CN111936144B - Jak抑制剂 - Google Patents
Jak抑制剂 Download PDFInfo
- Publication number
- CN111936144B CN111936144B CN201980020463.5A CN201980020463A CN111936144B CN 111936144 B CN111936144 B CN 111936144B CN 201980020463 A CN201980020463 A CN 201980020463A CN 111936144 B CN111936144 B CN 111936144B
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- CN
- China
- Prior art keywords
- methyl
- pyrrolo
- pyrimidin
- amino
- azaspiro
- 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.)
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- 229940122245 Janus kinase inhibitor Drugs 0.000 title abstract description 8
- -1 cyano, hydroxy Chemical group 0.000 claims description 182
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 81
- 150000001875 compounds Chemical class 0.000 claims description 60
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 54
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 48
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- KWVQZNXGJOENFF-UHFFFAOYSA-N 1-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptan-2-yl]ethanone Chemical compound CN(C1CC2(C1)CN(C2)C(C)=O)C1=NC=NC2=C1C=CN2 KWVQZNXGJOENFF-UHFFFAOYSA-N 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
- 125000005038 alkynylalkyl group Chemical group 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- ICLZZFBCSCMVAR-UHFFFAOYSA-N 2-fluoro-4-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptane-2-carbonyl]benzonitrile Chemical compound FC1=C(C#N)C=CC(=C1)C(=O)N1CC2(C1)CC(C2)N(C=1C2=C(N=CN=1)NC=C2)C ICLZZFBCSCMVAR-UHFFFAOYSA-N 0.000 claims description 3
- AXFIKTLVDGBLEH-UHFFFAOYSA-N 2-methoxy-1-[9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-azaspiro[5.5]undecan-3-yl]ethanone Chemical compound COCC(=O)N1CCC2(CC1)CCC(CC2)N(C=1C2=C(N=CN=1)NC=C2)C AXFIKTLVDGBLEH-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 230000001404 mediated effect Effects 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- SCKAIBAFHJVEKP-UHFFFAOYSA-N (1-cyclopropylpyrazol-4-yl)-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptan-2-yl]methanone Chemical compound C1(CC1)N1N=CC(=C1)C(=O)N1CC2(C1)CC(C2)N(C=1C2=C(N=CN=1)NC=C2)C SCKAIBAFHJVEKP-UHFFFAOYSA-N 0.000 claims description 2
- KDOUHIDUYPIERE-UHFFFAOYSA-N (1-methylpyrazol-3-yl)-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptan-2-yl]methanone Chemical compound CN(C1CC2(CN(C2)C(=O)C2=NN(C=C2)C)C1)C=1C2=C(N=CN=1)NC=C2 KDOUHIDUYPIERE-UHFFFAOYSA-N 0.000 claims description 2
- DJJQOGRNMXRGGR-UHFFFAOYSA-N 1-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptan-2-yl]propan-1-one Chemical compound CCC(=O)N1CC2(CC(C2)N(C)C2=NC=NC3=C2C=CN3)C1 DJJQOGRNMXRGGR-UHFFFAOYSA-N 0.000 claims description 2
- BYISEBGOLCFZQT-UHFFFAOYSA-N 1-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptane-2-carbonyl]cyclopropane-1-carbonitrile Chemical compound CN(C1CC2(CN(C2)C(=O)C2(CC2)C#N)C1)C=1C2=C(N=CN=1)NC=C2 BYISEBGOLCFZQT-UHFFFAOYSA-N 0.000 claims description 2
- ANFHSFUVNIOWRN-UHFFFAOYSA-N 1-[9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-azaspiro[5.5]undecan-3-yl]-2-phenoxyethanone Chemical compound CN(C1CCC2(CC1)CCN(CC2)C(=O)COC1=CC=CC=C1)C1=NC=NC2=C1C=CN2 ANFHSFUVNIOWRN-UHFFFAOYSA-N 0.000 claims description 2
- KTOPVQNYKABUFY-UHFFFAOYSA-N 1-[9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-azaspiro[5.5]undecan-3-yl]-3-methylsulfonylpropan-1-one Chemical compound CS(=O)(=O)CCC(=O)N1CCC2(CC1)CCC(CC2)N(C=1C2=C(N=CN=1)NC=C2)C KTOPVQNYKABUFY-UHFFFAOYSA-N 0.000 claims description 2
- VQVZSMAERXBLDB-UHFFFAOYSA-N 1-[9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-azaspiro[5.5]undecan-3-yl]butan-1-one Chemical compound CCCC(=O)N1CCC2(CCC(CC2)N(C)C2=NC=NC3=C2C=CN3)CC1 VQVZSMAERXBLDB-UHFFFAOYSA-N 0.000 claims description 2
- QIQHXWYVKFNQFY-UHFFFAOYSA-N 1-[9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-azaspiro[5.5]undecan-3-yl]ethanone Chemical compound CN(C1CCC2(CC1)CCN(CC2)C(C)=O)C1=NC=NC2=C1C=CN2 QIQHXWYVKFNQFY-UHFFFAOYSA-N 0.000 claims description 2
- HOSLAXOWUINHCU-UHFFFAOYSA-N 1-[9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-azaspiro[5.5]undecan-3-yl]propan-1-one Chemical compound CCC(=O)N1CCC2(CCC(CC2)N(C)C2=NC=NC3=C2C=CN3)CC1 HOSLAXOWUINHCU-UHFFFAOYSA-N 0.000 claims description 2
- KBSLNJCFOFKELT-UHFFFAOYSA-N 1-[9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-azaspiro[5.5]undecane-3-carbonyl]cyclopropane-1-carbonitrile Chemical compound CN(C1CCC2(CC1)CCN(CC2)C(=O)C1(CC1)C#N)C1=NC=NC2=C1C=CN2 KBSLNJCFOFKELT-UHFFFAOYSA-N 0.000 claims description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 2
- JPRZCHJAVZPIMR-UHFFFAOYSA-N 2,3-difluoro-4-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptane-2-carbonyl]benzonitrile Chemical compound FC1=C(C#N)C=CC(=C1F)C(=O)N1CC2(C1)CC(C2)N(C=1C2=C(N=CN=1)NC=C2)C JPRZCHJAVZPIMR-UHFFFAOYSA-N 0.000 claims description 2
- IPSDQRYFGZNDAI-UHFFFAOYSA-N 2,3-difluoro-5-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptane-2-carbonyl]benzonitrile Chemical compound FC1=C(C#N)C=C(C=C1F)C(=O)N1CC2(C1)CC(C2)N(C=1C2=C(N=CN=1)NC=C2)C IPSDQRYFGZNDAI-UHFFFAOYSA-N 0.000 claims description 2
- QKCIVLFBPUAUSP-UHFFFAOYSA-N 2,6-difluoro-3-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptane-2-carbonyl]benzonitrile Chemical compound FC1=C(C#N)C(=CC=C1C(=O)N1CC2(C1)CC(C2)N(C=1C2=C(N=CN=1)NC=C2)C)F QKCIVLFBPUAUSP-UHFFFAOYSA-N 0.000 claims description 2
- ZWWIDAAVJZTVJH-UHFFFAOYSA-N 2-(1H-indol-3-yl)-1-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptan-2-yl]ethanone Chemical compound N1C=C(C2=CC=CC=C12)CC(=O)N1CC2(C1)CC(C2)N(C=1C2=C(N=CN=1)NC=C2)C ZWWIDAAVJZTVJH-UHFFFAOYSA-N 0.000 claims description 2
- XQCMLCLKZDEXCQ-UHFFFAOYSA-N 2-fluoro-4-[9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-azaspiro[5.5]undecane-3-carbonyl]benzonitrile Chemical compound FC1=C(C#N)C=CC(=C1)C(=O)N1CCC2(CC1)CCC(CC2)N(C=1C2=C(N=CN=1)NC=C2)C XQCMLCLKZDEXCQ-UHFFFAOYSA-N 0.000 claims description 2
- ZKVWEDANSGSWPD-UHFFFAOYSA-N 2-fluoro-5-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptane-2-carbonyl]benzonitrile Chemical compound FC1=C(C#N)C=C(C=C1)C(=O)N1CC2(C1)CC(C2)N(C=1C2=C(N=CN=1)NC=C2)C ZKVWEDANSGSWPD-UHFFFAOYSA-N 0.000 claims description 2
