NZ541823A - Substituted N-aryl heterocycles, method for production and uses thereof as medicaments - Google Patents

Substituted N-aryl heterocycles, method for production and uses thereof as medicaments

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Publication number
NZ541823A
NZ541823A NZ541823A NZ54182304A NZ541823A NZ 541823 A NZ541823 A NZ 541823A NZ 541823 A NZ541823 A NZ 541823A NZ 54182304 A NZ54182304 A NZ 54182304A NZ 541823 A NZ541823 A NZ 541823A
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New Zealand
Prior art keywords
alkyl
independently
another
phenyl
pyrrolidin
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NZ541823A
Inventor
Lothar Schwink
Siegfried Stengelin
Matthias Gossel
Gerhard Hessler
Petra Stahl
Dirk Gretzke
Thomas Boehme
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Sanofi Aventis Deutschland
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Application filed by Sanofi Aventis Deutschland filed Critical Sanofi Aventis Deutschland
Publication of NZ541823A publication Critical patent/NZ541823A/en

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    • 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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Abstract

Disclosed is a compound of formula I, wherein the substituents are as defined in the specification. The compounds have MCH-receptor antagonistic activity and are useful in the treatment of obesity and type II diabetes.

Description

New Zealand Paient Spedficaiion for Paient Number 541 823 54 1823 Substituted N-ary! heterocycles, method for production and uses thereof as medicaments The invention relates to substituted N-aryl heterocycles and to the physiologically tolerated salts and physiologically functional derivatives 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 ureido-substituted phenylpiperidines and -pyrrolidines as agents for the treatment of inflammatory and autoimmune diseases. Acylamido-15 substituted phenylpyrrolidines are proposed in WO 02/042271 for the treatment of diabetes, obesity and disorders of lipid metabolism.
In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art. intellectual property office of i\i,2. 2 4 OCT 2008 RECEIVED 2 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 I R11 • "K" NR^ R9 R8 in which the meanings are R1, R2 independently of one another H, (C-|-C8)-alkyl, -(CR78R79)0-R12, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, (C3-C8)-alkenyl, CO-(Ci-C8)-alkyl, -CO-(CH2)0-R12, CO-aryloxy-(Ci-C4)-alkyl, 15 COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), 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 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 20 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, CI, CF3, (Ci-C6)-alkyl, 0-(C-|-C4)-alkyl, (C-|-C4)-alkoxy-(C-|-C4)-alkyl, hydroxy-(Ci-C4)-alkyl, (Co-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), [ intellectual propi office of n z 2 4 OCT 2008 REHFIX/c 3 hydroxy, COO(R29), N(R30)CO(Ci-C6)-alkyl, N(R31)(R32) or S02CH3; 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, (C-|-C6)-alkyl; R18 H, (Ci-C6)-alkyl, CO(Ci-C6)-alkyl, CO(R33); 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-(Ci-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, CI, (C<|-C6)-alkyl, or 0-(Ci-C8)- alkyl; intellectual property office of n.i. 2 h OCT 2008 RECEIVED or R17 and 4 R12 OH, 0-(Ci-C6)-alkyl, O(C0-C8)-alkylene-aryl, CN, S-(C-|-C6)- alkyl, COO(R80), CON(R81)(R82), 3-12 membered mono-, bi- or spirocyclic ring which may comprise one or more heteroatoms 5 from the group of N, O and S, and the 3-12 membered ring may comprise further