-氨基甲酸叔丁酯(3.0g,7.2mmol)和1-(4-乙酰基苯基)哌嗪(7.4g,36mmol)根据一般程序14反应,提供0.6g产品(14%)。
LCMS(方法2,ES+)1.52分钟,582&584m/z(M+H)+。
中间体66
1-甲基-5-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-c]吡啶
将5-溴-1h-吡咯并[2,3-c]吡啶(2.5g,13mmol)的四氢呋喃(25mL)溶液脱气(3x抽真空5分钟,然后反填充N2),然后用冰/盐水浴冷却。然后分三批加入氢化钠(760mg,19mmol),搅拌混合物30分钟然后加入碘甲烷(1.04mL,16.5mmol),搅拌混合物5分钟然后除去冰浴,让其温热至室温。在1小时之后,反应用水(30ml)淬灭,产品用EtOAc(2x 30ml)萃取。经合并的有机物用盐水洗涤(20ml),干燥(Na2SO4)和真空浓缩。产品然后通过柱色谱法纯化,提供5-溴-1-甲基-1h-吡咯并[2,3-c]吡啶(2.5g,11.3mmol,89%),是橙色油状物,其放置后结晶。
将5-溴-1-甲基-1h-吡咯并[2,3-c]吡啶(1.0g,4.5mmol)与1-[4-(甲磺酰基)苯基]哌嗪(1.2g,5.0mmol)根据一般程序5反应,提供产品(1.3g,3.6mmol,80%)。
LCMS(方法2,ES+)1.12分钟,371m/z(M+H)+。
中间体67-69
中间体67-69能够用一般程序2合成自可商购的6-溴-1H-吡咯并[2,3-b]吡啶和适当的烷基卤
中间体70
2-(4-溴苯基)-1-甲基-咪唑
将2-(4-溴-苯基)-1H-咪唑(215mg,0.94mmol)溶于四氢呋喃(5mL)和N,N-二甲基甲酰胺(1mL)的混合物。将溶液冷却至0℃和加入氢化钠(45mg,1.12mmol,60质量%)。在大约5分钟之后加入碘甲烷(0.1mL,2mmol),反应混合物(悬浮液)在室温搅拌大约3小时。将悬浮液冷却至0℃,加水。在冷却浴存在下搅拌透明溶液1小时然后用50%饱和氯化铵(20mL)和二乙醚(20mL)稀释。有机层用水洗涤(2x 20mL),干燥(Na2SO4)和减压浓缩,提供标题中间体(215mg,96%)。
LCMS(方法2,ES+)1.02分钟,239m/z(M+H)+。
中间体71
1-[4-(2-吡啶基)苯基]哌嗪
将2-(4-溴苯基)吡啶(529mg,2.15mmol)和(S)-4-N-boc-2-甲基哌嗪(400mg,2.15mmol)用于一般程序3中,提供4-[4-(2-吡啶基)苯基]哌嗪-1-羧酸叔丁酯(736mg,定量)。然后将4-[4-(2-吡啶基)苯基]哌嗪-1-羧酸叔丁酯(185mg,0.54mmol)用于程序13,提供标题中间体(139mg,定量)
LCMS(方法2,ES+)0.84分钟,240m/z(M+H)+。
中间体72-73
中间体72-73根据一般程序9合成自下文列表的适当的杂环和醇和通过LCMS方法5分析。
中间体74-77
中间体74-77根据一般程序19制备和LCMS方法5分析。例外是中间体76用LCMS方法10分析。
中间体78-81
中间体78-81经由一般程序14、随后一般程序13制备自1-(4-氟苯基)乙酮和适当的N-Boc哌嗪。中间体用LCMS方法6分析。
中间体82-85
中间体82-85根据一般程序9合成自6-氯-1H-吡咯并[2,3-b]吡啶、下文列表的适当杂环和醇,用LCMS方法5分析,例外是中间体85用LCMS方法12分析
中间体86-89
中间体86-89根据一般程序20制备自适当的氮杂-吲哚。
中间体86&87用LCMS方法5分析
中间体88&89用LCMS方法10分析
中间体90-95
中间体90-95根据一般程序21制备自相应碘芳基中间体和商业取代硼酸酯/酸。
中间体90&93-95用LCMS方法10分析。
中间体91-92用LCMS方法5分析。
中间体96
N-甲基-N-[(1r,3r)-3-(6-{4'-乙酰基-[1,1'-联苯]-4-基}-3-氰基-1H-吡咯并[2,3-b]吡啶-1-基)环丁基]氨基甲酸叔丁酯
将N-[3-(6-氯-3-氰基-吡咯并[2,3-b]吡啶-1-基)环丁基]-N-甲基-氨基甲酸叔丁酯(中间体50)(84mg,0.23mmol),[4-(4-乙酰基苯基)苯基]取代硼酸(50.0mg,0.21mmol)和碳酸二钠(45mg,0.42mmol)在1,4-二噁烷(3mL)中的混合物用N2冲洗脱气,然后加入1,1'-二(二苯基膦基)二茂铁氯化钯(II)二氯甲烷复合物(17.4mg,0.02mmol)。在100℃搅拌反应混合物过夜然后冷却至RT,用DCM(5mL)稀释和过滤通过C盐。固体用DCM(2x 5mL)洗涤,将经合并的滤液减压浓缩至干。获得的残余物通过FCC(在DCM中湿加载至Biotage SNAPUltra 10g柱,5%至49%EtOAc/庚烷洗脱)纯化,产生120mg(84%)标题化合物,是米白色固体。
LCMS(方法10,ES+)1.49分钟,521m/z[M+H]+
中间体97
4-[3-(1-甲基-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基]哌嗪-1-羧酸叔丁酯
将4-{3-溴-1-[三(丙-2-基)甲硅烷基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-羧酸叔丁酯(2.2g,4.09mmol),中间体56(936.59mg,4.5mmol)和2M碳酸钠(2M aq)(6.14mL)在二噁烷(12mL)中的混合物用N2鼓泡脱气10分钟,然后加入四(三苯基膦)钯(0)(472.mg,0.41mmol),反应在100℃加热16h。反应混合物稀释于EtOAc,依次用水和盐水洗涤。水相用EtOAc(3x 30mL)萃取。经合并的有机相在Na2SO4上干燥和减压浓缩至干。通过FCC(BiotageIsolera,100g SNAP KP-Sil,10-100%EtOAc:庚烷、然后0-20%MeOH:EtOAc梯度洗脱)纯化提供标题化合物440mg(27.3%),是黄色固体。
LCMS(方法12,ES+)1.32分钟,383m/z[M+H]+
中间体98
4-(1-{1-[(苄氧基)羰基]哌啶-4-基}-3-(1-甲基-1H-吡唑-4-基)-1H-吡咯并[2,3-b]吡啶-6-基)哌嗪-1-羧酸叔丁酯
标题化合物根据一般程序9经由Mitsunobu制备自中间体97和4-羟基哌啶-1-羧酸苄酯。
LCMS(方法10,ES+)1.41min,600m/z[M+H]+
中间体99
4-[3-(1-甲基-1H-吡唑-4-基)-6-(哌嗪-1-基)-1H-吡咯并[2,3-b]吡啶-1-基]哌啶-1-羧酸苄酯
标题化合物根据一般程序13制备自中间体98。
LCMS(方法5,ES+)1.69分钟,500m/z[M+H]+
中间体100
4-[6-[4-(4-乙酰基苯基)哌嗪-1-基]-3-(1-甲基吡唑-4-基)吡咯并[2,3-b]吡啶-1-基]哌啶-1-羧酸苄酯
标题化合物根据一般程序14制备自中间体99和1-(4-溴苯基)乙烯酮。
LCMS(方法10,ES+)1.38分钟,618m/z[M+H]+
中间体101
5-氯-1-(1-甲基吡唑-4-基)吡咯并[3,2-b]吡啶
将5-氯-1H-吡咯并[3,2-b]吡啶(350mg,2.29mmol),4-溴-1-甲基-1H-吡唑(480mg,2.98mmol),碘化铜(1+)(87mg,0.46mmol),喹啉-8-醇(67mg,0.46mmol)和碳酸二钾(476mg,3.44mmol)的混合物悬浮于DMSO(6mL)和在130℃在微波辐射下搅拌16小时。将反应混合物冷却至室温和用10%氢氧化铵水溶液(20mL)稀释,然后用EtOAc(3×25mL)萃取。经合并的有机相在Na2SO4上干燥,过滤和真空蒸发至干。残余物通过快速二氧化硅柱色谱法纯化,从15%至100%EtOAc/庚烷梯度洗脱,产生标题化合物,是米白色固体(320mg,56%收率)。
LCMS(方法10,ES+)1.01分钟,233&235m/z[M+H]+
中间体102
3-溴-5-氯-1-(1-甲基吡唑-4-基)吡咯并[3,2-b]吡啶
在室温在5分钟内向中间体101(320mg,1.38mmol)的DCM(10mL)溶液分批加入NBS(269mg,1.51mmol)然后搅拌90分钟。反应混合物用DCM(10mL),水(10mL)和饱和Na2CO3水溶液(10mL)稀释。分离有机相,水相用DCM(2×10mL)萃取。经合并的有机相在MgSO4上干燥,过滤和蒸发至干。残余物通过快速二氧化硅柱色谱法纯化,从15%至100%EtOAc/庚烷梯度洗脱,产生标题化合物,是米白色固体(400mg,89%收率)。
LCMS(方法10,ES+)1.08分钟,311&313m/z[M+H]+
中间体103
3-溴-1-(1-甲基吡唑-4-基)-5-哌嗪-1-基-吡咯并[3,2-b]吡啶
向中间体102(260mg,0.83mmol)和哌嗪(1.08g,12.52mmol)在DMSO(3mL)中的混合物加入4N HCl/二噁烷(0.21mL)然后在136℃在微波辐射下搅拌16小时。反应混合物用水(20mL)稀释然后用EtOAc(4×25mL)萃取。经合并的有机相在MgSO4上干燥,过滤和真空蒸发。残余物通过快速NH-二氧化硅柱色谱法纯化,从EtOAc至11%MeOH/EtOAc梯度洗脱,产生标题化合物,是褐色胶状物(235mg,70%收率)。
LCMS(方法10,ES+)0.87分钟,361&363m/z[M+H]+
中间体104
1-[4-[4-[3-溴-1-(1-甲基吡唑-4-基)吡咯并[3,2-b]吡啶-5-基]哌嗪-1-基]苯基]乙酮
将中间体103(90%纯度,230mg,0.57mmol),1-(4-氟苯基)乙酮(158mg,1.15mmol)和碳酸二钾(207mg,1.5mmol)在DMSO(3mL)中的混合物在130℃在微波辐射下搅拌19小时。将反应混合物冷却至室温和用DCM(25mL)和水(25mL)稀释。分开有机层,水相用DCM(2×25mL)萃取。经合并的有机层在MgSO4上干燥,过滤和真空蒸发,产生米白色固体残余物。该固体与50%EtOAc/庚烷(5mL)研磨,过滤收集固体,用50%EtOAc/庚烷(2*3mL)洗涤,提供标题化合物,是米白色固体(250mg,82%收率)。
LCMS(方法10,ES+)1.21分钟,479,481m/z[M+H]+
中间体105
4-(5-溴-1H-吡咯并[3,2-b]吡啶-3-基)-3,6-二氢-2H-吡啶-1-羧酸叔丁酯
向5-溴-1H-吡咯并[3,2-b]吡啶(400mg,2.03mmol)和4-氧代哌啶-1-羧酸叔丁酯(607mg,3.05mmol)的MeOH(10mL)溶液加入氢氧化钾(167μL,6.09mmol)然后在回流下搅拌20小时。将反应混合物冷却至室温,用水(40mL)稀释和用EtOAc(3×30mL)萃取。经合并的有机相在MgSO4上干燥,过滤和真空蒸发至干。残余物通过快速二氧化硅柱色谱法纯化,从12%至100%EtOAc/庚烷梯度洗脱,产生标题化合物,是米白色固体(560mg,65%收率)。
LCMS(方法10,ES+)1.28分钟,378&380m/z[M+H]+
中间体106
4-[5-溴-1-(1-甲基吡唑-4-基)吡咯并[3,2-b]吡啶-3-基]-3,6-二氢-2H-吡啶-1-羧酸叔丁酯
将中间体105(460mg,1.09mmol),4-碘-1-甲基-1H-吡唑(342mg,1.64mmol),碘化铜(1+)(21mg,0.11mmol),喹啉-8-醇(16mg,0.11mmol)和K2CO3(227mg,1.64mmol)在DMSO(6mL)中的混合物在110℃在微波辐射下搅拌36分钟。然后将混合物冷却至室温,用10%氢氧化铵(20mL)稀释,用EtOAc(4×20mL)萃取,MgSO4干燥,过滤和真空蒸发至干。残余物通过快速二氧化硅柱色谱法纯化,从17%至59%EtOAc/庚烷梯度洗脱,产生标题化合物,是黄色固体(265mg,48%收率)。
LCMS(方法10,ES+)1.35分钟,458&460m/z[M+H]+
中间体107
4-[5-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(1-甲基吡唑-4-基)吡咯并[3,2-b]吡啶-3-基]-3,6-二氢-2H-吡啶-1-羧酸叔丁酯
该中间体按照一般程序21制备:使用中间体106和1-(4-哌嗪-1-基苯基)乙酮。
LCMS(方法10,ES+)1.37分钟,582m/z[M+H]+
中间体108
4-[5-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(1-甲基吡唑-4-基)吡咯并[3,2-b]吡啶-3-基]哌啶-1-羧酸叔丁酯
将中间体107(105mg,0.16mmol)的MeOH/EtOAc(1:1,15mL)溶液通过H-cube系统(20℃,5巴H2压)中的10%Pd/C柱,循环2次。然后真空蒸发溶液,粗制残余物通过快速NH-二氧化硅柱色谱法纯化,从18%至100%EtOAc/庚烷梯度洗脱,产生标题化合物,是褐色固体(40mg,31%收率)。
LCMS(方法10,ES+)1.29分钟,584m/z[M+H]+
中间体109
4-[4-[1-[3-[叔丁氧羰基(甲基)氨基]环丁基]-3-氰基-吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯甲酸甲酯
该中间体按照一般程序3制备:使用中间体40和4-(哌嗪-1-基)苯甲酸甲酯。
LCMS(方法2,ES+)1.56和1.62分钟,545m/z[M+H]+
中间体110
4-[4-[1-[3-[叔丁氧羰基(甲基)氨基]环丁基]-3-氰基-吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯甲酸
将中间体109(117mg,0.2mmol)溶于THF(5mL)和加入一水合氢氧化锂(45mg,1.1mmol)的水(2mL)溶液。在室温搅拌反应混合物2小时,加入第二份一水合氢氧化锂(45mg,1.1mmol)的水(0.5mL)溶液、随后1,4-二噁烷(1mL)。在室温搅拌反应混合物1小时然后在50℃加热~2小时。然后在室温静置2天。反应混合物用pH 4缓冲剂和乙酸乙酯稀释。水层用乙酸乙酯萃取三次。合并有机层,干燥(Na2SO4)和减压浓缩。残余物然后通过快速柱色谱法纯化,提供标题化合物(110mg,96%)。
LCMS(方法2,ES+)1.12分钟,531m/z[M+H]+
实施例1-16
下述化合物用一般程序3合成自下表所列的杂芳基卤和适当胺。
实施例1-8、实施例10和实施例15-16:LCMS方法1
实施例9:LCMS方法2
实施例11-14:LCMS方法4
实施例17-29
实施例17-29根据一般程序3随后一般程序13以2步制备,用LCMS方法1分析。
实施例30-33
下述化合物按照一般程序4合成自中间体6和适当的哌啶。
实施例用LCMS方法1分析。
实施例34-51
下述化合物按照一般程序3合成自中间体7和适当的芳基溴。
实施例34-45用LCMS方法3分析。
实施例46-51用LCMS方法1分析。
实施例52-54
实施例52-54按照一般程序6合成自中间体7和适当的羧酸,用LCMS方法3分析。
实施例55-66
下述化合物按照一般程序7合成自中间体17和适当的胺。
实施例55-65:LCMS方法3
实施例66:LCMS方法1
实施例67-81
下述化合物按照一般程序8合成自中间体15和适当的胺。
实施例67-81用LCMS方法3分析。
实施例82-85
将中间体23(70mg,0.11mmol),取代硼酸酯(2当量,0.23mmol),K2CO3(2当量,0.23mmol)和PdCl2(dppf)-DCM复合物(0.1当量,0.01mmol)溶于1,4-二噁烷(0.1M,1mL)。加H2O(1M,0.1mL),将混合物脱气1分钟。将混合物在100℃搅拌过夜。将混合物冷却至环境温度,加入DCM(3mL)和H2O(2mL),分层。将TFA(1mL)加入DCM溶液,在室温搅拌反应混合物2小时。残余物过滤通过SCX柱,用MeOH和DCM洗涤,然后用NH3(7N)/MeOH洗脱产品。减压除去挥发物,残余物通过反相柱色谱法纯化。
实施例82-85按照前述程序合成自中间体23和适当的可商购取代硼酸酯。
实施例用LCMS方法1分析。
实施例86-97
实施例86-97按照一般程序12合成自适当的胺和醛。
实施例86-97用LCMS方法1分析。
实施例98
5-(4-{1-[2-(1-氧杂-6-氮杂螺[3.4]辛-6-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶
实施例98按照一般程序8制备:使用中间体15(50mg,0.09mmol)和1-氧杂-7-氮杂螺[3.4]辛烷(17mg,1.5当量)。然后在密封小瓶中在80℃将反应混合物加热过夜。反应冷却至环境温度,加入H2O和DCM。分层,水相用DCM萃取。减压除去溶剂,残余物通过色谱法DCM至30%MeOH/DCM梯度洗脱纯化,产生实施例98(5mg,12%收率)。
LCMS(方法1,ES+)2.01分钟,458m/z(M+H)+。
实施例99
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-3-腈
将6-溴-1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶-3-腈(300mg,0.1mmol)溶于DMF:THF的混合物(10mL,1:1)。将粉色溶液冷却至0℃,在30分钟期间内分批缓慢加入氢化钠(79mg,0.11mmol,2.2当量,60质量%)。然后分批仔细加入1-(2-氯乙基)吡咯烷盐酸盐(1.5当量,1.4mmol),在80℃搅拌反应混合物过夜直至原料消耗。粗制物溶于DCM,加H2O。分层,水相用DCM萃取。减压除去溶剂,所得残余物与1-[4-(甲磺酰基)苯基]哌嗪(1.5当量,0.94mmol)用于一般程序3。残余物通过柱色谱法从DCM至30%MeOH/DCM梯度洗脱纯化,然后通过反相色谱法再纯化,产生实施例99(4mg,1%收率)。
