CA2511321A1 - Pyrazole-derivatives as factor xa inhibitors - Google Patents
Pyrazole-derivatives as factor xa inhibitors Download PDFInfo
- Publication number
- CA2511321A1 CA2511321A1 CA002511321A CA2511321A CA2511321A1 CA 2511321 A1 CA2511321 A1 CA 2511321A1 CA 002511321 A CA002511321 A CA 002511321A CA 2511321 A CA2511321 A CA 2511321A CA 2511321 A1 CA2511321 A1 CA 2511321A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- pyrazole
- chloro
- thiophen
- piperidin
- 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.)
- Abandoned
Links
- 229940123583 Factor Xa inhibitor Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 180
- 238000000034 method Methods 0.000 claims abstract description 37
- 108010074860 Factor Xa Proteins 0.000 claims abstract description 32
- 230000005764 inhibitory process Effects 0.000 claims abstract description 18
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 13
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 13
- 230000023555 blood coagulation Effects 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 230000008569 process Effects 0.000 claims abstract description 7
- 208000001435 Thromboembolism Diseases 0.000 claims abstract description 6
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 5
- 108010054265 Factor VIIa Proteins 0.000 claims abstract description 5
- 229940012414 factor viia Drugs 0.000 claims abstract description 5
- -1 phenylpyridyl Chemical group 0.000 claims description 656
- 125000000623 heterocyclic group Chemical group 0.000 claims description 176
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 141
- 125000000217 alkyl group Chemical group 0.000 claims description 130
- 125000003118 aryl group Chemical group 0.000 claims description 112
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 110
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 110
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 103
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 96
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 96
- 229910052736 halogen Inorganic materials 0.000 claims description 93
- 150000002367 halogens Chemical class 0.000 claims description 92
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 91
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 84
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 80
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 74
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 73
- 125000004122 cyclic group Chemical group 0.000 claims description 73
- 125000002950 monocyclic group Chemical group 0.000 claims description 69
- 229910052757 nitrogen Inorganic materials 0.000 claims description 69
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 68
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 66
- 125000002619 bicyclic group Chemical group 0.000 claims description 54
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 53
- ZRQQXFMGYSOKDF-UHFFFAOYSA-N 1-propan-2-ylpiperidin-4-amine Chemical compound CC(C)N1CCC(N)CC1 ZRQQXFMGYSOKDF-UHFFFAOYSA-N 0.000 claims description 52
- 125000004076 pyridyl group Chemical group 0.000 claims description 52
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 51
- GGURMRUSUXSEDS-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]pyrazole-3,5-dicarboxylic acid Chemical compound N1=C(C(=O)O)C=C(C(O)=O)N1CC1=NOC(C=2SC(Cl)=CC=2)=C1 GGURMRUSUXSEDS-UHFFFAOYSA-N 0.000 claims description 45
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 44
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 43
- 239000000203 mixture Substances 0.000 claims description 43
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical compound O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 claims description 42
- 125000005842 heteroatom Chemical group 0.000 claims description 41
- LRANPJDWHYRCER-UHFFFAOYSA-N 1,2-diazepine Chemical compound N1C=CC=CC=N1 LRANPJDWHYRCER-UHFFFAOYSA-N 0.000 claims description 39
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 39
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 39
- MSRJJSCOWHWGGX-UHFFFAOYSA-N 2h-1,3-diazepine Chemical compound C1N=CC=CC=N1 MSRJJSCOWHWGGX-UHFFFAOYSA-N 0.000 claims description 38
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 38
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 38
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 38
- 229910052717 sulfur Inorganic materials 0.000 claims description 38
- 239000011593 sulfur Substances 0.000 claims description 38
- 125000001544 thienyl group Chemical group 0.000 claims description 38
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 38
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 37
- 229910052760 oxygen Inorganic materials 0.000 claims description 37
- 239000001301 oxygen Substances 0.000 claims description 37
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 36
- 150000003536 tetrazoles Chemical class 0.000 claims description 36
- POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical compound N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 claims description 35
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 34
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical compound C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 claims description 34
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 claims description 34
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 34
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 claims description 34
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 34
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 34
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 34
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 34
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical compound C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 claims description 33
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 33
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 33
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 33
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 33
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 33
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 claims description 32
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- ZNGWEEUXTBNKFR-UHFFFAOYSA-N 1,4-oxazepane Chemical compound C1CNCCOC1 ZNGWEEUXTBNKFR-UHFFFAOYSA-N 0.000 claims description 31
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 30
- 230000015572 biosynthetic process Effects 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 29
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 28
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 28
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims description 27
- 239000000460 chlorine Substances 0.000 claims description 26
- 229910052801 chlorine Inorganic materials 0.000 claims description 26
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 26
- 125000000335 thiazolyl group Chemical group 0.000 claims description 26
- 229910052731 fluorine Inorganic materials 0.000 claims description 25
- 125000004429 atom Chemical group 0.000 claims description 24
- 125000001041 indolyl group Chemical group 0.000 claims description 24
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 24
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 claims description 23
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 23
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 23
- CZSRXHJVZUBEGW-UHFFFAOYSA-N 1,2-thiazolidine Chemical compound C1CNSC1 CZSRXHJVZUBEGW-UHFFFAOYSA-N 0.000 claims description 22
- GUUULVAMQJLDSY-UHFFFAOYSA-N 4,5-dihydro-1,2-thiazole Chemical compound C1CC=NS1 GUUULVAMQJLDSY-UHFFFAOYSA-N 0.000 claims description 22
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 22
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 22
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 22
- PPSZHCXTGRHULJ-UHFFFAOYSA-N dioxazine Chemical compound O1ON=CC=C1 PPSZHCXTGRHULJ-UHFFFAOYSA-N 0.000 claims description 22
- 125000002883 imidazolyl group Chemical group 0.000 claims description 22
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 22
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 22
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 claims description 22
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 22
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 22
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 22
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 22
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 21
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 claims description 21
- 239000011737 fluorine Substances 0.000 claims description 21
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 claims description 21
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 21
- BWCDLEQTELFBAW-UHFFFAOYSA-N 3h-dioxazole Chemical compound N1OOC=C1 BWCDLEQTELFBAW-UHFFFAOYSA-N 0.000 claims description 20
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 20
- 125000002971 oxazolyl group Chemical group 0.000 claims description 20
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 20
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 claims description 19
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 claims description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 claims description 19
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 19
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 19
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 claims description 19
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 19
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 18
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 18
- 125000002541 furyl group Chemical group 0.000 claims description 18
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 claims description 18
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 claims description 18
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 claims description 18
- 125000002053 thietanyl group Chemical group 0.000 claims description 18
