Spirohydantoin compounds and methods for the modulation of chemokine receptor activity 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
US2006014769 A1 2006-01-19 [US20060014769]US7709642 B2 2010-05-04 [US7709642] / 2006-01-192010-05-04
申请号/申请日
2005US-11159406 / 2005-06-23
发明人
CHAN CHUN KONG LAVAL;MOINET CHRISTOPHE;VAILLANCOURT LOUIS;BUBENIK MONICA;
申请人
VIROCHEM PHARMA;
主分类号
IPC分类号
A01N-043/42A61K-031/44C07D-401/00C07D-451/00C07D-453/00C07D-455/00C07D-471/00
摘要
(US7709642) Novel compounds represented by formula (I): wherein R1, R2, R3 and R4 are as defined herein, and pharmaceutically acceptable salts, hydrates and solvates thereof, are useful for the modulation of CCR5 chemokine receptor activity.
机翻摘要
暂无翻译结果,您可以尝试点击头部的翻译按钮。
地址
代理人
代理机构
;
优先权号
2004US-60582540 2004-06-25 2005US-11159406 2005-06-23
主权利要求
(US7709642) We claim: 1.  A compound represented by formula (I):       or a pharmaceutically acceptable salt thereof,   wherein R1 is C6-12 aryl optionally substituted by halogen, nitro, hydroxyl, SO3H, SO03 -- C1-6 alkyl, PO3H2, PO3H -- C1-6 alkyl, PO3H -- C6-12 aryl, PO03(C1-6 alkyl)2, PO03(C6-12 aryl)2, CONH2, CONH -- C1-6 alkyl, CONH -- C6-12 aryl, CON(C1-6 alkyl)2, CON(C6-12 aryl)2, NHCO -- C1-6 alkyl, NHCO -- C6-12 aryl, COOH, COO -- C1-6 alkyl, S -- C1-6 alkyl, O -- C1-6 alkyl, O -- C2-6 alkenyl, O -- C2-6 alkynyl, amino, NH -- C1-6 alkyl, NH -- C6-12 aryl, N(C1-6 alkyl)2, and/or N(C6-12 aryl)2;   R2 is H,    R3 and R4 are each independently H, C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl, which in each case is optionally substituted by halogen, nitro, hydroxyl, SO3H, SO3 -- C1-6 alkyl, PO3H2, PO3H -- C1-6 alkyl, PO3H -- C6-12 aryl, PO3(C1-6 alkyl)2, PO3(C6-12 aryl)2, CONH2, CONH -- C1-6 alkyl, CONH -- C6-12 aryl, CON(C1-6 alkyl)2, CON(C6-12 aryl)2, NHCO -- C1-6 alkyl, NHCO -- C6-12 aryl, COOH, COO -- C1-6 alkyl, S -- C1-6 alkyl, O -- C1-6 alkyl, O -- C2-6 alkenyl, O -- C2-6 alkynyl, amino, NH -- C1-6 alkyl, NH -- C6-12 aryl, N(C1-6 alkyl)2, N(C6-12 aryl)2, and/or C6-12 aryl,   C6-12 aryl optionally substituted by halogen, nitro, hydroxyl, SO3H, SO3 -- C1-6 alkyl, PO3H2, PO3H -- C1-6 alkyl, PO3H -- C6-12 aryl, PO3(C1-6 alkyl)2, PO3(C6-12 aryl)2, CONH2, CONH -- C1-6 alkyl, CONH -- C6-12 aryl, CON(C1-6 alkyl)2, CON(C6-12 aryl)2, NHCO -- C1-6 alkyl, NHCO -- C6-12aryl, COOH, COO -- C1-6 alkyl, S -- C1-6 alkyl, O -- C1-6 alkyl, O -- C2-6 alkenyl, O -- C2-6 alkynyl, amino, NH -- C1-6 alkyl, NH -- C6-12 aryl, N(C1-6 alkyl)2, and/or N(C6-12 aryl)2, or   C7-12 aralkyl optionally substituted by halogen, nitro, hydroxyl, SO3H, SO3 -- C1-6 alkyl, PO3H2, PO3H -- C1-6 alkyl, PO3H -- C6-12 aryl, PO3(C1-6 alkyl)2, PO3(C6-12 aryl)2, CONH2, CONH -- C1-6 alkyl, CONH -- C6-12 aryl, CON(C1-6 alkyl)2, CON(C6-12 aryl)2, NHCO -- C1-6 alkyl, NHCO -- C6-12 aryl, COOH, COO -- C1-6 alkyl, S -- C1-6 alkyl, O -- C1-6 alkyl, O -- C2-6 alkenyl, O -- C2-6 alkynyl, amino, NH -- C1-6 alkyl, NH -- C6-12 aryl, N(C1-6 alkyl)2, and/or N(C6-12 aryl)2;    R5 is H, C1-10 alkyl, C2-10alkenyl, or C2-10 alkynyl, which in each case is optionally substituted by halogen, nitro, hydroxyl, SO3H, SO3 -- C1-6 alkyl, PO3H2, PO3H -- C1-6 alkyl, PO3H -- C6-12 aryl, PO3(C1-6 alkyl)2, PO3(C1-12 aryl)2, CONH2, CONH -- C1-6 alkyl, CONH -- C6-12 aryl, CON(C1-6 alkyl)2, CON(C6-12 aryl)2, NHCO -- C1-6 alkyl, NHCO -- C6-12aryl, COOH COO -- C1-6 alkyl, S -- C1-6 alkyl, O -- C1-6 alkyl, O -- C2-6 alkenyl, O -- C2-6 alkynyl, amino, NH -- C1-6 alkyl, NH -- C6-12 aryl, N(C1-6 alkyl)2, N(C6-12 aryl)2, and/or C6-12 aryl,   C6-12 aryl optionally substituted by halogen, nitro, hydroxyl, SO3H, SO3 -- C1-6 alkyl, PO3H2, PO3H -- C1-6 alkyl, PO3H -- C6-12 aryl, PO3(C1-6 alkyl)2, PO3(C6-12 aryl)2, CONH2, CONH -- C1-6 alkyl, CONH -- C6-12 aryl, CON(C1-6 alkyl)2, CON(C6-12 aryl)2, NHCO -- C1-6 alkyl, NHCO -- C6-12 aryl, COOH, COO -- C1-6 alkyl, S -- C1-6 alkyl, O -- C1-6 alkyl, O -- C2-6 alkenyl, O -- C2-6 alkynyl, amino, NH -- C1-6 alkyl, NH -- C6-12 aryl, N(C1-6 alkyl)2, and/or N(C6-12 aryl)2, or   C7-12 aralkyl optionally substituted by halogen, nitro, hydroxyl, SO3H, SO3 -- C1-6 alkyl, PO3H2, PO3H -- C1-6 alkyl, PO3H -- C6-12 aryl, PO3(C1-6 alkyl)2, PO3(C6-12 aryl)2, CONH2, CONH -- C1-6 alkyl, CONH -- C6-12 aryl, CON(C1-6 alkyl)2, CON(C6-12 aryl)2, NHCO -- C1-6 alkyl, NHCO -- C6-12 aryl, COOH, COO -- C1-6 alkyl, S -- C1-6 alkyl, O -- C1-6 alkyl, O -- C2-6 alkenyl, O -- C2-6 alkynyl, amino, NH -- C1-6 alkyl, NH -- C6-12 aryl, N(C1-6 alkyl)2, and/or N(C6-12 aryl)2;    R6 is H, or C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl, which in each case is optionally substituted by halogen, nitro, hydroxyl, SO3H, SO3 -- C1-6 alkyl, PO3H2, PO3H -- C1-6 alkyl, PO3H -- C6-12 aryl, PO3(C1-6 alkyl)2, PO3(C6-12 aryl)2, CONH2, CONH -- C1-6 alkyl, CONH -- C6-12 aryl, CON(C1-6 alkyl)2, CON(C6-12 aryl)2, NHCO -- C1-6 alkyl, NHCO -- C6-12 aryl, COOH, COO -- C1-6 alkyl, S -- C1-6 alkyl, O -- C1-6 alkyl, O -- C2-6 alkenyl, O -- C2-6 alkynyl, amino, NH -- C1-6 alkyl, NH -- C6-12 aryl, N(C1-6 alkyl)2, N(C6-12 aryl)2, and/or C6-12 aryl; and    Rhd 7 is H, or C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl, which in each case is optionally substituted by halogen, nitro, hydroxyl, SO3H, SO3 -- C1-6 alkyl, PO3H2, PO3H -- C1-6 alkyl, PO3H -- C6-12 aryl, PO3(C1-6 alkyl)2, PO3(C6-12 aryl)2, CONH2, CONH -- C1-6 alkyl, CONH -- C6-12 aryl, CON(C1-6 alkyl)2, CON(C6-12 aryl)2, NHCO -- C1-6 alkyl, NHCO -- C6-12 aryl, COOH, COO -- C1-6 alkyl, S -- C1-6 alkyl, O -- C1-6 alkyl, O -- C2-6 alkenyl, O -- C2-6 alkynyl, amino, NH -- C1-6 alkyl, NH -- C6-12 aryl, N(C1-6 alkyl)2, N(C6-12 aryl)2, and/or C6-12 aryl. 2. A compound according to claim 1 wherein said compound is in the form of the (3R, 4R)-diastereomer. 3. A compound according to claim 1 wherein said compound is in the form of the (3S, 4R)-diastereomer. 4. A compound according to claim 1 wherein said compound is in the form of the (3R, 4S)-diastereomer. 5. A compound according to claim 1 wherein said compound is in the form of the (3S, 4S)-diastereomer. 6. A compound according to claim 1 wherein R1 is optionally substituted phenyl. 7. A compound according to claim 1 wherein R1 is unsubstituted phenyl or phenyl substituted by one or more substituent chosen from methyl, F, Cl and Br. 8. A compound according to claim 1 wherein R5 is H, optionally substituted C1-10 alkyl, optionally substituted C6-12 aryl, or optionally substituted C7-12 aralkyl. 9. A compound according to claim 1 wherein R5 is H or optionally substituted C1-6 alkyl. 10. A compound according to claim 1 wherein R5 is unsubstituted C1-6 alkyl or C1-6 alkyl substituted by one or more substituent chosen from  -- OCH3, F,Cl and Br. 11. A compound according to claim 1 wherein R5 is methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, CH2-tert-butyl, tert-butyl cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, cycloheptyl, CH2-cyclopropyl, CH2-cyclobutyl, CH2-cyclopentyl, or CH2-cyclohexyl. 12. A compound according to claim 1 wherein R5 is optionally substituted C6-12 aryl. 13. A compound according to claim 1 wherein R5 is unsubstituted C6-12 aryl or C6-12 aryl substituted by one or more substituent chosen from  -- OCH3, F, Cl and Br. 14. A compound according to claim 1 wherein R5 is optionally substituted phenyl. 15. A compound according to claim 1 wherein R5 is unsubstituted phenyl or phenyl substituted by one or more substituent chosen from  -- OCH3, F, Cl and Br. 16. A compound according to claim 1 wherein R2 is H,   17. A compound according to claim 1 wherein R2 is H,   18. A compound according to claim 1 wherein R2 is   19. A compound according to claim 1 wherein R4 is H, optionally substituted C1-10 alkyl, optionally substituted C2-10 alkenyl, or optionally substituted C2-10 alkynyl. 