LCMS(方法1,ES+)2.62分钟,479m/z(M+H)+。
实施例100
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-4-腈
按照一般程序2将4-氰基-6-溴-7-氮杂吲哚(200mg,0.9mmol)与1-(2-氯乙基)吡咯烷盐酸盐(1.5当量,1.35mmol)反应。加入H2O和EtOAc,分层,水相用EtOAc萃取。减压除去溶剂,残余物按照一般程序3不加进一步纯化地使用,用1-[4-(甲磺酰基)苯基]哌嗪(1.5当量,1.97mmol)。残余物通过柱色谱法DCM至30%MeOH/DCM梯度洗脱纯化,然后通过反相柱色谱法再纯化,提供实施例100(5mg,7%收率)。
LCMS(方法1,ES+)2.26分钟,479m/z(M+H)+。
实施例101
3-甲基-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶
将中间体18(100mg,0.28mmol),六水合四氟硼酸钴(0.1mmol),三[2-(二苯基膦基)乙基]膦(0.1mmol)和K2CO3(1mmol,1mmol)溶于甲醇(1mL)。在密封小瓶中加热混合物至100℃过夜。粗制反应混合物在C盐上过滤,减压除去挥发物。残余物按照一般程序2用1-(2-氯乙基)吡咯烷盐酸盐(1.5当量)进行烷基化。粗制反应混合物用EtOAc稀释,加H2O。分层,水相用EtOAc萃取。经合并的有机层在Na2SO4上干燥和减压除去溶剂。残余物在C盐上过滤,用DCM冲洗。在除去溶剂之后,残余物通过反相柱色谱法纯化,提供实施例101(2mg,2%收率)。
LCMS(方法1,ES+)2.83分钟,468m/z(M+H)+。
实施例102
反式-3-(3-溴-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)-N-甲基环丁烷胺
将中间体26(550mg,1.02mmol)溶于DCM(30mL),冷却至0℃。分批加入NBS(165mg,0.92mmol)。在冷却浴中搅拌反应混合物10分钟,然后用饱和NaHCO3水溶液(20mL)淬灭和用DCM(20mL)稀释。水层用DCM(2x 10mL)萃取,经合并的有机物在Na2SO4上干燥和减压浓缩。粗制物通过快速色谱法20%EtOAc至EtOAc然后至DCM/MeOH梯度洗脱纯化,提供溴化产品的混合物。将白色固体溶于DCM(0.25M)和TFA(5mL),在室温搅拌直至反应完成。减压除去挥发物,残余物溶于MeOH和过滤通过SCX柱,用MeOH和DCM洗涤,然后用NH3(4M)/MeOH洗脱。减压除去溶剂,残余物通过制备型HPLC纯化提供实施例102(7mg,1%收率)。
LCMS(方法1,ES+)1.89分钟,518&520m/z(M+H)+。
实施例103
6-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)吡啶-2-腈
将中间体7(107mg,0.35mmol),2-氰基-6-氟吡啶(44mg,0.36mmol)和碳酸钾(100mg,0.71mmol)的混合物溶于二甲亚砜(2mL),在100℃加热过夜。然后对冷却的反应混合物进行水性后处理,干燥有机溶剂(Na2SO4)和减压浓缩。将1/3粗制残余物通过反相柱色谱法纯化,提供标题化合物(19.5mg,14%收率)。
LCMS(方法1,ES+)2.53分钟,402m/z(M+H)+。
实施例104
2-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)吡啶-3-腈
将中间体7(90mg,0.30mmol)和3-氰基-2-氟吡啶(45mg,0.36mmol)的混合物溶于四氢呋喃(2mL),加入三乙胺(0.1mL,0.7mmol)。所得黄色溶液在100℃加热过夜。然后对冷却的反应混合物进行水性后处理,减压浓缩有机层。将1/2粗制残余物通过反相柱色谱法纯化,提供标题化合物(31.2mg,25%收率)。
LCMS(方法1,ES+)2.39分钟,402m/z(M+H)+。
实施例105
6-[4-(2-甲基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[3,2-c]吡啶
实施例105根据一般程序2用中间体22(46mg,0.16mmol)和1-(2-氯乙基)吡咯烷盐酸盐(33mg,0.19mmol)制备。最终用反相柱色谱法纯化提供标题化合物(16mg,26%收率)。
LCMS(方法1,ES+)2.61分钟,390m/z(M+H)+。
实施例106
顺式-3-(4-氯-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)-N-甲基环丁烷胺
将中间体24(330mg,1当量)和1-[4-(甲磺酰基)苯基]哌嗪(1.1当量,0.88mmol)按照一般程序3反应。残余物通过快速柱色谱法用己烷至EtOAc梯度洗脱纯化。将获得的产品溶于DCM(5mL),加入TFA(1mL)。混合物在环境温度搅拌1小时。然后将混合物过滤通过SCX-柱和用DCM和MeOH冲洗。产品用NH3(4N)/MeOH洗脱。减压除去挥发物,残余物然后通过反相柱色谱法纯化,产生标题化合物,是白色固体(19mg,5%收率)。
LCMS(方法1,ES+)1.81分钟,474m/z(M+H)+。
实施例107
顺式-N-甲基-3-[6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-3-(三氟甲基)-1H-吡咯并[2,3-b]吡啶-1-基]环丁烷胺
中间体25(160mg,0.36mmol)和1-[4-(甲磺酰基)苯基]哌嗪(1.1当量,0.4mmol)按照一般程序3反应。残余物通过快速柱色谱法用己烷至EtOAc梯度洗脱纯化。所得残余物溶于DCM(5mL),加入TFA(2mL)。混合物在环境温度搅拌2小时,减压除去挥发物。残余物通过快速柱色谱法用己烷至EtOAc然后20%MeOH/EtOAc梯度洗脱纯化,提供实施例107(2mg,8%收率)。
LCMS(方法1,ES+)1.92分钟,408m/z(M+H)+。
实施例108
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡唑并[3,4-b]吡啶
6-溴-1H-吡咯并[3,4-b]吡啶(100mg,0.51mmol)和1-(2-氯乙基)吡咯烷盐酸盐(1.2当量,0.61mmol)按照一般程序2反应。在后处理之后,按照一般程序3将混合物与1-[4-(甲磺酰基)苯基]哌嗪(1.5当量,0.76mmol)反应。残余物通过反相柱色谱法纯化,产生标题化合物,是白色固体(8mg,3%收率)。
LCMS(方法1,ES+)1.59分钟,455m/z(M+H)+。
实施例109
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-2-[2-(吡咯烷-1-基)乙基]-2H-吡唑并[3,4-b]吡啶
实施例109根据为实施例108描述的程序制备,在纯化期间作为另外的区域异构体分离。
LCMS(方法1,ES+)1.82分钟,455m/z(M+H)+。
实施例110
5-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[3,2-c]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶
中间体27(75mg,0.30mmol)和中间体5(75mg,0.37mmol)用一般程序3反应,提供标题化合物(63mg,50%收率)。
LCMS(方法1,ES+)1.79分钟,416m/z(M+H)+。
实施例111
2-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-7-[2-(吡咯烷-1-基)乙基]-7H-吡咯并[2,3-d]嘧啶
将2-氯-7H-吡咯并[2,3-D]嘧啶(120mg,0.76mmol)和中间体5(117mg,0.58mmol)的混合物悬浮在1-丁醇(3mL)中,加入三氟乙酸(0.07mL,0.9mmol)。然后将反应混合物在120℃加热过夜。将反应混合物冷却至室温和过滤通过SCX柱,首先用甲醇洗涤然后用2M氨/甲醇洗脱。减压浓缩氨的甲醇溶液,残余物用二氧化硅柱色谱法部分纯化。粗制混合物然后根据一般程序2与1-(2-氯乙基)吡咯烷盐酸盐(102mg,0.59mmol)反应,提供标题化合物(38mg,15%收率)。
LCMS(方法1,ES+)1.92分钟,417m/z(M+H)+。
实施例112
6-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[3,2-c]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶
标题化合物根据一般程序3用中间体28(48mg,0.16mmol)而不是中间体7制备。粗制反应混合物直接过滤通过C盐随后SCX过滤。SCX柱用甲醇洗涤,产品用2M氨/甲醇洗脱。残余物通过反相柱色谱法最终纯化提供标题化合物(3mg,4%收率)。
LCMS(方法1,ES+)1.58分钟,416m/z(M+H)+。
实施例113
5-(4-{1-[2-(哌嗪-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶
用一般程序3,中间体31(175mg,0.43mmol)和中间体5(90mg,0.44mmol)产生4-[2-[6-(4-咪唑并[1,2-a]吡啶-6-基哌嗪-1-基)吡咯并[2,3-b]吡啶-1-基]乙基]哌嗪-1-羧酸叔丁酯。然后将其溶于二氯甲烷(3mL)和用三氟乙酸(1mL)处理。在室温下搅拌反应混合物36小时然后通过SCX柱,首先用甲醇洗涤然后用2M氨/甲醇洗脱。减压浓缩氨的甲醇溶液,残余物通过反相色谱法纯化,提供标题化合物(10mg,8%收率)。
LCMS(方法1,ES+)1.69分钟,431m/z(M+H)+。
实施例114
5-(4-{1-[2-(2-甲基-1H-咪唑-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶
根据一般程序3处理中间体29(100mg,0.28mmol)和中间体5(60mg,0.29mmol),提供标题化合物(17mg,13%收率)。
LCMS(方法1,ES+)1.82分钟,427m/z(M+H)+。
实施例115
5-(4-{1-[2-(吡咯烷-3-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶
根据一般程序3处理中间体32(130mg,0.28mmol)和中间体5(60mg,0.29mmol),提供3-[2-[6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)吡咯并[2,3-b]吡啶-1-基]乙基]吡咯烷-1-羧酸叔丁酯,将其溶于DCM(4mL),用TFA(1mL)处理。在室温下搅拌反应混合物3小时然后通过SCX柱,首先用甲醇洗涤然后用2M氨/甲醇洗脱。减压浓缩氨的甲醇溶液,残余物级分(50mg)通过反相色谱法纯化,提供标题化合物(11mg)。
LCMS(方法1,ES+)1.62分钟,416m/z(M+H)+。
实施例116
2-{6-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}乙胺
将中间体33(110mg,0.23mmol)溶于二氯甲烷(3mL),加入三氟乙酸(0.5mL)。在室温下搅拌反应混合物3小时然后通过SCX柱,用甲醇然后用2M氨/甲醇洗脱。20%的所得残余物通过反相柱色谱法纯化,提供标题化合物(6mg,7%收率)
LCMS(方法1,ES+)1.60分钟,362m/z(M+H)+。
实施例117-118
下述化合物按照一般程序3合成自中间体7和适当的芳基溴。
实施例用LCMS方法3分析。
实施例119
5-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-3-[2-(吡咯烷-1-基)乙基]-3H-咪唑并[4,5-b]吡啶
将5-溴-1H-咪唑并[4,5,b]吡啶(150mg,0.75mmol)和1-(2-氯乙基)吡咯烷盐酸盐(1.2当量,0.8mmol)按照一般程序2反应。在水性后处理之后,按照一般程序3将粗制残余物与1-[4-(甲磺酰基)苯基]哌嗪(1.5当量)反应。残余物通过反相柱色谱法纯化,产生实施例119(2mg,1%收率)。
LCMS(方法1,ES+)1.52分钟,455m/z(M+H)+。
实施例120
5-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-咪唑并[4,5-b]吡啶
实施例120根据为实施例119描述的程序制备,在纯化期间作为另一区域异构体分离。
LCMS(方法1,ES+)1.61分钟,455m/z(M+H)+。
实施例121
1-(4-{1-[反式-3-(甲基氨基)环丁基]-1H-吡咯并[2,3-b]吡啶-6-基}苯基)乙酮
将中间体35(100mg,0.3mmol)和4-乙酰基苯基取代硼酸(1.5当量,0.4mmol)按照一般程序10反应。将残余物溶于DCM(0.05M),在0℃加入TFA(1mL),然后在环境温度搅拌反应额外2小时。残余物在SCX柱上过滤,用DCM和MeOH洗涤,然后用NH3(4M)/甲醇洗脱。产品通过反相色谱法纯化,产生实施例121(35mg,42%收率)。
LCMS(方法1,ES+)1.71分钟,320m/z(M+H)+。
实施例122
6-哌嗪-1-基-1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶
实施例122也是中间体7。合成和表征如上文描述。
实施例123-124
实施例123-124以2步根据一般程序3随后一般程序13制备,用LCMS方法1分析。
实施例125
1-(2-吡咯烷-1-基乙基)-6-[4-(3-噻吩基)哌嗪-1-基]吡咯并[2,3-b]吡啶
实施例125按照一般程序3制备自中间体7和3-溴噻吩,用LCMS方法3分析。
LCMS(方法3,ES+)1.73分钟,382m/z(M+H)+
实施例126
顺式-N,N-二甲基-1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-甲酰胺
将中间体48(20mg,0.05mmol),二甲胺(1.2当量,0.06mmol,2mmol/mL)和HATU(25mg,0.07mmol,1.4当量)溶于DMF(0.25mL,0.25M),加入DIPEA(0.04mL,0.2mmol,4当量)。然后在室温下在N2下搅拌混合物直至反应完成(1h)。然后,将DCM和NH4Cl饱和水溶液加入反应混合物,分层。水相用DCM萃取,分层和减压除去挥发物。所得残余物溶于1,4-二噁烷(0.05M),按照一般程序3与1-[4-(甲磺酰基)苯基]哌嗪(1.5当量,0.07mmol)反应。将反应混合物冷却至室温,加入DCM和H2O。分层,水相用EtOAc萃取。经合并的有机层在Na2SO4上干燥,减压除去溶剂。
残余物溶于DCM(5mL),加入TFA(1mL)。混合物在环境温度搅拌2小时。反应粗制物过滤通过SCX柱和用MeOH和DCM洗涤。产品用NH3(4N)/MeOH洗脱。减压除去挥发物,残余物通过制备型色谱法纯化,提供实施例126(8mg,34%收率)。
LCMS(方法1,ES+)1.44分钟,511m/z(M+H)+
实施例127
顺式-1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-羧酸甲酯
将中间体47(100mg,0.17mmol)溶于DCM(8mL,0.02M)和冷却至0℃。加入TFA(2mL),在室温搅拌混合物2小时。混合物过滤通过SCX柱,柱用MeOH洗涤然后用4N NH3/MeOH洗脱。在除去挥发物之后,残余物通过制备型柱色谱法纯化,提供实施例127(11mg,13%收率)。
LCMS(方法1,ES+)1.67分钟,498m/z(M+H)+
实施例128-169
实施例128-169根据一般程序3然后一般程序13以2步制备。
实施例128-152用LCMS方法1分析。
实施例153-165和实施例168用LCMS方法11分析。
实施例166-167和实施例169用LCMS方法13分析。
实施例170-186
实施例170-186根据一般程序14然后一般程序13以2步制备。
实施例170-182用LCMS方法1分析。实施例183-186用LCMS方法11分析。
实施例187-188
实施例187-188根据一般程序18然后一般程序13以2步制备,用LCMS方法1分析。
实施例189
实施例189根据一般程序9、14然后13以2步制备,用LCMS方法1分析。
实施例190-193
实施例190-193根据一般程序12然后13以2步制备,用LCMS方法1分析。
实施例194
反式-6-(4-乙基哌嗪-1-基)-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈
实施例194在合成UCB1711019实施例192中作为副产物分离
LCMS(方法1,ES+)1.71分钟,339m/z(M+H)+
实施例195-199
实施例195-199根据一般程序12制备自指定原料实施例(SM实施例),通过LCMS方法11分析。
实施例200-201
实施例200-201根据一般程序5(实施例200使用甲苯作为溶剂的修饰程序)然后一般程序13以2步制备。
实施例200用LCMS方法1分析。实施例201用LCMS方法9分析。