- 229910008338 Si—(CH3) Inorganic materials 0.000 claims description 16
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 16
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 16
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 15
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 claims description 15
- 125000001153 fluoro group Chemical group F* 0.000 claims description 15
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 15
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 claims description 14
- KGWNRZLPXLBMPS-UHFFFAOYSA-N 2h-1,3-oxazine Chemical compound C1OC=CC=N1 KGWNRZLPXLBMPS-UHFFFAOYSA-N 0.000 claims description 14
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 14
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 14
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 14
- 229930192474 thiophene Natural products 0.000 claims description 14
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 13
- ABADUMLIAZCWJD-UHFFFAOYSA-N 1,3-dioxole Chemical compound C1OC=CO1 ABADUMLIAZCWJD-UHFFFAOYSA-N 0.000 claims description 13
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 13
- YHWMFDLNZGIJSD-UHFFFAOYSA-N 2h-1,4-oxazine Chemical compound C1OC=CN=C1 YHWMFDLNZGIJSD-UHFFFAOYSA-N 0.000 claims description 13
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 13
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims description 13
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 claims description 13
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 13
- 125000001624 naphthyl group Chemical group 0.000 claims description 13
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 claims description 13
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 12
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 claims description 12
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 12
- WXLCDTBTIVJDCE-UHFFFAOYSA-N 1,4-oxazepine Chemical compound O1C=CC=NC=C1 WXLCDTBTIVJDCE-UHFFFAOYSA-N 0.000 claims description 12
- 125000003386 piperidinyl group Chemical group 0.000 claims description 12
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 12
- ZHKJHQBOAJQXQR-UHFFFAOYSA-N 1H-azirine Chemical compound N1C=C1 ZHKJHQBOAJQXQR-UHFFFAOYSA-N 0.000 claims description 11
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 11
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 11
- NTYABNDBNKVWOO-UHFFFAOYSA-N 2h-1,3-thiazine Chemical compound C1SC=CC=N1 NTYABNDBNKVWOO-UHFFFAOYSA-N 0.000 claims description 11
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 claims description 11
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 11
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 11
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 claims description 11
- JZFICWYCTCCINF-UHFFFAOYSA-N Thiadiazin Chemical compound S=C1SC(C)NC(C)N1CCN1C(=S)SC(C)NC1C JZFICWYCTCCINF-UHFFFAOYSA-N 0.000 claims description 11
- 208000007536 Thrombosis Diseases 0.000 claims description 11
- 125000002393 azetidinyl group Chemical group 0.000 claims description 11
- 125000002757 morpholinyl group Chemical group 0.000 claims description 11
- SJGALSBBFTYSBA-UHFFFAOYSA-N oxaziridine Chemical compound C1NO1 SJGALSBBFTYSBA-UHFFFAOYSA-N 0.000 claims description 11
- 125000004193 piperazinyl group Chemical group 0.000 claims description 11
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 11
- ZAISDHPZTZIFQF-UHFFFAOYSA-N 2h-1,4-thiazine Chemical compound C1SC=CN=C1 ZAISDHPZTZIFQF-UHFFFAOYSA-N 0.000 claims description 10
- 125000005602 azabenzimidazolyl group Chemical group 0.000 claims description 10
- OOFGXDQWDNJDIS-UHFFFAOYSA-N oxathiolane Chemical compound C1COSC1 OOFGXDQWDNJDIS-UHFFFAOYSA-N 0.000 claims description 10
- 125000005493 quinolyl group Chemical group 0.000 claims description 10
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 10
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 10
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 claims description 9
- 125000004529 1,2,3-triazinyl group Chemical group N1=NN=C(C=C1)* 0.000 claims description 9
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 9
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 9
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims description 9
- 125000002785 azepinyl group Chemical group 0.000 claims description 9
- 125000004069 aziridinyl group Chemical group 0.000 claims description 9
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 9
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 9
- 125000005512 benztetrazolyl group Chemical group 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 9
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 claims description 9
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 9
- 125000003838 furazanyl group Chemical group 0.000 claims description 9
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 9
- 125000002636 imidazolinyl group Chemical group 0.000 claims description 9
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 claims description 9
- 125000005438 isoindazolyl group Chemical group 0.000 claims description 9
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 claims description 9
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 claims description 9
- 125000005969 isothiazolinyl group Chemical group 0.000 claims description 9
- 125000003965 isoxazolidinyl group Chemical group 0.000 claims description 9
- 125000003971 isoxazolinyl group Chemical group 0.000 claims description 9
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 9
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 9
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 9
- 125000005968 oxazolinyl group Chemical group 0.000 claims description 9
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 claims description 9
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 claims description 9
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 claims description 9
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 claims description 9
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 claims description 9
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 9
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 claims description 9
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 claims description 9
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 claims description 9
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 claims description 9
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 claims description 9
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 9
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 claims description 9
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 8
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 claims description 8
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 claims description 8
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims description 8
- 125000005962 1,4-oxazepanyl group Chemical group 0.000 claims description 8
- 125000000183 1,4-thiazinyl group Chemical group S1C(C=NC=C1)* 0.000 claims description 8
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 8
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 8
- 125000004623 carbolinyl group Chemical group 0.000 claims description 8
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 8
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 claims description 8
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 8
- 125000004930 octahydroisoquinolinyl group Chemical group C1(NCCC2CCCC=C12)* 0.000 claims description 8
- OXUZCBDDXOMZAM-UHFFFAOYSA-N oxathiepane Chemical compound C1CCOSCC1 OXUZCBDDXOMZAM-UHFFFAOYSA-N 0.000 claims description 8
- 125000005954 phenoxathiinyl group Chemical group 0.000 claims description 8
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 8
- 125000002755 pyrazolinyl group Chemical group 0.000 claims description 8
- 125000001422 pyrrolinyl group Chemical group 0.000 claims description 8
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 8
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 claims description 7
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 7
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 claims description 7
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 7
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 claims description 7
- 239000003146 anticoagulant agent Substances 0.000 claims description 7
- DIXBSCZRIZDQGC-UHFFFAOYSA-N diaziridine Chemical compound C1NN1 DIXBSCZRIZDQGC-UHFFFAOYSA-N 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical compound O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 claims description 7
- 208000037803 restenosis Diseases 0.000 claims description 7
- 238000001356 surgical procedure Methods 0.000 claims description 7
- 125000001425 triazolyl group Chemical group 0.000 claims description 7
- 230000002792 vascular Effects 0.000 claims description 7
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 claims description 6
- 125000000164 1,3-thiazinyl group Chemical group S1C(N=CC=C1)* 0.000 claims description 6
- 125000005955 1H-indazolyl group Chemical group 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 6
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 claims description 6
- 230000020764 fibrinolysis Effects 0.000 claims description 6
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 6
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- 210000003462 vein Anatomy 0.000 claims description 6
- IYCMYOWBZQNVBV-UHFFFAOYSA-N (1-propan-2-ylpiperidin-4-yl)methanamine Chemical compound CC(C)N1CCC(CN)CC1 IYCMYOWBZQNVBV-UHFFFAOYSA-N 0.000 claims description 5
- 125000004530 1,2,4-triazinyl group Chemical group N1=NC(=NC=C1)* 0.000 claims description 5
- 125000003363 1,3,5-triazinyl group Chemical group N1=C(N=CN=C1)* 0.000 claims description 5
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 claims description 5
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 claims description 5
- 230000001154 acute effect Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 5