20. A compound according to claim 1 wherein R4 is H, or optionally substituted C1-10 alkyl. 21. A compound according to claim 1 wherein R4 is H, or optionally substituted C1-6 alkyl. 22. A compound according to claim 1 wherein R4 is H. 23. A compound according to claim 1 wherein R4 is unsubstituted C1-6 alkyl or C1-6 alkyl substituted by one or more substituent chosen from OCH3, F, Cl and Br. 24. A compound according to claim 1 wherein R4 is methyl, ethyl, propyl, pentyl, cyclopentyl, hexyl, cyclohexyl, CH2-cyclopropyl, CH2-cyclobutyl, CH2-cyclopentyl, or CH2-cyclohexyl. 25. A compound according to claim 1 wherein R3 is H, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C6-12 aryl, or optionally substituted C7-12 aralkyl. 26. A compound according to claim 1 wherein R3 is H, or optionally substituted C1-6 alkyl. 27. A compound according to claim 1 wherein R3 is optionally substituted C7-12 aralkyl. 28. A compound according to claim 1 wherein R3 is optionally substituted benzyl. 29. A compound according to claim 1 wherein R3 is unsubstituted benzyl or benzyl substituted by one or more substituent chosen from Br, F, Cl, C1-3 alkoxy, SO2C1-3alkyl. 30. A compound according to claim 1 wherein R3 is unsubstituted benzyl or benzyl substituted by one or more substituent chosen from Br, F, Cl,  -- OMe or methanesulfonyl. 31. A compound according to claim 1 wherein R3 is benzyl substituted in the para position by one substituent chosen from Br, F, Cl,  -- OMe or methanesulfonyl. 32. A compound chosen from: Compound 1 (3S,4S)-3-[3-(4-Bromo-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;   Compound 2 (3S,4S)-3-[3-(4-Methoxy-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;   Compound 3 (3S,4S)-3-[3-(4-Methanesulfonyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;   Compound 4 (3S,4S)-3-[1-Ethyl-3-(4-methanesulfonyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;   Compound 5 (3S,4S)-3-[1-Isopropyl-3-(4-methanesulfonyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;   Compound 6 (3S,4S)-3-[1-Isobutyl-3-(4-methanesulfonyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;   Compound 7 (3S,4S)-3-(1-Ethyl-2,4-dioxo-3-propyl-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl)-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;   Compound 8 3-(4-Bromo-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 9 3-(4-Methoxy-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 10 3-(4-Methanesulfonyl-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 11 1-Ethyl-3-(4-methanesulfonyl-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 12 1-Isopropyl-3-(4-methanesulfonyl-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 13 1-Isobutyl-3-(4-methanesulfonyl-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 14 1-Ethyl-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-3-propyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 15 3-(4-Methanesulfonyl-benzyl)-8-((3S,4S)-4-phenyl-1-propionyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 16 3-(4-Methanesulfonyl-benzyl)-8-[(3S,4S)-1-methyl-cyclopropanecarbonyl)-4-phenyl-pyrrolidin-3-ylmethyl]-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 17 8-[(3S,4S)-1-(2-Cyclopropyl-acetyl)-4-phenyl-pyrrolidin-3-ylmethyl]-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 18 8-((3S,4S)-1-Cyclopentanecarbonyl-4-phenyl-pyrrolidin-3-ylmethyl)-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 19 8-[(3S,4S)-1-(4,4-Difluoro-cyclohexanecarbonyl)-4-phenyl-pyrrolidin-3-ylmethyl]-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 20 8-[(3S,4S)-1-(2-Fluoro-benzoyl)-4-phenyl-pyrrolidin-3-ylmethyl]-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 21 8-[(3S,4S)-1-(2-Chloro-benzoyl)-4-phenyl-pyrrolidin-3-ylmethyl]-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 22 4-{8-[(3S,4S)-1-(4,4-Difluoro-cyclohexanecarbonyl)-4-phenyl-pyrrolidin-3-ylmethyl]-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-3-ylmethyl}-N,N-dimethyl-benzenesulfonamide;   Compound 23 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 24 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-ethyl-3-propyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 25 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-ethyl-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 26 1-Ethyl-3-(4-methanesulfonyl-benzyl)-8-[(3S,4S)-4-phenyl-1-(1-trifluoromethyl-cyclobutanecarbonyl)-pyrrolidin-3-ylmethyl]-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 27 8-((3S,4S)-1-Cyclopentanecarbonyl-4-phenyl-pyrrolidin-3-ylmethyl)-1-ethyl-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 28 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-isopropyl-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 29 1-Isopropyl-3-(4-methanesulfonyl-benzyl)-8-[(3S,4S)-4-phenyl-1-(1-trifluoromethyl-cyclobutanecarbonyl)-pyrrolidin-3-ylmethyl]-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 30 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-isobutyl-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 31 1-Isobutyl-3-(4-methanesulfonyl-benzyl)-8-[(3S,4S)-4-phenyl-1-(1-trifluoromethyl-cyclobutanecarbonyl)-pyrrolidin-3-ylmethyl]-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 32 8-((3S,4S)-1-Cyclopentanecarbonyl-4-phenyl-pyrrolidin-3-ylmethyl)-1-isobutyl-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 33 8-((3S,4S)-1-Cyclopropanecarbonyl-4-phenyl-pyrrolidin-3-ylmethyl)-3-(4-methoxy-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 34 8-((3S,4S)-1-Cyclopropanecarbonyl-4-phenyl-pyrrolidin-3-ylmethyl)-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 35 8-[(3S,4S)-1-(2-Cyclopropyl-acetyl)-4-phenyl-pyrrolidin-3-ylmethyl]-3-(4-methoxy-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 36 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-ethyl-3-methyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 37 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1,3-diethyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 38 3-Cyclopropylmethyl-8-[(3S,4S)-1-(3,3-dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-ethyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 39 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-isopropyl-3-methyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 40 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-isopropyl-3-ethyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 41 3-Cyclopropylmethyl-8-[(3S,4S)-1-(3,3-dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-isopropyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 42 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1 -isobutyl-3-methyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 43 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-isobutyl-3-ethyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione   Compound 44 3-Cyclopropylmethyl-8-[(3S,4S)-1-(3,3-dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-isobutyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 45 1-Cyclopropylmethyl-8-[(3S,4S)-1-(3,3-dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-3-methyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 46 1-Cyclopropylmethyl-8-[(3S,4S)-1 -(3,3-dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-3-ethyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 47 1,3-Bis-cyclopropylmethyl-8-[(3S,4S)-1-(3,3-dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 48 (3S,4S)-3-[3-(4-Methoxy-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1 -carboxylic acid dimethylamide;   Compound 49 (3S,4S)-3-[3-(4-Methanesulfonyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid dimethylamide;   Compound 50 8-((3S,4S)-1-Benzenesulfonyl-4-phenyl-pyrrolidin-3-ylmethyl)-3-(4-methoxy-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 51 8-((3S,4S)-1-Benzenesulfonyl-4-phenyl-pyrrolidin-3-ylmethyl)-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 52 8-((3S,4S)-1 -Cyclohexylmethyl-4-phenyl-pyrrolidin-3-ylmethyl)-3-(4-methoxy-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 53 8-((3S,4S)-1 -Cyclohexylmethyl-4-phenyl-pyrrolidin-3-ylmethyl)-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione; and pharmaceutically acceptable salts thereof. 