substituents such as F, CI, Br, I, OH, CF3, CN, oxo, 0-(Ci-C6)-alkyl, (C-|-C4)-alkoxy-(C-|-C4)-alkyl, (C-|-C6)-alkyl, (Co-C8)-alkylene-aryl, 0-(Co-C8)-alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(Ci-C6)-alkyl, COCOO(Ci-C6)-alkyl, COO(R40), S(0)U(R41) and COOH; t 0,1,2,3,4,5,6; u 0,1,2; R34, R35, R37, R38 independently of one another H, (C-|-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 25 atom, may also comprise 0-1 further heteroatoms from the group of N-(Ci-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 aromatic ring system which may comprise 0-2 further intellectual property office of n.z 2 4 OCT 2008 RECEIVED heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, CI, (Ci-C6)-alkyl, 0-(Ci-C8)-alkyl; R40 H, (Ci-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 nitrogen, oxygen and sulfur and may be substituted by F, CI, (Ci-C6)-alkyl, 0-(Ci-C8)-alkyl; R78, R79 independently of one another H, (Ci-C8)-alkyl, hydroxy-(C-|-C4)-alkyl, OH, (C-i-C4)-alkoxy-(Ci-C4)-alkyl; R80, R81, R82 independently of one another H, (C-|-C8)-alkyl; R3 H, (Ci-Ce)-alkyl; R4, R5 independently of one another H, (Ci-C6)-alkyl, OH, 0-(Ci-C6)-alkyl, 0-C0(Ci-C6)-alkyl, S-(Ci-C6)-alkyl; R6, R7, R8, R9 H; or R6 and R7, R8 and R9 independently of one another optionally oxo; INTEnf£^Ak PROpERV office of n.z. 2 4 OCT 2008 RECPI\/Pn 6 n 1; m 1; 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 an ortho-phenylene unit to result overall in a 1,4-bisubstituted napthalene system; R42 H, F, CI, Br, CF3, CN, 0-(Ci-C6)-alkyl, 0-(C-|-C4)-alkoxy- (Ci-C4)-alkyl, S-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (Co-C8)-alkylene- aryl, O-(C0-C8)-alkylene-aryl, N(R43)(R44), SO2-CH3, CON(R45)(R46), N(R47)CO(R48), CO(R51), -(CR84R85)X-15 0(R86); R43, R44, R45, R46, R47, R49 independently of one another H, (C-|-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 25 which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(Ci-C6)-alkyl, oxygen and sulfur; R48, R50, R51 independently of one another H, (Ci-C8)-alkyl, aryl; 'NTELnp?lr¥AkJ3R0PERTY office of n.2. 2 4 OCT 2008 R P o c 1 \ /1- r R84, R85 H; R86 H, (Ci-Ce)-alkyl; x 0, 1,2; R10 H, (Ci-Cs)-alkyl; X Y N(R52), a bond, C=C, C(R53)(R54), CH2-CH2; O, S, N(R89); R52, R53, R54 independently of one another H, (C-|-C8)-alkyl; R89 H, (Ci-Cs)-alkyl; E is selected from the group consisting of A N- j N' n j N- N" U N A N- J ra -N N- v_y n O r -N V and inte^f£ffial property office of n.z. 2 4 OCT 2008 RECEIVED 8 which may optionally have substituents from the group of H, F, CI, Br, OH, CF3, N02i OCF3, 0-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2-CH3, CO(R65); R57, R58 independently of one another H, (C-|-C8)-alkyl; R65 independently of one another H, (Ci-C8)-alkyl, aryl; K a bond, O, OCH2, CH20, S, SO, S02, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C^C, C=C, SCH2, S02CH2; v 1,2,3,4 R66, R67, R68, R69, R70 independently of one another H, (Ci-C8)-alkyl; R11 H, (Ci-C8)-alkyl, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl, a 3 to 10-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 additionally be substituted by F, CI, Br, CF3, CN, (C<|-C6)-alkyl, 0-(Ci-C8)-alkyl, (Ci-C4)-aIkoxy-(Ci-C4)-alkyl, (Co-C8)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, hydroxy-(Ci-C4)-alkyl, COO(R74), N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or S02CH3; intellectual property office of n.z. 2 4 OCT 2008 9 R71, R72, R73, R74, R75, R76, R77 independently of one another H, (C-|-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-(Ci-C6)-alkyl, oxygen and sulfur; and the N-oxides and physiologically tolerated salts thereof.