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 5
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 claims description 5
- 125000006565 (C4-C7) cyclic group Chemical group 0.000 claims description 4
- RFOHSZFQYMEWMH-UHFFFAOYSA-N 1,3-diazocan-2-one Chemical compound O=C1NCCCCCN1 RFOHSZFQYMEWMH-UHFFFAOYSA-N 0.000 claims description 4
- CXPUAWQOXQINEX-UHFFFAOYSA-N 1,4-diazocane Chemical compound C1CCNCCNC1 CXPUAWQOXQINEX-UHFFFAOYSA-N 0.000 claims description 4
- GYZMNNQUSLUCLP-UHFFFAOYSA-N 1,4-dioxocane Chemical compound C1CCOCCOC1 GYZMNNQUSLUCLP-UHFFFAOYSA-N 0.000 claims description 4
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical compound OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 claims description 4
- XWIYUCRMWCHYJR-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical compound C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 claims description 4
- LSEGQJLZOKJPKV-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-4-cyano-5-propylpyrazole-3-carboxylic acid Chemical compound OC(=O)C1=C(C#N)C(CCC)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 LSEGQJLZOKJPKV-UHFFFAOYSA-N 0.000 claims description 4
- VZLZVBNWIQBCGN-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-4-cyano-5-thiophen-2-ylpyrazole-3-carboxylic acid Chemical compound OC(=O)C1=C(C#N)C(C=2SC=CC=2)=NN1CC(=NO1)C=C1C1=CC=C(Cl)S1 VZLZVBNWIQBCGN-UHFFFAOYSA-N 0.000 claims description 4
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 230000003187 abdominal effect Effects 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 238000002399 angioplasty Methods 0.000 claims description 4
- 125000005334 azaindolyl group Chemical group N1N=C(C2=CC=CC=C12)* 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- 210000003127 knee Anatomy 0.000 claims description 4
- 210000003141 lower extremity Anatomy 0.000 claims description 4
- 230000001575 pathological effect Effects 0.000 claims description 4
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 claims description 4
- 125000005494 pyridonyl group Chemical group 0.000 claims description 4
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 4
- 230000002537 thrombolytic effect Effects 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- HIZVCIIORGCREW-UHFFFAOYSA-N 1,4-dioxene Chemical group C1COC=CO1 HIZVCIIORGCREW-UHFFFAOYSA-N 0.000 claims description 3
- 206010002388 Angina unstable Diseases 0.000 claims description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 3
- 239000005977 Ethylene Substances 0.000 claims description 3
- 208000007814 Unstable Angina Diseases 0.000 claims description 3
- 230000002159 abnormal effect Effects 0.000 claims description 3
- 206010000891 acute myocardial infarction Diseases 0.000 claims description 3
- CJYXCQLOZNIMFP-UHFFFAOYSA-N azocan-2-one Chemical compound O=C1CCCCCCN1 CJYXCQLOZNIMFP-UHFFFAOYSA-N 0.000 claims description 3
- WZVHPXGAWGWKTL-UHFFFAOYSA-N diazocan-3-one Chemical compound O=C1CCCCCNN1 WZVHPXGAWGWKTL-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229960002449 glycine Drugs 0.000 claims description 3
- 230000028709 inflammatory response Effects 0.000 claims description 3
- 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 3
- BTLSLHNLDQCWKS-UHFFFAOYSA-N oxocan-2-one Chemical compound O=C1CCCCCCO1 BTLSLHNLDQCWKS-UHFFFAOYSA-N 0.000 claims description 3
- HZIVRQOIUMAXID-UHFFFAOYSA-N oxocane Chemical compound C1CCCOCCC1 HZIVRQOIUMAXID-UHFFFAOYSA-N 0.000 claims description 3
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
- 150000004911 1,4-diazepines Chemical class 0.000 claims description 2
- QKWMBAGVNAGKFD-UHFFFAOYSA-N 1-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carboxylic acid Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(O)=O)=NN1CC(=O)NC1=CC=C(Cl)C=N1 QKWMBAGVNAGKFD-UHFFFAOYSA-N 0.000 claims description 2
- OVVDMXKWFMNGLN-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-3-n,5-n-bis(1-propan-2-ylpiperidin-4-yl)pyrazole-3,5-dicarboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)NC2CCN(CC2)C(C)C)=C1 OVVDMXKWFMNGLN-UHFFFAOYSA-N 0.000 claims description 2
- FUDWOSJPMAUSHR-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-4-cyano-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C(C(=C1)C#N)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 FUDWOSJPMAUSHR-UHFFFAOYSA-N 0.000 claims description 2
- VKYPCYFLMMYWQE-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(2,2-dimethylpyrrolidine-1-carbonyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)N2C(CCC2)(C)C)=C1 VKYPCYFLMMYWQE-UHFFFAOYSA-N 0.000 claims description 2
- SYZNRFJJOOJACM-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(3-hydroxyazetidine-1-carbonyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)N2CC(O)C2)=C1 SYZNRFJJOOJACM-UHFFFAOYSA-N 0.000 claims description 2
- YAJPOTSMMQSCCV-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[4-(2-hydroxyethyl)piperazine-1-carbonyl]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)N2CCN(CCO)CC2)=C1 YAJPOTSMMQSCCV-UHFFFAOYSA-N 0.000 claims description 2
- BYQPTZFMJUFDIB-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C(C(=N1)C(F)(F)F)=CN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 BYQPTZFMJUFDIB-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
- OIWIYLWZIIJNHU-UHFFFAOYSA-N 1-sulfanylpyrazole Chemical compound SN1C=CC=N1 OIWIYLWZIIJNHU-UHFFFAOYSA-N 0.000 claims description 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 2
- VKJBICQSBBONRC-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-azocin-8-one Chemical compound O=C1NCCCCC=C1 VKJBICQSBBONRC-UHFFFAOYSA-N 0.000 claims description 2
- LNADAGVTTQMLKX-UHFFFAOYSA-N 2-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-(3-hydroxyazetidine-1-carbonyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2CC(O)C2)=NN1CC(=O)NC1=CC=C(Cl)C=N1 LNADAGVTTQMLKX-UHFFFAOYSA-N 0.000 claims description 2
- PZZOECRCLGPXIK-UHFFFAOYSA-N 2-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-[2-(2-methoxyethoxy)ethoxy]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C=1C=C(Cl)C=NC=1NC(=O)CN1N=C(OCCOCCOC)C=C1C(=O)NC1CCN(C(C)C)CC1 PZZOECRCLGPXIK-UHFFFAOYSA-N 0.000 claims description 2
- TWCHZMYBQKOAJI-UHFFFAOYSA-N 2-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-n-(1-propan-2-ylpiperidin-4-yl)-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(OCC(F)(F)F)=NN1CC(=O)NC1=CC=C(Cl)C=N1 TWCHZMYBQKOAJI-UHFFFAOYSA-N 0.000 claims description 2
- AVAGFHKMVTVWEF-UHFFFAOYSA-N 2-[[2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carbonyl]amino]ethyl hydrogen sulfate Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)NCCOS(O)(=O)=O)=C1 AVAGFHKMVTVWEF-UHFFFAOYSA-N 0.000 claims description 2
- RVPWYEUJXQXLMA-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-4-cyano-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=C(C#N)C=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 RVPWYEUJXQXLMA-UHFFFAOYSA-N 0.000 claims description 2
- FCFBDEQSQTZCKX-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(2-oxo-3h-1,3,4-oxadiazol-5-yl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C=2OC(=O)NN=2)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 FCFBDEQSQTZCKX-UHFFFAOYSA-N 0.000 claims description 2
- BALWXLJIHCTWKH-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[4-(2-hydroxyethyl)piperazine-1-carbonyl]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2CCN(CCO)CC2)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 BALWXLJIHCTWKH-UHFFFAOYSA-N 0.000 claims description 2
- XNAJMQNQPFWKRR-UHFFFAOYSA-N 2-hydroxyethyl 1-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carboxylate Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)OCCO)=NN1CC(=O)NC1=CC=C(Cl)C=N1 XNAJMQNQPFWKRR-UHFFFAOYSA-N 0.000 claims description 2
- DECGKHKHBIAIRZ-UHFFFAOYSA-N 2-hydroxyethyl 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carboxylate Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)OCCO)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 DECGKHKHBIAIRZ-UHFFFAOYSA-N 0.000 claims description 2
- VJUJGBBDKJIPPK-UHFFFAOYSA-N 2-methoxyethyl 1-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carboxylate Chemical compound C=1C=C(Cl)C=NC=1NC(=O)CN1N=C(C(=O)OCCOC)C=C1C(=O)NC1CCN(C(C)C)CC1 VJUJGBBDKJIPPK-UHFFFAOYSA-N 0.000 claims description 2
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 2
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 2
- 206010002383 Angina Pectoris Diseases 0.000 claims description 2
- QANYYPZIKNYGFV-UHFFFAOYSA-N C1CC(C1)NC(=O)C1=NN(C(=C1)C(=O)O)CC(NC1=NC=C(C=C1)Cl)=O Chemical compound C1CC(C1)NC(=O)C1=NN(C(=C1)C(=O)O)CC(NC1=NC=C(C=C1)Cl)=O QANYYPZIKNYGFV-UHFFFAOYSA-N 0.000 claims description 2
- 206010053567 Coagulopathies Diseases 0.000 claims description 2
- 208000005189 Embolism Diseases 0.000 claims description 2
- 206010022562 Intermittent claudication Diseases 0.000 claims description 2
- 208000034486 Multi-organ failure Diseases 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 claims description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 208000032109 Transient ischaemic attack Diseases 0.000 claims description 2
- 206010047249 Venous thrombosis Diseases 0.000 claims description 2
- 208000036142 Viral infection Diseases 0.000 claims description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 2
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 2
- 210000001367 artery Anatomy 0.000 claims description 2
- 125000003725 azepanyl group Chemical group 0.000 claims description 2
- QXNDZONIWRINJR-UHFFFAOYSA-N azocane Chemical compound C1CCCNCCC1 QXNDZONIWRINJR-UHFFFAOYSA-N 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 238000007887 coronary angioplasty Methods 0.000 claims description 2
- 208000029078 coronary artery disease Diseases 0.000 claims description 2
- 238000001631 haemodialysis Methods 0.000 claims description 2
- 230000000322 hemodialysis Effects 0.000 claims description 2
- 208000021156 intermittent vascular claudication Diseases 0.000 claims description 2
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 2
- 230000007774 longterm Effects 0.000 claims description 2
