KR20040008142A - 트리아자스피로[5.5]운데칸 유도체 및 이들을유효성분으로 하는 약제 - Google Patents
트리아자스피로[5.5]운데칸 유도체 및 이들을유효성분으로 하는 약제 Download PDFInfo
- Publication number
- KR20040008142A KR20040008142A KR10-2003-7012168A KR20037012168A KR20040008142A KR 20040008142 A KR20040008142 A KR 20040008142A KR 20037012168 A KR20037012168 A KR 20037012168A KR 20040008142 A KR20040008142 A KR 20040008142A
- Authority
- KR
- South Korea
- Prior art keywords
- dioxo
- triazaspiro
- butyl
- undecane
- hydroxy
- Prior art date
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- 239000004480 active ingredient Substances 0.000 title claims abstract description 12
- RSJKGSCJYJTIGS-BJUDXGSMSA-N undecane Chemical class CCCCCCCCCC[11CH3] RSJKGSCJYJTIGS-BJUDXGSMSA-N 0.000 title abstract description 8
- 239000003814 drug Substances 0.000 title description 13
- 229940079593 drug Drugs 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 206
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 26
- 231100000252 nontoxic Toxicity 0.000 claims abstract description 22
- 230000003000 nontoxic effect Effects 0.000 claims abstract description 22
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 21
- 102000009410 Chemokine receptor Human genes 0.000 claims abstract description 13
- 108050000299 Chemokine receptor Proteins 0.000 claims abstract description 13
- 102000019034 Chemokines Human genes 0.000 claims abstract description 13
- 108010012236 Chemokines Proteins 0.000 claims abstract description 13
- 201000008383 nephritis Diseases 0.000 claims abstract description 10
- 206010003246 arthritis Diseases 0.000 claims abstract description 9
- 230000009471 action Effects 0.000 claims abstract description 8
- 208000006454 hepatitis Diseases 0.000 claims abstract description 6
- 231100000283 hepatitis Toxicity 0.000 claims abstract description 6
- 208000006673 asthma Diseases 0.000 claims abstract description 5
- -1 undecane derivative compounds Chemical class 0.000 claims description 159
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 61
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 56
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 claims description 52
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 48
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 42
- 229910052757 nitrogen Inorganic materials 0.000 claims description 32
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 30
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 19
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 11
- 230000002265 prevention Effects 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 10
- 208000030507 AIDS Diseases 0.000 claims description 9
- 125000002950 monocyclic group Chemical group 0.000 claims description 9
- 230000000172 allergic effect Effects 0.000 claims description 8
- 208000010668 atopic eczema Diseases 0.000 claims description 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
- 201000011510 cancer Diseases 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 201000002909 Aspergillosis Diseases 0.000 claims description 4
- 208000036641 Aspergillus infections Diseases 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
- 208000035143 Bacterial infection Diseases 0.000 claims description 4
- RWALKOOWHLHGEE-UHFFFAOYSA-N C1=CC(OC)=CC=C1CNC(=O)C(C=C1)=CC=C1CN1CC2(CCNCC2)NCC1 Chemical compound C1=CC(OC)=CC=C1CNC(=O)C(C=C1)=CC=C1CN1CC2(CCNCC2)NCC1 RWALKOOWHLHGEE-UHFFFAOYSA-N 0.000 claims description 4
- 206010010741 Conjunctivitis Diseases 0.000 claims description 4
- 206010027476 Metastases Diseases 0.000 claims description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 201000004681 Psoriasis Diseases 0.000 claims description 4
- 206010063837 Reperfusion injury Diseases 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 201000001564 eosinophilic gastroenteritis Diseases 0.000 claims description 4
- 230000008629 immune suppression Effects 0.000 claims description 4
- 230000000302 ischemic effect Effects 0.000 claims description 4
- 230000009401 metastasis Effects 0.000 claims description 4
- 201000006417 multiple sclerosis Diseases 0.000 claims description 4
- 206010039083 rhinitis Diseases 0.000 claims description 4
- 230000035939 shock Effects 0.000 claims description 4
- 230000001629 suppression Effects 0.000 claims description 4
- BBMKHMSUQONZQY-JWQCQUIFSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[(4-pyridin-3-yloxyphenyl)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=NC=CC=3)=CC=2)CC1 BBMKHMSUQONZQY-JWQCQUIFSA-N 0.000 claims description 3
- SRRFOPOXZBYBTQ-JWQCQUIFSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[(6-phenoxypyridin-3-yl)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=NC(OC=3C=CC=CC=3)=CC=2)CC1 SRRFOPOXZBYBTQ-JWQCQUIFSA-N 0.000 claims description 3
- PBBCRTVQGQJSDZ-VSGBNLITSA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[(6-phenoxypyridin-3-yl)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=N1)=CC=C1OC1=CC=CC=C1 PBBCRTVQGQJSDZ-VSGBNLITSA-N 0.000 claims description 3
- VKKOHAOLCPZVCT-LOYHVIPDSA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[[4-[4-(hydroxymethyl)phenoxy]phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(CO)C=C1 VKKOHAOLCPZVCT-LOYHVIPDSA-N 0.000 claims description 3
- PYGKLZQPZZABDK-KAYWLYCHSA-N (3r)-1-butyl-9-[[4-[4-(hydroxymethyl)phenoxy]phenyl]methyl]-3-[(1r)-1-hydroxy-2-methylpropyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(CO)=CC=3)=CC=2)CC1 PYGKLZQPZZABDK-KAYWLYCHSA-N 0.000 claims description 3
- HZGGFWDLTDCLMM-DEOSSOPVSA-N (3s)-1-butyl-3-(cyclohexylmethyl)-9-[(1-ethyl-3,5-dimethylpyrazol-4-yl)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound C([C@H]1C(=O)N(C2(CCN(CC3=C(N(CC)N=C3C)C)CC2)C(=O)N1)CCCC)C1CCCCC1 HZGGFWDLTDCLMM-DEOSSOPVSA-N 0.000 claims description 3
- JPHUZQAPKZTRLF-VWLOTQADSA-N (3s)-1-butyl-3-(cyclohexylmethyl)-9-[(3,5-dimethyl-1-propylpyrazol-4-yl)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound C([C@H]1C(=O)N(C2(CCN(CC3=C(N(CCC)N=C3C)C)CC2)C(=O)N1)CCCC)C1CCCCC1 JPHUZQAPKZTRLF-VWLOTQADSA-N 0.000 claims description 3
- IZZAGXONYJONMZ-LJAQVGFWSA-N (3s)-1-butyl-3-(cyclohexylmethyl)-9-[[1-(4-methoxyphenyl)-3,5-dimethylpyrazol-4-yl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound C([C@H]1C(=O)N(C2(CCN(CC3=C(N(N=C3C)C=3C=CC(OC)=CC=3)C)CC2)C(=O)N1)CCCC)C1CCCCC1 IZZAGXONYJONMZ-LJAQVGFWSA-N 0.000 claims description 3
- NTBMDXPOFGGJPF-PMERELPUSA-N (3s)-1-butyl-3-(cyclohexylmethyl)-9-[[4-[4-(hydroxymethyl)phenoxy]phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound C([C@H]1C(=O)N(C2(CCN(CC=3C=CC(OC=4C=CC(CO)=CC=4)=CC=3)CC2)C(=O)N1)CCCC)C1CCCCC1 NTBMDXPOFGGJPF-PMERELPUSA-N 0.000 claims description 3
- CIVCFUDJXGQFFO-YTTGMZPUSA-N (3s)-1-butyl-3-(cyclohexylmethyl)-9-[[4-[4-[(dimethylamino)methyl]phenoxy]phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound C([C@H]1C(=O)N(C2(CCN(CC=3C=CC(OC=4C=CC(CN(C)C)=CC=4)=CC=3)CC2)C(=O)N1)CCCC)C1CCCCC1 CIVCFUDJXGQFFO-YTTGMZPUSA-N 0.000 claims description 3
- SRRFOPOXZBYBTQ-DQEYMECFSA-N (3s)-1-butyl-3-[(1s)-1-hydroxy-2-methylpropyl]-9-[(6-phenoxypyridin-3-yl)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@H]([C@@H](O)C(C)C)NC(=O)C11CCN(CC=2C=NC(OC=3C=CC=CC=3)=CC=2)CC1 SRRFOPOXZBYBTQ-DQEYMECFSA-N 0.000 claims description 3
- QALUMWRPMASXCL-VWLOTQADSA-N (3s)-1-butyl-9-[(1-tert-butyl-3,5-dimethylpyrazol-4-yl)methyl]-3-(cyclohexylmethyl)-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound C([C@H]1C(=O)N(C2(CCN(CC3=C(N(N=C3C)C(C)(C)C)C)CC2)C(=O)N1)CCCC)C1CCCCC1 QALUMWRPMASXCL-VWLOTQADSA-N 0.000 claims description 3
- BSLWDMZWCJHGJE-QFIPXVFZSA-N (3s)-1-butyl-9-[(3,5-dimethyl-1-propylpyrazol-4-yl)methyl]-3-(2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@H](CC(C)C)NC(=O)C11CCN(CC2=C(N(CCC)N=C2C)C)CC1 BSLWDMZWCJHGJE-QFIPXVFZSA-N 0.000 claims description 3
- IYKWMIWGNIDBOQ-MHZLTWQESA-N (3s)-1-butyl-9-[3-(3,5-dimethyl-1-phenylpyrazol-4-yl)propyl]-3-(2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@H](CC(C)C)NC(=O)C11CCN(CCCC2=C(N(N=C2C)C=2C=CC=CC=2)C)CC1 IYKWMIWGNIDBOQ-MHZLTWQESA-N 0.000 claims description 3
- ZNHGVUZETFYGJL-SANMLTNESA-N (3s)-1-butyl-9-[[1-(4-methoxyphenyl)-3,5-dimethylpyrazol-4-yl]methyl]-3-(2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@H](CC(C)C)NC(=O)C11CCN(CC2=C(N(N=C2C)C=2C=CC(OC)=CC=2)C)CC1 ZNHGVUZETFYGJL-SANMLTNESA-N 0.000 claims description 3
- QRWMIMAHVYJWOW-NDEPHWFRSA-N (3s)-1-butyl-9-[[4-[4-(dimethylamino)phenoxy]phenyl]methyl]-3-(2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@H](CC(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(=CC=3)N(C)C)=CC=2)CC1 QRWMIMAHVYJWOW-NDEPHWFRSA-N 0.000 claims description 3
- RUMAPWOYEOQKHD-LJAQVGFWSA-N (3s)-1-butyl-9-[[4-[4-[(dimethylamino)methyl]phenoxy]phenyl]methyl]-3-(2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@H](CC(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(CN(C)C)=CC=3)=CC=2)CC1 RUMAPWOYEOQKHD-LJAQVGFWSA-N 0.000 claims description 3
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 3
- DTEQSVWFIARCBG-FQLXRVMXSA-N 4-[4-[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecane-9-carbonyl]phenoxy]-n-methylbenzamide Chemical compound N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1C(=O)C(C=C1)=CC=C1OC1=CC=C(C(=O)NC)C=C1 DTEQSVWFIARCBG-FQLXRVMXSA-N 0.000 claims description 3
- UDRJQBDRUJJHLN-VSGBNLITSA-N 4-[4-[[(3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]-3,5-dimethylpyrazol-1-yl]-n-(2-hydroxyethyl)-n-methylbenzenesulfonamide Chemical compound CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC2=C(N(N=C2C)C=2C=CC(=CC=2)S(=O)(=O)N(C)CCO)C)CC1 UDRJQBDRUJJHLN-VSGBNLITSA-N 0.000 claims description 3
- DFDBQERKSXXCOB-FIRIVFDPSA-N 4-[4-[[(3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]-3,5-dimethylpyrazol-1-yl]-n-(2-morpholin-4-ylethyl)benzenesulfonamide Chemical compound CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC2=C(N(N=C2C)C=2C=CC(=CC=2)S(=O)(=O)NCCN2CCOCC2)C)CC1 DFDBQERKSXXCOB-FIRIVFDPSA-N 0.000 claims description 3
- QFAACNPUGCFTOM-FIRIVFDPSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]-3,5-dimethylpyrazol-1-yl]-n-(2-hydroxyethyl)-n-methylbenzenesulfonamide Chemical compound N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(=C1C)C(C)=NN1C1=CC=C(S(=O)(=O)N(C)CCO)C=C1 QFAACNPUGCFTOM-FIRIVFDPSA-N 0.000 claims description 3
- YNOAIEYUABOTIZ-KKLWWLSJSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]-3,5-dimethylpyrazol-1-yl]-n-(2-morpholin-4-ylethyl)benzenesulfonamide Chemical compound N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(=C1C)C(C)=NN1C(C=C1)=CC=C1S(=O)(=O)NCCN1CCOCC1 YNOAIEYUABOTIZ-KKLWWLSJSA-N 0.000 claims description 3
- AZKHFIBTKZEVRY-ROJLCIKYSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]-3,5-dimethylpyrazol-1-yl]-n-[2-(dimethylamino)ethyl]benzamide Chemical compound N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(=C1C)C(C)=NN1C1=CC=C(C(=O)NCCN(C)C)C=C1 AZKHFIBTKZEVRY-ROJLCIKYSA-N 0.000 claims description 3
- PIIFLAAGJWOSIU-ROJLCIKYSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]-3,5-dimethylpyrazol-1-yl]-n-[2-(dimethylamino)ethyl]benzenesulfonamide Chemical compound N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(=C1C)C(C)=NN1C1=CC=C(S(=O)(=O)NCCN(C)C)C=C1 PIIFLAAGJWOSIU-ROJLCIKYSA-N 0.000 claims description 3
- LELDNBCNSVHJAS-LJAQVGFWSA-N 4-[4-[[(3s)-1-butyl-2,5-dioxo-3-(pyridin-2-ylmethyl)-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-methylbenzamide Chemical compound C([C@H]1C(=O)N(C2(CCN(CC=3C=CC(OC=4C=CC(=CC=4)C(=O)NC)=CC=3)CC2)C(=O)N1)CCCC)C1=CC=CC=N1 LELDNBCNSVHJAS-LJAQVGFWSA-N 0.000 claims description 3
- GURGJBGLKSILRK-LJAQVGFWSA-N 4-[4-[[(3s)-1-butyl-2,5-dioxo-3-(pyridin-3-ylmethyl)-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-methylbenzamide Chemical compound C([C@H]1C(=O)N(C2(CCN(CC=3C=CC(OC=4C=CC(=CC=4)C(=O)NC)=CC=3)CC2)C(=O)N1)CCCC)C1=CC=CN=C1 GURGJBGLKSILRK-LJAQVGFWSA-N 0.000 claims description 3
- WRAGUFPXNSINSH-LJAQVGFWSA-N 4-[4-[[(3s)-1-butyl-3-(cyclohexylmethyl)-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]-3,5-dimethylpyrazol-1-yl]-n-methylbenzamide Chemical compound C([C@H]1C(=O)N(C2(CCN(CC3=C(N(N=C3C)C=3C=CC(=CC=3)C(=O)NC)C)CC2)C(=O)N1)CCCC)C1CCCCC1 WRAGUFPXNSINSH-LJAQVGFWSA-N 0.000 claims description 3
- TVSIUQJKMVZESE-UHFFFAOYSA-N 4-[4-[[1-butyl-3-(morpholin-4-ylmethyl)-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-methylbenzamide Chemical compound N1C(=O)C2(CCN(CC=3C=CC(OC=4C=CC(=CC=4)C(=O)NC)=CC=3)CC2)N(CCCC)C(=O)C1CN1CCOCC1 TVSIUQJKMVZESE-UHFFFAOYSA-N 0.000 claims description 3
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 3
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- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 3
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 3
- 125000004450 alkenylene group Chemical group 0.000 claims description 3
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 claims description 3
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 3
- PLGQFEHMLOCQEU-QFIPXVFZSA-N methyl 2-[[4-[[(3s)-1-butyl-3-(2-methylpropyl)-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]benzoyl]amino]acetate Chemical compound CCCCN1C(=O)[C@H](CC(C)C)NC(=O)C11CCN(CC=2C=CC(=CC=2)C(=O)NCC(=O)OC)CC1 PLGQFEHMLOCQEU-QFIPXVFZSA-N 0.000 claims description 3
- JFTNMYGJJJBPJC-VWLOTQADSA-N methyl 2-[[4-[[(3s)-1-butyl-3-(cyclohexylmethyl)-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]benzoyl]amino]acetate Chemical compound C([C@H]1C(=O)N(C2(CCN(CC=3C=CC(=CC=3)C(=O)NCC(=O)OC)CC2)C(=O)N1)CCCC)C1CCCCC1 JFTNMYGJJJBPJC-VWLOTQADSA-N 0.000 claims description 3
- RWEJGXPNLWSJOW-LJAQVGFWSA-N methyl 4-[4-[[(3s)-1-butyl-3-(cyclohexylmethyl)-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]-3,5-dimethylpyrazol-1-yl]benzoate Chemical compound C([C@H]1C(=O)N(C2(CCN(CC3=C(N(N=C3C)C=3C=CC(=CC=3)C(=O)OC)C)CC2)C(=O)N1)CCCC)C1CCCCC1 RWEJGXPNLWSJOW-LJAQVGFWSA-N 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
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- QPFOPNUDCLUOTC-CLJLJLNGSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[(4-phenylsulfanylphenyl)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(SC=3C=CC=CC=3)=CC=2)CC1 QPFOPNUDCLUOTC-CLJLJLNGSA-N 0.000 claims description 2
- ZIIBPRTVXFURBW-JWQCQUIFSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[[1-(4-hydroxyphenyl)-3,5-dimethylpyrazol-4-yl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC2=C(N(N=C2C)C=2C=CC(O)=CC=2)C)CC1 ZIIBPRTVXFURBW-JWQCQUIFSA-N 0.000 claims description 2
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- LKALVDIESDYUMO-KAYWLYCHSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[[4-(4-methoxyphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(OC)=CC=3)=CC=2)CC1 LKALVDIESDYUMO-KAYWLYCHSA-N 0.000 claims description 2
- MSIAOYNRTUTTKM-KAYWLYCHSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[[4-(4-methylphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(C)=CC=3)=CC=2)CC1 MSIAOYNRTUTTKM-KAYWLYCHSA-N 0.000 claims description 2
- AIJIIHCOGCOBFN-KAYWLYCHSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[[4-(4-methylsulfanylphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(SC)=CC=3)=CC=2)CC1 AIJIIHCOGCOBFN-KAYWLYCHSA-N 0.000 claims description 2
- XZASINHSMFSJJI-CSBSULECSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[[4-(4-methylsulfinylphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(=CC=3)S(C)=O)=CC=2)CC1 XZASINHSMFSJJI-CSBSULECSA-N 0.000 claims description 2
- MUBLZVFUJVQLEM-KAYWLYCHSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[[4-(4-methylsulfonylphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(=CC=3)S(C)(=O)=O)=CC=2)CC1 MUBLZVFUJVQLEM-KAYWLYCHSA-N 0.000 claims description 2
- BCKOBNVFXDJFBX-JWQCQUIFSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[[4-(oxan-4-yloxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC3CCOCC3)=CC=2)CC1 BCKOBNVFXDJFBX-JWQCQUIFSA-N 0.000 claims description 2
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- HJDVPNQWVMKRNE-ROJLCIKYSA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[[3,5-dimethyl-1-(4-morpholin-4-ylsulfonylphenyl)pyrazol-4-yl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(=C1C)C(C)=NN1C(C=C1)=CC=C1S(=O)(=O)N1CCOCC1 HJDVPNQWVMKRNE-ROJLCIKYSA-N 0.000 claims description 2
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- ISHPDOIDKPYBRX-LOYHVIPDSA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[[4-(3-methoxyphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=CC(OC)=C1 ISHPDOIDKPYBRX-LOYHVIPDSA-N 0.000 claims description 2
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- OYYRQZVVDSNWAK-FQLXRVMXSA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[[4-(4-hydroxyphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(O)C=C1 OYYRQZVVDSNWAK-FQLXRVMXSA-N 0.000 claims description 2
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- SHJARFCNFXLLBY-CZNDPXEESA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[[4-[4-(morpholine-4-carbonyl)phenoxy]phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC(C=C1)=CC=C1C(=O)N1CCOCC1 SHJARFCNFXLLBY-CZNDPXEESA-N 0.000 claims description 2
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- GXTQSMIXRXSCKT-AJUXDCMMSA-N (3R)-1-butyl-9-[(3,5-dimethyl-1-phenylpyrazol-4-yl)methyl]-3-[(R)-hydroxy(oxan-4-yl)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione dihydrochloride Chemical compound Cl.Cl.C(CCC)N1C([C@H](NC(C12CCN(CC2)CC=2C(=NN(C2C)C2=CC=CC=C2)C)=O)[C@@H](C2CCOCC2)O)=O GXTQSMIXRXSCKT-AJUXDCMMSA-N 0.000 description 1
- YRZSJVHQYKZNHE-PKLMIRHRSA-N (3r)-1-butyl-3-(cyclohexylmethyl)-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.C([C@@H]1C(=O)N(C2(CCNCC2)C(=O)N1)CCCC)C1CCCCC1 YRZSJVHQYKZNHE-PKLMIRHRSA-N 0.000 description 1
- PMBAJLCQAGXILW-OJERSXHUSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCNCC1 PMBAJLCQAGXILW-OJERSXHUSA-N 0.000 description 1
- ZSMBFJXCNGHBSA-JUJAXGASSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[(4-phenylsulfanylphenyl)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(SC=3C=CC=CC=3)=CC=2)CC1 ZSMBFJXCNGHBSA-JUJAXGASSA-N 0.000 description 1
- ALOGMVWZHQJWQM-CNZCJKERSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[[4-(3-methoxyphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=C(OC)C=CC=3)=CC=2)CC1 ALOGMVWZHQJWQM-CNZCJKERSA-N 0.000 description 1
- CMWXDLGMTRFKFQ-JUJAXGASSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[[4-(4-hydroxyphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(O)=CC=3)=CC=2)CC1 CMWXDLGMTRFKFQ-JUJAXGASSA-N 0.000 description 1
- OWVBUPQCEBTUQD-CNZCJKERSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[[4-(4-methoxyphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(OC)=CC=3)=CC=2)CC1 OWVBUPQCEBTUQD-CNZCJKERSA-N 0.000 description 1
- LCPYGXZOCNBZSE-CNZCJKERSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[[4-(4-methylphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(C)=CC=3)=CC=2)CC1 LCPYGXZOCNBZSE-CNZCJKERSA-N 0.000 description 1
- XIQAYZXNYCXXHS-CNZCJKERSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[[4-(4-methylsulfanylphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(SC)=CC=3)=CC=2)CC1 XIQAYZXNYCXXHS-CNZCJKERSA-N 0.000 description 1
- MOEZYOGNGQPHKV-MWFYONGFSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[[4-(4-methylsulfinylphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(=CC=3)S(C)=O)=CC=2)CC1 MOEZYOGNGQPHKV-MWFYONGFSA-N 0.000 description 1
- JVCUMNAWCWXUOS-CNZCJKERSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[[4-(4-methylsulfonylphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(=CC=3)S(C)(=O)=O)=CC=2)CC1 JVCUMNAWCWXUOS-CNZCJKERSA-N 0.000 description 1
- SUOBFYNPROYECF-JIMLSGQQSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[[4-(oxan-4-yloxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC3CCOCC3)=CC=2)CC1 SUOBFYNPROYECF-JIMLSGQQSA-N 0.000 description 1
- UWQRUDOZBTZOBM-GAQUOPITSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[[4-[4-(morpholine-4-carbonyl)phenoxy]phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(=CC=3)C(=O)N3CCOCC3)=CC=2)CC1 UWQRUDOZBTZOBM-GAQUOPITSA-N 0.000 description 1
- WOUXBLTTWGDNPD-GAQUOPITSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[[4-[4-(pyrrolidine-1-carbonyl)phenoxy]phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(=CC=3)C(=O)N3CCCC3)=CC=2)CC1 WOUXBLTTWGDNPD-GAQUOPITSA-N 0.000 description 1
- FQJKCVQGZWNEOY-ZOCMOMSRSA-N (3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-9-[[4-[hydroxy(phenyl)methyl]phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(=CC=2)C(O)C=2C=CC=CC=2)CC1 FQJKCVQGZWNEOY-ZOCMOMSRSA-N 0.000 description 1
- POWQHOJGDPXNNB-JIMLSGQQSA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.C1([C@@H](O)[C@@H]2C(=O)N(C3(CCN(CC=4C=C5OCCOC5=CC=4)CC3)C(=O)N2)CCCC)CCCCC1 POWQHOJGDPXNNB-JIMLSGQQSA-N 0.000 description 1
- AOOTYIRLUTVCBQ-PQQSRXGVSA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[(4-phenoxyphenyl)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=CC=C1 AOOTYIRLUTVCBQ-PQQSRXGVSA-N 0.000 description 1
- HIZIAYBJTYIZMV-JUJAXGASSA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[(4-propan-2-ylphenyl)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC1=CC=C(C(C)C)C=C1 HIZIAYBJTYIZMV-JUJAXGASSA-N 0.000 description 1
- YSSDOWZWHCVCIH-GAQUOPITSA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[[4-(3-methoxyphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=CC(OC)=C1 YSSDOWZWHCVCIH-GAQUOPITSA-N 0.000 description 1
- HECIAHFXAMWPGJ-PQQSRXGVSA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[[4-(4-fluorophenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(F)C=C1 HECIAHFXAMWPGJ-PQQSRXGVSA-N 0.000 description 1
- QKJISACYTOLKPC-PQQSRXGVSA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[[4-(4-hydroxyphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(O)C=C1 QKJISACYTOLKPC-PQQSRXGVSA-N 0.000 description 1
- LVWGLWDYUVKKKI-GAQUOPITSA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[[4-(4-methoxyphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(OC)C=C1 LVWGLWDYUVKKKI-GAQUOPITSA-N 0.000 description 1
- NQZBVJPZFQMVOJ-QYJJNXCBSA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[[4-(4-methylsulfinylphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(S(C)=O)C=C1 NQZBVJPZFQMVOJ-QYJJNXCBSA-N 0.000 description 1
- FRPOWJMANFYJQV-GAQUOPITSA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[[4-(4-methylsulfonylphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(S(C)(=O)=O)C=C1 FRPOWJMANFYJQV-GAQUOPITSA-N 0.000 description 1
- COVPDNYQHUUTSJ-LTRMXRMOSA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[[4-(oxan-4-yloxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1CCOCC1 COVPDNYQHUUTSJ-LTRMXRMOSA-N 0.000 description 1
- WYBPZGDGLFLJAW-ZNBLAKOKSA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[[4-[4-(morpholine-4-carbonyl)phenoxy]phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC(C=C1)=CC=C1C(=O)N1CCOCC1 WYBPZGDGLFLJAW-ZNBLAKOKSA-N 0.000 description 1
- NBWTVOBJCIKQMU-ZNBLAKOKSA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[[4-[4-(pyrrolidine-1-carbonyl)phenoxy]phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC(C=C1)=CC=C1C(=O)N1CCCC1 NBWTVOBJCIKQMU-ZNBLAKOKSA-N 0.000 description 1
- JNDSYHZLVQSTIN-GCDWOPOESA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[[4-[hydroxy(phenyl)methyl]phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1C(O)C1=CC=CC=C1 JNDSYHZLVQSTIN-GCDWOPOESA-N 0.000 description 1
- YPDCUVMLWBBWLR-PQQSRXGVSA-N (3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-9-[[6-(4-methoxyphenoxy)pyridin-3-yl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=N1)=CC=C1OC1=CC=C(OC)C=C1 YPDCUVMLWBBWLR-PQQSRXGVSA-N 0.000 description 1
- AMEBCMFWYNJLFG-CTHHTMFSSA-N (3r)-1-butyl-3-[(r)-hydroxy(oxan-4-yl)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCOCC2)C(=O)C11CCNCC1 AMEBCMFWYNJLFG-CTHHTMFSSA-N 0.000 description 1
- VCUDTJSORBJGKQ-JUJAXGASSA-N (3r)-1-butyl-9-[(4-cyclohexyloxyphenyl)methyl]-3-[(1r)-1-hydroxy-2-methylpropyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC3CCCCC3)=CC=2)CC1 VCUDTJSORBJGKQ-JUJAXGASSA-N 0.000 description 1
- FFCYDGHVRPYSFU-JWQCQUIFSA-N (3r)-1-butyl-9-[[3,5-dimethyl-1-(1-methylsulfonylpiperidin-4-yl)pyrazol-4-yl]methyl]-3-[(1r)-1-hydroxy-2-methylpropyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC2=C(N(C3CCN(CC3)S(C)(=O)=O)N=C2C)C)CC1 FFCYDGHVRPYSFU-JWQCQUIFSA-N 0.000 description 1
- VZXYKSVOMAUOKP-LOYHVIPDSA-N (3r)-1-butyl-9-[[3,5-dimethyl-1-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]pyrazol-4-yl]methyl]-3-[(1r)-1-hydroxy-2-methylpropyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC2=C(N(N=C2C)C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C)CC1 VZXYKSVOMAUOKP-LOYHVIPDSA-N 0.000 description 1
- AEPZBEBJBQACFK-JUJAXGASSA-N (3r)-1-butyl-9-[[4-(4-chlorophenoxy)phenyl]methyl]-3-[(1r)-1-hydroxy-2-methylpropyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(Cl)=CC=3)=CC=2)CC1 AEPZBEBJBQACFK-JUJAXGASSA-N 0.000 description 1
- GYINQOLRWUJQAJ-PQQSRXGVSA-N (3r)-1-butyl-9-[[4-(4-chlorophenoxy)phenyl]methyl]-3-[(r)-cyclohexyl(hydroxy)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(Cl)C=C1 GYINQOLRWUJQAJ-PQQSRXGVSA-N 0.000 description 1
- FTTCWJGTKSDIGF-JUJAXGASSA-N (3r)-1-butyl-9-[[4-(4-fluorophenoxy)phenyl]methyl]-3-[(1r)-1-hydroxy-2-methylpropyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(F)=CC=3)=CC=2)CC1 FTTCWJGTKSDIGF-JUJAXGASSA-N 0.000 description 1
- OHHHUCGTUPYLMK-MNMPKAIFSA-N (3r)-3-[(1r)-1-hydroxy-2-methylpropyl]-1-propyl-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCNCC1 OHHHUCGTUPYLMK-MNMPKAIFSA-N 0.000 description 1
- WXSSHTSBMRGHJX-KAYWLYCHSA-N (3r)-9-[(1-cyclohexyl-3,5-dimethylpyrazol-4-yl)methyl]-3-[(r)-cyclohexyl(hydroxy)methyl]-1-propyl-1,4,9-triazaspiro[5.5]undecane-2,5-dione Chemical compound N([C@@H](C(=O)N1CCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(=C1C)C(C)=NN1C1CCCCC1 WXSSHTSBMRGHJX-KAYWLYCHSA-N 0.000 description 1
- XPWCVCNZGAASGT-JUJAXGASSA-N (3r)-9-[(4-benzoylphenyl)methyl]-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(=CC=2)C(=O)C=2C=CC=CC=2)CC1 XPWCVCNZGAASGT-JUJAXGASSA-N 0.000 description 1
- XVOVRYLYXUGDEN-XDSAXFAGSA-N (3r)-9-[(4-benzoylphenyl)methyl]-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1C(=O)C1=CC=CC=C1 XVOVRYLYXUGDEN-XDSAXFAGSA-N 0.000 description 1
- IQEUTVCMJZGJAI-ZOWNYOTGSA-N (3s)-1-butyl-3-(2-methylpropyl)-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@H](CC(C)C)NC(=O)C11CCNCC1 IQEUTVCMJZGJAI-ZOWNYOTGSA-N 0.000 description 1
- RVRNSAMNUBQCGQ-AQFWSOKCSA-N (3s)-1-butyl-3-(2-methylpropyl)-9-[(4-methylsulfinylphenyl)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@H](CC(C)C)NC(=O)C11CCN(CC=2C=CC(=CC=2)S(C)=O)CC1 RVRNSAMNUBQCGQ-AQFWSOKCSA-N 0.000 description 1
- MFZYUGXHOVZVMX-BOXHHOBZSA-N (3s)-1-butyl-3-(2-methylpropyl)-9-[(4-methylsulfonylphenyl)methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@H](CC(C)C)NC(=O)C11CCN(CC=2C=CC(=CC=2)S(C)(=O)=O)CC1 MFZYUGXHOVZVMX-BOXHHOBZSA-N 0.000 description 1
- JUUOWOHESKGMNB-KFXBVHSFSA-N (3s)-1-butyl-3-(2-methylpropyl)-9-[[4-(4-methylsulfinylphenoxy)phenyl]methyl]-1,4,9-triazaspiro[5.5]undecane-2,5-dione;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@H](CC(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(=CC=3)S(C)=O)=CC=2)CC1 JUUOWOHESKGMNB-KFXBVHSFSA-N 0.000 description 1
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- PSPFFCYIYIDUIS-ZNBLAKOKSA-N 4-[4-[[(3r)-1-benzyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-methylbenzamide;hydrochloride Chemical compound Cl.C1=CC(C(=O)NC)=CC=C1OC(C=C1)=CC=C1CN1CCC2(C(N[C@@H](C(=O)N2CC=2C=CC=CC=2)[C@H](O)C2CCCCC2)=O)CC1 PSPFFCYIYIDUIS-ZNBLAKOKSA-N 0.000 description 1
- PJGVNYPNQNQOGN-LTRMXRMOSA-N 4-[4-[[(3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-(2-hydroxyethyl)benzamide;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(=CC=3)C(=O)NCCO)=CC=2)CC1 PJGVNYPNQNQOGN-LTRMXRMOSA-N 0.000 description 1
- IQXVOOSGACBXSB-CNZCJKERSA-N 4-[4-[[(3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-methylbenzamide;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(=CC=3)C(=O)NC)=CC=2)CC1 IQXVOOSGACBXSB-CNZCJKERSA-N 0.000 description 1
- JPDHQUWBDLOJMR-JUJAXGASSA-N 4-[4-[[(3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]benzamide;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(=CC=3)C(N)=O)=CC=2)CC1 JPDHQUWBDLOJMR-JUJAXGASSA-N 0.000 description 1
- DBJVJTTWAZBBJN-JUJAXGASSA-N 4-[4-[[(3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]benzenesulfonamide;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(=CC=3)S(N)(=O)=O)=CC=2)CC1 DBJVJTTWAZBBJN-JUJAXGASSA-N 0.000 description 1
- JKFALRXDFFXYQN-JUJAXGASSA-N 4-[4-[[(3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]benzoic acid;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(=CC=3)C(O)=O)=CC=2)CC1 JKFALRXDFFXYQN-JUJAXGASSA-N 0.000 description 1
- VSJZXBMVKXUBNX-CNZCJKERSA-N 4-[4-[[(3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]benzonitrile;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(=CC=3)C#N)=CC=2)CC1 VSJZXBMVKXUBNX-CNZCJKERSA-N 0.000 description 1
- HJFGOKCIWCYOFS-LOYHVIPDSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]-3,5-dimethylpyrazol-1-yl]-n-(2-hydroxyethyl)benzenesulfonamide Chemical compound N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(=C1C)C(C)=NN1C1=CC=C(S(=O)(=O)NCCO)C=C1 HJFGOKCIWCYOFS-LOYHVIPDSA-N 0.000 description 1
- LMBRJWPAXVYTKL-HXFSWNFUSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]-3,5-dimethylpyrazol-1-yl]-n-methylbenzamide;dihydrochloride Chemical compound Cl.Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(=C1C)C(C)=NN1C1=CC=C(C(=O)NC)C=C1 LMBRJWPAXVYTKL-HXFSWNFUSA-N 0.000 description 1
- PYUQSGVUEHECRQ-XBPPRYKJSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-(2-hydroxyethyl)benzamide;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(C(=O)NCCO)C=C1 PYUQSGVUEHECRQ-XBPPRYKJSA-N 0.000 description 1
- WVVFUEXZRFDASC-ZNBLAKOKSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-[2-(dimethylamino)ethyl]benzamide;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(C(=O)NCCN(C)C)C=C1 WVVFUEXZRFDASC-ZNBLAKOKSA-N 0.000 description 1
- RZRLVRDRLDBDLY-FQLXRVMXSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-hydroxybenzamide Chemical compound N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(C(=O)NO)C=C1 RZRLVRDRLDBDLY-FQLXRVMXSA-N 0.000 description 1
- VMHGWRXVRSSLIK-PQQSRXGVSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-hydroxybenzamide;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(C(=O)NO)C=C1 VMHGWRXVRSSLIK-PQQSRXGVSA-N 0.000 description 1
- UKYNXVIHWHYXJK-GAQUOPITSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-methylbenzamide;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(C(=O)NC)C=C1 UKYNXVIHWHYXJK-GAQUOPITSA-N 0.000 description 1
- DMBPLMHLODCLNZ-PQQSRXGVSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]benzamide;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(C(N)=O)C=C1 DMBPLMHLODCLNZ-PQQSRXGVSA-N 0.000 description 1
- NZZFGBQSAXBDFB-PQQSRXGVSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]benzenesulfonamide;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(S(N)(=O)=O)C=C1 NZZFGBQSAXBDFB-PQQSRXGVSA-N 0.000 description 1
- QNNBMSGFNQRUEH-PQQSRXGVSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]benzoic acid;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(C(O)=O)C=C1 QNNBMSGFNQRUEH-PQQSRXGVSA-N 0.000 description 1
- AOKJUQWUSJXESV-GAQUOPITSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]benzonitrile;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(C#N)C=C1 AOKJUQWUSJXESV-GAQUOPITSA-N 0.000 description 1
- CXHQOVMRANHTEZ-PQQSRXGVSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-cyclopentyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-methylbenzamide;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(C(=O)NC)C=C1 CXHQOVMRANHTEZ-PQQSRXGVSA-N 0.000 description 1
- SRDDWTSYYBZRSG-LTRMXRMOSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-cyclopentyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]benzoic acid;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(C(O)=O)C=C1 SRDDWTSYYBZRSG-LTRMXRMOSA-N 0.000 description 1
- XLNPOMRSJFSKFV-PQQSRXGVSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-hydroxy(oxan-4-yl)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-methylbenzamide;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCOCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(C(=O)NC)C=C1 XLNPOMRSJFSKFV-PQQSRXGVSA-N 0.000 description 1
- MRQGSONSUZMWJF-LTRMXRMOSA-N 4-[4-[[(3r)-1-butyl-3-[(r)-hydroxy(oxan-4-yl)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]benzoic acid;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCOCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(C(O)=O)C=C1 MRQGSONSUZMWJF-LTRMXRMOSA-N 0.000 description 1
- VBYOLFOTEZQDCO-JUJAXGASSA-N 4-[4-[[(3r)-3-[(1r)-1-hydroxy-2-methylpropyl]-2,5-dioxo-1-propyl-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-methylbenzamide;hydrochloride Chemical compound Cl.CCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(=CC=3)C(=O)NC)=CC=2)CC1 VBYOLFOTEZQDCO-JUJAXGASSA-N 0.000 description 1
- XRCZOELOVBGMTE-PQQSRXGVSA-N 4-[4-[[(3r)-3-[(r)-cyclohexyl(hydroxy)methyl]-1-(2-methoxyethyl)-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-methylbenzamide;hydrochloride Chemical compound Cl.C1=CC(C(=O)NC)=CC=C1OC(C=C1)=CC=C1CN1CCC2(C(N[C@@H](C(=O)N2CCOC)[C@H](O)C2CCCCC2)=O)CC1 XRCZOELOVBGMTE-PQQSRXGVSA-N 0.000 description 1
- MYGVGHRCICNMBA-YDXXJHAFSA-N 4-[4-[[(3r)-3-[(r)-cyclohexyl(hydroxy)methyl]-1-[(4-methoxyphenyl)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-methylbenzamide;hydrochloride Chemical compound Cl.C1=CC(C(=O)NC)=CC=C1OC(C=C1)=CC=C1CN1CCC2(C(N[C@@H](C(=O)N2CC=2C=CC(OC)=CC=2)[C@H](O)C2CCCCC2)=O)CC1 MYGVGHRCICNMBA-YDXXJHAFSA-N 0.000 description 1
- FNAGOPQVBGMMDV-PQQSRXGVSA-N 4-[4-[[(3r)-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1-propyl-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-methylbenzamide;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(C(=O)NC)C=C1 FNAGOPQVBGMMDV-PQQSRXGVSA-N 0.000 description 1
- FJEZGBOYBGOPLQ-LTRMXRMOSA-N 4-[4-[[(3r)-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1-propyl-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]benzoic acid;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(C(O)=O)C=C1 FJEZGBOYBGOPLQ-LTRMXRMOSA-N 0.000 description 1
- XTOFINAWHNOYBA-JCOPYZAKSA-N 4-[4-[[(3s)-1-butyl-3-(2-methylpropyl)-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-(2-hydroxyethyl)benzamide;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@H](CC(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(=CC=3)C(=O)NCCO)=CC=2)CC1 XTOFINAWHNOYBA-JCOPYZAKSA-N 0.000 description 1
- KYHBXYHVDLMNLJ-SNYZSRNZSA-N 4-[4-[[(3s)-1-butyl-3-(2-methylpropyl)-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]benzoic acid;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@H](CC(C)C)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(=CC=3)C(O)=O)=CC=2)CC1 KYHBXYHVDLMNLJ-SNYZSRNZSA-N 0.000 description 1
- BFSLHJYJZVLSMC-YNMZEGNTSA-N 4-[4-[[(3s)-1-butyl-3-(cyclohexylmethyl)-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-(2-hydroxyethyl)benzamide;hydrochloride Chemical compound Cl.C([C@H]1C(=O)N(C2(CCN(CC=3C=CC(OC=4C=CC(=CC=4)C(=O)NCCO)=CC=3)CC2)C(=O)N1)CCCC)C1CCCCC1 BFSLHJYJZVLSMC-YNMZEGNTSA-N 0.000 description 1
- CUYAMHOHMUQZRU-JIDHJSLPSA-N 4-[4-[[(3s)-1-butyl-3-(hydroxymethyl)-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]-n-methylbenzamide;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@H](CO)NC(=O)C11CCN(CC=2C=CC(OC=3C=CC(=CC=3)C(=O)NC)=CC=2)CC1 CUYAMHOHMUQZRU-JIDHJSLPSA-N 0.000 description 1
- QNNBMSGFNQRUEH-OCPPCWRMSA-N 4-[4-[[(3s)-1-butyl-3-[(s)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]phenoxy]benzoic acid;hydrochloride Chemical compound Cl.N([C@H](C(=O)N1CCCC)[C@@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1OC1=CC=C(C(O)=O)C=C1 QNNBMSGFNQRUEH-OCPPCWRMSA-N 0.000 description 1
- VQDFOHHAAZXTKL-PQQSRXGVSA-N 4-[5-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]pyridin-2-yl]oxy-n-methylbenzamide;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=N1)=CC=C1OC1=CC=C(C(=O)NC)C=C1 VQDFOHHAAZXTKL-PQQSRXGVSA-N 0.000 description 1
- HJHARYOZKMQSJO-LTRMXRMOSA-N 4-[[(3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]-n-[(4-methoxyphenyl)methyl]benzamide;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(=CC=2)C(=O)NCC=2C=CC(OC)=CC=2)CC1 HJHARYOZKMQSJO-LTRMXRMOSA-N 0.000 description 1
- KXOYQHOPVAQQEH-JUJAXGASSA-N 4-[[(3r)-1-butyl-3-[(1r)-1-hydroxy-2-methylpropyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]-n-cyclohexylbenzamide;hydrochloride Chemical compound Cl.CCCCN1C(=O)[C@@H]([C@H](O)C(C)C)NC(=O)C11CCN(CC=2C=CC(=CC=2)C(=O)NC2CCCCC2)CC1 KXOYQHOPVAQQEH-JUJAXGASSA-N 0.000 description 1
- JMMRRXLXTLHKMC-JIMLSGQQSA-N 4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]-n,n-dimethylbenzamide;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC1=CC=C(C(=O)N(C)C)C=C1 JMMRRXLXTLHKMC-JIMLSGQQSA-N 0.000 description 1
- NXMIVLMVQBSBDB-CNZCJKERSA-N 4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]-n-(3-methoxypropyl)benzamide;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC1=CC=C(C(=O)NCCCOC)C=C1 NXMIVLMVQBSBDB-CNZCJKERSA-N 0.000 description 1
- XOVYYSDAOJOGSE-XBPPRYKJSA-N 4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]-n-[(4-methoxyphenyl)methyl]benzamide;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1C(=O)NCC1=CC=C(OC)C=C1 XOVYYSDAOJOGSE-XBPPRYKJSA-N 0.000 description 1
- KJRBHULQJVCPQZ-FQLXRVMXSA-N 4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]-n-cyclohexylbenzamide Chemical compound N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1C(=O)NC1CCCCC1 KJRBHULQJVCPQZ-FQLXRVMXSA-N 0.000 description 1
- GMDNIFKAWRTYNR-PQQSRXGVSA-N 4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]-n-cyclohexylbenzamide;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC(C=C1)=CC=C1C(=O)NC1CCCCC1 GMDNIFKAWRTYNR-PQQSRXGVSA-N 0.000 description 1
- VYDAWPIRCXMHAF-OHIDFYLOSA-N 4-[[(3r)-1-butyl-3-[(r)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undecan-9-yl]methyl]benzamide;hydrochloride Chemical compound Cl.N([C@@H](C(=O)N1CCCC)[C@H](O)C2CCCCC2)C(=O)C1(CC1)CCN1CC1=CC=C(C(N)=O)C=C1 VYDAWPIRCXMHAF-OHIDFYLOSA-N 0.000 description 1
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Abstract
본 발명은 화학식 (I)로 표시되는 트리아자스피로[5.5]운데칸 유도체, 이들의 4급 암모늄염, 이들의 N-옥사이드, 이들의 비독성염 및 그것을 유효성분으로서 함유하는 약제를 제공한다.
화학식 (I)
[상기 식에서 R1은 화학식 (II),의 기 또는 화학식 (III),의 기를 나타내고; R2는 알킬, 알키닐 등을 나타내며; R3및 R4는 각각 H, (치환)알킬 등을 나타내거나, 또는 R3과 R4은 함께 화학식 (IV),의 기를 나타낼 수 있으며; R5는 H, 알킬을 나타낸다.]
상기 화학식 (I)로 표시되는 화합물은 케모카인/케모카인 수용체의 작용을 제어하기 때문에, 각종 염증성 질환, 천식, 아토피성 피부염, 담마진, 알레르기 질환, 신장염, 신장증, 간염, 관절염, 만성 관절 류머티즘 등의 예방 및/또는 치료에유용하다.
Description
케모카인은 내인성의 백혈구 주화성(走化性), 활성화 작용을 가지며, 헤파린 결합성이 강한 염기성 단백질로서 알려져 있다. 현재에서는, 케모카인은 염증, 면역 반응시의 특이적 백혈구의 침윤을 제어할 뿐만 아니라, 발생, 생리적 조건 하에서의 림프구의 호밍, 혈구전구세포, 체세포의 이동에도 관계된다고 생각되고 있다.
혈구 세포는 여러 가지 시토킨에 의해, 그 분화, 증식, 세포사가 제어되고 있다. 생체내에서 염증은 국소적으로 보여지고, 림프구의 분화, 성숙 등은 어떤 특정한 부위에서 행해지고 있다. 즉, 필요로 되는 여러 가지 세포가 어떤 특정한 부위로 이동하고, 집적하여, 일련의 염증, 면역 반응이 일어난다. 따라서, 세포의 분화, 증식, 세포사에 덧붙여 세포의 이동도 면역계에 있어서 필요 불가결한 현상이다.
생체내에서의 혈구 세포의 이동은, 우선, 발생 과정에 있어서, AGM 영역에 시작되는 조혈이 태아의 간을 경유하여 골수에서의 영구 조혈로 이행함으로써 시작된다. 더욱이, 태아의 간, 골수에서 흉선으로, T 세포, 흉선 수상 세포의 전구 세포가 이동하고, 흉선 환경하에서 세포 분화한다. 클론 선택을 받은 T 세포는 2차 림프 조직으로 이동하여, 말초에 있어서의 면역 반응에 관여한다. 항원을 포착하여 활성화, 분화한 피부의 랑겔한스 세포는 국소 림프절의 T 세포 영역으로 이동하고, 수상 돌기 세포로서 나이브 T 세포를 활성화한다. 메모리 T 세포는 림프관, 혈관을 경유하여 다시 림프절에 호밍한다. 또한, B 세포, 장관상피내 T 세포, γδ T 세포, NKT 세포, 수상 세포는 골수로부터 흉선을 경유하지 않고 이동, 분화하여, 면역 반응에 관여한다.
케모카인은 이러한 여러 가지 세포의 이동에 깊게 관여하고 있다. 예컨대, MIP3β, SLC와 그 수용체인 CCR7은 항원을 포착한 성숙 수상 세포가 나이브 T 세포 및 메모리 T 세포와 효율적으로 만나기 위해서, 이들 세포의 국소 림프 조직에의이동, 호밍에 있어서 중요한 작용을 하고 하고 있다. SLC의 발현에 결손이 있는 PLT 마우스의 2차 림프절에는 항원 특이적인 면역 반응을 담당하기 위해서 필요한 T 세포 및 수상 세포가 거의 관찰되지 않는다(J. Exp. Med.,189(3), 451(1999)).
MDC, TARC와 그 수용체인 CCR4은, Th2세포가 관하는 면역, 염증 반응에 있어서, Th2 세포의 국소에의 이동에 중요한 작용을 하고 있다. 래트 극증 간염 모델(P.acnes+LPS)에 있어서, 항 TARC 항체는 혈중 ALT량의 상승 및 간장중 TNFα, FasL의 발현량의 상승을 억제하고, 추가로 래트 치사율을 개선하였다(J. Clin. Invest.,102, 1933(1998)). 또한, 마우스 OVA 유발 기도 과민성 모델에 있어서, 항 MDC 항체는 폐 간질에 집적되는 호산구 수를 줄여 기도 과민성을 억제하였다(J. Immunology,163, 403(1999)).
MCP-1과 그 수용체인 CCR2는 대식세포의 염증 부위에의 침윤에 관여하고 있다. 항 MCP-1 항체는 래트 항 Thy1.1 항체 신장염 모델에 있어서, 사구체에의 단구, 대식세포의 침윤에 대한 억제 효과를 보였다(Kidney Int.,51, 770(1997)).
이와 같이, 케모카인 수용체는 여러 가지 특이적인 세포에 있어서, 어떤 특정한 시기에 발현되어, 그 이펙터 세포가 케모카인의 생성되는 개소에 집적된다고 하는 메카니즘을 통해 염증, 면역 반응의 제어에 크게 관여하고 있다.
인간 면역부전 바이러스(이하, HIV라 약칭함) 감염에 의해 야기되는 후천성 면역부전 증후군(에이즈(AIDS)라 부르고 있음)은 최근 가장 그 치료법이 갈망되고 있는 질환의 하나이다. 주요한 표적 세포인 CD4 양성 세포에 HIV의 감염이 한번 성립되면, HIV는 환자의 체내에서 증식을 반복하고, 이윽고 면역 기능을 담당하는 T세포를 괴멸적으로 파괴한다. 이 과정에서 서서히 면역 기능이 저하되어, 발열, 설사, 림프절의 종창 등의 여러 가지 면역부전 상태를 보이게 되고, 카리니 폐렴 등의 여러 가지 기회감염증을 병발하기 쉽게 된다. 이러한 상태가 에이즈의 발증으로서, 카포시 육종 등의 악성종양을 유발하여, 중독화하는 것은 잘 알려져 있다.
현재 에이즈에 대한 각종 예방, 치료 방법으로서는, 예컨대, (1) 역전사 효소 억제제나 프로테아제 억제제의 투여에 의한 HIV의 증식 억제, (2) 면역 부활 작용이 있는 약품의 투여에 의한 기회감염증의 예방, 완화 등이 시도되고 있다.
HIV는 면역계의 중추를 담당하는 핼퍼 T 세포에 주로 감염된다. 그 때, T 세포의 막상에 발현하고 있는 막 단백질 CD4를 이용하는 것은 1985년부터 알려져 있다(Cell,52, 631(1985)). CD4 분자는 433개의 아미노산 잔기로 이루어지고, 성숙 핼퍼 T 세포 이외에 대식세포, 일부의 B 세포, 혈관 내피 세포, 피부 조직의 랑겔한스 세포, 림프 조직에 있는 수상 세포, 중추신경계의 그리아 세포 등에서 발현이 보인다. 그러나, CD4 분자만으로는 HIV의 감염이 성립되지 않는 것이 밝혀짐에 따라 HIV가 세포에 감염될 때에 관계되는 CD4 분자 이외의 인자의 존재 가능성이 시사되게 되었다.
1996년에 와서, CD4 분자 이외의 HIV 감염에 관계되는 인자로서 퓨신(Fusin)이라는 세포막 단백질이 확인되었다(Science,272, 872(1996)). 이 퓨신 분자는 스트로마 세포 유래 인자-1(Stromal Derived Factor-1: SDF-1이라 약칭함)의 수용체(즉, CXCR4임)인 것이 증명되었다. 더욱이, 시험관내에서 SDF-1이, T 세포 지향성(X4) HIV의 감염을 특이적으로 억제하는 것도 증명되었다(Nature,382,829(1996), Nature,382, 833(1996)). 즉, SDF-1이 HIV보다 먼저 CXCR4에 결합함으로써, HIV가 세포에 감염되기 위한 실마리를 없애어 HIV의 감염이 억제된 것으로 생각된다.
또한, 같은 무렵, 별도의 케모카인 수용체이며, RANTES, MIP-1α, MIP-1β의 수용체인 CCR5도 대식세포 지향성(R5) HIV가 감염될 때에 이용되는 것이 발견되었다(Science,272, 1955(1996)).
따라서, HIV와 CXCR4나 CCR5를 서로 없앨 수 있는 것, 혹은 HIV 바이러스에 결합하여, 그 바이러스가 CXCR4나 CCR5에 결합할 수 없는 상태로 만드는 것은 HIV 감염 억제제가 될 수 있을 것이다. 또한 당초, HIV 감염 억제제로서 발견된 저분자 화합물이 사실은 CXCR4의 길항 물질인 것이 표시된 예도 있다(Nature Medicine,4, 72(1998)).
이상으로부터, 케모카인/케모카인 수용체는, 염증, 면역질환 또는 HIV 감염에 깊게 관여하고 있는 것으로 생각된다. 예컨대, 각종 염증성 질환, 천식, 아토피성 피부염, 담마진, 알레르기 질환(알레르기성 기관지폐 아스페르길루스증, 알레르기성 호산구성 위장증 등), 신장염, 신장증, 간염, 관절염, 만성 관절 류머티즘, 건선, 비염, 결막염, 허혈 재관류 상해의 억제, 다발성 경화증, 궤양성 대장염, 급성 호흡 궁박 증후군, 세균 감염에 따른 쇼크, 당뇨병, 자기면역질환의 치료, 이식 장기 거절반응, 면역 억제, 암전이 예방, 후천성 면역부전 증후군에 관여하고 있는 것으로 생각된다.
한편, WO97/11940호 명세서에는 화학식 (Z)로 표시되는 화합물이 혈소판 응집 억제에 유용하다는 취지의 기재가 있다.
화학식 (Z)
[상기 식에서 AiZ및 BjZ는 각각 별개로 탄소, 질소, 산소 또는 황으로부터 선택되고(단, AiZ의 적어도 1개의 원자는 탄소이며, 또한 적어도 1개의 BjZ는 탄소임);
AiZ및 BjZ에 의해 형성되는 스피로 이환은 각각 경우에 따라 부분적으로 불포화이어도 좋고,
pZ 및 qZ는 각각 별개로 2에서 6까지의 수이며,
mZ는 0에서 pZ까지의 수이고,
R10Z는 동일하거나 또는 다르며, 수소, 알킬, 할로 치환 알킬, 알케닐, 알키닐, 시클로알킬, =O, =S 등으로부터 각각 별개로 선택되는 비간섭성 치환기이고,
nZ는 0에서 qZ까지의 수이며,
R0Z는 동일하거나 또는 다르고, 수소, 알킬, 할로 치환 알킬, 알케닐, 알키닐, 시클로알킬, =O, =S 등으로부터 각각 별개로 선택되는 비간섭성 치환기이며,
-(LZ)-는 결합이거나 또는 탄소, 질소, 황 및 산소로부터 선택되는 1개에서 10개의 원자로 이루어진 2가의 치환 혹은 비치환 쇄이고,
QZ는 1개 또는 2개 이상의 염기성 라디칼을 포함하는 염기성기이며, 또한 R3Z는 1개 또는 2개 이상의 산성 라디칼을 포함하는 산성기이다.]
또한, WO98/25605호 명세서에는, 화학식 (Y)로 표시되는 화합물이 케모카인 수용체 모듈레이터로서 유용하다는 취지의 기재가 있다.
화학식 (Y)
[상기 식에서 mY 또는 lY는 각각 독립적으로 0, 1, 2, 3, 4 또는 5를 나타내고,
R1Y는 수소 원자, C1∼8 알킬기, C2∼8 알케닐기, C2∼8 알키닐기 등을 나타내며,
WY는 단일 결합, C1∼3 알킬기, 옥소 등으로 치환한 C1∼3 알킬기 등을 나타내고,
QY는 -NR2-, -O-, -S-, -S(O)- 또는 -SO2-을 나타내며,
XY는 단일 결합, C1∼3 알킬기, 옥소 등으로 치환한 C1∼3 알킬기 등을 나타내고,
YY-ZY고리는 페닐, 나프틸, 헤테로아릴을 나타낸다. 단, 각 기호의 정의는 일부를 발췌한 것이다.]
본 발명은 트리아자스피로[5.5]운데칸 유도체 및 이들을 유효성분으로서 함유하는 약제에 관한 것이다.
더욱 상세하게는, 화학식 (I)로 표시되는 트리아자스피로[5.5]운데칸 유도체, 이들의 4급 암모늄염, 이들의 N-옥사이드, 이들의 비독성염, 이들의 제조 방법 및 이들을 유효성분으로서 함유하는 약제에 관한 것이다.
화학식 (I)
(상기 식에서 모든 기호는 후기와 동일한 의미를 나타낸다.)
발명의 개시
본 발명자들은 여러 가지 케모카인/케모카인 수용체의 작용을 제어하는 화합물을 발견하기 위해 예의 검토를 거듭한 결과, 화학식 (I)로 표시되는 트리아자스피로[5.5]운데칸 유도체가 본 발명의 목적을 달성하는 것을 발견하여 본 발명을 완성하였다.
즉, 본 발명은,
i) 화학식 (I)로 표시되는 트리아자스피로[5.5]운데칸 유도체 화합물, 이들의 4급 암모늄염, 이들의 N-옥사이드 또는 이들의 비독성염.
화학식 (I)
[상기 식에서 R1은 하기 식 (1) 또는 (2)로 표시되는 기:
(1),
(2)
(기 중, G는 단일 결합, C1∼4 알킬렌기, C2∼4 알케닐렌기 또는 -CO-를 나타내고,
A환은, (1) C5∼10의 단환식 또는 이환식 탄소환 또는 (2) 1∼2개의 질소 원자 및/또는 1∼2개의 산소 원자를 함유하는 5∼10원의 단환식 또는 이환식 복소환을 나타내며,
R6은,
(1) C1∼4 알킬기,
(2) 할로겐 원자,
(3) 니트릴기,
(4) 트리플루오로메틸기,
(5) -OR8기,
(6) -SR9기,
(7) -NR10R11기,
(8) -COOR12기,
(9) -CONR13R14기,
(10) -SO2NR15R16기,
(11) -NR17SO2R18기,
(12) -S(O)R19기,
(13) -SO2R20기,
(14) -N(SO2R21)2기,
(15) (a) -OR8기, (b) -NR10R11기 및 (c) Cyc1로부터 선택되는 1개의 기에 의해 치환된 C1∼4 알킬기, 또는
(16) -NR27COR28기를 나타내고,
R8∼R17은 각각 독립적으로 (1) 수소 원자, (2) C1∼4 알킬기, (3) Cyc1, (4) -OR22기 또는 (5) (a) -OR22기, (b) -NR23R24기, (c) -COOR25기 및 (d) Cyc1로부터 임의로 선택되는 1개의 기에 의해 치환된 C1∼4 알킬기를 나타내거나,
R10과 R11, R13과 R14, R15와 R16은 각각이 결합하는 질소 원자와 함께 1∼2개의 질소 원자 및/또는 1개의 산소 원자를 함유하는 5∼6원의 단환식 복소환을 나타내며(단, 그 복소환은 C1∼4 알킬기 또는 수산기로 치환되어 있어도 좋음),
R22∼R25는 각각 독립적으로 (1) 수소 원자, (2) C1∼4 알킬기, 또는 (3) C1∼4 알콕시기가 치환한 C1∼4 알킬기를 나타내거나,
R23과 R24는 결합하는 질소 원자와 함께 1∼2개의 질소 원자 및/또는 1개의 산소 원자를 함유하는 5∼6원의 단환식 복소환을 나타내고(단, 그 복소환은 C1∼4 알킬기 또는 수산기로 치환되어 있어도 좋음),
R18∼R21은 각각 독립적으로 C1∼4 알킬기를 나타내며,
R27은 (1) 수소 원자, (2) C1∼4 알킬기, (3) Cyc1 또는 (4) (a) -OR22기, (b) -NR23R24기, (c) -COOR25기 및 (d) Cyc1로부터 임의로 선택되는 1개의 기에 의해 치환된 C1∼4 알킬기를 나타내고,
R28은 (1) C1∼4 알킬기, (2) Cyc1 또는 (3) (a) -OR22기, (b) -NR23R24기, (c) -COOR25기 및 (d) Cyc1로부터 임의로 선택되는 1개의 기에 의해 치환된 C1∼4 알킬기를 나타내며,
Cyc1은 (1) C5∼6의 단환 탄소환 또는 (2) 1∼2개의 질소 원자 및/또는 1개의 산소 원자를 함유하는 5∼6원의 단환식 복소환을 나타내고(단, 그 탄소환 또는 복소환은 C1∼4 알콕시기, 할로겐 원자 또는 -COOR29기(R29는 (1) 수소 원자, (2) C1∼4 알킬기, (3) Cyc1 또는 (4) (a)-OR22기, (b) -NR23R24기, (c) -COOR25기 및 (d)Cyc1로부터 임의로 선택된 1개의 기에 의해 치환된 C1∼4 알킬기를 나타냄)로 치환되어 있어도 좋음),
E는 단일 결합, -O-, -S-, -CO- 또는 -CHOH-를 나타내며,
B환은 (1) C5∼6의 단환 탄소환 또는 (2) 1∼2개의 질소 원자 및/또는 1개의 산소 원자를 함유하는 5∼6원의 단환식 복소환을 나타내고,
R7은 C1∼4 알킬기 또는 할로겐 원자를 나타내며,
n은 0 또는 1∼4의 정수를 나타내고,
m은 0 또는 1∼4의 정수를 나타냄)를 나타내며,
R2는,
(1) C1∼4 알킬기,
(2) C2∼4 알키닐기, 또는
(3) (a) -OR30기, (b) -NR31R32기 및 (c) Cyc3으로부터 선택되는 1개의 기에 의해 치환된 C1∼4 알킬기(기 중, R30∼R32는 각각 독립적으로 (1) 수소 원자, (2) C1∼4 알킬기, (3) Cyc3 또는 (4) Cyc3에 의해 치환된 C1∼4 알킬기를 나타내고, Cyc3은 (1) C5∼6의 단환 탄소환 또는 (2) 1∼2개의 질소 원자 및/또는 1개의 산소 원자를 함유하는 5∼6원의 단환식 복소환을 나타냄(단, 그 탄소환 또는 복소환은 C1∼4 알콕시기로 치환되어 있어도 좋음))를 나타내며,
R3및 R4는 각각 독립적으로,
(1) 수소 원자,
(2) C1∼4 알킬기, 또는
(3) (a) Cyc2 및 (b) 수산기로부터 임의로 선택되는 1∼2개의 기에 의해 치환된 C1∼4 알킬기(기 중, Cyc2는 (1) C5∼6의 단환 탄소환 또는 (2) 1∼2개의 질소 원자 및/또는 1개의 산소 원자를 함유하는 5∼6원의 단환식 복소환을 나타냄)를 나타내거나,
R3과 R4는 함께,
(기 중, R26은 C1∼4 알킬기 또는 Cyc2를 나타냄)를 나타내고,
R5는 수소 원자 또는 C1∼4 알킬기를 나타낸다.]
ii) 전항 i) 기재의 화학식 (I) 중, R3및 R4가 수소 원자인 전항 i) 기재의 화합물.
iii) 전항 i) 기재의 화학식 (I) 중, R3이 수소 원자이고,
R4가
(1) C1∼4 알킬기, 또는
(2) (a) Cyc2 및 (b) 수산기로부터 임의로 선택되는 1∼2개의 기에 의해 치환된 C1∼4 알킬기인 전항 i) 기재의 화합물.
iv) 전항 i) 기재의 화학식 (I) 중, R3및 R4가 각각 독립적으로,
(1) C1∼4 알킬기, 또는 (2) (a) Cyc2 및 (b) 수산기로부터 임의로 선택되는 1∼2개의 기에 의해 치환된 C1∼4 알킬기인 전항 i) 기재의 화합물.
v) 전항 i) 기재의 화학식 (I) 중, R3과 R4가 함께,
(상기 식에서 R26은 전항 i) 기재와 동일한 의미를 나타냄)를 나타내는 전항 i) 기재의 화합물.
vi) 화합물이
(1) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-벤질-1,4,9-트리아자스피로[5.5]운데칸,
(2) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(6-페닐옥시피리딘-3-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(3) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메톡시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(4) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(3-메톡시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(5) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-플루오로페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(6) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-클로로페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(7) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(페닐카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(8) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(1-페닐-1-히드록시메틸)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(9) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-(모르폴린-4-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(10) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(6-메틸피리딘-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(11) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(피리딘-1-옥사이드-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(12) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-히드록시피페리딘-1-일메틸)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(13) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(14) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(1,3,5-트리메틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(15) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-아미노술포닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(16) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메틸티오페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(17) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메틸술포닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(18) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-시아노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(19) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(페닐티오)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(20) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-히드록시페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(21) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-메틸술포닐아미노페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(22) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-(N,N-디메틸아미노)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(23) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(피롤리딘-1-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(24) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(6-메틸피리딘-1-옥사이드-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(25) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-히드록시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(26) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(6-(4-메톡시페닐옥시)피리딘-3-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(27) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(메틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(28) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(N-메틸-N-(2-히드록시에틸)아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(29) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-히드록시에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(30) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(31) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-(모르폴린-4-일)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(32) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(피롤리딘-1-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(33) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메틸술피닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(34) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(35) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(모르폴린-4-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(36) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(37) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(38) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-메틸페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(39) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(N,N-디에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(40) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(4-메틸피페라진-1-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(41) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(5-클로로-3-메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(42) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(모르폴린-4-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(43) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-히드록시에틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(44) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-(2-(N,N-디메틸아미노)에틸아미노카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(45) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(피리딘-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(46) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(47) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메틸페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(48) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(2,4-디플루오로페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(49) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(피리딘-2-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(50) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-메틸아미노카르보닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(51) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-시클로헥실옥시페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(52) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(3,4,5,6-테트라히드로피란-4-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(53) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메톡시페닐메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(54) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(시클로헥실아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(55) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-(피롤리딘-1-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(56) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-플루오로페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(57) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-페닐에틸)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(58) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(1-벤질옥시카르보닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(59) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-(2-히드록시에틸아미노카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(60) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(1-메틸술포닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(61) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-히드록시메틸페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(62) (3S)-1-부틸-2,5-디옥소-3-((1S)-1-히드록시-2-메틸프로필)-9-(6-페닐옥시피리딘-3-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(63) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(64) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(피롤리딘-1-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(65) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(모르폴린-4-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(66) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-메틸술포닐페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(67) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-메틸술포닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(68) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-(모르폴린-4-일)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(69) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(4-메틸피페라진-1-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(70) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-메틸술피닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(71) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(피리딘-1-옥사이드-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(72) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-히드록시에틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(73) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-(모르폴린-4-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(74) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(N,N-디에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(75) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-(2-히드록시에틸아미노카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(76) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-(피롤리딘-1-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(77) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(시클로헥실아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(78) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(3-메톡시프로필아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(79) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-메틸술피닐페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(80) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-프로필피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(81) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-에틸피라졸
-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(82) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-시클로펜틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(83) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(1,1-디메틸에틸)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(84) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(1-벤질옥시카르보닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(85) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-((4-메톡시페닐)메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(86) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(3-메톡시프로필아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(87) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-메톡시카르보닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(88) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-메톡시페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(89) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(3-(모르폴린-4-일)프로필아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(90) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(피롤리딘-1-일카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(91) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(피페리딘-1-일카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(92) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(모르폴린-4-일카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(93) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(N-메틸-N-(2-(피리딘-2-일)에틸)아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(94) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(시클로헥실아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(95) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(N,N-디메틸아미노술포닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(96) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-메톡시카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(97) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(1-메틸피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(98) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(1-메틸술포닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(99) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(3-(N,N-디메틸아미노)프로필아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(100) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-(N,N-디메틸아미노)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(101) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(N-메틸-N-(2-(N',N'-디메틸아미노)에틸)아미노술포닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(102) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-((N,N-디메틸아미노)메틸)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(103) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(104) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-메틸아미노카르보닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(105) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-((메톡시카르보닐)메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(106) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3-(3,5-디메틸-1-페닐피라졸-4-일)-2E-프로페닐)-1,4,9-트리아자스피로[5.5]운데칸,
(107) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(카르복시메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(108) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3-(3,5-디메틸-1-페닐피라졸-4-일)프로필)-1,4,9-트리아자스피로[5.5]운데칸,
(109) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(110) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(피롤리딘-1-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(111) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(모르폴린-4-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(112) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(2-(N,N-디메틸아미노)에틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(113) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-(모르폴린-4-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(114) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-메틸술포닐페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(115) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-메틸술포닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(116) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(2-(모르폴린-4-일)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(117) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(4-메틸피페라진-1-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(118) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-메틸술피닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(119) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(2-히드록시에틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(120) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-(2-히드록시에틸아미노카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(121) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-(피롤리딘-1-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(122) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(시클로헥실아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(123) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(3-메톡시프로필아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(124) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-메틸술피닐페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(125) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-프로필피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(126) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-에틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(127) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-시클로펜틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(128) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(3-(모르폴린-4-일)프로필아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(129) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(N,N-디메틸아미노술포닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(130) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(피롤리딘-1-일카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(131) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-(N,N-디메틸아미노)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(132) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(시클로헥실아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(133) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-메톡시카르보닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(134) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(3-메톡시프로필아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(135) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(N-메틸-N-(2-(피리딘
-2-일)에틸)아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(136) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-((4-메톡시페닐)메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(137) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-메톡시카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(138) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-메톡시페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(139) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(1-메틸피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(140) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(1-메틸술포닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(141) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(3-(N,N-디메틸아미노)프로필아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(142) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(N-메틸-N-(2-(N',N'-디메틸아미노)에틸)아미노술포닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(143) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(피페리딘-1-일카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(144) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(모르폴린-4-일카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(145) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-((N,N-디메틸아미노)메틸)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(146) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-메틸아미노카르보닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(147) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(1,1-디메틸에틸)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(148) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(1-벤질옥시카르보닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(149) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-히드록시메틸페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(150) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-((메톡시카르보닐)메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(151) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(카르복시메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(152) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-페닐옥시페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(153) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(6-페닐옥시피리딘-3-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(154) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-플루오로페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(155) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-클로로페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(156) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-시아노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(157) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸술포닐아미노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(158) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(6-메틸피리딘-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(159) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(1-메틸에틸)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(160) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸술피닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(161) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(3,4,5,6-테트라히드로피란-4-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(162) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-페닐카르보닐페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(163) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(1-페닐-1-히드록시메틸)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(164) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(모르폴린-4-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(165) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-메틸아미노술포닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(166) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(N-메틸-N-(2-히드록시에틸)아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(167) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(피리딘-2-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(168) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(169) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(1,3,5-트리메틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(170) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(171) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(N,N-비스메틸술포닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(172) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-메틸술포닐아미노페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(173) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(N,N-디메틸술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(174) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(피롤리딘-1-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(175) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(모르폴린-4-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(176) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-아미노카르보닐페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(177) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(178) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-아미노술포닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(179) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(6-메틸피리딘-1-옥사이드-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(180) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-히드록시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(181) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-히드록시페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(182) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(2-히드록시에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(183) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(피롤리딘-1-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(184) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(5-클로로-3-메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(185) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메톡시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(186) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(3-메톡시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(187) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(N,N-디메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(188) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(189) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-메틸페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(190) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-플루오로페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(191) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(6-(4-메톡시페닐옥시)피리딘-3-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(192) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸술포닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(193) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-(2-(N,N-디메틸아미노)에틸아미노카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(194) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(2-히드록시에틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(195) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(2-(N,N-디메틸아미노)에틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(196) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(2-(모르폴린-4-일)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(197) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-(모르폴린-4-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(198) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(1,4-벤조디옥산-6-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(199) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(N,N-디에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(200) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(피리딘-1-옥사이드-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(201) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(4-메틸피페라진-1-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(202) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(203) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(2,4-디플루오로페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(204) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(2-(N,N-디메틸아미노)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(205) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-메틸아미노카르보닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(206) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(207) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-((4-메톡시페닐)메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(208) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(3-메톡시프로필아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(209) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(N-메틸-N-(2-(피리딘-2-일)에틸)아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(210) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-(피롤리딘-1-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(211) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-클로로페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(212) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-트리플루오로메틸페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(213) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-메톡시페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(214) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-에틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(215) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-프로필피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(216) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(1,1-디메틸에틸)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(217) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-시클로펜틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(218) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(2-페닐에틸)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(219) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(1-벤질옥시카르보닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(220) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(시클로헥실아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(221) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(1-메틸술포닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(222) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-(2-히드록시에틸아미노카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(223) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-히드록시메틸페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(224) (3S)-1-부틸-2,5-디옥소-3-((1S)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸술포닐아미노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(225) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-9-(3,5-디메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(226) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(227) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-9-(4-(4-(4-메톡시페닐메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(228) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노카르보닐)페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(229) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(230) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-9-(4-(4-메틸술포닐아미노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(231) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로펜틸메틸)-9-(3,5-디메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(232) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로펜틸메틸)-9-(4-(4-(4-메톡시페닐메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(233) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로펜틸메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(234) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로펜틸메틸)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(235) (3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(236) (3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(237) (3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메톡시페닐메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(238) (3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(239) (3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(240) (3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메톡시페닐메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(241) (3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(242) (3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(243) (3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메톡시카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(244) (3R)-1-프로필-2,5-디옥소-3-(1-시클로헥실메틸리덴)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(245) (3S)-1-프로필-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(246) (3S)-1-프로필-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-메틸술포닐아미노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(247) (3S)-1-프로필-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-(N,N-디메틸아미노)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(248) (3S)-1-프로필-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(249) (3S)-1-프로필-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-메틸술포닐아미노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(250) 1-부틸-2,5-디옥소-9-(4-(4-메틸술포닐아미노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(251) 1-부틸-2,5-디옥소-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(252) (3R)-1-(2-부티닐)-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)
-9-(3,5-디메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(253) (3S)-1-(2-부티닐)-2,5-디옥소-3-((1S)-1-히드록시-1-시클로헥실메틸) -9-(3,5-디메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(254) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(2-(4-페닐옥시페닐)에틸)-1,4,9-트리아자스피로[5.5]운데칸,
(255) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(2-(4-페닐옥시페닐)에틸)-1,4,9-트리아자스피로[5.5]운데칸,
(256) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(2-(4-메톡시페닐)에틸)-1,4,9-트리아자스피로[5.5]운데칸,
(257) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-에톡시카르보닐페닐)-1,4,9-트리아자스피로[5.5]운데칸,
(258) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-4-메틸-9-(4-페닐옥시페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(259) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(2-메틸프로파노일아미노)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(260) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(2-메톡시아세틸아미노)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(261) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(2-페닐아세틸아미노)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(262) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(2-(4-플루오로페닐)아세틸아미노)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(263) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메톡시카르보닐페닐아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(264) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메톡시페닐메틸옥시카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(265) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(2-(4-메틸아미노카르보닐페닐옥시)피리딘-5-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(266) (3S)-1-부틸-2,5-디옥소-3-((1S)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(267) (3S)-1-부틸-2,5-디옥소-3-(피리딘-3-일메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(268) (3S)-1-부틸-2,5-디옥소-3-페닐메틸-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(269) (3S)-1-부틸-2,5-디옥소-3-(피리딘-2-일메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(270) (3S)-1-부틸-2,5-디옥소-3-히드록시메틸-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(271) (3S)-1-부틸-2,5-디옥소-3-(피리딘-1-옥사이드-2-일메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(272) (3S)-1-부틸-2,5-디옥소-3-(피리딘-1-옥사이드-3-일메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(273) (3R)-1-(4-메톡시페닐메틸)-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(274) (3R)-1-페닐메틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(275) (3R)-1-(2-메톡시에틸)-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(276) (3R)-1-(피리딘-2-일메틸)-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(277) (3R)-1-(피리딘-3-일메틸)-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(278) (3R)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(279) (3S)-1-부틸-2,5-디옥소-3-(피리딘-1-옥사이드-2-일메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·9-옥사이드,
(280) 1-부틸-2,5-디옥소-3-(모르폴린-4-일메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(281) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-(N-히드록시카르바모일)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,
(282) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐카르보닐)-1,4,9-트리아자스피로[5.5]운데칸,
(283) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐)-1,4,9-트리아자스피로[5.5]운데칸,
이들의 4급 암모늄염, 이들의 N-옥사이드 또는 이들의 비독성염인 전항 i) 기재의 화합물.
vii) 전항 i)에 기재한 화학식 (I)로 표시되는 트리아자스피로[5.5]운데칸 유도체, 이들의 4급 암모늄염, 이들의 N-옥사이드 또는 이들의 비독성염을 유효성분으로서 함유하는 의약 조성물.
viii) 전항 i)에 기재한 화학식 (I)로 표시되는 트리아자스피로[5.5]운데칸 유도체, 이들의 4급 암모늄염, 이들의 N-옥사이드 또는 이들의 비독성염을 유효성분으로서 함유하는 케모카인/케모카인 수용체의 작용의 제어제.
viiii) 전항 i)에 기재한 화학식 (I)로 표시되는 트리아자스피로[5.5]운데칸 유도체, 이들의 4급 암모늄염, 이들의 N-옥사이드 또는 이들의 비독성염을 유효성분으로서 함유하는 천식, 아토피성 피부염, 담마진, 알레르기성 기관지폐 아스페르길루스증, 알레르기성 호산구성 위장증, 신장염, 신장증, 간염, 관절염, 만성 관절 류머티즘, 건선, 비염, 결막염, 허혈 재관류 상해의 억제, 다발성 경화증, 궤양성 대장염, 급성 호흡 궁박 증후군, 세균 감염에 따른 쇼크, 당뇨병, 자기면역질환의 치료, 이식 장기 거절반응, 면역 억제, 암전이 예방, 후천성 면역부전 증후군의 예방제 및/또는 치료제에 관한 것이다.
발명의 상세한 설명
본 발명에 있어서, C1∼4 알킬기로서는, 메틸, 에틸, 프로필, 부틸 기 및 이들의 이성체기 등을 들 수 있다.
C1∼4 알콕시기로서는, 메톡시, 에톡시, 프로폭시, 부톡시 기 및 이들의 이성체기 등을 들 수 있다.
할로겐 원자로서는, 염소, 브롬, 불소, 요오드 원자를 들 수 있다.
C1∼4 알킬렌기로서는, 메틸렌, 에틸렌, 트리메틸렌, 테트라메틸렌 기 및 이들의 이성체기 등을 들 수 있다.
C2∼4 알케닐렌기로서는, 비닐렌, 프로페닐렌, 부테닐렌 기 및 이들의 이성체기 등을 들 수 있다.
C2∼4 알키닐기로서는, 에티닐, 프로피닐, 부티닐 기 및 이것들의 이성체기 등을 들 수 있다.
C5∼10의 단환식 또는 이환식 탄소환으로서는, 예컨대, 시클로펜탄, 시클로헥산, 시클로헵탄, 시클로옥탄, 시클로펜텐, 시클로헥센, 시클로헵텐, 시클로옥텐, 시클로펜타디엔, 시클로헥사디엔, 시클로헵타디엔, 시클로옥타디엔, 벤젠, 인덴,나프탈렌, 인단, 테트라히드로나프탈렌, 비시클로[3,3,0]옥탄, 비시클로[4,3,0]노난, 비시클로[4,4,0]데칸 등을 들 수 있다.
1∼2개의 질소 원자 및/또는 1∼2개의 산소 원자를 함유하는 5∼10원의 단환식 또는 이환식 복소환이란, 1∼2개의 질소 원자 및/또는 1∼2개의 산소 원자를 함유하는 5∼10원의 단환식 또는 이환식 복소환아릴, 또는 그 일부 또는 전부가 포화된 것이다. 예컨대, 피롤, 이미다졸, 피라졸, 피리딘, 피라진, 피리미딘, 피리다진, 아제핀, 디아제핀, 푸란, 피란, 옥세핀, 옥사졸, 이소옥사졸, 프라잔, 옥사디아졸, 옥사진, 옥사디아진, 옥사제핀, 옥사디아제핀, 인돌, 이소인돌, 벤조푸란, 이소벤조푸란, 인다졸, 퀴놀린, 이소퀴놀린, 프탈라진, 나프틸리딘, 퀴녹살린, 퀴나졸린, 신놀린, 벤조옥사졸, 벤조이미다졸, 벤조프라잔, 벤조트리아졸, 피롤린, 피롤리딘, 이미다졸린, 이미다졸리딘, 피라졸린, 피라졸리딘, 디히드로피리딘, 테트라히드로피리딘, 피페리딘, 디히드로피라진, 테트라히드로피라진, 피페라진, 디히드로피리미딘, 테트라히드로피리미딘, 퍼히드로피리미딘, 디히드로피리다진, 테트라히드로피리다진, 퍼히드로피리다진, 디히드로아제핀, 테트라히드로아제핀, 퍼히드로아제핀, 디히드로디아제핀, 테트라히드로디아제핀, 퍼히드로디아제핀, 디히드로푸란, 테트라히드로푸란, 디히드로피란, 테트라히드로피란, 디히드로옥사졸, 테트라히드로옥사졸, 디히드로이소옥사졸, 테트라히드로이소옥사졸, 디히드로옥사디아졸, 테트라히드로옥사디아졸, 테트라히드로옥사디아진, 테트라히드로옥사아제핀, 테트라히드로옥사디아제핀, 퍼히드로옥사아제핀, 퍼히드로옥사디아제핀, 모르폴린, 인돌린, 이소인돌린, 디히드로벤조푸란, 퍼히드로벤조푸란, 디히드로이소벤조푸란, 퍼히드로이소벤조푸란, 디히드로인다졸, 퍼히드로인다졸, 디히드로퀴놀린, 테트라히드로퀴놀린, 퍼히드로퀴놀린, 디히드로이소퀴놀린, 테트라히드로이소퀴놀린, 퍼히드로이소퀴놀린, 디히드로프탈라진, 테트라히드로프탈라진, 퍼히드로프탈라진, 디히드로나프틸리딘, 테트라히드로나프틸리딘, 퍼히드로나프틸리딘, 디히드로퀴녹살린, 테트라히드로퀴녹살린, 퍼히드로퀴녹살린, 디히드로퀴나졸린, 테트라히드로퀴나졸린, 퍼히드로퀴나졸린, 디히드로신놀린, 테트라히드로신놀린, 퍼히드로신놀린, 디히드로벤조옥사졸, 퍼히드로벤조옥사졸, 디히드로벤조이미다졸, 퍼히드로벤조이미다졸, 디옥솔란, 디옥산, 벤조디옥살란, 벤조디옥산 등을 들 수 있다.
각각이 결합하는 질소 원자와 함께 1∼2개의 질소 원자 및/또는 1개의 산소 원자를 함유하는 5∼6원의 단환식 복소환이란, 1∼2개의 질소 원자 및/또는 1개의 산소 원자를 함유하는 5∼6원의 단환식 복소환아릴, 또는 그 일부 또는 전부가 포화된 것이다. 예컨대, 피롤, 이미다졸, 피라졸, 피롤린, 피롤리딘, 이미다졸린, 이미다졸리딘, 피라졸린, 피라졸리딘, 디히드로피리딘, 테트라히드로피리딘, 피페리딘, 디히드로피라진, 테트라히드로피라진, 피페라진, 디히드로피리미딘, 테트라히드로피리미딘, 퍼히드로피리미딘, 디히드로피리다진, 테트라히드로피리다진, 퍼히드로피리다진, 테트라히드로옥사졸, 테트라히드로이소옥사졸, 디히드로옥사디아졸, 테트라히드로옥사디아졸, 테트라히드로옥사디아진, 모르폴린환 등을 들 수 있다.
C5∼6의 단환 탄소환으로는, 예컨대, 시클로펜탄, 시클로헥산, 시클로펜텐, 시클로헥센, 시클로펜타디엔, 시클로헥사디엔, 벤젠 환 등을 들 수 있다.
1∼2개의 질소 원자 및/또는 1개의 산소 원자를 함유하는 5∼6원의 단환식복소환이란, 1∼2개의 질소 원자 및/또는 1개의 산소 원자를 함유하는 5∼6원의 단환식 복소환아릴, 또는 그 일부 또는 전부가 포화된 것이다. 예컨대, 피롤, 이미다졸, 피라졸, 피리딘, 피라진, 피리미딘, 피리다진, 푸란, 피란, 옥사졸, 이소옥사졸, 프라잔, 옥사디아졸, 옥사진, 옥사디아진, 피롤린, 피롤리딘, 이미다졸린, 이미다졸리딘, 피라졸린, 피라졸리딘, 디히드로피리딘, 테트라히드로피리딘, 피페리딘, 디히드로피라진, 테트라히드로피리딘, 피페라진, 디히드로피리미딘, 테트라히드로피리미딘, 퍼히드로피리미딘, 디히드로피리다진, 테트라히드로피리다진, 퍼히드로피리다진, 디히드로푸란, 테트라히드로푸란, 디히드로피란, 테트라히드로피란, 디히드로옥사졸, 테트라히드로옥사졸, 디히드로이소옥사졸, 테트라히드로이소옥사졸, 디히드로옥사디아졸, 테트라히드로옥사디아졸, 테트라히드로옥사디아진, 모르폴린 환 등을 들 수 있다.
본 발명에 있어서, R1기, R2기, R3기, R4기, R5기가 나타내는 각각의 기는 모두 바람직하다. 특히 실시예에 기재된 것이 바람직하다.
본 발명에 있어서는, 특별히 지시하지 않는 한 이성체는 이것을 전부 포함한다. 예컨대, 알킬기, 알콕시기 및 알킬렌기에는 직쇄인 것 및 분지쇄인 것이 포함된다. 또한, 이중 결합, 환, 축합환에 있어서의 이성체(E체, Z체, 시스체, 트랜스체), 비대칭 탄소의 존재 등에 의한 이성체(R체, S체, α체, β체, 거울상 이성체, 부분입체 이성체), 선광성을 갖는 광학 활성체(D체, L체, d체, l체), 크로마토그래프 분리에 의한 극성체(고극성체, 저극성체), 평형 화합물, 이들 임의의 비율의 혼합물, 라세미 혼합물은 전부 본 발명에 포함된다.
[염]
본 발명에 있어서는 모든 비독성염을 포함한다. 예컨대, 일반적인 염, 산부가염 등을 들 수 있다.
화학식 (I)로 표시되는 본 발명 화합물은 공지의 방법에 의해 해당하는 염으로 변환할 수 있다. 염은 독성이 없는 수용성인 것이 바람직하다. 적당한 염으로서는, 알칼리 금속(칼륨, 나트륨 등)의 염, 알칼리 토류 금속(칼슘, 마그네슘 등)의 염, 암모늄염, 약학적으로 허용되는 유기아민(테트라메틸암모늄, 트리에틸아민, 메틸아민, 디메틸아민, 시클로펜틸아민, 벤질아민, 페네틸아민, 피페리딘, 모노에탄올아민, 디에탄올아민, 트리스(히드록시메틸)아민, 리신, 아르기닌, N-메틸-D-글루카민 등)의 염을 들 수 있다.
화학식 (I)로 표시되는 본 발명 화합물은 공지의 방법에 의해 해당하는 산부가염으로 변환할 수 있다. 산부가염은 독성이 없는 수용성인 것이 바람직하다. 적당한 산부가염으로서는, 염산염, 브롬화수소산염, 황산염, 인산염, 질산염와 같은 무기산염, 또는 아세트산염, 트리플루오로아세트산염, 유산염, 타르타르산염, 옥살산염, 푸마르산염, 말레산염, 시트르산염, 안식향산염, 메탄술폰산염, 에탄술폰산염, 벤젠술폰산염, 톨루엔술폰산염, 이세티온산염, 글루쿠론산염, 글루콘산염과 같은 유기산염을 들 수 있다.
또한, 화학식 (I)로 표시되는 본 발명 화합물 또는 그 염은 공지의 방법에 의해 수화물로 변환할 수도 있다.
화학식 (I)로 표시되는 화합물 또는 이들의 비독성염은 전부 바람직하다. 구체적으로는, 실시예에 기재한 화합물 또는 이들의 비독성염을 들 수 있다.
화학식 (I)로 표시되는 화합물의 4급 암모늄염이란, 화학식 (I)로 표시되는 화합물의 질소 원자가 R0기에 의해 4급화된 것을 나타낸다.
R0기는 C1∼8 알킬기, 페닐기에 의해 치환된 C1∼8 알킬기를 나타낸다.
화학식 (I)로 표시되는 화합물의 N-옥사이드란, 화학식 (I)로 표시되는 화합물의 질소 원자가 산화된 것을 나타낸다.
[본 발명 화합물의 제조 방법]
화학식 (I)로 표시되는 본 발명 화합물은 이하의 방법 또는 실시예에 기재한 방법으로 제조할 수 있다.
화학식 (I)로 표시되는 본 발명 화합물 중, 질소 원자가 4급 암모늄염 또는 N-옥사이드를 나타내지 않는 화합물, 즉 화학식 (I-1)로 표시되는 화합물은 이하의 방법에 의해 제조할 수 있다.
화학식 (I-1)
(상기 식에서 R1-1, R2-1, R3-1, R4-1, R5-1은 R1, R2, R3, R4, R5와 동일한 의미를나타내고, N1은 질소 원자를 나타낸다. 단, 어느 쪽의 질소 원자도 4급 암모늄염 또는 N-옥사이드를 나타내지 않는 것으로 한다.)
화학식 (I-1) 중, R1-1, R2-1, R3-1, R4-1, R5-1기 중 어느 것도 카르복실기, 수산기, 아미노기 또는 티올기를 함유하는 기를 나타내지 않는 화합물, 즉, 화학식 (I-1A)로 표시되는 화합물은 화학식 (II)로 표시되는 화합물을 환화 반응시킴으로써 제조할 수 있다.
화학식 (I-1A)
(상기 식에서 R1-1A, R2-1A, R3-1A, R4-1A, R5-1A는 R1-1, R2-1, R3-1, R4-1, R5-1과 동일한 의미를 나타낸다. 단, 모두 카르복실기, 수산기, 아미노기 또는 티올기를 함유하는 기를 나타내지 않는 것으로 하고, 다른 기호는 상기와 동일한 의미를 나타낸다.)
화학식 (II)
(상기 식에서 T는 C1∼4 알킬기, C5∼6의 단환식 탄소환, 또는 C5∼6의 단환식 탄소환 또는 1∼2개의 질소 원자 및/또는 1개의 산소 원자를 함유하는 5∼6원환의 단환식 복소환에 의해 치환된 C1∼4 알킬기를 나타낸다.)
이 환화 방법은 공지이며, 예컨대, 유기용매(디클로로에탄, 톨루엔 등) 중, 3급 아민(트리에틸아민, 디이소프로필에틸아민 등)을 이용하거나, 산(아세트산, 트리플루오로아세트산 등)을 이용하거나, 또는 이용하지 않고 60∼120℃로 가열함으로써 행해진다. 이 반응은 T기의 절단과 동시에 환화되는 반응이다.
또한, 이 환화 반응은 R3또는 R4기가 수산기를 함유하는 기를 나타내는 화합물에 있어서도 행할 수 있다.
또한, 이 환화 반응은 R1, R2, R3또는 R4기 중의 질소 원자가 N-옥사이드를 나타내는 화합물에 대해서도 행할 수 있다.
또한, 필요하다면, 이 반응에 이어 공지의 방법에 의해 원하는 비독성염으로 변환하는 조작을 행하여도 좋다.
화학식 (I-1A) 중, R1-1A중의 G가 메틸렌기 또는 비닐렌기를 나타내는 화합물, 즉 화학식 (I-1A-1)로 표시되는 화합물은 화학식 (III) 또는 화학식 (IV)로 표시되는 화합물과 화학식 (V)로 표시되는 화합물을 환원적 아미노화 반응시킴으로써 제조할 수 있다.
화학식 (I-1A-1)
[상기 식에서 G1은 메틸렌기 또는 비닐렌기를 나타내고, R1-1A-1은
(1)또는
(2)
(기 중, R6-1A는 R6과 동일한 의미를 나타낸다. 단, 카르복실기, 수산기, 아미노기 또는 티올기를 함유하는 기를 나타내지 않는 것으로 하고, 다른 기호는 상기와 동일한 의미를 나타낸다)를 나타내고, 다른 기호는 상기와 동일한 의미를 나타낸다.]
화학식 (III)
(상기 식에서 모든 기호는 상기와 동일한 의미를 나타낸다.)
화학식 (IV)
화학식 (V)
이 환원적 아미노화 반응은 공지이며, 예를 들면, 유기용매(예컨대, 디클로로에탄, 디클로로메탄, 디메틸포름아미드, 아세트산 및 이들의 혼합물 등) 중, 환원제(수소화트리아세톡시붕소나트륨, 시아노수소화붕소나트륨 등)의 존재 하, 0∼40℃의 온도에서 행해진다.
또한, 이 환원적 아미노화 반응은 R1기 중의 질소 원자가 N-옥사이드를 나타내는 화합물에 있어서도 행할 수 있다.
또한, 이 환원적 아미노화 반응은 R3또는 R4기가 수산기를 함유하는 기를 나타내는 화합물에 있어서도 행할 수 있다.
화학식 (I-1A) 중, R1-`1A중의 G가 에틸렌기를 나타내는 화합물, 즉 화학식 (I-1A-2)로 표시되는 화합물은 화학식 (VI)으로 표시되는 화합물과 화학식 (V)로 표시되는 화합물을 반응시킴으로써 제조할 수 있다.
화학식 (I-1A-2)
(모든 기호는 상기와 동일한 의미를 나타낸다.)
화학식 (VI)
(모든 기호는 상기와 동일한 의미를 나타낸다.)
이 반응은 공지이며, 예를 들면, 우선, 유기용매(예컨대, 디클로로에탄, 디클로로메탄 등) 중, 3급 아민(트리에틸아민, 피리딘 등) 존재 하에 PS-TsCl-HL 수지(상품명, Argonaut Technologies사, 카탈로그 번호 800366)와 화학식 (VI)으로 표시되는 화합물을 0∼40℃의 온도에서 반응시키고, 추가로 얻어진 수지를 유기용매(예컨대, 아세토니트릴, 디클로로에탄, 디클로로메탄 등) 중, 3급 아민(디이소프로필에틸아민 등)의 존재 하에서 화학식 (V)로 표시되는 화합물과 40∼100℃의 온도에서 반응시킴으로써 행해진다.
또한, 이 반응은 R1, R2, R3또는 R4기 중의 질소 원자가 N-옥사이드를 나타내는 화합물에 대해서도 행할 수 있다.
화학식 (I-1A) 중, R1-1A중의 G가 단일 결합을 나타내는 화합물, 즉 화학식(I-1A-3)으로 표시되는 화합물은 화학식 (VII)로 표시되는 화합물과 화학식 (V)로 표시되는 화합물을 반응시킴으로써 제조할 수 있다.
화학식 (I-1A-3)
(모든 기호는 상기와 동일한 의미를 나타낸다.)
화학식 (VII)
(상기 식에서 X는 할로겐 원자를 나타내고, 다른 기호는 상기와 동일한 의미를 나타낸다.)
이 반응은 공지이며, 예를 들면, 유기용매(예컨대, 디메틸설폭사이드 등) 중, 알칼리(탄산칼륨, 탄산나트륨 등) 존재 하, 100∼150℃의 온도에서 행해진다.
또한, 이 반응은 R1, R2, R3또는 R4기 중의 질소 원자가 N-옥사이드를 나타내는 화합물에 대해서도 행할 수 있다.
화학식 (I-1A) 중, R1-1A중의 G가 -CO-를 나타내는 화합물, 즉 화학식 (I-1A-5)로 표시되는 화합물은 화학식 (XIII)으로 표시되는 화합물과 화학식 (V)로 표시되는 화합물을 아미드화 반응시킴으로써 제조할 수 있다.
화학식 (I-1A-5)
(모든 기호는 상기와 동일한 의미를 나타낸다.)
화학식 (XIII)
(모든 기호는 상기와 동일한 의미를 나타낸다.)
이 아미드화 반응은 공지이며, 예컨대
(1) 산할라이드를 이용하는 방법
(2) 혼합 산무수물을 이용하는 방법
(3) 축합제를 이용하는 방법 등을 들 수 있다.
이들 방법을 구체적으로 설명하면,
(1) 산할라이드를 이용하는 방법은, 예컨대, 카르복실산을 유기용매(클로로포름, 염화메틸렌, 디에틸에테르, 테트라히드로푸란 등) 중 또는 무용매로, 산할라이드화제(옥살릴클로라이드, 티오닐클로라이드 등)와 -20℃∼환류 온도에서 반응시키고, 얻어진 산할라이드를 3급 아민(피리딘, 트리에틸아민, 디메틸아닐린, 디메틸아미노피리딘 등)의 존재 하, 아민과 불활성 유기용매(클로로포름, 염화메틸렌, 디에틸에테르, 테트라히드로푸란 등) 중, 0∼40℃에서 반응시킴으로써 행해진다. 또한, 유기용매(디옥산, 테트라히드로푸란 등) 중, 알칼리 수용액(중조수 또는 수산화나트륨용액 등)을 이용하여, 산할라이드와 0∼40℃의 온도에서 반응시킴으로써 행할 수도 있다.
(2) 혼합 산무수물을 이용하는 방법은, 예컨대, 카르복실산을 유기용매(클로로포름, 염화메틸렌, 디에틸에테르, 테트라히드로푸란 등) 중 또는 무용매로, 3급 아민(피리딘, 트리에틸아민, 디메틸아닐린, 디메틸아미노피리딘 등)의 존재 하, 산할라이드(피발로일클로라이드, 토실클로라이드, 메실클로라이드 등), 또는 산 유도체(클로로포름산에틸, 클로로포름산이소부틸 등)와, 0∼40℃에서 반응시키고, 얻어진 혼합 산무수물을 유기용매(클로로포름, 염화메틸렌, 디에틸에테르, 테트라히드로푸란 등) 중, 아민과 0∼40℃에서 반응시킴으로써 행해진다.
(3) 축합제를 이용하는 방법은, 예컨대, 카르복실산과 아민을 유기용매(클로로포름, 염화메틸렌, 디메틸포름아미드, 디에틸에테르, 테트라히드로푸란 등) 중, 또는 무용매로, 3급 아민(피리딘, 트리에틸아민, 디메틸아닐린, 디메틸아미노피리딘 등)의 존재 하 또는 비존재 하, 축합제(1,3-디시클로헥실카르보디이미드(DCC), 1-에틸-3-[3-(디메틸아미노)프로필]카르보디이미드(EDC), 1,1'-카르보닐디이미다졸
(CDI), 2-클로로-1-메틸피리디늄요오드, 1-프로필포스폰산 환상 무수물(1-propanephosphonic acid cyclic anhydride, PPA) 등)을 이용하여, 1-히드록시벤즈트리아졸(HOBt)을 이용하거나 이용하지 않고, 0∼40℃로 반응시킴으로써 행해진다.
이들 (1), (2) 및 (3)의 반응은 모두 불활성 가스(아르곤, 질소 등) 분위기 하, 무수 조건으로 행하는 것이 바람직하다.
또한, 이 아미드화 반응은 R3또는 R4기가 수산기를 함유하는 기를 나타내는 화합물에 있어서도 행할 수 있다.
또한, 이 아미드화 반응은 R1, R2, R3또는 R4기 중의 질소 원자가 N-옥사이드를 나타내는 화합물에 대해서도 행할 수 있다.
화학식 (I-1) 중, R1, R2, R3, R4, R5기 중 적어도 하나의 기가 카르복실기, 수산기, 아미노기 또는 티올기를 함유하는 기를 나타내는 화합물, 즉, 화학식 (I-1B)로 표시되는 화합물은 상기한 방법에 의해 제조한 화학식 (I-1A) 중, R1-1, R2-1, R3-1, R4-1, R5-1중 적어도 하나의 기가 보호기에 의해 보호된 카르복실기, 수산기, 아미노기 또는 티올기를 함유하는 기를 나타내는 화합물, 즉, 화학식 (I-1A-4)로 표시되는 화합물을 보호기의 탈보호 반응으로 처리함으로써 제조할 수 있다.
화학식 (I-1B)
(상기 식에서 R1-1B, R2-1B, R3-1B, R4-1B, R5-1B는 R1-1, R2-1, R3-1, R4-1, R5-1과 동일한 의미를 나타낸다. 단, 적어도 하나의 기가 카르복실기, 수산기, 아미노기 또는 티올기를 함유하는 기를 나타내고, 다른 기호는 상기와 동일한 의미를 나타낸다.)
화학식 (I-1A-4)
(상기 식에서 R1-1A-4, R2-1A-4, R3-1A-4, R4-1A-4, R5-1A-4는 R1-1, R2-1, R3-1, R4-1, R5-1과 동일한 의미를 나타낸다. 단, 적어도 하나의 기가 보호기에 의해 보호된 카르복실기, 수산기, 아미노기 또는 티올기를 함유하는 기를 나타내고, 다른 기호는 상기와 동일한 의미를 나타낸다.)
카르복실기의 보호기로서는, 예컨대 메틸기, 에틸기, t-부틸기, 벤질기, 알릴기를 들 수 있다.
수산기의 보호기로서는, 예컨대 메톡시메틸기, 2-테트라히드로피라닐기, t-부틸디메틸실릴기, t-부틸디페닐실릴기, 아세틸기, 벤질기를 들 수 있다.
아미노기의 보호기로서는, 예컨대 벤질옥시카르보닐기, 알릴옥시카르보닐기, t-부톡시카르보닐기, 트리플루오로아세틸기, 9-플루오레닐메톡시카르보닐기를 들 수 있다.
티올기의 보호기로서는, 예컨대 벤질기, 메톡시벤질기, 아세트아미드메틸기, 트리페닐메틸기, 아세틸기를 들 수 있다.
카르복실기, 수산기, 아미노기 또는 티올기의 보호기는, 상기한 것 이외에도 용이하게 또한 선택적으로 이탈할 수 있는 기라면 특별히 한정되지 않는다. 예컨대, 문헌[T. W. Greene 등, Protective Groups in Organic Synthesis, Third Edition, Wiley-Interscience, New York, 1999]에 기재된 것이 이용된다.
아미노기의 보호기의 탈보호 반응은 상기한 방법에 의해 행해진다.
카르복실기, 수산기 또는 티올기의 보호기의 탈보호 반응은 잘 알려져 있고, 예컨대
(1) 알칼리 가수분해
(2) 산성 조건 하에 있어서의 탈보호 반응
(3) 가수소분해에 의한 탈보호 반응
(4) 실릴기의 탈보호 반응
(5) 금속 착체를 이용하는 탈보호 반응 등을 들 수 있다.
이들 방법을 구체적으로 설명하면,
(1) 알칼리 가수분해에 의한 탈보호 반응(예컨대, 트리플루오로아세틸기)은, 예컨대, 유기용매(메탄올, 테트라히드로푸란, 디옥산 등) 중, 알칼리 금속의 수산화물(수산화나트륨, 수산화칼륨, 수산화리튬 등), 알칼리 토류 금속의 수산화물(수산화바륨, 수산화칼슘 등) 또는 탄산염(탄산나트륨, 탄산칼륨 등) 혹은 그 수용액 혹은 이들의 혼합물을 이용하여 0∼40℃의 온도에서 행해진다.
(2) 산 조건 하에서의 탈보호 반응(예컨대, t-부톡시카르보닐기)은, 예컨대, 유기용매(디클로로메탄, 클로로포름, 디옥산, 아세트산에틸, 아니솔 등) 중, 유기산(아세트산, 트리플루오로아세트산, 메탄술폰산 등), 또는 무기산(염산, 황산 등) 혹은 이들의 혼합물(브롬화수소/아세트산등) 중, 0∼100℃의 온도에서 행해진다.
(3) 가수소분해에 의한 탈보호 반응(예컨대, 벤질기, 벤질옥시카르보닐기, 알릴옥시카르보닐기)은, 예컨대, 용매(에테르계(테트라히드로푸란, 디옥산, 디메톡시에탄, 디에틸에테르 등), 알코올계(메탄올, 에탄올 등), 벤젠계(벤젠, 톨루엔 등), 케톤계(아세톤, 메틸에틸케톤 등), 니트릴계(아세토니트릴 등), 아미드계(디메틸포름아미드 등), 물, 아세트산에틸, 아세트산 또는 이들 2 이상의 혼합 용매 등) 중, 촉매(팔라듐-탄소, 팔라듐블랙, 수산화팔라듐, 산화백금, 라니-니켈 등)의 존재 하, 상압 또는 가압 하의 수소 분위기 하 또는 포름산암모늄 존재 하, 0∼200℃의 온도에서 행해진다.
(4) 실릴기의 탈보호 반응은, 예컨대, 유기용매(테트라히드로푸란, 아세토니트릴 등) 중, 테트라부틸암모늄플루오라이드를 이용하여 0∼40℃의 온도에서 행해진다.
(5) 금속 착체를 이용하는 탈보호 반응은, 예컨대, 유기용매(디클로로메탄, 디메틸포름아미드, 테트라히드로푸란 등) 중, 트랩 시약(수소화트리부틸주석, 디메돈 등) 및/또는 유기산(아세트산 등)의 존재 하, 금속 착체(테트라키스트리페닐포스핀팔라듐(0) 착체 등)를 이용하여 0∼40℃의 온도에서 행해진다.
당업자는 용이하게 이해할 수 있는 것이기는 하지만, 이들 탈보호 반응을 구별지어 사용함으로써, 목적으로 하는 본 발명 화합물을 용이하게 제조할 수 있다.
화학식 (I)로 표시되는 본 발명 화합물 중, 적어도 하나의 질소 원자가 4급 암모늄염을 나타내는 화합물, 즉 화학식 (I-2)로 표시되는 화합물은 화학식 (I-1)로 표시되는 화합물을 화학식 (XI)로 표시되는 화합물과 반응시킴으로써 제조할 수있다.
화학식 (I-2)
(상기 식에서 R1-2, R2-2, R3-2, R4-2, R5-2는 R1, R2, R3, R4, R5와 동일한 의미를 나타내고, N2는 질소 원자를 나타낸다. 단, 적어도 하나의 질소 원자가 4급 암모늄염을 나타내는 것으로 하고, Q는 할로겐 원자를 나타내는 것으로 한다.)
화학식 (XI)
(상기 식에서 R0은 C1∼4 알킬기 또는 페닐기에 의해 치환된 C1∼4 알킬기를 나타내고, Q는 할로겐 원자를 나타낸다.)
이 반응은 공지이며, 예컨대, 유기용매(아세톤, 디메틸포름아미드, 메틸에틸케톤 등) 중, 0∼40℃의 온도에서 행해진다.
화학식 (I)로 표시되는 본 발명 화합물 중, 적어도 하나의 질소 원자가 N-옥사이드를 나타내는 화합물, 즉 화학식 (I-3)으로 표시되는 화합물은 화학식 (I-1)로 표시되는 화합물을 산화 반응시킴으로써 제조할 수 있다.
화학식 (I-3)
(상기 식에서 R1-3, R2-3, R3-3, R4-3, R5-3은 R1, R2, R3, R4, R5와 동일한 의미를 나타내고, N3은 질소 원자를 나타낸다. 단, 적어도 하나의 질소 원자가 N-옥사이드를 나타내는 것으로 한다.)
이 산화 반응은 공지이며, 예컨대, 적당한 유기용매(디클로로메탄, 클로로포름, 벤젠, 헥산, t-부틸알코올 등) 중에서, 과잉의 산화제(과산화수소, 과요오드산나트륨, 아질산아실, 과붕산나트륨, 과산(예컨대, 3-클로로과벤조산, 과아세트산 등), 옥손(포타슘퍼옥시모노술페이트의 상품명), 과망간산칼륨, 크롬산 등)의 존재 하, 20∼60℃의 온도에서 반응시킴으로써 행해진다.
화학식 (II)로 표시되는 화합물은 다음에 나타내는 반응식 1에 의해 제조할 수 있다.
반응식 (1)
상기 반응식 중, 각 반응은 각각 공지의 방법에 의해 행해진다. 또한, 상기 반응식에 있어서, 출발 물질로서 이용하는 화학식 (IX), 화학식 (X), 화학식 (XI) 및 화학식 (XII)로 표시되는 화합물은 그 자체가 공지이거나 혹은 공지의 방법에 의해 용이하게 제조할 수 있다.
본 명세서중의 각 반응에 있어서, 반응생성물은 통상의 정제 수단, 예컨대, 상압 하 또는 감압 하에 있어서의 증류, 실리카겔 또는 규산마그네슘을 이용한 고속 액체 크로마토그래피, 박층 크로마토그래피, 혹은 컬럼 크로마토그래피 또는 세정, 재결정 등의 방법에 의해 정제할 수 있다. 정제는 각 반응마다 행하여도 좋고, 몇 개의 반응 종료 후에 행하여도 좋다.
본 발명에 있어서의 기타 출발 물질 및 각 시약은 그 자체가 공지이거나 또는 공지의 방법에 의해 제조할 수 있다.
[약리 활성]
화학식 (I)로 표시되는 본 발명 화합물의 유효성은, 예컨대, 이하의 실험에 의해 증명되었다.
전술한 바와 같이, HIV가 CD4 양성 세포상의 수용체인 CXCR4, 혹은 CCR5에 결합하는 것을 억제하는 화합물의 스크리닝을 하기 위해서는 HIV 바이러스를 이용한 분석계에서 행하는 것이 보다 직접적인 수법이다. 그러나, HIV 바이러스를 대량 스크리닝에 사용하는 것은, 그 취급의 어려움 때문에 실용적이지 못하다. 한편, 대식세포 지향성(R5) HIV-1과 RANTES, MIP-1α, MIP-1β가 모두 CCR5에 결합함으로써, HIV측과 RANTES, MIP-1α, MIP-1β측 쌍방의 CCR5 결합 부위 및 CCR5 측의 RANTES, MIP-1α, MIP-1β 및 HIV 결합 부위에는 어떠한 공통되는 특징이 있는 것으로 예측할 수 있다. 따라서, 기존의 항 AIDS약(역전사 억제제나 프로테아제 억제)과 다른 작용 기서인 HIV 바이러스의 세포에의 흡착을 억제하는 화합물을 발견하기 위해서, HIV 대신에 CCR5의 내인성 리간드인 RANTES, MIP-1α, MIP-1β를 이용한 분석계를 이용할 수 있다.
구체적으로는, RANTES와 CCR5의 결합을 억제하는 화합물을 스크리닝하는 계로서, 예컨대, CCR5는 G 단백질 공역 7회 막관통형 수용체이기 때문에, RANTES가 CCR5를 통해 유도하는 칼슘(Ca) 이온의 일과성 상승에 대한 효과를 측정하는 계를 실시할 수 있다. T 세포 지향성(X4) HIV와, SDF-1이 모두 CXCR4에 결합함으로써, 동일한 사고 방식이 가능하다.
[실험 방법]
(1) 인간 CCR5 유전자의 단리
인간 태반 cDNA는 Marathon cDNA amplification kit(Clontech)를 이용하여 작제하였다. PCR 프라이머인 hCCR5XbaI-F1:5'-AGCTAGTCTAGATCCGTTCCCCTACAAGAAACTCTCC-3'(배열 번호 1) 및 hCCR5XbaI-R1: 5'-AGCTAGTCTAGAGTGCACAACTCTGACTGGGTCACCA-3'(배열 번호 2)는 GenBank U54994의 배열에 기인하여 설계하였다.
인간 태반 cDNA를 주형으로서, Ex Taq(Takara)를 이용하여 PCR 반응(95℃에서 2분→[95℃에서 30초, 60℃에서 45초, 72℃에서 1분]×35회)을 행하였다. 증폭한 PCR 산물을 1% 아가로스 겔 전기 영동한 후, QIAquick Gel Extraction Kit(QIAGEN)를 이용하여 정제하고, 제한 효소 XbaI로 절단하였다. 절단한 단편을 발현 벡터 pEF-BOS-bsr에 DNA Ligation Kit Ver. 2(Takara)를 이용하여 연결하고, 대장균 DH5a로 형질 전환하였다. 이 플라스미드 pEF-BOS-bsr/hCCR5를 조제하여, DNA 배열을 확인하였다.
(2) CHO 세포의 배양
CHO-dhfr(-)는 Ham's F-12(소 태아 혈청(10%), 페니실린(50 U/㎖), 스트렙토마이신(50 ㎎/㎖) 함유)를 이용하여 배양하였다. 또한, 형질 도입한 세포는 상기에 블라스트사이딘(5 ㎎/㎖)을 첨가하여 배양하였다.
(3) CHO 세포에의 형질 도입
DMRIE-C reagent(Gibco BRL)를 이용하여 플라스미드 pEF-BOS-bsr/hCCR5를 CHO-dhfr(-) 세포에 형질 도입하였다. 48시간 후, 5 ㎎/㎖의 블라스트사이딘을 포함하는 배지로 교환하여 선택을 행하고, 안정 과잉 발현 세포를 수립하였다.
(4) RANTES와 CCR5의 결합(RANTES의 Ca 이온 일과성 상승 유도 활성)에 대한 억제 실험
수립한 인간 CCR5 안정 과잉 발현 CHO 세포(CCR5/CHO 세포)를 Ham's F-12 배지 및 FBS(10%)에 현탁하고, 96 웰 플레이트에 3.0×106세포/웰이 되도록 도말하였다. 37℃에서 하루 배양한 후, 배양 상청을 제거하고, Ham's F-12 배지(Fura-2AM(5 μM), Probenecid(2.5 mM) 및 HEPES(20 mM; pH 7.4) 함유)를 80 ㎕/웰로 첨가하여, 차광 상태로 37℃에서 1시간 항온 처리하였다. 1×Hanks/HEPES(20 mM; pH 7.4) 용액으로 2회 세정한 후, 동 용액을 100 ㎕/웰로 첨가하였다. 이 Fura-2AM을 혼입한 CCR5/CHO 세포에 대하여, 시험 화합물을 첨가한 후 3분 경과시에, 1×Hanks/HEPES(20 mM; pH 7.4) 용액으로 희석한 재조합 인간 RANTES(PeproTech)를 최종 농도 10 nM 첨가하였다. 인간 RANTES에 의해 유도되는 세포내 Ca2+농도의 일과성 상승을, 96 웰용 Ca2+검출기(하마마쯔 포토닉스)를 이용하여 측정하고, 시험 화합물의 억제율(%)을 이하의 계산식에 의해 산출하였다.
Ec: RANTES에 의한 Ca2+일과성 상승의 측정치
Ea: 시험 화합물을 첨가했을 때의 RANTES에 의한 Ca2+일과성 상승의 측정치
그 결과, 본 발명 화합물은 10 μM에서 50% 이상의 억제를 보였다. 예컨대, 실시예 2 화합물은 IC50치가 0.027 μM이고, 실시예 3 화합물은 IC50치가 0.37 μM였다.
CCR5 지향성의 HIV주에 대하여 흡착 억제 효과를 갖는 화합물을 발견하는 계에 관해서는 전술하였지만, 이 계를 이용하여 CCR5 혹은 그 리간드의 작용을 억제하는 화합물도 발견하는 것은 당연히 가능하다. 마찬가지로 하여, 다른 케모카인 수용체와 그 리간드의 작용을 억제하는 화합물을 발견하는 것이 가능하다. 예컨대, CCR2 혹은 그 리간드의 작용을 억제하는 화합물을 발견하는 계도 구축할 수 있다. CCR5와 마찬가지로 CCR2는 G 단백질 공역 7회 막관통형 수용체이기 때문에, 그 리간드인, 예컨대 MCP-1이 CCR2를 통해 유도하는 Ca 이온의 일과성 상승에 대한 효과를 측정함으로써 실시할 수 있다.
(5) MCP-1과 CCR2의 결합(MCP-1의 Ca 이온 일과성 상승 유도 활성)에 대한 억제 실험
인간 CCR2를 발현하고 있는 세포, 예컨대 인간 단구 세포주 THP-1(ATCC No. TIB-202)을 FBS(10%), Fura2-AM(5 μM), 프로베네시드(Probenecid, 2.5 mM) 및 HEPES(20 mM, pH 7.4)를 함유하는 RPMI1640 배지에 5.0×106세포/㎖가 되도록 현탁하여, 차광한 상태로 37℃에서 30분간 보온하였다. 4∼8배의 1×Hanks/HEPES(20 mM, pH 7.4)/Probenecid(2.5 mM)를 첨가하여, 차광한 상태로 추가로 37℃에서 30분간 보온하였다. 1×Hanks/HEPES(20 mM, pH 7.4)/Probenecid(2.5 mM) 용액으로 세포를 세정한 후, 동 용액으로 2.0×106세포/㎖에 재현탁하여, 96 웰 플레이트에 100 ㎕ 첨가하였다. 시험 화합물 용액을 첨가한 후, 3분 경과시에 1×Hanks/HEPES(20 mM, pH 7.4)/Probenecid(2.5 mM)로 희석한 재조합 인간 MCP-1(PeproTech)을 최종 농도 30 nM 첨가하였다. 인간 MCP-1에 의해 유도되는 세포내 Ca2+농도의 일과성 상승을 96 웰용 Ca2+검출기(하마마쯔 포토닉스)를 이용하여 측정하고, 시험 화합물의 억제율(%)을 이하의 계산식에 의해 산출하였다.
Ec: MCP-1에 의한 Ca2+일과성 상승의 측정치
Ea: 시험 화합물을 첨가했을 때의 MCP-1에 의한 Ca2+일과성 상승의 측정치
[독성]
본 발명 화합물의 독성은 매우 낮은 것으로서, 의약으로서 사용하기 위해서 충분히 안전하다고 판단할 수 있다.
산업상 이용 가능성
[의약품에의 적용]
인간을 포함한 동물, 특히 인간에게 있어서, 화학식 (I)로 표시되는 본 발명 화합물은 케모카인/케모카인 수용체의 작용을 제어하기 때문에, 각종 염증성 질환,천식, 아토피성 피부염, 담마진, 알레르기 질환(알레르기성 기관지폐 아스페르길루스증, 알레르기성 호산구성 위장증 등), 신장염, 신장증, 간염, 관절염, 만성 관절 류머티즘, 건선, 비염, 결막염, 허혈 재관류 상해의 억제, 다발성 경화증, 궤양성 대장염, 급성 호흡 궁박 증후군, 세균 감염에 따른 쇼크, 당뇨병, 자기면역질환의 치료, 이식 장기 거절반응, 면역 억제, 암전이 예방, 후천성 면역부전 증후군의 예방 및/또는 치료에 유용하다.
화학식 (I)로 표시되는 본 발명 화합물, 그 비독성의 염, 산부가염, 또는 그 수화물을 상기한 목적으로 이용하기 위해서는, 통상, 전신적 또는 국소적으로, 경구 또는 비경구의 형태로 투여한다.
투여량은, 연령, 체중, 증상, 치료 효과, 투여 방법, 처리 시간 등에 따라 다르지만, 통상, 성인 1인당, 1회에 대해, 1 ㎎ 내지 1000 ㎎의 범위에서, 1일 1회 내지 수회 경구 투여되거나, 또는 성인 1인당, 1회에 대해, 1 ㎎ 내지 100 ㎎의 범위에서, 1일 1회 내지 수회 비경구 투여(바람직하게는, 정맥내 투여)되거나, 또는 1일 1시간 내지 24시간의 범위에서 정맥내에 지속적으로 투여한다.
물론 상기한 바와 같이, 투여량은 여러 가지 조건에 따라 변동하기 때문에, 상기 투여량보다 적은 양으로 충분한 경우도 있고, 또한 범위를 초과하여 필요한 경우도 있다.
본 발명 화합물을 투여할 때에는, 경구 투여를 위한 내복용 고형제, 내복용 액제 및 비경구 투여를 위한 주사제, 외용제, 좌제 등으로서 이용된다.
경구 투여를 위한 내복용 고형제에는 정제, 환제, 캡슐제, 산제, 과립제 등이 포함된다. 캡슐제에는 경질 캡슐 및 연질 캡슐이 포함된다.
이러한 내복용 고형제에 있어서는, 하나 또는 그 이상의 활성 물질은 그 대로, 또는 부형제(락토오스, 만니톨, 글루코오스, 미결정 셀룰로오스, 전분 등), 결합제(히드록시프로필셀룰로오스, 폴리비닐피롤리돈, 메타규산알루민산마그네슘 등), 붕괴제(섬유소 글리콜산칼슘 등), 활택제(스테아린산마그네슘 등), 안정제, 용해 보조제(글루타민산, 아스파라긴산 등) 등과 혼합되어, 통상적인 방법에 따라 제제화하여 이용된다. 또한, 필요에 따라 코팅제(백당, 젤라틴, 히드록시프로필셀룰로오스, 히드록시프로필메틸셀룰로오스프탈레이트 등)로 피복되어 있어도 좋고, 또한 2이상의 층으로 피복되어 있어도 좋다. 더욱이 젤라틴과 같은 흡수될 수 있는 물질의 캡슐도 포함된다.
경구 투여를 위한 내복용 액제는 약제적으로 허용되는 수제, 현탁제, 유제, 시럽제, 엘릭시르제 등을 포함한다. 이러한 액제에 있어서는, 하나 또는 그 이상의 활성 물질이 일반적으로 이용되는 희석제(정제수, 에탄올 또는 이들 혼액 등)에 용해, 현탁 또는 유화된다. 더욱이 이 액제는 습윤제, 현탁화제, 유화제, 감미제, 풍미제, 방향제, 보존제, 완충제 등을 함유하고 있어도 좋다.
비경구 투여를 위한 주사제로서는, 용액, 현탁액, 유탁액 및 사용시 용제에 용해 또는 현탁하여 이용하는 고형의 주사제를 포함한다. 주사제는 하나 또는 그 이상의 활성 물질을 용제에 용해, 현탁 또는 유화시켜 이용된다. 용제로서, 예컨대 주사용 증류수, 생리식염수, 식물유, 프로필렌글리콜, 폴리에틸렌글리콜, 에탄올과 같은 알코올류 등 및 이들의 조합이 이용된다. 더욱이, 이 주사제는 안정제, 용해보조제(글루타민산, 아스파라긴산, 폴리솔베이트 80(등록상표) 등), 현탁화제, 유화제, 무통화제, 완충제, 보존제 등을 함유하고 있어도 좋다. 이들은 최종 공정에서 멸균하거나 무균 조작법에 의해 제조, 조제된다. 또한, 무균의 고형제, 예컨대 동결 건조품을 제조하여, 그 사용 전에 무균화 또는 무균의 주사용 증류수 또는 다른 용제에 용해하여 사용할 수도 있다.
비경구 투여를 위한 기타 제제로서는, 하나 또는 그 이상의 활성 물질을 함유하고, 통상법에 의해 처방되는 외용 액제, 연고제, 도포제, 흡입제, 스프레이제, 좌제 및 질내 투여를 위한 페서리 등이 포함된다.
스프레이제는, 일반적으로 이용되는 희석제 이외에 아황산수소나트륨과 같은 안정제와 등장성을 부여하는 완충제, 예컨대 염화나트륨, 시트르산나트륨 혹은 시트르산과 같은 등장제를 함유하고 있어도 좋다. 스프레이제의 제조 방법은, 예컨대 미국 특허 제2,868,691호 및 동 제3,095,355호에 상세히 기재되어 있다.
본 발명의 화학식 (I)로 표시되는 화합물, 이들의 4급 암모늄염, 이들의 N-옥사이드 또는 이들의 비독성염은 다른 약제, 예컨대, HIV 감염의 예방제 및/또는 치료제(특히, AIDS의 예방제 및/또는 치료제)와 조합하여 이용하여도 좋다. 이 경우, 이들 약품은 따로따로 혹은 동시에, 약리학적으로 허용될 수 있는 부형제, 결합제, 붕괴제, 활택제, 안정제, 용해 보조제, 희석제 등과 혼합하여 제제화하고, HIV 감염의 예방 및/또는 치료를 위한 의약 조성물로서 경구적으로 또는 비경구적으로 투여할 수 있다.
본 발명의 화학식 (I)로 표시되는 화합물, 이들의 4급 암모늄염, 이들의 N-옥사이드 또는 이들의 비독성염은 다른 HIV 감염의 예방제 및/또는 치료제(특히, AIDS의 예방제 및/또는 치료제)에 대하여 내성을 획득한 HIV-1에 대하여 감염 억제 작용을 갖는다. 따라서, 다른 HIV 감염의 예방제 및/또는 치료제가 효과를 보이지 않게 된 HIV 감염자에 대해서도 사용할 수 있다. 이 경우, 본 발명 화합물을 단일제로 사용하여도 좋지만, 감염되어 있는 HIV-1주가 내성을 획득한 HIV 감염의 예방제 및/또는 치료제 또는 그 이외의 약제와 병용하여 이용하여도 좋다.
본 발명은 화학식 (I)로 표시되는 화합물, 이들의 4급 암모늄염, 이들의 N-옥사이드 또는 이들의 비독성염과 HIV 감염을 억제하지 않는 약품을 조합하여 이루어지고, 단일제보다도 HIV 감염의 예방 및/또는 치료 효과가 증강된 것도 포함한다.
본 발명의 화학식 (I)로 표시되는 화합물, 이들의 4급 암모늄염, 이들의 N-옥사이드 또는 이들의 비독성염과 조합하여 이용되는 다른 HIV 감염의 예방제 및/또는 치료제의 예로서는, 역전사 효소 억제제, 프로테아제 억제제, 케모카인 길항제(예컨대, CCR2 길항제, CCR3 길항제, CCR4 길항제, CCR5 길항제, CXCR4 길항제 등), 퓨전 억제제, HIV-1의 표면 항원에 대한 항체, HIV-1의 백신 등을 들 수 있다.
역전사 효소 억제제로서, 구체적으로는, (1) 핵산계 역전사 효소 억제제의 지도부딘(상품명: 레트로비르), 디다노신(상품명: 바이덱스), 잘씨타빈(상품명: 하이비드), 스타부딘(상품명: 제리트), 라미부딘(상품명: 에피비르), 아바카비르(상품명: 자이아젠), 아데포비르, 아데포비르 디피복실, 엔트리시타빈(상품명: 코비라실), PMPA(상품명: 테노포비르) 등, (2) 비핵산계 역전사 효소 억제제의 네비라핀(상품명: 비라뮨), 델라비르딘(상품명: 레스크립터), 에파비렌쯔(상품명: 사스티바, 스토크린), 카푸라비린(AG1549) 등을 들 수 있다.
프로테아제 억제제로서, 구체적으로는, 인디나비르(상품명: 크릭시반), 리토나비르(상품명: 노르비어), 넬피나비르(상품명: 비라셉트), 사키나비르(상품명: 인비라제, 포토베이스), 암프레나비르(상품명: 에디네라제), 로피나비르(상품명: 카레트라), 티푸라나비르 등을 들 수 있다.
케모카인 길항제로서는, 케모카인 수용체의 내인성 리간드, 또는 그 유도체 및 비펩티드성 저분자 화합물, 또는 케모카인 수용체에 대한 항체가 포함된다.
케모카인 수용체의 내인성 리간드로서는, 구체적으로는, MIP-1α, MIP-1β, RANTES, SDF-1α, SDF-1β, MCP-1, MCP-2, MCP-4, 에오탁신(Eotaxin), MDC 등을 들 수 있다.
내인성 리간드의 유도체로서는, 구체적으로는, AOP-RANTES, Met-SDF-1α, Met-SDF-1β 등을 들 수 있다.
케모카인 수용체의 항체로서는, 구체적으로는, Pro-140 등을 들 수 있다.
CCR2 길항제로서는, 구체적으로는, WO99/07351호, WO99/40913호, WO00/46195호, WO00/46196호, WO00/46197호, WO00/46198호, WO00/46199호, WO00/69432호, WO00/69815호 또는 문헌[Bioorg. Med. Chem. Lett.,10, 1803(2000)]에 기재된 화합물 등을 들 수 있다.
CCR3 길항제로서는, 구체적으로는, DE19837386호, WO99/55324호, WO99/55330호, WO00/04003호, WO00/27800호, WO00/27835호, WO00/27843호, WO00/29377호, WO00/31032호, WO00/31033호, WO00/34278호, WO00/35449호, WO00/35451호, WO00/35452호, WO00/35453호, WO00/35454호, WO00/35876호, WO00/35877호, WO00/41685호, WO00/51607호, WO00/51608호, WO00/51609호, WO00/51610호, WO00/53172호, WO00/53600호, WO00/58305호, WO00/59497호, WO00/59498호, WO00/59502호, WO00/59503호, WO00/62814호, WO00/73327호 또는 WO01/09088호에 기재된 화합물 등을 들 수 있다.
CCR5 길항제로서는, 구체적으로는, WO99/17773호, WO99/32100호, WO00/06085호, WO00/06146호, WO00/10965호, WO00/06153호, WO00/21916호, WO00/37455호, EP1013276호, WO00/38680호, WO00/39125호, WO00/40239호, WO00/42045호, WO00/53175호, WO00/42852호, WO00/66551호, WO00/66558호, WO00/66559호, WO00/66141호, WO00/68203호, JP2000309598호, WO00/51607호, WO00/51608호, WO00/51609호, WO00/51610호, WO00/56729호, WO00/59497호, WO00/59498호, WO00/59502호, WO00/59503호, WO00/76933호, WO98/25605호, WO99/04794호, WO99/38514호 또는 문헌[Bioorg. Med. Chem. Lett.,10, 1803(2000)]에 기재된 화합물 등을 들 수 있다.
CXCR4 길항제로서는, 구체적으로는, AMD-3100, T-22, KRH-1120 또는 WO00/66112호에 기재된 화합물 등을 들 수 있다.
퓨전 억제제로서는, 구체적으로는, T-20(pentafuside), T-1249 등을 들 수있다.
이상의 병용 약제는 예시로서, 본 발명은 이들에 한정되지 않는다.
대표적인 역전사 효소 억제제 및 프로테아제 억제제의 통상의 임상 투여량은, 예컨대, 이하에 나타내는 바와 같지만, 본 발명은 이들에 한정되지 않는다.
지도부딘: 100 ㎎ 캡슐, 1회 200 ㎎, 1일 3회;
300 ㎎ 정제, 1회 300 ㎎, 1일 2회;
디다노신: 25∼200 ㎎ 정제, 1회 125∼200 ㎎, 1일 2회;
잘씨타빈: 0.375 ㎎∼0.75 ㎎ 정제, 1회 0.75 ㎎, 1일 3회;
스타부딘: 15∼40 ㎎ 캡슐, 1회 30∼40 ㎎, 1일 2회;
라미부딘: 150 ㎎ 정제, 1회 150 ㎎, 1일 2회;
아바카비르: 300 ㎎ 정제, 1회 300 ㎎, 1일 2회;
네비라핀: 200 ㎎ 정제, 1회 200 ㎎, 14일간 1일 1회, 그 후 1일 2회;
델라비르딘: 100 ㎎ 정제, 1회 400 ㎎, 1일 3회;
에파비렌쯔: 50∼200 ㎎ 캡슐, 1회 600 ㎎, 1일 1회;
인디나비르: 200∼400 캡슐, 1회 800 ㎎, 1일 3회;
리토나비르: 100 ㎎ 캡슐, 1회 600 ㎎, 1일 2회;
넬피나비르: 250 ㎎ 정제, 1회 750 ㎎, 1일 3회;
사키나비르: 200 ㎎ 캡슐, 1회 1, 200 ㎎, 1일 3회;
암프레나비르: 50∼150 ㎎ 정제, 1회 1, 200 ㎎, 1일 2회.
이하, 참고예 및 실시예에 의해 본 발명을 상세히 설명하지만, 본 발명은 이들에 한정되지 않는다.
크로마토그래피에 의한 분리의 개소 및 TLC에 표시되어 있는 괄호 안의 용매는 사용한 용출 용매 또는 전개 용매를 나타내고, 비율은 체적비를 나타낸다.
NMR의 개소에 표시되어 있는 괄호 안의 용매는 측정에 사용한 용매를 나타내고 있다.
참고예 1
(2R, 3R)-2-(t-부톡시카르보닐아미노)-3-히드록시-4-메틸-N-부틸-N-[4-벤질아미노카르보닐-1-벤질피페리딘-4-일]펜탄아미드
(2R,3R)-2-(t-부톡시카르보닐아미노)-3-히드록시-4-메틸펜탄산(10.5 g)의 메탄올(340 ㎖) 용액에 n-부틸아민(4.2 ㎖), N-벤질-4-피페리돈(7.9 ㎖), 벤질이소니트릴(5.2 ㎖)을 가하였다. 반응 혼합물을 55℃에서 밤새 교반하였다. 반응 혼합물을 농축하였다. 얻어진 잔류물을 실리카겔 컬럼 크로마토그래피(클로로포름:메탄올=100:1→75:1→50:1)에 의해 정제하여 이하의 물성치를 갖는 표제 화합물(19.8 g)을 얻었다.
TLC:Rf 0.49(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.38-7.15(m, 10H), 4.58(d, J=9.6Hz, 1H), 4.39(d, J=15.0Hz, 1H), 4.23(d, J=15.0Hz, 1H), 3.70-3.30(m, 3H), 3.50(s, 2H), 2.79-2.30(m, 6H), 2.08-1.88(m, 2H), 1.88-1.70(m, 3H), 1.50-1.28(m, 2H), 1.38(s, 9H), 0.98(t, J=7.2Hz, 3H), 0.96(d, J=6.6Hz, 3H), 0.91(d, J=6.6Hz, 3H).
참고예 2
(2R,3R)-2-아미노-3-히드록시-4-메틸-N-부틸-N-[4-벤질아미노카르보닐-1-벤질피페리딘-4-일]펜탄아미드
참고예 1에서 제조한 화합물(19.8 g)의 디클로로메탄(65 ㎖) 용액에 빙냉 하에서, 트리플루오로아세트산(50 ㎖)을 가하였다. 반응 혼합물을 실온에서 1시간 교반하였다. 반응 혼합물에 디클로로메탄을 가하고, 탄산나트륨 수용액으로 중화하여, 추출하였다. 추출물을 물, 포화염화나트륨 수용액으로 세정하고, 무수황산나트륨으로 건조시켜, 농축하여, 이하의 물성치를 갖는 표제 화합물을 얻었다. 얻어진잔류물을 더 정제하지 않고, 다음 반응에 이용하였다.
TLC: Rf 0.38(클로로포름:메탄올=10:1).
실시예 1
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-벤질-1,4,9-트리아자스피로[5.5]운데칸
참고예 2에서 제조한 화합물의 톨루엔(200 ㎖) 용액에 아세트산(15 ㎖)을 가하였다. 반응 혼합물을 80℃에서 45분간 교반하였다. 반응 혼합물을 아세트산에틸로 희석하고, 탄산나트륨 수용액으로 중화하여, 추출하였다. 추출물을 포화염화나트륨 수용액으로 세정하고, 무수황산나트륨으로 건조시켜, 농축하였다. 얻어진 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸:메탄올=25:1)에 의해 정제하여 이하의 물성치를 갖는 본 발명 화합물(12.9 g)을 얻었다.
TLC: Rf 0.49(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.36-7.22(m, 5H), 4.10(d, J=2.7Hz, 1H), 3.60(s, 2H), 3.47(m, 1H), 3.38-3.25(m, 2H), 2.96(m, 1H), 2.87-2.73(m, 3H), 2.25-1.94(m, 4H), 1.82(m, 1H), 1.64(m, 1H), 1.53-1.27(m, 3H), 0.96(d, J=6.6Hz, 6H),0.95(t, J=7.5Hz, 3H).
참고예 3
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-1,4,9-트리아자스피로[5.5]운데칸·염산염
실시예 1에서 제조한 화합물(12.67 g)의 메탄올(160 ㎖) 용액에 아르곤 가스 분위기 하에 20% 수산화팔라듐탄소(1.3 g)를 가하였다. 반응 혼합물을 수소 가스 분위기 하의 실온에서 12시간 교반하였다. 반응 혼합물을 셀라이트(상품명)를 이용하여, 여과하고, 여과액을 농축하였다. 얻어진 잔류물을 실리카겔 컬럼 크로마토그래피(클로로포름:헥산=3:1→클로로포름:메탄올=100:1→50:1→30:1→20:1→10:1)에 의해 정제하였다. 얻어진 화합물에 4N 염화수소아세트산에틸 용액(10 ㎖)을 가하고, 농축하여 이하의 물성치를 갖는 본 발명 화합물(8.6 g)을 얻었다.
TLC: Rf 0.16(클로로포름:메탄올:아세트산=20:4:1);
NMR(CD3OD): δ 4.15(d, J=2.1Hz, 1H), 3.95(m, 1H), 3.71(m, 1H), 3.52(m, 1H), 3.42-3.31(m, 2H), 3.21(m, 1H), 3.21(dd, J=9.6, 2.1Hz, 1H), 2.48-2.32(m, 2H), 2.23(m, 1H), 2.14-1.96(m, 2H), 1.72(m, 1H), 1.55-1.33(m, 3H), 1.02-0.92(m, 9H);
비선광도: [α]D+13.9(c 1.00,메탄올, 28℃).
참고예 3(1)∼3(9)
(2R,3R)-2-(t-부톡시카르보닐아미노)-3-히드록시-4-메틸펜탄산 대신에 해당하는 아미노산 유도체를, n-부틸아민 대신에 해당하는 아민 유도체를 이용하고, 참고예 1→참고예 2→실시예 1→참고예 3과 동일한 조작을 하여, 이하에 나타낸 화합물을 얻었다.
참고예 3(1)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.18(클로로포름:메탄올=4:1);
NMR(CD3OD): δ 4.02(dd, J=7.8, 4.6Hz, 1H), 3.82-3.70(m, 2H), 3.39(m, 4H), 2.34-2.09(m, 4H), 1.88-1.50(m, 5H), 1.37(m, 2H), 0.97(t, J=7.5Hz, 3H), 0.95(d, J=6.5Hz, 3H), 0.94(d, J=6.5Hz, 3H);
비선광도: [α]D-38.8(c 1.04, 메탄올, 23℃).
참고예 3(2)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.08(클로로포름:메탄올:아세트산=90:10:1);
NMR(CD3OD): δ 4.05(dd, J=7.8, 4.8Hz, 1H), 3.84-3.68(m, 2H), 3.46-3.34(m, 4H), 2.40-2.04(m, 4H), 1.83-1.46(m, 10H), 1.39(sextet, J=7.5Hz, 2H), 1.05-0.86(m, 2H), 0.97(t, J=7.2Hz, 3H);
비선광도: [α]D-37.5(c 1.04, 메탄올, 18℃).
참고예 3(3)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.32(부탄올:아세트산:물=4:2:1);
NMR(CD3OD): δ 4.16(d, J=2.0Hz, 1H), 3.95(m, 1H), 3.70(m, 1H), 3.52(m, 1H), 3.37(m, 1H), 3.28(m, 1H), 3.22-3.13(m, 2H), 2.46-1.93(m, 6H), 1.80-1.64(m, 5H), 1.48-1.15(m, 6H), 1.02-0.87(m, 5H);
비선광도: [α]D+1.22(c 1.04, 메탄올, 26℃).
참고예 3(4)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.05(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.13(d, J=2.0Hz, 1H), 4.01-3.91(m, 3H), 3.70(m, 1H), 3.59-3.32(m, 6H), 3.20(m, 1H), 2.47-2.19(m, 3H), 2.11-1.69(m, 5H), 1.47-1.17(m, 5H), 0.70(t, J=7.0Hz, 3H).
참고예 3(5)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로펜틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.04(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.00(d, J=2.0Hz, 1H), 3.95(m, 1H), 3.70(m, 1H), 3.53(m, 1H), 3.40-3.34(m, 3H), 3.21(m, 1H), 2.46-2.19(m, 4H), 2.08(m, 1H), 1.92-1.83(m, 2H), 1.70-1.50(m, 6H), 1.45-1.26(m, 5H), 0.97(t, J=7.0Hz, 3H).
참고예 3(6)
(3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.15(클로로포름:메탄올:아세트산=20:4:1);
NMR(CD3OD): δ 4.15(d, J=2.1Hz, 1H), 3.96(m, 1H), 3.71(m, 1H), 3.56-3.25(m, 3H), 3.20(dd, J=9.6, 2.1Hz, 1H), 3.13(m, 1H), 2.51-1.95(m, 5H), 1.75(m, 1H), 1.49(m, 1H), 0.99(d, J=6.6Hz, 3H), 0.98(d, J=6.6Hz, 3H), 0.95(t, J=7.5Hz, 3H).
참고예 3(7)
(3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.16(클로로포름:메탄올:아세트산=20:4:1);
NMR(CD3OD): δ 4.16(d, J=2.1Hz, 1H), 3.95(m, 1H), 3.70(m, 1H), 3.47(m,1H), 3.41-3.24(m, 4H), 3.12(m, 1H), 2.44(m, 1H), 2.33(m, 1H), 2.19(m, 1H), 2.08(m, 1H), 2.03-1.89(m, 2H), 1.84-1.62(m, 4H), 1.50(m, 1H), 1.40-1.10(m, 3H), 1.05-0.80(m, 2H), 0.95(t, J=7.5Hz, 3H);
비선광도: [α]D-2.92(c 1.06, 메탄올, 25℃).
참고예 3(8)
(3S)-1-부틸-2,5-디옥소-3-((1S)-1-히드록시-2-메틸프로필)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.16(클로로포름:메탄올:아세트산=20:4:1);
NMR(CD3OD): δ 4.15(d, J=2.1Hz, 1H), 3.95(m, 1H), 3.71(m, 1H), 3.52(m, 1H), 3.42-3.31(m, 2H), 3.21(m, 1H), 3.21(dd, J=9.6, 2.1Hz, 1H), 2.48-2.32(m, 2H), 2.23(m, 1H), 2.14-1.96(m, 2H), 1.72(m, 1H), 1.55-1.33(m, 3H), 1.02-0.92(m, 9H);
비선광도: [α]D-13.8(c 1.00, 메탄올, 28℃).
참고예 3(9)
(3S)-1-부틸-2,5-디옥소-3-((1S)-1-히드록시-1-시클로헥실)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.17(클로로포름:메탄올:아세트산=20:4:1);
NMR(CD3OD): δ 4.16(d, J=2.1Hz, 1H), 3.95(m, 1H), 3.70(m, 1H), 3.52(m, 1H), 3.42-3.25(m, 3H), 3.17(m, 1H), 2.49-2.38(m, 2H), 2.21(m, 1H), 2.14-1.90(m, 3H), 1.84-1.61(m, 5H), 1.55-1.13(m, 6H), 1.04-0.81(m, 2H), 0.97(t, J=7.2Hz, 3H);
비선광도: [α]D-1.29(c 1.09, 메탄올, 26℃).
실시예 2
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(6-페닐옥시피리딘-3-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
참고예 3에서 제조한 화합물(120 ㎎)의 디메틸포름아미드(1 ㎖) 용액에 아세트산(59 ㎕)을 가하였다. 반응 혼합물에 수소화트리아세톡시붕소나트륨(146 ㎎)과 3-포르밀-6-페닐옥시피리딘(89 ㎎)을 가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 반응 혼합물에 메탄올을 가하고, 농축하였다. 얻어진 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸→클로로포름:메탄올=25:1)에 의해 정제하고, 통상의 방법으로 염산염으로 변환하여 이하의 물성치를 갖는 본 발명 화합물(118 ㎎)을 얻었다.
TLC: Rf 0.48(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.35(d, J=2.1Hz, 1H), 8.12(dd, J=8.7, 2.1Hz, 1H), 7.49-7.40(m, 2H), 7.27(t, J=7.8Hz, 1H), 7.15(d, J=7.8Hz, 2H), 7.06(d, J=8.7, 1H), 4.39(s, 2H), 4.14(d, J=2.1Hz, 1H), 4.07-3.93(m, 1H), 3.82-3.67(m, 1H), 3.58-3.40(m, 3H), 3.30-3.15(m, 1H), 3.19(dd, J=9.6, 2.1Hz, 1H), 2.60-2.28(m, 3H), 2.18-2.05(m, 1H), 2.05-1.90(m, 1H), 1.80-1.55(m, 1H), 1.50-1.25(m, 3H), 0.99(d, J=6.6Hz, 3H), 0.97(d, J=6.6Hz, 3H), 0.95(t, J=7.2Hz, 3H);
비선광도: [α]D+10.8°(c 1.05, 메탄올, 24℃);
HPLC 조건
사용한 컬럼: CHIRALCEL OJ-R, 0.46×15 ㎝, DAICEL, OJR0CD-JB026;
사용한 유속: 0.7 mL/min;
사용한 용매 A액: 0.1M 인산이수소칼륨 수용액, B액: 아세토니트릴(A:B=76:24);
사용한 UV: 225 nm;
유지 시간: 11.53 min.
실시예 2(1)∼2(59)
3-포르밀-6-페닐옥시피리딘 대신에 해당하는 알데히드 유도체를 이용하고, 실시예 2와 동일한 조작을 하여, 이하에 나타낸 본 발명 화합물을 얻었다.
실시예 2(1)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메톡시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.36(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.45(d, J=8.7Hz, 2H), 7.00-6.96(m, 6H), 4.27(s, 2H), 4.14(d, J=2.1Hz, 1H), 3.94-3.69(m, 2H), 3.79(s, 3H), 3.60-3.05(m, 5H), 2.50-1.95(m, 5H), 1.70(m, 1H), 1.50-1.30(m, 3H), 1.00-0.93(m, 9H).
실시예 2(2)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(3-메톡시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.41(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.51(d, J=8.4Hz, 2H), 7.28(t, J=8.4Hz, 1H), 7.08(d, J=9.0Hz, 2H), 6.75(m, 1H), 6.61-6.57(m, 2H), 4.32(s, 2H), 4.14(d J=2.1Hz, 1H), 3.99-3.73(m, 2H), 3.77(s, 3H), 3.60-3.10(m, 5H), 2.55-1.95(m, 5H), 1.70(m, 1H), 1.50-1.30(m, 3H), 1.00-0.93(m, 9H).
실시예 2(3)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-플루오로페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.33(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.50(d, J=8.7Hz, 2H), 7.17-7.03(m, 6H), 4.30(s, 2H), 4.14(d, J=2.1Hz, 1H), 3.97-3.71(m, 2H), 3.60-3.10(m, 5H), 2.55-1.95(m, 5H), 1.70(m, 1H), 1.50-1.30(m, 3H), 1.00-0.93(m, 9H).
실시예 2(4)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-클로로페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.31(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.53(d, J=8.7Hz, 2H), 7.38(d, J=9.3Hz, 2H), 7.09(d, J=8.7Hz, 2H), 7.02(d, J=9.3Hz, 2H), 4.32(s, 2H), 4.14(d, J=1.8Hz, 1H), 3.98-3.72(m, 2H), 3.60-3.10(m, 5H), 2.55-2.00(m, 5H), 1.70(m, 1H), 1.50-1.30(m, 3H), 1.00-0.93(m, 9H).
실시예 2(5)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(페닐카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.57(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.87(d, J=8.4Hz, 2H), 7.83-7.72(m, 4H), 7.67(m, 1H), 7.59-7.48(m, 2H), 4.48(s, 2H), 4.14(d, J=2.1Hz, 1H), 4.05(m, 1H), 3.80(m, 1H), 3.59-3.37(m, 3H), 3.20(m, 1H), 3.19(dd, J=9.6, 2.1Hz, 1H), 2.60-2.28(m, 3H), 2.14(m, 1H), 2.00(m, 1H), 1.70(m, 1H), 1.52-1.23(m, 3H), 0.99(d, J=6.6Hz, 3H), 0.97(d, J=6.6Hz, 3H), 0.95(t, J=7.2Hz, 3H).
실시예 2(6)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(1-페닐-1-히드록시메틸)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.32(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.62-7.40(m, 4H), 7.40-7.18(m, 5H), 5.81(s, 1H), 4.32(s, 2H), 4.13(d, J=2.1Hz, 1H), 3.99(m, 1H), 3.73(m, 1H), 3.55-3.38(m, 3H), 3.13(m, 1H), 3.19(dd, J=9.6, 2.1Hz, 1H), 2.52-2.33(m, 2H), 2.24(m, 1H), 2.09(m, 1H), 1.98(m, 1H), 1.67(m, 1H), 1.50-1.25(m, 3H), 0.98(d, J=6.6Hz, 3H), 0.96(d, J=6.6Hz, 3H), 0.93(t, J=7.2Hz, 3H).
실시예 2(7)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-(모르폴린-4-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.47(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.59(d, J=8.7Hz, 2H), 7.48(d, J=8.7Hz, 2H), 7.14(d, J=8.7Hz, 2H), 7.10(d, J=8.7Hz, 2H), 4.35(s, 2H), 4.14(d, J=1.8Hz, 1H), 3.99(m, 1H), 3.85-3.35(m, 12H), 3.23(m, 1H), 3.19(dd, J=9.3, 1.8Hz, 1H), 2.55-2.41(m, 2H), 2.32(m, 1H), 2.12(m, 1H), 2.01(m, 1H), 1.68(m, 1H), 1.50-1.25(m, 3H), 0.99(d, J=6.6Hz, 3H), 0.97(d, J=6.6Hz, 3H), 0.95(t, J=7.2Hz, 3H).
실시예 2(8)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(6-메틸피리딘-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.19(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 8.58(d, J=2.7, 0.6Hz, 1H), 8.17(dd, J=9.0, 2.7Hz, 1H), 7.89(d, J=9.0Hz, 1H), 7.74(d, J=9.0Hz, 2H), 7.31(d, J=9.0Hz, 2H), 4.40(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.02(m, 1H), 3.78(m, 1H), 3.60-3.42(m, 3H), 3.30-3.16(m, 2H), 2.76(s, 3H), 2.64-2.32(m, 3H), 2.18-1.94(m, 2H), 1.70(m, 1H), 1.48-1.26(m, 3H), 1.00(d, J=6.3Hz, 3H), 0.98(d, J=6.3Hz, 3H), 0.96(t, J=7.2Hz, 3H).
실시예 2(9)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(피리딘-1-옥사이드-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.54(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 8.56(m, 1H), 8.45(m, 1H), 7.81-7.68(m, 2H), 7.75(d, J=8.4Hz, 2H), 7.33(d, J=8.4Hz, 2H), 4.41(s, 2H), 4.15(d, J=1.8Hz, 1H), 4.00(m, 1H), 3.78(m, 1H), 3.58-3.42(m, 3H), 3.28-3.16(m, 2H), 2.64-2.26(m, 3H), 2.20-1.92(m, 2H), 1.68(m, 1H), 1.52-1.28(m, 3H), 1.00(d, J=6.6Hz, 3H), 0.98(d, J=6.6Hz, 3H), 0.96(t, J=7.2Hz, 3H).
실시예 2(10)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-히드록시피페리딘-1-일메틸)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.69(클로로포름:메탄올:28% 암모니아수=100:10:1);
NMR(CD3OD): δ 7.75(d, J=8.4Hz, 2H), 7.67(d, J=8.4Hz, 2H), 4.41(s, 2H), 4.38(s, 2H), 4.14(d, J=2.1Hz, 1H), 4.14-3.94(m, 2H), 3.78(m, 1H), 3.58-3.40(m, 4H), 3.30-3.00(m, 4H), 2.68-2.36(m, 3H), 2.20-1.58(m, 8H), 1.50-1.26(m, 3H), 0.99(d, J=6.6Hz, 3H), 0.98(d, J=6.6Hz, 3H), 0.95(t, J=6,9Hz, 3H).
실시예 2(11)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.65(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 4.32(m, 1H), 4.27(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.00(m, 1H), 3.76(m, 1H), 3.60-3.42(m, 3H), 3.36-3.16(m, 2H), 2.64-2.42(m, 3H), 2.49(s, 3H), 2.44(s, 3H), 2.18-1.22(m, 16H), 1.00(d, J=6.6Hz, 3H), 0.99(d, J=6.6Hz, 3H), 0.95(t, J=7.5Hz, 3H).
실시예 2(12)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(1,3,5-트리메틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.50(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 4.27(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.00(m, 1H), 3.85(s, 3H), 3.76(m, 1H), 3.60-3.44(m, 3H), 3.28-3.16(m, 2H), 2.64-2.32(m, 3H), 2.44(s, 3H), 2.40(s, 3H), 2.18-1.92(m, 2H), 1.70(m, 1H), 1.48-1.26(m, 3H), 1.00(d, J=6.6Hz, 3H) 0.99(d, J=6.6Hz, 3H), 0.95(t, J=7.5Hz, 3H).
실시예 2(13)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-아미노술포닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.50(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 7.91(d, J=8.7Hz, 2H), 7.60(d, J=8.7Hz, 2H), 7.19(d, J=8.7Hz, 2H), 7.14(d, J=8.7Hz, 2H), 4.35(s, 2H), 4.15(d, J=2.4Hz, 1H), 3.98(m, 1H), 3.72(m, 1H), 3.58-3.38(m, 3H), 3.28-3.18(m, 2H), 2.56-1.92(m, 5H), 1.70(m, 1H), 1.54-1.28(m, 3H), 1.00(d, J=6.9Hz, 3H), 0.98(d, J=6.9Hz, 3H), 0.96(t, J=7.5Hz, 3H).
실시예 2(14)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메틸티오페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.45(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.53(d, J=9.0Hz, 2H), 7.32(d, J=9.0Hz, 2H), 7.05(d, J=9.0Hz, 2H), 6.99(d, J=9.0Hz, 2H), 4.33(s, 2H), 4.14(d, J=2.1Hz, 1H), 3.98(m, 1H), 3.72(m, 1H), 3.58-3.40(m, 3H), 3.28-3.10(m, 2H), 2.52-1.92(m, 5H), 2.47(s, 3H), 1.70(m, 1H), 1.50-1.28(m, 3H), 1.02-0.86(m, 9H).
실시예 2(15)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메틸술포닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.36(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.95(d, J=9.0Hz, 2H), 7.63(d, J=8.1Hz, 2H), 7.24-7.18(m, 4H), 4.39(s, 2H), 4.14(d, J=2.4Hz, 1H), 4.02(m, 1H), 3.78(m, 1H), 3.60-3.46(m, 3H), 3.28-3.10(m, 2H), 3.12(s, 3H), 2.54- 1.94(m, 5H), 1.70(m, 1H), 1.50-1.30(m, 3H), 1.02-0.86(m, 9H).
실시예 2(16)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-시아노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.36(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.73(d, J=8.7Hz, 2H), 7.64(d, J=9.0Hz, 2H), 7.21(d,J=9.0Hz, 2H), 7.14(d, J=8.7Hz, 2H), 4.38(s, 2H), 4.14(d, J=2.1Hz, 1H), 4.02(m, 1H), 3.76(m, 1H), 3.60-3.40(m, 3H), 3.28-3.14(m, 2H), 2.54-2.26(m, 3H), 2.20-1.90(m, 2H), 1.66(m, 1H), 1.50-1.28(m, 3H), 1.02-0.84(m, 9H).
실시예 2(17)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(페닐티오)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.36(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.50-7.34(m, 7H), 7.30(d, J=8.4Hz, 2H), 4.31(s, 2H), 4.13(d, J=2.1Hz, 1H), 3.98(m, 1H), 3.72(m, 1H), 3.56-3.36(m, 3H), 3.24-3.08(m, 2H), 2.50-2.18(m, 3H), 2.18-1.94(m, 2H), 1.68(m, 1H), 1.50-1.28(m, 3H), 1.10-0.88(m, 9H).
실시예 2(18)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-히드록시페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.70(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 7.31(d, J=8.7Hz, 2H), 6.94(d, J=8.7Hz, 2H), 4.32(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.04(m, 1H), 3.80(m, 1H), 3.64-3.48(m, 3H), 3.38-3.18(m, 2H), 2.70-2.30(m, 3H), 2.44(s, 3H), 2.36(s, 3H), 2.20-1.94(m, 2H), 1.68(m, 1H), 1.50-1.26(m, 3H), 1.02-0.84(m, 9H).
실시예 2(19)
(
3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-메틸술포닐아미노페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.72(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.47(d, J=9.0Hz, 2H), 7.41(d, J=9.0Hz, 2H), 4.31(s, 2H), 4.15(d, J=1.8Hz, 1H), 4.02(m, 1H), 3.78(m, 1H), 3.62-3.48(m, 3H), 3.38-3.18(m, 2H), 3.04(s, 3H), 2.68-2.36(m, 3H), 2.41(s, 3H), 2.39(s, 3H), 2.20-1.96(m, 2H), 1.68(m, 1H), 1.50-1.30(m, 3H), 1.02-0.88(m, 9H).
실시예 2(20)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-(N,N-디메틸아미노)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.12(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 8.07(d, J=9.0Hz, 2H), 7.78(d, J=9.0Hz, 2H), 4.30(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.02(m, 1H), 3.76(m, 1H), 3.62-3.48(m, 3H), 3.40-3.18(m, 6H), 2.95(s, 6H), 2.64(m, 1H), 2.49(s, 3H), 2.42-2.36(m, 2H), 2.41(s, 3H), 2.18-1.96(m, 2H), 1.68(m, 1H), 1.50-1.32(m, 3H), 1.08-0.90(m, 9H).
실시예 2(21)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(피롤리딘-1-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.36(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.01(d, J=8.7Hz, 2H), 7.77(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.15(d, J=1.8Hz, 1H), 4.04(m, 1H), 3.78(m, 1H), 3.62-3.48(m, 3H), 3.40-3.18(m, 6H), 2.66(m, 1H), 2.54-2.38(m, 2H), 2.49(s, 3H), 2.42(s, 3H), 2.20-1.94(m, 2H), 1.82-1.62(m, 5H), 1.50-1.30(m, 3H), 1.02-0.88(m, 9H).
실시예 2(22)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(6-메틸피리딘-1-옥사이드-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.26(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.58(m, 1H), 7.81-7.71(m, 2H), 7.73(d, J=8.4Hz, 2H), 7.30(d, J=8.4Hz, 2H), 4.40(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.00(m, 1H), 3.78(m, 1H), 3.62-3.40(m, 3H), 3.30-3.16(m, 2H), 2.66-2.38(m, 3H), 2.66(s, 3H), 2.18-1.94(m, 2H), 1.70(m, 1H), 1.50-1.28(m, 3H), 1.00(d, J=6.6Hz, 3H), 0.98(d, J=6.6Hz, 3H), 0.96(t, J=6.9Hz, 3H).
실시예 2(23)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-히드록시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.48(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.46(d, J=8.7Hz, 2H), 6.97(d, J=8.7Hz, 2H), 6.88(d, J=9.0Hz, 2H), 6.80(d, J=9.0Hz, 2H), 4.30(s, 2H), 4.13(d, J=2.0Hz, 1H), 3.98(m, 1H), 3.72(m, 1H), 3.53-3.42(m, 3H), 3.23-3.11(m, 2H), 2.50-1.97(m, 6H), 1.70(m, 1H), 1.39-1.30(m, 3H), 0.98(d, J=6.5Hz, 3H), 0.96(d, J=6.5Hz, 3H), 0.95(t, J=7.0Hz, 3H).
실시예 2(24)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(6-(4-메톡시페닐옥시)피리딘-3-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.42(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.41(m, 1H), 8.18(m, 1H), 7.13-6.99(m, 5H), 4.40(s, 2H), 4.13(d, J=2.0Hz, 1H), 4.00(m, 1H), 3.82(s, 3H), 3.75(m, 1H), 3.53-3.45(m, 3H), 3.24(m, 1H), 3.19(dd, J=9.5, 2.0Hz, 1H), 2. 59-2.39(m, 3H), 2.15-1.95(m, 2H), 1.70(m, 1H), 1.40-1.31(m, 3H), 0.98(d, J=6.5Hz, 3H), 0.97(d, J=6.5Hz, 3H), 0.94(t, J=7.5Hz, 3H).
실시예 2(25)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(메틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.29(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 8.00(d, J=9.0Hz, 2H), 7.73(d, J=9.0Hz, 2H), 4.32(s, 2H), 4.16(d, J=2.0Hz, 1H), 4.05(m, 1H), 3.79(m, 1H), 3.64-3.50(m, 3H), 3.29-3.19(m, 2H), 2.59-2.35(m, 3H), 2.58(s, 3H), 2.47(s, 3H), 2.40(s, 3H), 2.15(m, 1H), 2.02(m, 1H), 1.72(m, 1H), 1.41-1.35(m, 3H), 0.99(d, J=6.5Hz, 3H), 0.98(d, J=6.5Hz, 3H), 0.96(t, J=7.5Hz, 3H).
실시예 2(26)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(N-메틸-N-(2-히드록시에틸)아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.21(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 7.98(d, J=8.5Hz, 2H), 7.75(d, J=8.5Hz, 2H), 4.31(s, 2H), 4.15(d, J=2.0Hz, 1H), 4.04(m, 1H), 3.79(m, 1H), 3.69(t, J=6.0Hz, 2H), 3.61-3.51(m, 3H), 3.23-3.17(m, 4H), 2.87(s, 3H), 2.58-2.44(m, 3H), 2.48(s, 3H), 2.40(s, 3H), 2.15(m, 1H), 2.02(m, 1H), 1.71(m, 1H), 1.41-1.35(m, 3H), 0.99(d, J=6.5Hz, 3H), 0.98(d, J=6.5Hz, 3H), 0.95(t, J=7.0Hz, 3H).
실시예 2(27)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-히드록시에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.20(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 8.03(d, J=8.7Hz, 2H), 7.72(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.15(d, J=2.0Hz, 1H), 4.04(m, 1H), 3.79(m, 1H), 3.63-3.51(m, 3H), 3.56(t, J=6.0Hz, 2H), 3.34-3.29(m, 1H), 3.20(dd, J=9.5, 2.0Hz, 1H), 3.01(t, J=6.0Hz, 2H), 2.59-2.43(m, 3H), 2.47(s, 3H), 2.40(s, 3H), 2.15(m, 1H), 2.02(m, 1H), 1.71(m, 1H), 1.41-1.35(m, 3H), 0.99(d, J=6.5Hz, 3H), 0.98(d, J=6.5Hz, 3H), 0.95(t, J=7.2Hz, 3H).
실시예 2(28)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.35(아세트산에틸:메탄올=2:1);
NMR(CD3OD): δ 7.62(d, J=9.0Hz, 2H), 7.58(d, J=9.0Hz, 2H), 4.32(s, 2H), 4.16(d, J=2.0Hz, 1H), 4.05(m, 1H), 3.79(m, 1H), 3.61-3.49(m, 3H), 3.34-3.29(m, 1H), 3.20(dd, J=9.5, 2.0Hz, 1H), 3.13(s, 3H), 3.04(s, 3H), 2.55-2.34(m, 3H), 2.42(s, 3H), 2.39(s, 3H), 2.18(m, 1H), 2.02(m, 1H), 1.73(m, 1H), 1.41-1.34(m, 3H), 0.99(d, J=6.5Hz, 3H), 0.98(d, J=6.5Hz, 3H), 0.96(t, J=7.0Hz, 3H).
실시예 2(29)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-(모르폴린-4-일)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.33(아세트산에틸:메탄올=2:1);
NMR(CD3OD): δ 8.06(d, J=8.7Hz, 2H), 7.77(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.15(d, J=2.0Hz, 1H), 4.10-4.01(m, 3H), 3.88-3.76(m, 3H), 3.61-3.53(m, 5H), 3.37-3.19(m, 8H), 2.59-2.37(m, 3H), 2.48(s, 3H), 2.40(s, 3H), 2.15(m, 1H), 2.02(m, 1H), 1.71(m, 1H), 1.40-1.35(m, 3H), 0.99(d, J=6.5Hz, 3H), 0.98(d, J=6.5Hz, 3H), 0.95(t, J=7.0Hz, 3H).
실시예 2(30)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(피롤리딘-1-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.41(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.72(d, J=8.7Hz, 2H), 7.59(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.05(m, 1H), 3.79(m, 1H), 3.66-3.46(m, 7H), 3.25(m, 1H), 3.21(dd, J=9.6, 2.1Hz, 1H), 2.65-2.35(m, 3H), 2.43(s, 3H), 2.40(s, 3H), 2.16(m, 1H), 2.09-1.87(m, 5H), 1.70(m, 1H), 1.53-1.30(m, 3H), 1.00(d, J=6.6Hz, 3H), 0.98(d, J=6.6Hz, 3H), 0.95(t, J=7.2Hz, 3H).
실시예 2(31)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메틸술피닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.39(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.74(d, J=8.7Hz, 2H), 7.60(d, J=8.7Hz, 2H), 7.22(d, J=8.7Hz, 2H), 7.17(d, J=8.7Hz, 2H), 4.37(s, 2H), 4.14(d, J=2.4Hz, 1H), 4.02(m, 1H), 3.76(m, 1H), 3.58-3.42(m, 3H), 3.25-3.14(m, 2H), 2.80(s, 3H), 2.55-2.38(m, 2H), 2.29(m, 1H), 2.15(m, 1H), 2.01(m, 1H), 1.70(m, 1H), 1.50-1.27(m, 3H), 1.04-0.90(m, 9H).
실시예 2(32)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.31(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.96(d, J=8.7Hz, 2H), 7.77(d, J=8.7Hz, 2H), 4.32(s, 2H), 4.15(d, J=2.4Hz, 1H), 4.06(m, 1H), 3.79(m, 1H), 3.64-3.46(m, 3H), 3.29-3.14(m, 2H), 2.73(s, 6H), 2.59-2.44(m, 2H), 2.47(s, 3H), 2.39(s, 3H), 2.35(m, 1H), 2.17(m, 1H), 2.02(m, 1H), 1.71(m, 1H), 1.51-1.26(m, 3H), 1.05-0.89(m,9H).
실시예 2(33)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(모르폴린-4-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.25(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.95(d, J=8.7Hz, 2H), 7.78(d, J=8.7Hz, 2H), 4.32(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.06(m, 1H), 3.80(m, 1H), 3.74-3.68(m, 4H), 3.64-3.48(m, 3H), 3.28-3.14(m, 2H), 3.05-2.98(m, 4H), 2.59-2.44(m, 2H), 2.47(s, 3H), 2.39(s, 3H), 2.35(m, 1H), 2.17(m, 1H), 2.02(m, 1H), 1.71(m, 1H), 1.52-1.30(m, 3H), 1.05-0.90(m, 9H).
실시예 2(34)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.22(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.92(d, J=8.7Hz, 2H), 7.62(d, J=8.7Hz, 2H), 7.16(d, J=8.7Hz, 2H), 7.09(d, J=8.7Hz, 2H), 4.37(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.00(m, 1H), 3.78(m, 1H), 3.60-3.38(m, 3H), 3.28-3.10(m, 2H), 2.60-2.26(m, 3H), 2.20-1.88(m, 2H), 1.68(m, 1H), 1.54-1.22(m, 3H), 1.00(d, J=6.6Hz, 3H), 0.98(d, J=6.6Hz, 3H), 0.96(t, J=7.5Hz, 3H).
실시예 2(35)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.24(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.85(d, J=8.7Hz, 2H), 7.62(d, J=8.7Hz, 2H), 7.15(d, J=8.7Hz, 2H), 7.08(d, J=8.7Hz, 2H), 4.37(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.00(m, 1H), 3.76(m, 1H), 3.56-3.42(m, 3H), 3.26-3.18(m, 2H), 2.92(s, 3H), 2.60-2.28(m, 3H), 2.18-1.94(m, 2H), 1.70(m, 1H), 1.50-1.30(m, 3H), 1.00(d, J=6.6Hz, 3H), 0.98(d, J=6.6Hz, 3H), 0.96(t, J=7.5Hz, 3H).
실시예 2(36)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-메틸페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.46(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.41(s, 4H), 4.34(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.04(m, 1H), 3.79(m, 1H), 3.65-3.50(m, 3H), 3.34(m, 1H), 3.21(dd, J=9.6, 2.1Hz, 1H), 2.66(m, 1H), 2.55-2.42(m, 2H), 2.47(s, 3H), 2.45(s, 3H), 2.40(s, 3H), 2.14(m, 1H), 2.01(m, 1H), 1.69(m, 1H), 1.52-1.30(m, 3H), 1.00(d, J=6.6Hz, 3H), 0.98(d, J=6.6Hz, 3H), 0.95(t, J=7.2Hz, 3H).
실시예 2(37)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(N,N-디에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.35(클로로포름:메탄올=9:1);
NMR(CD3OD): δ 7.99(d, J=8.7Hz, 2H), 7.72(d, J=8.7Hz, 2H), 4.32(s, 2H), 4.16(d, J=2.1Hz, 1H), 4.06(m, 1H), 3.80(m, 1H), 3.63-3.48(m, 3H), 3.32-3.17(m, 2H), 3.29(q, J=7.2Hz, 4H), 2.54-2.13(m, 4H), 2.45(s, 3H), 2.39(s, 3H), 2.02(m, 1H), 1.72(m, 1H), 1.52-1.33(m, 3H), 1.15(t, J=7.2Hz, 6H), 1.00(d, J=6.6Hz, 3H), 0.98(d, J=6.6Hz, 3H), 0.96(t, J=6.9Hz, 3H).
실시예 2(38)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(4-메틸피페라진-1-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.22(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.01(d, J=8.7Hz, 2H), 7.82(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.15(d, J=1.8Hz, 1H), 4.11-3.94(m, 3H), 3.80(m, 1H), 3.65-3.48(m, 5H), 3.34-3.18(m, 4H), 2.91(s, 3H), 2.86-2.70(m, 2H), 2.68-2.36(m, 3H), 2.49(s, 3H), 2.40(s, 3H), 2.15(m, 1H), 2.02(m, 1H), 1.70(m, 1H), 1.50-1.27(m, 3H), 1.05-0.90(m, 9H).
실시예 2(39)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(5-클로로-3-메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.53(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.63-7.48(m, 5H), 4.33(s, 2H), 4.14(d, J=1.8Hz, 1H), 4.10(m, 1H), 3.83(m, 1H), 3.66-3.45(m, 3H), 3.29-3.16(m, 2H), 2.62-2.32(m, 3H), 2.44(s, 3H), 2.17(m, 1H), 2.01(m, 1H), 1.71(m, 1H), 1.52-1.11(m, 3H), 1.05-0.88(m, 9H).
실시예 2(40)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(모르폴린-4-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.39(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.66-7.57(m, 4H), 4.31(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.05(m, 1H), 3.88-3.39(m, 12H), 3.25(m, 1H), 3.20(dd, J=9.6, 2.1Hz, 1H), 2.65-2.27(m, 3H), 2.43(s, 3H), 2.40(s, 3H), 2.17(m, 1H), 2.02(m, 1H), 1.71(m, 1H), 1.54-1.27(m, 3H), 1.00(d, J=6.6Hz, 3H), 0.98(d, J=6.6Hz, 3H), 0.96(t, J=7.2Hz, 3H).
실시예 2(41)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-히드록시에틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.42(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 8.03(d, J=8.7Hz, 2H), 7.61(d, J=8.7Hz, 2H), 4.32(s, 2H), 4.16(d, J=1.8Hz, 1H), 4.04(m, 1H), 3.80(m, 1H), 3.74(t, J=5.7Hz, 2H), 3.64-3.48(m, 3H), 3.54(t, J=5.7Hz, 2H), 3.30-3.16(m, 2H), 2.64-2.34(m, 3H), 2.45(s, 3H), 2.41(s, 3H), 2.22-1.92(m, 2H), 1.72(m, 1H), 1.52-1.26(m, 3H), 1.01(d, J=6.6Hz, 3H), 0.99(d, J=6.6Hz, 3H), 0.96(t, J=7.2Hz, 3H).
실시예 2(42)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-(2-(N,N-디메틸아미노)에틸아미노카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.19(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 7.93(d, J=9.0Hz, 2H), 7.61(d, J=8.4Hz, 2H), 7.18-7.08(m, 4H), 4.36(s, 2H), 4.14(d, J=1.8Hz, 1H), 4.00(m, 1H), 3.80-3.70(m, 3H), 3.54-3.42(m, 3H), 3.38(t, J=6.3Hz, 2H), 3.26-3.18(m, 2H), 2.98(s, 6H), 2.60-2.30(m, 3H), 2.18-1.96(m, 2H), 1.68(m, 1H), 1.50-1.30(m, 3H), 1.00-0.90(m, 9H).
실시예 2(43)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(피리딘-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.31(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.74(m, 1H), 8.62(d, J=5.4Hz, 1H), 8.24(m, 1H), 8.14(m, 1H), 7.76(d, J=8.4Hz, 2H), 7.34(d, J=8.4Hz, 2H), 4.40(s, 2H), 4.14(d, J=2.1Hz, 1H), 4.00(m, 1H), 3.76(m, 1H), 3.60-3.44(m, 3H), 3.30-3.16(m, 2H), 2.60(m, 1H), 2.50-2.40(m, 2H), 2.26-1.86(m, 2H), 1.66(m, 1H), 1.50-1.30(m, 3H), 1.02-0.88(m, 9H).
실시예 2(44)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.42(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 8.04(d, J=8.7Hz, 2H), 7.59(d, J=8.4Hz, 2H), 7.18(d, J=8.4Hz, 2H), 7.07(d, J=8.7Hz, 2H), 4.37(s, 2H), 4.15(d, J=2.4Hz, 1H), 4.02(m, 1H), 3.76(m, 1H), 3.60-3.44(m, 3H), 3.24-3.08(m, 2H), 2.56-1.92(m, 5H), 1.70(m, 1H), 1.50-1.26(m, 3H), 1.08-0.90(m, 9H).
실시예 2(45)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메틸페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.36(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.49(d, J=9.0Hz, 2H), 7.20(d, J=9.0Hz, 2H), 7.02(d, J=9.0Hz, 2H), 6.92(d, J=9.0Hz, 2H), 4.32(s, 2H), 4.14(d, J=2.1Hz, 1H), 3.98(m, 1H), 3.72(m, 1H), 3.58-3.36(m, 3H), 3.26-3.08(m, 2H), 2.52-1.82(m, 5H), 2.33(s, 3H), 1.68(m, 1H), 1.50-1.28(m, 3H), 1.02-0.86(m, 9H).
실시예 2(46)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(2,4-디플루오로페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.63(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 7.56(m, 1H), 7.33-7.16(m, 2H), 4.32(s, 2H), 4.16(d, J=2.1Hz, 1H), 4.06(m, 1H), 3.80(m, 1H), 3.62-3.44(m, 3H), 3.28-3.16(m, 2H), 2.62-1.84(m, 5H), 2.39(s, 3H), 2.28(s, 3H), 1.72(m, 1H), 1.54-1.28(m, 3H), 1.01(d, J=6.6Hz, 3H), 0.99(d, J=6.6Hz, 3H), 0.97(t, J=7.2Hz, 3H).
실시예 2(47)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(피리딘-2-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.28(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.52(m, 1H), 8.01(m, 1H), 7.81(m, 1H), 7.41(m, 1H), 4.33(s, 2H), 4.16(d, J=1.8Hz, 1H), 4.06(m, 1H), 3.80(m, 1H), 3.64-3.46(m, 3H), 3.26-3.12(m, 2H), 2.68(s, 3H), 2.58-2.24(m, 3H), 2.41(s, 3H), 2.18(m, 1H), 2.04(m, 1H), 1.70(m, 1H), 1.54-1.26(m, 3H), 1.00(d, J=6.6Hz, 3H), 0.99(d, J=6.6Hz, 3H), 0.96(t, J=7.5Hz, 3H).
실시예 2(48)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-메틸아미노카르보닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.18(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.99(d, J=8.7Hz, 2H), 7.61(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.04(m, 1H), 3.79(m, 1H), 3.64-3.49(m, 3H), 3.30-3.17(m, 2H), 2.94(s, 3H), 2.59(m, 1H), 2.51-2.36(m, 2H), 2.44(s, 3H), 2.41(s, 3H), 2.15(m, 1H), 2.02(m, 1H), 1.70(m, 1H), 1.52-1.27(m, 3H), 1.05-0.91(m, 9H).
실시예 2(49)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-시클로헥실옥시페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.44(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.44(d, J=8.7Hz, 2H), 7.01(d, J=8.7Hz, 2H), 4.38(m, 1H), 4.27(s, 2H), 4.14(d, J=2.1Hz, 1H), 3.96(m, 1H), 3.70(m, 1H), 3.58-3.36(m, 3H), 3.26-3.08(m, 2H), 2.54-1.26(m, 19H), 0.99(d, J=6.6Hz, 3H), 0.98(d, J=6.6Hz, 3H), 0.96(t, J=7.5Hz, 3H).
실시예 2(50)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(3,4,5,6-테트라히드로피란-4-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.33(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.47(d, J=8.7Hz, 2H), 7.07(d, J=8.7Hz, 2H), 4.64(m, 1H), 4.29(s, 2H), 4.14(d, J=2.4Hz, 1H), 4.04-3.86(m, 3H), 3.80-3.36(m, 6H), 3.26-3.08(m, 2H), 2.52-1.90(m, 7H), 1.80-1.58(m, 3H), 1.50-1.26(m, 3H), 0.99(d, J=6.6Hz, 3H), 0.98(d, J=6.6Hz, 3H), 0.96(t, J=7.5Hz, 3H).
실시예 2(51)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메톡시페닐메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.37(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.96(d, J=8.4Hz, 2H), 7.67(d, J=8.4Hz, 2H), 7.28(d, J=8.4Hz, 2H), 6.88(d, J=8.4Hz, 2H), 4.52(s, 2H), 4.43(s, 2H), 4.14(d, J=2.1Hz, 1H), 4.04(m, 1H), 3.77(s, 3H), 3.77(m, 1H), 3.58-3.40(m, 3H), 3.26-3.10(m, 2H), 2.54-2.22(m, 3H), 2.20-1.90(m, 2H), 1.66(m, 1H), 1.50-1.26(m, 3H), 0.99(d, J=6.6Hz, 3H), 0.98(d, J=6.6Hz, 3H), 0.95(t, J=7.5Hz, 3H).
실시예 2(52)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(시클로헥실아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.44(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 7.91(d, J=8.3Hz, 2H), 7.66(d, J=8.3Hz, 2H), 4.42(s, 2H), 4.13(d, J=2.0Hz, 1H), 4.03(m 1H), 3.90-3.72(m, 2H), 3.56-3.43(m, 3H), 3.25(m, 1H), 3.18(dd, J=9.6, 2.0Hz, 1H), 2.53-2.40(m, 2H), 2.30(m, 1H), 2.14(m, 1H), 2.06-1.67(m, 8H), 1.50-1.33(m, 7H), 0.98(d, J=6.6Hz, 3H), 0.96(d, J=6.6Hz, 3H), 0.94(t, J=7.5Hz, 3H).
실시예 2(53)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-(피롤리딘-1-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.34(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 7.61-7.57(m, 4H), 7.14(d, J=8.7Hz, 2H), 7.09(d, J=8.7Hz, 2H), 4.36(s, 2H), 4.14(d, J=2.0Hz, 1H), 4.00(m, 1H), 3.74(m, 1H), 3.62-3.45(m, 7H), 3.24(m, 1H), 3.19(dd, J=9.6, 2.0Hz, 1H), 2.56-2.29(m, 3H), 2.15-1.89(m, 6H), 1.70(m, 1H), 1.40-1.33(m, 3H), 0.98(d, J=6.6Hz, 3H), 0.97(d, J=6.6Hz, 3H), 0.95(t, J=7.2Hz, 3H).
실시예 2(54)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-플루오로페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.37(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 7.56-7.51(m, 2H), 7.35-7.28(m, 2H), 4.31(s, 2H), 4.15(d, J=2.0Hz, 1H), 4.03(m, 1H), 3.78(m, 1H), 3.61-3.49(m, 3H), 3.34(m, 1H), 3.20(dd, J=9.6, 2.0Hz, 1H), 2.68-2.42(m, 6H), 2.38(s, 3H), 2.17(m, 1H), 2.02(m, 1H), 1.70(m, 1H), 1.50-1.35(m, 3H), 0.99(d, J=6.6Hz, 3H), 0.98(d, J=6.6Hz, 3H), 0.95(t, J-7.2Hz, 3H).
실시예 2(55)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-페닐에틸)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.13(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.32-7.20(m, 3H), 7.11-7.08(m, 2H), 4.45(t, J=6.6Hz, 2H), 4.20(s, 2H), 4.16(d, J=1.8Hz, 1H), 3.90(m, 1H), 3.70-3.48(m, 3H), 3.42-3.30(m, 2H), 3.21(m, 1H), 3.14(t, J=6.6Hz, 2H), 2.76-2.38(m, 3H), 2.50(s, 3H), 2.20-1.88(m, 2H), 1.97(s, 3H), 1.74(m, 1H), 1.56-1.34(m, 3H), 1.01(d,J=6.6Hz, 3H), 1.00(d, J=6.6Hz, 3H), 0.97(t, J=6.9Hz, 3H).
실시예 2(56)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(1-벤질옥시카르보닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.13(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.44-7.24(m, 5H), 5.16(s, 2H), 4.54(m, 1H), 4.40-4.20(m, 2H), 4.25(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.00(m, 1H), 3.82-3.42(m, 5H), 3.30-2.88(m, 3H), 2.64-2.30(m, 3H), 2.47(s, 3H), 2.37(s, 3H), 2.20-1.84(m, 6H), 1.70(m, 1H), 1.52-1.26(m, 3H), 1.00(d, J=6.6Hz, 3H), 0.98(d, J=6.6Hz, 3H), 0.95(t, J=7.5Hz, 3H).
실시예 2(57)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-(2-히드록시에틸아미노카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.47(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 7.89(d, J=9.0Hz, 2H), 7.61(d, J=9.0Hz, 2H), 7.16(d, J=9.0Hz, 2H), 7.09(d, J=9.0Hz, 2H), 4.37(s, 2H), 4.16(d, J=2.1Hz, 1H), 4.00(m, 1H), 3.78(m, 1H), 3.71(t, J=5.7Hz, 2H), 3.60-3.40(m, 3H), 3.51(t, J=5.7Hz, 2H), 3.30-3.12(m, 2H), 2.60-2.24(m, 3H), 2.22-1.92(m, 2H), 1.70(m, 1H), 1.56-1.24(m, 3H), 1.00(d, J=6.6Hz, 3H), 0.98(d, J=6.6Hz, 3H), 0.96(t, J=7.5Hz, 3H).
실시예 2(58)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(1-메틸술포닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.41(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 4.44(m, 1H), 4.25(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.06-3.64(m, 4H), 3.60-3.44(m, 3H), 3.28-3.16(m, 2H), 3.06-2.92(m, 2H), 2.90(s, 3H), 2.64-1.90(m, 9H), 2.47(s, 3H), 2.37(s, 3H), 1.68(m, 1H), 1.50-1.24(m, 3H), 1.00(d, J=6.6Hz, 3H), 0.99(d, J=6.6Hz, 3H), 0.95(t, J=7.5Hz, 3H).
실시예 2(59)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-히드록시메틸페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸
TLC: Rf 0.32(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.36(d, J=8.4Hz, 2H), 7.35(d, J=8.4Hz, 2H), 6.97(d, J=8.4Hz, 4H), 4.58(s, 2H), 4.12(d, J=2.4Hz, 1H), 3.73(s, 2H), 3.47(m, 1H), 3.30-2.90(m, 6H), 2.31-1.83(m, 5H), 1.64(m, 1H), 1.55-1.23(m, 3H), 0.97(d, J=6.6Hz, 6H), 0.95(t, J=7.5Hz, 3H).
실시예 3
(3S)-1-부틸-2,5-디옥소-3-((1S)-1-히드록시-2-메틸프로필)-9-(6-페닐옥시피리딘-3-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
참고예 3에서 제조한 화합물 대신에 참고예 3(8)에서 제조한 화합물을 이용하고, 실시예 2와 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물(110 ㎎)을 얻었다.
TLC: Rf 0.48(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.35(d, J=2.1Hz, 1H), 8.12(dd, J=8.7, 2.1Hz, 1H), 7.49-7.40(m, 2H), 7.27(t, J=7.8Hz, 1H), 7.15(d, J=7.8Hz, 2H), 7.06(d, J=8.7, 1H), 4.39(s, 2H), 4.14(d, J=2.1Hz, 1H), 4.07-3.93(m, 1H), 3.82-3.67(m, 1H), 3.58-3.40(m, 3H), 3.30-3.15(m, 1H), 3.19(dd, J=9.6, 2.1Hz, 1H), 2.60-2.28(m, 3H),2.18-2.05(m, 1H), 2.05-1.90(m, 1H), 1.80-1.55(m, 1H), 1.50-1.25(m, 3H), 0.99(d, J=6.6Hz, 3H), 0.97(d, J=6.6Hz, 3H), 0.95(t, J=7.2Hz, 3H);
비선광도: [α]D-10.1(c 1.04, 메탄올, 25℃);
HPLC 조건
사용한 컬럼: CHIRALCEL OJ-R, 0.46×15 ㎝, DAICEL, OJR0CD-JB026;
사용한 유속: 0.7 mL/min;
사용한 용매 A액: 0.1M 인산이수소칼륨 수용액, B액: 아세토니트릴(A:B=76:24);
사용한 UV: 225 nm;
유지 시간: 8.65 min.
실시예 4
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
참고예 3에서 제조한 화합물 대신에 참고예 3(1)에서 제조한 화합물을, 3-포르밀-6-페닐옥시피리딘 대신에 [4-(4-포르밀-3,5-디메틸피라졸릴)페닐]-N,N-디메틸카르복사미드를 이용하고, 실시예 2와 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.62(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 7.65-7.52(m, 4H), 4.33(s, 2H), 4.03(dd, J=7.8, 4.5Hz, 1H), 3.96-3.72(m, 2H), 3.64-3.54(m, 2H), 3.50-3.36(m, 2H), 3.14(s, 3H), 3.05(s, 3H), 2.60-2.42(m, 2H), 2.44(s, 3H), 2.41(s, 3H), 2.36-2.10(m, 2H), 1.90-1.24(m, 7H), 0.97(t, J=7.2Hz, 3H), 0.96(d, J=6.6Hz, 3H), 0.95(d, J=6.6Hz, 3H).
실시예 4(1)∼4(43)
[4-(4-포르밀-3,5-디메틸피라졸릴)페닐]-N,N-디메틸카르복사미드 대신에 해당하는 알데히드 유도체를 이용하고, 실시예 4와 동일한 조작을 하여, 이하에 나타낸 본 발명 화합물을 얻었다.
실시예 4(1)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(피롤리딘-1-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.56(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 7.73(d, J=8.7Hz, 2H), 7.60(d, J=8.7Hz, 2H), 4.33(s, 2H), 4.03(dd, J=7.5, 4.5Hz, 1H), 3.96-3.74(m, 2H), 3.66-3.36(m, 8H), 2.58-2.40(m, 2H), 2.44(s, 3H), 2.41(s, 3H), 2.34-2.12(m, 2H), 2.06-1.26(m, 11H), 0.97(t, J=7.2Hz, 3H), 0.96(d, J=6.3Hz, 3H), 0.95(d, J=6.3Hz, 3H).
실시예 4(2)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(모르폴린-4-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.57(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 7.64(d, J=9.0Hz, 2H), 7.60(d, J=9.0Hz, 2H), 4.33(s, 2H), 4.03(dd, J=7.5, 4.5Hz, 1H), 3.98-3.36(m, 14H), 2.58-2.36(m, 2H), 2.44(s, 3H), 2.40(s, 3H), 2.32-2.14(m, 2H), 1.90-1.24(m, 7H), 0.97(t, J=7.2Hz, 3H), 0.96(d, J=6.3Hz, 3H), 0.95(d, J=6.3Hz, 3H).
실시예 4(3)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-메틸술포닐페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.49(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.09(d, J=8.4Hz, 2H), 7.85(d, J=8.4Hz, 2H), 4.48(s, 2H), 4.02(dd, J=7.8, 4.5Hz, 1H), 3.92-3.70(m, 2H), 3.56-3.36(m, 4H), 3.16(s, 3H), 2.48-2.30(m, 2H), 2.28-2.06(m, 2H), 1.90-1.24(m, 7H), 0.96(t, J=7.2Hz, 3H), 0.95(d, J=6.3Hz, 3H), 0.94(d, J=6.3Hz, 3H).
실시예 4(4)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-메틸술포닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.45(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.96(d, J=8.7Hz, 2H), 7.66(d, J=8.7Hz, 2H), 7.23(d, J=8.7Hz, 2H), 7.21(d, J=8.7Hz, 2H), 4.40(s, 2H), 4.02(dd, J=7.5, 4.5Hz, 1H), 3.94-3.72(m, 2H), 3.58-3.36(m, 4H), 3.12(s, 3H), 2.54-2.36(m, 2H), 2.18-2.08(m, 2H), 1.88-1.26(m, 7H), 0.96(t, J=6.9Hz, 3H), 0.95(d, J=6.3Hz, 3H), 0.94(d, J=6.3Hz, 3H).
실시예 4(5)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-(모르폴린-4-일)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.60(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 8.07(d, J=8.4Hz, 2H), 7.78(d, J=8.4Hz, 2H), 4.32(s, 2H), 4.16-3.98(m, 3H), 3.94-3.76(m, 4H), 3.64-3.40(m, 6H), 3.38-3.18(m, 6H), 2.62-2.44(m, 2H), 2.49(s, 3H), 2.41(s, 3H), 2.36-2.12(m, 2H), 1.90-1.24(m, 7H), 0.97(t, J=6.6Hz, 3H), 0.96(d, J=6.3Hz, 3H), 0.95(d, J=6.3Hz, 3H).
실시예 4(6)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(4-메틸피페라진-1-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.50(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 8.02(d, J=9.0Hz, 2H), 7.83(d, J=9.0Hz, 2H), 4.32(s, 2H), 4.03(dd, J=7.8, 4.5Hz, 1H), 4.03-3.76(m, 4H), 3.68-3.56(m, 4H), 3.54-3.42(m, 2H), 3.30-3.20(m, 2H), 2.92(s, 3H), 2.86-2.72(m, 2H), 2.64-2.48(m, 2H), 2.51(s, 3H), 2.42(s, 3H), 2.32-2.12(m, 2H), 1.90-1.26(m, 7H), 0.97(t, J=6.6Hz, 3H), 0.96(d, J=6.3Hz, 3H), 0.95(d, J=6.3Hz, 3H).
실시예 4(7)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-메틸술피닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.28(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.75(d, J=9.0Hz, 2H), 7.62(d, J=9.0Hz, 2H), 7.23(d, J=9.0Hz, 2H), 7.18(d, J=9.0Hz, 2H), 4.38(s, 2H), 4.02(dd, J=7.5, 4.5Hz, 1H), 3.92-3.72(m, 2H), 3.58-3.36(m, 4H), 2.81(s, 3H), 2.52-2.36(m, 2H), 2.30-2.10(m, 2H), 1.90-1.26(m, 7H), 0.96(t, J=7.2Hz, 3H), 0.95(d, J=6.3Hz, 3H), 0.94(d, J=6.3Hz, 3H).
실시예 4(8)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(피리딘-1-옥사이드-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.48(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 8.66(s, 1H), 8.53-8.52(m, 1H), 7.88-7.78(m, 2H), 7.77(d, J=8.7Hz, 2H), 7.34(d, J=8.7Hz, 2H), 4.41(s, 2H), 4.03(dd, J=7.5, 4.5Hz, 1H), 3.92-3.70(m, 2H), 3.66-3.40(m, 4H), 2.66-2.48(m, 2H), 2.26-2.08(m, 2H), 1.90-1.26(m,H), 0.96(t, J=7.5Hz, 3H), 0.95(d, J=6.6Hz, 3H), 0.94(d, J=6.6Hz, 3H).
실시예 4(9)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-히드록시에틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.53(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 8.03(d, J=8.4Hz, 2H), 7.62(d, J=8.4Hz, 2H), 4.33(s, 2H), 4.03(dd, J=7.8, 4.5Hz, 1H), 3.98-3.76(m, 2H), 3.74(t, J=5.7Hz, 2H), 3.68-3.58(m, 2H), 3.54(t, J=5.7Hz, 2H), 3.54-3.40(m, 2H), 2.64-2.48(m, 2H), 2.46(s, 3H), 2.43(s, 3H), 2.32-2.10(m, 2H), 1.90-1.30(m, 7H), 0.97(t, J=6.6Hz, 3H), 0.96(d, J=6.3Hz, 3H), 0.95(d, J=6.3Hz, 3H).
실시예 4(10)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-(모르폴린-4-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.55(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 7.61(d, J=8.7Hz, 2H), 7.49(d, J=8.7Hz, 2H), 7.15(d, J=8.7Hz, 2H), 7.11(d, J=8.7Hz, 2H), 4.37(s, 2H), 4.02(dd, J=7.8, 4.8Hz, 1H), 3.90-3.36(m, 14H), 2.58-2.38(m, 2H), 2.28-2.08(m, 2H), 1.88-1.28(m, 7H), 0.96(t, J=7.2Hz, 3H), 0.95(d, J=6.3Hz, 3H), 0.94(d, J=6.3Hz, 3H).
실시예 4(11)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(N,N-디에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.66(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 8.00(d, J=8.4Hz, 2H), 7.73(d, J=8.4Hz, 2H), 4.34(s, 2H), 4.04(dd, J=7.8, 4.5Hz, 1H), 3.96-3.76(m, 2H), 3.68-3.56(m, 2H), 3.48-3.38(m, 2H), 3.36-3.22(m, 4H), 2.52-2.38(m, 2H), 2.46(s, 3H), 2.40(s, 3H), 2.36-2.14(m, 2H), 1.90-1.28(m, 7H), 1.20-1.08(m, 6H), 0.97(t, J=7.5Hz, 3H),0.96(d, J=6.3Hz, 3H), 0.95(d, J=6.3Hz, 3H).
실시예 4(12)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-(2-히드록시에틸아미노카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.36(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.88(d, J=8.7Hz, 2H), 7.60(d, J=8.4Hz, 2H), 7.15(d, J=8.4Hz, 2H), 7.07(d, J=8.7Hz, 2H), 4.36(s, 2H), 4.01(dd, J=7.8, 4.5Hz, 1H), 3.90-3.76(m, 2H), 3.70(t, J=6.0Hz, 2H), 3.56-3.36(m, 4H), 3.50(t, J=6.0Hz, 2H), 2.52-2.38(m, 2H), 2.24-2.08(m, 2H), 1.88-1.16(m, 7H), 1.02-0.88(m, 9H).
실시예 4(13)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-(피롤리딘-1-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.22(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.59(d, J=8.4Hz, 2H), 7.58(d, J=8.4Hz, 2H), 7.16(d, J=8.4Hz, 2H), 7.09(d, J=8.4Hz, 2H), 4.38(s, 2H), 4.02(dd, J=7.5, 4.5Hz, 1H), 3.92-3.72(m, 2H), 3.64-3.36(m, 8H), 2.48-2.10(m, 4H), 2.04-1.26(m, 11H), 0.96(t, J=6.9Hz, 3H), 0.95(d, J=6.3Hz, 3H), 0.94(d, J=6.3Hz, 3H).
실시예 4(14)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(시클로헥실아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.42(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.02(d, J=8.4Hz, 2H), 7.70(d, J=8.4Hz, 2H), 4.31(s, 2H), 4.05(dd, J=7.8, 4.8Hz, 1H), 3.92-3.72(m, 2H), 3.68-3.58(m, 2H), 3.56-3.44(m, 2H), 3.06(m, 1H), 2.68-2.50(m, 2H), 2.47(s, 3H), 2.41(s, 3H), 2.38-2.08(m, 2H), 1.82-1.06(m, 25H), 1.02-0.86(m, 5H).
실시예 4(15)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(3-메톡시프로필아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.42(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.01(d, J=8.7Hz, 2H), 7.73(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.02(dd, J=7.8, 4.8Hz, 1H), 3.94-3.72(m, 2H), 3.68-3.58(m, 2H), 3.56-3.46(m, 2H), 3.39(t, J=6.0Hz, 2H), 3.26(s, 3H), 2.98(t, J=6.9Hz, 2H), 2.72-2.58(m, 2H), 2.48(s, 3H), 2.42(s, 3H), 2.26-2.10(m, 2H), 1.90-1.28(m, 9H), 0.98-0.90(m, 9H).
실시예 4(16)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-메틸술피닐페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.13(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.88(d, J=8.7Hz, 2H), 7.81(d, J=8.7Hz, 2H), 4.47(s, 2H), 4.02(dd, J=7.8, 4.8Hz, 1H), 3.96-3.74(m, 2H), 3.56-3.36(m, 4H), 2.83(s, 3H), 2.52-2.34(m, 2H), 2.28-2.08(m, 2H), 1.90-1.26(m, 7H), 0.95(t, J=7.2Hz, 3H), 0.95(d, J=6.3Hz, 3H), 0.94(d, J=6.3Hz, 3H).
실시예 4(17)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-프로필피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.58(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 4.26(s, 2H), 4.10(t, J=7.2Hz, 2H), 4.02(dd, J=7.5, 4.5Hz, 1H), 3.90-3.68(m, 2H), 3.58-3.36(m, 4H), 2.58-2.38(m, 2H), 2.44(s, 3H), 2.38(s, 3H), 2.30-2.10(m, 2H), 1.92-1.24(m, 9H), 0.96(t, J=7.2Hz, 6H), 0.96(d, J=6.6Hz, 3H), 0.95(d, J=6.6Hz, 3H).
실시예 4(18)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-에틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.58(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.34-4.24(m, 4H), 4.01(dd, J=7.8, 4.5Hz, 1H), 3.92-3.68(m, 2H), 3.62-3.46(m, 4H), 2.74-2.60(m, 2H), 2.53(s, 3H), 2.50(s, 3H), 2.24-2.06(m, 2H), 1.88-1.26(m, 10H), 1.02-0.86(m, 9H).
실시예 4(19)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-시클로펜틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.53(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 5.00-4.82(m, 1H), 4.31(s, 2H), 4.01(dd, J=7.5, 4.5Hz, 1H), 3.92-3.70(m, 2H), 3.62-3.46(m, 4H), 2.78-2.58(m, 2H), 2.55(s, 3H), 2.53(s, 3H), 2.32-2.04(m, 4H), 2.04-1.26(m, 13H), 0.98-0. 84(m, 9H).
실시예 4(20)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(1,1-디메틸에틸)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.15(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 4.23(s, 2H), 4.02(dd, J=7.5, 4.5Hz, 1H), 3.90-3.68(m, 2H), 3.58-3.36(m, 4H), 2.56(s, 3H), 2.56-2.38(m, 2H), 2.32(s, 3H), 2.32-2.10(m, 2H), 1.88-1.26(m, 7H), 1.67(s, 9H), 0.96(t, J=7.2Hz, 3H), 0.96(d, J=6.3Hz, 3H), 0.95(d, J=6.3Hz, 3H).
실시예 4(21)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(1-벤질옥시카르보닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.17(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.42-7.26(m, 5H), 5.15(s, 2H), 4.48-4.22(m, 3H), 4.23(s, 2H), 4.02(dd, J=7.8, 4.5Hz, 1H), 3.88-3.68(m, 2H), 3.58-3.36(m, 4H), 3.12-2.90(m, 2H), 2.50-1.28(m, 15H), 2.42(s, 3H), 2.30(s, 3H), 0.96(t, J=6.9Hz, 3H), 0.95(d, J=6.3Hz, 3H), 0.94(d, J=6.3Hz, 3H).
실시예 4(22)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-((4-메톡시페닐)메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.50(클로로포름:메탄올=9:1);
NMR(CD3OD): δ 7.95(d, J=8.7Hz, 2H), 7.67(d, J=8.7Hz, 2H), 7.27(d, J=8.7Hz, 2H), 6.87(d, J=8.7Hz, 2H), 4.51(s, 2H), 4.42(s, 2H), 4.00(dd, J=7.5, 4.8Hz, 1H), 3.91-3.72(m, 2H), 3.76(s, 3H), 3.53-3.35(m, 4H), 2.50-2.35(m, 2H), 2.26-2.08(m, 2H), 1.87-1.28(m, 7H), 0.94(t, J=7.5Hz, 3H), 0.94(d, J=6.6Hz, 3H), 0.93(d, J=6.6Hz, 3H).
실시예 4(23)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(3-메톡시프로필아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.48(클로로포름:메탄올=9:1);
NMR(CD3OD): δ 7.92(d, J=8.4Hz, 2H), 7.67(d, J=8.4Hz, 2H), 4.43(s, 2H), 4.00(dd, J=7.8, 4.5Hz, 1H), 3.92-3.75(m, 2H), 3.53-3.35(m, 8H), 3.34(s, 3H), 2.50-2.35(m, 2H), 2.27-2.10(m, 2H), 1.92-1.28(m, 9H), 0.94(t, J=7.2Hz, 3H), 0.94(d, J=6.6Hz, 3H), 0.93(d, J=6.6Hz, 3H).
실시예 4(24)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-메톡시카르보닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.29(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 8.19(d, J=9.0Hz, 2H), 7.63(d, J=9.0Hz, 2H), 4.28(s, 2H), 4.03(m, 1H), 3.94(s, 3H), 3.95-3.30(m, 6H), 2.50-2.15(m, 4H), 2.44(s, 3H), 2.39(s, 3H), 1.90-1.30(m, 7H), 0.96(t, J=7.2Hz, 3H), 0.95(d, J=6.6Hz, 3H) 0.94(d, J=6.6Hz, 3H).
실시예 4(25)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-메톡시페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.31(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.37(d, J=9.0Hz, 2H), 7.09(d, J=9.0Hz, 2H), 4.31(s, 2H), 4.02(m, 1H), 4.00-3.30(m, 6H), 3.86(s, 3H), 2.65-2.15(m, 4H), 2.39(s, 3H), 2.34(s, 3H), 1.90-1.30(m, 7H), 0.96(t, J=7.2Hz, 3H), 0.95(d, J=6.6Hz, 3H) 0.94(d, J=6.6Hz, 3H).
실시예 4(26)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(3-(모르폴린-4-일)프로필아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.18(아세트산에틸:메탄올=3:1);
NMR(CD3OD): δ 8.02(d, J=8.7Hz, 2H), 7.74(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.10-4.00(m, 3H), 4.00-3.00(m, 16H), 2.70-2.10(m, 4H), 2.48(s, 3H), 2.40(s, 3H), 2.10-1.90(m, 2H), 1.90-1.30(m, 7H), 0.96(t, J=7.2Hz, 3H), 0.95(d, J=6.6Hz, 3H), 0.94(d, J=6.6Hz, 3H).
실시예 4(27)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(피롤리딘-1-일카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.55(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.71-7.59(m, 4H), 4.41(s, 2H), 4.01(dd, J=7.8, 4.5Hz, 1H), 3.83-3.72(m, 2H), 3.60(t, J=6.9Hz, 2H), 3.55-3.32(m, 4H), 3.45(t, J=6.9Hz, 2H), 2.57-2.37(m, 2H), 2.27-2.08(m, 2H), 2.05-1.44(m, 9H), 1.44-1.27(m, 2H), 0.99-0.90(m, 9H).
실시예 4(28)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(피페리딘-1-일카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.60(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.69(d, J=8.4Hz, 2H), 7.50(d, J=8.4Hz, 2H), 4.41(s, 2H), 4.01(dd, J=7.5, 4.5Hz, 1H), 3.93-3.72(m, 4H), 3.55-3.30(m, 6H), 2.57-2.39(m, 2H), 2.26-2.07(m, 2H), 1.90-1.44(m, 11H), 1.44-1.26(m, 2H), 0.98-0.90(m, 9H).
실시예 4(29)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(모르폴린-4-일카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.59(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.69(d, J=8.1Hz, 2H), 7.55(d, J=8.1Hz, 2H), 4.41(s, 2H), 4.01(dd, J=7.8, 4.5Hz, 1H), 3.93-3.55(m, 8H), 3.55-3.34(m, 6H), 2.55-2.36(m,2H), 2.27-2.08(m, 2H), 1.88-1.44(m, 5H), 1.44-1.28(m, 2H), 0.98-0.90(m, 9H).
실시예 4(30)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(N-메틸-N-(2-(피리딘-2-일)에틸)아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.49(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.80(d, J=6.0Hz, 1H), 8.58(m, 1H), 8.10(d, J=8.4Hz, 1H), 7.98(m, 1H), 7.70(d, J=7.8Hz, 2H), 7.41(d, J=7.8Hz, 2H), 4.39(s, 2H), 4.05-3.95(m, 3H), 3.94-3.69(m, 2H), 3.60-3.37(m, 6H), 3.08(s, 3H), 2.70-2.43(m, 2H), 2.26-2.05(m, 2H), 1.90-1.44(m, 5H), 1.44-1.26(m, 2H), 0.99-0.90(m, 9H).
실시예 4(31)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(시클로헥실아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.33(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.92(d, J=8.1Hz, 2H), 7.69(d, J=8.1Hz, 2H), 4.43(s, 2H), 4.01(dd, J=7.5, 4.5Hz, 1H), 3.96-3.70(m, 2H), 3.58-3.36(m, 4H), 2.58-2.38(m, 2H), 2.28-2.06(m, 2H), 2.04-1.12(m, 18H), 0.95(t, J=6.9Hz, 3H), 0.94(d, J=6.3Hz, 3H), 0.93(d, J=6.3Hz, 3H).
실시예 4(32)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(N,N-디메틸아미노술포닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.44(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.91(d, J=8.7Hz, 2H), 7.86(d, J=8.7Hz, 2H), 4.49(s, 2H), 4.02(dd, J=7.5, 4.8Hz, 1H), 3.96-3.76(m, 2H), 3.56-3.38(m, 4H), 2.72(s, 6H), 2.60-2.40(m, 2H), 2.28-2.06(m, 2H), 1.90-1.28(m, 7H), 0.95(t, J=7.2Hz, 3H), 0.95(d, J=6.3Hz, 3H), 0.94(d, J=6.3Hz, 3H).
실시예 4(33)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-메톡시카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.50(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 8.04(d, J=9.0Hz, 2H), 7.63(d, J=9.0Hz, 2H), 7.19(d, J=9.0Hz, 2H), 7.08(d, J=9.0Hz, 2H), 4.38(s, 2H), 4.02(dd, J=7.5, 4.5Hz, 1H), 3.90(s, 3H), 3.88-3.72(m, 2H), 3.58-3.36(m, 4H), 2.58-2.38(m, 2H), 2.30-2.08(m, 2H), 1.90-1.28(m, 7H), 0.96(t, J=6.9Hz, 3H), 0.95(d, J=6.3Hz, 3H), 0.94(d, J=6.3Hz, 3H).
실시예 4(34)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(1-메틸피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.15(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 4.56(m, 1H), 4.20(s, 2H), 4.01(dd, J=7.8, 4.8Hz, 1H), 3.86-3.42(m, 8H), 3.30-3.20(m, 2H), 2.93(s, 3H), 2.64-2.48(m, 2H), 2.44-2.28(m, 2H), 2.44(s, 3H), 2.31(s, 3H), 2.22-2.06(m, 4H), 1.86-1.28(m, 7H), 0.98-0.88(m, 9H).
실시예 4(35)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(1-메틸술포닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.36(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.46(m, 1H), 4.25(s, 2H), 4.01(dd, J=7.8, 4.8Hz, 1H), 3.92-3.68(m, 4H), 3.60-3.42(m, 4H), 3.04-2.90(m, 2H), 2.89(s, 3H), 2.62-2.46(m, 2H), 2.48(s, 3H), 2.38(s, 3H), 2.24-1.98(m, 6H), 1.90-1.28(m, 7H), 0.98-0.90(m, 9H).
실시예 4(36)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(3-(N,N-디메틸아미노)프로필아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.22(클로로포름:메탄올:28% 암모니아수=100:10:1);
NMR(CD3OD): δ 8.02(d, J=8.7Hz, 2H), 7.74(d, J=8.7Hz, 2H), 4.30(s, 2H), 4.02(dd, J=7.8, 4.5Hz, 1H), 3.84-3.73(m, 2H), 3.66-3.56(m, 2H), 3.55-3.44(m, 2H), 3.27-3.18(m, 2H), 3.02(t, J=6.3Hz, 2H), 2.89(s, 6H), 2.70-2.52(m, 2H), 2.48(s, 3H), 2.40(s, 3H), 2.28-2.11(m, 2H), 2.00-1.28(m, 9H), 1.00-0.90(m, 9H).
실시예 4(37)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-(N,N-디메틸아미노)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.61(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.68-7.60(m, 4H), 7.21(d, J=8.7Hz, 2H), 7.14(d, J=8.7Hz, 2H), 4.35(s, 2H), 4.00(dd, J=7.8, 4.8Hz, 1H), 3.89-3.77(m, 2H), 3.54-3.40(m, 4H), 3.28(s, 6H), 2.62-2.44(m, 2H), 2.26-2.07(m, 2H), 1.90-1.26(m, 7H), 1.00-0.90(m, 9H).
실시예 4(38)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(N-메틸-N-(2-(N',N'-디메틸아미노)에틸)아미노술포닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.34(클로로포름:메탄올:28% 암모니아수=100:10:1);
NMR(CD3OD): δ 8.04(d, J=8.7Hz, 2H), 7.81(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.02(dd, J=7.8, 4.5Hz, 1H), 3.95-3.73(m, 2H), 3.66-3.54(m, 2H), 3.54-3.43(m, 2H), 3.42(s, 4H), 3.01(s, 6H), 2.85(s, 3H), 2.68-2.52(m, 2H), 2.50(s, 3H), 2.41(s, 3H), 2.29-2.10(m, 2H), 1.90-1.28(m, 7H), 1.00-0.90(m, 9H).
실시예 4(39)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-((N,N-디메틸아미노)메틸)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.29(클로로포름:메탄올:28% 암모니아수=100:10:1);
NMR(CD3OD): δ 7.62(d, J=8.7Hz, 2H), 7.53(d, J=8.7Hz, 2H), 7.18-7.10(m, 4H), 4.35(s, 2H), 4.30(s, 2H), 4.00(dd, J=7.8, 4.5Hz, 1H), 3.88-3.68(m, 2H), 3.54-3.38(m, 4H), 2.86(s, 6H), 2.59-2.42(m, 2H), 2.26-2.07(m, 2H), 1.88-1.25(m, 7H), 1.02-0.89(m, 9H).
실시예 4(40)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.25(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.03(d, J=8.7Hz, 2H), 7.58(d, J=8.7Hz, 2H), 7.16(d, J=8.7Hz, 2H), 7.05(d, J=8.7Hz, 2H), 4.32(s, 2H), 4.01(dd, J=7.8, 4.5Hz, 1H), 3.84-3.64(m, 2H), 3.52-3.35(m, 4H), 2.48-2.32(m, 2H), 2.27-2.10(m, 2H), 1.90-1.44(m, 5H), 1.44-1.26(m, 2H), 0.99-0.90(m, 9H).
실시예 4(41)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-메틸아미노카르보닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.35(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.01(d, J=8.7Hz, 2H), 7.64(d, J=8.7Hz, 2H), 4.34(s, 2H), 4.03(dd, J=7.8, 4.8Hz, 1H), 3.96-3.74(m, 2H), 3.70-3.42(m, 4H), 2.96(s, 3H), 2.74-2.54(m, 2H), 2.47(s, 3H), 2.46(s, 3H), 2.30-2.10(m, 2H), 1.92-1.28(m, 7H), 0.96(t, J=6.9Hz, 3H), 0.96(d, J=6.6Hz, 3H), 0.95(d, J=6.6Hz, 3H).
실시예 4(42)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-((메톡시카르보닐)메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸
NMR(CDCl3): δ 7.78(d, J=8.1Hz, 2H), 7.42(d, J=8.1Hz, 2H), 6.70(t,J=4.8Hz, 1H), 6.40(brs, 1H), 4.26(d, J=4.8Hz, 2H), 3.96(m, 1H), 3.81(s, 3H), 3.62(s, 2H), 3.50-3.28(m, 2H), 3.00-2.48(m, 8H), 2.26-1.20(m, 7H), 0.99-0.94(m, 9H).
실시예 4(43)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3-(3,5-디메틸-1-페닐피라졸-4-일)-2E-프로페닐)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
NMR(CDCl3): δ 7.56-7.32(m, 5H), 6.54(m, 1H), 6.38(brs, 1H), 5.96(m, 1H), 4.00(m, 1H), 3.76-2.90(m, 8H), 2.38(s, 3H), 2.34(s, 3H), 2.14-1.22(m, 11H), 1.00-0.86(m, 9H).
실시예 5
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(카르복시메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
실시예 4(42)에서 제조한 화합물(106 ㎎)의 메탄올(3 ㎖) 용액에 5N 수산화나트륨 수용액(0.1 ㎖)을 가하였다. 반응 혼합물을 실온에서 3시간 교반하였다. 반응 혼합물을 농축시키고, 잔류물을 디옥산에 용해시켰다. 이 용액에 4N 염화수소아세트산에틸 용액을 가하였다. 반응 혼합물을 농축시키고, 얻어진 잔류물에 디옥산을 가한 후, 여과하였다. 여과액을 농축하고, 얻어진 잔류물을 에테르 세정한 다음, 건조시켜 이하의 물성치를 갖는 본 발명 화합물(62 ㎎)을 얻었다.
TLC: Rf 0.28(부탄올:아세트산:물=4:2:1);
NMR(CD3OD): δ 7.99(d, J=8.7Hz, 2H), 7.70(d, J=8.7Hz, 2H), 4.44(s, 2H), 4.11(s, 2H), 4.02(dd, J=7.5, 4.8Hz, 1H), 3.94-3.74(m, 2H), 3.56-3.36(m, 4H), 2.48-2.32(m, 2H), 2.28-2.08(m, 2H), 1.88-1.30(m, 7H), 0.96(t, J=7.2Hz, 3H), 0.95(d, J=6.3Hz, 3H), 0.94(d, J=6.3Hz, 3H).
실시예 6
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3-(3,5-디메틸-1-페닐피라졸-4-일)프로필)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
실시예 4(43)에서 제조한 화합물(85 ㎎)을 메탄올(10 ㎖) 용액에 5% 팔라듐탄소(10 ㎎)를 가하였다. 반응 혼합물을 수소 가스 분위기 하의 실온에서 22시간 교반하였다. 반응 혼합물을 셀라이트(상품명)를 이용하여, 여과하고, 여과액을 농축하였다. 얻어진 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸:메탄올=15:1)에 의해 정제하였다. 얻어진 화합물의 메탄올 용액에 4N 염화수소아세트산에틸 용액을 가하였다. 반응 혼합물을 농축하고, 얻어진 잔류물을 에테르 세정하고, 건조시켜 이하의 물성치를 갖는 본 발명 화합물(23 ㎎)을 얻었다.
TLC: Rf 0.18(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.70-7.50(m, 5H), 4.03(dd, J=7.2, 4.2Hz, 1H), 3.86-3.68(m, 2H), 3.66-3.40(m, 4H), 3.30-3.16(m, 2H), 2.74-2.48(m, 4H), 2.46(s, 3H), 2.35(s, 3H), 2.28-1.98(m, 4H), 1.90-1.24(m, 7H), 0.97(t, J=7.2Hz, 3H), 0.96(d, J=6.6Hz, 3H), 0.95(d, J=6.6Hz, 3H).
실시예 7
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
참고예 3에서 제조한 화합물 대신에 참고예 3(2)에서 제조한 화합물을, 3-포르밀-6-페닐옥시피리딘 대신에 [4-(4-포르밀-3,5-디메틸피라졸릴)페닐]-N,N-디메틸카르복사미드를 이용하고, 실시예 2와 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.59(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.62(d, J=9.0Hz, 2H), 7.58(d, J=9.0Hz, 2H), 4.32(s, 2H), 4.05(dd, J=7.8, 4.5Hz, 1H), 3.96-3.78(m, 2H), 3.66-3.58(m, 2H), 3.46-3.34(m, 2H), 3.13(s, 3H), 3.04(s, 3H), 2.52-2.38(m, 2H), 2.42(s, 3H), 2.39(s, 3H), 2.32-2.14(m, 2H), 1.82-1.16(m, 15H), 1.02-0.88(m, 5H).
실시예 7(1)∼7(41)
[4-(4-포르밀-3,5-디메틸피라졸릴)페닐]-N,N-디메틸카르복사미드 대신에 해당하는 알데히드 유도체를 이용하고, 실시예 7과 동일한 조작을 하여, 이하에 나타낸 본 발명 화합물을 얻었다.
실시예 7(1)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(피롤리딘-1-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.53(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.72(d, J=8.7Hz, 2H), 7.58(d, J=8.7Hz, 2H), 4.33(s, 2H), 4.05(dd, J=7.5, 4.5Hz, 1H), 3.98-3.78(m, 2H), 3.64-3.56(m, 4H), 3.56-3.44(m, 2H), 3.44-3.32(m, 2H), 2.50-2.10(m, 4H), 2.4 2(s, 3H), 2.39(s, 3H), 2.10-1.88(m, 4H), 1.88-1.10(m, 15H), 1.10-0.90(m, 5H).
실시예 7(2)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(모르폴린-4-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.53(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.65-7.56(m, 4H), 4.32(s, 2H), 4.05(dd, J=7.5, 4.5Hz, 1H), 3.96-3.30(m, 14H), 2.54-2.32(m, 2H), 2.43(s, 3H), 2.39(s, 3H), 2.32-2.12(m, 2H), 1.84-1.10(m, 15H), 1.02-0.86(m, 5H).
실시예 7(3)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(2-(N,N-디메틸아미노)에틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.15(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.07(d, J=8.1Hz, 2H), 7.64(d, J=8.1Hz, 2H), 4.31(s, 2H), 4.05(dd, J=7.2, 5.1Hz, 1H), 3.94-3.76(m, 2H), 3.79(t, J=6.0Hz, 2H), 3.66-3.54(m, 2H), 3.54-3.36(m, 2H), 3.41(t, J=6. 0Hz, 2H), 3.00(s, 6H), 2.66-2.48(m, 2H), 2.46(s, 3H), 2.41(s, 3H), 2.28-2.10(m, 2H), 1.82-1.10(m, 15H), 1.02-0.86(m, 5H).
실시예 7(4)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-(모르폴린-4-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.60(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.59(d, J=8.4Hz, 2H), 7.48(d, J=8.7Hz, 2H), 7.22-7.09(m, 4H), 4.36(s, 2H), 4.04(dd, J=7.5, 4.8Hz, 1H), 3.88-3.34(m, 14H), 2.52-2.34(m, 2H), 2.28-2.08(m, 2H), 1.81-1.10(m, 15H), 1. 04-0.84(m, 5H).
실시예 7(5)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-메틸술포닐페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.57(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.08(d, J=8.4Hz, 2H), 7.87(d, J=8.4Hz, 2H), 4.50(s, 2H), 4.03(dd, J=7.5, 4.5Hz, 1H), 3.94-3.76(m, 2H), 3.52-3.36(m, 4H), 3.15(s, 3H), 2.56-2.38(m, 2H), 2.26-2.08(m, 2H), 1.80-1.10(m, 15H), 1. 02-0.86(m, 5H).
실시예 7(6)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-메틸술포닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.57(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.95(d, J=9.0Hz, 2H), 7.64(d, J=8.7Hz, 2H), 7.25-7.18(m,4H), 4.39(s, 2H), 4.04(dd, J=7.8, 4.8Hz, 1H), 3.90-3.76(m, 2H), 3.58-3.34(m, 4H), 3.12(s, 3H), 2.50-2.36(m, 2H), 2.30-2.1 0(m, 2H), 1.82-1.10(m, 15H), 1.02-0.88(m, 5H).
실시예 7(7)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(2-(모르폴린-4-일)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.43(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.06(d, J=8.7Hz, 2H), 7.57(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.12-4.01(m, 3H), 3.92-3.76(m, 4H), 3.65-3.40(m, 6H), 3.40-3.16(m, 6H), 2.64-2.44(m, 2H), 2.48(s, 3H), 2.41(s, 3H), 2.28-2. 12(m, 2H), 1.84-1.10(m, 15H), 1.02-0.86(m, 5H).
실시예 7(8)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(4-메틸피페라진-1-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.43(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.01(d, J=8.7Hz, 2H), 7.83(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.08-3.95(m, 3H), 3.95-3.74(m, 2H), 3.68-3.46(m, 6H), 3.28-3.20(m, 2H), 2.91(s, 3H), 2.88-2.72(m, 2H), 2.70-2.52(m, 2H), 2. 51(s, 3H), 2.42(s, 3H), 2.26-2.08(m, 2H), 1.82-1.10(m, 15H), 1.02-0.86(m, 5H).
실시예 7(9)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-메틸술피닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.53(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.74(d, J=9.0Hz, 2H), 7.62(d, J=8.7Hz, 2H), 7.25-7.14(m, 4H), 4.37(s, 2H), 4.04(dd, J=7.5, 4.5Hz, 1H), 3.88-3.72(m, 2H), 3.54-3.36(m, 4H), 2.80(s, 3H), 2.52-2.36(m, 2H), 2.26-2.10(m, 2H), 1.80-1.10(m, 15H), 1.02-0.86(m, 5H).
실시예 7(10)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(2-히드록시에틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.41(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.01(d, J=8.7Hz, 2H), 7.60(d, J=8.7Hz, 2H), 4.30(s, 2H), 4.05(dd, J=7.5, 4.2Hz, 1H), 3.92-3.68(m, 4H), 3.66-3.42(m, 6H), 2.70-2.50(m, 2H), 2.45(s, 3H), 2.40(s, 3H), 2.28-2.08(m, 2H), 1.82-1.10(m, 15H), 1.02-0.84(m, 5H).
실시예 7(11)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-(2-히드록시에틸아미노카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.36(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.89(d, J=9.0Hz, 2H), 7.58(d, J=8.7Hz, 2H), 7.16(d, J=8.7Hz, 2H), 7.08(d, J=9.0Hz, 2H), 4.37(s, 2H), 4.04(dd, J=7.5, 4.5Hz, 1H), 3.90-3.70(m, 2H), 3.70(t, J=6.0Hz, 2H), 3 . 58-3.46(m, 2H), 3.50(t, J=6.0Hz, 2H), 3.42-3.34(m, 2H), 2.44-2.30(m, 2H), 2.30-2.08(m, 2H), 1.82-1.12(m, 15H), 1.02-0.84(m, 5H).
실시예 7(12)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-(피롤리딘-1-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.25(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.59(d, J=8.7Hz, 2H), 7.59(d, J=8.7Hz, 2H), 7.16(d, J=8.7Hz, 2H), 7.10(d, J=8.7Hz, 2H), 4.37(s, 2H), 4.05(dd, J=7.5, 4.8Hz, 1H), 3.90-3.74(m, 2H), 3.62-3.36(m, 8H), 2.48-2.08(m, 4H), 2.04-1.08(m, 19H), 0.96(t, J=7.2Hz, 3H), 1.04-0.84(m, 2H).
실시예 7(13)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(시클로헥실아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.42(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.03(d, J=8.7Hz, 2H), 7.70(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.05(dd, J=7.8, 4.8Hz, 1H), 3.92-3.72(m, 2H), 3.68-3.58(m, 2H), 3.56-3.44(m, 2H), 3.06(m, 1H), 2.68-2.50(m, 2H), 2.47(s, 3H), 2.41(s, 3H), 2.38-2.08(m, 2H), 1.82-1.06(m, 25H), 1.02-0.86(m, 5H).
실시예 7(14)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(3-메톡시프로필아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.48(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.01(d, J=8.4Hz, 2H), 7.74(d, J=8.4Hz, 2H), 4.31(s, 2H), 4.05(dd, J=7.8, 4.8Hz, 1H), 3.92-3.72(m, 2H), 3.68-3.58(m, 2H), 3.56-3.46(m, 4H), 3.39(t, J=6.0Hz, 2H), 3.26(s, 3H), 2 . 98(t, J=6.9Hz, 2H), 2.72-2.56(m, 2H), 2.48(s, 3H), 2.43(s, 3H), 2.26-2.08(m, 2H), 1.82-1.10(m, 15H), 1.02-0.86(m, 5H).
실시예 7(15)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-메틸술피닐페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.15(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.85(d, J=8.7Hz, 2H), 7.81(d, J=8.7Hz, 2H), 4.47(s, 2H), 4.05(dd, J=7.2, 4.8Hz, 1H), 3.94-3.76(m, 2H), 3.58-3.36(m, 4H), 2.83(s, 3H), 2.54-2.34(m, 2H), 2.18-2.06(m, 2H), 1.82-1.10(m, 15H), 0.96(t, J=7.5Hz, 3H), 1.06-0.86(m, 2H).
실시예 7(16)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-프로필피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.61(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.28(s, 2H), 4.13(t, J=7.2Hz, 2H), 4.05(dd, J=7.5, 4.5Hz, 1H), 3.88-3.72(m, 2H), 3.60-3.38(m, 4H), 2.62-2.32(m, 2H), 2.46(s, 3H), 2.42(s, 3H), 2.28-2.08(m, 2H), 1.94-1.08(m, 17H), 0.96(t, J=7.2Hz, 6H), 1.06-0.86(m, 2H).
실시예 7(17)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-에틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.51(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.34-4.20(m, 4H), 4.04(dd, J=7.8, 4.8Hz, 1H), 3.88-3.70(m, 2H), 3.62-3.46(m, 4H), 2.72-2.54(m, 2H), 2.52(s, 3H), 2.48(s, 3H), 2.24-2.06(m, 2H), 1.82-1.08(m, 18H), 1.02-0.86(m, 5H).
실시예 7(18)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-시클로펜틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.49(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 5.02-4.82(m, 1H), 4.33(s, 2H), 4.04(dd, J=7.5, 4.8Hz, 1H), 3.90-3.70(m, 2H), 3.64-3.48(m, 4H), 2.80-2.60(m, 2H), 2.58(s, 3H), 2.57(s, 3H), 2.36-1.08(m, 25H), 1.04-0.84(m, 5H).
실시예 7(19)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(3-(모르폴린-4-일)프로필아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.20(아세트산에틸:메탄올=3:1);
NMR(CD3OD): δ 8.02(d, J=8.7Hz, 2H), 7.74(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.10-4.00(m, 3H), 4.00-3.00(m, 16H), 2.65-2.10(m, 4H), 2.47(s, 3H), 2.40(s, 3H), 2.05-1.95(m, 2H), 1.85-1.15(m, 15H), 1.10-0.90(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 7(20)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(N,N-디메틸아미노술포닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.60(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.90(d, J=8.4Hz, 2H), 7.84(d, J=8.4Hz, 2H), 4.48(s, 2H), 4.04(dd, J=7.5, 4.5Hz, 1H), 3.94-3.76(m, 2H), 3.56-3.36(m, 4H), 2.71(s, 6H), 2.56-2.36(m, 2H), 2.28-2.06(m, 2H), 1.83-1.10(m, 15H), 1.08-0.85(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 7(21)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(피롤리딘-1-일카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.59(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.68(d, J=8.7Hz, 2H), 7.63(d, J=8.7Hz, 2H), 4.41(s, 2H), 4.04(dd, J=7.5, 4.5Hz, 1H), 3.92-3.73(m, 2H), 3.60(t, J=6.9Hz, 2H), 3.55-3.34(m, 4H), 3.45(t, J=6.9Hz, 2H), 2.56-2.36(m, 2H), 2.27-2.07(m, 2H), 2.06-1.84(m, 4H), 1.83-1.10(m, 15H), 1.06-0.83(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 7(22)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-(N,N-디메틸아미노)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.51(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.70-7.62(m, 4H), 7.22(d, J=9.0Hz, 2H), 7.14(d, J=8.4Hz, 2H), 4.36(s, 2H), 4.03(dd, J=7.5, 4.5Hz, 1H), 3.86-3.70(m, 2H), 3.52-3.40(m, 4H), 3.30(s, 6H), 2.62-2.44(m, 2H), 2.24-2.06(m, 2H), 1.80-1.14(m, 15H), 1.02-0.86(m, 5H).
실시예 7(23)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(시클로헥실아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.38(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.91(d, J=8.1Hz, 2H), 7.68(d, J=8.1Hz, 2H), 4.42(s, 2H), 4.03(dd, J=7.5, 4.5Hz, 1H), 3.90-3.72(m, 3H), 3.52-3.36(m, 4H), 2.56-2.38(m, 2H), 2.24-2.06(m, 2H), 2.00-1.10(m, 25H), 1. 04-0.86(m, 5H).
실시예 7(24)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-메톡시카르보닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.33(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 8.18(d, J=8.7Hz, 2H), 7.64(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.05(m, 1H), 3.94(s, 3H), 3.94-3.45(m, 6H), 2.70-2.50(m, 2H), 2.46(s, 3H), 2.41(s, 3H), 2.30-2.10(m, 2H), 1.85-1.10(m, 15H), 1.10-0.90(m, 2H), 0.95(t, J=6.9Hz, 3H).
실시예 7(25)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(3-메톡시프로필아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.18(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.93(d, J=8.4Hz, 2H), 7.69(d, J=8.4Hz, 2H), 4.44(s, 2H), 4.04(dd, J=7.5, 4.8Hz, 1H), 3.92-3.74(m, 2H), 3.58-3.36(m, 10H), 3.35(s, 3H), 2.54-2.36(m, 2H), 2.28-2.06(m, 2H), 1.94-1.08(m, 15H), 1.04-0.84(m, 2H), 0.95(t, J=6.9Hz, 3H).
실시예 7(26)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(N-메틸-N-(2-(피리딘-2-일)에틸)아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.27(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 8.81(m, 1H), 8.59(m, 1H), 8.16-7.94(m, 2H), 7.71(d, J=7.8Hz, 2H), 7.42(d, J=7.8Hz, 2H), 4.40(s, 2H), 4.06-3.70(m, 5H), 3.60-3.36(m, 6H), 3.09(s, 3H), 2.72-2.42(m, 2H), 2.26-2.02(m, 2H), 1.84-1.14(m, 15H), 1.06-0.84(m, 2H), 0.95(t, J=6.9Hz, 3H).
실시예 7(27)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-((4-메톡시페닐)메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.38(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.96(d, J=9.0Hz, 2H), 7.69(d, J=9.0Hz, 2H), 7.28(d, J=9.0Hz, 2H), 6.88(d, J=9.0Hz, 2H), 4.52(s, 2H), 4.43(s, 2H), 4.04(dd, J=7.5, 4.5Hz, 1H), 3.92-3.78(m, 2H), 3.77(s, 3H), 3.56-3.36(m, 4H), 2.52-2.34(m, 2H), 2.26-2.06(m, 2H), 1.82-1.10(m, 15H), 1.06-0.84(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 7(28)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-메톡시카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.54(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.04(d, J=9.0Hz, 2H), 7.63(d, J=9.0Hz, 2H), 7.19(d, J=9.0Hz, 2H), 7.08(d, J=9.0Hz, 2H), 4.38(s, 2H), 4.05(dd, J=7.5, 4.5Hz, 1H), 3.90(s, 3H), 3.88-3.72(m, 2H), 3.58-3.38(m, 4H), 2.58-2.38(m, 2H), 2.28-2.08(m, 2H), 1.84-1.08(m, 15H), 1.06-0.86(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 7(29)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-메톡시페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.40(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.42(d, J=9.0Hz, 2H), 7.12(d, J=9.0Hz, 2H), 4.33(s, 2H), 4.06(dd, J=7.5, 4.5Hz, 1H), 3.96-3.76(m, 2H), 3.88(s, 3H), 3.68-3.40(m, 4H), 2.68-2.48(m, 2H), 2.45(s, 3H), 2.38(s, 3H), 2.32-2.08(m, 2H), 1.84-1.12(m, 15H), 1.06-0.84(m, 2H), 0.97(t, J=7.2Hz, 3H).
실시예 7(30)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(1-메틸피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.18(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 4.58(m, 1H), 4.21(s, 2H), 4.03(dd, J=7.5, 4.5Hz, 1H), 3.86-3.42(m, 8H), 3.32-3.20(m, 2H), 2.93(s, 3H), 2.70-2.50(m, 2H), 2.50-2.26(m, 2H), 2.45(s, 3H), 2.33(s, 3H), 2.24-2.04(m, 4H), 1.82-1.06(m, 15H) , 1.02-0.86(m, 5H).
실시예 7(31)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(1-메틸술포닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.41(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.44(m, 1H), 4.24(s, 2H), 4.04(dd, J=7.8, 4.8Hz, 1H), 3.92-3.68(m, 4H), 3.60-3.40(m, 4H), 3.02-2.90(m, 2H), 2.89(s, 3H), 2.60-2.40(m, 2H), 2.46(s, 3H), 2.36(s, 3H), 2.26-1.96(m, 6H), 1.82-1.10(m, 15H), 1.02-0.86(m, 5H).
실시예 7(32)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(3-(N,N-디메틸아미노)프로필아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.22(클로로포름:메탄올:28% 암모니아수=100:10:1);
NMR(CD3OD): δ 8.02(d, J=8.7Hz, 2H), 7.74(d, J=8.7Hz, 2H), 4.30(s, 2H), 4.04(dd, J=7.5, 4.5Hz, 1H), 3.94-3.73(m, 2H), 3.66-3.56(m, 2H), 3.54-3.43(m, 2H), 3.27-3.18(m, 2H), 3.05-2.97(m, 2H), 2.89(s, 6H), 2.68-2.51(m, 2H), 2.48(s, 3H), 2.40(s, 3H), 2.28-2.08(m, 2H), 2.00-1.88(m, 2H), 1.84-1.10(m, 15H), 1.04-0.88(m, 5H).
실시예 7(33)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(N-메틸-N-(2-(N',N'-디메틸아미노)에틸)아미노술포닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.32(클로로포름:메탄올:28% 암모니아수=100:10:1);
NMR(CD3OD): δ 8.04(d, J=8.7Hz, 2H), 7.82(d, J=8.7Hz, 2H), 4.30(s, 2H), 4.04(dd, J=7.5, 4.5Hz, 1H), 3.94-3.74(m, 2H), 3.67-3.56(m, 2H), 3.55-3.45(m, 2H), 3.42(s, 4H), 3.01(s, 6H), 2.85(s, 3H), 2.72-2.53(m, 2H), 2.50(s, 3H), 2.41(s, 3H), 2.27-2.08(m, 2H), 1.84-1.11(m, 15H), 1.06-0.84(m, 5H).
실시예 7(34)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(피페리딘-1-일카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.56(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.68(d, J=8.1Hz, 2H), 7.50(d, J=8.1Hz, 2H), 4.41(s, 2H), 4.04(dd, J=7.5, 4.8Hz, 1H), 3.92-3.65(m, 4H), 3.56-3.30(m, 6H), 2.57-2.36(m, 2H), 2.26-2.07(m, 2H), 1.83-1.10(m, 21H), 1.06-0.83(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 7(35)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(모르폴린-4-일카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.54(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.69(d, J=8.1Hz, 2H), 7.55(d, J=8.1Hz, 2H), 4.41(s, 2H), 4.04(dd, J=7.5, 4.5Hz, 1H), 3.91-3.55(m, 8H), 3.55-3.30(m, 6H), 2.57-2.37(m, 2H), 2.27-2.05(m, 2H), 1.83-1.08(m, 15H), 1.06-0.83(m, 2H), 0.94(t, J=7.2Hz, 3H).
실시예 7(36)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-((N,N-디메틸아미노)메틸)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.37(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.62(d, J=8.7Hz, 2H), 7.53(d, J=8.7Hz, 2H), 7.16-7.10(m, 4H), 4.35(s, 2H), 4.31(s, 2H), 4.04(dd, J=7.5, 4.5Hz, 1H), 3.86-3.70(m, 2H), 3.52-3.38(m, 4H), 2.86(s, 6H), 2.62-2.46(m, 2H), 2.26-2.06(m, 2H), 1.82-1.12(m, 15H), 1.06-0.88(m, 5H).
실시예 7(37)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-메틸아미노카르보닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.13(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 8.00(d, J=8.7Hz, 2H), 7.61(d, J=8.7Hz, 2H), 4.33(s, 2H), 4.06(dd, J=7.8, 4.8Hz, 1H), 3.94-3.76(m, 2H), 3.66-3.56(m, 2H), 3.52-3.40(m, 2H), 2.95(s, 3H), 2.62-2.38(m, 2H), 2.50(s, 3H), 2.42(s, 3H), 2.32-2.10(m, 2H), 1.84-1.18(m, 15H), 1.06-0.84(m, 2H), 0.97(t, J=6.9Hz, 3H).
실시예 7(38)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(1,1-디메틸에틸)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.38(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 4.25(s, 2H), 4.04(dd, J=7.8, 4.8Hz, 1H), 3.88-3.73(m, 2H), 3.59-3.50(m, 2H), 3.47-3.42(m, 2H), 2.60(s, 3H), 2.57-2.45(m, 2H), 2.38(s, 3H), 2.23-2.10(m, 2H), 1.80-1.15(m, 24H), 1.02-0. 92(m, 5H).
실시예 7(39)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(1-벤질옥시카르보닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.33(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 7.39-7.29(m, 5H), 5.14(s, 2H), 4.52(m, 1H), 4.33-4.29(m, 2H), 4.25(s, 2H), 4.04(dd, J=7.8, 4.8Hz, 1H), 3.87-3.72(m, 2H), 3.55-3.42(m, 4H), 3.10-2.98(m, 2H), 2.60-2.43(m, 5H), 2.36(s, 3H), 2.23-1.95(m, 6H), 1.80-1.15(m, 15H), 1.02-0.92(m, 5H).
실시예 7(40)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-히드록시메틸페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸
TLC: Rf 0.24(클로로포름:메탄올=20:1);
NMR(CD3OD): δ 7.34(d, J=8.7Hz, 2H), 7.31(d, J=8.7Hz, 2H), 6.95(d, J=8.7Hz, 2H), 6.94(d, J=8.7Hz, 2H), 4.57(s, 2H), 4.00(dd, J=7.5, 4.5Hz, 1H), 3.55(s, 2H), 3.47-3.38(m, 2H), 2.93-2.74(m, 4H), 2.24-2.04(m, 2H), 2.00-1.83(m, 2H), 1.83-1.08(m, 15H), 1.05-0.84(m, 2H), 0.95(t, J=7.5Hz, 3H).
실시예 7(41)
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-((메톡시카르보닐)메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸
NMR(CDCl3): δ 7.78(d, J=8.1Hz, 2H), 7.43(d, J=8.1Hz, 2H), 6.71(t, J=4.8Hz, 1H), 6.32(brs, 1H), 4.26(d, J=4.8Hz, 2H), 4.00(m, 1H), 3.81(s, 3H), 3.64(s, 2H), 3.54-3.28(m, 2H), 3.06-2.72(m, 8H), 2.26-1.10(m, 15H), 1.06-0.82(m, 2H), 0.94(t, J=6.9Hz, 3H).
실시예 8
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(카르복시메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
실시예 4(42)에서 제조한 화합물 대신에 실시예 7(41)에서 제조한 화합물을 이용하고, 실시예 5와 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.36(부탄올:아세트산:물=4:2:1);
NMR(CD3OD): δ 7.99(d, J=8.1Hz, 2H), 7.70(d, J=8.1Hz, 2H), 4.45(s, 2H), 4.11(s, 2H), 4.04(dd, J=7.2, 4.5Hz, 1H), 3.94-3.74(m, 2H), 3.58-3.36(m, 4H), 2.56-2.34(m, 2H), 2.30-2.06(m, 2H), 1.84-1.16(m, 15H), 1.06-0.86(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-페닐옥시페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
참고예 3에서 제조한 화합물 대신에 참고예 3(3)에서 제조한 화합물을, 3-포르밀-6-페닐옥시피리딘 대신에 4-페닐옥시벤조알데히드를 이용하고, 실시예 2와 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.46(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.50(d, J=8.7Hz, 2H), 7.42-7.37(m, 2H), 7.18(m, 1H), 7.07-7.01(m, 4H), 4.31(s, 2H), 4.15(d, J=2.1Hz, 1H), 3.97(m, 1H), 3.71(m, 1H), 3.60-3.05(m, 5H), 2.55-1.90(m, 6H), 1.90-1.60(m, 5H), 1.60-1.10(m, 6H), 1.10-0.90(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 9(1)∼9(71)
4-페닐옥시벤조알데히드 대신에 해당하는 알데히드 유도체를 이용하고, 실시예 9와 동일한 조작을 하여, 이하에 나타낸 본 발명 화합물을 얻었다.
실시예 9(1)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(6-페닐옥시피리딘-3-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.36(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 8.28(d, J=2.7Hz, 1H), 8.01(dd, J=8.4, 2.7Hz, 1H), 7.43(t, J=8.4Hz, 2H), 7.25(t, J=8.4Hz, 1H), 7.13(d, J=8.4Hz, 2H), 7.06(d, J=8.4Hz, 1H), 4.38(s, 2H), 4.15(d, J=1.8Hz, 1H), 4.02(m, 1H), 3.77(m, 1H), 3.60-3.05(m, 5H), 2.55-1.90(m, 6H), 1.90-1.60(m, 5H), 1.60-1.10(m, 6H), 1.10-0.90(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 9(2)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-플루오로페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.48(클로로포름:메탄올=9:1);
NMR(CD3OD): δ 7.54-7.48(m, 2H), 7.14(dd, J=9.6, 8.1Hz, 2H), 7.09-7.02(m, 4H), 4.33(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.00(m, 1H), 3.73(m, 1H), 3.57-3.40(m, 3H), 3.33-3.08(m, 2H), 2.54-1.88(m, 6H), 1.82-1.63(m, 5H), 1.48-1.12(m, 6H), 1.03-0.85(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 9(3)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-클로로페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.50(클로로포름:메탄올=9:1);
NMR(CD3OD): δ 7.58-7.51(m, 2H), 7.38(d, J=9.3Hz, 2H), 7.09(brd, J=8.4Hz, 2H), 7.02(d, J=9.3Hz, 2H), 4.34(s, 2H), 4.15(d, J=2.1Hz, 1H), 3.99(m, 1H), 3.73(m, 1H), 3.58-3.40(m, 3H), 3.32-3.09(m, 2H), 2.53-1.89(m, 6H), 1.81-1.62(m, 5H), 1.48-1.13(m, 6H), 1.03-0.82(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 9(4)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-시아노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.52(클로로포름:메탄올=9:1);
NMR(CD3OD): δ 7.74(d, J=9.0Hz, 2H), 7.64-7.58(m, 2H), 7.21(d, J=8.4Hz, 2H), 7.13(d, J=9.0Hz, 2H), 4.38(s, 2H), 4.16(d, J=2.1Hz, 1H), 4.02(m, 1H), 3.77(m, 1H), 3.57-3.43(m, 3H), 3.33-3.08(m, 2H), 2.54-1.90(m, 6H), 1.80-1.63(m, 5H), 1.48-1.13(m, 6H), 1.03-0.82(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9(5)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸술포닐아미노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.41(클로로포름:메탄올=9:1);
NMR(CD3OD): δ 7.53(d, J=8.7Hz, 2H), 7.29(d, J=8.7Hz, 2H), 7.06(d, J=8.7Hz, 2H), 7.03(d, J=8.7Hz, 2H), 4.33(s, 2H), 4.15(d, J=1.8Hz, 1H), 3.98(m, 1H), 3.73(m, 1H), 3.58-3.40(m, 3H), 3.32-3.03(m, 2H), 2.95(s, 3H), 2.52-2.24(m, 3H), 2.17-1.88(m, 3H), 1.80-1.62(m, 5H), 1.48-1.08(m, 6H), 1.03-0.82(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 9(6)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(6-메틸피리딘-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.21(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 8.54(d, J=3.0Hz, 1H), 8.08(m, 1H), 7.82(d, J=9.0Hz, 1H), 7.70(d, J=9.0Hz, 2H), 7.28(d, J=9.0Hz, 2H), 4.39(s, 2H), 4.10(d, J=2.1Hz, 1H), 4.01(m, 1H), 3.75(m, 1H), 3.60-3.20(m, 5H), 2.73(s, 3H), 2.70-2.35(m, 3H), 2.20-1.90(m, 3H), 1.90-1.60(m, 5H), 1.50-1.15(m, 6H), 1.10-0.90(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 9(7)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(1-메틸에틸)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.41(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.45(d, J=8.1Hz, 2H), 7.37(d, J=8.1Hz, 2H), 4.30(s, 2H), 4.15(d, J=2.1Hz, 1H), 3.98(m, 1H), 3.72(m, 1H), 3.60-3.05(m, 5H), 2.95(quint, J=6.9Hz, 1H), 2.50-1.90(m, 6H), 1.85-1.60(m, 5H), 1.50-1.10(m, 6H), 1.25(d, J=6.9Hz, 6H), 1.10-0.90(m, 2H), 0.95(t, J=6.9Hz, 3H).
실시예 9(8)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸술피닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.32(클로로포름:메탄올=9:1);
NMR(CD3OD): δ 7.74(d, J=9.0Hz, 2H), 7.61(d, J=9.0Hz, 2H), 7.22(d, J=9.0Hz, 2H), 7.17(d, J=9.0Hz, 2H), 4.36(s, 2H), 4.16(d, J=2.1Hz, 1H), 4.00(dt, J=3.6, 12.6Hz, 1H), 3.75(dt, J=3.6, 12.6Hz, 1H), 3.58-3.42(m, 3H), 3.32-3.13(m, 2H), 2.80(s, 3H), 2.54-2.25(m, 3H), 2.17-1.88(m, 3H), 1.80-1.63(m, 5H), 1.49-1.13(m, 6H), 1.02-0.82(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9(9)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(3,4,5,6-테트라히드로피란-4-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.43(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 7.45(d, J=9.0Hz, 2H), 7.06(d, J=9.0Hz, 2H), 4.63(m, 1H), 4.28(s, 2H), 4.15(d, J=2.0Hz, 1H), 4.01-3.90(m, 3H), 3.72(m, 1H), 3.63-3.53(m, 2H), 3.50-3.41(m, 3H), 3.27(m, 1H), 3.15(m, 1H), 2.50-1.91(m, 8H), 1.68-1.65(m, 7H), 1.39-1.15(m, 6H), 1.01-0.87(m, 5H).
실시예 9(10)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-페닐카르보닐페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.75(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 7.87(d, J=7.5Hz, 2H), 7.81-7.72(m, 4H), 7.67(t, J=7.5Hz, 1H), 7.54(t, J=7.5Hz, 2H), 4.48(s, 2H), 4.16(d, J=2.0Hz, 1H), 4.07(m, 1H), 3.81(m, 1H), 3.53-3.47(m, 3H), 3.33-3.17(m, 2H), 2.51-2.31(m, 3H), 2.17-1.92(m, 3H), 1.76-1.70(m, 5H), 1.40-1.15(m, 6H), 1.01-0.87(m, 5H).
실시예 9(11)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(1-페닐-1-히드록시메틸)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.57(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 7.53(d, J=8.0Hz, 2H), 7.48(d, J=8.0Hz, 2H), 7.39-7.20(m, 5H), 5.81(s, 1H), 4.33(s, 2H), 4.14(d, J=2.0Hz, 1H), 4.00(m, 1H), 3.74(m, 1H), 3.45-3.41(m, 3H), 3.26(m, 1H), 3.10(m, 1H), 2.48-1.91(m, 6H), 1.80-1.60(m, 5H), 1.44-1.14(m, 6H), 1.00-0.86(m, 5H).
실시예 9(12)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(모르폴린-4-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.49(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.95(d, J=8.7Hz, 2H), 7.79(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.17(d, J=2.1Hz, 1H), 4.04(m, 1H), 3.79(m, 1H), 3.75-3.67(m, 4H), 3.64-3.49(m, 3H), 3.35-3.18(m, 2H), 3.05-2.97(m, 4H), 2.66-2.34(m, 3H), 2.49(s, 3H), 2.40(s, 3H), 2.20-1.87(m, 3H), 1.84-1.60(m, 5H), 1.52-1.10(m, 6H), 1.05-0.80(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9(13)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-메틸아미노술포닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.36(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 8.01(d, J=8.7Hz, 2H), 7.73(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.16(d, J=2.0Hz, 1H), 4.05(m, 1H), 3.80(m, 1H), 3.63-3.53(m, 3H), 3.34-3.23(m, 2H), 2.59-2.34(m, 3H), 2.57(s, 3H), 2.46(s, 3H), 2.39(s, 3H), 2.16(m, 1H), 2.05-1.93(m, 2H), 1.77-1.66(m, 5H), 1.45-1.17(m, 6H), 1.01-0.88(m, 5H).
실시예 9(14)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(N-메틸-N-(2-히드록시에틸)아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.44(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.98(d, J=8.7Hz, 2H), 7.75(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.17(d, J=2.0Hz, 1H), 4.04(m, 1H), 3.78(m, 1H), 3.69(t, J=5.7Hz, 2H), 3.64-3.50(m, 3H), 3.38-3.24(m, 2H), 3.19(t, J=5.7Hz, 2H), 2.87(s, 3H), 2.60-2.34(m, 3H), 2.47(s, 3H), 2.40(s, 3H), 2.20-1.88(m, 3H), 1.82-1.60(m, 5H), 1.50-1.12(m, 6H), 1.04-0.82(m, 5H).
실시예 9(15)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(피리딘-2-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.40(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 8.51(d, J=4.5Hz, 1H), 8.01(m, 1H), 7.80(d, J=8.0Hz, 1H), 7.41(m, 1H), 4.32(s, 2H), 4.16(d, J=2.0Hz, 1H), 4.05(m, 1H), 3.80(m, 1H), 3.60-3.49(m, 3H), 3.33-3.10(m, 2H), 2.67(s, 3H), 2.53-2.35(m, 3H), 2.41(s, 3H), 2.16(m, 1H), 2.05-1.93(m, 2H), 1.80-1.65(m, 5H), 1.50-1.15(m, 6H), 1.01-0.88(m, 5H).
실시예 9(16)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.34(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 4.32(m, 1H), 4.27(s, 2H), 4.15(d, J=2.0Hz, 1H), 4.00(m, 1H), 3.73(m, 1H), 3.60-3.50(m, 3H), 3.37-3.20(m, 2H), 2.58-2.40(m, 9H), 2.13-1.70(m, 15H), 1.58-1.15(m, 9H), 1.01-0.88(m, 5H).
실시예 9(17)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(1,3,5-트리메틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.28(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.27(s, 2H), 4.15(d, J=2.1Hz, 1H), 3.98(m, 1H), 3.85(s, 3H), 3.73(m, 1H), 3.62-3.56(m, 3H), 3.40-3.20(m, 2H), 2.60(m, 1H), 2.50-2.36(m, 2H), 2.45(s, 3H), 2.41(s, 3H), 2.16-1.88(m, 3H), 1.84-1.60(m, 5H), 1.50-1.10(m, 6H), 1.04-0.80(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 9(18)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.19(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 7.62(d, J=9.0Hz, 2H), 7.58(d, J=9.0Hz, 2H), 4.32(s, 2H), 4.17(d, J=2.0Hz, 1H), 4.05(m, 1H), 3.80(m, 1H), 3.60-3.53(m, 3H), 3.33-3.27(m, 2H), 3.13(s, 3H), 3.04(s, 3H), 2.53-2.35(m, 3H), 2.42(s, 3H), 2.39(s, 3H), 2.17(m, 1H), 2.05-1.92(m, 2H), 1.77-1.65(m, 5H), 1.39-1.15(m, 6H), 1.01-0.88(m, 5H).
실시예 9(19)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(N,N-비스메틸술포닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.47(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.69(d, J=8.4Hz, 2H), 7.60(d, J=8.4Hz, 2H), 4.42(s, 2H), 4.16(d, J=2.1Hz, 1H), 4.06(m, 1H), 3.80(m, 1H), 3.60-3.10(m, 5H), 3.46(s, 6H), 2.55-1.90(m, 6H), 1.90-1.60(m, 5H), 1.50-1.10(m, 6H), 1.10-0.90(m, 2H), 0.95(t, J=6.9Hz, 3H).
실시예 9(20)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-메틸술포닐아미노페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.30(클로로포름:메탄올=9:1);
NMR(CD3OD): δ 7.48-7.38(m, 4H), 4.30(s, 2H), 4.17(d, J=2.1Hz, 1H), 4.03(m, 1H), 3.78(m, 1H), 3.62-3.49(m, 3H), 3.37-3.21(m, 2H), 3.04(s, 3H), 2.62-2.35(m, 3H), 2.40(s, 3H), 2.38(s, 3H), 2.18-1.90(m, 3H), 1.83-1.63(m, 5H), 1.48-1.13(m, 6H), 1.03-0.82(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9(21)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(N,N-디메틸술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.36(클로로포름:메탄올=9:1);
NMR(CD3OD): δ 7.96(d, J=8.7Hz, 2H), 7.77(d, J=8.7Hz, 2H), 4.32(s, 2H), 4.17(d, J=2.1Hz, 1H), 4.05(m, 1H), 3.79(m, 1H), 3.63-3.48(m, 3H), 3.34-3.15(m, 2H), 2.74(s, 6H), 2.58-2.32(m, 3H), 2.47(s, 3H), 2.40(s, 3H), 2.21-1.90(m, 3H), 1.82-1.62(m, 5H), 1.48-1.13(m, 6H), 1.03-0.82(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9(22)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(피롤리딘-1-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.38(클로로포름:메탄올=9:1);
NMR(CD3OD): δ 7.72(d, J=8.7Hz, 2H), 7.59(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.17(d, J=2.4Hz, 1H), 4.04(m, 1H), 3.78(m, 1H), 3.65-3.47(m, 3H), 3.62(t, J=6.6Hz, 2H), 3.50(t, J=6.6Hz, 2H), 3.33-3.18(m, 2H), 2.60-2.32(m, 3H), 2.43(s, 3H), 2.39(s, 3H), 2.20-1.87(m, 7H), 1.82-1.62(m, 5H), 1.48-1.13(m, 6H), 1.03-0.82(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9(23)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(모르폴린-4-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.38(클로로포름:메탄올=9:1);
NMR(CD3OD): δ 7.65-7.57(m, 4H), 4.31(s, 2H), 4.17(d, J=2.4Hz, 1H), 4.04(m, 1H), 3.85-3.46(m, 12H), 3.34-3.17(m, 2H), 2.60-2.32(m, 3H), 2.43(s, 3H), 2.39(s, 3H), 2.20-1.90(m, 3H), 1.82-1.62(m, 5H), 1.48-1.13(m, 6H), 1.03-0.82(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9(24)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-아미노카르보닐페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.40(아세트산에틸:메탄올=3:1);
NMR(CD3OD): δ 7.99(d, J=8.4Hz, 2H), 7.70(d, J=8.4Hz, 2H), 4.44(s, 2H), 4.16(d, J=2.1Hz, 1H), 4.04(m, 1H), 3.78(m, 1H), 3.60-3.38(m, 3H), 3.30-3.08(m, 2H), 2.60-2.24(m, 3H), 2.20-1.86(m, 3H), 1.82-1.58(m, 5H), 1.50-1.06(m, 6H), 1.04-0.80(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9(25)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.25(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.90(d, J=8.7Hz, 2H), 7.57(d, J=8.7Hz, 2H), 7.16(d, J=8.7Hz, 2H), 7.07(d, J=8.7Hz, 2H), 4.36(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.02(m, 1H), 3.76(m, 1H), 3.56-3.42(m, 3H), 3.33- 2.99(m, 2H), 2.54-1.88(m, 6H), 1.81-1.60(m, 5H), 1.48-1.12(m, 6H), 1.04-0.81(m, 5H).
실시예 9(26)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-아미노술포닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.28(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.89(d, J=8.7Hz, 2H), 7.61(d, J=8.7Hz, 2H), 7.17(d, J=8.7Hz, 2H), 7.13(d, J=8.7Hz, 2H), 4.36(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.01(m, 1H), 3.75(m, 1H), 3.58-3.42(m, 3H), 3.32-3.14(m, 2H), 2.55-2.40(m, 2H), 2.32(m, 1H), 2.13(m, 1H), 2.07-1.89(m, 2H), 1.82-1.60(m, 5H), 1.50-1.12(m, 6H), 1.06-0.80(m, 5H).
실시예 9(27)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(6-메틸피리딘-1-옥사이드-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.62(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 8.51(s, 1H), 7.80-7.56(m, 2H), 7.72(d, J=8.7Hz, 2H), 7.29(d, J=8.7Hz, 2H), 4.39(s, 2H), 4.16(d, J=2.1Hz, 1H), 4.00(m, 1H), 3.78(m, 1H), 3.62-3.40(m, 3H), 3.36-3.18(m, 2H), 2.64-2.30(m, 3H), 2.63(s, 3H), 2.20-1.86(m, 3H), 1.84-1.58(m, 5H), 1.52-1.08(m, 6H), 1.04-0.82(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9(28)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-히드록시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.35(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.46(d, J=9.0Hz, 2H), 6.97(d, J=9.0Hz, 2H), 6.88(d, J=9.0Hz, 2H), 6.80(d, J=9.0Hz, 2H), 4.30(s, 2H), 4.15(d, J=2.1Hz, 1H), 3.98(m, 1H), 3.72(m, 1H), 3.67-3.39(m, 3H), 3.27(m, 1H), 3.15(m, 1H), 2.53-2.35(m, 2H), 2.26(m, 1H), 2.18-1.87(m, 3H), 1.84-1.60(m, 5H), 1.51-1.05(m, 6H), 1.04-0.80(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 9(29)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-히드록시페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.25(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.34(d, J=8.7Hz, 2H), 6.96(d, J=8.7Hz, 2H), 4.34(s, 2H), 4.16(d, J=2.1Hz, 1H), 4.04(m, 1H), 3.79(m, 1H), 3.65-3.50(m, 3H), 3.32(m, 1H), 3.29(m, 1H), 2.64(m, 1H), 2.55-2.42(m, 2H), 2.48(s, 3H), 2.38(s, 3H), 2.20-1.88(m, 3H), 1.83-1.60(m, 5H), 1.52-1.05(m, 6H), 1.04-0.81(m, 2H),0.96(t, J=6.9Hz, 3H).
실시예 9(30)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(2-히드록시에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.32(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.03(d, J=8.7Hz, 2H), 7.71(d, J=8.7Hz, 2H), 4.32(s, 2H), 4.17(d, J=2.1Hz, 1H), 4.06(m, 1H), 3.80(m, 1H), 3.62-3.48(m, 5H), 3.38-3.18(m, 2H), 3.01(t, J=5.7Hz, 2H), 2.58-2.30(m, 3H), 2.46(s, 3H), 2.39(s, 3H), 2.20-1.88(m, 3H), 1.82-1.62(m, 5H), 1.50-1.10(m, 6H), 1.02-0.82(m, 5H).
실시예 9(31)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(피롤리딘-1-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.59(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.01(d, J=8.7Hz, 2H), 7.75(d, J=8.7Hz, 2H), 4.32(s, 2H), 4.17(d, J=2.4Hz, 1H), 4.06(m, 1H), 3.80(m, 1H), 3.62-3.48(m, 3H), 3.38-3.18(m, 6H), 2.60-2.30(m, 3H), 2.47(s, 3H), 2.39(s, 3H), 2.20-1.88(m, 3H), 1.82-1.60(m, 9H), 1.50-1.10(m, 6H), 1.02-0.82(m, 5H).
실시예 9(32)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(5-클로로-3-메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.52(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.62-7.46(m, 5H), 4.34(s, 2H), 4.17(d, J=1.8Hz, 1H), 4.10(m, 1H), 3.83(m, 1H), 3.66-3.47(m, 3H), 3.39-3.13(m, 2H), 2.60-2.28(m, 3H), 2.44(s, 3H), 2.18(m, 1H), 2.09-1.88(m, 2H), 1.85-1.62(m, 5H), 1.54-1.13(m, 6H), 1.03-0.81(m, 2H), 0.97(t, J=7.2Hz, 3H).
실시예 9(33)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메톡시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.50(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.49(d, J=8.7Hz, 2H), 6.98(d, J=8.7Hz, 2H), 7.02-6.92(m, 4H), 4.30(s, 2H), 4.15(d, J=2.1Hz, 1H), 3.97(m, 1H), 3.79(s, 3H), 3.72(m, 1H), 3.58-3.38(m, 3H), 3.30-3.13(m, 2H), 2.55-2.40(m, 2H), 2.32(m, 1H), 2.16-1.86(m, 3H), 1.81-1.60(m, 5H), 1.50-1.10(m, 6H), 1.03-0.80(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 9(34)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(3-메톡시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.50(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.54(d, J=8.7Hz, 2H), 7.28(m, 1H), 7.70(d, J=8.7Hz, 2H), 6.75(ddd, J=8.7, 2.1, 1.2Hz, 1H), 6.63-6.56(m, 2H), 4.33(s, 2H), 4.15(d, J=2.1Hz, 1H), 3.98(m, 1H), 3.77(s, 3H), 3.75(m, 1H), 3.58-3.40(m, 3H), 3.30-3.11(m, 2H), 2.55-2.23(m, 3H), 2.17-1.88(m, 3H), 1.81-1.59(m, 5H), 1.50-1.06(m, 6H), 1.03-0.80(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 9(35)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(N,N-디메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.43(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.66(d, J=8.4Hz, 2H), 7.55(d, J=8.4Hz, 2H), 4.41(s, 2H), 4.15(d, J=1.8Hz, 1H), 4.04(m, 1H), 3.78(m, 1H), 3.59-3.42(m, 3H), 3.30-3.10(m, 2H), 3.11(s, 3H), 2.99(s, 3H), 2.53-2.20(m, 3H), 2.14(m, 1H), 2.08-1.88(m, 2H), 1.83-1.60(m, 5H), 1.52-1.10(m, 6H), 1.06-0.80(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 9(36)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.48(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.63-7.43(m, 5H), 4.32(s, 2H), 4.17(d, J=2.1Hz, 1H), 4.04(m, 1H), 3.79(m, 1H), 3.64-3.49(m, 3H), 3.30-3.20(m, 2H), 2.70-2.30(m, 9H), 2.20-1.88(m, 3H), 1.83-1.58(m, 5H), 1.52-1.06(m, 6H), 1.06-0.80(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9(37)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-메틸페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.48(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.37(d, J=8.7Hz, 2H), 7.34(d, J=8.7Hz, 2H), 4.30(s, 2H), 4.17(d, J=2.1Hz, 1H), 4.04(m, 1H), 3.79(m, 1H), 3.63-3.47(m, 3H), 3.35-3.06(m, 2H), 2.63-2.26(m, 3H), 2.43(s, 3H), 2.38(s, 3H), 2.35(s, 3H), 2.16(m, 1H), 2.09-1.88(m, 2H), 1.83-1.60(m, 5H), 1.55-1.10(m, 6H), 1.08-0.80(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9(38)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-플루오로페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.49(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.50(dd, J=8.4, 4.8Hz, 2H), 7.30(dd, J=8.4, 8.4Hz, 2H), 4.30(s, 2H), 4.17(d, J=2.1Hz, 1H), 4.04(m, 1H), 3.78(m, 1H), 3.63-3.45(m, 3H), 3.30-3.12(m, 2H), 2.61-2.30(m, 3H), 2.37(s, 3H), 2.36(s, 3H), 2.16(m, 1H), 2.08-1.88(m, 2H), 1.82-1.60(m, 5H), 1.52-1.07(m, 6H), 1.04-0.80(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9(39)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(6-(4-메톡시페닐옥시)피리딘-3-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.38(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.36(m, 1H), 8.12(m, 1H), 7.12-6.98(m, 5H), 4.39(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.00(m, 1H), 3.81(s, 3H), 3.74(m, 1H), 3.60-3.42(m, 3H), 3.30-3.16(m, 2H), 2.58-2.30(m, 3H), 2.16-1.86(m, 3H), 1.80-1.62(m, 5H), 1.50-1.10(m, 6H), 1.02-0.80(m, 5H).
실시예 9(40)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸술포닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.46(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.95(d, J=9.0Hz, 2H), 7.65(d, J=8.4Hz, 2H), 7.25-7.16(m, 4H), 4.38(s, 2H), 4.15(d, J=2.4Hz, 1H), 4.02(m, 1H), 3.76(m, 1H), 3.60-3.44(m, 3H), 3.30-3.10(m, 2H), 3.11(s, 3H), 2.54- 2.26(m, 3H), 2.18-1.88(m, 3H), 1.82-1.62(m, 5H), 1.50-1.10(m, 6H), 1.02-0.82(m, 5H).
실시예 9(41)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-(2-(N,N-디메틸아미노)에틸아미노카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.15(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 7.93(d, J=9.0Hz, 2H), 7.62(d, J=8.4Hz, 2H), 7.20-7.08(m, 4H), 3.98(s, 2H), 4.16(d, J=2.1Hz, 1H), 3.98(m, 1H), 3.75(m, 1H), 3.75(t, J=5.4Hz, 2H), 3.58-3.42(m, 3H), 3.38(t, J=5.4Hz, 2H), 3.30-3.18(m, 2H), 2.98(s, 6H), 2.56-2.28(m, 3H), 2.18-1.88(m, 3H), 1.82-1.62(m, 5H), 1.46-1.14(m, 6H), 1.02-0.84(m, 5H).
실시예 9(42)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(2-히드록시에틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.46(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.01(d, J=8.7Hz, 2H), 7.60(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.17(d, J=2.4Hz, 1H), 4.04(m, 1H), 3.80(m, 1H), 3.73(t, J=6.0Hz, 2H), 3.72-3.48(m, 5H), 3.30-3.16(m, 2H), 2.60-2.30(m, 3H), 2.43(s, 3H), 2.39(s, 3H), 2.22-1.88(m, 3H), 1.80-1.62(m, 5H), 1.50-1.12(m, 6H), 1.06-0.82(m, 5H).
실시예 9(43)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(2-(N,N-디메틸아미노)에틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.14(클로로포름:메탄올:28% 암모니아수=200:20:1);
NMR(CD3OD): δ 8.07(d, J=8.7Hz, 2H), 7.64(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.17(d, J=2.1Hz, 1H), 4.04(m, 1H), 3.79(t, J=5.7Hz, 2H), 3.78(m, 1H), 3.63-3.49(m, 3H), 3.41(t, J=5.7Hz, 2H), 3.32-3.20(m, 2H), 3.00(s, 6H), 2.63-2.35(m, 3H), 2.45(s, 3H), 2.39(s, 3H), 2.20-1.90(m, 3H), 1.82-1.63(m, 5H), 1.48-1.13(m, 6H), 1.03-0.82(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9(44)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(2-(모르폴린-4-일)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.42(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.07(d, J=9.0Hz, 2H), 7.77(d, J=9.0Hz, 2H), 4.30(s, 2H), 4.17(d, J=2.4Hz, 1H), 4.12-3.96(m, 3H), 3.90-3.70(m, 4H), 3.62-3.48(m, 6H), 3.20-3.16(m, 6H), 2.70-2.30(m, 3H), 2.49(s, 3H), 2.41(s, 3H), 2.20-1.88(m,3H), 1.82-1.62(m, 5H), 1.50-1.10(m, 6H), 1.04-0.84(m, 5H).
실시예 9(45)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-(모르폴린-4-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.31(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.58(d, J=8.4Hz, 2H), 7.48(d, J=8.7Hz, 2H), 7.18-7.06(m, 4H), 4.36(s, 2H), 4.16(d, J=2.4Hz, 1H), 4.00(m, 1H), 3.82-3.40(m, 12H), 3.38-3.12(m, 2H), 2.52-2.24(m, 3H), 2.18-1.86(m, 3H), 1.82-1.62(m, 5H), 1.50-1.10(m, 6H), 1.02-0.82(m, 5H).
실시예 9(46)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(1,4-벤조디옥산-6-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.38(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.05(d, J=2.1Hz, 1H), 7.00-6.90(m, 2H), 4.26(s, 4H), 4.23(s, 2H), 4.15(d, J=1.8Hz, 1H), 3.94(m, 1H), 3.68(m, 1H), 3.58-3.34(m, 3H), 3.30-3.08(m, 2H), 2.50-1.86(m, 6H), 1.80-1.62(m, 5H), 1.50-1.04(m, 6H), 1.02-0.82(m, 5H).
실시예 9(47)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(N,N-디에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.36(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.99(d, J=9.0Hz, 2H), 7.73(d, J=9.0Hz, 2H), 4.31(s, 2H), 4.17(d, J=2.1Hz, 1H), 4.06(m, 1H), 3.78(m, 1H), 3.62-3.48(m, 3H), 3.34-3.14(m, 6H), 2.60-2.30(m, 3H), 2.45(s, 3H), 2.39(s, 3H), 2.20-1.88(m, 3H), 1.82-1.62(m, 5H), 1.50-1.08(m, 6H), 1.15(t, J=7.5Hz, 6H), 1.02-0.82(m, 5H).
실시예 9(48)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(피리딘-1-옥사이드-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.10(아세트산에틸:메탄올=3:1);
NMR(CD3OD): δ 8.48-8.37(m, 2H), 7.73(d, J=9.0Hz, 2H), 7.73-7.60(m, 2H), 7.31(d, J=9.0Hz, 2H), 4.39(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.01(m, 1H), 3.76(m, 1H), 3.60-3.20(m, 5H), 2.70-2.40(m, 3H), 2.20-1.90(m, 3H), 1.90-1.60(m, 5H), 1.60-1.10(m, 6H), 1.10-0.80(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 9(49)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(4-메틸피페라진-1-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.34(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.01(d, J=8.7Hz, 2H), 7.85(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.17(d, J=2.4Hz, 1H), 4.10-3.94(m, 3H), 3.78(m, 1H), 3.66-3.56(m, 5H), 3.40-3.20(m, 4H), 2.91(s, 3H), 2.88-2.72(m, 2H), 2.70-2.40(m, 3H), 2.50(s, 3H), 2.40(s, 3H), 2.20-1.88(m, 3H), 1.84-1.60(m, 5H), 1.56-1.10(m, 6H), 1.04-0.82(m, 5H).
실시예 9(50)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.44(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.84(d, J=9.0Hz, 2H), 7.59(d, J=8.7Hz, 2H), 7.15(d, J=8.7Hz, 2H), 7.07(d, J=9.0Hz, 2H), 4.36(s, 2H), 4.16(d, J=2.1Hz, 1H), 4.00(m, 1H), 3.74(m, 1H), 3.60-3.44(m, 3H), 3.28-3.16(m, 2H), 2.91(s, 3H), 2.52-2.26(m, 3H), 2.18-1.88(m, 3H), 1.82-1.62(m, 5H), 1.50-1.10(m, 6H), 1.02-0.82(m, 5H).
실시예 9(51)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(2,4-디플루오로페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.63(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 7.56(m, 1H), 7.33-7.16(m, 2H), 4.32(s, 2H), 4.18(d, J=2.4Hz, 1H), 4.04(m, 1H), 3.80(m, 1H), 3.64-3.46(m, 3H), 3.30-3.16(m, 2H), 2.62-1.88(m, 6H), 2.39(s, 3H), 2.28(s, 3H), 1.84-1.60(m, 5H), 1.52-1.10(m, 6H), 1.06-0.82(m, 2H), 0.97(t, J=6.9Hz, 3H).
실시예 9(52)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(2-(N,N-디메틸아미노)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.21(클로로포름:메탄올:28% 암모니아수=100:10:1);
NMR(CD3OD): δ 8.07(d, J=8.7Hz, 2H), 7.78(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.17(d, J=2.1Hz, 1H), 4.04(m, 1H), 3.80(m, 1H), 3.64-3.50(m, 3H), 3.40-3.22(m, 6H), 2.96(s, 6H), 2.74-2.38(m, 3H), 2.49(s, 3H), 2.41(s, 3H), 2.22-1.88(m, 3H), 1.84-1.60(m, 5H), 1.52-1.10(m, 6H), 1.06-0.82(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9(53)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-메틸아미노카르보닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.21(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.98(d, J=8.7Hz, 2H), 7.60(d, J=8.7Hz, 2H), 4.31(s, 2H), 4.16(d, J=2.1Hz, 1H), 4.04(m, 1H), 3.79(m, 1H), 3.64-3.49(m, 3H), 3.37-3.20(m, 2H), 2.94(s, 3H), 2.63-2.33(m, 3H), 2.43(s, 3H), 2.40(s, 3H), 2.16(m,1H), 2.09-1.90(m, 2H), 1.83-1.62(m, 5H), 1.50-1.12(m, 6H), 1.04-0.82(m, 5H).
실시예 9(54)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.43(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 8.05(d, J=9.0Hz, 2H), 7.61(d, J=9.0Hz, 2H), 7.19(d, J=9.0Hz, 2H), 7.08(d, J=9.0Hz, 2H), 4.38(s, 2H), 4.17(d, J=2.1Hz, 1H), 4.02(m, 1H), 3.78(m, 1H), 3.60-3.40(m, 3H), 3.30-3.10(m, 2H), 2.56-1.86(m, 6H), 1.82-1.60(m, 5H), 1.52-1.16(m, 6H), 1.06-0.82(m, 2H), 0.97(t, J=7.2Hz, 3H).
실시예 9(55)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-((4-메톡시페닐)메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.33(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.96(d, J=8.4Hz, 2H), 7.66(d, J=8.4Hz, 2H), 7.28(d, J=8.4Hz, 2H), 6.88(d, J=8.4Hz, 2H), 4.52(s, 2H), 4.43(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.02(m, 1H), 3.77(s, 3H), 3.77(m, 1H), 3.58-3.38(m, 3H), 3.30-3.10(m, 2H), 2.54-2.22(m, 3H), 2.18-1.86(m, 3H), 1.82-1.60(m, 5H), 1.50-1.08(m, 6H), 1.04-0.80(m, 2H), 0.95(t, J=6.9Hz, 3H).
실시예 9(56)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(3-메톡시프로필아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.27(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.93(d, J=8.1Hz, 2H), 7.68(d, J=8.1Hz, 2H), 4.43(s, 2H), 4.16(d, J=1.8Hz, 1H), 4.04(m, 1H), 3.78(m, 1H), 3.60-3.40(m, 7H), 3.35(s, 3H), 3.30-3.10(m, 2H), 2.58-1.60(m, 13H), 1.52-1.08(m, 6H), 1.06-0.80(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9(57)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(N-메틸-N-(2-(피리딘-2-일)에틸)아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.22(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.80(m, 1H), 8.57(m, 1H), 8.08(m, 1H), 7.96(m, 1H), 7.69(d, J=8.4Hz, 2H), 7.43(d, J=8.4Hz, 2H), 4.40(s, 2H), 4.16(d, J=2.1Hz, 1H), 4.06-3.90(m, 3H), 3.80(m, 1H), 3.62-3.38(m, 5H), 3.30-3.10(m, 2H), 3.08(s, 3H), 2.64-2.30(m, 3H), 2.18-1.84(m, 3H), 1.82-1.60(m, 5H), 1.50-1.06(m, 6H), 1.04-0.80(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9(58)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-(피롤리딘-1-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.41(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 7.59-7.56(m, 4H), 7.15(d, J=8.7Hz, 2H), 7.09(d, J=8.7Hz, 2H), 4.36(s, 2H), 4.15(d, J=2.0Hz, 1H), 4.01(m, 1H), 3.75(m, 1H), 3.60-3.46(m, 7H), 3.30-3.13(m, 2H), 2.51-2.11(m, 4H), 2.04-1.89(m, 6H), 1.80-1.65(m, 5H), 1.50-1.15(m, 6H), 1.00-0.87(m, 5H).
실시예 9(59)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-클로로페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.51(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.58(d, J=9.0Hz, 2H), 7.49(d, J=9.0Hz, 2H), 4.31(s, 2H), 4.17(d, J=2.1Hz, 1H), 4.04(m, 1H), 3.78(m, 1H), 3.62-3.48(m, 3H), 3.30-3.16(m, 2H), 2.62-2.32(m, 3H), 2.40(s, 3H), 2.39(s, 3H), 2.22-1.86(m, 3H), 1.84-1.60(m, 5H), 1.54-1.10(m, 6H), 1.06-0.82(m, 2H), 0.97(t, J=7.2Hz, 3H).
실시예 9(60)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-트리플루오로메틸페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.53(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.88(d, J=8.7Hz, 2H), 7.73(d, J=8.7Hz, 2H), 4.33(s, 2H), 4.18(d, J=2.1Hz, 1H), 4.04(m, 1H), 3.80(m, 1H), 3.64-3.46(m, 3H), 3.30-3.16(m, 2H), 2.62-2.28(m, 3H), 2.46(s, 3H), 2.40(s, 3H), 2.24-1.88(m, 3H), 1.84-1.60(m, 5H), 1.56-1.06(m, 6H), 1.06-0.82(m, 2H), 0.97(t, J=7.2Hz, 3H).
실시예 9(61)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-메톡시페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.44(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.40(d, J=8.7Hz, 2H), 7.11(d, J=8.7Hz, 2H), 4.32(s, 2H), 4.18(d, J=2.4Hz, 1H), 4.04(m, 1H), 3.88(s, 3H), 3.80(m, 1H), 3.66-3.48(m, 3H), 3.30-3.18(m, 2H), 2.64-2.30(m, 3H), 2.42(s, 3H), 2.36(s, 3H), 2.22-1.88(m, 3H), 1.84-1.60(m, 5H), 1.54-1.10(m, 6H), 1.06-0.82(m, 2H), 0.97(t, J=7.2Hz, 3H).
실시예 9(62)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-에틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.27(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.28(s, 2H), 4.23(q, J=7.2Hz, 2H), 4.17(d, J=2.4Hz, 1H), 4.00(m, 1H), 3.78(m, 1H), 3.64-3.44(m, 3H), 3.30-3.18(m, 2H), 2.70-2.34(m, 3H), 2.48(s, 3H), 2.43(s, 3H), 2.22-1.86(m, 3H), 1.84-1.60(m, 5H), 1.52-1.08(m, 6H), 1.43(t, J=7.2Hz, 3H), 1.06-0.80(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9(63)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-프로필피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.31(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.28(s, 2H), 4.16(d, J=2.4Hz, 1H), 4.15(t, J=7.2Hz, 2H), 4.00(m, 1H), 3.76(m, 1H), 3.62-3.46(m, 3H), 3.30-3.18(m, 2H), 2.66-2.36(m, 3H), 2.47(s, 3H), 2.43(s, 3H), 2.20-1.60(m, 10H), 1.52-1.10(m, 6H), 1.18(t, J=7.2Hz, 3H), 1.06-0.80(m, 2H), 0.96(t, J=7.2Hz, 3H).
실시예 9(64)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(1,1-디메틸에틸)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.33(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.26(s, 2H), 4.17(d, J=2.4Hz, 1H), 4.02(m, 1H), 3.78(m, 1H), 3.62-3.46(m, 3H), 3.30-3.22(m, 2H), 2.64-2.40(m, 3H), 2.63(s, 3H), 2.42(s, 3H), 2.20-1.86(m, 3H), 1.84-1.62(m, 5H), 1.72(s, 9H), 1.54-1.16(m, 6H), 1.04-0.82(m, 2H), 0.96(t, J=6.9Hz, 3H).
실시예 9(65)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-시클로펜틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.33(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.27(s, 2H), 4.16(d, J=2.1Hz, 1H), 4.00(m, 1H), 3.78(m, 1H), 3.64-3.44(m, 4H), 3.30-3.20(m, 2H), 2.66-2.36(m, 3H), 2.47(s, 3H), 2.42(s, 3H), 2.28-1.60(m, 16H), 1.58-1.10(m, 6H), 1.08-0.82(m, 2H), 0.96(t, J=6.9Hz, 3H).
실시예 9(66)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(2-페닐에틸)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.25(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.36-7.18(m, 3H), 7.16-7.00(m, 2H), 4.39(t, J=6.3Hz, 2H), 4.18(s, 2H), 4.17(d, J=2.4Hz, 1H), 3.88(m, 1H), 3.72-3.46(m, 2H), 3.42-3.22(m, 4H), 3.12(t, J=6.3Hz, 2H), 2.66-2.34(m, 3H), 2.44(s, 3H), 2.18-1.86(m, 3H), 1.92(s, 3H), 1.84-1.62(m, 5H), 1.54-1.10(m, 6H), 1.06-0.82(m, 2H), 0.97(t, J=6.9Hz, 3H).
실시예 9(67)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(1-벤질옥시카르보닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.40(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.42-7.25(m, 5H), 5.14(s, 2H), 4.56(m, 1H), 4.36-4.25(m, 2H), 4.25(s, 2H), 4.15(d, J=2.1Hz, 1H), 3.98(m, 1H), 3.73(m, 1H), 3.62-3.45(m, 3H), 3.40-3.20(m, 2H), 3.18-2.94(m, 2H), 2.67-2.30(m, 9H), 2.20-1.85(m, 7H), 1.83-1.58(m, 5H), 1.50-1.08(m, 6H), 1.05-0.80(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 9(68)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(시클로헥실아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.45(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.92(d, J=8.7Hz, 2H), 7.67(d, J=8.7Hz, 2H), 4.42(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.02(m, 1H), 3.92-3.69(m, 2H), 3.60-3.39(m, 3H), 3.30-3.12(m, 2H), 2.56-2.26(m, 3H), 2.17-1.58(m, 14H), 1.51-1.08(m, 10H), 1.06-0.80(m, 2H), 0.95(t, J=6.9Hz, 3H).
실시예 9(69)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(1-메틸술포닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.26(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.48(m, 1H), 4.25(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.05-3.83(m, 3H), 3.74(m, 1H), 3.60-3.46(m, 3H), 3.40-3.20(m, 2H), 3.05-2.92(m, 2H), 2.90(s, 3H), 2.60(m, 1H), 2.52-2.40(m, 2H), 2.49(s, 3H), 2.39(s, 3H), 2.26-1.88(m, 7H), 1.84-1.60(m, 5H), 1.50-1.10(m, 6H), 1.05-0.80(m, 2H), 0.95(t, J=6.9Hz, 3H).
실시예 9(70)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-(2-히드록시에틸아미노카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.50(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 7.89(d, J=9.0Hz, 2H), 7.60(d, J=9.0Hz, 2H), 7.16(d, J=9.0Hz, 2H), 7.09(d, J=9.0Hz, 2H), 4.37(s, 2H), 4.17(d, J=2.1Hz, 1H), 4.02(m, 1H), 3.78(m, 1H), 3.71(t, J=5.7Hz, 2H), 3.60-3.40(m, 3H), 3.51(t, J=5.7Hz, 2H), 3.30-3.10(m, 2H), 2.58-1.84(m, 6H), 1.82-1.56(m, 5H), 1.54-1.06(m, 6H), 1.04-0.80(m, 2H), 0.96(t, J=6.9Hz, 3H).
실시예 9(71)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-히드록시메틸페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸
TLC: Rf 0.37(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.34(d, J=8.7Hz, 4H), 6.97(d, J=8.7Hz, 2H), 6.96(d, J=8.7Hz, 2H), 4.57(s, 2H), 4.13(d, J=2.1Hz, 1H), 3.71(s, 2H), 3.47(m, 1H), 3.35(dd, J=9.0, 2.1Hz, 1H), 3.30-2.88(m, 5H), 2.31-1.81(m, 6H), 1.81-1.58(m, 5H), 1.55-1.05(m, 6H), 1.05-0.83(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 10
(3S)-1-부틸-2,5-디옥소-3-((1S)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸술포닐아미노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
참고예 3에서 제조한 화합물 대신에 참고예 3(9)에서 제조한 화합물을, 3-포르밀-6-페닐옥시피리딘 대신에 4-(4-메틸술포닐아미노페닐옥시)벤조알데히드를 이용하고, 실시예 2와 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.54(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 7.54(d, J=8.4Hz, 2H), 7.29(d, J=8.7Hz, 2H), 7.06(d, J=8.4Hz, 2H), 7.03(d, J=8.7Hz, 2H), 4.32(s, 2H), 4.15(d, J=2.0Hz, 1H),3.98(m, 1H), 3.73(m, 1H), 3.55-3.43(m, 3H), 3.30-3.16(m, 2H), 2.95(s, 3H), 2.52-2.28(m, 3H), 2.14-1.91(m, 3H), 1.76-1.65(m, 5H), 1.50-1.15(m, 6H), 1.00-0.86(m, 5H).
실시예 11
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-9-(3,5-디메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
참고예 3에서 제조한 화합물 대신에 참고예 3(4)에서 제조한 화합물을, 3-포르밀-6-페닐옥시피리딘 대신에 4-포르밀-3,5-디메틸-1-페닐피라졸을 이용하고, 실시예 2와 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.31(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 7.67-7.56(m, 5H), 4.37(s, 2H), 4.13(d, J=2.0Hz, 1H), 4.06(m, 1H), 3.98-3.91(m, 2H), 3.80(m, 1H), 3.64-3.53(m, 4H), 3.46-3.37(m, 3H), 2.80-2.52(m, 5H), 2.45(s, 3H), 2. 16-2.01(m, 2H), 1.91-1.82(m, 2H), 1.71(m, 1H), 1.50-1.17(m, 6H), 0.95(t, J=7.5Hz, 3H).
실시예 11(1)∼11(5)
4-포르밀-3,5-디메틸-1-페닐피라졸 대신에 해당하는 알데히드 유도체를 이용하고, 실시예 11과 동일한 조작을 하여, 이하에 나타낸 본 발명 화합물을 얻었다.
실시예 11(1)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.28(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 7.84(d, J=8.7Hz, 2H), 7.59(d, J=8.7Hz, 2H), 7.15(d, J=8.7Hz, 2H), 7.07(d, J=8.7Hz, 2H), 4.36(s, 2H), 4.12(d, J=2.0Hz, 1H), 4.06-3.90(m, 3H), 3.75(m, 1H), 3.56-3.34(m, 5H), 3.30-3.20(m, 2H), 2.91(s, 3H), 2.51-2.28(m, 3H), 2.16-1.69(m, 5H), 1.50-1.15(m, 5H), 0.95(t, J=7.0Hz, 3H).
실시예 11(2)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-9-(4-(4-(4-메톡시페닐메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.36(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 7.95(d, J=8.3Hz, 2H), 7.66(d, J=8.3Hz, 2H), 7.27(d, J=8.8Hz, 2H), 6.87(d, J=8.8Hz, 2H), 4.51(s, 2H), 4.42(s, 2H), 4.11(d, J=2.0Hz, 1H), 4.04-3.91(m, 3H), 3.76(m, 1H), 3.76(s, 3H), 3.56-3.37(m, 5H), 3.30-3.13(m, 2H), 2.50-1.70(m, 8H), 1.39-1.15(m, 5H), 0.95(t, J=7.0Hz, 3H).
실시예 11(3)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노카르보닐)페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.55(클로로포름:메탄올=4:1);
NMR(CD3OD): δ 7.63(d, J=9.0Hz, 2H), 7.60(d, J=9.0Hz, 2H), 4.32(s, 2H), 4.13(d, J=2.0Hz, 1H), 4.06(m, 1H), 4.00-3.91(m, 2H), 3.79(m, 1H), 3.63-3.52(m, 4H), 3.46-3.34(m, 3H), 3.13(s, 3H), 3.04(s, 3H), 2.62-2.37(m, 2H), 2.44(s, 3H), 2.41(s, 3H), 2.15(m, 1H), 2.03(m, 1H), 1.90-1.70(m, 3H), 1.50-1.15(m, 6H), 0.96(t, J=7.0Hz, 3H).
실시예 11(4)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.30(클로로포름:메탄올=4:1);
NMR(CD3OD): δ 8.04(d, J=9.0Hz, 2H), 7.60(d, J=8.5Hz, 2H), 7.18(d, J=8.5Hz, 2H), 7.07(d, J=9.0Hz, 2H), 4.37(s, 2H), 4.12(d, J=2.0Hz, 1H), 4.08-3.93(m, 3H), 3.75(m, 1H), 3.57-3.34(m, 5H), 3.30-3.15(m, 2H), 2.52-1.69(m, 8H), 1.50-1.18(m, 5H), 0.96(t, J=7.2Hz, 3H).
실시예 11(5)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-9-(4-(4-메틸술포닐아미노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.35(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 7.53(d, J=8.7Hz, 2H), 7.29(d, J=8.7Hz, 2H), 7.06(d, J=8.7Hz, 2H), 7.03(d, J=8.7Hz, 2H), 4.33(s, 2H), 4.12(d, J=2.0Hz, 1H), 4.04-3.92(m, 3H), 3.72(m, 1H), 3.54-3.38(m, 5H), 3.30-3.13(m, 2H), 2.95(s, 3H), 2.51-2.26(m, 3H), 2.16-2.00(m, 2H), 1.89-1.70(m, 3H), 1.50-1.15(m, 5H), 0.95(t, J=7.0Hz, 3H).
실시예 12
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로펜틸메틸)-9-(3,5-디메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
참고예 3에서 제조한 화합물 대신에 참고예 3(5)에서 제조한 화합물을, 3-포르밀-6-페닐옥시피리딘 대신에 4-포르밀-3,5-디메틸-1-페닐피라졸을 이용하고, 실시예 2와 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.45(아세트산에틸:메탄올=4:1);
NMR(CD3OD): δ 7.64-7.51(m, 5H), 4.34(s, 2H), 4.05(m, 1H), 4.01(d, J=2.0Hz, 1H), 3.79(m, 1H), 3.63-3.52(m, 3H), 3.39(dd, J=9.9, 2.0Hz, 1H),3.30(m, 1H), 2.64(m, 1H), 2.48(m, 1H), 2.47(s, 3H), 2.42(s, 3H), 2.37-2.12(m, 2H), 1.90-1.82(m, 2H), 1.74-1.15(m, 11H), 0.96(t, J=7.5Hz, 3H).
실시예 12(1)∼12(3)
4-포르밀-3,5-디메틸-1-페닐피라졸 대신에 해당하는 알데히드 유도체를 이용하고, 실시예 12와 동일한 조작을 하여, 이하에 나타낸 본 발명 화합물을 얻었다.
실시예 12(1)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로펜틸메틸)-9-(4-(4-(4-메톡시페닐메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.35(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.96(d, J=8.7Hz, 2H), 7.66(d, J=8.7Hz, 2H), 7.28(d, J=8.7Hz, 2H), 6.88(d, J=8.7Hz, 2H), 4.52(s, 2H), 4.42(s, 2H), 4.02(m, 1H), 4.00(d, J=1.8Hz, 1H), 3.77(s, 3H), 3.77(m, 1H), 3.60-3.02(m, 5H), 2.58-2.04(m, 5H), 2.00-1.06(m, 12H), 0.96(t, J=7.5Hz, 3H).
실시예 12(2)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로펜틸메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.25(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.85(d, J=8.7Hz, 2H), 7.60(d, J=8.7Hz, 2H), 7.16(d, J=8.7Hz, 2H), 7.08(d, J=8.7Hz, 2H), 4.37(s, 2H), 4.02(m, 1H), 4.01(d, J=2.1Hz, 1H), 3.78(m, 1H), 3.40-3.12(m, 5H), 2.92(s, 3H), 2.60-2.06(m, 5H), 2.00-1.08(m, 12H), 0.96(t, J=7.2Hz, 3H).
실시예 12(3)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로펜틸메틸)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.36(클로로포름:메탄올=5:1);
NMR(CD3OD): δ 8.05(d, J=8.7Hz, 2H), 7.61(d, J=8.7Hz, 2H), 7.19(d, J=8.7Hz, 2H), 7.08(d, J=8.7Hz, 2H), 4.38(s, 2H), 4.02(m, 1H), 4.01(d, J=1.8Hz, 1H), 3.78(m, 1H), 3.62-3.08(m, 5H), 2.60-2.06(m, 5H), 2.00-1.08(m, 12H), 0.96(t, J=6.9Hz, 3H).
실시예 13
(3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
참고예 3에서 제조한 화합물 대신에 참고예 3(6)에서 제조한 화합물을, 3-포르밀-6-페닐옥시피리딘 대신에 4-(4-메틸아미노카르보닐페닐옥시)벤즈알데히드를 이용하고, 실시예 2와 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.35(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.84(d, J=9.0Hz, 2H), 7.61(d, J=8.7Hz, 2H), 7.14(d, J=8.7Hz, 2H), 7.07(d, J=9.0Hz, 2H), 4.36(s, 2H), 4.14(d, J=1.8Hz, 1H), 3.99(m, 1H), 3.74(m, 1H), 3.55-3.40(m, 3H), 3.20(m, 1H), 3.19(dd, J=9.6, 1.8Hz, 1H), 2.91(s, 3H), 2.59-2.29(m, 3H), 2.12(m, 1H), 2.00(m, 1H), 1.74(m, 1H), 1.46(m, 1H), 0.99(d, J=6.6Hz, 3H), 0.97(d, J=6.6Hz, 3H), 0.93(t, J=7.5Hz, 3H).
실시예 13(1) 및 13(2)
4-(4-메틸아미노카르보닐페닐옥시)벤즈알데히드 대신에 해당하는 알데히드 유도체를 이용하고, 실시예 13과 동일한 조작을 하여, 이하에 나타낸 본 발명 화합물을 얻었다.
실시예 13(1)
(3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.39(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.40(m, 1H), 4.30(s, 2H), 4.14(d, J=2.1Hz, 1H), 4.00(m, 1H), 3.76(m, 1H), 3.59-3.43(m, 3H), 3.22(m, 1H), 3.20(dd, J=9.6, 2.1Hz, 1H), 2.66(m, 1H), 2.53(s, 3H), 2.49(s, 3H), 2.50-2.38(m, 2H), 2.15-1.10(m, 14H), 0.99(d, J=6.6Hz, 3H), 0.98(d, J=6.6Hz, 3H), 0.93(t, J=7.5Hz, 3H).
실시예 13(2)
(3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메톡시페닐메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.41(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.95(d, J=8.7Hz, 2H), 7.69(d, J=8.7Hz, 2H), 7.27(d, J=8.7Hz, 2H), 6.87(d, J=8.7Hz, 2H), 4.51(s, 2H), 4.42(s, 2H), 4.13(d, J=2.1Hz, 1H), 4.01(m, 1H), 3.76(m, 1H), 3.76(s, 3H), 3.54-3.39(m, 3H), 3.19(m, 1H), 3.18(dd, J=9.6, 2.1Hz, 1H), 2.58-2.26(m, 3H), 2.10(m, 1H), 1.99(m, 1H), 1.72(m, 1H), 1.46(m, 1H), 0.98(d, J=6.6Hz, 3H), 0.96(d, J=6.6Hz, 3H), 0.92(t, J=7.5Hz, 3H).
실시예 14
(3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
참고예 3에서 제조한 화합물 대신에 참고예 3(7)에서 제조한 화합물을, 3-포르밀-6-페닐옥시피리딘 대신에 4-(4-메틸아미노카르보닐페닐옥시)벤즈알데히드를 이용하고, 실시예 2와 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.38(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.84(d, J=9.0Hz, 2H), 7.60(d, J=9.0Hz, 2H), 7.15(d, J=9.0Hz, 2H), 7.07(d, J=9.0Hz, 2H), 4.36(s, 2H), 4.15(d, J=2.1Hz, 1H), 3.99(m, 1H), 3.75(m, 1H), 3.54-3.39(m, 3H), 3.30-3.10(m, 2H), 2.91(s, 3H), 2.56-2.27(m, 3H), 2.18-1.88(m, 3H), 1.83-1.60(m, 5H), 1.46(m, 1H), 1.37-1.11(m, 3H), 1.04-0.80(m, 2H), 0.93(t, J=7.5Hz, 3H).
실시예 14(1)∼14(5)
4-(4-메틸아미노카르보닐페닐옥시)벤즈알데히드 대신에 해당하는 알데히드 유도체를 이용하고, 실시예 14와 동일한 조작을 하여, 이하에 나타낸 본 발명 화합물을 얻었다.
실시예 14(1)
(3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.41(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.39(m, 1H), 4.29(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.00(m,1H), 3.76(m, 1H), 3.60-3.42(m, 3H), 3.40-3.20(m, 2H), 2.65(m, 1H), 2.53(s, 3H), 2.49(s, 3H), 2.53-2.35(m, 2H), 2.15-1.05(m, 22H), 1.05-0.80(m, 2H), 0.93(t, J=7.2Hz, 3H).
실시예 14(2)
(3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메톡시페닐메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.42(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.94(d, J=8.7Hz, 2H), 7.68(d, J=8.7Hz, 2H), 7.27(d, J=8.7Hz, 2H), 6.87(d, J=8.7Hz, 2H), 4.51(s, 2H), 4.41(s, 2H), 4.14(d, J=1.8Hz, 1H), 4.01(m, 1H), 3.76(m, 1H), 3.76(s, 3H), 3.54-3.38(m, 3H), 3.27(dd, J=9.6, 1.8Hz, 1H), 3.18(m, 1H), 2.57-2.26(m, 3H), 2.16-1.86(m, 3H), 1.82-1.60(m, 5H), 1.54-1.05(m, 4H), 1.03-0.80(m, 2H), 0.92(t, J=7.5Hz, 3H).
실시예 14(3)
(3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.36(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.63(s, 4H), 4.32(s, 2H), 4.16(d, J=2.1Hz, 1H), 4.04(m, 1H), 3.79(m, 1H), 3.64-3.43(m, 3H), 3.34-3.20(m, 2H), 3.13(s, 3H), 3.04(s, 3H), 2.62(m, 1H), 2.53-2.39(m, 2H), 2.45(s, 3H), 2.44(s, 3H), 2.19-1.88(m, 3H), 1.83-1.60(m, 5H), 1.46(m, 1H), 1.38-1.10(m, 3H), 1.05-0.80(m, 2H), 0.95(t, J=7.5Hz, 3H).
실시예 14(4)
(3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.21(클로로포름:메탄올:아세트산=20:2:1);
NMR(CD3OD): δ 8.04(d, J=9.0Hz, 2H), 7.62(d, J=8.4Hz, 2H), 7.17(d, J=8.4Hz, 2H), 7.07(d, J=9.0Hz, 2H), 4.37(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.01(m, 1H), 3.75(m, 1H), 3.55-3.38(m, 3H), 3.30-3.09(m, 2H), 2.55-2.26(m, 3H), 2.18-1.88(m, 3H), 1.83-1.60(m, 5H), 1.57-1.10(m, 4H), 1.04-0.80(m, 2H), 0.93(t, J=7.5Hz, 3H).
실시예 14(5)
(3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메톡시카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.54(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.03(d, J=8.7Hz, 2H), 7.62(d, J=8.7Hz, 2H), 7.17(d, J=8.7Hz, 2H), 7.07(d, J=8.7Hz, 2H), 4.37(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.00(m, 1H), 3.88(s, 3H), 3.75(m, 1H), 3.54-3.41(m, 3H), 3.30-3.10(m, 2H), 2.58-2.27(m, 3H), 2.18-1.87(m, 3H), 1.84-1.61(m, 5H), 1.56-1.08(m, 4H), 1.04-0.80(m, 2H), 0.94(t, J=7.2Hz, 3H).
실시예 15
(3R)-1-프로필-2,5-디옥소-3-(1-시클로헥실메틸리덴)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
실시예 4(42)에서 제조한 화합물 대신에 실시예 14(5)에서 제조한 화합물을 이용하고, 실시예 5와 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.42(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.03(d, J=8.7Hz, 2H), 7.62(d, J=8.7Hz, 2H), 7.17(d,J=8.7Hz, 2H), 7.07(d, J=8.7Hz, 2H), 5.87(d, J=10.5Hz, 1H), 4.37(s, 2H), 3.78-3.62(m, 2H), 3.58-3.38(m, 4H), 2.54-2.36(m, 3H), 2.27-2.15(m, 2H), 1.80-1.51(m, 7H), 1.50-1.08(m, 5H), 0.93(t, J=7.2Hz, 3H).
실시예 16
(3S)-1-프로필-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
(2R,3R)-2-(t-부톡시카르보닐아미노)-3-히드록시-4-메틸펜탄산 대신에 해당하는 아미노산 유도체를, n-부틸아민 대신에 해당하는 아민 유도체를, 3-포르밀-6-페닐옥시피리딘 대신에 해당하는 알데히드 유도체를 이용하고, 참고예 1→참고예 2→실시예 1→참고예 3→실시예 2와 동일한 조작을 하여, 이하에 나타낸 화합물을 얻었다.
TLC: Rf 0.51(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.39-4.27(m, 1H), 4.28(s, 2H), 4.01(dd, J=7.8, 4.5Hz, 1H), 3.92-3.68(m, 2H), 3.61-3.50(m, 2H), 3.47-3.38(m, 2H), 2.68-2.50(m, 2H), 2.49(s, 3H), 2.45(s, 3H), 2.25-2.05(m, 2H), 2.03-1.20(m, 15H), 0.98-0.89(m,9H).
실시예 16(1)∼16(6)
1-시클로헥실-4-포르밀-3,5-디메틸피라졸 대신에, 해당하는 알데히드 유도체를 이용하고, 실시예 16과 동일한 조작을 하여, 이하에 나타낸 본 발명 화합물을 얻었다.
실시예 16(1)
(3S)-1-프로필-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-메틸술포닐아미노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.53(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.53(d, J=8.7Hz, 2H), 7.29(d, J=9.0Hz, 2H), 7.07(d, J=8.7Hz, 2H), 7.03(d, J=9.0Hz, 2H), 4.34(s, 2H), 4.01(dd, J=7.8, 4.8Hz, 1H), 3.90-3.69(m, 2H), 3.55-3.43(m, 2H), 3.39-3.30(m, 2H), 2.95(s, 3H), 2.48-2.29(m, 2H), 2.28-2.09(m, 2H), 1.90-1.44(m, 5H), 0.94(d, J=6.6Hz, 3H), 0.93(d, J=6.6Hz, 3H), 0.93(t, J=7.5Hz, 3H).
실시예 16(2)
(3S)-1-프로필-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-(N,N-디메틸아미노)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·3염산염
TLC: Rf 0.09(클로로포름:메탄올:아세트산=10:5:1);
NMR(CD3OD): δ 8.07(d, J=9.0Hz, 2H), 7.78(d, J=9.0Hz, 2H), 4.31(s, 2H), 4.02(dd, J=7.8, 4.5Hz, 1H), 3.95-3.73(m, 2H), 3.66-3.56(m, 2H), 3.50-3.40(m, 2H), 3.35-3.20(m, 4H), 2.95(s, 6H), 2.72-2.53(m, 2H), 2.49(s, 3H), 2.41(s, 3H), 2.30-2.08(m, 2H), 1.92-1.45(m, 5H), 0.99-0.89(m, 9H).
실시예 16(3)
(3S)-1-프로필-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.57(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.43-4.25(m, 1H), 4.29(s, 2H), 4.04(dd, J=7.8, 4.5Hz, 1H), 3.92-3.70(m, 2H), 3.60-3.50(m, 2H), 3.48-3.38(m, 2H), 2.70-2.50(m, 2H), 2.51(s, 3H), 2.47(s, 3H), 2.25-2.03(m, 2H), 2.03-1.40(m, 19H), 1.40-1.08(m, 4H), 1.05-0.83(m, 2H), 0.93(t, J=7.5Hz, 3H).
실시예 16(4)
(3S)-1-프로필-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-메틸술포닐아미노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.55(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.53(d, J=9.0Hz, 2H), 7.29(d, J=9.0Hz, 2H), 7.07(d, J=9.0Hz, 2H), 7.03(d, J=9.0Hz, 2H), 4.33(s, 2H), 4.04(dd, J=7.5, 4.5Hz, 1H), 3.89-3.69(m, 2H), 3.54-3.43(m, 2H), 3.39-3.30(m, 2H), 2.95(s, 3H), 2.50-2.30(m, 2H), 2.28-2.06(m, 2H), 1.83-1.40(m, 10H), 1.40-1.10(m, 3H), 1.05-0.85(m, 2H), 0.93(t, J=7.5Hz, 3H).
실시예 16(5)
1-부틸-2,5-디옥소-9-(4-(4-메틸술포닐아미노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.48(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.54(d, J=8.7Hz, 2H), 7.29(d, J=8.7Hz, 2H), 7.06(d, J=8.7Hz, 2H), 7.03(d, J=8.7Hz, 2H), 4.32(s, 2H), 3.97(s, 2H), 3.77-3.62(m, 2H), 3.55-3.35(m, 4H), 2.95(s, 3H), 2.48-2.33(m, 2H), 2.33-2.22(m, 2H), 1.60-1.46(m, 2H), 1.43-1.26(m, 2H), 0.95(t, J=7.2Hz, 3H).
실시예 16(6)
1-부틸-2,5-디옥소-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.50(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.34(m, 1H), 4.27(s, 2H), 3.97(s, 2H), 3.78-3.65(m, 2H), 3.62-3.47(m, 4H), 2.65-2.50(m, 2H), 2.50(s, 3H), 2.45(s, 3H), 2.31-2.20(m, 2H), 2.04-1.70(m, 6H), 1.65-1.42(m, 4H), 1.42-1.20(m, 4H), 0.94(t, J=7.2Hz, 3H).
실시예 17
(3R)-1-(2-부티닐)-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
(2R,3R)-2-(t-부톡시카르보닐아미노)-3-히드록시-4-메틸펜탄산 대신에(2R,3R)-2-(t-부톡시카르보닐아미노)-3-시클로헥실-3-히드록시프로판산을, n-부틸아민 대신에 2-부티닐아민을, N-벤질-4-피페리돈 대신에 N-(3,5-디메틸-1-페닐피라졸-4-일)메틸-4-피페리돈을, 벤질이소니트릴 대신에 n-부틸이소니트릴을 이용하고, 참고예 1→참고예 2→실시예 1과 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.45(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.60-7.45(m, 5H), 4.44-4.28(m, 3H), 4.21(d, J=2.1Hz, 1H), 4.10-3.94(m, 2H), 3.79(m, 1H), 3.66-3.54(m, 2H), 3.32(m, 1H), 2.74(m, 1H), 2.56-2.34(m, 8H), 2.24(m, 1H), 2.08-1.90(m, 2H), 1.84-1.62(m, 7H), 1.44-1.12(m, 3H), 1.05-0.82(m, 2H).
실시예 17(1)
(3S)-1-(2-부티닐)-2,5-디옥소-3-((1S)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
(2R,3R)-2-(t-부톡시카르보닐아미노)-3-시클로헥실-3-히드록시프로판산 대신에 (2S,3S)-2-(t-부톡시카르보닐아미노)-3-시클로헥실-3-히드록시프로판산을 이용하고, 실시예 17과 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.45(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.60-7.45(m, 5H), 4.44-4.28(m, 3H), 4.21(d, J=2.1Hz, 1H), 4.10-3.94(m, 2H), 3.79(m, 1H), 3.66-3.54(m, 2H), 3.32(m, 1H), 2.74(m, 1H), 2.56-2.34(m, 8H), 2.24(m, 1H), 2.08-1.90(m, 2H), 1.84-1.62(m, 7H), 1.44-1.12(m, 3H), 1.05-0.82(m, 2H).
실시예 18
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(2-(4-페닐옥시페닐)에틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
PS-TsCl-HL 수지(상품명, Argonaut Technologies사, 카탈로그 번호800366)(305 ㎎)에 2-(4-페닐옥시페닐)에틸알코올(112 ㎎)의 디클로로메탄(2 ㎖), 피리딘(2 ㎖) 용액을 가하였다. 반응 혼합물을 실온에서 5시간 교반하였다. 수지를 디클로로메탄으로 3회, 디메틸포름아미드로 5회, 디메틸포름아미드:물=3:1로 5회, 테트라히드로푸란으로 3회, 디클로로메탄으로 3회, 아세토니트릴로 3회 세정하였다. 얻어진 수지에 참고예 3(2)에서 제조한 화합물(116 ㎎)의 아세토니트릴(5 ㎖) 용액과 디이소프로필에틸아민(0.366 ㎖)을 가하였다. 반응 혼합물을 70℃에서 18시간 교반하였다. 방냉 후, 아세토니트릴로 수지를 세정하고, 얻어진 세정액을 농축하였다. 얻어진 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸:메탄올=20:1)에 의해 정제하고, 추가로 염산으로 처리함으로써, 이하의 물성치를 갖는 본 발명 화합물(82 ㎎)을 얻었다.
TLC: Rf 0.54(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.37-7.29(m, 4H), 7.11(t, J=7.2Hz, 1H), 6.97-6.95(m, 4H), 4.06(d, J=7.5, 4.5Hz, 1H), 3.88-3.77(m, 2H), 3.65(m, 2H), 3.46-3.36(m, 4H), 3.13-3.07(m, 2H), 2.48(m, 2H), 2.28-2.14(m, 2H) ,1.80-1.21(m, 15H), 0.98(t, J=7.0Hz, 3H), 0.99-0.91(m, 2H).
실시예 18(1) 및 18(2)
2-(4-페닐옥시페닐)에틸알코올 대신에 해당하는 알코올 유도체를, 참고예 3(2)에서 제조한 화합물 대신에 참고예 3(1)에서 제조한 화합물을 이용하고, 실시예 18과 동일한 조작을 하여, 이하에 나타낸 본 발명 화합물을 얻었다.
실시예 18(1)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(2-(4-페닐옥시페닐)에틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.37(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.37-7.29(m, 4H), 7.11(t, J=7.5Hz, 1H), 6.98-6.95(m, 4H), 4.03(d, J=7.5, 4.5Hz, 1H), 3.89-3.77(m, 2H), 3.64(m, 2H), 3.42-3.32(m, 4H), 3.12-3.07(m, 2H), 2.45(m, 2H), 2.29-2.16(m, 2H), 1.88-1.36(m, 7H), 0.98(t, J=7.0Hz, 3H), 0.95(d, J=6.3Hz, 3H), 0.94(d, J=6.3Hz, 3H).
실시예 18(2)
(3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(2-(4-메톡시페닐)에틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.37(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.22(d, J=9.0Hz, 2H), 6.90(d, J=9.0Hz, 2H), 4.01(d, J=7.5, 4.5Hz, 1H), 3.87-3.77(m, 2H), 3.77(s, 3H), 3.63(m, 2H), 3.43-3.32(m, 4H), 3.03(m, 2H), 2.44(m, 2H), 2.28-2.15(m, 2H), 1.85-1.36(m, 7H), 0.97(t, J=7.5Hz, 3H), 0.95(d, J=6.3Hz, 3H), 0.94(d, J=6.3Hz, 3H).
실시예 19
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-에톡시카르보닐페닐)-1,4,9-트리아자스피로[5.5]운데칸·염산염
참고예 3(2)에서 제조한 화합물(186 ㎎)의 디메틸설폭사이드(3 ㎖) 용액에 에틸 4-플루오로벤조에이트(164 ㎎)와 탄산칼륨(141 ㎎)을 가하였다. 반응 혼합물을 140℃에서 24시간 교반하였다. 반응 혼합물에 물을 가하고, t-부틸메틸에테르로 추출하였다. 추출물을 포화염화나트륨 수용액으로 세정하고, 무수황산마그네슘으로 건조시켜 농축하였다. 얻어진 잔류물을 실리카겔 컬럼 크로마토그래피(헥산:아세트산에틸=4:1→3:1)에 의해 정제하고, 추가로 4N 염화수소아세트산에틸 용액으로 처리하여, 이하의 물성치를 갖는 본 발명 화합물(67 ㎎)을 얻었다.
TLC: Rf 0.27(헥산:아세트산에틸=2:1);
NMR(CD3OD): δ 8.13(d, J=8.7Hz, 2H), 7.59(d, J=8.7Hz, 2H), 4.37(q, J=7.2Hz, 2H), 4.31-4.15(m, 2H), 4.07(dd, J=7.5, 4.5Hz, 1H), 3.85-3.75(m, 2H), 3.47-3.38(m, 2H), 2.67-2.50(m, 2H), 2.30-2.12(m, 2H), 1.85-1.46(m, 10H), 1.44-1.19(m, 5H), 1.38(t, J=7.2Hz, 3H), 1.05-0.88(m, 2H), 0.95(t, J=7.2Hz, 3H).
참고예 4
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-벤질옥시카르보닐-1,4,9-트리아자스피로[5.5]운데칸
(2R,3R)-2-(t-부톡시카르보닐아미노)-3-히드록시-4-메틸펜탄산 대신에 (3S)-2-(t-부톡시카르보닐아미노)-3-시클로헥실프로판산을, N-벤질-4-피페리돈 대신에 N-벤질옥시카르보닐-4-피페리돈을 이용하고, 참고예 1→참고예 2→실시예 1과 동일한 조작을 하여, 이하의 물성치를 갖는 표제 화합물을 얻었다.
TLC: Rf 0.35(헥산:아세트산에틸=1:1);
NMR(CD3OD): δ 7.39-7.31(m, 5H), 6.48(brs, 1H), 5.16(s, 2H), 4.15(brs, 2H), 4.00(ddd, J=9.6, 4.8, 1.5Hz, 1H), 3.76-3.16(m, 4H), 2.02-1.12(m, 19H),1.08-0.88(m, 2H), 0.92(t, J=7.2Hz, 3H).
참고예 5
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-4-메틸-9-벤질옥시카르보닐-1,4,9-트리아자스피로[5.5]운데칸
참고예 4에서 제조한 화합물(1 g)의 디메틸포름아미드(20 ㎖) 용액에 빙냉 하에서 60% 수소화나트륨(164 ㎎)을 가하였다. 혼합물을 실온에서 1시간 교반하였다. 혼합물에 빙냉 하에서 요오드화메틸(0.3 ㎖)을 가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 반응 혼합물에 얼음물을 가하고, 아세트산에틸로 추출하였다. 추출물을 물, 포화염화나트륨 수용액으로 세정하고, 무수황산마그네슘으로 건조시켜 농축하였다. 얻어진 잔류물을 실리카겔 컬럼 크로마토그래피(헥산:아세트산에틸=2:1)에 의해 정제하여 이하의 물성치를 갖는 표제 화합물(1 g)을 얻었다.
TLC: Rf 0.34(헥산:아세트산에틸=1:1);
NMR(CD3OD): δ 7.40-7.32(m, 5H), 5.16(s, 2H), 4.12(brs, 2H), 3.91(t, J=5.7Hz, 1H), 3.88(brs, 1H), 3.49(m, 1H), 3.35(m, 1H), 2.92(s, 3H), 2.90(m, 1H), 2.04-1.10(m, 19H), 1.04-0.82(m, 2H), 0.92(t, J=7.2Hz, 3H).
참고예 6
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-4-메틸-1,4,9-트리아자스피로[5.5]운데칸·염산염
참고예 5에서 제조한 화합물(1 g)의 메탄올(20 ㎖) 용액에 10% 팔라듐탄소(60 ㎎)를 가하였다. 반응 혼합물을 수소 가스 분위기 하의 실온에서 8시간 교반하였다. 반응 혼합물을 셀라이트(상품명)를 이용하여, 여과하고, 여과액에 4N 염화수소아세트산에틸 용액을 가하고, 농축하여, 이하의 물성치를 갖는 표제 화합물(799 ㎎)을 얻었다.
TLC: Rf 0.28(클로로포름:메탄올:아세트산=90:10:1);
NMR(CD3OD): δ 4.05(dd, J=7.5, 4.2Hz, 1H), 4.01(dt, J=4.2, 12.9Hz, 1H), 3.59(dt, J=3.3, 12.9Hz, 1H), 3.51(m, 1H), 3.40(brd, J=5.4Hz, 1H), 3.36(brd, J=5.4Hz, 1H), 3.25(m, 1H), 2.93(s, 3H), 2.37(dt, J=5.4, 14.4Hz, 1H), 2.32(dt, J=5.4, 14.4Hz, 1H), 2.11(brd, J=14.4Hz, 1H), 1.99(brd, J=14.4Hz, 1H), 1.86-1.14(m, 15H), 1.07-0.87(m, 2H), 0.97(t, J=7.2Hz, 3H).
실시예 20
(3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-4-메틸-9-(4-페닐옥시페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
참고예 3에서 제조한 화합물 대신에 참고예 6에서 제조한 화합물을 이용하고, 실시예 2와 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.32(아세트산에틸);
NMR(CD3OD): δ 7.53(d, J=8.7Hz, 2H), 7.39(dd, J=8.7, 7.5Hz, 2H), 7.18(t, J=7.5Hz, 1H), 7.09-7.01(m, 4H), 4.34(s, 2H), 4.05(m, 1H), 4.04(dd, J=7.2, 3.9Hz, 1H), 3.68-3.43(m, 4H), 3.27(m, 1H), 2.93(s, 3H), 2.48(dd, J=14.4, 5.4Hz, 1H), 2.39(dd, J=14.4, 5.4Hz, 1H), 2.16(brd, J=14.4Hz, 1H), 2.03(brd, J=14.4Hz, 1H), 1.86-1.58(m, 8H), 1.53-1.14(m, 7H), 1.07-0.86(m, 2H), 0.95(t, J=7.5Hz, 3H).
실시예 21
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(2-메틸프로파노일아미노)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
참고예 3에서 제조한 화합물 대신에 참고예 3(3)에서 제조한 화합물을, 3-포르밀-6-페닐옥시피리딘 대신에 4-(2-메틸프로파노일아미노)벤조알데히드를 이용하고, 실시예 2와 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.28(클로로포름:메탄올=10:1);
NMR(d6-DMSO): δ 10.6(s, 1H), 10.0(s, 1H), 8.02(m, 1H), 7.68(d, J=8.7Hz, 2H), 7.52(d, J=8.7Hz, 2H), 5.24(s, 1H), 4.22(s, 2H), 3.96(m, 1H), 3.70(m, 1H), 3.66-3.12(m, 6H), 2.68-2.20(m, 4H), 2.02-1.42(m, 8H), 1.40-1.00(m, 6H), 1.10(d, J=6.9Hz, 6H), 0.98-0.64(m, 2H), 0.88(t, J=6.9Hz, 3H).
실시예 21(1)∼21(6)
4-(2-메틸프로파노일아미노)벤조알데히드 대신에 해당하는 알데히드 유도체를 이용하고, 실시예 21과 동일한 조작을 하여, 이하에 나타낸 본 발명 화합물을 얻었다.
실시예 21(1)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(2-메톡시아세틸아미노)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.36(클로로포름:메탄올=10:1);
NMR(d6-DMSO): δ 10.5(s, 1H), 9.95(s, 1H), 8.02(m, 1H), 7.75(d, J=8.4Hz, 2H), 7.55(d, J=8.4Hz, 2H), 4.26(s, 2H), 4.02(s, 2H), 3.96(m, 1H), 3.80-3.10(m, 7H), 3.38(s, 3H), 2.60-2.18(m, 4H), 2.02-1.44(m, 8H), 1.40-1.00(m, 6H), 0.98-0.64(m, 2H), 0.88(t, J=7.2Hz, 3H).
실시예 21(2)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(2-페닐아세틸아미노)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.27(클로로포름:메탄올=10:1);
NMR(d6-DMSO): δ 10.6(s, 1H), 10.4(s, 1H), 8.01(m, 1H), 7.67(d, J=9.0Hz, 2H), 7.54(d, J=9.0Hz, 2H), 7.40-7.18(m, 5H), 4.24(s, 2H), 3.96(s, 1H), 3.84-3.10(m, 8H), 2.62-2.18(m, 4H), 2.04-1.42(m, 8H), 1.40-1.00(m, 6H), 0.98-0.64(m, 2H), 0.88(t, J=7.2Hz, 3H).
실시예 21(3)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(2-(4-플루오로페닐)아세틸아미노)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.26(클로로포름:메탄올=10:1);
NMR(d6-DMSO): δ 10.8(s, 1H), 10.4(s, 1H), 8.01(m, 1H), 7.66(d, J=8.4Hz, 2H), 7.54(d, J=8.4Hz, 2H), 7.37(dd, J=8.4, 5.4Hz, 2H), 7.14(t, J=8.4Hz, 2H), 4.34-3.10(m, 8H), 4.24(s, 2H), 3.96(s, 1H), 2.66-2.18(m, 4H), 2.02-1.42(m, 8H), 1.40-1.00(m, 6H), 0.98-0.64(m, 2H), 0.88(t, J=6.9Hz, 3H).
실시예 21(4)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메톡시카르보닐페닐아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.35(클로로포름:메탄올=10:1);
NMR(d6-DMSO): δ 10.90(br.s, 1H), 10.70(s, 1H), 8.05(m, 1H), 8.04(d, J=8.4Hz, 2H), 7.97(s, 4H), 7.83(d, J=8.4Hz, 2H), 5.24(m, 1H), 4.43(s, 2H), 3.97(m, 1H), 3.90-3.06(m, 7H), 3.84(s, 3H), 2.62-2.20(m, 3H), 2.06-1.42(m,8H), 1.40-1.02(m, 6H), 0.98-0.66(m, 2H), 0.89(t, J=6.9Hz, 3H).
실시예 21(5)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메톡시페닐메틸옥시카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.41(클로로포름:메탄올=10:1);
NMR(d6-DMSO): δ 10.6(s, 1H), 8.03(d, J=8.7Hz, 2H), 8.02(m, 1H), 7.78(d, J=8.7Hz, 2H), 7.42(d, J=8.7Hz, 2H), 6.96(d, J=8.7Hz, 2H), 5.30(s, 2H), 5.24(m, 1H), 4.42(s, 2H), 3.96(m, 1H), 3.86-3.10(m, 7H), 3.76(s, 3H), 2.64-2.20(m, 3H), 2.02-1.42(m, 8H), 1.40-1.00(m, 6H), 0.96-0.68(m, 2H), 0.88(t, J=6.3Hz, 3H).
실시예 21(6)
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(2-(4-메틸아미노카르보닐페닐옥시)피리딘-5-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.37(클로로포름:메탄올=9:1);
NMR(CD3OD): δ 8.35(d, J=2.5Hz, 1H), 8.15(dd, J=8.5, 2.5Hz, 1H), 7.89(d, J=8.5Hz, 2H), 7.23(d, J=8.5Hz, 2H), 7.14(d, J=8.5Hz, 1H), 4.39(s, 2H), 4.15(d, J=2.0Hz, 1H), 4.00(m, 1H), 3.75(m, 1H), 3.57-3.45(m, 3H), 3.30-3.22(m, 2H), 2.92(s, 3H), 2.56(m, 1H), 2.50-2.39(m, 2H), 2.14-1.91(m, 3H), 1.80-1.60(m, 5H), 1.50-1.10(m, 6H), 1.00-0.87(m, 2H), 0.95(t, J=7.0Hz, 3H).
실시예 22
(3S)-1-부틸-2,5-디옥소-3-((1S)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
참고예 3에서 제조한 화합물 대신에 참고예 3(9)에서 제조한 화합물을, 3-포르밀-6-페닐옥시피리딘 대신에 4-(4-카르복시페닐옥시)벤조알데히드를 이용하고, 실시예 2와 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.45(클로로포름:메탄올=5:1);
NMR(d6-DMSO): δ 10.4(s, 1H), 8.05(m, 1H), 7.97(d, J=8.7Hz, 2H), 7.69(d, J=8.7Hz, 2H), 7.19(d, J=8.7Hz, 2H), 7.09(d, J=8.7Hz, 2H), 5.28(d, J=6.9Hz, 1H) 4.35(s, 2H), 3.97(m, 1H), 3.88-3.12(m, 7H), 2.64-2.20(m, 3H), 2.06-1.42(m, 8H), 1.40-1.00(m, 6H), 0.89(t, J=6.9Hz, 3H), 0.80(m, 2H).
실시예 23
(3S)-1-부틸-2,5-디옥소-3-(피리딘-3-일메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
(2R,3R)-2-(t-부톡시카르보닐아미노)-3-히드록시-4-메틸펜탄산 대신에 N-t-부톡시카르보닐-3-피리딜-L-알라닌을, N-벤질-4-피페리돈 대신에 N-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-4-피페리돈을, 벤질이소니트릴 대신에 2-모르폴리노에틸이소니트릴을 이용하고, 참고예 1→참고예 2→실시예 1과 동일한 조작을 하여,이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.25(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 8.82-8.76(m, 2H), 8.55(d, J=8.4Hz, 1H), 8.06(dd, J=7.8, 5.7Hz, 1H), 7.84(d, J=9.0Hz, 2H), 7.63(d, J=8.7Hz, 2H), 7.15-7.02(m, 4H), 4.55(t, J=5.4Hz, 1H), 4.33(s, 2H), 3.80(m, 1H), 3.68-3.28(m, 7H), 2.91(s, 3H), 2.56-2.40(m, 2H), 2.20(m, 1H), 1.70(m, 1H), 1.50-1.20(m, 4H), 0.92(t, J=6.9Hz, 3H).
실시예 23(1)∼23(5)
N-t-부톡시카르보닐-3-피리딜-L-알라닌 대신에 해당하는 아미노산 유도체를 이용하고, 실시예 23과 동일한 조작을 하여, 이하에 나타낸 본 발명 화합물을 얻었다.
실시예 23(1)
(3S)-1-부틸-2,5-디옥소-3-페닐메틸-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.51(클로로포름:메탄올:아세트산=20:2:1);
NMR(CD3OD): δ 7.84(d, J=9.0Hz, 2H), 7.56(d, J=9.0Hz, 2H), 7.30-7.04(m, 9H), 4.36(dd, J=4.5, 3.6Hz, 1H), 4.25(s, 2H), 3.78(m, 1H), 3.50-3.02(m, 6H), 3.00-2.84(m, 4H), 2.38(m, 1H), 2.02(m, 1H), 1.86(m, 1H), 1.60-1.24(m, 4H), 0.93(t, J=6.9Hz, 3H), 0.04(m, 1H).
실시예 23(2)
(3S)-1-부틸-2,5-디옥소-3-(피리딘-2-일메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.46(클로로포름:메탄올:아세트산=20:2:1);
NMR(CD3OD): δ 8.78(dd, J=7.5, 1.5Hz, 1H), 8.57(td, J=7.8, 1.5Hz, 1H), 8.06(d, J=8.4Hz, 1H), 8.00(m, 1H), 7.84(d, J=8.2Hz, 2H), 7.64(d, J=6.6Hz, 2H), 7.16-7.04(m, 4H), 4.68(dd, J=6.9, 5.7Hz, 1H), 4.38(s, 2H), 3.84(m, 1H), 3.70-3.32(m, 7H), 2.91(s, 3H), 2.64-2.44(m, 2H), 2.16(m, 1H), 2.06(m, 1H), 1.50-1.22(m, 4H), 0.91(t, J=6.9Hz, 3H).
실시예 23(3)
(3S)-1-부틸-2,5-디옥소-3-히드록시메틸-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.28(클로로포름:메탄올:아세트산=20:2:1);
NMR(CD3OD): δ 7.84(d, J=9.0Hz, 2H), 7.61(d, J=8.7Hz, 2H), 7.14(d, J=8.7Hz, 2H), 7.07(d, J=9.0Hz, 2H), 4.36(s, 2H), 4.02-3.88(m, 3H), 3.80-3.44(m, 5H), 3.30(m, 1H), 2.91(s, 3H), 2.60-2.36(m, 3H), 2.18(m, 1H), 1.64(m, 1H), 1.50-1.26(m, 3H), 1.02-0.90(m, 3H).
실시예 23(4)
(3S)-1-부틸-2,5-디옥소-3-(피리딘-1-옥사이드-2-일메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.86(클로로포름:메탄올:아세트산=10:2:1);
NMR(CD3OD): δ 8.70(dd, J=5.4, 1.0Hz, 1H), 8.05(td, J=6.6, 1.2Hz, 1H), 7.92-7.72(m, 4H), 7.64(d, J=9.0Hz, 2H), 7.20-7.06(m, 4H), 4.67(d, J=6.3Hz, 1H), 4.36(s, 2H), 3.86-3.18(m, 8H), 2.91(s, 3H), 2.70-2.26(m, 2H), 2.34-2.06(m, 2H), 1.60-1.44(m, 2H), 1.44-1.24(m, 2H), 0.92(t, J=7.5Hz, 3H).
실시예 23(5)
(3S)-1-부틸-2,5-디옥소-3-(피리딘-1-옥사이드-3-일메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.65(클로로포름:메탄올:아세트산=10:2:1);
NMR(CD3OD): δ 8.74-8.60(m, 2H), 8.06(d, J=7.8Hz, 1H), 7.88(m, 1H), 7.84(d, J=8.7Hz, 2H), 7.62(d, J=8.7Hz, 2H), 7.12(d, J=8.7Hz, 2H), 7.06(d, J=8.7Hz, 2H), 4.52(t, J=5.1Hz, 1H), 4.33(s, 2H), 4.00(m, 1H), 3.78(m, 1H), 3.60(m, 1H), 3.56-3.18(m, 5H), 2.91(s, 3H), 2.56-2.18(m, 2H), 2.20(m, 1H), 1.66(m, 1H), 1.52-1.22(m, 4H), 0.93(t, J=6.9Hz, 3H).
실시예 24
(3R)-1-(4-메톡시페닐메틸)-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
(2R,3R)-2-(t-부톡시카르보닐아미노)-3-히드록시-4-메틸펜탄산 대신에 (2R,3R)-2-(t-부톡시카르보닐아미노)-3-시클로헥실-3-히드록시프로판산을, n-부틸아민 대신에 4-메톡시벤질아민을, N-벤질-4-피페리돈 대신에 N-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-4-피페리돈을, 벤질이소니트릴 대신에 2-모르폴리노에틸이소니트릴을 이용하고, 참고예 1→참고예 2→실시예 1과 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.24(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.84(d, J=8.7Hz, 2H), 7.56(d, J=8.7Hz, 2H), 7.18(d, J=8.7Hz, 2H), 7.13(d, J=8.7Hz, 2H), 7.07(d, J=8.7Hz, 2H), 6.85(d, J=8.7Hz, 2H), 4.48(m, 1H), 4.33(s, 4H), 3.96(m, 1H), 3.75(m, 1H), 3.75(s, 3H), 3.58-3.18(m, 3H), 2.92(s, 3H), 2.66-2.28(m, 3H), 2.16-1.58(m, 7H), 1.40-0.82(m,5H).