- PVDXJOHUPFBJLL-UHFFFAOYSA-N 2-hydroxy-1-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptan-2-yl]ethanone Chemical compound OCC(=O)N1CC2(C1)CC(C2)N(C=1C2=C(N=CN=1)NC=C2)C PVDXJOHUPFBJLL-UHFFFAOYSA-N 0.000 claims description 2
- PQGAOWILIFAGPY-UHFFFAOYSA-N 2-hydroxy-1-[9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-azaspiro[5.5]undecan-3-yl]ethanone Chemical compound OCC(=O)N1CCC2(CC1)CCC(CC2)N(C=1C2=C(N=CN=1)NC=C2)C PQGAOWILIFAGPY-UHFFFAOYSA-N 0.000 claims description 2
- DXWXXMLXNSSPGK-UHFFFAOYSA-N 3,4-difluoro-5-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptane-2-carbonyl]benzonitrile Chemical compound FC=1C=C(C#N)C=C(C=1F)C(=O)N1CC2(C1)CC(C2)N(C=1C2=C(N=CN=1)NC=C2)C DXWXXMLXNSSPGK-UHFFFAOYSA-N 0.000 claims description 2
- TVBKULHUOUDGIL-UHFFFAOYSA-N 3,5-difluoro-4-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptane-2-carbonyl]benzonitrile Chemical compound FC=1C=C(C#N)C=C(C=1C(=O)N1CC2(C1)CC(C2)N(C=1C2=C(N=CN=1)NC=C2)C)F TVBKULHUOUDGIL-UHFFFAOYSA-N 0.000 claims description 2
- XSWHAOGCTCBDIT-UHFFFAOYSA-N 3-Methyloctan-2-one Chemical compound CCCCCC(C)C(C)=O XSWHAOGCTCBDIT-UHFFFAOYSA-N 0.000 claims description 2
- QEAYNZFIPVTVML-UHFFFAOYSA-N 3-[2-[9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-azaspiro[5.5]undecan-3-yl]-2-oxoethoxy]benzonitrile Chemical compound CN(C1CCC2(CCN(CC2)C(COC=2C=C(C#N)C=CC=2)=O)CC1)C=1C2=C(N=CN=1)NC=C2 QEAYNZFIPVTVML-UHFFFAOYSA-N 0.000 claims description 2
- UYAIPRMOKFAMMH-UHFFFAOYSA-N 3-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptan-2-yl]-3-oxopropanenitrile Chemical compound CN(C1CC2(CN(C2)C(CC#N)=O)C1)C=1C2=C(N=CN=1)NC=C2 UYAIPRMOKFAMMH-UHFFFAOYSA-N 0.000 claims description 2
- MNVUSJNTPTYIAS-UHFFFAOYSA-N 3-ethylsulfonyl-N-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3-azaspiro[5.5]undecan-9-amine Chemical compound C(C)S(=O)(=O)N1CCC2(CC1)CCC(CC2)N(C=1C2=C(N=CN=1)NC=C2)C MNVUSJNTPTYIAS-UHFFFAOYSA-N 0.000 claims description 2
- RSVWDCQCHSMMND-UHFFFAOYSA-N 3-fluoro-5-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptane-2-carbonyl]benzonitrile Chemical compound FC=1C=C(C#N)C=C(C=1)C(=O)N1CC2(C1)CC(C2)N(C=1C2=C(N=CN=1)NC=C2)C RSVWDCQCHSMMND-UHFFFAOYSA-N 0.000 claims description 2
- NLTNWHIVTSQFOR-UHFFFAOYSA-N 3-methyl-4-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptane-2-carbonyl]benzonitrile Chemical compound CC=1C=C(C#N)C=CC=1C(=O)N1CC2(C1)CC(C2)N(C=1C2=C(N=CN=1)NC=C2)C NLTNWHIVTSQFOR-UHFFFAOYSA-N 0.000 claims description 2
- QWKUTEQPAJGRLZ-UHFFFAOYSA-N 4-(1-methylpyrazol-3-yl)benzaldehyde Chemical compound CN1C=CC(C=2C=CC(C=O)=CC=2)=N1 QWKUTEQPAJGRLZ-UHFFFAOYSA-N 0.000 claims description 2
- BLZMXOQDHLRLNE-UHFFFAOYSA-N 4-[2-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptan-2-yl]-2-oxoethyl]benzonitrile Chemical compound CN(C1CC2(CN(C2)C(CC2=CC=C(C#N)C=C2)=O)C1)C=1C2=C(N=CN=1)NC=C2 BLZMXOQDHLRLNE-UHFFFAOYSA-N 0.000 claims description 2
- JMMCTEYNTCZHTP-UHFFFAOYSA-N 4-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptane-2-carbonyl]benzenesulfonamide Chemical compound CN(C1CC2(CN(C2)C(=O)C2=CC=C(C=C2)S(=O)(=O)N)C1)C=1C2=C(N=CN=1)NC=C2 JMMCTEYNTCZHTP-UHFFFAOYSA-N 0.000 claims description 2
- OPARRXAAPGSVPZ-UHFFFAOYSA-N 4-[9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-azaspiro[5.5]undecane-3-carbonyl]benzenesulfonamide Chemical compound CN(C1CCC2(CCN(CC2)C(=O)C2=CC=C(C=C2)S(=O)(=O)N)CC1)C=1C2=C(N=CN=1)NC=C2 OPARRXAAPGSVPZ-UHFFFAOYSA-N 0.000 claims description 2
- WTPATCQZIMFXCI-UHFFFAOYSA-N 4-[9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-azaspiro[5.5]undecane-3-carbonyl]cyclohexan-1-one Chemical compound CN(C1CCC2(CCN(CC2)C(=O)C2CCC(CC2)=O)CC1)C=1C2=C(N=CN=1)NC=C2 WTPATCQZIMFXCI-UHFFFAOYSA-N 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- GORVKYKEYCQOMR-UHFFFAOYSA-N 5-fluoro-2-methyl-4-[6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptane-2-carbonyl]benzonitrile Chemical compound FC=1C(=CC(=C(C#N)C=1)C)C(=O)N1CC2(C1)CC(C2)N(C=1C2=C(N=CN=1)NC=C2)C GORVKYKEYCQOMR-UHFFFAOYSA-N 0.000 claims description 2
- TZZCOSKZMZQKRT-UHFFFAOYSA-N 9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-(1,3-thiazol-2-yl)-3-azaspiro[5.5]undecane-3-carboxamide Chemical compound CN(C1CCC2(CCN(CC2)C(=O)NC=2SC=CN=2)CC1)C=1C2=C(N=CN=1)NC=C2 TZZCOSKZMZQKRT-UHFFFAOYSA-N 0.000 claims description 2
- KEBCLGFCDNZXSO-UHFFFAOYSA-N 9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-(5-methyl-1,3-thiazol-2-yl)-3-azaspiro[5.5]undecane-3-carboxamide Chemical compound CN(C1CCC2(CCN(CC2)C(=O)NC=2SC(=CN=2)C)CC1)C=1C2=C(N=CN=1)NC=C2 KEBCLGFCDNZXSO-UHFFFAOYSA-N 0.000 claims description 2
- WDAYNCDLBOQLBM-UHFFFAOYSA-N N-(1-methylpyrazol-3-yl)-9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-azaspiro[5.5]undecane-3-carboxamide Chemical compound CN(C1CCC2(CCN(CC2)C(=O)NC2=NN(C=C2)C)CC1)C=1C2=C(N=CN=1)NC=C2 WDAYNCDLBOQLBM-UHFFFAOYSA-N 0.000 claims description 2
- FKHQJSSTWDXZTM-UHFFFAOYSA-N N-(3-cyanophenyl)-9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-azaspiro[5.5]undecane-3-carboxamide Chemical compound C(#N)C=1C=C(C=CC=1)NC(=O)N1CCC2(CC1)CCC(CC2)N(C=1C2=C(N=CN=1)NC=C2)C FKHQJSSTWDXZTM-UHFFFAOYSA-N 0.000 claims description 2
- WYWWHIQQIUMFIF-UHFFFAOYSA-N N-(3-methoxy-1,2,4-thiadiazol-5-yl)-6-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2-azaspiro[3.3]heptane-2-carboxamide Chemical compound COC1=NSC(NC(=O)N2CC3(CC(C3)N(C)C3=NC=NC4=C3C=CN4)C2)=N1 WYWWHIQQIUMFIF-UHFFFAOYSA-N 0.000 claims description 2
- WXXYIUCRGXQTIQ-UHFFFAOYSA-N N-(3-methoxyphenyl)-9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-azaspiro[5.5]undecane-3-carboxamide Chemical compound COC=1C=C(C=CC=1)NC(=O)N1CCC2(CC1)CCC(CC2)N(C=1C2=C(N=CN=1)NC=C2)C WXXYIUCRGXQTIQ-UHFFFAOYSA-N 0.000 claims description 2
- DCVLNAFSEGHRSD-UHFFFAOYSA-N N-(4-cyanophenyl)-9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-azaspiro[5.5]undecane-3-carboxamide Chemical compound C(#N)C1=CC=C(C=C1)NC(=O)N1CCC2(CC1)CCC(CC2)N(C=1C2=C(N=CN=1)NC=C2)C DCVLNAFSEGHRSD-UHFFFAOYSA-N 0.000 claims description 2
- NKUQNCLCIQSSRV-UHFFFAOYSA-N N-(4-methoxyphenyl)-9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-azaspiro[5.5]undecane-3-carboxamide Chemical compound COC1=CC=C(C=C1)NC(=O)N1CCC2(CC1)CCC(CC2)N(C=1C2=C(N=CN=1)NC=C2)C NKUQNCLCIQSSRV-UHFFFAOYSA-N 0.000 claims description 2