- 238000012423 maintenance Methods 0.000 claims description 2
- CCDHBZSYRBQDKM-UHFFFAOYSA-N methyl 1-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carboxylate Chemical compound C=1C=C(Cl)C=NC=1NC(=O)CN1N=C(C(=O)OC)C=C1C(=O)NC1CCN(C(C)C)CC1 CCDHBZSYRBQDKM-UHFFFAOYSA-N 0.000 claims description 2
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 claims description 2
- 208000010125 myocardial infarction Diseases 0.000 claims description 2
- 230000002093 peripheral effect Effects 0.000 claims description 2
- 125000004928 piperidonyl group Chemical group 0.000 claims description 2
- 238000010577 post-coronary angioplasty Methods 0.000 claims description 2
- 230000009885 systemic effect Effects 0.000 claims description 2
- 201000010875 transient cerebral ischemia Diseases 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 238000007891 venous angioplasty Methods 0.000 claims description 2
- 230000009385 viral infection Effects 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 3
- WWFRSWPBUNIUJR-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(2-oxo-1,3-oxazolidine-3-carbonyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2C(OCC2)=O)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 WWFRSWPBUNIUJR-UHFFFAOYSA-N 0.000 claims 2
- LTXWLSOMNVDSON-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(3-hydroxyazetidine-1-carbonyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2CC(O)C2)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 LTXWLSOMNVDSON-UHFFFAOYSA-N 0.000 claims 2
- VULRIWHYXFKIIN-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(4,4-difluoropiperidine-1-carbonyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2CCC(F)(F)CC2)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 VULRIWHYXFKIIN-UHFFFAOYSA-N 0.000 claims 2
- IKJWKUWNJONWCL-UHFFFAOYSA-N 5-(azetidine-1-carbonyl)-1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)N2CCC2)=C1 IKJWKUWNJONWCL-UHFFFAOYSA-N 0.000 claims 2
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims 2
- 108010081348 HRT1 protein Hairy Proteins 0.000 claims 2
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims 2
- FIDRAVVQGKNYQK-UHFFFAOYSA-N 1,2,3,4-tetrahydrotriazine Chemical compound C1NNNC=C1 FIDRAVVQGKNYQK-UHFFFAOYSA-N 0.000 claims 1
- 150000000192 1,4-thiazines Chemical class 0.000 claims 1
- JACMHXRHWPTUSH-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carboxylic acid Chemical compound COC1=CC=CC(CN2C(=CC(=N2)C(O)=O)C(=O)NC2CCN(CC2)C(C)C)=C1 JACMHXRHWPTUSH-UHFFFAOYSA-N 0.000 claims 1
- VTKBCWRRNUNUTE-UHFFFAOYSA-N 1-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-(hydroxymethyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC(=O)NC=2N=CC(Cl)=CC=2)C(CO)=C1 VTKBCWRRNUNUTE-UHFFFAOYSA-N 0.000 claims 1
- ZDNFVEPSUQEOMF-UHFFFAOYSA-N 1-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-[2-(2-methoxyethoxy)ethoxymethyl]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound COCCOCCOCC1=CC(C(=O)NC2CCN(CC2)C(C)C)=NN1CC(=O)NC1=CC=C(Cl)C=N1 ZDNFVEPSUQEOMF-UHFFFAOYSA-N 0.000 claims 1
- QREXSVFXXKWBAJ-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-3-n-methylsulfonyl-5-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3,5-dicarboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)NS(C)(=O)=O)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 QREXSVFXXKWBAJ-UHFFFAOYSA-N 0.000 claims 1
- RHTSVKCTKSQNAB-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(2-oxo-1,3-oxazolidine-3-carbonyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)N2C(OCC2)=O)=C1 RHTSVKCTKSQNAB-UHFFFAOYSA-N 0.000 claims 1
- JPQGPWDWWPQYEU-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(2-oxo-3h-1,3,4-oxadiazol-5-yl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C=2OC(=O)NN=2)=C1 JPQGPWDWWPQYEU-UHFFFAOYSA-N 0.000 claims 1
- UNUMMFIBPNTOPT-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(3-hydroxypyrrolidine-1-carbonyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)N2CC(O)CC2)=C1 UNUMMFIBPNTOPT-UHFFFAOYSA-N 0.000 claims 1
- MCFPQJDETZLHHJ-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(3-methylsulfonylpyrrolidine-1-carbonyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)N2CC(CC2)S(C)(=O)=O)=C1 MCFPQJDETZLHHJ-UHFFFAOYSA-N 0.000 claims 1
- WUMLJYCGGKNFLS-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(3-oxopiperazine-1-carbonyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)N2CC(=O)NCC2)=C1 WUMLJYCGGKNFLS-UHFFFAOYSA-N 0.000 claims 1
- OUKSVIDVIAYXAP-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(4,4-difluoropiperidine-1-carbonyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)N2CCC(F)(F)CC2)=C1 OUKSVIDVIAYXAP-UHFFFAOYSA-N 0.000 claims 1
- ZNHVVTLYJIFLQX-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(4-hydroxypiperidine-1-carbonyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)N2CCC(O)CC2)=C1 ZNHVVTLYJIFLQX-UHFFFAOYSA-N 0.000 claims 1
- CSWIFDWSGAPZQQ-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(furan-2-yl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C=2OC=CC=2)=C1 CSWIFDWSGAPZQQ-UHFFFAOYSA-N 0.000 claims 1
- IGFMAGLCUPICTQ-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(furan-2-yl)-n-[4-(3-oxomorpholin-4-yl)phenyl]pyrazole-3-carboxamide Chemical compound S1C(Cl)=CC=C1C1=CC(CN2C(=CC(=N2)C(=O)NC=2C=CC(=CC=2)N2C(COCC2)=O)C=2OC=CC=2)=NO1 IGFMAGLCUPICTQ-UHFFFAOYSA-N 0.000 claims 1
- UDAUGUQIALOTKL-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[2-(hydroxymethyl)pyrrolidine-1-carbonyl]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)N2C(CCC2)CO)=C1 UDAUGUQIALOTKL-UHFFFAOYSA-N 0.000 claims 1
- UTCLQHBUZZGUBS-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[4-(hydroxymethyl)piperidine-1-carbonyl]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)N2CCC(CO)CC2)=C1 UTCLQHBUZZGUBS-UHFFFAOYSA-N 0.000 claims 1
- WOZBYUXMCLGDEF-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)-5-(thiomorpholine-4-carbonyl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)N2CCSCC2)=C1 WOZBYUXMCLGDEF-UHFFFAOYSA-N 0.000 claims 1
- UBLJZAIYKTXMGT-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)-5-[2-(trifluoromethyl)pyrrolidine-1-carbonyl]pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)N2C(CCC2)C(F)(F)F)=C1 UBLJZAIYKTXMGT-UHFFFAOYSA-N 0.000 claims 1
- RWCRMRXVVDJHMG-UHFFFAOYSA-N 2-[1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carbonyl]oxyacetic acid Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)OCC(O)=O)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 RWCRMRXVVDJHMG-UHFFFAOYSA-N 0.000 claims 1
- LPMNHRZHTYWBHS-UHFFFAOYSA-N 2-[2-(4-chloroanilino)-2-oxoethyl]-4-cyano-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=C(C#N)C=NN1CC(=O)NC1=CC=C(Cl)C=C1 LPMNHRZHTYWBHS-UHFFFAOYSA-N 0.000 claims 1
- PHEQJVWSHMERPD-UHFFFAOYSA-N 2-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-(1,4-oxazepane-4-carbonyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2CCOCCC2)=NN1CC(=O)NC1=CC=C(Cl)C=N1 PHEQJVWSHMERPD-UHFFFAOYSA-N 0.000 claims 1
- LNSAXVOIIHJKAG-UHFFFAOYSA-N 2-[[1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carbonyl]amino]-3,3,3-trifluoropropanoic acid Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)NC(C(O)=O)C(F)(F)F)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 LNSAXVOIIHJKAG-UHFFFAOYSA-N 0.000 claims 1
- PHTBBVXSIJPAJE-UHFFFAOYSA-N 2-[[1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carbonyl]amino]ethyl dihydrogen phosphate Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)NCCOP(O)(O)=O)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 PHTBBVXSIJPAJE-UHFFFAOYSA-N 0.000 claims 1
- RBHADQWGSYUDMU-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(1,4-oxazepane-4-carbonyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2CCOCCC2)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 RBHADQWGSYUDMU-UHFFFAOYSA-N 0.000 claims 1
- UJYSLQLGXWWMBS-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(2,2-dimethylpyrrolidine-1-carbonyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2C(CCC2)(C)C)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 UJYSLQLGXWWMBS-UHFFFAOYSA-N 0.000 claims 1
- OPWGMMQINUFSCR-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(3-hydroxypyrrolidine-1-carbonyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2CC(O)CC2)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 OPWGMMQINUFSCR-UHFFFAOYSA-N 0.000 claims 1
- QXNISAJLGKODCE-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(3-methylsulfonylpyrrolidine-1-carbonyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2CC(CC2)S(C)(=O)=O)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 QXNISAJLGKODCE-UHFFFAOYSA-N 0.000 claims 1
- YFQPTTHWCHRRNO-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(4-hydroxypiperidine-1-carbonyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2CCC(O)CC2)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 YFQPTTHWCHRRNO-UHFFFAOYSA-N 0.000 claims 1
- YKHIOPPDUVHGCL-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carboxylic acid Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(O)=O)=C1 YKHIOPPDUVHGCL-UHFFFAOYSA-N 0.000 claims 1
- XIOCGHJMVWFOQW-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[2-(hydroxymethyl)pyrrolidine-1-carbonyl]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2C(CCC2)CO)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 XIOCGHJMVWFOQW-UHFFFAOYSA-N 0.000 claims 1
- NCGXAVOHHUAIOV-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[4-(2-oxopyrrolidin-1-yl)piperidine-1-carbonyl]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2CCC(CC2)N2C(CCC2)=O)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 NCGXAVOHHUAIOV-UHFFFAOYSA-N 0.000 claims 1
- PZLBMPDRVKGEDJ-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[4-(hydroxymethyl)piperidine-1-carbonyl]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2CCC(CO)CC2)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 PZLBMPDRVKGEDJ-UHFFFAOYSA-N 0.000 claims 1
- RLLIVYAPBPIXDT-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)-5-(1,3-thiazolidine-3-carbonyl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2CSCC2)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 RLLIVYAPBPIXDT-UHFFFAOYSA-N 0.000 claims 1
