AU2004212043A1 - Nitrogen-substituted hexahydropyrazino(1,2-a)pyrimidine-4,7-dione derivatives, method for the production and use thereof as medicaments - Google Patents
Nitrogen-substituted hexahydropyrazino(1,2-a)pyrimidine-4,7-dione derivatives, method for the production and use thereof as medicaments Download PDFInfo
- Publication number
- AU2004212043A1 AU2004212043A1 AU2004212043A AU2004212043A AU2004212043A1 AU 2004212043 A1 AU2004212043 A1 AU 2004212043A1 AU 2004212043 A AU2004212043 A AU 2004212043A AU 2004212043 A AU2004212043 A AU 2004212043A AU 2004212043 A1 AU2004212043 A1 AU 2004212043A1
- Authority
- AU
- Australia
- Prior art keywords
- alkyl
- monoisotopic
- calculated
- measured value
- pyrimidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- -1 Nitrogen-substituted hexahydropyrazino(1,2-a)pyrimidine-4,7-dione Chemical class 0.000 title claims description 136
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- 125000003118 aryl group Chemical group 0.000 claims description 34
- 239000000556 agonist Substances 0.000 claims description 32
- 229910004013 NO 2 Inorganic materials 0.000 claims description 31
- 239000004480 active ingredient Substances 0.000 claims description 31
- 125000000623 heterocyclic group Chemical group 0.000 claims description 28
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- 229910052740 iodine Inorganic materials 0.000 claims description 23
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
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- HSJIZSDHJFLHSY-UHFFFAOYSA-N n-[1-(5-chloro-2-fluorophenyl)sulfonyl-6-[(4-chlorophenyl)methyl]-4,7-dioxo-8-propan-2-yl-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Chemical compound O=C1N2C(CC=3C=CC(Cl)=CC=3)C(=O)N(C(C)C)CC2N(S(=O)(=O)C=2C(=CC=C(Cl)C=2)F)CC1NC(=O)C1CC1 HSJIZSDHJFLHSY-UHFFFAOYSA-N 0.000 description 1
- MBTOJWXCXMOCFH-UHFFFAOYSA-N n-[1-(5-chloro-2-methoxyphenyl)sulfonyl-6-[(4-chlorophenyl)methyl]-4,7-dioxo-8-propan-2-yl-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide Chemical compound COC1=CC=C(Cl)C=C1S(=O)(=O)N1C2CN(C(C)C)C(=O)C(CC=3C=CC(Cl)=CC=3)N2C(=O)C(NC(=O)C2CCC2)C1 MBTOJWXCXMOCFH-UHFFFAOYSA-N 0.000 description 1
- SJUVOIVNBIAAJG-UHFFFAOYSA-N n-[1-(5-chloro-2-methoxyphenyl)sulfonyl-6-[(4-chlorophenyl)methyl]-4,7-dioxo-8-propan-2-yl-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide Chemical group COC1=CC=C(Cl)C=C1S(=O)(=O)N1C2CN(C(C)C)C(=O)C(CC=3C=CC(Cl)=CC=3)N2C(=O)C(NC(=O)C2CCCC2)C1 SJUVOIVNBIAAJG-UHFFFAOYSA-N 0.000 description 1
- WDKMKBYYDYFAOQ-UHFFFAOYSA-N n-[1-(5-chloro-2-methoxyphenyl)sulfonyl-6-[(4-chlorophenyl)methyl]-4,7-dioxo-8-propan-2-yl-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Chemical compound COC1=CC=C(Cl)C=C1S(=O)(=O)N1C2CN(C(C)C)C(=O)C(CC=3C=CC(Cl)=CC=3)N2C(=O)C(NC(=O)C2CC2)C1 WDKMKBYYDYFAOQ-UHFFFAOYSA-N 0.000 description 1
- YEDZGILAJKMBCA-UHFFFAOYSA-N n-[1-(5-chloro-2-methoxyphenyl)sulfonyl-6-[(4-chlorophenyl)methyl]-4,7-dioxo-8-propan-2-yl-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide Chemical compound COC1=CC=C(Cl)C=C1S(=O)(=O)N1C2CN(C(C)C)C(=O)C(CC=3C=CC(Cl)=CC=3)N2C(=O)C(NS(C)(=O)=O)C1 YEDZGILAJKMBCA-UHFFFAOYSA-N 0.000 description 1
- JLPAYOIIXHNESP-UHFFFAOYSA-N n-[6-[(3,4-dichlorophenyl)methyl]-1-(2,4-dichlorophenyl)sulfonyl-4,7-dioxo-8-propan-2-yl-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide Chemical group O=C1N2C(CC=3C=C(Cl)C(Cl)=CC=3)C(=O)N(C(C)C)CC2N(S(=O)(=O)C=2C(=CC(Cl)=CC=2)Cl)CC1NC(=O)C1CCC1 JLPAYOIIXHNESP-UHFFFAOYSA-N 0.000 description 1
- JWABEPHDAIMVJA-UHFFFAOYSA-N n-[6-[(3,4-dichlorophenyl)methyl]-1-(2,4-dichlorophenyl)sulfonyl-4,7-dioxo-8-propan-2-yl-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide Chemical group O=C1N2C(CC=3C=C(Cl)C(Cl)=CC=3)C(=O)N(C(C)C)CC2N(S(=O)(=O)C=2C(=CC(Cl)=CC=2)Cl)CC1NC(=O)C1CCCC1 JWABEPHDAIMVJA-UHFFFAOYSA-N 0.000 description 1
- JALBIZAIQBNDNI-UHFFFAOYSA-N n-[6-[(3,4-dichlorophenyl)methyl]-1-(2,4-dichlorophenyl)sulfonyl-4,7-dioxo-8-propan-2-yl-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Chemical group O=C1N2C(CC=3C=C(Cl)C(Cl)=CC=3)C(=O)N(C(C)C)CC2N(S(=O)(=O)C=2C(=CC(Cl)=CC=2)Cl)CC1NC(=O)C1CC1 JALBIZAIQBNDNI-UHFFFAOYSA-N 0.000 description 1
- RPJXSTWUFJLIEK-UHFFFAOYSA-N n-[6-[(3,4-dichlorophenyl)methyl]-1-(2,4-dichlorophenyl)sulfonyl-4,7-dioxo-8-propan-2-yl-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide Chemical compound O=C1N(C(C)C)CC2N(S(=O)(=O)C=3C(=CC(Cl)=CC=3)Cl)CC(NS(C)(=O)=O)C(=O)N2C1CC1=CC=C(Cl)C(Cl)=C1 RPJXSTWUFJLIEK-UHFFFAOYSA-N 0.000 description 1
- SFPVGXDWZMDZPY-UHFFFAOYSA-N n-[6-[(3-chlorophenyl)methyl]-1-(2,4-dichlorophenyl)sulfonyl-4,7-dioxo-8-propan-2-yl-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]-4-(dimethylamino)benzamide Chemical compound O=C1N2C(CC=3C=C(Cl)C=CC=3)C(=O)N(C(C)C)CC2N(S(=O)(=O)C=2C(=CC(Cl)=CC=2)Cl)CC1NC(=O)C1=CC=C(N(C)C)C=C1 SFPVGXDWZMDZPY-UHFFFAOYSA-N 0.000 description 1
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- LXZBSXVDAZVFGS-UHFFFAOYSA-N n-[6-[(3-chlorophenyl)methyl]-1-(2,4-dichlorophenyl)sulfonyl-4,7-dioxo-8-propan-2-yl-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide Chemical group O=C1N2C(CC=3C=C(Cl)C=CC=3)C(=O)N(C(C)C)CC2N(S(=O)(=O)C=2C(=CC(Cl)=CC=2)Cl)CC1NC(=O)C1CCC1 LXZBSXVDAZVFGS-UHFFFAOYSA-N 0.000 description 1
- DTQSYVSQZJBVSG-UHFFFAOYSA-N n-[6-[(3-chlorophenyl)methyl]-1-(2,4-dichlorophenyl)sulfonyl-4,7-dioxo-8-propan-2-yl-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide Chemical group O=C1N2C(CC=3C=C(Cl)C=CC=3)C(=O)N(C(C)C)CC2N(S(=O)(=O)C=2C(=CC(Cl)=CC=2)Cl)CC1NC(=O)C1CCCC1 DTQSYVSQZJBVSG-UHFFFAOYSA-N 0.000 description 1
- BKXOOPALXVIDQC-UHFFFAOYSA-N n-[6-[(3-chlorophenyl)methyl]-8-cyclopropyl-1-(2,4-dichlorophenyl)sulfonyl-4,7-dioxo-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]-4-(dimethylamino)benzamide Chemical compound C1=CC(N(C)C)=CC=C1C(=O)NC1C(=O)N2C(CC=3C=C(Cl)C=CC=3)C(=O)N(C3CC3)CC2N(S(=O)(=O)C=2C(=CC(Cl)=CC=2)Cl)C1 BKXOOPALXVIDQC-UHFFFAOYSA-N 0.000 description 1
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- WYMODHBPZAVNIU-UHFFFAOYSA-N n-[6-[(3-chlorophenyl)methyl]-8-cyclopropyl-1-(2,4-dichlorophenyl)sulfonyl-4,7-dioxo-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Chemical group ClC1=CC=CC(CC2C(N(C3CC3)CC3N2C(C(NC(=O)C2CC2)CN3S(=O)(=O)C=2C(=CC(Cl)=CC=2)Cl)=O)=O)=C1 WYMODHBPZAVNIU-UHFFFAOYSA-N 0.000 description 1
- DZBYAQYNACMQAY-UHFFFAOYSA-N n-[6-[(3-chlorophenyl)methyl]-8-cyclopropyl-1-(2,4-dichlorophenyl)sulfonyl-4,7-dioxo-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide Chemical group O=C1C(CC=2C=C(Cl)C=CC=2)N2C(=O)C(NS(=O)(=O)C)CN(S(=O)(=O)C=3C(=CC(Cl)=CC=3)Cl)C2CN1C1CC1 DZBYAQYNACMQAY-UHFFFAOYSA-N 0.000 description 1
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- DRAKWOLGTKFBMI-UHFFFAOYSA-N n-[6-[(4-bromophenyl)methyl]-1-(2,4-dichlorophenyl)sulfonyl-4,7-dioxo-8-propan-2-yl-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide Chemical compound O=C1N(C(C)C)CC2N(S(=O)(=O)C=3C(=CC(Cl)=CC=3)Cl)CC(NS(C)(=O)=O)C(=O)N2C1CC1=CC=C(Br)C=C1 DRAKWOLGTKFBMI-UHFFFAOYSA-N 0.000 description 1
- SGNRUFGLCUAODY-UHFFFAOYSA-N n-[6-[(4-bromophenyl)methyl]-1-(2,4-dichlorophenyl)sulfonyl-4,7-dioxo-8-propan-2-yl-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]pyridine-3-carboxamide Chemical compound O=C1N2C(CC=3C=CC(Br)=CC=3)C(=O)N(C(C)C)CC2N(S(=O)(=O)C=2C(=CC(Cl)=CC=2)Cl)CC1NC(=O)C1=CC=CN=C1 SGNRUFGLCUAODY-UHFFFAOYSA-N 0.000 description 1
- JCTMOMFRTCEPEV-UHFFFAOYSA-N n-[6-[(4-bromophenyl)methyl]-1-(5-chloro-2-methoxyphenyl)sulfonyl-8-cyclopropyl-4,7-dioxo-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]-4-(dimethylamino)benzamide Chemical compound COC1=CC=C(Cl)C=C1S(=O)(=O)N1C(CN(C2CC2)C(=O)C2CC=3C=CC(Br)=CC=3)N2C(=O)C(NC(=O)C=2C=CC(=CC=2)N(C)C)C1 JCTMOMFRTCEPEV-UHFFFAOYSA-N 0.000 description 1
- ASMCJWLEEOWPOA-UHFFFAOYSA-N n-[6-[(4-bromophenyl)methyl]-1-(5-chloro-2-methoxyphenyl)sulfonyl-8-cyclopropyl-4,7-dioxo-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]acetamide Chemical compound COC1=CC=C(Cl)C=C1S(=O)(=O)N1C2CN(C3CC3)C(=O)C(CC=3C=CC(Br)=CC=3)N2C(=O)C(NC(C)=O)C1 ASMCJWLEEOWPOA-UHFFFAOYSA-N 0.000 description 1
- JSXYFIAUWNJCCH-UHFFFAOYSA-N n-[6-[(4-bromophenyl)methyl]-1-(5-chloro-2-methoxyphenyl)sulfonyl-8-cyclopropyl-4,7-dioxo-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide Chemical group COC1=CC=C(Cl)C=C1S(=O)(=O)N1C2CN(C3CC3)C(=O)C(CC=3C=CC(Br)=CC=3)N2C(=O)C(NC(=O)C2CCC2)C1 JSXYFIAUWNJCCH-UHFFFAOYSA-N 0.000 description 1
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- FCWUMXWFBZKELX-UHFFFAOYSA-N n-[6-[(4-bromophenyl)methyl]-8-cyclopropyl-1-(2,4-dichlorophenyl)sulfonyl-4,7-dioxo-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide Chemical group ClC1=CC(Cl)=CC=C1S(=O)(=O)N1C2CN(C3CC3)C(=O)C(CC=3C=CC(Br)=CC=3)N2C(=O)C(NC(=O)C2CCC2)C1 FCWUMXWFBZKELX-UHFFFAOYSA-N 0.000 description 1
- QTHZXHLDZUUNRK-UHFFFAOYSA-N n-[6-[(4-bromophenyl)methyl]-8-cyclopropyl-1-(2,4-dichlorophenyl)sulfonyl-4,7-dioxo-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide Chemical group ClC1=CC(Cl)=CC=C1S(=O)(=O)N1C2CN(C3CC3)C(=O)C(CC=3C=CC(Br)=CC=3)N2C(=O)C(NC(=O)C2CCCC2)C1 QTHZXHLDZUUNRK-UHFFFAOYSA-N 0.000 description 1
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- UYJUGRWHXCYFKI-UHFFFAOYSA-N n-[6-[(4-chlorophenyl)methyl]-1-(2,4-dichlorophenyl)sulfonyl-4,7-dioxo-8-(2,2,2-trifluoroethyl)-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Chemical compound O=C1N2C(CC=3C=CC(Cl)=CC=3)C(=O)N(CC(F)(F)F)CC2N(S(=O)(=O)C=2C(=CC(Cl)=CC=2)Cl)CC1NC(=O)C1CC1 UYJUGRWHXCYFKI-UHFFFAOYSA-N 0.000 description 1
- OUMWTOXLIKKELN-UHFFFAOYSA-N n-[6-[(4-chlorophenyl)methyl]-1-(2,4-dichlorophenyl)sulfonyl-4,7-dioxo-8-(2,2,2-trifluoroethyl)-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]piperidine-4-carboxamide Chemical compound O=C1N2C(CC=3C=CC(Cl)=CC=3)C(=O)N(CC(F)(F)F)CC2N(S(=O)(=O)C=2C(=CC(Cl)=CC=2)Cl)CC1NC(=O)C1CCNCC1 OUMWTOXLIKKELN-UHFFFAOYSA-N 0.000 description 1
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- LPHZVNQGOIOEIS-UHFFFAOYSA-N n-[6-[(4-chlorophenyl)methyl]-1-(2,4-dichlorophenyl)sulfonyl-4,7-dioxo-8-propan-2-yl-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]-2-pyridin-3-ylacetamide Chemical compound O=C1N2C(CC=3C=CC(Cl)=CC=3)C(=O)N(C(C)C)CC2N(S(=O)(=O)C=2C(=CC(Cl)=CC=2)Cl)CC1NC(=O)CC1=CC=CN=C1 LPHZVNQGOIOEIS-UHFFFAOYSA-N 0.000 description 1
- HHSXTDJUZSTXBP-UHFFFAOYSA-N n-[6-[(4-chlorophenyl)methyl]-1-(2,4-dichlorophenyl)sulfonyl-4,7-dioxo-8-propan-2-yl-3,6,9,9a-tetrahydro-2h-pyrazino[1,2-a]pyrimidin-3-yl]-4-(dimethylamino)benzamide Chemical group O=C1N2C(CC=3C=CC(Cl)=CC=3)C(=O)N(C(C)C)CC2N(S(=O)(=O)C=2C(=CC(Cl)=CC=2)Cl)CC1NC(=O)C1=CC=C(N(C)C)C=C1 HHSXTDJUZSTXBP-UHFFFAOYSA-N 0.000 description 1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Description
IN THE MATTER OF an Australian Application corresponding to PCT Application PCT/EP2004/000770 RWS Group Ltd, of Europa House, Marsham Way, Gerrards Cross, Buckinghamshire, England, hereby solemnly and sincerely declares that, to the best of its knowledge and belief, the following document, prepared by one of its translators competent in the art and conversant with the English and German languages, is a true and correct translation of the PCT Application filed under No. PCT/EP2004/000770. Date: 3 May 2005 C. E. SITCH Deputy Managing Director - UK Translation Division For and on behalf of RWS Group Ltd WO 2004/072077 1 PCT/EP2004/000770 Description Nitrogen-substituted hexahydropyrazino[1,2-a]pyrimidine-4,7-dione derivatives, 5 method for the production and use thereof as medicaments The invention relates to substituted hexahydropyrazino[1,2-a]pyrimidine-4,7-dione derivatives and to the physiologically tolerated salts thereof. 10 The invention was based on the object of providing compounds which bring about a weight reduction in mammals and are suitable for the prevention and treatment of obesity. The invention therefore relates to compounds of the formula I, 15 R4 R3 R5 O=S=O (CH On N R6 N 2 0
(CH
2 )m A in which the meanings are 20 A 3-12 membered mono-, bi- or spirobicyclic ring which may comprise one or more heteroatoms from the group of N, 0 and S and which 3 12 membered ring may have further substituents such as F, Cl, Br,
NO
2 , CF 3 , OCF 3 , CN, (CrC 6 )-alkyl, aryl, CON(R11)(R12), 2 N(R13)(R14), OH, O-(OC0)-alkyl, S-(PC)-alkyl, N(R15)CO(CrC6) alkyl or COO-( 1 C0)-alkyl; R11, R12, R13, R14, R15 independently of one another H, (PC)-alkyl, 5 heterocycle; n 0, 1; m 0, 1, 2, 3, 4, 5, 6; 10 R1 R8, (C-C)-alkylene-R8, (C 2 -Cs)-alkenylene-R9, (SO 2 )-R8, (S0 2
)-(C
C)-alkylene-R8, (S0 2
)-(C
2
-C
6 )-alkenylene-R9, (C=O)-R8, (C=O)-(C
C
6 )-alkylene-R8, (C=O)NH-R8, (C=O)-(C 2
-C
6 )-alkenylene-R9, (C=0) NH-(Cr-C 6 )-alkylene-R8, (C=O)-NH- (C 2 -C)-alkenylene-R9, COO-R8, 15 COO-(C-C)-alkylene-R8, COO-(C 2
-C
6 )-alkenylene-R9, alkynylene R9, (Cr 1
C
4 -alkyl)-heterocycle, where the alkylene groups may be substituted by F; R8, R9 independently of one another H, F, Cl, Br, I, OH, CF 3 , aryl, 20 heterocycle, (C 3
-C
8 )-cycloalkyl, where the rings or ring systems may be substituted up to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O-(OiC)-alkyl, (PC)-alkyl, NH 2 , CON(R1 1)(R1 2), N(R1 3)(R1 4), S0 2
-CH
3 , COOH, COO-(C-C 6 )-alkyl, CONH 2 ; 25 R2 NH 2 , NO 2 , N(R13)(R14), NH-S0 2
-CH
3 , NH-S0 2 -R12, NR11-S0 2 R12, N(CO)R1 1, a nitrogen-containing heterocycle, where the heterocycle is bonded via a nitrogen atom, NHCONR1 1, N(Cr 1
C
6 alkyl)N*(Cr-C4-alkyl)3; 30 R3, R4, R5 independently of one another H, F, Cl, Br, 1, OH, CF 3 , NO 2 , CN,
OCF
3 , O-(0C)-alkyl, 0-(C-C4)-alkoxy-(C-C 4 )-alkyl, S-(OiC)-alkyl, (0-C)-alkyl, (C 2 -C)-alkenyl, (C 3 -C)-cycloalkyl, 0-(C 3
-C
8 )-cycloalkyl, 3
(C
3
-C
8 )-cycloalkenyl, O-(C 3
-C
8 )-cycloalkenyl, (C 2
-C
6 )-alkynyl, aryl, 0 aryl (C1-Cs)-alkylene-aryl, 0-(C1-C 8 )-alkylene-aryl, S-aryl, N((C 1
-C
6
)
alkyl) 2 , SO 2
-CH
3 , COOH, COO-(C 1 -C)-alkyl, CO-N((C 1
-C
6 )-alkyl) 2 ; 5 R6 H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , 0-(C1-C 6 )-alkyl, O-(C1-C4) alkoxy-(C1-C4)-alkyl, S-(C-Ce)-alkyl, (C-Ce)-alkyl, (C2-Cs)-alkenyl,
(C
3
-C
8 )-cycloalkyl, O-(C 3 -C8)-cycloalkyl, (C3-Cs)-cycloalkenyl, O-(C3 C8)-cycloalkenyl, (C 2
-C
6 )-alkynyl, (Co-Ca)-alkylene-aryl, 0-(Co-C8) alkylene-aryl, S-aryl, N((C1-C 6 )-alkyl) 2 , SO 2
-CH
3 , COOH, COO-(C1 10 C)-alkyl, CO-N((C1-C 6 )-alkyl) 2 ; and the physiologically tolerated salts thereof. Preference is given to compounds of the formula I of the following structure la 15 R4 R3 R5 O=S=O N N R1 R6 N O R2I 0
(CH
2 )m A la in which the meanings are 20 A 3-12 membered mono-, bi- or spirobicyclic ring which may comprise one or more heteroatoms from the group of N, 0 and S and which 3 12 membered ring may have further substituents such as F, Cl, Br, 4
NO
2 , CF 3 , OCF 3 , CN, (C1-C)-alkyl, aryl, CON(R11)(R12), N(R13)(R14), OH, O-(C1-C)-alkyl, S-(C1-C)-alkyl, N(R15)CO(C1-C6) alkyl or COO-(C 1 -Cs)-alkyl; 5 R11, R12, R13, R14, R15 independently of one another H, (C 1 -C)-alkyl, heterocycle; m 0, 1, 2, 3, 4, 5, 6; 10 R1 R8, (C1-C)-alkylene-R8, (C 2 -C)-alkenylene-R9, (S0 2 )-R8, (S0 2
)-(C
1 C)-alkylene-R8, (S0 2
)-(C
2
-C
6 )-alkenylene-R9, (C=O)-R8, (C=O)-(C1 C)-alkylene-R8, (C=O)NH-R8, (C=O)-(C 2
-C
6 )-alkenylene-R9, (C=0)
NH-(C
1
-C
6 )-alkylene-R8, (C=0)-NH- (C 2
-C
6 )-alkenylene-R9, COO-R8,
COO-(C
1 -C)-alkylene-R8, COO-(C 2
-C
6 )-alkenylene-R9, alkynylene 15 R9, (C1-C 4 -alkyl)-heterocycle; R8, R9 independently of one another H, F, C, Br, I, OH, CF 3 , aryl, heterocycle, (C 3
-C
8 )-cycloalkyl, where the rings or ring systems may be substituted up to 3 times by F, C, Br, 1, OH, CF 3 , NO 2 , CN, OCF 3 , 20 0-(C1-C 6 )-alkyl, (C 1 -C)-alkyl, NH 2 , CON(R1 1)(R1 2), N(R1 3)(R14), S0 2
-CH
3 , COOH, COO-(C1-C)-alkyl, CONH 2 ; R2 NH 2 , NO 2 , N(R13)(R14), NH-S0 2
-CH
3 , NH-S0 2 -R12, NR11-S0 2 -R12, N(CO)R1 1, a nitrogen-containing heterocycle, where the heterocycle 25 is bonded via a nitrogen atom, NHCONRI 1, N(C1-CO 6 -alkyl)N*(C 1
-C
4 alkyl) 3 ; R3, R4, R5 independently of one another H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN,
OCF
3 , O-(C 1 -C)-alkyl, 0-(C 1
-C
4 )-alkoxy-(C 1
-C
4 )-alkyl, S-(C 1 -C)-alkyl, 30 (C1-C 6 )-alkyl, (C 2 -C)-alkenyl, (C 3
-C
8 )-cycloalkyl, 0-(C 3
-C
8 )-cycloalkyl,
(C
3
-C
8 )-cycloalkenyl, 0-(C 3
-C
8 )-cycloalkenyl, (C 2
-C
6 )-alkynyl, aryl, 0- 5 aryl (Co-C 8 )-alkylene-aryl, 0-(Co-C 8 )-alkylene-aryl, S-aryl, N((C 1 -C6) alkyl) 2 , S0 2
-CH
3 , COOH, COO-(Cr-0)-alkyl, CO-N((CrC 6 )-alkyl) 2 ; R6 H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O-(C-C)-alkyl, 0-(Cr1C4) 5 alkoxy-(Cr-C 4 )-alkyl, S-(0 1
-C
6 )-alkyl, (C-C 6 )-alkyl, (C 2
-C
6 )-alkenyl,
(C
3 -C)-cycloalkyl, 0-(C 3 -C8)-cycloalkyl, (C 3
-C
8 )-cycloalkenyl, 0-(C3
C
8 )-cycloalkenyl, (C 2
-C
6 )-alkynyl, aryl, 0-aryl, (Cr 1
C
8 )-alkylene-aryl, O-(CrCs)-alkylene-aryl, S-aryl, N((C 1
-C
6 )-alkyl) 2 , S0 2
-CH
3 , COOH, COO-(OiC)-alkyl, CO-N((Cr-C 6 )-alkyl) 2 ; 10 and the physiologically tolerated salts thereof. Particular preference is given to compounds of the formula la 15 in which the meanings are A aryl, where the aryl ring may be substituted by F, Cl, Br, NO 2 , CF 3 ,
OCF
3 , CN, (0C)-alkyl, aryl, CON(R11)(R12), N(R13)(R14), OH, 0 (Cr-0)-alkyl, S-(Cr-0)-alkyl, N(R1 5)CO(Cr-C 6 )-alkyl or COO-(Cr1C6) 20 alkyl; R1 1, R12, R13, R14, R15 independently of one another H, (0C)-alkyl, heterocycle; 25 m 1; R1 R8, (CrO0)-alkylene-R8, (C 2
-C
6 )-alkenylene-R9, (S0 2 )-R8, (S0 2
)-(C
C
6 )-alkylene-R8, (S0 2
)-(C
2
-C
6 )-alkenylene-R9, (C=O)-R8, (C=O)-(C
C
6 )-alkylene-R8, (C=O)NH-R8, (C=0)-(C 2
-C
6 )-alkenylene-R9, (C=0) 30 NH-(Cr 1
C
6 )-alkylene-R8, (C=O)-NH-(C 2
-C
6 )-alkenylene-R9, COO-R8, COO-(Cr 1
C
6 )-alkylene-R8, COO-(C 2
-C
6 )-alkenylene-R9, alkynylene R9, (Cr 1
C
4 -alkyl)-heterocycle; 6 R8, R9 independently of one another H, F, Cl, Br, I, OH, CF 3 , aryl, heterocycle, (C3-C8)-cycloalkyl, where the rings or ring systems may 5 be substituted up to 3 times by F, CI, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 ,
O-(C
1 -Cs)-alkyl, (C1-C)-alkyl, NH 2 , CON(R11)(R1 2), N(R13)(R14), S0 2
-CH
3 , COOH, COO-(C1-C)-alkyl, CONH 2 ; R2 NH 2 , NO 2 , N(R13)(R14), NH-S0 2
-CH
3 , NH-S0 2 -R12, NR11-S0 2 -R12, 10 N(CO)R1 1, a nitrogen-containing heterocycle, where the heterocycle is bonded via a nitrogen atom, NHCONR1 1, N(C-CO 6 -alkyl)N*(C 1
-C
4 alkyl) 3 ; R3 H 15 R4, R5 independently of one another H, F, C, Br, OH, CF 3 , OCF 3 , 0-(C1-C6) alkyl, (C 1 -C)-alkyl; R6 H; 20 and the physiologically tolerated salts thereof. Very particular preference is given to compounds of the formula la 25 in which the meanings are A aryl, where the aryl ring may be substituted by F, CI, Br, NO 2 , CF 3 ,
OCF
3 , CN, (C 1
-C
6 )-alkyl, aryl, CON(R11)(R12), N(R13)(R14), OH, 0 (C1-C)-alkyl, S-(C 1 -C)-alkyl, N(R15)CO(C 1
-C
6 )-alkyl or COO-(C1-C6) 30 alkyl; 7 R11, R12, R13, R14, R15 independently of one another H, (C1-Cs)-alkyl, heterocycle; m 1; 5 R1 (C 1 -C)-alkyl, (C 1 -CO)-alkylene-R8; R8, R9 independently of one another F, Cl, Br, I, OH, CF 3 ; 10 R2 NH 2 , NO 2 , CN, N(R13)(R14), NH-S0 2
-CH
3 , NH-SO 2 -R12, NR11-S0 2 R1 2, N(CO)R1 1, a nitrogen-containing heterocycle, where the heterocycle is bonded via a nitrogen atom, NHCONR1 1, N(C1-C 6 alkyl)N'(C1-C4-alkyl)3; 15 R3 H R4 F, Cl, Br, OH, CF 3 , OCF 3 , O-(C1-C)-alkyl, (C1-C 6 )-alkyl; R5 H, F, Cl, Br, OH, CF 3 , OCF 3 , O-(C 1 -C)-alkyl, (C 1 -C)-alkyl; 20 R6 H; and the physiologically tolerated salts thereof. 25 If radicals or substituents may occur more than once in the compounds of the formula I, such as, for example, CON(R1 1)(R12), they may all have, independently of one another, the stated meanings and be identical or different. The invention relates to compounds of the formula I in the form of their racemates, 30 enantiomer-enriched mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.
8 The alkyl, alkenyl and alkynyl radicals in the substituents A, R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, R14, R15 may be either straight-chain, branched or optionally halogenated. 5 The term "aryl" means a phenyl or naphthyl group. Heterocycle or heterocyclic radical means ring systems which, apart from carbon, also comprise heteroatoms such as, for example, nitrogen, oxygen or sulfur. This definition also includes ring systems in which the heterocycle or the heterocyclic 10 radical is fused to benzene nuclei. Suitable "heterocyclic rings" or "heterocyclic radicals" are acridinyl, azocinyl, benzimidazolyl, benzofuryl, benzothienyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, 15 benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]-tetrahydrofuran, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, 20 isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, 25 pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazoles, pyridoimidazoles, pyridothiazoles, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl, thiazolyl, 1,2,3 thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, 30 triazolyl, tetrazolyl and xanthenyl.
9 Pyridyl stands both for 2-, 3- and 4-pyridyl. Thienyl stands both for 2- and 3-thienyl. Furyl stands both for 2- and 3-furyl. The corresponding N-oxides of these compounds are also included, that is to say, 5 for example, 1-oxy-2-, 3- or 4-pyridyl. Also included are derivatives of these heterocycles which are benzo-fused one or more times. 10 The heterocyclic rings or heterocyclic radicals may be substituted one or more times by suitable groups such as, for example, F, Cl, Br, I, CF 3 , NO 2 , N 3 , CN, COOH, COO( 1 -Ce)alkyl, CONH 2 , CONH(C 1
-C
6 )alkyl, CON[(C 1
-C
6 )alkyl] 2 , (C1-C6) alkyl, (C 2
-C
6 )-alkenyl, (C 2
-C
6 )-alkynyl, O-(C 1
-C
6 )-alkyl, where one or more than one, or all hydrogen(s) in the alkyl radicals may be replaced by fluorine; 15 P0 3
H
2 , SO 3 H, S0 2
-NH
2 , SO 2
NH(C
1
-C
6 )-alkyl, SO 2 N[(C1-C 6 )-alkyl] 2 , S-(C1-C 6
)
alkyl, S-(CH 2 )n-phenyl, SO-(C1-C 6 )-alkyl, SO-(CH 2 )n-phenyl, S0 2
-(C
1
-C
6 )-alkyl,
SO
2
-(CH
2 )n-phenyl, where n can be 0-6, and the phenyl radical may be substituted up to twice by F, C, Br, OH, CF 3 , NO 2 , CN, OCF 3 , 0-(C1-C 6 )-alkyl, (C1-C 6 )-alkyl,
NH
2 ; 20 C(NH)(NH 2 ), NH 2 , NH-(C 1
-C
6 )-alkyl, N((C 1
-C
6 )-alkyl) 2 , NH(C 1
-C
7 )-acyl, phenyl, 0-(CH 2 )n-phenyl, where n may be 0-6, and where the phenyl ring may be substituted one to 3 times by F, C, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , 0-(C1-C6) alkyl, (C 1
-C
6 )-alkyl, NH 2 , NH(C 1
-C
6 )-alkyl, N((C 1
-C
6 )-alkyl) 2 , SO 2
-CH
3 , COOH, COO-(C1-C 6 )-alkyl, CONH 2 . 25 Pharmaceutically acceptable salts are particularly suitable for medical applications because their solubility in water is higher than the initial or basic compounds. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention 30 are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric, metaphosphoric, nitric, sulfamic and sulfuric acids, and organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, 10 fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric and trifluoroacetic acids. The chloride salt is particularly preferably used for medical purposes. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts 5 (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Salts with a pharmaceutically unacceptable anion likewise fall within the scope of the invention as useful intermediates for preparing or purifying pharmaceutically 10 acceptable salts and/or for use in nontherapeutic, for example in vitro, applications. The term "physiologically functional derivative" used herein refers to any physiologically tolerated derivative of a compound according to the invention of the 15 formula 1, for example an ester, which is able on administration to a mammal such as, for example, a human to form (directly or indirectly) a compound of the formula I or an active metabolite thereof. The physiologically functional derivatives also include prodrugs of the compounds 20 according to the invention. Such prodrugs can be metabolized in vivo to a compound according to the invention. These prodrugs may themselves be active or not. The compounds according to the invention may also exist in various polymorphous 25 forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds according to the invention lie within the scope of the invention and are a further aspect of the invention. All references hereinafter to "compound(s) of formula (1)" refer to compound(s) of 30 the formula (1) as described above, and the salts, solvates and physiologically functional derivatives thereof as described herein.
11 The amount of a compound of formula (1) which is necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. In general, the daily dose is in the range from 0.3 mg to 5 100 mg (typically from 3 mg to 50 mg) per day and per kilogram of body weight, for example 3-10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.3 mg to 1.0 mg/kg, which can most suitably be administered as infusion of from 10 ng to 100 ng per kilogram and per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 10 ng to 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active ingredient. It is thus possible for ampoules for injections to contain, for example, from 1 mg to 100 mg, and single-dose formulations which can be administered orally, such as, for example, tablets or capsules, to contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case of 15 pharmaceutically acceptable salts, the aforementioned weight data are based on the weight of the salt - underlying free compound. For the prophylaxis or therapy of the abovementioned conditions, the compounds of formula (1) can be used as the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier must, of course, be acceptable 20 in the sense that it is compatible with the other ingredients of the composition and is not hazardous for the patient's health. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as single dose, for example as tablet which may contain from 0.05% to 95% by weight of the active ingredient. Further pharmaceutically active substances may likewise be present, including 25 other compounds of formula (1). The pharmaceutical compositions according to the invention can be produced by one of the known pharmaceutical methods which essentially consist of mixing the ingredients with pharmacologically acceptable carriers and/or excipients. 30 Pharmaceutical compositions according to the invention are those suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration although 12 the most suitable mode of administration in each individual case depends on the nature and severity of the condition to be treated and on the nature of the compound of formula (I) used in each case. Coated formulations and coated slow release formulations also lie within the scope of the invention. Formulations 5 resistant to acid and gastric fluid are preferred. Suitable coatings resistant to gastric fluid comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hyd roxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate. 10 Suitable pharmaceutical compounds for oral administration may be in the form of separate units such as, for example, capsules, cachets, suckable tablets or tablets, each of which contain a defined amount of the compound of formula (1); as powders or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as 15 already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact. In general, the compositions are produced by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely divided solid carrier, after which the product is 20 shaped if necessary. Thus, for example, a tablet can be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients. Compressed tablets can be produced by tableting the compound in free-flowing form, such as, for example, a powder or granules, where appropriate mixed with a binder, lubricant, inert diluent and/or a (plurality of) 25 surface-active/dispersing agent(s) in a suitable machine. Molded tablets can be produced by molding the compound which is in powder form and is moistened with an inert liquid diluent in a suitable machine. Pharmaceutical compositions suitable for peroral (sublingual) administration 30 comprise suckable tablets which contain a compound of formula (1) with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which 13 comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic. Suitable pharmaceutical compositions for parenteral administration comprise 5 preferably sterile aqueous preparations of a compound of formula (1), which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also take place by subcutaneous, intramuscular or intradermal injection. These preparations can preferably be produced by mixing the compound with water and making the 10 resulting solution sterile and isotonic with blood. Injectable compositions according to the invention generally contain from 0.1 to 5% by weight of the active compound. Suitable pharmaceutical compositions for rectal administration are preferably in the 15 form of single-dose suppositories. These can be produced by mixing a compound of formula (1) with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture. Suitable pharmaceutical compositions for topical application to the skin are 20 preferably in the form of ointment, cream, lotion, paste, spray, aerosol or oil. Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is generally present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%. 25 Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal uses can be in the form of single plasters which are suitable for long-term close contact with the patient's epidermis. Such plasters suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and/or 30 dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is about 1 % to 35%, preferably about 3% to 15%. As a special 14 possibility, the active ingredient can be released as described, for example, in Pharmaceutical Research, 2(6): 318 (1986) by electrotransport or iontophoresis. The compounds of the formula I are distinguished by beneficial effects on lipid 5 metabolism, and they are particularly suitable for weight reduction and for maintaining a reduced weight after weight reduction has taken place in mammals and as anorectic agents. The compounds are distinguished by their low toxicity and their few side effects. The compounds can be employed alone or in combination with other weight 10 reducing or anorectic active ingredients. Further anorectic active ingredients of this type are mentioned, for example, in the Rote Liste, chapter 01 under weight reducing agents/appetite suppressants, and may also include active ingredients which increase the energy turnover of the organism and thus lead to weight reduction or else those which influence the general metabolism of the organism in 15 such a way that an increased calorie intake does not lead to an enlargement of the fat depots and a normal calorie intake leads to a reduction of the fat depots of the organism. The compounds are suitable for the prophylaxis and, in particular, for the treatment of excessive weight or obesity. The compounds are further suitable for the prophylaxis and, in particular, for the treatment of type II diabetes, of 20 arteriosclerosis and for normalizing lipid metabolism and for the treatment of high blood pressure. The compounds act as melanocortin receptor agonists and are also suitable for the treatment of disturbances of wellbeing and other psychiatric indications such as, for example, depressions, anxiety states, anxiety neuroses, schizophrenia and for the treatment of disorders associated with the circadian 25 rhythm and for the treatment of drug abuse. They are additionally suitable for the treatment of cancer, arthritis, sleep disorders, sleep apnoea, female and male sexual disorders, inflammations, acne, pigmentation of the skin, of metabolic syndrome, disorders of steroid metabolism, skin diseases, psoriasis, mycoses, neurodegenerative diseases and Alzheimer's 30 disease.