- BYGYNEAFWJJNLV-UHFFFAOYSA-N N-(5-cyanopyridin-2-yl)-9-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3-azaspiro[5.5]undecane-3-carboxamide Chemical compound C(#N)C=1C=CC(=NC=1)NC(=O)N1CCC2(CC1)CCC(CC2)N(C=1C2=C(N=CN=1)NC=C2)C BYGYNEAFWJJNLV-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
本发明提供一种具有下式(I)的JAK抑制剂：
Description
本申请要求优先于2018年3月21日提交的第62/646167号美国临时专利申请，该申请以引用的方式并入本申请中，如同在本申请中充分阐述的那样。
技术领域
本发明涉及某些抑制Janus激酶(JAKs)活性并可用于治疗与JAKs活性相关的疾病的某些新化合物，或医药上可接受的盐及其组合物和使用方法，包括例如炎症性疾病、自身免疫性疾病、癌症，以及其他疾病。
背景技术
Janus激酶(Janus kinases，JAKs)是细胞内非受体酪氨酸激酶家族，通过JAK-STAT途径介导细胞因子介导的信号。已知的四个哺乳动物JAK家族成员是：Janus激酶1(JAK1)、Janus激酶2(JAK2)、Janus激酶3(JAK3)和酪氨酸激酶2(TYK2)。
JAK/STAT通路，尤其是四种JAK通路，被认为在哮喘反应、慢性阻塞性肺疾病、支气管炎和其他下呼吸道相关炎症性疾病的发病机制中起作用。通过JAKs发出信号的多种细胞因子与炎症性疾病/上呼吸道疾病有关，例如那些影响鼻腔和鼻窦的疾病，无论是否典型的过敏反应。
JAK1在调节生物反应中起着重要作用，JAK1广泛表达并与几种主要的细胞因子受体家族相关。参与IL-2受体家族成员(IL-2、IL-4、IL-7R、IL-9R、IL-15R和IL-21R)、IL-4受体家族(IL-4R、IL-13R)、gp130受体家族和II类细胞因子受体的信号传导。JAK1还介导信号转导子和转录激活子3，STAT3的激活。持续的STAT3激活是致瘤的，并促进癌细胞的生存和增殖。为了开发新的、更有效的针对免疫和炎症途径的药物，以及用于预防和治疗自身免疫性疾病、过度活跃的炎症反应、过敏、癌症和其他疗法引起的一些免疫反应的药物，需要抑制JAK1。抑制JAK1可以阻断STAT3的激活，从而抑制肿瘤生长和肿瘤免疫监视。此外，激活的JAK1突变在T系急性淋巴细胞白血病和亚洲肝细胞癌中都被发现，并被证明是致癌的。
众所周知，JAK2可形成同型二聚体，介导EPO和TPO受体信号传导至STAT5通路，后者调节红细胞和血小板的生成。JAK2的抑制可导致贫血和血小板减少。
JAK1和JAK2具有高度的结构相似性。JAK1抑制剂也可以抑制JAK2。选择性抑制JAK1的化合物可能比选择性抑制JAK2或JAK1/2双重抑制剂的化合物具有更好的肝毒性和免疫原性。
仍然需要提供选择性抑制JAK1和减少或避免JAK2和JAK3抑制的JAK1抑制剂。本发明的化合物以及本文所述的其组合物和方法针对这些需要和其他目的。
发明内容
本发明提供一种JAK抑制剂，其为结构式(I)的化合物，或其医药上可接受的盐、前药、水合物或其溶剂化物。
在结构式(I)中，n是0-5的整数；
A、B，C，D，E独立地为N或C-R5，并强调这里的B不代表硼原子，C不代表碳原子；
R5选自氢、氘、卤素、羟基、氨基、硝基、氰基、-SO2NH2、-SONH2、-NHOH、-CONH2、-OR5a、-N(R5a)2和-SR5a；或R5选自烷基、环烷基、烷氧基、烷基硫基、烷基磺酰基、杂环基、芳基、杂芳基、-CF3、-CF2H、-OCF3、-OCF2H，用1到5个氟取代的C1-6烷基，用1到5个氟取代的C3-6环烷基，用1到5个氟取代的C1-4烷氧基，用1到5个氟取代的C1-4烷基硫酰基，1到5个氟取代的C1-4烷基磺酰基，羧基，C1-4烷基氧羰基和C1-4烷基羰基；
R5a选自烷基、环烷基、烷氧基、烷基硫基、烷基磺酰基、杂环基、芳基、杂芳基、-CF3、-CF2H、-OCF3、-OCF2H、C1-6烷基，任选被一到五个氟取代、C3-6环烷基，可含有一至五个独立的氟取代基，C1-4烷氧基，可含有一至五个独立的氟取代基、C1-4烷硫基，可含有一至五个独立的氟取代基、C1-4烷基磺酰基，可含有一至五个独立的氟取代基、羧基、C1-4烷氧基羰基，和C1-4烷基羰基；
R2、R3和R4独立地选自氢、烷基、烯基、炔基、环烷基、环烯基、环烷基烷基、环烷基烯基、环烷基炔基、环烯基烷基、环烯基烯基、环烯基炔基、杂环基、杂环烷基、杂环烯基、杂环炔基、芳基、芳烷基、芳基烯基、芳基炔基、芳基环烷基、芳氧基烷基、芳氧环烷基，杂芳基、杂芳基烷基、杂芳基烯基、杂芳基炔基、杂芳基环烷基、杂芳氧基烷基，和杂芳氧环烷基，这些基团中的任一个可任选被一个或多个R2a取代；
R2a选自卤素、氰基、羟基、氧代基、氨基、-NH2，-SO2NH2，-SONH2，-CONH2、烷基，烯基，炔基，环烷基，环烯基，杂环基，R2bO-L-，R2bS-L-，(R2b)2N-L-，R2b-C(＝O)L-，R2b-C(＝O)-L-，(R2b)2N-C(＝O)-L-，R2b-C(＝O)N(R2b)-L-，R2bO-C(＝O)N(R2b)-L-，(R2b)2NC(＝O)N(R2b)-L-，R2b-C(＝O)O-L-，R2bO-C(＝O)O-L-，(R2b)2N-C(＝O)O-L-，R2bO-S(＝O)2-L-，(R2b)2N-S(＝O)2-L-，R2b-S(＝O)2N(R2b)-L-，R2b-S(＝O)2N(R2b)-L-，(R2b)2N-S(＝O)2N(R2b)-L-，R2bS(＝O)2O-L-，R2b-S(＝O)2O-L-，(R2b)N-S(＝O)2O-L-，芳基，芳氧基，杂芳基和杂芳基氧基；
R2b独立地选自烷基，烯基，炔基，环烷基，杂环基，芳基和杂芳基；
R1是氢，烷基，杂烷基，芳基，芳氧基，杂芳基或杂芳氧基，其可以任选地被一个或多个R1a取代，其中任何两个R1a与它们所连接的环原子一起形成环烷基或杂环，并且两个R1a连接至相同的C原子或两个不相邻的C原子；R1a独立地选自卤素，氰基，羟基，氧代，-NH2，-SO2NH2，-SONH2，-CONH2，烷基，烯基，炔基，烯基烷基，炔基烷基，环烷基，环烯基，环烷基烷基，环烷基烯基，杂环基，R1bO-L-，R1bS-L-，(R1b)2N-L-，R1b-C(＝O)L-，R1b-C(＝O)-L-，(R1b)2N-C(＝O)-L-，R1b-C(＝O)N(R1b)-L-，R1bO-C(＝O)N(R1b)-L-，(R1b)2NC(＝O)N(R1b)-L-，R1b-C(＝O)O-L-，R1bO-C(＝O)O-L-，(R1b)2N-C(＝O)O-L-，R1bO-S(＝O)2-L-，(R1b)2N-S(＝O)2-L-，R1b-S(＝O)2N(R1b)-L-，R1b-S(＝O)2N(R1b)-L-，(R1b)2N-，S(＝O)2N(R1b)-L-，R1bS(＝O)2O-L-，R1b-S(＝O)2O-L-，(R1b)N-S(＝O)2O-L-，芳基，芳氧基，杂芳基和杂芳基氧基；
R1b独立地选自烷基，烯基，炔基，环烷基，杂环基，芳基和杂芳基；
L为共价键或是在各种情况下独立地选自烷基、环烷基、烷基环烷基和环烷基；
X是一个共价键或X是-C(＝O)-，-S(＝O)-，-S(＝O)2-，-C(＝O)O-，-C(＝O)NH-，-S(＝O)NH-，-S(＝O)2NH-，
在另一个实施方案中，在式(I)中，n为1和2。
在另一个实施方案中，在式(I)中，R3和R4均为氢。
在另一个实施方案中，在式(I)中，R5是氢。
在另一个实施方案中，在式(I)中，R2是烷基。
在另一个实施方案中，在式(I)中，Xis-C(＝O)-，-S(＝O)-，-S(＝O)2-，-C(＝O)O-，-C(＝O)NH-，-S(＝O)NH-，-S(＝O)2NH-。
在另一个实施方案中，在式(I)中，其中R1是
或者/>
其中m是1-3的整数；并且R1a独立地选自卤素，氰基，羟基，-NH2，-SO2NH2，-SONH2，-CONH2，烷基，烯基，炔基，烯基烷基，炔基烷基，环烷基，环烷基烷基，环烷基烯基，杂环基，芳基，芳氧基，杂芳基和杂芳氧基。
在另一个实施方案中，在式(I)中，其中R1是
在另一个实施方案中，在式(I)中，其中R1是
m是1-3的整数；R1a选自卤素，氰基，羟基，-NH2，-SO2NH2，-SONH2，-CONH2，烷基，烯基，炔基，烯基烷基，炔基烷基，环烷基，环烯基，环烷基烷基，环烷基烯基，杂环基，芳基，芳氧基，杂芳基和杂芳基氧基。
在另一个实施方案中，在式(I)中，A和B是CH，C是N，D是CH，并且E是N。
在另一个实施方案中，式(I)的化合物选自2-氟-4-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)苯腈；3-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)-3-氧代丙腈；2-羟基-1-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)乙酮；1-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)乙酮；1-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)丙烷-1-酮；N-(2-(乙磺酰基)-2-氮杂螺环[3.3]庚烷-6基)-N-甲基-7H-吡咯并[2，3-d]嘧啶-4-胺；6(甲基(7H吡咯并[2，3-d]嘧啶-4-)氨基)-2-氮杂螺环[3.3]-庚烷-2-羧酸甲酯；乙基6-(甲基(7H吡咯并[2，3-d]嘧啶-4-)氨基)-2-氮杂螺环[3.3]庚烷-2-羧酸乙酯；(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)(吡啶-3-基)甲烷酮；(4-6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)-4-氧代丁腈；3-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]正庚烷-2-羰基)苯腈；(4-6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]正庚烷-2-羰基环己酮；(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)(3-(三氟甲基)苯基)甲烷酮；3-氟-4-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]正庚烷-2-羰基)苯腈；4-(2-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)-2-氧代乙基)苯腈；1-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)-3-(甲磺酰基)丙烷-1-酮；6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)(3-(三氟甲氧基)苯甲基酮)；(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)吡嗪-2-基)甲基酮；1-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)环丙烷腈；苯并[b]噻吩(6-(甲基(7H吡咯并[2，3-d]嘧啶-4-)氨基)-2-氮杂螺环[3.3]庚烷-2-基甲基酮；4，4，4-三氟-1-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)-1-酮丁烷；苯并[b]噻吩-3-基(6-(甲基(7H吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺环[3.3]庚烷-2-基)甲基酮)；2-(1H-吲哚-3-基)-1-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)乙酮；(4-甲氧基苯基)(6-(甲基(7H吡咯并[2，3-d]嘧啶-4-)氨基)-2-氮杂螺环[3.3]庚烷-2-基)甲基酮)；(4-氯苯基)(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)甲基酮；4-乙炔基苯基)(6-(甲基(7H吡咯并[2，3-d]嘧啶-4-)氨基)-2-氮杂螺环[3.3]庚烷2-基)甲基酮；(4-氟苯基)(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)甲基酮；(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)(3-噻吩-2-基)甲基酮；6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)-(6-甲基吡嗪-2-基)甲基酮；吲哚-2-基)-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)甲基酮；(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)(4-(三氟甲基)苯基)甲基酮；(五氯吡啶-2-基)-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)甲基酮；N-(3-氯苯基)-6-甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]正庚烷-2-甲酰胺；2-甲基-4-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]正庚烷-2-羰基)苯腈；5-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]正庚烷-2-羰基)腈吡啶；2-氯-4-