ES2655899T3 - Compuestos de pirazolo[1,5-a]pirimidina sustituidos como inhibidores de la Trk cinasa - Google Patents
Compuestos de pirazolo[1,5-a]pirimidina sustituidos como inhibidores de la Trk cinasa Download PDFInfo
- Publication number
- ES2655899T3 ES2655899T3 ES10732606.8T ES10732606T ES2655899T3 ES 2655899 T3 ES2655899 T3 ES 2655899T3 ES 10732606 T ES10732606 T ES 10732606T ES 2655899 T3 ES2655899 T3 ES 2655899T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- pyrimidine
- pyrazolo
- pyrrolidin
- carboxamide
- 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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- 229940043355 kinase inhibitor Drugs 0.000 title 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 title 1
- LDIJKUBTLZTFRG-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine Chemical group N1=CC=CN2N=CC=C21 LDIJKUBTLZTFRG-UHFFFAOYSA-N 0.000 title 1
- -1 (R) -2- (5-fluoro-2-methylpyridin-3-yl) pyrrolidin-1-yl Chemical group 0.000 claims description 114
- XMRIUEGHBZTNND-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1=CC=NC2=C(C(=O)N)C=NN21 XMRIUEGHBZTNND-UHFFFAOYSA-N 0.000 claims description 39
- LPCQBTAOTIZGAE-UHFFFAOYSA-N 2h-pyrimidine-1-carboxamide Chemical compound NC(=O)N1CN=CC=C1 LPCQBTAOTIZGAE-UHFFFAOYSA-N 0.000 claims description 2
- GSRZAXNWBZUUOT-MRXNPFEDSA-N 5-[(2r)-2-(5-fluoro-1-methyl-2-oxopyridin-3-yl)pyrrolidin-1-yl]-n-propan-2-ylpyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1([C@H]2CCCN2C=2C=CN3N=CC(=C3N=2)C(=O)NC(C)C)=CC(F)=CN(C)C1=O GSRZAXNWBZUUOT-MRXNPFEDSA-N 0.000 claims description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- CABSRBXIZHPYSN-MRXNPFEDSA-N n-tert-butyl-5-[(2r)-2-(5-fluoro-1-methyl-2-oxopyridin-3-yl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound O=C1N(C)C=C(F)C=C1[C@@H]1N(C2=NC3=C(C(=O)NC(C)(C)C)C=NN3C=C2)CCC1 CABSRBXIZHPYSN-MRXNPFEDSA-N 0.000 claims description 2
- CXFMNHBMKOIQLW-QGZVFWFLSA-N 5-[(2r)-2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl]-n-[2-[(2-methylpropan-2-yl)oxy]ethoxy]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1([C@H]2CCCN2C=2C=CN3N=CC(=C3N=2)C(=O)NOCCOC(C)(C)C)=CC(F)=CN=C1Cl CXFMNHBMKOIQLW-QGZVFWFLSA-N 0.000 claims 1
- YFZGYNMBIQOANX-TWOQFEAHSA-N 5-[(2r)-2-(2-ethyl-5-fluoropyridin-3-yl)pyrrolidin-1-yl]-n-[(1s,3s)-3-hydroxycyclopentyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound CCC1=NC=C(F)C=C1[C@@H]1N(C2=NC3=C(C(=O)N[C@@H]4C[C@@H](O)CC4)C=NN3C=C2)CCC1 YFZGYNMBIQOANX-TWOQFEAHSA-N 0.000 claims 1
- LTWRCYLYOAZNPD-FQNRMIAFSA-N 5-[(2r)-2-[2-(2,3-dihydroxypropoxy)-5-fluorophenyl]pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1([C@H]2CCCN2C=2C=CN3N=CC(=C3N=2)C(=O)N)=CC(F)=CC=C1OCC(O)CO LTWRCYLYOAZNPD-FQNRMIAFSA-N 0.000 claims 1
- JDIGZDKHSLPKGP-KPMSDPLLSA-N 5-[(2r)-2-[2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-5-fluorophenyl]pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound O1C(C)(C)OCC1COC1=CC=C(F)C=C1[C@@H]1N(C2=NC3=C(C(N)=O)C=NN3C=C2)CCC1 JDIGZDKHSLPKGP-KPMSDPLLSA-N 0.000 claims 1
- UGWUALPBTGHKQH-FBMWCMRBSA-N 5-[(2r)-2-[3-(2,3-dihydroxypropoxy)-5-fluorophenyl]pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1([C@H]2CCCN2C=2C=CN3N=CC(=C3N=2)C(=O)N)=CC(F)=CC(OCC(O)CO)=C1 UGWUALPBTGHKQH-FBMWCMRBSA-N 0.000 claims 1