실시예 24(1)∼24(4)
4-메톡시벤질아민 대신에 해당하는 아민을 이용하고, 실시예 24와 동일한 조작을 하여, 이하에 나타낸 본 발명 화합물을 얻었다.
실시예 24(1)
(3R)-1-페닐메틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.28(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.85(d, J=8.7Hz, 2H), 7.56(d, J=8.7Hz, 2H), 7.40-7.02(m, 5H), 7.13(d, J=8.7Hz, 2H), 7.06(d, J=8.7Hz, 2H), 4.58(m, 1H), 4.33(s, 4H), 3.96(m, 1H), 3.76(m, 1H), 3.54-3.18(m, 3H), 2.92(s, 3H), 2.64-2.28(m, 3H), 2.14-1.58(m, 7H), 1.40-0.80(m, 5H).
실시예 24(2)
(3R)-1-(2-메톡시에틸)-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
TLC: Rf 0.35(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.84(d, J=8.7Hz, 2H), 7.57(d, J=8.7Hz, 2H), 7.15(d, J=8.7Hz, 2H), 7.07(d, J=8.7Hz, 2H), 4.36(s, 2H), 4.18(d, J=2.1Hz, 1H), 3.98(m, 1H), 3.86-3.18(m, 8H), 3.31(s, 3H), 2.91(s, 3H), 2.60-1.58(m, 10H), 1.42-0.80(m, 5H).
실시예 24(3)
(3R)-1-(피리딘-2-일메틸)-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.83(클로로포름:메탄올:아세트산=10:2:1);
NMR(CD3OD): δ 8.76(dd, J=6.6, 1.8Hz, 1H), 8.54(td, J=8.4, 1.8Hz, 1H), 8.12(d, J=8.4Hz, 1H), 7.93(dd, J=8.4, 6.6Hz, 1H), 7.83(d, J=9.0Hz, 2H), 7.65(d, J=8.7Hz, 2H), 7.14-7.02(m, 4H), 5.34-5.20(m, 2H), 4.38(s, 2H), 4.30(d, J=1.8Hz, 1H), 3.96(m, 1H), 3.78(m, 1H), 3.52-3.38(m, 2H), 3.32(m, 1H), 2.90(s, 3H), 2.72-2.54(m, 3H), 2.30(m, 1H), 2.06(m, 1H), 1.88(m, 1H), 1.82-1.50(m, 4H), 1.28-1.06(m, 3H), 1.06-0.80(m, 2H).
실시예 24(4)
(3R)-1-(피리딘-3-일메틸)-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
TLC: Rf 0.58(클로로포름:메탄올:아세트산=10:2:1);
NMR(CD3OD): δ 8.89(s, 1H), 8.73(d, J=5.7Hz, 1H), 8.64(d, J=8.1Hz, 1H), 8.03(dd, J=8.1, 5.7Hz, 1H), 7.83(d, J=8.7Hz, 2H), 7.65(d, J=8.4Hz, 2H), 7.18-7.02(m, 4H), 5.19(d, J=18.0Hz, 1H), 5.11(d, J=18.0Hz, 1H), 4.40-4.26(m, 3H), 3.90(m, 1H), 3.78(m, 1H), 3.50-3.38(m, 2H), 3.30(m, 1H), 2.90(s, 3H), 2.74-2.42(m, 3H), 2.20-1.88(m, 3H), 1.82-1.56(m, 4H), 1.32-1.06(m, 3H), 1.02-0.80(m, 2H).
참고예 7
(3R)-1-부틸-2,5-디옥소-3-시클로헥실메틸-1,4,9-트리아자스피로[5.5]운데칸·염산염
(2R,3R)-2-(t-부톡시카르보닐아미노)-3-히드록시-4-메틸펜탄산 대신에 N-t-부톡시카르보닐-D-시클로헥실알라닌을 이용하고, 참고예 1→참고예 2→실시예 1→참고예 3과 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.59(n-부탄올:아세트산:물=4:2:1);
NMR(CD3OD): δ 4.05(dd, J=7.5, 4.8Hz, 1H), 3.83-3.69(m, 2H), 3.42-3.37(m, 4H), 2.39-2.07(m, 4H), 1.80-1.49(m, 10H), 1.45-1.19(m, 5H), 1.03-0.91(m, 5H);
비선광도: [α]D+35.5(c 1.05, 메탄올, 21℃).
실시예 25
(3R)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
참고예 3에서 제조한 화합물 대신에 참고예 7에서 제조한 화합물을, 3-포르밀-6-페닐옥시피리딘 대신에 4-(4-카르복시페닐옥시)벤조알데히드를 이용하고, 실시예 2와 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.36(클로로포름:메탄올=10:1);
NMR(d6-DMSO): δ 10.92(br-s, 1H), 8.41(br-s, 1H), 7.95(d, J=8.7Hz, 2H), 7.69(d, J=8.7Hz, 2H), 7.17(d, J=8.7Hz, 2H), 7.07(d, J=8.7Hz, 2H), 4.32(s, 2H), 3.91(m, 1H), 3.59-3.35(m, 6H), 2.56-2.35(m, 2H), 2.10(m, 1H), 1.98(m, 1H), 1.72-1.35(m, 10H), 1.32-1.14(m, 5H), 0.90-0.78(m, 5H).
실시예 26
(3S)-1-부틸-2,5-디옥소-3-(피리딘-1-옥사이드-2-일메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·9-옥사이드
실시예 23(2)에서 제조한 화합물의 유리체(117 ㎎)의 클로로포름(10 ㎖) 용액에 실온에서 3-클로로과벤조산(114 ㎎)의 클로로포름(4 ㎖) 용액을 적가하였다. 반응 혼합물을 실온에서 밤새 교반한 후 용매를 증류 제거하였다. 얻어진 잔류물을 실리카겔 컬럼 크로마토그래피(후지실리시아사, NH-DM1020, 클로로포름)에 의해 정제하여, 이하의 물성치를 갖는 본 발명 화합물(100 ㎎)을 얻었다.
TLC: Rf 0.23(클로로포름:메탄올:아세트산=20:2:1);
NMR(CDCl3): δ 8.81(s, 1H), 8.28(dd, J=6.0, 1.2Hz, 1H), 7.77(d, J=8.7Hz, 2H), 7.52-7.46(m, 3H), 7.32-7.22(m, 2H), 7.16-6.98(m, 4H), 6.32(m, 1H), 4.40-4.24(m, 4H), 3.87(dd, J=11.0, 5.1Hz, 1H), 3.66-3.34(m, 4H), 3.16-2.86(m, 4H), 3.01(d, J=4.5Hz, 3H), 1.84-1.20(m, 6H), 0.90(t, J=7.2Hz, 3H).
참고예 8
1-부틸-2,5-디옥소-3-(모르폴린-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
(2R,3R)-2-(t-부톡시카르보닐아미노)-3-히드록시-4-메틸펜탄산 대신에 2-(t-부톡시카르보닐아미노)-3-(모르폴린-4-일)프로판산을 이용하고, 참고예 1→참고예 2→실시예 1→참고예 3과 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.07(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 4.76(dd, J=8.4, 4.8Hz, 1H), 4.05-3.82(m, 6H), 3.71-3.40(m, 10H), 2.41(m, 1H), 2.31-2.21(m, 3H), 1.98-1.54(m, 2H), 1.46-1.36(m, 2H), 0.97(t, J=7.5Hz, 3H).
실시예 27
1-부틸-2,5-디옥소-3-(모르폴린-4-일메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염
참고예 3에서 제조한 화합물 대신에 참고예 8에서 제조한 화합물을, 3-포르밀-6-페닐옥시피리딘 대신에 4-(4-메틸아미노카르보닐)페닐옥시벤조알데히드를 이용하고, 실시예 2와 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.41(클로로포름:메탄올=10:1);
NMR(CD3OD): δ 7.84(d, J=9.0Hz, 2H), 7.63(d, J=8.5Hz, 2H), 7.14(d, J=8.5Hz, 2H), 7.07(d, J=9.0Hz, 2H), 4.73(dd, J=8.1, 5.1Hz, 1H), 4.37(s, 2H), 4.10-3.85(m, 5H), 3.76-3.43(m, 9H), 3.40-3.20(m, 2H), 2.91(s, 3H), 2.63-2.43(m, 2H), 2.33-2.24(m, 2H), 1.65-1.50(m, 2H), 1.44-1.34(m, 2H), 0.96(t, J=7.0Hz, 3H).
실시예 28
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-(N-히드록시카르바모일)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·염산염
실시예 9(54)에서 제조한 화합물(120 ㎎)과 (1-메톡시-이소프로필)옥시아민(31 ㎎)의 디메틸포름아미드(1.6 ㎖) 현탁액에 디이소프로필에틸아민(68 ㎕), 1-에틸-3-[3-(디메틸아미노)프로필]카르보디이미드·염산염(56 ㎎), 1-히드록시벤즈트리아졸(40 ㎎)을 가하였다. 반응 혼합물을 실온에서 1시간 교반하였다. 반응 혼합물에 1N 염산(2 ㎖)을 가하여, 실온에서 15분간 교반하였다. 반응 혼합물을 물로 희석하고, 아세트산에틸로 추출하였다. 추출물을 물, 포화탄산수소나트륨 수용액, 포화염화나트륨 수용액으로써 세정하고, 무수황산나트륨으로 건조시켜 농축하였다. 얻어진 잔류물의 메탄올 용액에, 4N 염화수소아세트산에틸 용액을 가하고, 농축하였다. 얻어진 잔류물을 아세트산에틸로 세정하여, 이하의 물성치를 갖는 표제 화합물(116 ㎎)을 얻었다.
TLC: Rf 0.43(클로로포름:메탄올:아세트산=20:4:1);
NMR(CD3OD): δ 7.79(d, J=8.7Hz, 2H), 7.60(d, J=8.7Hz, 2H), 7.14(d, J=8.7Hz, 2H), 7.06(d, J=8.7Hz, 2H), 4.36(s, 2H), 4.15(d, J=2.1Hz, 1H), 4.00(m, 1H), 3.75(m, 1H), 3.60-3.40(m, 3H), 3.30-3.11(m, 2H), 2.58-2.27(m,3H), 2.19-1.96(m, 3H), 1.93-1.60(m, 5H), 1.50-1.09(m, 6H), 1.05-0.80(m, 2H), 0.94(t, J=7.2Hz, 3H).
실시예 29
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐카르보닐)-1,4,9-트리아자스피로[5.5]운데칸
4-(4-메틸아미노카르보닐페닐옥시)안식향산(53.8 ㎎)의 디메틸포름아미드(4 ㎖) 용액에 1-히드록시벤즈트리아졸(34.9 ㎎)과 1-에틸-3-[3-(디메틸아미노)프로필]카르보디이미드·염산염(49.5 ㎎)을 가하였다. 반응 혼합물을 실온에서 40분간 교반하였다. 반응 혼합물에 실시예 3(3)에서 제조한 화합물(100 ㎎)을 가하며, 실온에서 19시간 교반하였다. 반응 혼합물을 염화메틸렌으로 희석하고, 물을 가하여, 염화메틸렌으로 추출하였다. 추출물을 10% 시트르산 수용액과 포화염화나트륨 수용액으로 세정하고, 무수황산나트륨으로 건조시켜 농축하였다. 얻어진 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸:메탄올=10:1)에 의해 정제하고, 에테르로 세정하여, 이하의 물성치를 갖는 표제 화합물(56.1 ㎎)을 얻었다.
TLC: Rf 0.41(아세트산에틸:메탄올=10:1);
NMR(CD3OD): δ 7.84(d, J=8.7Hz, 2H), 7.49(t, J=8.7Hz, 2H), 7.13-7.06(m, 4H), 3.70(m, 1H), 4.16(m, 1H), 4.12-2.98(m, 6H), 2.91(s, 3H), 2.42-0.80(m, 19H), 0.96(t, J=6.9Hz, 3H).
실시예 30
(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐)-1,4,9-트리아자스피로[5.5]운데칸·염산염
(2R,3R)-2-(t-부톡시카르보닐아미노)-3-히드록시-4-메틸펜탄산 대신에 (2R,3R)-2-(t-부톡시카르보닐아미노)-3-시클로헥실-3-히드록시프로판산을, N-벤질-4-피페리돈 대신에 N-(4-(4-메틸아미노카르보닐페닐옥시)페닐)-4-피페리돈을, 벤질이소니트릴 대신에 2-모르폴리노에틸이소니트릴을 이용하고, 참고예 1→참고예 2→실시예 1과 동일한 조작을 하여, 이하의 물성치를 갖는 본 발명 화합물을 얻었다.
TLC: Rf 0.40(아세트산에틸);
NMR(CD3OD): δ 7.87(d, J=9.0Hz, 2H), 7.78(d, J=9.0Hz, 2H), 7.25(d, J=9.0Hz, 2H), 7.10(d, J=9.0Hz, 2H), 4.65(m, 1H), 4.39(m, 1H), 4.20(d, J=1.8Hz, 1H), 3.73-3.65(m, 3H), 3.43-3.27(m, 2H), 2.91(s, 3H), 2.90-2.52(m,3H), 2.25(m, 1H), 2.10-1.90(m, 2H), 1.85-1.60(m, 5H), 1.60-1.10(m, 6H), 0.99(t, J=7.2Hz, 3H), 1.00-0.82(m, 2H).
제제예 1
이하의 각 성분을 통상의 방법에 의해 혼합한 후 타정하여, 1정 속에 50 ㎎의 활성 성분을 함유하는 정제 100정을 얻었다.
·(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(6-페닐옥시피리딘-3-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염·····5.0 g
·카르복시메틸셀룰로오스칼슘(붕괴제)·····0.2 g
·스테아린산마그네슘(윤활제)······ 0.1 g
·미결정 셀룰로오스·····4.7 g
제제예 2
이하의 각 성분을 통상의 방법에 의해 혼합한 후, 용액을 통상의 방법에 의해 멸균하여, 5 ㎖씩 앰플에 충전하고, 통상의 방법에 의해 동결 건조시켜 1앰플 속에 20 ㎎의 활성 성분을 함유하는 앰플 100개를 얻었다.
·(3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(6-페닐옥시피리딘-3-일메틸)-1,4,9-트리아자스피로[5.5]운데칸·2염산염 ···· 2.0 g
·만니톨 ······ 20 g
·증류수 ······ 500 ㎖
Claims (9)
- 화학식 (I)로 표시되는 트리아자스피로[5.5]운데칸 유도체 화합물, 이들의 4급 암모늄염, 이들의 N-옥사이드 또는 이들의 비독성염.화학식 (I)[상기 식에서 R1은 하기 식 (1) 또는 (2)로 표시되는 기:(1),(2)(기 중, G는 단일 결합, C1∼4 알킬렌기, C2∼4 알케닐렌기 또는 -CO-를 나타내고,A환은, (1) C5∼10의 단환식 또는 이환식 탄소환 또는 (2) 1∼2개의 질소 원자 및/또는 1∼2개의 산소 원자를 함유하는 5∼10원의 단환식 또는 이환식 복소환을 나타내며,R6은,(1) C1∼4 알킬기,(2) 할로겐 원자,(3) 니트릴기,(4) 트리플루오로메틸기,(5) -OR8기,(6) -SR9기,(7) -NR10R11기,(8) -COOR12기,(9) -CONR13R14기,(10) -SO2NR15R16기,(11) -NR17SO2R18기,(12) -S(O)R19기,(13) -SO2R20기,(14) -N(SO2R21)2기,(15) (a) -OR8기, (b) -NR10R11기 및 (c) Cyc1로부터 선택되는 1개의 기에 의해 치환된 C1∼4 알킬기, 또는(16) -NR27COR28기를 나타내고,R8∼R17은 각각 독립적으로 (1) 수소 원자, (2) C1∼4 알킬기, (3) Cyc1, (4) -OR22기 또는 (5) (a) -OR22기, (b) -NR23R24기, (c) -COOR25기 및 (d) Cyc1로부터 임의로 선택되는 1개의 기에 의해 치환된 C1∼4 알킬기를 나타내거나,R10과 R11, R13과 R14, R15와 R16은 각각이 결합하는 질소 원자와 함께 1∼2개의 질소 원자 및/또는 1개의 산소 원자를 함유하는 5∼6원의 단환식 복소환을 나타내며(단, 그 복소환은 C1∼4 알킬기 또는 수산기로 치환되어 있어도 좋음),R22∼R25는 각각 독립적으로 (1) 수소 원자, (2) C1∼4 알킬기, 또는 (3) C1∼4 알콕시기가 치환한 C1∼4 알킬기를 나타내거나,R23과 R24는 결합하는 질소 원자와 함께 1∼2개의 질소 원자 및/또는 1개의 산소 원자를 함유하는 5∼6원의 단환식 복소환을 나타내고(단, 그 복소환은 C1∼4 알킬기 또는 수산기로 치환되어 있어도 좋음),R18∼R21은 각각 독립적으로 C1∼4 알킬기를 나타내며,R27은 (1) 수소 원자, (2) C1∼4 알킬기, (3) Cyc1 또는 (4) (a) -OR22기, (b) -NR23R24기, (c) -COOR25기 및 (d) Cyc1로부터 임의로 선택되는 1개의 기에 의해치환된 C1∼4 알킬기를 나타내고,R28은 (1) C1∼4 알킬기, (2) Cyc1 또는 (3) (a) -OR22기, (b) -NR23R24기, (c) -COOR25기 및 (d) Cyc1로부터 임의로 선택되는 1개의 기에 의해 치환된 C1∼4 알킬기를 나타내며,Cyc1은 (1) C5∼6의 단환 탄소환 또는 (2) 1∼2개의 질소 원자 및/또는 1개의 산소 원자를 함유하는 5∼6원의 단환식 복소환을 나타내고(단, 그 탄소환 또는 복소환은 C1∼4 알콕시기, 할로겐 원자 또는 -COOR29기(R29는 (1) 수소 원자, (2) C1∼4 알킬기, (3) Cyc1 또는 (4) (a)-OR22기, (b) -NR23R24기, (c) -COOR25기 및 (d) Cyc1로부터 임의로 선택된 1개의 기에 의해 치환된 C1∼4 알킬기를 나타냄)로 치환되어 있어도 좋음),E는 단일 결합, -O-, -S-, -CO- 또는 -CHOH-를 나타내며,B환은 (1) C5∼6의 단환 탄소환 또는 (2) 1∼2개의 질소 원자 및/또는 1개의 산소 원자를 함유하는 5∼6원의 단환식 복소환을 나타내고,R7은 C1∼4 알킬기 또는 할로겐 원자를 나타내며,n은 0 또는 1∼4의 정수를 나타내고,m은 0 또는 1∼4의 정수를 나타냄)를 나타내며,R2는,(1) C1∼4 알킬기,(2) C2∼4 알키닐기, 또는(3) (a) -OR30기, (b) -NR31R32기 및 (c) Cyc3으로부터 선택되는 1개의 기에 의해 치환된 C1∼4 알킬기(기 중, R30∼R32는 각각 독립적으로 (1) 수소 원자, (2) C1∼4 알킬기, (3) Cyc3 또는 (4) Cyc3에 의해 치환된 C1∼4 알킬기를 나타내고, Cyc3은 (1) C5∼6의 단환 탄소환 또는 (2) 1∼2개의 질소 원자 및/또는 1개의 산소 원자를 함유하는 5∼6원의 단환식 복소환을 나타냄(단, 그 탄소환 또는 복소환은 C1∼4 알콕시기로 치환되어 있어도 좋음))를 나타내며,R3및 R4는 각각 독립적으로,(1) 수소 원자,(2) C1∼4 알킬기, 또는(3) (a) Cyc2 및 (b) 수산기로부터 임의로 선택되는 1∼2개의 기에 의해 치환된 C1∼4 알킬기(기 중, Cyc2는 (1) C5∼6의 단환 탄소환 또는 (2) 1∼2개의 질소 원자 및/또는 1개의 산소 원자를 함유하는 5∼6원의 단환식 복소환을 나타냄)를 나타내거나,R3과 R4는 함께,(기 중, R26은 C1∼4 알킬기 또는 Cyc2를 나타냄)를 나타내고,R5는 수소 원자 또는 C1∼4 알킬기를 나타낸다.]
- 제1항에 있어서, 제1항에 기재한 화학식 (I) 중 R3및 R4가 수소 원자인 화합물.
- 제1항에 있어서, 제1항에 기재한 화학식 (I) 중 R3이 수소 원자이고,R4가(1) C1∼4 알킬기, 또는(2) (a) Cyc2 및 (b) 수산기로부터 임의로 선택되는 1∼2개의 기에 의해 치환된 C1∼4 알킬기인 화합물.
- 제1항에 있어서, 제1항에 기재한 화학식 (I) 중 R3및 R4가 각각 독립적으로,(1) C1∼4 알킬기, 또는(2) (a) Cyc2 및 (b) 수산기로부터 임의로 선택되는 1∼2개의 기에 의해 치환된 C1∼4 알킬기인 화합물.
- 제1항에 있어서, 제1항에 기재한 화학식 (I) 중 R3과 R4가 함께,(상기 식에서 R26은 제1항 기재와 동일한 의미를 나타냄)를 나타내는 화합물.
- 제1항에 있어서, 화합물이(1) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-벤질-1,4,9-트리아자스피로[5.5]운데칸,(2) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(6-페닐옥시피리딘-3-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(3) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메톡시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(4) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(3-메톡시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(5) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-플루오로페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(6) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-클로로페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(7) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(페닐카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(8) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(1-페닐-1-히드록시메틸)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(9) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-(모르폴린-4-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(10) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(6-메틸피리딘-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(11) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(피리딘-1-옥사이드-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(12) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-히드록시피페리딘-1-일메틸)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(13) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(14) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(1,3,5-트리메틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(15) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-아미노술포닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(16) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메틸티오페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(17) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메틸술포닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(18) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-시아노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(19) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(페닐티오)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(20) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-히드록시페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(21) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-메틸술포닐아미노페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(22) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-(N,N-디메틸아미노)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(23) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(피롤리딘-1-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(24) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(6-메틸피리딘-1-옥사이드-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(25) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-히드록시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(26) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(6-(4-메톡시페닐옥시)피리딘-3-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(27) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(메틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(28) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(N-메틸-N-(2-히드록시에틸)아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(29) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-히드록시에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(30) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(31) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-(모르폴린-4-일)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(32) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(피롤리딘-1-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(33) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메틸술피닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(34) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(35) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(모르폴린-4-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(36) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(37) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(38) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-메틸페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(39) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(N,N-디에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(40) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(4-메틸피페라진-1-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(41) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(5-클로로-3-메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(42) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(모르폴린-4-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(43) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-히드록시에틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(44) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-(2-(N,N-디메틸아미노)에틸아미노카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(45) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(피리딘-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(46) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(47) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메틸페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(48) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(2,4-디플루오로페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(49) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(피리딘-2-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(50) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-메틸아미노카르보닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(51) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-시클로헥실옥시페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(52) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(3,4,5,6-테트라히드로피란-4-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(53) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메톡시페닐메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(54) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(시클로헥실아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(55) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-(피롤리딘-1-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(56) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-플루오로페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(57) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-페닐에틸)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(58) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(1-벤질옥시카르보닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(59) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-(2-히드록시에틸아미노카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(60) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-(1-메틸술포닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(61) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-히드록시메틸페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(62) (3S)-1-부틸-2,5-디옥소-3-((1S)-1-히드록시-2-메틸프로필)-9-(6-페닐옥시피리딘-3-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(63) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(64) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(피롤리딘-1-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(65) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(모르폴린-4-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(66) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-메틸술포닐페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(67) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-메틸술포닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(68) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-(모르폴린-4-일)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(69) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(4-메틸피페라진-1-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(70) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-메틸술피닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(71) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(피리딘-1-옥사이드-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(72) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-히드록시에틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(73) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-(모르폴린-4-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(74) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(N,N-디에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(75) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-(2-히드록시에틸아미노카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(76) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-(피롤리딘-1-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(77) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(시클로헥실아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(78) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(3-메톡시프로필아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(79) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-메틸술피닐페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(80) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-프로필피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(81) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-에틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(82) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-시클로펜틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(83) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(1,1-디메틸에틸)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(84) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(1-벤질옥시카르보닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(85) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-((4-메톡시페닐)메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(86) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(3-메톡시프로필아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(87) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-메톡시카르보닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(88) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-메톡시페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(89) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(3-(모르폴린-4-일)프로필아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(90) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(피롤리딘-1-일카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(91) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(피페리딘-1-일카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(92) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(모르폴린-4-일카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(93) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(N-메틸-N-(2-(피리딘-2-일)에틸)아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(94) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(시클로헥실아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(95) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(N,N-디메틸아미노술포닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(96) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-메톡시카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(97) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(1-메틸피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(98) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(1-메틸술포닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(99) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(3-(N,N-디메틸아미노)프로필아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(100) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-(N,N-디메틸아미노)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(101) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(N-메틸-N-(2-(N',N'-디메틸아미노)에틸)아미노술포닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(102) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-((N,N-디메틸아미노)메틸)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(103) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(104) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-메틸아미노카르보닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(105) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-((메톡시카르보닐)메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(106) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3-(3,5-디메틸-1-페닐피라졸-4-일)-2E-프로페닐)-1,4,9-트리아자스피로[5.5]운데칸,(107) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(4-(카르복시메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(108) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(3-(3,5-디메틸-1-페닐피라졸-4-일)프로필)-1,4,9-트리아자스피로[5.5]운데칸,(109) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(110) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(피롤리딘-1-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(111) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(모르폴린-4-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(112) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(2-(N,N-디메틸아미노)에틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(113) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-(모르폴린-4-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(114) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-메틸술포닐페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(115) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-메틸술포닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(116) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(2-(모르폴린-4-일)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(117) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(4-메틸피페라진-1-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(118) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-메틸술피닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(119) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(2-히드록시에틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(120) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-(2-히드록시에틸아미노카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(121) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-(피롤리딘-1-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(122) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(시클로헥실아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(123) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(3-메톡시프로필아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(124) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-메틸술피닐페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(125) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-프로필피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(126) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-에틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(127) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-시클로펜틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(128) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(3-(모르폴린-4-일)프로필아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(129) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(N,N-디메틸아미노술포닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(130) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(피롤리딘-1-일카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(131) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-(N,N-디메틸아미노)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(132) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(시클로헥실아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(133) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-메톡시카르보닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(134) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(3-메톡시프로필아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(135) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(N-메틸-N-(2-(피리딘-2-일)에틸)아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(136) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-((4-메톡시페닐)메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(137) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-메톡시카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(138) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-메톡시페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(139) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(1-메틸피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(140) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(1-메틸술포닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(141) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(3-(N,N-디메틸아미노)프로필아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(142) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-(N-메틸-N-(2-(N',N'-디메틸아미노)에틸)아미노술포닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(143) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(피페리딘-1-일카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(144) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(모르폴린-4-일카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(145) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-((N,N-디메틸아미노)메틸)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(146) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(4-메틸아미노카르보닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(147) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(1,1-디메틸에틸)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(148) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-(1-벤질옥시카르보닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(149) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-히드록시메틸페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(150) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-((메톡시카르보닐)메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(151) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(카르복시메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(152) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-페닐옥시페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(153) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(6-페닐옥시피리딘-3-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(154) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-플루오로페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(155) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-클로로페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(156) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-시아노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(157) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸술포닐아미노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(158) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(6-메틸피리딘-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(159) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(1-메틸에틸)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(160) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸술피닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(161) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(3,4,5,6-테트라히드로피란-4-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(162) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-페닐카르보닐페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(163) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(1-페닐-1-히드록시메틸)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(164) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(모르폴린-4-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(165) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-메틸아미노술포닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(166) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(N-메틸-N-(2-히드록시에틸)아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(167) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(피리딘-2-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(168) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(169) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(1,3,5-트리메틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(170) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(171) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(N,N-비스메틸술포닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(172) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-메틸술포닐아미노페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(173) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(N,N-디메틸술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(174) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(피롤리딘-1-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(175) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(모르폴린-4-일카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(176) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-아미노카르보닐페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(177) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(178) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-아미노술포닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(179) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(6-메틸피리딘-1-옥사이드-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(180) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-히드록시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(181) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-히드록시페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(182) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(2-히드록시에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(183) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(피롤리딘-1-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(184) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(5-클로로-3-메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(185) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메톡시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(186) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(3-메톡시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(187) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(N,N-디메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(188) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(189) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-메틸페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(190) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-플루오로페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(191) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(6-(4-메톡시페닐옥시)피리딘-3-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(192) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸술포닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(193) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-(2-(N,N-디메틸아미노)에틸아미노카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(194) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(2-히드록시에틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(195) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(2-(N,N-디메틸아미노)에틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(196) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(2-(모르폴린-4-일)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(197) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-(모르폴린-4-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(198) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(1,4-벤조디옥산-6-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(199) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(N,N-디에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(200) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(피리딘-1-옥사이드-3-일옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(201) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(4-메틸피페라진-1-일술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(202) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(203) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(2,4-디플루오로페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(204) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(2-(N,N-디메틸아미노)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(205) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-메틸아미노카르보닐페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(206) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(207) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-((4-메톡시페닐)메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(208) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(3-메톡시프로필아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(209) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(N-메틸-N-(2-(피리딘-2-일)에틸)아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(210) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-(피롤리딘-1-일카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(211) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-클로로페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(212) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-트리플루오로메틸페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(213) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-메톡시페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(214) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-에틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(215) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-프로필피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(216) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(1,1-디메틸에틸)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(217) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-시클로펜틸피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(218) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(2-페닐에틸)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(219) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(1-벤질옥시카르보닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(220) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(시클로헥실아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(221) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(1-메틸술포닐피페리딘-4-일)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(222) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-(2-히드록시에틸아미노카르보닐)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(223) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-히드록시메틸페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(224) (3S)-1-부틸-2,5-디옥소-3-((1S)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸술포닐아미노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(225) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-9-(3,5-디메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(226) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(227) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-9-(4-(4-(4-메톡시페닐메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(228) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노카르보닐)페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(229) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(230) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-(3,4,5,6-테트라히드로피란-4-일)메틸)-9-(4-(4-메틸술포닐아미노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(231) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로펜틸메틸)-9-(3,5-디메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(232) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로펜틸메틸)-9-(4-(4-(4-메톡시페닐메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(233) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로펜틸메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(234) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로펜틸메틸)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(235) (3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(236) (3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(237) (3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-2-메틸프로필)-9-(4-(4-메톡시페닐메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(238) (3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(239) (3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(240) (3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메톡시페닐메틸아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(241) (3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-(4-(N,N-디메틸아미노카르보닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(242) (3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(243) (3R)-1-프로필-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메톡시카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(244) (3R)-1-프로필-2,5-디옥소-3-(1-시클로헥실메틸리덴)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(245) (3S)-1-프로필-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(246) (3S)-1-프로필-2,5-디옥소-3-(2-메틸프로필)-9-(4-(4-메틸술포닐아미노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(247) (3S)-1-프로필-2,5-디옥소-3-(2-메틸프로필)-9-(3,5-디메틸-1-(4-(2-(N,N-디메틸아미노)에틸아미노술포닐)페닐)피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(248) (3S)-1-프로필-2,5-디옥소-3-시클로헥실메틸-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(249) (3S)-1-프로필-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-메틸술포닐아미노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(250) 1-부틸-2,5-디옥소-9-(4-(4-메틸술포닐아미노페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(251) 1-부틸-2,5-디옥소-9-(3,5-디메틸-1-시클로헥실피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(252) (3R)-1-(2-부티닐)-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(253) (3S)-1-(2-부티닐)-2,5-디옥소-3-((1S)-1-히드록시-1-시클로헥실메틸)-9-(3,5-디메틸-1-페닐피라졸-4-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(254) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(2-(4-페닐옥시페닐)에틸)-1,4,9-트리아자스피로[5.5]운데칸,(255) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(2-(4-페닐옥시페닐)에틸)-1,4,9-트리아자스피로[5.5]운데칸,(256) (3S)-1-부틸-2,5-디옥소-3-(2-메틸프로필)-9-(2-(4-메톡시페닐)에틸)-1,4,9-트리아자스피로[5.5]운데칸,(257) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-에톡시카르보닐페닐)-1,4,9-트리아자스피로[5.5]운데칸,(258) (3S)-1-부틸-2,5-디옥소-3-시클로헥실메틸-4-메틸-9-(4-페닐옥시페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(259) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(2-메틸프로파노일아미노)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(260) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(2-메톡시아세틸아미노)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(261) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(2-페닐아세틸아미노)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(262) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(2-(4-플루오로페닐)아세틸아미노)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(263) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메톡시카르보닐페닐아미노카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(264) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메톡시페닐메틸옥시카르보닐)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(265) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(2-(4-메틸아미노카르보닐페닐옥시)피리딘-5-일메틸)-1,4,9-트리아자스피로[5.5]운데칸,(266) (3S)-1-부틸-2,5-디옥소-3-((1S)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(267) (3S)-1-부틸-2,5-디옥소-3-(피리딘-3-일메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(268) (3S)-1-부틸-2,5-디옥소-3-페닐메틸-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(269) (3S)-1-부틸-2,5-디옥소-3-(피리딘-2-일메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(270) (3S)-1-부틸-2,5-디옥소-3-히드록시메틸-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(271) (3S)-1-부틸-2,5-디옥소-3-(피리딘-1-옥사이드-2-일메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(272) (3S)-1-부틸-2,5-디옥소-3-(피리딘-1-옥사이드-3-일메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(273) (3R)-1-(4-메톡시페닐메틸)-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(274) (3R)-1-페닐메틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(275) (3R)-1-(2-메톡시에틸)-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(276) (3R)-1-(피리딘-2-일메틸)-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(277) (3R)-1-(피리딘-3-일메틸)-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(278) (3R)-1-부틸-2,5-디옥소-3-시클로헥실메틸-9-(4-(4-카르복시페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(279) (3S)-1-부틸-2,5-디옥소-3-(피리딘-1-옥사이드-2-일메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸·9-옥사이드,(280) 1-부틸-2,5-디옥소-3-(모르폴린-4-일메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(281) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-(N-히드록시카르바모일)페닐옥시)페닐메틸)-1,4,9-트리아자스피로[5.5]운데칸,(282) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐카르보닐)-1,4,9-트리아자스피로[5.5]운데칸,(283) (3R)-1-부틸-2,5-디옥소-3-((1R)-1-히드록시-1-시클로헥실메틸)-9-(4-(4-메틸아미노카르보닐페닐옥시)페닐)-1,4,9-트리아자스피로[5.5]운데칸,이들의 4급 암모늄염, 이들의 N-옥사이드 또는 이들의 비독성염인 화합물.
- 제1항에 기재한 화학식 (I)로 표시되는 트리아자스피로[5.5]운데칸 유도체 화합물, 이들의 4급 암모늄염, 이들의 N-옥사이드 또는 이들의 비독성염을 유효성분으로서 함유하는 의약 조성물.
- 제1항에 기재한 화학식 (I)로 표시되는 트리아자스피로[5.5]운데칸 유도체 화합물, 이들의 4급 암모늄염, 이들의 N-옥사이드 또는 이들의 비독성염을 유효성분으로서 함유하는 케모카인/케모카인 수용체의 작용 제어제.
- 제1항에 기재한 화학식 (I)로 표시되는 트리아자스피로[5.5]운데칸 유도체 화합물, 이들의 4급 암모늄염, 이들의 N-옥사이드 또는 이들의 비독성염을 유효성분으로서 함유하는 천식, 아토피성 피부염, 담마진, 알레르기성 기관지폐 아스페르길루스증, 알레르기성 호산구성 위장증, 신장염, 신장증, 간염, 관절염, 만성 관절류머티즘, 건선, 비염, 결막염, 허혈 재관류 상해의 억제, 다발성 경화증, 궤양성 대장염, 급성 호흡 궁박 증후군, 세균 감염에 따른 쇼크, 당뇨병, 자기면역질환의 치료, 이식 장기 거절반응, 면역 억제, 암전이 예방, 후천성 면역부전 증후군의 예방제 및/또는 치료제.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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JPJP-P-2001-00079610 | 2001-03-19 | ||
JP2001079610 | 2001-03-19 | ||
JP2001160251 | 2001-05-29 | ||
JPJP-P-2001-00160251 | 2001-05-29 | ||
PCT/JP2002/002554 WO2002074770A1 (fr) | 2001-03-19 | 2002-03-18 | Derives de triazaspiro[5.5]undecane et medicaments les contenant en tant que principe actif |
Publications (2)
Publication Number | Publication Date |
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KR20040008142A true KR20040008142A (ko) | 2004-01-28 |
KR100714154B1 KR100714154B1 (ko) | 2007-05-07 |
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KR1020037012168A KR100714154B1 (ko) | 2001-03-19 | 2002-03-18 | 트리아자스피로[5.5]운데칸 유도체 및 이들을유효성분으로 하는 약제 |
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US (2) | US7053090B2 (ko) |
EP (2) | EP1619194A3 (ko) |
JP (1) | JP3558079B2 (ko) |
KR (1) | KR100714154B1 (ko) |
CN (1) | CN1291988C (ko) |
AT (1) | ATE328884T1 (ko) |
AU (1) | AU2002238947B2 (ko) |
BR (1) | BR0208167A (ko) |
CA (1) | CA2440264A1 (ko) |
CZ (1) | CZ20032531A3 (ko) |
DE (1) | DE60212110T2 (ko) |
DK (1) | DK1378510T3 (ko) |
ES (1) | ES2266452T3 (ko) |
HU (1) | HUP0400229A2 (ko) |
IL (1) | IL157819A0 (ko) |
MX (1) | MXPA03008529A (ko) |
NO (1) | NO20034148L (ko) |
NZ (1) | NZ528249A (ko) |
PL (1) | PL364427A1 (ko) |
PT (1) | PT1378510E (ko) |
RU (1) | RU2269528C2 (ko) |
TW (1) | TWI254047B (ko) |
WO (1) | WO2002074770A1 (ko) |
Families Citing this family (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002074769A1 (fr) * | 2001-03-19 | 2002-09-26 | Ono Pharmaceutical Co., Ltd. | Medicaments contenant comme principe actif des derives du triazaspiro [5.5] undecane |
CN1688577A (zh) * | 2002-09-18 | 2005-10-26 | 小野药品工业株式会社 | 三氮杂螺[5.5]十一烷衍生物及以它为活性成分的药物 |
EP1541573A4 (en) * | 2002-09-18 | 2007-05-02 | Ono Pharmaceutical Co | NEW CRYSTALS OF DERIVATIVE TRIAZASPIRO 5.5 | UNDECANES |
ATE402176T1 (de) * | 2002-12-13 | 2008-08-15 | Smithkline Beecham Corp | Pyrrolidin- und azetidinverbindungen alsccr5- antagonisten |
AU2003289329A1 (en) * | 2002-12-13 | 2004-07-09 | Ono Pharmaceutical Co., Ltd. | Antagonist and agonist binding to strong binding site of chemokine receptor |
EP1569647B1 (en) | 2002-12-13 | 2008-08-20 | Smithkline Beecham Corporation | Cyclohexyl compounds as ccr5 antagonists |
WO2004080966A1 (ja) | 2003-03-14 | 2004-09-23 | Ono Pharmaceutical Co., Ltd. | 含窒素複素環誘導体およびそれらを有効成分とする薬剤 |
US7498323B2 (en) | 2003-04-18 | 2009-03-03 | Ono Pharmaceuticals Co., Ltd. | Spiro-piperidine compounds and medicinal use thereof |
EP1621540A4 (en) * | 2003-04-21 | 2008-07-23 | Ono Pharmaceutical Co | HETEROCYCLIC COMPOUNDS CONTAINING NITROGEN AND USE THEREOF |
JPWO2004098638A1 (ja) * | 2003-05-06 | 2006-07-13 | 小野薬品工業株式会社 | エフェクター細胞機能阻害剤 |
WO2006022454A1 (ja) | 2004-08-27 | 2006-03-02 | Ono Pharmaceutical Co., Ltd | 塩基性基を含有する化合物およびその用途 |
KR101231466B1 (ko) | 2004-09-13 | 2013-02-07 | 오노 야꾸힝 고교 가부시키가이샤 | 질소 함유 복소환 유도체 및 이들을 유효 성분으로 하는약제 |
EP1852432A4 (en) * | 2005-02-25 | 2010-04-14 | Ono Pharmaceutical Co | NITROGENIC HETEROCYCLIC COMPOUND AND THEIR MEDICAL USE |
JP2008536924A (ja) | 2005-04-20 | 2008-09-11 | メルク エンド カムパニー インコーポレーテッド | ベンゾチオフェンヒドロキサミン酸のカーバメート、ウレア、アミドおよびスルホンアミド置換誘導体 |
EP1874755A4 (en) | 2005-04-20 | 2010-04-28 | Merck Sharp & Dohme | BENZOTHIOPHENE-hydroxamic acid derivatives |
EP1874295A4 (en) | 2005-04-20 | 2009-08-12 | Merck & Co Inc | benzothiophene |
JPWO2006129679A1 (ja) | 2005-05-31 | 2009-01-08 | 小野薬品工業株式会社 | スピロピペリジン化合物およびその医薬用途 |
US8158825B2 (en) | 2005-06-24 | 2012-04-17 | Merck Sharp & Dohme Corp. | Modified malonate derivatives |
ES2407115T3 (es) | 2005-11-18 | 2013-06-11 | Ono Pharmaceutical Co., Ltd. | Compuesto que contiene un grupo básico y uso del mismo |
AR057579A1 (es) | 2005-11-23 | 2007-12-05 | Merck & Co Inc | Compuestos espirociclicos como inhibidores de histona de acetilasa (hdac) |
JP2009528354A (ja) | 2006-02-28 | 2009-08-06 | メルク エンド カムパニー インコーポレーテッド | ヒストン脱アセチル化酵素のインヒビター |
CA2644368A1 (en) | 2006-03-10 | 2007-09-20 | Ono Pharmaceutical Co., Ltd. | Nitrogenated heterocyclic derivative, and pharmaceutical agent comprising the derivative as active ingredient |
US8119685B2 (en) | 2006-04-26 | 2012-02-21 | Merck Sharp & Dohme Corp. | Disubstituted aniline compounds |
JP5257068B2 (ja) | 2006-05-16 | 2013-08-07 | 小野薬品工業株式会社 | 保護されていてもよい酸性基を含有する化合物およびその用途 |
EP2023924B1 (en) | 2006-05-18 | 2016-08-03 | Merck Sharp & Dohme Corp. | Aryl-fused spirocyclic compounds |
AU2007275743A1 (en) | 2006-07-20 | 2008-01-24 | Merck Sharp & Dohme Corp. | Phosphorus derivatives as histone deacetylase inhibitors |
US8461189B2 (en) | 2007-06-27 | 2013-06-11 | Merck Sharp & Dohme Corp. | Pyridyl derivatives as histone deacetylase inhibitors |
US8389553B2 (en) | 2007-06-27 | 2013-03-05 | Merck Sharp & Dohme Corp. | 4-carboxybenzylamino derivatives as histone deacetylase inhibitors |
WO2010009196A1 (en) * | 2008-07-15 | 2010-01-21 | Temple University Of The Commonwealth System Of Higher Education | Synthesis of bis-peptides oligomers comprising at least one n-substituted diketopiperazine as structural moiety |
RU2455284C1 (ru) * | 2011-03-15 | 2012-07-10 | Государственное образовательное учреждение высшего профессионального образования "Пермский государственный университет" | Способ получения 5-арил-2-метил-1,3-диоксо-2-азаспиро[5,5]ундекан-4-карбонитрилов и средство, проявляющее анальгетическую активность |
TW202110844A (zh) * | 2019-06-04 | 2021-03-16 | 日商第一三共股份有限公司 | 具有二螺二酮哌構造之化合物 |
RU2752079C1 (ru) * | 2020-12-01 | 2021-07-22 | Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" | (Е)-(6-(2-гидроксифенил)-2-иминио-4,7,8-триоксо-1,3-дифенил-1,3,6-триазаспиро[4.4]нонан-9-илиден)(4-метоксифенил)метаноат, обладающий противомикробной активностью, и способ его получения |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69633245T2 (de) * | 1995-09-29 | 2005-09-08 | Eli Lilly And Co., Indianapolis | Spiroverbindungen als Inhibitoren der Fibrinogen-abhängigen Blutplättchenaggregation |
WO1998025605A1 (en) * | 1996-12-13 | 1998-06-18 | Merck & Co., Inc. | Spiro-substituted azacycles as modulators of chemokine receptor activity |
WO1998031364A1 (en) | 1997-01-21 | 1998-07-23 | Merck & Co., Inc. | 3,3-disubstituted piperidines as modulators of chemokine receptor activity |
US6288083B1 (en) * | 1998-09-04 | 2001-09-11 | Millennium Pharmaceuticals, Inc. | Chemokine receptor antagonists and methods of use therefor |
JP4721087B2 (ja) * | 1999-12-03 | 2011-07-13 | 小野薬品工業株式会社 | トリアザスピロ[5.5]ウンデカン誘導体およびそれらを有効成分とする薬剤 |
WO2002074769A1 (fr) * | 2001-03-19 | 2002-09-26 | Ono Pharmaceutical Co., Ltd. | Medicaments contenant comme principe actif des derives du triazaspiro [5.5] undecane |
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- 2002-03-18 ES ES02705301T patent/ES2266452T3/es not_active Expired - Lifetime
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- 2002-03-18 CN CNB028100824A patent/CN1291988C/zh not_active Expired - Fee Related
- 2002-03-18 AU AU2002238947A patent/AU2002238947B2/en not_active Ceased
- 2002-03-18 IL IL15781902A patent/IL157819A0/xx unknown
- 2002-03-18 AT AT02705301T patent/ATE328884T1/de not_active IP Right Cessation
- 2002-03-18 HU HU0400229A patent/HUP0400229A2/hu unknown
- 2002-03-18 RU RU2003128067/04A patent/RU2269528C2/ru not_active IP Right Cessation
- 2002-03-18 CA CA002440264A patent/CA2440264A1/en not_active Abandoned
- 2002-03-18 BR BR0208167-9A patent/BR0208167A/pt not_active IP Right Cessation
- 2002-03-18 CZ CZ20032531A patent/CZ20032531A3/cs unknown
- 2002-03-18 MX MXPA03008529A patent/MXPA03008529A/es active IP Right Grant
- 2002-03-18 US US10/472,555 patent/US7053090B2/en not_active Expired - Fee Related
- 2002-03-18 DK DK02705301T patent/DK1378510T3/da active
- 2002-03-18 KR KR1020037012168A patent/KR100714154B1/ko not_active IP Right Cessation
- 2002-03-18 PT PT02705301T patent/PT1378510E/pt unknown
- 2002-03-18 PL PL02364427A patent/PL364427A1/xx not_active Application Discontinuation
- 2002-03-18 JP JP2002573779A patent/JP3558079B2/ja not_active Expired - Fee Related
- 2002-03-18 NZ NZ528249A patent/NZ528249A/en unknown
- 2002-03-18 EP EP02705301A patent/EP1378510B1/en not_active Expired - Lifetime
- 2002-03-18 WO PCT/JP2002/002554 patent/WO2002074770A1/ja active IP Right Grant
- 2002-03-18 DE DE60212110T patent/DE60212110T2/de not_active Expired - Fee Related
- 2002-03-19 TW TW091105129A patent/TWI254047B/zh not_active IP Right Cessation
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2003
- 2003-09-17 NO NO20034148A patent/NO20034148L/no unknown
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