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]正庚烷-2-羰基)苯腈；3-氯-4-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]正庚烷-2-羰基)苯腈；(4-碘苯基)(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)甲基酮；4-苯基环丙基)(6-(甲基(7H吡咯并[2，3-d]嘧啶-4-)氨基)-2-氮杂螺环[3.3]庚烷2-基)甲基酮；(4-乙炔基-3-甲基苯基)-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)甲基酮；(4-乙炔基-2-氟苯基)(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基]氨基)-2-氮杂螺[3.3]庚-2-基)甲酮；(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)(4-(1-塞YN-1-基)苯基)甲基酮；(2-氯-4-乙炔基苯基)(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基]氨基)-2-氮杂螺[3.3]庚-2-基)甲酮；3-甲基-4-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)苯腈；(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚-2-基)(1H-吡唑-3-基)甲酮；(3-氯-4-乙炔基苯基)(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基]氨基)-2-氮杂螺[3.3]庚-2-基)甲酮；(4-乙炔基-3-氟苯基)(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基]氨基)-2-氮杂螺[3.3]庚-2-基)甲酮；(5-乙炔基吡啶-2-基)(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基]氨基)-2-氮杂螺[3.3]庚-2-基)甲酮；(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基]氨基)-2-氮杂螺[3.3]庚-2-基)(1-甲基-1H-苯并[d]咪唑-5-基)甲酮；(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚-2-基)(1-甲基-1H-吡唑-3-基)甲酮；2，5-二氟-4-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)苯腈；2，6-二氟-4-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)苯腈；2，3-二氟-4-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)苯腈；5-氟-2-甲基-4-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)苯腈；(2，3-二氟苯基)(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基]氨基)-2-氮杂螺[3.3]庚-2-基)甲酮；3，5-二氟-4-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)苯腈；2-氟-5-{6-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-2-氮杂-螺[3.3]庚烷-2-羰基}-苯腈；3-氟-5-{6-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基]-氨基]-2-氮杂-螺[3.3]庚烷-2-羰基}-苯腈；2，5-二氟-4-{6-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-2-氮杂-螺[3.3]庚烷-2-羰基}-苯腈；2，3-二氯-4-{6-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-2-氮杂-螺[3.3]庚烷-2-羰基}-苯腈；2，6-二氟-3-{6-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-2-氮杂-螺[3.3]庚烷-2-羰基}-苯腈；2，3-二氟-5-{6-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-2-氮杂-螺[3.3]庚烷-2-羰基}-苯腈；3，4-二氟-5-{6-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-2-氮杂-螺[3.3]庚烷-2-羰基}-苯腈；(4-乙炔基-3-氟-苯基)-{6-[-[3氘代甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-2-氮杂螺[3.3]庚-2-基}-甲酮；2-氟-4-{6-[-[3氘代甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-2-氮杂-螺环[3.3]庚烷-2-羰基}-苯腈；(4-丙-1-炔基-3-氟-苯基)-{6-[-[(3氘代甲基)-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-2-氮杂螺[3.3]庚-2-基}-甲酮；3，4-二氟-5-{6-[3氘代甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-2-氮杂-螺[3.3]庚烷-2-羰基}-苯腈；6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基]氨基)-2-氮杂螺[3.3]庚-2-基)(4-(1-甲基-1H-吡唑-3-基)苯基)甲酮；(1-环丙基-1H-吡唑-4-基)-{6-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-2-氮杂螺[3.3]庚烷-2-基}-甲酮；N-(3-甲氧基-1，2，4-噻二唑-5-基)-6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酰胺；4-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)苯磺酰胺；2-甲氧基-1-(9-(甲基(7H-吡咯[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一碳-3-基)乙烷-1-酮；1-{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-乙酮；(3-乙磺酰基-3-氮杂-螺[5.5]十一碳-9-基)-甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-胺；2-羟基-1-{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一-3-基}-乙酮；1-{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-丙-1-酮；甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-[3-(2，2，2-三氟乙基)-3-氮杂螺环[5.5]十一烷基-9-基]-胺；{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基]-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-吡啶-3-基-甲酮；4-{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基]-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-4-氧代-丁腈；4-{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一烷-3-羰基}-环己酮；9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基]-氨基]-3-氮杂-螺[5.5]十一烷基-3-基}-(3-三氟甲基-苯基)-甲酮；3-氟-4-{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-3-氮杂-螺[5.5]十一烷-3-羰基}-苯腈；4-(2-{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基]-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-2-氧-乙基)-苯腈；3-甲磺酰基-1-{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-3-氮杂螺环[5.5]十一-3-基}-丙烷-1-酮；2-氟-4-{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-3-氮杂-螺[5.5]十一烷-3-羰基}-苯腈；{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基]-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-吡嗪-2-基-甲酮；1-{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一烷-3-羰基}-环丙烷甲腈；(6-甲基-吡嗪-2-基)-{9-[甲基-(7H-吡咯[2，3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一-3-基]-甲酮；4，4，4-三氟-1-{9-[甲基-(7H-吡咯[2，3-d]嘧啶-4-基)-氨基]-3-氮杂-螺[5.5]十一-3-基]-丁烷-1-酮；苯并[b]噻吩-3-基-{9-[甲基-(7H-吡咯[2，3-d]嘧啶-4-基)-氨基]-3-氮杂螺[5.5]十一-3-基]-甲酮；2-(1H-吲哚-3-基)-1-{9-[甲基-(7H-吡咯[2，3-d]嘧啶-4-基)-氨基]-3-氮杂-螺[5.5]十一-3-基]-乙酮；{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基]-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-(3-甲基-噻吩-2-基)-甲酮；(1H-吲哚-2-基)-{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-3-氮杂螺[5.5]十一烷基-3-基}-甲酮；(N-甲基-3-(丙基磺酰基)-N-(7H-吡咯并[2，3-d]嘧啶-4-基)-3-氮杂螺[5.5]十一烷基-9-基]-胺；2-甲基氨基-1-{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一-3-基}-乙酮盐酸盐；异丙基9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酸酯；环丙基-{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-甲酮；1-{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-丁-1-酮；{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基]-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-(3-三氟甲氧基-苯基)-甲酮；3-{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一烷-3-羰基}-苯腈；甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-[3-(2，2，2-三氟乙磺酰基)-3-氮杂螺环[5.5]十一烷基-9-基]-胺；3-{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-3-氧代丙腈；苯并[b]噻吩-2-基-{9-[甲基-(7H-吡咯并[2，3-d]嘧啶-4-基]-氨基]-3-氮杂螺[5.5]十一烷基-3-基}-甲酮；9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯；1-(9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-基)-2-苯氧基乙烷-1-酮；2，2，2-三氟乙基9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酸酯；9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-N-(2，2，2-三氟乙基)-3-氮杂螺[5.5]十一烷-3-甲酰胺；N-甲基-9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N，N-二乙基-9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-磺酰胺；4-(9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羰基)苯磺酰胺；3-(9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基]氨基)-3-氮杂螺[5.5]十一烷-3-基)-3-氧丙烷-1-磺酰胺；3-氟-5-(2-(9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基]氨基])-3-氮杂螺[5.5]十一烷-3-基)-2-氧乙氧基)苯腈；4-(2-(9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基]氨基])-3-氮杂螺[5.5]十一烷基-3-基)-2-氧乙氧基)苯腈；3-(2-(9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基]氨基])-3-氮杂螺[5.5]十一烷基-3-基)-2-氧乙氧基)苯腈；2-氟-4-(2-(9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基]氨基])-3-氮杂螺[5.5]十一烷-3-基)-2-氧乙氧基)苯腈；2，3-二氟-4-(2-(9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基]-3-氮杂螺[5.5]十一烷基-3-基)-2-氧乙氧基)苯腈；N-(4-甲氧基苯基)-9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(3-甲氧基苯基)-9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(4-氰基苯基)-9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(3-氰基苯基)-9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(6-氰基吡啶-2-基)-9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(6-甲氧基吡啶-2-基)-9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(5-氰基吡啶-2-基)-9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-甲酰胺；9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-N-(5-甲基噻唑-2-基)-3-氮杂螺[5.5]十一烷-3-甲酰胺；9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-N-(1-甲基-1H-吡唑-3-基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-N-(5-甲基吡嗪-2-基)-3-氮杂螺[5.5]十一烷-3-甲酰胺；N-(5-甲氧基吡嗪-2-基)-9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(5-甲氧基吡啶-2-基)-9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(5-氟噻唑-2-基)-9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(5-氯噻唑-2-基)-9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(5-氯噻唑-2-基)-9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-N-(噻唑-2-基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(5-甲氧基噻唑并[5，4-b]吡啶-2-基)-9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺。
在另一个实施方案中，本发明提供了药物组合物，其包含治疗有效量的式(I)的化合物和药学上可接受的赋形剂。
在另一个实施方案中，本发明提供了一种治疗自身免疫疾病，癌症，肿瘤，炎性疾病或免疫介导的疾病的方法，该方法包括向有需要的受试者施用包含治疗有效量的式(I)的化合物，以及其他治疗剂。
在另一个实施方案中，该方法与选自以下的治疗剂组合施用：抗癌药，类固醇药物，甲氨蝶呤，来氟米特，抗TNFα剂，钙调神经磷酸酶抑制剂，抗组胺药及其混合物。
具体实施方式
本文所述的方法包括向需要的受试者施用包含治疗有效量的一种或多种本文所述的JAK抑制剂化合物的组合物。
前药是指当将这种前药给予哺乳动物受试者时，能够在体内释放化合物式(I)的活性母体药物的任何化合物。式I化合物的前药是通过修饰式I化合物中存在的官能团而制备的，该修饰可以在体内裂解以释放母体化合物。前药可以通过修饰化合物中存在的官能团来制备，使得修饰可以在常规操作中或在体内裂解为母体化合物。
互变异构体是指由分子的一个原子的质子移动到另一个原子的现象产生的化合物。互变异构体还指以平衡存在的两种或多种结构异构体之一，并且容易从一种异构体形式转化为另一种异构体形式。本领域普通技术人员将认识到其它互变异构的环原子排列是可能的。这些化合物的所有这些异构形式明确地包括在本公开内容中。
异构体是指具有相同分子式但其原子键合的性质或顺序或其原子在空间排列方面不同的化合物。在其原子的空间排列上不同的异构体称为立体异构体。彼此不是镜像的立体异构体被称为非对映异构体，彼此不可重叠的镜像的那些被称为对映异构体。当化合物具有不对称中心时，例如，其键合四个不同的基团，一对对映异构体是可能的。手性化合物可以作为单独的对映异构体或作为其混合物存在。除非另外指明，该描述旨在包括单独的立体异构体以及混合物。
本公开的某些化合物可以以非溶剂化物形式以及包括水合形式的溶剂化物形式存在。溶剂合物是指通过溶剂分子与式I化合物的结合而形成的络合物。溶剂可以是有机化合物，无机化合物或其混合物。
药学上可接受的盐表示在医学判断范围内适合用于接触人和低等动物的组织而没有不适当的毒性、刺激和过敏反应等的那些盐，并且具有合理的利益/风险比。它们可以在本发明化合物的最终分离和纯化期间获得，或者通过使游离碱官能团与合适的无机酸如盐酸、磷酸或硫酸，或与有机酸例如抗坏血酸、柠檬酸、酒石酸、乳酸、马来酸、丙二酸、富马酸、乙醇酸、琥珀酸、丙酸、乙酸或甲磺酸等。酸官能团可以与有机或无机碱，如氢氧化钠、氢氧化钾或氢氧化锂反应。
治疗有效量是指有效抑制布鲁顿酪氨酸激酶并因此产生所需治疗效果的本发明化合物或组合物的量。
如本文所用，术语烷基是指具有在指定范围内的碳原子数的单价直链或支链的饱和脂族烃基。例如，烷基是指任何的己基烷基和戊基烷基异构体以及正，异，仲和叔丁基，正和异丙基，乙基和甲基。烷基还包括饱和的脂族烃基，其中一个或多个氢被氘取代，例如CD3。
术语支链烷基是指如上定义的烷基，除了在指定范围内的直链烷基。如本文所定义，支链烷基包括烷基通过仲碳或叔碳连接到化合物其余部分的烷基化合物。例如：异丙基是支链烷基。
术语环烷基是指具有在指定范围内的碳原子数的烷烃的任何单环。例如，环烷基是指环丙基，环丁基，环戊基和环己基。
术语卤素是指氟、氯、溴和碘(或者称为氟基、氯基、溴基和碘基)。
术语卤代烷基是指其中一个或多个氢原子已被卤素(即，F，Cl，Br和/或I)取代的上述烷基。例如，卤代烷基是指具有一个或多个卤素取代基的如上所定义的直链或支链烷基。术语氟代烷基具有类似的含义，除了卤素取代基限于氟。合适的氟代烷基包括(CH2)0- 4CF3系列
术语C(O)或CO是指羰基。术语S(O)2或SO2是指磺酰基。
术语S(O)或SO是指亚磺酰基。
术语芳基是指苯基，萘基，四氢萘基，异戊二烯基，二氢茚基等。特别关注的芳基是苯基。
术语杂芳基是指(i)含有1至4个独立地选自N，O和S的杂原子的5或6元杂芳族环，或(ii)是选自喹啉基，异喹啉基和喹喔啉基的杂双环。例如，合适的5元和6元杂芳族环包括，吡啶基(也称为吡啶基)，吡咯基，吡嗪基，嘧啶基，哒嗪基，三嗪基，噻吩基，呋喃基，咪唑基，吡唑基，***基，四唑基，恶唑基，异恶唑基，氧杂***基，噻唑基，异噻唑基和噻二唑基。感兴趣的杂芳基类由(i)含有1-3个独立地选自N，O和S的杂原子的5-和6-元杂芳族环和(ii)选自喹啉基，异喹啉基和喹喔啉基的杂双环组成。
特别感兴趣的杂芳基是吡咯基，咪唑基，吡啶基，吡嗪基，喹啉基(或喹啉基)，异喹啉基(或异喹啉基)和喹喔啉基。在本发明范围内的4至7元饱和杂环的实例包括如氮杂环丁烷基，哌啶基，吗啉基，硫吗啉基，噻唑烷基，异噻唑烷基，恶唑烷基，异恶唑烷基，吡咯烷基，咪唑烷基，哌嗪基，四氢呋喃基、六氢嘧啶基，噻嗪基，硫氮杂环庚烷基、氮杂环庚烷基、二氮杂环庚烷基、四氢吡喃基、四氢噻喃基和二氧杂环己烷基。在本发明范围内的4至7元不饱和杂环的实例包括与前述句中列出的饱和杂环相对应的单不饱和杂环，其中单键被双键取代(例如，碳-碳单键替换为碳-碳双键)。
应当理解的是，上面列出的特定环不限制可用于本发明的环。这些环仅仅是代表性的。在以下方案，方法和实施例中说明了制备本发明化合物的合成方法。起始原料是可商购的，或者可以根据本领域已知的方法或本文所述的方法制备。
通过下面所示的具体实施例说明本发明的化合物。然而，这些具体实施例不应被解释为本发明的唯一种类。这些实施例进一步说明了制备本发明化合物的细节，本领域技术人员将容易地理解，可以使用这些条件和方法的已知变化来制备这样的化合物。
本发明提供具有通式(I)的JAK抑制剂化合物结构式：
结构式I中JAK抑制剂化合物可以通过有机化学领域中熟知的方法来制备。用于这些化合物合成的起始原料既可以合成又可以从商业来源获得。但不局限于购自中国化学试剂公司或Sigma-Aldrich中国分公司。本文所述的化合物，以及使用的技术、材料和具有不同取代基的其它相关化合物的合成可以在下面专业书中得到描述，例如：高等有机化学第4版，(1992威利)；凯里和桑德博格，高等有机化学第4版，A卷和B卷(普利纳姆2000、2001年)；菲泽和菲泽的有机合成试剂，1-17卷(约翰威利父子，1991年)；罗德碳化合物，第1-5卷和增刊(Elsevier科学出版社，1989)；有机反应，1-40卷(约翰威利父子，1991年)；Larock综合有机转化(VCH出版公司，1989)。本文所述的化合物的其它合成方法可以在国际专利WO2011/003418 A1中找到，也可以在迪莫克铝等的未来的药物化学(2014)6(12)，1439-1471中找到。本申请中使用化学术语的定义可以在这些参考中找到(如果本文没有另外定义)。作为指导，以下合成方法也可以使用。
在合成步骤中，也许有必要或希望保护所涉及的任何分子中敏感或反应性基团，这通常需要用常规的保护基，诸如那些在T.W Greene和P.G.M.Wutts“有机合成中的保护基”第3版，John Wiley&Sons，1999描述的方法来实现；保护基可以选择性地在适当的阶段中用熟知的方法除去。反应的产物是可以分离和纯化的，如果需要的话，使用常规技术，但不限于，过滤、蒸馏、结晶、色谱等。这些化合物可用常规手段，包括物理常数和光谱数据来表征。
本文描述的化合物可以具有一个或多个手性中心并且每个中心可以存在R或S构型。本文提供的化合物包括所有非对映体、对映体和差向异构体以及其适当的混合物。
例如，式(I)的JAK抑制剂化合物可以是6-(1-氮杂基)-2-氮杂螺[3.3]庚烷衍生物，其可以通过方案I所示的一般合成路线来制备。
方案I
参照方案I，将不同的市售化合物或由市售分子转化为酮(A)，其中PG为保护基(例如BOC，苄基等)。通过中间体亚胺将羰基转化为胺，该中间体可用合适的还原剂(例如硼氢化钠)还原，接下来在DMF为溶剂，碳酸钾为碱的条件下取代吡咯并嘧啶F上的Cl，得到取代产品C，然后(a)在酸性条件下进行Boc保护基的脱保护反应，以及(b)在氢解下进行苄基型保护基的脱保护反应，得到中间体D。
在通式D的化合物中引入X-R1，可以使通式D的化合物与合适的X-R1的衍生物在偶联条件下，得到化合物E。例如R1的异氰酸酯衍生物，R1的异硫氰酸酯衍生物，R1的磺酰卤化物或酯衍生物，亚磺酰基卤化物，R1的酯衍生物，R1的羧酸衍生物以及具有合适的羰基化剂的R1的胺衍生物。
应当理解，前面的一般描述和下面的详细描述都是示例性和解释性的，并且旨在提供对所要求保护的本发明的进一步解释。
通用的实验条件：
制备薄层层析色谱(PTLC)是在20x20厘米板上进行(500微米厚的硅胶)。硅胶色谱法是在Biotage Horizon快速色谱***上进行的。1H NMR光谱是在298°K下于400MHz的Bruker Ascend TM 400光谱仪上记录，化学位移以相对于氘代溶剂的残留质子信号的百万分率(ppm)表示：δ＝7.26ppm的CDCl3且δ＝3.30ppm的CH3OH或CH3OD。LCMS光谱是在安捷伦1260 Infinity或6120四极杆光谱仪上获得的。
质谱(MS)采用电喷雾离子质谱(ESI)。所有的温度是摄氏度，除非另有说明。
HPLC分析的质谱条件：LC1：柱：SB-C1850mm×4.6mm×2.7μm/多孔壳120EC-C183.0X50mm 2.7微米；检测器：DAD；检测波长：214nm 254nm 280nm；溶剂：A：MEOH B：0.1％FA的H2O溶液；片长：8分钟；干燥气体流量12.01/min；雾化器压力35psig；干燥气体温度250。
梯度：
英文缩写词列表：
AcOH＝乙酸；烷基＝烷基；Ar＝芳基；Boc＝叔丁氧羰基；bs＝宽的单峰；CH2Cl2＝二氯甲烷；d＝双重峰；dd＝两个双重峰；DBU＝1，8-二氮杂双环[5.4.0]十一碳-7-烯；DCM＝二氯甲烷；DEAD＝偶氮二羧酸二乙酯；DMF＝N，N-二甲基甲酰胺；DMSO＝二甲基亚砜；EA＝乙酸乙酯；ESI＝电喷雾电离；Et＝乙基；EtOAc＝乙酸乙酯；EtOH＝乙醇；h＝小时；HOAc＝乙酸；LiOH＝氢氧化锂；m＝多重峰；Me＝甲基；MeCN＝乙腈；MeOH＝甲醇；MgSO4＝硫酸镁；min＝分钟；MS＝质谱；NaCl＝氯化钠；NaOH＝氢氧化钠；Na2SO4＝硫酸钠；NMR＝核磁共振谱；PE＝石油醚；PG＝保护基；Ph＝苯基；rt＝室温；s＝单峰；t＝三重峰；TFA＝三氟乙酸；THF＝四氢呋喃；Ts＝对甲苯磺酰基(甲苯磺酰基)。
本发明的化合物可以通过以下详述的通用方法制备。在某些实施方案中，本文提供的是制备本文所描述的酪氨酸激酶抑制剂化合物的方法。在某些实施方案中，本文描述的化合物是使用下面的合成方案合成。在其他实施方案中，化合物合成使用下面描述的类似方法合成，只是起始原料不同。所有关键中间体也是按照下列方法制备。
实施例1：2-氟-4-(6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)苯腈
步骤A：6-(甲基氨基)-2-氮杂螺[3.3]庚烷-2-羧酸叔丁酯(2)
25℃下，向1的(10g，0.048mol)甲醇溶液(100mL)中加入甲胺醇溶液(9.8g，0.095mol)，反应混合物在此温度下搅拌15小时。然后分小批加入硼氢化钠(3.6g，0.095mol)，在25℃下搅拌2小时，TLC监测表明反应已进行完全。因此，将其倒入氯化铵水溶液(100mL)中，浓缩，EtOAc(3×100mL)萃取，将合并的有机相用饱和盐水洗涤，有机层减压浓缩，残余物通过柱色谱纯化，得到2(9.5g，收率：88％)为无色油。MS：m/z[M+H]+227.3。
步骤B.叔丁基6-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酸盐(3)
将2(9.5g，0.042mol)，K2CO3(11.6g，0.084mol)和4-氯-7H-吡咯并[2，3-d]嘧啶(6.4g，0.042mol)的DMF(100mL)混合物加热到90℃，并搅拌15小时。TLC监测反应，显示反应混合物完全耗尽。然后将反应混合物倒入水(200mL)中，用乙酸乙酯(3×100mL)萃取，合并的有机相用饱和盐水洗涤，减压浓缩有机层，残余物通过柱色谱法纯化，得到3(9.8g，产率：68％)，为黄色固体。MS：m/z[M+H]+344.3。
步骤C：N-甲基-N-(2-氮杂螺[3.3]庚-6-6基)-7H-吡咯并[2，3-d]嘧啶-4-胺(4)
向3(9.8g，0.029mol)的MeOH(50mL)悬浮液中逐滴加入EtOAc(4M，50mL)的盐酸盐，并搅拌15小时。浓缩反应混合物，将残余物溶于EtOH和水中，然后用饱和碳酸钠水溶液将其调节至pH＝8，减压浓缩有机相，将残余物通过柱色谱法纯化(DCM∶MeOH＝20∶1至2∶1)得到黄色固体状的4(4.0g，产率：57％)。
1H NMR(600MHz，DMSO)δ11.69(s，1H)，8.10(s，1H)，7.15(s，1H)，6.61(s，1H)，5.12(m，1H)，4.08(s，2H)，3.92(s，2H)，3.21(s，3H)，2.48(d，J＝11.4Hz，4H).MS：m/z[M+H]+244.3。
步骤D：2-氟-4-(6-(甲基(7H吡咯并[2，3-d]嘧啶-4-)氨基)-2-氮杂螺环[3.3]
庚烷-2-羰基)苯腈(5)
25℃下，向4(2g，8mmol)，4-氰基-3-氟苯甲酸(1.32g，8mmol)和TEA(1.7g，16mmol)的DCM(200mL)溶液中分小批加入HATU(3.65g，9.6mmol)，并搅拌16小时，TLC监测反应已完成。用水(100mL)洗涤，减压浓缩有机相，将残余物通过柱色谱法纯化(DCM∶MeOH＝50∶1)，得到目标化合物5(800mg，收率25％)，为白色固体。1H NMR(600MHz，D6-DMSO)δ11.67(s，1H)，8.08(m，2H)，7.74(t，J＝8.6Hz，1H)，7.64(dd，J＝12.1，8.5Hz，1H)，7.15(m，1H)，6.60(d，J＝7.7Hz，1H)，5.14(ddt，J＝53.9，16.9，8.4Hz，1H)，4.49(s，1H)，4.32(s，1H)，4.23(s，1H)，4.08(s，1H)，3.22(d，J＝8.9Hz，3H)，2.47(s，5H).MS：m/z[M+1]+391.1。
如示例1所详述用上面的一般方法制备了如下表所示例子2-71。
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实施例72：2-甲氧基-1-(9-(甲基(7H-吡咯[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一碳-3-基)乙烷-1-酮
步骤A：9-(甲基氨基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(2)
在冷却条件下，向6-氧代-2-氮杂螺并[3.3]庚烷-2-甲酸叔丁酯(1，3.0g，11.22mmol)的MeOH(40mL)混合物中加入30％MeNH2的MeOH(5.8g，56.10mmol)溶液。在25℃下，将所得混合物在N2下搅拌5小时，并冷却至-10℃，然后分批少量加入NaBH4(0.85g，22.40mmol)，将反应混合物在室温搅拌3小时。TLC显示起始混合物被消耗。反应混合物用饱和NaHCO3淬灭。NH4Cl(25mL)，减压除去溶剂。用柠檬酸盐溶液(50mL)将残余物的pH调节至3。水层用EA(20mL×2)洗涤，用30％NaOH碱化至pH＝10，并用EA(50mL×3)萃取。有机相用盐水洗涤，经Na2SO4干燥并过滤，浓缩滤液，得到所需产物2(3.1g，95.7％)，为无色油状。1H NMR(400MHz，CDCl3)：δ3.40-3.30(m，4H)，2.42(s，3H)，2.33(dd，J＝11.7，7.9Hz，1H)，1.80-1.64(m，4H)，1.47(d，J＝11.9Hz，12H)，1.33-1.28(m，2H)，1.19(dd，J＝24.5，13.3Hz，4H)。
步骤B：9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(3)
将2(1.55g，5.50mmol)，4-氯-7H-吡咯并[2，3-d]嘧啶(0.85g，5.50mmol)和碳酸钠(1.20g，11.0mol)的n-BnOH(30mL)的混合物在氮气下于120℃搅拌16小时。将反应混合物冷却至室温，加入二氯甲烷(150mL)。有机相用盐水(50mL×2)洗涤，经Na2SO4干燥并过滤。浓缩滤液。残余物用EA重结晶，得到期望的产物3(1.5g，68.3％)，为白色固体。1H NMR(400MHz，CDCl3)：δ8.07(s，1H)，7.07(d，J＝3.6Hz，1H)，6.60(d，J＝3.6Hz，1H)，4.66(d，J＝11.6Hz，1H)，3.42(d，J＝4.6Hz，4H)，3.28(d，J＝19.4Hz，3H)，1.88(d，J＝12.1Hz，4H)，1.70-1.57(m，4H)，1.46(s，9H)，1.42-1.29(m，4H).LC-MS：(ES+)：m/z 400.3[M+H]+.tR＝1.92min。
步骤C：N-甲基-N-(7H-吡咯并[2，3-d]嘧啶-4-基)-3-氮杂螺[5.5]十一烷9-胺2，2，2-三氟乙酸盐(4)
向9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(3，50mg，0.125mmol的DCM(2.0mL)的混合物中加入TFA(1.0mL)，并将其在室温下搅拌1小时。浓缩反应混合物，得到粗产物4(60mg)。LC-MS：(ES+)：m/z300.2[M+H]+。tR＝0.92分钟。
步骤D：2-甲氧基-1-(9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-基)乙烷-1-酮(5)
在-40℃下，向粗产物4(0.125mmol)和三乙胺(36mg，0.36mmol)的二氯甲烷(2.0mL)混合物中滴加2-甲氧基乙酰氯(13mg，0.125mmol)的二氯甲烷(1.0mL)溶液。将反应混合物在室温下搅拌1小时。加入二氯甲烷(50mL)，有机相用5％碳酸氢钠溶液(20mL)，盐水(20mL)洗涤，经硫酸钠干燥并过滤。将滤液浓缩并通过Prep-TLC纯化(DCM/MeOH＝20/1)，得到所需产物5(15mg，32.2％)。1H NMR(400MHz，CDCl3)：δ11.45(s，1H)，8.32(s，1H)，7.06(d，J＝3.0Hz，1H)，6.47(s，1H)，4.77(s，1H)，4.11(d，J＝3.3Hz，2H)，3.60(s，2H)，3.44(s，5H)，3.27(s，3H)，1.93-1.61(m，8H)，1.41(s，4H).LC-MS：(ES+)：m/z 372.3[M+H]+.tR＝0.37min。
实施例73：9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酸甲酯
在室温下向通过与实施例72相同的方法制得的1(0.2g，0.67mmol)和TEA(0.135g，1.3μL)的DCM(30mL)溶液中加入碳酰氯甲酯(0.06g 0.67μL)，搅拌15小时。TLC监测，直到反应完成为止，将反应混合物用水(10mL)洗涤，减压浓缩有机层，残余物通过柱色谱法纯化(DCM∶MeOH＝50∶1)得到目标化合物(50mg，产率：25％)，为白色固体。1H NMR(600MHz，DMSO)δ11.60(s，1H)，8.09(s，1H)，7.11(m，1H)，6.53(s，1H)，4.67(s，1H)，3.58(s，3H)，3.35(dd，J＝8.4，4.5Hz，4H)，3.18(s，3H)，1.77(dd，J＝25.7，12.8Hz，4H)，1.50(m，4H)，1.28(dd，J＝16.9，9.8Hz，4H).MS：m/z[M+H]+357.1。
实施例74：N-(3-甲氧基-1，2，4-噻二唑-5-基)-9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺
步骤A：4-硝基苯基(3-甲氧基-1，2，4-噻二唑-5-基)氨基甲酸酯(2)
将3-甲氧基-1，2，4-噻二唑-5-胺(1)(104mg，0.8mmol)，DMAP(10mg，0.8mmol)的吡啶(5mL)溶液冷却至0℃，然后加入4-硝基苯基碳氯化物(160mg，0.8mmol)，将混合物在0℃下搅拌0.5小时。将反应混合物加热至室温，并进一步搅拌20小时。TLC显示几乎没有残留SM。加入水(10mL)，并将得到的悬浮液过滤。用水和Et2O洗涤滤饼。干燥得白色固体2(100mg)。
步骤B：N-(3-甲氧基-1，2，4-噻二唑-5-基)-9-(甲基(7H-吡咯并[2，3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺(4)
向3(45mg，0.15mmol)，TEA(45mg，0.45mmol)的DMF(2mL)溶液中加入2(44mg，0.15mmol)。将混合物搅拌16小时。将反应混合物浓缩并将残余物通过HPLC法纯化，得到4(14mg)，为白色固体。1HNMR(400MHz，DMSO-d6)：δ12.62(s，1H)，11.69(s，1H)，8.34(s，1H)，7.43(s，1H)，6.84(s，1H)，4.43(s，1H)，3.90(s，3H)，3.53(s，4H)，3.32(s，3H)，1.87-1.84(m，4H)，1.64-1.59(m，4H)，1.36-1.31(m，4H).LCMS：(ES+)：m/z 457.2[M]+，tR＝1.50min。
如示例1、72、73和74所详述的一般方法制备了如下表所示例子75-135。
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JAK激酶活性分析：
整个分析过程在384孔板中进行，反应体系为25μL，反应成分包括JAK1激酶(10nM)、底物(荧光标记的小肽，5-FAM-EEPLYWSFPAKKK-CONH2，3μM)、ATP(76.5μM)、反应缓冲液(20mM HEPES(pH 7.5)，10mM MgCl2，0.01％TritonX-100，0.01％Brij35，0.5mM EGTA和2mM DTT)、抑制剂(浓度梯度，1％DMSO)，混合反应各组分，室温静置120分钟，添加30μL反应终止液(50mM EDTA)终止反应。最后，使用Caliper EZ ReaderII读取并计算抑制剂影响底物磷酸化的比例(不加酶抑制剂的反应结果为阴性对照100％，加过量抑制剂的反应结果为阳性对照)，以抑制百分比为纵坐标，抑制剂浓度为横坐标，绘制剂量效应曲线，求出IC50。
JAK2激酶活性分析
整个分析过程在384孔板中进行，反应体系为25μL，反应成分包括JAK2激酶(0.25nM)、底物(荧光标记的小肽，5-FAM-EEPLYWSFPAKKK-CONH2，3μM)、ATP(11.4μM)、反应缓冲液(50mM HEPES(pH 7.5)，10mM MgCl2，0.01％TritonX-100，0.01％Brij35，0.5mMEGTA和2mM DTT)、抑制剂(浓度梯度，1％DMSO)，混合反应各组分，室温静置15分钟，添加30μL反应终止液(50mM EDTA)终止反应。最后，使用Caliper EZ ReaderII读取并计算抑制剂影响底物磷酸化的比例(不加酶抑制剂的反应结果为阴性对照100％，加过量抑制剂的反应结果为阳性对照)，以抑制百分比为纵坐标，抑制剂浓度为横坐标，绘制剂量效应曲线，求出IC50。
JAK3激酶活性分析
整个分析过程在384孔板中进行，反应体系为25μL，反应成分包括JAK3激酶(0.5nM)、底物(荧光标记的小肽，5-FAM-EEPLYWSFPAKKK-CONH2，3μM)、ATP(3.5μM)、反应缓冲液(50mM HEPES(pH 7.5)，10mM MgCl2，0.01％TritonX-100，0.01％Brij35，0.5mM EGTA和2mM DTT)、抑制剂(浓度梯度，1％DMSO)，混合反应各组分，室温静置30分钟，添加30μL反应终止液(50mM EDTA)终止反应。最后，使用Caliper EZ ReaderII读取并计算抑制剂影响底物磷酸化的比例(不加酶抑制剂的反应结果为阴性对照100％，加过量抑制剂的反应结果为阳性对照)，以抑制百分比为纵坐标，抑制剂浓度为横坐标，绘制剂量效应曲线，求出IC50。
TYK2活性分析
整个分析过程在384孔板中进行，反应体系为25μL，反应成分包括TYK2激酶(10nM)、底物(荧光标记的小肽，5-FAM-EEPLYWSFPAKKK-CONH2，3μM)、ATP(35.4μM)、反应缓冲液(50mM HEPES(pH 7.5)，10mM MgCl2，0.01％TritonX-100，0.01％Brij35，0.5mM EGTA和2mM DTT)、抑制剂(浓度梯度，1％DMSO)，混合反应各组分，室温静置10分钟，添加30μL反应终止液(50mM EDTA)终止反应。最后，使用Caliper EZ ReaderII读取并计算抑制剂影响底物磷酸化的比例(不加酶抑制剂的反应结果为阴性对照100％，加过量抑制剂的反应结果为阳性对照)，以抑制百分比为纵坐标，抑制剂浓度为横坐标，绘制剂量效应曲线，求出IC50。
实施例136
下表显示了在JAK抑制测定中本发明的所选化合物的活性。化合物编号对应于先前表中的化合物编号。具有“A”活性的化合物的IC50≤10nM；具有“B”活性的化合物的IC50为10-100nM；具有“C”活性的化合物的IC50为100-1000nM；具有“D”活性的化合物的IC50为1000-10000nM；具有“E”活性的化合物的IC50≥10000nM。
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Claims (6)
1.通式(I)的化合物或其药学上可接受的盐
其中：
n为1或2；
A、B、D是CH，并且C、E是N；
R2为甲基或氘代甲基，R3、R4为氢；
R1为氢、烷基、
其可以任选地被一个或多个R1a取代，或R1选自以下结构中的一种：
其中R1a选自卤素，氰基，羟基，-NH2，-SO2NH2，烷基，炔基，炔基烷基，环烷基，；
X是一个共价键或X是-C(＝O)-，-S(＝O)-，-S(＝O)2-，-C(＝O)O-，-C(＝O)NH-，-S(＝O)NH-，-S(＝O)2NH-。
2.根据权利要求1中的通式(I)的化合物，其中X为-C(＝O)-，-S(＝O)-，
-S(＝O)2-，-C(＝O)O-，-C(＝O)NH-，-S(＝O)NH-，-S(＝O)2NH-。
3.权利要求1的通式(I)的化合物，所述化合物选自2-氟-4-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)苯腈；3-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)-3-氧代丙腈；2-羟基-1-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)乙酮；1-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)乙酮；1-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)丙烷-1-酮；N-(2-(乙磺酰基)－2－氮杂螺环[3.3]庚烷--6-)-N-甲基·7H-吡咯并[2,3-d]嘧啶-4-胺；6(甲基(7H吡咯并[2,3-d]嘧啶-4-)氨基)-2-氮杂螺环[3.3]-庚烷-2-羧酸甲酯；乙基6-(甲基(7H吡咯并[2,3-d]嘧啶-4-)氨基)-2-氮杂螺环[3.3]庚烷-2-羧酸乙酯；(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)(吡啶-3-基)甲烷酮；(4-6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)-4-氧代丁腈；3-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]正庚烷-2-羰基)苯腈；(4-6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]正庚烷-2-羰基环己酮；(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)(3-(三氟甲基)苯基)甲烷酮；3-氟-4-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]正庚烷-2-羰基)苯腈；4-(2-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)-2-氧代乙基)苯腈；1-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)-3-(甲磺酰基)丙烷-1-酮；6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)(3-(三氟甲氧基)苯甲基酮)；(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)吡嗪-2-基)甲基酮；1-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)环丙烷腈；苯并[b]噻吩(6-(甲基(7H吡咯并[2,3-d]嘧啶-4-)氨基)－2－氮杂螺环[3.3]庚烷-2-基甲基酮；4,4,4-三氟-1-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)-1-酮丁烷；苯并[b]噻吩-3-yl(6-(甲基(7H吡咯并[2,3-d]嘧啶-4-)氨基)-2-氮杂螺环[3.3]庚烷-2-基)甲基酮)；2-(1H-吲哚-3-基)-1-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)乙酮；(4-甲氧基苯基)(6-(甲基(7H吡咯并[2,3-d]嘧啶-4-)氨基)－2－氮杂螺环[3.3]庚烷-2-基)甲基酮)；(4-氯苯基)(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)甲基酮；4-乙炔基苯基)(6-(甲基(7H吡咯并[2,3-d]嘧啶-4-)氨基)－2－氮杂螺环[3.3]庚烷2-基)甲基酮；4-氟苯基)(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)甲基酮；(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)(3-噻吩-2-基)甲基酮；6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)-(6-甲基吡嗪-2-基)甲基酮；吲哚-2-基)-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)甲基酮；(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)(4-(三氟甲基)苯基)甲基酮；(五氯吡啶-2-基)-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)甲基酮；N-(3-氯苯基)-6-甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]正庚烷-2-甲酰胺；2-甲基-4-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]正庚烷-2-羰基)苯腈；5-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]正庚烷-2-羰基)腈吡啶；2-氯-4-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]正庚烷-2-羰基)苯腈；3-氯-4-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]正庚烷-2-羰基)苯腈；(4-碘苯基)(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)甲基酮；4-苯基环丙基)(6-(甲基(7H吡咯并[2,3-d]嘧啶-4-)氨基)－2－氮杂螺环[3.3]庚烷2-基)甲基酮；(4-乙炔基-3-甲基苯基)-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)甲基酮；(4-乙炔基-2-氟苯基)(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基]氨基)-2-氮杂螺[3.3]庚-2-基)甲酮；(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-基)(4-(1-塞YN-1-基)苯基)甲基酮；(2-氯-4-乙炔基苯基)(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基]氨基)-2-氮杂螺[3.3]庚-2-基)甲酮；3-甲基-4-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)苯腈；(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚-2-基)(1H-吡唑-3-基)甲酮；(3-氯-4-乙炔基苯基)(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基]氨基)-2-氮杂螺[3.3]庚-2-基)甲酮；(4-乙炔基-3-氟苯基)(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基]氨基)-2-氮杂螺[3.3]庚-2-基)甲酮；(5-乙炔基吡啶-2-基)(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基]氨基)-2-氮杂螺[3.3]庚-2-基)甲酮；(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基]氨基)-2-氮杂螺[3.3]庚-2-基)(1-甲基-1H-苯并[d]咪唑-5-基)甲酮；(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚-2-基)(1-甲基-1H-吡唑-3-基)甲酮；2,5-二氟-4-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)苯腈；2,6-二氟-4-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)苯腈；2,3-二氟-4-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)苯腈；5-氟-2-甲基-4-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)苯腈；(2,3-二氟苯基)(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基]氨基)-2-氮杂螺[3.3]庚-2-基)甲酮；3,5-二氟-4-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)苯腈；2-氟-5-{6-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-2-氮杂-螺[3.3]庚烷-2-羰基}-苯腈；3-氟-5-{6-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基]-氨基]-2-氮杂-螺[3.3]庚烷-2-羰基}-苯腈；2,5-二氟-4-{6-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-2-氮杂-螺[3.3]庚烷-2-羰基}-苯腈；2,3-二氯-4-{6-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-2-氮杂-螺[3.3]庚烷-2-羰基}-苯腈；2,6-二氟-3-{6-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-2-氮杂-螺[3.3]庚烷-2-羰基}-苯腈；2,3-二氟-5-{6-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-2-氮杂-螺[3.3]庚烷-2-羰基}-苯腈；3,4-二氟-5-{6-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-2-氮杂-螺[3.3]庚烷-2-羰基}-苯腈；(4-乙炔基-3-氟-苯基)-{6-[-[3氘代甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-2-氮杂螺[3.3]庚-2-基}-甲酮；2-氟-4-{6-[-[3氘代甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-2-氮杂-螺环[3.3]庚烷-2-羰基}-苯腈；(4-丙-1-炔基-3-氟-苯基)-{6-[-[(3氘代甲基)-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-2-氮杂螺[3.3]庚-2-基}-甲酮；3,4-二氟-5-{6-[3氘代甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-2-氮杂-螺[3.3]庚烷-2-羰基}-苯腈；6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基]氨基)-2-氮杂螺[3.3]庚-2-基)(4-(1-甲基-1H-吡唑-3-基)苯基)甲酮；(1-环丙基-1H-吡唑-4-基)-{6-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-2-氮杂螺[3.3]庚烷-2-基}-甲酮；N-(3-甲氧基-1,2,4-噻二唑-5-基)-6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羧酰胺；4-(6-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-2-氮杂螺[3.3]庚烷-2-羰基)苯磺酰胺；2-甲氧基-1-(9-(甲基(7H-吡咯[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一碳-3-基)乙烷-1-酮；1-{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-乙酮；(3-乙磺酰基-3-氮杂-螺[5.5]十一碳-9-基)-甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-胺；2-羟基-1-{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一-3-基}-乙酮；1-{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-丙-1-酮；甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-[3-(2,2,2-三氟乙基)-3-氮杂螺环[5.5]十一烷基-9-基]-胺；{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基]-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-吡啶-3-基-甲酮；4-{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基]-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-4-氧代-丁腈；4-{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一烷-3-羰基}-环己酮；9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基]-氨基]-3-氮杂-螺[5.5]十一烷基-3-基}-(3-三氟甲基-苯基)-甲酮；3-氟-4-{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3-氮杂-螺[5.5]十一烷-3-羰基}-苯腈；4-(2-{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基]-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-2-氧-乙基)-苯腈；3-甲磺酰基-1-{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3-氮杂螺环[5.5]十一-3-基}-丙烷-1-酮；2-氟-4-{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3-氮杂-螺[5.5]十一烷-3-羰基}-苯腈；{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基]-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-吡嗪-2-基-甲酮；1-{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一烷-3-羰基}-环丙烷甲腈；(6-甲基-吡嗪-2-基)-{9-[甲基-(7H-吡咯[2,3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一-3-基]-甲酮；4,4,4-三氟-1-{9-[甲基-(7H-吡咯[2,3-d]嘧啶-4-基)-氨基]-3-氮杂-螺[5.5]十一-3-基]-丁烷-1-酮；苯并[b]噻吩-3-基-{9-[甲基-(7H-吡咯[2,3-d]嘧啶-4-基)-氨基]-3-氮杂螺[5.5]十一-3-基]-甲酮；2-(1H-吲哚-3-基)-1-{9-[甲基-(7H-吡咯[2,3-d]嘧啶-4-基)-氨基]-3-氮杂-螺[5.5]十一-3-基]-乙酮；{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基]-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-(3-甲基-噻吩-2-基)-甲酮；(1H-吲哚-2-基)-{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3-氮杂螺[5.5]十一烷基-3-基}-甲酮；(N-甲基-3-(丙基磺酰基)-N-(7H-吡咯并[2,3-d]嘧啶-4-基)-3-氮杂螺[5.5]十一烷基-9-基]-胺；2-甲基氨基-1-{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一-3-基}-乙酮盐酸盐；异丙基9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酸酯；环丙基-{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-甲酮；1-{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-丁-1-酮；{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基]-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-(3-三氟甲氧基-苯基)-甲酮；3-{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一烷-3-羰基}-苯腈；甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-[3-(2,2,2-三氟乙磺酰基)-3-氮杂螺环[5.5]十一烷基-9-基]-胺；3-{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基)-氨基]-3-氮杂-螺环[5.5]十一烷基-3-基}-3-氧代丙腈；苯并[b]噻吩-2-基-{9-[甲基-(7H-吡咯并[2,3-d]嘧啶-4-基]-氨基]-3-氮杂螺[5.5]十一烷基-3-基}-甲酮；9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯；1-(9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-基)-2-苯氧基乙烷-1-酮；2,2,2-三氟乙基9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酸酯；9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-N-(2,2,2-三氟乙基)-3-氮杂螺[5.5]十一烷-3-甲酰胺；N-甲基-9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N，N-二乙基-9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-磺酰胺；4-(9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羰基)苯磺酰胺；3-(9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基]氨基)-3-氮杂螺[5.5]十一烷-3-基)-3-氧丙烷-1-磺酰胺；3-氟-5-(2-(9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基]氨基])-3-氮杂螺[5.5]十一烷-3-基)-2-氧乙氧基)苯腈；4-(2-(9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基]氨基])-3-氮杂螺[5.5]十一烷基-3-基)-2-氧乙氧基)苯腈；3-(2-(9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基]氨基])-3-氮杂螺[5.5]十一烷基-3-基)-2-氧乙氧基)苯腈；2-氟-4-(2-(9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基]氨基])-3-氮杂螺[5.5]十一烷-3-基)-2-氧乙氧基)苯腈；2,3-二氟-4-(2-(9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]-3-氮杂螺[5.5]十一烷基-3-基)-2-氧乙氧基)苯腈；N-(4-甲氧基苯基)-9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(3-甲氧基苯基)-9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(4-氰基苯基)-9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(3-氰基苯基)-9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(6-氰基吡啶-2-基)-9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(6-甲氧基吡啶-2-基)-9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(5-氰基吡啶-2-基)-9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-甲酰胺；9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-N-(5-甲基噻唑-2-基)-3-氮杂螺[5.5]十一烷-3-甲酰胺；9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-N-(1-甲基-1H-吡唑-3-基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-N-(5-甲基吡嗪-2-基)-3-氮杂螺[5.5]十一烷-3-甲酰胺；N-(5-甲氧基吡嗪-2-基)-9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(5-甲氧基吡啶-2-基)-9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(5-氟噻唑-2-基)-9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(5-氯噻唑-2-基)-9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(5-氯噻唑-2-基)-9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-N-(噻唑-2-基)-3-氮杂螺[5.5]十一烷-3-羧酰胺；N-(5-甲氧基噻唑并[5,4-b]吡啶-2-基)-9-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)-3-氮杂螺[5.5]十一烷-3-羧酰胺。
4.包含治疗有效量的权利要求1的式(I)化合物和药学上可接受的赋形剂的药物组合物。
5.一种用于治疗自身免疫疾病，癌症，炎性疾病或免疫介导的疾病的药物，该药物包含治疗有效量的权利要求1-3任一项所述的式(I)化合物的组合物，以及其他治疗剂。
6.根据权利要求5所述的药物，其与选自以下的治疗剂组合施用：抗癌药，类固醇药物，来氟米特，钙调神经磷酸酶抑制剂，抗组胺药及其混合物。
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| EA201992253A1 (ru) | 2017-03-23 | 2020-03-31 | Джакобио Фармасьютикалс Ко., Лтд. | Новые гетероциклические производные, применимые в качестве ингибиторов shp2 |
| AU2019375412A1 (en) * | 2018-11-05 | 2021-06-03 | Avista Pharma Solutions, Inc. | Chemical compounds |
| US10851102B2 (en) | 2019-01-23 | 2020-12-01 | Theravance Biopharma R&D Ip, Llc | Imidazole and triazole containing bicyclic compounds as JAK inhibitors |
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| SI3318565T1 (sl) * | 2013-12-05 | 2021-07-30 | Pfizer Inc. | Pirolo(2,3-D)pirimidinil, pirolo(2,3-B)pirazinil in pirolo(2,3-D)piridinil akrilamidi |
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| Chieyeon Chough等.Design, synthesis and evaluation of (R)-3-(7-(methylIJ7H-pyrroloij2,3-d]pyrimidin-4-yl)amino)-5-azaspiroij2.4]heptan-5-yl)-3-oxopropanenitrile as a JAK1-selective inhibitor.《MedChemComm》.2018,(第undefined期),第477-489页. * |
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| EP3768272A4 (en) | 2021-08-11 |
| WO2019182924A1 (en) | 2019-09-26 |
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