RU2485106C2 - Соединения, проявляющие активность в отношении jak-киназы (варианты), способ лечения заболеваний, опосредованных jak-киназой, способ ингибирования активности jak-киназы (варианты), фармацевтическая композиция на основе указанных соединений - Google Patents
Соединения, проявляющие активность в отношении jak-киназы (варианты), способ лечения заболеваний, опосредованных jak-киназой, способ ингибирования активности jak-киназы (варианты), фармацевтическая композиция на основе указанных соединений Download PDFInfo
- Publication number
- RU2485106C2 RU2485106C2 RU2007148812/04A RU2007148812A RU2485106C2 RU 2485106 C2 RU2485106 C2 RU 2485106C2 RU 2007148812/04 A RU2007148812/04 A RU 2007148812/04A RU 2007148812 A RU2007148812 A RU 2007148812A RU 2485106 C2 RU2485106 C2 RU 2485106C2
- Authority
- RU
- Russia
- Prior art keywords
- pyrimidinediamine
- fluoro
- phenyl
- aminosulfonyl
- aminosulfonylphenyl
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract 30
- 230000000694 effects Effects 0.000 title claims abstract 5
- 230000001404 mediated effect Effects 0.000 title claims abstract 3
- 230000002401 inhibitory effect Effects 0.000 title claims 5
- 238000000034 method Methods 0.000 title claims 4
- 239000008194 pharmaceutical composition Substances 0.000 title claims 2
- 201000010099 disease Diseases 0.000 title 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title 1
- 230000001747 exhibiting effect Effects 0.000 title 1
- 125000005842 heteroatom Chemical group 0.000 claims abstract 47
- 229910052760 oxygen Inorganic materials 0.000 claims abstract 14
- 229910052717 sulfur Inorganic materials 0.000 claims abstract 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract 11
- 150000002367 halogens Chemical class 0.000 claims abstract 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 11
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 10
- 239000001257 hydrogen Substances 0.000 claims abstract 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract 9
- 102000042838 JAK family Human genes 0.000 claims abstract 5
- 108091082332 JAK family Proteins 0.000 claims abstract 5
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract 4
- 239000003814 drug Substances 0.000 claims abstract 4
- 208000027930 type IV hypersensitivity disease Diseases 0.000 claims abstract 3
- QYCGBAJADAGLLK-UHFFFAOYSA-N 1-(cyclohepten-1-yl)cycloheptene Chemical compound C1CCCCC=C1C1=CCCCCC1 QYCGBAJADAGLLK-UHFFFAOYSA-N 0.000 claims abstract 2
- 210000001744 T-lymphocyte Anatomy 0.000 claims abstract 2
- 206010053613 Type IV hypersensitivity reaction Diseases 0.000 claims abstract 2
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims abstract 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract 2
- 230000037361 pathway Effects 0.000 claims abstract 2
- -1 amino, aminocarbonyl Chemical group 0.000 claims 359
- 229910052757 nitrogen Inorganic materials 0.000 claims 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 27
