ZA200509861B - Fused compounds that inhibit vanilloid receptor subtype 1(VR1) receptor - Google Patents

Info

Publication number

ZA200509861B

ZA200509861B ZA200509861A ZA200509861A ZA200509861B ZA 200509861 B ZA200509861 B ZA 200509861B ZA 200509861 A ZA200509861 A ZA 200509861A ZA 200509861 A ZA200509861 A ZA 200509861A ZA 200509861 B ZA200509861 B ZA 200509861B

Authority

ZA

South Africa

Prior art keywords

compound

formula

dihydro

inden

indazol

Prior art date

2003-06-12

Links

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• 150000001875 compounds Chemical class 0.000 title claims description 667
• 108010025083 TRPV1 receptor Proteins 0.000 title claims description 37
• 102100029613 Transient receptor potential cation channel subfamily V member 1 Human genes 0.000 title claims description 26
• 102000005962 receptors Human genes 0.000 title description 7
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 372
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 231
• -1 {[(1S)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl Chemical group 0.000 claims description 177
• 238000000034 method Methods 0.000 claims description 149
• 239000000203 mixture Substances 0.000 claims description 121
• 125000000217 alkyl group Chemical group 0.000 claims description 116
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 105
• 229910052739 hydrogen Inorganic materials 0.000 claims description 101
• 239000001257 hydrogen Substances 0.000 claims description 101
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 94
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 90
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 87
• 239000002904 solvent Substances 0.000 claims description 74
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 67
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 63
• 239000004202 carbamide Substances 0.000 claims description 63
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 57
• 150000003839 salts Chemical class 0.000 claims description 56
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
• 230000008569 process Effects 0.000 claims description 44
• 150000002431 hydrogen Chemical class 0.000 claims description 37
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 36
• 229910052736 halogen Inorganic materials 0.000 claims description 34
• 150000002367 halogens Chemical class 0.000 claims description 34
• 239000000651 prodrug Substances 0.000 claims description 32
• 229940002612 prodrug Drugs 0.000 claims description 32
• 125000003545 alkoxy group Chemical group 0.000 claims description 30
• 125000003118 aryl group Chemical group 0.000 claims description 29
• 239000002253 acid Substances 0.000 claims description 28
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 27
• 241000124008 Mammalia Species 0.000 claims description 26
• 238000011282 treatment Methods 0.000 claims description 26
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 25