实施例202-205
实施例202-205根据一般程序9、5然后13以3步制备。实施例202用LCMS方法1分析。实施例203-205用LCMS方法9分析。
实施例206-211
实施例206-211根据一般程序17、5然后13以3步制备,用LCMS方法9分析。
实施例212-217
实施例212-217根据一般程序9然后13以2步制备自中间体18和仲醇,用LCMS方法3分析。
实施例218-220
实施例218-220根据一般程序9制备自中间体18和仲醇,用LCMS方法3分析。
实施例221-227
下述化合物按照一般程序7或一般程序8(取决于中间体)合成自所述中间体和适当胺,用LCMS方法3分析。
实施例228-233
下述化合物按照一般程序7合成自中间体7和适当的羧酸,用LCMS方法3分析。
实施例234
6-[4-(3-甲氧基-2-吡啶基)哌嗪-1-基]-1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶
按照一般程序3用中间体7和2-氯-3-甲氧基吡啶制备。
LCMS(方法3,ES+)1.34分钟,407m/z(M+H)+
实施例235
反式-N-甲基-3-[5-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环丁烷胺
一般程序9用5-溴-1H-吡咯并[2,3-b]吡啶和顺式-3-羟基环丁基氨基甲酸叔丁酯,随后一般程序5用1-[4-(甲磺酰基)苯基]哌嗪。
将中间体反式-N-[3-[5-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环丁基]氨基甲酸叔丁酯(36mg,0.07mmol)溶于DMF(0.7ml)然后在氮下加入NaH(4mg,0.1mmol)。在搅拌5分钟之后,加入MeI(0.006ml,0.1mmol),将混合物再搅拌10分钟。混合物用盐水(10ml)淬灭,产品用DCM(3x 10ml)萃取。经合并的有机物用盐水(2x 10ml)洗涤,干燥(Na2SO4)和真空浓缩。然后对残余物进行一般程序13,提供所希望的产品(7mg)。
LCMS(方法1,ES+)1.45分钟,440m/z(M+H)+
实施例236
3-[4-(4-甲磺酰基苯基)哌嗪-1-基]-5-哌嗪-1-基-1,2-苯并噁唑
将1-[4-(甲磺酰基)苯基]哌嗪(216mg,0.90mmol),5-溴-3-氯苯并[d]异噁唑(200mg,0.82mmol)和1,8-二氮杂二环[5.4.0]十一烷-7-烯(0.15ml,1.0mmol)的吡啶(4.1ml)溶液在100℃加热3天。混合物冷却至室温,用水(20ml)稀释和用CHCl3(3x 30ml)萃取。经合并的有机物用盐水洗涤(20ml),干燥(Na2SO4)和真空浓缩。产品通过柱色谱法(己烷至EtOAc,10CVs)纯化,提供5-溴-3-[4-(4-甲磺酰基苯基)哌嗪-1-基]-1,2-苯并噁唑(140mg,40%)。一般程序5用1-boc-哌嗪随后一般程序13,提供所希望的产品(10mg)。
LCMS(方法1,ES+)1.39分钟,442m/z(M+H)+
实施例237
5-[4-(4-甲磺酰基苯基)哌嗪-1-基]-3-哌嗪-1-基-1,2-苯并噁唑
将1-boc-哌嗪(171mg,0.90mmol),5-溴-3-氯苯并[d]异噁唑(200mg,0.82mmol)和1,8-二氮杂二环[5.4.0]十一烷-7-烯(0.15mL,1.0mmol)的吡啶(4.1mL)溶液在120℃加热5天。混合物冷却至室温,用水(10ml)和盐水(10ml)稀释然后用CHCl3(3x 20ml)萃取。经合并的有机物用盐水洗涤(20ml),干燥(Na2SO4),真空浓缩和通过柱色谱法纯化(己烷/EtOAc),提供152mg 4-(5-溴-1,2-苯并噁唑-3-基)哌嗪-1-羧酸叔丁酯。
按照一般程序5将中间体与1-[4-(甲磺酰基)苯基]哌嗪(115mg)反应,随后进行一般程序13,提供23mg产品。
LCMS(方法1,ES+)1.43分钟,442m/z(M+H)+
实施例238
反式-6-[6-(4-乙酰基苯基)-3-吡啶基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈
将脱气N,N-二甲基甲酰胺(1.0mL)中的2-氯吡啶-5-取代硼酸(50mg,0.305mmol),中间体40(124mg,0.306mmol)和四(三苯基膦)钯(0)(18mg,0.0154mmol)在室温搅拌40分钟。加入脱气的碳酸钠(48.5mg,0.458mmol)水(0.5mL)溶液,然后在80℃在N2下加热混合物2小时。加入4-乙酰基苯基取代硼酸(75mg,0.457mmol),然后将反应混合物加热至80℃再持续16小时。混合物用EtOAc(20ml)、水(10ml)和盐水(10ml)稀释,分层。水层进一步用EtOAc(2x 20ml)萃取,然后经合并的有机物用盐水(3x 10ml)洗涤。盐水洗涤液用DCM(2x 10ml)反萃取,然后干燥(Na2SO4)经合并的有机物和真空浓缩。残余物通过柱色谱法(己烷/EtOAc)纯化,然后进行一般程序13,提供2mg产品。
LCMS(方法1,ES+)2.05分钟,422m/z(M+H)+
实施例239
反式-1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基苯基)苯基]吡咯并[2,3-b]吡啶-3-腈
向炉干的微波瓶加入4'-溴-4-甲磺酰基-联苯(85mg,0.273mmol),二(频哪醇基)二硼(69mg,0.272mmol),2nd代XPhos预催化剂(19mg,0.024mmol)和乙酸钾(67mg,0.683mmol),随后加入无水1,4-二噁烷(1.2mL)。将所得混合物排空和反填充N2三次,然后在100℃搅拌。在1小时之后,混合物冷却至室温和加入新鲜制备的中间体40(100mg,0.247mmol)的无水且脱气的1,4-二噁烷(0.5mL)溶液、随后新鲜制备的且脱气的三碱式磷酸钾(79mg,0.372mmol)的水(0.5mL)溶液。所得混合物在100℃在N2下搅拌3小时。混合物冷却至室温,用EtOAc(20ml)稀释,用水(10ml)和盐水(10ml)的1:1混合物洗涤。水相进一步用EtOAc(2x20ml)萃取,然后干燥(Na2SO4)经合并的有机物和真空浓缩。残余物通过柱色谱法纯化然后进行一般程序13,提供44mg产品。
LCMS(方法1,ES+)2.27分钟,457m/z(M+H)+
实施例240
反式-6-[4-[4-[(E)-N-甲氧基-C-甲基-亚氨代甲酰]苯基]哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈
对中间体40和1-(4-乙酰基苯基)哌嗪进行一般程序3。随后,将所得反式-N-[3-[6-[4-(4-乙酰基苯基)哌嗪-1-基]-3-氰基-吡咯并[2,3-b]吡啶-1-基]环丁基]-N-甲基-氨基甲酸叔丁酯(10mg,0.0189mmol)和O-甲基盐酸羟胺(2mg,0.0239mmol)溶于甲醇(1.0mL)和在50℃搅拌。在3小时之后,真空浓缩混合物并进行一般程序13,提供1mg产品。
LCMS(方法1,ES+)2.47分钟,458m/z(M+H)+
实施例241
1-甲基-5-[4-(4-甲磺酰基苯基)哌嗪-1-基]螺[吲哚啉-3,4'-哌啶]
将5-溴螺[吲哚啉-3,4'-哌啶]-1'-羧酸叔丁酯(200mg,0.52mmol)的四氢呋喃(5mL)溶液脱气,然后用冰/盐水浴冷却。加入氢化钠(31mg,0.78mmol),搅拌混合物30分钟。然后加入碘甲烷(0.04mL,0.6mmol,1),搅拌混合物5分钟然后除去冰浴,在40℃加热16小时。反应用水(20ml)淬灭,产品用DCM(2x 20ml)萃取。经合并的有机物用盐水(20ml)洗涤,干燥(Na2SO4)和真空浓缩。产品5-溴-1-甲基-螺[吲哚啉-3,4'-哌啶]-1'-羧酸叔丁酯通过柱色谱法(己烷/EtOAc)纯化然后与1-[4-(甲磺酰基)苯基]哌嗪进行一般程序5、随后进行一般程序13,提供17mg产品。
LCMS(方法1,ES+)1.44分钟,441m/z(M+H)+
实施例242
N-甲基-3-[6-[4-(4-甲磺酰基苯基)哌嗪-1-基]-2,3-二氢吡咯并[2,3-b]吡啶-1-基]环丁烷胺
在0℃将n-甲基-n-(3-氧代环丁基)氨基甲酸叔丁酯(269mg,1.35mmol),三乙酰氧基硼氢化钠(603mg,2.70mmol)和乙酸(0.007mL)加入6-氯-1H,2H,3H-吡咯并[2,3-b]吡啶(200mg,1.2mmol)的二氯甲烷(1.2mL)溶液。在5小时之后,混合物用EtOAc(30ml)和水(10ml)稀释,用饱和NaHCO3水溶液(2x 10ml)和盐水(10ml)洗涤,干燥(Na2SO4)和真空浓缩,提供N-[3-(6-氯-2,3-二氢吡咯并[2,3-b]吡啶-1-基)环丁基]-N-甲基-氨基甲酸叔丁酯(440mg)。
对N-[3-(6-氯-2,3-二氢吡咯并[2,3-b]吡啶-1-基)环丁基]-N-甲基-氨基甲酸叔丁酯(200mg)和1-[4-(甲磺酰基)苯基]哌嗪(157mg)进行一般程序3、随后一般程序13,提供74mg产品,是3:1比率的异构体。
LCMS(方法1,ES+)1.61分钟,442m/z(M+H)+[顺式];LCMS(方法1,ES+)1.66分钟,442m/z(M+H)+[反式]
实施例243
反式-1-[4-[1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-4-基]哌嗪-1-基]乙烯酮
对4,6-二氯-1H-吡咯并[2,3-b]吡啶和顺式-N-(顺式-3-羟基环丁基)-N-甲基氨基甲酸叔丁酯进行一般程序9。所得产品然后按照一般程序14与哌嗪(5当量)反应,随后用1-[4-(甲磺酰基)苯基]哌嗪进行一般程序3,提供反式-N-甲基-N-[3-[6-[4-(4-甲磺酰基苯基)哌嗪-1-基]-4-哌嗪-1-基-吡咯并[2,3-b]吡啶-1-基]环丁基]氨基甲酸叔丁酯。
将乙酰氯(0.001mL,0.01mmol)加入反式-N-甲基-N-[3-[6-[4-(4-甲磺酰基苯基)哌嗪-1-基]-4-哌嗪-1-基-吡咯并[2,3-b]吡啶-1-基]环丁基]氨基甲酸叔丁酯(10mg,0.016mmol)和三乙胺(0.01mL,0.07mmol)的二氯甲烷(0.50mL)溶液和在室温搅拌5分钟然后将三氟乙酸(0.1mL)加入反应混合物。在30分钟之后浓缩混合物,用NH3/MeOH中和并通过制备型HPLC纯化,提供3mg产品。
LCMS(方法1,ES+)1.56分钟,566m/z(M+H)+
实施例244
3:1异构体
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(5-氮杂螺[3.4]辛烷-2-基)吡咯并[2,3-b]吡啶-3-腈
将硼氢化钠(66mg,1.71mmol)加入5-boc-5-氮杂-螺[3.4]辛烷-2-酮(200mg,0.86mmol)的乙醇(10mL)溶液,然后在室温在N2下搅拌30分钟。反应用饱和NH4Cl水溶液(20ml)淬灭,减压除乙醇。产品然后用EtOAc(3x 20ml)萃取,干燥(Na2SO4)和真空浓缩,提供2-羟基-5-氮杂螺[3.4]辛烷-5-羧酸叔丁酯(169mg,86%)。
按照一般程序9将2-羟基-5-氮杂螺[3.4]辛烷-5-羧酸叔丁酯(72mg,0.32mmol)与6-氯-1H-吡咯并[2,3-b]吡啶-3-腈(55mg,0.29mmol)反应,提供2-(6-氯-3-氰基-吡咯并[2,3-b]吡啶-1-基)-5-氮杂螺[3.4]辛烷-5-羧酸叔丁酯(66mg,58%)。
对2-(6-氯-3-氰基-吡咯并[2,3-b]吡啶-1-基)-5-氮杂螺[3.4]辛烷-5-羧酸叔丁酯(30mg,0.078mmol)和1-(4-乙酰基苯基)哌嗪(18mg,0.088mmol)进行一般程序14、随后一般程序13,提供3mg产品,是3:1的异构体混合物。
LCMS(方法1,ES+)2.28分钟,455m/z(M+H)+
实施例245
反式-1-(5-氮杂螺[3.4]辛烷-2-基)-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈
对反式-2-(6-氯-3-氰基-吡咯并[2,3-b]吡啶-1-基)-5-氮杂螺[3.4]辛烷-5-羧酸叔丁酯(30mg,0.078mmol,参见实施例244)和1-[4-(甲磺酰基)苯基]哌嗪(37mg,0.15mmol)进行一般程序14、随后一般程序13,提供7mg产品。
LCMS(方法1,ES+)2.15分钟,491m/z(M+H)+
实施例246
反式-1-[4-[3-溴-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]乙烯酮
中间体59(30mg,0.06mmol)按照一般程序13反应,提供产品,是白色固体(22mg,91%收率)。
LCMS(方法1,ES+)1.59分钟,406&408m/z(M+H)+。
实施例247
5-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(1-甲基吡唑-4-基)-3-(4-哌啶基)苯并咪唑-2-酮
在室温在氩下将碳酸钠(3.59g,34.2mmol)和4-氨基哌啶-1-羧酸叔丁酯(2.74g,13.7mmol)加入搅拌的4-氯-2-氟-1-硝基-苯(2.00g,11.4mmol)的DMF(30mL)溶液。所得反应混合物在80℃加热2小时。在原料完全消耗之后,加入冰冷水(100mL),用乙酸乙酯(100mLx 3)萃取。有机层用冰冷水(200mL x 2)和盐水溶液(200mL)洗涤,在硫酸钠上干燥和真空浓缩。粗制物质通过柱色谱法用15%乙酸乙酯/己烷纯化,提供4-(5-氯-2-硝基-苯胺基)哌啶-1-羧酸叔丁酯(3.80g,10.7mmol,94%)。
对4-(5-氯-2-硝基-苯胺基)哌啶-1-羧酸叔丁酯(3.8g,10.7mmol)进行一般程序15然后一般程序16,提供4-(6-氯-2-氧代-3H-苯并咪唑-1-基)哌啶-1-羧酸叔丁酯(2.50g,7.1mmol,66%,两步)。
产品以3个额外步骤制备:根据一般程序17用4-碘-1-甲基-吡唑,一般程序5用1-(4-哌嗪-1-基苯基)乙酮然后一般程序13,提供5-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(1-甲基吡唑-4-基)-3-(4-哌啶基)苯并咪唑-2-酮(41mg,6%,3步)。
LCMS(方法9,ES+)2.03分钟,500m/z(M+H)+
实施例248
5-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(氧杂环丁烷-3-基)-3-(4-哌啶基)咪唑并[4,5-b]吡啶-2-酮
在室温将碳酸铯(1.35g,4.14mmol)加入搅拌的中间体63(500mg,1.38mmol)和3-碘氧杂环丁烷(585mg,3.18mmol)的DMF(10mL)溶液。在100℃加热混合物4小时。冷却至室温之后,反应混合物用水(100mL)稀释和用乙酸乙酯(100mL x 2)萃取。分开有机层,用盐水洗涤(200mL),在硫酸钠上干燥和减压浓缩。粗制化合物通过柱色谱法用2%甲醇/DCM纯化,提供4-[5-氯-1-(氧杂环丁烷-3-基)-2-氧代-咪唑并[4,5-b]吡啶-3-基]哌啶-1-羧酸叔丁酯(400mg,0.92mmol,66%)。
在室温向搅拌的4-[5-氯-1-(氧杂环丁烷-3-基)-2-氧代-咪唑并[4,5-b]吡啶-3-基]哌啶-1-羧酸叔丁酯(200mg,0.46mmol)的甲苯(20mL)溶液加入1-(4-哌嗪-1-基苯基)乙酮(143mg,0.687mmol)和三碱式磷酸钾(292mg,1.37mmol)。将反应混合物用氩脱气15分钟。然后加入三(二亚苄基丙酮)二钯(0)(83.8mg,0.0916mmol)和X-Phos(39.7mg,0.0916mmol),将混合物再次用氩脱气15分钟。在100℃加热4小时之后,反应混合物用乙酸乙酯稀释(100mL)和用水洗涤(100mL x 2)。分开有机层,用盐水洗涤(150mL),在硫酸钠上干燥和减压浓缩获得粗制产品。通过制备型HPLC纯化,提供4-[5-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(氧杂环丁烷-3-基)-2-氧代-咪唑并[4,5-b]吡啶-3-基]哌啶-1-羧酸叔丁酯(150mg,0.26mmol,56%)。
对4-[5-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(氧杂环丁烷-3-基)-2-氧代-咪唑并[4,5-b]吡啶-3-基]哌啶-1-羧酸叔丁酯(150mg,0.258mmol)进行一般程序13,提供产品(60mg,0.13mmol,49%)。
LCMS(方法9,ES+)1.99分钟,477m/z(M+H)+
实施例249
反式-1-[4-[4-[3-溴-2-甲基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮
将6-氯-2-甲基-1H-吡咯并[2,3-b]吡啶(200mg,1.20mmol)和顺式-N-(3-羟基环丁基)-N-甲基-氨基甲酸叔丁酯(266mg,1.32mmol)用一般程序9反应,提供反式-N-[3-(6-氯-2-甲基-吡咯并[2,3-b]吡啶-1-基)环丁基]-N-甲基-氨基甲酸叔丁酯(400mg,1.06mmol,88%)。