- HXCIDYGTACKSQQ-UHFFFAOYSA-N 5-fluoro-6-phenylpyrimidine-2,4-diamine Chemical compound NC1=NC(N)=C(F)C(C=2C=CC=CC=2)=N1 HXCIDYGTACKSQQ-UHFFFAOYSA-N 0.000 claims 26
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims 16
- 229910052799 carbon Inorganic materials 0.000 claims 15
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 13
- FUVWRUJASRBHEK-UHFFFAOYSA-N 5-phenylpyrimidine-2,4-diamine Chemical compound NC1=NC(N)=NC=C1C1=CC=CC=C1 FUVWRUJASRBHEK-UHFFFAOYSA-N 0.000 claims 12
- 125000000217 alkyl group Chemical group 0.000 claims 12
- 125000001424 substituent group Chemical group 0.000 claims 12
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims 10
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 7
- 125000002252 acyl group Chemical group 0.000 claims 6
- 150000001733 carboxylic acid esters Chemical class 0.000 claims 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 6
- 125000004442 acylamino group Chemical group 0.000 claims 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 5
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 5
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 4
- 239000000203 mixture Substances 0.000 claims 4
- IGLNXKVGKIFNBQ-UHFFFAOYSA-N n-[5-[[5-fluoro-4-(4-prop-2-ynoxyanilino)pyrimidin-2-yl]amino]-2-methylphenyl]sulfonylpropanamide Chemical compound C1=C(C)C(S(=O)(=O)NC(=O)CC)=CC(NC=2N=C(NC=3C=CC(OCC#C)=CC=3)C(F)=CN=2)=C1 IGLNXKVGKIFNBQ-UHFFFAOYSA-N 0.000 claims 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 3
- PFBXADYZVJGUAF-UHFFFAOYSA-N 3-[[5-fluoro-4-[4-(pyridin-4-ylmethyl)anilino]pyrimidin-2-yl]amino]benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC(NC=2N=C(NC=3C=CC(CC=4C=CN=CC=4)=CC=3)C(F)=CN=2)=C1 PFBXADYZVJGUAF-UHFFFAOYSA-N 0.000 claims 3
- YTLYLLTVENPWFT-UHFFFAOYSA-N 3-aminoprop-2-enoic acid Chemical group NC=CC(O)=O YTLYLLTVENPWFT-UHFFFAOYSA-N 0.000 claims 3
- YSWHPGYAPJLREH-UHFFFAOYSA-N 5-[[5-fluoro-4-(4-prop-2-ynoxyanilino)pyrimidin-2-yl]amino]-2-methylbenzenesulfonamide Chemical compound C1=C(S(N)(=O)=O)C(C)=CC=C1NC1=NC=C(F)C(NC=2C=CC(OCC#C)=CC=2)=N1 YSWHPGYAPJLREH-UHFFFAOYSA-N 0.000 claims 3
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical group C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 claims 3
- 125000004411 C5-C6 heterocyclyl group Chemical group 0.000 claims 3
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims 3
- 150000001721 carbon Chemical group 0.000 claims 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims 3
- 125000000623 heterocyclic group Chemical group 0.000 claims 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 3
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims 2
- CHQBVMBVYQAHES-UHFFFAOYSA-N 3-[[4-[[4-(cyanomethyl)-3-oxo-1,4-benzothiazin-6-yl]amino]-5-fluoropyrimidin-2-yl]amino]benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC(NC=2N=C(NC=3C=C4N(CC#N)C(=O)CSC4=CC=3)C(F)=CN=2)=C1 CHQBVMBVYQAHES-UHFFFAOYSA-N 0.000 claims 2
- ICGZTNBBOSFBDI-UHFFFAOYSA-N 3-[[5-fluoro-4-[[4-(pyridin-3-ylmethyl)-1,4-benzoxazin-7-yl]amino]pyrimidin-2-yl]amino]benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC(NC=2N=C(NC=3C=C4OC=CN(CC=5C=NC=CC=5)C4=CC=3)C(F)=CN=2)=C1 ICGZTNBBOSFBDI-UHFFFAOYSA-N 0.000 claims 2
- VSJPKSVDCDOVJB-UHFFFAOYSA-N 4-[[5-fluoro-4-[(2,2,4-trimethyl-1,1,3-trioxo-1$l^{6},4-benzothiazin-6-yl)amino]pyrimidin-2-yl]amino]benzenesulfonamide Chemical compound C1=C2N(C)C(=O)C(C)(C)S(=O)(=O)C2=CC=C1NC(C(=CN=1)F)=NC=1NC1=CC=C(S(N)(=O)=O)C=C1 VSJPKSVDCDOVJB-UHFFFAOYSA-N 0.000 claims 2
- 125000004863 4-trifluoromethoxyphenyl group Chemical group [H]C1=C([H])C(OC(F)(F)F)=C([H])C([H])=C1* 0.000 claims 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims 2
- ZOOCTCGQLVQUPD-UHFFFAOYSA-N 5-[[4-[(6-amino-5-methoxypyridin-2-yl)amino]-5-fluoropyrimidin-2-yl]amino]-2-methylbenzenesulfonamide Chemical compound N1=C(N)C(OC)=CC=C1NC1=NC(NC=2C=C(C(C)=CC=2)S(N)(=O)=O)=NC=C1F ZOOCTCGQLVQUPD-UHFFFAOYSA-N 0.000 claims 2
- SOKJMSBSBGDGIG-UHFFFAOYSA-N 5-[[5-fluoro-4-[(3-oxo-4h-1,4-benzothiazin-6-yl)amino]pyrimidin-2-yl]amino]-2-methylbenzenesulfonamide Chemical compound C1=C(S(N)(=O)=O)C(C)=CC=C1NC1=NC=C(F)C(NC=2C=C3NC(=O)CSC3=CC=2)=N1 SOKJMSBSBGDGIG-UHFFFAOYSA-N 0.000 claims 2
- UTUUAIPSQMYOEQ-UHFFFAOYSA-N 5-[[5-fluoro-4-[[3-oxo-4-(pyridin-2-ylmethyl)-1,4-benzoxazin-6-yl]amino]pyrimidin-2-yl]amino]-2-methylbenzenesulfonamide Chemical compound C1=C(S(N)(=O)=O)C(C)=CC=C1NC1=NC=C(F)C(NC=2C=C3N(CC=4N=CC=CC=4)C(=O)COC3=CC=2)=N1 UTUUAIPSQMYOEQ-UHFFFAOYSA-N 0.000 claims 2
- 239000005977 Ethylene Substances 0.000 claims 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims 2
- 125000003277 amino group Chemical group 0.000 claims 2
- 229910052731 fluorine Inorganic materials 0.000 claims 2
- 239000011737 fluorine Substances 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- 238000000338 in vitro Methods 0.000 claims 2
- 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims 2
- GJVFBWCTGUSGDD-UHFFFAOYSA-L pentamethonium bromide Chemical group [Br-].[Br-].C[N+](C)(C)CCCCC[N+](C)(C)C GJVFBWCTGUSGDD-UHFFFAOYSA-L 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 2
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims 1
- ZVIOPXFLYBAWKR-UHFFFAOYSA-N 2-(cyclohepten-1-yl)cycloheptene-1-carbonitrile Chemical group C1CCCCC(C#N)=C1C1=CCCCCC1 ZVIOPXFLYBAWKR-UHFFFAOYSA-N 0.000 claims 1
- PAGNBLYFLCXVTH-UHFFFAOYSA-N 2-[2-chloro-4-[[2-(4-chloro-3-sulfamoylanilino)-5-fluoropyrimidin-4-yl]amino]phenoxy]-n-methylacetamide Chemical compound C1=C(Cl)C(OCC(=O)NC)=CC=C1NC1=NC(NC=2C=C(C(Cl)=CC=2)S(N)(=O)=O)=NC=C1F PAGNBLYFLCXVTH-UHFFFAOYSA-N 0.000 claims 1
- VERPDJRVAVSZSI-UHFFFAOYSA-N 2-[2-chloro-4-[[2-(4-chloro-3-sulfamoylanilino)-5-methylpyrimidin-4-yl]amino]phenoxy]-n-methylacetamide Chemical compound C1=C(Cl)C(OCC(=O)NC)=CC=C1NC1=NC(NC=2C=C(C(Cl)=CC=2)S(N)(=O)=O)=NC=C1C VERPDJRVAVSZSI-UHFFFAOYSA-N 0.000 claims 1
- HXSQERZRQVDYES-UHFFFAOYSA-N 2-[2-chloro-4-[[5-fluoro-2-(3-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]-n-methylacetamide Chemical compound C1=C(Cl)C(OCC(=O)NC)=CC=C1NC1=NC(NC=2C=C(C=CC=2)S(N)(=O)=O)=NC=C1F HXSQERZRQVDYES-UHFFFAOYSA-N 0.000 claims 1
- VYJIKNSWKDRLET-UHFFFAOYSA-N 2-[2-chloro-4-[[5-fluoro-2-(3-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]acetamide Chemical compound C1=C(Cl)C(OCC(=O)N)=CC=C1NC1=NC(NC=2C=C(C=CC=2)S(N)(=O)=O)=NC=C1F VYJIKNSWKDRLET-UHFFFAOYSA-N 0.000 claims 1
- WBOHISCPBCMXEQ-UHFFFAOYSA-N 2-[2-chloro-4-[[5-fluoro-2-(4-methyl-3-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]-n-methylacetamide Chemical compound C1=C(Cl)C(OCC(=O)NC)=CC=C1NC1=NC(NC=2C=C(C(C)=CC=2)S(N)(=O)=O)=NC=C1F WBOHISCPBCMXEQ-UHFFFAOYSA-N 0.000 claims 1
- YLARHXSJSZAVGW-UHFFFAOYSA-N 2-[2-chloro-4-[[5-fluoro-2-(4-methyl-3-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]acetamide Chemical compound C1=C(S(N)(=O)=O)C(C)=CC=C1NC1=NC=C(F)C(NC=2C=C(Cl)C(OCC(N)=O)=CC=2)=N1 YLARHXSJSZAVGW-UHFFFAOYSA-N 0.000 claims 1
- DEODYXOEQQKAQB-UHFFFAOYSA-N 2-[2-chloro-4-[[5-fluoro-2-(4-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]-n,n-dimethylacetamide Chemical compound C1=C(Cl)C(OCC(=O)N(C)C)=CC=C1NC1=NC(NC=2C=CC(=CC=2)S(N)(=O)=O)=NC=C1F DEODYXOEQQKAQB-UHFFFAOYSA-N 0.000 claims 1
- ZFSPAWFQNPWUJO-UHFFFAOYSA-N 2-[2-chloro-4-[[5-fluoro-2-(4-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]-n-methylacetamide Chemical compound C1=C(Cl)C(OCC(=O)NC)=CC=C1NC1=NC(NC=2C=CC(=CC=2)S(N)(=O)=O)=NC=C1F ZFSPAWFQNPWUJO-UHFFFAOYSA-N 0.000 claims 1
- BMVVDJQCGBKYHI-UHFFFAOYSA-N 2-[2-chloro-4-[[5-fluoro-2-(4-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]acetamide Chemical compound C1=C(Cl)C(OCC(=O)N)=CC=C1NC1=NC(NC=2C=CC(=CC=2)S(N)(=O)=O)=NC=C1F BMVVDJQCGBKYHI-UHFFFAOYSA-N 0.000 claims 1
- GWGOEXLEOGAHBT-UHFFFAOYSA-N 2-[2-chloro-4-[[5-methyl-2-(4-methyl-3-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]-n,n-dimethylacetamide Chemical compound C1=C(Cl)C(OCC(=O)N(C)C)=CC=C1NC1=NC(NC=2C=C(C(C)=CC=2)S(N)(=O)=O)=NC=C1C GWGOEXLEOGAHBT-UHFFFAOYSA-N 0.000 claims 1
- IQEVGBCZQXHLEN-UHFFFAOYSA-N 2-[2-chloro-4-[[5-methyl-2-(4-methyl-3-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]-n-methylacetamide Chemical compound C1=C(Cl)C(OCC(=O)NC)=CC=C1NC1=NC(NC=2C=C(C(C)=CC=2)S(N)(=O)=O)=NC=C1C IQEVGBCZQXHLEN-UHFFFAOYSA-N 0.000 claims 1
- OJRWJMADJBXUHN-UHFFFAOYSA-N 2-[2-chloro-4-[[5-methyl-2-(4-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]-n,n-dimethylacetamide Chemical compound C1=C(Cl)C(OCC(=O)N(C)C)=CC=C1NC1=NC(NC=2C=CC(=CC=2)S(N)(=O)=O)=NC=C1C OJRWJMADJBXUHN-UHFFFAOYSA-N 0.000 claims 1
- RFNYPHNLDVTBGE-UHFFFAOYSA-N 2-[2-chloro-4-[[5-methyl-2-(4-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]-n-methylacetamide Chemical compound C1=C(Cl)C(OCC(=O)NC)=CC=C1NC1=NC(NC=2C=CC(=CC=2)S(N)(=O)=O)=NC=C1C RFNYPHNLDVTBGE-UHFFFAOYSA-N 0.000 claims 1
- NQZFYIVEXVBSCH-UHFFFAOYSA-N 2-[2-fluoro-4-[[5-fluoro-2-(3-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]acetamide Chemical compound C1=C(F)C(OCC(=O)N)=CC=C1NC1=NC(NC=2C=C(C=CC=2)S(N)(=O)=O)=NC=C1F NQZFYIVEXVBSCH-UHFFFAOYSA-N 0.000 claims 1