In a further embodiment, the invention therefore relates to compounds of the formula I in which the meanings are: R11 -K' -x O A N R10 R7 R6 A=B t G-D ^~R4 R9 R8 R5 NR1R2 R1, R2 independently of one another H, (C-|-C8)-alkyl, (C-|-C4)-alkoxy-(Ci-C4)-alkyl, (C3-C8)-alkenyl, CO-(Ci-C8)-alkyl, -CO-(CH2)0-R12, CO-aryloxy-(Ci-C4)-alkyl, COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), 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 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 intellectual property office of n.z. 2 \ OCT 2008 n ■ 11 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, CI, CF3, (C-|-C6)-alkyl, 0-(C-|-C4)-alkyl, (C-i-C4)-alkoxy-(Ci-C4)-alkyl, (Co-C2)-alkylene-5 aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(Ci-C6)-alkyl, N(R31)(R32) or SO2CH3; o 0,1,2,3,4,5,6; ^ 10 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 15 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, (C-|-C6)-alkyl; # R18 H, (Ci-C6)-alkyl, CO(Ci-C6)-alkyl, CO(R33); 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-(Ci-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 intellectual property office of n.2. 2 4 OCT 2008 11 and may be substituted by F, CI, (C-|-C6)-alkyl, 0-(C-|-C8)-alkyl; R12 OH, 3-12 membered mono-, bi- or spirocyclic ring which may comprise one or more heteroatoms from the group of N, O and 5 S, and the 3-12 membered ring may comprise further substituents such as F, CI, Br, I, OH, CF3, CN, oxo, 0-(C-|-C6)- alkyl, (Ci-C4)-alkoxy-(C-|-C4)-alkyl, (C-|-C6)-alkyl, 0-(Co-C8)-alkylene-aryl, N(R34)(R35), (C0-C8)-alkylene-aryl), COCH=CH(R36), (C(R37)(R38))t(R39), CO(C(R37)(R38))t(R39), CO(Ci-C6)-alkyl, COCOO(Ci-C6)-alkyl, COO(R40), S(0)U(R41) and COOH; t 0,1,2,3,4,5,6; u 0,1,2; R34, R35, R37, R38 independently of one another H, (Ci-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 atom, may also comprise 0-1 further heteroatoms from the group of N-(C-|-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 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, (Ci-C6)-alkyl, 0-(C-|-C8)-alkyl; intellectual property office of n.z. 2 4 OCT 2008 D C r m r» p\ 12 R40 H, (C-|-C8)-alkyl, (C2-C6)-alkenyl, (Co-C3)-alkylene-aryl; R41 (Ci-C6)-alkyl, 5-10 membered aromatic ring system which may 5 comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and sulfur and may be substituted by F, CI, (Ci-C6)-alkyl, 0-(Ci-C8)-alkyl; R3 H, (Ci-C6)-alkyl; R4, R5 independently of one another H, (Ci-C6)-alkyl, OH, 0-(Ci-C6)-alkyl, 0-C0(Ci-C6)-alkyl, S-fC^CeJ-alkyl; R6, R7, R8, R9 15 H; or R6 and R7, R8 and R9 20 independently of one another optionally oxo; n 1; m 1; A, B, D, G independently of one another N, C(R42); R42 H, F, CI, Br, CF3, CN, 0-(Ci-C6)-alkyl, 0-(Ci-C4)-alkoxy-(Ci- C4)-alkyl, S-(C-|-C6)-alkyl, (Ci-C6)-alkyl, (Co-Cs)-alkylene-aryl, O-(C0-C8)-alkylene-aryl, N(R43)(R44), SO2-CH3, 30 CON(R45)(R46), N(R47)CO(R48), CO(R51); intellectual property office of N.z. 2 h OCT 2008 RPPCl\/cn 13 R43, R44, R45, R46, R47, R49 independently of one another H, (Ci-Cs)-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 10 which, apart from the nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(Ci-C6)-alkyl, oxygen and sulfur; R48, R50, R51 independently of one another H, (Ci-C8)-alkyl, aryl; R10 H, (Ci-C8)-alkyl; X N(R52), a bond, C=C, C(R53)(R54), CH2-CH2; R52, R53, R54 independently of one another H, (Ci-C8)-alkyl; intellectual property office of N.Z. 2 4 OCT 2008 14 E is selected from a group consisting of O n A N- J J N- /~A ■N N" v_y n —N V ,N, N' N' A N— y and which may optionally have substituents from the group of H, F, CI, Br, OH, CF3, N02, OCF3i 0-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), S02-CH3, CO(R65); R57, R58 independently of one another H, (C-|-C8)-alkyl; R65 independently of one another H, (C-|-C8)-alkyl, aryl; K a bond, O, OCH2, CH20, S, SO, S02, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C^C, SCH2, S02CH2; 1,2, 3, 4; 'ntcllectual. property office of N.Z. 2 4 OCT 2008 R66, R67, R68, R69, R70 independently of one another H, (Ci-C8)-alkyl; R11 H, (Ci-C8)-alkyl, (Ci-C4)-alkoxy-(C-|-C4)-alkyl, (C3-C3)-alkenyl, (C3-C8)-alkynyl, a 3 to 10-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 additionally be substituted by F, CI, Br, CF3, CN, (Ci-C6)-alkyl, 0-(C 1 -C8)-alkyl, (C1 -C4)-alkoxy-(C 1 -C4)-alkyl, (Co-C8)-alkylene-# 10 aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(Ci-C6)-alkyl, N(R76)(R77) or S02CH3; R71, R72, R73, R74, R75, R76, R77 independently of one another H, (C<|-C3)-alkyl; 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-(Ci-C6)-alkyl, oxygen and sulfur; and the physiologically tolerated salts thereof.