• 125000001188 haloalkyl group Chemical group 0.000 claims description 25
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 24
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 24
• 208000035475 disorder Diseases 0.000 claims description 24
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 22
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 22
• 125000004966 cyanoalkyl group Chemical group 0.000 claims description 21
• 239000012298 atmosphere Substances 0.000 claims description 20
• 238000004519 manufacturing process Methods 0.000 claims description 20
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
• 125000000623 heterocyclic group Chemical group 0.000 claims description 19
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 19
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
• LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 18
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 16
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 16
• 230000002401 inhibitory effect Effects 0.000 claims description 16
• 230000036407 pain Effects 0.000 claims description 16
• 238000003756 stirring Methods 0.000 claims description 16
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 16
• 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 14
• 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 13
• VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 13
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
• 125000005243 carbonyl alkyl group Chemical group 0.000 claims description 12
• 239000000126 substance Substances 0.000 claims description 12
• QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
• 125000003342 alkenyl group Chemical group 0.000 claims description 11
• 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 11
• 125000004414 alkyl thio group Chemical group 0.000 claims description 11
• 125000000304 alkynyl group Chemical group 0.000 claims description 11
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
• 239000003814 drug Substances 0.000 claims description 11
• 125000005093 alkyl carbonyl alkyl group Chemical group 0.000 claims description 10
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 10
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
• 125000004995 haloalkylthio group Chemical group 0.000 claims description 10
• 125000005358 mercaptoalkyl group Chemical group 0.000 claims description 10
• YTZKOQUCBOVLHL-UHFFFAOYSA-N tert-butylbenzene Chemical compound CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 claims description 10
• XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 9
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
• 229910052757 nitrogen Inorganic materials 0.000 claims description 9
• 235000010288 sodium nitrite Nutrition 0.000 claims description 9
• 208000004454 Hyperalgesia Diseases 0.000 claims description 8
• 125000004967 formylalkyl group Chemical group 0.000 claims description 8