- DGNUPCRLEZEJHY-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)-5-(pyrrolidine-1-carbonyl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2CCCC2)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 DGNUPCRLEZEJHY-UHFFFAOYSA-N 0.000 claims 1
- HMVSSZRUJOAIER-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)-5-(thiomorpholine-4-carbonyl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2CCSCC2)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 HMVSSZRUJOAIER-UHFFFAOYSA-N 0.000 claims 1
- JDAJKZAZEKHTPQ-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)-5-[2-(trifluoromethyl)pyrrolidine-1-carbonyl]pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2C(CCC2)C(F)(F)F)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 JDAJKZAZEKHTPQ-UHFFFAOYSA-N 0.000 claims 1
- AFFMCTJYSNDYMU-UHFFFAOYSA-N 5-(8-azaspiro[4.5]decane-8-carbonyl)-1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)N2CCC3(CCCC3)CC2)=C1 AFFMCTJYSNDYMU-UHFFFAOYSA-N 0.000 claims 1
- RNCXJFOQGRMEAD-UHFFFAOYSA-N 5-(8-azaspiro[4.5]decane-8-carbonyl)-2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2CCC3(CCCC3)CC2)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 RNCXJFOQGRMEAD-UHFFFAOYSA-N 0.000 claims 1
- RPRYVADYLZGDNO-UHFFFAOYSA-N 5-(azetidine-1-carbonyl)-2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2CCC2)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 RPRYVADYLZGDNO-UHFFFAOYSA-N 0.000 claims 1
- ZODUIPOEAJGRJM-UHFFFAOYSA-N 5-[2,5-bis(methoxymethyl)pyrrolidine-1-carbonyl]-1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound COCC1CCC(COC)N1C(=O)C1=CC(C(=O)NC2CCN(CC2)C(C)C)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 ZODUIPOEAJGRJM-UHFFFAOYSA-N 0.000 claims 1
- AJMOIBNRYSRGLV-UHFFFAOYSA-N 5-[2,5-bis(methoxymethyl)pyrrolidine-1-carbonyl]-2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound COCC1CCC(COC)N1C(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)NC2CCN(CC2)C(C)C)=C1 AJMOIBNRYSRGLV-UHFFFAOYSA-N 0.000 claims 1
- DTJYNOXDIRTSPQ-UHFFFAOYSA-N C1CC(C1)NC(=O)C1=NN(C(=C1)C(=O)O)CC1=NOC(=C1)C=1SC(=CC1)Cl Chemical compound C1CC(C1)NC(=O)C1=NN(C(=C1)C(=O)O)CC1=NOC(=C1)C=1SC(=CC1)Cl DTJYNOXDIRTSPQ-UHFFFAOYSA-N 0.000 claims 1
- LTORGPPRBRMWNA-UHFFFAOYSA-N C1CC1NC(=O)C1=NN(C(=C1)C(=O)O)CC1=NOC(=C1)C=1SC(=CC1)Cl Chemical compound C1CC1NC(=O)C1=NN(C(=C1)C(=O)O)CC1=NOC(=C1)C=1SC(=CC1)Cl LTORGPPRBRMWNA-UHFFFAOYSA-N 0.000 claims 1
- 206010040070 Septic Shock Diseases 0.000 claims 1
- CNAQDILHKPTOLS-UHFFFAOYSA-N cyclopropylmethyl 1-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carboxylate Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)OCC2CC2)=NN1CC(=O)NC1=CC=C(Cl)C=N1 CNAQDILHKPTOLS-UHFFFAOYSA-N 0.000 claims 1
- AWIBUZFDEFXBLU-UHFFFAOYSA-N ethyl 1-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]-4-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylate Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=C(OCC(F)(F)F)C(C(=O)OCC)=NN1CC(=O)NC1=CC=C(Cl)C=N1 AWIBUZFDEFXBLU-UHFFFAOYSA-N 0.000 claims 1
- XWKGAXDFEWMTKF-UHFFFAOYSA-N ethyl 1-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carboxylate Chemical compound C=1C=C(Cl)C=NC=1NC(=O)CN1N=C(C(=O)OCC)C=C1C(=O)NC1CCN(C(C)C)CC1 XWKGAXDFEWMTKF-UHFFFAOYSA-N 0.000 claims 1
- KCYLYUSKPIMYGP-UHFFFAOYSA-N ethyl 2-[[1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carbonyl]amino]-3-methylbutanoate Chemical compound C1=C(C=2SC(Cl)=CC=2)ON=C1CN1N=C(C(=O)NC(C(=O)OCC)C(C)C)C=C1C(=O)NC1CCN(C(C)C)CC1 KCYLYUSKPIMYGP-UHFFFAOYSA-N 0.000 claims 1
- CNJGKWDHDUQANJ-UHFFFAOYSA-N methyl 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carboxylate Chemical compound C1=C(C=2SC(Cl)=CC=2)ON=C1CN1N=C(C(=O)OC)C=C1C(=O)NC1CCN(C(C)C)CC1 CNJGKWDHDUQANJ-UHFFFAOYSA-N 0.000 claims 1
- RPLKYGCVVVGFAT-UHFFFAOYSA-N propan-2-yl 2-[[1-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carbonyl]amino]acetate Chemical compound C=1C=C(Cl)C=NC=1NC(=O)CN1N=C(C(=O)NCC(=O)OC(C)C)C=C1C(=O)NC1CCN(C(C)C)CC1 RPLKYGCVVVGFAT-UHFFFAOYSA-N 0.000 claims 1
- 230000036303 septic shock Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 17
- 238000011321 prophylaxis Methods 0.000 abstract description 12
- 239000003112 inhibitor Substances 0.000 abstract description 8
- 230000002441 reversible effect Effects 0.000 abstract description 7
- 239000004480 active ingredient Substances 0.000 abstract description 6
- 230000002265 prevention Effects 0.000 abstract description 4
- 230000002785 anti-thrombosis Effects 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 45
- 239000000243 solution Substances 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
- 239000000651 prodrug Substances 0.000 description 29
- 229940002612 prodrug Drugs 0.000 description 29
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 28
- 230000002829 reductive effect Effects 0.000 description 27
- 238000003786 synthesis reaction Methods 0.000 description 23
- 239000002904 solvent Substances 0.000 description 22
- 125000001424 substituent group Chemical group 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- 125000001309 chloro group Chemical group Cl* 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
- 229940093499 ethyl acetate Drugs 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 239000003153 chemical reaction reagent Substances 0.000 description 12
- 238000010828 elution Methods 0.000 description 12
- 125000000524 functional group Chemical group 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- 150000003217 pyrazoles Chemical class 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 8
- NTCRDZSJYGZRIE-UHFFFAOYSA-N ethyl 5-thiophen-2-yl-1h-pyrazole-3-carboxylate Chemical compound N1N=C(C(=O)OCC)C=C1C1=CC=CS1 NTCRDZSJYGZRIE-UHFFFAOYSA-N 0.000 description 8
- 239000002243 precursor Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- FPQVGDGSRVMNMR-JCTPKUEWSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.CCOC(=O)C(\C#N)=N/OC(N(C)C)=[N+](C)C FPQVGDGSRVMNMR-JCTPKUEWSA-N 0.000 description 7
- 125000003367 polycyclic group Chemical group 0.000 description 7
- 238000002953 preparative HPLC Methods 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- WHYHFYNRCMGJPY-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-thiophen-2-ylpyrazole-3-carboxylic acid Chemical compound OC(=O)C1=CC(C=2SC=CC=2)=NN1CC(=NO1)C=C1C1=CC=C(Cl)S1 WHYHFYNRCMGJPY-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 150000001735 carboxylic acids Chemical class 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 238000010561 standard procedure Methods 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- FWSBBOBJHUATLP-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-[(1-pyridin-4-ylpiperidin-4-yl)methyl]-5-thiophen-2-ylpyrazole-3-carboxamide Chemical compound S1C(Cl)=CC=C1C1=CC(CN2C(=CC(=N2)C=2SC=CC=2)C(=O)NCC2CCN(CC2)C=2C=CN=CC=2)=NO1 FWSBBOBJHUATLP-UHFFFAOYSA-N 0.000 description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Substances IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 5
- 125000002015 acyclic group Chemical group 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 229910052792 caesium Inorganic materials 0.000 description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 125000004185 ester group Chemical group 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 4
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 4
- UBIXPIXAVFHKMM-UHFFFAOYSA-N 3-(bromomethyl)-5-(5-chlorothiophen-2-yl)-1,2-oxazole Chemical compound S1C(Cl)=CC=C1C1=CC(CBr)=NO1 UBIXPIXAVFHKMM-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 239000003130 blood coagulation factor inhibitor Substances 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 125000002843 carboxylic acid group Chemical group 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 230000015271 coagulation Effects 0.000 description 4
- 238000005345 coagulation Methods 0.000 description 4
- VLNZUSMTOFYNPS-UHFFFAOYSA-N diethylphosphorylformonitrile Chemical compound CCP(=O)(CC)C#N VLNZUSMTOFYNPS-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 125000004043 oxo group Chemical group O=* 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- JVTMDVFGRFFOOB-UHFFFAOYSA-N (1-pyridin-4-ylpiperidin-4-yl)methanamine Chemical compound C1CC(CN)CCN1C1=CC=NC=C1 JVTMDVFGRFFOOB-UHFFFAOYSA-N 0.000 description 3
- TWISVFOVRXGVDH-UHFFFAOYSA-N 1-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]pyrazole-3,5-dicarboxylic acid Chemical compound N1=C(C(=O)O)C=C(C(O)=O)N1CC(=O)NC1=CC=C(Cl)C=N1 TWISVFOVRXGVDH-UHFFFAOYSA-N 0.000 description 3
- SKZUXKOWTWFPPH-UHFFFAOYSA-N 1-propan-2-ylpiperidin-4-amine;hydrochloride Chemical compound Cl.CC(C)N1CCC(N)CC1 SKZUXKOWTWFPPH-UHFFFAOYSA-N 0.000 description 3
- KLDLRDSRCMJKGM-UHFFFAOYSA-N 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one Chemical compound C1COC(=O)N1P(=O)(Cl)N1CCOC1=O KLDLRDSRCMJKGM-UHFFFAOYSA-N 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 208000032843 Hemorrhage Diseases 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 238000007126 N-alkylation reaction Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 108090000190 Thrombin Proteins 0.000 description 3
- 108010000499 Thromboplastin Proteins 0.000 description 3
- 102000002262 Thromboplastin Human genes 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 229940127219 anticoagulant drug Drugs 0.000 description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 3
- 208000034158 bleeding Diseases 0.000 description 3
- 230000000740 bleeding effect Effects 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000006165 cyclic alkyl group Chemical group 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 229960004072 thrombin Drugs 0.000 description 3
- 229910052723 transition metal Inorganic materials 0.000 description 3
- 150000003624 transition metals Chemical class 0.000 description 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 2
- BTDZSVPICJLNIN-UHFFFAOYSA-N 1-pyridin-4-ylpiperidin-4-amine Chemical compound C1CC(N)CCN1C1=CC=NC=C1 BTDZSVPICJLNIN-UHFFFAOYSA-N 0.000 description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 2