The invention also provides a medicament comprising one or more of the compounds of the present invention.
The invention also provides a medicament comprising one or more of the compounds of the present invention and one or more anorectic active intellectual property office of n.2. 2 4 OCT 2008 ft P" r\ r- 1 \ 1 r- ^ ingredients. 16 The invention also provides a compound of the formula I of the present invention for use as medicament for the prophylaxis or treatment of obesity.
The invention also provides a compound of the formula I of the present invention for use as medicament for the prophylaxis or treatment of type II diabetes.
In a further aspect, the invention provides a compound of the formula I of the present invention in combination with at least one further anorectic active ingredient for use as medicament for the prophylaxis or treatment of obesity.
In a further aspect, the invention provides a compound of the formula I of the present invention in combination with at least one further anorectic active ingredient for use as medicament for the prophylaxis or treatment of of type II diabetes.
The invention also provides a process for producing a medicament comprising one or more of the compounds of the formula I of the present invention, which comprises mixing the active ingredient with a pharmaceutical^ suitable carrier and converting this mixture into a form suitable for administration. ,ntellectual property office of N.Z. 2 4 OCT 2008 RPPCIl/cn 17 In another aspect, the inention relates to the use of the compounds of the formula I of the present invention for producing a medicament for weight reduction in mammals.
The invention also relates to the use of the compounds of the formula I of the present invention for producing a medicament for the prophylaxis or treatment of obesity.
The invention further relates to the use of the compounds of the formula I of 10 the present invention for producing a medicament for the prophylaxis or treatment of type II diabetes.
The invention further relates to the use of the compounds of the formula I of the present invention for producing a medicament for the treatment of 15 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.
The invention also relates to the use of the compounds of the formula I of 20 the present invention for preparing a medicament having a MCH-receptor antagonistic activity.
The invention also provides a pharmaceutical composition comprising one or more of the compounds of the present invention and a pharmaceutical^ 25 acceptable carrier, excipient, or both. intellectual property office of n.z. 2 4 OCT 2008 RFnPlx/cn 18 The invention relates to compounds of the formula I in the form of their 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, 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, R50, R51, R52, R53, R56, R57, R58, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R84, R85, R86, and R89 may be either straight-chain, branched or optionally halogenated.
The term "aryl" means in particular a phenyl or naphthyl group.
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 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 19 which are linked by one and the same atom to the two adjacent groups K and X.
The term "comprising" as used in this specification means "consisting at 5 least in part of. When interpreting each statement in this specification that includes the term "comprising", features other than that or those prefaced by the term may also be present. Related terms such as "comprise" and "comprises" are to be interpreted in the same manner.