• 238000010438 heat treatment Methods 0.000 claims description 8
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
• 239000012279 sodium borohydride Substances 0.000 claims description 7
• 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
• VPSCJCQPUGKRNC-UHFFFAOYSA-N 1-(5-tert-butyl-2,3-dihydro-1h-inden-1-yl)-3-isoquinolin-5-ylurea Chemical group N1=CC=C2C(NC(=O)NC3C4=CC=C(C=C4CC3)C(C)(C)C)=CC=CC2=C1 VPSCJCQPUGKRNC-UHFFFAOYSA-N 0.000 claims description 6
• INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 claims description 6
• 206010037211 Psychomotor hyperactivity Diseases 0.000 claims description 6
• 206010046543 Urinary incontinence Diseases 0.000 claims description 6
• 238000000605 extraction Methods 0.000 claims description 6
• 125000001072 heteroaryl group Chemical group 0.000 claims description 6
• TYOYXJNGINZFET-GOSISDBHSA-N 1-[(1r)-5-tert-butyl-2,3-dihydro-1h-inden-1-yl]-3-(1h-indazol-4-yl)urea Chemical compound N([C@H]1C2=CC=C(C=C2CC1)C(C)(C)C)C(=O)NC1=CC=CC2=C1C=NN2 TYOYXJNGINZFET-GOSISDBHSA-N 0.000 claims description 5
• 230000002757 inflammatory effect Effects 0.000 claims description 5
• 125000002757 morpholinyl group Chemical group 0.000 claims description 5
• 125000004193 piperazinyl group Chemical group 0.000 claims description 5
• 125000003386 piperidinyl group Chemical group 0.000 claims description 5
• 125000004076 pyridyl group Chemical group 0.000 claims description 5
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
• GNRVWTIJRDMIID-UHFFFAOYSA-N 1-(5-tert-butyl-2-fluoro-2,3-dihydro-1h-inden-1-yl)-3-(1h-indazol-4-yl)urea Chemical compound FC1CC2=CC(C(C)(C)C)=CC=C2C1NC(=O)NC1=CC=CC2=C1C=NN2 GNRVWTIJRDMIID-UHFFFAOYSA-N 0.000 claims description 4
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 4
• UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
• 125000005961 oxazepanyl group Chemical group 0.000 claims description 4
• PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 4
• ICPVUQZAKSTNQF-UHFFFAOYSA-N 1-(1h-indazol-4-yl)-3-(6-methyl-2,3-dihydro-1h-inden-1-yl)urea Chemical compound C12=CC(C)=CC=C2CCC1NC(=O)NC1=CC=CC2=C1C=NN2 ICPVUQZAKSTNQF-UHFFFAOYSA-N 0.000 claims description 3
• PCUDEEPQUVIGBR-UHFFFAOYSA-N 1-(4,5-dimethoxy-2,3-dihydro-1h-inden-1-yl)-3-(1h-indazol-4-yl)urea Chemical compound C1CC2=C(OC)C(OC)=CC=C2C1NC(=O)NC1=CC=CC2=C1C=NN2 PCUDEEPQUVIGBR-UHFFFAOYSA-N 0.000 claims description 3
• XJCVRTZCHMZPBD-UHFFFAOYSA-N 3-nitroaniline Chemical class NC1=CC=CC([N+]([O-])=O)=C1 XJCVRTZCHMZPBD-UHFFFAOYSA-N 0.000 claims description 3
• 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 3
• 125000004429 atom Chemical group 0.000 claims description 3
• SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 3
• 229940077388 benzenesulfonate Drugs 0.000 claims description 3
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 3
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 3
• MPEBZIGFRKPVHV-UHFFFAOYSA-N methyl 4-[(5-tert-butyl-2,3-dihydro-1h-inden-1-yl)carbamoylamino]indazole-1-carboxylate Chemical compound C1CC2=CC(C(C)(C)C)=CC=C2C1NC(=O)NC1=C2C=NN(C(=O)OC)C2=CC=C1 MPEBZIGFRKPVHV-UHFFFAOYSA-N 0.000 claims description 3
• QDWZACMXOZMDBC-UHFFFAOYSA-N 1-(1h-indazol-4-yl)-3-(7-methyl-2,3-dihydro-1h-inden-1-yl)urea Chemical compound C1=2C(C)=CC=CC=2CCC1NC(=O)NC1=CC=CC2=C1C=NN2 QDWZACMXOZMDBC-UHFFFAOYSA-N 0.000 claims description 2
• KJRJYJCHGDZPPX-UHFFFAOYSA-N 1-(1h-indazol-4-yl)-3-[5-(1-methoxy-2-methylpropan-2-yl)-2,3-dihydro-1h-inden-1-yl]urea Chemical compound C1CC2=CC(C(C)(C)COC)=CC=C2C1NC(=O)NC1=CC=CC2=C1C=NN2 KJRJYJCHGDZPPX-UHFFFAOYSA-N 0.000 claims description 2
• NBBJYIVJMJCFCE-UHFFFAOYSA-N 1-(1h-indazol-4-yl)-3-[5-(2-methylpiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]urea Chemical compound CC1CCCCN1C1=CC=C(C(CC2)NC(=O)NC=3C=4C=NNC=4C=CC=3)C2=C1 NBBJYIVJMJCFCE-UHFFFAOYSA-N 0.000 claims description 2
• CJHYHNWJRPRTDB-UHFFFAOYSA-N 1-[4-(4-fluoropiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]-3-(1h-indazol-4-yl)urea Chemical compound C1CC(F)CCN1C1=CC=CC2=C1CCC2NC(=O)NC1=CC=CC2=C1C=NN2 CJHYHNWJRPRTDB-UHFFFAOYSA-N 0.000 claims description 2
• 229910019567 Re Re Inorganic materials 0.000 claims description 2
• 150000001555 benzenes Chemical class 0.000 claims description 2
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims 4
• UJHPWLQNPUIFJU-UHFFFAOYSA-N 1-(5-tert-butyl-2,3-dihydro-1h-inden-1-yl)-3-(3-methylisoquinolin-5-yl)urea Chemical compound C1CC2=CC(C(C)(C)C)=CC=C2C1NC(=O)NC1=C2C=C(C)N=CC2=CC=C1 UJHPWLQNPUIFJU-UHFFFAOYSA-N 0.000 claims 2
• UIIWXLYPGXOGTO-UHFFFAOYSA-N 1-(1h-indazol-4-yl)-3-(4-pyridin-3-yl-2,3-dihydro-1h-inden-1-yl)urea Chemical compound C=1C=CC=2NN=CC=2C=1NC(=O)NC1CCC2=C1C=CC=C2C1=CC=CN=C1 UIIWXLYPGXOGTO-UHFFFAOYSA-N 0.000 claims 1
• OYQRPDVQQSMHBP-UHFFFAOYSA-N 1-(1h-indazol-4-yl)-3-(4-pyridin-4-yl-2,3-dihydro-1h-inden-1-yl)urea Chemical compound C=1C=CC=2NN=CC=2C=1NC(=O)NC1CCC2=C1C=CC=C2C1=CC=NC=C1 OYQRPDVQQSMHBP-UHFFFAOYSA-N 0.000 claims 1
• VEHLEPIVJNKFAH-UHFFFAOYSA-N 1-(1h-indazol-4-yl)-3-(5-propan-2-yl-2,3-dihydro-1h-inden-1-yl)urea Chemical compound C1CC2=CC(C(C)C)=CC=C2C1NC(=O)NC1=CC=CC2=C1C=NN2 VEHLEPIVJNKFAH-UHFFFAOYSA-N 0.000 claims 1
• ZQOHBQZZPJFTBS-IBGZPJMESA-N 1-(1h-indazol-4-yl)-3-[(1s)-4-piperidin-1-yl-2,3-dihydro-1h-inden-1-yl]urea Chemical compound C([C@@H]1NC(=O)NC=2C=3C=NNC=3C=CC=2)CC2=C1C=CC=C2N1CCCCC1 ZQOHBQZZPJFTBS-IBGZPJMESA-N 0.000 claims 1
• ZBISBOUCIVCJOF-INIZCTEOSA-N 1-(1h-indazol-4-yl)-3-[(1s)-5-methoxy-2,3-dihydro-1h-inden-1-yl]urea Chemical compound N([C@@H]1C2=CC=C(C=C2CC1)OC)C(=O)NC1=CC=CC2=C1C=NN2 ZBISBOUCIVCJOF-INIZCTEOSA-N 0.000 claims 1
• PNBWVYYXZCLQRU-UHFFFAOYSA-N 1-(1h-indazol-4-yl)-3-[5-(3-methylpiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]urea Chemical compound C1C(C)CCCN1C1=CC=C(C(CC2)NC(=O)NC=3C=4C=NNC=4C=CC=3)C2=C1 PNBWVYYXZCLQRU-UHFFFAOYSA-N 0.000 claims 1
• UKSFKXHTHRJUIA-UHFFFAOYSA-N 1-(1h-indazol-4-yl)-3-[5-(4-phenylpiperazin-1-yl)-2,3-dihydro-1h-inden-1-yl]urea Chemical compound C=1C=CC=2NN=CC=2C=1NC(=O)NC(C1=CC=2)CCC1=CC=2N(CC1)CCN1C1=CC=CC=C1 UKSFKXHTHRJUIA-UHFFFAOYSA-N 0.000 claims 1
• RZFOJZILWOUWLX-UHFFFAOYSA-N 1-(1h-indazol-4-yl)-3-[5-(4-piperidin-1-ylpiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]urea Chemical compound C=1C=CC=2NN=CC=2C=1NC(=O)NC(C1=CC=2)CCC1=CC=2N(CC1)CCC1N1CCCCC1 RZFOJZILWOUWLX-UHFFFAOYSA-N 0.000 claims 1
• OUIHQJINQZAAFC-UHFFFAOYSA-N 1-(4-bromo-2,3-dihydro-1h-inden-1-yl)-3-(1h-indazol-4-yl)urea Chemical compound C1CC=2C(Br)=CC=CC=2C1NC(=O)NC1=CC=CC2=C1C=NN2 OUIHQJINQZAAFC-UHFFFAOYSA-N 0.000 claims 1
• FCINXFUMHCCMJT-UHFFFAOYSA-N 1-(4-chloro-2,3-dihydro-1h-inden-1-yl)-3-(1h-indazol-4-yl)urea Chemical compound C1CC=2C(Cl)=CC=CC=2C1NC(=O)NC1=CC=CC2=C1C=NN2 FCINXFUMHCCMJT-UHFFFAOYSA-N 0.000 claims 1
• JBNOOOTYPGAENR-UHFFFAOYSA-N 1-(5-fluoro-2,3-dihydro-1h-inden-1-yl)-3-(1h-indazol-4-yl)urea Chemical compound C1CC2=CC(F)=CC=C2C1NC(=O)NC1=CC=CC2=C1C=NN2 JBNOOOTYPGAENR-UHFFFAOYSA-N 0.000 claims 1
• JMWSQSYRBYDBND-UHFFFAOYSA-N 1-(5-tert-butyl-2,3-dihydro-1h-inden-2-yl)-3-(1h-indazol-4-yl)urea Chemical compound C1C2=CC(C(C)(C)C)=CC=C2CC1NC(=O)NC1=CC=CC2=C1C=NN2 JMWSQSYRBYDBND-UHFFFAOYSA-N 0.000 claims 1
• HAXBPCKYPQIUOW-GMUIIQOCSA-N 1-[(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]-3-(1H-indazol-4-yl)urea hydrochloride Chemical compound Cl.C(C)(C)(C)C=1C=C2CC[C@H](C2=CC1)NC(=O)NC1=C2C=NNC2=CC=C1 HAXBPCKYPQIUOW-GMUIIQOCSA-N 0.000 claims 1
• PCUDEEPQUVIGBR-OAHLLOKOSA-N 1-[(1r)-4,5-dimethoxy-2,3-dihydro-1h-inden-1-yl]-3-(1h-indazol-4-yl)urea Chemical compound N([C@H]1C2=CC=C(C(=C2CC1)OC)OC)C(=O)NC1=CC=CC2=C1C=NN2 PCUDEEPQUVIGBR-OAHLLOKOSA-N 0.000 claims 1
• SIKZBZHXHBSSEA-UHFFFAOYSA-N 1-[4-(3-fluoropiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]-3-(1h-indazol-4-yl)urea Chemical compound C1C(F)CCCN1C1=CC=CC2=C1CCC2NC(=O)NC1=CC=CC2=C1C=NN2 SIKZBZHXHBSSEA-UHFFFAOYSA-N 0.000 claims 1
• PTNSZWWOWPKUIY-UHFFFAOYSA-N 1-[5-(azepan-1-yl)-2,3-dihydro-1h-inden-1-yl]-3-(1h-indazol-4-yl)urea Chemical compound C=1C=CC=2NN=CC=2C=1NC(=O)NC(C1=CC=2)CCC1=CC=2N1CCCCCC1 PTNSZWWOWPKUIY-UHFFFAOYSA-N 0.000 claims 1
• JKKTYHDGGQGMAY-UHFFFAOYSA-N 2-methylpropyl 4-[(5-tert-butyl-2,3-dihydro-1h-inden-1-yl)carbamoylamino]indazole-1-carboxylate Chemical compound C1CC2=CC(C(C)(C)C)=CC=C2C1NC(=O)NC1=C2C=NN(C(=O)OCC(C)C)C2=CC=C1 JKKTYHDGGQGMAY-UHFFFAOYSA-N 0.000 claims 1
• 101150099236 Acly gene Proteins 0.000 claims 1
• 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 claims 1
• ZDKNTXGRYNRQDK-UHFFFAOYSA-N propan-2-yl 4-[(5-tert-butyl-2,3-dihydro-1h-inden-1-yl)carbamoylamino]indazole-1-carboxylate Chemical compound C1CC2=CC(C(C)(C)C)=CC=C2C1NC(=O)NC1=C2C=NN(C(=O)OC(C)C)C2=CC=C1 ZDKNTXGRYNRQDK-UHFFFAOYSA-N 0.000 claims 1
• 238000005481 NMR spectroscopy Methods 0.000 description 112
• 239000000243 solution Substances 0.000 description 88
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• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 62
• 239000007787 solid Substances 0.000 description 62
• 238000010511 deprotection reaction Methods 0.000 description 54
• RCPFHUXEZIREGX-UHFFFAOYSA-N 5-(1-methoxy-2-methylpropan-2-yl)-2,3-dihydro-1h-inden-1-amine Chemical compound COCC(C)(C)C1=CC=C2C(N)CCC2=C1 RCPFHUXEZIREGX-UHFFFAOYSA-N 0.000 description 51
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
• 239000007858 starting material Substances 0.000 description 41
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 37
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
• 239000000047 product Substances 0.000 description 35
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
• 235000019439 ethyl acetate Nutrition 0.000 description 34
• YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 33
• 238000006243 chemical reaction Methods 0.000 description 33
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
• 235000013877 carbamide Nutrition 0.000 description 29
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
• 235000019441 ethanol Nutrition 0.000 description 26
• 230000002829 reductive effect Effects 0.000 description 26
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 25
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 24
• 239000003921 oil Substances 0.000 description 24
• 235000019198 oils Nutrition 0.000 description 24
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 22
• 239000011541 reaction mixture Substances 0.000 description 22
• 150000001412 amines Chemical class 0.000 description 21
• 239000000706 filtrate Substances 0.000 description 21
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• IKMAFQOFXZVFFB-UHFFFAOYSA-N methyl 4-[(4,5-dimethoxy-2,3-dihydro-1h-inden-1-yl)carbamoylamino]indazole-1-carboxylate Chemical compound C1CC(C(=C(OC)C=C2)OC)=C2C1NC(=O)NC1=C2C=NN(C(=O)OC)C2=CC=C1 IKMAFQOFXZVFFB-UHFFFAOYSA-N 0.000 description 1
• SHULNPNMJUEARE-UHFFFAOYSA-N methyl 4-[(4-chloro-2,3-dihydro-1h-inden-1-yl)carbamoylamino]indazole-1-carboxylate Chemical compound C1CC(C(=CC=C2)Cl)=C2C1NC(=O)NC1=C2C=NN(C(=O)OC)C2=CC=C1 SHULNPNMJUEARE-UHFFFAOYSA-N 0.000 description 1
• UVPSPECMYNRLHF-UHFFFAOYSA-N methyl 4-[(4-morpholin-4-yl-2,3-dihydro-1h-inden-1-yl)carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC1CCC2=C1C=CC=C2N1CCOCC1 UVPSPECMYNRLHF-UHFFFAOYSA-N 0.000 description 1
• XSDPTLVVYRZEMI-UHFFFAOYSA-N methyl 4-[(4-pyridin-4-yl-2,3-dihydro-1h-inden-1-yl)carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC1CCC2=C1C=CC=C2C1=CC=NC=C1 XSDPTLVVYRZEMI-UHFFFAOYSA-N 0.000 description 1
• SPKWKCREQOXOKQ-UHFFFAOYSA-N methyl 4-[(4-pyrrolidin-1-yl-2,3-dihydro-1h-inden-1-yl)carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC1CCC2=C1C=CC=C2N1CCCC1 SPKWKCREQOXOKQ-UHFFFAOYSA-N 0.000 description 1
• OIFGSAWJSYXFHR-UHFFFAOYSA-N methyl 4-[(5,6-dimethoxy-2,3-dihydro-1h-inden-1-yl)carbamoylamino]indazole-1-carboxylate Chemical compound C1CC2=CC(OC)=C(OC)C=C2C1NC(=O)NC1=C2C=NN(C(=O)OC)C2=CC=C1 OIFGSAWJSYXFHR-UHFFFAOYSA-N 0.000 description 1
• PRMCPKIMSQBDDE-UHFFFAOYSA-N methyl 4-[(5-methoxy-2,3-dihydro-1h-inden-1-yl)carbamoylamino]indazole-1-carboxylate Chemical compound C1CC2=CC(OC)=CC=C2C1NC(=O)NC1=C2C=NN(C(=O)OC)C2=CC=C1 PRMCPKIMSQBDDE-UHFFFAOYSA-N 0.000 description 1
• VTPFIEVFSGYGMI-UHFFFAOYSA-N methyl 4-[(5-methyl-2,3-dihydro-1h-inden-1-yl)carbamoylamino]indazole-1-carboxylate Chemical compound C1CC2=CC(C)=CC=C2C1NC(=O)NC1=C2C=NN(C(=O)OC)C2=CC=C1 VTPFIEVFSGYGMI-UHFFFAOYSA-N 0.000 description 1
• ASAHPOSAEWXJEA-UHFFFAOYSA-N methyl 4-[(5-piperidin-1-yl-2,3-dihydro-1h-inden-1-yl)carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC(C1=CC=2)CCC1=CC=2N1CCCCC1 ASAHPOSAEWXJEA-UHFFFAOYSA-N 0.000 description 1
• UYTPTIUWKWGGFJ-UHFFFAOYSA-N methyl 4-[(5-tert-butyl-2,2-difluoro-1,3-dihydroinden-1-yl)carbamoylamino]indazole-1-carboxylate Chemical compound C12=CC=C(C(C)(C)C)C=C2CC(F)(F)C1NC(=O)NC1=C2C=NN(C(=O)OC)C2=CC=C1 UYTPTIUWKWGGFJ-UHFFFAOYSA-N 0.000 description 1
• KGKOJERJAHOSLJ-UHFFFAOYSA-N methyl 4-[(5-tert-butyl-2-fluoro-2,3-dihydro-1h-inden-1-yl)carbamoylamino]indazole-1-carboxylate Chemical compound FC1CC2=CC(C(C)(C)C)=CC=C2C1NC(=O)NC1=C2C=NN(C(=O)OC)C2=CC=C1 KGKOJERJAHOSLJ-UHFFFAOYSA-N 0.000 description 1
• FPSNNQLSQVNQIG-UHFFFAOYSA-N methyl 4-[(6-methyl-2,3-dihydro-1h-inden-1-yl)carbamoylamino]indazole-1-carboxylate Chemical compound C1CC2=CC=C(C)C=C2C1NC(=O)NC1=C2C=NN(C(=O)OC)C2=CC=C1 FPSNNQLSQVNQIG-UHFFFAOYSA-N 0.000 description 1
• TYAABGAELRZLIC-UHFFFAOYSA-N methyl 4-[(7-methyl-2,3-dihydro-1h-inden-1-yl)carbamoylamino]indazole-1-carboxylate Chemical compound C1CC2=CC=CC(C)=C2C1NC(=O)NC1=C2C=NN(C(=O)OC)C2=CC=C1 TYAABGAELRZLIC-UHFFFAOYSA-N 0.000 description 1
• MPEBZIGFRKPVHV-LJQANCHMSA-N methyl 4-[[(1r)-5-tert-butyl-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1CC2=CC(C(C)(C)C)=CC=C2[C@@H]1NC(=O)NC1=C2C=NN(C(=O)OC)C2=CC=C1 MPEBZIGFRKPVHV-LJQANCHMSA-N 0.000 description 1
• MPEBZIGFRKPVHV-IBGZPJMESA-N methyl 4-[[(1s)-5-tert-butyl-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1CC2=CC(C(C)(C)C)=CC=C2[C@H]1NC(=O)NC1=C2C=NN(C(=O)OC)C2=CC=C1 MPEBZIGFRKPVHV-IBGZPJMESA-N 0.000 description 1
• NALNAVBKNGSVOX-UHFFFAOYSA-N methyl 4-[[4-(2-methylpyrrolidin-1-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC1CCC2=C1C=CC=C2N1CCCC1C NALNAVBKNGSVOX-UHFFFAOYSA-N 0.000 description 1
• GDPNCWQZKYVQBV-UHFFFAOYSA-N methyl 4-[[4-(3,4,4a,5,6,7,8,8a-octahydro-1h-isoquinolin-2-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1CC2CCCCC2CN1C1=CC=CC2=C1CCC2NC(=O)NC1=C2C=NN(C(=O)OC)C2=CC=C1 GDPNCWQZKYVQBV-UHFFFAOYSA-N 0.000 description 1
• JNKHNFFHNSIESN-UHFFFAOYSA-N methyl 4-[[4-(3-fluoropiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC1CCC2=C1C=CC=C2N1CCCC(F)C1 JNKHNFFHNSIESN-UHFFFAOYSA-N 0.000 description 1
• SLLDSDHFZJGDFP-UHFFFAOYSA-N methyl 4-[[4-(4-fluoropiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC1CCC2=C1C=CC=C2N1CCC(F)CC1 SLLDSDHFZJGDFP-UHFFFAOYSA-N 0.000 description 1
• QLSDIPPOJRPNRQ-UHFFFAOYSA-N methyl 4-[[4-(4-methylpiperazin-1-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC1CCC2=C1C=CC=C2N1CCN(C)CC1 QLSDIPPOJRPNRQ-UHFFFAOYSA-N 0.000 description 1
• NUDKIPGPGOMILW-UHFFFAOYSA-N methyl 4-[[4-(azepan-1-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC1CCC2=C1C=CC=C2N1CCCCCC1 NUDKIPGPGOMILW-UHFFFAOYSA-N 0.000 description 1
• CBAZUQGZIKZHCU-UHFFFAOYSA-N methyl 4-[[4-(cyanomethyl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1CC(C(=CC=C2)CC#N)=C2C1NC(=O)NC1=C2C=NN(C(=O)OC)C2=CC=C1 CBAZUQGZIKZHCU-UHFFFAOYSA-N 0.000 description 1
• KQBMUYAVISVWCU-UHFFFAOYSA-N methyl 4-[[4-(trifluoromethoxy)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1CC(C(=CC=C2)OC(F)(F)F)=C2C1NC(=O)NC1=C2C=NN(C(=O)OC)C2=CC=C1 KQBMUYAVISVWCU-UHFFFAOYSA-N 0.000 description 1
• XUNOUBBDMRUCKC-UHFFFAOYSA-N methyl 4-[[4-(trifluoromethyl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1CC(C(=CC=C2)C(F)(F)F)=C2C1NC(=O)NC1=C2C=NN(C(=O)OC)C2=CC=C1 XUNOUBBDMRUCKC-UHFFFAOYSA-N 0.000 description 1
• REIZEKOMNQWLFO-UHFFFAOYSA-N methyl 4-[[5-(1-methoxy-2-methylpropan-2-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1CC2=CC(C(C)(C)COC)=CC=C2C1NC(=O)NC1=CC=CC2=C1C=NN2C(=O)OC REIZEKOMNQWLFO-UHFFFAOYSA-N 0.000 description 1
• NMPGZWMZBITHHN-UHFFFAOYSA-N methyl 4-[[5-(2-methylpiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC(C1=CC=2)CCC1=CC=2N1CCCCC1C NMPGZWMZBITHHN-UHFFFAOYSA-N 0.000 description 1
• HLKIFUNNYMMIRU-UHFFFAOYSA-N methyl 4-[[5-(2-oxopiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC(C1=CC=2)CCC1=CC=2N1CCCCC1=O HLKIFUNNYMMIRU-UHFFFAOYSA-N 0.000 description 1
• BSKBHPZXNHKEHT-UHFFFAOYSA-N methyl 4-[[5-(3-methylpiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC(C1=CC=2)CCC1=CC=2N1CCCC(C)C1 BSKBHPZXNHKEHT-UHFFFAOYSA-N 0.000 description 1
• IBQAKRHZYKYKTO-UHFFFAOYSA-N methyl 4-[[5-(4-phenylpiperazin-1-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC(C1=CC=2)CCC1=CC=2N(CC1)CCN1C1=CC=CC=C1 IBQAKRHZYKYKTO-UHFFFAOYSA-N 0.000 description 1
• GMGBGLPUPLVXKK-UHFFFAOYSA-N methyl 4-[[5-(4-phenylpiperidin-1-yl)-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC(C1=CC=2)CCC1=CC=2N(CC1)CCC1C1=CC=CC=C1 GMGBGLPUPLVXKK-UHFFFAOYSA-N 0.000 description 1
• YFWYJIUSAJYGKB-UHFFFAOYSA-N methyl 4-[[5-[4-(trifluoromethyl)piperidin-1-yl]-2,3-dihydro-1h-inden-1-yl]carbamoylamino]indazole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC)N=CC2=C1NC(=O)NC(C1=CC=2)CCC1=CC=2N1CCC(C(F)(F)F)CC1 YFWYJIUSAJYGKB-UHFFFAOYSA-N 0.000 description 1
• VPVPFBUHEJIPSH-UHFFFAOYSA-N methyl 4-aminoindazole-1-carboxylate methyl 4-[(2,5-dioxopyrrolidin-1-yl)oxycarbonylamino]indazole-1-carboxylate Chemical compound COC(=O)N1N=CC2=C(C=CC=C12)N.COC(=O)N1N=CC2=C(C=CC=C12)NC(=O)ON1C(CCC1=O)=O VPVPFBUHEJIPSH-UHFFFAOYSA-N 0.000 description 1
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