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- RDBUONFQFSETIY-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)-5-thiophen-2-ylpyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C=2SC=CC=2)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 RDBUONFQFSETIY-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 2
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 2
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 238000006619 Stille reaction Methods 0.000 description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 238000006254 arylation reaction Methods 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 150000001879 copper Chemical class 0.000 description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000006880 cross-coupling reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000012039 electrophile Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- SFJLQSHTMKIBHW-UHFFFAOYSA-N ethyl 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-thiophen-2-ylpyrazole-3-carboxylate Chemical compound CCOC(=O)C1=CC(C=2SC=CC=2)=NN1CC(=NO1)C=C1C1=CC=C(Cl)S1 SFJLQSHTMKIBHW-UHFFFAOYSA-N 0.000 description 2
- GXVOUCPKCKBWPW-UHFFFAOYSA-N ethyl 4-cyano-5-propyl-1h-pyrazole-3-carboxylate Chemical compound CCCC1=NNC(C(=O)OCC)=C1C#N GXVOUCPKCKBWPW-UHFFFAOYSA-N 0.000 description 2
- AIOGKWBVNUPXKV-UHFFFAOYSA-N ethyl 4-cyano-5-thiophen-2-yl-1h-pyrazole-3-carboxylate Chemical compound N#CC1=C(C(=O)OCC)NN=C1C1=CC=CS1 AIOGKWBVNUPXKV-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 2
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 2
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 description 2
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000003094 microcapsule Substances 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- CNLRJYRSBJSKBY-UHFFFAOYSA-N n-(1-propan-2-ylpiperidin-4-yl)-1h-pyrazole-5-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC=NN1 CNLRJYRSBJSKBY-UHFFFAOYSA-N 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- AQNQGBUEVCAVML-UHFFFAOYSA-N oxazepane Chemical compound C1CCNOCC1 AQNQGBUEVCAVML-UHFFFAOYSA-N 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 description 2
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 108010014806 prothrombinase complex Proteins 0.000 description 2
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 2
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 2
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 2
- 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 2
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 238000006268 reductive amination reaction Methods 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000003001 serine protease inhibitor Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 150000003457 sulfones Chemical class 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 238000005694 sulfonylation reaction Methods 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- SYXBLASQKPONBN-UHFFFAOYSA-N tert-butyl n-(1-propan-2-ylpiperidin-4-yl)carbamate Chemical compound CC(C)N1CCC(NC(=O)OC(C)(C)C)CC1 SYXBLASQKPONBN-UHFFFAOYSA-N 0.000 description 2
- AUFRDMQSECOCAZ-UHFFFAOYSA-N tert-butyl n-(1-pyridin-4-ylpiperidin-4-yl)carbamate Chemical compound C1CC(NC(=O)OC(C)(C)C)CCN1C1=CC=NC=C1 AUFRDMQSECOCAZ-UHFFFAOYSA-N 0.000 description 2
- QSOQTGMDBTXCKG-UHFFFAOYSA-N tert-butyl n-[(1-propan-2-ylpiperidin-4-yl)methyl]carbamate Chemical compound CC(C)N1CCC(CNC(=O)OC(C)(C)C)CC1 QSOQTGMDBTXCKG-UHFFFAOYSA-N 0.000 description 2
- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 2
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- PCZOZSATUTWXIC-UHFFFAOYSA-N tetraethylazanium;cyanide Chemical compound N#[C-].CC[N+](CC)(CC)CC PCZOZSATUTWXIC-UHFFFAOYSA-N 0.000 description 2
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000005809 transesterification reaction Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000004607 1,2,3,4-tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- CFGDUGSIBUXRMR-UHFFFAOYSA-N 1,2-dihydropyrrol-2-ide Chemical compound C=1C=[C-]NC=1 CFGDUGSIBUXRMR-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- TXLLFXVNIJXUQJ-UHFFFAOYSA-N 1,3-oxazocan-2-one Chemical compound O=C1NCCCCCO1 TXLLFXVNIJXUQJ-UHFFFAOYSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- NZBVQPIZDGSDNN-UHFFFAOYSA-N 1,4-oxazocane Chemical compound C1CCOCCNC1 NZBVQPIZDGSDNN-UHFFFAOYSA-N 0.000 description 1
- CAAQBRKOAURIKO-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-dien-3-one;hydrochloride Chemical compound Cl.C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1 CAAQBRKOAURIKO-UHFFFAOYSA-N 0.000 description 1
- SXGPRVYYMMLEIT-UHFFFAOYSA-N 1-[(4-chlorophenyl)methyl]-4-cyano-n-(1-propan-2-ylpiperidin-4-yl)-5-thiophen-2-ylpyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C(C(=C1C=2SC=CC=2)C#N)=NN1CC1=CC=C(Cl)C=C1 SXGPRVYYMMLEIT-UHFFFAOYSA-N 0.000 description 1
- NJWXOMPUITXUKP-UHFFFAOYSA-N 1-[(6-chloro-1-benzothiophen-2-yl)methyl]-n-(1-propan-2-ylpiperidin-4-yl)-5-thiophen-2-ylpyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC=2SC3=CC(Cl)=CC=C3C=2)C(C=2SC=CC=2)=C1 NJWXOMPUITXUKP-UHFFFAOYSA-N 0.000 description 1
- JOCCOIPBVWXHIU-UHFFFAOYSA-N 1-[1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carbonyl]azetidine-2-carboxylic acid Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2C(CC2)C(O)=O)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 JOCCOIPBVWXHIU-UHFFFAOYSA-N 0.000 description 1
- QOCNSCGBIFXKNQ-UHFFFAOYSA-N 1-[2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carbonyl]azetidine-2-carboxylic acid Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)N2C(CC2)C(O)=O)=C1 QOCNSCGBIFXKNQ-UHFFFAOYSA-N 0.000 description 1
- LLATVTSYXRUZGU-UHFFFAOYSA-N 1-[[2-(5-chlorothiophen-2-yl)-1,3-thiazol-4-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)-5-thiophen-2-ylpyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC=2N=C(SC=2)C=2SC(Cl)=CC=2)C(C=2SC=CC=2)=C1 LLATVTSYXRUZGU-UHFFFAOYSA-N 0.000 description 1
- CRGJLBUKLXMBCG-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-4-(2,4-dichlorophenyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C(C(=C1)C=2C(=CC(Cl)=CC=2)Cl)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 CRGJLBUKLXMBCG-UHFFFAOYSA-N 0.000 description 1
- IATLXOOKFSXVKJ-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-4-cyano-n-(1-propan-2-ylpiperidin-4-yl)-5-thiophen-2-ylpyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C(C(=C1C=2SC=CC=2)C#N)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 IATLXOOKFSXVKJ-UHFFFAOYSA-N 0.000 description 1
- RRACFGKIZHEVEL-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(furan-2-yl)pyrazole-3-carboxylic acid Chemical compound C1=C(C=2SC(Cl)=CC=2)ON=C1CN1N=C(C(=O)O)C=C1C1=CC=CO1 RRACFGKIZHEVEL-UHFFFAOYSA-N 0.000 description 1
- FQRGFMDCLSIWKO-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(hydroxymethyl)-n-[4-(3-oxomorpholin-4-yl)phenyl]pyrazole-3-carboxamide Chemical compound OCC1=CC(C(=O)NC=2C=CC(=CC=2)N2C(COCC2)=O)=NN1CC(=NO1)C=C1C1=CC=C(Cl)S1 FQRGFMDCLSIWKO-UHFFFAOYSA-N 0.000 description 1
- XPHYXMPQRNUKIY-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[2-(2-methoxyethoxy)ethoxymethyl]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound COCCOCCOCC1=CC(C(=O)NC2CCN(CC2)C(C)C)=NN1CC(=NO1)C=C1C1=CC=C(Cl)S1 XPHYXMPQRNUKIY-UHFFFAOYSA-N 0.000 description 1
- APJTWABYLSQNNY-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[2-(methoxymethyl)pyrrolidine-1-carbonyl]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound COCC1CCCN1C(=O)C1=CC(C(=O)NC2CCN(CC2)C(C)C)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 APJTWABYLSQNNY-UHFFFAOYSA-N 0.000 description 1
- NHKUXTFAVAZNQR-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[3-(2-hydroxyethyl)-2-oxoimidazolidine-1-carbonyl]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)N2C(N(CCO)CC2)=O)=C1 NHKUXTFAVAZNQR-UHFFFAOYSA-N 0.000 description 1
- QDRSPPYZRUQRBQ-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)-5-(pyrrolidine-1-carbonyl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)N2CCCC2)=C1 QDRSPPYZRUQRBQ-UHFFFAOYSA-N 0.000 description 1
- WRKCZKRSMVVCAC-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)-5-propylpyrazole-3-carboxamide Chemical compound CCCC1=CC(C(=O)NC2CCN(CC2)C(C)C)=NN1CC(=NO1)C=C1C1=CC=C(Cl)S1 WRKCZKRSMVVCAC-UHFFFAOYSA-N 0.000 description 1
- IUQSVRWEHBDOPQ-UHFFFAOYSA-N 1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)-5-thiophen-2-ylpyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C=2SC=CC=2)=C1 IUQSVRWEHBDOPQ-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- QBXXNVICTXTMPL-UHFFFAOYSA-N 2-(6-chloro-1,3-benzothiazol-2-yl)-5-methyl-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C)=NN1C1=NC2=CC=C(Cl)C=C2S1 QBXXNVICTXTMPL-UHFFFAOYSA-N 0.000 description 1
- ADHOYTZCOJVUPR-UHFFFAOYSA-N 2-(6-chloro-1,3-benzothiazol-2-yl)-5-methylpyrazole-3-carboxylic acid Chemical compound N1=C(C)C=C(C(O)=O)N1C1=NC2=CC=C(Cl)C=C2S1 ADHOYTZCOJVUPR-UHFFFAOYSA-N 0.000 description 1
- BBTKFFLJVORJDU-UHFFFAOYSA-N 2-(bromomethyl)-6-chloro-1-benzothiophene Chemical compound ClC1=CC=C2C=C(CBr)SC2=C1 BBTKFFLJVORJDU-UHFFFAOYSA-N 0.000 description 1
- VQHJDLDGIZTKSI-UHFFFAOYSA-N 2-[(4-chlorophenyl)methyl]-4-cyano-n-(1-propan-2-ylpiperidin-4-yl)-5-thiophen-2-ylpyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=C(C#N)C(C=2SC=CC=2)=NN1CC1=CC=C(Cl)C=C1 VQHJDLDGIZTKSI-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- WWNZQGLZVPZENW-UHFFFAOYSA-N 2-[2-(4-chloroanilino)-2-oxoethyl]-4-cyanopyrazole-3-carboxylic acid Chemical compound OC(=O)C1=C(C#N)C=NN1CC(=O)NC1=CC=C(Cl)C=C1 WWNZQGLZVPZENW-UHFFFAOYSA-N 0.000 description 1
- IQWFSLOAOQZUGI-UHFFFAOYSA-N 2-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-(2,2-difluoro-3-methoxypropoxy)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C=1C=C(Cl)C=NC=1NC(=O)CN1N=C(OCC(F)(F)COC)C=C1C(=O)NC1CCN(C(C)C)CC1 IQWFSLOAOQZUGI-UHFFFAOYSA-N 0.000 description 1
- SYQXSKWEGFCWGJ-UHFFFAOYSA-N 2-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-(2,2-difluoroethoxy)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(OCC(F)F)=NN1CC(=O)NC1=CC=C(Cl)C=N1 SYQXSKWEGFCWGJ-UHFFFAOYSA-N 0.000 description 1