15 In a further aspect of the invention, the compounds of the formula I can be administered in combination with one or more other pharmacologically active substances which are selected, for example, from antidiabetics, antiobesity agents, active ingredients which lower blood pressure, lipid-lowering agents and 5 active ingredients for the treatment and/or prevention of complications caused by diabetes or associated with diabetes. Suitable antidiabetics include insulins, amylin, derivatives of GLP-1 and GLP-2 such as, for example, those disclosed in WO 98/08871 of Novo Nordisk A/S, and orally active hypoglycemic active ingredients. 10 The orally active hypoglycemic active ingredients preferably comprise sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon receptor antagonists, GLP-1 agonists, potassium channel openers such as, for example, those disclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin sensitizers, activators of insulin 15 receptor kinase, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, for example inhibitors of glycogen phosphorylase, modulators of glucose uptake and glucose excretion, compounds which alter lipid metabolism, such as antihyperlipidemic active ingredients and antilipidemic active ingredients, for example HMGCoA reductase inhibitors, 20 inhibitors of cholesterol transport/of cholesterol uptake, inhibitors of bile acid reabsorption or inhibitors of the microsomal triglyceride transfer protein (MTP), compounds which reduce food intake, PPAR and RXR agonists and active ingredients which act on the ATP-dependent potassium channel of the beta cells. In one embodiment of the invention, the present compounds are administered in 25 combination with insulin. In a further embodiment, the present compounds are administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glimepiride, glipizide, gliquidone, glisoxepide, glibornuride or gliclazide. In another embodiment, the present compounds are administered in combination 30 with a biguanide such as, for example, metformin. In yet another embodiment, the present compounds are administered in combination with a meglitinide such as, for example, repaglinide.
16 In yet a further embodiment, the present compounds are administered in combination with a thiazolidinedione such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation, in particular 5 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenylmethyl] 2,4-thiazolidinedione. In a further embodiment, the present compounds are administered in combination with an a-glucosidase inhibitor such as, for example, miglitol or acarbose. In another embodiment, the present compounds are administered in combination 10 with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glimepiride, glipizide, gliclazide or repaglinide. In yet another embodiment, the present compounds are administered in combination with an antihyperlipidemic active ingredient or an antilipidemic active 15 ingredient such as, for example, cholestyramine, colestipol, clofibrate, fenofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, probucol, ezetimibe or dextrothyroxine. In a further embodiment, the present compounds are administered in combination with more than one of the aforementioned compounds, e.g. in combination with a 20 sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc. The compounds of the invention may additionally be administered in combination with one or more antiobesity agents or appetite-regulating active ingredients. 25 Active ingredients of these types may be selected from the group consisting of CART agonists, NPY antagonists, MCH antagonists, orexin antagonists, H3 antagonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, P3 agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin-reuptake inhibitors, mixed serotonin- and noradrenaline 30 reuptake inhibitors, 5HT modulators, MAO inhibitors, bombesin agonists, galanin antagonists, growth hormone, growth hormone-releasing compounds, TRH agonists, modulators of uncoupling proteins 2 or 3, leptin agonists, dopamine 17 agonists (bromocriptine, Doprexin), lipase/amylase inhibitors, antagonists of cannabinoid receptor 1, modulators of acylation-stimulating protein (ASP), PPAR modulators, RXR modulators, hCNTF agonists or TR-p agonists. In one embodiment of the invention, the antiobesity agent is leptin or modified 5 leptin. In another embodiment, the antiobesity agent is dexamphetamine or amphetamine. In another embodiment, the antiobesity agent is fenfluramine or dexfenfluramine. In yet another embodiment, the antiobesity agent is sibutramine or the mono- and 10 bisdemethylated active metabolites of sibutramine. In a further embodiment, the antiobesity agent is orlistat. In another embodiment, the antiobesity agent is mazindol, diethylpropion or phentermine. The present compounds may additionally be administered in combination with one 15 or more antihypertensive active ingredients. Examples of antihypertensive active ingredients are beta blockers such as alprenolol, atenol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as, for example, benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and rampril, calcium channel blockers such as nifedipine, felodipine, nicardipine, 20 isradipine, nimodipine, diltiazem and verapamil, and alpha blockers such as doxazosin, urapidil, prazosin and terazosin. Reference may furthermore be made to Remington: The Science and Practice of Pharmacy, 19th edition, Gennaro, editor, Mack Publishing Co., Easton, PA, 1995. It will be appreciated that every suitable combination of the compounds of the 25 invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances is to be regarded as covered by the scope of protection of the present invention. The efficacy of the compounds was tested as follows: Biological test model: 30 The anorectic effect was tested on female NMRI mice. After withdrawal of food for 24 hours, the test product was administered by gavage. The animals were housed singly with free access to drinking water and were offered condensed milk 18 30 minutes after administration of the product. The condensed milk consumption was determined every half hour for 7 hours, and the general wellbeing of the animals was observed. The measured milk consumption was compared with the vehicle-treated control animals.
19 Table 1: Anorectic effect measured as the reduction in the cumulative milk consumption of treated compared with control animals. Example Oral Number of Number of Reduction in the dose animals/ animals/ cumulative milk [mg/kg] cumulative milk cumulative milk consumption as consumption of consumption of % of the control the treated the control animals animals N/[ml] N/[ml] 5 50 5/2.4 5/3.40 31 9 50 5/2.06 5/3.86 47 It is evident from the table that the compounds of the formula I show a good 5 anorectic effect and are thus very suitable as antiobesity agent. The examples and preparation methods detailed below serve to illustrate the invention without, however, restricting it. General processes 10 The starting materials used in the synthesis were purchased from chemical suppliers such as Aldrich, Acros, Sigma, Fluka, Nova Biochem, Advanced Chemtech, Bachem, Lancaster and other companies. 15 In the synthesis, the functional groups of the amino acid derivatives used were protected by protective groups to prevent side reactions during the coupling steps. Examples of suitable protective groups and their use are described in The Peptides, supra, 1981 and in Vol. 9, Udenfriend and Meienhofer (Editors) 1987 (included herein by reference). 20 20 General methods of solid-phase synthesis were used to prepare the compounds of the invention. Methods of this type are described for example by Steward and Young in Solid Phase Peptide Synthesis (Freeman & Co., San Francisco 1969) (included herein by reference). 5 Unless indicated otherwise, the compounds were synthesized using TentaGel HL12019 Resin (Rapp Polymere, TObingen). This commercially available polymer contains a bromoacetal linker. This type of coupling can be incorporated in all types of hydroxy-tentagel by the process described by Vojkovsky, T. et al., J. Org. 10 Chem. 1998, 63, 3162-3163, and Patek, M., Contribution to Combinatorial Chemistry 2000, London, 11. - 14. 7. 2000 (included herein by reference). In the first synthesis step (see scheme 1 for general synthetic scheme), amine was used in DMSO to replace bromine in the bromoacetal link at an elevated 15 temperature. Fmoc-protected amino acid was coupled onto the secondary amine produced thereby on the polymer. The coupling was effected by means of DIC/HOAt or HATU/DIEA, usually in DMF. The coupling was carried out at room temperature (RT) for 16 hours or at 55 0 C for 4-5 hours. Protection by the Fmoc group was eliminated by using 50% piperidine in DMF (5 + 15 minutes). The 20 substitution can be determined by measuring the amount of liberated Fmoc from the absorbance of the solution at 302 nm after elimination of the protection, the volume of the washing liquid and the weight of the polymer employed in the synthesis in accordance with the description in Krchnak, V. et al., Collect. Czech. Chem. Commun. 53 (1988) 2542 (included herein by reference). 25 The free amino group of the structure bound to the solid phase was then coupled to Fmoc-beta-alanine (or Fmoc-alpha-amino acid or substituted beta-amino acid). The coupling was effected with N,N'-diisopropylcarbodiimide (DIC) in the presence of HOBt, usually in DMF. The completeness of the coupling was monitored by the 30 ninhydrin test.
21 A protection by the Fmoc group was eliminated with 50% piperidine in DMF for 5 + 15 minutes. The amount of liberated Fmoc was measured from the absorbance of the solution at 302 nm after elimination of the protection, the volume of the washing liquid and the weight of the polymer employed in the 5 synthesis. The free amino groups of the structure bound to the solid phase was then sulfonylated with up to 2 equivalents of a suitable sulfonyl chloride/DIEA in DCM or acetonitrile. The completeness of the sulfonylation was monitored by the ninhydrin test. 10 After completion of the assembly of the precursor of the linear compound on the polymer, the solid phase was washed successively with DMF and DCM or THF and dried in vacuo. 15 The desired compound was subjected to cyclative cleavage off with formic acid at room temperature for 18 - 24 hours, at 500C for 6 hours or by a combination of the two conditions. The polymer was filtered off and washed with DCM or formic acid. The washing liquid was introduced into the formic acid solution. The solution was evaporated. The residue was dissolved in a mixture of water and acetonitrile and 20 freeze dried. The dried compound was purified with HPLC with a suitable gradient of 0.1% TFA in water and acetonitrile (ACN). After collection of the peak containing the desired synthetic product, the solution of the compound was freeze dried. To confirm that 25 the correct compound had been synthesized, the compound was subjected to a qualitative determination with electrospray mass spectrum (LC/MS) and/or an NMR analysis. For HPLC analysis a sample of the compound was analyzed with the Beckman 30 HPLC system (consisting of the solvent supply system 126, the programmable detector module 166 and the autosampler 507e and controlled by data station with Gold Nouveau sofware) using a YMC ODS-AM 4.6 x 250 mm column (S-5 (5 pm), 22 YMC, Inc. Wilmington, NC, USA) at 230 nm. With this setting, a flow rate of 1 ml/min was used and a gradient of water/0.1% TFA buffer and ACN (HPL quality) was used as eluent. 5 Scheme 1: AlocN
H
2 NiPr R2 LH0 NFmoc Br N DIC, HOAT N R2 O 0 0 R3-~ Piperidine -LN NH 2 / N 0 N 04 R2 DIC, HOBT 0 R N 0 L N N R3 HCOOH R3,0N R2 R4 R4 The compounds can also be prepared in solution in analogy to the described synthesis on the resin. (Scheme 2). In place of the functionalized resin, in the first 10 stage 2-bromo-1,1-diethoxyethane is reacted with a primary amine.
23 Scheme 2: 0 AocN KO KirL0) OH 0
H
2 NiPr 0 R2 O )_-N- ' NAloc O Br 0 N DIC, HOAT N Pd(PPh 3
)
4 0 0 Dimethylbarbituric O R3 N acid L00 "" 0
NH
2 R4 -0 1 R2 EDC, HOBT RR R2 RI
K
0 0 Ny''"'
NS\\
3 HC0OH R3 , // T H R4_____ C N 'R2 Ri R2 R R1i N R4 R4 = NHCbz R3, 0 further R1 HBr, HOAc 's N functionalization ,N 0 R3 N N R2
NH
2 0 0 R5 NH The resulting product is reacted with the amino acid in analogy to the solid-phase 5 synthesis. The allyloxycarbonyl protective group (Aloc) can be used in place of FMOC as amino-protective group for the amino acid, and is introduced (Aloc-Cl, triethylamine) and eliminated (Pd(PPh 3
)
4 , dimethylbarbituric acid) by methods known from the literature. 10 The amino carboxylic acid with the radical R4 is reacted with the sulfonyl chloride in the presence of triethylamine. The free carboxylic acid is coupled by the carbodiimide method (EDC, HOBt) or with use of uranium salts (HATU, HOAt) to the free amine which has been obtained by elimination of the Aloc group.
24 The cyclization proceeds under acidic conditions and the benzyloxycarbonyl (Cbz) group is eliminated with HBr in glacial acid. Subsequent functionalization proceeds in analogy to the above description. 5 The product was purified by developing a sample of the freeze-dried crude substance in a mixture of 0.1% strength aqueous TFA with 10 - 50% acetonitrile or in acetic acid. The solution of the compound was usually filtered through a syringe connected to an ACRODISC 13 CR PTFE 0.45 pm filter (Gelman Sciences; Ann Arbor, MI, USA). An appropriate volume of the filtered solution of the compound 10 was injected into a semipreparative C 18 column (YMC ODS-AM, S-5 (5 pm), 20 x 150 mm, YMC, Inc., Wilmington, NC, USA). The flow rate of the gradient of water/0.1% TFA buffer and ACN (HPL quality) as eluent was maintained by means of the Beckman SYSTEM GOLD HPLC (System Gold, programmable solvent module 126 and programmable detector module 166, controlled by SYSTEM 15 GOLD software). Elution of the compound was monitored by UV detection at 230 or 280 nm. After identification of the peak of the compound to be synthesized by LC/MS, the compound was collected, freeze dried and subjected to biological testing. After purification, compounds with basic groups were obtained as trifluoroacetates. 20 Hydrochlorides of these compounds can easily be prepared by treating the trifluoroacetate of the compound with an excess of HCI/dioxane. After evaporation of the solvents, the hydrochloride of the compound was precipitated with diethyl ether and isolated by filtration. 25 LC/MS was carried out with PE Sciex API 150EX and Sciex MassChrom software, equipped with a Gilson 215 liquid handler, two Shimadzu LC-10AD liquid modules, a Shimadzu SPD-1 0A detector,a Keystone Betasil C-1 8 column (2 x 30 mm, 3 pm, flow rate of the acetonitrile/water/0.1%TFA gradient 0.7 ml/min) in ES+ mode. For the NMR analysis, the samples were measured in DMSO-d 6 (Aldrich) with a 30 Bruker Avance DPX 300.
25 Scheme 3: 0 NHFmoc O R1 O R1 1 R2 N 0 ONH -_2 DMTMM DMF 2 H2N R2 2. 10% Diethylamine DCM 1. Z-DAP(Fmoc)-OH DMTMM DMF 2. 10% Diethylamine DCM R1 O\ ,,O O CIO 0 NI011C 0 O HN X HN R2 Y N HbDIEA, DCM Y-:r H NHCbz H 2 N 0 NHCbz 4 3 Formic acid 600C Ri R1 R1 R N R2 TMSI N N Y-Cr ~ C H 3 CN N ' X 00C to RT x NHCbz NH 2 5 6 The synthesis shown in Scheme 3 was carried out in analogy to the other solution synthesis. In this case, the amide couplings were carried out in each case with 5 DMTMM as coupling reagent. In addition, Fmoc was employed as protective group in the solid-phase chemistry, and was eliminated again with diethylamine. The 26 sulfonamide was not introduced along with the second amide coupling, but was formed after the latter with use of diethylamine as base. The Cbz group was eliminated with TMSI in acetonitrile. All further functionalizations were carried out in analogy to the above description. 5 The reagents and building blocks used in the syntheses originated from various suppliers such as Aldrich, Acros, Sigma, Fluka, Nova Biochem, Advanced Chemtech, Bachem, Lancaster, Rapp Polymere etc. Unless indicated otherwise, the following methods were used for the chemical analysis: 10 liquid chromatography/mass spectrometry analysis (LC/MS): Agilent 1100 LC with mass spectrometer detector. The following were used: Waters (YMC) Combiscreen Pro C18 4.6 x 33.5 p, 120 A, 3 minutes with 10% acetonitrile (0.1% trifluoroacetic acid) and 90% water (0.1% trifluoroacetic acid) to 0% acetonitrile (0.1% trifluoroacetic acid) and 100% water (0.1% trifluoroacetic acid). 1-minute 15 flow-through time and subsequently 1-minute equilibration to the starting conditions. Electrospray mass spectrometry, positive mode (unless indicated otherwise). Preparative LC: semipreparative liquid chromatograms were recorded with a Gilson 215 liquid handler, an apparatus which is suitable for analyses and 20 semipreparative processes. Mobile phase: water (0.1% TFA) and acetonitrile (0.1% TFA). The samples were initially investigated by analytical methods. An appropriate semipreparative process was then used. 5% to 100% acetonitrile, 12 minutes (unless indicated otherwise). Waters (YMC) Combiscreen columns for analysis, 4.6 x 50 per C18, 5 p, 120 A are used. Waters Combiscreen 20 x 50.5 p, 25 120 A semipreparative columns. Thin-layer chromatograms (TLC) were recorded with glass-reinforced 60F-254 silica gel plates 0.25 mm thick. Flash chromatography: this process was carried out by the method described by Still, W. C., Kahn, M. and Mitra, A. in J. Org. Chem. 1978, 43, 2923, or adapted to 30 commercially available systems such as Biotage Horizon, Isco Opix or Companion. The solvent systems indicated in the experimental examples were used in these cases.
27 Microwave synthesis: unless indicated otherwise, the microwave reactions were carried out in a personal chemistry creator, optimizer or synthesizer. All the calculated masses indicated are monoisotopic. 5 Abbreviations Unless indicated otherwise, the abbreviations in the examples below have the following meaning: 10 ACN = Acetonitrile Aloc = Allyloxycarbonyl DIC = Diisopropylcarbodiimide EDC = 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide FMOC = 9-Fluorenylmethyloxycarbonyl 15 DCE = 1,2-Dichloroethane DEA = Diethylamine DIEA = Diisopropylethylamine NaBH 3 CN = Sodium cyanoborohydride DMAP = N,N-Dimethylaminopyridine 20 DMF = N,N-Dimethylformamide THF = Tetrahydrofuran DIC = Diisopropylcarbodiimide DMSO = Dimethyl sulfoxide DCM = Dichloromethane (also referred to as methylene chloride) 25 DMTMM = 4-(4,6-Dimethoxy[1,3,5]triazin-2-yl]-4-methylmorpholinium chloride HOBt = 1-Hydroxybenzotriazole HOAt = 1-Hydroxy-7-azabenzotriazole HATU = Dimethylamino([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylenedimethyl ammonium hexafluorophosphate 30 EtOAc = Ethyl acetate HOAc = Acetic acid Et 3 N = Triethylamine 28 HCI = Hydrochloric acid HBr = Hydrobromic acid HPLC = High performance liquid chromatography TEA = Triethylamine 5 TMSI = Trimethylsilyl iodide The following examples serve to explain the invention in more detail without restricting it to the products and embodiments described in the examples.
29 Example 1 3-Amino-6-(4-chlorobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8-isopropyl hexahydropyrazino[1,2-a]pyrimidine-4,7-dione 5 Structure: CI C1 N N '/0 / N 0 0
NH
2 0.35 g of TentaGel HL12019 (bromoacetal linker, S = 0.5 mmol/g, Rapp Polymere, 10 TObingen) was washed with DMSO. 20 equivalents of 2M isopropylamine solution in DMSO were added, and the mixture was kept in a closed vessel at 60 0 C for 15 hours. The polymer was washed 7 times with DMF. Fmoc-(S)-4-chlorophenylalanine (3 equivalents) were coupled to the secondary amine on the polymer using HOAt (3 equivalents) and DIC (3 equivalents) in DMF. 15 The final concentration was 0.2 - 0.3 M. The reaction mixture was left to stand at room temperature overnight. The polymer was washed 6 times with DMF. The Fmoc protective group was eliminated with 50% piperidine in DMF (5 + 15 minutes). Z-Dap(Fmoc) (3 equivalents) were then coupled on using HOBt (3 equivalents) 20 and DIC (3 equivalents) in DMF (final concentration: about 0.2 M) over a period of at least 4 hours. The Fmoc protective group was eliminated with 50% piperidine in DMF (5 + 15 minutes). The polymer was washed 5 times with DMF and 4 times with DCM and mixed with a solution of 1.5 equivalents of 2-methoxy-5-chlorobenzenesufonyl chloride and 3 25 equivalents of DIEA in DCM (final concentration: 0.1 - 0.15 M) and reacted at 30 room temperature for 5 hours. It was then washed 5 times with DMF and 5 times with DCM and dried in vacuo. For the cyclative cleavage off, the dried polymer was mixed with 10 ml of formic acid and shaken at room temperature for 16 hours and at 50 - 550C for 6 hours. 5 The polymer was filtered off and washed with DCM. The combined filtrates were evaporated in vacuo. The residue was treated with 5 ml of 37% HBr/HOAc at room temperature for 2 hours and evaporated in vacuo. The hydrobromide of the product was precipitated by adding diethyl ether and was filtered off. The pure title compound was removed after purification by HPLC. The system and process 10 described under "general process" was used for this. MW = 554.12 (calculated, monoisotopic); measured value (M+H)*: 555.3. Example 2 3-Amino-6-(4-chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8 15 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: C1 'N 0 0
NH
2 20 0.7 g of TentaGel HL12019 (bromoacetal linker, S = 0.5 mmol/g, Rapp Polymere, TObingen) was washed with DMSO. 20 equivalents of 2M isopropylamine solution in DMSO were added, and the mixture was kept in a closed vessel at 600C for 15 hours. The polymer was washed 7 times with DMF. Fmoc-4-chlorophenylalanine (3 equivalents) were coupled to the secondary amine 25 on the polymer using HOAt (3 equivalents) and DIC (3 equivalents) in DMF. The final concentration was 0.2 - 0.3 M. The reaction mixture was left to stand at room 31 temperature overnight. The polymer was washed 6 times with DMF. The Fmoc protective group was eliminated with 50% piperidine in DMF (5 + 15 minutes). Cbz-Dap(Fmoc) (3 equivalents) were then coupled on using HOBt (3 equivalents) and DIC (3 equivalents) in DMF (final concentration: about 0.2 M) over a period of 5 at least 4 hours. The Fmoc protective group was eliminated with 50% piperidine in DMF (5 + 15 minutes). The polymer was washed 5 times with DMF and 4 times with DCM and mixed with a solution of 1.5 equivalents of 2,4-dichlorobenzenesulfonyl chloride and 3 equivalents of DIEA in DCM (final concentration: 0.1 - 0.15 M) and reacted at 10 room temperature for 5 hours. It was then washed 5 times with DMF and 5 times with DCM and dried in vacuo. For the cyclative cleavage off, the dried polymer was mixed with 15 ml of formic acid and shaken at room temperature for 16 hours and at 50 - 55*C for 6 hours. The polymer was filtered off and washed with DCM. The combined filtrates were 15 evaporated in vacuo. The residue was treated with 10 ml of 37% HBr/HOAc at room temperature for 2 hours and evaporated in vacuo. The hydrobromide of the product was precipitated by adding diethyl ether and was filtered off. The pure title compound was removed after purification by HPLC. The system and process described under "general processes" was used for this. MW = 558.07 (calculated, 20 monoisotopic); measured value (M+H)*: 559.3. Example 3 6-(4-Chlorobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-3-diethylamino-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 25 32 Structure: C1 ci N O N 0 N SIN 50 mg of 6-(4-chlorobenzyl)-1-(2-methoxy-5-chlorobenzenesulfonyl)-3-amino-8 5 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione hydrochloride (Example 1) were dissolved in 3 ml of methanol, and 100 pl of acetic acid were added. 100 pl of acetaldehyde and 1 ml of 1 M sodium cyanoborohyd ride solution in THF were added to this solution. After 2 hours, the reaction mixture was evaporated, suspended in 5% Et 3 N in ethyl acetate and filtered through a small silica gel 10 column. The eluent was evaporated, and the crude substance was dissolved in a mixture of acetonitrile and water and freeze dried. The pure title compound was removed after purification by HPLC. The system and process described under "general processes" was used for this. MW = 610.18 (calculated, monoisotopic); measured value (M+H)*: 611.4. 15 Example 4 6-(4-Chlorobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8-isopropyl-3 isopropylaminohexahydropyrazino[1,2-a]pyrimidine-4,7-dione 33 Structure: CN CI N NO 0 0 N 50 mg of 6-(4-chlorobenzyl)-1-(2-methoxy-5-chlorobenzenesulfonyl)-3-amino-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione (Example 1) were 5 dissolved in 5 ml of methanol, and 200 p1 of acetic acid were added. 400 pl of acetone and 1 ml of 1M sodium cyanoborohydride solution in THF were added to this solution. After 3 hours, the reaction mixture was evaporated, suspended in 5% Et 3 N in ethyl acetate and filtered through a small silica gel column. The eluent was evaporated, and the crude substance was dissolved in a mixture of acetonitrile and 10 water and freeze dried. The pure title compound was removed after purification by HPLC. The system and process described under "general processes" was used for this. MW = 596.16 (calculated, monoisotopic); measured value (M+H)*: 597.3. Example 5 15 6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-3-dimethylamino-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: C CI N \ C / N N o oN N
/N-
34 200 mg of 6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-3-amino-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione hydrobromide (Example 2) were dissolved in 15 ml of methanol, and 600 pl of acetic acid were added. 0.5 ml 5 of 37% strength aqueous formaldehyde and 3 ml of 1 M sodium cyanoborohydride solution in THF were added to this solution. After 2 hours, the reaction mixture was evaporated, suspended in 5% Et 3 N in ethyl acetate and filtered through a small silica gel column. The eluent was evaporated, and the crude substance was dissolved in a mixture of acetonitrile and water and freeze dried. The pure title 10 compound was removed after purification by HPLC. The system and process described under "general processes" was used for this. MW = 586.10 (calculated, monoisotopic); measured value (M+H)*: 587.3. Example 6 15 6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-3-pyrrol-1 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: C1 CI N CI N N O 0 20 64 mg of 6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-3-amino-8-isopropyl hexahydropyrazino[1,2-a]pyrimidine-4,7-dione hydrobromide (Example 2) were suspended in 1 ml of water, and 1 ml of DCE was added. This mixture was mixed with 2 equivalents of 2,5-dimethoxytetrahydrofuran and stirred at 800C for 1 hour. 25 The DCE phase was removed and the aqueous phase was extracted twice with 35 DCE. The combined extracts were evaporated, and the crude substance was dissolved in a mixture of acetonitrile and water and freeze dried. The pure title compound was removed after purification by HPLC. The system and process described under "general processes" was used for this. MW = 608.08 (calculated, 5 monoisotopic); measured value (M+H)*: 609.4. Example 7 3-Azetidin-1-yl-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl hexahydro-pyrazino[1,2-a]pyrimidine-4,7-dione 10 Structure: CI Ci N CI N 0 0 N 32 mg of 6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-3-amino-8-isopropyl 15 hexahydropyrazino[1,2-a]pyrimidine-4,7-dione hydrobromide (Example 2) were suspended in 1 ml of water, and 2 ml of 1-butanol were added. 1 mmol of potassium carbonate and 200 pl of 1,3-dibromopropane were added to this mixture. The reaction mixture was stirred at 900C for 16 hours and evaporated. The residue was suspended in 5% Et 3 N/ethyl acetate, filtered and evaporated. The 20 pure title compound was removed after purification by HPLC. The system and process described under "general processes" was used for this. MW = 598.10 (calculated, monoisotopic); measured value (M+H)*: 599.3.
36 Example 8 6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-3-pyrrolidin-1 -yl hexahydropyrazino[1,2-a]pyrimidine-4,7-dione 5 Structure: Cl CI N ' CI N N 0 0 32 mg of 6-(4-chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-3-amino-8-isopropyl hexahydropyrazino[1,2-a]pyrimidine-4,7-d ione hydrobromide (Example 2) were suspended in 1 ml of water, and 2 ml of 1-butanol were added. 1 mmol of 10 potassium carbonate and 200 pl of 1,4-dibromobutane were added to this mixture. The reaction mixture was stirred at 90 0 C for 16 hours and evaporated. The residue was suspended in 5% Et 3 N/ethyl acetate, filtered and evaporated. The pure title compound was removed after purification by HPLC. The system and process described under "general processes" was used for this. MW = 612.11 (calculated, 15 monoisotopic); measured value (M+H)*: 613.4. Example 9 N-[6-(4-Chlorobenzyl)-1 -(2,4-d ichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide 20 37 Structure: CI CI N \ CI N N C1 N o 0 N 64 mg of 6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-3-amino-8-isopropyl 5 hexahydropyrazino[1,2-a]pyrimidine-4,7-dione hydrobromide (Example 2) were dissolved in 3 ml of DCM. 0.5 mmol of triethylamine and 1.5 equivalents of methanesulfonyl chloride were added to the solution. After 2 hours, 0.5 ml of dimethylamine in THF was added, and the solvent was evaporated in vacuo. The pure title compound was removed after purification by HPLC. The system and 10 process described under "general processes" was used for this. MW = 636.04 (calculated, monoisotopic); measured value (M+H)*: 637.4. Example 10 6-(4-Chlorobenzyl)-1-(5-chloro-2-methoxybenzenesulfonyl)-3-dimethylamino-8 15 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: o N N c2 N 20 38 The compound in Example 10 was synthesized by the process described in Example 5 starting from 6-(4-chlorobenzyl)-1 -(2-methoxy-5 chlorobenzenesulfonyl)-3-amino-8-isopropylhexahydropyrazino[1,2-a]pyrimidine 4,7-dione (Example 1). 5 MW = 582.15 (calculated, monoisotopic); measured value (M+H)*: 583.3. Example 11 3-(Biscyclopropylmethylamino)-6-(4-chlorobenzyl)-1 -(5-chloro-2-methoxy benzenesulfonyl)-8-isopropylhexahyd ropyrazino[1,2-a]pyrimidine-4,7-dione 10 Structure: 0 S N C I C N N 15 The compound in Example 11 was synthesized by the process described in Example 3 using 10 equivalents of cyclopropanecarboxaldehyde. MW = 662.21 (calculated monoisotopic); measured value (M+H)*: 663.4.
39 Example 12 6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-3-isobutylamino-8-isopropyl hexahydropyrazino[1,2-a]pyrimidine-4,7-dione 5 Structure: C i 0 N N CI SN N 0 CI N The compound in Example 12 was synthesized by the process described in 10 Example 4 using 4 equivalents of isobutyraldehyde. MW = 614.13 (calculated, monoisotopic); measured value (M+H)*: 615.4. Example 13 6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-3-diisobutylamino-8-isopropyl 15 hexahydropyrazino[1,2-a]pyrimidine-4,7-dione 40 Structure: CI CI N CI N C 11 0 // N N 0 0 N 5 The compound in Example 13 was synthesized by the process described in Example 3 using 20 equivalents of isobutyraldehyde. MW = 670.19 (calculated, monoisotopic); measured value (M+H)*: 671.3. Example 14 10 6-(4-Chlorobenzyl)-3-(cyclopropylmethylamino)-1 -(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: C1 C1 N CI N N 1 0 15 41 The compound in Example 14 was synthesized by the process described in Example 4 using 5 equivalents of cyclopropanecarboxaldehyde. MW = 612.11 (calculated monoisotopic); measured value (M+H)*: 613.4. 5 Example 15 6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-3-diethylamino-8-isopropyl hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: Cl ci 0 C1 N CI N 0 0 10 N The compound in Example 15 was synthesized by the process described in Example 3 starting from 6-(4-chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-3 amino-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione (Example 2). 15 MW = 614.13 (calculated, monoisotopic); measured value (M+H)*: 615.3. Example 16 6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-3-isopropylamino hexahydropyrazino[1,2-a]pyrimidine-4,7-dione 20 42 Structure: C1 CCl N 1 C0 N // ~N o 0 N 5 The compound in Example 16 was synthesized by the process described in Example 4 starting from 6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-3 amino-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione (Example 2). MW = 600.11 (calculated, monoisotopic); measured value (M+H)*: 601.3. 10 Example 17 6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-isopropyl-3 (isopropylmethylamino)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: C1 CI N CI N N 0 0 15 The compound in Example 17 was synthesized by the process described in Example 5 starting from 6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8- 43 isopropyl-3-isopropylaminohexahydropyrazino[1,2-a]pyrimidine-4,7-dione (Example 16). MW = 614.13 (calculated, monoisotopic); measured value (M+H)*: 615.4. 5 Example 18 6-(4-Chlorobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8-isopropyl-3 pyrrolidin-1 -ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: 10 C l O C 1 CI N ,- 0 O N O 0 0 0N The compound in Example 18 was synthesized by the process described in Example 8 starting from 3-amino-6-(4-chlorobenzyl)-1-(5-chloro-2 15 methoxybenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7 dione (Example 1). MW = 608.16 (calculated monoisotopic); measured value (M+H)*: 609.4.
44 Example 19 {4-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 d ioxooctahyd ropyrazino[1,2-a]pyrimid in-3-ylamino]butyl}triethylammonium 5 Structure: C Cl N //IN 0 0 N 32 mg of 6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-3-amino-8-isopropyl 10 hexahydropyrazino[1,2-a]pyrimidine-4,7-dione hydrobromide (Example 2) in 1 ml of dichloroethane were treated with 200 pl of triethylamine and 100 pl of 1,4 dibromobutane. The reaction mixture was kept at 60*C for 60 hours. The precipitate was filtered off, and the filtrate was evaporated in vacuo. The pure title compound trifluoroacetate was removed after purification of the filter residue by 15 HPLC. The system and process described under "general processes" was used for this. MW = 714.24 (calculated, monoisotopic); measured value (M): 714.4.
45 Example 20 {3-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-ylamino]propyl}triethylammonium 5 Structure: C1 C1N I/ N 0 o N 32 mg of 6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-3-amino-8-isopropyl 10 hexahydropyrazino[1,2-a]pyrimidine-4,7-dione hydrobromide (Example 2) in 1 ml of dichloroethane were treated with 200 pl of triethylamine and 100 pl of 1,3 dibromopropane. The reaction mixture was kept at 60 0 C for 60 hours. The precipitate was filtered off, and the filtrate was evaporated in vacuo. The pure title compound trifluoroacetate was removed after purification of the filter residue by 15 HPLC. The system and process described under "general processes" was used for this. MW = 700.23 (calculated, monoisotopic); measured value (M): 700.4.
46 Example 21 N-[6-(4-Chlorobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide 5 Structure: O1 / CI N OI N O / 0 N 0 a) 2-Allyloxycarbonylamino-3-(4-chlorophenyl)propionic acid 10 The product is obtained by methods (ET 3 N, methanol) known from the literature starting from 10 g of 4-chlorophenylalanine and 8 ml of allyl chloroformate. MW = 283.71 (calculated monoisotopic); measured value (M+H)*: 284.1. 15 b) Allyl {2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl} carbamate 7.8 ml of DIC are added dropwise to a solution of 5.7 g of 2 allyloxycarbonylamino-3-(4-chlorophenyl)propionic acid, 3.5 g of (2,2 diethoxyethyl)isopropylamine, 6.8 g of HOAt in 30 ml of DMF and the mixture is 20 stirred for 12 h. The reaction solution is concentrated under reduced pressure and purified by flash chromatography on silica gel with the eluent ethyl acetate/n-heptane = 1/3. The desired product is obtained with MW = 440.97 (calculated monoisotopic); measured value (M+H)*: 441.15 25 c) 2-Amino-3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropylpropionamide 47 10 mg of palladium tetrakistriphenylphosphine are added to a solution of 13.2 g of allyl {2-(4-chlorophenyl)-1-[(2,2 diethoxyethyl)isopropylcarbamoyl]ethyl}carbamate, 18.9 g of dimethylbarbituric acid in 140 ml of methylene chloride under a protective argon gas atmosphere, 5 and the mixture is stirred for 12 h. The reaction solution is concentrated under reduced pressure and [lacuna] by flash chromatography on silica gel (eluent methylene chloride, 1% Et 3 N, 0-10% methanol). The desired product is obtained with MW = 356.90 (calculated monoisotopic); measured value (M
C
2
H
6 O+H)*: 311.10 10 d) 2-Benzyloxycarbonylamino-3-(5-chloro-2-methoxybenzenesulfonylamino) propionic acid A solution of 3.8 g of 5-chloro-2-methoxybenzenesulfony chloride in 5 ml of dioxane is added dropwise to a solution of 2.3 g of 3-amino-2 15 benzyloxycarbonylamino-propionic acid in 20 ml of 1N NaOH solution. The mixture is left to stir while controlling the pH (pH > 7) for 12 h, the pH is reduced below 7 by adding citric acid, and the reaction solution is then extracted with methylene chloride. The organic phase is dried over magnesium sulfate, concentrated under reduced pressure and employed without further 20 purification in the next reaction step. Product with MW = 442.06 (calculated monoisotopic); measured value (M+H)*: 442.95 e) Benzyl (2-(5-chloro-2-methoxybenzenesulfonylamino)-1-{2-(4 25 chlorophenyl)-1 -[(2,2 d iethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate ester 52 mg of EDC, 45 mg of HOBt and 100 pl of N-ethylmorpholine are added to a solution of 124 mg of 2-benzyloxycarbonylamino-3-(5-chloro-2 methoxybenzenesulfonylamino)propionic acid in 1 ml of DMF. A solution of 100 30 mg of 2-amino-3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N isopropylpropionamide in 1 ml of DMF is added dropwise thereto, and the mixture is left to stir for 12 h. The reaction solution is filtered mixed with ethyl 48 acetate and then extracted with 5% aqueous sodium bicarbonate solution and aqueous sodium chloride solution. Drying of the organic phase with Chromabond XTR is followed by concentration under reduced pressure, and the residue is separated by HPLC (Knauer Eurospher-100-10-C18, water 5 (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) = 80/20-+ 10/90). The desired product is obtained with MW = 780.24 (calculated); measured value (M-C 2
H
6 O+H)*: 735.1 f) Benzyl [6-(4-chlorobenzyl)-1-(5-chloro-2-methoxybenzenesulfonyl)-8 10 isopropyl-4,7-dioxooctahyd ropyrazino[1,2-a]pyrimid in-3-yl]carbamate A solution of 218 mg of benzyl (2-(5-chloro-2-methoxybenzenesulfonylamino) 1 -{2-(4-chlorophenyl)-1 -[(2,2 diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate in 3 ml of formic acid is stirred at room temperature for 12 h and then at 550C for 5 h. The 15 reaction solution is concentrated under reduced pressure, and the residue is separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) = 80/20 -* 10/90). The desired product is obtained with MW = 688.15 (calculated monoisotopic); measured value (M+H)*: 689.41 20 g) 3-Amino-6-(4-chlorobenzyl)-1-(5-chloro-2-methoxybenzenesulfonyl)-8 isopropylhexahyd ropyrazino[1,2-a]pyrimid ine-4,7-d ione A solution of 79 mg of benzyl [6-(4-chlorobenzyl)-1-(5-chloro-2 methoxybenzenesulfonyl)-8-isopropyl-4,7-dioxooctahydropyrazino[1,2 25 a]pyrimidin-3-yl]carbamate in 2 ml of a 33% solution of HBr in glacial acetic acid is stirred for 2 h. The reaction solution is mixed with aqueous sodium carbonate solution and extracted with ethyl acetate. The organic phase is dried over magnesium carbonate and concentrated under reduced pressure, and the residue is separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% 30 trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) = 80/20 -> 10/90). The desired product is obtained with MW = 554.12 (calculated monoisotopic); measured value (M+H)*: 555.12 49 h) N-[6-(4-Chlorobenzyl)-1-(5-chloro-2-methoxybenzenesulfonyl)-8-isopropyl 4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide A solution of 7 mg of 3-amino-6-(4-chlorobenzyl)-1-(5-chloro-2-methoxybenzene 5 sulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione, 2.4 pl of acetic anhydride, 0.5 mg of DMAP in 1.5 ml of pyridine is stirred for 12 h. The reaction solution is concentrated and purified by flash chromatography on silica gel with the eluent methylene chloride with a gradient of 0-10% methanol. The desired product is obtained with MW = 596.13 (calculated monoisotopic); 10 measured value (M+H)*: 597.13 Example 22 N-[6-(4-Chlorobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide ci N 0 Ci 42, N N o00 N 15 11 mg (0.105 mmol) of cyclopropanecarbonyl chloride are added to a solution of 3 amino-6-(4-chlorobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione (56 mg, 0.10 mmol) in 1 ml of dichloromethane and 26 mg (0.20 mmol) of diisopropylethylamine. After stirring 20 at room temperature for two hours, the reaction mixture is purified by chromatography on 1 g of silica gel (eluent EtOAc/DCM; gradient 0-20%). 42 mg of the desired product are obtained. MW = 622 (calculated, monoisotopic), measured value (M+H)* = 623.10 50 Example 23 N-[6-(4-Chlorobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide ci N N 0 C I 20 N N 00 00 5 Synthesis took place in analogy to Example 22 using cyclobutanecarbonyl chloride. The desired product is obtained with MW = 636.16 (calculated, monoisotopic); measured value (M+H)*: 637.11 Example 24 10 N-[6-(4-Chlorobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide Structure: ci , NN N 0=0 15 51 Synthesis took place in analogy to Example 22 using cyclopentanecarbonyl chloride. The desired product is obtained with MW = 650.17 (calculated, monoisotopic); measured value (M+H)*: 651.12 5 Example 25 4-Dimethylamino-N-[6-(4-chlorobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 isopropyl-4,7-d ioxooctahyd ropyrazino[1,2-a]pyrimidin-3-yl] benzamide Structure: cl N O cl N o
N
10 Synthesis took place in analogy to Example 22 using 4-dimethylaminobenzoyl chloride. The desired product is obtained with MW = 701.18 (calculated, monoisotopic); measured value (M+H)*: 702.12 Example 26 15 N-[6-(4-Chlorobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide 52 Structure: C l \ C I 0 N SN ON 0 0 N,0 o\ 5 1.8 pl of mesyl chloride are added dropwise to a solution of 5 mg of 3-amino-6-(4 chlorobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione in 1 ml of methylene chloride and 3 pl of Et 3 N at 0*C. The mixture is stirred for 2 h and then washed with aqueous sodium chloride solution. The organic phase is dried over 10 magnesium sulfate and concentrated under reduced pressure. The desired product is obtained as residue with MW = 632.09 (calculated, monoisotopic); measured value (M+H)*: 633.10 Example 27 15 N-[6-(4-Chlorobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[l,2-a]pyrimidin-3-yl]cyclopropanesulfonamide 53 Structure: C1 0Cl N / 0 I N O 0 0 0 0" Synthesis took place in analogy to Example 26 using cyclopropanesulfonyl chloride. The desired product is obtained with MW = 658.11 (calculated, 5 monoisotopic); measured value (M+H)*:659.10 Example 28 1 -tert-Butyl-3-[6-(4-chlorobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 isopropyl-4,7-dioxooctahydropyrazino[l,2-a]pyrimidin-3-yl]urea 10 Structure: I 'p N1 1 1 1 1 1 N NC o o N 5.4 mg of tert-butyl isocyanate are added to a solution of 30 mg of 3-amino-6-(4 chlorobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione and 7.6 pl of Et 3 N in 500 pl 15 of dioxane. The solution is heated at 50 0 C for 6 h. The solvent is removed in 54 vacuo. The residue is separated by HPLC (Waters-Xterra T M MS C18, 5 ptm, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) = 80/20 -- 10/90). The desired product is obtained with MW = 653.18 (calculated, monoisotopic); measured value (M+H)*: 654.13 5 Example 29 Structure: ci N / N N CI ci 0 N 0= 10 Method A: a) 2-Benzyloxycarbonylamino-3-(2,4-dichlorobenzenesulfonylamino)propionic acid Synthesis takes place in analogy to Example 21d) starting from 2,4 dichlorobenzenesulfonyl chloride. The desired product is obtained with MW = 446.01 (calculated, monoisotopic); measured value (M+H-CO 2 )*: 403.00. 15 b) N-{2-(4-Chlorophenyl)-1 -[(2,2-d iethoxyethyl)isopropylcarbamoyl]ethyl}-3-(2,4 dichlorobenzenesulfonylamino)-2-methanesulfonylaminopropionamide Synthesis takes place in analogy to Example 21e) starting from 2 benzyloxycarbonylamino-3-(2,4-dichlorobenzenesulfonylamino)propionic acid. The 20 desired product is obtained with MW = 784.186 (calculated, monoisotopic); measured value (M-CO 2 +H)*: 741.10 c) Benzyl [6-(4-chlorobenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate 55 Synthesis takes place in analogy to Example 21f) starting from N-{2-(4 chlorophenyl)-1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl}-3-(2,4 dichlorobenzenesulfonylamino)-2-methanesulfonylaminopropionamide. The desired product is obtained with MW = 692.10 (calculated, monoisotopic); 5 measured value (M+H)*: 693.05 d) 3-Amino-6-(4-chlorobenzyl)-1-(2,4-d ichlorobenzenesu lfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 21g) starting from benzyl [6-(4 10 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxooctahydro pyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 558.07 (calculated, monoisotopic); measured value (M+H)*: 559.10 e) N-[6-(4-Chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo 15 octahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide. A solution of 15 mg of 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl) 8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione, 3.2 mg of cyclopropanecarboxylic acid in 110 pl of DMF is cooled to OC, and 11.2 mg of HATU, 4.1 mg of HOAt and 11.6 pl of Et 3 N are added. The solution is stirred at 20 0*C for 10 min and then at room temperature for 4 h. The solvent is removed in vacuo. The residue is then taken up in ethyl acetate and water. The aqueous phase extracted twice with ethyl acetate. The combined organic phase is dried over Na 2
SO
4 and the solvent removed in vacuo. The crude product is separated by HPLC (Waters-XterraTM MS C18, 5 im, water (0.1% trifluoroacetic 25 acid)/acetonitrile (0.1% trifluoroacetic acid) = 80/20 -> 10/90). The desired product is obtained with MW = 626.09 (calculated, monoisotopic); measured value (M+H)*: 627.13 Method B a) 9H-Fluoren-9-ylmethyl (2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)isopropyl 30 carbamoyl]ethyl}carbamate 56 210 mg (1.2 mmol) of (2,2-diethoxyethyl)isopropylamine and 376 mg (1.20 mmol) of DMTMM are added to a solution of 505 mg (1.2 mmol) of N-Fmoc-4-CI-Phe-OH in 2 ml of DMF. The reaction mixture is stirred at room temperature overnight. It is then extracted with 40 ml of diethyl ether and washed with 10 ml of water. The 5 combined organic phases are dried over MgSO 4 and concentrated in vacuo. The crude product is purified by chromatography on 10 g SiO 2 (eluent DCM followed by 20%EtOAc/DCM). 530 mg of the desired product are obtained as an oil. MW = 578.26 (calculated, monoisotopic); measured value (M+H)*: 579 10 b) 2-Amino-3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropylpropionamide A solution of 530 mg (0.915 mmol) of 3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N isopropyl-2-methylpropionamide in 15 ml of a 20% diethylamine DCM solution is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo and purified by chromatography on 5 g of SiO 2 (eluent DCM followed by 15 20% EtOAc/DCM followed by 20% MeOH/DCM). 320 mg of the desired product are obtained as an oil. MW = 356.19 (calculated, monoisotopic); measured value (M+H)* = 357 c) 9H-Fluoren-9-ylmethyl (2-benzyloxycarbonylamino-2-{2-(4-chlorophenyl)-1 20 [(2,2-d iethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate Z-Dap-Fmoc-OH was coupled with 2-amino-3-(4-chlorophenyl)-N-(2,2 diethoxyethyl)-N-isopropylpropionamide under the same conditions as described under a). The desired product is obtained with MW = 798.34 (calculated, monoisotopic); measured value (M+Na)* = 821.43 25 d) Benzyl (2-amino-1-{2-(4-chlorophenyl)-1-[(2,2 d iethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carba mate The Fmoc protective group was eliminated from 9H-fluoren-9-ylmethyl (2 benzyloxycarbonylamino-2-{2-(4-chlorophenyl)-1 -[(2,2-diethoxyethyl)isopropyl 30 carbamoyl]ethylcarbamoyllethyl)carbamate using diethylamine and employing the method as described under b). The desired product is obtained with MW = 576.27 (calculated, monoisotopic); measured value (M+H)* = 577.22 57 e) Benzyl [1-{2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl] ethylcarbamoyl}-2-(2,4-dichlorobenzenesulfonylamino)ethyl]carbamate 1.94 ml (11.09 mmol) of DIEA and 1.5 g (6.1 mmol) of 2,4-dichlorophenylsulfonyl 5 chloride are added to a solution of 3.2 g (5.54 mmol) of benzyl (2-amino-1-{2-(4 chlorophenyl)-1 -[(2,2 d iethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate in 75 ml of DCM. The solution is stirred at room temperature overnight. The solution is then concentrated in vacuo, and the residue is purified by column chromatography on 10 100 g of SiO 2 (eluent DCM followed by 20% EtOAc/DCM). 2.78 g of the desired product are obtained as a colorless foam. MW = 784.19 (calculated, monoisotopic); measured value (M+Na)* = 807.24 f) Benzyl [6-(4-chlorobenzyl)-1 -(2,4-dichlorobenzenesu lfonyl)-8-isopropyl-4,7 15 d ioxooctahyd ropyrazino[1,2-a]pyrimidin-3-yl]carbamate A solution of 2.74 g (3.49 mmol) of benzyl [1-{2-(4-chlorophenyl)-1-[(2,2 diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}-2-(2,4 dichlorobenzenesulfonylamino)ethyl]carbamate in 45 ml of formic acid was heated at 600C for 6 h. The reaction mixture was then concentrated in vacuo, and the 20 residue was purified by chromatography on 40 g of SiO 2 (eluent DCM followed by 20% EtOAc/DCM). 2.25 g of the cyclized compound are obtained as a colorless solid. LC/MS MW = 692.1 (calculated, monoisotopic); measured value (M+H)* = 693 25 g) 3-Amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 206 ml (1.44 mmol) of trimethylsilyl iodide (TMSI) are added to a solution of 250 mg (0.36 mmol) of benzyl [6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl) 8-isopropyl-4,7-d ioxooctahydropyrazino[1 ,2-a]pyrimid in-3-yl]carbamate in 10 ml of 30 CH 3 CN at 00C. The reaction solution is allowed to reach room temperature and is stirred at this temperature for 2 h. 5 ml of MeOH are added to the reaction solution, and then the solution is concentrated in vacuo. The residue is purified on a 5 g 58 SCX cartridge (eluted with MeOH followed by 3N NH 3 /MeOH). 185 mg of the desired compound are obtained as a white powder. LC/MS 558.07(calculated, monoisotopic); measured value (M+H)*: 559.10 5 g) N-[6-(4-Chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo octahyd ropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide. Synthesis took place in analogy to Example 22. Example 30 10 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide Structure: cl ciN 0 ci // N N ci 0 0 -0 Synthesis took place in analogy to Example 22 using cyclobutanecarbonyl chloride 15 and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 640.11 (calculated, monoisotopic); measured value (M+H)*: 641.09 20 Example 31 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-isopropyl-4,7 d ioxoocta hyd ropyrazino[1,2-a] pyri mid in-3-yl]cyclopentanecarboxamide 59 Structure: cI N N 0 C1 " N N Ci 0 N 0 Synthesis took place in analogy to Example 22 using cyclopentanecarbonyl chloride and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8 5 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 654.12 (calculated, monoisotopic); measured value (M+H)*: 655.1 Example 32 10 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclohexanecarboxamide Structure: ci ci-~N, 0 ci N N CN 0-\<0 Synthesis took place in analogy to Example 22 using cyclohexanecarbonyl 15 chloride and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 668.14 (calculated, monoisotopic); measured value (M+H)*: 669.11 60 Example 33 N-[6-(4-Chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-2,2,2-trifluoroacetamide ci N 0CI 0 / N N F N F 0 5 40 mg (0.071 mmol) of 3-amino-6-(4-chlorobenzyl)-1-(2,4 dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione were dissolved in 1.5 ml of DCM, and 0.024 ml (0.17 mmol) of trifluoroacetic anhydride and 0.075 ml (0.43 mmol) of DIEA were added. The reaction mixture was stirred at 500C for 1 hour. After addition of 1 ml of water, the organic phase 10 was isolated, dried (MgSO 4 ) and concentrated in vacuo. Purification by flash chromatography on 4 g SiO 2 (elution with MeOH/DCM, gradient 0 - 4%) afforded 21 mg of substance. MW (calculated, monoisotopic) = 654.05; MW (measured value) = 655.06. 15 Example 34 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahyd ropyrazino[1,2-a]pyrimidin-3-yl]-N isopropylcyclopropanecarboxamide 61 NN N C ci 0 N O 0.2 g (0.36 mmol) of 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl) 8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione was dissolved in 12 ml of 5 MeOH, and 1.6 ml of acetone and then 0.8 ml of CH 3 COOH and 4 ml of NaCNBH 3 (1.OM in THF) were added. After 1 hour, the mixture was concentrated in vacuo, mixed with 5 ml of EtOAc and washed with 5 ml of water. The organic phase was isolated, dried (MgSO 4 ) and concentrated in vacuo. Flash chromatography of the crude substance on 20 g of SiO 2 (elution with EtOAc/DCM, gradient 0-50%) 10 afforded 182 mg of the intermediate as an oil which was used for the subsequent coupling step. 30 mg (0.05 mmol) of the intermediate were mixed in 1 ml of DCM with 0.026 ml (0.149 mmol) of DIEA and 0.0055 ml (0.0598 mmol) of cyclopropanecarbonyl chloride and stirred at room temperature overnight. After addition of 2 ml of water, the organic phase was isolated, dried (MgSO 4 ) and 15 concentrated in vacuo. The crude substance was chromatographed on 4 g of SiO 2 (elution with MeOH/DCM, gradient 0-5%). 21.4 mg of the desired compound were obtained. MW (calculated, monoisotopic) = 668.14; MW (measured value) (M*H) = 669.
62 Example 35 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-N cyclohexylcyclopentanecarboxamide N 0 Ci ci 0 /N O 0 ' 0 5 Example 35 was synthesized in analogy to Example 34 using cyclohexanone in the reductive amination. Cyclopentanecarbonyl chloride was used for the amide coupling. The desired product is obtained with MW = 736.20 (calculated, 10 monoisotopic), measured value: (M+H)* = 737.15 Example 36 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-1 -methylpiperidine-4-carboxamide C1 N N N Cl IN NCa CI 0 N 0 15 / 63 Synthesis took place in analogy to Example 29e using 1 -methylpiperidin-4 carboxylic acid hydrochloride. The desired product is obtained with MW = 683.15 (calculated, monoisotopic); measured value (M+H)*: 684.38 Example 37 5 N-[6-(4-Chlorobenzyl)-1 -(2,4-d ichlorobenzenesu lfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]piperidine-4-carboxamide ciN 0 c N N ci 0 N -0 A mixture of 100 mg (0.179 mmol) of 3-amino-6-(4-chlorobenzyl)-1-(2,4 10 dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7 dione, 2 ml of DCM, 23 mg (0.178 mmol) of DIEA and 51 mg (0.181 mmol) of benzyl 4-(chlorocarbonyl)tetrahydro-1 (2H)-pyridinecarboxylate was stirred at room temperature for 1 hour. The mixture was subjected to a flash chromatography on 2 g of SiO 2 (elution with EtOAc/DCM, gradient 0-20%). 119 mg of the intermediate 15 benzyl 4-[6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-ylcarbamoyl]piperidine-1 -carboxylate were obtained. The results obtained in LC/MS (expected monoisotopic MW = 803, measured value (M*H) = 804) agreed with the structure. 103 mg (0.517 mmol) of iodotrimethylsilane were added to a solution of 104 mg 20 (0.129 mmol) of benzyl 4-[6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8 isopropyl-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-ylcarbamoyl]piperidine-1 carboxylate in 2.5 ml of acetonitrile at room temperature with stirring. After 2 hours, the mixture was concentrated. The residue was purified on a Varian Bond-Elut SCX ion exchange cartridge (elution with methanol, then with 3N-NH 3 in 25 methanol). The purified amine was converted into the hydrochloride salt. 75 mg of 64 the desired compound were obtained. LC/MS (expected monoisotopic MW = 669.13; measured value (M*H) = 670) Example 38 5 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]morpholine-4-carboxamide c~ N 0 cl N NI ? N NC N )==o N 47 pl (0.268 mmol) of HOnig's base were added to a solution of 50 mg 10 (0.089 mmol) of the amine 3-amino-6-(4-chlorobenzyl)-1-(2,4 dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione in 1.8 ml of DCM/THF (1:1). Then 80 mg (0.268 mmol) of triphosgene were slowly added to the reaction mixture. The mixture was stirred at room temperature overnight. The reaction mixture was then diluted with EtOAc, washed with H 2 0, 15 dried over MgSO 4 and concentrated in vacuo. This intermediate was dissolved in 1 ml of THF, and 31 pl (0.178 mmol) of HOnig's base and 12 mg (0.134 mmol) of morpholine were added. The reaction mixture was stirred at room temperature overnight, diluted with EtOAc, washed with H 2 0, dried over MgSO 4 and concentrated. The residue was chromatographed on 4 g of SiO 2 (elution with 20 MeOH/DCM, gradient 1-8%). 36 mg of the desired substance were obtained as a colorless solid. LC/MS (expected MW = 671.11; measured value (M*H) = 672).
65 Example 39 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]piperidine-2-carboxamide ci N SI ' " N N cl cl 0 N 0 CN= 5 24.7 mg (0.089 mmol) of 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholine chloride x H 2 0 (DMTMM) and then 31.3 mg (0.089 mmol) of Fmoc-Pip-OH were added to a solution of 0.05 g (0.089 mmol) of 3-amino-6-(4-chlorobenzyl)-1-(2,4 dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 10 in 2 ml of DMF. The reaction mixture was stirred at room temperature overnight. Then 8 ml of diethyl ether and 5 ml of water were added. The organic phase was isolated, again washed with 5 ml of water, dried (MgSO 4 ) and concentrated in vacuo. Purification takes place by flash chromatography on 4 g of SiO 2 (MeOH/DCM as eluent system, gradient 0-2%) and afforded 82 mg of the FMOC 15 protected intermediate in the form of a white solid. It was possible to show by LC/MS that the product was the desired intermediate. A solution of 70 mg (0.078 mmol) of the FMOC intermediate in 2 ml of 10% strength diethylamine in DCM was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by preparative HPLC in a Gilson C18 20 apparatus (CH 3 CN (0.1% TFA)/H 2 0 (0.1% TFA), gradient 5-100%). The desired fractions were concentrated in vacuo. 33.9 mg of the corresponding TFA salt of the desired compound were obtained. LC/MS MW (calculated, monoisotopic) = 669.13; measured value (M*H) = 670.11.
66 Example 40 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]pyrrolidine-2-carboxamide N 0"c /1 N N ci o N CNo 5 A mixture of 50 mg (0.089 mmol) of 3-amino-6-(4-chlorobenzyl)-1-(2,4 dichlorobenzenesufonyl)-8-isopropyhexahydropyrazino[1,2-a]pyrimidine-4,7 dione, 1 ml of DCM, 23 mg (0.178 mmol) of DIEA and 32 mg (0.090 mmol) of Fmoc-Pro-Cl was stirred at room temperature for 1 hour. The mixture was purified 10 by chromatography on 2 g of SiO 2 (elution with EtOAc/DCM, gradient 0-20%). 72 mg of the intermediate 9H-fluoren-9-ylmethyl 2-[6-(4-chlorobenzyl)-1-(2,4 dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin 3-ylcarbamoyl]pyrrolidine-1 -carboxylate were obtained. LC/MS: (calculated, monoisotopic MW = 877, measured value (M*H) = 878) 15 A mixture of 60 mg (0.068 mmol) of 9H-fluoren-9-ylmethyl 2-[6-(4-chlorobenzyl)-1 (2,4-d ichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxooctahydropyrazino[1,2 a]pyrimidin-3-ylcarbamoyl]pyrrolidine-1-carboxylate and 2 ml of 15% strength diethylamine in DCM was stirred at room temperature overnight. The mixture was concentrated and subjected to a flash chromatography on 2 g of SiO 2 (elution with 20 DCM, EtOAc and then with 10% methanol/EtOAc). The amine was converted into the hydrochloride salt. 30 mg of solid were obtained. This was further purified by preparative reverse phase (RP) HPLC. 17 mg of the desired compound were obtained. LC/MS (calculated, monoisotopic MW = 655.12; measured value (M*H) = 656) 25 67 Example 41 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-1 -methylpyrrolidine-2-carboxamide CIN 0U Ci N N Ci 0 0 N 0 5 0.3 ml (5.2 mmol) of acetic acid, 0.25 ml (3.33 mmol) of formaldehyde (37% in water) and 1.5 ml (1.5 mmol) of sodium cyanoborohydride (1 M in THF) were added to a solution of 93 mg (0.142 mmol) of the amine from Example 40 in 7.5 ml of methanol. The reaction mixture was stirred at room temperature for 2 hours and 10 concentrated in vacuo. The residue was diluted with 10 ml of DCM, basified with 7N-NH 3 in methanol, filtered and concentrated. This residue was purified by preparative RP-HPLC. 50 mg of the desired compound were obtained. LC/MS (calculated, monoisotopic MW = 669; measured value (M*H) = 670) 15 Example 42 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]azetidine-3-carboxamide ciN 0 C // N N ci 0 N
N
68 49.5 mg (0.179 mmol) of 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholine chloride x H 2 0 (DMTMM) and then 58 mg (0.179 mmol) of 1-Fmoc-azetidine-3 carboxylic acid were added to a solution of 0.1 g (0.179 mmol) of the amine 3 amino-6-(4-chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8 5 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione in 5 ml of DMF. The reaction mixture was stirred at room temperature overnight. Then 50 ml of diethyl ether and 50 ml of water were added. The organic phase was isolated, washed twice with 50 ml of water each time, dried (MgSO 4 ) and concentrated in vacuo. Purification by flash chromatography on 20 g of SiO 2 (MeOH/DCM as eluent 10 system, gradient 0-10%) afforded 117 mg of the FMOC-protected intermediate in the form of a white solid. This was used in the next step. A solution of 50 mg (0,058 mmol) of the FMOC intermediate in 1.5 ml of 10% strength diethylamine in DCM was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified by preparative HPLC in a Gilson C18 15 apparatus (CH 3 CN (0.1% TFA)/H 2 0 (0.1% TFA)). The fractions were concentrated in vacuo. 21.6 mg of the TFA salt of the desired product were obtained. MW (calculated, monoisotopic) = 641.11; measured value (M*H) = 641.99. Example 43 20 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 d ioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-N', N-dimethylsuccinamide C1 N N CI cI 0 C1 0 N Os0 Synthesis took place in analogy to Example 29e using N,N-dimethylsuccinamic acid. The desired product is obtained with MW = 685.13 (calculated, 25 monoisotopic); measured value (M+H)*: 686.30 69 Example 44 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-N-isopropylcyclohexanecarboxamide 5 Structure: cl CIN 0 CI N N ci 0 N 0 Example 44 was synthesized in analogy to Example 34 using cyclohexanecarbonyl chloride in the amide coupling step. The desired product is obtained with MW = 710.19 (calculated, monoisotopic); measured value (M+H)*: 10 711.18 * Example 45 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-N-isopropylcyclopentanecarboxamide 15 Structure: S N 0 C1 N ci 0 N Example 45 was synthesized in analogy to Example 34 using cyclopentanecarbonyl chloride in the amide coupling step. The desired product is obtained with MW = 696.17 (calculated, monoisotopic); measured value (M+H)*: 20 697.17 70 Example 46 N-[6-(4-Chlorobenzyl)-1 -(2,4-d ichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-N-isopropylpiperidine-4-carboxamide 5 Structure: N 0 CI cI N I O N Synthesis in Example 46 took place by the process described for 34. Benzyl 4 chlorocarbonylpiperidine-1-carboxylate was used in the coupling step and afforded 10 the Cbz-protected compound. The Cbz protective group was eliminated by adding 0.0283 ml (0.199 mmol) of TMSI and 2 ml of CH 3 CN at 0*C. The reaction mixture was stirred for 3 days, concentrated in vacuo and eluted through a column packed with 1 g of SCX and moistened with MeOH. The impurities were eluted with MeOH. The desired amine was obtained by elution with 2N-NH 3 in MeOH. This 15 was followed by concentration in vacuo and addition of 0.1 ml of 1.0 M HCI in diethyl ether. The salt produced in this way was ground, washed 4 times with 2 ml of diethyl ether each time and dried. 0.025 g of the desired compound was obtained. LC/MS: MW (calculated, monoisotopic) = 711.18; measured value (M*H) = 712.11. 20 Example 47 N-[6-(4-Chlorobenzyl)- 1 -(2,4-d ichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-4-dimethylaminobenzamide Structure: 71 N N 0 Cl SN N 00 N O 0 /N Synthesis took place in analogy to Example 29e using 4-dimethylaminobenzoic acid. The desired product is obtained with MW = 705.13 (calculated, 5 monoisotopic); measured value (M+H)*: 706.21 Example 48 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-2-pyridin-3-ylacetamide 10 ci ci -N, 0 ci N N ci 0 N0 N Synthesis took place in analogy to Example 29e using 3-pyridylacetic acid. The desired product is obtained with MW = 677.10 (calculated, monoisotopic); measured value (M+H)*: 678.07 15 Example 49 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]pyridine-2-carboxamide 72 ciN 0 ci ,S N N ci 0 N 0 Synthesis took place in analogy to Example 29e using picolinic acid. The desired product is obtained with MW = 663.09 (calculated, monoisotopic); measured value 5 (M+H)*: 664.22 Example 50 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]nicotinamide 10 Structure: ci N N N 0CI1 // N N c, 0 )-o N 0 N Synthesis took place in analogy to Example 22 using nicotinoyl chloride *HCI and 3-amino-6-(4-chlorobenzyl)-1 -(2,4-d ichlorobenzenesufonyl)-8-isopropyl hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained 15 with MW = 663.09 (calculated, monoisotopic); measured value (M+H)*: 664.11 Example 51 N-[6-(4-Chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-6-trifluoromethylnicotinamide 20 Structure: 73 N N 0 C1 c N N CI 0 0 N O N F F F Synthesis took place in analogy to Example 22 using 6-(trifluoromethyl)nicotinoyl chloride and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8 isopropyl-hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 5 obtained with MW = 731.08 (calculated, monoisotopic); measured value (M+H)*: 732.01 Example 52 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 10 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-4-trifluoromethylnicotinamide Structure: ci c N N cl 0 N F F F ZN. N Synthesis took place in analogy to Example 29e using 4-(trifluoromethyl)nicotinic 15 acid and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 731.08 (calculated, monoisotopic); measured value (M+H)*: 732.07 74 Example 53 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-5-methylpyrazine-2-carboxamide Structure: co N N cl ci 0 N 0 N 5 N 5 Synthesis took place in analogy to Example 29e using 5-methylpyrazine-2 carboxylic acid and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 678.10 (calculated, monoisotopic); measured value (M+H)*: 10 679.06 Example 54 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]pyrazine-2-carboxamide 15 Structure: ci N S N N cl // N ci 0 N Synthesis took place in analogy to Example 22 using pyrazine-2-carbonyl chloride and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 75 obtained with MW = 664.08 (calculated, monoisotopic); measured value (M+H)*: 665.05 Example 55 5 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]quinoline-3-carboxamide Structure: N 0 CI N N CI 0 ' N 0 N 10 Synthesis took place in analogy to Example 29e using 3-quinolinecarboxylic acid and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 713.10 (calculated, monoisotopic); measured value (M+H)*:714 15 Example 56 1 -tert-Butyl-3-[6-(4-chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]urea Structure: cl NiN 0 ci NN N'r) ci 0 N N>= 20 Synthesis takes place in analogy to Example 28 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2- 76 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 657.13 (calculated, monoisotopic); measured value (M+H)*: 658.26 Example 57 5 1 -Ethyl-3-[6-(4-chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]urea N0 c N N ci o N ---o N Synthesis took place in analogy to Example 56 using ethyl isocyanate. The desired product is obtained with MW = 629.10 (calculated, monoisotopic); measured value 10 (M+H)*: 630.13 Example 58 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanesulfonamide 15 Structure: ci c / N N ci 0 N, O Synthesis takes place in analogy to Example 27 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-d ichlorobenzenesufonyl)-8-isopropylhexahydropyrazino[1 ,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 662.06 20 (calculated, monoisotopic); measured value (M+H)*: 663.05.
77 Example 59 6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-3-piperidin-1 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione ci N 0C N N C1 ci 0 N 0 5 A mixture of 50 mg (0.089 mmol) of 3-amino-6-(4-chlorobenzyl)-1-(2,4 dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7 dione, 2,0 ml of acetonitrile, 0.2 ml (0.2 mmol) of 1 M (H 2 0)-NaHCO 3 and 83 mg (0.361 mmol) of 1,5-dibromopropane was heated with stirring in a microwave oven at 175 0 C for 800 seconds. After cooling, the mixture was concentrated. The 10 residue was subjected to a flash chromatography on 2 g of SiO 2 (elution with EtOAc/DCM, gradient 0-20%). The purified amine was converted into the hydrochloride salt. 38 mg of the desired compound were obtained. LC/MS: (MW calculated, monoisotopic = 626.13; measured value (M*H) = 627.15) 15 Example 60 6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-3-morpholin-4-yl hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: C1 11.0 N NJ aC1 (N) 0 20 78 149 mg (0.64 mmol, 4.0 equiv.) of 2-bromoethyl ether and then 0.2 ml of 1 N NaHCO 3 solution were added to a solution of 90 mg (0.16 mmol) of the amine 3 amino-6-(4-chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione in 2 ml of CH 3 CN. The 5 reaction mixture was heated at 2000C in a microwave oven (Smith Creator) for 120 seconds. Cooling was followed by dilution with DCM and washing with 1 N NaHCO 3 . The organic phase was dried over MgSO 4 and concentrated. The residue was chromatographed on 12 g of SiO 2 (elution with MeOH/DCM, gradient 0-10%). 48 mg of the desired substance were obtained as a white solid. LC/MS 10 (calculated, monoisotopic MW = 628.18; measured value (M*H) = 629.1) agree with the structure. Example 61 6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-3-(4 15 methylpiperazin-1 -yl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ciN 0 ci N N cl 0 (N) N 20 50 mg of 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl hexahydropyrazino[1,2-a]pyrimidine-4,7-dione, 14.4 mg of mechlorethamine hydrochloride, 13 mg of NaHCO 3 are dissolved in just enough ethylene glycol to result a solution. 1.6 mg of Nal are added to this solution, and the solution is heated at 110*C for 6 h. After cooling, the solution is mixed with water and 25 extracted three times with 40 ml of ethyl acetate each time. The combined organic phases are dried over Na 2
SO
4 , and the solvent is removed in vacuo. The residue 79 is separated by HPLC (Waters-Xterra TM MS C18, 5 tm, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) = 80/20 -> 10/90). The desired product is obtained with MW = 641.14 (calculated, monoisotopic); measured value (M+H)*: 642.25 5 Example 62 3-(1 -Benzylpiperidin-4-ylamino)-6-(4-chlorobenzyl)-1 -(2,4 dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ci ciN 0 ci ; N N Cl ci 0 0 N,,C 10 N 115 mg (0.61 mmol) of 1-benzyl-4-piperidone and then 130 mg (4.1 mmol/g) of (polystyrylmethyl)trimethylammonium cyanoborohydride were added to a solution of 100 mg (0.18 mmol) of 3-amino-6-(4-chlorobenzyl)-1-(2,4 dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 15 in 1.2 ml of 5% HOAc/CH 3 CN and 3 drops of MeOH. The reaction mixture was shaken at room temperature for 18 hours, filtered and concentrated. 160 mg of beige oil were obtained. The crude product was isolated by flash chromatography in a column packed with 4 g of silica gel (elution with 5% MeOH/EtOAc). Concentration of the appropriate fractions resulted in 110 mg (85%) of the above 20 compound in the form of a clear oil. LC/MS (expected, monoisotopic MW = 731.19; measured value (M*H) = 732.20) Example 63 6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-3-(2-oxopyrrolidin 25 1 -yl)hexahyd ropyrazino[1,2-a]pyrimidine-4,7-d ione 80 Structure: N 0 ci / N N cN 0 A solution of 50 mg (0.089 mmol) of 3-amino-6-(4-chlorobenzyl)-1 -(2,4 5 dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7 dione, 0.012 ml (0.107 mmol) of 4-chlorobutyryl chloride and 0.031 ml of DIEA in 2 ml of DCM was stirred at room temperature overnight. After addition of 2 ml of water, the organic phase was isolated, washed with 2 ml of brine, dried (MgSO 4 ) and concentrated in vacuo. The crude substance was chromatographed on 4 g of 10 Si02 (elution with MeOH/DCM, gradient 0-6%). The concentrated fractions afforded 45.8 mg of chlorobutyramide intermediate in the form of a white solid and were used in the following step. 60 mg (0.36 mmol) of potassium iodide and 277 mg (2 mmol) of K 2
CO
3 were added to 45 mg (0.068 mmol) of the chloro amide intermediate dissolved in 2 ml of acetone. The mixture was heated at 130*C in a 15 microwave oven for 600 seconds, and then concentrated in vacuo and purified by flash chromatography on 4 g of SiO 2 (elution with MeOH/DCM, gradient 0-5%). 16.2 mg of white solid were obtained. LC/MS agreed with the desired structure. MW (calculated, monoisotopic) = 626.09 ; measured value (M*H) = 627.1.
81 Example 64 6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-3-(2-oxopiperidin 1 -yl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ciN 0 C1 cis / N N cl ci 0 N 0 5 Example 64 was synthesized in analogy to Example 63 using 5-chloropentanoyl chloride in the amide coupling step. The desired product is obtained with MW = 640.11 (calculated, monoisotopic); measured value (M+H)*: 641.1 10 Example 65 6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-3-(2-oxoazepan-1 yl)hexahydropyrazino[1,2-a]pyrimidine-4,7-d ione Structure: ci 0 "N N ci 0 N 0 15 Example 65 was synthesized in analogy to Example 63 using 6-chlorohexanoyl chloride in the amide coupling step. The desired product is obtained with MW = 654.12 (calculated, monoisotopic); measured value (M+H)*: 655.11.
82 Example 66 N-[6-(4-Chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl)acetamide F N 0 C1 N N N 5 a) Benzyl [6-(4-chlorobenzyl)-1-(5-fluoro-2-methoxybenzenesulfonyl)-8-isopropyl 4,7-dioxooctahydropyrazino[1 ,2-a]pyrimidin-3-yl]carbamate Solid-phase route: 7 g (3.64 mmol) of Tentagel HL 12 019 ( Rapp Polymer GmbH loaded with 10 bromoacetal linker) is heated in 26 ml of DMSO and 6 ml (70.44 mmol) of isopropylamine at 60*C in a solid-phase reactor overnight. The resin is washed four times each with DMSO, MeOH, DCM and diethyl ether (30 ml each time) and then dried in vacuo. DIEA (5.7 ml, 32.76 mmol) and HATU (4.15 g, 10.92 mmol) in 30 ml of DMF are added for the coupling with Fmoc(4-CIPhe)OH (4.6 g, 15 10.92 mmol). The reaction mixture is heated at 550C for 3 h. The resin is washed in analogy to the first step. The Fmoc group is eliminated by treating the resin twice with 30 ml of 20% piperidine in DMF each time, for 20 minutes each time, and it is then washed as described above. The resin is next reacted with Fmoc-ZDap(OH) (5.02 g, 10.92 mmol), DIC (1.71 ml, 10.92 mmol) and HOBt 20 (1.47 g, 10.92 mmol) in 30 ml of DMF at room temperature overnight. Washing was carried out in analogy to the procedure described above. 0.613 g (2.73 mmol) of 5-fluoro-2-methoxybenzenesulfony chloride (Butt Park 49/07-57), 0.95 ml (5.46 mmol) of DIEA and 30 ml of DCM were added to half of the resin (1.82 mmol). The reaction solution was shaken at room temperature overnight. 25 The resin was then washed as described above. The resin is subsequently mixed with 30 ml of 99% HCOOH and shaken at room temperature overnight. The resin 83 is decanted off and washed twice with 20 ml of HCOOH each time. The combined filtrates are heated at 60 0 C for 3 h. The reaction solution is concentrated in vacuo, and the crude product is purified by chromatography (100 g Si02, eluent EtOAc/DCM (gradient 0-50%)). 0.778 g of the desired product is obtained as a 5 white solid of MW = 672.18 (calculated, monoisotopic); measured value (M+H)*: 673.1 b) 3-Amino-6-(4-chlorobenzyl)-1-(5-fluoro-2-methoxybenzenesulfonyl)-8-isopropyl hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 22g (Method B) starting from benzyl 10 [6-(4-chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[l,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 538.14 (calculated, monoisotopic); measured value (M+H)*: 539.14 15 c) N-[6-(4-Chlorobenzyl)-1-(5-fluoro-2-methoxybenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide. Synthesis takes place in analogy to Example 21 h starting from 3-amino-6-(4 chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8-isopropylhexahydro pyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with 20 MW = 580.16 (calculated, monoisotopic); measured value (M+H)*: 581.13 Example 67 N-[6-(4-Chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide 84 Structure: F N N c NN Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(4 chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8 5 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 606.17 (calculated, monoisotopic); measured value (M+H)*: 607.14 Example 68 10 N-[6-(4-Chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide Structure: F N 0- ci 0 N N N Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(4 15 chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 620.19 (calculated, monoisotopic); measured value (M+H)*: 621.16 85 Example 69 N-[6-(4-Chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide Structure: F N N CI N 0 5 Synthesis takes place in analogy to Example 31 starting from 3-amino-6-(4 chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 634.20 (calculated, monoisotopic); measured value (M+H)*: 10 635.17 Example 70 1 -tert-Butyl-3-[6-(4-chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8 isopropyl-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]urea 15 Structure: F 4S N ci o o K NN Synthesis takes place in analogy to Example 28 starting from 3-amino-6-(4 chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8 isopropylhexahyd ropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 20 obtained with MW = 637.31(calculated, monoisotopic); measured value (M+Na)*: 660.17 86 Example 71 N-[6-(4-Chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide 5 Structure: F N 0 Ci S... 44 N N OC \ N , Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 10 obtained with MW = 616.12 (calculated, monoisotopic); measured value (M+H)*: 617.14. Example 72 6-(4-Chlorobenzyl)-3-dimethylamino-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8 15 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: F N 0 CI '0< N N 0 35 mg (0.065 mmol) of 3-amino-6-(4-chlorobenzyl)-1-(5-fluoro-2-methoxybenzene sulfonyl)-8-isopropylhexahydropyrazino[1 ,2-a]pyrimidine-4,7-dione were dissolved 20 in 3.5 ml of MeOH. Addition of 0.1 ml of CH 3 COOH, 0.1 ml of formaldehyde (37% in water) and 0.7 ml of NaCNBH 3 (1 .OM in THF) was followed by stirring at room temperature overnight. The mixture was then concentrated in vacuo, mixed with 87 1 ml of water and extracted twice with 1 ml of EtOAc each time. The organic phase was isolated, dried (MgS04) and concentrated. Further purification by flash chromatography on 4 g of Si02 (elution with MeOH/DCM, gradient 0-5% MeOH) resulted in the amine. The amine was triturated after addition of 0.2 ml of 1.0M HCI 5 in diethyl ether. The solid was washed 4 times with 1 ml of diethyl ether each time and dried in vacuo. 16.1 mg of HCI salt of the desired compound were obtained. LC/MS: MW (calculated, monoisotopic) = 567.08; measured value (M*H) = 567.14. Example 73 10 3-Azetidin-1 -yl-6-(4-chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: F -N N 0 ci N N N 50 mg (0.093 mmol) of 3-amino-6-(4-chlorobenzyl)-1-(5-fluoro-2-methoxybenzene 15 sulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione were introduced into a 2-5 ml microwave vessel and dissolved in 2 ml of CH 3 CN. 0.25 ml of NaHCO 3 (1 .OM, in water) and 0.0375 ml of dibromopropane were added to this solution. The reaction mixture was heated at 180*C in a Personal Chemistry Smith Synthesizer microwave oven (higher absorption mode with 30 seconds' 20 preliminary stirring time) for 1000 seconds. The mixture was then concentrated in vacuo, mixed with 2 ml of EtOAc and washed with 2 ml of water. The organic phase was isolated, dried (MgSO 4 ) and concentrated in vacuo. Purification took place by preparative RP HPLC in GILSON apparatus (CH 3 CN (0.1% TFA)/H 2 0 (0.1% TFA), gradient 5-100%). 6.9 mg of TFA salt of the desired compound were 25 obtained. LC/MS: MW (calculated, monoisotopic)= 578.18; measured value (M*H) = 579.17.
88 Example 74 6-(4-Chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8-isopropyl-3-pyrrolidin 1 -ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: F 0 N 0 CI o N 5 0 40 mg (0.074 mmol) of 3-amino-6-(4-chlorobenzyl)-1-(5-fluoro-2-methoxybenzene sulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione were introduced into a 2-5 ml microwave vessel and dissolved in 2 ml of CH 3 CN. 0.2 ml of NaHCO 3 (1 .0M, in water) and 0.036 ml of dibromobutane were added to this 10 solution. The reaction mixture was heated at 190 0 C in a Personal Chemistry Smith Synthesizer microwave oven (high absorption mode with 30 seconds' preliminary stirring time) for 800 seconds. The mixture was then concentrated in vacuo, mixed with 1 ml of EtOAc and washed with 1 ml of water. The organic phase was isolated, dried (MgSO 4 ) and concentrated in vacuo. Purification took place by flash 15 chromatography on 4 g of SiO 2 (MeOH/DCM, gradient 0-5%). The concentrated substance was converted into the HCI salt by adding 0.2 ml of 1.OM HCI in diethyl ether. The solid was ground, washed 4 times with diethyl ether and dried in vacuo. 22.7 mg of HCI salt of the desired compound were obtained. LC/MS: MW (calculated, monoisotopic)= 592.19; measured value (M'H) = 593.18. 20 Example 75 6-(4-Chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8-isopropyl-3-piperidin 1 -ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 89 Structure: F -N N 0 Ci N N C o 0 0 Ir1 N 0 Synthesis takes place in analogy to Example 59 starting from 3-amino-6-(4 chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8 5 isopropylhexahydropyrazino(1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 606.21 (calculated, monoisotopic); measured value (M+H)*:607.19 Example 76 10 6-(4-Chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8-isopropyl-3 morpholin-4-ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: F -N N 0 ci 421N N C N) 0 Synthesis takes place in analogy to Example 60 starting from 3-amino-6-(4 15 chlorobenzyl)-1 -(5-fluoro-2-methoxybenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 608.19 (calculated, monoisotopic); measured value (M+H)*:609.16 90 Example 77 Cl 4N 0 C1 /S' 2, N N
F
0 0 N a) Benzyl [6-(4-chlorobenzyl)-1-(5-chloro-2-fluorobenzenesulfonyl)-8-isopropyl-4,7 5 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate Synthesis takes place in analogy to Example 66a) using 5-chloro-2 fluorobenzenesulfonyl chloride. The desired product is obtained with MW = 676.13 (calculated, monoisotopic); measured value (M+H)*: 677.1 b) 3-Amino-6-(4-chlorobenzyl)-1-(5-chloro-2-fluorobenzenesulfonyl)-8 10 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes in analogy to Example 66b) starting from benzyl [6-(4 chlorobenzyl)-1 -(5-chloro-2-fluorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 542.1 (calculated, monoisotopic); measured value (M+H)*: 15 543.1 c) N-[6-(4-Chlorobenzyl)-1-(5-chloro-2-fluorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide. Synthesis takes place in analogy to Example 66c) starting from 3-amino-6-(4-chlorobenzyl)-1-(5-chloro-2 20 fluorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 584.11 (calculated, monoisotopic); measured value (M+H)*: 585.08 Example 78 25 N-[6-(4-Chlorobenzyl)- 1 -(5-chloro-2-fluorobenzenesulfonyl)-8-isopropyl-4,7-dioxo octahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide 91 Structure: cI S'. I ,oC 21 N N F O 0 N Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(4 chlorobenzyl)-1 -(5-chloro-2-fluorobenzenesulfonyl)-8 5 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 610.12 (calculated, monoisotopic); measured value (M+H)*: 611.09 Example 79 10 N-[6-(4-Chlorobenzyl)-1-(5-chloro-2-fluorobenzenesulfonyl)-8-isopropyl-4,7-dioxo octahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide Structure: Ci s' N N CI N FOO Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(4 15 chlorobenzyl)-1 -(5-chloro-2-fluorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 624.14 (calculated, monoisotopic); measured value (M+H)*: 625.10 20 Example 80 N-[6-(4-Chlorobenzyl)-1 -(5-chloro-2-fluorobenzenesulfonyl)-8-isopropyl-4,7-dioxo octahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide 92 Structure: ci N C1 /N NC F O 0 N 0 Synthesis takes place in analogy to Example 31 starting from 3-amino-6-(4 chlorobenzyl)-1 -(5-chloro-2-fluorobenzenesulfonyl)-8 5 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 638.15 (calculated, monoisotopic); measured value (M+H)*: 639.12 Example 81 10 1 -tert-Butyl-3-[6-(4-chlorobenzyl)-1 -(5-chloro-2-fluorobenzenesulfonyl)-8-isopropyl 4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]urea ci 4 1 Nll 0 ci /, , NN C F 0 _0 N NO Synthesis takes place in analogy to Example 28 starting from 3-amino-6-(4 chlorobenzyl)-1 -(5-chloro-2-fluorobenzenesulfonyl)-8 15 isopropylhexahyd ropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 641.16 (calculated, monoisotopic); measured value (M+Na)*: 664.12 Example 82 20 6-(4-Chlorobenzyl)-1 -(5-chloro-2-fluorobenzenesulfonyl)-3-dimethylamino-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 93 Structure: CI N 0 Ci 0 N N F OO 00 N Synthesis takes place in analogy to Example 72 starting from 3-amino-6-(4 chlorobenzyl)-1 -(5-chloro-2-fluorobenzenesulfonyl)-8 5 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 570.13 (calculated, monoisotopic); measured value (M+H)*: 571.09. Example 83 10 3-Azetidin-1 -yl-6-(4-chlorobenzyl)-1 -(5-chloro-2-fluorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ci N N o C S/A 42, N N F 0 O N Synthesis takes place in analogy to Example 73 starting from 3-amino-6-(4 15 chlorobenzyl)-1 -(5-chloro-2-fluorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 582.13 (calculated, monoisotopic); measured value (M+H)*: 583.11. 20 Example 84 6-(4-Chlorobenzyl)-1-(5-chloro-2-fluorobenzenesulfonyl)-8-isopropyl-3-pyrrolidin-1 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 94 Structure: CI cN 0 c "N N F O N 0 Synthesis takes place in analogy to Example 74 starting from 3-amino-6-(4 chlorobenzyl)-1 -(5-chloro-2-fluorobenzenesulfonyl)-8 5 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 596.14 (calculated, monoisotopic); measured value (M+H)*: 597.14. Example 85 10 6-(4-Chlorobenzyl)-1 -(5-chloro-2-fluorobenzenesulfonyl)-8-isopropyl-3-piperidin-1 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ci N N c F O O 0 Synthesis takes place in analogy to Example 59 starting from 3-amino-6-(4 15 chlorobenzyl)-1 -(5-chloro-2-fluorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 610.16 (calculated, monoisotopic); measured value (M+H)*: 611.15 95 Example 86 6-(4-Chlorobenzyl)-1 -(5-chloro-2-fluorobenzenesulfonyl)-8-isopropyl-3-morpholin 1 -ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: cl //0 N 0~ C I N N F 0 O _0 CN) 5 0 Synthesis takes place in analogy to Example 60 starting from 3-amino-6-(4 chlorobenzyl)-1 -(5-chloro-2-fluorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 612.14 (calculated, monoisotopic); measured value (M+H)*: 10 613.13. Example 87 F S N O
.
ci N 15 a) 2-Chloro-5-fluorobenzenesulfonyl chloride 5 g (34.3 mmol) of 2-chloro-5-fluoroaniline were slowly added to a solution of 17 ml of concentrated hydrochloric acid solution and 11 ml of water at 0"C. The reaction mixture was stirred at 0*C for 1 hour. Addition of 2.49 g (36.1 mmol) of NaNO 2 in 20 6 ml of H 2 0 was followed by stirring the mixture at 00C for 15 minutes and then adding to a solution of 692 mg (5.15 mmol) of sulfur dioxide and copper(II) chloride in 10 ml of acetic acid. The reactants were stirred at 00C for 15 minutes and then 96 at room temperature for a further 15 minutes. The reaction mixture was extracted with EtOAc. The organic phase was concentrated, dissolved in EtOAc, washed with 1 N NaHCO 3 solution, dried over MgSO 4 and concentrated. 7.86 g of the desired sulfonyl chloride were obtained as a yellow oil. 5 b) Benzyl (2-(2-chloro-5-fluorobenzenesulfonylamino)-1-{2-(4-chlorophenyl)-1 [(2,2-diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate Et 3 N was added to a solution of 800 mg (1.39 mmol) of the amine benzyl (2 amino-1 -{2-(4-chlorophenyl)-1 -[(2,2 diethoxyethyl)isopropylcarbamoyllethylcarbamoyl}ethyl)carbamate in 4 ml of DCM. 10 The sulfonyl chloride prepared as described above (476 mg, 2.08 mmol) in solution in 3 ml of DCM was then added at room temperature. The reaction mixture was stirred at room temperature for 1 hour and washed with 1 N NaHCO 3 . The organic phase was dried on MgSO 4 and concentrated. The residue was chromatographed on 40 g of SiO 2 (elution with 30-70% EtOAc in heptane). 860 mg 15 of the desired substance was taken as a white solid. LC/MS: MG (calculated, monoisotopic) = 769.72; measured value (M*Na) = 791. c) Benzyl [6-(4-chlorobenzyl)-1-(2-chloro-5-fluorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahyd ropyrazino[l ,2-a]pyrimidin-3-yl]carbamate Synthesis takes place in analogy to Example 29f) (Method B) starting from N-{2-(4 20 chlorophenyl)-1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl}-3-(2-chloro-5-fluoro benzenesulfonylamino)-2-methanesulfonylaminopropionamide. The desired product is obtained when MW = 676.13 (calculated, monoisotopic); measured value (M+H)*: 677.16 d) 3-Amino-6-(4-chlorobenzyl)-1 -(2-chloro-5-fluorobenzenesufonyl)-8 25 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 29g) (Method B) starting from benzyl [6-(4-chlorobenzyl)-1 -(2-chloro-5-fluorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimid in-3-yl]carbamate. The desired product is obtained with MW = 542.1 (calculated, monoisotopic); measured value (M+H)*: 30 543.10 97 e) N-[6-(4-Chlorobenzyl)-1-(2-chloro-5-fluorobenzenesulfonyl)-8-isopropyl-4,7 d ioxooctahyd ropyrazino[1,2-a]pyrimid in-3-yl]acetamide. Synthesis takes place in analogy to Example 21h) starting from 3-amino-6-(4 chlorobenzyl)-1 -(2-chloro-5-fluorobenzenesulfonyl)-8 5 isopropylhexahydropyrazino[1 ,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 584.11 (calculated, monoisotopic); measured value (M+H)*: 585.10 Example 88 10 N-[6-(4-Chlorobenzyl)-1 -(2-chloro-5-fluorobenzenesulfonyl)-8-isopropyl-4,7-dioxo octahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Structure: F I NN ci 0 N 0 Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(4 15 chlorobenzyl)-1 -(2-chloro-5-fluorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 610.12 (calculated, monoisotopic); measured value (M+H)*: 611.14 20 Example 89 N-[6-(4-Chlorobenzyl)-1 -(2-chloro-5-fluorobenzenesulfonyl)-8-isopropyl-4,7-d ioxo octahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide 98 Structure: F N N 0 CI N' n/ NN ci o Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2-chloro-5-fluorobenzenesulfonyl)-8 5 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 624.14 (calculated, monoisotopic); measured value (M+H)*: 625.14 Example 90 10 1 -tert-Butyl-3-[6-(4-chlorobenzyl)-1 -(2-chloro-5-fluorobenzenesulfonyl)-8-isopropyl 4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]urea Structure: F 4S N NCI cN i 11 1 , N N'" N N Synthesis takes place in analogy to Example 28 starting from 3-amino-6-(4 15 chlorobenzyl)-1 -(2-chloro-5-fluorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 641.16 (calculated, monoisotopic); measured value (M+Na)*: 664.15 99 Example 91 N-[6-(4-Chlorobenzyl)-1 -(2-chloro-5-fluorobenzenesulfonyl)-8-isopropyl-4,7-dioxo octahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide F Nll 0 Ci " N N C, 1--N,o N% \ 0"s \ 5 Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2-chloro-5-fluorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 620.07 (calculated, monoisotopic); measured value (M+H)*:621.0 10 Example 92 F 0NY F O 1 NN cN ci 0 NO a) 2-Chloro-4-trifluoromethoxybenzenesulfony chloride 15 2-Chloro-4-trifluoromethoxyaniline was reacted to give the corresponding sulfonyl chloride by the same protocol as in Example 87a). b) Benzyl [1-{2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl carbamoyl}-2-(2-chloro-4-trifluoromethoxybenzenesulfonylamino)ethyl]carbamate Synthesis takes place in analogy to Example 87b) starting from 2-chloro-4 20 trifluoromethoxybenzenesulfonyl chloride. The desired product is obtained with MW = 834.21 (calculated, monoisotopic); measured value (M+Na)*: 857.0 100 c) Benzyl [6-(4-chlorobenzyl)-1-(2-chloro-4-trifluoromethoxybenzenesulfonyl)-8 isopropyl-4,7-d ioxooctahydropyrazino[1,2-a]pyrimid in-3-yl]carbamate Synthesis takes place in analogy to Example 29f) (Method B) starting from N-{2-(4 chlorophenyl)-1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl}-3-(2-chloro-4 5 trifluoromethoxybenzenesulfonylamino)-2-methanesulfonylaminopropionamide. The desired product is obtained with MW = 742.12 (calculated, monoisotopic); measured value (M+H)*: 743.14 d) 3-Amino-6-(4-chlorobenzyl)-1-(2-chloro-5-trifluoromethoxybenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-ajpyrimidine-4,7-dione 10 Synthesis takes place in analogy to Example 29g) (Method B) starting from benzyl [6-(4-chlorobenzyl)-1 -(2-chloro-4-trifluoromethoxybenzenesulfonyl)-8-isopropyl 4,7-d ioxooctahyd ropyrazino[1,2-a]pyrimid in-3-yl]carbamate. The desired product is obtained with MW = 608.09 (calculated, monoisotopic); measured value (M+H)*: 609.07 15 e) N-[6-(4-Chlorobenzyl)-1 -(2-chloro-4-trifluoromethoxybenzenesulfonyl)-8 isopropyl-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide. Synthesis takes place in analogy to Example 21 h) starting from 3-amino-6-(4 chlorobenzyl)-1 -(2-chloro-4-trifluoromethoxybenzenesulfonyl)-8 20 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 650.1 (calculated, monoisotopic); measured value (M+H)*: 651.09 Example 93 25 N-[6-(4-Chlorobenzyl)-1 -(2-chloro-4-trifluoromethoxybenzenesulfonyl)-8-isopropyl 4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide 101 Structure: F FON N Ci 0 IrI0 N 0 Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2-chloro-4-trifluoromethoxybenzenesulfonyl)-8 5 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 676.11 (calculated, monoisotopic); measured value (M+H)*: 677.13 Example 94 10 N-[6-(4-Chlorobenzyl)-1 -(2-chloro-4-trifluoromethoxybenzenesulfonyl)-8-isopropyl 4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide Structure: F F oo N ci 21 N N ci 0 Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(4 15 chlorobenzyl)-1 -(2-chloro-4-trifluoromethoxybenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 690.13 (calculated, monoisotopic); measured value (M+H)*: 691.13 20 Example 95 1 -tert-Butyl-3-[6-(4-chlorobenzyl)-1 -(2-chloro-4-trifluoromethoxybenzenesulfonyl) 8-isopropyl-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]u rea 102 Structure: F F*O N0 N 0 CI 'N N ci o 0 N Synthesis takes place in analogy to Example 28 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2-chloro-4-trifluoromethoxybenzenesulfonyl)-8 5 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 707.16 (calculated, monoisotopic); measured value (M+Na)*: 730.14 Example 96 10 N-[6-(4-Chlorobenzyl)-1 -(2-chloro-4-trifluoromethoxybenzenesulfonyl)-8-isopropyl 4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide Structure: F F ON 0Cl F //0 " 11 N N: cl 0 0 o's \ 15 Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2-chloro-4-trifluoromethoxybenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 686.07 (calculated, monoisotopic); measured value (M+H)*: 20 687.0 103 Example 97 C1 c N 0 CI N N C F O0 N FOO 0 5 a) Benzyl [1-{2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl carbamoyl}-2-(4-chloro-2-fluorobenzenesulfonylamino)ethyl]carbamate Synthesis takes place in analogy to Example 87b) starting from 4-chloro-2 fluorobenzenesulfonyl chloride. The desired product is obtained with MW = 768.22 (calculated, monoisotopic); measured value (M+Na)*: 791.0 10 b) Benzyl [6-(4-chlorobenzyl)-1 -(4-chloro-2-fluorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahyd ropyrazino[1,2-a]pyrimidin-3-yl]carbamate Synthesis takes place in analogy to Example 29f) (Method B) starting from N-{2-(4 chlorophenyl)-1 -[(2,2-diethoxyethyl)isopropycarbamoyl]ethyl}-3-(4-chloro-2 15 fluorobenzenesulfonylamino)-2-methanesulfonylaminopropionamide. The desired product is obtained with MW = 676.13 (calculated, monoisotopic); measured value (M+H)*: 677.14 c) 3-Amino-6-(4-chlorobenzyl)-1-(4-chloro-2-fluorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 20 Synthesis takes place in analogy to Example 29g) (Method B) starting from benzyl [6-(4-chlorobenzyl)-1 -(4-chloro-2-fluorobenzenesulfonyl)-8-isopropyl-4,7 d ioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 542.1 (calculated, monoisotopic); measured value (M+H)*: 543.1 25 104 d) N-[6-(4-Chlorobenzyl)-1-(4-chloro-2-fluorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide. Synthesis takes place in analogy to Example 21 h) starting from 3-amino-6-(4 chlorobenzyl)-1 -(4-chloro-2-fluorobenzenesulfonyl)-8 5 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 584.11 (calculated, monoisotopic); measured value (M+H)*:585.1 Example 98 10 N-[6-(4-Chlorobenzyl)-1 -(4-chloro-2-fluorobenzenesufonyl)-8-isopropyl-4,7 d ioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Structure: ciN 0 ci /P N N F 0 O N Synthesis takes place in analogy to Example 29e) starting from 3-amino-6-(4 15 chlorobenzyl)-1 -(4-chloro-2-fluorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 610.12 (calculated, monoisotopic); measured value (M+H)*: 611.14 20 Example 99 N-[6-(4-Chlorobenzyl)-1 -(4-chloro-2-fluorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide Structure: 105 0 N 0 Ci1 N N F 0 O N Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(4 chlorobenzyl)-1 -(4-chloro-2-fluorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 5 obtained with MW = 624.12 (calculated, monoisotopic); measured value (M+H)*: 625.14 Example 100 1 -tert-Butyl-3-[6-(4-chlorobenzyl)-1 -(4-chloro-2-fluorobenzenesulfonyl)-8-isopropyl 10 4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]urea Structure: ciN o ci N N cl F O N N Synthesis takes place in analogy to Example 28 starting from 3-amino-6-(4 chlorobenzyl)-1 -(4-chloro-2-fluorobenzenesulfonyl)-8 15 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 641.16 (calculated, monoisotopic); measured value (M+Na)*: 664.14 106 Example 101 N-[6-(4-Chlorobenzyl)-1 -(4-chloro-2-fluorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide Structure: ci CI -* 0 CI // N N F o N,0 N, -S. 5 0,s Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 chlorobenzyl)-1 -(4-chloro-2-fluorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 620.07 (calculated, monoisotopic); measured value (M+H)*: 10 621.0 Example 102 N-[6-(4-Chlorobenzyl)-1 -(2,5-dimethoxybenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide 15 Structure: c1 0 N N 0 0 0, \ a) 2-Benzyloxycarbonylamino-3-(2,5-dimethoxybenzenesulfonylamino)propionic acid 20 Synthesis takes place in analogy to Example 21d) starting from 2,5 dimethoxybenzenesulfonyl chloride. The desired product is obtained with MW = 438.46 (calculated, monoisotopic); measured value (M+H)*: 439.1 107 b) N-{2-(4-Chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl}-3-(2,5 dimethoxybenzenesulfonylamino)-2-methanesulfonylaminopropionamide Synthesis takes place in analogy to Example 21e) starting from 2 benzyloxycarbonylamino-3-(2,5-dimethoxybenzenesulfonylamino)propionic acid. 5 The desired product is obtained with MW = 777.34 (calculated, monoisotopic); measured value (M-C 2
H
6 O+H)*: 731.9 c) Benzyl [6-(4-chlorobenzyl)-1 -(2,5-dimethoxybenzenesufonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate Synthesis takes place in analogy to Example 21f) starting from N-{2-(4 10 chlorophenyl)-1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl}-3-(2,5 dimethoxybenzenesulfonylamino)-2-methanesulfonylaminopropionamide. The desired product is obtained with MW = 684 (calculated, monoisotopic); measured value (M+H)*: 685.38 15 d) 3-Amino-6-(4-chlorobenzyl)-1-(2,5-dimethoxybenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 21g) starting from benzyl [6-(4 chlorobenzyl)-1 -(2,5-dimethoxybenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is 20 obtained with MW = 550 (calculated, monoisotopic); measured value (M+H)*: 551.15 e) 3-Amino-6-(4-chlorobenzyl)-1-(2,5-dimethoxybenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 25 Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,5-dimethoxybenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 628.14 (calculated, monoisotopic); measured value (M+H)*: 629.15 30 108 Example 103 N-[6-(4-Chlorobenzyl)-1 -(3-fluorobenzenesulfonyl)-8-isopropyl-4,7-dioxooctahydro pyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide Structure: 5 c1 N ' 0 //N F 0 o N O=S / so a) 2-Benzyloxycarbonylamino-3-(3-fluorobenzenesulfonylamino)propionic acid Synthesis takes place in analogy to Example 21d) starting from 3-fluorobenzene sulfonyl chloride. The desired product is obtained with MW = 396.40 (calculated, 10 monoisotopic); measured value (M+H)*: 397.10 b) N-{2-(4-Chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl}-3-(3 fluorobenzenesulfonylamino)-2-methanesulfonylaminopropionamide Synthesis takes place in analogy to Example 21 e) starting from 2 15 benzyloxycarbonylamino-3-(3-fluorobenzenesulfonylamino)propionic acid. The desired product is obtained with MW = 735.28 (calculated, monoisotopic); measured value (M-C 2
H
6 O+H)*: 689.8 c) Benzyl [6-(4-chlorobenzyl)-1 -(3-fluorobenzenesulfonyl)-8-isopropyl-4,7-dioxo octahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate 20 Synthesis takes place in analogy to Example 21f) starting from N-{2-(4 chlorophenyl)-1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl}-3-(3 fluorobenzenesulfonylamino)-2-methanesulfonylaminopropionamide. The desired product is obtained with MW = 642 (calculated, monoisotopic); measured value (M+H)*: 643.31 25 109 d) 3-Amino-6-(4-chlorobenzyl)-1-(3-fluorobenzenesulfonyl)-8-isopropylhexahydro pyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 21g) starting from benzyl [6-(4 chlorobenzyl)-1 -(3-fluorobenzenesulfonyl)-8-isopropyl-4,7 5 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 508 (calculated, monoisotopic); measured value (M+H)*: 509.15 e) 3-Amino-6-(4-chlorobenzyl)-1-(3-fluorobenzenesulfonyl)-8-isopropylhexahydro 10 pyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 chlorobenzyl)-1 -(3-fluorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 586.11 (calculated, monoisotopic); measured value (M+H)*: 587.41 15 Example 104 N-[1 -Benzenesulfonyl-6-(4-chlorobenzyl)-8-isopropyl-4,7 d ioxooctahyd ropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide Structure: 20 Cl N N N 0 0 N / '0 a) 2-Benzyloxycarbonylamino-3-(benzenesulfonylamino)propionic acid Synthesis takes place in analogy to Example 21d) starting from benzenesulfonyl chloride. The desired product is obtained with MW = 378.41 (calculated, 25 monoisotopic); measured value (M+H)*: 397.10 110 b) N-{2-(4-Chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl}-3 (benzenesulfonylamino)-2-methanesulfonylaminopropionamide Synthesis takes place in analogy to Example 21e) starting from 2 5 benzyloxycarbonylamino-3-(benzenesulfonylamino)propionic acid. The desired product is obtained with MW = 717.29 (calculated, monoisotopic); measured value
(M-C
2 HeO+H)*: 671.7 c) Benzyl [6-(4-chlorobenzyl)-1-(benzenesulfonyl)-8-isopropyl-4,7-dioxooctahydro pyrazino[1,2-a]pyrimidin-3-yl]carbamate 10 Synthesis takes place in analogy to Example 21f) starting from N-{2-(4 chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl}-3 (benzenesulfonylamino)-2-methanesulfonylaminopropionamide. The desired product is obtained with MW = 642 (calculated, monoisotopic); measured value (M+H)*: 625.33 15 d) 3-Amino-6-(4-chlorobenzyl)-1-(benzenesulfonyl)-8-isopropylhexahydro pyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 21g) starting from benzyl [6-(4 chlorobenzyl)-1 -(benzenesulfonyl)-8-isopropyl-4,7-dioxooctahydropyrazino[1,2 20 a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 490 (calculated, monoisotopic); measured value (M+H)*: 491.10 e) 3-Amino-6-(4-chlorobenzyl)-1-(benzenesulfonyl)-8-isopropylhexahydro pyrazino[1,2-a]pyrimidine-4,7-dione 25 Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 chlorobenzyl)-1-(benzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine 4,7-dione. The desired product is obtained with MW = 568.12 (calculated, monoisotopic); measured value (M+H)*: 569.13 30 Example 105 N-[6-(4-Chlorobenzyl)- 1 -(2-fluorobenzenesulfonyl)-8-isopropyl-4,7-dioxooctahydro pyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide 111 Structure: CI N F 00 F N% 0 a) 2-Benzyloxycarbonylamino-3-(2-fluorobenzenesulfonylamino)propionic acid 5 Synthesis takes place in analogy to Example 21d) starting from 2 fluorobenzenesulfonyl chloride. The desired product is obtained with MW = 396.40 (calculated, monoisotopic); measured value (M+H)*: 397.10 b) N-{2-(4-Chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl}-3-(2 10 fluorobenzenesulfonylamino)-2-methanesulfonylaminopropionamide Synthesis takes place in analogy to Example 21e) starting from 2 benzyloxycarbonylamino-3-(2-fluorobenzenesulfonylamino)propionic acid. The desired product is obtained with MW = 735.28 (calculated, monoisotopic); measured value (M-C 2
H
6 0+H)*: 689.7 15 c) Benzyl [6-(4-chlorobenzyl)-1 -(2-fluorobenzenesufonyl)-8-isopropyl-4,7-dioxo octahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate Synthesis takes place in analogy to Example 21f) starting from N-{2-(4 chlorophenyl)-1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl}-3-(2 fluorobenzenesulfonylamino)-2-methanesulfonylaminopropionamide. The desired 20 product is obtained with MW = 642 (calculated, monoisotopic); measured value (M+H)*: 643.31 d) 3-Amino-6-(4-chlorobenzyl)-1-(2-fluorobenzenesulfonyl)-8-isopropylhexahydro pyrazino[1,2-a]pyrimidine-4,7-dione 112 Synthesis takes place in analogy to Example 21g) starting from benzyl [6-(4 chlorobenzyl)-1 -(2-fluorobenzenesulfonyl)-8-isopropyl-4,7 d ioxooctahyd ropyrazino[ 1,2-a]pyrimid in-3-yl]carbamate. The desired product is obtained with MW = 508 (calculated, monoisotopic); measured value (M+H)*: 5 509.15 e) 3-Amino-6-(4-chlorobenzyl)-1-(2-fluorobenzenesufonyl)-8-isopropylhexa hydro pyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 10 chlorobenzyl)-1 -(2-fluorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 586.11 (calculated, monoisotopic); measured value (M+H)*: 587.12 Example 106 15 N-[6-(4-Chlorobenzyl)-1 -(2,4-d ifluorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide Structure: Cl
N
0 F 0 O N 0 0 0 20 a) 2-Benzyloxycarbonylamino-3-(2,4-difluorobenzenesulfonylamino)propionic acid Synthesis takes place in analogy to Example 21d) starting from 2,4 difluorobenzenesulfonyl chloride. The desired product is obtained with MW = 414.40 (calculated, monoisotopic); measured value (M+H)*: 415.10 113 b) N-{2-(4-Chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl}-3-(2,4 difluorobenzenesulfonylamino)-2-methanesulfonylaminopropionamide Synthesis takes place in analogy to Example 21e) starting from 2 benzyloxycarbonylamino-3-(2,4-difluorobenzenesulfonylamino)propionic acid. The 5 desired product is obtained with MW = 753.27 (calculated, monoisotopic); measured value (M-C 2
H
6 O+H)*: 707.7 c) Benzyl [6-(4-chlorobenzyl)-1-(2,4-difluorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate Synthesis takes place in analogy to Example 21f) starting from N-{2-(4 10 chlorophenyl)-1 -[(2,2-d iethoxyethyl)isopropylcarbamoyl]ethyl}-3-(2,4 difluorobenzenesulfonylamino)-2-methanesulfonylaminopropionamide. The desired product is obtained with MW = 660 (calculated, monoisotopic); measured value (M+H)*: 661.32 15 d) 3-Amino-6-(4-chlorobenzyl)-1-(2,4-d ifluorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 21g) starting from benzyl [6-(4 chlorobenzyl)-1 -(2,4-difluorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is 20 obtained with MW = 526 (calculated, monoisotopic); measured value (M+H)*: 527.10 e) 3-Amino-6-(4-chlorobenzyl)-1-(2,4-difluorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 25 Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-difluorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 604.1 (calculated, monoisotopic); measured value (M+H)*: 605.11 30 Example 107 N-[6-(4-Chlorobenzyl)-1 -(3,4-difluorobenzenesulfonyl)-8-isopropyl-4,7 d ioxooctahydropyrazino[1,2-ajpyrimidin-3-yl] methanesulfonamide 114 Structure: C1 N F0 F / N // N F o N ,s=o 5 a) 2-Benzyloxycarbonylamino-3-(3,4-difluorobenzenesulfonylamino)propionic acid Synthesis takes place in analogy to Example 21d) starting from 3,4-difluoro benzenesulfonyl chloride. The desired product is obtained with MW = 414.40 (calculated, monoisotopic); measured value (M+H)*: 415.10 10 b) N-{2-(4-Chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl}-3-(3,4 difluorobenzenesulfonylamino)-2-methanesulfonylaminopropionamide Synthesis takes place in analogy to Example 21e) starting from 2 benzyloxycarbonylamino-3-(3,4-difluorobenzenesulfonylamino)propionic acid. The desired product is obtained with MW = 753.27 (calculated, monoisotopic); 15 measured value (M-C 2
H
6 O+H)*: 707.7 c) Benzyl [6-(4-chlorobenzyl)-1 -(3,4-difluorobenzenesulfonyl)-8-isopropyl-4,7 d ioxooctahydropyrazino[1,2-a]pyrimid in-3-yl]carbamate Synthesis takes place in analogy to Example 21f) starting from N-{2-(4 chlorophenyl)-1-[(2,2-diethoxyethyl )isopropylcarbamoyl]ethyl}-3-(3,4 20 difluorobenzenesulfonylamino)-2-methanesulfonylaminopropionamide. The desired product is obtained with MW = 660 (calculated, monoisotopic); measured value (M+H)*: 661.31 d) 3-Amino-6-(4-chlorobenzyl)-1-(3,4-difluorobenzenesulfonyl)-8 25 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 115 Synthesis takes place in analogy to Example 21g) starting from benzyl [6-(4 chlorobenzyl)-1 -(3,4-difluorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 526 (calculated, monoisotopic); measured value (M+H)*: 5 527.10 e) 3-Amino-6-(4-chlorobenzyl)-1-(3,4-difluorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 10 chlorobenzyl)-1 -(3,4-difluorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 604.1 (calculated, monoisotopic); measured value (M+H)*: 605.11 Example 108 F ci YF N F~ ci N N ci 0 N 15 a) 9H-fluoren-9-ylmethyl [1-[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-(4-trifluoro methylphenyl)ethyl]carbamate Synthesis takes place in analogy to Example 29a) (Method B) starting from N Fmoc-4-CF 3 -Phe-OH. The desired product is obtained with MW = 612.28 20 (calculated, monoisotopic); measured value (M+Na)*: 635.28 b) 2-Amino-3-(4-trifluoromethylphenyl)-N-(2,2-diethoxyethyl)-N isopropylpropionamide Synthesis takes place in analogy to Example 29b) (Method B) starting from 9H 25 fluoren-9-ylmethyl [1-[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-(4- 116 trifluoromethylphenyl)ethyl]carbamate. The desired product is obtained with MW = 390.21 (calculated, monoisotopic); measured value (M+Na)*: 413.22 c) 9H-Fluoren-9-ylmethyl (2-benzyloxycarbonylamino-2-{2-(4 5 trifluoromethylphenyl)-1-[(2,2 diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate Synthesis took place in analogy to Example 29c) (Method B) starting from 2 amino-3-(4-trifluoromethylphenyl)-N-(2,2-diethoxyethyl)-N-isopropylpropionamide. The desired product is obtained with MW = 832.37 (calculated, monoisotopic); 10 measured value (M+Na)*: 855.0 d) Benzyl (2-amino-1-{2-(4-trifluoromethylphenyl)-1-[(2,2 d iethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate Synthesis took place in analogy to Example 29d) (Method B) starting from 9H 15 fluoren-9-ylmethyl (2-benzyloxycarbonylamino-2-{2-(4-trifluoromethylphenyl)-1 [(2,2-diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate. The desired product is obtained with MW = 610.30 (calculated, monoisotopic); measured value (M+Na)*: 611.33 20 e) Benzyl [1 -{2-(4-trifluoromethylphenyl)-1 -[(2,2-d iethoxyethyl)isopropylcarbamoyl] ethylcarbamoyl}-2-(2,4-dichlorobenzenesulfonylamino)ethyl]carbamate Synthesis took place in analogy to Example 29e) (Method B) starting from benzyl (2-amino-1 -{2-(4-trifluoromethylphenyl)-1 -[(2,2 diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate. The desired 25 product is obtained with MW = 818.21 (calculated, monoisotopic); measured value (M+Na)*: 841.2. f) Benzyl [6-(4-trifluoromethylbenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-isopropyl 4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate 30 Synthesis took place in analogy to Example 29f) (Method B) starting from benzyl [1 -{2-(4-trifluoromethylphenyl)-1 -[(2,2 diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}-2-(2,4- 117 dichlorobenzenesulfonylamino)ethyl]carbamate. The desired product is obtained with MW = 726.13 (calculated, monoisotopic); measured value (M+H)*: 727.14 g) 3-Amino-6-(4-trifluoromethylbenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8 5 isopropylhexahydropyrazino[1 ,2-a]pyrimidine-4,7-dione Synthesis took place in analogy to Example 29g) (Method B) starting from benzyl [6-(4-trifluoromethylbenzyl)-1 -(2,4-d ichlorobenzenesufonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 592.09 (calculated, monoisotopic); measured value (M+Na)*: 10 593.09 h) N-[6-(4-Trifluoromethylbenzyl)-1-(2,4-d ichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide Synthesis takes place in analogy to Example 21 h) starting from 3-amino-6-(4 15 trifluoromethylbenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 634.10 (calculated, monoisotopic); measured value (M+H)*: 635.12 20 Example 109 N-[1 -(2,4-Dichlorobenzenesufonyl)-8-isopropyl-4,7-d ioxo-6-(4 trifluoromethylbenzyl)octahydropyrazino[1,2-a]pyrimidin-3 yl]cyclopropanecarboxamide Structure: F ci YF NN ci N NF ci 0 25 118 Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(4 trifluoromethylbenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 660.12 (calculated, monoisotopic); measured value (M+H)*: 5 661.13 Example 110 N-[1 -(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-(4 trifluoromethylbenzyl)octahydropyrazino[1,2-a]pyrimidin-3 10 yl]cyclobutanecarboxamide Structure: F ci N F 'IN N IF ci 0 0 N Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(4 trifluoromethylbenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 15 obtained with MW = 674.13 (calculated, monoisotopic); measured value (M+H)*: 675.15 Example 111 N-[1 -(2,4-Dichlorobenzenesufonyl)-8-isopropyl-4,7-d ioxo-6-(4 20 trifluoromethylbenzyl)octahydropyrazino[1,2-a]pyrimidin-3 yl]cyclopentanecarboxamide 119 Structure: F CI - N 0 F ciN N F CI 0 1r1 N ci 0 Synthesis takes place in analogy to Example 31 starting from 3-amino-6-(4 trifluoromethylbenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8 5 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 688.15 (calculated, monoisotopic); measured value (M+H)*: 689.16 Example 112 10 N-[1 -(2,4-Dichlorobenzenesufonyl)-8-isopropyl-4,7-dioxo-6-(4 trifluoromethylbenzyl)octahydropyrazino[1 ,2-a]pyrimid in-3-yl]pyrrolid ine-2 carboxamide Structure: F ci / F /10IF / N N ci 0 0 N N Synthesis takes place in analogy to Example 40 starting from 3-amino-6-(4 15 trifluoromethylbenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 689.15 (calculated, monoisotopic); measured value (M+H)*: 690.10.
120 Example 113 N-[1 -(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-(4 trifluoromethylbenzyl)octahydropyrazino[1,2-a]pyrimid in-3-yl]-4 dimethylaminobenzamide 5 Structure: F C N 00 FF c" N N cI 0 N N Synthesis takes place in analogy to Example 25 starting from 3-amino-6-(4 trifluoromethylbenzyl)-l -(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 10 obtained with MW = 739.16 (calculated, monoisotopic); measured value (M+H)*: 740.15 Example 114 1 -tert-Butyl-3-[1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-(4-trifluoro 15 methylbenzyl)octahydropyrazino[1,2-a]pyrimidin-3-yl]urea Structure: F ci F N 0 // N N: ci 0 >0 N Synthesis takes place in analogy to Example 28 starting from 3-amino-6-(4 trifluoromethylbenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8 20 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 121 obtained with MW = 691.16 (calculated, monoisotopic); measured value (M+H)*: 692.18 Example 115 5 N-[1 -(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-(4 trifluoromethylbenzyl)octahydropyrazino[1,2-ajpyrimidin-3-yl]methanesulfonamide Structure: F "N N F ci 0 Ns 0 o \ Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 10 trifluoromethylbenzyl)-1 -(2,4-d ichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 670.07 (calculated, monoisotopic); measured value (M+H)*: 671.08 15 Example 116 N-[1 -(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-4,7-d ioxo-6-(4 trifluoromethylbenzyl)octahydropyrazino[1,2-a]pyrimidin-3 yl]cyclopropanecarboxamide Structure: F ci / N NN F "'N "N ci 0 N o 20 Synthesis takes place in analogy to Example 27 starting from 3-amino-6-(4 trifluoromethylbenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8- 122 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 696.09 (calculated, monoisotopic); measured value (M+H)*: 697.0 5 Example 117 1-(2,4-Dichlorobenzenesulfonyl)-3-dimethylamino-8-isopropyl-6-(4-trifluoromethyl benzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: F N 0N F SN N C, 0 -- , N 1 10 Synthesis takes place in analogy to Example 72 starting from 3-amino-6-(4 trifluoromethylbenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 620.12 (calculated, monoisotopic); measured value (M+H)*: 621.09 15 Example 118 3-Azetidin-1 -yl-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-6-(4 trifluoromethylbenzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: F cI N 0F 1" F CI 0 100 N 20 Synthesis takes place in analogy to Example 73 starting from 3-amino-6-(4 trifluoromethylbenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8- 123 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 632.12 (calculated, monoisotopic); measured value (M+H)*: 633.0 5 Example 119 1-(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-3-pyrrolidin-1 -yl-6-(4-trifluoromethyl benzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: F / N N ci 0 0 10 Synthesis takes place in analogy to Example 74 starting from 3-amino-6-(4 trifluoromethylbenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 646.14 (calculated, monoisotopic); measured value (M+H)*: 647.14 15 Example 120 1-(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-3-piperidin-1-yl-6-(4-trifluoromethyl benzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ci F N O F cl N NF ci 0 200 20 0 Synthesis takes place in analogy to Example 59 starting from 3-amino-6-(4 trifluoromethylbenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8- 124 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 660.16 (calculated, monoisotopic); measured value (M+H)*: 661.13 5 Example 121 1-(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-3-morpholin-4-yl-6-(4-trifluoromethyl benzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: F // N N ci 0 (N) 0 10 Synthesis takes place in analogy to Example 60 starting from 3-amino-6-(4 trifluoromethylbenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 662.13 (calculated, monoisotopic); measured value (M+H)*: 663.07 15 Example 122 /0 N N N CI ci 0 N a) 9H-Fluoren-9-ylmethyl [1-[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-(3 chlorophenyl)ethyl]carbamate 125 Synthesis takes place in analogy to Example 29a) (Method B) starting from N Fmoc-3-CI-Phe-OH. The desired product is obtained with MW = 578.25 (calculated, monoisotopic); measured value (M+H)*: 579.27 5 b) 2-Amino-3-(3-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropylpropionamide Synthesis takes place in analogy to Example 29b) (Method B) starting from 9H fluoren-9-ylmethyl [1-[(2,2-diethoxyethyl )isopropylcarbamoyl]-2-(3 chlorophenyl)ethyl]carbamate. The desired product is obtained with MW = 356.19 (calculated, monoisotopic); measured value (M+Na)*: 379.18 10 c) 9H-Fluoren-9-ylmethyl (2-benzyloxycarbonylamino-2-{2-(3-chlorophenyl)-1 [(2,2-d iethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate Synthesis took place in analogy to Example 29c) (Method B) starting from 2 amino-3-(3-chlorophenyl)-N-(2,2-diethoxyethyl)-N-isopropylpropionamide. The 15 desired product is obtained with MW = 798.34 (calculated, monoisotopic); measured value (M+H)*: 799.35 d) Benzyl (2-amino-1-{2-(3-chlorophenyl)-1-[(2,2 d iethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate 20 Synthesis took place in analogy to Example 29d) (Method B) starting from 9H fluoren-9-ylmethyl (2-benzyloxycarbonylamino-2-{2-(3-chlorophenyl)-1-[(2,2 diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate. The desired product is obtained with MW = 576.27 (calculated, monoisotopic); measured value (M+H)*: 577.22 25 e) Benzyl [1 -{2-(3-chlorophenyl)-1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl carbamoyl}-2-(2,4-dichlorobenzenesulfonylamino)ethyl]carbamate Synthesis took place in analogy to Example 29e) (Method B) starting from benzyl (2-amino-1 -{2-(3-chlorophenyl)-1 -[(2,2-d iethoxyethyl)isopropylcarbamoyl]ethyl 30 carbamoyl}ethyl)carbamate. The desired product is obtained with MW = 784.19 (calculated, monoisotopic); measured value (M+H)*: 785.18 126 f) Benzyl [6-(3-chlorobenzyl)- 1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-ajpyrimidin-3-yl]carbamate Synthesis took place in analogy to Example 29f) (Method B) starting from benzyl [1 -{2-(3-chlorophenyl)-1 -[(2,2-diethoxyethyl )isopropylcarbamoyl]ethylcarbamoyl}-2 5 (2,4-dichlorobenzenesulfonylamino)ethyl]carbamate. The desired product is obtained with MW = 692.10 (calculated, monoisotopic); measured value (M+H)*: 693.08 g) 3-Amino-6-(3-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexa 10 hydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis took place in analogy to Example 29g) (Method B) starting from benzyl [6-(3-chlorobenzyl)-1 -(2,4-d ichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 558.07 (calculated, monoisotopic); measured value (M+H)*: 15 559.07 h) N-[6-(3-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide Synthesis takes place in analogy to Example 21 h) starting from 3-amino-6-(3 20 chlorobenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 600.08 (calculated, monoisotopic); measured value (M+H)*: 601.07 Example 123 25 N-[6-(3-Chlorobenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide 127 Structure: ci C I0 N1 0 ~~ N N ] CI C, 0 IT- N Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(3 5 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 626.09 (calculated, monoisotopic); measured value (M+H)*: 627.08 Example 124 10 N-[6-(3-Chlorobenzyl)-1 -(2,4-d ichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide Structure: N C "N N CI CI 0 N 15 Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(3 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 640.11 (calculated, monoisotopic); measured value (M+H)*: 641.08 128 Example 125 N-[6-(3-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide Structure: "N N CI ci o N,0 N 5 Synthesis takes place in analogy to Example 31 starting from 3-amino-6-(3 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 654.12 10 (calculated, monoisotopic); measured value (M+H)*: 655.09 Example 126 N-[6-(3-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-4-dimethylaminobenzamide 15 Structure: ci N CN i N N C' 0 1Y1 N -N l Synthesis takes place in analogy to Example 25 starting from 3-amino-6-(3 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 705.13 20 (calculated, monoisotopic); measured value (M+H)*: 706.10 129 Example 127 1 -tert-Butyl-3-[6-(3-chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[l ,2-a]pyrimidin-3-yljurea 5 Structure: ci cl o "'N N CCI CI 0 I - N --N Synthesis takes place in analogy to Example 28 starting from 3-amino-6-(3 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 657.13 10 (calculated, monoisotopic); measured value (M+H)*: 658.11 Example 128 N-[6-(3-Chlorobenzyl)-1 -(2,4-d ichlorobenzenesufonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide 15 Structure: NN N0 N N cI cN 0 N0 o* \ Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(3 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 636.04 20 (calculated, monoisotopic); measured value (M+H)*: 637.03 130 Example 129 6-(3-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-3-dimethylamino-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 5 Structure: C1 N N CI C' 0 Synthesis takes place in analogy to Example 72 starting from 3-amino-6-(3 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 586.10 10 (calculated, monoisotopic); measured value (M+H)*: 587.09 Example 130 6-(3-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-3-pyrrolidin-1 ylhexahydropyrazino[1 ,2-a]pyrimidine-4,7-dione 15 Structure: ci N N cI ci 0 0 Synthesis takes place in analogy to Example 74 starting from 3-amino-6-(3 chlorobenzyl)-1 -(2,4-d ichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 20 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 612.11 (calculated, monoisotopic); measured value (M+H)*: 613.10 131 Example 131 6-(3-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-3-piperidin-1 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: N, N N CI ci 0 1- 0 5 0 Synthesis takes place in analogy to Example 59 starting from 3-amino-6-(3 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 626.13 (calculated, monoisotopic); measured value (M+H)*: 627.13 10 Example 132 6-(3-Chlorobenzyl)-1 -(2,4-d ichlorobenzenesulfonyl)-8-isopropyl-3-morpholin-4 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ci N N N Cl cl 00 (N) 150 Synthesis takes place in analogy to Example 60 starting from 3-amino-6-(3 chlorobenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 628.11 (calculated, monoisotopic); measured value (M+H)*: 629.09 20 132 Example 133 ci N o.. N, 0 . // N N ci 0 a) 9H-Fluoren-9-ylmethyl [1-[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-(4 5 fluorophenyl)ethyl]carbamate Synthesis takes place in analogy to Example 29a) (Method B) starting from N Fmoc-4-F-Phe-OH. The desired product is obtained with MW = 562.28 (calculated, monoisotopic); measured value (M+H)*: 563.27 10 b) 2-Amino-3-(4-fluorophenyl)-N-(2,2-diethoxyethyl)-N-isopropylpropionamide Synthesis takes place in analogy to Example 29b) (Method B) starting from 9H fluoren-9-ylmethyl [1-[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-(4 fluorophenyl)ethyl]carbamate. The desired product is obtained with MW = 340.22 (calculated, monoisotopic); measured value (M+H)*: 341.20 15 c) 9H-Fluoren-9-ylmethyl (2-benzyloxycarbonylamino-2-{2-(4-fluorophenyl)-1-[(2,2 diethoxyethyl )isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate Synthesis took place in analogy to Example 29c) (Method B) starting from 2 amino-3-(4-fluorophenyl)-N-(2,2-diethoxyethyl)-N-isopropylpropionamide. The 20 desired product is obtained with MW = 782.37 (calculated, monoisotopic); measured value (M+Na)*: 805.37 d) Benzyl (2-amino-1-{2-(4-fluorophenyl)-1-[(2,2 d iethoxyethyl)isopro pylcarba moyl]ethylcarba moyl}ethyl)carbamate 25 Synthesis took place in analogy to Example 29d) (Method B) starting from 9H fluoren-9-ylmethyl (2-benzyloxycarbonylamino-2-{2-(4-fluorophenyl)-1-[(2,2 d iethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate. The desired 133 product is obtained with MW = 560.30 (calculated, monoisotopic); measured value (M+H)*: 561.31 e) Benzyl [1-{2-(4-fluorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl 5 carbamoyl}-2-(2,4-dichlorobenzenesulfonylamino)ethyl]carbamate Synthesis took place in analogy to Example 29e) (Method B) starting from benzyl (2-amino-1 -{2-(4-fluorophenyl)-1 -[(2,2-d iethoxyethyl)isopropylcarbamoyl]ethyl carbamoyl}ethyl)carbamate. The desired product is obtained with MW = 768.22 (calculated, monoisotopic); measured value (M+Na)*: 791.23 10 f) Benzyl [6-(4-fluorobenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-isopropyl-4,7 d ioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate Synthesis took place in analogy to Example 29f) (Method B) starting from benzyl [1 -{2-(4-fluorophenyl)-1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}-2 15 (2,4-d ichlorobenzenesulfonylamino)ethyl]carbamate. The desired product is obtained with MW = 676.13 (calculated, monoisotopic); measured value (M+H)*: 677.1 g) 3-Amino-6-(4-fluorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexa 20 hydropyrazino[1,2-a]pyrimidine-4,7-d ione Synthesis took place in analogy to Example 29g) (Method B) starting from benzyl [6-(4-fluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 d ioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 542.1 (calculated, monoisotopic); measured value (M+H)*: 25 543.12 h) N-[6-(4-Fluorobenzyl)-1-(2,4-d ichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide Synthesis takes place in analogy to Example 21 h) starting from 3-amino-6-(4 30 fluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 584.11 (calculated, monoisotopic); measured value (M+H)*: 585.08 134 Example 134 N-[1 -(2,4-Dichlorobenzenesulfonyl)-6-(4-fluorobenzyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide 5 Structure: ci CI0 NN 0 F N N Ci 0 N 0 Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(4 fluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 10 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 610.12 (calculated, monoisotopic); measured value (M+H)*: 611.09 Example 135 15 N-[1 -(2,4-Dichlorobenzenesulfonyl)-6-(4-fluorobenzyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide Structure: /ci N 0 F "N N a ci 0 010 N =0 Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(4 20 fluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyhexahydropyrazino[1,2- 135 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 624.14 (calculated, monoisotopic); measured value (M+H)*: 625.13 Example 136 5 N-[1 -(2,4-Dichlorobenzenesufonyl)-6-(4-fluorobenzyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide Structure: ci N 0 F // N N ci 0 N e0 10 Synthesis takes place in analogy to Example 31 starting from 3-amino-6-(4 fluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1 ,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 638.15 (calculated, monoisotopic); measured value (M+H)*: 639.14 15 Example 137 N-[1 -(2,4-Dichlorobenzenesufonyl)-6-(4-fluorobenzyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-4-dimethylaminobenzamide Structure: N N F 20S N -NO 20 1 136 Synthesis takes place in analogy to Example 25 starting from 3-amino-6-(4 fluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 689.16 5 (calculated, monoisotopic); measured value (M+H)*: 690.10 Example 138 N-[1 -(2,4-Dichlorobenzenesulfonyl)-6-(4-fluorobenzyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide 10 Structure: ci N 0 F /N NF cl 0 I- Nc O 0 '' . o Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 fluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[l,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 620.07 (calculated, monoisotopic); measured value (M+H)*: 621.04 15 Example 139 1-(2,4-Dichlorobenzenesulfonyl)-3-dimethylamino-6-(4-fluorobenzyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-d ione Structure: ci ci
-
N 0 F / N N F Cl 0 N 20 137 Synthesis takes place in analogy to Example 72 starting from 3-amino-6-(4 fluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 570.13 (calculated, monoisotopic); measured value (M+H)*: 571.09 5 Example 140 3-Azetid in-1 -yl- 1 -(2,4-dichlorobenzenesulfonyl)-6-(4-fluorobenzyl)-8-isopropylhexa hydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: 10 ci ciN 0 F N N ci 0 '0 KN Synthesis takes place in analogy to Example 73 starting from 3-amino-6-(4 fluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 15 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 582.13 (calculated, monoisotopic); measured value (M+H)*: 583.04 Example 141 1 -(2,4-Dichlorobenzenesufonyl)-6-(4-fluorobenzyl)-8-isopropyl-3-pyrrolidin-1 20 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-d ione Structure: ci N 0 F N N ci 0 0 138 Synthesis takes place in analogy to Example 74 starting from 3-amino-6-(4 fluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 596.14 5 (calculated, monoisotopic); measured value (M+H)*: 597.12 Example 142 1 -(2,4-Dichlorobenzenesulfonyl)-6-(4-fluorobenzyl)-8-isopropyl-3-piperidin- 1 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 10 Structure: ciN 0F N N ci 0 0 0 Synthesis takes place in analogy to Example 59 starting from 3-amino-6-(4 fluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[l,2 15 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 610.16 (calculated, monoisotopic); measured value (M+H)*: 611.16 Example 143 1 -(2,4-Dichlorobenzenesufonyl)-6-(4-fluorobenzyl)-8-isopropyl-3-morpholin-4 20 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ci / N N ci 0 (N) 0 139 Synthesis takes place in analogy to Example 60 starting from 3-amino-6-(4 fluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1 ,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 612.14 5 (calculated, monoisotopic); measured value (M+H)*: 613.13 Example 144 ci N N N ci 0 N 0 10 a) 9H-Fluoren-9-ylmethyl [1-[(2,2-d iethoxyethyl)isopropylcarbamoyl]-2-(4 bromophenyl)ethyl]carbamate Synthesis takes place in analogy to Example 29a) (Method B) starting from N Fmoc-4-Br-Phe-OH. The desired product is obtained with MW = 622.20 15 (calculated, monoisotopic); measured value (M+Na)*: 645.30 b) 2-Amino-3-(4-bromophenyl)-N-(2,2-d iethoxyethyl)-N-isopropylpropionamide Synthesis takes place in analogy to Example 29b) (Method B) starting from 9H fluoren-9-ylmethyl [1 -[(2,2-d iethoxyethyl)isopropylcarbamoyl]-2-(4 20 bromophenyl)ethyl]carbamate. The desired product is obtained with MW = 400.14 (calculated, monoisotopic); measured value (M+H)*: 401.10 c) 9H-Fluoren-9-ylmethyl (2-benzyloxycarbonylamino-2-{2-(4-bromophenyl)-1 [(2,2-diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate 25 Synthesis took place in analogy to Example 29c) (Method B) starting from 2 amino-3-(4-bromophenyl)-N-(2,2-diethoxyethyl)-N-isopropylpropionamide. The 140 desired product is obtained with MW = 842.29 (calculated, monoisotopic); measured value (M+Na)*: 865.4 d) Benzyl (2-amino-1-{2-(4-bromophenyl)-1-[(2,2 5 d iethoxyethyl )isopropylcarbamoyl]ethylcarbamoy}ethyl)carbamate Synthesis took place in analogy to Example 29d) (Method B) starting from 9H fluoren-9-ylmethyl (2-benzyloxycarbonylamino-2-{2-(4-bromophenyl)-1-[(2,2 d iethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate. The desired product is obtained with MW = 620.22 (calculated, monoisotopic); measured value 10 (M+H)*: 621.20 e) Benzyl [1-{2-(4-bromophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl carbamoyl}-2-(2,4-d ichlorobenzenesulfonylamino)ethyl]carbamate Synthesis took place in analogy to Example 29e) (Method B) starting from benzyl 15 (2-amino-1 -{2-(4-bromophenyl)-1 -[(2,2-d iethoxyethyl)isopropylcarbamoyl]ethyl carbamoyl}ethyl)carbamate. The desired product is obtained with MW = 828.14 (calculated, monoisotopic); measured value (M+H)*: 829.11 f) Benzyl [6-(4-bromobenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-isopropyl-4,7 20 d ioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate Synthesis took place in analogy to Example 29f) (Method B) starting from benzyl [1 -{2-(4-bromophenyl)-1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}-2 (2,4-dichlorobenzenesulfonylamino)ethyl]carbamate. The desired product is obtained with MW = 736.05 (calculated, monoisotopic); measured value (M+H)*: 25 737.1 g) 3-Amino-6-(4-bromobenzyl)-1-(2,4-d ichlorobenzenesulfonyl)-8-isopropylhexa hydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis took place in analogy to Example 29g) (Method B) starting from benzyl 30 [6-(4-bromobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 d ioxooctahydropyrazino[1 ,2-a]pyrimidin-3-yl]carbamate. The desired product is 141 obtained with MW = 602.02 (calculated, monoisotopic); measured value (M+H)*: 603.01 h) N-[6-(4-Bromobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 5 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide Synthesis takes place in analogy to Example 21 h) starting from 3-amino-6-(4 bromobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 644.03 (calculated, monoisotopic); measured value (M+H)*: 645.0 10 Example 145 N-[6-(4-Bromobenzyl)- 1 -(2,4-d ichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Structure: ci N N N ci 0 N 10 15 Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(4 bromobenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 670.04 (calculated, monoisotopic); measured value (M+H)*: 671.06 20 Example 146 N-[6-(4-Bromobenzyl)-1 -(2,4-d ichlorobenzenesufonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide 142 Structure: N 0 Br SN N C1 0 N O Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(4 bromobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 5 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 684.06 (calculated, monoisotopic); measured value (M+H)*: 685.04 Example 147 N-[6-(4-Bromobenzyl)- 1 -(2,4-d ichlorobenzenesufonyl)-8-isopropyl-4,7 10 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide Structure: ci/0 N 0 Br N N CI 0 0 N e0 Synthesis takes place in analogy to Example 31 starting from 3-amino-6-(4 bromobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 15 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 698.07 (calculated, monoisotopic); measured value (M+H)*: 699.1 143 Example 148 N-[6-(4-Bromobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 d ioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]pyrrolid ine-2-carboxamide Structure: N N Br ci 0 0 N 5 N Synthesis takes place in analogy to Example 40 starting from 3-amino-6-(4 bromobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 699.07 (calculated, monoisotopic); measured value (M+H)*: 700.2 10 Example 149 N-[6-(4-Bromobenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-4-dimethylaminobenzamide Structure: ci N 0 Br 'N N' ci 0 N 15 Synthesis takes place in analogy to Example 25 starting from 3-amino-6-(4 bromobenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-isopropylhexahydropyrazino[1 ,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 749.08 (calculated, monoisotopic); measured value (M+H)*: 750.10 144 Example 150 N-[6-(4-Bromobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]nicotinamide 5 Structure: ci "N N Br ci 0 N e0 N Synthesis takes place in analogy to Example 50 starting from 3-amino-6-(4 bromobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 707.04 10 (calculated, monoisotopic); measured value (M+H)*: 708.07 Example 151 1 -[6-(4-Bromobenzyl)-1 -(2,4-d ichlorobenzenesulfonyl)-8-isopropyl-4,7 d ioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-3-tert-butylurea 15 Structure: cl 0N Br // N N a CI 0 I--I N N Synthesis takes place in analogy to Example 28 starting from 3-amino-6-(4 bromobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 701.08 20 (calculated, monoisotopic); measured value (M+H)*: 702.0 145 Example 152 N-[6-(4-Bromobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide 5 Structure: cl N N 0 Br ci o NNN o 0 Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 bromobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl hexahyd ropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 679.99 (calculated, monoisotopic); measured value (M+H)*: 681.0 10 Example 153 N-[6-(4-Bromobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanesulfonamide Structure: ci N 0 Br cl0 ,O // N N c, 0 11-1 N,0 ,,s 15 Synthesis takes place in analogy to Example 27 starting from 3-amino-6-(4 bromobenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 706.01 (calculated, monoisotopic); measured value (M+H)*: 707.01 20 146 Example 154 6-(4-Bromobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-3-pyrrolidin-1 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: cl N 0Br 'N N ci 0 0 5 Synthesis takes place in analogy to Example 74 starting from 3-amino-6-(4 bromobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 656.06 (calculated, monoisotopic); measured value (M+H)*: 657.06 10 Example 155 cl ciN 0C1 C 0 N a) 9H-Fluoren-9-ylmethyl [1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-(3,4 dichlorophenyl)ethyl]carbamate 15 Synthesis takes place in analogy to Example 29a) (Method B) starting from N Fmoc-3,4-Cl 2 -Phe-OH. The desired product is obtained with MW = 612.22 (calculated, monoisotopic); measured value (M+Na)*: 635.2 b) 2-Amino-3-(3,4-dichlorophenyl)-N-(2,2-d iethoxyethyl)-N-isopropyl propionamide 147 Synthesis takes place in analogy to Example 29b) (Method B) starting from 9H fluoren-9-ylmethyl [1-[(2,2-diethoxyethyl)isopropylcarba moyl]-2-(3,4 dichlorophenyl)ethyl]carbamate. The desired product is obtained with MW = 390.34 (calculated, monoisotopic); measured value (M+Na)*: 391.16 5 c) 9H-Fluoren-9-ylmethyl (2-benzyloxycarbonylamino-2-{2-(3,4-dichlorophenyl)-1 [(2,2-diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate Synthesis took place in analogy to Example 29c) (Method B) starting from 2 amino-3-(3,4-dichlorophenyl)-N-(2,2-d iethoxyethyl)-N-isopropylpropionamide. The 10 desired product is obtained with MW = 832.30 (calculated, monoisotopic); measured value (M+H)*: 833.30 d) Benzyl (2-amino-1-{2-(3,4-dichlorophenyl)-1-[(2,2 d iethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carba mate 15 Synthesis took place in analogy to Example 29d) (Method B) starting from 9H fluoren-9-ylmethyl (2-benzyloxycarbonylamino-2-{2-(3,4-dichlorophenyl)-1-[(2,2 diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate. The desired product is obtained with MW = 610.23 (calculated, monoisotopic); measured value (M+H)*: 611.27 20 e) Benzyl [1-{2-(3,4-dichlorophenyl)-1-[(2,2 d iethoxyethyl)isopropylcarbamoyl]ethylcarba moyl}-2-(2,4 dichlorobenzenesulfonylamino)ethyl]carbamate Synthesis took place in analogy to Example 29e) (Method B) starting from benzyl 25 (2-amino-1 -{2-(3,4-dichlorophenyl)-1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl carbamoyl}ethyl)carbamate. The desired product is obtained with MW = 818.15 (calculated, monoisotopic); measured value (M+H)*: 819.20 f) Benzyl [6-(3,4-dichlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 30 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate Synthesis took place in analogy to Example 29f) (Method B) starting from benzyl [1 -{2-(3,4-dichlorophenyl)-1 -[(2,2- 148 d iethoxyethyl )isopropylcarbamoyl]ethylcarbamoyl}-2-(2,4 dichlorobenzenesulfonylamino)ethyl]carbamate. The desired product is obtained with MW = 726.06 (calculated, monoisotopic); measured value (M+H)*: 727.1 5 g) 3-Amino-6-(3,4-dichlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis took place in analogy to Example 29g) (Method B) starting from benzyl [6-(3,4-d ichlorobenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-isopropyl-4,7 d ioxooctahydropyrazino[l ,2-a]pyrimid in-3-yl]carbamate. The desired product is 10 obtained with MW = 592.03 (calculated, monoisotopic); measured value (M+H)*: 593.00 h) N-[6-(3,4-Dichlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 d ioxooctahydropyrazino[1,2-a]pyrimid in-3-yl]acetamide 15 Synthesis takes place in analogy to Example 21h) starting from 3-amino-6-(3,4 dichlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 634.04 (calculated, monoisotopic); measured value (M+H)*: 635.0 20 Example 156 N-[1 -(2,4-Dichlorobenzenesulfonyl)-6-(3,4-d ichlorobenzyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Structure: N N ci YI-0 N 25 Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(3,4 dichlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 149 obtained with MW = 660.05 (calculated, monoisotopic); measured value (M+H)*: 661.0 Example 157 5 N-[1 -(2,4-Dichlorobenzenesulfonyl)-6-(3,4-dichlorobenzyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide Structure: ci N, 0 C1 N N ci ci 0 0 N C =0 Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(3,4 dichlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8 10 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 674.07 (calculated, monoisotopic); measured value (M+H)*: 675.05 Example 158 15 N-[1 -(2,4-Dichlorobenzenesulfonyl)-6-(3,4-dichlorobenzyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide Structure: ciN cl Yc N N C1 ci 0 0 N Synthesis takes place in analogy to Example 31 starting from 3-amino-6-(3,4 20 dichlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8- 150 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 688.08 (calculated, monoisotopic); measured value (M+H)*: 689.09 5 Example 159 N-[1 -(2,4-Dichlorobenzenesu Ifonyl)-6-(3,4-d ichlorobenzyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-4-dimethylaminobenzamide Structure: ci 0 C1 0 N -N 10 Synthesis takes place in analogy to Example 25 starting from 3-amino-6-(3,4 dichlorobenzyl)-1 -(2,4-d ichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 739.10 (calculated, monoisotopic); measured value (M+H)*: 740.0 15 Example 160 1 -tert-Butyl-3-[1 -(2,4-dichlorobenzenesufonyl)-6-(3,4-d ichlorobenzyl)-8-isopropyl 4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]urea Structure: Ci // N N N 20 151 Synthesis takes place in analogy to Example 28 starting from 3-amino-6-(3,4 dichlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 691.10 (calculated, monoisotopic); measured value (M+H)*: 5 692.0 Example 161 N-[1 -(2,4-Dichlorobenzenesulfonyl)-6-(3,4-dichlorobenzyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide 10 Structure: NI 00 N~ N0 ' \ Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(3,4 dichlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 15 obtained with MW = 670.0 (calculated, monoisotopic); measured value (M+H)*: 670.98 Example 162 1 -(2,4-Dichlorobenzenesufonyl)-6-(3,4-dichlorobenzyl)-8-isopropyl-3-pyrroid in-1 20 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: CI - ~ N 0CI "N NI a CI C1 0 N c0 152 Synthesis takes place in analogy to Example 74 starting from 3-amino-6-(3,4 dichlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 646.07 (calculated, monoisotopic); measured value (M+H)*: 5 647.05 Example 163 1-(2,4-Dichlorobenzenesulfonyl)-6-(3,4-dichlorobenzyl)-8-isopropyl-3-morpholin-4 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 10 Structure: ciN N N C ci 0 N 0 Synthesis takes place in analogy to Example 60 starting from 3-amino-6-(3,4 dichlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 15 obtained with MW = 662.07 (calculated, monoisotopic); measured value (M+H)*: 663.06 Example 164 C1 N N F Ci 0 20 a) 9H-Fluoren-9-ylmethyl [1 -[(2,2-d iethoxyethyl)isopropylcarbamoyl]-2-(3,4 difluorophenyl)ethyl]carbamate 153 Synthesis takes place in analogy to Example 29a) (Method B) starting from N Fmoc-3,4-F 2 -Phe-OH. The desired product is obtained with MW = 580.27 (calculated, monoisotopic); measured value (M+Na)*: 603.25 5 b) 2-Amino-3-(3,4-d ifluorophenyl)-N-(2,2-diethoxyethyl)-N-isopropyl propiona mide Synthesis takes place in analogy to Example 29b) (Method B) starting from 9H fluoren-9-ylmethyl [1 -[(2,2-d iethoxyethyl)isopropylcarbamoyl]-2-(3,4 difluorophenyl)ethyl]carbamate. The desired product is obtained with MW = 358.21 (calculated, monoisotopic); measured value (M+H)*: 359.2 10 c) 9H-Fluoren-9-ylmethyl (2-benzyloxycarbonylamino-2-{2-(3,4-difluorophenyl)-1 [(2,2-diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate Synthesis took place in analogy to Example 29c) (Method B) starting from 2 amino-3-(3,4-difluorophenyl)-N-(2,2-diethoxyethyl)-N-isopropylpropionamide. The 15 desired product is obtained with MW = 800.36 (calculated, monoisotopic); measured value (M+H)*: 801.35 d) Benzyl (2-amino-1-{2-(3,4-difluorophenyl)-1-[(2,2 d iethoxyethyl)isopropylcarbamoyl]ethylcarba moyl}ethyl)carbamate 20 Synthesis took place in analogy to Example 29d) (Method B) starting from 9H fluoren-9-ylmethyl (2-benzyloxycarbonylamino-2-{2-(3,4-difluorophenyl)-1-[(2,2 d iethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate. The desired product is obtained with MW = 578.29 (calculated, monoisotopic); measured value (M+H)*: 579.31 25 e) Benzyl [1 -{2-(3,4-difluorophenyl)-1 -[(2,2-d iethoxyethyl)isopropylcarbamoyl]ethyl carbamoyl}-2-(2,4-dichlorobenzenesulfonylamino)ethyl]carbamate Synthesis took place in analogy to Example 29e) (Method B) starting from benzyl (2-amino-1 -{2-(3,4-d ifluorophenyl)-1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl 30 carbamoyl}ethyl)carbamate. The desired product is obtained with MW = 786.21 (calculated, monoisotopic); measured value (M+Na)*: 809.19 154 f) Benzyl [6-(3,4-difluorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 d ioxoocta hydropyrazino[1,2-a] pyrimid in-3-yl]carbamate Synthesis took place in analogy to Example 29f) (Method B) starting from benzyl [1 -{2-(3,4-difluorophenyl)-1 -[(2,2 5 d iethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}-2-(2,4 dichlorobenzenesulfonylamino)ethyl]carbamate. The desired product is obtained with MW = 694.12 (calculated, monoisotopic); measured value (M+H)*: 695.10 g) 3-Amino-6-(3,4-difluorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8 10 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis took place in analogy to Example 29g) (Method B) starting from benzyl [6-(3,4-difluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 560.09 (calculated, monoisotopic); measured value (M+H)*: 15 561.13 h) N-[1-(2,4-dichlorobenzenesufonyl)-6-(3,4-d ifluorobenzyl)-8-isopropyl-4,7 d ioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(3,4 20 difluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 628.11 (calculated, monoisotopic); measured value (M+H)*: 629.18 Example 165 25 N-[1 -(2,4-Dichlorobenzenesulfonyl)-6-(3,4-difluorobenzyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide 155 Structure: cl CI0 N - 0 F "N N F ci 0 0 N Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(3,4 difluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 5 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 642.13 (calculated, monoisotopic); measured value (M+H)*: 643.21 Example 166 N-[1 -(2,4-Dichlorobenzenesufonyl)-6-(3,4-difluorobenzyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide 10 Structure: N N U C1I N~ NF CI 0 [ N ci 0 Synthesis takes place in analogy to Example 31 starting from 3-amino-6-(3,4 difluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 656.14 15 (calculated, monoisotopic); measured value (M+H)*: 657.21 Example 167 N-[1-(2,4-Dichlorobenzenesulfonyl)-6-(3,4-difluorobenzyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclohexanecarboxamide 156 Structure: "I
-
N 0 F N N:CF c CI
-
0 N ci=0 Synthesis takes place in analogy to Example 32 starting from 3-amino-6-(3,4 difluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 5 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 670.16 (calculated, monoisotopic); measured value (M+H)*: 671.24 Example 168 N-[1 -(2,4-Dichlorobenzenesufonyl)-6-(3,4-d ifluorobenzyl)-8-isopropyl-4,7-d ioxo octahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide 10 Structure: ci N N N F ci 0 0 ;S Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(3,4 difluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 638.06 15 (calculated, monoisotopic); measured value (M+H)*: 639.02 Example 169 1 -(2,4-Dichlorobenzenesulfonyl)-6-(3,4-difluorobenzyl)-3-dimethylamino-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 157 Structure: /0
-
N 0 F "N N F CI 0 Synthesis takes place in analogy to Example 72 starting from 3-amino-6-(3,4 difluorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 5 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 588.12 (calculated, monoisotopic); measured value (M+H)*: 589.10 Example 170 1 -(2,4-Dichlorobenzenesulfonyl)-6-(3,4-difluorobenzyl)-8-isopropyl-3-pyrrolid in-i 10 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ci "I N, N N F ci 0 0 Synthesis takes place in analogy to Example 74 starting from 3-amino-6-(3,4 difluorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 15 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 614.13 (calculated, monoisotopic); measured value (M+H)*: 615.10 Example 171 1 -(2,4-Dichlorobenzenesufonyl)-6-(3,4-difluorobenzyl)-8-isopropyl-3-piperidin-1 -yl 20 hexahydropyrazino[1,2-a]pyrimidine-4,7-dione 158 Structure: cl N N F CI O C1 0 N 0 Synthesis takes place in analogy to Example 59 starting from 3-amino-6-(3,4 difluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 5 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 628.15 (calculated, monoisotopic); measured value (M+H)*: 629.22 Example 172 1 -(2,4-Dichlorobenzenesulfonyl)-6-(3,4-d ifluorobenzyl)-8-isopropyl-3-morpholin-4 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 10 Structure: ci N "N N F ci 0 (N) 0 Synthesis takes place in analogy to Example 60 starting from 3-amino-6-(3,4 difluorobenzyl)-1 -(2,4-d ichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 630.13 15 (calculated, monoisotopic); measured value (M+H)*: 631.10 159 Example 173 ci N N 0 F /N N CI 0 I-0 oF N 5 2-Allyloxycarbonylamino-3-(2,4-difluorophenyl)propionic acid Synthesis takes place in analogy to Example 21a) starting from 2-amino-3-(2,4 difluorophenyl)propionic acid. The desired product is obtained with MW = 285.08 (calculated, monoisotopic); measured value (M+H)*: 286.05 b) Allyl {2-(2,4-d ifluorophenyl)-1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl} 10 carbamate. Synthesis takes place in analogy to Example 21b) starting from 2 allyloxycarbonylamino-3-(2,4-difluorophenyl)propionic acid. The desired product is obtained with MW = 442.23 (calculated, monoisotopic); measured value (M+H)*: 443.2 15 c) 2-Amino-3-(2,4-difluorophenyl)-N-(2,2-diethoxyethyl)-N-isopropylpropionamide Synthesis takes place in analogy to Example 21 c) starting from allyl {2-(2,4 d ifluorophenyl)-1 -[(2,2-d iethoxyethyl)isopropylcarbamoyl]ethyl}carbamate. The desired product is obtained with MW = 358.21 (calculated, monoisotopic); measured value (M+H)*: 359.2 20 d) Benzyl (2-(2,4-dichlorobenzenesufonylamino)-1 -{2-(2,4-difluorophenyl)-1 -[(2,2 d iethoxyethyl)isopropylcarbamoyl]ethylcarba moyl}ethyl)carba mate Synthesis takes place in analogy to Example 29b) starting from 2-amino-3-(2,4 difluorophenyl)-N-(2,2-diethoxyethyl)-N-isopropylpropionamide. The desired 25 product is obtained with MW = 786.21 (calculated, monoisotopic); measured value (M+H)*: 787.30 160 e) Benzyl [6-(2,4-difluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 d ioxooctahyd ropyrazino[1,2-a]pyrimid in-3-yl]carbamate Synthesis takes place in analogy to Example 21f) starting from benzyl (2-(2,4 dichlorobenzenesulfonylamino)-1 -{2-(2,4-difluorophenyl)-1 -[(2,2 5 d iethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate. The desired product is obtained with MW = 694.12 (calculated, monoisotopic); measured value (M+H)*: 695.05 f) 3-Amino-6-(2,4-difluorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexa 10 hydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 21g) starting from benzyl (2-(2,4 dichlorobenzenesulfonylamino)-1 -{2-(2,4-difluorophenyl)-1 -[(2,2 d iethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate. The desired product is obtained with MW = 560.09 (calculated, monoisotopic); measured value 15 (M+H)*: 561.0 g) N-[1-(2,4-Dichlorobenzenesulfonyl)-6-(2,4-difluorobenzyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Synthesis takes place in analogy to Example 29e) (Method A) starting from 3 20 amino-6-(2,4-difluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 628.11 (calculated, monoisotopic); measured value (M+H)*: 629.31 25 Example 174 1-(2,4-Dichlorobenzenesulfonyl)-6-(2,4-difluorobenzyl)-3-dimethylamino-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: 161 Ci N N 0 F 'N N OF N Synthesis takes place in analogy to Example 72 starting from 3-amino-6-(2,4 difluorobenzyl)-1 -(2,4-d ichlorobenzenesu Ifonyl)-8-isopropylhexahyd ropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 588.12 5 (calculated, monoisotopic); measured value (M+H)*: 589.07 Example 175 3-Azetidin-1-yl-1-(2,4-dichlorobenzenesulfonyl)-6-(2,4-difluorobenzyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimid ine-4,7-d ione 10 Structure: cl ci N 0 F / N N CI 0 N Synthesis takes place in analogy to Example 73 starting from 3-amino-6-(2,4 d ifluorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 600.12 (calculated, monoisotopic); measured value (M+H)*: 600.81 15 162 Example 176 F N OF F / N N F 0F N 0 N a) 9H-Fluoren-9-ylmethyl [1-[(2,2-diethoxyethyl )isopropylcarbamoyl]-2-pentafluoro 5 phenylethyl]carbamate Synthesis takes place in analogy to Example 29a) (Method B) starting from N Fmoc-2,3,4,5,6-F 5 -Phe-OH. The desired product is obtained with MW = 634.25 (calculated, monoisotopic); measured value (M+Na)*: 657.17 10 b) 2-Amino-3-pentafluorophenyl-N-(2,2-diethoxyethyl)-N-isopropylpropionamide Synthesis takes place in analogy to Example 29b) (Method B) starting from 9H fluoren-9-ylmethyl [1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]-2 pentafluorophenylethyl]carbamate. The desired product is obtained with MW = 412.18 (calculated, monoisotopic); measured value (M+Na)*: 435.17 15 c) 9H-Fluoren-9-ylmethyl (2-benzyloxycarbonylamino-2-{2-(pentafluorophenyl)-1 [(2,2-diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate Synthesis took place in analogy to Example 29c) (Method B) starting from 2 amino-3-pentafluorophenyl-N-(2,2-diethoxyethyl)-N-isopropylpropionamide. The 20 desired product is obtained with MW = 854.33 (calculated, monoisotopic); measured value (M+Na)*: 877.41 d) Benzyl (2-amino-1-{2-pentafluorophenyl-1-[(2,2 d iethoxyethyl)isopropylcarbamoyl]ethylcarba moyl}ethyl)ca rbamate 25 Synthesis took place in analogy to Example 29d) (Method B) starting from 9H fluoren-9-ylmethyl (2-benzyloxycarbonylamino-2-{2-pentafluorophenyl-1-[(2,2 d iethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}ethyl)carbamate. The desired 163 product is obtained with MW = 632.26 (calculated, monoisotopic); measured value (M+Na)*: 655.24 e) Benzyl [1-{2-pentafluorophenyl-1-[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl 5 carbamoyl}-2-(2,4-d ichlorobenzenesu lfonylamino)ethyl]carba mate Synthesis took place in analogy to Example 29e) (Method B) starting from benzyl (2-amino-1 -{2-pentafluorophenyl-1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl carbamoyl}ethyl)carbamate. The desired product is obtained with MW = 840.18 (calculated, monoisotopic); measured value (M+Na)*: 863.18. 10 f) Benzyl [1 -(2,4-dichlorobenzenesufonyl)-8-isopropyl-4,7-d ioxo-6 pentafluorophenylmethyloctahydropyrazino[1,2-a]pyrimid in-3-yl]carbamate Synthesis takes place in analogy to Example 29f) starting from benzyl (2-(2,4 dichlorobenzenesulfonylamino)-1-{1-[(2,2-diethoxyethyl)isopropylcarbamoyl]-2 15 pentafluorophenylethylcarbamoyl}ethyl)carbamate. The desired product is obtained with MW = 748.09 (calculated, monoisotopic); measured value (M+H)*: 749.15 g) 3-Amino-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-6 20 pentafluorophenylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 29g) starting from benzyl [1-(2,4 dichloro-benzenesulfonyl)-8-isopropyl-4,7-dioxo-6 pentafluorophenylmethyloctahydropyrazino[1,2-a]pyrimid in-3-yl]carbamate. The desired product is obtained with MW = 614.06 (calculated, monoisotopic); 25 measured value (M+H)*: 615.05 h) N-[1-(2,4-Dichlorobenzenesufonyl)-8-isopropyl-4,7-d ioxo-6 pentafluorophenylmethyloctahydropyrazino[1,2-a]pyrimidin-3-yl]pyrrolidine-2 carboxamide 30 Synthesis takes place in analogy to Example 40 starting from 3-amino-1 -(2,4 dichlorobenzenesufonyl)-8-isopropyl-6 pentafluorophenylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The 164 desired product is obtained with MW = 711.11 (calculated, monoisotopic); measured value (M+H)*: 712.06 Example 177 5 1-(2,4-Dichlorobenzenesulfonyl)-3-dimethylamino-8-isopropyl-6-pentafluorophenyl methylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: C1 F NI
-
N O F F /N N #F CI 0 Synthesis takes place in analogy to Example 72 starting from 3-amino-1 -(2,4 10 dichlorobenzenesulfonyl)-8-isopropyl-6 pentafluorophenylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 620.12 (calculated, monoisotopic); measured value (M+H)*: 621.09 15 Example 178 3-Azetidin-1 -yl-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-6 pentafluorophenylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ci F "N N F CI 0 C1 o F <N IK> Synthesis takes place in analogy to Example 73 starting from 3-amino-1-(2,4 20 dichlorobenzenesufonyl)-8-isopropyl-6 pentafluorophenylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The 165 desired product is obtained with MW = 654.09 (calculated, monoisotopic); measured value (M+H)*: 655.1 Example 179 5 1-(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-6-pentafluorophenylmethyl-3 pyrrolidin-1 -ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: CI F N OF F / N N F 0 N 0 Synthesis takes place in analogy to Example 74 starting from 3-amino-1-(2,4 10 dichlorobenzenesulfonyl)-8-isopropyl-6 pentafluorophenylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 668.11 (calculated, monoisotopic); measured value (M+H)*: 669.11 15 Example 180 1-(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-6-pentafluorophenylmethyl-3 piperidin-1 -ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ciN OF F // N N F CI 0 NF 0 Synthesis takes place in analogy to Example 59 starting from 3-amino-1-(2,4 20 dichlorobenzenesulfonyl)-8-isopropyl-6- 166 pentafluorophenylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 682.12 (calculated, monoisotopic); measured value (M+H)*: 683.09 5 Example 181 1-(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-3-morpholin-4-yl-6-pentafluorophenyl methylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: C1 F ciN OF F N N F CI 0 C1 O F (N) 10 10 Synthesis takes place in analogy to Example 60 starting from 3-amino-1-(2,4 dichlorobenzenesulfonyl)-8-isopropyl-6 pentafluorophenylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 684.10 (calculated, monoisotopic); 15 measured value (M+H)*: 685.01 Example 182 ci N cl0 N N ci o N N'1=0 20 a) 9H-Fluoren-9-ylmethyl {1-[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-pyridin-3-yl ethyl}carbamate 167 Synthesis takes place in analogy to Example 29a) (Method B) starting from Fmoc 3-pyridylalanine. The desired product is obtained with MW = 545.29 (calculated, monoisotopic); measured value (M+H)*: 546.24 5 b) 2-Amino-N-(2,2-d iethoxyethyl)-N-isopropyl-3-pyrid in-3-ylpropiona mide Synthesis takes place in analogy to Example 29b) (Method B) starting from 9H fluoren-9-ylmethyl {1-[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-pyrid in-3 ylethyl}carbamate. The desired product is obtained with MW = 323.22 (calculated, monoisotopic); measured value (M+H)*: 324.22 10 c) Benzyl [1-[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-pyridin-3-ylethylcarbamoyl} 2-(9H-fluoren-9-ylmethoxycarbonylamino)ethyl]carbamate Synthesis took place in analogy to Example 29c) (Method B) starting from 2 amino-N-(2,2-diethoxyethyl)-N-isopropyl-3-pyrid in-3-ylpropionamide. The desired 15 product is obtained with MW = 765.37 (calculated, monoisotopic); measured value (M+H)*: 766.31 d) Benzyl (2-amino-{1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-pyrid in-3-ylethyl carbamoyllethyl)carbamate 20 Synthesis took place in analogy to Example 29d) (Method B) starting from benzyl [1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-pyridin-3-ylethylcarbamoyl}-2-(9H fluoren-9-ylmethoxycarbonylamino)ethyl]carbamate. The desired product is obtained with MW = 543.31 (calculated, monoisotopic); measured value (M+H)*: 544.4 25 e) Benzyl (2-(2,4-dichlorobenzenesulfonylamino)-1-{1-[(2,2 diethoxyethyl)isopropylcarbamoyl]-2-pyridin-3-ylethylcarbamoyl}ethyl)carbamate Synthesis took place in analogy to Example 29e) (Method B) starting from benzyl (2-amino-{1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-pyridin-3 30 ylethylcarbamoyl}ethyl)carbamate. The desired product is obtained with MW = 751.22 (calculated, monoisotopic); measured value (M+H)*: 752.19.
168 f) Benzyl [1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-pyridin-3 yl methyloctahydropyrazino[1,2-a]pyrimid in-3-yl]carbamate Synthesis takes place in analogy to Example 29f) starting from benzyl (2-(2,4 dichloro-benzenesulfonylamino)-1 -{1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]-2 5 pyrid in-3-ylethylcarbamoyl}ethyl)carbamate. The desired product is obtained with MW = 659.14 (calculated, monoisotopic); measured value (M+H)*: 660.10 g) 3-Amino-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-6-pyridin-3 ylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 10 Synthesis takes place in analogy to Example 29g) starting from benzyl [1-(2,4 dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-pyridin-3 ylmethyloctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 525.10 (calculated, monoisotopic); measured value (M+H)*: 526.1 15 h) N-[1-(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-pyridin-3 ylmethyloctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide Synthesis takes place in analogy to Example 21h) starting from 3-amino-1 -(2,4 dichlorobenzenesulfonyl)-8-isopropyl-6-pyridin-3-ylmethylhexahydropyrazino[1,2 20 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 567.11 (calculated, monoisotopic); measured value (M+H)*: 568.11 Example 183 N-[1 -(2,4-Dichlorobenzenesufonyl)-8-isopropyl-4,7-d ioxo-6-pyridin-3-ylmethylocta 25 hydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Structure: ci N N NN ci 0 N 0 169 Synthesis takes place in analogy to Example 22 starting from 3-amino-1-(2,4 d ichlorobenzenesulfonyl)-8-isopropyl-6-pyridin-3-yl methyl hexahydropyrazino[1 ,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 593.13 (calculated, monoisotopic); measured value (M+H)*: 594.13 5 Example 184 N-[1 -(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-pyridin-3-ylmethylocta hydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide Structure: Ci N N ci 0 10 N 10 Synthesis takes place in analogy to Example 30 starting from 3-amino-1-(2,4 d ichlorobenzenesulfonyl)-8-isopropyl-6-pyridin-3-ylmethylhexahydropyrazino[1 ,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 607.14 (calculated, monoisotopic); measured value (M+H)*: 608.15 15 Example 185 N-[1 -(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-pyrid in-3-ylmethylocta hydropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide Structure: ci N o "N N ci 0 20 e Synthesis takes place in analogy to Example 31 starting from 3-amino-1 -(2,4 dichlorobenzenesulfonyl)-8-isopropyl-6-pyridin-3-ylmethylhexahydropyrazino[1,2- 170 alpyrimidine-4,7-dione. The desired product is obtained with MW = 621.16 (calculated, monoisotopic); measured value (M+H)*: 622.17 Example 186 5 N-[1 -(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-pyridin-3-ylmethylocta hydropyrazino[1,2-a]pyrimidin-3-yl]pyrrolidine-2-carboxamide Structure: ci Y clC N N ci 0 N N Synthesis takes place in analogy to Example 40 starting from 3-amino-1 -(2,4 10 dichlorobenzenesulfonyl)-8-isopropyl-6-pyridin-3-ylmethylhexahydropyrazino[1,2 alpyrimidine-4,7-dione. The desired product is obtained with MW = 622.15 (calculated, monoisotopic); measured value (M+H)*: 623.14 Example 187 15 N-[1 -(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-4,7-d ioxo-6-pyridin-3-ylmethylocta hydropyrazino[1,2-a]pyrimidin-3-yl]-4-d imethylaminobenzamide Structure: ?0 N N C1 1?-0 N N 0 Synthesis takes place in analogy to Example 25 starting from 3-amino-1 -(2,4 20 dichlorobenzenesulfonyl)-8-isopropyl-6-pyridin-3-ylmethylhexahydropyrazino[1,2- 171 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 672.17 (calculated, monoisotopic); measured value (M+H)*: 673.18 Example 188 5 N-[1 -(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-pyridin-3-ylmethylocta hydropyrazino[1,2-a]pyrimidin-3-yl]nicotinamide Structure: ci N N N ci 0 cl 0 N e10 N Synthesis takes place in analogy to Example 50 starting from 3-amino-1-(2,4 10 dichlorobenzenesulfonyl)-8-isopropyl-6-pyridin-3-ylmethylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 630.12 (calculated, monoisotopic); measured value (M+H)*: 631.16 Example 189 15 1 -tert-Butyl-3-[1 -(2,4-d ichlorobenzenesufonyl)-8-isopropyl-4,7-dioxo-6-pyridin-3 ylmethyloctahydropyrazino[1,2-a]pyrimidin-3-yl]urea Structure: ci ;N 0 " N N ci 0 0 N N Synthesis takes place in analogy to Example 28 starting from 3-amino-1-(2,4 20 dichlorobenzenesulfonyl)-8-isopropyl-6-pyridin-3-ylmethylhexahydropyrazino[1,2- 172 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 624.17 (calculated, monoisotopic); measured value (M+H)*: 625.1 Example 190 5 N-[1 -(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-pyridin-3-ylmethylocta hydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide Structure: /N N ci 0 0 Synthesis takes place in analogy to Example 26 starting from 3-amino-1-(2,4 10 dichlorobenzenesulfonyl)-8-isopropyl-6-pyridin-3-ylmethylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 603.08 (calculated, monoisotopic); measured value (M+H)*: 604.06 Example 191 15 N-[1 -(2,4-Dichlorobenzenesufonyl)-8-isopropyl-4,7-dioxo-6-pyrid in-3-ylmethylocta hydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanesulfonamide Structure: ci N N N N~ N o* Synthesis takes place in analogy to Example 27 starting from 3-amino-1 -(2,4 20 dichlorobenzenesulfonyl)-8-isopropyl-6-pyridin-3-ylmethylhexahydropyrazino[1,2- 173 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 629.09 (calculated, monoisotopic); measured value (M+H)*: 630.09 Example 192 5 1-(2,4-Dichlorobenzenesulfonyl)-3-dimethylamino-8-isopropyl-6-pyridin-3 ylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ciN C1 o N N ci 0 Synthesis takes place in analogy to Example 72 starting from 3-amino-1-(2,4 10 dichlorobenzenesulfonyl)-8-isopropyl-6-pyridin-3-ylmethylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 553.13 (calculated, monoisotopic); measured value (M+H)*: 554.08 Example 193 ci N AN N ci 0 N 15 a) 9H-Fluoren-9-ylmethyl {1-[(2,2-d iethoxyethyl )isopropylcarbamoyl]-2-pyridin-4-yl ethyl}carbamate Synthesis takes place in analogy to Example 29a) (Method B) starting from Fmoc 4-pyridylalanine. The desired product is obtained with MW = 545.29 (calculated, 20 monoisotopic); measured value (M+H)*: 546.26 b) 2-Amino-N-(2,2-diethoxyethyl)-N-isopropyl-3-pyridin-4-ylpropionamide 174 Synthesis takes place in analogy to Example 29b) (Method B) starting from 9H fluoren-9-ylmethyl {1-[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-pyridin-4 ylethyl}carbamate. The desired product is obtained with MW = 323.22 (calculated, monoisotopic); measured value (M+H)*: 324.22 5 c) Benzyl [1-[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-pyridin-4-ylethylcarbamoyl} 2-(9H-fluoren-9-yl methoxycarbonylamino)ethyl]carbamate Synthesis took place in analogy to Example 29c) (Method B) starting from 2 amino-N-(2,2-diethoxyethyl)-N-isopropyl-3-pyridin-4-ylpropionamide. The desired 10 product is obtained with MW = 809.36 (calculated, monoisotopic); measured value (M+Na)*: 832.3 d) Benzyl (2-amino-{1 -[(2,2-d iethoxyethyl )isopropylcarbamoyl]-2-pyrid in-4-ylethyl carbamoyl}ethyl)carbamate 15 Synthesis took place in analogy to Example 29d) (Method B) starting from benzyl [1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-pyridin-4-ylethylcarbamoyl}-2-(9H fluoren-9-ylmethoxycarbonylamino)ethyl]carbamate. The desired product is obtained with MW = 543.31 (calculated, monoisotopic); measured value (M+H)*: 544.4 20 e) Benzyl (2-(2,4-dichlorobenzenesulfonylamino)-1-{1-[(2,2 diethoxyethyl)isopropylcarbamoyl]-2-pyrid in-4-ylethylcarbamoyl}ethyl)carbamate Synthesis took place in analogy to Example 29e) (Method B) starting from benzyl (2-amino-{1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-pyridin-4 25 ylethylcarbamoyl}ethyl)carbamate. The desired product is obtained with MW = 751.22 (calculated, monoisotopic); measured value (M+H)*: 752.19. f) Benzyl [1-(2,4-dichlorobenzenesufonyl)-8-isopropyl-4,7-dioxo-6-pyrid in-4 ylmethyloctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate 30 Synthesis takes place in analogy to Example 29f) (Method B) starting from benzyl (2-(2,4-dichloro-benzenesulfonylamino)-1 -{1 -[(2,2 d iethoxyethyl)isopropylcarbamoyl]-2-pyridin-4-ylethylcarbamoyl}ethyl)carbamate.
175 The desired product is obtained with MW = 659.14 (calculated, monoisotopic); measured value (M+H)*: 660.17 g) 3-Amino-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-6-pyridin-4 5 ylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 29g) (Method B) starting from benzyl [1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-pyridin-4 ylmethyloctahydropyrazino[1,2-a]pyrimid in-3-yl]carbamate. The desired product is obtained with MW = 525.10 (calculated, monoisotopic); measured value (M+H)*: 10 526.10 h) N-[1-(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-pyridin-4 ylmethyloctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide Synthesis takes place in analogy to Example 21h) starting from 3-amino-1-(2,4 15 dichlorobenzenesulfonyl)-8-isopropyl-6-pyridin-4-ylmethylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 567.11 (calculated, monoisotopic); measured value (M+H)*: 568.13 Example 194 20 N-[1 -(2,4-Dichlorobenzenesufonyl)-8-isopropyl-4,7-d ioxo-6-pyridin-4-ylmethylocta hydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Structure: cl 'N N ci 0 0 N 10 Synthesis takes place in analogy to Example 22 starting from 3-amino-1 -(2,4 25 d ichlorobenzenesufonyl)-8-isopropyl-6-pyridin-4-ylmethylhexahydropyrazino[1 ,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 593.13 (calculated, monoisotopic); measured value (M+H)*: 594.13 176 Example 195 N-[1 -(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-pyridin-4-ylmethylocta hydropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide 5 Structure: ci N N // ,N N:N Ci 0 0 N /10 Synthesis takes place in analogy to Example 31 starting from 3-amino-1-(2,4 dichlorobenzenesulfonyl)-8-isopropyl-6-pyridin-4-ylmethylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 621.16 10 (calculated, monoisotopic); measured value (M+H)*: 622.17 Example 196 N-[1 -(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-pyridin-4-ylmethylocta hydropyrazino[1,2-a]pyrimidin-3-yl]-4-dimethylaminobenzamide Structure: "'0 N 0 / N N CI 00 N -N l 15 Synthesis takes place in analogy to Example 25 starting from 3-amino-1-(2,4 dichlorobenzenesufonyl)-8-isopropyl-6-pyridin-4-ylmethylhexahydropyrazino[1 ,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 672.17 (calculated, monoisotopic); measured value (M+H)*: 673.2 20 177 Example 197 1 -tert-Butyl-3-[1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-pyridin-4 ylmethyloctahydropyrazino[1,2-a]pyrimidin-3-yl]urea Structure: "0 N 0 N N ci 0 N -- N 5 Synthesis takes place in analogy to Example 28 starting from 3-amino-1-(2,4 dichlorobenzenesulfonyl)-8-isopropyl-6-pyridin-4-ylmethylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 624.17 (calculated, monoisotopic); measured value (M+H)*: 625.2 10 Example 198 N-[1 -(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-pyridin-4-ylmethylocta hydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide Structure: ciN N N CI 0O 15 Synthesis takes place in analogy to Example 26 starting from 3-amino-1-(2,4 d ichlorobenzenesufonyl)-8-isopropyl-6-pyridin-4-ylmethylhexahydropyrazino[1 ,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 603.08 (calculated, monoisotopic); measured value (M+H)*: 604.08 20 178 Example 199 N-[1-(2,4-Dichlorobenzenesulfonyl)-8-isopropyl-4,7-dioxo-6-pyridin-4-ylmethylocta hydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanesulfonamide Structure: ci "N N ci 0 N, O 5 s Synthesis takes place in analogy to Example 27 starting from 3-amino-1-(2,4 dichlorobenzenesulfonyl)-8-isopropyl-6-pyridin-4-ylmethylhexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 629.09 (calculated, monoisotopic); measured value (M+H)*: 630.06 10 Example 200 CI+. N N 0NO / N N.I C' 0 /N a) 9H-Fluoren-9-ylmethyl [1-[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-(4 nitrophenyl)ethyl]carbamate Synthesis takes place in analogy to Example 29a) (Method B) starting from N 15 Fmoc-4-nitro-Phe-OH. The desired product is obtained with MW = 589.28 (calculated, monoisotopic); measured value (M+H)*: 590.3 b) 2-Amino-N-(2,2-diethoxyethyl)-N-isopropyl-3-(4-nitrophenyl)propionamide Synthesis takes place in analogy to Example 29b) (Method B) starting from 9H 20 fluoren-9-ylmethyl [1-[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-(4 nitrophenyl)ethyl]carbamate.
179 c) Benzyl [1-[1-[(2,2-d iethoxyethyl)isopropylcarbamoyl]-2-(4 nitrophenyl)ethylcarbamoyl]-2-(9H-fluoren-9 ylmethoxycarbonylamino)ethyl]carbamate 5 Synthesis took place in analogy to Example 29c) (Method B) starting from 2 amino-N-(2,2-diethoxyethyl)-N-isopropyl-3-(4-nitrophenyl)propionamide. The desired product is obtained with MW = 765.37 (calculated, monoisotopic); measured value (M+H)*: 766.31 10 d) Benzyl {2-amino-1-[1-[(2,2-diethoxyethyl)isopropylcarbamoyl]-2-(4 nitrophenyl)ethylcarbamoyl]ethyl)carbamate Synthesis took place in analogy to Example 29d) (Method B) starting from benzyl 1 -[(2,2-d iethoxyethyl)isopropylcarbamoyl]-2-pyridin-4-ylethylcarbamoyl}-2-(9H fluoren-9-ylmethoxycarbonylamino)ethyl]carbamate. The desired product is 15 obtained with MW = 587.68 (calculated, monoisotopic); measured value (M-OEt): 542 e) Benzyl {2-(2,4-dichlorobenzenesulfonylamino)-1-[1-[(2,2 diethoxyethyl)isopropylcarbamoyl]-2-(4 nitrophenyl)ethylcarbamoyl]ethyl}carbamate 20 Synthesis took place in analogy to Example 29e) (Method B) starting from benzyl {2-amino-1 -[1 -[(2,2-d iethoxyethyl)isopropylcarbamoyl]-2-(4 nitrophenyl)ethylcarbamoyl]ethyl}carbamate. The desired product is obtained with MW = 795.21 (calculated, monoisotopic); measured value (M+Na)*: 818.21 25 f) Benzyl [1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-6-(4-nitrobenzyl)-4,7 dioxooctahydropyrazino[1 ,2-a]pyrimidin-3-yl]carbamate Synthesis takes place in analogy to Example 29f) (Method B) starting from benzyl {2-(2,4-dichlorobenzenesulfonylamino)-1 -[1 -(2,2 d iethoxyethyl)isopropylcarbamoyl]-2-(4-nitro 30 phenyl)ethylcarbamoyl]ethyl}carbamate. The desired product is obtained with MW = 703.13 (calculated, monoisotopic); measured value (M+H)*: 704.1 180 g) 3-Amino-1-(2,4-dichlorobenzenesulfonyl)-8-isopropyl-6-(4 nitrobenzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 29g) (Method B) starting from benzyl 5 [1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-6-(4-nitrobenzyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 525.10 (calculated, monoisotopic); measured value (M+H)*: 526.10 10 h) 1-(2,4-Dichlorobenzenesulfonyl)-3-dimethylamino-8-isopropyl-6-(4 nitrobenzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione 0.15 ml of acetic acid and then 0.15 ml of formaldehyde (37% in H 2 0) and 1 ml of sodium cyanoborohydride (1M in THF) were added to a solution of 100 mg (0.17 mmol) of 3-amino-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-6-(4 15 nitrobenzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione in 5 ml of methanol. The mixture was stirred at room temperature for 1 hour, concentrated in vacuo, diluted with ethyl acetate and washed with water and brine. It was then dried (MgSO 4 ) and concentrated in vacuo. The residue was chromatographed on 12 g of SiO 2 (elution with ethyl acetate/methanol, gradient 0-5% methanol). 25 mg of the dimethylamine 20 were obtained. The amine was treated with 1 ml of 1M HCI in ether. The mixture . was concentrated in vacuo. 35 mg of dimethylamine HCI salt were obtained as a white solid. LC/MS MW = 597.12 (calculated, monoisotopic) measured value (M*H) = 598.12 25 Example 201 N-[6-(4-Aminobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-y]cyclopentanecarboxamide 181 ci NiN 0 N *'N I/ Z-1 "N N' a ci 0 Y10 N e0 3-Amino-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-6-(4-nitrobenzyl)hexahydro pyrazino[1,2-a]pyrimidine-4,7-dione was reacted in analogy to Example 31 to give 5 the cyclopentane carboxamide. The latter was reacted further in the following way: 71 mg (0.3 mmol) of tin(II) chloride were added to a solution of 50 mg (0.07 mmol) of N-[1 -(2,4-d ichlorobenzenesufonyl)-8-isopropyl-6-(4-nitrobenzyl)-4,7-d ioxoocta hydropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide (Example 200) in 3 ml of ethanol. The mixture was heated at 100*C in a microwave oven for 5 10 minutes and concentrated in vacuo. The residue was diluted with ethyl acetate, filtered through kieselguhr and concentrated in vacuo. It was then chromatographed on 4 g of SiO 2 (elution with ethyl acetate/heptane, gradient 0-100% ethyl acetate). 25 mg of the desired aniline were obtained as an oil. LC/MS MW (calculated, monoisotopic) = 635.17 and measured value (M*H) 15 636.14. Example 202 6-(4-Aminobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-3-dimethylamino-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione N N N CI N N 20 182 Example 202 was reduced in analogy to Example 201 starting from compound 1 (2,4-d ichlorobenzenesulfonyl)-3-d imethyla mino-8-isopropyl-6-(4 nitrobenzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 567.15 (calculated, monoisotopic); measured value (M+H)*: 5 568.1 Example 203 6-(4-Aminobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-3-piperidin-1 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 10 ci N //0 N40; N N cl 0 N .0 Synthesis takes place in analogy to Example 59 starting from 3-amino-1-(2,4 dichlorobenzenesufonyl)-8-isopropyl-6-(4-nitrobenzyl)hexahydropyrazino[1,2 a]pyrimidine-4,7-dione to give the corresponding piperidine derivative. Subsequent 15 reduction of the nitro group took place as described in Example 201. The desired product is obtained with MW = 607.18 (calculated, monoisotopic); measured value (M+H)*: 608.2 Example 204 20 4-Chloro-N-{4-[3-(cyclopentanecarbonylamino)-1 -(2,4-dichlorobenzenesulfonyl)-8 isopropyl-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-6 ylmethyl]phenyl}benzamide 183 ci N0 N C1 N1 0 N N ci o CI 0 N 010 5 mg (0.04 mmol) of diisopropylethylamine and then 7 mg (0.04 mmol) of 4 chlorobenzoyl chloride were added to a solution of 25 mg (0.03 mmol) of benzyl [6 (4-aminobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-4,7 5 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate in 1 ml of dichloromethane. The mixture was stirred at room temperature overnight, diluted with dichloromethane and washed with brine. The organic phase was isolated, dried (MgSO 4 ) and concentrated in vacuo. The residue was chromatographed on 8 g of SiO 2 (elution with ethyl acetate/heptane, gradient 0-100% ethyl acetate). 28.5 mg 10 of amide were obtained as oil. This compound was used directly in the next step. 28 mg (0.14 mmol) of TMSI were added to a solution of 28.5 mg (0.03 mmol) of the abovementioned Cbz-carbamate in 2 ml of acetonitrile at 0 0 C. The mixture was left to stand at room temperature overnight, concentrated in vacuo, diluted with 15 methanol and filtered through an SCX (5 g) cartridge (elution with 5 ml of methanol and then with 15 ml of 7N ammonia in methanol). 18 mg of the desired amine were obtained as a brown oil. This compound was used without further purification in the next step. 20 3 mg (0.02 mmol) of DIEA and then 2.7 mg (0.02 mmol) of cyclopentanecarbonyl chloride were added to a solution of 18 mg (0.02 mmol) of the deblocked compound in 1 ml of DCM. The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was dissolved in 2 ml of ethyl acetate, washed with water, dried (MgSO 4 ) and concentrated in vacuo. It was then 25 chromatographed on 4 g of SiO 2 (elution with ethyl acetate/heptane, gradient 184 0-100% ethyl acetate). 11 mg of the desired amide were obtained as an oil. LC/MS MW = 773.16 (calculated, monoisotopic); measured value (M*H) = 774.12 Example 205 5 C1 ci - ~ N 0 :Br N N CI 0 N a) Cyclopropyl(2,2-diethoxyethyl)amine A solution of 2.36 g (12 mmol) of 2-bromoacetaldehyde diethyl acetal and 4.94 g (86.6 mmol) of cyclopropylamine was heated in a closed vessel at 120*C for 2 h. 10 The reaction mixture was cooled to room temperature and diluted with 75 ml of ether and washed with 5% aq NaOH, followed by water and saturated sodium chloride solution. The organic phase was dried (MgSO 4 ) and concentrated in vacuo. The residue was distilled in vacuo (130'C-140 0 C). 2.01 g of the desired compound were obtained. LC/MS M+H = 173 15 b) 9H-Fluoren-9-ylmethyl [1-[cyclopropyl(2,2-d iethoxyethyl)carbamoyl]-2-(4-bromo phenyl)ethyl]carbamate Synthesis takes place in analogy to Example 29a) (Method B) starting from N Fmoc-4-Br-Phe-OH and cyclopropyl(2,2-d iethoxyethyl)amine. The desired product 20 is obtained with MW = 629.19 (calculated, monoisotopic); measured value (M+Na)*: 643.16 c) 2-Amino-3-(4-bromophenyl)-N-cyclopropyl-N-(2,2-diethoxyethyl)propionamide Synthesis takes place in analogy to Example 29b) (Method B) starting from 9H 25 fluoren-9-ylmethyl [1-[cyclopropyl(2,2-diethoxyethyl)carbamoyl]-2-(4- 185 bromophenyl)ethyl]carbamate. The desired product is obtained with MW = 398.12 (calculated, monoisotopic); measured value (M+H)*: 399.11 d) Benzyl [1-{2-(4-bromophenyl)-1-[cyclopropyl(2,2-d iethoxyethyl)carbamoyl]ethyl 5 carbamoyl}-2-(9H-fluoren-9-yl methoxycarbonylamino)ethyl]carbamate Synthesis took place in analogy to Example 29c) (Method B) starting from 2 amino-3-(4-bromophenyl)-N-cyclopropyl-N-(2,2-diethoxyethyl)propionamide. The desired product is obtained with MW = 840.27 (calculated, monoisotopic); measured value (M+Na)*: 863.23 10 e) Benzyl (2-amino-1-{2-(4-bromophenyl)-1-[cyclopropyl(2,2 diethoxyethyl)carbamoyl]ethylcarbamoyl}ethyl)carba mate. Synthesis took place in analogy to Example 29d) (Method B) starting from benzyl [1 -{2-(4-bromophenyl)-1 -[cyclopropyl(2,2 15 diethoxyethyl)carbamoyl]ethylcarbamoyl}-2-(9H-fluoren-9 ylmethoxycarbonylamino)ethyl]carbamate. The desired product is obtained with MW = 618.21 (calculated, monoisotopic); measured value (M+H)*: 619.2 f) Benzyl [1 -{2-(4-bromophenyl)-1 -[cyclopropyl(2,2-d iethoxyethyl)carbamoyl]ethyl 20 carbamoyl}-2-(2,4-dichlorobenzenesulfonylamino)ethyl]carbamate Synthesis took place in analogy to Example 29e) (Method B) starting from benzyl (2-amino-1 -{2-(4-bromophenyl)-1 -[cyclopropyl(2,2-d iethoxyethyl)carbamoyl]ethyl carbamoyl}ethyl)carbamate. The desired product is obtained with MW = 826.12 (calculated, monoisotopic); measured value (M+Na)*: 849.14. 25 g) Benzyl [6-(4-bromobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesufonyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. Synthesis took place in analogy to Example 29f) (Method B) starting from benzyl [1 -{2-(4-bromophenyl)-1 -[cyclopropyl(2,2 30 diethoxyethyl)carbamoyl]ethylcarbamoyl}-2-(2,4 dichlorobenzenesulfonylamino)ethyl]carbamate. The desired product is obtained with MW = 734.04 (calculated, monoisotopic); measured value (M+H)*: 735.02 186 h) 3-Amino-6-(4-bromobenzyl)-8-cyclopropyl-1-(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis took place in analogy to Example 29g) (Method B) starting from benzyl [6-(4-bromobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 5 dioxooctahydropyrazino[1 ,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 600.0 (calculated, monoisotopic); measured value (M+H)*: 600.99 i) N-[6-(4-Bromobenzyl)-8-cyclopropyl-1-(2,4-dichlorobenzenesulfonyl)-4,7 10 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide Synthesis takes place in analogy to Example 21 h) starting from 3-amino-6-(4 bromobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 642.01 (calculated, monoisotopic); 15 measured value (M+H)*: 643.02 Example 206 N-[6-(4-Bromobenzyl)-8-cyclopropyl-1-(2,4-dichlorobenzenesulfonyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide 20 Structure: cl ci -11 0 Br N N ci 0 N Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(4 bromobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesufonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The 187 desired product is obtained with MW = 668.03 (calculated, monoisotopic); measured value (M+H)*: 669.04 Example 207 5 N-[6-(4-Bromobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide Structure: CI ci N 0 Br // N NT::) CI 0 N Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(4 10 bromobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 682.04 (calculated, monoisotopic); measured value (M+H)*: 683.06 15 Example 208 N-[6-(4-Bromobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide Structure: ci/N NNB ci 0 0 N e0 20 Synthesis takes place in analogy to Example 31 starting from 3-amino-6-(4 bromobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The 188 desired product is obtained with MW = 696.06 (calculated, monoisotopic); measured value (M+H)*: 697.08 Example 209 N-[6-(4-Bromobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 5 d ioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]pyrrolidine-2-carboxamide Structure: ci 7 N 0 Br ' N N ci 0 N CN=0 Synthesis takes place in analogy to Example 40 starting from 3-amino-6-(4 bromobenzyl)-8-cyclopropyl-1 -(2,4 10 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 697.05 (calculated, monoisotopic); measured value (M+H)*: 698.02 Example 210 15 N-[6-(4-Bromobenzyl)-8-cyclopropyl-1 -(2,4-d ichlorobenzenesufonyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-4-dimethylaminobenzamide Structure: ci N 0 Br N O 0 N
--
N le 0 189 Synthesis takes place in analogy to Example 47 starting from 3-amino-6-(4 bromobenzy)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 747.07 (calculated, monoisotopic); 5 measured value (M+H)*: 748.08 Example 211 N-[6-(4-Bromobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]nicotinamide 10 Structure: ci N N 0 Br 'N N:C ci 0 N e,0 N Synthesis takes place in analogy to Example 50 starting from 3-amino-6-(4 bromobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesufonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The 15 desired product is obtained with MW = 705.02 (calculated, monoisotopic); measured value (M+H)*: 706.06 Example 212 1-[6-(4-Bromobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 20 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-3-tert-butylurea 190 Structure: ci 7 N 0 Br ci o N No Synthesis takes place in analogy to Example 28 starting from 3-amino-6-(4 bromobenzyl)-8-cyclopropyl-1 -(2,4 5 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 699.07 (calculated, monoisotopic); measured value (M+H)*: 700.09 Example 213 10 N-[6-(4-Bromobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide Structure: I N N 0 B r 21, N N ci 0 N, 0 ,s Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 15 bromobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 677.98 (calculated, monoisotopic); measured value (M+H)*: 679.0 191 Example 214 N-[6-(4-Bromobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-y]cyclopropanesulfonamide Structure: CI N N N ci 0 Y'-0 N O 5 Synthesis takes place in analogy to Example 27 starting from 3-amino-6-(4 bromobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 703.99 (calculated, monoisotopic); 10 measured value (M+H)*: 705.01 Example 215 6-(4-Bromobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-3 dimethylaminohexahydropyrazino[1,2-a]pyrimidine-4,7-dione 15 Structure: C1 0N Br SN N C' 0 /N Synthesis takes place in analogy to Example 72 starting from 3-amino-6-(4 bromobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The 20 desired product is obtained with MW = 628.03 (calculated, monoisotopic); measured value (M+H)*: 629.04 192 Example 216 3-Azetidin-1 -yl-6-(4-bromobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione 5 Structure: cl 10 Nf B N N Ci 0 N Synthesis takes place in analogy to Example 73 starting from 3-amino-6-(4 bromobenzyl)-8-cyclopropyl-1 -(2,4 10 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 636.08 (calculated, monoisotopic); measured value (M+H)*: 637.1 Example 217 15 6-(4-Bromobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-3-pyrrolidin-1 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: cl 7 "o /N N ci 0 0 0 Synthesis takes place in analogy to Example 74 starting from 3-amino-6-(4 20 bromobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The 193 desired product is obtained with MW = 654.05 (calculated, monoisotopic); measured value (M+H)*: 655.04 Example 218 5 6-(4-Bromobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-3-piperidin-1 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ci 7 N 0 Br 'N N ci 0 N 0 Synthesis takes place in analogy to Example 59 starting from 3-amino-6-(4 10 bromobenzyl)-8-cyclopropyl-1 -(2,4 d ichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimid ine-4,7-dione. The desired product is obtained with MW = 668.06 (calculated, monoisotopic); measured value (M+H)*: 669.08 15 Example 219 6-(4-Bromobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-3-morpholin-4 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ci 7 -N, 0 Br N 0 20 Synthesis takes place in analogy to Example 60 starting from 3-amino-6-(4 bromobenzyl)-8-cyclopropyl-1 -(2,4- 194 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 670.04 (calculated, monoisotopic); measured value (M+H)*: 670.97 5 Example 220 CY N 0 Br o 42/ N N 0 Y1 N a) Benzyl [1 -{2-(4-bromophenyl)-1 -[cyclopropyl(2,2-diethoxyethyl)carbamoyl]ethyl carbamoyl}-2-(5-chloro-2-methoxybenzenesulfonylamino)ethyl]carbamate 10 Synthesis takes place in analogy to Example 29e) (Method B) starting from benzyl (2-amino-1 -{2-(4-bromophenyl)-1 -[cyclopropyl(2,2-diethoxyethyl)carbamoyl]ethyl carbamoyl}ethyl)carbamate. The desired product is obtained with MW = 822.17 (calculated, monoisotopic); measured value (M+Na)*: 845.19 15 b) Benzyl [6-(4-bromobenzyl)-1-(5-chloro-2-methoxybenzenesulfonyl)-8 cyclopropyl-4,7-d ioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate Synthesis takes place in analogy to Example 29f) (Method B) starting from benzyl [1 -{2-(4-bromophenyl)-1 -[cyclopropyl(2,2 diethoxyethyl)carbamoyl]ethylcarbamoyl}-2-(5-chloro-2 20 methoxybenzenesulfonylamino)ethyljcarbamate. The desired product is obtained with MW = 730.09 (calculated, monoisotopic); measured value (M+H)*: 731.09 c) 3-Amino-6-(4-bromobenzyl)-1-(5-chloro-2-methoxybenzenesulfonyl)-8 cyclopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 195 Synthesis takes place in analogy to Example 29g) (Method B) starting from benzyl [6-(4-bromobenzyl)-1 -(5-chloro-2-methoxybenzenesu Ifonyl)-8-cyclo propyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 596.05 (calculated, monoisotopic); measured value (M+H)*: 5 597.04 d) N-[6-(4-Bromobenzyl)-1-(5-chloro-2-methoxybenzenesulfonyl)-8-cyclopropyl 4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide Synthesis takes place in analogy in Example 21 h) starting from 3-amino-6-(4 10 bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 cyclopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 638.06 (calculated, monoisotopic); measured value (M+H)*: 639.11 15 Example 221 N-[6-(4-Bromobenzyl)- 1 -(5-chloro-2-methoxybenzenesu Ifonyl)-8-cyclopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Structure: ci 7 NO Br 'N N 0 o N 20 Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(4 bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 cyclopropylhexahydropyrazino[1,2-a]pyrimid ine-4,7-dione. The desired product is obtained with MW = 664.08 (calculated, monoisotopic); measured value (M+H)*: 665.13 25 196 Example 222 N-[6-(4-Bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8-cyclopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide Structure: N Br 0 5 Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(4 bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 cyclopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 678.09 (calculated, monoisotopic); measured value (M+H)*: 10 679.15 Example 223 N-[6-(4-Bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8-cyclopropyl-4,7 d ioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide 15 Structure: ci 7 S N 0 Br N Synthesis takes place in analogy to Example 31 starting from 3-amino-6-(4 bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 cyclopropylhexahydropyrazino[1 ,2-a]pyrimidine-4,7-d ione. The desired product is 20 obtained with MW = 692.11 (calculated, monoisotopic); measured value (M+H)*: 693.16 197 Example 224 N-[6-(4-Bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8-cyclopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]pyrrolidine-2-carboxamide Structure: ci 7 /'P N 0~ Br 21 N N 0 ' N 0 5 N Synthesis takes place in analogy to Example 40 starting from 3-amino-6-(4 bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 cyclopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 693.10 (calculated, monoisotopic); measured value (M+H)*: 10 694.06 Example 225 N-[6-(4-Bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8-cyclopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-4-dimethylaminobenzamide 15 Structure: cl N 0 Br /0 -- N Synthesis takes place in analogy to Example 25 starting from 3-amino-6-(4 bromobenzyl)-l -(5-chloro-2-methoxybenzenesulfonyl)-8- 198 cyclopropylhexahydropyrazino[1 ,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 743.12 (calculated, monoisotopic); measured value (M+H)*: 744.17 5 Example 226 N-[6-(4-Bromobenzyl)-1 -(5-chloro-2-methoxybenzenesufonyl)-8-cyclopropyl-4,7 d ioxooctahydropyrazino[1,2-a]pyrimid in-3-yl]nicotinamide Structure: N 0 Br o N e_0 N 10 Synthesis takes place in analogy to Example 50 starting from 3-amino-6-(4 bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 cyclopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 701.07 (calculated, monoisotopic); measured value (M+H)*: 702.08 15 Example 227 1-[6-(4-Bromobenzyl)-1 -(5-chloro-2-methoxybenzenesufonyl)-8-cyclopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-3-tert-butylurea Structure: Ci N N Br 200 N 20 +
=
199 Synthesis takes place in analogy to Example 28 starting from 3-amino-6-(4 bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 cyclopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 695.12 (calculated, monoisotopic); measured value (M+H)*: 5 696.17 Example 228 N-[6-(4-Bromobenzyl)-1 -(5-chloro-2-methoxybenzenesu Ifonyl)-8-cyclopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide 10 Structure: ci N 0 Br 0 0 ' 0 N o 0 S\ Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 cyclopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 15 obtained with MW = 674.03 (calculated, monoisotopic); measured value (M+H)*: 675.08 Example 229 N-[6-(4-Bromobenzyl)-1-(5-chloro-2-methoxybenzenesulfonyl)-8-cyclopropyl-4,7 20 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanesulfonamide 200 Structure: C1 N N 0Br N N 0 :' Synthesis takes place in analogy to Example 27 starting from 3-amino-6-(4 bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 5 cyclopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 700.04 (calculated, monoisotopic); measured value (M+H)*: 701.1 Example 230 10 6-(4-Bromobenzyl)- 1 -(5-chloro-2-methoxybenzenesulfonyl)-8-cyclopropyl-3 dimethylaminohexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: cl NO 0. Br N N Br /N Synthesis takes place in analogy to Example 72 starting from 3-amino-6-(4 15 bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 cyclopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 743.12 (calculated, monoisotopic); measured value (M+H)*: 744.17 20 Example 231 3-Azetidin-1 -yl-6-(4-bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8-cyclo propylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 201 Structure: ci S N 0 Br o No 'I N N Synthesis takes place in analogy to Example 73 starting from 3-amino-6-(4 bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 5 cyclopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 640.03 (calculated, monoisotopic); measured value (M+H)*: 641.0 Example 232 10 6-(4-Bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8-cyclopropyl-3 pyrrolidin-1 -ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ci NN 0 Br o oI // N N 0 Synthesis takes place in analogy to Example 74 starting from 3-amino-6-(4 15 bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 cyclopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 650.10 (calculated, monoisotopic); measured value (M+H)*: 651.07 202 Example 233 6-(4-Bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8-cyclopropyl-3 piperidin-1 -ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: CI N 0 Br /so 421 N N N 5 Synthesis takes place in analogy to Example 59 starting from 3-amino-6-(4 bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 cyclopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 664.11 (calculated, monoisotopic); measured value (M+H)*: 10 665.12 Example 234 6-(4-Bromobenzyl)-1 -(5-chloro-2-methoxybenzenesufonyl)-8-cyclopropyl-3 morpholin-4-ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 15 Structure: ci 7 SI 1 Br (N) 0 Synthesis takes place in analogy to Example 60 starting from 3-amino-6-(4 bromobenzyl)-1 -(5-chloro-2-methoxybenzenesulfonyl)-8 cyclopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 20 obtained with MW = 666.09 (calculated, monoisotopic); measured value (M+H)*: 667.02 203 Example 235 ci Y 0~ NII 0 F // N N ci 0 N 5 a) Benzyl [6-(4-fluorobenzyl)-8-cyclopropyl-1-(2,4-dichlorobenzenesulfonyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate Synthesis takes place in analogy to Example 66a. The desired product is obtained with MW = 689.16 (calculated, monoisotopic); measured value (M+H)*: 690.10 10 b) 3-Amino-6-(4-fluorobenzyl)-8-cyclopropyl- 1-(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 66b) starting from benzyl [6-(4 fluorobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 15 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 540.08 (calculated, monoisotopic); measured value (M+H)*: 541.06 c) N-[6-(4-Fluorobenzyl)-8-cyclopropyl-1-(2,4-dichlorobenzenesulfonyl)-4,7 20 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide Synthesis takes place in analogy to Example 21h) starting from 3-amino-6-(4 fluorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 582.09 (calculated, monoisotopic); 25 measured value (M+H)*: 583.10 204 Example 236 N-[8-Cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-(4-fluorobenzyl)-4,7-dioxoocta hydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Structure: ci N 0 F i N N CI 0 N 5 Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(4 fluorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 608.11 (calculated, monoisotopic); 10 measured value (M+H)*: 609.11 Example 237 N-[8-Cyclopropyl-1 -(2,4-d ichlorobenzenesulfonyl)-6-(4-fluorobenzyl)-4,7-d ioxoocta hydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide 15 Structure: NN ci' N N ci 0 Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(4 fluorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The 20 desired product is obtained with MW = 622.12 (calculated, monoisotopic); measured value (M+H)*: 623.13 205 Example 238 N-[8-Cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-(4-fluorobenzyl)-4,7-dioxoocta hydropyrazino[1,2-a]pyrimid in-3-yl]cyclopentanecarboxamide Structure: ci 7 N 0 F /N N ci 0 0 N 5 01=0 5 Synthesis takes place in analogy to Example 31 starting from 3-amino-6-(4 fluorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The 10 desired product is obtained with MW = 636.14 (calculated, monoisotopic); measured value (M+H)*: 637.14 Example 239 N-[8-Cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-(4-fluorobenzyl)-4,7-dioxoocta 15 hydropyrazino[1,2-a]pyrimidin-3-yl]-4-dimethylaminobenzamide Structure: ci Y 7 N N ci 0 Y--0 N 0 206 Synthesis takes place in analogy to Example 25 starting from 3-amino-6-(4 fluorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 687.15 (calculated, monoisotopic); 5 measured value (M+H)*: 688.15 Example 240 1 -tert-Butyl-3-[8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-(4-fluorobenzyl) 4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]urea 10 Structure: CI Ni N 0 F ci 0 N -- N Synthesis takes place in analogy to Example 28 starting from 3-amino-6-(4 fluorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The 15 desired product is obtained with MW = 639.15 (calculated, monoisotopic); measured value (M+H)*: 640.18 Example 241 N-[8-Cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-(4-fluorobenzyl)-4,7-dioxoocta 20 hydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide 207 Structure: C1Y N N 0 F S, 'p '/ N N C 1 0 0 N, 0 Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 5 fluorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 618.06 (calculated, monoisotopic); measured value (M+H)*: 619.08 10 Example 242 8-Cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-3-dimethylamino-6-(4 fluorobenzyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: CI N NN F "N N C1 0 15 Synthesis takes place in analogy to Example 72 starting from 3-amino-6-(4 fluorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 568.11 (calculated, monoisotopic); measured value (M+H)*: 569.12 20 208 Example 243 8-Cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-(4-fluorobenzyl)-3-piperidin-1 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: 0 F C11 "N N Ci 0 0 5 0 Synthesis takes place in analogy to Example 59 starting from 3-amino-6-(4 fluorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimid ine-4,7-dione. The 10 desired product is obtained with MW = 608.14 (calculated, monoisotopic); measured value (M+H)*: 609.14 Example 244 8-Cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-(4-fluorobenzyl)-3-morpholin-4 15 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: Cl7 N N ci 0 0 (N) 0 Synthesis takes place in analogy to Example 60 starting from 3-amino-6-(4 fluorobenzyl)-8-cyclopropyl-1 -(2,4 20 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-alpyrimidine-4,7-dione. The 209 desired product is obtained with MW = 610.12 (calculated, monoisotopic); measured value (M+H)*: 611.1 Example 245 5 C17 N CI ci o ll 0 N a) Benzyl [6-(3-chlorobenzyl)-8-cyclopropyl-1 -(2,4-d ichlorobenzenesulfonyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate Synthesis takes place in analogy to Example 66a). The desired product is obtained 10 with MW = 690.09 (calculated, monoisotopic); measured value (M+H)*: 691.0 b) 3-Amino-6-(3-chlorobenzyl)-8-cyclopropyl- 1-(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 66b) starting from benzyl [6-(3 15 chlorobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 d ioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 556.05 (calculated, monoisotopic); measured value (M+H)*: 557.04 20 c) N-[6-(3-Chlorobenzyl)-8-cyclopropyl-1-(2,4-dichlorobenzenesulfonyl)-4,7 d ioxooctahyd ropyrazino[1,2-a]pyrimidin-3-yl]acetamide Synthesis takes place in analogy to Example 21 h) starting from 3-amino-6-(3 chlorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The 25 desired product is obtained with MW = 598.06 (calculated, monoisotopic); measured value (M+H)*: 599.0 210 Example 246 N-[6-(3-Chlorobenzyl)-8-cyclopropyl- 1 -(2,4-dichlorobenzenesulfonyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Structure: cl "N N CI Cl 0 0 N 5 Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(3 chlorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 624.08 (calculated, monoisotopic); 10 measured value (M+H)*: 625.0 Example 247 N-[6-(3-Chlorobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide 15 Structure: ci / N C /I"N N C1 cl o Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(3 chlorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The 20 desired product is obtained with MW = 638.09 (calculated, monoisotopic); measured value (M+H)*: 639.08 211 Example 248 N-[6-(3-Chlorobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 d ioxooctahyd ropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide Structure: cl N 10 // N CI c S o C, 0 --- N 5 CT 0 5 Synthesis takes place in analogy to Example 31 starting from 3-amino-6-(3 chlorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 652.11 (calculated, monoisotopic); 10 measured value (M+H)*: 653.0 Example 249 N-[6-(3-Chlorobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-4-dimethylaminobenzamide 15 Structure: ci N %I N N cl c' 0 =0 N O Synthesis takes place in analogy to Example 25 starting from 3-amino-6-(3 chlorobenzyl)-8-cyclopropyl-1 -(2,4 20 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The 212 desired product is obtained with MW = 703.12 (calculated, monoisotopic); measured value (M+H)*: 704.0 Example 250 5 1 -tert-Butyl-3-[6-(3-chlorobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl) 4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]urea Structure: ci "N N Cl ci 0 N Synthesis takes place in analogy to Example 28 starting from 3-amino-6-(3 10 chlorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 655.12 (calculated, monoisotopic); measured value (M+H)*: 656.11 15 Example 251 N-[6-(3-Chlorobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide Structure: C1 /N N CI ci 0 N , 0 5, o' \ 20 Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(3 chlorobenzyl)-8-cyclopropyl-1 -(2,4- 213 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 634.03 (calculated, monoisotopic); measured value (M+H)*: 635.0 Example 252 5 6-(3-Chlorobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-3 dimethylaminohexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ci / N N cl ci 0 Synthesis takes place in analogy to Example 72 starting from 3-amino-6-(3 10 chlorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 584.08 (calculated, monoisotopic); measured value (M+H)*: 585.1 15 Example 253 3-Azetidin-1-yl-6-(3-chlorobenzyl)-8-cyclopropyl-1-(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ci N7 CI o N N ci ci 0 N 20 Synthesis takes place in analogy to Example 73 starting from 3-amino-6-(3 chlorobenzyl)-8-cyclopropyl-1 -(2,4- 214 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 596.08 (calculated, monoisotopic); measured value (M+H)*: 597.07 Example 254 5 6-(3-Chlorobenzyl)-8-cyclopropyl-1-(2,4-dichlorobenzenesulfonyl)-3-pyrrolidin-1 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: c1 "N N cl cl 0 0 Synthesis takes place in analogy to Example 74 starting from 3-amino-6-(3 10 chlorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 610.10 (calculated, monoisotopic); measured value (M+H)*: 611.09 15 Example 255 6-(3-Chlorobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-3-piperidin-1 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: C1 Y ciN "N N Cl cN 0 N 0 215 Synthesis takes place in analogy to Example 59 starting from 3-amino-6-(3 chlorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 624.11 (calculated, monoisotopic); 5 measured value (M+H)*: 625.11 Example 256 6-(3-Ch lorobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-3-morpholin-4 ylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ci N NC ci 0 (N) 100 Synthesis takes place in analogy to Example 60 starting from 3-amino-6-(3 chlorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 626.09 (calculated, monoisotopic); 15 measured value (M+H)*: 627.09 Example 257 cI Y NI N 0 F "N N F C1 0 N 10 216 a) 9H-Fluoren-9-ylmethyl [1 -[cyclopropyl(2,2-d iethoxyethyl)carba moyl]-2-(3,4 difluorophenyl)ethyl]carbamate Synthesis takes place in analogy to Example 29a) (Method B) starting from N Fmoc-3,4-F 2 -Phe-OH and cyclopropyl(2,2-diethoxyethyl)amine. The desired 5 product is obtained with MW = 578.26 (calculated, monoisotopic); measured value (M+H)*: 579.3 b) 2-Amino-3-(3,4-d ifluorophenyl)-N-cyclopropyl-N-(2,2 diethoxyethyl)propionamide 10 Synthesis takes place in analogy to Example 29b) (Method B) starting from 9H fluoren-9-ylmethyl [1-[cyclopropyl (2,2-diethoxyethyl)carbamoyl]-2-(3,4 difluorophenyl)ethyl]carbamate. The desired product is obtained with MW = 356.19 (calculated, monoisotopic); measured value (M+H)*: 357.23 15 c) Benzyl [1-{2-(3,4-difluorophenyl)-1-[cyclopropyl(2,2 diethoxyethyl)carbamoyl]ethylcarbamoyl}-2-(9H-fluoren-9 ylmethoxycarbonylamino)ethyl]carbamate Synthesis took place in analogy to Example 29c) (Method B) starting from 2 amino-3-(3,4-difluorophenyl)-N-cyclopropyl-N-(2,2-diethoxyethyl)propionamide. 20 The desired product is obtained with MW = 798.34 (calculated, monoisotopic); measured value (M+Na)*: 821.35 d) Benzyl (2-amino-1-{2-(3,4-difluorophenyl)-1-[cyclopropyl(2,2-diethoxyethyl) ca rbamoyl]ethylcarbamoyl}ethyl)carbamate. 25 Synthesis took place in analogy to Example 29d) (Method B) starting from benzyl [1 -{2-(3,4-difluorophenyl)-1 -[cyclopropyl(2,2 diethoxyethyl)carbamoyl]ethylcarbamoyl}-2-(9H-fluoren-9 ylmethoxycarbonylamino)ethyl]carbamate. The desired product is obtained with MW = 576.28 (calculated, monoisotopic); measured value (M+Na)*: 599.27 30 217 f) Benzyl [1 -{2-(3,4-difluorophenyl)-1 -[cyclopropyl(2,2 diethoxyethyl)carbamoyl]ethylcarbamoyl}-2-(2,4 dichlorobenzenesulfonylamino)ethyl]carbamate Synthesis took place in analogy to Example 29e) (Method B) starting from benzyl 5 (2-amino-1 -{2-(3,4-difluorophenyl)-1 -[cyclopropyl(2,2 diethoxyethyl)carbamoyl]ethylcarbamoyl}ethyl)carbamate. The desired product is obtained with MW = 784.19 (calculated, monoisotopic); measured value (M+Na)*: 807.18. 10 e) Benzyl [6-(3,4-difluorobenzyl)-8-cyclopropyl-1 -(2,4-d ichlorobenzenesulfonyl) 4,7-d ioxooctahydropyrazino[1,2-a]pyrimid in-3-yl]carbamate Synthesis takes place in analogy to Example 29f) (Method B) starting from benzyl [1 -{2-(3,4-difluorophenyl)-1 -[cyclopropyl(2,2 diethoxyethyl)carbamoyl]ethylcarbamoyl}-2-(2,4 15 dichlorobenzenesulfonylamino)ethyl]carbamate. The desired product is obtained with MW = 692.11 (calculated, monoisotopic); measured value (M+H)*: 693.0 f) 3-Amino-6-(3,4-difluorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione 20 Synthesis takes place in analogy to Example 29g) (Method B) starting from benzyl [6-(3,4-difluorobenzyl)-8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 558.07 (calculated, monoisotopic); measured value (M+H)*: 559.05 25 g) N-[8-Cyclopropyl-1 -(2,4-dichlorobenzenesufonyl)-6-(3,4-difluorobenzyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(3,4 difluorobenzyl)-8-cyclopropyl-1 -(2,4 30 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 626.10 (calculated, monoisotopic); measured value (M+H)*: 627.18 218 Example 258 N-[8-Cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-(3,4-difluorobenzyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide 5 Structure: ci 7 "0 N, 0 F "N N F cl 0 '0 N 0 Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(3,4 difluorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The 10 desired product is obtained with MW = 640.11 (calculated, monoisotopic); measured value (M+H)*: 641.1 Example 259 N-[8-Cyclopropyl-1 -(2,4-dichlorobenzenesufonyl)-6-(3,4-d ifluorobenzyl)-4,7 15 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide Structure: ci N N OUF cis, /I N NF C1 0 0 N C=0 Synthesis takes place in analogy to Example 31 starting from 3-amino-6-(3,4 difluorobenzyl)-8-cyclopropyl-1 -(2,4 20 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The 219 desired product is obtained with MW = 654.13 (calculated, monoisotopic); measured value (M+H)*: 655.21 Example 260 5 N-[8-Cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-(3,4-difluorobenzyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclohexanecarboxamide Structure: N NF ci o cl 0 N Synthesis takes place in analogy to Example 32 starting from 3-amino-6-(3,4 10 d ifluorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 668.14 (calculated, monoisotopic); measured value (M+H)*: 669.22 15 Example 261 N-[8-Cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-(3,4-difluorobenzyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide Structure: "N N F ci 0 N 0 N o s 220 Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(3,4 difluorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 636.05 (calculated, monoisotopic); 5 measured value (M+H)*: 637.07 Example 262 8-Cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-(3,4-difluorobenzyl)-3 dimethylaminohexahydropyrazino[1,2-a]pyrimidine-4,7-dione 10 Structure: Cl ci0 N 0F N N F C1 0 /NN Synthesis takes place in analogy to Example 72 starting from 3-amino-6-(3,4 difluorobenzyl)-8-cyclopropyl-1 -(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The 15 desired product is obtained with MW = 586.10 (calculated, monoisotopic); measured value (M+H)*: 587.10 Example 263 ci0 N 0 N N ci 0 0 20 a) 9H-Fluoren-9-ylmethyl {1-[cyclopropyl(2,2-diethoxyethyl)carbamoyl]-2-pyridin-3 yl-ethyl}carbamate 221 Synthesis takes place in analogy to Example 29a) (Method B) starting from Fmoc PAL-OH and cyclopropyl(2,2-diethoxyethyl)amine. The desired product is obtained with MW = 543.27 (calculated, monoisotopic); measured value (M+H)*: 544.21 5 b) 2-Amino-N-cyclopropyl-N-(2,2-diethoxyethyl)-3-pyridin-3-ylpropionamide Synthesis takes place in analogy to Example 29b) (Method B) starting from 9H fluoren-9-ylmethyl {1-[cyclopropyl(2,2-diethoxyethyl)carbamoyl]-2-pyridin-3-yl ethyl}carbamate. The desired product is obtained with MW = 321.21 (calculated, monoisotopic); measured value (M+H)*: 322.20 10 c) Benzyl [1 -{1 -[cyclopropyl(2,2-diethoxyethyl)carbamoyl]-2-pyridin-3-ylethyl carbamoyl}-2-(9H-fluoren-9-ylmethoxycarbonylamino)ethyl]carbamate Synthesis took place in analogy to Example 29c) (Method B) starting from 2 amino-N-cyclopropyl-N-(2,2-diethoxyethyl)-3-pyridin-3-ylpropionamide. The 15 desired product is obtained with MW = 798.34 (calculated, monoisotopic); measured value (M+Na)*: 821.35 d) Benzyl (2-amino-1 -{1 -[cyclopropyl(2,2-diethoxyethyl)carbamoyl]-2-pyridin-3 ylethylcarbamoyl}ethyl)carbamate. 20 Synthesis took place in analogy to Example 29d) (Method B) starting from benzyl [1 -{1 -[cyclopropyl(2,2-diethoxyethyl)carbamoyl]-2-pyrid in-3-ylethylcarbamoyl}-2 (9H-fluoren-9-ylmethoxycarbonylamino)ethyl]carbamate. The desired product is obtained with MW = 541.29 (calculated, monoisotopic); measured value (M+H)*: 542.30 25 e) Benzyl [1-{1-[cyclopropyl(2,2-diethoxyethyl)carbamoyl]-2-pyridin-3-ylethyl carbamoyl}-2-(2,4-dichlorobenzenesulfonylamino)ethyl]carbamate Synthesis took place in analogy to Example 29e) (Method B) starting from benzyl (2-amino-1 -{1 -[cyclopropyl(2,2-diethoxyethyl)carbamoyl]-2-pyrid in-3 30 ylethylcarbamoyl}ethyl)carbamate. The desired product is obtained with MW = 826.12 (calculated, monoisotopic); measured value (M+Na)*: 849.14.
222 f) Benzyl [8-cyclopropyl-1-(2,4-dichlorobenzenesulfonyl)-4,7-dioxo-6-pyridin-3 yl methyloctahydropyrazino[1,2-a]pyrimid in-3-yl]carba mate Synthesis takes place in analogy to Example 29f) (Method B) starting from benzyl [1 -{1 -[cyclopropyl(2,2-d iethoxyethyl)carbamoyl]-2-pyrid in-3-ylethylcarbamoyl}-2 5 (2,4-dichlorobenzenesulfonylamino)ethyl]carbamate. The desired product is obtained with MW = 657.12 (calculated, monoisotopic); measured value (M+H)*: 658.11 g) 3-Amino-8-cyclopropyl-1-(2,4-dichlorobenzenesulfonyl)-6-pyridin-3 10 ylmethylhexahydropyrazino[1,2-a]pyrimid ine-4,7-dione Synthesis takes place in analogy to Example 29g) (Method B) starting from benzyl [8-cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7-dioxo-6-pyridin-3 ylmethyloctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 523.08 (calculated, monoisotopic); measured value (M+H)*: 15 524.09 h) N-[8-Cyclopropyl-1-(2,4-dichlorobenzenesulfonyl)-4,7-dioxo-6-pyridin-3 ylmethyloctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide Synthesis takes place in analogy to Example 21 h) starting from 3-amino-8 20 cyclopropyl-1 -(2,4-dichlorobenzenesufonyl)-6-pyridin-3 ylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 565.10 (calculated, monoisotopic); measured value (M+H)*: 566.10 25 Example 264 N-[8-Cyclopropyl-1 -(2,4-d ichlorobenzenesulfonyl)-4,7-dioxo-6-pyridin-3 ylmethyloctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Structure: 223 ci o ' N N ci 0 N Synthesis takes place in analogy to Example 22 starting from 3-amino-8 cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-pyridin-3 ylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 5 obtained with MW = 591.11 (calculated, monoisotopic); measured value (M+H)*: 592.09 Example 265 N-[8-Cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7-d ioxo-6-pyrid in-3 10 ylmethyloctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide Structure: ci N N N Synthesis takes place in analogy to Example 30 starting from 3-amino-8 cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-pyridin-3 15 ylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 605.13 (calculated, monoisotopic); measured value (M+H) : 606.12 Example 266 N-[8-Cyclopropyl-1 -(2,4-dichlorobenzenesufonyl)-4,7-dioxo-6-pyridin-3 20 ylmethyloctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide 224 Structure: ci 7 N N ci 0 11 0 N e0 Synthesis takes place in analogy to Example 31 starting from 3-amino-8 cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-pyridin-3 5 ylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 619.14 (calculated, monoisotopic); measured value (M+H)*: 620.14 Example 267 10 N-[8-Cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7-dioxo-6-pyridin-3 ylmethyloctahydropyrazino[1,2-a]pyrimidin-3-yl]pyrrolidine-2-carboxamide Structure: ci "0 N N NN ci 0 0 N eN0 Synthesis takes place in analogy to Example 40 starting from 3-amino-8 15 cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-pyridin-3 ylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-d ione. The desired product is obtained with MW = 620.14 (calculated, monoisotopic); measured value (M+H)*: 621.12 225 Example 268 N-[8-Cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7-dioxo-6-pyridin-3 ylmethyloctahydropyrazino[1,2-a]pyrimidin-3-yl]-4-dimethylaminobenzamide Structure: cl NN " N N ci 0 N 0 -N 5 Synthesis takes place in analogy to Example 25 starting from 3-amino-8 cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-pyridin-3 ylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 670.15 (calculated, monoisotopic); measured value (M+H)*: 10 671.16 Example 269 N-[8-Cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7-dioxo-6-pyridin-3 ylmethyloctahydropyrazino[1,2-a]pyrimidin-3-yl]pyridine-2-carboxamide 15 Structure: ci N N cio ' N N CI 0 N Synthesis takes place in analogy to Example 49 starting from 3-amino-8 cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-pyridin-3 ylmethylhexahydropyrazino[1,2-ajpyrimidine-4,7-dione. The desired product is 226 obtained with MW = 628.11 (calculated, monoisotopic); measured value (M+H)*: 629.14 Example 270 5 1 -tert-Butyl-3-[8-cyclopropyl- 1 -(2,4-dichlorobenzenesulfonyl)-4,7-dioxo-6-pyridin-3 ylmethyloctahydropyrazino[1,2-a]pyrimidin-3-yl]urea Structure: ci / N NN ci 0 N N Synthesis takes place in analogy to Example 28 starting from 3-amino-8 10 cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-pyridin-3 ylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 622.15 (calculated, monoisotopic); measured value (M+H)*: 623.16 15 Example 271 N-[8-Cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7-dioxo-6-pyridin-3 ylmethyloctahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide Structure: C1 cN NX)N1 Ci 0 N, ;0 0s \ 20 Synthesis takes place in analogy to Example 26 starting from 3-amino-8 cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-pyridin-3 ylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 227 obtained with MW = 601.06 (calculated, monoisotopic); measured value (M+H)*: 602.06 Example 272 5 N-[8-Cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7-dioxo-6-pyridin-3 ylmethyloctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanesulfonamide Structure: CI -~N 0U // N N ci 0 N,0 No 0s Synthesis takes place in analogy to Example 27 starting from 3-amino-8 10 cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-6-pyridin-3 ylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 627.08 (calculated, monoisotopic); measured value (M+H)*: 628.09 15 Example 273 8-Cyclopropyl-1 -(2,4-dichlorobenzenesulfonyl)-3-dimethylamino-6-pyridin-3 ylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: ci / N Q C, / N N c-, 0 20 Synthesis takes place in analogy to Example 72 starting from 3-amino-8 cyclopropyl-1 -(2,4-dichlorobenzenesufonyl)-6-pyridin-3 ylmethylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 228 obtained with MW = 551.12 (calculated, monoisotopic); measured value (M+H)*: 552.14 Example 274 -~N 0 ci NN ci/ N NC ci 0 -0 a) Cyclobutyl(2,2-diethoxyethyl)amine A solution of 1.75 ml (11.65 mmol) of 1-bromo-2,2-diethoxyethane and 2 ml (23.3 mmol) of cyclobutylamine was heated at 80'C in a closed vessel overnight. The reaction mixture was mixed with 40% NaOH (in H 2 0) and extracted with ether. 10 The organic phase was isolated, dried (MgSO 4 ) and concentrated in vacuo. 2.39 g of substance were obtained as an orange liquid. b) 2-Amino-3-(4-chlorophenyl)-N-cyclobutyl-N-(2,2-d iethoxyethyl)propionamide A solution of 1.0 g (2.37 mmol) of Fmoc-Phe(4-CI)-OH and 489 mg (2.61 mmol) of 15 the amine cyclobutyl(2,2-diethoxyethyl)amine was dissolved in 9.5 ml of dimethylformamide. 722 mg (2.61 mmol) of DMTMM were added to this solution. The mixture was stirred at room temperature overnight, diluted with ethyl acetate and washed with water and brine. The organic phase was isolated, dried (MgSO 4 ) and concentrated in vacuo. The residue was chromatographed on 40 g of SiO 2 20 (elution with EtOAc/heptane, gradient 10-70%). 890 mg of the substance were obtained as a white foam. LC/MS M*= 591, measured value (M*Na) = 613 and M OEt = 545 agreed with the desired substance. A solution of 890 mg (1.5 mmol) of said substance was dissolved in 7.5 ml of dimethylformamide, and 0.8 ml of diethylamine was added. The reaction mixture was stirred at room temperature for 25 10 minutes and concentrated in vacuo. The residue was subjected to a flash chromatography on 12 g of SiO 2 (elution with MeOH in DCM, gradient 1-10%). 470 mg of the desired amine 2-amino-3-(4-chlorophenyl)-N-cyclobutyl-N-(2,2- 229 diethoxyethyl)propionamide were obtained as a colorless oil. LC/MS M* = 368, measured value (M*Na) = 391 and M-OEt = 323 agree with the structure. c) Benzyl [1-{2-(4-chlorophenyl)-1-[cyclobutyl(2,2-diethoxyethyl)carbamoyl]ethyl 5 carbamoyl}-2-(2,4-dichlorobenzenesulfonylamino)ethyl]carbamate A solution of 2.5 g (10.5 mmol) of Z-Dap-OH in 21 ml of 1 N NaOH was stirred until homogeneous. A solution of 2.83 g (11.5 mmol) of 2,4-dichlorophenylsulfonyl chloride in 29 ml of dioxane was slowly added to the Z-Dap-OH solution. The mixture was then stirred for 2 hours. The reaction mixture was acidified with citric 10 acid and extracted with DCM. The organic phase was dried (MgSO 4 ) and concentrated in vacuo. 4.08 g of the desired sulfonamide were obtained and were employed without further purification in the process described below. 755 mg (2.73 mmol) of DMTMM were added to a solution of 840 mg (2.28 mmol) of 2 amino-3-(4-chlorophenyl)-N-cyclobutyl-N-(2,2-diethoxyethyl)propionamide and 15 1.22 g (2.73 mmol) of said sulfonamide in 9 ml of DMF. The mixture was stirred at room temperature for 2 days, diluted with ethyl acetate and washed with water and brine. The organic phase was isolated, dried (MgSO 4 ) and concentrated in vacuo. 1.9 g of crude substance were obtained as a white foam. The residue was subjected to a flash chromatography on 40 g of SiO 2 (elution with EtOAc/heptane, 20 gradient 10-80%). 1.09 g of the desired substance benzyl [1-{2-(4-chlorophenyl)-1 [cyclobutyl-(2,2-diethoxyethyl)carbamoyl]ethylcarbamoyl}-2-(2,4 dichlorobenzenesulfonylamino)ethyl]carbamate were obtained as a white solid. LC/MS M* = 798, measured value (M*Na) = 819 and M-OEt = 753 agree with the structure. 25 d) Benzyl [6-(4-chlorobenzyl)-8-cyclobutyl-1-(2,4-dichlorobenzenesulfonyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate Synthesis takes place in analogy to Example 29f) (Method B) starting from benzyl [1 -{2-(4-chlorophenyl)- 1 -[cyclobutyl(2,2-diethoxyethyl)carbamoyl]ethylcarbamoyl} 30 2-(2,4-d ichlorobenzenesulfonylamino)ethyl]carbamate. The desired product is obtained with MW = 704.10 (calculated, monoisotopic); measured value (M+H)*: 705.1 230 e) 3-Amino-6-(4-chlorobenzyl)-8-cyclobutyl-1-(2,4 dichlorobenzenesulfonyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 29g) (Method B) starting from benzyl [6-(4-chlorobenzyl)-8-cyclobutyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 5 d ioxooctahydropyrazino[1 ,2-a]pyrimid in-3-yl]carbamate. The desired product is obtained with MW = 570.07 (calculated, monoisotopic); measured value (M+H)*: 570.99 f) N-[6-(4-Chlorobenzyl)-8-cyclobutyl-1-(2,4-dichlorobenzenesulfonyl)-4,7 10 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide Synthesis takes place in analogy to Example 21h) starting from 3-amino-6-(4 chlorobenzyl)-8-cyclobutyl-1 -(2,4-dichlorobenzenesulfonyl)hexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 612.08 (calculated, monoisotopic); measured value (M+H)*: 613.07 15 Example 275 N-[6-(4-Chlorobenzyl)-8-cyclobutyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Structure: C1 NI 00 ci / N N ci 0 N 20 Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(4 chlorobenzyl)-8-cyclobutyl-1 -(2,4-dichlorobenzenesulfonyl)hexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 638.09 (calculated, monoisotopic); measured value (M+H)*: 639.09 25 231 Example 276 1-[6-(4-Chlorobenzyl)-8-cyclobutyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]-3-ethylurea Structure: 0 CI N N Cl 0 N #=0 5 N Synthesis takes place in analogy to Example 57 starting from 3-amino-6-(4 chlorobenzyl)-8-cyclobutyl-1 -(2,4-dichlorobenzenesulfonyl)hexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 641.10 (calculated, monoisotopic); measured value (M+H)*: 642.09 10 Example 277 N-[6-(4-Chlorobenzyl)-8-cyclobutyl-1 -(2,4-dichlorobenzenesulfonyl)-4,7 d ioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide Structure: ci/N N' c1 N 15 0-s Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 chlorobenzyl)-8-cyclobutyl-1 -(2,4-dichlorobenzenesulfonyl)hexahydropyrazino[1,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 648.04 (calculated, monoisotopic); measured value (M+H)*: 649.15 232 Example 278 6-(4-Chlorobenzyl)-8-cyclobutyl-1 -(2,4-dichlorobenzenesulfonyl)-3 dimethylaminohexahydropyrazino[1,2-a]pyrimidine-4,7-dione Structure: C1 ci -l 0 ci //N N ci 0 5N Synthesis takes place in analogy to Example 72 starting from 3-amino-6-(4 chlorobenzyl)-8-cyclobutyl-1 -(2,4-dichlorobenzenesulfonyl)hexahydropyrazino[l,2 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 598.10 (calculated, monoisotopic); measured value (M+H)*: 599.07 10 Example 279 F ci N cl " N N ci 0 0 N 15 a) (2,2-Diethoxyethyl)-(2-fluoroethyl)amine A solution of 3.1 ml (21.5 mmol) of 1-amino-2,2-diethoxyethane, 3.0 g (23.6 mmol) of 1-bromo-2-fluoroethane and 5.56 g (43 mmol) of diisopropylethylamine was heated at 100*C in a closed vessel for 6 hours. The reaction mixture was diluted with ether and washed with 1 N NaOH and water. The organic phase was dried 20 (MgSO 4 ) and concentrated in vacuo. The residue was distilled in vacuo. 1.3 g of substance were obtained as a clear liquid.