33. A pharmaceutical formulation comprising a compound as defined in claim 32 with a pharmaceutically acceptable carrier or excipient. 34. A composition comprising a compound as defined in claim 1 with a pharmaceutically acceptable carrier or excipient. 35. A composition comprising a compound as defined in claim 1 with a pharmaceutically acceptable carrier or excipient and at least one further therapeutic agent. 36. A compound according to claim 1, wherein R1 is unsubstituted phenyl or phenyl substituted by one or more substituent chosen from methyl, F, Cl and Br;   R5 is H, unsubstituted C1-6 alkyl, or C1-6 alkyl substituted by one or more substituent chosen from  -- OCH3, F, Cl and Br;   R4 is H, unsubstituted C1-6 alkyl, or C1-6 alkyl substituted by one or more substituent chosen from OCH3, F, Cl and Br;   R3 is unsubstituted C1-6 alkyl, or C1-6 alkyl substituted by one or more halogen, unsubstituted benzyl or benzyl substituted by one or more substituent chosen from Br, F, Cl, C1-3 alkoxy, SO2C1-3alkyl; and   R6 and R7 are each H. 37. A compound according to claim 17, wherein R1 is unsubstituted phenyl or phenyl substituted by one or more substituent chosen from methyl, F, Cl and Br;   R5 is H, unsubstituted C1-6 alkyl, or C1-6 alkyl substituted by one or more substituent chosen from  -- OCH3, F, Cl and Br;   R4 is H, unsubstituted C1-6 alkyl, or C1-6 alkyl substituted by one or more substituent chosen from OCH3, F, Cl and Br;   R3 is unsubstituted C1-6 alkyl, or C1-6 alkyl substituted by one or more halogen, unsubstituted benzyl or benzyl substituted by one or more substituent chosen from Br, F, Cl, C1-3 alkoxy, SO2C1-3 alkyl; and   R6 is H. 38. A compound according to claim 32 selected from: Compound 1 (3S,4S)-3-[3-(4-Bromo-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;   Compound 2 (3S,4S)-3-[3-(4-Methoxy-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;   Compound 3 (3S,4S)-3-[3-(4-Methanesulfonyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;   Compound 4 (3S,4S)-3-[1-Ethyl-3-(4-methanesulfonyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;   Compound 5 (3S,4S)-3-[1-Isopropyl-3-(4-methanesulfonyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;   Compound 6 (3S,4S)-3-[1-Isobutyl-3-(4-methanesulfonyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1 -carboxylic acid tert-butyl ester;   Compound 7 (3S,4S)-3-( 1 -Ethyl-2,4-dioxo-3-propyl-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl)-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;   Compound 8 3-(4-Bromo-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 9 3-(4-Methoxy-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 10 3-(4-Methanesulfonyl-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 11 1-Ethyl-3-(4-methanesulfonyl-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 12 1-Isopropyl-3-(4-methanesulfonyl-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 13 1-Isobutyl-3-(4-methanesulfonyl-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 14 1-Ethyl-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-3-propyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 15 3-(4-Methanesulfonyl-benzyl)-8-((3S,4S)-4-phenyl-1-propionyl-pyrrlidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 16 3-(4-Methanesulfonyl-benzyl)-8-[(3S,4S)-1-(1-methyl-cyclopropanecarbonyl)-4-phenyl-pyrrolidin-3-ylmethyl]-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 17 8-[(3S,4S)-1-(2-Cyclopropyl-acetyl)-4-phenyl-pyrrolidin-3-ylmethyl]-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 18 8-((3S,4S)-1 -Cyclopentanecarbonyl-4-phenyl-pyrrolidin-3-ylmethyl)-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 19 8-[(3S,4S)-1-(4,4-Difluoro-cyclohexanecarbonyl)-4-phenyl-pyrrolidin-3-ylmethyl]-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 20 8-[(3S,4S)-1-(2-Fluoro-benzoyl)-4-phenyl-pyrrolidin-3-ylmethyl]-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 21 8-[(3S,4S)-1-(2-Chloro-benzoyl)-4-phenyl-pyrrolidin-3-ylmethyl]-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 22 4-{8-[(3S,4S)-1-(4,4-Difluoro-cyclohexanecarbonyl)-4-phenyl-pyrrolidin-3-ylmethyl]-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-3-ylmethyl}-N,N-dimethyl -benzenesulfonamide hydrochloride;   Compound 23 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 24 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-ethyl-3-propyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 25 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1 -ethyl-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 26 1-Ethyl-3-(4-methanesulfonyl-benzyl)-8-[(3S,4S)-4-phenyl-1-(1-trifluoromethyl-cyclobutanecarbonyl)-pyrrolidin-3-ylmethyl]-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 27 8-((3S,4S)-1-Cyclopentanecarbonyl-4-phenyl-pyrrolidin-3-ylmethyl)-1 -ethyl-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 28 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-isopropyl-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 29 1-Isopropyl-3-(4-methanesulfonyl-benzyl)-8-[(3S,4S)-4-phenyl-1-(1-trifluoromethyl-cyclobutanecarbonyl)-pyrrolidin-3-ylmethyl]-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 30 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-isobutyl-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 31 1-Isobutyl-3-(4-methanesulfonyl-benzyl)-8-[(3S,4S)-4-phenyl-1-(1-trifluoromethyl-cyclobutanecarbonyl)-pyrrolidin-3-ylmethyl]-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 32 8-((3S,4S)-1-Cyclopentanecarbonyl-4-phenyl-pyrrolidin-3-ylmethyl)-1-isobutyl-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 33 8-((3S,4S)-1 -Cyclopropanecarbonyl-4-phenyl-pyrrolidin-3-ylmethyl)-3-(4-methoxy-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 34 8-((3S,4S)-1-Cyclopropanecarbonyl-4-phenyl-pyrrolidin-3-ylmethyl)-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 35 8-[(3S,4S)-1-(2-Cyclopropyl-acetyl)-4-phenyl-pyrrolidin-3-ylmethyl]-3-(4-methoxy-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 36 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-ethyl-3-methyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 37 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1,3-diethyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 38 3-Cyclopropylmethyl-8-[(3S,4S)-1-(3,3-dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-ethyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 39 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-isopropyl-3-methyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 40 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-isopropyl-3-ethyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 41 3-Cyclopropylmethyl-8-[(3S,4S)-1-(3,3-dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-isopropyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 42 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-isobutyl-3-methyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 43 8-[(3S,4S)-1-(3,3-Dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-isobutyl-3-ethyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride   Compound 44 3-Cyclopropylmethyl-8-[(3S,4S)-1-(3,3-dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1-isobutyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 45 1-Cyclopropylmethyl-8-[(3S,4S)-1-(3,3-dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-3-methyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 46 1-Cyclopropylmethyl-8-[(3S,4S)-1-(3,3-dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-3-ethyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 47 1,3-Bis-cyclopropylmethyl-8-[(3S,4S)-1-(3,3-dimethyl-butyryl)-4-phenyl-pyrrolidin-3-ylmethyl]-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 48 (3S,4S)-3-[3-(4-Methoxy-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid dimethylamide hydrochloride;   Compound 49 (3S,4S)-3-[3-(4-Methanesulfonyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid dimethylamide hydrochloride;   Compound 50 8-((3S,4S)-1-Benzenesulfonyl-4-phenyl-pyrrolidin-3-ylmethyl)-3-(4-methoxy-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 51 8-((3S,4S)-1-Benzenesulfonyl-4-phenyl-pyrrolidin-3-ylmethyl)-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 52 8-((3S,4S)-1-Cyclohexylmethyl-4-phenyl-pyrrolidin-3-ylmethyl)-3-(4-methoxy-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione dihydrochloride; and   Compound 53 8-((3S,4S)-1-Cyclohexylmethyl-4-phenyl-pyrrolidin-3-ylmethyl)-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione dihydrochioride. 39. A compound according to claim 32, wherein said compound is: Compound 1 (3S,4S)-3-[3-(4-Bromo-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;   Compound 2 (3S,4S)-3-[3-(4-Methoxy-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;   Compound 3 (3S,4S)-3-[3-(4-Methanesulfonyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;   Compound 4 (3S,4S)-3-[1-Ethyl-3-(4-methanesulfonyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;   Compound 5 (3S,4S)-3-[1-Isopropyl-3-(4-methanesulfonyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester;   Compound 6 (3S,4S)-3-[1-Isobutyl-3-(4-methanesulfonyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester; or   Compound 7 (3S,4S)-3-(1-Ethyl-2,4-dioxo-3-propyl-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl)-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester. 40. A compound according to claim 32, wherein said compound is: Compound 8 3-(4-Bromo-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 9 3-(4-Methoxy-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 10 3-(4-Methanesulfonyl-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 11 1-Ethyl-3-(4-methanesulfonyl-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione;   Compound 12 1-Isopropyl-3-(4-methanesulfonyl-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane2,4-dione;   Compound 13 1-Isobutyl-3-(4-methanesulfonyl-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione; or   Compound 14 1-Ethyl-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-3-propyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione. 41. A compound according to claim 32, wherein said compound is: Compound 15 3-(4-Methanesulfonyl-benzyl)-8-((3S,4S)-4-phenyl-1-propionyl-pyrrolidin-3-ylmethyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 16 3-(4-Methanesulfonyl-benzyl)-8-[(3S,4S)-1-(1-methyl-cyclopropanecarbonyl)-4-phenyl-pyrrolidin-3-ylmethyl]-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 17 8-[(3S,4S)-1-(2-Cyclopropyl-acetyl)-4-phenyl-pyrrolidin-3-ylmethyl]-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 18 8-((3S,4S)-1-Cyclopentanecarbonyl-4-phenyl-pyrrolidin-3-ylmethyl)-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 19 8-[(3S,4S)-1-(4,4-Difluoro-cyclohexanecarbonyl)-4-phenyl -pyrrolidin-3-ylmethyl]-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 20 8-[(3S,4S)-1-(2-Fluoro-benzoyl)-4-phenyl-pyrrolidin-3-ylmethyl]-3-(4-methanesulfonyl-benzyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione hydrochloride;   Compound 21 8-[(3S,4S)-1-(2-Chloro-benzoyl)-4-p(...)
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