- QXACJSRSZMVUQK-WHCXFUJUSA-N 5-[(2r)-2-[3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-5-fluorophenyl]pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound O1C(C)(C)OCC1COC1=CC(F)=CC([C@@H]2N(CCC2)C2=NC3=C(C(N)=O)C=NN3C=C2)=C1 QXACJSRSZMVUQK-WHCXFUJUSA-N 0.000 claims 1
- TUPCMOPJDADTAY-DZGCQCFKSA-N 5-[(2r,4s)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl]-n-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1([C@H]2C[C@H](O)CN2C=2C=CN3N=CC(=C3N=2)C(=O)NC)=CC=CC(F)=C1 TUPCMOPJDADTAY-DZGCQCFKSA-N 0.000 claims 1
- VEFAIJAFTRTKSA-DOTOQJQBSA-N 5-[(2r,4s)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl]-n-propan-2-ylpyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1([C@H]2C[C@H](O)CN2C=2C=CN3N=CC(=C3N=2)C(=O)NC(C)C)=CC=CC(F)=C1 VEFAIJAFTRTKSA-DOTOQJQBSA-N 0.000 claims 1
- HHFHBMCHRPJYLX-DOTOQJQBSA-N 5-[(2r,5s)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl]-n-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1=NN2C=CC(N3[C@H](CC[C@H]3CO)C=3C=C(F)C=NC=3)=NC2=C1C(=O)NC1(C)CC1 HHFHBMCHRPJYLX-DOTOQJQBSA-N 0.000 claims 1
- AROVXDKGPGGRBP-DIOULYMOSA-N 5-[(2r,5s)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl]-n-[(2r)-1,1,1-trifluoropropan-2-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1([C@H]2CC[C@@H](CO)N2C=2C=CN3N=CC(=C3N=2)C(=O)N[C@H](C)C(F)(F)F)=CN=CC(F)=C1 AROVXDKGPGGRBP-DIOULYMOSA-N 0.000 claims 1
- YYCRCMXHHDOWEV-DOTOQJQBSA-N 5-[(2r,5s)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl]-n-propan-2-ylpyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1([C@H]2CC[C@@H](CO)N2C=2C=CN3N=CC(=C3N=2)C(=O)NC(C)C)=CN=CC(F)=C1 YYCRCMXHHDOWEV-DOTOQJQBSA-N 0.000 claims 1
- JPAYSBNMHYNPLA-KRYHZZBUSA-N 5-[(2s,5r)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl]-n-[(2s)-1,1,1-trifluoropropan-2-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1([C@@H]2N([C@](CC2)(C)CO)C=2C=CN3N=CC(=C3N=2)C(=O)N[C@@H](C)C(F)(F)F)=CN=CC(F)=C1 JPAYSBNMHYNPLA-KRYHZZBUSA-N 0.000 claims 1
- COJJJJKXTCQCLW-UHFFFAOYSA-N 5-[2-(2-ethyl-5-fluoropyridin-3-yl)pyrrolidin-1-yl]-n-(4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound CCC1=NC=C(F)C=C1C1N(C2=NC3=C(C(=O)NC4CCC(O)CC4)C=NN3C=C2)CCC1 COJJJJKXTCQCLW-UHFFFAOYSA-N 0.000 claims 1
- GYPXDOPFEWTHRF-CTWPCTMYSA-N 5-[2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl]-N-[(2R)-2-hydroxycyclopentyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound CC1=C(C=C(F)C=N1)C1CCCN1C1=NC2=C(C=NN2C=C1)C(=O)NC1CCC[C@H]1O GYPXDOPFEWTHRF-CTWPCTMYSA-N 0.000 claims 1
- IHXVXJVXFFLYQL-OAHLLOKOSA-N [5-[(2r)-2-(2-amino-5-fluoropyridin-3-yl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-(azetidin-1-yl)methanone Chemical compound NC1=NC=C(F)C=C1[C@@H]1N(C2=NC3=C(C(=O)N4CCC4)C=NN3C=C2)CCC1 IHXVXJVXFFLYQL-OAHLLOKOSA-N 0.000 claims 1
- RWIYPTPMXPGFTG-CQSZACIVSA-N n-(2-chloroethyl)-5-[(2r)-2-(5-fluoro-2-oxo-1h-pyridin-3-yl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound FC1=CNC(=O)C([C@@H]2N(CCC2)C2=NC3=C(C(=O)NCCCl)C=NN3C=C2)=C1 RWIYPTPMXPGFTG-CQSZACIVSA-N 0.000 claims 1
- DKIDZDUYOIVIOB-OAHLLOKOSA-N n-(3-aminopropyl)-5-[(2r)-2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1([C@H]2CCCN2C=2C=CN3N=CC(=C3N=2)C(=O)NCCCN)=CC(F)=CN=C1Cl DKIDZDUYOIVIOB-OAHLLOKOSA-N 0.000 claims 1
- ZGPOATYOAANSTK-LRTDYKAYSA-N n-cyclopropyl-5-[(2r)-2-[2-(2,3-dihydroxypropoxy)-5-fluorophenyl]pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound OCC(O)COC1=CC=C(F)C=C1[C@@H]1N(C2=NC3=C(C(=O)NC4CC4)C=NN3C=C2)CCC1 ZGPOATYOAANSTK-LRTDYKAYSA-N 0.000 claims 1