- RHSAJDRIACSFRF-UHFFFAOYSA-N 2-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-(difluoromethoxymethyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(COC(F)F)=NN1CC(=O)NC1=CC=C(Cl)C=N1 RHSAJDRIACSFRF-UHFFFAOYSA-N 0.000 description 1
- DLBZIAUEEPDHFU-UHFFFAOYSA-N 2-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-(hydroxymethyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(CO)=NN1CC(=O)NC1=CC=C(Cl)C=N1 DLBZIAUEEPDHFU-UHFFFAOYSA-N 0.000 description 1
- CLKIFGHXDOIIHW-UHFFFAOYSA-N 2-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-[3-(difluoromethoxy)-2,2-difluoropropoxy]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(OCC(F)(F)COC(F)F)=NN1CC(=O)NC1=CC=C(Cl)C=N1 CLKIFGHXDOIIHW-UHFFFAOYSA-N 0.000 description 1
- YRLQXHOITOTREO-UHFFFAOYSA-N 2-[[1-[2-[(5-chloropyridin-2-yl)amino]-2-oxoethyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carbonyl]amino]acetic acid Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)NCC(O)=O)=NN1CC(=O)NC1=CC=C(Cl)C=N1 YRLQXHOITOTREO-UHFFFAOYSA-N 0.000 description 1
- JRERQIIMFSBVDW-UHFFFAOYSA-N 2-[[1-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carbonyl]amino]ethyl hydrogen sulfate Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)NCCOS(O)(=O)=O)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 JRERQIIMFSBVDW-UHFFFAOYSA-N 0.000 description 1
- YBIUGSBCWFNIKH-UHFFFAOYSA-N 2-[[2-(5-chlorothiophen-2-yl)-1,3-thiazol-4-yl]methyl]-n-(1-propan-2-ylpiperidin-4-yl)-5-thiophen-2-ylpyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C=2SC=CC=2)=NN1CC1=CSC(C=2SC(Cl)=CC=2)=N1 YBIUGSBCWFNIKH-UHFFFAOYSA-N 0.000 description 1
- FTXXAQUNJLQPEJ-UHFFFAOYSA-N 2-[[2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carbonyl]amino]acetic acid Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=NN(CC2=NOC(=C2)C=2SC(Cl)=CC=2)C(C(=O)NCC(O)=O)=C1 FTXXAQUNJLQPEJ-UHFFFAOYSA-N 0.000 description 1
- MWSZMNDLBBGRLJ-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-4-cyano-n-(1-propan-2-ylpiperidin-4-yl)-5-thiophen-2-ylpyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=C(C#N)C(C=2SC=CC=2)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 MWSZMNDLBBGRLJ-UHFFFAOYSA-N 0.000 description 1
- RWVJSGWRJYETJA-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(2,2-difluoro-3-methoxypropoxy)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1=C(C=2SC(Cl)=CC=2)ON=C1CN1N=C(OCC(F)(F)COC)C=C1C(=O)NC1CCN(C(C)C)CC1 RWVJSGWRJYETJA-UHFFFAOYSA-N 0.000 description 1
- VTJINSMYXBLMRN-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(2,2-difluoroethoxy)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(OCC(F)F)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 VTJINSMYXBLMRN-UHFFFAOYSA-N 0.000 description 1
- SWBMLZSWIROPSM-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(2-methoxyethoxymethyl)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1=C(C=2SC(Cl)=CC=2)ON=C1CN1N=C(COCCOC)C=C1C(=O)NC1CCN(C(C)C)CC1 SWBMLZSWIROPSM-UHFFFAOYSA-N 0.000 description 1
- FWJWVALILXRDBT-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-(difluoromethoxy)-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(OC(F)F)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 FWJWVALILXRDBT-UHFFFAOYSA-N 0.000 description 1
- YVVKSMCOHJQRQU-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[2-(trifluoromethyl)pyrrolidine-1-carbonyl]pyrazole-3-carboxylic acid Chemical compound OC(=O)C1=CC(C(=O)N2C(CCC2)C(F)(F)F)=NN1CC(=NO1)C=C1C1=CC=C(Cl)S1 YVVKSMCOHJQRQU-UHFFFAOYSA-N 0.000 description 1
- YJACJUIYRFJBHZ-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[3-(2-hydroxyethyl)-2-oxoimidazolidine-1-carbonyl]-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C(=O)N2C(N(CCO)CC2)=O)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 YJACJUIYRFJBHZ-UHFFFAOYSA-N 0.000 description 1
- QHFCHZAABCKOPQ-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-methyl-n-(1-propan-2-ylpiperidin-4-yl)pyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C1=CC(C)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 QHFCHZAABCKOPQ-UHFFFAOYSA-N 0.000 description 1
- RFFGUFZBXCOTFQ-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-propylpyrazole-3-carboxylic acid Chemical compound N1=C(CCC)C=C(C(O)=O)N1CC1=NOC(C=2SC(Cl)=CC=2)=C1 RFFGUFZBXCOTFQ-UHFFFAOYSA-N 0.000 description 1
- QXOLXDBDQWEGIY-UHFFFAOYSA-N 2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-n-[(1-propan-2-ylpiperidin-4-yl)methyl]-5-thiophen-2-ylpyrazole-3-carboxamide Chemical compound C1CN(C(C)C)CCC1CNC(=O)C1=CC(C=2SC=CC=2)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 QXOLXDBDQWEGIY-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000006029 2-methyl-2-butenyl group Chemical group 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- MHCRLDZZHOVFEE-UHFFFAOYSA-N 4-(4-aminophenyl)morpholin-3-one Chemical compound C1=CC(N)=CC=C1N1C(=O)COCC1 MHCRLDZZHOVFEE-UHFFFAOYSA-N 0.000 description 1
- PVMNPAUTCMBOMO-UHFFFAOYSA-N 4-chloropyridine Chemical compound ClC1=CC=NC=C1 PVMNPAUTCMBOMO-UHFFFAOYSA-N 0.000 description 1
- XGAFCCUNHIMIRV-UHFFFAOYSA-N 4-chloropyridine;hydron;chloride Chemical compound Cl.ClC1=CC=NC=C1 XGAFCCUNHIMIRV-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- QLFJDHGFRNTOTD-UHFFFAOYSA-N 5-tert-butyl-2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]pyrazole-3-carboxylic acid Chemical compound N1=C(C(C)(C)C)C=C(C(O)=O)N1CC1=NOC(C=2SC(Cl)=CC=2)=C1 QLFJDHGFRNTOTD-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010003162 Arterial injury Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 101100134927 Gallus gallus COR8 gene Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 241000907681 Morpho Species 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical class ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 230000006181 N-acylation Effects 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000282520 Papio Species 0.000 description 1
- 101100477602 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) SIR3 gene Proteins 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000012382 advanced drug delivery Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 150000001501 aryl fluorides Chemical class 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 235000013527 bean curd Nutrition 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical group C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000004651 carbonic acid esters Chemical class 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- ZIQIQOUPRHPOIT-UHFFFAOYSA-N cyclobutylazanide Chemical compound [NH-]C1CCC1 ZIQIQOUPRHPOIT-UHFFFAOYSA-N 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- 239000004914 cyclooctane Substances 0.000 description 1
- URYYVOIYTNXXBN-UPHRSURJSA-N cyclooctene Chemical compound C1CCC\C=C/CC1 URYYVOIYTNXXBN-UPHRSURJSA-N 0.000 description 1
- 239000004913 cyclooctene Substances 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- QPMLSUSACCOBDK-UHFFFAOYSA-N diazepane Chemical compound C1CCNNCC1 QPMLSUSACCOBDK-UHFFFAOYSA-N 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000000597 dioxinyl group Chemical group 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- AXEWDBITUNKKHA-UHFFFAOYSA-N ethyl 1-[2-[[5-(5-chlorothiophen-2-yl)-1,2-oxazol-3-yl]methyl]-5-[(1-propan-2-ylpiperidin-4-yl)carbamoyl]pyrazole-3-carbonyl]piperidine-4-carboxylate Chemical compound C1CC(C(=O)OCC)CCN1C(=O)C1=CC(C(=O)NC2CCN(CC2)C(C)C)=NN1CC1=NOC(C=2SC(Cl)=CC=2)=C1 AXEWDBITUNKKHA-UHFFFAOYSA-N 0.000 description 1
- SUALHSUMUQQLJP-UHFFFAOYSA-N ethyl 5-propyl-1h-pyrazole-3-carboxylate Chemical compound CCCC1=CC(C(=O)OCC)=NN1 SUALHSUMUQQLJP-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- ORTFAQDWJHRMNX-UHFFFAOYSA-N hydroxidooxidocarbon(.) Chemical group O[C]=O ORTFAQDWJHRMNX-UHFFFAOYSA-N 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 description 1
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 1
- 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004551 isoquinolin-3-yl group Chemical group C1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 125000004552 isoquinolin-4-yl group Chemical group C1=NC=C(C2=CC=CC=C12)* 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000006263 metalation reaction Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- JCZCEFJKLXQLPX-UHFFFAOYSA-N methyl 4-(2,4-dichlorophenyl)-1h-pyrazole-5-carboxylate Chemical compound N1N=CC(C=2C(=CC(Cl)=CC=2)Cl)=C1C(=O)OC JCZCEFJKLXQLPX-UHFFFAOYSA-N 0.000 description 1
- OTTWGMLIFRGCPX-UHFFFAOYSA-N methyl 5-(5-chlorothiophen-2-yl)-1h-pyrazole-3-carboxylate Chemical compound N1C(C(=O)OC)=CC(C=2SC(Cl)=CC=2)=N1 OTTWGMLIFRGCPX-UHFFFAOYSA-N 0.000 description 1
- GFEZEVUIYRGWNU-UHFFFAOYSA-N methyl 5-methyl-1h-pyrazole-3-carboxylate Chemical compound COC(=O)C=1C=C(C)NN=1 GFEZEVUIYRGWNU-UHFFFAOYSA-N 0.000 description 1
- ULVCLXDTHLSVBS-UHFFFAOYSA-N methyl 5-propyl-1h-pyrazole-3-carboxylate Chemical compound CCCC=1C=C(C(=O)OC)NN=1 ULVCLXDTHLSVBS-UHFFFAOYSA-N 0.000 description 1
- ITVYLUILHAMHAN-UHFFFAOYSA-N methyl 5-tert-butyl-1h-pyrazole-3-carboxylate Chemical compound COC(=O)C=1C=C(C(C)(C)C)NN=1 ITVYLUILHAMHAN-UHFFFAOYSA-N 0.000 description 1
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-M nitrite group Chemical group N(=O)[O-] IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229920005990 polystyrene resin Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229940095574 propionic acid Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- IWRRRCZSVINKHU-UHFFFAOYSA-N pyrazol-3-ylidenemethanone Chemical class O=C=C1C=CN=N1 IWRRRCZSVINKHU-UHFFFAOYSA-N 0.000 description 1
- KOPFEFZSAMLEHK-UHFFFAOYSA-N pyrazolecarboxylic acid Natural products OC(=O)C=1C=CNN=1 KOPFEFZSAMLEHK-UHFFFAOYSA-N 0.000 description 1
- 125000004159 quinolin-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C([H])C(*)=NC2=C1[H] 0.000 description 1
- 125000004548 quinolin-3-yl group Chemical group N1=CC(=CC2=CC=CC=C12)* 0.000 description 1
- 125000004549 quinolin-4-yl group Chemical group N1=CC=C(C2=CC=CC=C12)* 0.000 description 1