- BMJWKCTUJCEKBF-UHFFFAOYSA-N 2-[2-fluoro-4-[[5-fluoro-2-(4-methyl-3-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]acetamide Chemical compound C1=C(S(N)(=O)=O)C(C)=CC=C1NC1=NC=C(F)C(NC=2C=C(F)C(OCC(N)=O)=CC=2)=N1 BMJWKCTUJCEKBF-UHFFFAOYSA-N 0.000 claims 1
- KPQGOCBYEBQLPS-UHFFFAOYSA-N 2-[2-fluoro-4-[[5-fluoro-2-(4-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]acetamide Chemical compound C1=C(F)C(OCC(=O)N)=CC=C1NC1=NC(NC=2C=CC(=CC=2)S(N)(=O)=O)=NC=C1F KPQGOCBYEBQLPS-UHFFFAOYSA-N 0.000 claims 1
- PEQSIFUSETVFAK-UHFFFAOYSA-N 2-[2-fluoro-4-[[5-methyl-2-(3-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]-n,n-dimethylacetamide Chemical compound C1=C(F)C(OCC(=O)N(C)C)=CC=C1NC1=NC(NC=2C=C(C=CC=2)S(N)(=O)=O)=NC=C1C PEQSIFUSETVFAK-UHFFFAOYSA-N 0.000 claims 1
- NXNXCNDJPAKNTG-UHFFFAOYSA-N 2-[2-fluoro-4-[[5-methyl-2-(4-methyl-3-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]-n,n-dimethylacetamide Chemical compound C1=C(F)C(OCC(=O)N(C)C)=CC=C1NC1=NC(NC=2C=C(C(C)=CC=2)S(N)(=O)=O)=NC=C1C NXNXCNDJPAKNTG-UHFFFAOYSA-N 0.000 claims 1
- PFTCYGBPJSYQST-UHFFFAOYSA-N 2-[2-fluoro-4-[[5-methyl-2-(4-methyl-3-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]-n-methylacetamide Chemical compound C1=C(F)C(OCC(=O)NC)=CC=C1NC1=NC(NC=2C=C(C(C)=CC=2)S(N)(=O)=O)=NC=C1C PFTCYGBPJSYQST-UHFFFAOYSA-N 0.000 claims 1
- ONUISJRMJLHATK-UHFFFAOYSA-N 2-[2-fluoro-4-[[5-methyl-2-(4-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]-n-methylacetamide Chemical compound C1=C(F)C(OCC(=O)NC)=CC=C1NC1=NC(NC=2C=CC(=CC=2)S(N)(=O)=O)=NC=C1C ONUISJRMJLHATK-UHFFFAOYSA-N 0.000 claims 1
- XEFLFDXINZQYQV-UHFFFAOYSA-N 2-[4-[[2-(4-chloro-3-sulfamoylanilino)-5-fluoropyrimidin-4-yl]amino]phenyl]ethyl carbamate Chemical compound C1=CC(CCOC(=O)N)=CC=C1NC1=NC(NC=2C=C(C(Cl)=CC=2)S(N)(=O)=O)=NC=C1F XEFLFDXINZQYQV-UHFFFAOYSA-N 0.000 claims 1
- FBZNTBMTVUVJAR-UHFFFAOYSA-N 2-[4-[[2-(4-chloro-3-sulfamoylanilino)-5-fluoropyrimidin-4-yl]amino]phenyl]ethyl n,n-dimethylcarbamate Chemical compound C1=CC(CCOC(=O)N(C)C)=CC=C1NC1=NC(NC=2C=C(C(Cl)=CC=2)S(N)(=O)=O)=NC=C1F FBZNTBMTVUVJAR-UHFFFAOYSA-N 0.000 claims 1
- ISAZBVFGUNPQRM-UHFFFAOYSA-N 2-[4-[[2-(4-chloro-3-sulfamoylanilino)-5-fluoropyrimidin-4-yl]amino]phenyl]ethyl n-methylcarbamate Chemical compound C1=CC(CCOC(=O)NC)=CC=C1NC1=NC(NC=2C=C(C(Cl)=CC=2)S(N)(=O)=O)=NC=C1F ISAZBVFGUNPQRM-UHFFFAOYSA-N 0.000 claims 1
- GZMMPQHNBJBISB-UHFFFAOYSA-N 2-[4-[[2-(4-chloro-3-sulfamoylanilino)-5-methylpyrimidin-4-yl]amino]-2-fluorophenoxy]-n,n-dimethylacetamide Chemical compound C1=C(F)C(OCC(=O)N(C)C)=CC=C1NC1=NC(NC=2C=C(C(Cl)=CC=2)S(N)(=O)=O)=NC=C1C GZMMPQHNBJBISB-UHFFFAOYSA-N 0.000 claims 1
- OFQUFWOFGLNWAM-UHFFFAOYSA-N 2-[4-[[5-fluoro-2-(3-sulfamoylanilino)pyrimidin-4-yl]amino]-2-methoxyphenoxy]acetamide Chemical compound C1=C(OCC(N)=O)C(OC)=CC(NC=2C(=CN=C(NC=3C=C(C=CC=3)S(N)(=O)=O)N=2)F)=C1 OFQUFWOFGLNWAM-UHFFFAOYSA-N 0.000 claims 1
- AMXVSAWZCGFLLC-UHFFFAOYSA-N 2-[4-[[5-fluoro-2-(3-sulfamoylanilino)pyrimidin-4-yl]amino]phenoxy]-n,n-dimethylacetamide Chemical compound C1=CC(OCC(=O)N(C)C)=CC=C1NC1=NC(NC=2C=C(C=CC=2)S(N)(=O)=O)=NC=C1F AMXVSAWZCGFLLC-UHFFFAOYSA-N 0.000 claims 1
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- 210000004072 lung Anatomy 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 229940098779 methanesulfonic acid Drugs 0.000 claims 1
- INYMRBPXQGHHDR-ZFWWWQNUSA-N methyl (2s,4s)-1-(2-cyanoacetyl)-4-[[5-fluoro-2-(4-methyl-3-sulfamoylanilino)pyrimidin-4-yl]amino]pyrrolidine-2-carboxylate Chemical compound C1N(C(=O)CC#N)[C@H](C(=O)OC)C[C@@H]1NC1=NC(NC=2C=C(C(C)=CC=2)S(N)(=O)=O)=NC=C1F INYMRBPXQGHHDR-ZFWWWQNUSA-N 0.000 claims 1
- QHBREUPPKZDCEW-UHFFFAOYSA-N methyl 2-[4-[[5-fluoro-2-[4-methyl-3-(propanoylsulfamoyl)anilino]pyrimidin-4-yl]amino]phenoxy]acetate Chemical compound C1=C(C)C(S(=O)(=O)NC(=O)CC)=CC(NC=2N=C(NC=3C=CC(OCC(=O)OC)=CC=3)C(F)=CN=2)=C1 QHBREUPPKZDCEW-UHFFFAOYSA-N 0.000 claims 1
- VAWRULOLYNMUKJ-UHFFFAOYSA-N methyl 5-[[5-fluoro-2-(3-sulfamoylanilino)pyrimidin-4-yl]amino]thiophene-2-carboxylate Chemical compound S1C(C(=O)OC)=CC=C1NC1=NC(NC=2C=C(C=CC=2)S(N)(=O)=O)=NC=C1F VAWRULOLYNMUKJ-UHFFFAOYSA-N 0.000 claims 1
- ARNQNZSUMHALMJ-UHFFFAOYSA-N methyl 5-[[5-fluoro-2-(4-fluoro-3-sulfamoylanilino)pyrimidin-4-yl]amino]thiophene-2-carboxylate Chemical compound S1C(C(=O)OC)=CC=C1NC1=NC(NC=2C=C(C(F)=CC=2)S(N)(=O)=O)=NC=C1F ARNQNZSUMHALMJ-UHFFFAOYSA-N 0.000 claims 1
- BRIYDDLCTBTABF-UHFFFAOYSA-N methyl 5-[[5-fluoro-2-(4-methyl-3-sulfamoylanilino)pyrimidin-4-yl]amino]thiophene-2-carboxylate Chemical compound S1C(C(=O)OC)=CC=C1NC1=NC(NC=2C=C(C(C)=CC=2)S(N)(=O)=O)=NC=C1F BRIYDDLCTBTABF-UHFFFAOYSA-N 0.000 claims 1
- KTAOVBTVFRRSRF-UHFFFAOYSA-N methyl 5-[[5-fluoro-2-(4-sulfamoylanilino)pyrimidin-4-yl]amino]thiophene-2-carboxylate Chemical compound S1C(C(=O)OC)=CC=C1NC1=NC(NC=2C=CC(=CC=2)S(N)(=O)=O)=NC=C1F KTAOVBTVFRRSRF-UHFFFAOYSA-N 0.000 claims 1
- 125000006261 methyl amino sulfonyl group Chemical group [H]N(C([H])([H])[H])S(*)(=O)=O 0.000 claims 1
- VFRPECLJKCUOSI-UHFFFAOYSA-N n-[2-chloro-5-[[4-(3-chloro-4-methoxyanilino)-5-fluoropyrimidin-2-yl]amino]phenyl]sulfonylacetamide Chemical compound C1=C(Cl)C(OC)=CC=C1NC1=NC(NC=2C=C(C(Cl)=CC=2)S(=O)(=O)NC(C)=O)=NC=C1F VFRPECLJKCUOSI-UHFFFAOYSA-N 0.000 claims 1
- HKNYUKDSEKARSG-UHFFFAOYSA-N n-[5-[[4-[4-(2-cyanoethyl)-3-methylanilino]-5-fluoropyrimidin-2-yl]amino]-2-methylphenyl]sulfonylpropanamide Chemical compound C1=C(C)C(S(=O)(=O)NC(=O)CC)=CC(NC=2N=C(NC=3C=C(C)C(CCC#N)=CC=3)C(F)=CN=2)=C1 HKNYUKDSEKARSG-UHFFFAOYSA-N 0.000 claims 1
- WEESIHZPAWGRAS-UHFFFAOYSA-N n-[5-[[4-[4-(2-cyanoethyl)-3-methylanilino]-5-fluoropyrimidin-2-yl]amino]-2-methylphenyl]sulfonylpropanamide;sodium Chemical compound [Na].C1=C(C)C(S(=O)(=O)NC(=O)CC)=CC(NC=2N=C(NC=3C=C(C)C(CCC#N)=CC=3)C(F)=CN=2)=C1 WEESIHZPAWGRAS-UHFFFAOYSA-N 0.000 claims 1
- YCXPJQRBHJYSBB-UHFFFAOYSA-N n-[5-[[4-[4-(cyanomethoxy)-3-fluoroanilino]-5-fluoropyrimidin-2-yl]amino]-2-methylphenyl]sulfonylpropanamide Chemical compound C1=C(C)C(S(=O)(=O)NC(=O)CC)=CC(NC=2N=C(NC=3C=C(F)C(OCC#N)=CC=3)C(F)=CN=2)=C1 YCXPJQRBHJYSBB-UHFFFAOYSA-N 0.000 claims 1
- AGGATGGPXQZYRZ-UHFFFAOYSA-N n-[5-[[4-[4-(cyanomethoxy)-3-fluoroanilino]-5-fluoropyrimidin-2-yl]amino]-2-methylphenyl]sulfonylpropanamide;sodium Chemical compound [Na].C1=C(C)C(S(=O)(=O)NC(=O)CC)=CC(NC=2N=C(NC=3C=C(F)C(OCC#N)=CC=3)C(F)=CN=2)=C1 AGGATGGPXQZYRZ-UHFFFAOYSA-N 0.000 claims 1
- PNNWNUOANAFYQR-UHFFFAOYSA-N n-[[4-[[5-fluoro-2-(3-sulfamoylanilino)pyrimidin-4-yl]amino]phenyl]methyl]prop-2-enamide Chemical compound NS(=O)(=O)C1=CC=CC(NC=2N=C(NC=3C=CC(CNC(=O)C=C)=CC=3)C(F)=CN=2)=C1 PNNWNUOANAFYQR-UHFFFAOYSA-N 0.000 claims 1
- QRPYJOBHCPHHFZ-UHFFFAOYSA-N n-[[4-[[5-fluoro-2-(4-methyl-3-sulfamoylanilino)pyrimidin-4-yl]amino]phenyl]methyl]prop-2-enamide Chemical compound C1=C(S(N)(=O)=O)C(C)=CC=C1NC1=NC=C(F)C(NC=2C=CC(CNC(=O)C=C)=CC=2)=N1 QRPYJOBHCPHHFZ-UHFFFAOYSA-N 0.000 claims 1
- SWPWQZKUUXDYOE-UHFFFAOYSA-N n-[[4-[[5-fluoro-2-(4-sulfamoylanilino)pyrimidin-4-yl]amino]phenyl]methyl]prop-2-enamide Chemical compound C1=CC(S(=O)(=O)N)=CC=C1NC1=NC=C(F)C(NC=2C=CC(CNC(=O)C=C)=CC=2)=N1 SWPWQZKUUXDYOE-UHFFFAOYSA-N 0.000 claims 1
- LYONXLVTXIGPMN-UHFFFAOYSA-N n-butyl-3-[[4-(3-chloro-4-fluoroanilino)-5-fluoropyrimidin-2-yl]amino]benzenesulfonamide Chemical compound CCCCNS(=O)(=O)C1=CC=CC(NC=2N=C(NC=3C=C(Cl)C(F)=CC=3)C(F)=CN=2)=C1 LYONXLVTXIGPMN-UHFFFAOYSA-N 0.000 claims 1
- HRFUUBPJXLQCQU-UHFFFAOYSA-N n-butyl-3-[[4-(3-cyano-4-methylanilino)-5-fluoropyrimidin-2-yl]amino]benzenesulfonamide Chemical compound CCCCNS(=O)(=O)C1=CC=CC(NC=2N=C(NC=3C=C(C(C)=CC=3)C#N)C(F)=CN=2)=C1 HRFUUBPJXLQCQU-UHFFFAOYSA-N 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 208000016021 phenotype Diseases 0.000 claims 1
- 239000003755 preservative agent Substances 0.000 claims 1
- 230000002335 preservative effect Effects 0.000 claims 1
- 229940002612 prodrug Drugs 0.000 claims 1
- 239000000651 prodrug Substances 0.000 claims 1
- PPEWHLALFBYRLD-UHFFFAOYSA-N prop-2-ynyl n-[[4-[[5-fluoro-2-(3-sulfamoylanilino)pyrimidin-4-yl]amino]phenyl]methyl]carbamate Chemical compound NS(=O)(=O)C1=CC=CC(NC=2N=C(NC=3C=CC(CNC(=O)OCC#C)=CC=3)C(F)=CN=2)=C1 PPEWHLALFBYRLD-UHFFFAOYSA-N 0.000 claims 1
- ZOWQVEWBYLBZRO-UHFFFAOYSA-N prop-2-ynyl n-[[4-[[5-fluoro-2-(4-methyl-3-sulfamoylanilino)pyrimidin-4-yl]amino]phenyl]methyl]carbamate Chemical compound C1=C(S(N)(=O)=O)C(C)=CC=C1NC1=NC=C(F)C(NC=2C=CC(CNC(=O)OCC#C)=CC=2)=N1 ZOWQVEWBYLBZRO-UHFFFAOYSA-N 0.000 claims 1
- 230000000069 prophylactic effect Effects 0.000 claims 1
- YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical compound NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 claims 1
- QQAWZFHHCJBJRB-UHFFFAOYSA-N pyrimidine-2,4-diamine;sodium Chemical compound [Na].NC1=CC=NC(N)=N1 QQAWZFHHCJBJRB-UHFFFAOYSA-N 0.000 claims 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 claims 1
- XXULMLOENPXCIO-UHFFFAOYSA-N s-[2-[4-[[5-fluoro-2-(3-sulfamoylanilino)pyrimidin-4-yl]amino]phenyl]-2-oxoethyl] ethanethioate Chemical compound C1=CC(C(=O)CSC(=O)C)=CC=C1NC1=NC(NC=2C=C(C=CC=2)S(N)(=O)=O)=NC=C1F XXULMLOENPXCIO-UHFFFAOYSA-N 0.000 claims 1
- SMIIULRICOQUSH-UHFFFAOYSA-N s-[2-[4-[[5-fluoro-2-(4-methyl-3-sulfamoylanilino)pyrimidin-4-yl]amino]phenyl]-2-oxoethyl] ethanethioate Chemical compound C1=CC(C(=O)CSC(=O)C)=CC=C1NC1=NC(NC=2C=C(C(C)=CC=2)S(N)(=O)=O)=NC=C1F SMIIULRICOQUSH-UHFFFAOYSA-N 0.000 claims 1
- FLQARCWVMWZRRY-UHFFFAOYSA-N s-[2-[4-[[5-fluoro-2-(4-sulfamoylanilino)pyrimidin-4-yl]amino]phenyl]-2-oxoethyl] ethanethioate Chemical compound C1=CC(C(=O)CSC(=O)C)=CC=C1NC1=NC(NC=2C=CC(=CC=2)S(N)(=O)=O)=NC=C1F FLQARCWVMWZRRY-UHFFFAOYSA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 230000019491 signal transduction Effects 0.000 claims 1
- 230000008054 signal transmission Effects 0.000 claims 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims 1
- 229960002930 sirolimus Drugs 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 239000003381 stabilizer Substances 0.000 claims 1
- 239000011593 sulfur Substances 0.000 claims 1
- 229960001967 tacrolimus Drugs 0.000 claims 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 claims 1
- AVWRKZWQTYIKIY-UHFFFAOYSA-N urea-1-carboxylic acid Chemical compound NC(=O)NC(O)=O AVWRKZWQTYIKIY-UHFFFAOYSA-N 0.000 claims 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 208000006313 Delayed Hypersensitivity Diseases 0.000 abstract 1
- 125000003262 carboxylic acid ester group Chemical class [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- 229940043355 kinase inhibitor Drugs 0.000 abstract 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 229940124597 therapeutic agent Drugs 0.000 abstract 1
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Classifications
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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Applications Claiming Priority (7)
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| PCT/US2006/022590 WO2006133426A2 (en) | 2005-06-08 | 2006-06-08 | Compositions and methods for inhibition of the jak pathway |
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| RU2783723C2 (ru) * | 2017-10-18 | 2022-11-16 | Хк Инно.Н Корпорейшн | Гетероциклическое соединение в качестве ингибитора протеинкиназы |
| US11524968B2 (en) | 2017-10-18 | 2022-12-13 | Hk Inno.N Corporation | Heterocyclic compound as a protein kinase inhibitor |
| US12180185B2 (en) | 2018-11-15 | 2024-12-31 | Hk Inno.N Corporation | Compound as protein kinase inhibitor, and pharmaceutical composition comprising thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2783723C2 (ru) * | 2017-10-18 | 2022-11-16 | Хк Инно.Н Корпорейшн | Гетероциклическое соединение в качестве ингибитора протеинкиназы |
| US11524968B2 (en) | 2017-10-18 | 2022-12-13 | Hk Inno.N Corporation | Heterocyclic compound as a protein kinase inhibitor |
| US12180185B2 (en) | 2018-11-15 | 2024-12-31 | Hk Inno.N Corporation | Compound as protein kinase inhibitor, and pharmaceutical composition comprising thereof |
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