在室温向搅拌的反式-N-[3-(6-氯-2-甲基-吡咯并[2,3-b]吡啶-1-基)环丁基]-N-甲基-氨基甲酸叔丁酯(300mg,0.796mmol)的甲苯(10mL)溶液加入1-(4-哌嗪-1-基苯基)乙酮(249mg,1.19mmol)和三碱式磷酸钾(507mg,2.39mmol)。将反应混合物用氩脱气15分钟。然后加入三(二亚苄基丙酮)二钯(0)(146mg,0.159mmol)和X-Phos(69mg,0.159mmol),混合物再次用氩脱气15分钟。在100℃加热2小时之后,反应混合物用水(50mL)稀释和用乙酸乙酯(50mL x 2)萃取。分开有机层,用盐水洗涤(75mL),在硫酸钠上干燥和减压浓缩获得粗制产品。通过制备型HPLC纯化,提供反式-N-[3-[6-[4-(4-乙酰基苯基)哌嗪-1-基]-2-甲基-吡咯并[2,3-b]吡啶-1-基]环丁基]-N-甲基-氨基甲酸叔丁酯(130mg,0.248mmol,31%)。
在-50℃向搅拌的反式-N-[3-[6-[4-(4-乙酰基苯基)哌嗪-1-基]-2-甲基-吡咯并[2,3-b]吡啶-1-基]环丁基]-N-甲基-氨基甲酸叔丁酯(130mg,0.248mmol)的DCM(10mL)溶液加入NBS(37.5mg,0.211mmol)。所得反应混合物在-50至-20℃搅拌15分钟。在原料完全消耗之后,混合物用水(25mL)淬灭和用DCM(25mL x 2)萃取。收集的有机层用盐水洗涤(50mL),在硫酸钠上干燥和减压蒸发获得粗制物质。粗制产品通过柱色谱法用25%EtOAc/己烷纯化,然后进行一般程序13,提供产品(25mg,0.047mmol,19%,两步)。
LCMS(方法9,ES+)2.76分钟,496&498m/z(M+H)+
实施例250
反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-2-羧酸甲酯
将6-氯-1H-吡咯并[2,3-b]吡啶-2-羧酸甲酯(400mg,1.90mmol)和顺式-N-(3-羟基环丁基)-N-甲基-氨基甲酸叔丁酯(459mg,2.28mmol)用一般程序9反应,提供反式-1-[3-[叔丁氧羰基(甲基)氨基]环丁基]-6-氯-吡咯并[2,3-b]吡啶-2-羧酸甲酯(650mg,1.61mmol,85%)。
在室温向搅拌的反式-1-[3-[叔丁氧羰基(甲基)氨基]环丁基]-6-氯-吡咯并[2,3-b]吡啶-2-羧酸甲酯(300mg,0.741mmol)的甲苯(20mL)溶液加入1-(4-哌嗪-1-基苯基)乙酮(232mg,1.11mmol)和三碱式磷酸钾(472mg,2.22mmol)。将反应混合物用氩脱气15分钟。然后加入三(二亚苄基丙酮)二钯(0)(136mg,0.148mmol)和X-Phos(64.3mg,0.148mmol),混合物再次用氩脱气15分钟。在100℃加热2小时之后,反应混合物用水(75mL)稀释和用乙酸乙酯(75mL x 2)萃取。分开有机层,用盐水洗涤(100mL),在硫酸钠上干燥,减压浓缩和通过柱色谱法用30%乙酸乙酯/己烷纯化,提供反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[3-[叔丁氧羰基(甲基)氨基]环丁基]吡咯并[2,3-b]吡啶-2-羧酸甲酯(250mg,0.35mmol,48%)。
在-50℃向搅拌的反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[3-[叔丁氧羰基(甲基)氨基]环丁基]吡咯并[2,3-b]吡啶-2-羧酸甲酯(250mg,0.35mmol)的DCM(15mL)溶液加入NBS(53.3mg,0.300mmol)。在-50℃搅拌所得反应混合物30分钟。在原料完全消耗之后,加水(50mL),混合物用DCM(50mL x 3)萃取。收集的有机层用盐水洗涤(25mL),在硫酸钠上干燥和通过柱色谱法用20%EtOAc/己烷纯化,提供反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-3-溴-1-[3-[叔丁氧羰基(甲基)氨基]环丁基]吡咯并[2,3-b]吡啶-2-羧酸甲酯(100mg,0.14mmol,39%)。
在室温向搅拌的反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-3-溴-1-[3-[叔丁氧羰基(甲基)氨基]环丁基]吡咯并[2,3-b]吡啶-2-羧酸甲酯(50mg,0.069mmol)的NMP(2mL)溶液加入氰化铜(I)(37mg,0.41mmol)。在130℃加热内容物16小时。冷却至室温之后,反应混合物用乙酸乙酯稀释(50mL)和用水洗涤(50mL x 2)。分开有机层,用盐水洗涤(30mL),在硫酸钠上干燥,减压浓缩和通过柱色谱法用20%EtOAc/己烷纯化,提供反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[3-[叔丁氧羰基(甲基)氨基]环丁基]-3-氰基-吡咯并[2,3-b]吡啶-2-羧酸甲酯(50mg,0.061mmol,89%)。
对反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[3-[叔丁氧羰基(甲基)氨基]环丁基]-3-氰基-吡咯并[2,3-b]吡啶-2-羧酸甲酯(50.0mg,0.0611mmol)进行一般程序13,提供标题化合物(30mg,0.034mmol,55%)。
LCMS(方法9,ES+)2.41分钟,487m/z(M+H)+
实施例251
反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-5-氟-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈
将中间体42(300mg,0.75mmol)溶于DMF(2.5mL)和乙腈(2.5mL)的混合物。将溶液冷却至0℃,加入氯磺酰异氰酸酯(0.07mL,0.84mmol),在冰浴存在下搅拌反应30分钟,然后在室温再进行2小时。将反应混合物冷却至0℃,加入第二份氯磺酰异氰酸酯(0.07mL,0.84mmol)。除去冰浴,搅拌反应混合物15分钟。返回冰浴,反应用水(10mL)仔细淬灭。搅拌两相溶液10分钟然后用50%饱和氯化铵(50mL)、二乙醚(30mL)和乙酸乙酯(10mL)稀释。有机层用水(50mL)萃取,然后干燥(Na2SO4)和减压浓缩。将所得残余物,1-(4-乙酰基苯基)哌嗪(184mg,0.90mmol),RuPhos G3(62mg,0.07mmol)和叔丁醇钠(217mg,2.26mmol)的混合物悬浮于脱气的1,4-二噁烷(4mL,46.9mmol)。反应混合物在90℃加热~3小时然后在室温静置过夜。反应混合物通过C盐塞,用乙酸乙酯洗脱。除去溶剂,粗制物通过快速柱色谱法纯化,提供反式-N-[3-[6-[4-(4-乙酰基苯基)哌嗪-1-基]-3-氰基-5-氟-吡咯并[2,3-b]吡啶-1-基]环丁基]-N-甲基-氨基甲酸叔丁酯(253mg,61%)。
反式-N-[3-[6-[4-(4-乙酰基苯基)哌嗪-1-基]-3-氰基-5-氟-吡咯并[2,3-b]吡啶-1-基]环丁基]-N-甲基-氨基甲酸叔丁酯(167mg,0.3mmol)然后根据一般程序13处理,提供标题化合物(110mg,80%)
LCMS(方法1,ES+)2.15分钟,447m/z(M+H)+
实施例252
6-[4-[4-(1,1-二甲氧基乙基)苯基]哌嗪-1-基]-5-氟-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈
实施例252在合成实施例251期间作为副产物分离(42mg,28%)。
LCMS(方法1,ES+)2.56分钟,461m/z(M+H)+
实施例253
1-甲基-5-[4-(4-甲磺酰基苯基)哌嗪-1-基]-3-(1,2,3,6-四氢吡啶-4-基)吡咯并[2,3-c]吡啶
将N-碘琥珀酰亚胺(491mg,2.07mmol)加入中间体66(641mg,1.73mmol)的丙酮(15mL)悬浮液,在室温搅拌反应混合物30分钟。然后减压浓缩反应混合物,用DCM稀释和用饱和碳酸氢盐水溶液洗涤。水层用DCM萃取,合并有机层,干燥(Na2SO4)和减压浓缩。粗制残余物然后通过快速柱色谱法纯化,提供3-碘-1-甲基-5-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-c]吡啶(350mg,40%)。将碘化产品级分(100mg,0.20mmol)与N-boc-1,2,5,6-四氢吡啶-4-取代硼酸频哪醇酯(75mg,0.24mmol),碳酸钾(60mg,0.43mmol)和1,1'-二(二苯基膦基)二茂铁二氯化钯(ii)二氯甲烷复合物(17mg,0.02mmol)混合并溶于预先脱气的DMF(1mL)。混合物然后在100℃加热1小时和在室温静置72小时。粗制混合物通过SCX柱,用MeOH和乙酸乙酯洗脱,减压浓缩。残余物通过快速柱色谱法纯化,提供4-[1-甲基-5-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-c]吡啶-3-基]-3,6-二氢-2H-吡啶-1-羧酸叔丁酯(20mg,0.04mmol,18%),然后根据一般程序13处理,提供标题化合物(5mg,30%)。
LCMS(方法1,ES+)1.36分钟,452m/z(M+H)+。
实施例254
反式-1-[4-[4-[1-[3-(甲基氨基)环丁基]-3-(3-吡啶基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮三氟乙酸盐
向中间体65(21mg,0.04mmol)和吡啶-3-取代硼酸(11mg,0.09mmol)在脱气1,4-二噁烷(0.4mL)中的混合物加入Na2CO3(0.1mL,2M,在二噁烷中)和Pd(PPh3)4(7.8mg,0.007mmol)。反应混合物在微波设备中在140℃加热2小时。过滤混合物,用0.6mL MeCN/H2O(7/3)冲洗,随后注射至制备型HPLC上并用碱性模式纯化。减压除去溶剂,黄色固体溶于1mLDCM/TFA(1/1)。在室温搅拌混合物1小时直至反应完成。减压除去溶剂,提供白色固体(4.4mg,20%两步收率。)
LCMS(方法3,ES+)2.78分钟,481m/z(M+H)+。
实施例255和256
7-[4-(4-甲磺酰基苯基)哌嗪-1-基]-2-哌啶-4-基吡唑并[3,4-c]吡啶和7-[4-(4-甲磺酰基苯基)哌嗪-1-基]-1-(4-哌啶基)吡唑并[3,4-c]吡啶
将7-溴-1H-吡唑并[3,4-c]吡啶(266mg,1.34mmol)和4-羟基哌啶-1-羧酸叔丁酯(405.52mg,2.0149mmol)的混合物溶于THF(13ml)。加入三苯基膦(422mg,1.61mmol)和偶氮二羧酸二异丙基酯(428mg,2.01mmol),搅拌反应混合物过夜。反应混合物然后在EtOAc(50ml)与NaHCO3水溶液(50ml)间分配。分开有机层,用盐水洗涤,然后减压浓缩。粗制物质用己烷/乙酸乙酯0-100%梯度洗脱过柱,然后将区域异构体的96:4混合物与1-[4-(甲磺酰基)苯基]哌嗪(311mg,1.3mmol)混合。将其用1,4-二噁烷(12.4ml)中的NaOtBu(297mg,3.1mmol)、RuPhos G3(102.1mg,0.12mmol)处理,脱气和在50℃搅拌2小时然后在90℃再进行2小时。反应混合物在EtOAc(100ml)与NaHCO3(100ml)间分配。分开有机层,水相用额外EtOAc洗涤。经合并的有机物用硫酸钠干燥,然后减压浓缩为褐色油状物。将其用Hex/EtOAc10-100%过柱,提供褐色油状物。产品用DCM(1ml)和TFA(1ml)处理,然后搅拌30分钟。减压浓缩溶液,在NaHCO3和DCM间分配。分开有机层,浓缩,通过反相HPLC分离产品。
实施例255:LCMS(方法1,ES+)1.29分钟,441m/z(M+H)+
实施例256:LCMS(方法1,ES+)1.37分钟,441m/z(M+H)+
实施例257
6-[4-(4-乙酰基哌嗪-1-基)苯基]-1-[反式-3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈
将中间体50(68mg,0.18mmol),4-(4-乙酰基-1-哌嗪基)苯基取代硼酸(70.14mg,0.28mmol)和(XPhos)苯乙胺氯化钯(II)(28mg,0.038mmol)溶于1,4-二噁烷(3.8ml)和Na2CO3水溶液(0.40mmol)然后脱气。在100℃加热反应3小时,让其冷却至室温。反应混合物在DCM与水间分配,然后分离,减压浓缩有机层。将残余物溶于DCM(1.5ml),加入TFA(1.5ml)。反应在室温搅拌1小时。产品捕获于SCX柱上,用NH3/MeOH(7M)洗脱。减压蒸发溶液,将油状物与MeCN研磨。滤出固体并干燥,提供标题化合物(40mg),是白色固体。
LCMS(方法1,ES+)1.91分钟,429m/z(M+H)+
实施例258
1-[4-[4-[5-(1-甲基吡唑-4-基)-1,2,3,4-四氢吡啶并[4,3-b]吲哚-8-基]哌嗪-1-基]苯基]乙酮
在0℃向8-氯-2,3,4,5-四氢-1H-吡啶并[4,3-b]吲哚(400mg,1.94mmol)的THF(40mL)溶液加入BOC酸酐(0.534mL,2.32mmol)。在室温搅拌反应混合物10分钟然后用水稀释(50mL)和用EtOAc(2x 50mL)萃取。有机层用水(50mL)、盐水(50mL)洗涤,在硫酸钠上干燥和减压蒸发。粗制物质通过柱色谱法在二氧化硅上用30%乙酸乙酯/己烷纯化,提供8-氯-1,3,4,5-四氢吡啶并[4,3-b]吲哚-2-羧酸叔丁酯(420mg,1.34mmol,70%)。
对8-氯-1,3,4,5-四氢吡啶并[4,3-b]吲哚-2-羧酸叔丁酯(1当量)进行修饰的一般程序17(用所述中间体而不是芳基咪唑-2-酮),使用4-碘-1-甲基-吡唑(1.5当量)。然后对所得产品进行一般程序3(用1-(4-哌嗪-1-基苯基)乙烯酮)、然后一般程序13,提供标题产品(125mg,28%,3步)。
LCMS(方法9,ES+)1.83分钟,455m/z(M+H)+
实施例259
反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-3-溴-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-2-羧酸甲酯
将6-氯-1H-吡咯并[2,3-b]吡啶-2-羧酸甲酯(400mg,1.90mmol)和顺式-N-(3-羟基环丁基)-N-甲基-氨基甲酸叔丁酯(459mg,2.28mmol)用一般程序9反应,提供反式-1-[3-[叔丁氧羰基(甲基)氨基]环丁基]-6-氯-吡咯并[2,3-b]吡啶-2-羧酸甲酯(650mg,1.61mmol,85%)。
在室温向搅拌的反式-1-[3-[叔丁氧羰基(甲基)氨基]环丁基]-6-氯-吡咯并[2,3-b]吡啶-2-羧酸甲酯(300mg,0.741mmol)的甲苯(20mL)溶液加入1-(4-哌嗪-1-基苯基)乙酮(232mg,1.11mmol)和三碱式磷酸钾(472mg,2.22mmol)。将反应混合物用氩脱气15分钟。然后加入三(二亚苄基丙酮)二钯(0)(136mg,0.148mmol)和X-Phos(64.3mg,0.148mmol),混合物再次用氩脱气15分钟。在100℃加热2小时之后,反应混合物用水(75mL)稀释和用乙酸乙酯(75mL x 2)萃取。分开有机层,用盐水洗涤(100mL),在硫酸钠上干燥,减压浓缩和通过柱色谱法用30%乙酸乙酯/己烷纯化,提供反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[3-[叔丁氧羰基(甲基)氨基]环丁基]吡咯并[2,3-b]吡啶-2-羧酸甲酯(250mg,0.35mmol,48%)。
在-50℃向搅拌的反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[3-[叔丁氧羰基(甲基)氨基]环丁基]吡咯并[2,3-b]吡啶-2-羧酸甲酯(250mg,0.35mmol)的DCM(15mL)溶液加入NBS(53.3mg,0.300mmol)。在-50℃搅拌所得反应混合物30分钟。在原料完全消耗之后,加水(50mL),混合物用DCM(50mL x 3)萃取。收集的有机层用盐水洗涤(25mL),在硫酸钠上干燥和通过柱色谱法用20%EtOAc/己烷纯化,提供反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-3-溴-1-[3-[叔丁氧羰基(甲基)氨基]环丁基]吡咯并[2,3-b]吡啶-2-羧酸甲酯(100mg,0.14mmol,39%)。
对反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-3-溴-1-[3-[叔丁氧羰基(甲基)氨基]环丁基]吡咯并[2,3-b]吡啶-2-羧酸甲酯(45mg,0.07mmol)进行一般程序13,提供标题产品(28mg,0.05mmol,74%)。
LCMS(方法9,ES+)2.52分钟,540&542m/z(M+H)+
实施例260
5-[4-(4-乙酰基苯基)哌嗪-1-基]-3-(4-甲基-4-哌啶基)-1-(氧杂环丁烷-3-基)咪唑并[4,5-b]吡啶-2-酮
在室温向搅拌的中间体64(300mg,0.789mmol)和3-碘氧杂环丁烷(218mg,1.18mmol)的DMF(30mL)溶液加入碳酸铯(771mg,2.37mmol)。混合物在100℃加热5小时,然后用水(50mL)稀释和用乙酸乙酯(50mL x 2)萃取。分开有机层,用盐水洗涤(50mL),在硫酸钠上干燥和减压浓缩。粗制化合物通过柱色谱法用2%甲醇/DCM纯化,提供4-[5-氯-1-(氧杂环丁烷-3-基)-2-氧代-咪唑并[4,5-b]吡啶-3-基]-4-甲基-哌啶-1-羧酸叔丁酯(280mg,0.58mmol,73%)。
对4-[5-氯-1-(氧杂环丁烷-3-基)-2-氧代-咪唑并[4,5-b]吡啶-3-基]哌啶-1-羧酸叔丁酯进行一般程序3(用1-(4-哌嗪-1-基苯基)乙酮)、然后一般程序13,提供标题产品(27%,两步)。
LCMS(方法9,ES+)2.19分钟,491m/z(M+H)+
实施例261
反式-5-[4-(4-乙酰基苯基)哌嗪-1-基]-3-[3-(甲基氨基)环丁基]-1-(氧杂环丁烷-3-基)咪唑并[4,5-b]吡啶-2-酮
在室温向搅拌的中间体62(250mg,0.69mmol)和3-碘氧杂环丁烷(191mg,1.04mmol)的DMF(15mL)溶液加入碳酸铯(677mg,2.08mmol)。在100℃加热混合物5小时,然后用水(50mL)稀释和用乙酸乙酯(50mL x 2)萃取。分开有机层,用盐水洗涤(50mL),在硫酸钠上干燥和减压浓缩。粗制化合物通过柱色谱法用2%甲醇/DCM纯化,提供反式-N-[3-[5-氯-1-(氧杂环丁烷-3-基)-2-氧代-咪唑并[4,5-b]吡啶-3-基]环丁基]-N-甲基-氨基甲酸叔丁酯(240mg,0.56mmol,80%)。
对反式-N-[3-[5-氯-1-(氧杂环丁烷-3-基)-2-氧代-咪唑并[4,5-b]吡啶-3-基]环丁基]-N-甲基-氨基甲酸叔丁酯进行一般程序3(用1-(4-哌嗪-1-基苯基)乙酮)、然后一般程序13,提供标题产品(58%,两步)。
LCMS(方法9,ES+)2.03分钟,477m/z(M+H)+
实施例262
6-[4-(4-乙酰基苯基)苯基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈
标题化合物根据一般程序13经由中间体96的boc脱保护制备。
LCMS(方法11,ES+)2.42分钟,421m/z[M+H]+。
实施例263
6-[4-(4-乙酰基-2-甲基苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈
标题化合物根据一般程序3和一般程序13通过Buchwald胺化和脱Boc制备自中间体50和1-(4-溴-3-甲基苯基)乙酮。
LCMS(方法11,ES+)2.30分钟,443m/z[M+H]+
实施例264
反式-4-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯甲酸甲酯
标题化合物根据一般程序13用中间体109制备。
LCMS(方法1)2.16分钟,445m/z[M+H]+
实施例265
6-[4-[4-(氮杂环丁烷-1-羰基)苯基]哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈
在室温向中间体110(70mg,0.132mmol)和N-乙基-N-异丙基-丙-2-胺(46uL,0.264mmol)在DMF(3mL)中的混合物加入HATU(75mg,0.198mmol),搅拌5分钟,然后加入氮杂环丁烷(18uL,0.264mmol),在室温搅拌30分钟。反应然后用水(0.2ml)淬灭。然后真空蒸发混合物,残余物通过Biotage[湿加载至SNAP KP NH 11g柱,0%至58%(10%MeOH/DCM)/DCM洗脱液]纯化。真空蒸发产品级分,产生标题化合物,是米白色固体。
LCMS(方法11,ES+)3.08分钟,470m/z[M+H]+
实施例266
1-[4-[4-[3-(1-甲基吡唑-4-基)-1-哌啶-4-基吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙酮
将10%Pd/C(50%润湿)(41.3mg,0.04mmol)和中间体100(80mg,0.13mmol)的THF(4mL)和EtOH(1mL)悬浮液排空和反填充氮三次,然后排空和反填充氢三次。悬浮液在室温在氢气氛下搅拌16小时。
过滤反应混合物通过C盐垫和玻璃纤维滤纸,真空浓缩滤液,提供粗制标题化合物(65mg),是褐色胶状物。残余物通过高pH制备型HPLC纯化。合并含产品级分并真空除去溶剂,提供7mg(12%)标题化合物,是米白色固体。
LCMS(方法11,ES+)2.03分钟,484m/z[M+H]+
实施例267
1-[4-[4-[1-(1-甲基吡唑-4-基)-3-哌嗪-1-基-吡咯并[3,2-b]吡啶-5-基]哌嗪-1-基]苯基]乙酮
标题化合物按照一般程序1制备自中间体104和哌嗪-1-羧酸叔丁酯。
LCMS(方法11,ES+)1.70分钟,485m/z[M+H]+
实施例268
1-[4-[4-[1-(1-甲基吡唑-4-基)-3-哌啶-4-基吡咯并[3,2-b]吡啶-5-基]哌嗪-1-基]苯基]乙酮
向中间体108(40mg,0.05mmol)的DCM(5mL)/MeOH(2mL)溶液加入4N HCl/二噁烷(0.5mL),然后在室温搅拌过夜。然后真空蒸发反应,残余物通过低pH制备型HPLC纯化。所希望的级分用2N NH3/MeOH碱化,真空蒸发至干。残余物然后加载至DCM/MeOH(1:1)中的SCX 2柱(1g),用MeOH(10mL)洗涤。然后用2N NH3/DCM/MeOH(1:1)冲洗柱以释放产品。真空蒸发所希望的级分,产生标题化合物,是白色固体(13mg,52%)。
LCMS(方法11,ES+)1.58分钟,484m/z[M+H]+。
-生物学测试
在细胞测试中研究本发明所涵盖的这些化合物调节2’3’-cGAMP刺激的STING信号转导的能力。在37℃、5%CO2将HEK Blue ISG渗透化细胞与化合物预温育60分钟。然后用2’3’-cGAMP刺激细胞。化合物对2’3’-cGAMP诱导I型干扰素产生的效果通过ISG54报道者测试来间接测定。细胞所产生的1型干扰素用HEK Blue检测试剂测量。化合物抑制2’3’-cGAMP刺激HEK Blue ISG细胞产生I型干扰素的能力测量为pIC50 WT(野生型)。
用HEK Blue ISG KO STING细胞测试化合物活性的STING依赖性(反向筛选)。2’3’-cGAMP并不诱导缺少受体STING的细胞产生I型干扰素。
在反向筛选中,测试化合物调节I型干扰素产生的能力:在37℃、5%CO2用化合物预处理渗透化HEK Blue ISG KO STING细胞60分钟,然后用干扰素刺激。化合物对干扰素诱导I型干扰素产生的效果通过ISG54报道者测试来间接确定。细胞所产生的1型干扰素用HEKBlue检测试剂来测量。化合物抑制干扰素刺激HEK Blue ISG KO STING细胞产生I型干扰素的能力测量为pIC50 KO。
本文描述的全部药学上活性的化合物在HEK Blue ISG细胞中具有比4.5更优异的pIC50而在HEK Blue ISG KO STING测试中具有较差的pIC50。
本发明化合物显著地展示在HEK Blue ISG细胞中约4.5至大于8.5,优选5至大于8.5的pIC50。
IC50的范围是约30μM至约小于10nM;显著地约30μM至小于10nM。
Claims (19)
1.通式I化合物,或其药学上可接受的酸加成盐、外消旋混合物或其相应的对映体和/或旋光异构体,
其中
-作为含有选自O、N、S的至少一个杂原子和C原子的6,5杂双环的中央核A能够任选由下述取代:卤素,氰基,C1-6烷基,三氟甲基,二氟甲基,(C2-6)烯基,羟基,(C1-6)烷氧基,二氟甲氧基,三氟甲氧基,三氟乙氧基,(C1-6)烷硫基,(C1-6)烷基磺酰基,氨基,(C1-6)烷基氨基,二(C1-6)烷基氨基,(C1-6)烷氧基(C1-6)烷基-氨基,N-[(C1-6)烷基]-N-[羟基(C1-6)烷基]氨基,(C2-6)烷基羰基氨基,(C2-6)烷氧羰基氨基,(C1-6)烷基磺酰基氨基,甲酰基,(C2-6)烷基羰基,羧基,(C2-6)烷氧羰基,氨基羰基,(C1-6)烷基氨基羰基,二(C1-6)烷基氨基羰基,氨基磺酰基,(C1-6)烷基氨基磺酰基或二(C1-6)烷基氨基磺酰基;(C3-7)杂环烷基或(C3-7)螺杂环烷基,所述基团中任一种可以任选由一个或多个取代基取代;
-R1代表任选经取代的烷基胺或环烷基胺,包括稠合环烷基胺和螺环烷基胺,包括(C1-3)氨基烷基,(C3-7)氨基环烷基,(C1-3)烷基咪唑,(C1-3)烷基异吲哚啉,(C1-3)烷基哌嗪,(C1-3)烷基哌啶,(C1-3)烷基咪唑并哌嗪,(C1-3)烷基(C4-7)氨基环烷基,(C1-3)烷基(C4-7)氨基二环烷基;和
-R2代表芳基,杂芳基,杂双环,(C4-7)氨基环烷基,环烷基,杂环烷基,(C6-8)二氨基环烷基,吗啉代,(C4-7)环烷基甲基,哌嗪基,哌啶基;R2任选用包括下述的基团取代:羟基,(C1-6)烷基,乙酰基,卤素,氰基,C1-6烷基,三氟甲基,二氟甲基,(C2-6)烯基,羟基,(C1-6)烷氧基,二氟甲氧基,三氟甲氧基,三氟乙氧基,(C1-6)烷硫基,(C1-6)烷基磺酰基,氨基,(C1-6)烷基氨基,二(C1-6)烷基氨基,(C1-6)烷氧基(C1-6)烷基-氨基,N-[(C1-6)烷基]-N-[羟基(C1-6)烷基]氨基,(C2-6)烷基羰基氨基,(C2-6)烷氧羰基氨基,(C1-6)烷基磺酰基氨基,甲酰基,(C2-6)烷基羰基,羧基,(C2-6)烷氧羰基,氨基羰基,(C1-6)烷基氨基羰基,二(C1-6)烷基氨基羰基,氨基磺酰基,(C1-6)烷基氨基磺酰基或二(C1-6)烷基氨基磺酰基;(C3-7)杂环烷基或(C3-7)螺杂环烷基,所述基团中任一种可以任选由一个或多个取代基取代。
4.根据权利要求1的化合物,其中中央核A选自:
其中
L、U、V、W是C或N;
X、T是C、N或O;
Y是C、N或S;
-R1代表(C4-7)环烷基;(4-9-元)-杂环烷基;稠合环烷基胺;稠合杂环烷基胺;螺环烷基胺;螺杂环烷基胺;(C1-3)氨基烷基;(C3-7)氨基环烷基;(C1-3)烷基咪唑;(C1-3)烷基异吲哚啉;(C1-3)烷基哌嗪;(C1-3)烷基哌啶;(C1-3)烷基咪唑并哌嗪;(C1-3)烷基(C4-7)氨基环烷基;(C1-3)烷基(C4-7)氨基二环烷基;用一个或多个基团取代的(C1-3)烷基,所述基团选自(C4-7)环烷基,(4-9-元)-杂环烷基,稠合环烷基胺,稠合杂环烷基胺,螺环烷基胺,螺杂环烷基胺,(C1-C3)氨基烷基,(C3-C7)氨基环烷基,(C1-C3)烷基咪唑,(C1-C3)烷基异吲哚啉,(C1-C3)烷基哌嗪,(C1-C3)烷基哌啶,(C1-C3)烷基咪唑并哌嗪,(C1-C3)烷基(C4-C7)氨基环烷基,(C1-C3)烷基(C4-C7)氨基二环烷基;
R1任选用下述取代:卤素,羟基,(C1-C3)烷基,(C1-C3)烷基羧基,(C1-C3)烷基氨基,(C5-C6)杂芳基,其任选用下述取代:(C1-C3)烷基,卤素,(C3-C7)氨基环烷基,其用下述取代:卤素,芳基,芳基(C1-C3)烷基,芳基(C1-C3)烷基(C1-C3)二烷基胺,芳氧基;
-R2代表H;卤素;芳基;杂芳基;杂双环;(C4-C7)氨基环烷基;环烷基;杂环烷基;(C6-C8)二氨基环烷基;吗啉代;(C4-C7)环烷基甲基;哌嗪基;哌啶基;
R2任选用包括下述的基团取代:芳基;杂芳基;羟基;(C1-C6)烷基;乙酰基;卤素;氰基;(C1-C6)烷基;三氟甲基;二氟甲基;(C2-C6)烯基;羟基;(C1-C6)烷氧基;二氟甲氧基;三氟甲氧基;三氟乙氧基;(C1-C6)烷硫基;(C1-6)烷基磺酰基;氨基;(C1-C6)烷基氨基;二(C1-6)烷基氨基;(C1-C6)烷氧基(C1-6)烷基-氨基;N-[(C1-6)烷基]-N-[羟基(C1-C6)烷基]氨基;(C2-C6)烷基羰基氨基;(C2-C6)烷氧羰基氨基;(C1-C6)烷基磺酰基氨基;甲酰基;(C2-C6)烷基羰基;羧基;(C2-C6)烷氧羰基:氨基羰基:(C1-C6)烷基氨基羰基;二(C1-C6)烷基氨基羰基;氨基磺酰基,(C1-6)烷基氨基磺酰基或二(C1-6)烷基氨基磺酰基;(C3-7)杂环烷基或(C3-7)螺杂环烷基;所述基团中任一种可以任选由一个或多个取代基取代,所述取代基选自羟基,卤素,氨基,甲基氨基,二甲基氨基,(C1-3)烷基,(C1-3)烷氧基,磺酰基,(C1-3)羰基,(C1-4)烷基羧基,氰基,氧代,(C1-6)烷基(C5-10)杂芳基(C1-3)羰基,磺酰基,甲磺酰基,吡啶基;
-R3相互独立地选自H;卤素;氰基;(C4-7)杂环烷基,其任选用下述取代:(甲磺酰基)芳基,乙酰基,(C1-C3)烷基羰基;
-R4选自H;卤素;二氟甲基;三氟甲基;苯基;氰基;(C1-3)烷基;氨基(C1-3)烷基;(C4-C7)杂环烷基;(C4-C7)杂芳基,其中所述杂芳基任选用(C1-C3)烷基取代;(C4-C7)杂芳基-(C1-C3)烷基,其中所述杂芳基任选用(C1-C3)烷基取代;(C4-C7)杂芳基,其任选用下述取代:(C1-C3)烷基,氨基-羰基,(C1-C3)-烷基氨基-羰基;(C1-C3)-烷氧羰基;(C1-C3)烷基-磺酰基;(C4-C7)杂烷基-羰基;(C1-C3)烷基氨基-羰基;二(C1-C3)烷基氨基-羰基;
R5选自H;氧代;(C1-C3)烷基;(C4-C7)杂环烷基-(C1-C3)烷基;甲氧羰基;
其中
在T是O,X是N的情况下,则L、U、V、W是C;
在W和T是N的情况下,则X、Y、V、U、L是C;
在W和Y是N的情况下,则L、T、X、V、U是C;
在W、T、X是N的情况下,则Y、V、U、L是C;
在W、T、Y是N的情况下,L、X、V、U是C;
在V、W、T是N的情况下,L、X、Y、U是C;
在U、T是N的情况下,则L、X、Y、V、W是C;
在L、T、X是N的情况下,则Y、V、U是C;
在W是N,Y是N或S的情况下,则T、X、V、U、L是C;
在T是N而W、X、Y、V、U是C的情况下,则R4形成6-元碳环;并且R1、R3是甲基,R2、R5是H;
在Y是N和L、U、V、W,T是C的情况下,则R1和R5一起形成6-元杂环,R3、R4是氢。
5.根据权利要求1或4的化合物,其中核心A选自下述:
其中
X是O、C或N,其中C任选用氧代部分取代,
Y是C、S或N,
A是C或N,任选用下述取代:1-C(1-4)-4-芳基-哌嗪或1-C(1-4)-4-杂芳基-哌嗪或1-(4-C(1-4)-芳基)哌嗪或1-(4-C(1-4)-杂芳基)哌嗪或1-C(1-4)-4-芳基-哌啶或1-C(1-4)-4-杂芳基-哌啶或1-(4-C(1-4)-芳基)哌啶或1-(4-C(1-4)-杂芳基)哌啶,其中芳基、杂芳基、哌嗪或哌啶基团上有任选取代;
R1选自H,乙基-氮杂二环[3.2.0]庚烷;或2-取代的-5-氮杂螺[3.4]辛烷;或任选用一个或多个(C1-3)烷基取代的乙基-2-吡咯烷,或(C4-7)环烷基胺,包括3-取代的-N-甲基-环丁烷胺和哌啶;
R2选自1-C(1-4)-4-芳基-哌嗪或1-C(1-4)-4-杂芳基-哌嗪或1-(4-C(1-4)-芳基)哌嗪或1-(4-C(1-4)-杂芳基)哌嗪或1-C(1-4)-4-芳基-哌啶或1-C(1-4)-4-杂芳基-哌啶或1-(4-C(1-4)-芳基)哌啶或1-(4-C(1-4)-杂芳基)哌啶,其中芳基、杂芳基、哌嗪或哌啶基团上有任选取代;
R3、R4相互独立地选自H,卤素,氰基,C1-6烷基,三氟甲基,二氟甲基,(C2-6)烯基,羟基,(C1-6)烷氧基,二氟甲氧基,三氟甲氧基,三氟乙氧基,(C1-6)烷硫基,(C1-6)烷基磺酰基,氨基,(C1-6)烷基氨基,二(C1-6)烷基氨基,(C1-6)烷氧基(C1-6)烷基-氨基,N-[(C1-6)烷基]-N-[羟基(C1-6)烷基]氨基,(C2-6)烷基羰基氨基,(C2-6)烷氧羰基氨基,(C1-6)烷基磺酰基氨基,甲酰基,(C2-6)烷基羰基,羧基,(C2-6)烷氧羰基,氨基羰基,(C1-6)烷基氨基羰基,二(C1-6)烷基氨基羰基,氨基磺酰基,(C1-6)烷基氨基磺酰基或二(C1-6)烷基氨基磺酰基;(C3-7)杂环烷基或(C3-7)螺杂环烷基
R5选自H,2-(吡咯烷-1-基)乙基。
7.根据前述权利要求中任一项的化合物,其中R1是乙基-氮杂二环[3.2.0]庚烷;或2-取代的-5-氮杂螺[3.4]辛烷;或乙基-2-甲基-吡咯烷或(C4-7)环烷基胺,包括3-取代的-N-甲基-环丁烷胺和哌啶。
8.根据权利要求7的化合物,其中R1是3-取代的-N-甲基-环丁烷胺。
9.根据权利要求7的化合物,其中R1是2-取代的-5-氮杂螺[3.4]辛烷。
10.根据权利要求7的化合物,其中R1是(C4-7)环烷基胺,包括3-取代的-N-甲基-环丁烷胺和哌啶。
11.根据前述权利要求中任一项的化合物,其中R2是1-取代的-4-芳基-哌嗪或1-取代的-4-杂芳基-哌嗪或1-(4-取代的-芳基)哌嗪或1-(4-取代的-杂芳基)哌嗪或1-取代的-4-芳基-哌啶或1-取代的4-杂芳基-哌啶或1-(4-取代的-芳基)哌啶或1-(4-取代的-杂芳基)哌啶,其中芳基、杂芳基、哌嗪或哌啶基团上有任选取代。
12.根据权利要求11的化合物,其中R2是1-取代的-4-芳基-哌嗪或1-取代的-4-杂芳基-哌嗪,1-取代的-4-芳基-哌啶或1-取代的-4-杂芳基-哌啶。
15.根据权利要求1的化合物,选自包含下述的组:
6-[(3S)-3-甲基-4-(2-甲基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[(2S)-2-甲基-4-(2-甲基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-{4-[2-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[(2R)-2-甲基-4-(2-甲基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-(4-苯基哌嗪-1-基)-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-{4-[3-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
4-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)苯甲酸乙酯;
5-(4-{1-[2-(哌啶-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
N,N-二乙基-2-{6-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}乙胺;
6-[4-(吡啶-2-基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(吡啶-3-基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(吡啶-4-基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-(吡咯烷-1-基)-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
1-(1-甲基吡咯烷-3-基)-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶;
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[3,2-c]吡啶;
顺式-N-甲基-3-(6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)环丁烷胺;
反式-N-甲基-3-(6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)环丁烷胺;
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[(3R)-吡咯烷-3-基]-1H-吡咯并[2,3-b]吡啶;
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[(3S)-吡咯烷-3-基]-1H-吡咯并[2,3-b]吡啶;
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-(哌啶-4-基)-1H-吡咯并[3,2-c]吡啶;
顺式-3-{6-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}-N-甲基环丁烷胺;
反式-3-{6-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}-N-甲基环丁烷胺;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[反式-3-(甲基氨基)环丁基]-1H-吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[顺式-3-(甲基氨基)环丁基]-1H-吡咯并[2,3-b]吡啶-3-腈;
6-[4-(6-氰基吡啶-2-基)哌嗪-1-基]-1-[反式-3-(甲基氨基)环丁基]-1H-吡咯并[2,3-b]吡啶-3-腈;
6-[4-(6-氰基吡啶-2-基)哌嗪-1-基]-1-[顺式-3-(甲基氨基)环丁基]-1H-吡咯并[2,3-b]吡啶-3-腈;
1-[4-(4-{5-氟-1-[反式-3-(甲基氨基)环丁基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)苯基]乙烯酮;
反式-3-(5-氟-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)-N-甲基环丁烷胺;
1-(4-苯基-1-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌啶-4-基)乙烯酮;
4-苯基-1-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌啶-4-醇;
6-(4-苯基哌啶-1-基)-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
4-苯基-1-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌啶-4-腈;
6-[4-(3-甲氧基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(3-氯苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
3-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)苄腈;
1-[2-(吡咯烷-1-基)乙基]-6-[4-(噻吩-2-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(3-甲基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(4-甲基吡啶-3-基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(4-甲氧基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(2-甲氧基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
4-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)苄腈;
6-[4-(4-氯苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(4-甲基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(3-甲基吡啶-4-基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
2-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)喹啉;
1-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)异喹啉;
6-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
5-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
6-[4-(3-甲基吡啶-2-基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(5-甲基吡啶-2-基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
1-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)乙烯酮;
(1-甲基哌啶-3-基)(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)甲酮;
(1-甲基哌啶-2-基)(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)甲酮;
6-[4-(2-甲基苯基)哌嗪-1-基]-1-[2-(4-甲基哌嗪-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
N-(2-{6-[4-(2-甲基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}乙基)丙-2-胺;
N,N-二甲基-1-(2-{6-[4-(2-甲基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}乙基)吡咯烷-3-胺;
1-{2-[2-(甲氧基甲基)吡咯烷-1-基]乙基}-6-[4-(2-甲基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶;
1-[2-(3-甲氧基吡咯烷-1-基)乙基]-6-[4-(2-甲基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶;
1-[2-(2-氮杂二环[3.1.0]己-2-基)乙基]-6-[4-(2-甲基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶
6-甲基-1-(2-{6-[4-(2-甲基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}乙基)八氢-1H-吡咯并[2,3-c]吡啶;
6-甲基-1-(2-{6-[4-(2-甲基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}乙基)八氢-1H-吡咯并[3,4-b]吡啶;
1-[2-(5-甲基六氢吡咯并[3,4-b]吡咯-1(2H)-基)乙基]-6-[4-(2-甲基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶;
1-[2-(3-甲氧基氮杂环丁烷-1-基)乙基]-6-[4-(2-甲基苯基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶;
6-[4-(2-甲基苯基)哌嗪-1-基]-1-{2-[(2R)-2-甲基吡咯烷-1-基]乙基}-1H-吡咯并[2,3-b]吡啶;
6-[4-(2-甲基苯基)哌嗪-1-基]-1-{2-[3-(吡啶-2-基)吡咯烷-1-基]乙基}-1H-吡咯并[2,3-b]吡啶;
1-(2-{6-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}乙基)-N,N-二甲基吡咯烷-3-胺;
5-(4-{1-[2-(6-氮杂二环[3.2.0]庚-6-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
5-[4-(1-{2-[3-(1-甲基-1H-咪唑-2-基)吡咯烷-1-基]乙基}-1H-吡咯并[2,3-b]吡啶-6-基)哌嗪-1-基]咪唑并[1,2-a]吡啶;
5-[4-(1-{2-[2-(1-甲基-1H-吡唑-4-基)吡咯烷-1-基]乙基}-1H-吡咯并[2,3-b]吡啶-6-基)哌嗪-1-基]咪唑并[1,2-a]吡啶;
5-[4-(1-{2-[3-(4,4-二氟哌啶-1-基)氮杂环丁烷-1-基]乙基}-1H-吡咯并[2,3-b]吡啶-6-基)哌嗪-1-基]咪唑并[1,2-a]吡啶;
5-[4-(1-{2-[3-(吡咯烷-1-基)氮杂环丁烷-1-基]乙基}-1H-吡咯并[2,3-b]吡啶-6-基)哌嗪-1-基]咪唑并[1,2-a]吡啶;
5-(4-{1-[2-(2-氧杂-7-氮杂螺[3.5]壬-7-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
5-(4-{1-[2-(5-氮杂螺[3.4]辛-5-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
5-(4-{1-[2-(6-氮杂螺[3.5]壬-6-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
N-苄基-2-{6-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}-N-甲基乙胺;
5-(4-{1-[2-(3-苯氧基吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
5-(4-{1-[2-(2-苯基氮杂环丁烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
5-[4-(1-{2-[3-(2-氟苯基)氮杂环丁烷-1-基]乙基}-1H-吡咯并[2,3-b]吡啶-6-基)哌嗪-1-基]咪唑并[1,2-a]吡啶;
5-(4-{1-[2-(3-苯氧基氮杂环丁烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
1-(2-{6-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}乙基)-3-苯基氮杂环丁烷-3-醇;
反式-N-甲基-3-[3-(1-甲基-1H-吡唑-4-基)-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基]环丁烷胺;
反式-N-甲基-3-[3-(1-甲基-1H-吡唑-5-基)-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基]环丁烷胺;
反式-N-甲基-3-[6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-3-(1H-吡唑-5-基)-1H-吡咯并[2,3-b]吡啶-1-基]环丁烷胺;
反式-N-甲基-3-[3-(1-甲基-1H-吡唑-3-基)-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基]环丁烷胺;
5-(4-{1-[2-(1-甲基吡咯烷-3-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
顺式-N,N-二甲基-3-(6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)环丁烷胺;
反式-N,N-二甲基-3-(6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)环丁烷胺;
1-[(3S)-1-甲基吡咯烷-3-基]-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶;
1-[(3R)-1-甲基吡咯烷-3-基]-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶;
顺式-N-苄基-N-甲基-3-(6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)环丁烷胺;
反式-N-苄基-N-甲基-3-(6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)环丁烷胺;
5-(4-{1-[2-(1-苄基吡咯烷-3-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
1-[(3S)-1-苄基吡咯烷-3-基]-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶;
1-[(3R)-1-苄基吡咯烷-3-基]-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶;
6-(4-甲基哌嗪-1-基)-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
2-{6-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}-N,N-二甲基乙胺;
5-(4-{1-[2-(1-氧杂-6-氮杂螺[3.4]辛-6-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-3-腈;
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-4-腈;
3-甲基-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶;
反式-3-(3-溴-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)-N-甲基环丁烷胺;
6-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)吡啶-2-腈;
2-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)吡啶-3-腈;
6-[4-(2-甲基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[3,2-c]吡啶;
顺式-3-(4-氯-6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1H-吡咯并[2,3-b]吡啶-1-基)-N-甲基环丁烷胺;
顺式-N-甲基-3-[6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-3-(三氟甲基)-1H-吡咯并[2,3-b]吡啶-1-基]环丁烷胺;
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-吡唑并[3,4-b]吡啶;
6-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-2-[2-(吡咯烷-1-基)乙基]-2H-吡唑并[3,4-b]吡啶;
5-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[3,2-c]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
2-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-7-[2-(吡咯烷-1-基)乙基]-7H-吡咯并[2,3-d]嘧啶;
6-(4-{1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[3,2-c]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
5-(4-{1-[2-(哌嗪-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
5-(4-{1-[2-(2-甲基-1H-咪唑-1-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
5-(4-{1-[2-(吡咯烷-3-基)乙基]-1H-吡咯并[2,3-b]吡啶-6-基}哌嗪-1-基)咪唑并[1,2-a]吡啶;
2-{6-[4-(咪唑并[1,2-a]吡啶-5-基)哌嗪-1-基]-1H-吡咯并[2,3-b]吡啶-1-基}乙胺;
4-[4-[1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯酚;
6-[4-[1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]吡啶-3-腈;
5-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-3-[2-(吡咯烷-1-基)乙基]-3H-咪唑并[4,5-b]吡啶;
5-{4-[4-(甲磺酰基)苯基]哌嗪-1-基}-1-[2-(吡咯烷-1-基)乙基]-1H-咪唑并[4,5-b]吡啶;
1-(4-{1-[反式-3-(甲基氨基)环丁基]-1H-吡咯并[2,3-b]吡啶-6-基}苯基)乙烯酮;
6-哌嗪-1-基-1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶;
反式-N-甲基-3-[6-[4-(3-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环丁烷-1-胺;
5-[4-(4-甲磺酰基苯基)哌嗪-1-基]-3-哌嗪-1-基-噻吩并[3,2-b]吡啶;
1-(2-吡咯烷-1-基乙基)-6-[4-(3-噻吩基)哌嗪-1-基]吡咯并[2,3-b]吡啶;
顺式-N,N-二甲基-1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-甲酰胺;
顺式-1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-羧酸甲酯;
反式-6-[4-(6-乙酰基-3-吡啶基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(1-甲基-2-氧代-4-吡啶基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-(4-甲酰基苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
顺式-N-甲基-3-[3-甲磺酰基-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环丁烷胺;
反式-N-甲基-3-[7-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-c]吡啶-1-基]环丁烷胺;
反式-6-[4-(4-羟基苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(4-氧代色满-7-基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-[4-[(R)-甲基亚磺酰基]苯基]哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(2-甲基-4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(2-甲基-1-氧代-3H-异吲哚-5-基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-5-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]吡啶-3-羧酸甲酯;
反式-2-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]吡啶-4-羧酸甲酯;
反式-5-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]吡嗪-2-羧酸甲酯;
反式-4-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]-N,N-二甲基苯甲酰胺;
反式-1-[3-(甲基氨基)环丁基]-6-[4-[4-(2-氧代吡咯烷-1-基)苯基]哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(5-甲磺酰基吡啶-2-基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)-1-[2-(氧杂环戊烷-3-基)乙基]吡咯并[2,3-b]吡啶;
3-[2-[6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)吡咯并[2,3-b]吡啶-1-基]乙基]吡咯烷-1-羧酸叔丁酯;
1-[2-[6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)吡咯并[2,3-b]吡啶-1-基]乙基]吡咯烷-2-酮;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(3-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(4-吡啶-2-基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-N-甲基-3-[6-[4-(4-吡啶-2-基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环丁烷-1-胺;
反式-1-[3-(甲基氨基)环丁基]-6-[4-[4-(1-甲基咪唑-2-基)苯基]哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[(3R)-吡咯烷-3-基]吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[(3S)-吡咯烷-3-基]吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-哌啶-4-基吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-哌啶-4-基吡咯并[3,2-c]吡啶-3-腈;
6-[4-(4-甲磺酰基苯基)哌嗪-1-基]-1-[(3S)-吡咯烷-3-基]吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[rel-(3R,4R)-3-氟哌啶-4-基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[(3S)-4-(4-乙酰基苯基)-3-甲基哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[(3R)-4-(4-乙酰基苯基)-3-甲基哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[(2R)-4-(4-乙酰基苯基)-2-甲基哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[(2S)-4-(4-乙酰基苯基)-2-甲基哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
顺式-1-[4-[4-[1-[3-(甲基氨基)环丁基]-3-(1-甲基吡唑-4-基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮;
反式-1-[4-[4-[1-[3-(甲基氨基)环丁基]-3-(1-甲基吡唑-4-基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮;
反式-N-甲基-3-[3-(1-甲基吡唑-4-基)-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环丁烷-1-胺;
1-[4-[4-[3-(2-甲基吡啶-3-基)-1-哌啶-4-基吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮;
1-[4-[4-[3-(1-甲基吡唑-3-基)-1-哌啶-4-基吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮;
1-[4-[4-[3-(2-甲基嘧啶-5-基)-1-哌啶-4-基吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮;
1-[4-[4-[1-[3-(甲基氨基)环丁基]-3-(1-甲基吡唑-4-基)吡咯并[3,2-c]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮;
反式-6-[4-(4-乙酰基-3-羟基-苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-(4-乙酰基-3-氟-苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-(2-乙酰基-5-氟-苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-2-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]嘧啶-4-甲酰胺;
反式-6-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]-N,N-二甲基吡啶-2-甲酰胺;
反式-6-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]-N-甲基哒嗪-3-甲酰胺;
反式-6-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]-N,N-二甲基吡啶-3-甲酰胺;
反式-1-[3-(甲基氨基)环丁基]-6-[4-[4-(2-甲基丙酰基)苯基]哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(1-氧代四氢萘-6-基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-4-[4-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]-4-氧代-丁酸;
反式-6-[4-[4-(2,2-二甲基丙酰基)苯基]哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-4-[4-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]-2-甲基-4-氧代-丁酸;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(1-氧代茚满-5-基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-(5-乙酰基吡啶-2-基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-(5-乙酰基嘧啶-2-基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-(5-乙酰基吡嗪-2-基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-(6-乙酰基哒嗪-3-基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
顺式-[1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-基]-吗啉代-甲酮;
顺式-N-甲基-1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-甲酰胺;
反式-3-[6-氯-4-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]-N-甲基-环丁烷胺;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基环己基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基环己基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(1-甲磺酰基-4-哌啶基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-(1-乙酰基-4-哌啶基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-(4-乙基哌嗪-1-基)-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(1-甲基哌啶-4-基)吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[(3S)-1-甲基吡咯烷-3-基]吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[(3R)-1-甲基吡咯烷-3-基]吡咯并[2,3-b]吡啶-3-腈;
1-[(3S)-1-甲基吡咯烷-3-基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[3-(二甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-[4-(2,2,2-三氟乙酰基)苯基]哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-2-甲基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-3-[5-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环丁烷胺;
反式-N-甲基-3-[3-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡嗪-5-基]环丁烷胺;
反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-2-羧酸甲酯;
反式-1-[4-[4-[2-甲基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮;
反式-5-[4-(4-乙酰基苯基)哌嗪-1-基]-3-[3-(甲基氨基)环丁基]-1-(1-甲基吡唑-4-基)咪唑并[4,5-b]吡啶-2-酮;
5-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(1-甲基吡唑-4-基)-3-(4-哌啶基)咪唑并[4,5-b]吡啶-2-酮;
1-(1-甲基吡唑-4-基)-5-[4-(4-甲磺酰基苯基)哌嗪-1-基]-3-(4-哌啶基)咪唑并[4,5-b]吡啶-2-酮;
5-[4-(4-乙酰基苯基)哌嗪-1-基]-3-(4-甲基-4-哌啶基)-1-(1-甲基吡唑-4-基)咪唑并[4,5-b]吡啶-2-酮;
反式-5-[4-(4-乙酰基苯基)哌嗪-1-基]-3-[3-(甲基氨基)环丁基]-1-苯基-咪唑并[4,5-b]吡啶-2-酮;
5-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(1-甲基吡唑-3-基)-3-(4-哌啶基)咪唑并[4,5-b]吡啶-2-酮;
6-[4-(4-甲磺酰基苯基)哌嗪-1-基]-1-(4-哌啶基)吡咯并[2,3-b]吡啶;
(1R,3R)-3-[6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环戊烷胺;
1-(2-氮杂螺[3.3]庚烷-6-基)-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶;
(1R,3S)-3-[6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环戊烷胺;
顺式-N-甲基-4-[6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环己烷胺;
反式-N-甲基-4-[6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环己烷胺;
6-[4-(4-甲磺酰基苯基)哌嗪-1-基]-1-奎宁环-3-基-吡咯并[2,3-b]吡啶;
1-(1-甲基-3-哌啶基)-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶;
1-(1-甲基-4-哌啶基)-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶;
N,N-二甲基-1-[2-[6-[4-(邻-甲苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]乙基]氮杂环丁烷-3-甲酰胺;
1-[2-(3-咪唑-1-基吡咯烷-1-基)乙基]-6-[4-(邻-甲苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶;
N-[1-[2-[6-[4-(邻-甲苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]乙基]氮杂环丁烷-3-基]甲烷磺酰胺;
1-[2-(3-氟-3-甲基-吡咯烷-1-基)乙基]-6-[4-(邻-甲苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶;
6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)-1-[2-[4-(2-甲基吡唑-3-基)-1-哌啶基]乙基]吡咯并[2,3-b]吡啶;
6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)-1-[2-[4-(氧杂环丁烷-3-基)-1-哌啶基]乙基]吡咯并[2,3-b]吡啶;
2-[2-[6-(4-咪唑并[1,2-a]吡啶-5-基哌嗪-1-基)吡咯并[2,3-b]吡啶-1-基]乙基]-3,4-二氢-1H-异喹啉;
环戊基-[4-[1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]甲酮;
2-(2-吡啶基)-1-[4-[1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]乙烯酮;
环丁基-[4-[1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]甲酮;
苯基-[4-[1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]甲酮;
4-吡啶基-[4-[1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]甲酮;
4-哌啶基-[4-[1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]甲酮;
6-[4-(3-甲氧基-2-吡啶基)哌嗪-1-基]-1-(2-吡咯烷-1-基乙基)吡咯并[2,3-b]吡啶;
反式-N-甲基-3-[5-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-1-基]环丁烷胺;
3-[4-(4-甲磺酰基苯基)哌嗪-1-基]-5-哌嗪-1-基-1,2-苯并噁唑;
5-[4-(4-甲磺酰基苯基)哌嗪-1-基]-3-哌嗪-1-基-1,2-苯并噁唑;
反式-6-[6-(4-乙酰基苯基)-3-吡啶基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基苯基)苯基]吡咯并[2,3-b]吡啶-3-腈;
反式-6-[4-[4-[(E)-N-甲氧基-C-甲基-亚氨代甲酰]苯基]哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
1-甲基-5-[4-(4-甲磺酰基苯基)哌嗪-1-基]螺[吲哚啉-3,4'-哌啶];
N-甲基-3-[6-[4-(4-甲磺酰基苯基)哌嗪-1-基]-2,3-二氢吡咯并[2,3-b]吡啶-1-基]环丁烷胺;
反式-1-[4-[1-[3-(甲基氨基)环丁基]-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-4-基]哌嗪-1-基]乙烯酮;
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(5-氮杂螺[3.4]辛烷-2-基)吡咯并[2,3-b]吡啶-3-腈;
反式-1-(5-氮杂螺[3.4]辛烷-2-基)-6-[4-(4-甲磺酰基苯基)哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈;
反式-1-[4-[3-溴-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]乙烯酮;
5-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(1-甲基吡唑-4-基)-3-(4-哌啶基)苯并咪唑-2-酮;
5-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(氧杂环丁烷-3-基)-3-(4-哌啶基)咪唑并[4,5-b]吡啶-2-酮;
反式-1-[4-[4-[3-溴-2-甲基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮;
反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-2-羧酸甲酯;
反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-5-氟-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
6-[4-[4-(1,1-二甲氧基乙基)苯基]哌嗪-1-基]-5-氟-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
1-甲基-5-[4-(4-甲磺酰基苯基)哌嗪-1-基]-3-(1,2,3,6-四氢吡啶-4-基)吡咯并[2,3-c]吡啶;
反式-1-[4-[4-[1-[3-(甲基氨基)环丁基]-3-(3-吡啶基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙烯酮三氟乙酸盐;
7-[4-(4-甲磺酰基苯基)哌嗪-1-基]-2-哌啶-4-基吡唑并[3,4-c]吡啶;
7-[4-(4-甲磺酰基苯基)哌嗪-1-基]-1-(4-哌啶基)吡唑并[3,4-c]吡啶
6-[4-(4-乙酰基哌嗪-1-基)苯基]-1-[反式-3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
1-[4-[4-[5-(1-甲基吡唑-4-基)-1,2,3,4-四氢吡啶并[4,3-b]吲哚-8-基]哌嗪-1-基]苯基]乙酮;
反式-6-[4-(4-乙酰基苯基)哌嗪-1-基]-3-溴-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-2-羧酸甲酯;
5-[4-(4-乙酰基苯基)哌嗪-1-基]-3-(4-甲基-4-哌啶基)-1-(氧杂环丁烷-3-基)咪唑并[4,5-b]吡啶-2-酮;
反式-5-[4-(4-乙酰基苯基)哌嗪-1-基]-3-[3-(甲基氨基)环丁基]-1-(氧杂环丁烷-3-基)咪唑并[4,5-b]吡啶-2-酮;
6-[4-(4-乙酰基苯基)苯基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
6-[4-(4-乙酰基-2-甲基苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
反式-4-[4-[3-氰基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯甲酸甲酯;
6-[4-[4-(氮杂环丁烷-1-羰基)苯基]哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈;
1-[4-[4-[3-(1-甲基吡唑-4-基)-1-哌啶-4-基吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙酮;
1-[4-[4-[1-(1-甲基吡唑-4-基)-3-哌嗪-1-基-吡咯并[3,2-b]吡啶-5-基]哌嗪-1-基]苯基]乙酮;
1-[4-[4-[1-(1-甲基吡唑-4-基)-3-哌啶-4-基吡咯并[3,2-b]吡啶-5-基]哌嗪-1-基]苯基]乙酮。
16.根据前述权利要求中任一项的化合物,选自包含下述的组:
1-[4-[4-[3-(1-甲基吡唑-4-基)-1-(4-哌啶基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙酮,
1-[4-[4-[3-(2-甲基-3-吡啶基)-1-(4-哌啶基)吡咯并[2,3-b]吡啶-6-基]哌嗪-1-基]苯基]乙酮,
6-[(2S)-2-甲基-4-(2-甲基苯基)哌嗪-1-基]-1-[2-(吡咯烷-1-基)乙基]-1H-吡咯并[2,3-b]吡啶,
1-[4-[4-[1-(1-甲基吡唑-4-基)-3-(4-哌啶基)吡咯并[3,2-b]吡啶-5-基]哌嗪-1-基]苯基]乙酮,
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(5-氮杂螺[3.4]辛烷-2-基)吡咯并[2,3-b]吡啶-3-腈,
1-[3-(甲基氨基)环丁基]-6-[4-[4-(2,2,2-三氟乙酰基)苯基]哌嗪-1-基]吡咯并[2,3-b]吡啶-3-腈,
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-(4-哌啶基)吡咯并[2,3-b]吡啶-3-腈,6-[4-(4-乙酰基-3-羟基-苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈,
6-[4-(4-乙酰基-3-氟-苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈,
6-[(-4-(4-乙酰基苯基)-2-甲基-哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈,
6-[4-(4-乙酰基苯基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈,
5-[4-(4-乙酰基苯基)哌嗪-1-基]-3-[3-(甲基氨基)环丁基]-1-(1-甲基吡唑-4-基)咪唑并[4,5-b]吡啶-2-酮,
6-[4-(4-乙酰基苯基)-3-甲基-哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈,
6-[4-(4-乙酰基苯基)哌嗪-1-基]-2-甲基-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈,
6-[4-(5-乙酰基-2-吡啶基)哌嗪-1-基]-1-[3-(甲基氨基)环丁基]吡咯并[2,3-b]吡啶-3-腈。
17.根据权利要求1至16中任一项的化合物,用作药物。
18.药物组合物,包含有效量的根据权利要求1至16的化合物和与之组合的药学上可接受的稀释剂或载体。
19.根据权利要求1至16中任一项的化合物用于治疗受STING激活驱动的炎性病况。
Applications Claiming Priority (5)
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EP18157247.0A EP3527209A1 (en) | 2018-02-16 | 2018-02-16 | Pharmaceutical 6,5 heterobicyclic ring derivatives |
EP18157247.0 | 2018-02-16 | ||
EP18184724.5 | 2018-07-20 | ||
EP18184724.5A EP3597642A1 (en) | 2018-07-20 | 2018-07-20 | Pharmaceutical 6,5 heterobicyclic ring derivatives |
PCT/EP2019/053893 WO2019158731A1 (en) | 2018-02-16 | 2019-02-15 | Pharmaceutical 6,5 heterobicyclic ring derivatives |
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EP (1) | EP3752150A1 (zh) |
JP (1) | JP2021513976A (zh) |
KR (1) | KR20200121823A (zh) |
CN (1) | CN112105357A (zh) |
BR (1) | BR112020015976A2 (zh) |
CA (1) | CA3090746A1 (zh) |
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CR20220126A (es) * | 2019-09-25 | 2022-06-07 | Pfizer | Moduladores de sting (estimulador de genes de interferón) |
CN113024563B (zh) * | 2019-12-24 | 2023-01-03 | 药康众拓(江苏)医药科技有限公司 | 嘧啶并五元杂环类化合物或其可药用的盐、异构体及其制备方法、药物组合物和用途 |
EP4097099A4 (en) | 2020-02-07 | 2023-09-27 | Gasherbrum Bio, Inc. | HETEROCYCLIC GLP-1 AGONISTS |
EP4134098A4 (en) | 2020-04-10 | 2024-05-15 | Ono Pharmaceutical Co | CANCER THERAPY METHODS |
JP6912016B1 (ja) * | 2020-04-10 | 2021-07-28 | 小野薬品工業株式会社 | Sting作動化合物 |
JPWO2021205631A1 (zh) * | 2020-04-10 | 2021-10-14 | ||
KR102513463B1 (ko) * | 2020-11-26 | 2023-03-29 | 주식회사 에스앤케이테라퓨틱스 | 엔도솜 톨-유사 수용체를 제어하는 신규 소분자 화합물 및 이를 이용한 자가면역질환 치료제 |
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FR2852957B1 (fr) * | 2003-03-31 | 2005-06-10 | Sod Conseils Rech Applic | Nouveaux derives d'imidazo-pyridine et leur utilisation en tant que medicament |
WO2006096444A2 (en) * | 2005-03-04 | 2006-09-14 | Smithkline Beecham Corporation | Chemical compounds |
EP1904501A2 (en) * | 2005-07-11 | 2008-04-02 | Smithkline Beecham Corporation | Chemical compounds |
ZA200902382B (en) * | 2006-10-19 | 2010-08-25 | Signal Pharm Llc | Heteroaryl compounds, compositions thereof, and their use as protein kinase inhibitors |
US8466186B2 (en) * | 2010-12-10 | 2013-06-18 | Boehringer Ingelheim International Gmbh | Compounds |
FR2984325A1 (fr) * | 2011-12-14 | 2013-06-21 | Sanofi Sa | Derives de pyrazolopyridine, leur procede de preparation et leur application en therapeutique |
EP2733143A1 (en) * | 2012-11-14 | 2014-05-21 | Laboratorios Del Dr. Esteve, S.A. | Substituted pyrazolo[3,4-d]pyrimidine compounds, their preparation and use as sigma receptors ligands |
MX2016008257A (es) * | 2013-12-20 | 2016-10-14 | Gilead Sciences Inc | Compuestos heterociclicos fusionados como moduladores de canales ionicos. |
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- 2019-02-15 KR KR1020207025732A patent/KR20200121823A/ko not_active Application Discontinuation
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BR112020015976A2 (pt) | 2020-12-15 |
MX2020008265A (es) | 2020-09-21 |
KR20200121823A (ko) | 2020-10-26 |
RU2020129785A (ru) | 2022-03-16 |
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EP3752150A1 (en) | 2020-12-23 |
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