- 125000004550 quinolin-6-yl group Chemical group N1=CC=CC2=CC(=CC=C12)* 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- VHYXAWLOJGIJPC-UHFFFAOYSA-N tert-butyl n-(piperidin-4-ylmethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC1CCNCC1 VHYXAWLOJGIJPC-UHFFFAOYSA-N 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000004525 thiadiazinyl group Chemical group S1NN=C(C=C1)* 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Surgery (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP02028915A EP1433788A1 (en) | 2002-12-23 | 2002-12-23 | Pyrazole-derivatives as factor Xa inhibitors |
| EP02028915.3 | 2002-12-23 | ||
| EP03011308A EP1479678A1 (en) | 2003-05-19 | 2003-05-19 | Pyrazole-derivatives as factor xa inhibitors |
| EP03011308.8 | 2003-05-19 | ||
| PCT/EP2003/013979 WO2004056815A1 (en) | 2002-12-23 | 2003-12-10 | PYRAZOLE-DERIVATIVES AS FACTOR Xa INHIBITORS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2511321A1 true CA2511321A1 (en) | 2004-07-08 |
Family
ID=32683809
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002511321A Abandoned CA2511321A1 (en) | 2002-12-23 | 2003-12-10 | Pyrazole-derivatives as factor xa inhibitors |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP1581523B1 (https=) |
| JP (1) | JP4585448B2 (https=) |
| AR (1) | AR042648A1 (https=) |
| AT (1) | ATE444292T1 (https=) |
| AU (1) | AU2003292218A1 (https=) |
| BR (1) | BR0317659A (https=) |
| CA (1) | CA2511321A1 (https=) |
| DE (1) | DE60329529D1 (https=) |
| IL (1) | IL169323A0 (https=) |
| MX (1) | MXPA05006200A (https=) |
| PE (1) | PE20040925A1 (https=) |
| TW (1) | TW200505914A (https=) |
| WO (1) | WO2004056815A1 (https=) |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI372050B (en) | 2003-07-03 | 2012-09-11 | Astex Therapeutics Ltd | (morpholin-4-ylmethyl-1h-benzimidazol-2-yl)-1h-pyrazoles |
| ITMI20041032A1 (it) | 2004-05-24 | 2004-08-24 | Neuroscienze S C A R L | Compositi farmaceutici |
| DE102004047255A1 (de) * | 2004-09-29 | 2006-04-13 | Merck Patent Gmbh | Prolinderivate |
| US7446210B2 (en) | 2004-10-26 | 2008-11-04 | Janssen Pharmaceutica N.V. | Factor Xa compounds |
| US7381732B2 (en) | 2004-10-26 | 2008-06-03 | Bristol-Myers Squibb Company | Pyrazolobenzamides and derivatives as factor Xa inhibitors |
| EP1814860B1 (en) * | 2004-10-29 | 2009-06-03 | Schering Corporation | Substituted 5-carboxyamide pyrazoles and [1,2,4]triazoles as antiviral agents |
| EP1833819A1 (en) | 2004-12-30 | 2007-09-19 | Astex Therapeutics Limited | Pyrazole compounds that modulate the activity of cdk, gsk and aurora kinases |
| EP1724269A1 (en) * | 2005-05-20 | 2006-11-22 | Sanofi-Aventis Deutschland GmbH | Heteroaryl-carboxylic acid (sulfamoyl alkyl) amide - derivatives as factor Xa inhibitors |
| US8703805B2 (en) * | 2005-06-27 | 2014-04-22 | Exelixis Patent Company Llc | Modulators of LXR |
| EP1968579A1 (en) | 2005-12-30 | 2008-09-17 | Astex Therapeutics Limited | Pharmaceutical compounds |
| EP2049119A2 (en) | 2006-06-29 | 2009-04-22 | Astex Therapeutics Limited | Pharmaceutical combinations of 1-cyclopropyl-3-[3-(5-morphoolin-4-ylmethyl-1h-benzoimidazol-2-yl)-1h-1-pyrazol-4-yl]-urea |
| WO2009080227A2 (en) * | 2007-12-26 | 2009-07-02 | Sanofi-Aventis | Pyrazole-carboxamide derivatives as p2y12 antagonists |
| EP2238128B1 (en) * | 2007-12-26 | 2012-08-22 | Sanofi | Heterocyclic pyrazole-carboxamides as p2y12 antagonists |
| CN102056907B (zh) | 2008-04-04 | 2014-12-31 | 武田药品工业株式会社 | 杂环衍生物及其用途 |
| MX2010011288A (es) * | 2008-04-23 | 2010-11-09 | Rigel Pharmaceuticals Inc | Compuestos de carboxamida para el tratamiento de trastornos metabolicos. |
| TWI532725B (zh) | 2010-01-26 | 2016-05-11 | 賽諾菲阿凡提斯公司 | 經氧取代之３－雜芳醯基胺基－丙酸衍生物及其作為藥物之用途 |
| JP6155187B2 (ja) | 2010-03-30 | 2017-06-28 | ヴァーセオン コーポレイション | トロンビンの阻害剤としての多置換芳香族化合物 |
| AR085013A1 (es) | 2011-01-26 | 2013-08-07 | Sanofi Aventis | Derivados de acido 3-heteroaroilamino-propionico sustituidos y su uso como sustancias farmaceuticas |
| TWI523844B (zh) | 2011-01-26 | 2016-03-01 | 賽諾菲公司 | 經胺基取代之３－雜芳醯基胺基－丙酸衍生物及其作為藥物之用途 |
| JP6021910B2 (ja) | 2011-07-26 | 2016-11-09 | サノフイ | ３−ヘテロアロイルアミノ−プロピオン酸誘導体及び医薬としてのそれらの使用 |
| MY162786A (en) | 2011-07-26 | 2017-07-14 | Sanofi Sa | Substituted 3-thiazoloamino-propionic acid derivatives and their use as pharmaceuticals |
| WO2013072328A1 (en) | 2011-11-14 | 2013-05-23 | Sanofi | Use of telaprevir and related compounds in atherosclerosis, heart failure, renal diseases, liver diseases or inflammatory diseases |
| US20130123325A1 (en) | 2011-11-14 | 2013-05-16 | Sven Ruf | Use of boceprevir and related compounds in atherosclerosis, heart failure, renal diseases, liver diseases or inflammatory diseases |
| HK1214252A1 (zh) | 2013-03-15 | 2016-07-22 | Verseon Corporation | 作為凝血酶抑制劑的鹵代吡唑 |
| CN110179795A (zh) | 2013-03-15 | 2019-08-30 | 维颂公司 | 作为丝氨酸蛋白酶抑制剂的多取代芳族化合物的制药用途 |
| CA2907903A1 (en) | 2013-03-28 | 2014-10-02 | Sanofi | Biaryl-propionic acid derivatives and their use as pharmaceuticals |
| EP2978747B1 (en) | 2013-03-28 | 2017-04-19 | Sanofi | Biaryl-propionic acid derivatives and their use as pharmaceuticals |
| EP3184095A1 (en) | 2013-05-23 | 2017-06-28 | IP Gesellschaft für Management mbH | Administration units comprising polymorph 1 of 2-(2-methylamino-pyrimidin-4-yl]-1h-indole-5-carboxylic acid [(s)-1-carbamoyl-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-amide |
| US10189810B2 (en) | 2014-09-17 | 2019-01-29 | Verseon Corporation | Pyrazolyl-substituted pyridone compounds as serine protease inhibitors |
| CN107405333A (zh) | 2015-02-27 | 2017-11-28 | 维颂公司 | 作为丝氨酸蛋白酶抑制剂的被取代的吡唑化合物 |
| WO2016202756A1 (en) | 2015-06-18 | 2016-12-22 | Bayer Pharma Aktiengesellschaft | Substituted 2-(1h-pyrazol-1-yl)-1h-benzimidazole compounds |
| JOP20190192A1 (ar) * | 2017-03-01 | 2019-08-08 | Glaxosmithkline Ip No 2 Ltd | مشتقات بيرازول بوصفها مثبطات برومودومين |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6020357A (en) * | 1996-12-23 | 2000-02-01 | Dupont Pharmaceuticals Company | Nitrogen containing heteroaromatics as factor Xa inhibitors |
| US5998424A (en) * | 1997-06-19 | 1999-12-07 | Dupont Pharmaceuticals Company | Inhibitors of factor Xa with a neutral P1 specificity group |
| US6339099B1 (en) * | 1997-06-20 | 2002-01-15 | Dupont Pharmaceuticals Company | Guanidine mimics as factor Xa inhibitors |
| EP1045846B1 (en) * | 1997-11-28 | 2003-05-02 | Lg Chemical Limited | Imidazole derivatives having an inhibitory activity for farnesyl transferase and process for preparation thereof |
| IL136637A0 (en) * | 1997-12-22 | 2001-06-14 | Du Pont Pharm Co | Nitrogen containing heteroaromatics with ortho-substituted pi's as factor xa inhibitors |
| DE69921358T2 (de) * | 1998-12-23 | 2006-03-09 | Bristol-Myers Squibb Pharma Co. | Stickstoffhaltige heterobicyclen als faktor-xa-hemmer |
| JP2004507439A (ja) * | 1999-07-16 | 2004-03-11 | ブリストル−マイヤーズ スクイブ ファーマ カンパニー | Ｘａ因子阻害剤としての窒素含有ヘテロ二環式化合物 |
| JP2003509412A (ja) * | 1999-09-17 | 2003-03-11 | シーオーアール セラピューティクス インコーポレイテッド | Ｘａ因子阻害剤 |
| US6632815B2 (en) * | 1999-09-17 | 2003-10-14 | Millennium Pharmaceuticals, Inc. | Inhibitors of factor Xa |
| WO2001032628A1 (en) * | 1999-11-03 | 2001-05-10 | Bristol-Myers Squibb Pharma Company | Cyano compounds as factor xa inhibitors |
| AU2001268711A1 (en) * | 2000-06-23 | 2002-01-08 | Bristol-Myers Squibb Pharma Company | Heteroaryl-phenyl substituted factor xa inhibitors |
| WO2002000651A2 (en) * | 2000-06-27 | 2002-01-03 | Bristol-Myers Squibb Pharma Company | Factor xa inhibitors |
| CA2444571A1 (en) * | 2001-04-18 | 2002-10-31 | Bristol-Myers Squibb Company | 1, 4, 5, 6-tetrahydropyrazolo-¬3, 4-c|-pyridin-7-ones as factor xa inhi bitors |
-
2003
- 2003-12-10 JP JP2005502535A patent/JP4585448B2/ja not_active Expired - Fee Related
- 2003-12-10 DE DE60329529T patent/DE60329529D1/de not_active Expired - Lifetime
- 2003-12-10 BR BR0317659-2A patent/BR0317659A/pt not_active IP Right Cessation
- 2003-12-10 EP EP03767776A patent/EP1581523B1/en not_active Expired - Lifetime
- 2003-12-10 AT AT03767776T patent/ATE444292T1/de not_active IP Right Cessation
- 2003-12-10 WO PCT/EP2003/013979 patent/WO2004056815A1/en not_active Ceased
- 2003-12-10 AU AU2003292218A patent/AU2003292218A1/en not_active Abandoned
- 2003-12-10 CA CA002511321A patent/CA2511321A1/en not_active Abandoned
- 2003-12-10 MX MXPA05006200A patent/MXPA05006200A/es unknown
- 2003-12-19 TW TW092136068A patent/TW200505914A/zh unknown
- 2003-12-22 AR ARP030104773A patent/AR042648A1/es unknown
-
2004
- 2004-01-05 PE PE2004000015A patent/PE20040925A1/es not_active Application Discontinuation
-
2005
- 2005-06-21 IL IL169323A patent/IL169323A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE60329529D1 (de) | 2009-11-12 |
| WO2004056815A1 (en) | 2004-07-08 |
| ATE444292T1 (de) | 2009-10-15 |
| AR042648A1 (es) | 2005-06-29 |
| PE20040925A1 (es) | 2004-12-24 |
| IL169323A0 (en) | 2007-07-04 |
| EP1581523B1 (en) | 2009-09-30 |
| AU2003292218A1 (en) | 2004-07-14 |
| JP2006511608A (ja) | 2006-04-06 |
| TW200505914A (en) | 2005-02-16 |
| MXPA05006200A (es) | 2005-08-19 |
| BR0317659A (pt) | 2005-12-06 |
| EP1581523A1 (en) | 2005-10-05 |
| JP4585448B2 (ja) | 2010-11-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7910606B2 (en) | Pyrazole-derivatives as factor Xa inhibitors | |
| CA2511321A1 (en) | Pyrazole-derivatives as factor xa inhibitors | |
| US7365088B2 (en) | Indazole-derivatives as factor Xa inhibitors | |
| US7223780B2 (en) | Triazole-derivatives as blood clotting enzyme factor Xa inhibitors | |
| EP1568698A1 (en) | Pyrrole-derivatives as factor Xa inhibitors | |
| EP1433788A1 (en) | Pyrazole-derivatives as factor Xa inhibitors | |
| CA2526082C (en) | Triazole-derivatives as factor xa inhibitors | |
| US7741341B2 (en) | Benzimidazole-derivatives as factor Xa inhibitors | |
| EP1636216B1 (en) | BENZIMIDAZOLE-DERIVATIVES AS FACTOR Xa INHIBITORS | |
| CA2507624A1 (en) | Imidazole-derivatives as factor xa inhibitors | |
| EP1479678A1 (en) | Pyrazole-derivatives as factor xa inhibitors | |
| CA2526084A1 (en) | Azaindole-derivatives as factor xa inhibitors | |
| EP1479674A1 (en) | Imidiazole-derivatives as factor xa inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |