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AU2004212145B2 - Substituted N-arylheterocycles, method for production and use thereof as medicaments - Google Patents

Substituted N-arylheterocycles, method for production and use thereof as medicaments Download PDF

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AU2004212145B2
AU2004212145B2 AU2004212145A AU2004212145A AU2004212145B2 AU 2004212145 B2 AU2004212145 B2 AU 2004212145B2 AU 2004212145 A AU2004212145 A AU 2004212145A AU 2004212145 A AU2004212145 A AU 2004212145A AU 2004212145 B2 AU2004212145 B2 AU 2004212145B2
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alkyl
independently
another
group
nitrogen atom
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AU2004212145A1 (en
Inventor
Thomas Boehme
Matthias Gossel
Dirk Gretzke
Gerhard Hessler
Lothar Schwink
Petra Stahl
Siegfried Stengelin
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Sanofi Aventis Deutschland GmbH
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Hydrogenated Pyridines (AREA)
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Description

AS ORIGINALLY FILED 5 Substituted N-aryl heterocycles, process for their preparation and their use as medicaments The invention relates to substituted N-aryl heterocycles and to the physiologically tolerated salts and physiologically functional derivatives 10 thereof. Compounds having a pharmacological effect and similar in their overall structure to the N-aryl heterocycles described herein have already been described in the prior art. Thus, for example, WO 00/35454 describes 15 ureido-substituted phenylpiperidines and -pyrrolidines as agents for the treatment of inflammatory and autoimmune diseases. Acylamido substituted phenylpyrrolidines are proposed in WO 02/042271 for the treatment of diabetes, obesity and disorders of lipid metabolism. 20 The invention was based on the object of providing compounds which bring about a weight reduction in mammals and are suitable for preventing and treating obesity and diabetes. The invention therefore relates to compounds of the formula 1 25 0 R7 R 6
R
3 R11K EXA=B N n RNRR 2 R10 G-D (m R4 R9 R8 R5 in which the meanings are 30 R1, R2 independently of one another H, (C1-C8)-alkyl, -(CR78R79) 0 R12, (C 1 -C4)-alkoxy-(C1-C 4 )-alkyl, aryloxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, (C3-C)-alkynyl, CO-(CI-C8)-alkyl, -CO-(CH 2
)
0 R12, CO-aryloxy-(C1-C4)-alkyl, CO-(C2-C8)-alkenyl, CO-(C2-C8)-alkynyl, COCH=CH(R13), COCC(R14), CO-(C1-C4) 35 alkyl-S(0)p-(C1-C4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), 2 CO(C(R19)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 1 0-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, may comprise 0 to 4 5 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, Cl, Br, CF 3 , NO 2 , CN, (C1-C6) alkyl, O-(C1-08)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, hydroxy-(C1 C4)-alkyl, (Co-C8)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), 10 hydroxy, COO(R29), N(R30)CO(C1-C6)-alkyl, N(R31)(R32) or S02CH 3 ; o 0,1,2,3,4,5,6; 15 p 0,1,2 q, r, s independently of one another 0, 1, 2, 3, 4; R13, R14 independently of one another a 5-10 membered aromatic ring 20 system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, Br, CF 3 , NO 2 , CN, (C1-C6)-alkyl, 0-(Cl-C8)-alkyl; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, 25 R30, R31, R32 independently of one another H, (C1 -C6)-alkyl; R18 H, (C1-C6)-alkyl, CO(C1-C6)-alkyl, CO(R33); or 30 R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1 -C6)-alkyl, oxygen 35 and sulfur; R33 a 5-10 membered aromatic ring system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and 3 sulfur and may be substituted by F, Cl, Br, CF 3 , N02, CN, (C1-C6)-alkyl, O-(C1-Cs)-alkyl; R12 OH, O-(C1-C6)-alkyl, O(CO-C8)-alkylene-aryl, CN, S-(C1-C6) 5 alkyl, COO(R80), CON(R81)(R93), N(R82)(R83), 3-12 membered mono-, bi- or spirocyclic ring which may comprise one or more heteroatoms from the group of N, 0 and S, and the 3-12 membered ring may comprise further substituents such as F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , oxo, O-(C1-C)-alkyl, 10 (C1-C4)-alkoxy-(C1-C4)-alkyl, S-(01-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, 0-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, 0-(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, 0-(CO-C)-alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(C1-C)-alkyl, 15 COCOO(C1-C6)-alkyl, COO(R40), S(O)u(R41) and COOH; t 0,1,2,3,4,5,6; u 0, 1, 2; 20 R34, R35, R37, R38 independently of one another H, (C1 -C8)-alkyl; or R34 and R35 25 optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyI, oxygen and sulfur and may optionally be substituted by 1-2 oxo groups; 30 R36, R39 independently of one another (C3-C8)-cycloalkyl, 5-10 membered aromatic ring system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, Br, CF 3 , NO 2 , CN, (C1 -C6)-alkyl, 35 O-(C1-C)-alkyl; R40 H, (C-C8)-alkyl, (C2-C6)-alkenyl, (CO-C8)-alkylene-aryl; 4 R41 (C1 -C 6 )-alkyl, 5-10 membered aromatic ring system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, Br, CF 3 ,
NO
2 , CN, (C1-C6)-alkyl, 0-(C1-C8)-alkyl; 5 R78, R79 independently of one another H, (C1 -C8)-alkyl, hydroxy-(C1 -C4) alkyl, OH, (C1-C4)-alkoxy-(C1-C4)-alkyl; R80, R81 10 R93 independently of one another H, (Ci -C8)-alkyl, (C2-C6)-alkenyl, (CO-C8)-alkylene-aryl; R82, R83 independently of one another H, (Ci -C6)-alkyl; or 15 R82 and R83 optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen and sulfur and may optionally be 20 substituted by 1-2 oxo groups; R3 H, (C1 -C6)-alkyl; R4, R5 independently of one another H, (C1-C6)-alkyl, OH, 25 0-(C1-C6)-alkyl, O-CO(C1-C6)-alkyl, S-(C1-C6)-alkyl; R6, R7, R8, R9 independently of one another H, (C1-C8)-alkyl; or 30 R6 and R7, R8 and R9 independently of one another optionally oxo; n, m independently of one another 0, 1, 2; 35 A, B, D, G independently of one another N, C(R42); or the groups A and B or the groups D and G are each C(R42) and together form a 5- or 6 membered carbocyclic or heterocyclic 5 radical to result overall in a bicyclic system; R42 H, F, Cl, Br, I, OH, CF 3 , N02, CN, OCF 3 , 0-(Cl-C6)-alkyl, 0-(C1 -C4)-alkoxy-(C1 -C4)-alkyl, S-(C1 -C6)-alkyl, (Ci -C6)-alkyl, 5 (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, 0-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, 0-(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (Co-C8)-alkylene-aryl, 0-(Co-C8)-alkylene-aryl, S-aryl, N(R43)(R44), S02-CH 3 , COOH, COO-(C1-C6)-alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO 2 (R50), CO(R51), 10 -(CR84R85)x-O(R86); R43, R44, R45, R46, R47, R49 independently of one another H, (C1-Cs)-alkyl; or 15 R43 and R44, R45 and R46 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen 20 and sulfur; R48, R50, R51 independently of one another H, (C1-C8)-alkyl, aryl; 25 R84, R85 independently of one another H, (C1-C8)-alkyl; R86 H, (C1-C6)-alkyl, aryl; x 1, 2, 3, 4, 5, 6; 30 R10 H, (C1-C8)-alkyl, (C3-C6)-alkenyl, (C3-C6)-alkynyl; X N(R52), 0, a bond, C=C, C(R53)(R54), C(R55)(R56)O, CO, C=C, a group of the formula -(CR87R88)y- in which one or more 35 -(CR87R88)- groups may be replaced by Y to result in a chemically reasonable radical; Y O, S, N(R89); 6 R52, R53, R54, R55, R56 independently of one another H, (C1-C8)-alkyl; 5 R87, R88 independently of one another H, (C1-C 4 )-alkyl, where R87 and R88 in the y groups may in each case have the same or different meanings; y 2, 3, 4, 5, 6; 10 R89 H, (C1 -C8)-alkyl; E 3-14 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group of N, 0 and S, which may 15 optionally have substituents from the group of H, F, CI, Br, I, OH,
CF
3 , NO 2 , CN, OCF 3 , oxo, O-(C1-C6)-alkyl, 0-(C1-C4)-alkoxy (C1-C4)-alkyl, S-(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, 0-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, 0-(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (CO-C8)-alkylene-aryl, 20 0-(Co-C8)-alkylene-aryl, S-aryl, N(R57)(R58), S02-CH 3 , COOH, COO-(C1-C6)-alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO 2 (R64), CO(R65) and may be mono- or bicyclic; R57, R58,R59, R60, R61, R63 25 independently of one another H, (Ci -C8)-alkyl; or R57 and R58, R59 and R60 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring 30 which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1 -C6)-alkyl, oxygen and sulfur; R62, R64, R65 35 independently of one another H, (C1-C 8 )-alkyl, aryl; K a bond, 0, OCH 2 , CH 2 0, S, SO, S02, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO, C=C, C=C, a group of the 7 formula -(CR90R91)z- in which one or more -(CR90R91)- groups may be replaced by Z to result in a chemically reasonable radical; 5 v 1,2,3,4 R66, R67, R68, R69,R70 independently of one another H, (C1 -C8)-alkyl; 10 Z O, S, N(R92), CO, SO, S0 2 ; R90, R91 independently of one another H, (C1 -C8)-alkyl, hydroxy-(C 1 -C4) alkyl, hydroxy, (Ci -C4)-alkoxy-(C1 -C 4 )-alkyl, where R90 and R91 in the z groups may in each case have the same of different 15 meanings; z 2, 3, 4, 5, 6; R92 H, (C1 -C8)-alkyl; 20 R11 H, (C1-C8)-alkyl, (C1-C 4 )-alkoxy-(C 1 -C4)-alkyl, (C3-C8)-alkenyl, (C3-C)-alkynyl, a 3 to 1 0-membered mono-, bi- or spirocyclic ring which may comprise 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may 25 additionally be substituted by F, Cl, Br, CF 3 , NO 2 , CN, (C1-C6) alkyl, O-(C 1
-C
8 )-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (Co-C 8
)
alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, hydroxy (C1-C4)-alkyl, COO(R74), N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or SO 2
CH
3 , SCF 3 ; 30 R71, R72, R73, R74, R75, R76, R77 independently of one another H, (C1-C8)-alkyl; or R72 and R73, R76 and R77 35 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1 -C6)-alkyl, oxygen 8 and sulfur; or E, K and R1 1 together form a tricyclic system where the rings may independently of one another [lacuna] saturated, partially 5 saturated or unsaturated and may each comprise 3-8 ring atoms; and the N-oxides and physiologically tolerated salts thereof. In a further embodiment, the invention therefore relates to compounds of 10 the formula I in which the meanings are: 0 R7 R 6
R
3 R11 K ,E ~X i N A B N
NR
1
R
2 R10 G-D (m R4 R9 R8 R5 R1, R2 independently of one another H, (C 1 -C8)-alkyl, -(CH2)o-R1 2, 15 (C1-C 4 )-alkoxy-(C1-C4)-akyl, aryloxy-(C1-C4)-alkyl, (C3-C8) alkenyl, (C3-C8)-alkynyl, CO-(C1-C8)-alkyl, -CO-(CH 2
)
0 -R12, CO-aryloxy-(C1-C4)-alkyl, CO-(C2-C)-alkenyl, CO-(C2-C8) alkynyl, COCH=CH(R13), COCC(R14), CO-(C1-C 4 )-alkyl-S(O)p (C1-C4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), 20 CO(C(R19)(R20))rCON(R21) (R22), CO(C(R23)(R24))sO(R25); or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 1 0-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, may comprise 0 to 4 additional heteroatoms selected from the group of oxygen, 25 nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, Cl, Br, CF3, NO 2 , CN, (01-06) alkyl, 0-(C1-C)-alkyl, (C1-C4)-alkoxy-(C1-C4)-akyl, (CO-C8)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C1-C6)-alkyl, N(R31)(R32) or SO 2
CH
3 ; 30 o 0,1,2,3,4,5,6; p 0,1,2 9 q, r, s independently of one another 0, 1, 2, 3, 4; R1 3, R1 4 independently of one another a 5-10 membered aromatic ring system which may comprise 0-2 further heteroatoms from the 5 group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, Br, CF 3 , NO 2 , CN, (C1-C6)-alkyl, 0-(C1-C)-alkyl; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 10 independently of one another H, (C1 -C6)-alkyl; R18 H, (C1-C6)-alkyl, CO(C1-C6)-alkyl, CO(R33); R17 and R18, R21 and R22, R27 and R28, R31 and R32 15 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C 6 )-alkyl, oxygen and sulfur; 20 R33 a 5-10 membered aromatic ring system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, Br, CF 3 , NO 2 , CN, (C1-C6)-alkyl, 0-(C1-C8)-alkyl; 25 R12 OH, 3-12 membered mono-, bi- or spirocyclic ring which may comprise one or more heteroatoms from the group of N, 0 and S, and the 3-12 membered ring may comprise further substituents such as F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , oxo, 30 O-(C -C6)-alkyl, (Ci -C4)-alkoxy-(C1 -C4)-alkyl, S-(C1 -C6)-alkyl, (C1-06)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, 0-(C3-C8) cycloalkyl, (C3-C)-cycloalkenyl, 0-(C3-C8)-cycloalkenyl, (C2 C6)-alkynyl, 0-(CO-C8)-alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), 35 CO(C1-C6)-alkyl, COCOO(C1-C6)-alkyl, COO(R40), S(O)u(R41) and COOH; t 0,1,2,3,4,5,6; 10 u 0, 1, 2; R34, R35, R37, R38 5 independently of one another H, (C1 -C8)-alkyl; R34 and R35 optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen 10 atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen and sulfur and may optionally be substituted by 1-2 oxo groups; R36, R39 independently of one another (C3-C8)-cycloalkyl, 5-10 membered 15 aromatic ring system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, Br, CF 3 , NO 2 , CN, (C1 -C6)-alkyl, 0-(C-C8)-alkyl; 20 R40 H, (C1-C8)-alkyl, (C2-C6)-alkenyl, (CO-C8)-alkylene-aryl; R41 (C1-C6)-alkyl, 5-10 membered aromatic ring system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, Br, CF 3 , NO 2 , 25 CN, (C1-C6)-alkyl, 0-(C1-C8)-alkyl; R3 H, (C1-C6)-alkyl; R4, R5 independently of one another H, (C1-C6)-alkyl, OH, 30 0-(C1-C6)-alkyl, O-CO(C1-C6)-alkyl, S-(C1-C6)-alkyl; R6, R7, R8, R9 independently of one another H, (Ci -C8)-alkyl; 35 R6 and R7, R8 and R9 independently of one another optionally oxo; n, m independently of one another 0, 1, 2; 11 A, B, D, G independently of one another N, C(R42); R42 H, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , 0-(Cl-C6)-alkyl, 0-(C1 5 C 4 )-alkoxy-(C1-C4)-alkyl, S-(C1-C 6 )-alkyl, (C1-C6)-alkyl, (C2-C6) alkenyl, (C3-C8)-cycloalkyl, 0-(C3-C8)-cycloalkyl, (C3-C8) cycloalkenyl, 0-(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (Co-Ca) alkylene-aryl, 0-(Co-C8)-alkylene-aryl, S-aryl, N(R43)(R44), S02
CH
3 , COOH, COO-(C1-C6)-alkyl, CON(R45)(R46), 10 N(R47)CO(R48), N(R49)SO 2 (R50), CO(R51) R43, R44, R45, R46,R47, R49 independently of one another H, (C1 -C8)-alkyl; 15 R43 and R44, R45 and R46 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen 20 and sulfur; R48, R50, R51 independently of one another H, (Ci -C8)-alkyl, aryl; 25 R10 H, (C1-C8)-alkyl, (C3-C6)-alkenyl, (C3-C6)-alkynyl; X N(R52), 0, a bond, C=C, C(R53)(R54), C(R55)(R56)O; R52, R53, R54, R55, R56 30 independently of one another H, (Ci -C8)-alkyl; E 3-8 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group of N, 0 and S, which may optionally have substituents from the group of H, F, Cl, Br, I, OH, 35 CF 3 , NO 2 , CN, OCF 3 , 0-(C1-C6)-alkyl, 0-(Cl-C4)-alkoxy-(C1 C4)-alkyl, S-(C 1 -C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3 C)-cycloalkyl, 0-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, 0 (C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (Co-C8)-alkylene-aryl, 0- 12 (Co-C8)-alkylene-aryl, S-aryl, N(R57)(R58), S0 2
-CH
3 , COOH, COO-(C1-C6)-alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO 2 (R64), CO(R65) and may be mono- or bicyclic; 5 R57, R58,R59, R60, R61, R63 independently of one another H, (Ci -C8)-alkyl; R57 and R58, R59 and R60 independently of one another optionally together with the 10 nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C 6 )-alkyl, oxygen and sulfur; 15 R62,1R64,1R65 independently of one another H, (C1-C 8 )-alkyl, aryl; K a bond, 0, OCH 2 , CH 2 0, S, SO, S02, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO, C=C; 20 v 1, 2, 3, 4; R66, R67, R68, R69, R70 independently of one another H, (Ci -C8)-alkyl; 25 R11 H, (C1-C8)-alkyl, (C 1
-C
4 )-alkoxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl, a 3 to 1 0-membered mono-, bi- or spirocyclic ring which may comprise 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may 30 additionally be substituted by F, Cl, Br, CF 3 , NO 2 , CN, (C 1
-C
6
)
alkyl, O-(C1-08)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (Co-C 8
)
alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or SO 2
CH
3 ; 35 R71, R72, R73, R74, R75, R76, R77 independently of one another H, (C1 -C8)-alkyl; R72 and R73, R76 and R77 13 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1 -C6)-alkyl, oxygen 5 and sulfur; or E, K and R11 together form a tricyclic system where the rings may independently of one another [lacuna] saturated, partially 10 saturated or unsaturated and may each comprise 3-8 ring atoms; and the physiologically tolerated salts thereof. The invention relates to compounds of the formula I in the form of their 15 racemates, enantiomer-enriched mixtures and pure enantiomers, and to their diastereomers and mixtures thereof. The alkyl, alkenyl and alkynyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, 20 R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, R84, R85, R86, R87, R88, R89, 25 R90, R91, R92 and R93 may be either straight-chain, branched or optionally halogenated. The term "aryl" means in particular a phenyl or naphthyl group. 30 A "tricyclic system" means structures having 3 rings which are connected together by more than one bond. Examples of such systems are fused systems with 3 rings and spirocycles with a ring system fused on. In the case where R1 and R2 form together with the nitrogen atom to which 35 they are bonded a ring, this ring may be substituted by one or more of the substituents mentioned. The bivalent carbo- or heterocyclic ring structure E includes structures which are linked by one and the same atom to the two adjacent groups K 14 and X. Pharmaceutically acceptable salts are, because their solubility in water is greater than that of the initial or basic compounds, particularly suitable for 5 medical applications. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acid, and of organic acids such as, for example, acetic acid, 10 benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric and trifluoroacetic acid. For medical purposes the chlorine salt is particularly preferably used. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as 15 sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts). Salts with a pharmaceutically unacceptable anion likewise belong within the framework of the invention as useful intermediates for the preparation or 20 purification of pharmaceutically 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 of the formula I of the 25 invention, for example an ester, which on administration to a mammal such as, for example, a human is able to form (directly or indirectly) a compound of the formula I or an active metabolite thereof. Physiologically functional derivatives include prodrugs of the compounds of 30 the invention. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves be active or not. The compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All 35 polymorphous forms of the compounds of the invention belong within the framework of the invention and are a further aspect of the invention. All references to "compound(s) of formula (1)" hereinafter refer to compound(s) of the formula (1) as described above, and their salts, solvates 15 and physiologically functional derivatives as described herein. If radicals or substituents can occur more than once in the compounds of the formula 1, they may all have independently of one another the stated 5 meanings and be identical or different. In a particularly preferred embodiment, the present invention relates to compounds of the formula I in which the meanings are: 10 R1, R2 independently of one another, H, (C1 -C8)-alkyl, -(CH 2
)
0 -R1 2, (C1 -C 4 )-alkoxy-(C1 -C4)-alkyl, CO-(C1 -C8)-alkyl, -CO-(CH 2 )o R12, COCH=CH(R13), COCC(R14), CO-(C1-C4)-akyl-S(O)p (C1-C4)-alkyl, CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22), 15 CO(C(R23)(R24))sO(R25); or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 1 0-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and 20 sulfur, where the heterocyclic ring system may additionally be substituted by F, (C1-C6)-alkyl, 0-(Cl-C8)-alkyl, (C0-C8) alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C1-C6)-alkyl, N(R31)(R32) or
SO
2
CH
3 , where R1 and R2 are preferably not both H, and R1 25 and R2 together with the nitrogen atom are preferably not a morpholino radical; 0 0,1,2,3,4; 30 p 0,1,2; 16 q, r, s independently of one another 0, 1, 2, 3, preferably q, s are independently of one another 1, 2, 3 and r is 0, 1, 2, 3; R13, R14 independently of one another a 5-10 membered aromatic ring 5 system which may comprise a further heteroatom from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C1 -C6)-alkyl, O-(C1-C8)-alkyl; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, 10 R27, R28, R29, R30, R31, R32 independently of one another H, (C1 -C6)-alkyl; R18 H, (C1-C6)-alkyl, CO(C1-C6)-alkyl, CO(R33); 15 R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen 20 and sulfur; R33 a 5-10 membered aromatic ring system which may comprise a further heteroatom from the group of nitrogen, oxygen and sulfur and may be substituted by F, CI, (Ci -C6)-alkyl, 0-(C1 25 C8)-alkyl; R12 OH, 3-12 membered mono-, bi- or spirocyclic ring which may comprise one or more heteroatoms from the group of N, 0 and S, and the 3-12 membered ring may comprise further 30 substituents such as F, Cl, CF 3 , CN, oxo, O-(C1-C6)-alkyl, (C1-C6)-alkyl, O-(Co-C)-alkylene-aryl, N(R34) (R35), 17 COCH=CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t (R39), CO(C1-C6)-alkyl, COCOO(C1-C6)-alkyl, COO(R40) and S(O)u (R41), where in a preferred embodiment the substituent O-(C1-C6)-alkyl is excluded when the 3-12 5 membered ring is phenyl; t 0,1,2,3,4; u 0, 1, 2; 10 R34, R35, R37, R38 independently of one another H, (C1 -C)-alkyl; R34 and R35 optionally together with the nitrogen atom to which they are 15 bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C 6 )-alkyl, oxygen and sulfur and may optionally be substituted by 1-2 oxo groups; 20 R36, R39 independently of one another (C3-C8)-cycloalkyl, 5-10 membered aromatic ring system which may comprise a further heteroatom from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C1-C6)-alkyl, 0-(C1 C8)-alkyl; 25 R40 H, (C1-C8)-alkyl, (C2-C6)-alkenyl, (Co-C8)-alkylene-aryl; R41 (Ci -C6)-alkyl, 5-10 membered aromatic ring system which may comprise 0-2 further heteroatoms from the group of 30 nitrogen, oxygen and sulfur and may be substituted by F, Cl, 18 (C1-C6)-alkyl, 0-(C1-C8)-alkyl; R3 H, (C1-C 6 )-alkyl; 5 R4, R5 independently of one another H, (C1-C6)-alkyl, OH, O-(C1-06)-alkyl, 0-CO(C1-C6)-alkyl; R6, R7, R8, R9 independently of one another H, (C1-C 8 )-Alkyl; 10 R6 and R7, R8 and R9 independently of one another optionally oxo; n, m independently of one another 0, 1, 2, preferably m is 0, 1, 2 15 and n is 1; A, B, D, G independently of one another N, C(R42); R42 is H, F, Cl, Br, CF 3 , CN, 0-(C1-C6)-alkyl, (C1-C6)-alkyl, 20 (C3-C8)-cycloalkyl, (C0-C2)-alkylene-aryl, 0-(CO-C2)-alkylene aryl, N(R43)(R44), SO 2
-CH
3 , COO-(C1-C6)-alkyl, CON(R45)(R46), N(R47)CO(R48), N(R49)SO 2 (R50), CO(R51) 25 R43, R44, R45, R46,R47, R49 independently of one another H, (Ci -C8)-alkyl; R43 and R44, R45 and R46 independently of one another optionally together with the 30 nitrogen atom to which they are bonded a 5-6 membered ring 19 which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1 -C6)-alkyl, oxygen and sulfur; 5 R48, R50, R51 independently of one another H, (Ci -C8)-alkyl, aryl; R10 H, (C1-C8)-alkyl; 10 X N(R52), 0, a bond, C=C, C(R53)(R54), C(R55)(R56)O; R52, R53, R54, R55, R56 independently of one another H, (Ci -C8)-alkyl 15 E 3-8 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group of N, 0 and S, which may optionally have substituents from the group of H, F, Cl, CF3, NO 2 , OH, CN, 0-(Cl-C6)-alkyl, (C1-C6)-alkyl, (C0-C8) alkylene-aryl, 0-(Co-C8)-alkylene-aryl, N(R57)(R58), S02 20 CH 3 , COO-(C1-C6)-alkyl, CON(R59)(R60), N(R61)CO(R62), N(R63)SO 2 (R64), CO(R65) and may be mono- or bicyclic, preferably the group E has no substituents from the group of (CO-C8)-alkylene-aryl, 0-(Co-C8)-alkylene-aryl and N(R57)(R58), in which R57 and R58 form together with the 25 nitrogen atom a 5-6 membered ring, in the position ortho to the point of attachment of X; particularly preferably E is monocyclic; 30 R57, R58, R59, R60, R61, R63 independently of one another H, (C1 -C8)-alkyl; 20 R57 and R58, R59 and R60 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring 5 which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1 -C6)-alkyl, oxygen and sulfur, where R59 and R60 are preferably not both H; R62, R64, R65 10 independently of one another H, (Ci -C)-alkyl, aryl; K a bond, 0, CH 2 0, N(R66), (C(R69)(R70))v, C=C, OCH2, CON(R68), preferably a bond, 0, CH 2 0, ((CR69)(R70))v, C=C, N(R66); 15 v 1, 2; R66, R68, R69, R70 independently of one another H, (C1 -C8)-alkyl; 20 R11 H, (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C3-C8) alkenyl, a 3 to 1 0-membered mono-, bi- or spirocyclic ring which may comprise 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system 25 may additionally be substituted by F, Cl, Br, CF 3 , NO 2 , CN, (Ci -C6)-alkyl, O-(C1 -C8)-alkyl, (C1 -C4)-alkoxy-(C1 -C4)-alkyl, (Co-CB)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or
SO
2
CH
3 , preferably R1 1 is not COO(R74); 30 21 R71, R72, R73, R74, R75, R76, R77 independently of one another H, (C1 -C 8 )-alkyl; R72 and R73, R76 and R77 5 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C 1 -C6)-alkyl, oxygen and sulfur. 10 Particularly preferred compounds of the formula I are those in which A, B, D, G are independently of one another N or C(R42), and the total number of nitrogen atoms in this ring is 0-2, preferably 0 or 1. 15 Very particularly preferred compounds of the formula I are those in which n is 1 and m is 1 or 2. 20 Especially preferred compounds of the formula I are those in which A, B, D, G are independently of one another N or C(R42) and the total number of nitrogen atoms in this ring is 0-2, preferably 0 or 1; 25 n is 1 and m is 1 or 2. 30 In a further preferred embodiment, the present invention relates to compounds of the formula I in which the meanings are: 22 R1, R2 independently of one another are H, (C1 -C8)-alkyl, (CR78R79) 0 -R1 2, (Ci -C4)-alkoxy-(C1 -C4)-alkyl, (C3-C8) alkenyl, CO-(C1-C)-alkyl, -CO-(CH 2 )o-R12, CO-aryloxy (C1-C4)-alkyl, COCH=CH(R13), COCC(R14), 5 CO(C(R15)(R16))qN(R17)(R18), CO(C(R1 9) (R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 1 0-membered mono-, bi- or spirocyclic ring which, apart from 10 the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, Cl, CF 3 , (Cl -C6)-alkyl, O-(CI-C 4 )-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C0-C2) 15 alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C1-C6)-alkyl, N(R31)(R32) or S0 2
CH
3 ; preferably independently of one another H, (Ci -C8)-alkyl, -(CR78R79) 0 -R1 2, (Ci -C4)-alkoxy-(C1 -C4)-alkyl, CO-(Ci 20 C)-alkyl, -CO-(CH 2 )o -R1 2, COCH=CH(Ri 3), COCC(R1 4), CO(C(R15)(R16))qN(R17)(R18), CO(C(R23)(R24))sO(R25); or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 1 0-membered mono- or bicyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 25 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, Cl, CF 3 , (C1-C6)-alkyl, 0-(Ci C4)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (CO-C2)-alkylene-aryl, 23 oxo, CO(R26), hydroxy, N(R31)(R32) or SO 2
CH
3 ; particularly preferably independently of one another H, (C1 -C8)-alkyl, -(CR78R79)o -R1 2, (C1 -C4)-alkoxy-(C1 -C4) alkyl, CO-(C1-C8)-alkyl, -CO-(CH 2 )o -R12, 5 CO(C(R15)(R16))qN(R17)(R18), or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 10 membered mono - or bicyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen and nitrogen, where the 10 heterocyclic ring system may be additionally substituted by F, (C1-C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, oxo, CO(R26), hydroxy, N(R31)(R32); o 0, 1, 2, 3, 4, 5, 6; preferably 0, 1, 2, 3, 4; particularly 15 preferably 0, 1, 2, 3; q, r independently of one another 1, 2, 3; preferably q is 1 or 2; s 0, 1, 2, 3, 4; preferably 0, 1, 2, 3; particularly preferably 0, 1, 20 2; R13, R14 independently of one another are a phenyl ring which may comprise 0-1 nitrogen atoms; 25 R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 independently of one another H, (Ci -C6)-alkyl; R18 H, (C1-C6)-alkyl, CO(C1-C6)-alkyl, CO(R33); preferably H, 30 (Ci -C6)-alkyl, CO(C1-C6)-alkyl; particularly preferably H, (C1 -C6)-alkyl; 24 or R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of one another optionally form together with the nitrogen atom to which they are bonded a 5-6 membered ring 5 which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C 6 )-alkyl, oxygen and sulfur; preferably the ring is pyrrolidine, piperidine, N methylpiperazine, morpholine; 10 R33 a 5-10 membered aromatic ring system which may comprise a further heteroatom from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C1-C 6 )-alkyl, O-(C1-08)-alkyl; 15 R12 OH, O-(C1-C6)-alkyl, O-(Co-C)-alkylene-aryl, CN, S-(C1 -C6) alkyl, COO(R80), CON(R81)(R82), 3-12 membered mono-, bi or spirocyclic ring which may comprise one or more heteroatoms from the group of N, 0 and S, and the 3-12 membered ring may comprise further substituents such as F, 20 Cl, Br, OH, CF 3 , CN, oxo, O-(C1-C6)-alkyl, (C1-C 4 )-alkoxy (C1-C4)-alkyl, (C1-C6)-alkyl, O-(Co-C)-alkylene-aryl, (CO-C) alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t (R39), CO(C1-C6)-alkyl, COCOO(C -C6)-alkyl, COO(R40), S(O)u (R41); 25 preferably OH, O-(C1-C6)-alkyl, 0-(Co-C)-alkylene-aryl, CN, 3-10 membered mono- or bicyclic ring which may comprise 1 3 heteroatoms from the group of N, 0 and S, and the 3-10 membered ring may comprise further substituents such as F, Cl, Br, OH, CF 3 , CN, oxo, O-(C1-C6)-alkyl, (C1-C4)-alkoxy 30 (C1-C4)-alkyl, (C1-06)-alkyl, (CO-C2)-alkylene-aryl, 25 N(R34)(R35), CO(C1-C6)-alkyl; particularly preferably OH, 0-(C1 -C6)-alkyl, 3-10 membered mono- or bicyclic ring which may comprise 1-2 heteroatoms from the group of N, 0 and S, and the 3-10 membered ring 5 may comprise further substituents such as F, OH, oxo, (C1-C6)-alkyl, CO(C 1 -C6)-alkyl; t 0,1,2,3,4,5,6; 10 u 0, 1, 2; preferably 0 or 2; particularly preferably 2; R34, R35, R37, R38 independently of one another H, (C1 -C8)-alkyl; or R34 and R35 15 optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C 6 )-alkyl, oxygen and sulfur and may optionally be substituted by 1-2 oxo groups; 20 R36, R39 independently of one another (C3-C8)-cycloalkyl, 5-10 membered aromatic ring system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C1 -C6)-alkyl, 0-(C1 25 C8)-alkyl; R40 H, (C1-C8)-alkyl, (C2-C6)-alkenyl, (CO-C8)-alkylene-aryl; R41 (C1-C6)-alkyl, 5-10 membered aromatic ring system which 30 may comprise 0-2 further heteroatoms from the group of 26 nitrogen, oxygen and sulfur and may be substituted by F, CI, (C1-C6)-alkyl, 0-(C1-C8)-alkyl; R78, R79 independently of one another H, (C1-C8)-alkyl, hydroxy 5 (C1-C4)-alkyl, OH, (C1-C 4 )-alkoxy-(C1-C4)-alkyl; R80, R81 independently of one another H, (C1-C8)-alkyl; R3 H, (C1-C6)-alkyl; preferably H; 10 R4, R5 independently of one another H, (C1 -C6)-alkyl, OH, 0-(C1-C6)-alkyl, 0-CO-(C1-C6)-alkyl, S-(C1-C6)-alkyl; preferably independently of one another H, (C1 -C6)-alkyl, OH, 0-(C1 -C6)-alkyl, O-CO-(C1 -C 6 )-alkyl; particularly preferably independently of one another H, OH, 0-(C1 -C6)-alkyl; 15 R6, R7, R8, R9 H; or R6 and R7, R8 and R9 20 independently of one another optionally oxo; preferably R6, R7, R8, R9 are H; n 1 m 1 or 2; preferably 1; 25 A, B, D, G independently of one another N, C(R42); or the groups A and B or D and G are each C(R42) and together form an ortho-phenylene unit to result overall in a 1,4 bisubstituted naphthalene system; 30 preferably 27 B is N, C(R42); and A, D, G C(R42); particularly preferably A, B, D, G are C(R42); 5 R42 H, F, Cl, Br, CF3, CN, O-(C1-C6)-alkyl, 0-(C1-C4)-alkoxy-(C1
C
4 )-alkyl, S-(C1-C6)-alkyl, (C1-C6)-alkyl, (Co-C 8 )-alkylene aryl, 0-(Co-C8)-alkylene-aryl, N(R43)(R44), S0 2
-CH
3 , CON(R45)(R46), N(R47)CO(R48), CO(R51), -(CR84R85)x O(R86); 10 preferably H, F, Cl, Br, CF 3 , CN, 0-(C1-C6)-alkyl, (C1-C6) alkyl, S0 2
-CH
3 , CON(R45)(R46), N(R47)CO(R48), CO(R51), -(CR84R85)x-O(R86); particularly preferably H, F, Cl, CF 3 , CN, (C1-C6)-alkyl, -(CR84R85)x-O(R86); 15 R43,R44, R45, R46,R47 independently of one another H, (C1 -C8)-alkyl; or R43 and R44, R45 and R46 independently of one another optionally together with the 20 nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen and sulfur; 25 R48, R50, R51 independently of one another H, (Ci -C)-alkyl, aryl; preferably independently of one another H, (C1 -C8)-alkyl; R84, R85 H; 28 R86 H, (C1-C6)-alkyl; x 0, 1, 2; preferably 0, 1; particularly preferably 1; R10 H, (C1-C8)-alkyl; 5 X N(R52), a bond, C=C, C(R53)(R54), C(R55)(R56)O, C=C, CH2-CH 2 , YCH 2 ; preferably N(R52), a bond, C=C, C(R53)(R54), CH 2
-CH
2 ; particularly preferably a bond, C=C, C(R53)(R54),
CH
2
-CH
2 ; 10 Y O, S, N(R89); R89 H, (C1-C8)-alkyl; R52, R53,R54, R55, R56 15 independently of one another H, (C1 -C8)-alkyl; E 3-8 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group of N, 0 and S, which may optionally have substituents from the group of H, F, Cl, 20 Br, OH, CF 3 , NO 2 , CN, OCF 3 , 0-(C1-C6)-alkyl, 0-(C1-C4) alkoxy-(C1-C4)-alkyl, S-(C 1 -C6)-alkyl, (C1-C6)-alkyl, (C2-C6) alkenyl, 0-(C3-C8)-cycloalkyl, (C3-C)-cycloalkenyl, (C2-C6) alkynyl, (CO-C8)-alkylene-aryl, 0-(Co-C)-alkylene-aryl, S-aryl, N(R57)(R58), S02-CH 3 , N(R61)CO(R62), N(R63)SO 2 (R64), 25 CO(R65) and may be mono- or bicyclic; preferably 5-7 membered bivalent carbo- or heterocyclic ring structure with 0-3 heteroatoms from the group of N, 0 and S, which may optionally have substituents from the group of H, F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , 0-(C1-C6)-alkyl, 29
S-(C
1 -C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, 0-(CO-C8) alkylene-aryl, S-aryl, N(R57)(R58), S0 2
-CH
3 , N(R61)CO(R62), CO(R65) and may be mono- or bicyclic; particularly preferably 5-7 membered bivalent carbo- or 5 heterocyclic ring structure with 0-2 heteroatoms from the group of N, 0 and S, which may optionally have substituents from the group of H, F, Cl, Br, OH, CF3, NO 2 , OCF 3 , 0-(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), S0 2
-CH
3 , CO(R65) 10 e.g. E is selected from the group consisting of NNN 0 S N -N N- -N N-N S N NndN and N-0 which may optionally have substituents from the group of H, F, Cl, Br, OH, 15 CF 3 , NO 2 , OCF 3 , 0-(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), S0 2 -CH3, CO(R65); preferably 30 0 N
N
0\/ __ \ N N-N N and which may optionally have the aforementioned substituents; 5 R57, R58, R61, R63 independently of one another H, (C1 -C8)-alkyl; R62, R64, R65 independently of one another H, (C1 -C8)-alkyl, aryl; preferably 10 independently of one another H, (Ci -C8)-alkyl; K a bond, 0, OCH 2 , CH20, S, SO, S02, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO, C=C, C=C, SCH 2 , SO 2
CH
2 ; preferably a bond, 0, OCH 2 , CH 2 0, N(R66), CON(R68), 15 (C(R69)(R70))v, CO, C-C, SCH 2 ; particularly preferably a bond, 0, OCH 2 , CH 2 0, CON(R68), (C(R69)(R70))v, CO, C=C; v 1, 2, 3, 4; preferably 1, 2, 3; particularly preferably 1,2; 20 R66, R67, R68, R69, R70 independently of one another H, (C1-C8)-alkyl; R11 H, (C1-08)-alkyl, (C1-C 4 )-alkoxy-(C1-C4)-alkyl, (C3-C8) 25 alkenyl, (C3-C8)-alkynyl, a 3 to 1 0-membered mono-, bi-, tri- 31 or spirocyclic ring, which may comprise 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O-(C1-C8)-alkyl, (C1-C4) 5 alkoxy-(C1-C4)-alkyl, hydroxy-(C1-C 4 )-alkyl, (Co-C)-alkylene aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or S02CH 3 ; preferably (Ci -C8)-alkyl, (Ci -C4)-alkoxy-(C1 -C4)-alkyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which may 10 comprise 0 to 3 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF 3 , CN, (01-06) alkyl, 0-(C1-C8)-alkyl, (CO-C2)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, N(R75)CO(C1-C6)-alkyl, 15 N(R76)(R77) or SO 2
CH
3 ; particularly preferably (Ci -C8)-alkyl, (Ci -C 4 )-alkoxy-(C1 -C 4
)
alkyl, a 3 to 1 0-membered mono- or bicyclic ring which may comprise 0 to 2 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may 20 additionally be substituted by F, Cl, Br, CF 3 , CN, (C1-C6) alkyl, O-(C1-Cs)-alkyl, oxo, CO(R71), CON(R72)(R73), N(R75)CO(C 1
-C
6 )-alkyl, or S02CH 3 ; R71, R72, R73, R74, R75, R76, R77 25 independently of one another H, (Ci -C8)-alkyl; or R72 and R73, R76 and R77 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring 32 which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C 6 )-alkyl, oxygen and sulfur; or 5 the N-oxides and the physiologically tolerated salts thereof. In a further preferred embodiment, A, B, G and D in formula I are CH or: If E is 1,4-phenylene, the preferred meanings for A, B, G and D are 10 furthermore those listed in table I below: Table I: A B G D N CH CH CH CH N CH CH C-CI N CH CH C-F CH C-F CH CH CH C-F CH CH C-F CH CH CH CH CH CF CH C-Br CH CH CH CH C-Br CH CH C-CI CH CH CH CH C-Cl CH CH CH C-CN CH CH CH CH C-CN CH CH C-CH3 CH CH CH CHC-H CH H CCF3CHCF CH CH CHC-CF3
CHCHCHCHO
33 CH C-F CH C-F CH C-F C-F CH CH CH C-F C-F CH CH C-F C-CI CH CH C-CI C-CN CH CCH3C-CI CH L CH N CHC-CH N-N -- CCH If E is , the preferred meanings for A, B, G and D are furthermore those listed in table 11 below: 5 Table II: -C-CH3 CH C-F CH C CH CH C-CH3 C -C-F CH N CH C CH CH CHN C-F CH C-F C If E is , the preferred meanings for A, B, G and D are furthermore those listed in table Ill below: 10 34 Table Ill: A BG CH CH C-F C CH N CH C CH CH CHN Further preferred combinations for E and A, B, G and D are listed in table 5 IV. Table IV: ErA--rGn CH- - CH-C CH-H- -- C CH- -- C -C CH- -- C -C
---
CH-F-C -C CH-F-C -C CH- -- C -O CH- -- C -C CH- -- C -C 35 The radicals R1 1, K, X and E in formula I have in a particularly preferred embodiment one of the following meanings: 5 R1 1 is preferably selected from the group consisting of: n-propyl, n-butyl, iso-butyl, iso-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohex-(1)-enyl, phenyl, p-fluorophenyl, p-chlorophenyl, p bromophenyl, p-tolyl, p-methoxyphenyl, p-trifluoromethylphenyl, p 10 methylthiophenyl, o-fluorophenyl, o-chlorophenyl, o-cyanophenyl, m fluorophenyl, 2,4-difluorophenyl, 3-fluoro-4-methylphenyl, 2-nitro-4 methylphenyl, 2-amino-4-methylphenyl, C l FH C1HO O N and . 15 K is preferably selected from the group consisting of: -0-, bond, C=C, CH 2 , CH 2 0, CONH, OCH 2 , CO, SCH 2 and (CH 2
)
2 0. X is preferably selected from the group consisting of bond, NH and CH 2
.
36 E is preferably selected from the group consisting of: -F F N N- --N N N / N- , and. 50 S ad N Preferred combinations of R1 1, K, X and E are listed below: 10 If K and X are each a bond, the particularly preferred meanings for E and R11 are as follows: - If E is 1,4-phenylene, R1 1 is selected from the group consisting of: cyclohexyl, p-tolyl, p-fluorophenyl, o-fluorophenyl, p-methoxyphenyl, 15 p-chlorophenyl, o-chlorophenyl, 2,4-difluorophenyl, 3-fluoro-4 methylphenyl, o-cyanophenyl, NI
H
3 C s and0
-N
- If E is , R1 1 selected from the group consisting of: 20 p-chlorophenyl, p-tolyl, p-fluorophenyl, p-methoxyphenyl, p trifluoromethylphenyl, o-fluorophenyl, phenyl and 37 S N Further combinations of E and R1 1 for the case where K and X are each a bond are listed in table V: 5 Table V: R11 E p-Chlorophenyl 1,4-Cyclohexylene 2-Nitro-4-methylphenyl p-Chlorophenyl p-Bromophenyl p-Fluorophenyl p-Chlorophenyl p-Chlorophenyl 38 p-Methylthiophenyl 2-Amino-4-methylphenyl If K is -0- and X is a bond, NH or CH 2 , the particularly preferred meanings for E and R1 1 are as follows: 5 If E is 1,4-phenylene, R11 is selected from the group consisting of: phenyl, cyclopentyl, n-butyl, iso-butyl, iso-pentyl, 2,4-difluorophenyl and p-fluorophenyl. 10 Further combinations of E and R1 1 for the case where K is -0- and X is a bond, NH or CH 2 are listed in table VI: Table VI: R11 Phenyl Cyclopentyl 15 If K is C=C and X is a bond, the particularly preferred meanings of E and R11 are as follows: 39 If E is 0 , R1 1 is selected from the group consisting of: phenyl, p-fluorophenyl and p-chlorophenyl. 5 If K is CH 2 and X is a bond, the particularly preferred meanings of E and R1 1 are indicated in table VII below: Table VII: R11 E Phenyl 1,4-Phenylene 1,4-Phenylene p-Chlorophenyl 10 If K is CH 2 0 and X is a bond, the particularly preferred meanings of E and R11 are as follows: 15 - If E is 1,4-phenylene, R11 is selected from the group consisting of: phenyl, cyclopropyl and cyclohexyl. If K is CONH and X is a bond, the particularly preferred meanings of E and 20 R1 1 are indicated in table VIII below: Table VIII: R11 E Cyclopentyl 1,4-Phenylene Cyclohex-(1)-enyl 1,4-Phenylene 40 Cyclopentyl If K is OCH 2 and X is a bond, the particularly preferred meanings of E and R1 1 are indicated in table IX below: 5 Table IX: R11 E o-Chlorophenyl p-Tolyl 1,4-Phenylene n-Propyl 1,4-Phenylene Cyclobutyl 1,4-Phenylene The combinations of R1 1, K and E listed in table X below are furthermore particularly preferred in addition to the aforementioned combinations, with 10 X very particularly preferably being a bond: Table X: R11 KE o-Fluorophenyl C PheylSCH2 1,4-Phenylene Cyclopropyl(C20 15 The compounds of the formula I are in a very particularly preferred embodiment compounds of the formula la 41 R42 O NR1R2 R1''-E'X N / N R10 R42' la in which the radicals R1, R2, R10, R1 1, R42, and groups X, E, K have the aforementioned meanings, and R42' is defined as R42, where R42 and 5 R42' in the compounds of the formula la may be identical or different, or the N-oxides and the physiologically tolerated salts thereof. In a preferred embodiment of the invention, the radicals R1, R2, R10, R1 1, R42, R42' and groups X, E, K have the following meanings: 10 R1, R2 independently of one another H, (C1-C8)-alkyl, -(CR78R79) 0 -R12, (C1-C4)-alkoxy-(C1-C4)-alkyl, or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 1 0-membered mono-, bi- or spirocyclic ring which, apart 15 from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, (C1-C6)-alkyl, O-(C1-C4)-alkyl, (C 1
-C
4
)
alkoxy-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (CO-C2)-alkylene 20 aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, N(R31)(R32) or SO 2
CH
3 ; where R 1 and R 2 are not both CO(R26), preferably H, (C1 -C8)-alkyl, -(CR78R79)o-R12, (C1-C4) alkoxy-(C1-C4)-alkyl, or R1 and R2 form together with the 25 nitrogen atom to which they are bonded a 4 to 1 0-membered mono- or bicyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen and nitrogen, where the heterocyclic ring 42 system may additionally be substituted by F, (C1 -C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, oxo, CO(R26), hydroxy, N (R3 1) (R32); 5 o 0, 1, 2, 3, 4, preferably 0, 1, 2, 3; q 1, 2, 3, preferably 1 or 2; 10 s 0,1,2; R15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31, R32 independently of one another H, (Ci -C6)-alkyl; 15 or R17 and R18, R27 and R28, R31 and R32 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 20 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen and sulfur, preferably the ring is a pyrrolidine, piperidine, N-methylpiperazine, morpholine ring; R12 OH, O-(C1-C6)-alkyl, 0-(CO-C2)-alkylene-aryl, CN, S-(C1-C6) 25 alkyl, 3-12 membered mono-, bi- or spirocyclic ring which may comprise 1 to 3 heteroatoms from the group of N, 0 and S, and the 3-12 membered ring may comprise further substituents such as F, OH, CF 3 , CN, oxo, (C1-C6)-alkyl, (Co C2)-alkylene-aryl, N(R34)(R35), COO(R40), CO(C1-C6)-alkyl, 30 preferably OH, O-(C1-C6)-alkyl, 3-10 membered mono- or bicyclic ring which may comprise 1-2 heteroatoms from the 43 group of N, 0 and S, and the 3-10 membered ring may comprise further substituents such as F, OH, oxo, (C1 -C6) alkyl, CO(C1-C6)-alkyl; R34, R35 5 independently of one another H, (C1-C4)-alkyl; R40 H, (C1-C6)-alkyl, (C0-C2)-alkylene-aryl; 10 R78, R79 independently of one another H, (C1-C8)-alkyl, hydroxy (C1-C4)-alkyl, OH, (C1-C4)-alkoxy-(C1-C4)-alkyl; R42, R42' independently of one another H, F, Cl, Br, CF3, CN, (C1-C 6
)
alkyl; 15 R10 H, (C1-C8)-alkyl; X N(R52), a bond, C=C, C(R53)(R54), CH 2
CH
2 ; 20 R52, R53, R54 independently of one another H, (C1-C8)-alkyl; E 5-7 membered bivalent carbo- or heterocyclic ring structure with 0-3 heteroatoms from the group of N, 0 and S, which 25 may optionally have substituents from the group of H, F, Cl, Br, CF 3 , OH, CN, OCF 3 , N02, 0-(C1-C6)-alkyl, (C1-C6)-alkyl, S0 2
-CH
3 , CO(R65); preferably 5-7 membered bivalent carbo- or heterocyclic ring 44 structure with 0-2 heteroatoms from the group of N, 0 and S, which may optionally have substituents from the group of H, F, Cl, Br, OH, CF 3 , N02, OCF 3 , 0-(C1-C6)-alkyl, (C 1
-C
6
)
alkyl, (C2-C6)-alkenyl, N(R57)(R58), S0 2
-CH
3 , CO(R65) 5 e.g. E is selected from the group consisting of 'NNI 0 S N / N-N N- -- N N-N
S\
-- N _ NNN N- / N--7 NN and N-O 10 which may optionally have substituents from the group of H, F, Cl, Br, OH,
CF
3 , NO 2 , OCF 3 , 0-(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO 2
-CH
3 , CO(R65); preferably 15 45 0 S \/ -N N- N N-N N and which may optionally have the aforementioned substituents; 5 R65 H, (C1-C8)-alkyl; K a bond, 0, OCH 2 , CH 2 0, S, SO 2 , N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO, C=C, SCH 2 , SO 2
CH
2 ; preferably a bond, 0, OCH 2 , CH 2 0, CON(R68), 10 (C(R69)(R70))v, particularly preferably CH 2 , CO, C=C; v 1, 2, 3, preferably 1, 2; 15 R66, R67, R68, R69, R70 independently of one another H, (C1-C8)-alkyl; R11 (Cl-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, a 3 to 10 membered mono-, bi-, tri- or spirocyclic ring which may 20 comprise 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF 3 , CN, (C1-C6) alkyl, O-(C1-C8)-alkyl, oxo, CO(R71), hydroxy, N(R75)CO(C1-C6)-alkyl, or SO 2
CH
3 ; 25 preferably (C1 -C8)-alkyl, (C1-C4)-alkoxy-(C1-C 4 )-alkyl, a 3 to 46 1 0-membered mono- or bicyclic ring which may comprise 0 to 2 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF 3 , CN, (C1-C6)-alkyl, 0-(C1-C8) 5 alkyl, oxo, CO(R71), CON(R72)(R73), N(R75)CO(C 1 -C6) alkyl, or SO 2
CH
3 ; R71, R72, R73, R74, R75, R76, R77 independently of one another H, (Ci -C8)-alkyl; 10 or R72 and R73, R76 and R77 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 15 further heteroatoms from the group of N-(C1-C 6 )-alkyl, oxygen and sulfur. In a preferred embodiment, the present invention relates to compounds of the formula la, 20 in which X is CH 2
CH
2 , N(R52), CH 2 , OCH 2 , SCH 2 , CH=CH, preferably
CH
2
CH
2 , CH=CH; 25 E is 47 N~ 14 N ~preferably K is a bond, 0 or C(R69)(R70); 5 and the other symbols R1, R2, R10, R1 1, R42, R42', R52, R69 and R70 have the meanings indicated above in relation to a definition of the radicals of the compound of the formula Ia. 10 In a further preferred embodiment, the present invention relates to compounds of the formula Ia, in which 15 X is N(R52), preferably NH, or C(R53)(R54); E is N NN N -~N-S S -C N~N preferably I or 20 K is a bond, 0 or C(R69)(R70), preferably 0; 48 preferably 0 and the other symbols R1, R2 R10, R1 1, R42, R42',R52, R53, R54, R69 and R70 have the meanings indicated above in relation to a definition of the 5 radicals of the compound of the formula Ia. In a further particularly preferred embodiment, the compounds of the formula I are compounds of the formula lb 0
NR
1
R
2 K E N N R11 R10 D 10 (lb) in which the radicals R1, R2, R1 0 and R1 1 and the groups E and D have the aforementioned meanings, or the N-oxides and the physiologically tolerated salts thereof. 15 In a preferred embodiment, the radicals R1, R2, R1 0 and R1 1 the groups E and D have the following meanings: R1, R2 independently of one another H, (Ci -C8)-alkyl, -(CR78R79) 0 20 -R12, (C1-C4)-alkoxy-(C1-C4)-akyl, (C3-C8)-alkenyl, CO (C1 -C8)-alkyl, -CO-(CH 2
)
0 -R1 2, CO-aryloxy-(C1 -C4)-alkyl, COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R2 1)(R22), 25 CO(C(R23)(R24))sO(R25); or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 10 membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where 49 the heterocyclic ring system may additionally be substituted by F, Cl, CF 3 , (C1-C6)-alkyl, 0-(C1-C4)-alkyl, (C1-C4)-alkoxy (C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (CO-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), 5 N(R30)CO(C1-C6)-alkyl, N(R31)(R32) or SO 2
CH
3 , where R1 and R2 are not both CO(R26); preferably independently of one another H, (Ci -C8)-alkyl, -(CR78R79) 0 -R1 2, (Ci -C4)-alkoxy-(C1 -C4)-alkyl, CO-(C1 C8)-alkyl, -CO-(CH 2
)
0 -R1 2, COCH=CH(R1 3), COCC(R1 4), 10 CO(C(R15)(R16))qN(R17)(R18), CO(C(R23)(R24))sO(R25); or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 1 0-membered mono- or bicyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, 15 nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, Cl, CF 3 , (C1 -C6)-alkyl, 0-(C1 C4)-alkyl, (C1-C 4 )-alkoxy-(C1-C4)-alkyl, (CO-C2)-alkylene-aryl, oxo, hydroxy, N(R31)(R32) or SO 2
CH
3 , where R1 and R2 are not both CO-(C1-C8)-alkyl; 20 particularly preferably independently of one another H, (Ci -C8)-alkyl, -(CR78R79) 0 -R1 2, (Ci -C4)-alkoxy-(C1 -C4) alkyl, CO-(C1 -C8)-alkyl, -CO-(CH 2
)
0 -R1 2, CO(C(R15)(R16))qN(R17)(R18), or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 10 25 membered mono- or bicyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen and nitrogen, where the heterocyclic ring system may additionally be substituted by F, (C1-C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, oxo, CO(C1-C8)- 50 alkyl, hydroxy, N(R31)(R32), where R1 and R2 are not both CO(C1-C)-alkyl; o 0, 1, 2, 3, 4, 5, 6; preferably 0, 1, 2, 3, 4; particularly 5 preferably 0, 1, 2, 3; q, r independently of one another 1, 2, 3; preferably q is 1 or 2; s 0, 1, 2, 3, 4; preferably 0, 1, 2, 3; particularly preferably 0, 1, 10 2; R13, R14 independently of one another a phenyl ring which may comprise 0-1 nitrogen atoms; 15 R15, R16, R17, R19, R20,R21, R22, R23,R24, R25, R26, R27, R28, R29, R30, R31, R32 independently of one another H, (Ci -C6)-alkyl; R18 H, (C1-C6)-alkyl, CO(C1-C6)-alkyl, CO(R33); preferably H, 20 (Ci -C6)-alkyl, CO(C -C6)-alkyl; particularly preferably H, (C1-C6)-alkyl; or R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of one another optionally together with the 25 nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1 -C6)-alkyl, oxygen and sulfur; preferably the ring is pyrrolidine, piperidine, N-methylpiperazine, morpholine; 30 R33 a 5-10 membered aromatic ring system which may comprise a further heteroatom from the group of nitrogen, oxygen and 51 sulfur and may be substituted by F, Cl, (C1 -C6)-alkyl, 0-(C1 -C8)-alkyl; R12 is OH, O-(C1-C6)-alkyl, 0-(Co-C6)-alkylene-aryl, CN, S 5 (C1-C6)-alkyl, COO(RBO), CON(R81)(R82), 3-12 membered mono-, bi- or spirocyclic ring which may comprise one or more heteroatoms from the group of N, 0 and S and the 3-12 membered ring may comprise further substituents such as F, Cl, Br, OH, CF 3 , CN, oxo, O-(C1-C6)-alkyl, (C1-C4)-alkoxy 10 (C1-C4)-alkyl, (C1-06)-alkyl, O-(CO-CO)-alkylene-aryl, (Co-C6) alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t (R39), CO(C1-C6)-alkyl, COCOO(C1-C6)-alkyl, COO(R40), S(0)u (R41); preferably OH, O-(C1-C6)-alkyl, O-(Co-C8)-alkylene-aryl, CN, 15 3-10 membered mono- or bicyclic ring which may comprise 1 3 heteroatoms from the group of N, 0 and S, and the 3-10 membered ring may comprise further substituents such as F, Cl, Br, OH, CF3, CN, oxo, O-(C1-C6)-alkyl, (C1-C 4 )-alkoxy (C1-C4)-alkyl, (C1-C6)-alkyl, (CO-C2)-alkylene-aryl, 20 N(R34)(R35), CO(C1-C6)-alkyl; particularly preferably OH, O-(C -C6)-alkyl, 3-10 membered mono- or bicyclic ring which may comprise 1-2 heteroatoms from the group of N, 0 and S and the 3-10 membered ring may comprise further substituents such as F, OH, oxo, (Ci 25 C6)-alkyl, CO(C1-C6)-alkyl; t 0,1,2,3,4,5,6; 52 u 0, 1, 2; preferably 0 or 2; particularly preferably 2; R34, R35, R37, R38 independently of one another H, (Ci -C8)-alkyl; or 5 R34 and R35 optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen and sulfur and may 10 optionally be substituted by 1-2 oxo groups; R36, R39 independently of one another (C3-C8)-cycloalkyl, 5-10 membered aromatic ring system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and 15 sulfur and may be substituted by F, Cl, (C1 -C6)-alkyl, 0 (C1-C8)-alkyl; R40 H, (C1-C8)-alkyl, (C2-C6)-alkenyl, (CO-C8)-alkylene-aryl; 20 R41 (C1 -C6)-alkyl, 5-10 membered aromatic ring system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C1-C6)-alkyl, 0-(C1-C8)-alkyl; 25 R78, R79 independently of one another H, (C1-C8)-alkyl, hydroxy (C1-C4)-alkyl, OH, (C1-C4)-alkoxy-(C1-C4)-alkyl; R80, R81 independently of one another H, (Ci -C8)-alkyl; 30 R10 H, (C1-C8)-alkyl; 53 E 3-8 membered bivalent carbo- or heterocyclic ring structure with 0-4 heteroatoms from the group of N, 0 and S, which may optionally have substituents from the group of H, F, Cl, 5 Br, OH, CF3, NO 2 , CN, OCF 3 , 0-(Cl-C6)-alkyl, 0-(C1-C4) alkoxy-(C1-C4)-alkyl, S-(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6) alkenyl, 0-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C2-C6) alkynyl, (CO-C8)-alkylene-aryl, 0-(Co-C6)-alkylene-aryl, S-aryl, N(R57)(R58), S0 2
-CH
3 , N(R61)CO(R62), N(R63)SO 2 (R64), 10 CO(R65) and may be mono- or bicyclic; preferably 5-7 membered bivalent carbo- or heterocyclic ring structure with 0-3 heteroatoms from the group of N, 0 and S, which may optionally have substituents from the group of H, F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , 0-(C1-C6)-alkyl, S-(C1 15 C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, 0-(Co-C6)-alkylene aryl, S-aryl, N(R57)(R58), S0 2
-CH
3 , N(R61)CO(R62), CO(R65) and may be mono- or bicyclic; particularly preferably 5-7 membered bivalent carbo- or heterocyclic ring structure with 0-2 heteroatoms from the 20 group of N, 0 and S, which may optionally have substituents from the group of H, F, Cl, Br, OH, CF 3 , NO 2 , OCF 3 , 0-(C1 C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), S0 2
-CH
3 , CO(R65) e.g. E is selected from the group consisting of 25 54 s 'N oI N-N , SD/ -N N- -N N- / N NN - , a N-N-0 which may optionally have substituents from the group of H, F, CI, Br, OH, 5 CE 3 , NO 2 , OCF 3 , 0-(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO 2 -CH3, CO(R65); preferably 0 S I \ / \ /-N\ N N-N N N- and 10 which may optionally have the aforementioned substituents; 55 R57, R58, R61, R63 independently of one another H, (C1-C8)-alkyl; 5 R62, R64, R65 independently of one another H, (C1-C8)-alkyl, aryl; preferably independently of one another H, (C1 -C8)-alkyl; K a bond, 0, OCH 2 , CH20, S, SO, S02, N(R66), N(R67)CO, 10 CON(R68), (C(R69)(R70))v, CO, C=C, C=C, SCH 2 , SO 2
CH
2 ; preferably a bond, 0, OCH 2 , CH 2 0, N(R66), CON(R68), (C(R69)(R70))v, CO, C=C, SCH 2 ; particularly preferably a bond, 0, OCH 2 , CH 2 0, CON(R68), (C(R69)(R70))v, CO, C=C; 15 v 1, 2, 3, 4; preferably 1, 2, 3; particularly preferably 1,2; R66, R67, R68, R69, R70 independently of one another H, (Ci -C8)-alkyl; 20 R11 H, (C1-08)-alkyl, (C1-C 4 )-alkoxy-(C 1
-C
4 )-alkyl, (C 3
-C
8
)
alkenyl, (C3-C8)-alkynyl, a 3 to 1 0-membered mono-, bi-, tri or spirocyclic ring which may comprise 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where 25 the ring system may additionally be substituted by F, Cl, Br,
CF
3 , CN, (C1-C6)-alkyl, 0-(C1-C)-alkyl, (C1-C4)-alkoxy (C1-04)-alkyl, hydroxy-(C1-C4)-alkyl, (Co-C)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or SO 2
CH
3
SCF
3
;
56 preferably (Ci -C8)-alkyl, (C1 -C 4 )-alkoxy-(C1 -C4)-alkyl, a 3 to 1 0-membered mono-, bi-, tri- or spirocyclic ring which may comprise 0 to 3 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may 5 additionally be substituted by F, Cl, Br, CF 3 , CN, (C1-C 6
)
alkyl, O-(C1-Cs)-alkyl, (Co-C2)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or SO 2
CH
3 ; particularly preferably (Ci -C8)-alkyl, (C1 -C4)-alkoxy-(C1 -C 4
)
10 alkyl, a 3 to 1 0-membered mono- or bicyclic ring which may comprise 0 to 2 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF 3 , CN, (C1-C6) alkyl, O-(C1-Cs)-alkyl, oxo, CO(R71), CON(R72)(R73), 15 N(R75)CO(C1-C 6 )-akyl, or S02CH 3 ; R71, R72, R73, R74, R75, R76, R77 independently of one another H, (C1 -C8)-alkyl; or 20 R72 and R73, R76 and R77 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen and sulfur. 25 In a preferred embodiment, the present invention relates to compounds of the formula lb in which 30 57 X is a bond, E is 0 S 'N N-N 5' -N N-- -N N- /- N N N or where 5 N-0 the aforementioned groups may optionally have substituents from the group of H, F, CI, Br, OH, CF 3 , NO 2 , OCF 3 , 0-(C1-C6)-alkyl, (C1-C6)-alkyl, 10 (C2-C6)-alkenyl, N(R57)(R58), S02-CH 3 , CO(R65); preferably E is 58 N0 S -N N N-N \, N- / N- N or in which the groups may have the aforementioned substituents; 5 K is a bond; and the other radicals R1, R2, R10 and R1 1 and the group D have the meanings indicated above in relation to the definition of the radicals of the 10 compound of the formula lb. R1 1 in the aforementioned compounds of the formula lb is particularly preferably a substituted mono- or bicyclic ring system with 5-10 members, which may have 0-3 heteroatoms, in particular N, 0 and/or S, particularly 15 preferably phenyl with 0-1 N atom, cyclohexyl or a bicyclic system with 8-10 members and 1-2 heteroatoms, in particular N, 0 and/or S. In a further preferred embodiment, the present invention relates to compounds of the formula lb 20 in which X is a bond; 59 E is S N- or where the aforementioned groups may optionally have substituents from 5 the group of H, F, Cl, Br, OH, CF 3 , NO 2 , OCF 3 , 0-(C1-C6)-alkyl, (C1-C6) alkyl, (C2-C6)-alkenyl, N(R57)(R58), S02CH 3 and CO(R65); preferably NN-ZN 0 10 or 10 in which the groups may have the aforementioned substituents; K is CH2, CH2CH 2 , 0, CH20, OCH2, CON(R68), N(R67)CO, S, S02, 15 SCH 2 , S02, S02CH 2 , CO or a triple bond; preferably CH 2 , 0, CH 2 0, OCH 2 , CON(R68), SCH 2 , CO or a triple bond; and the other radicals R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R1 1, R67 and 20 R68 and the group D have the meanings indicated above in relation to the definition of the radicals of the compound of the formula lb. The amount of a compound of formula (1) necessary to achieve the desired biological effect depends on a number of factors, for example the specific 25 compound chosen, the intended use, the mode of administration and the 60 clinical condition of the patient. The daily dose is generally in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day and per kilogram of bodyweight, 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 5 suitably be administered as infusion of 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 ng to 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the.active ingredient. Thus, ampoules for injections may contain, for example, from 10 1 mg to 100 mg, and single-dose formulations which can be administered orally, such as, for example, tablets or capsules, may contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case of pharmaceutically acceptable salts, the aforementioned weight data are based on the weight of the free compound from which the salt is derived. 15 For the prophylaxis and therapy of the abovementioned conditions, the compounds of formula (1) may 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 in the sense that it is compatible with the other ingredients of the composition and is not harmful 20 for the patient's health. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which may contain from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances may likewise be present, including other compounds of formula (1). The pharmaceutical 25 compositions of 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. Pharmaceutical compositions of the invention are those suitable for oral, 30 rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of formula (1) used in each case. Coated 35 formulations and coated slow-release formulations also belong within the framework of the invention. Preference is given to acid- and gastric juice resistant formulations. Suitable coatings resistant to gastric juice comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of 61 methacrylic acid and methyl methacrylate. Suitable pharmaceutical compounds for oral administration may be in the form of separate units such as, for example, capsules, cachets, suckable 5 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 already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the 10 active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact. The compositions are generally produced by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary. Thus, for example, a tablet can be 15 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, glidant, inert diluent and/or one or more 20 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 which are suitable for peroral (sublingual) 25 administration comprise suckable tablets which contain a compound of formula (1) with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic. 30 Pharmaceutical compositions suitable for parenteral administration comprise 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, 35 intramuscular or intradermal injection. These preparations can preferably be produced by mixing the compound with water and making the resulting solution sterile and isotonic with blood. Injectable compositions of the invention generally contain from 0.1 to 5% by weight of the active compound.
62 Pharmaceutical compositions suitable for rectal administration are preferably in the form of single-dose suppositories. These can be produced by mixing a compound of the formula (1) with one or more conventional 5 solid carriers, for example cocoa butter, and shaping the resulting mixture. Pharmaceutical compositions suitable for topical use on the skin are preferably in the form of ointment, cream, lotion, paste, spray, aerosol or oil. Carriers which can be used are petrolatum, lanolin, polyethylene 10 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%. Transdermal administration is also possible. Pharmaceutical compositions 15 suitable 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 aqueous solution which is buffered where appropriate, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is about 20 1% to 35%, preferably about 3% to 15%. A particular possibility is for the active ingredient to be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2(6): 318 (1986). The compounds of the formula I are distinguished by beneficial effects on 25 lipid 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-reducing or anorectic 30 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 they 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 35 metabolism of the organism in 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 63 suitable for the prophylaxis and, in particular, for the treatment of type 11 diabetes, of arteriosclerosis and for normalizing lipid metabolism and for the treatment of high blood pressure. The compounds act as MCH antagonists and are also suitable for the treatment of disturbances of 5 wellbeing and of psychiatric indications such as, for example, depressions, anxiety states, anxiety neuroses, schizophrenia and for the treatment of disorders associated with the circadian rhythm and for the treatment of drug abuse. 10 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 active ingredients for the treatment and/or prevention 15 of complications caused by diabetes or associated with diabetes. Further pharmacologically active substances suitable in particular are: all antidiabetics mentioned in the Rote Liste 2001, chapter 12. They may be 20 combined with the compounds of the formula I of the invention in particular for a synergistic improvement of the effect. Administration of the active ingredient combination may take place either by separate administration of the active ingredients to the patient or in the form of combination products in which a plurality of active ingredients are present in one pharmaceutical 25 preparation. Most of the active ingredients listed below are disclosed in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001. Suitable antidiabetics include insulin and insulin derivatives such as, for 30 example, Lantus* or HMR 1964, fast-acting insulins (see US 6,221,633), amylin, GLP-1 and GLP-2 derivatives such as, for example, those disclosed in WO 98/08871 of Novo Nordisk A/S, and orally effective hypoglycemic active ingredients. 35 The orally effective hypoglycemic active ingredients include, preferably, 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 64 sensitizers, activators of insulin 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, 5 such as antihyperlipidemic active ingredients and antilipidemic active ingredients, e.g. HMGCoA reductase inhibitors, inhibitors of cholesterol transport/of cholesterol uptake, inhibitors of bile acid reabsorption or inhibitors of microsomal triglyceride transfer protein (MTP), compounds which reduce food intake, PPAR and RXR agonists and active ingredients 10 which act on the ATP-dependent potassium channel of the beta cells. In one embodiment of the invention, the present compounds are administered in combination with insulin. 15 In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin. 20 In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor such as, for example, ezetimibe, tiqueside, pamaqueside. In one embodiment of the invention, the compounds of the formula I are 25 administered in combination with a PPAR gamma agonist, such as, for example, rosiglitazone, pioglitazone, JTT-501, GI 262570. In one embodiment of the invention, the compounds of the formula I are administered in combination with PPAR alpha agonist, such as, for 30 example, GW 9578, GW 7647. In one embodiment of the invention, the compounds of the formula I are administered in combination with a mixed PPAR alpha/gamma agonist, such as, for example, GW 1536, AVE 8042, AVE 8134, AVE 0847, or as 35 described in PCT/US 11833, PCT/US 11490, DE10142734.4. In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate such as, for example, fenofibrate, clofibrate, bezafibrate.
65 In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor such as, for example, implitapide, BMS-201038, R-103757. 5 In one embodiment of the invention, the compounds of the formula I are administered in combination with bile acid absorption inhibitor (see, for example, US 6,245,744 or US 6,221,897), such as, for example, HMR 1741. 10 In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, such as, for example, JTT-705. 15 In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorbent such as, for example, cholestyramine, colesevelam. In one embodiment of the invention, the compounds of the formula I are 20 administered in combination with an LDL receptor inducer (see US 6,342,512), such as, for example, HMR1 171, HMR1 586. In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor, such as, for example, 25 avasimibe. In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant, such as, for example, OPC-14117. 30 In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor, such as, for example, NO-1886. 35 In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP-citrate lyase inhibitor, such as, for example, SB-204990. In one embodiment of the invention, the compounds of the formula I are 66 administered in combination with a squalene synthetase inhibitor, such as, for example, BMS-188494. In one embodiment of the invention, the compounds of the formula I are 5 administered in combination with a lipoprotein(a) antagonist, such as, for example, Cl-1 027 or nicotinic acid. In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor, such as, for example, 10 orlistat. In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin. 15 In one embodiment, the compounds of the formula I are administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glipizide or glimepiride. In one embodiment, the compounds of the formula I are administered in 20 combination with a biguanide, such as, for example, metformin. In one further embodiment, the compounds of the formula I are administered in combination with a meglitinide, such as, for example, repaglinide. 25 In one embodiment, the compounds of the formula I 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-[[4-[(3,4 30 dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4 thiazolidinedione. In one embodiment, the compounds of the formula I are administered in combination with an a-glucosidase inhibitor, such as, for example, miglitol 35 or acarbose. In one embodiment, the compounds of the formula I are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, 67 glibenclamide, glipizide, glimepiride or repaglinide. In one embodiment, the compounds of the formula I are administered in combination with more than one of the aforementioned compounds, e.g. in 5 combination with a sulfonylurea and metformin, with 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 moreover be administered in combination with one or more antiobesity agents or appetite-controlling active 10 ingredients. In a further embodiment, the compounds of the formula I are administered in combination with CART modulators (see "Cocaine-amphetamine regulated transcript influences energy metabolism, anxiety and gastric 15 emptying in mice" Asakawa, A, et al., M.: Hormone and Metabolic Research (2001), 33(9), 554-558), NPY antagonists, e.g. naphthalene-1 sulfonic acid {4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexyl methyl}amide; hydrochloride (CGP 71683A)), MC4 agonists (e.g. 1-amino 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2-(3a-benzyl-2-methyl-3 20 oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-y)-1 -(4-chlorophenyl) 2-oxoethyl]-amide; (WO 01/91752)), orexin antagonists (e.g. 1-(2 methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea; hydrochloride (SB 334867-A)), H3 agonists (3-cyclohexyl-1 -(4,4-dimethy-1,4,6,7 tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1 -one oxalic acid salt (WO 25 00/63208)); TNF agonists, CRF antagonists (e.g. [2-methyl-9-(2,4,6 trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine (WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists, P3 agonists (e.g. 1 (4-chloro-3-methanesufonylmethylphenyl)-2-[2- (2,3-dimethyl-1 H-indol-6 yloxy)ethylamino]-ethanol hydrochloride (WO 01/83451)), MSH 30 (melanocyte-stimulating hormone) agonists, CCK-A agonists (e.g. {2-[4-(4 chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl] 5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid salt (WO 99/15525)), serotonin reuptake inhibitors (e.g. dexfenfluramine), mixed sertoninergic and noradrenergic compounds (e.g. WO 00/71549), 5HT agonists e.g. 1-(3 35 ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (e.g. human growth hormone), growth hormone-releasing compounds (6-benzyloxy-1 -(2 diisopropylaminoethylcarbamoyl)-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid tert-butyl ester (WO 01/85695)), TRH agonists (see, for example, EP 0 68 462 884), uncoupling protein 2 or 3 modulators, leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873-881), DA 5 agonists (bromocriptine, Doprexin), lipase/amylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO 00/78312), RXR modulators or TR p agonists. In one embodiment of the invention, the other active ingredient is leptin; 10 see, for example, "Perspectives in the therapeutic use of leptin", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10), 1615-1622. In one embodiment, the other active ingredient is dexamphatamine or 15 amphetamine. In one embodiment, the other active ingredient is fenfluramine or dexfenfluramine. 20 In another embodiment, the other active ingredient is sibutramine or the mono- and bisdemethylated active metabolites of sibutramine. In one embodiment, the other active ingredient is orlistat. 25 In one embodiment, the other active ingredient is mazindol or phentermine. In one embodiment, the compounds of the formula I are administered in combination with bulking agents, preferably insoluble bulking agents (see, for example, carob/Caromax* (Zunft H J; et al., Carob pulp preparation for 30 treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 Sep Oct), 18(5), 230-6.) Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark H6chst, 65926 Frankfurt/Main)). Combination with Caromax® is possible in one preparation or by separate administration of compounds of the formula 35 I and Caromax*. Caromax® can in this connection also be administered in the form of food products such as, for example, in bakery products or muesli bars.
69 C H 3 0 N 0 CH 3 OH HN N 0 NH CH 3
H
3 C CH 3 S C CH 3 CH 3 OPC-14117
CH
3 JTT-705 Cl N. CI Br C0 SB-204990 HO OH N O O CH 3 H O CH, N NO-1886 0 OH 0 H 3C OCHa3
H
3 C CH, O C1-1027 S 0 H 3 O H 3 OOCH OH 3 O H1C 0CH BMS-188494 CH 0 0 H 3 OH NOHN 00
OH
3 NO N
O
0 GI 262570 NQ 0 H JTT-501 The present compounds may additionally be administered in combination with one or more antihypertensive active ingredients. Examples of 5 antihypertensive active ingredients are beta blockers such as alprenolol, atenol, timolol, pindolol, propanolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as, for example, benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and rampril, calcium channel 70 blockers such as nifedipine, felodipine, nicardipine, 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, 5 editor, Mack Publishing Co., Easton, PA, 1995. It will be appreciated that every suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances is to be 10 regarded as covered by the scope of protection of the present invention. Examples The efficacy of the compounds was tested as follows: 15 Biological test model: The anorectic effect was tested on female NMRI mice. After withdrawal of food for 17 hours, the test product was administered by gavage. The 20 animals were housed singly with free access to drinking water and were offered condensed milk 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. 25 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 dose animals/- animals/- the cumulative milk cumulative milk cumulative [mg/kg] consumption of consumption of milk the treated the control consumption animals animals as % of the control N/[ml] N/[ml] Example 4 30 5/3.55 5/1.76 50 Example 13 30 5/3.70 5/1.34 64 71 DESCRIPTION OF EXPERIMENTS 5 Functional measurements to find IC50 values The cloning of the cDNA for the human MCH receptor, preparation of a recombinant HEK293 cell line which expresses the human MCH receptor, and functional measurements with the recombinant cell line took place in 10 analogy to the description by Audinot et al. (J. Biol. Chem. 276, 13554 13562, 2001). A difference from the reference was, however, the use of the plasmid pEAK8 from EDGE Biosystems (USA) to construct the expression vector. The host used for the transfection was a transformed HEK cell line named "PEAK Stable Cells" (likewise from EDGE Biosystems). The 15 functional measurements of the cellular calcium flux after addition of agonist (MCH) in the presence of ligand of the invention took place with the aid of the FLIPR apparatus from Molecular Devices (USA) using the protocols of the apparatus manufacturer. 20 The examples and preparation methods detailed below serve to illustrate the invention without, however, restricting it. The compounds of the formula I of the invention can be prepared with the aid of reactions which are known in principle. For example, the compounds 25 were obtained in accordance with the following general reaction schemes.
72
NO
2 H NRIR 2
NO
2 NH 2 HN/ RR R R H2, Pd(OH)2 R K2CO3, DMF Method B F Method C N
NRR
2
NRR
2 A R 1=H Alkyl-X, NaH Method F R1= Alkyl - (for R2 = Ac, Boc) R R2 = Ac H I NaOH CDI, NHR3R4 R3 NN N/ NRR 2 Method D A -N--
RL
Method A R4 R2 = BOc TFA R2 = H Method G R H / NR R 2 A R3COOH, TOTU R3N / RN,2 Method E O R2 0 R R R H /N NHR R2COOH H / NHR 1 N lN 1 TOTU N O No O' Method E 00 Other compounds of the invention can be obtained by further routes which are outlined by way of example in the following scheme.
73 (L = Linker) ) R3LOH L H R HO R3 C 2 O3N NRR 1)L O L N A Method I R3 O 2) R3-X, Cs2CO3NRR 2 Method H ods OH o LOH H A x Methods A, E L NC R N 2) Methods 0 R NR R 2 or R 1 Methods R 0~.< Ra N R NRR2R NjR3000I
-
R' HMethod Q 0i
H
2 NbN R3 N N H R R N NRR2 R N --. H N R 1RN R ' N H I Method N R) N RI
NR
1 RRN R N NRH O=CR2R3 O R N R2 R0N Methods N, M, K R3 ,, R" 74 Yet other examples were obtained as indicated in the following scheme. 0 R2 0 R 2 R' R Ntr X HNR1 R2 R- - l ,R R' / N Method R' 1) Nu- R Niy- NR 1
R
2 0 2) MOH O Methods P O N X 3) A, MethodsE Nu (M = Metal Nu- = nucleophile) R Nc 1 1 2 R N'r 1 R2 NRNR IMethod R N N " H ON NH N NN R" 5 Descriptions of the general methods used are to be found by way of example described at the following places: Methods A, B and C in example 1; 10 Method D in example 2; Method E in example 3; Method E-a in example 275; 15 Method E-b in example 286; 75 Method F in example 4; Method F-a in example 264; 5 Method G in example 15; Method H in example 237; Method H-a in example 298; Method I in example 238; Method J in example 245; 10 Method J-a in example 297; Method K in example 250; Method L in example 254; Method M in example 274; Method N in example 277; 15 Method 0 in example 279; Method O-a in example 292; Method 0-b in example 280; Method P in example 285; Method Q in example 290; 20 Method R in example 309. General explanations a) Mode of drawing the structural formulae 25 Only non-hydrogen atoms are depicted for clarity in the structural formulae of the given examples.
76 In tables 6-13, enantiomer-enriched compounds are identified by a marked hydrogen atom on the stereogenic center. Unless expressly noted otherwise, the enantiomer-enriched examples shown have the (R) configuration on the 3-aminopyrrolidine stereocenter. 5 b) Salt forms Many of the compounds of the invention are bases and can form salts with appropriately strong acids. In particular, after purification of the compounds by HPLC chromatography using a trifluoroacetic acid-containing mobile 10 phase they may be in the form of hydrotrifluoroacetates. These can be converted into the free bases shown by simple treatment of a solution of the salts for example with sodium carbonate solution. c) Units of the characterizing data 15 The unit of the stated molecular weight is "g/mol". Peaks observed in the mass spectrum are indicated as the integral quotient of the molar molecular ion mass and the charge of the molecular ion (m/z). Example 1 20 N-Methyl-N-(1 -{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin 3-yl)acetamide N N N Oja 0 0 Method A 25 A solution of 4-phenoxyaniline (3.33 g) in DMF (10 ml) was added dropwise to a solution of carbonyldiimidazole (2.92 g) in DMF (12 ml) cooled to 0*C. After 30 minutes, N-[1 -(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide (3.80 g) in DMF (10 ml) was added dropwise. The reaction solution was kept initially at room temperature for 2 hours and then at 800C for 30 30 minutes. The mixture was added dropwise to water (600 ml) and the resulting precipitate was filtered off with suction and washed with water. Alternatively, the product can also be extracted with ethyl acetate and 77 purified by chromatography after concentration. This resulted in the product with the molecular weight of 444.54 (C26H28N403); MS (ESI): 445 (M+H+). 5 N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide Method B A suspension of N-methyl-N-[1 -(4-nitrophenyl)pyrrolidin-3-yl]acetamide (3.5 g) and palladium(II) hydroxide (20% on carbon; 0.9 g) in ethanol (150 ml) and ethyl acetate (300 ml) was vigorously stirred under a 10 hydrogen atmosphere (atmospheric pressure) for 3 hours. The catalyst was then removed by filtration, and the filtrate was concentrated. This resulted in the product with the molecular weight of 233.32 (Cl 3H19N30); MS (ESI): 234 (M+H+). 15 N-Methyl-N-[1 -(4-nitrophenyl)pyrrolidin-3-yl]acetamide Method C 4-Fluoronitrobenzene (25.0 g) was slowly added to a suspension of N-methyl-N-pyrrolidin-3-ylacetamide (25.2 g) and cesium carbonate (57.6 g) in DMF (300 ml). After 2 hours, the reaction mixture was poured 20 into water, and the resultant precipitate was filtered off with suction. Alternatively, the product can also be extracted with ethyl acetate and purified by chromatography after concentration. This results in the product with the molecular weight of 263.30 (Cl 3H1 7N303): MS (ESI): 264 (M+H+). 25 Example 2 1-[4-(3-Methylaminopyrrolidin-1 -yl)phenyl]-3-(4-phenoxyphenyl)urea 0 N N NH 30 Method D A mixture of N-methyl-N-(1 -{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrroldin 3-yl)acetamide (6.0 g), ethanol (250 ml), water (60 ml) and sodium hydroxide solution (10 M; 80 ml) was heated under reflux for 12 hours. The 35 alcohol was distilled out and the resulting precipitate was filtered off with 78 suction and washed with dichloromethane. Additional product was obtained by concentration of the organic phase and chromatography (silica gel, dichloromethane/methanol 9:1 with 1% triethylamine). This resulted in the product with the molecular weight of 402.50 (C24H26N402); MS (ESI): 403 5 (M+H+). Example 3 N-Methyl-N-(1 -{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl) 2-phenylacetamide 10 0 N N 0 Method E TOTU (327 mg) was added to a solution of 1-[4-(3-methylaminopyrrolidin 15 1-yl)phenyl]-3-(4-phenoxyphenyl)urea (402 mg) in DMF (3 ml) at 00C. After 10 minutes, Hinig's base (130 mg) and then a solution of phenylacetic acid (136 mg) in DMF (1 ml) was added. After a reaction time of 12 hours at room temperature, water was added to the mixture, and it was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate 20 and concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 520.64 (C32H32N403); MS (ESI): 521 (M+H+) as hydrotrifluoroacetate. 25 Example 4 (R)-N-Methyl-N-(1 -{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin 3-yl)acetamide N0 N N 0 "-Cl N ' N J 30 (R)-N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted 79 with 4-phenoxyaniline by method A. This resulted in the product with the molecular weight of 444.54 (C26H28N403); MS (ESI): 445 (M+H+). (R)-N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide 5 (R)-N-Methyl-N-[1 -(4-nitrophenyl)pyrrolidin-3-yl]acetamide was hydrogenated by method B. This resulted in the product with the molecular weight of 233.32 (Cl 3H19N30); MS (ESI): 234 (M+H+). (R)-N-Methyl-N-[1 -(4-nitrophenyl)pyrrolidin-3-yl]acetamide 10 Method F (R)-N-[1 -(4-Nitrophenyl)pyrrolidin-3-yl]acetamide (1.3 g) was added in portions to a suspension of sodium hydride (50% in oil; 0.25 g) in DMF (50 ml). After gas evolution had ceased, iodomethane (0.82 g) was added. 15 After one hour, the reaction mixture was cautiously hydrolyzed with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 263.30 (Cl 3H1 7N303); MS (ESI): 264 (M+H+). 20 (R)-N-[1 -(4-Nitrophenyl)pyrrolidin-3-yl]acetamide (R)-N-pyrrolidin-3-ylacetamide was reacted with 4-fluoronitrobenzene by method C. This resulted in the product with the molecular weight of 249.27 (C12H15N303); MS (ESI): 250 (M+H+). 25 Example 5 (S)-N-Methyl-N-(1 -{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin 3-yl)acetamide 30 N NN The sequence described in example 4 was applied to (S)-N-pyrrolidin 3-ylacetamide. This resulted in the product with the molecular weight of 444.54 (C26H28N403); MS (ESI): 445 (M+H+).
80 Example 6 (R)-1 -[4-(3-Methylaminopyrrolidin-1 -yl)phenyl]-3-(4-phenoxyphenyl)urea H 0 N N 5 (R)-N-Methyl-N-(1 -{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin 3-yl)acetamide was reacted by method D. This resulted in the product with the molecular weight of 402.50 (C24H26N402); MS (ESI): 403 (M+H+). 10 Example 7 (S)-1 -[4-(3-Methylaminopyrrolidin-1 -yl)phenyl]-3-(4-phenoxyphenyl)urea H 0 N N N N :r 15 (S)-N-Methyl-N-(1 -{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin 3-yl)acetamide was reacted by method D. This resulted in the product with the molecular weight of 402.50 (C24H26N402); MS (ESI): 403 (M+H+). 20 Example 8 (R)-N-(1 -{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-N methylacetamide ON N N aaN 'kN 'a0 25 (R)-N-[1 -(4-Aminophenyl)pyrrolidin-3-yl)-N-methylacetamide was reacted 81 with 4-cyclopentyloxyaniline by method A. This resulted in the product with the molecular weight of 436.56 (C25H32N403); MS (ESI): 437 (M+H+). (S)-N-(1 -{4-[3-(4-cyclopentyloxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-N 5 methyl-acetamide was obtained analogously from (S)-N-[1 -(4-amino phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide. 4-Cyclopentyloxyaniline A mixture of 4-nitrophenol (63.7 g), bromocyclopentane (68.2 g), potassium 10 carbonate (63.3 g) and DMF (300 ml) was heated at 800C for 24 hours. After cooling, it was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was hydrogenated by method B. This resulted in the product with the molecular weight of 177.25 (Cl1 H15NO); MS (ESI): 15 178 (M+H+). Example 9 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1 -yl)phenyl]urea 20 H 0 N N aN Nr N-(1 -{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-N methylacetamide was reacted by method D. This resulted in the product 25 with the molecular weight of 394.52 (C23H30N402); MS (ESI): 395 (M+H+). (R)- and (S)-1 -(4-cyclopentyloxy-phenyl)-3-[4-(3-methylamino-pyrrolidin-1 yl)-phenyl]-urea was obtained analogously from (R)- and (S)-N-(1 -{4-[3-(4 30 cyclopentyloxy-phenyl)-ureido-phenyl}-pyrrolidin-3-yl) -N-methyl-acetamide. Example 10 Ethyl (1 -{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)methyl carbamate 35 82 0 N N N (I ?I 0 N Na Ethyl chloroformate (8 [d) was added dropwise to a solution of 1-(4-cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1 -yl)phenyl]urea 5 (20 mg) and Hunig's base (10 mg) in dichloromethane (3 ml). After 12 hours, the reaction mixture was concentrated and the residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 466.59 (C26H34N404); MS (ESI): 467 (M+H+) as 10 hydrotrifluoroacetate. Example 11 1 -(1 -{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-3-ethyl-1 methylurea 15 /NNN N N N a Ethyl isocyanate (7 stl) was added dropwise to a solution of 1-(4-cyclo pentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea (20 mg) and Hinig's base (10 mg) in dichloromethane (3 ml). After 12 hours, the 20 reaction mixture was concentrated and the residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 465.60 (C26H35N503); MS (ESI): 466 (M+H+) as hydrotrifluoroacetate. 25 Example 12 1-(4-Cyclopentyloxyphenyl)-3-(4-{3-[methyl-((R)-5-oxo-pyrrolidin-2 ylmethyl)amino]pyrrolidin-1 -yl}phenyl)urea 83 NN H NN N N 0N N O (R)-5-Bromomethylpyrrolidin-2-one (15 mg) was added to a suspension of 1-(4-cyclopentyloxyphenyl)-3-[4-(3-methyaminopyrrolidin-1 -yl)phenyl]urea 5 (30 mg) and potassium carbonate (20 mg) in DMF (3 ml). After 2 hours, the reaction mixture was filtered and concentrated, and the residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 491.64 (C28H37N503); MS (ESI): 492 (M+H+) as hydrotrifluoroacetate. 10 Example 13 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino) pyrrolidin-1 -yl]phenyl}amide 15 C0 N N N Cl N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and then with 4-(4-chlorophenyl)piperidine by 20 method A. This resulted in the product with the molecular weight of 455.00 (C25H31CIN402); MS (ESI): 455 (M+H+). (R)- and (S)-4-(4-chlorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetyl methylamino)pyrrolidin-1 -yl]phenyl}amide were obtained analogously from (R)- and (S)-N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methyacetamide. 25 Example 14 tert-Butyl (R)-[1-(4-{[4-(4-chlorophenyl)piperidine-1-carbonyl]amino} phenyl)pyrrolidin-3-yl]methylcarbamate 84 0N 0 CIN N N tert-Butyl (R)-[1 -(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate was reacted with carbonyldiimidazole and then with 4-(4-chlorophenyl)piperidine 5 by method A. This resulted in the product with the molecular weight of 513.09 (C28H37CIN403); MS (ESI): 513 (M+H+). tert-Butyl (R)-[1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate 10 tert-Butyl (R)-methyl-[1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate was hydrogenated by method B. This resulted in the product with the molecular weight of 291.40 (C1 6H25N302); MS (ESI): 292 (M+H+). 15 tert-Butyl (R)-methyl-[1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate tert-Butyl (R)-[1 -(4-nitrophenyl)pyrrolidin-3-yl]carbamate was alkylated with iodomethane by method F. This resulted in the product with the molecular 20 weight of 321.38 (Cl 6H23N304); MS (ESI): 322 (M+H+). tert-Butyl (R)-[1 -(4-nitrophenyl)pyrrolidin-3-yl]carbamate 25 tert-Butyl (R)-pyrrolidin-3-ylcarbamate was reacted with 4-fluoronitro benzene by method C. This resulted in the product with the molecular weight of 307.35 (Cl 5H21 N304); MS (ESI): 308 (M+H+). 30 Example 15 (R)-4-(4-Chlorophenyl)piperidine-1-carboxylic acid [4-(3-methylamino pyrrolidin-1 -yl)phenyl]amide 85 0 C H Method G 5 Trifluoroacetic acid (6.67 g) was added to a solution of tert-butyl (R)-[1 -(4 {[4-(4-chlorophenyl)piperidin-1 -carbonyl]amino}phenyl)pyrrolidin 3-yl]methylcarbamate (1.5 g) in dichloromethane (50 ml). After 3 hours, volatile fractions were removed and the residue was taken up in dichloromethane. After washing with sodium carbonate solution, the 10 organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 412.97 (C23H29CIN40); MS (ESI): 413 (M+H+). Example 16 15 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid (4-{(R) -3-[methyl-(1 -methyl piperidin-3-ylcarbonyl)amino]pyrrolidin-1 -yl}phenyl)amide 0 0 C\N NN Nk / N 20 (R)-4-(4-Chlorophenyl)piperidine-1 -carboxylic acid [4-(3-methylamino pyrrolidin-1 -yl)phenyl]amide was reacted with 1 -methylpiperidine-3 carboxylic acid by method E. This resulted in the product with the molecular weight of 538.14 (C30H40CIN502); MS (ESI): 538 (M+H+). 25 Example 17 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid (4-(R) -{3-[methyl-(2 piperidin-1 -ylacetyl)amino]pyrrolidin-1 -yl}phenyl)amide 86 00 ci\N N N N _ CI-( (R)-4-(4-Chlorophenyl)piperidine-1 -carboxylic acid [4-(3-methylamino pyrrolidin-1 -yl)phenyl]amide was reacted with piperidin-1 -ylacetic acid by 5 method E. This resulted in the product with the molecular weight of 538.14 (C30H40CIN502); MS (ESI): 538 (M+H+). Example 18 10 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid (4-(R) -{3-[methyl-(2-oxo thiazolidine-4-carbonyl)amino]pyrrolidin-1 -yl}phenyl)amide 0 0 H clN N N N (R)-4-(4-Chlorophenyl)piperidin-1 -carboxylic acid [4-(3-methylamino 15 pyrrolidin-1 -yl)phenyl]amide was reacted with 2-oxothiazolidine 4-carboxylic acid by method E. This resulted in the product with the molecular weight of 542.10 (C27H32CIN503S); MS (ESI): 542 (M+H+). 20 Example 19 (R)-4-(4-Chlorophenyl)piperidine-1-carboxylic acid (4-{3-[methyl-(2,2,2 trifluoroacetyl)amino]pyrrolidin-1 -yl}phenyl)amide 0 0 N N N F Cl I F F 25 (R)-[N-[1 -(4-aminophenyl)pyrrolidin-3-yl]-2,2,2-trifluoro-N-methylacetamide was reacted with carbonyldiimidazole and then with 4-(4-chlorophenyl) piperidine by method A. This resulted in the product with the molecular 87 weight of 508.98 (C25H28CIF3N402); MS (ESI): 509 (M+H+). (R)-[N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-2,2,2-trifluoro-N-methylacetamide 5 (R)-2,2,2-Trifluoro-N-methyl-N-[1 -(4-nitrophenyl)pyrrolidin-3-yl]acetamide was hydrogenated by method B. This resulted in the product with the molecular weight of 287.29 (Cl 3H16F3N30); MS (ESI): 288 (M+H+). 10 (R)-2,2,2-Trifluoro-N-methyl-N-[1 -(4-nitrophenyl)pyrrolidin-3-yllacetamide Trifluoroacetic anhydride (0.5 ml) was added dropwise to a solution of (R)-methyl-[1 -(4-nitrophenyl)pyrrolidin-3-yl]amine (0.48 g) in pyridine (2 ml). After 3 hours, the reaction mixture was diluted with water and extracted 15 with ethyl acetate. The organic phase was washed with citric acid solution, dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 317.27 (Cl 3H14F3N303); MS (ESI): 318 (M+H+). 20 (R)-Methyl-[1 -(4-nitrophenyl)pyrrolidin-3-yl]amine A solution of tert-butyl (R)-methyl-[1 -(4-nitrophenyl)pyrrolidin-3-yl] carbamate (0.7 g) in dichloromethane (5 ml) was treated with trifluoroacetic acid (3 ml) for 1 hour. The reaction solution was concentrated and the 25 residue was taken up in dichloromethane. After washing with sodium carbonate solution, the organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 221.26 (C11H15N302); MS (ESI): 222 (M+H+). 30 Example 20 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino) pyrrolidin-1 -yl]phenyl}methylamide 35 88 o 0 I N N 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino) pyrrolidin-1 -yl]phenyl}amide was reacted with iodomethane by method F. 5 This resulted in the product with the molecular weight of 469.03 (C26H33CIN402); MS (ESI): 469 (M+H+). Example 21 10 (R)-4-(4-Chlorophenyl)piperidine-1 -carboxylic acid (4-{3-[acetyl-(2 diethylaminoethyl)amino]pyrrolidin-1 -yl}phenyl)amide 0 N NK N N C1 N Cl_ 0o - 15 (R)-N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-(2-diethylaminoethyl)acetamide was reacted with 4-(4-chlorophenyl)piperidine by method A. This resulted in the product with the molecular weight of 540.15 (C30H42CIN502); MS (ESI): 540 (M+H+). 20 (R)-N-[1 -(4-Aminophenyl)pyrrolidin-3-y]-N-(2-diethylaminoethyl)acetamide (R)-N-(2-Diethylaminoethyl)-N-[1 -(4-nitrophenyl)pyrrolidin-3-yl]acetamide was hydrogenated by method B. This resulted in the product with the molecular weight of 318.47 (Cl 8H30N40); MS (ESI): 319 (M+H+). 25 (R)-N-(2-Diethylaminoethyl)-N-[1 -(4-nitrophenyl)pyrrolidin-3-yl]acetamide (R)-N-[1 -(4-nitrophenyl)pyrrolidin-3-yl]acetamide was reacted with 30 2-chloroethyldiethylamine by method F. This resulted in the product with the molecular weight of 348.45 (C1 8H28N403); MS (ESI): 349 (M+H+).
89 Example 22 1-[4-(3-Dimethylaminopyrrolidin-1 -yl)phenyl]-3-(4-phenoxyphenyl)urea 0 N N N 5 Dimethylpyrrolidin-3-ylamine was reacted with 4-fluoronitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-phenoxyaniline by method A, B and C. This 10 resulted in the product with the molecular weight of 416.53 (C25H28N402); MS (ESI): 417 (M+H+). Example 23 N-{4-[3-(Acetylmethylamino)pyrrolidin-1 -yl]phenyl}-2-(4-isobutoxy 15 phenyl)propionamide 0 N N N N-[1 -(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 20 2-(4-isobutoxyphenyl)propionic acid by method E. This resulted in the product with the molecular weight of 437.59 (C26H35N303); MS (ESI): 438 (M+H+). 25 Example 24 N-(1 -{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide 90 oN O N-Pyrrolidin-3-ylacetamide was reacted with 4-fluoronitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline 5 was reacted with CDI and 4-cyclopentyloxyaniline by method A, B and C. This resulted in the product with the molecular weight of 422.53 (C24H30N403); MS (ESI): 423 (M+H+). (R)- and (S)-N-(1 -{4-[3-(4-cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3 10 yl)acetamide were obtained in an analogous manner starting from (R)- and (S)-N-pyrrolidin-3-ylacetamide. Example 25 15 N-(1 -{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-N ethylacetamide oN N N N 0 20 N-Ethyl-N-pyrrolidin-3-ylacetamide was reacted with 4-fluoronitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-cyclopentyloxyaniline by method A, B and C. This resulted in the product with the molecular weight of 450.59 (C26H34N403); MS (ESI): 451 (M+H+). 25 Example 26 4-(4-Chlorophenyl)piperidin-1 -carboxylic acid {4-[3-(acetylmethyl amino) pyrrolidin-1 -yl]-3-methylphenyl}amide 91 0 C N N N N O N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 1 -fluoro-2-methyl 5 4-nitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-(4 chlorophenyl)piperidine by method A, B and C. This resulted in the product with the molecular weight of 469.03 (C26H33CIN402); MS (ESI): 469 (M+H+). 10 Example 27 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino) pyrrolidin-1 -yl)-3-fluorophenyl}amide 15 F 0 CIN N N O N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 1,2-difluoro 4-nitrobenzene, the resulting nitro compound was reduced with hydrogen 20 and finally the aniline was reacted with CDI and 4-(4 chlorophenyl)piperidine by method A, B and C. This resulted in the product with the molecular weight of 472.99 (C25H30CIFN402); MS (ESI): 473 (M+H+). 25 Example 28 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino) pyrrolidin-1 -yl]-2,6-difluorophenyl}amide 92 O F C N - N 0 F N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 1,3,5-trifluoro-2 nitrobenzene, the resulting nitro compound was reduced with hydrogen and 5 finally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine by method A, B and C. This resulted in the product with the molecular weight of 490.99 (C25H29CIF2N402); MS (ESI): 491 (M+H+). 10 Example 29 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino) pyrrolidin-1 -yl]-2-methylphenyl}amide F CI \N N N 15 N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 4-fluoro-2-methyl-1 nitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperictine by method A, B and C. This resulted in the product with the molecular weight of 469.03 (C26H33CIN402); MS (ESI): 469 (M+H+). 20 Example 30 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino) pyrrolidin-1 -yl]-2-fluorophenyl}amide 25 0 CI N N 0 F N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 2,4-difluoro- 1- 93 nitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine by method A, B and C. This resulted in the product with the molecular weight of 472.99 (C25H30CIFN402); MS (ESI): 473 (M+H+). 5 Example 31 tert-Butyl (R)-[1 -(5-{[4-(4-Chlorophenyl)piperidin-1 -carbonyl]amino}pyridin 2-yl) pyrrolidin-3-yl] methylcarbamate 10 0 0 NN N N O The synthetic sequence for preparing tert-butyl (R)-[1 -(4-{[4-(4-chloro phenyl)piperidin-1 -carbonyl]amino}phenyl)pyrrolidin-3-yl]methylcarbamate 15 was carried out starting from 2-chloro-5-nitropyridine instead of 4-fluoronitrobenzene. This resulted in the product with the molecular weight of 514.07 (C27H36CIN503); MS (ESI): 514 (M+H+). Example 32 20 (R)-[4-(4-Chlorophenyl)piperidine-1 -carboxylic acid [6-(3-methylamino pyrrolidin-1 -yl)pyridin-3-yl]amide 0 NN Cl NN 25 tert-Butyl (R)-[1-(5-{[4-(4-chlorophenyl)piperidine-1-carbonyl]amino}pyridin 2-yl) pyrrolidin-3-yl] methylcarbamate was treated with trifluoroacetic acid by method G. This resulted in the product with the molecular weight of 413.95 (C22H28CIN50); MS (ESI): 414 (M+H+). 30 It was possible to obtain racemic [4-(4-chlorophenyl)piperidine-1 -carboxylic acid [6-(3-methylaminopyrrolidin-yl)pyridin-3-yl]amide in a similar manner.
94 Example 33 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid {6-[3-(acetylmethylamino) pyrrolidin-1 -yl]pyridin-3-yl}amide 0 C- O - N 4 N--/\ N CI N N 0 5 N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 2-chloro-5-nitro pyridine, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-(4-chlorophenyl)piperidine by 10 method A, B and C. This resulted in the product with the molecular weight of 490.99 (C25H29CIF2N402); MS (ESI): 491 (M+H+). Example 34 1-[4-(4-Dimethylaminopiperidin-1 -yl)phenyl]-3-(4-phenoxyphenyl)urea ,, N N N 0 0 N N 15 Dimethylpiperidin-4-ylamine was reacted with 4-fluoronitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline ([1 -(4-aminophenyl)piperidin-4-yl]dimethylamine) was reacted with CDI and 4-phenoxyaniline by method A, B and C. This resulted in the product with 20 the molecular weight of 430.55 (C26H30N402); MS (ESI): 431 (M+H+). Example 35 1-(4-Cyclopentyloxyphenyl)-3-[4-(4-morpholin-4-ylpiperidin-1 -yl)phenyl]urea 25 NN / N N NN 0 0 95 4-Piperidin-4-ylmorpholine was reacted with 4-fluoronitrobenzene, the resulting nitro compound was reduced with hydrogen and finally the aniline was reacted with CDI and 4-cyclopentyloxyaniline by method A, B and C. 5 This resulted in the product with the molecular weight of 464.61 (C27H36N403); MS (ESI): 465 (M+H+). Example 36 10 4-Butoxy-N-[4-(4-dimethylaminopiperidin-1 -yl)phenyl]benzamide ON N o ([1 -(4-Aminophenyl)piperidin-4-yl]dimethylamine) was reacted with 4 15 4-butoxybenzoic acid by method E. This resulted in the product with the molecular weight of 395.55 (C24H33N302); MS (ESI): 396 (M+H+). Example 37 4-(4-Chlorophenyl)piperidin-1 -carboxylic acid {4-[3-(acetylmethylamino) 20 azetidin-1 -yl]phenyl}amide C N N /\N N O CN N 0 N-[1 -(4-aminophenyl)azetidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and 4-(4-chlorophenyl)piperidine by method A. This 25 resulted in the product with the molecular weight of 440.98 (C24H29CIN402); MS (ESI): 441 (M+H+). N-[1 -(4-Aminophenyl)azetidin-3-yl]-N-methylacetamide 30 N-Methyl-N-[1 -(4-nitrophenyl)azetidin-3-yl]acetamide was hydrogenated by method B. This resulted in the product with the molecular weight of 219.29 (C12H17N30); MS (ESI): 220 (M+H+).
96 N-Methyl-N-[1 -(4-nitrophenyl)azetidin-3-yl]acetamide N-[1 -(4-nitrophenyl)azetidin-3-yl]acetamide was alkylated with iodomethane by method F. This resulted in the product with the molecular weight of 5 249.27 (C12H15N303); MS (ESI): 250 (M+H+). N-[1 -(4-Nitrophenyl)azetidin-3-yl]acetamide Acetic anhydride (0.6 ml) was added to a solution of 1-(4-nitrophenyl) 10 azetidin-3-ylamine (0.5 g ) in pyridine (1.2 ml). After one hour, volatile fractions were removed. This resulted in the product with the molecular weight of 235.24 (Cl1 H13N303); MS (ESI): 236 (M+H+). 15 1-(4-Nitrophenyl)azetidin-3-ylamine tert-Butyl [1 -(4-nitrophenyl)azetidin-3-yl]carbamate was treated with trifluoroacetic acid by method G. This resulted in the product with the molecular weight of 193.21 (C9H11N302); MS (ESI): 194 (M+H+). 20 tert-Butyl [1-(4-nitrophenyl)azetidin-3-yl]carbamate tert-Butyl azetidin-3-ylcarbamate was reacted with 4-fluoronitrobenzene by method C. This resulted in the product with the molecular weight of 293.33 (C14H19N304); MS (ESI): 294 (M+H+). 25 Example 38 tert-Butyl [1-(4-{[4-(4-Chlorophenyl)piperidin-1-carbonyl]amino} phenyl)azetidin-3-yl]methylcarbamate 30 ciN N N N O tert-Butyl [1-(4-aminophenyl)azetidin-3-yl]methylcarbamate was reacted with carbonyldiimidazole and 4-(4-chlorophenyl)piperidine by method A. 35 This resulted in the product with the molecular weight of 499.06 (C27H35CIN403; MS (ESI): 499 (M+H+).
97 tert-Butyl [1-(4-aminophenyl)azetidin-3-yl]methylcarbamate tert-Butyl methyl-[1 -(4-nitrophenyl)azetidin-3-yl]carbamate was 5 hydrogenated by method B. This resulted in the product with the molecular weight of 277.37 (Cl 5H23N302); MS (ESI): 278 (M+H+). tert-Butyl methyl-[1 -(4-nitrophenyl)azetidin-3-yl]carbamate 10 tert-Butyl [1 -(4-nitrophenyl)azetidin-3-yl]carbamate was alkylated with iodomethane by method F. This resulted in the product with the molecular weight of 307.35 (C1 5H21 N304); MS (ESI): 308 (M+H+). 15 Example 39 4-(4-Chlorophenyl)piperidin-1 -carboxylic acid [4-(3-methylaminoazetidin 1 -yl)phenyl]amide 0/ C - N /\N N N ~ N 20 tert-Butyl [1-(4-{[4-(4-chlorophenyl)piperidin-1-carbonyl]amino} phenyl)azetidin-3-yl] methylcarbamate was reacted with trifluoroacetic acid by method G. This resulted in the product with the molecular weight of 398.94 (C22H27CIN40); MS (ESI): 399 (M+H+). 25 Example 40 N-Methyl-N-[1 -(4-{3-[4-(pyridin-3-yloxy)phenyl]ureido}phenyl)pyrrolidin 3-yl]acetamide C 0 ON N N 30 N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 98 carbonyldiimidazole and then with 4-(pyridin-3-yloxy)phenylamine by method A. This resulted in the product with the molecular weight of 445.53 (C25H27N503); MS (ESI): 446 (M+H+). 5 Example 41 N-Methyl-N-(1 -{4-[3-(4-piperidin-1 -ylphenyl)ureido]phenyl}pyrrolidin 3-yl)acetamide 0 N N N( N-N 100 10 N N N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and then with 4-piperidin-1 -ylphenylamine by method A. This resulted in the product with the molecular weight of 435.57 15 (C25H33N502); MS (ESI): 436 (M+H+). Example 42 N-{4-[3-(Acetylmethylamino)pyrrolidin-1 -yl]phenyl}-4-phenoxybenzamide 0 20 N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4-phenoxybenzoic acid by method E. This resulted in the product with the molecular weight of 429.52 (C26H27N303); MS (ESI): 430 (M+H+). 25 Example 43 N-{4-[3-(Acetylmethylamino)pyrrolidin-1 -yl]phenyl}-4-butoxybenzamide 99 0 0 N NN 0 N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4-butoxybenzoic acid by method E. This resulted in the product with the 5 molecular weight of 409.53 (C24H31 N303); MS (ESI): 410 (M+H+). Example 44 4-(4-Chlorophenyl)cyclohexanecarboxylic acid {4-[3-(acetylmethylamino) 10 pyrrolidin-1 -yl]phenyl}amide 0 C l ,,,N NN N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 15 4-(4-chlorophenyl)cyclohexanecarboxylic acid by method E. This resulted in the product with the molecular weight of 454.02 (C26H32ClN302); MS (ESI): 454 (M+H+). 20 Example 45 N-{4-[3-(Acetylmethylamino)pyrrolidin-1 -yl]phenyl}-3-(4-isopropylphenyl) acrylamide 0 0 N- N
N
25 N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 3-(4-isopropylphenyl)acrylic acid by method E. This resulted in the product 100 with the molecular weight of 405.54 (C25H31 N302); MS (ESI): 406 (M+H+). 5 Example 46 Tetrahydrofuran-2-carboxylic acid (1 -{4-[3-(4-cyclopentyloxyphenyl) ureido]phenyl}pyrrolidin-3-yl)methylamide 0 Cr0 0 O / O N N Na N 10 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1 -yl)phenyl]urea was reacted with tetrahydrofuran-2-carboxylic acid by method E. This resulted in the product with the molecular weight of 492.62 (C28H36N404); MS (ESI): 493 (M+H+). 15 Example 47 1 -Acetylpyrrolidin-2-carboxylic acid (1 -{4-[3-(4-cyclopentyloxyphenyl) ureido]phenyl}pyrrolidin-3-yl)methylamide 0 O O 0 N N N 20 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1 -yl)phenyl]urea was reacted with 1 -acetylpyrrolidine-2-carboxylic acid by method E. This resulted in the product with the molecular weight of 533.68 (C30H39N504); 25 MS (ESI): 534 (M+H+). Example 48 5-Oxopyrrolidine-2-carboxylic acid (1 -{4-[3-(4-cyclopentyloxyphenyl) 30 ureido]phenyl}pyrrolidin-3-yl)methylamide 101 0 o N NO N NN 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1 -yl)phenyl]urea was reacted with 5-oxopyrrolidine-2-carboxylic acid by method E. This 5 resulted in the product with the molecular weight of 505.62 (C28H35N504); MS (ESI): 506 (M+H+). Example 49 10 2-Oxothiazolidine-4-carboxylic acid (1 -{4-[3-(4-cyclopentyloxyphenyl) ureido]phenyl}pyrrolidin-3-yl)methylamide 0 00 0 N N No O 15 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1 -yl)phenyl]urea was reacted with 2-oxothiazolidine-4-carboxylic acid by method E. This resulted in the product with the molecular weight of 523.66 (C27H33N504S); MS (ESI): 524 (M+H+). 20 Example 50 (R)-1 -Methylpiperidine-3-carboxylic acid {1 -[4-(4-cyclohexylbenzoyl amino)phenyl]pyrrolidin-3-yl}methylamide 0/ 0 N N N 25 (R)-4-Cyclohexyl-N-[4-(3-methylaminopyrrolidin-1 -yl)phenyl]benzamide was 102 reacted with 1 -methylpiperidine-3-carboxylic acid by method E. This resulted in the product with the molecular weight of 502.71 (C31 H42N402); MS (ESI): 503 (M+H+). 5 Example 51 N-(1 -{4-[3-(6-Cyclopentyloxypyridin-3-yl)ureido]phenyl}pyrrolidin-3-y) N-methylacetamide 0 N 0 N NN N' N 10 N-[1 -(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and then 6-cyclopentyloxypyridin-3-ylamine by method A. This resulted in the product with the molecular weight of 437.55 (C24H31 N503); MS (ESI): 438 (M+H+). 15 6-Cyclopentyloxypyridin-3-ylamine A mixture of 5-nitropyridin-2-ol (14.0 g), bromocyclopentane (8.0 g), potassium carbonate (14 g) and DMF (200 ml) was heated at 800C for 20 6 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel. The resulting product (2-cyclopentyloxy 5-nitropyridine) was hydrogenated by method B. This resulted in the 25 product with the molecular weight of 178.24 (Cl OH1 4N20); MS (ESI): 179 (M+H+). Example 52 30 1-(6-Cyclopentyloxypyridin-3-yl)-3-[4-(3-methylaminopyrrolidin-1 -yl) phenyl]urea 103 o N N N o N-(1 -{4-[3-(6-Cyclopentyloxypyridin-3-yl)ureido]phenyl}pyrrolidin-3-yl)-N methylacetamide was treated with sodium hydroxide solution by method D. 5 This resulted in the product with the molecular weight of 395.51 (C22H29N502); MS (ESI): 395 (M+H+). Example 53 10 4'-Fluorobiphenyl-4-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 yl]phenyl}amide 0 0 FJ -N N FO 15 N-[1 -(4-Aminophenyl)pyrrolidin-3-y]-N-methylacetamide was reacted with 4' fluorobiphenyl-4-carboxylic acid by method E. This resulted in the product with the molecular weight of 431.51 (C26H26FN302); MS (ESI): 432 (M+H+). Example 54 4'-Trifluoromethylbiphenyl-4-carboxylic acid {4-[3-(acetylmethylamino) 20 pyrrolidin-1 -yl]phenyl}amide 0 0 N F N-[1 -(4-Aminophenyl)pyrrolidin-3-yI]-N-methylacetamide was reacted with 25 4'-trifluoromethylbiphenyl-4-carboxylic acid by method E. This resulted in 104 the product with the molecular weight of 481.52 (C27H26F3N302); MS (ESI): 482 (M+H+). 5 Examples 55-103 1-(4-Phenoxyphenyl)-3-[4-(3-methylaminopyrrolidin-1 -yl)phenyl]urea was reacted with various carboxylic acids by method E. The products are compiled in table 2. 10 Examples 104-144 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1 -yl)phenyl]urea was reacted with various carboxylic acids by method E. The products are compiled in table 3. 15 Examples 145-185 N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with various carboxylic acids by method E. The products are compiled in table 20 4. Examples 186-234 N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and then with various amines by method A. The 25 products are compiled in table 5.
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156 N-{4-[3-(Acetylmethylamino)pyrrolidin-1 -yl]phenyl}-2-(4 hydroxyphenyl)acetamide Method I 4-Hydroxyphenylacetic acid (305 mg), 1 -hydroxybenzotriazole (300 mg) 5 and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (480 mg) in DMF (5 ml) were stirred with N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N methylacetamide (470 mg) at room temperature for 3 hours. Water was then added to the mixture, which was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried 10 over sodium sulfate, concentrated and crystallized from diethyl ether. This resulted in the product with the molecular weight of 367.45 (C21 H25N303); MS(ESI): 368 (M+H+). 15 Example 239 (R)-N-{4-[3-(Acetylmethylamino)pyrrolidin-1 -yl]phenyl}-2-(4 butoxyphenyl)acetamide N O N 0-0 (R)-N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted 20 with 4-butoxyphenylacetic acid by method E. This resulted in the product with the molecular weight of 423.56 (C25H33N303); MS(ESI): 424 (M+H+). Example 240 25 N-{4-[3-(Acetylmethylamino)pyrrolidin-1 -yl]phenyl}-2-(4 cyclopropylmethoxyphenyl)propionamide 0 N0 N0 157 N-{4-[3-(Acetylmethylamino)pyrrolidin-1 -yl]phenyl}-2-(4 hydroxyphenyl)propionamide was reacted with bromomethylcyclopropane by method H. This resulted in the product with the molecular weight of 435.57 (C26H33N303); MS(ESI): 436 (M+H+). 5 Example 241 N-{4-[3-(Acetylmethylamino)pyrrolidin-1 -yl]phenyl}-2-(4 cyclobutylmethoxyphenyl)propionamide Nj 0 0 100 1 0O 0 NN N-{4-[3-(Acetylmethylamino)pyrrolidin-1 -yl]phenyl}-2-(4 hydroxyphenyl)propionamide was reacted with bromomethylcyclobutane by method H. This resulted in a product with the molecular weight 449.60 (C27H35N303); MS(ESI): 450 (M+H+). 15 Example 242 1-(4-Methoxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethyl amino)pyrrolidin-1 -yl]phenyl}amide 0 ON N N 20 N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 1-(4-methoxyphenyl)-1 -cyclopropanecarboxylic acid by method E. This resulted in the product with the molecular weight of 407.52 (C24H29N303); MS(ESI): 408 (M+H+). 25 158 Example 243 1-(4-Butoxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethylamino) pyrrolidin-1 -yl]phenyl}amide O N N O 0 Na N 5 1-(4-Hydroxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethyl amino)pyrrolidin-lyl]phenyl}amide was reacted with n-butyl bromide by method H. This resulted in the product with the molecular weight of 449.60 (C27H35N303); MS(ESI): 450 (M+H+). 10 1-(4-Hydroxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethyl amino)pyrrolidin-1 -yl]phenyl}amide Boron tribromide-dimethyl sulfide (460 mg) was added to a solution of 1-(4 methoxyphenyl)cyclopropanecarboxylic acid {4-[3 (acetylmethylamino)pyrrolidin-1-yl]phenyl}amide (540 mg) in 15 dichloromethane (5.5 ml) at 0*C. After a reaction time of 12 hours at room temperature, water was added to the mixture, the phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate, concentrated and purified by chromatography (silica gel, toluene/ethanol/ethyl acetate 20 8:1:1 with addition of 0.1% triethylamine). This resulted in the product with the molecular weight of 393.49 (C23H27N303); MS(ESI): 394 (M+H+). Example 244 25 (R)-4-(4-Fluorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethyl amino)pyrrolidin-1 -yl]phenyl}-N-methylamide F N0 N NKJ~i F0
N
159 (R)-4-(4-Fluorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethyl amino)pyrrolidin-1 -yl]phenyl}amide (22 mg) was added to a suspension of sodium hydride (95% in oil; 0.005 g) in DMF (1 ml). After evolution of gas ceased, iodomethane (0.02 ml) was added. After two hours, the reaction 5 mixture was cautiously hydrolyzed with water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated, and the residue was crystallized from pentane. This resulted in the product with the molecular weight of 452,58 (C26H33FN402); MS (ESI): 453 (M+H+). 10 Example 245 5-2-[(2-Fluorophenyl)ethynyl]furan-2-carboxylic acid {4-[3 (acetylmethylamino)pyrrolidin-1 -yl]phenyl}amide N-O Na N 0 0 0 15 Method J Firstly diisopropylamine (14.9 mg) and then a solution of 5-bromofuran-2 carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 -yljphenyl}amide (50.0 mg) and 1 -ethynyl-2-fluorobenzene (17.7 mg) in dioxane (0.5 ml) and 20 DMF (0.2 ml) were added under inert conditions to a suspension of palladium bis(tri-tert-butylphosphine) dichloride (3.8 mg) and copper(l) iodide (0.9 mg) in DMF (0.5 ml). After a reaction time of 12 hours at room temperature, the mixture was diluted with ethyl acetate and filtered through silica gel, and the filtrate was concentrated and purified by preparative 25 HPLC. This resulted in the product with the molecular weight of 445.18 (C26H24FN303); MS(ESI): 446 (M+H+) as hydrotrifluoroacetate. 5-Bromofuran-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 yl]phenyl}amide 160 N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 5-bromo-2-furancarboxylic acid by method E. This resulted in the product with the molecular weight of 406.28 (Cl 8H20BrN303); MS(ESI): 407 (M+H+). 5 Example 246 5-2-[(4-Fluorophenyl)ethynyl]furan-2-carboxylic acid {4-[3 (acetylmethylamino)pyrrolidin-1 -yl]phenyl}amide N aNa N 0 0 0 10 F 5-Bromofuran-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 yl]phenyl}amide was reacted with 1 -ethynyl-4-fluorobenzene by method J. This resulted in the product with the molecular weight of 445.18 (C26H24FN303); MS(ESI): 446 (M+H+) as hydrotrifluoroacetate. 15 Example 247 5-2-[(2-Chlorophenyl)ethynyl]furan-2-carboxylic acid {4-[3 (acetylmethylamino)pyrrolidin-1 -yl]phenyl}amide N 0 0 0 20 5-Bromofuran-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 yl]phenyl}amide was reacted with 1 -ethynyl-2-chlorobenzene by method J. This resulted in the product with the molecular weight of 461.15 (C26H24CIN303); MS(ESI): 462 (M+H+) as hydrotrifluoroacetate.
161 Example 248 R-4-Butoxy-N-(3-fluoro-4-{3-[(2-hydroxy-2-methylpropyl)methylamino] 5 pyrrolidin-1 -yl}-phenyl)benzamide 0 N , N O N F A solution of (R)-4-butoxy-N-[3-fluoro-4-(3-methylaminopyrrolidin-1 yl)phenyl]benzamide (0,03 g) and isobutylene oxide in ethanol (5 ml) were heated under reflux for 3 hours. It was then concentrated in vacuo. This 10 resulted in the product with the molecular weight of 457.59 (C26H36FN303); MS (ESI): 458 (M+H+). Example 249 15 R-4-Butoxy-N-(3-fluoro-4-{3-[(3-hydroxy-3 methylbutyl)methylamino]pyrrolidin-1 -yI}-phenyl)-N-methylbenzamide 0 o N N ON F A solution of (R)-4-butoxy-N-[3-fluoro-4-(3-methylaminopyrrolidin-1 yl)phenyl]benzamide (0.03 g), triethylamine (0.02 g) and 4-bromo-2 20 methylbutan-2-ol (0.03 g) in DMF (2 ml) was heated at 80 0 C for 16 hours. After cooling, ethyl acetate (100 ml) was added, the mixture was washed with water (2 x 50 ml), and the organic phase was dried with sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 471.62 25 (C27H38FN303); MS (ESI): 472 (M+H+).
162 4-Bromo-2-methylbutan-2-ol Methylmagnesium bromide (3M in diethyl ether, 46 ml) was added to a solution of ethyl 3-bromopropionate (10 g) in diethyl ether (100 ml) at room temperature under argon. During this, the mixture was kept at above 200C 5 and below 350C. After 2 hours, the mixture was poured into a saturated ammonium chloride solution. This was followed by extraction with diethyl ether, drying with sodium sulfate, filtration and concentration. This resulted in the desired product. 10 Example 250 R-4-Butoxy-N-[6-(3-dicyclopropylaminopyrrolidin-1 -yl)-pyridin-3 yl]benzamide N N N N 15 Method K A solution of (R)-N-[6-(3-aminopyrrolidin-1 -yl)pyridin-3-yl]-4 butoxybenzamide (0.065 g) in methanol (2 ml) was mixed with glacial acetic acid (0.11 ml) and [(1 -ethoxycyclopropyl)oxy]trimethylsilane (0.19 g). Then sodium cyanoborohydride (0.051 g) was added and the mixture was 20 heated under reflux for 16 hours. The mixture was then filtered, concentrated, taken up in dichloromethane, washed with sodium hydroxide (2N; 20 ml) and sodium chloride solution (20 ml), dried with magnesium sulfate and concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 434.59 25 (C26H34N402); MS (ESI): 435 (M+H+). Example 251 R-4-Butoxy-N-[6-(3-dicyclopropylaminopyrrolidin-1 -yl)pyridin-3-yl]-N 30 methylbenzamide 163 NN N (R)-4-Butoxy-N-[6-(3-dicyclopropylaminopyrrolidin-1 -yl)pyridin-3 yl]benzamide was methylated by method F. This resulted in the product with the molecular weight of 448.61 (C27H36N402); MS (ESI): 449 5 (M+H+). Example 252 R-4-Butoxy-N-{6-[3-(cyclopropylmethylamino)pyrrolidin-1 -yl]pyridin-3 10 yl}benzamide NN N o NI: (R)-4-Butoxy-N-[6-(3-methylaminopyrrolidin-1 -yl)pyridin-3-yl]benzamide was cyclopropylated by method K. This resulted in the product with the molecular weight of 408.551 (C24H32N402); MS (ESI): 409 (M+H+). 15 Example 253 tert-Butyl {1 -[4-(2-amino-4-butoxybenzoylamino)-3-fluorophenyl]pyrrolidin 3-yl}methylcarbamate 0> N N 20 N F tert-Butyl [1 -(4-amino-3-fluorophenyl)pyrrolidin-3-yl]methylcarbamate was 164 reacted with 4-butoxy-2-nitrobenzoic acid by method E, followed by hydrogenation. This resulted in the product with the molecular weight of 500.62 (C27H37FN404); MS (ESI): 501 (M+H+). 5 4-Butoxy-2-nitrobenzoic acid A solution of 4-fluoro-2-nitrobenzoic acid (1.81 g) in butanol (20 ml) was mixed with sulfuric acid (3 ml) and stirred at 110*C for 4 hours. Ethyl acetate (100 ml) was added, and the mixture was washed with saturated sodium bicarbonate solution (3 x 50 ml), dried with sodium sulfate, filtered 10 and concentrated in vacuo. The residue (2.2 g) was added dropwise at 1 0C to a sodium butoxylate solution prepared from butanol (20 ml) and sodium hydride (2.18 g) at -1 0*C under argon and then stirred for 20 hours. Ethyl acetate (100 ml) was added, and the mixture was washed with water (2 x 50 ml), dried over sodium sulfate, filtered and concentrated in 15 vacuo. The residue was purified by preparative HPLC. The butyl 4-butoxy 2-nitrobenzoate was hydrolyzed with sodium hydoxide (5N; 100 ml) in ethanol at room temperature for 3 hours. The mixture was acidified with hydrochloric acid (1 ON; 100 ml) and extracted with dichloromethane, and the organic phase was dried over sodium sulfate, filtered and concentrated. 20 This resulted in the product with the molecular weight of 239.23 (C11H13NO5); MS (ESI): 240 (M+H+). Example 254 25 N-{4-[3-(7-Azabicyclo[2.2.1]hept-7-yl)-2-oxopyrrolidin-1 -yl]phenyl}-4 cyclohexyl-N-methylbenzamide 0 0 NW Method L A mixture of N-[4-(3-bromo-2-oxopyrrolidin-1 -yl)phenyl]-4-cyclohexyl-N 30 methylbenzamide (100 mg), potassium carbonate (60 mg), 7 azabicyclo[2.2.1]heptane (44 mg) and DMF (2 ml) was kept at 500C for 6 hours. The mixture was diluted with water and extracted with ethyl acetate.
165 The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 471.65 (C30H37N302); MS (ESI): 472 (M+H+). 5 N-[4-(3-Bromo-2-oxo-pyrrolidin-1 -yl)phenyl]-4-cyclohexyl-N methylbenzamide N-(4-Aminophenyl)-4-cyclohexyl-N-methylbenzamide (3.0 g) in acetonitrile (30 ml) was mixed with trisodium phosphate (0.95 g) and, at 0*C, 2-bromo 10 4-chlorobutyryl bromide (2.9 g) was added. After one hour, a solution of sodium hydroxide (0.85 g) in water (10 ml) was added and the mixture was stirred vigorously at room temperature for 6 hours. The same amount of sodium hydroxide solution was then added, and stirring was continued for 48 hours. The reaction solution was diluted with water and extracted with 15 ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase ethyl acetate/heptane 1:2). This resulted in the product with the molecular weight of 455.40 (C24H27BrN2O2); MS (ESI): 456 (M+H+). 20 N-(4-Aminophenyl)-4-cyclohexyl-N-methylbenzamide 4-Cyclohexylcarboxylic acid (5.0 g) and 4-nitrophenylisocyanate (4.0 g) were stirred in toluene (150 ml) for 3 hours and then left to stand overnight. The precipitate was filtered off with suction and washed with diethyl ether. The resulting amide was ethylated by method F and hydrogenated by 25 method B. This resulted in the product with the molecular weight of 308.43 (C20H24N20); MS (ESI): 309 (M+H+). Example 255 30 4-Cyclohexyl-N-methyl-N-[4-(3-morpholin-4-yl-2-oxopyrrolidin-1 yl)phenyl]benzamide N N O 0 | NN 0 166 N-[4-(3-Bromo-2-oxo-pyrrolidin-1 -yl)phenyl]-4-cyclohexyl-N methylbenzamide was reacted with morpholine by method L. This resulted in the product with the molecular weight 461.61 (C28H35N303); MS (ESI): 462 (M+H+). 5 Example 256 4-Cyclohexyl-N-methyl-N-[4-(2-oxo-3-piperidin- 1 -ylpyrrolidin-1 yl)phenyl]benzamide o N N 4 O N 0 10 N-[4-(3-Bromo-2-oxopyrrolidin-1 -yl)phenyl]-4-cyclohexyl-N methylbenzamide was reacted with piperidine by method L. This resulted in the product with the molecular weight of 459.64 (C29H37N302); MS (ESI): 460 (M+H+). 15 Example 257 4-Cyclohexyl-N-methyl-N-[4-(2'-oxo[1,3']bipyrrolidinyl-1' yl)phenyl]benzamide o N N2 1 0 N | | 20 N-[4-(3-Bromo-2-oxopyrrolidin-1 -yl)phenyl]-4-cyclohexyl-N methylbenzamide was reacted with pyrrolidine by method L. This resulted in the product with the molecular weight of 445.61 (C28H35N302); MS (ESI): 446 (M+H+).
167 Example 258 4-Cyclohexyl-N-methyl-N-[4-(3-methylamino-2-oxopyrrolidin- 1 5 yl)phenyl]benzamide H o N N N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N methylbenzamide was reacted with methylamine by method L. This resulted in the product with the molecular weight of 405.54 (C25H31 N302); 10 MS (ESI): 406 (M+H+). Example 259 4-Cyclohexyl-N-[4-(3-cyclohexylamino-2-oxopyrrolidin-1 -yl)phenyl]-N 15 methylbenzamide o N N 0 N-[4-(3-Bromo-2-oxo-pyrrolidin-1 -yl)phenyl]-4-cyclohexyl-N methylbenzamide was reacted with cyclohexylamine by method L. This resulted in the product with the molecular weight of 473.66 (C30H39N302); 20 MS (ESI): 474 (M+H+). Example 260 4-Cyclohexyl-N-{4-[3-(cyclopropylmethylamino)-2-oxopyrrolidin-1 - 168 yl]phenyl}-N-methylbenzamide O N N N-[4-(3-Bromo-2-oxopyrrolidin-1 -yl)phenyl]-4-cyclohexyl-N methylbenzamide was reacted with cyclopropylmethylamine by method L. 5 This resulted in the product with the molecular weight of 445.61 (C28H35N302); MS (ESI): 446 (M+H+). Example 261 10 N-{4-[3-(Acetylmethylamino)-2-oxopyrrolidin-1 -yl]phenyl}-4-cyclohexyl-N methyl-benzamide 0> ON -N NN o N 0N ~ 0 4-Cyclohexyl-N-methyl-N-[4-(3-methylamino-2-oxopyrrolidin-1 yl)phenyl]benzamide (52 mg) was mixed with pyridine (0.5 ml) and acetic 15 anhydride (130 mg) and, after 3 hours, volatile fractions were removed in vacuo. This resulted in the product with the molecular weight of 447.58 (C27H33N303); MS (ESI): 448 (M+H+). Example 262 20 4-Cyclohexyl-N-methyl-N-[4-(4-methylamino-2-oxopyrrolidin-1 yl)phenyl]benzamide 169 0 N
-
NN 0 tert-Butanol (8 ml), triethylamine (350 mg) and finally diphenylphosphoryl azide (1.18 g) were added to 1 -{4-[(4 cyclohexylbenzoyl)methylamino]phenyl}-5-oxo-pyrrolidin-3-carboxylic acid 5 (1.5 g), and the mixture was heated at 95*C for 48 hours. The reaction solution was diluted with ethyl acetate and washed twice with water. The organic phase was dried over magnesium sulfate and concentrated. The crude product was reacted further by method G. This resulted in the product with the molecular weight of 405.54 (C25H31 N302); MS (ESI): 406 10 (M+H+). 1 -{4-[(4-Cyclohexylbenzoyl)methylamino]phenyl}-5-oxo-pyrrolidine-3 carboxylic acid N-(4-Aminophenyl)-4-cyclohexyl-N-methylbenzamide (3.0 g) was heated 15 with itaconic acid (1.27 g) at 100*C for 3 hours. Purification took place by filtration through silica gel (mobile phase ethyl acetate/methanol 5:1). This resulted in the product with the molecular weight of 420.51 (C25H28N204); MS (ESI): 421 (M+H+). 20 Example 263 N-{4-[4-(Acetylmethylamino)-2-oxopyrrolidin-1 -yl]phenyl}-4-cyclohexyl-N methylbenzamide O N N 0 25 4-Cyclohexyl-N-methyl-N-[4-(4-methylamino-2-oxo-pyrrolidin-1 yl)phenyl]benzamide (101 mg) was mixed with pyridine (20 mg) and acetic 170 anhydride (25 mg) and, after 3 hours, volatile fractions were removed in vacuo. This resulted in the product with the molecular weight of 447.58 (C27H33N303); MS (ESI): 448 (M+H+). 5 Example 264 tert-Butyl (1 -{5-[(4-cyclohexylbenzoyl) propylamino]pyridin-2-yl}pyrrolidin-3 yl)methyl-carbamate O -N N
-
N N 10 Method F-a tert-Butyl {1 -[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3 yl}methylcarbamate (50 mg), cesium carbonate (249 mg), potassium iodide (17 mg), N-methylpyrrolidone (1.5 ml) and propyl iodide (40 mg) were stirred at 60 0 C for 5 hours. If conversion was incomplete, the mixture was 15 heated to 100*C and, after addition of further propyl iodide (40 mg), heated at 1400C for 12 hours. The reaction mixture was diluted with ethyl acetate, washed with water and sodium bicarbonate solution, dried over Chromabond XTR and concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 20 520.72 (C31 H44N403); MS (ESI): 521 (M+H+). Example 265 tert-Butyl (1 -{5-[(4-cyclohexylbenzoyl)-(1 -ethylpropyl)amino]pyridin-2 25 yl}pyrrolidin-3-yl)-methylcarbamate 171 OY OY - N N tert-Butyl {1 -[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3 yl}methylcarbamate was reacted with 2-ethylbutyl bromide by method F-a. This resulted in the product with the molecular weight of 548.78 5 (C33H48N403); MS (ESI): 549 (M+H+). Example 266 tert-Butyl (1 -{5-[(4-cyclohexylbenzoyl)-(3-methylbut-2-enyl)amino]pyridin-2 10 yl}pyrrolidin-3-yl)methylcarbamate o O /0 N O N N N NN tert-Butyl {1 -[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3 yl}methylcarbamate was reacted with 3-methyl-2-butenyl bromide by method F-a. This resulted in the product with the molecular weight of 15 546.76 (C33H46N403); MS (ESI): 547 (M+H+). Example 267 tert-Butyl (1-{5-[(4-cyclohexylbenzoyl)methylamino]pyridin-2-yl}pyrrolidin-3 20 yl)methylcarbamate 172 0 0 0 N N
-
N tert-Butyl {1 -[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3 yl}methylcarbamate was reacted with methyl iodide by method F-a. This resulted in the product with the molecular weight of 492.67 (C29H40N403); 5 MS (ESI): 493 (M+H+). The following further compounds were obtained by method F-a from tert butyl {1 -[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3 yl}methylcarbamate and the appropriate alkylating agent: tert-Butyl (1 -{5-[sec-butyl-(4-cyclohexylbenzoyl)amino]pyridin-2 10 yl}pyrrolidin-3-yl)methylcarbamate tert-Butyl (1 -{5-[(4-cyclohexylbenzoyl)isopropylamino]pyridin-2-yl}pyrrolidin 3-yl)methylcarbamate tert-Butyl (1 -{5-[(4-cyclohexylbenzoyl)prop-2-inylamino]pyridin-2 yl}pyrrolidin-3-yl)-methylcarbamate 15 Example 268 5-p-Tolylethinylfuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 yl)phenyl]amide 20 N 0 N / 0 N - N 0.042 ml of diisopropylamine was added under argon to 3.8 mg of Pd(tBu)2Cl 2 and 0.95 mg of Cul in 0.2 ml of DMF. A solution of 94.6 mg of 173 5-bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl] amide in 0.3 ml of DMF and a solution of 4-ethynyltoluene in 0.3 ml of DMF were then added dropwise. The solution was stirred at room temperature overnight. The precipitate which had separated out was filtered off with 5 suction and the filtrate purified by preparative HPLC. The desired product with the molecular weight of 413.52; MS (ESI): 414 was obtained as hydrotrifluoroacetate. 5-Bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 10 yl)phenyl]amide [1 -(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with 5-bromo 2-furancarboxylic acid by method E. The product with a molecular weight of 378.27 (C17H20BrN302); MS (ESI): 379 (M+H+) was obtained as hydrotrifluoroacetate. 15 Examples 269-273 were prepared analogously: Ex.No. Structure Molecular Molecular M+H+ formula weight 269 \O N \- \ C26H27N303 429.21 430 270 F C25H23F2N302 435.18 436 F ON 271 0/ C26H27N303 429.21 430 N - N 174 272 F C25H24FN302 417.19 418 - N 0 '-,N _ 273 c N N C25H24CIN302 433.16 434 Example 274 (R)-4'-Fluorobiphenyl-4-carboxylic acid [6-(3-dimethylaminopyrrolidin-1 5 yl)pyridin-3-yl]-amide 0 F N> N - H "N Method M (R)-4'-Fluorobiphenyl-4-carboxylic acid [6-(3-methylaminopyrrolidin-1 yl)pyridin-3-y]-amide (390 mg) dissolved in formic acid (230 mg) was 10 mixed with formaldehyde solution (37% aq.; 0.4 ml) and the mixture was heated at 800C for 3 hours. The cooled reaction solution was concentrated and partitioned between ethyl acetate and a saturated sodium carbonate solution. The organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC. This 15 resulted in the product with the molecular weight of 404.49 (C24H25FN40); MS (ESI): 405 (M+H+). Example 275 1-(4-Fluorophenyl)piperidine-4-carboxylic acid {4-[3 20 (acetylmethylamino)pyrrolidin-1 -yl]phenyl}amide 175 0 N N 0 O N N Method E-a A mixture of 0.048 g of 1-(4-fluorophenyl)piperidine-4-carboxylic acid and 0.5 ml of SOC12 and one drop of DMF were stirred at room temperature for 5 2 hours. The excess SOC12 was then removed in vacuo. The residue was dissolved in 0.4 ml of DMF, and 0.033 ml of triethylamine and 0.048 g of N [1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide were added. The solution was stirred at room temperature overnight. The solution was then filtered and purified by preparative HPLC. This resulted in the product with 10 the molecular weight of 438.20 (C25H31 FN402); MS (ESI): 439 (M+H+) as hydrotrifluoroacetate. 1-(4-Fluorophenyl)piperidine-4-carboxylic acid 0.875 g of 4-bromofluorobenzene, 0.016 g of Pd(dba)3*CHC3, 0.022 g 15 2-(dicyclohexylphosphino)bipheny and 2.28 g of cesium carbonate were put in a heat-dried and argon-flushed flask, and 0.943 g of ethyl 4 piperidinecarboxylate in 5 ml of degassed toluene was added. The solution was heated at 100 0 C overnight. The mixture was cooled and then concentrated in vacuo. The residue was taken up in ethyl acetate/water. 20 The organic phase was washed with 10% NaHCO3 solution, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC. 4.4 ml of a 2N potassium hydroxide solution were added to a solution of 1.1 25 g of ethyl 1-(4-fluorophenyl)piperidine-4-carboxylate in 100 ml of methanol. The mixture was stirred at room temperature overnight. The pH was then adjusted to 6 with 5% hydrochloric acid, and the solution was concentrated 176 in vacuo. The residue was purified by preparative HPLC. Example 276 5 4-Phenoxycyclohexanecarboxylic acid {4-[3-(acetylmethylamino)pyrrolidin 1 -yl]phenyl}amide 0 N N 0 a0e 0.251 g of PyBOP and 0.135 ml of triethylamine were added to a solution of 0.106 g of 4-phenoxycyclohexanecarboxylic acid and 0.113 g of N-[1-(4 10 aminophenyl)pyrrolidin-3-yl]-N-methylacetamide in 9 ml of DMF at 0*C. After 10 minutes, the solution was allowed to reach room temperature and was stirred at this temperature overnight. The solvent was then removed in vacuo, and the residue was taken up in water/ethyl acetate. The ethyl acetate phase was washed with 10% citric acid and 10% NaHCO3 solution 15 and dried over sodium sulfate, and the solvent was removed in vacuo. The residue was purified by preparative HPLC. The desired product was obtained. Molecular weight 435.25 (C26H33N303), MS: 436 (M+H+). 4-Phenoxycyclohexanecarboxylic acid 20 0.63 g of p-toluenesulfonyl chloride was added to a solution of 0.522 g of ethyl 4-hydroxycyclohexanecarboxylate in 5.0 ml of pyridine. The reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. The resulting solid was taken up in water and ethyl acetate, and the organic phase was washed three times with 2N 25 hydrochloric acid and once with saturated NaCl solution. The organic phase was dried over sodium sulfate and concentrated in vacuo. The resulting product was employed without further purification in the next step. The resulting product (0.55 g) was dissolved in 11.2 ml of DMF, and 0.159 g of phenol and 0.549 g of cesium carbonate were added. The solution was 177 then heated at 800C for 6 hours. After cooling, the mixture was concentrated in vacuo and purified by column chromatography on silica gel (eluent: ethyl acetate /n-heptane 1:1). The desired product was obtained. Molecular weight 248.32 (Cl 5H2003), MS: 249 (M+H+). 5 0.06 ml of 2N potassium hydroxide solution was added to a solution of 0.12 g of ethyl 4-phenoxycyclohexanecarboxylate in 8 ml of water/THF (1:1). The solution was heated at 600C for 3 hours. Ethyl acetate and 10% citric acid were added to the mixture. The aqueous phase was extracted three times with ethyl acetate, dried over sodium sulfate and concentrated in 10 vacuo. The resulting compound was employed without further purification in the next stage. Example 277 15 N-[4-(3-Cyclohexylaminopyrrolidin-1 -yl)phenyl]-4-isobutoxybenzamide 0 O N\/ N Method N (4-Isobutoxy-N-[4-(3-oxopyrrolidin-1 -yl)phenyl]benzamide (50 mg) in methanol (2 ml) was mixed with aminocyclohexane (28 mg) and glacial 20 acetic acid (10 mg), and a solution of sodium cyanoborohydride (1 M in toluene; 0.17 ml) was added. After 8 hours, the reaction solution was concentrated and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated. The crude product was purified by preparative HPLC. This resulted in the product with 25 the molecular weight of 435.61 (C27H37N302); MS (ESI): 436 (M+H+). 4-Isobutoxy-N-[4-(3-oxopyrrolidin-1 -yl)phenyl]benzamide 4-lsobutoxybenzoic acid was reacted with 4-(1,4-dioxa-7-azaspiro[4.4]non 7-yl)phenylamine by method E-a. The resulting amide (0.25 g) in acetone 30 (10 ml) was mixed with para-toluene sulfonic acid (monohydrate, 109 mg), and the mixture was boiled under reflux for 8 hours. After adding triethylamine (0.5 ml), the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 178 352.44 (C21 H24N203); MS (ESI): 353 (M+H+). 4-Butoxy-N-[4-(3-oxopyrrolidin-1 -yl)-phenyl]benzamide was obtained using 4-butoxybenzoic acid in an analogous way. Likewise, 4-butoxybenzoic acid and 4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-3-fluorophenylamine initially 5 resulted in 4-butoxy-N-[4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-3 fluorophenyl]benzamide which, after methylation by method F and treatment with para-toluenesulfonic acid as described above, afforded 4-butoxy-N-[3-fluoro-4-(3-oxopyrrolidin-1 -yl)phenyl]benzamide. 4-(1,4-Dioxa-7-azaspiro[4.4] non-7-yl)phenylamine 10 Trimethylchlorosilane (9.3 g) was slowly added to a solution of 1 -benzyl-3 pyrrolidinone (5.0 g) in dichloromethane (30 ml) and ethylene glycol (2.67 g). After 18 hours, the mixture was poured into sodium hydroxide solution (1 N). The organic phase was separated off, dried over magnesium sulfate and concentrated. The residue was dissolved in methanol (30 ml) and 15 ammonium formate (5.2 g) and palladium hydroxide (10% on carbon, 300 mg) were added. The mixture was boiled under reflux for 8 hours, filtered and concentrated. The residue was reacted with 4-fluoronitrobenzene by method C. Hydrogenation was finally carried out by method B. This resulted in the product with the molecular weight of 220.27 (Cl 2H1 6N202); 20 MS (ESI): 221 (M+H+). 4-(1,4-Dioxa-7-azaspiro[4.4] non-7-yl)-3-fluorophenylamine was obtained analogously using 3,4-difluoronitrobenzene. 25 Example 278 (R)-4-(4-Chlorophenyl)piperidin-1 -carboxylic acid {4-[3-(methylpyrimidin-2 yl-amino)pyrrolidin-1 -yl]-phenyl}amide CI -C N ClN NN N' (R)-4-(4-Chlorophenyl)piperidine-1 -carboxylic acid [4-(3 30 methylaminopyrrolidin-1 -yl)phenyl]amide (100 mg) was reacted with potassium carbonate (100 mg) and 2-bromopyrimidine (50 mg) in N methylpyrrolidone (3 ml) at 100*C for 4 hours. The reaction solution was then partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated. The crude product was 179 purified by preparative HPLC. This resulted in the product with the molecular weight of 491.04 (C27H31 CIN60); MS (ESI): 491 (M+H+). 5 Example 279 tert-Butyl [1 -(4-{[5-(2-fluorophenyl)furan-2 carbonyl]amino}phenyl) pyrrolidin-3-yl]methylcarbamate O N N N0 10 Method 0 Tetrakis(triphenylphosphine)palladium(0) (20 mg) was added to a solution of tert-butyl (1 -{4-[(5-bromofuran-2-carbonyl)amino]phenyl}pyrrolidin-3 yl)methylcarbamate (252 mg) in degassed touene (4 ml) under argon in a 10 ml two-necked flask and stirred at room temperature for 10 minutes. 15 Then a solution of 2-fluorobenzeneboronic acid (73 mg in 1 ml of ethanol) and 0.35 ml of 2M sodium carbonate solution were added, and the mixture was stirred at 100 C for 24 hours. Then water (5 ml) and ethyl acetate (5 ml) were added to the reaction mixture, the organic phase was separated off, and the aqueous phase was 20 extracted 2 x with ethyl acetate (10 ml). The combined organic phases were concentrated and the residue was purified by preparative HPLC. The desired product with the molecular weight of 479.56 (C27H30FN304); MS (ESI): 480 (M+H+) was obtained as hydrotrifluoroacetate. It is alternatively possible to use cesium carbonate as base and to heat the reaction at 25 1500C in a microwave apparatus for 3 minutes. tert-Butyl (1 -{4-[(5-bromofuran-2-carbonyl)amino]phenyl}pyrrolidin-3 yl)methylcarbamate 5-Bromofuran-2-carboxylic acid was reacted with tert-butyl [1 -(4 30 aminophenyl)pyrrolidin-3-yl]methylcarbamate by method E. This resulted in 180 the product with the molecular weight of 464.36 (C21 H26BrN304); MS (ESI): 464 (M+H+). The following compounds were prepared analogously: 5-Bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 5 yl)phenyl]amide tert-Butyl (1 -{4-[(5-bromothiophene-2-carbonyl)amino]phenyl}pyrrolidin-3 yl)methylcarbamate 2-Bromothiazole-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 yl)phenyl]amide 10 4-lodo-N-[4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]benzamide (R)-N-[4-(3-Dimethylaminopyrrolidin-1 -yl)-3-fluorophenyl]-4-iodobenzamide 4-Bromo-N-[4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]-3-fluorobenzamide 15 Example 280 (3R)-3'-Cyanobiphenyl-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 yl)-3-fluorophenyl]amide F N Na N Method O-b 20 0.002 mg of Pd(PPh3)4 were added to a solution of 0.022 g of (R)-N-[4-(3 dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-iodobenzamide in 0.45 ml of degassed DMF and stirred at room temperature for 10 minutes. 0.035 ml of water, 0.021 g of K3PO4 and 0.008 g of 3-cyanophenylboronic acid were then added to the solution. The reaction solution was heated at 800C 25 overnight. The solution was then filtered and purified by preparative HPLC. This resulted in the product with the molecular weight of 428.20 181 (C26H25FIN40); MS (ESI): 429 (M+H+) as hydrotrifluoroacetate. Example 281 5 3,2',4'-Trifluorobiphenyl-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 yl)phenyl]-amide F N N F F 1 -Bromo-2,4-difluorobenzene was reacted with N-[4-(3 dimEthylaminopyrrolidin-1 -yl)phenyl]-2-fluoro-4-boronic acid benzamide by 10 metf od 0-b. This resulted in the product with the molecular weight of 439.19 (C25H24F3N30); MS (ESI): 440 (M+H+) as hydrotrifluoroacetate. N-[4. (3-Dimethylaminopyrrolidin-1 -yl)phenyl]-2-fluoro-4-boronic acid benzamide 15 4-Cz rboxy-3-fluorophenylboronic acid was reacted with [1 -(4 aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 371.18 (Cl 9H23BFN303); MS (ES'): 372 (M+H+) as hydrotrifluoroacetate. 20 Example 282 5-(2,4-Difluorophenyl)thiophen-2-carboxylic acid [4-(3 dimethylaminopyrrolidin-1 -yl)-phenyl]amide F N NN F 25 1-Bromo-2,4-difluorobenzene was reacted with 2-boronic acid thiophen-5- 182 carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide by method 0-b. This resulted in the product with molecular weight of 427.52 (C23H23F2N30S); MS (ESI): 428 (M+H+) as hydrotrifluoroacetate. 5 2-Boronic acid thiophene-5-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 yl)phenyl]amide 5-Carboxy-2-thiopheneboronic acid was reacted with [1-(4 aminophenyl)pyrrolidin-3-yl]-dimethylamine by method E-b. This resulted in the product with the molecular weight of 359.15 (C17H22BN303S); MS 10 (ESI): 360 (M+H+) as hydrotrifluoroacetate. Example 283 N-[4-(3-Dimethylaminopyrrolidin-1 -yl)phenyl]-6-(4 15 fluorophenyl)nicotinamide F N N N-~~
-
N - 0 N 5-[4-(3-Dimethylaminopyrrolidin-1-yl)phenylcarbamoyl]pyridin-2-y [trifluoro methanesulfonate was reacted with 4-fluorobenzeneboronic acid under the conditions of method O-b. (Heating at 1400C in a microwave apparatus for 20 15 minutes). This resulted in the product with the molecular weight of 404.20 (C24H25FN40); MS (ESI): 405 (M+H+) as hydrotrifluoroacetate. 5-[4-(3-Dimethylaminopyrrolidin-1 -yl)phenylcarbamoyl]pyridin-2-y [trifluoromethanesulfonate 25 A suspension of 0.0.5 g of N-[4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]-6 hydroxynicotinamide in 0.4 ml of DME was added to a solution of 0.084 ml of LDA solution (2M) in 0.4 ml of DME at 00C. The mixture was stirred at 00C for 2 hours. A solution of 0.055 g of N phenyltrifluoromethanesulfonimide in 0.2 ml of DME was then added to the 30 mixture. The reaction solution was allowed to reach room temperature and 183 was heated at 800C for 3 hours. After cooling, the solution was concentrated in vacuo. The residue was taken up in ethyl acetate/water, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in 5 vacuo and purified by preparative HPLC. N-[4-(3-Dimethylaminopyrrolidin-1 -yl)-phenyl]-6-hydroxynicotinamide 6-Hydroxynicotinic acid was reacted with [1 -(4-aminophenyl)pyrrolidin-3 yl]dimethylamine by method E-b. This resulted in the product with the 10 molecular weight of 326.17 (C18H22N402); MS (ESI): 327 (M+H+) as hydrotrifluoroacetate. Example 284 15 N-[4-(3-Dimethylaminopyrrolidin-1 -yl)phenyl]-6-(2,4 difluorophenyl)nicotinamide F N N N - N 01 F 2,4-Difluorophenylboronic acid was reacted with 5-[4-(3 20 dimethylaminopyrrolidin-1 -yI)-phenylcarbamoyl]pyridin-2-yl [trifluoromethanesulfonate by method O-b. This resulted in the product with the molecular weight of 422.00 (C24H24F2N40); MS (ESI): 423 (M+H+) as hydrotrifluoroacetate. 25 Example 285 2',4'-Difluorobiphenyl-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 yl)phenyl]amide 184 F F N O N 2',4'-Difluorobiphenyl-4-carboxylic acid was reacted with [1-(4 aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-a. This resulted in the product with the molecular weight of 421.20 (C25H25F2N30); MS 5 (ESI): 422 (M+H+) as hydrotrifluoroacetate. 2',4'-Difluorobiphenyl-4-carboxylic acid Method P 0.098 ml of 1 N lithium hydroxide solution was added to a solution of 0.051 10 g of Ethyl 2',4'-difluorobiphenyl-4-carboxylate in 1 ml THF/water (1:1), and the mixture was stirred at room temperature overnight. 5% hydrochloric acid was used to neutralize the solution, which was concentrated in vacuo, and the residue was purified by preparative HPLC. 15 Ethyl 2',4'-difluorobiphenyl-4-carboxylate 0.009 g of Pd(PPh3)4 was added to a solution of 0.091 g of ethyl 4-iodobenzoate in 0.96 ml of degassed toluene and stirred at room temperature for 10 minutes. Then a solution of 0.047 g of 2,4 difluorophenylboronic acid in 0.114 ml of ethanol and 0.201 ml of a 2N 20 Na2CO3 solution was added to the reaction solution. The solution was heated at 100*C overnight. The reaction mixture was then concentrated in vacuo, and water/ethyl acetate were added to the residue. The aqueous phase was extracted three times with ethyl acetate and dried over sodium sulfate, and the solvent was removed in vacuo and purified by preparative 25 HPLC.
185 Example 286 2',4'-Difluorobiphenyl-4-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin 1 -yl]phenyl}-amide F F N N / N 5 Method E-b 0.095 g of HATU, 0.068 g of HOBT and 0.035 ml of triethylamine were added to a solution of 0.047 g of 2',4'-difluorobiphenyl-4-carboxylic acid and 0.058 g of N-[1-(4-aminophenyl)pyrrolidin-3-yl]-N-methylacetamide in 2 ml of DMF at 0*C. After 10 minutes, the solution was allowed to reach room 10 temperature and was stirred at this temperature overnight. The solvent was then removed in vacuo, and the residue was taken up in water/ethyl acetate. The ethyl acetate phase was washed with 10% NaHCO3 solution and water. The ethyl acetate phase was dried over sodium sulfate, and the solvent was removed in vacuo. The residue was purified by preparative 15 HPLC. The desired product was obtained. Molecular weight 449.19 (C26H25F2N302), MS: 450 (M+H+). Example 287 20 N-[4-(3-Dimethylaminopyrrolidin-1 -yl)phenyl]-3-fluoro-4-(4-methylpiperidin 1 -yl)-benzamide 186 N F NN NN
/N
3-Fluoro-4-(4-methylpiperidin-1-yl)benzoic acid was reacted with [1-(4 aminophenyl)-pyrrolidin-3-yl]dimethylamine by method E-a. This resulted in the product with the molecular weight of 424.00 (C25H33FN40); MS (ESI): 5 425 (M+H+) as hydrotrifluoroacetate. 3-FItioro-4-(4-methylpiperidin-1 -yl)benzoic acid Methyl 3-fluoro-4-(4-methylpiperidin-1-yl)benzoate was treated with lithium hydroxide by method P. This resulted in the product with the molecular 10 weight of 237.28 (Cl 3H16FN02); MS (ESI): 238 (M+H+). Methyl 3-fluoro-4-(4-methylpiperidin-1 -yl)benzoate 0.073 g of potassium carbonate was added to a solution of 0.086 g of methyl 3,4-difluorobenzoate and 0.050 g of 4-methylpiperidine in 0.5 ml of 15 DMF. The reaction was heated at 600C for 2 days, filtered and purified by preparative HPLC. This resulted in the product with the molecular weight of 251.3 (C14H18FNO2); MS (ESI): 252 (M+H+) as hydrotrifluoroacetate. 20 Example 288 4-Butoxy-N-(4-{3-[(2-dimethylaminoacetyl)methylamino]pyrrolidin-1 yl}phenyl)-N-methylbenzamide 187 o N N N o N / / 0 4-Butoxy-N-methyl-N-[4-(3-methylaminopyrrolidin-1 -yl)phenyl]benzamide was reacted with N,N-dimethylglycine by method E. This resulted in the product with the molecular weight of 466.63 (C27H38N403); MS (ESI): 467 5 (M+H+). (R)-4-Butoxy-N-(4-{3-[(2-dimethylaminoacetyl)methylamino]pyrrolidin-1 yl}phenyl)-N-methylbenzamide was obtained analogously. 10 Example 289 N-{4-[3-(Acetylmethylamino)pyrrolidin-1 -yl]phenyl}-4-butoxy-N methylbenzamide o N N N \NON OC o N4l 4-Butoxy-N-methyl-N-[4-(3-methylaminopyrrolidin-1 -yl)phenyl]benzamide 15 was mixed with pyridine and acetic anhydride. Volatile fractions were removed after 2 hours. This resulted in the product with the molecular weight of 423.56 (C25H33N303); MS (ESI): 424 (M+H+). 20 Example 290 4-Butyrylamino-N-[4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]benzamide 0 Na N N 0 188 Method Q 4-Amino-N-[4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]benzamide (32 mg) in dichloromethane (2 ml) was mixed with potassium carbonate (50 mg) and 5 butyryl chloride (11 mg). The mixture was filtered and concentrated after 12 hours. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight of 394.52 (C23H30N403); MS (ESI): 395 (M+H+). An alternative possibility is to react 4-amino-N-[4-(3 10 dimethylaminopyrrolidin-1 -yl)-phenyl]benzamide with butyric acid by method E. 4-Amino-N-[4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]benzamide 4-tert-Butoxycarbonylaminobenzoic acid was reacted with 1-(4 15 aminophenyl)pyrrolidin-3-yl]dimethylamine by method E, and the product was treated by method G. This resulted in the product with the molecular weight of 324.43 (C19H24N40); MS (ESI): 325 (M+H+). 20 Example 291 2-Phenylethynylthiazole-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 yl)phenyl]-amide N NN N 2-Bromothiazole-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 25 yl)phenyl]amide (100 mg) was dissolved in tetrahydrofuran (2 ml), and phenylacetylene (52 mg), triethylamine (52 mg), triphenylphosphine (17 mg), bis(triphenylphosphine)palladium dichloride (89 mg) and copper (1) iodide (9.6 mg) were added. The reaction mixture was heated at 1500C in a microwave apparatus for 3 minutes and then concentrated. The residue 30 was purified by preparative HPLC. This resulted in the product with the 189 molecular weight of 416.55 (C24H24N40S); MS (ESI): 417 (M+H+). Example 292 5 5-(4-Fluorophenyl)pyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin 1 -yl)phenyl]-amide F /N O N' Method O-a 5-Chloropyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 10 yl)phenyl]amide (100 mg) dissolved in toluene was mixed with 4 fluorophenylboronic acid (81 mg), POPD (15 mg) and cesium carbonate (2M aq.; 0.5 ml). The reaction was heated at 1500C in a microwave apparatus for 10 minutes and then concentrated. The residue was purified by preparative HPLC. This resulted in the product with the molecular weight 15 of 404.49 (C24H25FN40); MS (ESI): 405 (M+H+). 5-Chloropyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 yl)phenyl]amide [1 -(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with 5 20 chloropyridine-2-carboxylic acid by method E. This resulted in the product with the molecular weight of 344.85 (Cl 8H21CIN40); MS (ESI): 345 (M+H+). 25 Example 293 5-(4-Fluorophenyl)pyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin 1 -yl)phenyl]-amide 190 N / N \ N N N' 5-Chloropyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 yl)phenyl]amide was reacted with 4-methylphenylboronic acid by method O-a. This resulted in the product with the molecular weight of 400.53 5 (C25H28N40); MS (ESI): 401 (M+H+). Example 294 1 -Benzenesulfonylpiperidine-4-carboxylic acid [4-(3 10 dimethylarminopyrrolidin-1 -yl)-phenyl]amide I I ' -N N 0 \/-jNC 0 N Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 yl)phenyl]Emide (70 mg) dissolved in N-methylpyrrolidone (2 ml) was mixed with potassium carbonate (45 mg) and benzenesulfonyl chloride (35 mg). 15 After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. This resulted in the product with the molecular weight of 456.61 (C24H32N403S); MS (ESI): 457 (M+H+). 20 Example 295 1 -(4-Fluorobenzenesufonyl) piperidine-4-carboxylic acid [4-(3 dimethylaminopyrrolidin-1 -yl)phenyl]amide 191 0 F N N NC 0 N Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 yl)phenyl]amide (70 mg) dissolved in N-methylpyrrolidone (2 ml) was mixed with potassium carbonate (45 mg) and 4-fluorobenzenesulfonyl chloride (40 5 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. This resulted in the product with the molecular weight of 474.60 (C24H31 FN403S); MS (ESI): 475 (M+H+). Example 296 10 1 -(Butane-1 -sulfonyl)piperidine-4-carboxylic acid [4-(3 dimethylaminopyrrolidin-1 -yl)-phenyl]amide 0 S-N N 00 N'~ Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 yl)phenyl]amide (70 mg) dissolved in N-methylpyrrolidone (2 ml) was mixed 15 with potassium carbonate (45 mg) and butylsulfonyl chloride (30 mg). After 12 hours, the mixture was filtered and the filtrate was purified by preparative HPLC. This resulted in the product with the molecular weight of 436.62 (C22H36N403S); MS (ESI): 437 (M+H+). 20 Example 297 5-(4-Butoxyphenylethynyl)furan-2-carboxylic acid [4-(3 dimethylaminopyrrolidin-1 -yl)-phenyl]amide 192 0 O N N N Method J-a 5-Bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 5 yl)phenyl]amide (75 mg) was dissolved together with 1-butoxy-4 ethynylbenzene (35 mg) in N,N-dimethylformamide (1 ml) and, under argon, added dropwise to a suspension of Pd(tBu3P)2Cl2 (4 mg), copper (1) iodide (75 mg) and N,N-diisopropylamine (20 mg) in anhydrous tetrahydrofuran (3 ml). The mixture was stirred at room temperature for 10 8 hours. The reaction was worked up by filtration through a syringe filter and concentrated, and the crude product was purified by preparative HPLC. This resulted in the product with the molecular weight of 471.6 (C29H33N303); MS (ESI): 472 (M+H+) as hydrotrifluoroacetate. 15 Example 298 6-Butoxy-N-[4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]nicotinamide N N 0 N Method H-a 20 A solution of 0.1 g of potassium hydroxide in 1 ml of DMSO was stirred at room temperature for 10 minutes and then 0.1 g of N-[4-(3 dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide was added. The reaction solution was stirred for 10 minutes and then 0.084 g of 1 bromobutane was added. The mixture was stirred at room temperature 25 overnight. After addition of water and ethyl acetate, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by 193 preparative HPLC. This resulted in the product with the molecular weight of 382.24 (C22H30N402); MS (ESI): 383 (M+H+) as hydrotrifluoroacetate. 5 Example 299 6-Cyclopropylmethoxy-N-[4-(3-dimethylaminopyrrolidin-1 yl)phenyl]nicotinamide 0 o N (Bromomethyl)cyclopropane was reacted with N-[4-(3 10 dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide by method H a. This resulted in the product with the molecular weight of 380.22 (C22H28N402); MS (ESI): 381 (M+H+) as hydrotrifluoroacetate. 15 Example 300 N-[4-(3-Dimethylaminopyrrolidin-1 -yl)phenyl]-6-isobutoxynicotinamide 0 N N 1 -Bromo-2-methylpropane was reacted with N-[4-(3 dimethylaminopyrrolidin-1-yl)-phenyl]-6-hydroxynicotinamide by method H 20 a. This resulted in the product with the molecular weight of 382.24 (C22H30N402); MS (ESI): 383 (M+H+) as hydrotrifluoroacetate. Example 301 25 N-[4-(3-Dimethylaminopyrrolidin-1 -yl)phenyl]-6-(4- 194 fluorophenoxy)nicotinamide FON N- Na O N 49 mg of potassium carbonate were added to a solution of 0.041 g of 6 chloro-N-[4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]nicotinamide and 4 5 fluorophenol (30 mg) in 0.8 ml of DMF, and the reaction was heated at 1400C in a microwave apparatus for 90 minutes. After addition of water and ethyl acetate, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This resulted in 10 the product with the molecular weight of 420.2 (C24H25FN402); MS (ESI): 421 (M+H+) as hydrotrifluoroacetate. 6-Chloro-N-[4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]nicotinamide 6-Chloronicotinic acid was reacted with [1 -(4-amino-phenyl)pyrrolidin-3 15 yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 344.14 (C18H21CIN40); MS (ESI): 345 (M+H+) as hydrotrifluoroacetate. 20 The following examples were prepared analogously. Ex. Structure Molecular formula Mole- M+H+ No. cular weight 302 C24H26N402 402.21 403 N0 N 303 I C24H25CIN402 436.17 437 c - N. NN 0
N
195 304 C Nf N Na 025H28N402 416.22 417 Example 305 N-[4-(3-Dimethylaminopyrrolidin-1 -yl)phenyl]-2-fluoro-4-phenoxybenzamide 0 F N N O N' 5 Powdered molecular sieves (4 A), 0.01 g of copper acetate and 0.02 g of N-[4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]-2-fluoro-4-boronic acid benzamide were added to a solution of 0.008 g of phenol in 0.5 ml of methylene chloride and stirred at 400C for 24 hours. The solvent was then 10 removed in vacuo, the residue was taken up in water/ethyl acetate, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This resulted in the product with the molecular weight of 419.2 (C25H26FN302); MS (ESI): 420 (M+H+) as 15 hydrotrifluoroacetate. N-[4-(3-Dimethylaminopyrrolidin-1 -yl)phenyl]-2-fluoro-4-boronic acid benzamide 4-Carboxy-3-fluorophenylboronic acid was reacted with [1-(4 20 aminophenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 371.18 (C19H23BFN303); MS (ESI): 372 (M+H+) as hydrotrifluoroacetate. 25 Example 306 196 4-(3-Cyanophenyl)-3,6-dihydro-2H-pyridine-1 -carboxylic acid [4-(3 dimethylaminopyrrolidin-1 -yl)phenyl]amide N N N N 0 I 4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 5 carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]amide was reacted with 3-bromobenzonitrile by method O-a. This resulted in the product with the molecular weight of 415.54 (C25H29N50); MS (ESI): 416 (M+H+) 10 4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]amide 4-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- 1,2,3,6-tetrahydropyridine was reacted with [1 -(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method A. This resulted in the product with the molecular weight of 440.40 15 (C24H37BN403); MS (ESI): 441 (M+H+) Example 307 4-(2-Cyanophenyl)-3,6-dihydro-2H-pyridine-1 -carboxylic acid [4-(3 20 dimethylamino-pyrrolidin-1 -yl)phenyl]amide N / N N N 0 / 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]amide was reacted with 2-bromobenzonitrile by method O-a. This resulted in the 25 product with the molecular weight of 415.54 (C25H29N50); MS (ESI): 416
(M+H+)
197 Example 308 4-(3-Methylsulfanylphenyl)-3,6-dihydro-2H-pyridine-1 -carboxylic acid [4-(3 5 dimethylaminopyrrolidin-1 -yl)phenyl]amide S N N 0 / 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]amide was reacted with 3-bromothioanisole by method 0-a. This resulted in the 10 product with the molecular weight of 436.62 (C25H32N40S); MS (ESI): 437 (M+H+) Example 309 15 4-(5-Chloropyridin-2-yloxy)-N-[4-(3-dimethylaminopyrrolidin-1 yl)phenyl]benzamide 0 Cl O N /\ N 0 N 0.143 g of potassium carbonate was added to a solution of 0.19 g of 4-[4 (3-dimethylaminopyrrolidin-1 -yl)phenylcarbamoyl]phenyl acetate in 2 ml of 20 DMF, and the solution was heated at 1300C in a microwave apparatus for 15 minutes. The solution was then mixed with water and ethyl acetate, the aqueous phase was freeze-dried, and the residue was employed without further purification in the next stage. 25 Method R A solution of 0.05 g of N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-4 hydroxybenzamide, 0.017 g of 2,5-dichloropyridine and 0.064 g of 198 potassium carbonate in 0.8 ml of DMF was heated at 230 0 C in a microwave apparatus for 30 minutes. The solution was filtered and purified by preparative HPLC. This resulted in the product with the molecular weight of 436.17 (C24H25CIN402); MS (ESI): 437 (M+H+) as hydrotrifluoroacetate. 5 4-[4-(3-Dimethylaminopyrrolidin-1 -yl)phenylcarbamoyl]phenyl acetate 4-Acetoxybenzoic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3 yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 367.19 (C21H25N303); MS (ESI): 368 (M+H+) as 10 hydrotrifluoroacetate. Example 310 N-[4-(3-Dimethylaminopyrrolidin-1 -yl)phenyl]-4-(5-fluoropyridin-2 15 yloxy)benzamide 0 FON N 0 N 2-Chloro-5-fluoropyridine was reacted with N-[4-(3-dimethylaminopyrrolidin 1 -yl)phenyl]-4-hydroxybenzamide by method R. This resulted in the product with the molecular weight of 420.2 (C24H25FN402); MS (ESI): 421 20 (M+H+) as hydrotrifluoroacetate. Example 311 4-(6-Chloropyridin-3-yloxy)-N-[4-(3-dimethylaminopyrrolidin-1 25 yl)phenyl]benzamide C 0 C, -'N N 7 Na O N was obtained as by-product of the reaction in example 310. This resulted in 199 the product with the molecular weight of 436.95 (C24H25CIN402); MS (ESI): 437 (M+H+) as hydrotrifluoroacetate. 5 Example 312 5-Chloro-3',6'-dihydro-2'H-[2,4']bipyridinyl-1'-carboxylic acid [4-(3 dimethylamino- pyrrolidin-1 -yl)phenyl]amide 0 N II CI N N N [1 -(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine (32 mg) and 10 carbonyldiimidazole (27.1 mg) were dissolved in acetonitrile (1.5 ml), and the mixture was stirred for 3 hours. Triethylamine (63.4 p) was added to a solution of 5-chlbro-1',2',3',6'- tetrahydro-[2,4']bipyridine (40.7 mg) in THF (1 ml) and chloroform (0.5 ml). After 15 minutes, the mixture was added dropwise to the first solution and stirred overnight. The mixture was 15 concentrated and the residue was partitioned between dichloromethane and water. The organic phase was dried over sodium sulfate, filtered and concentrated. Contamination by the primary and/or secondary amine was removed by dissolving the residue in dichloromethane (1.5 ml) and adding the solution to a stirred suspension of polymer-bound p-toluenesulfonyl 20 chloride (0.5 g) in dichloromethane (6 ml) and triethylamine (128 pl). After 3 hours, the resin was filtered off and washed several times with dichloromethane. The combined organic phases were concentrated. The residue was purified by chromatography (silica gel, mobile phase: ethyl acetate/dichloromethane (5%), ammonia (7N in methanol, 2%), later ethyl 25 acetate/dichloromethane (5%), ammonia (7N in methanol, 3%). This resulted in the product with the molecular weight of 425.97 (C23H28CIN50); MS (ESI): 426 (M+H+). 5-Chloro-1',2',3',6'- tetrahydro-[2,4']bipyridine 30 A solution of tert-butyl 5-chloro-3',6'-dihydro-2'H-[2,4']bipyridine-1' carboxylate (50 mg) in chloroform (2.4 ml) was mixed with hydrogen chloride (4N in dioxane; 0.8 ml) and the mixture was concentrated after 13 200 hours. This resulted in the product with the molecular weight of 194.67 (C1OH11CIN2); MS (ESI): 195 (M+H+). tert-Butyl 5-chloro-3',6'-dihydro-2'H-[2,4']bipyridine-1'-carbamate 5 A solution of 2-bromo-5-chloropyridine (131 mg) in DMF (degassed with nitrogen; 4.5 ml) was added to a mixture of tert-butyl 4-(4,4,5,5 tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1 -carbamate (Eastwood, Paul R., Tetrahedron Lett, 41, 19, 2000, 3705-3708; 200 mg), potassium carbonate (0.265 g) and Pd(dppf)C12 (50 mg). The mixture was 10 heated at 800C for 8 hours. After cooling, the mixture was diluted with dichloromethane and washed with sodium carbonate solution and water. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, mobile phase: heptane/ethyl acetate (2%)/dichloromethane (5%), later 15 heptane/ethyl acetate (5%)/dichloromethane (5%). Example 313 5-(2-Amino-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino 20 pyrrolidin-1 -yl)- phenyl]amide 0 N 0 Nc N N 0 5-(2-Nitro-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino pyrrolidin-1 -yl)- phenyl]amide was hydrogenated by method B. This resulted in the product with the molecular weight of 404.22 (C24H28N402); 25 MS (ESI): 405 (M+H+). Example 314 5-(2-Acetylamino-4-methylphenyl)furan-2-carboxylic acid [4-(3 30 dimethylaminopyrrolidin- 1-yl)phenyl]amide 201 0 N N O N N O1/ 0I 5-(2-Amino-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino pyrrolidin-1-yl)- phenyl]amide was reacted with acetyl chloride by method Q. This resulted in the product with the molecular weight of 446.23 5 (C26H30N403); MS (ESI): 447 (M+H+). Example 315 5-(2-Isobutyrylamino-4-methylphenyl)furan-2-carboxylic acid [4-(3 10 dimethylamino- pyrrolidin-1 -yl)phenyl]amide 0 N N O N N o/ 5-(2-Amino-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino pyrrolidin-1-yl)- phenyl]amide was reacted with isobutyryl chloride by method Q. This resulted in the product with the molecular weight of 474.26 15 (C28H34N403); MS (ESI): 475 (M+H+). Example 316 5'-Chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid [4-(3 20 dimethylamino- pyrrolidin-1 -yl)phenyl]methylamide 0 C 1- NNNN /\N N Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyl] methylamide (44.4 mg) and 2,5-dichloropyridine (60 mg) were heated at 1600C for 15 minutes. o-Xylene (0.5 ml) was added and heating at 1600C 202 was continued for 2 hours. The cooled crude mixture was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (7N in methanol)). This resulted in the product with the molecular weight of 442.01 (C24H32ClN50); MS (ESI): 442 (M+H+). 5 Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin- 1 yl)phenyl]methylamide tert-Butyl 4-{[4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]methylcarbamoyl} piperidine-1-carboxylate was treated with trifluoroacetic acid by method G. 10 This resulted in the product with the molecular weight of 330.48 (C1 9H30N40); MS (ESI): 331 (M+H+). Piperidine-4-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1 -yl)phenyl] amide can be prepared analogously. tert-Butyl 4-{[4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]methylcarbamoyl} 15 piperidine-1 -carboxylate A solution of N-Boc-piperidine-4-carboxylic acid (550 mg) and pyridine (0.47 ml) in dichloromethane (15 ml) was mixed with thinoyl chloride (0.21 ml) and, after 30 minutes, a solution of dimethyl[1 -(4 methylaminophenyl)pyrrolidin-3-yl]amine (0.5 g), triethylamine (1.17 ml), 20 DMAP (0.44 g) and dichloromethane (10 ml) was added dropwise. After 16 hours, the mixtur3 was diluted with dichloromethane, washed with water and saturated brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (7N in methanol)). This resulted in the product with the 25 molecular weight of 430.60 (C24H38N403); MS (ESI): 431 (M+H+). tert-Butyl 4-{[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]carbamoyl}piperidin 1 -carboxylate can be prepared analogously. 30 The following examples were prepared analogously.
203 Ex. Structure Molecular formula Mole- M+H+ No. cular weight 317 c / C25H30CIN50 466.03 466 C N\N/ NC( N 318 c 2 C24H30CIN503 471.99 472 2O
N
319 C24H30FN503 455.54 456 F--N 01
NO
2 N N N N Example 320 5 3,4,5,6-Tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid [4-(3 dimethylaminopyrrolidin-1 -yl)phenyl]amide 0 N a NN N Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyll amide (30 mg) and 2-chloropyridine (90 mg) were heated at 1600C for 2 10 hours. 2-Chloropyridine (0.2 ml) was added and the mixture was again heated at 1600C for 4 hours. The cooled crude mixture was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (3N in methanol)). This resulted in the product with the molecular weight of 393.54(C23H31 N50); MS (ESI): 394 (M+H+). 15 The following examples were prepared analogously.
204 Ex. Structure Molecular formula Mole- M+H+ No. cular weight 321 c / \ 4' C25H32CIN503 486.02 486
NO
2 / N 322 F / \ N C24H30FN503 469.56 470
NO
2 / N Example 323 5 5'-Chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid [4-(3 dimethylamino- pyrrolidin-1-yl)phenyl]amid 0 /1 N NN N NN Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 yl)phenyl]amide (30 mg), 2,5-dichloropyridine (30 mg) and tributylamine 10 (0.2 ml) were heated at 1600C for 2 hours. The cooled crude mixture was washed with heptane and purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (3N in methanol)). This resulted in the product with the molecular weight of 427.98 (C23H30CIN50); MS (ESI): 428 (M+H+). 15 Example 324 1 -(4-Chloro-2-cyanophenyl)piperidine-4-carboxylic acid [4-(3 dimethylaminopyrrolidin-1 - yl)phenyl]amide 205 0 N CI- N N N Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 yl)phenyl]amide was reacted with 2,5-dichlorobenzonitrile as described in example 323. This resulted in the product with the molecular weight of 5 452.00 (C25H30CIN50); MS (ESI): 452 (M+H+). Example 325 1-(2-Acetylamino-4-chlorophenyl)piperidine-4-carboxylic acid [4-(3 10 dimethylamino- pyrrolidin-1 -yl)phenyl]methylamide C1 / N NN NN /NN o=K Palladium on carbon (10%; 10 mg) was added to a solution of 1-(4-chloro 2-nitro-phenyl)piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 yl)phenyl]methylamide (50 mg) in glacial acetic acid (5 ml). The solution 15 was stirred under a hydrogen atmosphere (1 bar), and acetic anhydride (14 pl) was added. After one hour, further acetic anhydride (6 pl) were added and the mixture was stirred for 15 minutes. The suspension was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica gel, eluent: ethyl acetate/ammonia (7N in 20 methanol)). This resulted in the product with the molecular weight of 498.07 (C27H36CIN502); MS (ESI): 498 (M+H+). The following examples were prepared analogously. Ex. Structure Molecular Mole- M+H+ No. formula cular weight 206 326 F N N NaN C27H36FN502 481.62 482 N4 327 0 C26H34CIN502 484.05 484 N 328 F N C26H34FN503 467.59 468 NI o= Example 329 (R)-N-[4-(3-Dimethylaminopyrrolidin-1 -yl)phenyl]-2-(4-phenylpiperidin-1 5 yl)acetamide N N N Cesium carbonate (100 mg) and 4-phenylpiperidine (48 mg) were added to a solution of (R)-2-chloro-N-[4-(3-dimethylaminopyrrolidin-1 yl)phenyl]acetamide (80 mg) in acetonitrile (5 ml) and DMF (1 ml), and the 10 mixture was kept at 650C for 12 hours. The mixture was freed of volatile fractions and the residue was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). This resulted in the product with the 15 molecular weight of 406.58 (C25H34N40); MS (ESI): 407 (M+H+). It is alternatively possible to use potassium carbonate or pyridine as auxiliary bases, to add potassium iodide as catalyst, or to carry out the reaction at 1500C in a microwave apparatus. 20 207 (R)-2-Chloro-N-[4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]acetamide Triethylamine (2.03 g) was added to a solution of (R)- [1 -(4 aminophenyl)pyrrolidin-3-yl]-dimethylamine (3.15 g) in dichloromethane (120 ml), and then chloroacetyl chloride (2.26 g) was added dropwise. After 5 3 hours, the mixture was diluted with dichloromethane and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). This resulted in the product with the molecular weight of 281.79 (Cl 4H20CIN30); MS (ESI): 282 (M+H+). 10 The following were obtained analogously: N-{4-[3-(Acetylmethylamino)pyrrolidin-1 -yl]phenyl}-2-chloroacetamide 2-Chloro-N-[4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]acetamide (R)-2-Chloro-N-[6-(3-dimethylaminopyrrolidin-1 -yl)pyridin-3-yl]acetamide 15 The following examples were prepared in analogy to the method given in example 329: Ex. Structure Molecular formula Mole- M+H+ No. cular weight 330 0 N NhN C25H34N40 406.58 407 331 43 03 C26H34N402 434.59 4 332 ci C26H33CIN402 469.03 469 N~ N.J N 333 C27H30N403 458.57 459 ON N N
N
208 334NN C25H29N502 431.54 432 N N 335 N C25H28CIN502 465.99 466 CI'a j) N YNN 336 N N C26H33N503 463.59 464 N N 0T 0 337 N N rN C25H33CIN40 441.02 441 338 N C25H34N402 422.58 423 N NN 339 C24H33N502 423.56 424 N N\ Example 340 (R)-4-Benzylpiperidine-1 -carboxylic acid [6-(3-dimethylaminopyrrolidin-1 5 yl)pyridin-3-yl]-amide N0 N3 N/ (R)-6-(3-Dimethylaminopyrrolidin-1 -yl)pyridin-3-ylamine was added to a solution of carbonyldiimidazole (53 mg) in DMF (0.5 ml) at 0*C. After 15 minutes, 4-benzylpiperidine (57 mg) was added and the mixture was 10 heated at 90 0 C for one hour. The cooled mixture was freed of volatile fractions. The residue was purified by chromatography (silica gel, eluent: methanol/dichloromethane). This resulted in the product with the molecular weight of 407.56 (C24H33N50); MS (ESI): 408 (M+H+).
209 The following examples were prepared analogously: Ex. Structure Molecular formula Molecu M+H+ No. lar weight 341 C24H31N502 421.55 422 NY N J 0 342 N2N C24H33N50 407.56 408 34-N C26H34N403 450.59 451 N 0 34-N C25H31 CIN402 455.00 455 2N N C' N 0 345 N NC NC26H30N40 414.56 415 346 N2N C24H39N50 413.61 414 N' N 347 C26H37N50 435.62 436 5 Example 348 (R)-4-Cyclopropylmethoxy-N-[4-(3-dimethylaminopyrrolidin-1 -yl)-3 fluorophenyl]- benzamide 210 (R)-4-Benzyloxy-N-[4-(3-dimethylaminopyrrolidin-1 -yl)-3 fluorophenyl]benzamide underwent debenzylating hydrogenation by method B. The resulting (R)-N-[4-(3-dimethylaminopyrrolidin-1 -yl)-3 5 fluorophenyl]-4-hydroxybenzamide was alkylated with cyclopropylmethyl bromide by method H. This resulted in the product with the molecular weight of 397.50 (C23H28N302); MS (ESI): 398 (M+H+). The following examples were likewise obtained by method H: Ex. Structure Molecular formula Mole- M+H+ No. cular weight 349 N NC26H34FN302 439.5844 N F 3510 C24H30FN302 411.52 412 CO 10 Example 352 (R)-N-[4-(3-Dimethylaminopyrrolidin-1 -yl)-3-fluorophenyl]-4-(pyridin-2 yloxy)benzamide 211 N N F Nj0 I (R)-N-[4-(3-Dimethylaminopyrrolidin-1 -yl)-3-fluorophenyl]-4 hydroxybenzamide was reacted with 2-chloropyridine by method R. This resulted in the product with the molecular weight of 434.52 (C25H27N402); 5 MS (ESI): 435 (M+H+). Example 353 - example 507 Various pyrrolidinylanilines were reacted with diverse amines by method A. 10 The resulting products are summarized in table 6. Example 508 - example 1130 Various pyrrolidinylanilires were reacted with diverse acids by methods E. The resulting products ure summarized in table 7. 15 Example 1131 - example 1232 Various (hetero)aryl habides were reacted with diverse boronic acids by methods 0. The resulting products are summarized in table 8. 20 Example 1233 - example 1237 Various aryl halides were reacted with diverse acetylenes by methods J. The resulting products are summarized in table 9. Example 1238 - example 1403 25 Various aminopyrrolidines and N-arylpyrrolidinones were reacted with diverse aldehydes, ketones and amines by method N. The resulting products are summarized in table 10. Example 1404 - example 1423 30 Various aminopyrrolidines were reductively methylated with formaldehyde by method E. The resulting products are summarized in table 11.
212 Example 1424 - example 1443 Various amides were alkylated by method F. The resulting products are summarized in table 12. 5 Example 1444 - example 1618 Various tert-butyl carbamates were cleaved by method G. The resulting products were summarized in table 13. Table 6 10 Ex. Structure Molecular formula Monoisotopic M+H + No. molecular wt. 353 C25H31FN402 438.24 439 354 C25H30N404 450.23 451 CoUDON N N't N 355 C25H31CIN403 470.21 471 clN N N O 356 ... C26H30N402 430.24 431 NO, N 357 N. C24H29CIN40 424.20 425 358 C25H35N50 421.28 422 N\, NNN 359 N. C23H3OBrN50 471.16 472 Br- Nr N N N 360 o Nry'T& C24H34N40 394.27 395 31 Q N N N4.4 361 N N Nr- - N C26H28N403 444.22 445 213 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 362 N C24H29N50 403.24 404 0 r2 NAN N) 363 N N, C27H29N50S 471.21 472 S '-N N N 364 C26H30N402 430.24 431 365 o' N- C25H30N603 462.24 463 0 ' N N 366 N- C22H25N502 391.20 392 N N 367 N IfO C26H28N60 440.23 441 N N
N
368 N, C24H29FN40 408.23 409 369 N- C26H30N403 446.23 447 OoN N N 370 N N' C25H27CIN402 450.18 451 371 N' C25H27FN402 434.21 435 F a 'N N N'C 372 N- C26H30N402 430.24 431 'CrocaN 0NcrN 373 N- C26H30N402 430.24 431 &Oo N N rN _ 214 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 374 N- C26H30N403 446.23 447 o~o~crN Uq'O'O N 0N-O 375 ci -N C25H27CIN402 450.18 451 ON 376 N- C23H32N402 396.25 397 ,IO N Nr 377 N- C25H29N502 431.23 432 O' ' N 0Na 378 N- C24H27N502 417.22 418 N o N Nr 379 O C25H35N502 437.28 438 (NT'ON ONNN 380 FN C25H27FN402 434.21 435 381 F FN' C26H27F3N402 484.21 485 F 4aoO N N N'C 382 F C26H27F3N40 468.21 469 F N N 383 N C24H31CIN402 442.21 443 cl N N ''N 384 N- C25H28N40 400.23 401 N ANa 385 C26H30N402 430.24 431 _0NAN 0 215 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 386 N- C23H32N402 396.25 397 NNb 387 N C25H34N402 422.27 423 NN N 388 N, C24H31CIN40 426.22 427 389 N C25H34N40 406.27 407 N Nr 390 N.. C25H31F3N40 460.24 461 F 391 C25H31F3N402 476.24 477 F F O O 392 0 r~ , C23H31N504 441.24 442 0 N NN 393 C24H30N403 422.23 423 394 Nr C24H32CIN50 441.23 442 395 c' NNrN N C25H27CIN40 434.19 435 396 \N- C25H28N40 400.23 401 crlQNN _ N_ _ _ 216 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 397 'N- C24H28N60 416.23 417 SN N0 398 L C25H34N402 422.27 423 N Nr 399 N. C28H34N40 442.27 443 400 0Q C25H27N503 445.21 446 N N 401 , C25H27ClN40 434.19 435 N NN 402 . C24H31 CIN402 442.21 443 c ~ r 403 N- C24H33N50 407.27 408 N N N 404 N- C22H30N402 382.24 383 405 N- C25H34N40 406.27 407 o NQN 406 F F C NrN' C22H22Cl2F6N402 558.10 559 FF CI N N N 407 OaO0 N 2 N' C26H27F3N402 484.21 485 F O N AN F F 408 . C24H31FN40 410.25 411 F0 NrN3 217 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 409 N C24H31FN40 410.25 411 F N N r 410 N.. C24H31FN40 410.25 411 410N N N2H1F 411 N. C25H34N40 406.27 407 412 .. C25H34N40 406.27 407 N4 NGN3 413 N C24H32N402 408.25 409 __ 0 414 N-( C22H26N60 390.22 391 415 Brc N NN r/ C26H27BrN40 490.14 491 416 N0-( C21H24N60S 408.17 409 NJ N 417 N O C26H27N50 425.22 426 418 N C24H32N40 392.26 393 NrO- N-G N) 419 O QN' C25H27CIN402 450.18 451 420 'N- C24H30N403 422.23 423 IOOaN N N'C 218 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 421 O N C24H29CIN402 440.20 441 01 N N O 42 C26H31CIN402 466.21 467 O NQ N N 423 H)H C28H35CIN40 478.25 479 N N0N 2N 424 g C28H38N404 494.29 495 Cr'ON N N'O)= 425 H.. C24H31CIN402 442.21 443 -CN N' HO 426 C25H33CIN402 456.23 457 427 N- C25H28N403 432.22 433 kl- O N N N O 428 C25H29FN402 436.23 437 429 C24H30BrN502 499.16 500 Br-O N N N 430 C25H29CIN402 452.20 453 CIr~ 0 431 C25H32N403 436.25 437 __ 04-N,
_
219 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 432 N C24H32BrN502 501.17 502 433 .. C22H30N60 394.25 395 43 N C22N -ON N 434 N. C24H30F3N50 461.24 462 F F 0O N, FNN N N 435 N. C21H29N70 395.24 396 N rNk N 436 .C23H31N50 393.25 394 _N N 437 N. C22H30N60 394.25 395 N N NNN N 438 N. C21H29N70 395.24 396 N N rN N) 439 N. C23H30CIN50 427.21 428 N NN 440 . C23H30CIN50 427.21 428 441 N. C23H30CIN50 427.21 428 ci442 N24 442 N.. C23H30FN50 411.24 412 &ryN NaN3 220 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 443 N- C23H30FN50 411.24 412 F N N N, 444 N.. C24H33N50 407.27 408 F N_ N Nr 445 N- C24H33N50 407.27 408 N, N N~ N 446 N- C24H33N50 407.27 408 N, N N_ N 447 N- C24H33N50 407.27 408 N- Y N N) 448 F N- C24H30F3N50 461.24 462 N-4 N) 449 N-.. C24H30F3N50 461.24 462 0 F 450 N- C24H30N60 418.25 419 N NaN3 N 451 N- C24H33N502 423.26 424 N Nr 0 452 N- C24H33N502 423.26 424 0 221 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 453 N. C24H33N502 423.26 424 rNA N \ N, 454 N. C25H33N502 435.26 436 00 455 N C24H29C1F3N50 495.20 496 N-' N N N F 456 ci C24H32CIN50 441.23 442 0\Nj NNN 457 N C25H35N50 421.28 422 N N N 458 N C23H29Cl2N50 461.17 462 Ci__QN N orNr CI 459 F N- C23H29F3N60 462.24 463 N N NN 460 . C23H29F3N60 462.24 463 FN N ND F 461 N.. C23H28CIF3N60 496.20 497 F N rNN N F CI 462 . C25H35N502 437.28 438 \N- N r 222 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 463 .. C23H29Cl2N50 461.17 462 464 N C25H35N50 421.28 422 \N ND 465 N C23H29Cl2N50 461.17 462 CN N- N N Ci 466 N C25H35N503 453.27 454 rN N N) 467N. C24H32CIN502 457.22 458 Cir N N N N 0 468 N C23H38N60 414.31 415 ..- N N N s N 469 N. C23H29F2N50 429.23 430 F N, NA NCNr 470 . C24H30N60 418.25 419 471 N. C25H35N50 421.28 422 N N N 472 N. C23H37N50 399.30 400 _Q N N
N
223 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 473 .... C23H32N60 408.26 409 R-N N 474 N C23H32N60 408.26 409 rO-YN N N 475 C26H37N50 435.30 436 6N.N N 476 N C28H36CIN502 509.26 510
CIQ
0 r_ __ __0_ _ 477 N N C25H34N40 406.27 407 478 F C25H31FN402 438.24 439 0_NA N N 0 479 'N C23H27CIFN50 443.96 444 F_ N 480 F N N N C23H30FN502 427.53 428 0 FrN 481 F NN N'N C23H29F2N502 445.52 446 '0 F 482 F N N "rNKI, C23H27F2N50 427.50 428 CI N 483 N N N C23H29CIFN502 461.97 462 0 F 484 0N)_g C28H37FN404 512.28 513 F Nh_________ 224 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 485 NO O C28H32FN504 521.24 522 QN N N O4 F 486 N N \N / C23H30CIN502 443.98 444 0 487 Cr N'( N NYN C23H29CIFN502 461.97 462 0 488 . C26H34N402 434.27 435 NN N 489 C30H36N40 468.29 469 I N- NGN) 490 N C26H34N403 450.26 451 O N-N N) 0 491 N- C25H32N402 420.25 421 492 C26H34N403 450.26 451 & NA NaN3 493 C25H30N403 434.23 435 O NN N 494 . C26H35N502 449.28 450 rN NrO- N-C N' 495 ... C25H30FN502 451.24 452 0-N 225 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 496 N. C25H31N50S 449.23 450 S q NrN 497 N. C26H33N50 431.27 432 __~ ~ f3NQN __ _ N NI 498 N C27H35N50 445.28 446 NONN 499 F F . C25H31 F3N402 476.24 477 F 0 Nr N 500 N C26H35N503S 497.25 498 N4 NCNj 501 N C25H31N503 449.24 450 Nc NN 0 502 C23H29CIN40 412.20 413 50 N N21-2CN4 503 CN- 23H29FN40 396.23 397 504 N- C25H31N50 417.25 418 N Nr 505 N - C24H30N603 450.24 451 N N 0 506 N. C24H31FN402 426.24 427 F N0 226 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 507 N.. C25H31FN40 422.25 423 Table 7 5 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 508 N N C26H33N302 419.26 420 509 C26H34N402 434.27 435 N N N QCN-Q N-Or 510 C26H27N302 413.21 414 N N 0 511 C30H35N302 469.27 470 512 C27H29N302 427.23 428 N N 513 C27H28N406S 536.17 537 51 N N 514 C25H33N303 423.25 424 o _N r N 227 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 515 C24H29N303 407.22 408 o N0 516 C25H33N303 423.25 424 517 C27H29N303 443.22 444 518 C27H29N302 427.23 428 -0-0 N N-G 519 C27H29N302 427.23 428 b-I~N N 520 C27H29N302 427.23 428 N N 521 F C27H26F3N302 481.20 482 522 C27H26F3N302 481.20 482 F N 523 C28H31N304 473.23 474 N N 524 C27H28N404S 504.18 505 S N0 0*'b 525 c C26H25CIFN303 481.16 482 F- O N 0 228 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 526 C24H25N303 403.19 404 N N 527 0 N O C24H25N302S 419.17 420 WN N 528 0 N O C25H28N402 416.22 417 N 529 c C24H24CIN303 437.15 438 530 C24H24FN303 421.18 422 FO N, 531 N- C25H33N30 391.26 392 N N Q-O-N-Oa__ __ ____ 532 N. C25H27N302 401.21 402 533 ... C25H27N30 385.21 386 N-ON 534 N- C23H31N302 381.24 382 O Nr 535 N- C26H29N302 415.23 416 536 N- C25H27N30 385.21 386 N N 537 N... C24H31N30 377.25 378 No 229 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 538 - .. C25H26N404 446.20 447 N-- N-C 0 539 N- C26H29N30 399.23 400 540 N C26H29N302 415.23 416 Cr'C NJ N 541 ,28H33N302 443.26 444 542 N 542 0 N C25H29N504 463.22 464 543 N- C23H31N302 381.24 382 N N 544 N. C25H27N302 401.21 402 545 N. C25H31N302 405.24 406 O0
N
546 N C27H31N30 413.25 414 N ND 547 N. C28H33N30 427.26 428 N ND 548 F... C21H22FN502 395.18 396 F N N 549 N. C25H25N302 399.20 400 0 N r 230 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 550 '... C29H35N30 441.28 442 N- N 551 C23H23CIN404 454.14 455 ci Nr N 552 F C25H26FN302 419.20 420 553 N- C26H29N30 399.23 400 oN 554 C27H29N302 427.23 428 555 N D C28H38N403 478.29 479 N N' O 556 C25H26FN30 403.21 404 FN N% 557 C23H24FN30S 409.16 410 558 C26H26F3N302 469.20 470 0 0 F 559 C29H34N402 470.27 471 O N
N
O- NOGr 560 C25H26N404 446.20 447 O N Nr,
ON
231 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 561 'N- C24H33N302 395.26 396 O N _N 562 .. C24H33N302 395.26 396 563 N. C25H26FN30 403.21 404 F N- -N 564 N- C26H29N302 415.23 416 NN 565 N-. C25H26CIN30 419.18 420 CI N 566 N- C26H29N302 415.23 416 567 N. C26H29N302 415.23 416 568 N, C25H26FN30 403.21 404 F N N 569 N. C26H27N303 429.20 430 O-QN N O 570 N- C26H29N30 399.23 400 5 7N 571 ... C26H29N30 399.23 400 No 232 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 572 N.. C26H26F3N30 453.20 454 573 N- C26H26F3N30 453.20 454 574 N C26H35N302 421.27 422 O Nr 575 N. C27H31N302 429.24 430 N N 576 N- C25H26CIN30 419.18 420 577 N- C25H25C12N30 453.14 454 Ci 578 N. C24H28N402 404.22 405 N N 579 N.. C27H31N303S 477.21 478 AN Nr 580 0 C25H31N503 449.24 450 581 N- C24H31N302 393.24 394 8 2N3 582 ... C23H-31N302 381.24 382 O Nr 233 ______ Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 583 FF C25H25F3N402 470.19 471 F N N N 584 N.-. C24H39N30 385.31 386 H N 585 N- C25H25Cl2N30 453.14 454 o Nr Ci 586 N- C25H26BrN30 463.13 464 Br N N 587 N- C25H32CIN30 425.22 426 e NN 588 N-&; Na o C25H32N402 420.25 421 589 C24H26N404 434.20 435 NO N 590 0 N C24H30FN302 411.23 412 59 N.qC2H8N0 47241 F 591 F N N C26H28FN30 417.22 418 592 C.... C25H25N502 427.20 428 N N NN4 593 0N... C26H26N40 410.21 1411 N 0 -AN-O
N
234 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 594 F N. C26H32FN302 437.25 438 O N N 595 N-. C25H26CIN30 419.18 420 596 N. C24H26N40 386.21 387 N ND 597 N. C26H26F3N30 453.20 454 F 598 N. C27H31N303 445.24 446 N-G N3 599 0 0ON ' C28H29N303 455.22 456 C~ N O 600 N C24H33N302 395.26 396 601 N- C25H27N30 385.21 386 oN 602 N. C28H30N402 454.24 455 N N 603 o C26H36N404 468.27 469 0 N N H O 604 C28H38N403 478.29 479 N N H 00 \J? 605 .. N- C22H28FN302S 417.55 418
F
235 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 606 0 C23H29N303 395.22 396 607 >N N C27H33N303 447.25 448 608 N N N, C27H37N304 467.28 468 _ O O 609 0 - N' C29H39N303 477.30 478 610 F N N NyO C27H29FN403 476.22 477 611 N N O C25H34N404 454.26 455 612 N H C27H35N302 433.27 434 613 N N H C25H31N303 421.24 422 00 614 N C28H32N404 488.24 489 0 ~~ .x6 0 _ 615 c N NyO C27H35CIN403 498.24 499 616 N N C26H29N504 475.22 476 617 NO C28H36F3N304 535.27 536 617 007K O N r-ArN O7( FF F 618 N 0N C27H38N404 482.29 483 -a , N 236 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 619 N C27H38N404 482.29 483 ON NAO 620 0 C28H39N305 497.29 498 0 N o 621 QN N NO C23H23N503 417.18 418 622 C25H26N402 414.21 415 623 C28H35CIN404 526.23 527 0 N O CI N 624 0 C28H39N304 481.29 482 O0 N O 07 625 c O C27H36CIN304 501.24 502 O N i N O O-C 4N_& N 07( -I-i 626 F C27H35F2N304 503.26 504 O N N 07 F 627 F C27H36FN304 485.27 486 0 N NO 628 F 0 C27H36FN304 485.27 486 ON N
O
237 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 629 O C28H39N304 481.29 482 O0 N-O N_.qN 07( 630 0 C28H36F3N304 535.27 536 0N 0 F F F 631 0v C27H3501FN304 519.23 520 632 % C28H36N404 492.27 493 0 Q _?NQZ2: 0-/, N N 633 N C28H38CIN304 515.26 516 ci 634 0 C31H39N304 517.29 518 O C N N 635 C27H36BrN304 545.19 546 O0 N-O OC ANQrN 07<( Br 636 0 C28H36N404 492.27 493 0 N-O N 637 I O C26H35CIN404 502.23 503 O N Na 638 0 C27H35F2N304 503.26 504 O0 N-O F 0 F
F
238 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 639 Br 0 C27H36BrN304 545.19 546 NN 07( 640 F 0 C27H35F2N304 503.26 504 O ON AN O f F 641 C23H31N303 397.24 398 O N NO 642 H....C24H33N303 411.25 412 O NN HO 643 N O 027H37N305 483.27 484 N N 0 644 N O C25H34N404 454.26 455 645 F 0 C27H36FN304 485.27 486 0 07 O_ N_& N O 646 C27H24FN303 457.18 458 647 N C27H33N302 431.26 432 648 N C23H31N303 397.24 398 OF N N4 649 F L .. C5H4N0 417.18 418 N~a
,
239 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 650 N 4N9N C27H36N403 464.28 465 651 C25H26N402 414.21 415 652 C31H33FN403 528.25 529 F N~N 65 0 Nr~' 653 ) N C32H38N402 510.30 511 654 GN NrjH C28H38N402 462.30 463 N,
N
655 0 N, C29H34N402 470.27 471 656 C26H26CIN302 447.17 448 657 0 N0 N 658 C27H29N303 443.22 444 N N 659 0 C24H29N504 451.22 452 0107 N N 660 N, C25H33N302 407.26 408 661 N 0 C25H30N403S2 498.18 499 s oN 240 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 662 F 0C28H29FN403 488.22 489 NN 663 ( C31H44N402 504.35 505 N-a N 0N 664 ( C32H40N402 512.32 513 N N 0 N 665 0 C25H30N603 462.24 463 N-NN 666 0 C25H30N603 462.24 463 N N N-N NjN' 7 667 N-1 C30H33N504 527.25 528 0 a-NN N-aN, 668 0 C27H27N304 457.20 458 N 0 669 0 C26H31N503 461.24 462 N-N N 670 C21H27N304 385.20 386 0N N 671 \0 C25H30N603 462.24 463 NN QN 07K N N 672 \..'N C31H35FN403 530.27 531
NN
_____241 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 673 C26H32N603 476.25 477 N N< O 674 %00 C27H42FN304 491.32 492 o N ,; N O-/ 675 .. C25H32N40 404.26 405 NYN 676 N. C27H30N402 442.24 443 0 rN NIN 677 N.... C29H34N402 470.27 471 678 0 N C26H28FN30 417.22 418 679 N- C25H32FN302 425.55 426 F 680 N- C23H30N402 394.24 395 N Nr 681 N- C25H32N402 420.25 421 N-4 N- N, 682 0 C24H30N402 406.24 407 N- N 683 N. C26H28N402 428.22 429 N N0 684 N' O C23H28N402 392.22 393 0_ N-Q-Na 242 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 685 N C26H34N402 434.27 435 N N0 686 N 0N N C24H27N503 433.21 434 687 N- C24H32N402 408.25 409 N NON 688 N. C22H30N402 382.24 383 O N N 689 N. C24H33N50 407.27 408 N N N 690 .. C25H28N402 416.22 417 N N N 691 N. C24H26N40 386.21 387 N N 692 C22H24N40S 392.17 393 N N 693 C21H24N40S 380.17 381 N N 694 C19H21N30S2 371.11 372 SN N 695 N. C23H24CIN302 409.16 410 SC1N___ 243 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 696 C22H24CIN30S 413.13 414 697 C21H21CIFN30S 417.11 418 F /C N-CN) 698 C21 H21 Cl2N30S 433.08 434 699 N. C21H21CIN403S 444.10 445 N ND 700 N. C22H23Cl2N302 463.09 464 cl O O N N S CI 701 C22H24CIN302S 429.13 430 0 702 cC23H26CIN30S 427.15 428 P NaN 703 C24H26CIN302S 455.14 456 704 ... C22H24F3N50S 463.17 464 F N 705 F C24H23CIF3N30 477.14 478
N
o, 0 2 C\/ _o \) F 706 F F C24H24F3N302 443.18 444 O N NCrN 244 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 707 N- C23H28BrN502 485.14 486 Br NN 708 F - C24H25F3N402S 490.17 491 S,,,p N N 709 C22H22N40S 390.15 391 710 N- C23H25N302 375.20 376 o 711 N. C24H27N302S 421.18 422 N N 0 712 ci N- C24H26CIN303 439.17 440 o N N 713 N- C21H22CIN30S 399.12 400 c No C, 714 F F F C25H23F6N302 511.17 512
N
FF Nx 715 N- C23H30FN302 399.51 400 o N F 716 N o C26H34FN304 471.25 472 717 N- C26H29N302 415.23 416 O WNN 245 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 718 N- C27H31N302 429.24 430 o N'N ouo 0 N N_ _ 720 C25H28N404 448.21 449 NNN 721 'O C24H33N302 395.26 396 / N- N 722 F C26H28FN302 433.22 434 O N N 723 N- C26H27N302 413.21 414 o N N 724 N C25H33N302 407.26 408 725 .. C26H28BrN30 477.14 478 Br N N 726 C24H26FN30S 423.18 424 727 N- C26H28FN30 417.22 418 7 2N 728 N... C27H31N302 429.24 430 N
N
246 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 729 '... C26H28CIN30 433.19 434 730 N-. C26H28CIN30 433.19 434 ei N N 731 N-. C26H28CIN30 433.19 .434 Nay N 732 C24H25CIN404 468.16 469 733 N-. C26H28FN30 417.22 418 F o N 734 N-. C27H29N303 443.22 444 ( NGN 735 N-. C27H31N30 413.25 414 736 N-. C27H31N30 413.25 414 N N 737 C26H26FN302 431.20 432 N N 738 N-. C27H29N302 427.23 428 N-N 0 739 N.. C25H35N302 409.27 410 0 N N 247 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 740 N C26H34CIN30 439.24 440 ci NN 741 ,TN'\ N .
C32H36N603 552.28 553 -N O A o 742 C26H36FN302 411.59 412 743 N.. C25H32N402 420.25 421 o-N 744 N- C24H 30N402 406.24 407 o-N 745 N-. C26H:28N402 428.22 429 O Nr 746 N-. C27H30N402 442.24 443 o Nr -N 747 N-. C24H32N402 408.25 409 N N 748 kNO PON' C24H30N402 406.24 407 749 C24H32N402 408.25 409 NN N o rN 0 750 N- C25H32N402 420.25 421 __ 0 ___o 248 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 751 N- C24H30N402 406.24 407 N 752 N.. C25H34N402 422.27 423 0 753 N N2 C22H30N402 382.24 383 754 C \ C27H35FN406 530.25 531 O drN N I F 755 N- C24H32N402 408.25 409 N Nr 756 N- C26H27FN402 446.21 447 757 N- C25H34N402 422.27 423 OQ N 758 N.-. C24H32N402 408.25 409 0 759 N- C24H26N403 418.20 419 0N- N-aNr ON&NO 760 N- C24H30N402 406.24 407 761 N. C26H32N402 432.25 433 N N N3 249 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 762 N. C26H34N402 434.27 435 763 N. C26H34N403 450.26 451 _O N N 764 N. C25H31 CIN402 454.21 455 N NON C O C1 765 N. C24H30N402 406.24 407 N N0 766 N. C25H34N402 422.27 423 N Nr 767 N- C24H26N402S 434.18 435 768 N. C26H34N402 434.27 435 o&r 769 N- C23H30CIN302 415.20 416 o Nr 770 N- C24H32FN302 413.25 414 F 771 N- C23H28FN302 397.22 398
F
250 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 772 .. C24H30FN302 411.23 412 o NrN 773 N... C24H30FN302 411.23 412 F 774 .. C25H33FN402 440.26 441 -- N O N-N F 775 N. C26H33FN403 468.25 469 F 776 N... C23H26N40 374.21 375 777 N... C28H30N40 438.24 439 778 NC 21 H25N502 379.20 380 N) N 779 N-. C26H27N302 413.21 414 oNiN 780 C26H26N40 410.21 411 0 781 N. C25H31N50 417.25 418 NN
N-
251 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 782 N-. C21H24N60S 408.17 409 N oNCN) N 783 N- C22H25N50 375.21 376 N Nf N= 784 N- C24H28F3N50 459.23 460 N N N) F N F F 785 .. C25H30N60 430.25 431 N NN NQ 786 N...C26H32N60 444.26 445 787 C25H27N30S 417.19 418 S0 N N 788 N. C30HZ14N40 466.27 467 N N 789 N. C24H30N40S 422.21 423 790 0 C24H26CIN303S 503.11 504 CV&6 N-N3yN 2 791 c' c C23H23C12N303 459.11 460 PcI 0N - N- 252 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 792 .. C24H26CIN302 423.17 424 CI 793 N. C23H26N40S 406.18 407 N N 794 N- C25H27N303S 449.18 450 o Nr 795 N- C23H25CIN40S 440.14 441 796 N- C23H25N303 391.19 392 797 F C23H23F3N402 444.18 445 O -N 798 N- C23H28N403 408.22 409 N0 N 799 C25H30N40 402.24 403 NN 800 d C26H29N302 415.23 416 N N 801 N- C27H29N50 439.24 440 NN 1> 802 O C22H24F3N302 419.18 420 O F F F 253 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 803 N. C22H25N303 379.19 380 804 N- C22H24N40 360.20 361 No 805 0 N C22H23F4N30 421.18 422 I NJ F F F 806 N. C23H29N302 379.23 380 N N 807 C26H29N302 415.23 416 N N 808 / F C27H30FN30 431.24 432 N N 809 N- C22H23F3N402 432.18 433 FON Nr F 810 N- C25H25N302 399.20 400 0NGNr, 811 %N- C25H28N40 400.23 401 N- N ,J 812 N _rN C21H24F3N303 423.18 424 F O- r FF F 813 N. C22H30N40 366.24 367
NN
254 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 814 N. C24H31FN402 426.24 427 N O N N r, F 815 . C25H31FN403 454.24 455 F 816 C25H30FN302 423.23 424 FN 817 N- C23H30N40 378.24 379 818 N. C24H27N304 421.20 422 0 819 F H 1-t 0 C30H34FN304 519.25 520 N N O / N07& 0_O 820 F H 1 0 C30H34FN304 519.25 520 821 F H0 C29H34FN304S 539.22 540 N N O 822 F H O C29H38FN303 495.29 496 823 F H 0 C30H40FN303 509.30 510 N0N 7 255 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 824 F C31H35F2N303 535.27 536 - '0 F HN-{ - (S': 07 825 N N'OO O C28H38FN304 499.29 500 826 F H 0 C30H39CIFN303 543.27 544 CI N N 07K 827 O F C29H33CIFN305 557.21 558 r, 0 N. N . 828 F H C29H38FN304 511.29 512 829 Q0 C29H33FN406 552.24 553 rKt N j F 07K N_&N 830 F H 0 C28H38FN304 499.29 500 0 N N 07 831 F CO C30H34FN303 503.26 504 ' 07( 832 C31H36FN304 533.27 534 N_& N O-/ 833 F C33H37FN404 572.28 573 O N N-O 834 F H--t C31H36FN303 517.27 518 N 5N O5 835 F N C29H40FN304 513.30 514 O N N Y 256 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 836 F H0 C30H33F2N303 521.25 522 F \N O 0/ 837 N. C25H32N402 420.25 421 0 NrNON 6 838 N-. C23H30N402S 426.21 427 o N N 6N 839 N-. C23H30N403 410.23 411 0 Nr N'N 0 840 N-. C25H36N402 424.28 425 N0 NN 841 .. C24H36N402 412.28 413 o 0 N5 Nr 842 N. C23H34N402 398.27 399 0 N NrD N 843 N.... C23H34N402 398.27 399 0 844 F eC25H31FN402 438.24 439 C N, N-C N O 845 N-. C26H34N402 434.27 435 0 N§YNON 257 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 846 ci N.. C25H31 CIN402 454.21 455 zeN,_ N N 0 847 N- C23H36N402 400.28 401 0 848 N- C23H36N402 400.28 401 o N 3 "No 849 . C26H25N304S 475.16 476 '0 N 0 850 0 N- C21H23N30 333.18 334 851 N- C22H25N50 375.21 376 CN- /N 'N' 852 N- C21H23N50S 393.16 394 N N 853 NN - C20H22N60S 394.16 395 s N N 854 C20H25N50S 383.18 384 N N 855 N- C23H29N504 439.22 440 856 r N 856N \- .. C25H32N403S 468.22 469 258 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 857 N. C22H30N4OS2 430.19 431 S N N 858 N- C24H31 BrN40S 502.14 503 S N Nr, Br 859 C24H24FN303 421.18 422 F 0 0,~.y§ 860 N- C28H27CIN40 470.19 471 Cj 861 N. C23H31 N50S 425.23 426 N yN Nr 862 C22H30N405S 462.19 463 2) Nt r'N N N, 863 N C23H32N404S 460.21 461 o) NN 864 C27H29N50 439.24 440 0 rNN 865 N-. C22H25N502 391.20 392 N 866 N- C26H29N304S 479.19 480 0 o NQ oso 259 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. F 867 FF NF C23H23F3N40S 460.15 461 NN s 868 N. C22H29N702 423.24 424 N N N 0 869 .. C25H26N60 426.22 427 N
N
870 N- C26H32N402 432.25 433 N N 0 871 C24H27N302 389.21 390 N
N
872 N- C27H29N50 439.24 440 N _ Nr, 873 ... C23H28N403S 440.19 441 874 N- C28H34N40S 474.24 475 N N 875 . C24H28N403S 452.19 453 N N N 876 N C23H23CIN403 438.15 439 c 1 N 0 877 N. C23H26FN50 407.21 408
F
260 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. i 878 N- C25H27CIN402 450.18 451 N4 N, 879 C24H27N50 401.22 402 N- NGN3 880 .. C24H30F3N50 461.24 462 FF- Nj N-ON F 881 N-0 o C22H23CIN402 410.15 411 cNa N, 882 C23H26N403 406.18 407 \ N 883 Q C24H26N40 386.21 387 N N N 884 N\ o C24H26N40 386.21 387 N/N 885 N C24H26N40 386.21 387 886 N C21 H23F3N60S 464.16 465 F NFN 887 N. C23H30N403S 442.20 443 N.N 888 N. C24H26N402 402.21 403 0N N 261 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 889 N. C24H25F3N40S 474.17 475 F-F N0 890 N. C27H29N30 411.23 412 N-GN 891 NDN' C26H29N30 399.23 400 892 0 0 N C28H31N302 441.24 442
N
893 C, C23H28N402 392.22 393 894 N- C27H29N302 427.23 428 N N3 or 0 895 N C21H25N70 391.21 392 fN 896 C21 H28N40S 384.20 385 897 N-N0N 'N-. C23H26CIN50 423.18 424 CI 898 C21 H23N50S 393.16 394 N!/ 0 N,) N NN 899 N- C26H26CIN50 459.18 460 N N N,
CI
262 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 900 C23H27N50 389.22 390 N0 N N-N "N-a' 901 N. C25H34N40 406.27 407 N Nf QGNQCANO __ ____ 902 N. C24H30N402 406.24 407 O N 903 c -. C23H30CIN302 415.20 416 _o -IN, 904 F N. C25H25F2N302 437.19 438 F - N N 905 F O C29H39FN402 494.31 495 N N N 906 F C29H32F2N402 506.25 507 FN N 907 F C30H35FN402 502.27 503 N N: N 908 0C27H37FN403 484.29 485 O N NN 909 F O C27H37FN403 484.29 485 910 F -- C25H34FN303 443.26 444 O NN O-CA 0 _____ 263 ___ Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 911 C24H30Cl2FN30 481.17 482 O 4N_ N 2 C 912 C24H31FN404 458.23 459 F N o~ _& N_ __ __ _ ON 913 C24H31CIFN302 447.21 448 F N C1 914 C26H36FN302 441.28 442 OF N 915 F C25H32Cl2FN30 511.18 512 O N-' N 3 0 916 C24H28F5N302 485.21 486 F F 0 -HN F F 917 F - C24H31F2N302 431.24 432 ON N F 918 F -- C26H34FN303 455.26 456 rO N, N /if'N~ 0 919 C28H40FN303 485.30 486 O0N N 920 0 F --- C25H34FN50 439.27 440 _N--NW&
N
264 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 921 F C23H31FN402 414.24 415 F N 922 F C24H26FN303 423.20 424 O N N 923 F C26H28FN302 433.22 434 O NN 924 F ,N C26H33FN402 452.26 453 N N Nl O 925 C F --- C26H32CIFN402 486.22 487 N\r N N 926 N. C25H31FN402 438.24 439 N- N N NO F 927 N. C26H31 F3N403 504.23 505 r-NS/ N-ON O F F F 928 ... C26H33CIN403 484.22 485 CrN-O N- N) CI 929 N. C25H31CIN402 454.21 455 N00 N N) CI 930 C F -- C24H31CIFN302 447.21 448 O 6-N
N
265 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 931 F C25H34FN302 427.26 428 O\ N 932 F C27H33FN402 464.26 465 N N N 933F C26H28FN302 433.22 434 N N 0 _____ O 934 J NO F C25H28FN302S 453.19 454 935 >< F C25H32FN30 409.25 410 936 C26H34FN30 423.27 424 F N NN 937 F C27H29F2N30 449.23 450
FNN
938 N N C24H32FN302 413.25 414 939 F C26H33CIFN30 457.23 458 940 F C24H32FN302 413.25 414 941N N 941 F --- C26H28FN30 417.22 418 0_,ON
N_&
266 Ex. Structure Molecular formula Monoisotopic M+H + No. molecular wt. 942 F Q N' C27H30FN302 447.23 448 943 C29H31FN402 486.24 487 O N N 944F C27H30FN30 431.24 432 N &N 945 NI C25H34FN302 427.26 428 946 F C26H27F2N30 435.21 436 F N N 947 N- C25H27FN402 434.52 435 N OC N P N 948 C25H27FN404 466.20 467 NoF N-. 949 C24H29FN403 440.22 441 O N-N 950 F C27H30FN302 447.23 448
N
951 F C23H31FN40 398.25 399 N N 952 Nl 0 F C24H26CIFN40S 472.15 473 C N - NdN'_ 953 C25H25F2N303 453.19 454 F N 267 Ex. Structure Molecular formula Monoisotopic M+H + No. molecular wt. 954 C24H27F2N50 439.22 440 hN_& Nr F 955 C26H31F2N302 455.24 456 H o F "N- N 956 N- C23H31N302 381.24 382 0 957 C24H33N302 395.26 396 958 N- C24H33N302 395.26 396 959 N.-. C26H29N302 415.23 416 N N 960 N- C25H-29N502 431.23 432 961 F N- C24H24CIFN403 470.15 471 N N 962 N. C27H36FN302 453.61 454 963 N- C24H30N402 406.24 407 _ N N 268 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 964 0 C24H28N402 404.22 405 NICO N N aN 965 C27H29N50 439.24 440 N N 966 N. C25H28N404S 480.18 481 O Nj o:s.o 967 N- C24H26N402 402.21 403 968 Br ". C27H27BrN402 518.13 519 969 N-N O C22H24CIN50 409.17 410 ciDAt N aN,',~ 970 0 N N C22H23F2N303 415.17 416 FSO F 971 N. C21H23N50S 393.16 394 NN NN 972 N... C23H24CIN30S 425.13 426 /i N 'O r J ' CIN N 973 N- C22H24N403 392.18 393
"NCN,
269__ _ _ _ _ _ _ _ _ Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 974 N- C25H27CIN402 450.18 451 o 975 N- C25H30N40 402.24 403 N Nr 976 N- C22H25N50 375.21 376 N0 N N, 977 0 N'-- C22H27N303S 413.18 414 N 978 r NCN'Y., C20H23F3N40S 424.15 425 F{F S 979 0 C21 H24F3N30S 423.16 424 F 980 F .... C26H24BrF3N60 572.11 573 N N / N Br 981 cN N' C23H25CIN4C0S 440.14 441 982 C24H32N403S 456.22 457 N N 983 N, C24H31CIN403S 490.18 491 0 984 -0 C23H25N304S 439.16 440 N N, _____ ~~~270 _ _ _ _ _ _ _ _ Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 985 N-. C26H32N403 448.25 449 0 986 C26H32N40 416.26 417 N N N N' 987 0 N C22H27N30S 381.19 382 S N 988 N.. C24H31N302 393.24 394 O Nr 989 F N7N C22H24F3N30S 435.16 436 FF F 990 N-. C24H33N30 379.26 380 N ND 991 N. C22H29N302 367.23 368 o N0 992 - C25H35N30 393.28 394
"N
993 0 N N-. - C25H30N40 402.24 403 994 s C22H26N4OS2 426.15 427 N N
N
995 0 C29H32N402 468.25 469 N, 996 0 N N N C23H26FN50 407.21 408 F
_N
271 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 997 C28H28CIN50 485.20 486 e N 0N 998 C20H23N502S 397.16 398 o.N N N S 999 C25H26N60 426.22 427 N 1 N N N 1000 N- C22H24N402 376.19 377 N N 1001 N- C26H35FN402 454.27 455 o o 1002 N- C25H34FN302 427.57 428 o o F F 1003 N- C24H25FN40 404.20 405 N F 1004 N- C25H30N402 418.24 419 N NON Odo 1005 F .. C26H31FN402 450.24 451 o N- N4- N 1006 N- C25H34N402 422.27 423 N N 272 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1007 N- C24H30N402 406.24 407 oQ r 1008 N O C27H30N402 442.24 443 0/0 N- N N 1009 .. C27H29FN402 460.23 461 F 1010 N N N C26H34N402 434.27 435 1011 N.... C26H26CIFN402 480.17 481 F-& N- N- N, 1012 N C26H27FN402 446.21 447 1013 N- C25H27N502 429.22 430 N N N 1014 N- C27H36N402 448.28 449 N N 1015 N. C25H29N503 447.23 448 NO O 1016 0 C29H32N402 468.25 469 1017 N. C26H27FN402 446.21 447 F N N0 __273 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1018 N C23H30N403 410.23 411 N Nr r o 1019 N. C23H30N403 410.23 411 o r 1020 N. C24H30N402 406.24 407 1021 N. C24H28N602 432.23 433 N N N-aN 1022 N. C25H27N502 429.22 430 N N 1023 C25H34N402 422.27 423 o 1024 C25H28N402S 448.19 449 1025 N- C25H29N502 431.23 432 N N N 1026 N C26H26F2N402 464.20 465 1027 N... C24H27N502 417.22 418
N
274 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1028 N C29H38N402 474.30 475 0
H
0 1029 C27H36N403 464.28 465 O N N N 1030 N- C24H27N502 417.22 418 CI4N- N-C N 1031 N. C27H36N402 448.28 449 N N0 1032 N- C27H36N402 448.28 449 N _ _ &0 1033 NC27H-38N402 450.30 451 1034 N C29H32N402 468.25 469 0 1035 H O C27H34N402 446.27 447 1036 N. C26H27CIN402 462.18 463 1037 N- C22H24N602S 436.17 437 3 N No N 1038 N... C23H-25N503 419.20 420 N Nr
NLO
275 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1039 N-. C25H32N402 420.25 421 N Nr /0 1040 N, C26H27CIN402 462.18 463 1041 N.. C27H30N402 442.24 443 N N N 1042 N- C24H30N403 422.23 423 0N- N-a N OQ N 1043 N. C27H30N402 442.24 443 N N0 1044 N., C30H38N402 486.30 487 H N N0 H 1045 N. C29H34N403 486.26 487 1046 .... C27H28F2N403 494.21 495 F O- N N N 1047 N C25H32N403 436.25 437 1048 N. C27H36N402 448.28 449 N N0 1049 N. C23H27F3N402 448.21 449 F NQ N N F
O'F
276 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1050 N C26H32N402 432.25 433 N N0 1051 .. C26H36N402 436.28 437 1052 C22H28FN302 385.22 386 0 N
N
1053 N. C27H30N402 442.24 443 N_ A NG N 1054 N- C21H24N60 376.20 377 N No 1055 C25H27N50S 445.19 446 NN 1056 .. C24H26N40 386.21 387 1057 N.. C22H24N402 376.19 377 -N N 1058 N-. C27H30N40 426.24 427 N4 No N 1059 C24H32N40 392.26 393 N N N 1060 N.. C22H26N60 390.22 391 9N 277 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1061 N. C24H27N502 417.22 418 1062 ... C23H26CIN50 423.18 424 NNQN 1063 N-. C24H26CIN302 423.17 424 o N N 1064 0... 24H25CIN602 464.17 465 N 1065 N-. C24H27N30S 405.19 406 1066 N C20H21CIN402S 416.11 417 o N N cN 1067 N C25H26N403S 462.17 463 PIS N 'N 1068 C26H28N404 460.21 461 ON 1069 'V C30H42FN304 527.32 528 00 F N O 0 F y j 278 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1070 C311H42FN304 539.32 540 O N N' O dF 1071 C27H30N402 442.24 443 N oN
N
1072 0 C28H32N403 472.25 473 N~ NbA 1073 FN C25H32FN302 425.25 426 1074 C27H30FN302 447.L:3 448 OF
N
oof 1075 F C27H30FN30 431.24 432 N N 1076 F C28H27FN403 486.21 487 1077 C28H28BrFN402 550.14 551 1078 C28H31FN402 474.24 475 1079 F C26H31FN40 434.25 435 N N6N 1080 C26H29FN402 448.23 449 NN O- A- 279 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1081 C28H30FN50 471.24 472 N N 0-N_ 1084 N0 29H31FN40S 465.20 466 AN NN 1085 F0- 27H30FN30S 464.20 465 NN 1086 F - C25H28FN40S 472.23 473 10N N0H 4N3 1088 1 -N,9CF32 8.1 8 1089 F ---- C26H3FN30S 464.27 465 fN N N NN 108 C25H30FN302 427.26 428 3N9 NN C fO \NN 1090F5- C25H34FN302 427.26 428 O N N A NN 280 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1092 F C24H32FN302 413.25 414 O N N 1093 - C26H32FN302 437.25 438 1094 C30H36N404 516.27 517 1095 C25H31F2N302 443.24 444 1096 \ C25H31F2N302 443.24 444 1097 F C26H27F2N302 451.21 452 1098 C26H34F2N40 456.27 457 1099 C27H27FN402 458.21 459 1100 C27H27FN402 458.21 459 1101 C24H30FN302 411.23 412 1102 C23H25FN40S 424.17 425 1103 C28H29FN402 472.23 473 1104 C25H32FN302 425.25 426 281 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1105 C24H27FN40S 438.19 439 1106 C25H34FN303 443.26 444 1107 F C26H27F2N302 451.21 452 1108 C27H36FN302 453.28 454 1109 - C26H26F3N302 469.20 470 110 C25H27FN402 434.21 435 1111 C25H34FN302 427.26 428 1112 LC26H34FN302 439.26 440 1113 C27H36FN302 453.28 454 1114 C25H34FN302 427.26 428 1115 C25H33CIFN303 477.22 478 1116 C24H31F2N302 431.24 432 1117 N\C25H32FN302 425.25 426 282 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1118 C27H30FN303S 495.62 496 1119 F C23H27F4N30 437.21 438 1120 C26H36FN302 441.28 442 1121 C25H27FN402 434.21 435 1122 C25H33N302 407.26 408 1123 C24H31N302 393.24 394 1124 C25H34FN302 427.26 428 1125 C23H30FN302 399.23 400 1126 C27H29CIFN302 481.19 482 1127 C22H25F4N30S 455.17 456 1128 C25H32FN302 425.25 426 1129 /NI C25H32F2N40 442.25 443 1130 C26H29FN402 448.23 449 5 283 Table 8 Ex. Structure Molecular formula Monoisotopic M+H No. molecular wt. + 1131 ci C23H23Cl2N302 443.12 444 ci N 1132 F C23H23CIFN302 427.15 428 1133 C24H26FN302 407.20 408 1134 \ C28H33N304 475.25 476 ON N 07, 1135 C29H34N405 518.25 519
N
1136 0 C33H41N304 543.31 544 0~ NQ o 1137 O C29H36N404 504.27 505 Na -NN 1138 '0 029H32N404 500.24 501 1139 F F C28H30F3N304 529.22 530 F_7N 284 Ex. Structure Molecular formula Monoisotopic M+H No. molecular wt. + 1140 N. C22H22Cl2N40S 460.09 461 CI S" N N CI 1141 N C22H23CIN40S 426.13 427 S 0 N r , CI 1142 N. C22H23FN40S 410.16 411 S NN F 1143 N. C23H25FN40S 424.17 425 S NN F 1144 N. C23H22CIF3N40S 494.12 495 SIF : NN FF 1145 N. C26H26N40S 442.18 443 N'N N 1146 N.. C25H25Cl2N30 453.14 454 C N 1147 N-. C23H25N30S 391.17 392 SN N 1148 N. C23H23F3N40S 460.15 461 F N2N
F
285 Ex. Structure Molecular formula Monoisotopic M+H No. molecular wt. + 1149 N C22H23N503S 437.15 438 0- S N N 1150 . C22H24N40S 392.17 393 sN-CN 1151 N. C22H22Cl2N40S 460.09 461 S1N CI-OI Ci 1152 N C22H22CIFN40S 444.12 445 F 1153 N. C20H22N4OS2 398.12 399 S N N0 1154 C23H26N402S 422.18 423 N OND 1155 N. C23H23F3N40S 460.15 461 S NN F FF 1156 N. C23H26N40S 406.18 407 s N-O N 1157 N C231H26N402S 422.18 423 O N O 1158 N. C24H27N502S 449.19 450 0 N N N 286 Ex. Structure Molecular formula Monoisotopic M+H No. molecular wt. + 1159 N C22H23CIN40S 426.13 427 SN N C1 1160 N. C22H23FN40S 410.16 411 F~e 1161 N C26H26N40S 442.18 443 N/ O N N 1162 N- C23H26N4OS2 438.15 439 S N O 1163 C22H22Cl2N40S 460.09 461 S NN CI C_ _ _ 1164 N C24H28N402S 436.19 437 O N-ONN) 1165 i C24H28N402S 436.19 437 1166 N C26H32N40S 448.23 449 SN NrN 1167 N. C23H23N50S 417.16 418 1168 . C28H28N40S 468.20 469 NN 1169 N. C24H28N402S 436.19 437 0 287 Ex. Structure Molecular formula Monoisotopic M+H No. molecular wt. + 1170 &o.. C23H24N403S 436.16 437 N Nr 1171 C26H32N402S 464.23 465 §- N 0
N
1172 C23H26N4OS2 438.15 439 N N r 1173 C24H28N4OS2 452.17 453 Sr
N
1174 L C24H28N40S 420.20 421 N- O1 N N 1175 N, C23H23F3N402S 476.15 477 SN N F F+. F 1176 N C24H28N403S 452.19 453 )N ON N3 0 % N-rN' 1177 N. C25H30N40S 434.21 435 1178 N C25H30N40S 434.21 435 s N-CN 1179 ... C23H26N402S 422.18 423 1180 0.... C22H25N502S 423.17 424 N N 1181 C24H24N4OS2 448.14 449 S- S 4N -aN 288 Ex. Structure Molecular formula Monoisotopic M+H No. molecular wt. + 1182 . C23H23F3N402S 476.15 477 F O N 1183 N. C24H22F6N40S 528.14 529 S NN F F F F F 1184 . C23H25FN40S 424.17 425 S N F 1185 C24H28N40S 420.20 421 N -N 1186 C24H28N40S 420.20 421 N N 1187 N. C25H26N403 430.20 431 o.N Cr N ON) 1188 N.. C27H31N302 429.24 430 1189 N. C25H25CIFN30 437.17 438 1190 N C25H25Cl2N30 453.14 454 C9 1191 N.... C26H26N40 410.21 411 N N0 N 289 Ex. Structure Molecular formula Monoisotopic M+H No. molecular wt. + 1192 C27H29N302 427.23 428 1193 N C27H29N302 427.23 428 1194 N C25H25F2N30 421.20 422 F N N F 1195 . C25H25F2N30 421.20 422 F Nr F 1196 N C26H28N403 444.22 445 N N ON 1197 N. C27H32N40 428.26 429 N ND 1198 N, C25H28N402 416.22 417 % NN N 1199 N C27H29N303 443.22 444 1200 . C24H28N402 404.22 405 N N N 290 Ex. Structure Molecular formula Monoisotopic M+H No. molecular wt. + 1201 C23H25N302 375.20 376 O1N0N 1202 . C24H25FN40 404.20 405 F 1203 N- C22H25N50 375.21 376 N Nr 1204 N- C26H28FN30 417.22 418 N ND F 1205 N- C26H28FN30 417.22 418 F 1208 N- C24H25FN40 404.20 405 FNN 1209 N- C26H28FN302 433.22 434 NN N 1210 0. C27H30N402 442.24 443 N- N 1211 .. C25H26N403 430.20 431 N N
O%
291 Ex. Structure Molecular formula Monoisotopic M+H No. molecular wt. + 1212 C26H25FN40 428.20 429 F N 1213 F C24H25FN40 404.20 405 N N 1214 C24H25FN40 404.20 405 N N N 1215 F - C26H28FN303S 481.18 482 0 N N O 1216 F C27H29FN402 460.23 461 NN 1217 F N- C28H31 FN402 474.24 475 -N 1218 F C26H25F4N302 487.19 488 O N 1219 F -- C26H28FN303S 481.18 482 NN 1220 F F C26H25F4N302 487.19 488 1221. -4 1221 N F --- C26H25FN40 428.20 429 ON N H- 292 Ex. Structure Molecular formula Monoisotopic M+H No. molecular wt. + 1222 F - C27H29FN402 460.23 461 N -I N N 1223 F - C26H25F4N302 487.19 488 o ~rk FF N N3 F O-\0,I 1224 N. C25H25F2N30 421.20 422 F-C N N F 1225 N C25H32N403S 468.22 469 1226 N C24H31N50 405.25 406 _ NCN NO N3 1227 N. C24H31N502 421.25 422 %~ N N N 1228 N. C23H28FN50 409.23 410 1229 N. C26H31N50 429.25 430 0r N N N N 1230 N... C25H29N50S 447.21 448 1s I N C 4 1N24 123 N .. C2 H3 N4 418.27 419 1231N N N2H44 293 Ex. Structure Molecular formula Monoisotopic M+H No. molecular wt. 1232 N. C26H32N402 432.25 433 N NaN Table 9 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1233 C311H29N302 475.23 476
N
1234 -. C30H35N302 469.27 470 0 'D 1235 C28H30N403S 502.20 503 N^ \s/ N O 1236 F 0 C29H30FN303S 519.20 520 \I N N O 1237 0 C28H30N403S 502.20 503 N S 0 N 0 5 Table 10 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1238 0N'N N C26H35N302 421.27 422 1239 N N N C26H35N302 421.27 422 294 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1240 F 25H31F2N302 443.24 444 O0 N N N F 1241 0N N C27H35N302 433.27 434 1242 N C26H35N302 421.27 422 1243 N/N C25H36N402 424.28 425 1244 N-'o' C24H33N303 411.25 412 o N_ __ 1245 o C26H37N303 439.28 440 N o-Q-4N-OrN 1246 o N NjC27H37N302 435.29 436 1247 N C27H37N302 435.29 436 1248 N C27H33N502 459.26 460 N N N N 1249 0 C26H35N303 437.27 438 O23NN 4N7 1250 N0 F C29H34FN302 475.26 476 295 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1251 C27H32N402 444.25 445 0 NN N 1252 N C24H33N302 395.26 396 1253 N-/ C23H31N302 381.24 382 1254 0N N C25H33N303 423.25 424 12550 OO N N N F C23H28F3N02 435.21 436 F 1256 0 N N N C23H30FN302 399.23 400 F 1257 C27H37N303 451.28 452 o-C N- N -N 1258 N C24H33N303 411.25 412 1259 0 N-,C C25H33N302 407.26 408 1260 o N. C25H33N302 407.26 408 126N N4 1261 N-) C25H-35N302 409.27 410 0 No Nr 296 Ex. Structure Molecular Monoisotopic M+H + No. formula molecular wt. 1262 N C25H35N302 409.27 410 1263 C25H35N302 409.27 410 0 N N 1264 N-./-/ C25H35N302 409.27 410 0 Na<N O-Q AN 1265 0 N C27H35N502 461.28 462 N 1266 NC28H38N403 478.29 479 N 1267 ( N'NN N/C26H36N402 436.28 437 1268 N C26H38N402 438.30 439 1269 N C30H35N302 469.27 470 0 NNN 1270 C27H32N402 444.25 445 N N N 1271 0 N NNN C27H36N403 464.28 465 1272 i N N iC27H37N302 435.29 436 297 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1273 N N N C30H35N302 469.27 470 1274 N C26H35N302 421.27 422 O ONN 1275 C29H39N302 461.30 462 1276 C29H43N302 465.34 466 O NO NN 1277 C28H39N302 449.30 450 N- N N 1278 H C28H37N302 447.29 448 0 _Nr, NI 1279 N C28H40N402 464.32 465 1280 N C30H35N302 469.27 470 0 0 1281 N C30H34N402 482.27 483 1282 o N C30H35N303 485.27 486 1283 0 r C25H33N304S 471.22 472 298 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1284 0 N C29H39N302 461.30 462 1285 N'N- E C26H33N303 435.25 436 YN H 1286 C27H35N502 461.28 462 1287 C25H35N302 409.27 410 \1-j 1288 N C26H35N304S 485.23 486 1289 N C27H38N402 450.30 451 1290 N C26H31N302S 449.21 450 1291 0N5NN C29H41N302 463.32 464 \1-j 1292 N N C25H32N403 436.25 437 \r-j 0 1293 0, rN-Cb C26H35N303 437.27 438 NN O 1294 N N C25H30N402S 450.21 451 142S 1295 00 24H31 N302 393.24 394 299 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1296 N' C25H35N502 437.28 438 N'-4 N N 1297 NDUN' C27H37N502 463.30 464 Cr N,, N N 1298 N N C26H32N602S 492.23 493 O N ANa N N 4s 1299 ou -Y C24H33N503 439.26 440 NN N N 1300 F N C28H40FN303 485.30 486 O__ N_& N O 1301 F C27H36FN302 453.28 454 0 ,N N 1302 NrY C31H37N502 511.30 512 0O N N 1303 r-N C28H39N502 477.31 478 OcN0 N N 1304 C27H39N502 465.31 466 0n N la_ ONI N_________ 1305 r N' C27H39N502 465.31 466 O 0 ND 1306 N' C26H35N502S 481.25 482 OrN,, N )N~l N 1307 rD N C26H33N702 475.27 476 NNNN N 4. 450 1308 rN' C26H-35N502 449.28 450 Cf NAA N Nr 300 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1309 NN C26H37N503 467.29 468 Or N N N O 1310 NUN' C26H37N503 467.29 468 O N Na N 1311 YN' C26H37N503 467.29 468 crnN' N N 1312 N' C27H37N503 479.29 480 0 N N 1313 O N2Y)N C27H39N503 481.30 482 N N N'CO 1314 DON. C28H38N602 490.31 491 N N 1315 N C28H39N504 509.30 510 0 N N N 01 1316 CLN ry C28H-39N502 477.31 478 1317 N N C29H40N603 520.32 521 1319 c NN.N O/-- C30H44N603 536.35 537 a O N N 1320 0 C30H34N602 510.27 511 NN N N
N
301 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1321 N N C33H42N602 554.34 555 OA, 0 0 NI 1322 N C27H35N702 489.29 490 ,O, N NL N' 1323 ON C29H38F3N502 545.30 546 OT N-N N Fp F F 1324 C29H39N702 517.32 518 N N 1325 o NN C31 H37N702 539.30 540 1326 N.-JN C26H33N702 475.27 476 N 0 N N 1327 N N C26H37N502S 483.27 484 N N 1328 C26H35N502 449.28 450 or N,, N 1329 N>NN C27H35N702 489.29 490 1330 Qot 2 NH N' C28H41N503 495.32 496 NN N _ 1331 CrN 025H31N702S 493.23 494 11N N05 1332 o C31H39N503 529.30 530 N NL N' N 302 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1333 rN' C30H42N604 550.33 551 o N~k N N ,>=0 /-0 1334 C28H41N502 479.33 480 NION N N 1335 F N C29H30F2N402 504.58 505 F 1336 C25H32FN302 425.25 426 F N 1337 F 'DN-< C25H34FN302 427.26 428 1338 F N-fo C24H32FN303 429.24 430 0 Nr 1339 C26H34FN302 439.26 440 O N NN 1340 (I C26H34FN302 439.26 440 1341 F0 25H34FN303 443.26 444 1342 F N>O C25H34FN303 443.26 444 F N 1343 F N O C25H34FN303 443.26 444 O3 N4 1344 F N)O C27H36FN302 453.28 44 O NN 303 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1345 C27H38FN302 455.30 456 O N N 1346 \. - C27H38FN302 455.30 456 F N 1349 N 5 ' C27H38FN302 457.27 458 1350~ r2H4N0 492 6 O NA N 134 C26H36FN303 459.25 456 O N N N 1352 oF&N o C26H36FN303 467.30 468 O NA N, 1353 F Ny o C25H34FN304 471.29 472 o. N- N 1354 \-o C25H34FN303 457.29 472 F N O N.N 1352 F 0 C28H38FN302 467.30 468 OF NJ 1353 0 C27H38FN303 471.29 472 O NA NN 1354 F N o C27H38FN303 471.29 472 O NA N) 1355 )-F N o C27H34FN502 479.27 480 o N NN 304 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1356 C29H40FN302 481.31 482 o NN 1357 0 F r N C29H40FN302 481.31 482 1358 0 F r N -C' C28H39FN402 482.31 483 N1NN-.). 1359 F NH 0 C28H38FN303 483.29 484 1360 F C28H38FN303 483.29 484 o N N 1361 N\ C28H36FN502 493.29 494 FN o N N 1362 C27H35FN602 494.28 495 FN O NiN 1363 F C28H37FN403 496.29 497 1364 F N-N C29H41FN402 496.32 497 1365 F C28H39FN403 498.30 499 N 1366 F N-! C26H32FN304 469.24 470 0 N N H 1367 0 F r-fN-1, C29H40FN303 497.30 498 o J,\lN N 305 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1368 F C25H31FN402 438.24 439 O N N 1369 F NO C26H34FN302 439.26 440 0-o N-N 1370 C26H36FN302 441.28 442 0-O N-N 1371 C25H34FN303 443.26 444 A N N O 1372 C27H36FN302 453.28 454 FN O- N- N 1373 0 C26H34FN303 455.26 456 1374 F C28H38FN302 467.30 468 1375 F ' C27H37FN402 468.29 469 0N NJ 1376 (s C26H34FN302S 471.24 472 F N NN 1377 O F 0 C26H36FN304 473.27 474 1378 0 , C28H41FN402 484.32 485 -\o ,C N & Nr)
N
306 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1379 0 C28H37FN403 496.29 497 F N N N 1380 4 C28H37FN403 496.29 497 F N 0 r .c N N) 1381 0 C32H38FN302 515.29 516 o ; ,N N 1382 C311H38FN303 519.29 520 0 N FN 1383 o F C311H43FN402 522.34 523 o$ ,N N 1384 F O C27H36FN303 469.27 470 o- N- N 1385 C27H36FN303 469.27 470 0 r co -N N, 1386 0 N N C28H34F3N303 517.26 518 F F F F 1387 F C27H36FN304S 517.24 518 F N-C9N2I O0 N5 1388 0 C30H41FN403 524.32 525 18ON N2 1389 0 F rN-C C27H36FN303 469.27 470 307 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1390 0 F N N C22H28FN302 385.22 386 1391 O' C29H38FN304 511.29 512 0 F O O -N N3 1392 F N O C26H36FN303 457.27 458 O N N 1393 F N- O' C25H34FN303 443.26 444 O. N- N 1394 O C27H36FN303 469.27 470 1395 (0 C26H34FN303 455.26 456 S N) O. N- N 1396 C28H38FN303 483.29 484 F O NA N, 1397 F N O/' 0 C26H36FN303 457.27 458 1398 O' C26H34FN304 471.25 472 ()O F N 1399 C28H38FN304 499.29 500 0~~ N0 F N 1400 NO-/ 27H38FN303 471.29 472 01F 308 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1401 N-/< C28H40FN303 485.30 486 O IN-& N 1402 0 C27H36FN304 485.27 486 F N 1403 { 0 C27H36FN303 469.27 470 F No O, -1AN -&Nr 5 Table 11 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1404 C22H30N402 382.24 383 O N N H 1405 N N C24H31 CIN40 426.22 427 1406 C23H32N402 396.25 397 Ni N N 1407 F0 y 25H27FN40 418.22 419 1408 C23H32N402 396.25 397 N'N
H
O0O 309 1409 C22H30N402 382.24 383 N NH 1410 C23H25N502 403.20 404 N .N H o o N 1411 N H, C24H33N302 395.26 396 1412 0 , 1 N NHN, C23H31N302 381.24 382
(S)
Konfiguration 1413 N NH C23H31N302 381.24 382 1414 F --- C23H30FN302 399.23 400 1415 C24H32FN302 413.25 414 O N N_ 1416 C24H32N40 392.26 393 N QNH 1417 - C24H32FN302 413.25 414 141 F rN 1418 C24H32FN302 413.25 414 O N_ N (S)-configuration 1419 N N C25H34FN302 427.26 428 F 1420 C26H36FN302 441.28 442 O N N _ 310 1421 0 N C26H36FN302 441.28 442 __- F 1422 N C27H36FN302 453.28 454 1423 F N C27H38FN303 471.29 472 N Table 12 5 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1424 NDNH C27H35N302 433.27 434 1425 O N H C28H39N304 481.29 482 1426 0 NQN C27H38N404 482.29 483 N O8O _O_'-t 1427 N N C24H32N403 424.25 425 N. OLr O 1428 . C24H33N302 395.26 396 1429 O0 N ' C24H31N303 409.24 410 0--\J 0 1430 ' 0 C29H33FN403 504.25 505 0 N
HN-O
311 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1431 o NCN C27H38N404 482.29 483 0 f y rO I - 1432 0 cN N C30H43N305 525.32 526 0, 1433 )NI C25H33N303 423.25 424 1434 ~ yQN5IN. C29H41 N305 511.30 512 1435 C26H28FN30 417.22 418 F - Na
N
1436 0 C27H30FN30 431.24 432 1437 28H38FN304 499.29 500 0~~ N0 07 F 1438 F ro C28H38FN304 499.29 500 1439 F 0 C28H38FN304 499.29 500 1 44 N40-. C25H32N402 420.25 421 N 1441 c .. C24H32CIN302 429.22 430 1 N N25 1442 0 C29H40FN304 513.30 514 O N N -O C A-& N' 0 SF 312 Ex. Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1443 F C30H42FN304 527.32 528 O N N O-/ 5 Table 13 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1444 C23H30N40 378.24 379 1445 0 C23H30N40 378.24 379 N -N'f 1446 OH ' C21H28N402 368.22 369 O-0-N 1447 N C27H38N40 434.30 435 N N 1448 N C26H36N40 420.29 421 1449 N C29H42N40 462.34 463
N
1450 0N N C28H38N40 446.30 447 313 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1451 C24H32N40 392.26 393 1452 O N DN C26H36N40 420.29 421 1453 O QN D C26H32N40 416.26 417 N 1454 N C23H31N302 381.24 382 O j N N 1455 C24H31N30 377.25 378 0 N 1456 C22H29N302 367.23 368 O N N 1457 O N N C22H21FN40 376.17 377 1458 0 N C20H26N402 354.21 355 N N 1459 C23H24N402 388.19 389 ON N 1460 HN C22H27CIN40 398.19 399 C6 N N3 1461 O N N C22H30N402 382.24 383 314 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1462 O N C21H21N502 375.17 376 ON NO 1463 1463F C22H27F2N302 403.21 404 F 1464 F N C22H28FN302 385.22 386 1465 c N C22H28CIN302 401.19 402 1466 N C23H31N302 381.24 382 O Nr 1467 N C23H28F3N302 435.21 436 F F 1468 C23H28F3N302 435.21 436 O- N \ N) _FF F 1469 C22H27F2N302 403.21 404 N N F F 1470 0 N C22H27CIFN302 419.18 420 F CI 1471 N C23H28N402 392.22 393
N
315 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1472 N C23H27CIN402 426.18 427 Ci N 1473 Br N C22H28BrN302 445.14 446 o N_&N 1474 C26H31N302 417.24 418 0 1475 F C22H27F2N302 403.21 404 O N N F 1476 C22H28BrN302 445.14 446 O N N Br 1477 C23H30CIN302 415.20 416 O Nr 1478 j ci 1478 ci ' C21H27CIN402 402.18 403 N- N 1479 N N C22H30N402 382.24 383 -IN -ND-N 1480 C22H30N402 382.24 383 O N N. 1481 N NO N C22H30N402 382.24 383 1482 N C24H25FN40 404.20 405 316 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1483 0 N C22H29N303 383.22 384 1484 0 HN C20H26N402 354.21 355 o-N N 1485 F C22H28FN302 385.22 386 -J_&N 1486 N C22H29N302 367.23 368 1487 0N N N C22H28N40 364.23 365 1488 N C25H35N303 425.27 426 O,0- N-0 N 0 1489 C24H33N303 411.25 412 O, N- N 0 1490 N C22H29N502 395.23 396 HN 1491 HN 023 H25N502 403.20 404 N_ N O N N N 1492 N C23H25N502 403.20 404 Cr AN N N 1493 C20H22N60 362.19 363 NN
N
317 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1494 N C25H25N502 427.20 428 N N 1495 N C23H25N302 375.20 376 0 14aN 1496 C19H21N502 351.17 352 -O' 1497 C20H22N4OS2 398.12 399 1498 NC21H23N50 361.19 362 NNN 1499 N C20H22N60 362.19 363
N
0
N
1500 N C22H28FN302 385.22 386 1501 N C23H29FN402 412.23 413 OCN ANq F 1502 N C22H34FN302 391.26 392 oC N N_,r _ f F 1503 C23H30FN302 399.23 400 0 N
N
318 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1504 N C22H28FN502 413.22 414 c N N N N F 1505 % N C23H24FN502 421.19 422 N O N N F 1506 F F C23H22F3N302 429.17 430 F NlIi 1507 N C24H28N402 404.22 405
-
NN Nf 1508 N C28H33N302 443.26 444 1509 C24H24N402 400.19 401 1510 i\O NN C24H26N403 418.20 419 T N' 1511 N C23H30FN302 399.23 400 F ~o NQN F 1513 N C22H29FN402 400.23 401
F
319 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1514 N C24H26N403 418.20 419 S'DN 1515 C23H30FN302 399.23 400 00 N 1516 C24H29FN40 408.23 409 1517 F C. 25H26FN302 419.20 420 0-O0 _ _ _ __N NN 1518 F C25H26FN302 419.20 420 0N Nt 1519 F C24H26FN302S 439.17 440 NN 0 1520 F H C24H30FN30 395.24 396 1521 F C25H32FN30 409.25 410 NN 1522 F C26H27F2N30 435.21 436 N N 1523 c C22H21CIFN302 413.13 414 F,.: N \0 1524 N C22H22FN302 379.17 380 F 0
N
320 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1525 0 C23H25N303 391.19 392 O0 O N-&NON 1526 N 0 C23H25N303 391.19 392 0 1527 F C22H22FN302 379.17 380 K- 0 r -N 1528 N C23H25N302S 407.17 408 S1 N 1529 N C23H25N302 375.20 376 N N 1530 0 NN C24H27N303 405.20 406 QO N 0 1531 F H C23H30FN302 399.23 400 1532 F r C25H31 CIFN30 443.21 444 ci NN 1533 O F C24H25CIFN303 457.16 458 1534 4 'F C24H30FN302 411.23 412 1535 0 C24H27N303 405.20 406 1--1 1536 N- O N- C23H22N402 386.17 387 Nj N 321 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1537 N C24H25N303 403.19 404 0 1538 N N C24H27N304 421.20 422 _o 1539 C24H25N303 403.19 404 00 0N N 1540 Q C24H25FN404 452.19 453 F N 1541 F C23H30FN302 399.23 400 0 N N N N 1542 F N C25H26FN30 403.21 404 0 1543 N C26H28FN302 433.22 434 F N N 1544 C28H29FN402 472.23 473 0_& 1545 F N C26H28FN30 417.22 418 N-N 1546 F H C24H32FN302 413.25 414 1547 F F C22H18F5N302 451.13 452 F JN
F
322 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1548 N C24H25N303 403.19 404 1549 F C22H21F2N302 397.16 398 F N 1550 C22H21F2N302 397.16 398 F N -N 1551 F C22H21F2N302 397.16 398 FN 1552 C23H23N304 405.17 406 0 " N-aNr 1553 C- C28H26FN302 - 455.20 456 - N 0 F \O/ 1554 N C26H31N303 433.24 434 N N-O ' ~~0 1555 F N C25H25F2N30 421.20 422 0 F4 N &N 1556 C23H25N302S 407.17 408 NN 1557 C24H27N302S 421.18 422 S- J N N 1558 C24H27N302 389.21 390 N N 323 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1559 N C24H27N302 389.21 390 N N 1560 F+F C23H22F3N303 445.16 446 1561 N C25H29N302 403.23 404 \ NG N3 1562 N N C25H29N302 403.23 404 1563 C21H22N402 362.17 363 0r 0NaN3 1564 N C22H21F2N302 397.16 398 0 fQN F O 1565 N C22H24N403 392.18 393 0 NN -O 1566 , C23H25N304S 439.16 440 INCN 1567 F C22H21F2N302 397.16 398 1568 N C23H22F3N303 445.16 446 F O
FN
324 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1569 N C23H24FN302 393.18 394 1570 C20H21N502 363.17 364 N N N 1571 C21H21FN402 380.17 381 F ON0 N 1572 F C23H30FN302 399.23 400 0 N N 1573 O C22H22N403S 422.14 423 NN 1574 C23H25N302S 407.17 408 N N 0 1575 C23H25N302S 407.17 408 0 N 1576 C23H25N3OS2 423.14 424 0Nr s s 1577 N C24H27N302S 421.18 422 0 N 0 325 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1578 N C24H27N302S 421.18 422 N N /-0 1579 N C23H22N40S 402.15 403 0 NNN 1580 N C24H27N303S 437.18 438 0N 1581s NC N 042N3 191 2 0 0 1581 N C24H25N302S 419.17 420 o N 0 1582 N C24H25N302S 419.17 420 N N S 1583 N C23H23N303S 421.15 422 O Na N3 1584 NC23H25N3OS2 423.14 424 N N 1585 N C24H27N3OS2 437.16 438 N
N
326 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1586 N C24H27N30S 405.19 406 N N s 1587 N C24H27N30S 405.19 406 N N 1588 F+F C23H22F3N302S 461.14 462 0_0N NN 1589 N C25H29N30S 419.20 420 N 1590 C25H29N30S 419.20 420 sNN 1591 N C24H25N303S 435.16 436 0 N 0r 1592 C22H24N402S 408.16 409 SN N 1593 F F C23H22F3N302S 461.14 462 N
N
327 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1594 C24H26N402S 434.18 435 N N r , 1595 N C21H24N402S 396.16 397 N N- N 1596 C21H21FN40S 396.14 397 F ON- _ Nr, 1597 C25H27N303S 449.18 450 N N s 1598 C28H33N30S 459.23 460 Na N 1599 N C24H26N402S 434.18 435 0 N 0 5NN O 1601 N C25H28N402S 448.19 449 N 0 " NP1 328 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1602 N C24H28N40S 420.20 421 -NN N" 1603 N C24H26N402S 434.18 435 - N N 0 1604 N C24H25N302S 419.17 420 0 ' N N Q' O 1605 C20H21 N30S2 383.11 384 0 N "S 1606 C26H28FN302 433.22 434 1607 F C26H27CIFN302 467.18 468 0 NN 1608 C21H21FN40S 396.14 397 N N 1609 N NC24H32FN302 413.25 414 or F 1610 C25H34FN302 427.26 428 0 N N 329 Ex. Structure Molecular formula Monoisotopic M+H+ No. molecular wt. 1611 N C25H34FN302 427.26 428 _ f KF 1612 0 N C26H34FN302 439.26 440 0 - N-/ HN _ J -J IF 1613 N N C25H25N30S 415.17 416 s Nk N 1614 C23H22N40S 402.15 403 'N S O 1615 IF IN C24H22FN30S 419.15 420 S N 1616 C23H22N40S 402.15 403 N N N9 0 1617 ~/N N ON &N 021 H27N503 397.21 398 1618 0 / N N N C25H28N402 416.22 417 Syntheses of pyrrolidinylanilines required as intermediates [1 -(4-Amino-2-chlorophenyl)pyrrolidin-3-yl]dimethylamine 5 Method C-a 3-Dimethylaminopyrrolidine (0.34 g) was slowly added to a solution of 2-chloro-1 fluoro-4-nitrobenzene (0.52 g) in DMF (5 ml). After 1 hour, ethyl acetate (30 ml) was added to the reaction mixture, and it was extracted with 10% hydrochloric acid (2 x 20 ml). The aqueous phase was washed 10 with ethyl acetate (2 x 20 ml), adjusted to pH > 10 with 10% ammonia and extracted with ethyl acetate. The yellow solution was dried with sodium sulfate, filtered and concentrated in a rotary evaporator. The residue was then dissolved in dichloromethane (50 ml), zinc (10 g) was added, and 330 glacial acetic acid (5 ml) was slowly added dropwise while cooling in ice. The suspension was stirred for 15 minutes, filtered, washed with 10% ammonia (2 x 20 ml) and concentrated. This resulted in the product with the molecular weight of 239.75 (Cl 2H18CIN3); MS (ESI): 239 (M+H+), 240 5 (M+H+), 5-Amino-2-(3-dimethylaminopyrrolidin-1 -yl)benzonitrile Dimethylaminopyrrolidine was treated with 2-fluoro-5-nitrobenzonitrile and subsequently reduced by method C-a. This resulted in the product with the 10 molecular weight of 230.32 (Cl 3H18N4); MS (ESI): 231 (M+H+), [1 -(4-Amino-3-chlorophenyl)pyrrolidin-3-yl]dimethylamine Dimethylaminopyrrolidine was treated with 3-chloro-1 -fluoro-4-nitrobenzene and subsequently reduced by method C-a. This resulted in the product with 15 the molecular weight of 239.75 (Cl 2H1 8CIN3); MS (ESI): 239 (M+H+), 240 (M+H+), [1 -(4-Amino-3-methylphenyl)pyrrolidin-3-yl]dimethylamine Dimethylaminopyrrolidine was treated with 4-fluoro-2-methyl-1 20 nitrobenzene and subsequently reduced by method C-a. This resulted in the product with the molecular weight of 219.33 (Cl 3H21 N3); MS (ESI): 220 (M+H+). tert-Butyl (R)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate 25 Method C-b tert-Butyl (R)-(+)-pyrrolidin-3-ylcarbamate (1.86 g) was slowly added to a suspension of 3,4-difluoronitrobenzene (1.59 g) and potassium carbonate (2.8 g) in DMF (10 ml). After 10 minutes, ethyl acetate (50 ml) was added, and the mixture was washed with water (3 x 50 ml) in a separating funnel, 30 dried with sodium sulfate, filtered and concentrated. The residue was dissolved in DMF (10 ml), and sodium hydride (0.48 g) was added. After 15 minutes, methyl iodide (1.41 g) was then added while cooling in ice. After 30 minutes, ethyl acetate (50 ml) was added, and the mixture was washed with water (3 x 50 ml) in a separating funnel, dried with sodium sulfate, 35 filtered and concentrated. The substance was then treated as described for method B. This resulted in the product with the molecular weight of 309.39 (Cl 6H24FN302); MS (ESI): 310 (M+H+). tert-Butyl (S)-[l-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate 331 was obtained analogously. tert-Butyl (R)-[1-(2-fluoro-4-isopropylaminophenyl)pyrrolidin-3 yl]methylcarbamate 5 tert-Butyl (R)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate was alkylated with acetone using triacetoxyborohydride as reducing agent by method N. This resulted in the product with the molecular weight of 351.47 (C19H30FN302); MS (ESI): 352 (M+H+). 10 tert-Butyl (R)-[1 -(2-Fluoro-4-cyclobutylaminophenyl)pyrrolidin-3-yl]methyl carbamate tert-Butyl (R)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate was alkylated with cyclobutanone using triacetoxyborohydride as reducing agent by method N. This resulted in the product with the molecular weight 15 of 363.48 (C20H30FN302); MS (ESI): 364 (M+H+). tert-Butyl (R)-[1-(2-fluoro-4-methylaminophenyl)pyrrolidin-3 yl]methylcarbamate tert-Butyl (R)-{1 -[4-(benzyloxycarbonylmethylamino)-2- 20 fluorophenyl]pyrrolidin-3-yl}-methylcarbamate was treated as described for method B. This resulted in the product with the molecular weight of 323.41 (Cl 7H26FN302); MS (ESI): 324 (M+H+). tert-Butyl (R)-{1-[4-(benzyloxycarbonylmethylamino)-2 25 fluorophenyl]pyrrolidin-3-yl}-methylcarbamate tert-Butyl (R)-(+)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3 yl]methylcarbamate (0.93 g) was added to a solution of N (benzyloxycarbonyloxy)succinimide (2.49 g) in dichloromethane (30 ml). After 12 hours, the mixture was washed with water (2 x 30 ml), dried 30 sodium sulfate, filtered and concentrated. The residue was recrystallized from acetonitrile. The product obtained in this way was dissolved in DMF (10 ml), and sodium hydride (0.24 g) was added. After 15 minutes, methyl iodide (0.71 g) was added while cooling in ice. After 15 minutes, ethyl acetate (50 ml) was added, and the mixture was washed with water (3 x 30 35 ml), dried sodium sulfate, filtered and concentrated. This resulted in the product with the molecular weight of 457.55 (C25H32FN304); MS (ESI): 458 (M+H+). (R)-[1 -(2-Fluoro-4-methylaminophenyl)pyrrolidin-3-yl]dimethylamine 332 (R)-{1 -[4-(Benzyloxycarbonylmethylamino)-2-fluorophenyl]pyrrolidin-3 yl}methylcarbamic acid tert-butyl ester was treated by method G, and the resulting amine was methylated by method M. Finally, hydrogenation was carried out by method B. This resulted in the product with the molecular 5 weight of 237.32 (C13H20FN3); MS (ESI): 238 (M+H+). Dimethyl-[1 -(4-methylaminophenyl)pyrrolidin-3-yl]amine can be prepared analogously. 2-Dimethylamino-N-[1 -(2-fluoro-4-methylaminophenyl)pyrrolidin-3-yl]-N 10 methylacetamide (R)-{1 -[4-(Benzyloxycarbonylmethylamino)-2-fluorophenyl]pyrrolidin-3 yl}methylcarbamic acid tert-butyl ester was treated by method G, and the resulting amine was reacted with N,N-dimethylglycine by method E. Finally, hydrogenation was carried out by method B. This resulted in the product 15 with the molecular weight of 308.40 (Cl 6H25FN40); MS (ESI): 309 (M+H+). tert-Butyl (R)-[1-(4-amino-3-fluorophenyl)pyrrolidin-3-yl]methylcarbamate 2,4-Difluoronitrobenzene was treated with tert-butyl (R)-(+)-pyrrolidin-3 20 ylcarbamate, methylated and subsequently hydrogenated by method C-b. This resulted in the product with the molecular weight of 309.39 (C16H24FN302); MS (ESI): 310 (M+H+). tert-Butyl [1 -(4-aminonaphthalen-1 -yl)pyrrolidin-3-yl]methylcarbamate 25 Method C-c tert-Butyl methylpyrrolidin-3-ylcarbamate (1.86 g) was slowly added to a suspension of 4-fluoro-1 -nitronaphthalene (1.91 g) and potassium carbonate (2.8 g) in DMF (10 ml). After 10 minutes, ethyl acetate (50 ml) was added, and the mixture was washed with water (3 x 50 ml) in a 30 separating funnel, dried with sodium sulfate, filtered and concentrated. The substance was then treated as described for method B. This resulted in the product with the molecular weight of 341.46 (C20H27N302); MS (ESI): 342 (M+H+). 35 tert-Butyl [1-(4-amino-3-bromophenyl)pyrrolidin-3-yl]methylcarbamate 2-Bromo-4-fluoro-1 -nitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently reduced by method C-a. This resulted in the product with the molecular weight of 370.29 (C16H24BrN302); MS (ESI): 370 (M+H+), 372 (M+H+).
333 Tert-butyl [1 -(4-amino-3-cyanophenyl) pyrrolidin-3-yl]methylcarbamate 2-Cyano-4-fluoro-1 -nitrobenzene was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently reduced by method C-a. 5 This resulted in the product with the molecular weight of 316.41 (Cl7H24N402); MS (ESI): 317 (M+H+). tert-Butyl [1-(5-amino-6-chloropyridin-2-yl)pyrrolidin-3-yl]methylcarbamate 2-Chloro-6-fluoro-3-nitropyridine was treated with tert-butyl 10 methylpyrrolidin-3-ylcarbamate and subsequently reduced by method C-c. This resulted in the product with the molecular weight of 326.83 (Cl5H23CIN402); MS (ESI): 326 (M+H+), 327 (M+H+). tert-Butyl [1-(4-amino-2,3-difluorophenyl)pyrrolidin-3-yl]methylcarbamate 15 2,3,4-Trifluoronitrobenzene was treated with tert-butyl methylpyrrolidin-3 ylcarbamate and subsequently reduced by method C-c. This resulted in the product with the molecular weight of 327.38 (Cl 6H23F2N302); MS (ESI): 328 (M+H+). 20 tert-Butyl [1-(4-amino-2-bromophenyl)pyrrolidin-3-y]methylcarbamate 3-Bromo-4-fluoro-1 -nitrobenzene was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently reduced by method C-a. This resulted in the product with the molecular weight of 370.29 (C16H24BrN302); MS (ESI): 370 (M+H+), 372 (M+H+). 25 tert-Butyl [1-(4-amino-2,6-difluorophenyl)pyrrolidin-3-yl]methylcarbamate 3,4,5-Trifluoronitrobenzene was treated with tert-butyl methylpyrrolidin-3-yl carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 327.38 (Cl 6H23F2N302); MS 30 (ESI): 328 (M+H+). tert-Butyl (R)-[1-(4-amino-2-hydroxymethylphenyl)pyrrolidin-3-yl]carbamate (2-Fluoro-5-nitrophenyl)methanol was treated with tert-butyl (R)-(+) pyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. 35 This resulted in the product with the molecular weight of 307.40 (C16H25N303); MS (ESI): 308 (M+H+). tert-Butyl [1 -(4-amino-2-chlorophenyl)pyrrolidin-3-yl]methylcarbamate 2-Chloro-1 -fluoro-4-nitrobenzene was treated with tert-butyl 334 methylpyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 311.81 (C15H22CIN302); MS (ESI): 311 (M+H+), 312 (M+H+). 5 tert-Butyl [1 -(4-amino-2,5-difluorophenyl)pyrrolidin-3-yl]methylcarbamate 3,4,6-Trifluoronitrobenzene was treated with tert-butyl methylpyrrolidin-3 ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 327.38 (Cl 6H23F2N302); MS (ESI): 328 (M+H+). 10 tert-Butyl [1 -(4-amino-2-methylphenyl)pyrrolidin-3-yl]methylcarbamate tert-Butyl 4-fluoro-3-methylnitrobenzene was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 15 291.40 (C16H25N302); MS (ESI): 292 (M+H+). tert-Butyl [1 -(4-amino-3-trifluoromethylphenyl)pyrrolidin-3 yl]methylcarbamate 4-Fluoro-2-trifluoromethylnitrobenzene was treated with tert-butyl 20 methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 345.37 (C16H22F3N302); MS (ESI): 346 (M+H+). tert-Butyl [1-(4-amino-2-chloro-3-fluorophenyl)pyrrolidin-3 25 yl]methylcarbamate 2,4-Difluoro-3-chloronitrobenzene was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 329.80 (Cl 5H21 CIN302); MS (ESI): 329 (M+H+), 330 (M+H+). 30 tert-Butyl [1 -(4-amino-2-cyanophenyl)pyrrolidin-3-yl]methylcarbamate 3-Cyano-4-fluoronitrobenzene was treated with tert-butyl methylpyrrolidin 3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 302.38 (Cl 6H22N402); 35 MS (ESI): 303 (M+H+). tert-Butyl [1 -(4-amino-5-chloro-2-methylphenyl)pyrrolidin-3 yl]methylcarbamate 1 -Chloro-5-fluoro-4-methyl-2-nitrobenzene was treated with tert-butyl 335 methylpyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 325.84 (Cl6H24CIN302); MS (ESI): 325 (M+H+), 326 (M+H+). 5 tert-Butyl (R)-[1 -(5-aminopyridin-2-yl)pyrrolidin-3-yl]methylcarbamate 2-Chloro-5-nitropyridine was treated with tert-butyl (R)-(+)-pyrrolidin-3-yl carbamate and subsequently hydrogenated by method C-b. This resulted in the product with the molecular weight of 322.37 (Cl 6H24FN302); MS (ESI): 323 (M+H+). 10 tert-Butyl [1 -(5-aminopyridin-2-yl)pyrrolidin-3-yl]methylcarbamate 2-Chloro-5-nitropyridine was treated with tert-butyl methylpyrrolidin-3-yl carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 322.37 (Cl 6H24FN302); MS 15 (ESI): 323 (M+H+). tert-Butyl (R)-[1-(4-aminophenyl) pyrrolidin-3-yl]methylcarbamate 4-Fluoronitrobenzene was treated with tert-butyl (R)-(+)-pyrrolidin-3-yl carbamate and subsequently hydrogenated by method C-b. This resulted in 20 the product with the molecular weight of 291.40 (Cl 6H25N302); MS (ESI): 292 (M+H+). tert-Butyl [1-(4-amino-2-trifluoromethylphenyl)pyrrolidin-3 yl]methylcarbamate 25 4-Fluoro-3-trifluoromethylnitrobenzene was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 345.37 (C16H22F3N302); MS (ESI): 346 (M+H+). 30 tert-Butyl [1 -(5-amino-4-methylpyridin-2-yl)pyrrolidin-3-yl]methylcarbamate 2-Chloro-4-methyl-5-nitropyridine was treated with tert-butyl methylpyrrolidin-3-ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 306.419 (Cl 6H26N402); MS (ESI): 306 (M+H+), 307 (M+H+). 35 tert-Butyl [1-(5-amino-3-methylpyridin-2-yl)pyrrolidin-3-yl]methylcarbamate 2-Chloro-3-methyl-5-nitropyridine was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 336 306.419 (C1 6H26N402); MS (ESI): 306 (M+H+), 307 (M+H+). tert-Butyl [1 -(4-amino-2-hydroxymethylphenyl)pyrrolidin-3 yl]methylcarbamate 5 (2-Fluoro-5-nitrophenyl)methanol was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 321.42 (C17H27N303); MS (ESI): 322 (M+H+). 10 tert-Butyl [1-(4-amino-3-chloro-2-cyanophenyl)pyrrolidin-3 yl]methylcarbamate 2-Chloro-6-fluoro-3-nitrobenzonitrile was treated with tert-butyl methylpyrrolidin-3-yl-carbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 350.5 15 (Cl 7H23CIN402); MS (ESI): 350 (M+H+), 351 (M+H+). tert-Butyl [1 -(4-amino-3-methylphenyl)pyrrolidin-3-yl]methylcarbamate 4-Fluoro-2-methylnitrobenzene was treated with tert-butyl methylpyrrolidin 3-ylcarbamate and subsequently hydrogenated by method C-c. This 20 resulted in the product with the molecular weight of 291.40 (Cl 6H25N302); MS (ESI): 292 (M+H+). tert-Butyl [1 -(5-aminopyridin-2-yl)pyrrolidin-3-yl]carbamate 2-Chloro-5-nitropyridine was treated with tert-butyl (R)-(+)-pyrrolidin-3 25 ylcarbamate and subsequently hydrogenated by method C-c. This resulted in the product with the molecular weight of 278.36 (Cl 4H22N402); MS (ESI): 279 (M+H+). 5-(3-Dimethylaminopyrrolidin-1 -yl)pyridin-2-ylamine 30 A suspension of 5-bromo-2-nitropyridine (2 g), 3-(dimethylamino)pyrrolidine (1.14 g), (R)-(+)2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.5 g), palladium(II) acetate (0.09 g), cesium carbonate (4.5 g) in toluene (20 ml) was heated at 100 C for 3 hours. Cooling to room temperature was followed by extraction with 1 N hydrochloric acid (2 x 100 ml). The aqueous 35 phase was adjusted to pH > 10 with ammonia, extracted with ethyl acetate (2 x 100 ml), dried with sodium sulfate, filtered and concentrated. The substance was then treated as described for method B. This resulted in the product with the molecular weight of 206.29 (Cl1 H18FN4); MS (ESI): 207
(M+H+).
337 N-[1 -(4-Aminophenyl)-4-hydroxypyrrolidin-3-yl]-N-methylacetamide trans-N-(4-Hydroxypyrrolidin-3-yl)-N-methylacetamide was reacted with 4-fluoronitrobenzene by method C, and the product was subsequently 5 hydrogenated by method B. This resulted in the product with the molecular weight of 249.32 (Cl 3H19N302); MS (ESI): 250 (M+H+). trans-N-(4-Hydroxypyrrolidin-3-yl)-N-methylacetamide tert-Butyl trans-3-hydroxy-4-methylaminopyrrolidin-1 -carboxylate (1.0 g, 10 tetrahedron: Asymmetry 2001, 12, 2989) was mixed with pyridine (1.5 g) and acetic anhydride (0.567 g). After 3 hours, volatile fractions were removed under high vacuum. The residue was treated by method G. This resulted in the product with the molecular weight of 158.20 (C7H14N202); MS (ESI): 159 (M+H+). 15 trans-1 -(4-Aminopheryl)-4-dimethylaminopyrrolidin-3-o tert-Butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.0 g, tetrahedron: Asymmetry 2001, 12, 2989) was stirred with dimethylamine (40% aq., 10 ml) for 12 hours. The mixture was concentrated and 20 partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The crude product was treated by method G. The resulting amine was reacted with 4-fluoronitrobenzene by method C. The resulting nitro compound was hydrogenated by method B. This resulted in the product with the molecular weight of 221 25 (C12H19N30); MS (ESI): 222 (M+H+). [1-(4-Aminophenyl)-4-methoxypyrrolidin-3-yl]dimethylamine An alternative possibility is for the nitro compound prepared in the preceding method to be alkylated with methyl iodide by method F and then 30 hydrogenated by method B. This resulted in the product with the molecular weight of 235 (C13H21 N30); MS (ESI): 236 (M+H+). [1 -(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine Dimethylpyrrolidin-3-ylamine was reacted with 4-fluoronitrobenzene by 35 method C, and the product was subsequently hydrogenated by method B. This resulted in the product with the molecular weight of 205.31 (C12H19N3); MS (ESI): 206 (M+H+). 1-(4-Aminophenyl)-3-dimethylaminopyrrolidin-2-one 338 Trisodium phosphate (3.56 g) was added to a solution of 4-nitroaniline (5.0 g) in acetonitrile (30 ml) and, at 0*C, 2-bromo-4-chlorobutyryl bromide (11 g) was added. After one hour, a solution of sodium hydroxide (3.2 g) in water (10 ml) was added, and the mixture was vigorously stirred at room 5 temperature. After 6 hours, the same amount of sodium hydroxide solution was again added, and the mixture was left to stand overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The crude product (0.5 g) was heated with dimethylamine (160 mg) in toluene 10 (20 ml) at 800C for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The crude product was hydrogenated by method B. This resulted in the product with the molecular weight of 219.29 (Cl 2H17N30); MS (ESI): 220 (M+H+). 15 1-(4-Aminophenyl)-3-(7-azabicyclo[2.2.1]hept-7-yl)pyrrolidin-2-one was obtained in an analogous manner. 4-[3-(7-Azabicyclo[2.2.1 ]hept-7-yl)pyrrolidin-1 -yl]phenylamine 1-(4-Nitrophenyl)-3-(7-azabicyclo[2.2.1]hept-7-yl)pyrrolidin-2-one (0.25 g) in 20 THF (10 ml) was mixed with borane-THF complex (1 M in THF, 0.83 ml) and boiled under reflux for 3 hours. After the reaction was complete, the mixture was diluted with water and adjusted to pH 9-10 with hydrochloric acid (4N). Extraction in ethyl acetate, drying and concentration of the organic phase afforded a crude product that was hydrogenated by method 25 B. This resulted in the product with the molecular weight of 257.38 (C16H23N3); MS (ESI): 258 (M+H+). (R)-1'-(4-Aminophenyl)-[1,3']bipyrrolidinyl-2-one tert-Butyl [1-(4-Nitrophenyl)pyrrolidin-3-yl]carbamate was treated by 30 method G. The crude product (1.4 g) was dissolved in acetonitrile (20 ml) and mixed with trisodium phosphate (0.67 g) and 4-chlorobutyryl chloride (1.1 g). After 2 hours, sodium hydroxide (0.6 g) in water (10 ml) was added and the mixture was vigorously stirred. After 12 hours, the same amount of sodium hydroxide solution was again added, and the mixture was stirred for 35 a further 24 hours. The concentrated reaction solution was partitioned between water and ethyl acetate, and the organic phase was dried and concentrated. The residue was hydrogenated by method B. This resulted in the product with the molecular weight of 245.33 (C1 4H19N30); MS (ESI): 246 (M+H+).
339 1 -Methylpiperidine-3-carboxylic acid [(R)-1 -(4-aminophenyl)pyrrolidin-3 yl]methylamide tert-Butyl (R)-[1 -(4-nitrophenyl)pyrrolidin-3-yl]methylcarbamate was treated 5 by method G and reacted with 1 -methylpiperidine-3-carboxylic acid by method E. Finally, hydrogenation was also carried out by method E. This resulted in the product with the molecular weight of 316.45 (Cl 8H28N40); MS (ESI): 317 (M+H+). (R)-N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-2-dimethylamino-N 10 methylacetamide was obtained in an analogous manner using N,N dimethylglycine. N-[(R)-1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-(2-diethylaminoethyl)acetamide N-(2-Diethylaminoethyl)-N-[(R)-1 -(4-nitrophenyl)pyrrolidin-3-yl]acetamide 15 was hydrogenated by method B. This resulted in the product with the molecular weight of 318.47 (Cl 8H30N40); MS (ESI): 319 (M+H+). N-(2-Diethylaminoethyl)-N-[(R)-1 -(4-nitrophenyl)pyrrolidin-3-yl]acetamide Acetyl chloride (2.9 g) was dissolved in 50 ml of dry dichloromethane, 20 mixed with 5.3 ml of triethylamine, and after addition of N,N-diethyl-N'-[(R) 1-(4-nitrophenyl)pyrrolidin-3-yl]-ethane-1,2-diamine (5.8 g), stirred at room temperature for 30 minutes. Subsequently, (LCMS check), water (10 ml) was added to the reaction, and the mixture was extracted with dichloromethane (2 x 10 ml). The combined organic phases were dried 25 over magnesium sulfate, the solvent was removed, and the crude product was separated by chromatography on silica gel (dichloromethane/methanol 10:1). This resulted in the product with the molecular weight of 348.45 (C1 8H28N403); MS (ESI): 349 (M+H+). 30 N,N-Diethyl-N'-[(R)-1 -(4-nitrophenyl)pyrrolidin-3-yl]ethane-1,2-diamine tert-Butyl (2-diethylaminoethyl)-[(R)-1 -(4-nitrophenyl)pyrrolidin-3 yl]carbamate (7.9 g) was reacted with trifluoroacetic acid by method G. This resulted in the product with the molecular weight of 306.41 (C16H26N402); MS (ESI): 307 (M+H+). 35 340 tert-Butyl (2-diethylaminoethyl)-[(R)-1-(4-nitrophenyl)pyrrolidin-3 yl]carbamate tert-Butyl [(R)-1 -(4-nitrophenyl)pyrrolidin-3-yl]carbamate (6.0 g) was dissolved in 50 ml of N,N-dimethylformamide and, after addition of sodium 5 hydride (1.1 g), stirred at room temperature for 30 minutes, and subsequently chlorethyldiethylamine hydrochloride (4.1 g) was added. The mixture was subsequently stirred at room temperature with exclusion of moisture for 4 hours. The reaction was stopped by adding water (50 ml), and this was followed by extraction with ethyl acetate (3 x 50 ml) and 10 drying of the combined organic phases over magnesium sulfate, and removal of the solvent. This resulted in the product with the molecular weight of 406.53 (C21 H34N404); MS (ESI): 407 (M+H+). Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 15 yl)phenyl]amide Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester was reacted with [1 (4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method E, and the product was then treated by method G. This resulted in the product with the molecular weight of 316.45 (C18H28N40); MS (ESI): 317 (M+H+). 20 Synthesis of amines required as intermediates Spiro[1,3-benzodioxol-2, 1'-cyclopentane]-5-amine 25 A solution of spiro[5-nitro-1,3-benzodioxol-2,1'-cyclopentane] (8.8 g) in methanol (90 ml) was hydrogenated under 6 bar in the presence of palladium on carbon (10%, 0.1 g). After 30 minutes at room temperature, the mixture was filtered and concentrated. This resulted in the product with the molecular weight of 191.23 (C11H13NO2); MS(ESI): 192 (M+H+). 30 Spiro[5-nitro-1,3-benzodioxol-2,1'-cyclopentane] A solution of spiro[1,3-benzodioxol-2,1'-cyclopentane] (8.5 g) in 20 ml of dichloromethane was added dropwise at 100C to 65% strength nitric acid (65 ml). After 2 hours at 5-1 0*C, the mixture was diluted with water, the 35 organic phase was separated off, and the aqueous phase was extracted 341 twice with dichloromethane. The combined organic phases were washed with water until neutral, dried over sodium sulfate, concentrated and crystallized from heptane. This resulted in the product with the molecular weight of 221.21 (C11 H 1 N04); MS(ESI): 222 (M+H+). 5 Spiro[1,3-benzodioxol-2,1 '-cyclopentane] Catechol (11 g) and cyclopentanone (9 ml) were heated under reflux in toluene (150 ml) with p-toluenesulfonic acid (0.18 g) with a water trap. After 18 hours, the mixture was concentrated and purified by chromatography 10 (silica gel, heptane/ethyl acetate 4:1). This resulted in the product with the molecular weight of 176.22 (Cl1 H1 202); MS(ESI): 177 (M+H+). 5-Chloro-2',3',5',6'-tetrahydro-1'H-[2,4']bipyridinyl-4'-ol Butyllithium (15% in hexane; 7.6 ml) was added dropwise to a solution of 2 15 bromo-5-chloropyridine (2.0 g) in diethyl ether (50 ml) at -78*C and, after one hour, a solution of N-tert-butoxycarbonyl-4-piperidinone (2.1 g) in diethyl ether (10 ml) was added dropwise. After 30 minutes, water was cautiously added, and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. 20 The residue was treated by method G. This resulted in the product with the molecular weight of 212.68 (Cl OH13CIN20); MS(ESI): 213 (M+H+). The following were obtained analogously: 5-Fluoro-2',3',5',6'-tetrahydro-1'H-[2,4']bipyridinyl-4'-ol 6-Chloro-2',3',5',6'-tetrahydro-1'H-[3,4']bipyridinyl-4'-ol. 25 6-Cyclopentyloxypyridin-3-ylamine A mixture of 2-hydroxy-5-nitropyridine (1.4 g), cyclopentyl bromide (1.5 g) and potassium carbonate (3 g) was heated in DMF (20 ml) at 800C for 6 hours. The mixture was diluted with water and extracted with ethyl acetate. 30 The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase ethyl acetate/heptane 1:2). The nitro compound obtained in this way was hydrogenated by method B. This resulted in the product with the molecular weight of 178.24 (C10H14N202); MS(ESI): 179 (M+H+).
342 6-(4-Fluorophenyl) -3-azabicyclo[4. 1.0]heptane Diethylzinc (1M in hexane, 19 ml) in dichloromethane (100 ml) was mixed with trifluoroacetic acid (3 ml) at 00C. After 20 minutes, diiodomethane (3 5 ml) in dichloromethane (10 ml) was added. Then 4-(4-fluorophenyl)-1,2,3,6 tetrahydropyridine (3.0 g) in dichloromethane (10 ml) was added, and the mixture was stirred at room temperature overnight. After addition of hydrochloric acid (1 N), the phases were separated and the organic phase was washed with water, dried over magnesium sulfate and concentrated. 10 This resulted in the product with the molecular weight of 191.25 (C12H14FN); MS(ESI): 192 (M+H+). Synthesis of carboxylic acids required as intermediates 15 4-(4-Methylpiperidin-1 -yl)benzoic acid 4-(4-Methylpiperidinl -yl)benzonitrile (1.2 g) was heated to reflux with potassium hydroxide (0.7 g) in water (2 ml) and ethylene glycol (8 ml) for 3 hours. The mixture was diluted with water, washed with ethyl acetate and 20 acidified with 2N hydrochloric acid. The precipitated product was filtered off with suction, dissolved in dichloromethane, dried over sodium sulfate, concentrated and crystallized from diethyl ether. This resulted in the product with the molecular weight of 219.29 (C13H17NO2); MS(ESI): 220 (M+H+). 25 4-(4-Methylpiperidin1-yl)benzonitrile 4-Fluorobenzonitrile (1.21 g) was heated with 4-methylpiperidine (1.00 g) at 1800C for 1 hour. The mixture was then taken up in ethyl acetate, washed with water, 2N sodium hydroxide solution and saturated sodium 30 bicarbonate solution, dried over sodium sulfate, concentrated and crystallized from n-pentane. This resulted in the product with the molecular weight of 200.29 (Cl 3H16N2); MS(ESI): 201 (M+H+). 4-Butoxycyclohexanecarboxylic acid 343 Sodium hydride (2.78 g) was added to a solution of ethyl 4 hydroxycyclocarboxylate (10 g) and butyl iodide (10.6 g) in DMF while cooling in ice under argon. After 12 hours, the mixture was poured onto ice (200 g), extracted with ethyl acetate (100 ml) and then washed with water 5 (3 x 50 ml). The organic phase was concentrated and mixed with ethanol (50 ml) and 5N sodium hydroxide (30 ml). The solution was heated at 60*C for 4 hours. Cooling to room temperature was followed by adjustment to pH < 2 with 2N hydrochloric acid, extraction with ethyl acetate (3 x 50 ml), drying with magnesium sulfate, filtration and concentration. This resulted in 10 the product with the molecular weight of 200.28 (Cl 1 H2003); MS (ESI): 201 (M+H+). 1 -Benzyl-1 H-[1,2,3]triazole-4-carboxylic acid Methyl 1 -benzyl-1 H-[1,2,3]triazol-4-carboxylate (217 mg) was dissolved in 4 15 ml of methanol and hydrolyzed with 2 ml of 2N sodium hydroxide solution. After acidification with 4 ml of 2N hydrochloric acid, the resulting precipitate was filtered off, taken up in 5 ml of ethyl acetate and purified by preparative HPLC. This resulted in the product with the molecular weight of 203.2 (Cl 0H9N302); MS (ESI): 204 (M+H+). 20 Methyl 1 -benzyl-1 H-[1,2,3]triazole-4-carboxylate Benzyl azide (266 mg) was dissolved together with sodium ascorbate (20 mg) and copper sulfate (5 mg) in 8 ml of the solvent mixture (tert butanol/water 3:1), and methyl propionate (336 mg) was added. The 25 solution was stirred at room temperature for 2 hours. A white precipitate separated out and was filtered off with suction on a frit and subsequently dried. This resulted in the product with the molecular weight of 217.23 (C11H11N302); MS (ESI): 218 (M+H+). 1 -Biphenyl-4-yl-1 H-[1,2,3]triazole-4-carboxylic acid was prepared 30 analogously from 4-Ethynylbiphenyl and ethyl azidoacetate. 1 -Butyl-1 H-indole-5-carboxylic acid Sodium hydride (50% in oil, 1.4 g) was added to methyl 1 H-indole-5 carboxylate (5.0 g) in DMF (100 ml) and, after gas evolution ceased, 35 bromobutane (3.9 g) was added. After 12 hours, the reaction solution was diluted with ethyl acetate and washed three times with water. The organic 344 phase was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (mobile phase ethyl acetate/heptane 1:6). The resulting ester was dissolved in methanol (10 ml) and boiled under reflux with sodium hydroxide (0.6 g ) in water (10 ml) for 5 12 hours. The mixture was diluted with water and acidified with hydrochloric acid, followed by extraction with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 217.27 (Cl 3H15NO2); MS (ESI): 218 (M+H+). 10 3'-Acetylaminobiphenyl-4-carboxylic acid 3'-Aminobiphenyl-4-carboxylic acid (0.2 g) was mixed with pyridine (0.7 g) and acetic anhydride (180 mg) and, after 14 hours, volatile fractions were removed. The residue was taken up in sodium hydroxide solution (2N) and washed with diethyl ether. The aqueous phase was acidified with 15 hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 255.28 (Cl 1H1 3NO3); MS (ESI): 256 (M+H+). 20 3'-lsobutyrylaminobiphenyl-4-carboxylic acid 3'-Aminobiphenyl-4-carboxylic acid (0.2 g) was mixed in dichloromethane with potassium carbonate (121 mg) and isobutyryl chloride (94 mg). After 12 hours, the mixture was diluted with sodium hydroxide solution and washed with diethyl ether. The aqueous phase was acidified with 25 hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. This resulted in the product with the molecular weight of 283.33 (Cl 7H1 7NO3); MS (ESI): 284 (M+H+). 30 5-Butoxypyridine-2-carboxylic acid Sodium hydride (50% in oil, 250 mg) was added to benzhydryl 5 hydroxypyridine-2-carboxylate (2.0 g) dissolved in DMF (20 ml) and, after gas evolution ceased, 1 -bromobutane (0.72 g) was added. The mixture 35 was heated at 900C for 6 hours. It was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and 345 concentrated. The residue was hydrogenated in analogy to method B. This resulted in the product with the molecular weight of 195.22 (Cl 0H13NO3); MS (ESI): 196 (M+H+). 5 4-Methyl-3,4,5,6-tetrahydro-2H-[1,3']bipyridinyl-6'-carboxylic acid Benzhydryl 5-trifluoromethanesulfonyloxypyridine-2-carboxylate (3.0 g) was heated with 4-methylpiperidine (1.4 g) at 80*C for one hour. The reaction mixture was immediately purified by preparative HPLC and then hydrogenated in analogy to method. This resulted in the product with the 10 molecular weight of 220.27 (Cl 2H16N202); MS (ESI): 221 (M+H+). N-[4-(3-Dimethylaminopyrrolidin-1 -yl)phenyl]terephthalamic acid Method P-a N-[4-(3-Dimethylaminopyrrolidin-1 -yl)phenyl]terephthalamic acid methyl 15 ester (1.7 g) dissolved in methanol (20 ml) was stirred with sodium hydroxide solution (2N, 15 ml) at room temperature for 24 hours. If conversion is incomplete, it is also possible to heat to reflux. The organic solvent was distilled off, and the mixture was acidified with hydrochloric acid. The precipitate which separated out was filtered off with suction and 20 dried. This resulted in the product with the molecular weight of 353.42 (C20H23N303); MS (ESI): 354 (M+H+). N-[4-(3-Dimethylaminopyrrolidin-1 -yl)phenyl]terephthalamic acid methyl ester 25 [1 -(4-Aminophenyl)pyrrolidin-3-yl]dimethylamine was reacted with terephthalic acid monomethyl ester by method E. This resulted in the product with the molecular weight of 367.45 (C21 H25N303); MS (ESI): 368 (M+H+). 30 4-(Cyclopentanecarbonylmethylamino)benzoic acid Methyl 4-methylaminobenzoate was reacted with cyclopentanecarboxylic acid by method E and then hydrolyzed by method P-a. This resulted in the product with the molecular weight of 247.30 (Cl 4H17NO3); MS (ESI): 248 (M+H+). 35 The following compounds were obtained analogously: 4-(Cyclopentanecarbonylamino)-3-methoxybenzoic acid 2-Chloro-4-(cyclopentanecarbonylamino)benzoic acid 2-Fluoro-4-(cyclopentanecarbonylamino)benzoic acid 4-(Cyclopentanecarbonylamino)-3-methylbenzoic acid 346 4-(Cyclopentanecarbonylamino)benzoic acid 4-(Cyclopentanecarbonylamino)-3-trifluoromethoxybenzoic acid 3-Chloro-4-(cyclopentanecarbonylamino)benzoic acid 5-Chloro-4-(cyclopentanecarbonylamino)-2-methoxybenzoic acid 5 4-[(Cyclohex-1 -enecarbonyl)amino]benzoic acid 4-[(Cyclopent-1 -enecarbonyl)amino]benzoic acid 3-Fluoro-4-(1 -methylbutoxy)benzoic acid 10 A solution of 0.449 g of 1-[3-fluoro-4-(1-methylbutoxy)phenyl]ethanone in 6.8 ml of dioxane was dropped dropwise into 1.36 g of NaOH, 1.6 g of bromine in 6.8 ml of water. The mixture was stirred at room temperature for 30 minutes and then heated at 500C for 1 h. The excess bromide was decomposed by adding a sodium disulfite solution, and then the solution 15 was poured into 25% strength hydrochloric acid solution and stirred for 20 minutes. The solution was extracted with ethyl acetate. The combined organic phases dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This resulted in the product with the molecular weight of 226.1 (C12H15F03); MS (ESI): 227 (M+H+). 20 1-[3-Fluoro-4-(1 -methylbutoxy)phenyl]ethanone 0.058 g of NaH was added to a solution of 0.176 g of 2-pentanol in 2 ml of DMF, and the solution wa3 stirred at room temperature for 1 hour. Then 0.312 g of 3,4-difluoroacetophenone was added, and the mixture was 25 stirred at room temperature overnight. The reaction solution was taken up in ethyl acetate and washed twice with water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The resulting compound was reacted further without further purification. The following compounds were obtained analogously: 30 4-Cyclobutoxy-3-fluorobenzoic acid 3-Fluoro-4-(2-methylcyclopropylmethoxy)benzoic acid 4-(2-Cyclopropylethoxy)-3-fluorobenzoic acid 3-Fluoro-4-(1 -methylpiperidin-3-yloxy)benzoic acid 4-(1 -Acetylpiperidin-3-yloxy)-3-fluorobenzoic acid 35 3-Fluoro-4-(1 -methylpyrrolidin-3-yloxy)benzoic acid 4-(1 -Acetylpyrrolidin-3-yloxy)-3-fluorobenzoic acid 347 3-Fluoro-4-(1-methylpiperidin-3-ylmethoxy)benzoic acid 4-(2,4-Difluorophenoxy)benzoic acid 5 0.518 g of potassium hydroxide was added to a solution of 0.428 g of ethyl 4-(2,4-difluorophenoxy)benzoate in 2 ml of THF/water (1:1). The solution was heated at 110*C for 6 hours. The THF was then removed in vacuo, and the aqueous phase was freeze dried and purified by preparative HPLC. This resulted in the product with the molecular weight of 250.04 10 (C13H8F203); MS (ESI): 251 (M+H+). Ethyl 4-(2,4-difluorophenoxy)benzoate 0.018 g of NaH was added to a solution of 0.1 g of 2,4-difluorophenol in 0.5 ml of DMF. The reaction was stirred at room temperature for 45 minutes. 15 Then 0.129 g of ethyl 4-fluorobenzoate in 0.5 ml of DMF was added dropwise. The reaction was heated at 1100C overnight. After cooling concentrated in vacuo and the residue taken up in ethyl acetate/water. The ethyl acetate phase was washed three times with water, dried over sodium sulfate, concentrated in vacuo and purified by preparative HPLC. This 20 resulted in the product with the molecular weight of 278.08 (Cl 5H12F203); MS (ESI): 279 (M+H+) 4-(2,4-Difluorophenoxy)benzoic acid was reacted with [1-(4 aminophenyl)pyrrolidin-3-yl]-dimethylamine by method E-b. This resulted in the product with the molecular weight of 437.19 (C25H25F2N302); MS 25 (ESI): 438 (M+H+) as hydrotrifluoroacetate. 4-Butoxy-3-methoxybenzoic acid Methyl 4-hydroxy-3-methoxybenzoate was alkylated with bromobutane by method H and hydrolyzed by method P-a. This resulted in the product with 30 the molecular weight of 224.26 (C1 2H1604); MS (ESI): 225 (M+H+). The following compounds were prepared analogously: 4-Butoxy-3,5-dichlorobenzoic acid 4-Butoxy-3-nitrobenzoic acid 4-Butoxy-3-chlorobenzoic acid 35 4-Butoxy-3,5-dimethylbenzoic acid 348 4-Butoxy-2,3-dichloro-5-methoxybenzoic acid 4-Butoxy-2,3,5,6-tetrafluorobenzoic acid 4-Butoxy-3-fluorobenzoic acid 3-Acetyl-4-butoxybenzoic acid 5 2,4-Dibutoxybenzoic acid 4-Butoxy-2-chlorobenzoic acid 4-Propoxymethylbenzoic acid Sodium hydride (50% in oil; 0.42 g) was cautiously added to a solution of 10 propanol (0.6 g) in DMF (8 ml). After gas evolution ceased, methyl 4 bromomethylbenzoate (1.0 g) was added. After 4 hours, the mixture was partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The residue was hydrolyzed by method P-a. This resulted in the product with the molecular weight of 15 194.23 (C11H1403); MS (ESI): 195 (M+H+). The following compounds were prepared analogously: 4-Ethoxymethylbenzoic acid 4-Butoxymethylbenzoic acid 4-lsobutoxymethylbenzoic acid 20 4-Phenoxymethylbenzoic acid 4-(Pyridin-3-yloxymethyl)benzoic acid 4-(Pyridin-2-yloxymethyl)benzoic acid 4-Benzoimidazol-1 -ylmethylbenzoic acid 4-Indol-1 -ylmethylbenzoic acid 25 4-Phenylsulfanylmethylbenzoic acid 4-(Pyrimidin-2-ylsulfanylmethyl)benzoic acid 4-(Pyridin-2-ylsulfanylmethyl)benzoic acid 4-(2-Cyanophenoxymethyl)benzoic acid 4-(2-Chlorophenoxymethyl)benzoic acid 30 4-Cyclobutoxymethylbenzoic acid 4-Cyclopentyloxymethylbenzoic acid 4-Cyclohexyloxymethylbenzoic acid 4-sec-Butoxymethylbenzoic acid 4-Pentoxymethylbenzoic acid 35 4-(3-Oxo-3a,4,5,6-tetrahydro-3H-cyclopentapyrazol-2-yl)benzoic acid A solution of 4-hydrazinobenzoic acid (0.3 g), ethyl-2 oxocyclopentanecarboxylate (0.31 g) and p-toluenesulfonic acid (340 mg) 349 in ethanol (12 ml) was boiled under reflux for 12 hours. The concentrated reaction solution was purified by preparative HPLC. The isolated reaction product (as ethyl ester) was hydrolyzed by method P-a. This resulted in the product with the molecular weight of 244.25 (Cl 3H12N203); MS (ESI): 245 5 (M+H+). 4-Butoxy-2-methoxybenzoic acid 4-Hydroxy-2-methoxybenzaldehyde was alkylated with 1 -bromobutane by 10 method H. The resulting aldehyde (6.4 g) in dioxane (100 ml) was mixed with sodium dihydrogen phosphate (14.4 g) and sulfuric acid (2.4 ml), and the solution was cooled to 10*C. A solution of sodium chlorite (3.61 g) in water (100 ml) was added in such a way that the temperature did not exceed 10 C. 15 minutes after the addition was complete, sodium sulfite 15 (4.6 g) was added. After a further 15 minutes, the pH was adjusted to 2 with hydrochloric acid and the dioxane was removed in a rotary evaporator. The aqueous phase was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. This resulted in the product with the 20 molecular weight of 224.26 (Cl 2H1604); MS (ESI): 225 (M+H+). 4-Butoxy-5-chloro-2-methoxybenzoic acid was obtained as by-product. 4-(1 -Propoxyethyl)benzoic acid Methyl 4-(1 -hydroxyethyl)benzoate (2.0 g) dissolved in DMF (30 ml) was 25 mixed with propyl iodide (3.8 g), and then sodium hydride (50% in oil, 0.53 g) was added. After the end of the exothermic reaction, the mixture was stirred for 1 hour and then water was cautiously added. It was extracted with ethyl acetate, and the organic phase was dried over sodium sulfate, filtered and concentrated. The residue was hydrolyzed by method P-a. 30 This resulted in the product with the molecular weight of 208.26 (C12H1603); MS (ESI): 209 (M+H+).
The following examples show ICso values in the range of 50 - 10000 nM: 1,2,4, 5,6,7,8,9,11,12,13,14,15,16,17,18,19,21,22,25,26,27,28,29,30,31, 32,33) 35,37,39,42,43,44,45,46, 47,48,49,50,5.1,52,53,54,55,56,57,58,60,61,62, 64,65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 79, 80, 81, 82, 84, 86, 87, 88, 89, 90, 91, 92, 93, 94,95,96,97,98,99,101,102,103, 104,j05, 106, 107, 108,109,110,111,112,113,114, 115, 116,117,118,119,120,121,122,123, 124,125,126,127,128, 129,130,131, 132,133, 134,135,136,137,138, 139,140,141, 142,143, 144,146,148, 159,163,164,165, 167,168, 169, 175, 176, 178,180, 187, 188, 189, 191, 194,195,196,203,206,210,211,212,213,214, 215, 217, 219, 235, 236, 244, 245, 246,247, 248, 249, 250, 251, 252, 254,255, 256,257,258, 259 260, 262, 263, 268, 269,270,271, 272, 273, 274, 277,281,282, 283,284, 285, 286, 287, 288, 289,291,292,293, 300,304,305,309,310,312,313,314,315,327,338, 340,341,343, 345, 348, 350, 351, 352, 353, 354, 355, 357, 358, 359, 364, 368, 369, 370, 371, 372, 373, 374, 375, 376, 378, 380,383, 384,385, 386, 387, 388, 389, 390, 391, 393, 394,396, 398, 399,402, 403, 404,405,408,409,410,411,412, 413,'416, 418, 419,420,422, 423,424,425, 426,427, 428, 429, 430,431,432, 439,441,442, 443, 445, 447, 449, 453, 457, 458, 462, 463, 464, 469, 476,478,484,485,486, 487,491,495,496,497,499, 502,504, 506, 506,508, 509, 510, 512, 514, 515,516, 517,518,519,520,521,526, 527,529,530,531, 532, 534,535, 536,537,539, 540, 543, 544, 545, 546, 549,551,552, 553, 555, 556, 557, 562, 563, 564,565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 576,.581, 582, 583, 585, 586, 587, 588, 589, 590, 591, 595, 597, 600, 602; 603, 604, 608, 612,613, 618, 619, 620, 624, 632, 646, 647, 649, 650, 652, 653, 654,. 655, 656, 657, 659, 662, 663,664,665, 678, 681, 682, 683, 684, 685, 687,688, 691, 703, 704, 711, 712, 720, 723, 725, 726,728, 729, 731, 732,735, 736,738, 742, 753, 756, 758, 759, 760, 761, 762, 764, 765,767, 768, 769, 770, 772, 773, 779, 787, 795, 796, 798, 800, 807, 813, 816, 831, 859, 876, 877, 897, 900,902, 903, 904, 905, 906,907,908, 909, 910, 912, 913, 914, 917, 920, 921, 922, 923, 924, 926, 928, 929, 930, 931,932, 933, 934, 935, 936, 938, 939, 940, 941, 944, 945, 946, 948, 950, 951, 953, 954, 955, 956, 957, 958, 959, 960, 962, 968, 969, 972, 973, 978, 979, 981, 987, 989, 990,991,993, 1002, 1004, 1005,1006, 1007, 1010,1020, 1023, 1024, 1025, 1030, 1032, 1042, 1049, 1050, 1052,1062,1063, 1065, 1073, 1074, 1075, 1076, 1079, 1080, 1082, 1083, 1084, 1085, 1086, 1087, 1088,.1089, 1090, 1091, 1092,1093, 1097, 1098, 1099, 1100, 1102, 1103, 1104,1105, 1106,1107,1108,1111,1112,1113,1116,1117, 1119, 1120, 1121, 1122, 1123, 1124,1125, 1126, 1127, 1128, 1129, 1131, 1132, 1133, 1146, 1187, 1189,1190,1194,1195,1197,1198,1204,1205,1206,1207, 1209,1220,1221, 1224, 1226, 1227, 1228, 1229, 1230, 1231, 1238, 1239, 1240, 1241, 1242, 1243,1244, 1245, 1246, 1247, 1248, 1249, 1251, 1252, 1253, 1254, 1256, 1257, 1258, 1259, 1260, 1261, 1262, 1263, 1264, 1265, 1266, 1267, 1268, 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278, 1279, 1281, 1282, 1283, 1284, 1285, 1286,1287, 1288, 1289, 1290, 1292, 1293, 1294, 1295, 1296, 1297, 1298, 1299, 1300, 1301, 1303, 1304, 1305, 1306, 1307, 1308, 1309, 1310, 1311, 1312,1313,1314, 1315, 1316,1317,1318,1319,1320, 1321, 1322,1323, 1324,1325, 1326, 1327, 1328, 1329, 1330, 1331, 1332, 1333, 1334, 1336, 1337, 1338, 1339, 1340,1341, 1342, 1343, 1344,1345, 1346, 1347,1348, 1349, 1350,1351, 1352, 1353, 1354, 1355, 1356, 1357, 1358, 1359,1360,1361, 1362, 1363, 1364, 1365, 1366, 1367, 1368, 1369, 1370, 1371, 1372, 1373, 1374, 1375, 1376, 1377,1378, 1379, 1380, 1382, 1383, 1384, 1385, 1386,1387,1388, 1389, 1390, 1391, 1392, 1393, 1394, 1395, 1396, 1397, 1398, 1399, 1400, 1401, 1402, 1403, 1404, 1405, 1406,1407, 1408, 1409, 1411, 1412, 1413, 1414, 1415, 1416, 1417, 1418, 1419, 1423, 1424,1426, 1427, 1428,1429,1430,1431, 1432, 1433, 1434, 1435, 1436,1438, 1439, 1440, 1441, 1444, 1445, 1446, 1447, 1450, 1451, 1453, 1454, 1455, 1456, 1457, 1458, 1460, 1461, 1463, 1464, 1465, 1466, 1468, 1469, 1470, 1471, 1474, 1476, 1477, 1479,1480,1481, 1482, 1483, 1484, 1485, 1486, 1487, 1488, 1489, 1490, 1491, 1492, 1498, 1500,1501,1503, 1504,1505, 1507, 1511, 1515,1518,1519,1520,1521, 1528, 1531, 1532, 1541, 1542, 1545, 1546, 1555, 1558, 1561, 1572, 1574, 1576, 1584, 1586, 1587, 1589, 1592, 1602,1606,1607, 1609, 1614, 1615, 1616, 1617, 1618. For the further examples mentioned in the present application the activity is characterized by < 50% inhibition at a concentration of 10 F.M.
In the following table specific IC 5 o values are shown for some representative examples: Example No. ICso / 33 148 97 80 118 712 246 471 312 64 425 717 589 .431 928 7843 969 156 981 3732 990 356 1121 87 1343 148 1477 3779 1489 135 In the case of examples 4 and 13 of the present invention the anorectic effect (MCH antagonistic activity) was shown on female NMRI-mice (page 70, lines 12 to the end of page 70).

Claims (17)

1. A compound of the formula I 0 R7 R6 R11''-E A= RNRR 2 R10 G-D m R4 R9 R8 R5 in which the meanings are R1, R2 independently of one another H, (C1-C8)-alkyl, -(CR78R79) 0 -R12, (C1-C4) alkoxy-(C 1 -C4)-alkyl, (C3-C8)-alkenyl, CO-(C1-C8)-alkyl, -CO-(CH2)o-R12, CO-aryloxy-(C 1 -C4)-alkyl, COCH=CH(R13), COCC(R14), CO(C(R1 5)(R1 6))qN(R1 7)(R1 8), CO(C(R1 9)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally b'k substituted by F, Cl, CF 3 , (C1-C6)-alkyl, 0-(C1-C4)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C1-C6)-alkyl, N(R31)(R32) or SO2CH 3 ; o 0,1,2,3,4, 5,6; q, r independently of one another 1, 2, 3; s 0,1,2,3,4; R13, R14 independently of one another a phenyl ring which may comprise 0-1 nitrogen atoms; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 independently of one another H, (C1-C6)-alkyl; 353 R18 H, (C1-C6)-alkyl, CO(C1-C6)-alkyl, CO(R33); or R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen and sulfur; R33 a 5-10 membered aromatic ring system which may comprise a further heteroatom from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C1-C6)-alkyl, 0-(C1-C8)-alkyl; R12 OH, O-(C1-C6)-alkyl, 0-(CO-C8)-alkylene-aryl, CN, S-(C 1 -C6)-alkyl, COO(R80), CON(R81)(R82), 3-12 membered mono-, bi- or spirocyclic ring which may comprise one or more heteroatoms from the group of N, 0 and S, and the 3-12 membered ring may comprise further substituents such as F, Cl, Br, OH, CF 3 , CN, oxo, O-(C1-C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C1-C6)-alkyl, 0-(CO-C8)-alkylene-aryl, (CO-C8)-alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(C-C6)-alkyl, COCOO(C1-C6)-alkyl, COO(R40), S(O)u(R41); t 0, 1, 2, 3, 4, 5, 6; u 0, 1, 2; R34, R35, R37, R38 independently of one another H, (C1-Cs)-alkyl; or R34 and R35 optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen and sulfur and may optionally be substituted by 1-2 oxo groups; R36, R39 independently of one another (C3-C)-cycloalkyl, 5-10 membered aromatic ring system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C1-C6)-alkyl, 0-(C1-C8)-alkyl; 354 R40 H, (C1-C8)-alkyl, (C2-C 6 )-alkenyl, (CO-C8)-alkylene-aryl; R41 (C1 -C6)-alkyl, 5-10 membered aromatic ring system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C1-C6)-alkyl, 0-(C1-C8)-alkyl; R78, R79 independently of one another H, (C1-C8)-alkyl, hydroxy-(Cl-C4)-alkyl, (C 1 -C4)-alkoxy-(C1-C4)-alkyl; R80, R81 independently of one another H, (C1-C8)-alkyl; R3 H, (C1-C6)-alkyl; R4, R5 independently of one another H, (C1-C6)-alkyl, OH, 0-(C1-C6)-alkyl, 0 CO(C1-C6)-alkyl, S-(C1-C6)-alkyl; R6, R7, R8, R9 H; or R6 and R7, R8 and R9 independently of one another optionally oxo; n 1; m 1; A, B, D, G independently of one another N, C(R42); or the groups A and B or D and G are each C(R42) and together form an ortho-phenylene unit to result overall in a 1,4-bisubstituted naphthalene system; R42 H, F, Cl, Br, CF3, CN, 0-(C1-C6)-alkyl, O-(C1-C4)-alkoxy-(C1-C4)-alkyl, S (C 1 -C6)-alkyl, (C1-C6)-alkyl, (C0-C8)-alkylene-aryl, 0-(CO-C8)-alkylene-aryl, N(R43)(R44), S02-CH 3 , CON(R45)(R46), N(R47)CO(R48), CO(R51), (CR84R85)r-O(R86); 355 R43, R44, R45, R46, R47 independently of one another H, (C1-C8)-alkyl; or R43 and R44, R45 and R46 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen and sulfur; R48, R50, R51 independently of one another H, (C1-C8)-alkyl, aryl; R84, R85 H; R86 H, (C1-C6)-alkyl; x 0,1,2; R10 H, (C1-C8)-alkyl; X N(R52), a bond, C=C, C(R53)(R54), CH 2 -CH 2 ; Y 0, S, N(R89); R89 H, (C1-C8)-alkyl; R52, R53, R54 independently of one another H, (C1-C8)-alkyl; E is selected from the group consisting of 356 NS N -- N N-NS, N- / N- N N N' N- and N--O which may optionally have substituents from the group of H, F, Cl, Br, OH, CF 3 , NO 2 , OCF 3 , O-(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), S02-CH 3 , CO(R65); R57, R58 independently of one another H, (C1-C8)-alkyl; R65 independently of one another H, (C1-C 8 )-alkyl, aryl; K a bond, 0, OCH 2 , CH20, S, SO, S02, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO, C=C, C=C, SCH2, SO2CH2; v 1, 2, 3, 4; R66, R67, R68, R69, R70 independently of one another H, (C1-C8)-alkyl; R11 H, (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, (C 3 -C 8 ) alkynyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which may comprise 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF 3 , CN, (C1-C6)-alkyl, 0-(C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C 4 )-alkyl, 357 hydroxy-(C 1 -C4)-alkyl, (CO-C8)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C 1 -C6)-alkyl, N(R76)(R77) or SO2CH 3 ; R71, R72, R73, R74, R75, R76, R77 independently of one another H, (C1-C8)-alkyl; or R72 and R73, R76 and R77 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N (C1-C6)-alkyl, oxygen and sulfur; or the N-oxides and the physiologically tolerated salts thereof.
2. A compound of formula I as claimed in claim 1, in which the meanings are R1, R2 independently of one another are H, (C1-C8)-alkyl, -(CR78R79) 0 --R12, (C1-C4)-alkoxy-(C1-C4)-alkyl, CO-(C 1 -C8)-alkyl, -CO-(CH 2 )o -R12, COCH=CH(R1 3), COCC(R1 4), CO(C(R1 5)(R1 6))qN(R1 7)(R1 8), CO(C(R23)(R24))sO(R25); or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 1 0-membered mono- or bicyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, Cl, CF 3 , (C1-C6)-alkyl, 0 (C1-C4)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (CO-C2)-alkylene-aryl, oxo, CO(R26), hydroxy, N(R31)(R32) or SO 2 CH 3 ; o 0,1,2,3,4; q 1 or2; 358 s 0,1,2,3; R13, R14 independently of one another are a phenyl ring which may comprise 0-1 nitrogen atoms; R15, R16, R17, R23, R24, R26, R31, R32 independently of one another H, (C1-C6)-alkyl; R18 H, (C1-C6)-alkyl, CO(Cl-C6)-alkyl; or R17 and R18, R31 and R32 independently of one another optionally form together with the nitrogen atom to which they are bonded a 5-6 membered ring selected from pyrrolidine, piperidine, N-methylpiperazine, morpholine; R12 OH, 0-(C1-C6)-alkyl, 0-(CO-C6)-alkylene-aryl, CN, 3-10 membered mono- or bicyclic ring which may comprise 1-3 heteroatoms from the group of N, 0 and S, and the 3-10 membered ring may comprise further substituents such as F, Cl, Br, OH, CF 3 , CN, oxo, 0-(C1-C6)-alkyl, (C1 C4)-alkoxy-(C1-C4)-alkyl, (C1-C6)-alkyl, (CO-C2)-alkylene-aryl, N(R34)(R35), CO(C1-C6)-alkyl; t 0,1,2,3,4, 5,6; u 0 or 2; R34, R35 independently of one another H, (C1-C8)-alkyl; or R34 and R35 optionally together with the nitrogen atom to which they are bonded a 5 6 membered ring which, apart from the nitrogen atom, may also 359 comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen and sulfur and may optionally be substituted by 1-2 oxo groups; R78, R79 independently of one another H, (C1-C8)-alkyl, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkoxy-(C 1 -C4)-alkyl; R3 H; R4, R5 independently of one another H, (C1-C6)-alkyl, OH, 0-(C1-C6)-alkyl, 0 CO-(C1-C6)-alkyl; R6, R7, R8, R9 H; n 1 m 1; A, B, D, G B is N, C(R42); and A, D, G C(R42); R42 H, F, Cl, Br, CF 3 , CN, 0-(C1-C6)-alkyl, (C1-C6)-alkyl, S0 2 -CH 3 , CON(R45)(R46), N(R47)CO(R48), CO(R51), -(CR84R85)x-O(R86); R45, R46, R47 independently of one another H, (C1-C8)-alkyl; or R45 and R46 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the 360 group of N-(C1-C6)-alkyl, oxygen and sulfur; R48, R51 independently of one another H, (C1-C8)-alkyl; R84, R85 H; R86 H, (C1-C6)-alkyl; x 0, 1; R10 H, (C1-C8)-alkyl; X N(R52), a bond, C=C, C(R53)(R54), CH2-CH 2 ; R52, R53, R54 independently of one another H, (C1-C8)-alkyl; E is selected from the group consisting of 0 /r -N N- -N N-N- N N N __ N- /_ N N- NN S -N- and N-O - 361 which may optionally have substituents from the group of H, F, Cl, Br, OH, CF3, NO 2 , OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C 6 )-alkenyl, N(R57)(R58), SO2-CH 3 , CO(R65); R57, R58 independently of one another H, (C1-C8)-alkyl; R65 independently of one another H, (C1-C8)-alkyl; K a bond, 0, OCH2, CH20, N(R66), CON(R68), (C(R69)(R70))v, CO, C=C, SCH 2 ; v 1, 2, 3; R66, R68, R69, R70 independently of one another H, (C1-C8)-alkyl; R11 (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which may comprise 0 to 3 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF 3 , CN, (C1-C6)-alkyl, O-(C1-C8)-alkyl, (Co-C2)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or SO2CH 3 ; R71, R72, R73, R75, R76, R77 independently of one another H, (C1-C8)-alkyl; or R72 and R73, R76 and R77 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the 362 nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen and sulfur; or the N-oxides and the physiologically tolerated salts thereof.
3. A compound of formula I as claimed in claim 1, in which the meanings are R1, R2 independently of one another are H, (C1-C8)-alkyl, -(CR78R79) 0 -R12, (C1-C4)-alkoxy-(C1-C4)-alkyl, CO-(C1-C8)-alkyl, -CO-(CH 2 ) 0 -R12, CO(C(R1 5)(R1 6))qN(R1 7)(R1 8), or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 10-membered mono - or bicyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen and nitrogen, where the heterocyclic ring system may be additionally substituted by F, (C 1 -C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, oxo, CO(R26), hydroxy, N(R31)(R32); o 0,1,2,3; q 1 or2; R15, R16, R17, R26, R31, R32 independently of one another H, (C1-C6)-alkyl; R18 H, (C1-C6)-alkyl; or R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of one another optionally form together with the nitrogen atom to which they are bonded a 5-6 membered ring selected from pyrrolidine, piperidine, N-methylpiperazine, morpholine; 363 R12 OH, 0-(C1-C6)-alkyl, 3-10 membered mono- or bicyclic ring which may comprise 1-2 heteroatoms from the group of N, 0 and S, and the 3-10 membered ring may comprise further substituents such as F, OH, oxo, (C1-C6)-alkyl, CO(1-C6)-alkyl; R78, R79 independently of one another H, (C1-C8)-alkyl, hydroxy-(C1-C4)-alkyl, (C1 -C4)-alkoxy-(C 1 -C4)-alkyl; R3 H; R4, R5 independently of one another H, OH, 0-(C1-C6)-alkyl; R6, R7, R8, R9 H; n 1 m 1; A, B, D, G are C(R42); R42 H, F, CI, CF 3 , CN, (C1-C6)-alkyl, -(CR84R85)x-O(R86); R84, R85 H; R86 H, (C1-C6)-alkyl; x 0, 1, 2; preferably 0, 1; particularly preferably 1; R10 H, (C1-C8)-alkyl; 364 X a bond, C=C, C(R53)(R54), CH2-CH2; R53, R54 independently of one another H, (C1-C8)-alkyl; E 0 S S\/-N N- N N and which may optionally have substituents from the group of H, F, Cl, Br, OH, CF 3 , NO 2 , OCF 3 , 0-(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), S0 2 -CH 3 , CO(R65); R57, R58 independently of one another H, (C1-C8)-alkyl; R65 independently of one another H, (C1-C8)-alkyl; K a bond, 0, OCH 2 , CH20, CON(R68), (C(R69)(R70))v, CO, C=C; v 1, 2; R68, R69, R70 independently of one another H, (C1-C8)-alkyl; R11 (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, a 3 to 10-membered mono or bicyclic ring which may comprise 0 to 2 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF 3 , CN, (C1-C6)-alkyl, 0-(C1- 365 C8)-alkyl, oxo, CO(R71), CON(R72)(R73), N(R75)CO(C1-C6)-alkyl, or SO 2 CH 3 ; R71, R72, R75 independently of one another H, (C1-C 8 )-alkyl; or R72 and R73 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen and sulfur; or the N-oxides and the physiologically tolerated salts thereof.
4. A compound as claimed in claim 1, characterized in that it has the formula la R42 0 NR1R2 R11'K \EX/ N R10 R42' la in which R1, R2 independently of one another H, (C1-C8)-alkyl, -(CR78R79) 0 -R12, (C1-C4)-alkoxy-(C 1 -C 4 )-alkyl, or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, (C 1 -C6)-alkyl, 0-(C1-C4)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, hydroxy (C1-C4)-alkyl, (CO-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, N(R31)(R32) or SO 2 CH 3 ; where R1 and R2 are not both CO(R26); 366 o 0,1,2,3,4; q 1,2,3; s 0,1,2; R15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31, R32 independently of one another H, (C1-C6)-alkyl; or R17 and R18, R27 and R28, R31 and R32 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen and sulfur; R12 OH, 0-(C1-C6)-alkyl, 0-(CO-C2)-alkylene-aryl, CN, S-(C1-C6)-alkyl, 3-12 membered mono-, bi- or spirocyclic ring which may comprise 1 to 3 heteroatoms from the group of N, 0 and S, and the 3-12 membered ring may comprise further substituents such as F, OH, CF3, CN, oxo, (C1 C6)-alkyl, (C0-C2)-alkylene-aryl, N(R34)(R35), COO(R40), CO(C1-C6) alkyl; R34, R35 independently of one another H, (C1-C4)-alkyl; R40 H, (C1-C6)-alkyl, (C0-C2)-alkylene-aryl; R78, R79 independently of one another H, (C1-C8)-alkyl, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl; R42, R42' independently of one another H, F, Cl, Br, CF 3 , CN, (C1-C6)-alkyl; 367 R10 H, (C1-C8)-alkyl; X N(R52), a bond, C=C, C(R53)(R54), CH 2 CH 2 ; R52, R53, R54 independently of one another H, (C1-C8)-alkyl; E N s N -N N- -N N-- N N-- and N-O which may optionally have substituents from the group of H, F, CI, Br, OH, CF 3 , N02, OCF 3 , 0-(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), S0 2 -CH 3 , CO(R65); R57, R58 independently of one another H, (C1-C8)-alkyl; R65 H, (C1-C8)-alkyl; K a bond, 0, OCH 2 , CH 2 0, S, SO 2 , N(R66), N(R67)CO, CON(R68), 368 (C(R69)(R70))v, CO, C=C, SCH2, S02CH2; v 1,2,3, R66, R67, R68, R69, R70 independently of one another H, (C1-C8)-alkyl; R11 (C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C 4 )-alkyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which may comprise 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, 0-(C1-C8)-alkyl, oxo, CO(R71), hydroxy, N(R75)CO(C1-C 6 )-alkyl, or SO2CH 3 ; R71, R72, R73, R74, R75, R76, R77 independently of one another H, (C1-C8)-alkyl; or R72 and R73, R76 and R77 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen and sulfur; or the N-oxides or the physiologically tolerated salts thereof.
5. Compounds as claimed in claim 1, characterized in that they have the formula lb 0 NR 1 R 2 EK)E N N NRR R11 R10 D (I b) 369 in which: R1, R2 independently of one another H, (C1-C8)-alkyl, -(CR78R79) 0 -R12, (C1-C4)-alkoxy-(C 1 -C4)-alkyl, (C3-C8)-alkenyl, CO-(C 1 -C8)-alkyl, -CO (CH2)o -R1 2, CO-aryloxy-(C 1 -C4)-alkyl, COCH=CH(R1 3), COCC(R1 4), CO(C(R1 5)(R1 6))qN(R1 7)(R1 8), CO(C(R1 9)(R20))rCON(R21)(R22), CO(C(R23)(R24))sO(R25); or R1 and R2 form together with the nitrogen atom to which they are bonded a 4 to 10-membered mono-, bi or spirocyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, Cl, CF3, (C1-C6)-alkyl, 0-(C1-C4)-alkyl, (C 1 -C 4 ) alkoxy-(C1-C4)-alkyl, hydroxy-(C1-C4)-alkyl, (C0-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(C 1 -C 6 ) alkyl, N(R31)(R32) or SO 2 CH 3 , where R1 and R2 are not both CO(R26); o 0,1,2,3,4, 5,6; q, r independently of one another 1, 2, 3; s 0,1,2,3,4; R13, R14 independently of one another a phenyl ring which may comprise 0-1 nitrogen atoms; R15, R16, R17, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 independently of one another H, (C1-C6)-alkyl; R18 H, (C1-C6)-alkyl, CO(C 1 -C6)-alkyl, CO(R33);; 370 or R17 and R18, R21 and R22, R27 and R28, R31 and R32 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom may, also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen and sulfur; R33 a 5-10 membered aromatic ring system which may comprise a further heteroatom from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C1-C6)-alkyl, 0-(C1-C8)-alkyl; R12 is OH, 0-(C1-C6)-alkyl, 0-(CO-C8)-alkylene-aryl, CN, S-(C1-C6)-alkyl, COO(R80), CON(R81)(R82), 3-12 membered mono-, bi- or spirocyclic ring which may comprise one or more heteroatoms from the group of N, O and S and the 3-12 membered ring may comprise further substituents such as F, Cl, Br, OH, CF 3 , CN, oxo, 0-(C1-C6)-alkyl, (C1 C4)-alkoxy-(C1-C4)-alkyl, (C1-C6)-alkyl, 0-(CO-C8)-alkylene-aryl, (CO C8)-alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t (R39), CO(C1-C6)-alkyl, COCOO(C1-06) alkyl, COO(R40), S(O)u (R41); t 0,1,2,3,4,5,6; u 0, 1, 2; R34, R35, R37, R38 independently of one another H, (C1-C8)-alkyl; or R34 and R35 optionally together with the nitrogen atom to which they are bonded a 5 6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen and sulfur and may optionally be substituted by 1-2 oxo groups; 371 R36, R39 independently of one another (C3-C8)-cycloalkyl, 5-10 membered aromatic ring system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, CI, (C1-C6)-alkyl, 0-(C1-C8)-alkyl; R40 H, (C1-C8)-alkyl, (C2-C6)-alkenyl, (CO-C8)-alkylene-aryl; R41 (C1-C6)-alkyl, 5-10 membered aromatic ring system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, Cl, (C1-C6)-alkyl, 0-(C 1 -C 8 ) alkyl; R78, R79 independently of one another H, (C1-C 8 )-alkyl, hydroxy-(C1-C4)-alkyl, (C 1 -C4)-alkoxy-(C 1 -C4)-alkyl; R80, R81 independently of one another H, (C1-C8)-alkyl; R10 H, (C1-C8)-alkyl; E 372 -N N-- -N N-NS N- -N SI N 11N~N N-- and N--O which may optionally have substituents from the group of H, F, Cl, Br, OH, CF 3 , NO 2 , OCF 3 , O-(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), S02-CH3, CO(R65); R57, R58 independently of one another H, (C1-C)-alkyl; R65 independently of one another H, (C1-C8)-alkyl, aryl; K a bond, 0, OCH2, CH20, S, SO, S02, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))v, CO, C=C, C=C, SCH 2 , SO 2 CH 2 ; v 1, 2, 3, 4; R66, R67, R68, R69, R70 independently of one another H, (C1-C8)-alkyl; R11 H, (C 1 -CW)-alkyl, (C 1 -C4)-alkoxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, (C3 C8)-alkynyl, a 3 to 1 0-membered mono-, bi-, tri- or spirocyclic ring which 373 may comprise 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, 0-(C1-C8)-alkyl, (C1 C4)-alkoxy-(C 1 -C4)-alkyl, hydroxy-(C1-C4)-alkyl, (CO-C8)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C 1 C6)-alkyl, N(R76)(R77) or SO 2 CH 3 ; R71, R72, R73, R74, R75, R76, R77 independently of one another H, (C1-C 8 )-alkyl; or R72 and R73, R76 and R77 independently of one another optionally together with the nitrogen atom to which they are bonded a 5-6 membered ring which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C1-C6)-alkyl, oxygen and sulfur; the N-oxides and the physiologically tolerated salts thereof.
6. A medicament comprising one or more of the compounds as claimed in any one of claims 1 to 5.
7. A medicament comprising one or more of the compounds as claimed in any one of claims 1 to 5 and one or more anorectic active ingredients.
8. A compound of the formula I as claimed in any one of claims 1 to 5 for use as medicament for the prophylaxis or treatment of obesity.
9. A compound of the formula I as claimed in any one of claims 1 to 5 for use as medicament for the prophylaxis or treatment of type 11 diabetes.
10. A compound of the formula I as claimed in any one of claims 1 to 5 in combination with at least one further anorectic active ingredient for use as medicament for the prophylaxis or treatment of obesity.
11. A compound of the formula I as claimed in any one of claims 1 to 5 in combination with at least one further anorectic active ingredient for use as 374 medicament for the prophylaxis or treatment of type 11 diabetes.
12. A process for producing a medicament comprising one or more of the compounds of the formula I as claimed in any one of claims 1 to 5, which comprises mixing the active ingredient with a pharmaceutically suitable carrier and converting this mixture into a form suitable for administration.
13. The use of the compounds of the formula I as claimed in any one of claims 1 to 5 for producing a medicament for weight reduction in mammals.
14. The use of the compounds of the formula I as claimed in any one of claims 1 to 5 for producing a medicament for the prophylaxis or treatment of obesity.
15. The use of the compounds of the formula I as claimed in any one of claims 1 to 5 for producing a medicament for the prophylaxis or treatment of type Il diabetes.
16. The use of the compounds of the formula I as claimed in any one of claims 1 to 5 for producing a medicament for the treatment of disturbances of well being and other psychiatric indications, and for the treatment of disorders associated with the circadian rhythm and for the treatment of drug abuse.
17. The use of the compounds of the formula I as claimed in any one of claims 1 to 5 for preparing a medicament having a MCH-receptor antagonistic activity.
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Families Citing this family (118)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7351719B2 (en) 2002-10-31 2008-04-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Amide compounds having MCH-antagonistic activity and medicaments comprising these compounds
CA2526285A1 (en) 2003-05-15 2004-12-23 Arqule, Inc. Inhibitors of p38 and methods of using the same
PL1867644T3 (en) * 2003-07-24 2009-10-30 Euro Celtique Sa Heteroaryl-tetrahydropiperidyl compounds useful for treating or preventing pain
CN1856484B (en) * 2003-07-24 2010-09-22 欧洲凯尔蒂克公司 Heteroaryl-tetrahydropyridinyl compounds for the treatment or prevention of pain
WO2005016910A1 (en) * 2003-08-18 2005-02-24 Sankio Chemical Co., Ltd. Pyridyltetrahydropyridines, pyridylpiperidines, and process for the production of both
US7592373B2 (en) 2003-12-23 2009-09-22 Boehringer Ingelheim International Gmbh Amide compounds with MCH antagonistic activity and medicaments comprising these compounds
DE10360745A1 (en) * 2003-12-23 2005-07-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg New amide compounds having MCH antagonist activity and medicaments containing these compounds
US7319108B2 (en) 2004-01-25 2008-01-15 Sanofi-Aventis Deutschland Gmbh Aryl-substituted heterocycles, process for their preparation and their use as medicaments
DE102004003812A1 (en) * 2004-01-25 2005-08-11 Aventis Pharma Deutschland Gmbh Aryl-substituted heterocycles, methods of their preparation and their use as pharmaceuticals
US7829560B2 (en) 2004-07-08 2010-11-09 Arqule, Inc. 1,4-disubstituted naphthalenes as inhibitors of P38 MAP kinase
WO2006022442A1 (en) * 2004-08-24 2006-03-02 Santen Pharmaceutical Co., Ltd. Novel heterocyclic amide derivatives having dihydroorotate dehydrogenase inhibiting activity
GB0420722D0 (en) 2004-09-17 2004-10-20 Addex Pharmaceuticals Sa Novel allosteric modulators
US7777036B2 (en) * 2004-09-20 2010-08-17 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
CA2582327A1 (en) * 2004-10-01 2006-04-13 Takao Suzuki 2-arylcarboxamide-nitrogeneous heterocycle compound
WO2006044454A1 (en) 2004-10-18 2006-04-27 Eli Lilly And Company 1-(hetero)aryl-3-amino-pyrollidine derivatives for use as mglur3 receptor antagonists
EP1809636A1 (en) 2004-10-19 2007-07-25 Arqule, Inc. Synthesis of imidazooxazole and imidazothiazole inhibitors of p38 map kinase
DE102004051277A1 (en) * 2004-10-21 2006-04-27 Merck Patent Gmbh Heterocyclic carbonyl compounds
US8084492B2 (en) * 2004-11-19 2011-12-27 The New Industry Research Organization Benzofuran compound and pharmaceutical composition containing the same
EP2937341B1 (en) 2004-12-30 2017-07-05 Janssen Pharmaceutica N.V. 4-(benzyl)-piperazine-1-carboxylic acid phenylamide derivatives and related compounds as modulators of fatty acid amide hydrolase (faah) for the treatment of anxiety, pain and other conditions
WO2006081389A1 (en) * 2005-01-25 2006-08-03 Synta Pharmaceuticals Corp. Thiophene compounds for inflammation and immune-related uses
ATE429428T1 (en) 2005-09-30 2009-05-15 Hoffmann La Roche INDANDERIVATES AS ANTAGONISTS OF THE MCH RECEPTOR
EP2295432A1 (en) 2006-02-10 2011-03-16 TransTech Pharma Inc. Process for the preparation of aminobenzimidazole derivatives
AU2007214708A1 (en) * 2006-02-15 2007-08-23 Sanofi-Aventis Novel azacycly-substituted arylthienopyrimidinones, process for their preparation and their use as medicaments
BRPI0707870A2 (en) * 2006-02-15 2011-05-10 Sanofi Aventis Amino Alcohol-Substituted Arylthienopyrimidinones, Process for Preparation and Use as Medicines
TWI417095B (en) 2006-03-15 2013-12-01 Janssen Pharmaceuticals Inc 1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of mglur2-receptors
CA2649043C (en) * 2006-04-19 2013-09-17 Astellas Pharma Inc. Azolecarboxamide derivative
AU2007237904B2 (en) 2006-04-19 2011-03-03 Novartis Ag 6-O-substituted benzoxazole and benzothiazole compounds and methods of inhibiting CSF-1R signaling
UA93548C2 (en) 2006-05-05 2011-02-25 Айерем Елелсі Compounds and compositions as hedgehog pathway modulators
KR101441365B1 (en) 2006-05-08 2014-09-18 어리어드 파마슈티칼스, 인코포레이티드 Monocyclic heteroaryl compounds
AU2007249924B2 (en) 2006-05-08 2013-07-04 Ariad Pharmaceuticals, Inc. Acetylenic heteroaryl compounds
AU2007283113A1 (en) 2006-08-08 2008-02-14 Sanofi-Aventis Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use
JP2010501567A (en) * 2006-08-24 2010-01-21 ノバルティス アクチエンゲゼルシャフト 2- (pyrazin-2-yl) -thiazole and 2- (1H-pyrazole-3-) as stearoyl-CoA desaturase (SCD) inhibitors for the treatment of metabolic, cardiovascular and other disorders Yl) thiazole derivatives and related compounds
EP2064186A1 (en) * 2006-09-11 2009-06-03 Glaxo Group Limited Azabicyclic compounds as inhibitors of monoamines reuptake
EP2066642A1 (en) * 2006-09-25 2009-06-10 Arete Therapeutics, INC. Soluble epoxide hydrolase inhibitors
PE20080888A1 (en) 2006-10-18 2008-08-26 Novartis Ag HETEROCYCLIC COMPOUNDS AS ACIL-TRANSFERASE INHIBITORS OF ACIL-CoA-DIACIL-GLYCEROL 1 (DGAT1)
EP2118069B1 (en) * 2007-01-09 2014-01-01 Amgen Inc. Bis-aryl amide derivatives useful for the treatment of cancer
TW200845978A (en) 2007-03-07 2008-12-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
TW200900065A (en) 2007-03-07 2009-01-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives
GB0706793D0 (en) * 2007-04-05 2007-05-16 Evotec Ag Compounds
ES2483898T3 (en) 2007-06-08 2014-08-08 Janssen Pharmaceutica, N.V. Piperidine / Piperazine Derivatives
JO2972B1 (en) 2007-06-08 2016-03-15 جانسين فارماسوتيكا ان. في Piperidine/Piperazine derivatives
JP5443342B2 (en) 2007-06-08 2014-03-19 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Piperidine / piperazine derivatives
CN101678019B (en) * 2007-06-08 2016-03-30 詹森药业有限公司 Piperidine/piperazine derivatives
TWI452044B (en) 2007-06-15 2014-09-11 Mitsubishi Tanabe Pharma Corp Morpholine derivative
TW200918521A (en) * 2007-08-31 2009-05-01 Astrazeneca Ab Heterocyclic amides and methods of use thereof
CA2697399C (en) 2007-09-14 2016-01-19 Ortho-Mcneil-Janssen Pharmaceuticals, Inc. 1,3-disubstituted 4-(aryl-x-phenyl)-1h-pyridin-2-ones
MY152078A (en) 2007-09-14 2014-08-15 Ortho Mcneil Janssen Pharm 1',3'-disubstituted-4-phenyl-3,4,5,6-tetrahydro-2h,1'h-[1,4']bipyridinyl-2'-ones
NZ584148A (en) 2007-09-14 2011-05-27 Ortho Mcneil Janssen Pharm 1,3-disubstituted-4-phenyl-1 h-pyridin-2-ones
BRPI0818581A2 (en) * 2007-10-17 2015-07-21 Sanofi Aventis Substituted n-phenyl bipyrrolidine carboxamides and their therapeutic use
RU2477719C2 (en) * 2007-10-17 2013-03-20 Санофи-Авентис Substituted n-phenylbipyrrolidine carboxamides and therapeutic use thereof
PT2215058E (en) * 2007-10-17 2012-03-06 Sanofi Sa Substituted n-phenyl-bipyrrolidine ureas and therapeutic use thereof
WO2009052063A1 (en) * 2007-10-17 2009-04-23 Sanofi-Aventis Substituted n-phenyl-pyrrolidinylmethylpyrrolidine amides and therapeutic use thereof as histamine h3 receptor modulators
DK2206707T3 (en) 2007-10-24 2014-08-11 Astellas Pharma Inc AZOLCARBOXAMIDE COMPOUND OR SALT THEREOF
RU2492170C9 (en) 2007-11-14 2013-12-27 Орто-Макнейл-Янссен Фармасьютикалз, Инк. Imidazo[1,2-a]pyridine derivatives and their application as positive allosteric modulators of mglur2 receptors
EP2070925A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft New 2-substituted tiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
EP2070916A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft 2-Arylthiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
EP2070924A1 (en) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft New 2 hetarylthiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
RU2364597C1 (en) * 2007-12-14 2009-08-20 Андрей Александрович Иващенко HETEROCYCLIC INHIBITORS OF Hh-SYGNAL CASCADE, BASED ON THEM MEDICINAL COMPOSITIONS AND METHOD OF TREATING DISEASES INDUCED BY ABBARANT ACTIVITY OF Hh-SIGNAL SYSTEM
WO2009147170A2 (en) 2008-06-05 2009-12-10 Janssen Pharmaceutica Nv Drug combinations comprising a dgat inhibitor and a ppar-agonist
EP2310372B1 (en) 2008-07-09 2012-05-23 Sanofi Heterocyclic compounds, processes for their preparation, medicaments comprising these compounds, and the use thereof
AU2009289784B2 (en) 2008-09-02 2012-03-22 Addex Pharma S.A. 3-azabicyclo[3.1.0]hexyl derivatives as modulators of metabotropic glutamate receptors
WO2010033349A1 (en) * 2008-09-16 2010-03-25 Merck & Co., Inc. Phthalimide derivative metabotropic glutamate r4 ligands
JP2012006837A (en) * 2008-09-30 2012-01-12 Mochida Pharmaceut Co Ltd 2-indoleacrylamide analogue
ES2466341T3 (en) 2008-10-16 2014-06-10 Janssen Pharmaceuticals, Inc. Indole and benzomorpholine derivatives as modulators of metabotropic glutamate receptors
CA2743449C (en) 2008-11-12 2016-10-18 Ariad Pharmaceuticals, Inc. Pyrazinopyrazines and derivatives as kinase inhibitors
WO2010060589A1 (en) 2008-11-28 2010-06-03 Ortho-Mcneil-Janssen Pharmaceuticals, Inc. Indole and benzoxazine derivatives as modulators of metabotropic glutamate receptors
AR074466A1 (en) * 2008-12-05 2011-01-19 Sanofi Aventis PIPERIDINE ESPIRO PIRROLIDINONA AND PIPERIDINONA REPLACED AND ITS THERAPEUTIC USE IN DISEASES MEDIATED BY THE MODULATION OF H3 RECEPTORS.
WO2010068601A1 (en) 2008-12-08 2010-06-17 Sanofi-Aventis A crystalline heteroaromatic fluoroglycoside hydrate, processes for making, methods of use and pharmaceutical compositions thereof
UA103918C2 (en) 2009-03-02 2013-12-10 Айерем Элелси N-(hetero)aryl, 2-(hetero)aryl-substituted acetamides for use as wnt signaling modulators
US8889674B2 (en) 2009-03-05 2014-11-18 Shionogi & Co., Ltd. Piperidine and pyrrolidine derivatives having NPY Y5 receptor antagonism
WO2010101247A1 (en) 2009-03-05 2010-09-10 塩野義製薬株式会社 Cyclohexane derivative having npy y5 receptor antagonism
AU2010246609B2 (en) 2009-05-12 2013-09-05 Addex Pharma S.A. 1,2,4-triazolo [4,3-a] pyridine derivatives and their use for the treatment or prevention of neurological and psychiatric disorders
NZ596053A (en) 2009-05-12 2013-05-31 Janssen Pharmaceuticals Inc 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
MY153913A (en) 2009-05-12 2015-04-15 Janssen Pharmaceuticals Inc 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
ES2443016T3 (en) 2009-08-26 2014-02-17 Sanofi New crystalline hydrates of heteroaromatic fluoroglycosides, pharmaceutical products comprising these compounds, and their use
US20120225097A1 (en) 2009-11-12 2012-09-06 Hawryluk Natalie A Piperazinecarboxamide derivative useful as a modulator of fatty acid amide hydrolase (faah)
US9452980B2 (en) 2009-12-22 2016-09-27 Hoffmann-La Roche Inc. Substituted benzamides
UA108233C2 (en) 2010-05-03 2015-04-10 Fatty acid amide hydrolysis activity modulators
AR081383A1 (en) * 2010-05-11 2012-08-29 Sanofi Aventis N-HETEROARIL BIPIRROLIDIN SUBSTITUTED CARBOXAMIDS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND USE OF THE SAME FOR THE TREATMENT OF DISEASES OF THE CENTRAL NERVOUS SYSTEM.
WO2011143150A1 (en) * 2010-05-11 2011-11-17 Sanofi Substituted phenyl cycloalkyl pyrrolidine (piperidine) spirolactams and amides, preparation and therapeutic use thereof
TW201202251A (en) * 2010-05-11 2012-01-16 Sanofi Aventis Substituted N-heteroaryl spirolactam bipyrrolidines, preparation and therapeutic use thereof
UY33469A (en) 2010-06-29 2012-01-31 Irm Llc Y Novartis Ag COMPOSITIONS AND METHODS TO MODULATE THE WNT SIGNALING ROAD
EP2661435B1 (en) 2010-11-08 2015-08-19 Janssen Pharmaceuticals, Inc. 1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
CN103298810B (en) 2010-11-08 2016-03-16 杨森制药公司 The purposes of 1,2,4-triazolo [4,3-a] pyridine derivate and the positive allosteric modulators as MGLUR2 acceptor thereof
EP2643320B1 (en) 2010-11-08 2015-03-04 Janssen Pharmaceuticals, Inc. 1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
US8828995B2 (en) 2011-03-08 2014-09-09 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
US8846666B2 (en) 2011-03-08 2014-09-30 Sanofi Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
US8809324B2 (en) 2011-03-08 2014-08-19 Sanofi Substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
EP2683699B1 (en) 2011-03-08 2015-06-24 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
EP2683700B1 (en) 2011-03-08 2015-02-18 Sanofi Tetra-substituted oxathiazine derivatives, method for their preparation, their usage as medicament and medicament containing same and its use
WO2012120057A1 (en) 2011-03-08 2012-09-13 Sanofi Novel substituted phenyl-oxathiazine derivatives, method for producing them, drugs containing said compounds and the use thereof
EP2766349B1 (en) 2011-03-08 2016-06-01 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
US8809325B2 (en) 2011-03-08 2014-08-19 Sanofi Benzyl-oxathiazine derivatives substituted with adamantane and noradamantane, medicaments containing said compounds and use thereof
EP2683705B1 (en) 2011-03-08 2015-04-22 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
US9051265B2 (en) 2011-06-06 2015-06-09 The Scripps Research Institute N-benzylindole modulators of PPARG
WO2012170554A1 (en) 2011-06-06 2012-12-13 Theodore Mark Kamenecka N-biphenylmethylindole modulators of pparg
US9309227B2 (en) 2011-11-22 2016-04-12 The Scripps Research Institute N-biphenylmethylbenzimidazole modulators of PPARG
US9102669B2 (en) 2011-12-06 2015-08-11 Janssen Pharmaceutica Nv Substituted piperidinyl-pyridazinyl derivatives useful as SCD 1 inhibitors
US9238658B2 (en) 2011-12-06 2016-01-19 Janssen Pharmaceutica Nv Substituted piperidinyl-carboxamide derivatives useful as SCD 1 inhibitors
CA2873075A1 (en) * 2012-05-11 2013-07-14 Abbvie Inc. Nampt inhibitors
WO2014071298A1 (en) * 2012-11-05 2014-05-08 Nant Holdings Ip, Llc Cyclic sulfonamide containing derivatives as inhibitors of hedgehog signaling pathway
TW201444798A (en) 2013-02-28 2014-12-01 必治妥美雅史谷比公司 Phenylpyrazole derivatives as potent ROCK1 and ROCK2 inhibitors
WO2014134391A1 (en) 2013-02-28 2014-09-04 Bristol-Myers Squibb Company Phenylpyrazole derivatives as potent rock1 and rock2 inhibitors
JO3368B1 (en) 2013-06-04 2019-03-13 Janssen Pharmaceutica Nv 6, 7- dihydropyrazolu [5,1-a] pyrazine-4 (5 hands) -on compounds and their use as negative excretory regulators of Miglore 2 receptors.
JO3367B1 (en) 2013-09-06 2019-03-13 Janssen Pharmaceutica Nv 1,2,4-TRIAZOLO[4,3-a]PYRIDINE COMPOUNDS AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
KR20220038826A (en) 2014-01-21 2022-03-29 얀센 파마슈티카 엔.브이. Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
DK3096790T3 (en) 2014-01-21 2019-10-07 Janssen Pharmaceutica Nv COMBINATIONS INCLUDING POSITIVE ALLOSTERIC MODULATORS OR ORTHOSTERIC AGONISTS OF METABOTROP GLUTAMATERG SUBTYPE 2 RECEPTOR AND APPLICATION OF THESE
WO2015161108A1 (en) 2014-04-16 2015-10-22 The Scripps Research Institute Pparg modulators for treatment of osteoporosis
JP2017520612A (en) * 2014-07-16 2017-07-27 ノボジェン リミティッド Functionalized substituted indoles as anticancer agents
ES2838573T3 (en) * 2014-08-21 2021-07-02 Bristol Myers Squibb Co Benzamide derivatives linked as potent ROCK inhibitors
US10428029B2 (en) * 2014-09-10 2019-10-01 Epizyme, Inc. Isoxazole carboxamide compounds
PE20181178A1 (en) * 2015-08-28 2018-07-20 Glenmark Pharmaceuticals Sa NOVELTY CARBOCYLIC COMPOUNDS AS ROR GAMMA MODULATORS
CR20180443A (en) 2016-03-17 2018-11-21 Hoffmann La Roche MORPHOLINE DERIVATIVE
CN108815167B (en) * 2017-05-24 2021-04-13 四川晶华生物科技有限公司 Application of compound in preparing medicine for treating tumor
TW202136238A (en) * 2020-01-06 2021-10-01 大陸商廣東東陽光藥業有限公司 ROR[gamma]T inhibitor, preparation method therefor and use thereof
WO2022150962A1 (en) * 2021-01-12 2022-07-21 Westlake Pharmaceutical (Hangzhou) Co., Ltd. Protease inhibitors, preparation, and uses thereof
CN115160269A (en) * 2021-04-02 2022-10-11 北京大学 Arylcarboxamide derivatives as positive allosteric modulators of NMDAR
IL314330A (en) 2022-01-18 2024-09-01 Maze Therapeutics Inc APOL1 inhibitors and methods of use

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000061569A1 (en) * 1999-04-09 2000-10-19 Astrazeneca Ab Adamantane derivatives
WO2000071529A1 (en) * 1999-05-25 2000-11-30 Astrazeneca Ab Substituted phenyl compounds with immunosuppressing activity and pharmaceutical compositions
WO2002006232A1 (en) * 2000-07-17 2002-01-24 Wyeth Cyclic amine phenyl beta-3 adrenergic receptor agonists

Family Cites Families (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2663336B1 (en) 1990-06-18 1992-09-04 Adir NOVEL PEPTIDE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME.
PT788498E (en) * 1994-10-26 2002-02-28 Upjohn Co ANTIMICROBIAL COMPOUNDS OF PHENYLXAZOLIDINONE
WO1997026265A1 (en) 1996-01-17 1997-07-24 Novo Nordisk A/S Fused 1,2,4-thiadiazine and fused 1,4-thiazine derivatives, their preparation and use
EP1826216A1 (en) 1996-08-30 2007-08-29 Novo Nordisk A/S Glp-1 derivatives
ATE246190T1 (en) 1996-12-31 2003-08-15 Reddys Lab Ltd Dr HETEROCYCLIC COMPOUNDS, METHODS FOR THE PRODUCTION THEREOF, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME AND THEIR USE IN THE TREATMENT OF DIABETIS AND RELATED DISEASES
DE19726167B4 (en) 1997-06-20 2008-01-24 Sanofi-Aventis Deutschland Gmbh Insulin, process for its preparation and pharmaceutical preparation containing it
BR9810592A (en) 1997-07-16 2000-09-12 Novo Nordisk As Compound, processes for preparing a compound, for treating or preventing diseases of the endocrine system and for the manufacture of a drug, pharmaceutical composition, and, use of a compound
CO4970713A1 (en) 1997-09-19 2000-11-07 Sanofi Synthelabo DERIVATIVES OF CARBOXAMIDOTIAZOLES, THEIR PREPARATION, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM
CA2309121A1 (en) * 1997-11-07 1999-05-20 Schering Corporation Phenyl-alkyl-imidazoles as h3 receptor antagonists
US6221897B1 (en) 1998-06-10 2001-04-24 Aventis Pharma Deutschland Gmbh Benzothiepine 1,1-dioxide derivatives, a process for their preparation, pharmaceuticals comprising these compounds, and their use
DE19845405C2 (en) 1998-10-02 2000-07-13 Aventis Pharma Gmbh Aryl-substituted propanolamine derivatives and their use
AU3126700A (en) 1998-12-18 2000-07-03 Du Pont Pharmaceuticals Company N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
GB9900416D0 (en) 1999-01-08 1999-02-24 Alizyme Therapeutics Ltd Inhibitors
HK1046136A1 (en) * 1999-02-10 2002-12-27 三菱制药株式会社 Amide compounds and medicinal use thereof
JP2002542245A (en) 1999-04-16 2002-12-10 ノボ ノルディスク アクティーゼルスカブ Substituted imidazoles, their manufacture and use
JP2002543200A (en) 1999-04-30 2002-12-17 ニューロゲン コーポレイション 9H-pyrimido [4,5-b] indole derivative: CRF1 specific ligand
GB9911863D0 (en) 1999-05-21 1999-07-21 Knoll Ag Therapeutic agents
EP1194146B1 (en) 1999-06-18 2006-07-19 Merck & Co., Inc. Arylthiazolidinedione and aryloxazolidinedione derivatives
WO2001009111A1 (en) 1999-07-29 2001-02-08 Eli Lilly And Company Benzofurylpiperazines and benzofurylhomopiperazines: serotonin agonists
SK2682002A3 (en) 1999-09-01 2002-07-02 Aventis Pharma Gmbh Sulfonyl carboxamide derivatives, method for their production and their use as medicaments
AU5257401A (en) 2000-04-28 2001-11-12 Asahi Chemical Ind Novel bicyclic compounds
EP1280777B1 (en) 2000-05-11 2005-11-23 Bristol-Myers Squibb Company Tetrahydroisoquinoline analogs useful as growth hormone secretagogues
AU6497701A (en) 2000-05-30 2001-12-11 Merck & Co Inc Melanocortin receptor agonists
AU2001269370B2 (en) * 2000-07-17 2005-10-27 Ranbaxy Laboratories Limited Oxazolidinone derivatives as antimicrobials
KR20030059084A (en) * 2000-07-31 2003-07-07 스미스크라인 비참 피.엘.시. Carboxamide compounds and their use as antagonists of a human 11cby receptor
JO2654B1 (en) * 2000-09-04 2012-06-17 شركة جانسين فارماسوتيكا ان. في Polyarylcarboxamides useful as lipid lowering agents
JO2409B1 (en) * 2000-11-21 2007-06-17 شركة جانسين فارماسوتيكا ان. في Biphenylcarboxamides useful as lipid lowering agents
JP2002338537A (en) * 2001-05-16 2002-11-27 Mitsubishi Pharma Corp Amide compounds and their pharmaceutical uses
WO2002098839A1 (en) * 2001-06-01 2002-12-12 Tanabe Seiyaku Co., Ltd. Biphenylcarboxamides and process for preparation thereof
WO2002098871A1 (en) * 2001-06-01 2002-12-12 Tanabe Seiyaku Co., Ltd. Phenylcarboxamides and process for preparation thereof
WO2002099388A2 (en) * 2001-06-07 2002-12-12 Merck & Co., Inc. Benzodiazepine bradykinin antagonists
DE10142734A1 (en) 2001-08-31 2003-03-27 Aventis Pharma Gmbh New (((oxazolylalkyl)-cycloalkyl)-alkyl)-benzoic acid derivatives, are peroxisome proliferator activated receptor agonists or antagonists used e.g. for treating lipid metabolism disorders, type II diabetes, syndrome X and obesity
EP1505068A4 (en) * 2002-04-23 2008-03-19 Shionogi & Co PYRAZOLO (1,5-a) PYRIMIDINE DERIVATIVE AND NAD(P)H OXIDASE INHIBITOR CONTAINING THE SAME
JP2004175739A (en) * 2002-11-28 2004-06-24 Tanabe Seiyaku Co Ltd Pharmaceutical composition

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000061569A1 (en) * 1999-04-09 2000-10-19 Astrazeneca Ab Adamantane derivatives
WO2000071529A1 (en) * 1999-05-25 2000-11-30 Astrazeneca Ab Substituted phenyl compounds with immunosuppressing activity and pharmaceutical compositions
WO2002006232A1 (en) * 2000-07-17 2002-01-24 Wyeth Cyclic amine phenyl beta-3 adrenergic receptor agonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS Accession no. 2002: 946251 *

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