- SVIHXEVVNNRVEM-BDPMCISCSA-N n-cyclopropyl-5-[(2r)-2-[2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-5-fluorophenyl]pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound O1C(C)(C)OCC1COC1=CC=C(F)C=C1[C@@H]1N(C2=NC3=C(C(=O)NC4CC4)C=NN3C=C2)CCC1 SVIHXEVVNNRVEM-BDPMCISCSA-N 0.000 claims 1
- YDZSAJWQPHVDHL-UUSAFJCLSA-N n-cyclopropyl-5-[(2r)-2-[3-(2,3-dihydroxypropoxy)-5-fluorophenyl]pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound OCC(O)COC1=CC(F)=CC([C@@H]2N(CCC2)C2=NC3=C(C(=O)NC4CC4)C=NN3C=C2)=C1 YDZSAJWQPHVDHL-UUSAFJCLSA-N 0.000 claims 1
- HLAYAPGHRGSWFL-LWMIZPGFSA-N n-cyclopropyl-5-[(2r)-2-[3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-5-fluorophenyl]pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound O1C(C)(C)OCC1COC1=CC(F)=CC([C@@H]2N(CCC2)C2=NC3=C(C(=O)NC4CC4)C=NN3C=C2)=C1 HLAYAPGHRGSWFL-LWMIZPGFSA-N 0.000 claims 1
- SPGMDULIPMJULM-OAHLLOKOSA-N n-tert-butyl-5-[(2r)-2-(5-fluoro-2-oxo-1h-pyridin-3-yl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1([C@H]2CCCN2C=2C=CN3N=CC(=C3N=2)C(=O)NC(C)(C)C)=CC(F)=CNC1=O SPGMDULIPMJULM-OAHLLOKOSA-N 0.000 claims 1
- VFMSIBXMZDZEJB-GOSISDBHSA-N tert-butyl n-[3-[[5-[(2r)-2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]propyl]carbamate Chemical compound C1([C@H]2CCCN2C=2C=CN3N=CC(=C3N=2)C(=O)NCCCNC(=O)OC(C)(C)C)=CC(F)=CN=C1Cl VFMSIBXMZDZEJB-GOSISDBHSA-N 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 46
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract description 35
- 125000001424 substituent group Chemical group 0.000 abstract description 18
- 229910052736 halogen Inorganic materials 0.000 abstract description 15
- 150000002367 halogens Chemical group 0.000 abstract description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 12
- 150000001875 compounds Chemical class 0.000 abstract description 9
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract description 7
- 125000000217 alkyl group Chemical group 0.000 abstract description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 7
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract description 6
- 125000005842 heteroatom Chemical group 0.000 abstract description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 abstract description 3
- 125000004990 dihydroxyalkyl group Chemical group 0.000 abstract description 3
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 3
- 125000003545 alkoxy group Chemical group 0.000 abstract description 2
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 abstract 3
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 abstract 2
- 229910006074 SO2NH2 Inorganic materials 0.000 abstract 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract 2
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 2
- 125000000565 sulfonamide group Chemical group 0.000 abstract 2
- 125000006163 5-membered heteroaryl group Chemical group 0.000 abstract 1
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 abstract 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
- 208000035480 Ring chromosome 8 syndrome Diseases 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 abstract 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 67
- 239000000126 substance Substances 0.000 description 15
- 230000005764 inhibitory process Effects 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- 101150009057 JAK2 gene Proteins 0.000 description 10
- 101150111783 NTRK1 gene Proteins 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 5
- 125000002757 morpholinyl group Chemical group 0.000 description 5
- 239000007821 HATU Substances 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- HNYVPKNVKSTVJO-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine-3-carboxylic acid Chemical compound C1=CC=NC2=C(C(=O)O)C=NN21 HNYVPKNVKSTVJO-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 2
- BYHQTRFJOGIQAO-GOSISDBHSA-N 3-(4-bromophenyl)-8-[(2R)-2-hydroxypropyl]-1-[(3-methoxyphenyl)methyl]-1,3,8-triazaspiro[4.5]decan-2-one Chemical compound C[C@H](CN1CCC2(CC1)CN(C(=O)N2CC3=CC(=CC=C3)OC)C4=CC=C(C=C4)Br)O BYHQTRFJOGIQAO-GOSISDBHSA-N 0.000 description 2
- UEHKWTJSMNTTCC-SJKOYZFVSA-N 5-[(2R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]-N-[(2R)-2-hydroxypropyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C[C@@H](O)CNC(=O)C1=C2N=C(C=CN2N=C1)N1CCC[C@@H]1C1=C(F)C=CC(F)=C1 UEHKWTJSMNTTCC-SJKOYZFVSA-N 0.000 description 2
- OCOGRTZGTMVULM-CQSZACIVSA-N 5-[(2r)-2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid Chemical compound CC1=NC=C(F)C=C1[C@@H]1N(C2=NC3=C(C(O)=O)C=NN3C=C2)CCC1 OCOGRTZGTMVULM-CQSZACIVSA-N 0.000 description 2
- IXSCVLCXUSMFAU-CYBMUJFWSA-N 5-[(2r)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid Chemical compound C1([C@H]2CCCN2C=2C=CN3N=CC(=C3N=2)C(=O)O)=CN=CC(F)=C1 IXSCVLCXUSMFAU-CYBMUJFWSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 101150069380 JAK3 gene Proteins 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- MBOJMCCWZHTXSJ-UHFFFAOYSA-N [1-(trifluoromethyl)cyclopropyl]azanium;chloride Chemical compound Cl.FC(F)(F)C1(N)CC1 MBOJMCCWZHTXSJ-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001207 fluorophenyl group Chemical group 0.000 description 2
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical group O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- CSOYDALHEQEMAK-UHFFFAOYSA-N 2h-pyrimidine-1-carboxylic acid Chemical compound OC(=O)N1CN=CC=C1 CSOYDALHEQEMAK-UHFFFAOYSA-N 0.000 description 1
- OTCSCPHWCZZRDC-LBXVMSDZSA-N 5-[(2R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl]-N-(4-methylsulfonylcyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound COC1=NC=C(F)C=C1[C@H]1CCCN1C1=NC2=C(C=NN2C=C1)C(=O)NC1CCC(CC1)S(C)(=O)=O OTCSCPHWCZZRDC-LBXVMSDZSA-N 0.000 description 1
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- VTUVGNKQBUVKIW-MRXNPFEDSA-N 5-[(2r)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl]-n-(3-hydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound COC1=NC=C(F)C=C1[C@@H]1N(C2=NC3=C(C(=O)NCCCO)C=NN3C=C2)CCC1 VTUVGNKQBUVKIW-MRXNPFEDSA-N 0.000 description 1
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- ZYIYWAPOCQBZSM-UHFFFAOYSA-N 5-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]-n-[2-(4-hydroxypiperidin-1-yl)ethyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1CC(O)CCN1CCNC(=O)C1=C2N=C(N3C(CCC3)C=3C(=CC=C(F)C=3)F)C=CN2N=C1 ZYIYWAPOCQBZSM-UHFFFAOYSA-N 0.000 description 1
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- MZSVPTRXUHRPHP-UHFFFAOYSA-N 5-fluoro-1-methylpyridin-2-one Chemical compound CN1C=C(F)C=CC1=O MZSVPTRXUHRPHP-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- FVIGODVHAVLZOO-UHFFFAOYSA-N Dixanthogen Chemical compound CCOC(=S)SSC(=S)OCC FVIGODVHAVLZOO-UHFFFAOYSA-N 0.000 description 1
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 description 1
- 108010081348 HRT1 protein Hairy Proteins 0.000 description 1
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- IAQOHRSJLFSNIO-MRXNPFEDSA-N [5-[(2r)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-(3-hydroxyazetidin-1-yl)methanone Chemical compound C1C(O)CN1C(=O)C1=C2N=C(N3[C@H](CCC3)C=3C=C(F)C=NC=3)C=CN2N=C1 IAQOHRSJLFSNIO-MRXNPFEDSA-N 0.000 description 1
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- 239000012267 brine Substances 0.000 description 1
- DGLFSNZWRYADFC-UHFFFAOYSA-N chembl2334586 Chemical compound C1CCC2=CN=C(N)N=C2C2=C1NC1=CC=C(C#CC(C)(O)C)C=C12 DGLFSNZWRYADFC-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- HGBUMXKTCONBMP-FQNRMIAFSA-N n-(2,3-dihydroxypropyl)-5-[(2r)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound COC1=NC=C(F)C=C1[C@@H]1N(C2=NC3=C(C(=O)NCC(O)CO)C=NN3C=C2)CCC1 HGBUMXKTCONBMP-FQNRMIAFSA-N 0.000 description 1
- DLSRDRNPMPGSGU-OAHLLOKOSA-N n-(2-bromoethoxy)-5-[(2r)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound COC1=NC=C(F)C=C1[C@@H]1N(C2=NC3=C(C(=O)NOCCBr)C=NN3C=C2)CCC1 DLSRDRNPMPGSGU-OAHLLOKOSA-N 0.000 description 1
- VYIVOYKEWZBJNX-OAHLLOKOSA-N n-(2-chloroethyl)-5-[(2r)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound COC1=NC=C(F)C=C1[C@@H]1N(C2=NC3=C(C(=O)NCCCl)C=NN3C=C2)CCC1 VYIVOYKEWZBJNX-OAHLLOKOSA-N 0.000 description 1
- PKQNMQSZDCVFLD-GOSISDBHSA-N n-cyclobutyl-5-[(2r)-2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound CC1=NC=C(F)C=C1[C@@H]1N(C2=NC3=C(C(=O)NC4CCC4)C=NN3C=C2)CCC1 PKQNMQSZDCVFLD-GOSISDBHSA-N 0.000 description 1
- QVEBEDUBSUAZSH-UHFFFAOYSA-N n-cyclobutyl-5-[2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound FC1=CN=CC(C2N(CCC2)C2=NC3=C(C(=O)NC4CCC4)C=NN3C=C2)=C1 QVEBEDUBSUAZSH-UHFFFAOYSA-N 0.000 description 1
- HNJJBTOZBLOWTO-UHFFFAOYSA-N n-cyclopropyl-5-[2-(2-ethyl-5-fluoropyridin-3-yl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound CCC1=NC=C(F)C=C1C1N(C2=NC3=C(C(=O)NC4CC4)C=NN3C=C2)CCC1 HNJJBTOZBLOWTO-UHFFFAOYSA-N 0.000 description 1
- XCCJJNIKWGXTSP-UHFFFAOYSA-N n-cyclopropyl-5-[2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound CC1=NC=C(F)C=C1C1N(C2=NC3=C(C(=O)NC4CC4)C=NN3C=C2)CCC1 XCCJJNIKWGXTSP-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- GHEKGGDYVHWSBM-UHFFFAOYSA-N tert-butyl n-[1-(trifluoromethyl)cyclopropyl]carbamate Chemical compound CC(C)(C)OC(=O)NC1(C(F)(F)F)CC1 GHEKGGDYVHWSBM-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
- C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—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
- C07D471/22—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 systems contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Tropical Medicine & Parasitology (AREA)
- Rheumatology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US224196P | 2000-08-09 | ||
| US22419609P | 2009-07-09 | 2009-07-09 | |
| US34676710P | 2010-05-20 | 2010-05-20 | |
| US346767P | 2010-05-20 | ||
| PCT/US2010/041538 WO2011006074A1 (en) | 2009-07-09 | 2010-07-09 | SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINE COMPOUNDS AS TRK KINASE INHIBITORS |
Publications (1)
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