233 b) 2-Amino-3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-(2-fluoroethyl)propionamide Synthesis takes place in analogy to Example 274b). The desired product is obtained with MW = 360.16 (calculated, monoisotopic); measured value (M+H)*: 361.2 5 c) Benzyl [1-{2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)-(2 fluoroethyl)carbamoyl]ethylcarbamoyl}-2-(2,4 d ichlorobenzenesulfonylamino)ethyl]carbamate Synthesis takes place in analogy to Example 274c). The desired product is 10 obtained with MW = 788.16 (calculated, monoisotopic); measured value (M+Na)*: 811.19 d) Benzyl [6-(4-chlorobenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-(2-fluoroethyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate 15 Synthesis takes place in analogy to Example 29f) (Method B) starting from benzyl [1 -{2-(4-chlorophenyl)-1 -[(2,2-diethoxyethyl)-(2 fluoroethyl)carbamoyl]ethylcarbamoyl}-2-(2,4 dichlorobenzenesulfonylamino)ethyl]carbamate. The desired product is obtained with MW = 696.08 (calculated, monoisotopic); measured value (M+H)*: 697.04 20 e) 3-Amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesufonyl)-8-(2 fluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 29e) (Method B) starting from benzyl [6-(4-chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2-fluoroethyl)-4,7 25 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 562.04 (calculated, monoisotopic); measured value (M+H)*: 563.03 f) N-[6-(4-Chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-(2-fluoroethyl)-4,7 30 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide Synthesis takes place in analogy to Example 21 h) starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2- 234 fluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 604.05 (calculated, monoisotopic); measured value (M+H)*: 605.07 Example 280 5 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesu Ifonyl )-8-(2-fluoroethyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Structure: F ci No c / N N ci 0 N Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(4 10 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2 fluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 630.07 (calculated, monoisotopic); measured value (M+H)*: 631.06 15 Example 281 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2-fluoroethyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide 235 Structure: F cN N N ci o 0 N _0 Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2 5 fluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 644.08 (calculated, monoisotopic); measured value (M+H)*: 645.11 Example 282 10 1 -tert-Butyl-3-[6-(4-chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2-fluoroethyl) 4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]urea Structure: F c i N 0 c i / N N CI ci 0 0 N N+==o Synthesis takes place in analogy to Example 28 starting from 3-amino-6-(4 15 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2 fluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 661.11 (calculated, monoisotopic); measured value (M+H)*: 662.1 236 Example 283 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2-fluoroethyl)-4,7 dioxooctahydropyrazino[l,2-a]pyrimidin-3-yl]methanesulfonamide Structure: F N 0Ci // N NCI Ci 0 5 Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-(2 fluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 640.02 (calculated, monoisotopic); measured value (M+H)*: 10 641.03 Example 284 6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-3-dimethylamino-8-(2 fluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione 15 Structure: ci N ac // N N ci 0 N Synthesis takes place in analogy to Example 72 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2 fluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-d ione. The desired product is 237 obtained with MW = 590.07 (calculated, monoisotopic); measured value (M+H)*: 591.04 Example 285 5 F F ci 1 N, 0 Ci "N Nc ci 0 0 N I>0 a) (2,2-Diethoxyethyl)-(2,2-difluoroethyl)amine A solution of 3 g (22.5 mmol) of 1-amino-2,2-diethoxyethane, 3.1 g (24.8 mmol) of 10 difluoroacetaldehyde ethyl hemiacetal and 1 pellet of solid NaOH in 44 ml of toluene was heated at 120 0 C with a Dean-Stark trap for 1.5 hours. The mixture was left to stand until it had cooled to room temperature and was concentrated in vacuo. The residue was diluted with 80 ml of methanol, and 3.4 g (90 mmol) of sodium borohydride were added in small quantities. The reaction mixture was then 15 stirred overnight, concentrated in vacuo and partitioned between ethyl acetate and water. The organic phase was isolated, dried (MgSO 4 ) and concentrated in vacuo. 3.7 g of crude substance were obtained as a colorless oil. The residue was subjected to a flash chromatography on 40 g of SiO 2 (elution with DCM/MeOH, gradient 1-8%). 3.1 g of the desired amine were obtained as a colorless oil. 20 b) 2-Amino-3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-(2,2 difluoroethyl)propionamide Synthesis takes place in analogy to Example 274b). The desired product is obtained with MW = 378.15 (calculated, monoisotopic); measured value (M+H)*: 25 379.18 238 c) Benzyl [1-{2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)-(2,2 d if luoroethyl)carba moyl]ethylcarbamoyl}-2-(2,4 dichlorobenzenesulfonylamino)ethyl]carbamate Synthesis takes place in analogy to Example 274c). The desired product is 5 obtained with MW = 806.15 (calculated, monoisotopic); measured value (M+Na)*: 829.11 d) Benzyl [6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-(2,2-difluoroethyl) 4,7-d ioxooctahydropyrazino[1,2-a]pyrimid in-3-yl]carbamate Synthesis takes place in analogy to Example 29f) (Method B) starting from benzyl 10 [1 -{2-(4-chlorophenyl)-1 -[(2,2-diethoxyethyl)-(2,2 difluoroethyl)carbamoyl]ethylcarbamoyl}-2-(2,4 dichlorobenzenesulfonylamino)ethyl]carbamate. The desired product is obtained with MW = 714.07 (calculated, monoisotopic); measured value (M+H)*: 715.02 15 e) 3-Amino-6-(4-chlorobenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-(2,2 difluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 29e) (Method B) starting from benzyl [6-(4-chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2,2-difluoroethyl)-4,7 d ioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is 20 obtained with MW = 580.03 (calculated, monoisotopic); measured value (M+H)*: 580.99 f) N-[6-(4-Chlorobenzyl)-1-(2,4-d ichlorobenzenesufonyl)-8-(2,2-difluoroethyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide 25 Synthesis takes place in analogy to Example 21 h) starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2,2-difluoroethyl)hexahydro pyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 622.04 (calculated, monoisotopic); measured value (M+H)*: 623.03 239 Example 286 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2,2-difluoroethyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide Structure: F F N N 0 C1 ci o CI 0 Y 0 N 5 Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2,2 difluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 648.06 (calculated, monoisotopic); measured value (M+H)*: 10 649.04 Example 287 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2,2-difluoroethyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide 15 F Cl N N ci 0 N Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2,2 difluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 20 obtained with MW = 662.07 (calculated, monoisotopic); measured value (M+H)*: 663.06 240 Example 288 N-[6-(4-Chlorobenzyl)-1 -(2,4-d ichlorobenzenesulfonyl)-8-(2,2-d ifluoroethyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide 5 F F C1 N N 0 C1 N N N CI0 0 N ce 0 Synthesis takes place in analogy to Example 31 starting from 3-amino-6-(4 chlorobenzyl)-l -(2,4-dichlorobenzenesulfonyl)-8-(2,2 difluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 10 obtained with MW = 676.09 (calculated, monoisotopic); measured value (M+H)*: 677.07 Example 289 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2,2-difluoroethyl)-4,7 15 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]pyrrolidine-2-carboxamide F N N C S'"o /I N NC CI 0 0 N eN0 Synthesis takes place in analogy to Example 40 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2,2 20 difluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is 241 obtained with MW = 677.08 (calculated, monoisotopic); measured value (M+H)*: 678.08 Example 290 5 6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2,2-difluoroethyl)-3 dimethylaminohexahydropyrazino[1,2-a]pyrimidine-4,7-dione F F 0N CI 10~ / N N cl 0 0 N Synthesis takes place in analogy to Example 72 starting from 3-amino-6-(4 10 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2,2 difluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 608.06 (calculated, monoisotopic); measured value (M+H)*: 609.05 15 Example 291 6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2,2-difluoroethyl)-3 morpholin-4-ylhexahydropyrazino[1,2-a]pyrimidine-4,7-d ione F ci cl 0 1l 'N N ci 0 (N) 0 20 Synthesis takes place in analogy to Example 60 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2,2- 242 difluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 650.07 (calculated, monoisotopic); measured value (M+H)*: 651.07 5 Example 292 F c F cN N CF c i c C ' N N ci-, 0 N 10 a) (2,2-Diethoxyethyl)-(2,2,2-trifluoroethyl)amine 10 A solution of 1 g (7.5 mmol) of 1-amino-2,2-diethoxyethane, 1.26 g (7.9 mmol) of trifluoroacetaldehyde ethyl hemiacetal and 1 pellet of NaOH in 15 ml of toluene was heated at 1100C with a Dean-Stark trap for 3 hours. The mixture was heated at 1250C for a further 3 hours. The reaction mixture was left to stand until it had cooled to room temperature and was concentrated in vacuo. The residue was 15 diluted with 25 ml of methanol, and 1.13 g (30 mmol) of sodium borohydride were added. The reaction mixture was then heated to 700C and stirred overnight, concentrated in vacuo and partitioned between water and ethyl acetate. The organic phase was isolated, dried (MgSO 4 ) and concentrated in vacuo. 740 mg of the desired amine were obtained as a clear oil. 20 b) 2-Amino-3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N-(2,2,2-trifluoroethyl) propionamide Synthesis takes place in analogy to Example 274b). The desired product is obtained with MW = 378.15 (calculated, monoisotopic); measured value (M+H)*: 25 379.18 243 c) Benzyl [1-{2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)-(2,2,2 trifluoroethyl)carbamoyl]ethylcarbamoyl}-2-(2,4 dichlorobenzenesulfonylamino)ethyl]carbamate Synthesis takes place in analogy to Example 274c). The desired product is 5 obtained with MW = 806.15 (calculated, monoisotopic); measured value (M+Na)*: 829.11 d) Benzyl [6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-(2,2,2 trifluoroethyl)-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate 10 Synthesis takes place in analogy to Example 29f) (Method B) starting from benzyl [1 -{2-(4-chlorophenyl)-1 -[(2,2-diethoxyethyl)-(2,2,2 trifluoroethyl)carbamoyl]ethylcarbamoyl}-2-(2,4 dichlorobenzenesulfonylamino)ethyl]carbamate. The desired product is obtained with MW = 732.06 (calculated, monoisotopic); measured value (M+H)*: 732.12 15 e) 3-Amino-6-(4-chlorobenzyl)-1 -(2,4-d ichlorobenzenesulfonyl)-8-(2,2,2 trifluoroethyl)hexahydro pyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 29e) (Method B) starting from benzyl [6-(4-chlorobenzyl)-1 -(2,4-d ichlorobenzenesulfonyl)-8-(2,2,2-trifluoroethyl)-4,7 20 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 598.02 (calculated, monoisotopic); measured value (M+H)*: 599.06 f) N-[6-(4-Chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-(2,2,2-trifluoroethyl) 25 4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide Synthesis takes place in analogy to Example 21 h) starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2,2,2-trifluoroethyl)hexahydro pyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 640.03 (calculated, monoisotopic); measured value (M+H)*: 641.06 30 244 Example 293 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-4,7-dioxo-8-(2,2,2 trifluoroethyl)octahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide F " F c1 F 0 ci 00 N N c N 0 5 Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2,2,2 trifluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 666.05 (calculated, monoisotopic); measured value (M+H)*: 10 667.07 Example 294 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-4,7-dioxo-8-(2,2,2 trifluoroethyl)octahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide F -F ci F CI
-
0 N 0 CI / N N CI CI 0 -- o 15 U> Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2,2,2 trifluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 680.06 (calculated, monoisotopic); measured value (M+H)*: 20 681.02 245 Example 295 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-4,7-dioxo-8-(2,2,2 trifluoroethyl)octahyd ropyrazino[l ,2-a] pyrimid in-3-yl]cyclopentanecarboxa mide F CI F ci r F N 0 cl // N N ci 0 N 5 0 5 Synthesis takes place in analogy to Example 31 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-d ichlorobenzenesulfonyl)-8-(2,2,2 trifluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 694.08 (calculated, monoisotopic); measured value (M+H)*: 10 695.10 Example 296 N-[6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-4,7-dioxo-8-(2,2,2 trifluoroethyl)octahydropyrazino[1,2-a]pyrimidin-3-yl]piperidine-4-carboxamide F Cl FF S N N ci o N 0 15 N Synthesis takes place in analogy to Example 37 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2,2,2 trifluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 709.09 (calculated, monoisotopic); measured value (M+H)*: 20 710.09 246 Example 297 6-(4-Chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-3-dimethylamino-8-(2,2,2 trifluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione 5 F cF C1 F C N 0 CI "N N ci 0 0 Synthesis takes place in analogy to Example 72 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2,2,2 10 trifluoroethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 626.05 (calculated, monoisotopic); measured value (M+H)*: 627.05 Example 298 15 0 ci 'N N ci 0 N a) Benzyl [6-(4-chlorobenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-(2-hydroxyethyl) 4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate 20 A solution of 3.13 g (3.96 mmol) of benzyl [1-{2-(4-chlorophenyl)-1-[(2,2 diethoxyethyl)-(2-fluoroethyl)carbamoyl]ethylcarbamoyl}-2-(2,4- 247 dichlorobenzenesulfonylamino)ethyl]carbamate in 20 ml of formic acid was heated to 600C and stirred for 6 hours. The reaction mixture was concentrated in vacuo, diluted with EtOAc and washed with 1 N NaHCO 3 solution and brine. The organic phase was isolated, dried (MgSO 4 ) and concentrated in vacuo. This crude 5 substance was subjected to a flash chromatography on 120 g of SiO 2 (elution with EtOAc/heptane, gradient 50-100%). 350 mg of the substance benzyl [6-(4 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2-fluoroethyl)-4,7 dioxoocta hyd ropyrazino[1,2-a]pyrimid in-3-yl]carbamate were obtained. Further elution of the column provided 980 mg of the compound corresponding to the 10 benzyl [6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-(2-hydroxyethyl)-4,7 d ioxoocta hydropyrazino[1,2-a]pyrimidin-3-yl]carbamate byproduct. The monoisotopic MW expected in the LC/MS = 694 and the measured value of (M*H) = 695 agree with the structure. 15 b) 3-Amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-(2 hydroxyethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione Synthesis takes place in analogy to Example 29g) (Method B) starting from benzyl [6-(4-chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2-hydroxyethyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate. The desired product is 20 obtained with MW = 560.04 (calculated, monoisotopic); measured value (M+H)*: 561.03 c) N-[6-(4-Chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-(2-hydroxyethyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclobutanecarboxamide 25 Synthesis takes place in analogy to Example 30 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-dichlorobenzenesufonyl)-8-(2 hydroxyethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 642.09 (calculated, monoisotopic); measured value (M+H)*: 643.11 30 248 Example 299 N-[6-(4-Chlorobenzyl)-1 -(2,4-d ichlorobenzenesulfonyl)-8-(2-hydroxyethyl)-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]cyclopentanecarboxamide 0 ci-~ N, 0 Ci c / N Nc ci 0 N 5 e 0 5 Synthesis takes place in analogy to Example 31 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-(2 hydroxyethyl)hexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 656.10 (calculated, monoisotopic); measured value (M+H)*: 10 657.12 Example 300 ci N" N 0~ ci S/ N N ci 0 1- 0 o=- N 15 a) 2-Benzyloxycarbonylamino-3-(2,5-dichlorobenzenesulfonylamino)propionic acid Synthesis takes place in analogy to Example 21d) starting from 2,5 dichlorobenzenesulfonyl chloride. The desired product is obtained with MW = 446.01 (calculated, monoisotopic); measured value (M+H-CO 2 )*: 403.00. 20 a) N-{2-(4-Chlorophenyl)-1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl}-3-(2,5 dichlorobenzenesulfonylamino)-2-methanesulfonylaminopropionamide 249 Synthesis takes place in analogy to Example 21e) starting from 2 benzyloxycarbonylamino-3-(2,6-dichlorobenzenesulfonylamino)propionic acid. The desired product is obtained with MW = 784.186 (calculated, monoisotopic); measured value (M-CO 2 +H)*: 741.10 5 b) Benzyl [6-(4-chlorobenzyl)-1-(2,5-dichlorobenzenesulfonyl)-8-isopropyl-4,7 d ioxooctahyd ropyrazino[1,2-a]pyrimid in-3-yl]carbamate Synthesis takes place in analogy to Example 21f) starting from N-{2-(4 chlorophenyl)-1 -[(2,2-diethoxyethyl)isopropylcarbamoyl]ethyl}-3-(2,5 dichlorobenzenesulfonylamino)-2-methanesulfonylaminopropionamide. The 10 desired product is obtained with MW = 692.10 (calculated, monoisotopic); measured value (M+H)*: 693.05 d) 3-Amino-6-(4-chlorobenzyl)-1-(2,5-dichlorobenzenesulfonyl)-8 isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione 15 Synthesis takes place in analogy to Example 21g) starting from benzyl [6-(4 chlorobenzyl)-1 -(2,5-dichlorobenzenesulfonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1 ,2-a]pyrimidin-3-yl]carbamate. The desired product is obtained with MW = 558.07 (calculated, monoisotopic); measured value (M+H)*: 559.10 20 e) N-[6-(4-Chlorobenzyl)- 1 -(2,5-dichlorobenzenesufonyl)-8-isopropyl-4,7 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]acetamide Synthesis takes place in analogy to Example 21 h) starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,5-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 25 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 600.08 (calculated, monoisotopic); measured value (M+H)*: 601.13. Example 301 N-[6-(4-Chlorobenzyl)-1 -(2,5-d ichlorobenzenesulfonyl)-8-isopropyl-4,7 30 dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]methanesulfonamide 250 cl N 0 CI /l 42, N N CI 0 -r-0 N / "0 Synthesis takes place in analogy to Example 26 starting from 3-amino-6-(4 chlorobenzyl)-1 -(2,5-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2 5 a]pyrimidine-4,7-dione. The desired product is obtained with MW = 636.04 (calculated, monoisotopic); measured value (M+H)*: 637.02. Example 302 cl -~ N 0 CI ' NN "N N ci 0 N 10 a) Methyl 2-benzyloxycarbonylamino-3-hydroxy-2-methylpropionate: 250 mg (2.1 mmol) of 2-amino-3-methylhydroxypropanoic acid are dissolved in 9 ml of anhydrous MeOH. The reaction solution is cooled in an ice bath, and 0.153 ml (2.1 mmol) of SOC1 2 is slowly added dropwise. The solution is allowed to reach room temperature slowly overnight. The reaction solution is 15 concentrated in vacuo and then mixed with 1 ml of EtOAc and 5 ml of saturated NaHCO 3 (aqueous), followed by 0.285 ml (1.995 mmol) of benzyl chloroformate. The solution is stirred at room temperature overnight. Then 5 ml of EtOAc are added, and the organic phase is separated off and washed twice with 1 ml of 1 N HCI (aq) each time and twice with 2 ml of a saturated NaHCO 3 20 (aq) each time, dried over MgSO 4 and concentrated in vacuo. Purification took 251 place by chromatography (40 g of SiO 2 , eluent MeOH/DCM (gradient 0-10%). The desired product is obtained as colorless oil (0.130 g) with MW = 267 (calculated, monoisotopic), measured value:( M+ Na) + 290. b) Methyl 2-benzyloxycarbonylamino-2-methyl-3-oxopropionate: 5 A solution of 97.7 mg (0.23 mmol) of Dess Martin periodinane reagent (Aldrich) in 1 ml of DCM is slowly added dropwise to a solution of 56 mg (0.21 mmol) of methyl 2-benzyloxycarbonylamino-3-hydroxy-2-methylpropionate in 1 ml of DCM, and the mixture is left to stir at room temperature for 30 min. 5 ml of diethyl ether and a mixture of 4 ml of saturated NaHCO 3 and 0.36 g of 10 Na 2
S
2
O
3 .5H 2 0 are then added to the solution. It is stirred for 15 min until the solid has dissolved, and then the ether phase is washed with saturated NaHCO 3 and water, dried over MgSO 4 and concentrated in vacuo. The crude product is purified by chromatography on 4 g of SiO 2 with EtOAc/heptane (gradient 0-50%). 40 mg of the desired aldehyde are obtained. 15 c) Methyl 3-allylamino-2-benzyloxycarbonylamino-2-methylpropionate: 1.237 ml (16.5 mmol) of allylamine and 0.9 g (7.48 mmol) of MgSO 4 are added to a solution of 0.874 g (3.3 mmol) of methyl 2-benzyloxycarbonylamino-2 methyl-3-oxopropionate in 15 ml of DCM. The mixture is stirred at room 20 temperature overnight. The reaction mixture was then filtered and concentrated in vacuo. 50 ml of anhydrous MeOH, 6 ml of NaCNBH 3 (1.OM in THF) and 1.8 ml of acetic acid are added to the crude product. This mixture is stirred at RT for 2 h. The reaction solution is concentrated in vacuo, and then EtOAc and water are added. The organic phase is separated off and dried over MgSO 4 , 25 and the solvent is removed in vacuo. Purification takes place by chromatography (25 g of SiO 2 , eluent MeOH/DCM (gradient 0-10%). 1.035 g of the desired product are obtained as an oil. MW = 306 (calculated, monoisotopic), measured value: ( M+ H)+ 307. 30 d) Methyl 3-amino-2-benzyloxycarbonylamino-2-methylpropionate: A solution of 0.22 g (1.42 mmol) of N,N-dimethylbarbituric acid, 0.02 g (0.017 mmol) of Pd(PPh 3
)
4 , 1.5 ml of DCM and 0.145 g (0.47 mmol) of methyl 252 3-allylamino-2-benzyloxycarbonylamino-2-methylpropionate is heated at 350C for 2 h. The reaction solution is subsequently concentrated in vacuo, and then 20 ml of diethyl ether are added, and the solution is washed 3 times with 20 ml of saturated Na 2
CO
3 each time. A pH of 2 is adjusted by dropwise addition of 5 4N HCI. The aqueous phase is separated off and extracted with 2 ml of EtOAc, and the solvent is removed in vacuo. 0.105 g of the desired product are obtained. MW (calculated, monoisotopic) = 266, measured value: ( M+ H)* 267. e) Methyl 2-benzyloxycarbonylamino-3-(2,4-dichlorobenzenesulfonylamino)-2 10 methylpropionate: 0.103 g (0.341 mmol) of methyl 3-amino-2-benzyloxycarbonylamino-2-methyl propionate, 0.109 g (0.443 mmol) of 2,4 dichlorobenzenesulfonyl chloride and 0.237 ml (1.36 mmol) of DIEA are dissolved in 2 ml of DCM. The mixture is stirred at room temperature overnight. 2 ml are added to the reaction solution, 15 and then the organic phase is separated off and dried over MgSO 4 , and the solvent is removed in vacuo. The crude product is purified by chromatography on 4 g of SiO 2 , EtOAc/DCM as eluent (gradient of 0-40%). 0.081 g of the desired product is obtained as an oil. MW = 474 (calculated, monoisotopic), measured value: ( M+ H)* 475. 20 f) 2-Benzyloxycarbonylamino-3-(2,4-dichlorobenzenesulfonylamino)-2-methyl propionic acid: 0.08 g (0.168 mmol) of methyl 2-benzyloxycarbonylamino-3-(2,4 dichlorobenzenesulfonylamino)-2-methylpropionate and 0.093 g (0.674 mmol) 25 of potassium carbonate are stirred in a mixture of 4.5 ml of MeOH and 0.5 ml of water for 90 min. Then 3 ml of saturated NaHCO 3 solution are added, and the mixture is stirred at 600C for 2 h. 0.5 ml of water is added, followed by 4N HCI (aq) until a pH of 2 is reached. The solution is extracted 3 times with 10 ml of EtOAc each time, the combined organic phases are dried over MgSO 4 , and the 30 solvent is removed in vacuo. 68 mg of the desired product are obtained. MW = 460 (calculated, monoisotopic), measured value: (M+H)* 461.
253 g) Benzyl [1-{2-(4-chlorophenyl)-1-[(2,2-diethoxyethyl)isopropylcarbamoyl] ethylcarbamoyl-2-(2,4-dichlorobenzenesulfonylamino)-1 methylethyl]carba mate: 52.6 mg (0.15 mmol) of 2-amino-3-(4-chlorophenyl)-N-(2,2-diethoxyethyl)-N 5 isopropylpropionamide and 41 mg of 4-(4-6-dimethoxy[1,3,5]triazine-2-yl)4 methylmorpholinium chloride xH 2 0 (DMTMM) are added to a solution of 68 mg (0.15 mmol) of 2-benzyloxycarbonylamino-3-(2,4 dichlorobenzenesulfonylamino)-2-methylpropionic acid in 3 ml of DMF. This reaction solution is stirred at room temperature overnight and, after addition of 10 10 ml of diethyl ether, the organic phase is separated off and dried over MgSO 4 . The solvent is removed in vacuo, and the crude product is purified by chromatography on 4 g of SiO 2 (eluent MeOH/DCM, gradient 0-1 %). 83 mg of the desired product are obtained. MW = 798 (calculated, monoisotopic), measured value: (M+H)* 799. 15 h) Benzyl [6-(4-chlorobenzyl)-1 -(2,4-dichlorobenzenesu lfonyl)-8-isopropyl-3 methyl-4,7-dioxooctahydropyrazino[1 ,2-a]pyrimid in-3-yl]carbamate: A solution of 80 mg (0.1 mmol) of benzyl [1-{2-(4-chlorophenyl)-1-[(2,2 diethoxyethyl)isopropylcarbamoyl]ethylcarbamoyl}-2-(2,4 20 dichlorobenzenesulfonylamino)-1-methylethyl]carbamate in 1.5 ml of HCOOH (99%) is stirred at 60*C for 24 h. The reaction solution is concentrated in vacuo, and the crude product is purified by chromatography (4 g of SiO 2 , eluent EtOAc/heptane (gradient 0-50%)). 30 mg of the desired product are obtained as a white solid. MW (calculated, monoisotopic) = 706, measured value: 25 (M+H)* =707 i) 3-Amino-6-(4-chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-3 methylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione: A solution of benzyl [6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesufonyl)-8 30 isopropyl-3-methyl-4,7-dioxooctahydropyrazino[1,2-a]pyrimidin-3-yl]carbamate in 2 ml of acetonitrile is cooled to 0*C in an ice bath, and 0.05 ml (0.35 mmol) of TMSI is added. The solution is stirred at room temperature overnight and 254 then concentrated in vacuo, dissolved in 1 ml of MeOH and put on a 1 g SCX column, and impurities are washed out with 5 ml of MeOH, followed by 5 ml of 2N NH 3 in MeOH to elute the product. Concentration in vacuo results in 15 mg of the desired product. MW (calculated, monoisotopic) = 572, measured value: 5 ( M+ H) * 573. N-[1 -Benzenesulfonyl-6-(4-chlorobenzyl)-8-isopropyl-3-methyl-4,7-d ioxooctahydro pyrazino[1,2-a]pyrimidin-3-yl]cyclopropanecarboxamide: Synthesis takes place in analogy to Example 22 starting from 3-amino-6-(4 10 chlorobenzyl)-1 -(2,4-dichlorobenzenesulfonyl)-8-isopropyl-3 methylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW = 640 (calculated, monoisotopic); measured value (M+H)*: 641
Claims (17)
1. A compound of the formula I, 5 R4 R3 R5 O=S-O Iin N R1 (C H 2 N R6 N 2 0 (CH 2 )m A in which the meanings are 10 A 3-12 membered mono-, bi- or spirobicyclic ring which may comprise one or more heteroatoms from the group of N, 0 and S and which 3 12 membered ring may have further substituents such as F, Cl, Br, NO 2 , CF 3 , OCF 3 , CN, (C 1 -C 6 )-alkyl, aryl, CON(R11)(R12), N(R13)(R14), OH, O-(C1-C)-alkyl, S-(C1-C)-alkyl, N(R15)CO(C 1 -C 6 ) 15 alkyl or COO-(C 1 -C 6 )-alkyl; R11, R12, R13, R14, R15 independently of one another H, (C 1 -C 6 )-alkyl, heterocycle; 20 n 0, 1; m 0, 1, 2, 3, 4, 5, 6; 256 R1 R8, (C1-C)-alkylene-R8, (C 2 -C)-alkenylene-R9, (S0 2 )-R8, (S0 2 )-(C 1 Cs)-alkylene-R8, (S0 2 )-(C 2 -C 6 )-alkenylene-R9, (C=O)-R8, (C=O)-(C1 C)-alkylene-R8, (C=O)NH-R8, (C=O)-(C 2 -C 6 )-alkenylene-R9, (C=O) 5 NH-(C1-C 6 )-alkylene-R8, (C=O)-NH- (C 2 -CO)-alkenylene-R9, COO-R8, COO-(C1-C)-alkylene-R8, COO-(C 2 -C 6 )-alkenylene-R9, alkynylene R9, (C1-C 4 -alkyl)-heterocycle, where the alkylene groups may be substituted by F; 10 R8, R9 independently of one another H, F, CI, Br, I, OH, CF 3 , aryl, heterocycle, (C 3 -C 8 )-cycloalkyl, where the rings or ring systems may be substituted up to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O-(C 1 -C)-alkyl, (C 1 -C)-alkyl, NH 2 , CON(R1 1)(R1 2), N(R1 3)(R14), S0 2 -CH 3 , COOH, COO-(C 1 -C)-alkyl, CONH 2 ; 15 R2 NH 2 , NO 2 , N(R13)(R14), NH-S0 2 -CH 3 , NH-S0 2 -R12, NR11-S0 2 R12, N(CO)R1 1, a nitrogen-containing heterocycle, where the heterocycle is bonded via a nitrogen atom, NHCONR1 1, N(C1-C 6 alkyl)N'(C1-C4-alkyl)3; 20 R3, R4, R5 independently of one another H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O-(C1-C 6 )-alkyl, 0-(C 1 -C4)-alkoxy-(C1-C 4 )-alkyl, S-(C 1 -C)-alkyl, (C1-C 6 )-alkyl, (C 2 -CO)-alkenyl, (C 3 -Ca)-cycloalkyl, 0-(C 3 -CB)-cycloalkyl, (C 3 -C)-cycloalkenyl, 0-(C 3 -C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, aryl, 0 25 aryl (Co-C8)-alkylene-aryl, 0-(Co-C 8 )-alkylene-aryl, S-aryl, N((C1-C 6 ) alkyl) 2 , S0 2 -CH 3 , COOH, COO-(C1-C)-alkyl, CO-N((C1-C 6 )-alkyl) 2 ; R6 H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , 0-(C1-C 6 )-alkyl, 0-(C 1 -C 4 ) alkoxy-(C1-C4)-alkyl, S-(C1-Cs)-alkyl, (C1-Ce)-alkyl, (C 2 -C)-alkenyl, 30 (C 3 -C8)-cycloalkyl, 0-(C 3 -Ce)-cycloalkyl, (C 3 -Ca)-cycloalkenyl, 0-(C 3 C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, aryl, 0-aryl, (C 1 -C 8 )-alkylene-aryl, 257 O-(C-C 8 )-alkylene-aryl, S-aryl, N((0 1 -C 6 )-alkyl) 2 , S0 2 -CH 3 , COOH, COO-(C-C 6 )-alkyl, CO-N((C-C 6 )-alkyl) 2 ; and the physiologically tolerated salts thereof. 5
2. A compound of the formula I as claimed in claim 1, wherein I has the structure la R4 R3 R5 O=S=O N N R1 R6 N R2 0 (CH 2 )m A la 10 in which the meanings are A 3-12 membered mono-, bi- or spirobicyclic ring which may comprise one or more heteroatoms from the group of N, 0 and S and which 3 12 membered ring may have further substituents such as F, Cl, Br, 15 NO 2 , CF 3 , OCF 3 , CN, (C-C 6 )-alkyl, aryl, CON(RII1)(R12), N(R13)(R14), OH, O-(C-C 6 )-alkyl, S-(C-C 6 )-alkyl, N(R15)CO(C-C 6 ) alkyl or COO-(Cl-C 6 )-alkyl; R11, R12, R13, R14, R15 independently of one another H, (C-C 6 )-alkyl, 20 heterocycle; m 0, 1, 2, 3, 4, 5, 6; 258 R1 R8, (C-C)-alkylene-R8, (C 2 -CO)-alkenylene-R9, (S0 2 )-R8, (S0 2 )-(Ci C)-alkylene-R8, (SO 2 )-(C 2 -C 6 )-alkenylene-R9, (C=O)-R8, (C=0)-(C C 6 )-alkylene-R8, (C=O)NH-R8, (C=O)-(C 2 -C 6 )-alkenylene-R9, (C=O) 5 NH-(Cr-C 6 )-alkylene-R8, (C=0)-NH- (C 2 -Cs)-alkenylene-R9, COO-R8, COO-(OiC)-alkylene-R8, COO-(C 2 -C 6 )-alkenylene-R9, alkynylene R9, (C-C 4 -alkyl)-heterocycle; R8, R9 independently of one another H, F, Cl, Br, I, OH, CF 3 , aryl, 10 heterocycle, (C 3 -C 8 )-cycloalkyl, where the rings or ring systems may be substituted up to 3 times by F, CI, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O-(0C)-alkyl, (C-C)-alkyl, NH 2 , CON(R 1)(R1 2), N(R1 3)(R1 4), S0 2 -CH 3 , COOH, COO-(C-C 6 )-alkyl, CONH 2 ; 15 R2 NH 2 , NO 2 , N(R13)(R14), NH-S0 2 -CH 3 , NH-S0 2 -R12, NR11-S0 2 -R12, N(CO)R1 1, a nitrogen-containing heterocycle, where the heterocycle is bonded via a nitrogen atom, NHCONR1 1, N(CriC 6 -alkyl)N 4 (CriC 4 alkyl) 3 ; 20 R3, R4, R5 independently of one another H, F, C, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O-(OC)-alkyl, 0-(C-C 4 )-alkoxy-(C-C 4 )-alkyl, S-(C-C)-alkyl, (OC)-alkyl, (C 2 -C)-alkenyl, (C 3 -C 8 )-cycloalkyl, 0-(C 3 -C 8 )-cycloalkyl, (C 3 -C 8 )-cycloalkenyl, 0-(C 3 -C 8 )-cycloalkenyl, (C 2 -C 6 )-alkynyl, aryl, 0 aryl (Co-C 8 )-alkylene-aryl, 0-(Co-C)-alkylene-aryl, S-aryl, N((CrC 6 ) 25 alkyl) 2 , S0 2 -CH 3 , COOH, COO-(OiC)-alkyl, CO-N((C-C 6 )-alkyl) 2 ; R6 H, F, C, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O-(0C)-alkyl, 0-(Cr-C4) alkoxy-(C-C 4 )-alkyl, S-(0 1 C)-alkyl, (CrO0)-alkyl, (C 2 -C)-alkenyl, (C 3 -C 8 )-cycloalkyl, 0-(C 3 -C 8 )-cycloalkyl, (C 3 -Cs)-cycloalkenyl, 0-(C3 30 Cs)-cycloalkenyl, (C 2 -C 6 )-alkynyl, aryl, 0-aryl, (Cr-C 8 )-alkylene-aryl, O-(0C)-alkylene-aryl, S-aryl, N((Cr-C 6 )-alkyl) 2 , S0 2 -CH 3 , COOH, COO-(PC)-alkyl, CO-N((C-C6)-alkyl)2; 259 and physiologically tolerated salts thereof.
3. A compound of the formula I as claimed in claim 1 or 2, wherein the 5 meanings are A aryl, where the aryl ring may be substituted by F, Cl, Br, NO 2 , CF 3 , OCF 3 , CN, (C 1 -Ce)-alkyl, aryl, CON(R11)(R12), N(R13)(R14), OH, 0 (C1-C)-alkyl, S-(C1-C)-alkyl, N(R1 5)CO(C 1 -C 6 )-alkyl or COO-(C 1 -C 6 ) 10 alkyl; R11, R12, R13, R14, R15 independently of one another H, (C1-C)-alkyl, heterocycle; 15 m 1; R1 R8, (C1-C 6 )-alkylene-R8, (C 2 -C 6 )-alkenylene-R9, (S0 2 )-R8, (S0 2 )-(C 1 C 6 )-alkylene-R8, (S0 2 )-(C 2 -C 6 )-alkenylene-R9, (C=O)-R8, (C=O)-(C 1 CO)-alkylene-R8, (C=O)NH-R8, (C=O)-(C 2 -C 6 )-alkenylene-R9, (C=0) 20 NH-(C1-C 6 )-alkylene-R8, (C=O)-NH-(C 2 -C 6 )-alkenylene-R9, COO-R8, COO-(C1-C)-alkylene-R8, COO-(C 2 -C 6 )-alkenylene-R9, alkynylene R9, (C1-C 4 -alkyl)-heterocycle; 25 R8, R9 independently of one another H, F, Cl, Br, I, OH, CF 3 , aryl, heterocycle, (C 3 -C 8 )-cycloalkyl, where the rings or ring systems may be substituted up to 3 times by F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O-(C 1 -C)-alkyl, (C1-C)-alkyl, NH 2 , CON(R11)(R12), N(R13)(R14), S0 2 -CH 3 , COOH, COO-(C 1 -C 6 )-alkyl, CONH 2 ; 30 R2 NH 2 , NO 2 , N(R13)(R14), NH-S0 2 -CH 3 , NH-S0 2 -R12, NR11-S0 2 -R12, N(CO)R1 1, a nitrogen-containing heterocycle, where the heterocycle 260 is bonded via a nitrogen atom, NHCONR1 1, N(C 1 -C 6 -alkyl)N*(C-C 4 alkyl) 3 ; R3 H 5 R4, R5 independently of one another H, F, CI, Br, OH, CF 3 , OCF 3 , 0-(C-C 6 ) alkyl, (CrC 6 )-alkyl; R6 H; 10 and the physiologically tolerated salts thereof.
4. A compound as claimed in one or more of claims 1 to 3, wherein the meanings are 15 A aryl, where the aryl ring may be substituted by F, Cl, Br, NO 2 , CF 3 , OCF 3 , CN, (C-C)-alkyl, aryl, CON(R11)(R12), N(R13)(R14), OH, 0 (CrC 6 )-alkyl, S-(CrC 6 )-alkyl, N(R15)CO(C-C 6 )-alkyl or COO-(Cl-C 6 ) alkyl; 20 R11, R12, R13, R14, R15 independently of one another H, (CrC 6 )-alkyl, heterocycle; m 1; 25 R1 (CrC 6 )-alkyl, (C-C 6 )-alkylene-R8; R8, R9 independently of one another F, Cl, Br, I, OH, CF 3 ; 30 R2 NH 2 , NO 2 , CN, N(R13)(R14), NH-S0 2 -CH 3 , NH-S0 2 -R12, NR11-S0 2 R1 2, N(CO)R1 1, a nitrogen-containing heterocycle, where the 261 heterocycle is bonded via a nitrogen atom, NHCONR1 1, N(C1-C 6 alkyl)N*(C1-C4-alkyl)3; R3 H 5 R4 F, Cl, Br, OH, CF 3 , OCF 3 , O-(C1-C)-alkyl, (C 1 -C 6 )-alkyl; R5 H, F, Cl, Br, OH, CF 3 , OCF 3 , O-(C1-C)-alkyl, (C1-C)-alkyl; 10 R6 H; and the physiologically tolerated salts thereof.
5. A compound as claimed in one or more of claims 1 to 4 for use as 15 medicament.
6. A medicament comprising one or more of the compounds as claimed in one or more of claims 1 to 4. 20
7. A medicament comprising one or more of the compounds as claimed in one or more of claims 1 to 4 and one or more anorectic active ingredients.
8. A medicament comprising one or more of the compounds as claimed in one or more of claims 1 to 4 and one or more statins. 25
9. A medicament as claimed in claim 6, which comprises as further active ingredient one or more antidiabetics, hypoglycemic active ingredients, HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gamma agonists, fibrates, MTP inhibitors, bile 30 acid absorption inhibitors, CETP inhibitors, polymeric bile acid absorbents, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, 262 lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, a-glucosidase inhibitors, active ingredients acting on the ATP dependent potassium channel of beta cells, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF 5 BP antagonists, urocortin agonists, p3 agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotoninergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists 10 (bromocriptine, Doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-p agonists or amphetamines.
10. A compound as claimed in one or more of claims 1 to 4 in combination with at least one further anorectic active ingredient for use as medicament for the 15 prophylaxis or treatment of obesity.
11. A compound as claimed in one or more of claims 1 to 4 in combination with at least one further anorectic active ingredient for use as medicament for the prophylaxis or treatment of type 11 diabetes. 20
12. A process for producing a medicament comprising one or more of the compounds as claimed in one or more of claims 1 to 4, which comprises mixing the active ingredient with a pharmaceutically suitable carrier and converting this mixture into a form suitable for administration. 25
13. The use of the compound as claimed in one or more of claims 1 to 4 for producing a medicament for weight reduction in mammals.
14. The use of the compound as claimed in one or more of claims 1 to 4 for 30 producing a medicament for the prophylaxis or treatment of obesity. 263
15. The use of the compound as claimed in one or more of claims 1 to 4 for producing a medicament for the prophylaxis or treatment of type 11 diabetes.
16. The use of the compound as claimed in one or more of claims 1 to 4 for 5 producing a medicament for the prophylaxis or treatment of metabolic syndrome.
17. The use of the compound as claimed in one or more of claims 1 to 4 for producing a medicament for the treatment of female and male sexual disorders.
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DE10349671A DE10349671A1 (en) | 2003-10-24 | 2003-10-24 | New pyrazinopyrimidine or pyrazinoimidazole derivatives useful for weight reduction in mammals, for preventing or treating obesity, type II diabetes or metabolic syndrome and for treating sexual disorders |
DE10349671.8 | 2003-10-24 | ||
PCT/EP2004/000770 WO2004072077A1 (en) | 2003-02-13 | 2004-01-29 | Nitrogen-substituted hexahydropyrazino[1,2-a]pyrimidine-4,7-dione derivatives, method for the production and use thereof as medicaments |
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US6294525B1 (en) * | 1999-09-01 | 2001-09-25 | Molecumetics Ltd. | Reverse-turn mimetics and methods relating thereto |
RU2005128497A (en) * | 2003-02-13 | 2006-01-27 | Санофи-Авентис Дойчленд Гмбх (De) | SUBSTITUTED DERIVATIVES OF HEXAHYDROPYRAZINO (1,2-A) PYRIMIDIN-4,7-DION, METHODS FOR THEIR PRODUCTION AND THEIR APPLICATION AS MEDICINES |
-
2004
- 2004-01-29 MX MXPA05008288A patent/MXPA05008288A/en not_active Application Discontinuation
- 2004-01-29 AT AT04706145T patent/ATE393769T1/en not_active IP Right Cessation
- 2004-01-29 JP JP2006501650A patent/JP2006517551A/en active Pending
- 2004-01-29 DE DE502004007000T patent/DE502004007000D1/en not_active Expired - Lifetime
- 2004-01-29 WO PCT/EP2004/000770 patent/WO2004072077A1/en active IP Right Grant
- 2004-01-29 AU AU2004212043A patent/AU2004212043A1/en not_active Abandoned
- 2004-01-29 EP EP04706145A patent/EP1597259B1/en not_active Expired - Lifetime
- 2004-01-29 RU RU2005128499/04A patent/RU2005128499A/en not_active Application Discontinuation
- 2004-01-29 BR BR0407387-8A patent/BRPI0407387A/en not_active IP Right Cessation
- 2004-01-29 PL PL377660A patent/PL377660A1/en unknown
- 2004-01-29 RS YUP-2005/0572A patent/RS20050572A/en unknown
- 2004-01-29 KR KR1020057014986A patent/KR20050100686A/en not_active Application Discontinuation
- 2004-01-29 CA CA002514791A patent/CA2514791A1/en not_active Abandoned
- 2004-02-11 TW TW093103120A patent/TW200510417A/en unknown
- 2004-02-11 PE PE2004000150A patent/PE20040949A1/en not_active Application Discontinuation
- 2004-02-11 AR ARP040100426A patent/AR043154A1/en unknown
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2005
- 2005-08-11 MA MA28429A patent/MA27734A1/en unknown
- 2005-08-11 CO CO05079786A patent/CO5690596A2/en not_active Application Discontinuation
- 2005-08-12 HR HR20050711A patent/HRP20050711A2/en not_active Application Discontinuation
- 2005-09-09 NO NO20054208A patent/NO20054208L/en not_active Application Discontinuation
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RS20050572A (en) | 2007-09-21 |
JP2006517551A (en) | 2006-07-27 |
EP1597259B1 (en) | 2008-04-30 |
PE20040949A1 (en) | 2005-01-12 |
RU2005128499A (en) | 2006-01-27 |
AR043154A1 (en) | 2005-07-20 |
CA2514791A1 (en) | 2004-08-26 |
ATE393769T1 (en) | 2008-05-15 |
CO5690596A2 (en) | 2006-10-31 |
HRP20050711A2 (en) | 2006-09-30 |
TW200510417A (en) | 2005-03-16 |
WO2004072077A1 (en) | 2004-08-26 |
MA27734A1 (en) | 2006-02-01 |
KR20050100686A (en) | 2005-10-19 |
EP1597259A1 (en) | 2005-11-23 |
DE502004007000D1 (en) | 2008-06-12 |
MXPA05008288A (en) | 2006-03-21 |
NO20054208L (en) | 2005-09-09 |
BRPI0407387A (en) | 2006-02-07 |
PL377660A1 (en) | 2006-02-06 |
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