Pharmaceutically acceptable salts are, because their solubility in water is greater than that of the initial or basic compounds, particularly suitable for medical applications. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of 15 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, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, 20 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 sodium and potassium salts), alkaline earth metal salts (such as magnesium and calcium salts). 'ntellectualpr°pertv uf-fjce of n.2 2 4 OCT 2008 D C or iiir> Salts with a pharmaceutically unacceptable anion likewise belong within the framework of the invention as useful intermediates for the preparation or 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 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 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 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 (I)" hereinafter refer to compound(s) of the formula (I) as described above, and their salts, solvates and physiologically functional derivatives as described herein. 21 If radicals or substituents can occur more than once in the compounds of the formula I, they may all have independently of one another the stated meanings and be identical or different.
In the description in this specification reference may be made to subject matter that is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application.
In a particularly preferred embodiment, the present invention relates to compounds of the formula I in which the meanings are: R1, R2 independently of one another, H, (Ci-C8)-alkyl, -(CH2)o -R12, -(CR78R79)0-Ri2, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, CO-(Ci-C8)-15 alkyl, -CO-(CH2)0 -r12, COCH=CH(R13), COCC(R14), 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 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 20 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, CI, CF3, (Ci-C6)-alkyl, 0-(C-i-C4)-alkyl, (CrC4)-alkoxy-(Ci-C4)-alkyl, (Co-C2)-alkylene-aryl, oxo, CO(R26), hydroxy, N(R31)(R32) or SO2CH3, where R1 and R2 are preferably not both H, and R1 and R2 together with the nitrogen atom are preferably not a morpholino intellectual PROPPhtv OFFICE OF Tz 2 4 OCT 2008 REf!PI\/cn radical; 22 o 0,1,2,3,4; q 1 or 2; s 0, 1, 2, 3, preferably 1, 2, 3; R13, R14 independently of one another are a phenyl ring which may comprise 0-1 nitrogen atoms; R15, R16, R17, R31, R32 independently of one another H, (Ci-C6)-alkyl; R18 H, (Ci-C6)-alkyl, CO(Ci-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, O—(C0-C8)-alkylene-aryl, CN, 3-10 membered mono- or bicyclic ring which may comprise 1-3 heteroatoms from the group of N, O and S, and the 3-10 membered ring may comprise further substituents such as F, CI, CN, oxo, 0-(Ci-C6)-alkyl, (CrC^-alkoxy-CCi-C^-alkyl, (Ci-C6)-alkyl, O-(C0-C2)-alkylene-aryl, N(R34)(R35), intellectual property office of N.Z 2 4 OCT 2008 RCPcn/p^ 23 C0(C<|-C6)-alkyl. In a preferred embodiment the substituent 0-(C-|-C6)-alkyl is excluded when the 3-10 membered ring is phenyl; t 0, 1, 2, 3, 4, 5, 6; R34, R35 or 0 or 2; independently of one another H, (Ci-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 atom, may also comprise 0-1 further heteroatoms from the group of N-(Ci-C6)-alkyl, oxygen and sulfur and may optionally be substituted by 1-2 oxo groups; R78, R79 independently of one another H, (CfCsJ-alkyl, hydroxyl-(Cr C4)alkyl, OH, (Ci-C4)-alkoxy-(Ci-C4)-alkyl; R3 H; R4, R5 independently of one another H, (Ci-C6)-alkyl, OH, 0-(Ci-C6)-alkyl, 0-C0(Ci-C6)-alkyl; R6, R7, R8, R9 independently of one another H; intellectual property office of n.z. 2 4 OCT 2008 received 24 n 1; m 1; A, B, D, G B is N, C(R42) and A, D, G, C(R42); R42 is H, F, CI, Br, CF3, CN, 0-(Ci-C6)-alkyl, (Ci-C6)-alkyl, S02- CH3, CON(R45)(R46), N(R47)CO(R48), C0(R51), -(CR84R85)X-0(R86); R45, R46, R47 independently of one another H, (Ci-Cs)-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 group of N-(Ci-C6)-alkyl, oxygen and sulfur; R48, R51 independently of one another H, (Ci-C8)-alkyl; R86 H, (Ci-C6)alkyl; x 0,1; R10 H, (Ci-C8)-alkyl; intellectual property office of n.z 2 4 OCT 2008 RECEIVED X N(R52), O, a bond, C=C, C(R53)(R54), CH2-CH2; R52, R53, R54 independently of one another H, (C-|-C8)-alkyl; is selected from the group consisting of ~\ N- J N' n j N- N' n \ N- J r~\ -N N- \ / n O r -N V -N. and which may optionally have substituents from the group of H, F, CI, Br, CF3, 10 N02i OH, OCF3; 0-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2-CH3, CO(R65); R57, R58 independently of one another H, (C-|-C8)-alkyl; R65 independently of one another H, (Ci-C8)-aIkyl; K a bond, O, CH20, N(R66), (C(R69)(R70))V, C^C, OCH2> SCH2, CO, CON(R68), preferably a bond, O, CH2O, intellectual property office of n.z. 2 4 OCT 2008 26 ((CR69)(R70))V, CsC, N(R66); v 1,2,3; R66, R68, R69, R70 independently of one another H, (Ci-Cs)-alkyl; R11 (C-|-C8)-alkyl, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, a 3 to 10- membered mono-, bi- or spirocyciic ring which may comprise 10 0 to 3 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, CI, Br, CF3, CN, (Ci-C6)-alkyl, 0-(C-|-C8)-alkyl, (Co-C2)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, N(R75)CO(Ci-C6)-alkyl, N(R76)(R77) or SO2CH3,; R71, R72, R73, R75, R76, R77 independently of one another H, (C-|-C8)-alkyl; R72 and R73, R76 and R77 20 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-(Ci-C6)-alkyl, oxygen and sulfur.
Particularly preferred compounds of the formula I are those in which B is N or C(R42), A, D, G are C(R42), and the total number of nitrogen atoms in this ring is 0-2, preferably 0 or 1. intellectual property office of n.z 2 4 OCT 2008 R EC E I V F D 27 Very particularly preferred compounds of the formula I are those in which m is 1 and is 1.
Especially preferred compounds of the formula I are those in which B is N or C(R42), A, D, G are C(R42), and the total number of nitrogen atoms in this ring is 0-2, preferably 0 or 1; n is 1; and m is 1.
In a further preferred embodiment, the present invention relates to compounds of the formula I in which the meanings are: R1, R2 independently of one another are H, (Ci-C8)-alkyl, - (CR78R79)0 -R12, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, CO-(Ci- C8)-alkyl, -CO-(CH2)0-R12, 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 25 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-|-C6)-alkyl, (C-|-C4)-alkoxy-(Ci-C4)-alkyl, oxo, CO(R26), hydroxy, and N(R31)(R32) or 30 preferably independently of one another H, (Ci-C8)-alkyl, -(CR78R79)o -R12, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, CO-(Ci- intellectual property office of n.z. 2 4 OCT 2008 r f n f i \/ f n 28 C8)-alkyl, -CO-(CH2)o-R12, o 0,1,2,3; q, q is 1 or 2; R15, R16, R17, R31, R32 independently of one another H, (C-|-C6)-alkyl; R18 H, (Ci-C6)-alkyl,; R17 and R18, R21 and R22, R27 and R28, R31 and R32 15 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-(Ci-C6)-alkyl, 3-10 membered mono-, bicyclic ring which may comprise 1-2 heteroatoms from the group of N, O and S, and the 3-10 membered ring may comprise further substituents such as F, OH, oxo (C-|-C6)-alkyl, CO(Ci-C6)-alkyl; particularly preferably OH, 0-(C-|-C6)-alkyl, 3-10 membered mono- or bicyclic ring which may comprise 1-2 heteroatoms from the group of N, O and S, and the 3-10 membered ring may comprise further substituents such as F, OH, oxo, (Ci-C6)-alkyl, CO(C-|-C6)-alkyl; intellectual propertv office of n.z 2 h OCT 2008 29 R78, R79 independently of one another H, (Ci-C8)-alkyl, hydroxy-(Ci-C4)-alkyl, OH, (Ci-C4)-alkoxy-(C-|-C4)-alkyl; R3 H,; R4, R5 independently of one another H, OH, 0-(Ci-C6)-alkyl; R6, R7, R8, R9 H; m 1; A, B, D, G are C(R42); R42 H, F, CI, CF3, CN, (Ci-C6)-alkyl, -(CR84R85)X-0(R86); R43, R44, R45, R46, R47 independently of one another H, (Ci-C8)-alkyl; R84, R85 H; R86 H, (Ci-C6)-alkyl; x 0,1,2; preferably 0, 1; particularly preferably 1; R10 H, (Ci-C8)-alkyl; X a bond, C=C, C(R53)(R54), CH2-CH2; intellectual propertv office of n.z. 2 h OCT 2008 _ — i- i \ / r n R53, R54 independently of one another H, (C-|-C8)-alkyl; E which may optionally have substituents from the group of H, F, CI, Br, OH, CF3>, N02, OCF3, 0-(Ci-C6)-alkyl, (CrC6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), S02-CH3, CO(R65); R57, R58 independently of one another H, (C-|-C8)-alkyl; R65 independently of one another H, (C-i-C8)-alkyl; K a bond, O, OCH2, CH20, CON(R68), (C(R69)(R70))V, CO, v 1 or 2; R66, R67, R68, R69, R70 independently of one another H, (C-|-C8)-alkyl; R11 (Ci-C8)-alkyl, (C-|-C4)-alkoxy-(Ci-C4)-alkyl, a 3 to 10- membered mono- or bicyclic ring which may comprise 0 to 2 25 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted intellectual property office of n.z. 2 4 OCT 2008 31 by F, CI, Br, CF3, CN, (Ci-C6)-alkyl, 0-(Ci-C8)-alkyl, oxo, CO(R71), CON(R72)(R73), N(R75)CO(Ci-C6)-alkyl, or SO2CH3; R71, R72 independently of one another H, (C-j-Cs)-alkyl; 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-(Ci-C6)-alkyl, oxygen and sulfur; or 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 furthermore those listed in table I below: Table I: fintellectual property office of n.z. 2 4 OCT 2008 CH CH CH CH CH CH CH CH CH CH C-Br CH C-CI CH CH CH CH CH CH CH CH CH CH CH CH CH CH C-Br CH C-CI C-CN CH C-CH3 CH C-CF3 CH "TT Th* C-F C-F C-F C-CI C-CI ch ch ch ch ch c-cn ch c-ch3 ch c-cf3 ch2oh c-f ch c-f c-ci c-cn ch c-ch3 n : C-CH3 C-CH3 n— If E is N—/ , the preferred meanings for A, B, G and D are furthermore those listed in table II below: Table II: A I B I G ■ D intellectual propertv office of hi 2 h OCT 2008 DCPCI\/t-n 33 CH CH CH CH CH CH C-F C-CH3 C-F CH "TIT1 N CH CH CH "c!T C-CH3 C-F CH CH C-F CH CH CH CH CH N CH If E is N—' , the preferred meanings for A, B, G and D are 9 furthermore those listed in table III below: Table III: A B G D CH CH C-F CH CH N CH CH CH CH CH N Further preferred combinations for E and A, B, G and D are listed in table # 10 IV.
Table IV: A I B I G I D intellectual property office of N.Z. 2 4 OCT 2008 E 34 The radicals R11, K, X and E in formula I have in a particularly preferred embodiment one of the following meanings: R11 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- intellectual property office of N.Z. 2 4 OCT 2008 fluorophenyl, 2,4-difluorophenyl, 3-fluoro-4-methylphenyl, 2-nitro-4-methylpheriyl, 2-amino-4-methylphenyl, Cl- // \ r\ :N :N JO CI >- <iY and V- 0 K is preferably selected from the group consisting of: -0-, bond, C=C, CH2> CH20, CONH, OCH2, CO, SCH2 and (CH2)20.
X is preferably selected from the group consisting of bond, NH and CH2.
E is preferably selected from the group consisting of: // \ / \ ^4 \ / \ N- y v// -N N- v_y y N- O N, and N Preferred combinations of R11, K, X and E are listed below: If K and X are each a bond, the particularly preferred meanings for E and 20 R11 are as follows: 'ntellectual pr°pgrty office of N.Z. 2 4 OCT 2008 ^ "l Lj a « « —— _ 36 If E is 1,4-phenylerie, R11 is selected from the group consisting of: cyclohexyl, p-tolyl, p-fluorophenyl, o-fluorophenyl, p-methoxyphenyl, p-chlorophenyl, o-chlorophenyl, 2,4-difluorophenyl, 3-fluoro-4-methylphenyl, o-cyanophenyl, and n— If E is N—' , R11 selected from the group consisting of: p-chlorophenyl, p-tolyl, p-fluorophenyl, p-methoxyphenyl, trifluoromethylphenyl, o-fluorophenyl, phenyl and Further combinations of E and R11 for the case where K and X are each a bond are listed in table V: Table V: ,ntel^g™al property office of N.Z. 2 4 OCT 2008 RECEI VPn p-Chlorophenyl p-Chlorophenyl p-Methylthiophenyl 2-Amirio-4-methylpheny If K is -O- and X is a bond, NH or CH2, the particularly preferred meanings for E and R11 are as follows: ■ 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.
Further combinations of E and R11 for the case where K is -O- and X is a bond, NH or CH2 are listed in table VI: Table VI: intellectual property OFFICE OF Mi 2 4 OCT 2008 RECEIVED 38 Cyclopentyl Phenyl n-Butyl n-Butyl E If K is C=C and X is a bond, the particularly preferred meanings of E and R11 are as follows: ■ If E is 0 , R11 is selected from the group consisting of: phenyl, p-fluorophenyl and p-chlorophenyl.
If K is CH2 and X is a bond, the particularly preferred meanings of E and R11 are indicated in table VII below: Table VII: R11 Phenyl p-Chlorophenyl E 1,4-Phenylene 1,4-Phenylene intellectual property office of n.z. 2 4 OCT 2008 39 If K is CH2O and X is a bond, the particularly preferred meanings of E and R11 are as follows: ■ 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 R11 are indicated in table VIII below: Table VIII: Cyclopentyl Cyclohex-(1)-enyl Cyclopentyl 1,4-Phenylene 1,4-Phenylene If K is OCH2 and X is a bond, the particularly preferred meanings of E and R11 are indicated in table IX below: Table IX: o-Chlorophenyl p-Tolyl n-Propyl Cyclobutyl E 1,4-Phenylene 1,4-Phenylene 1,4-Phenylene intellectual property office of n.z. 2 4 OCT 2008 40 The combinations of R11, K and E listed in table X below are furthermore particularly preferred in addition to the aforementioned combinations, with X very particularly preferably being a bond: Table X: R11 I K o-Fluorophenyl I CO Phenyl | SCH2 Cyclopropyl | (CH2)20 E 1,4-Phenylene The compounds of the formula I are in a very particularly preferred embodiment compounds of the formula la R42 0 I A.. rh-k-e~X' -p-A ; N R10 HR42' NR1R2 la in which the radicals R1, R2, R10, R11, R42, and groups X, E, K have the aforementioned meanings, and R42' is defined as R42, where R42 and 15 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, R11, R42, R42' and groups X, E, K have the following meanings: R1, R2 independently of one another H, (C-|-C8)-alkyl, -(CR78R79)0 -R12, (C-|-C4)-alkoxy-(C-|-C4)-alkyl, or R1 and R2 form intellectual property office of N.Z 2 h OCT 2008 41 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 5 sulfur, where the heterocyclic ring system may additionally be substituted by F, (C-|-C6)-alkyl, 0-(Ci-C4)-alkyl, (C1-C4)- alkoxy-(Ci-C4)-alkyl, hydroxy-(Ci-C4)-alkyl, (Co-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, N(R31)(R32) or SO2CH3; where R1 and R2 are not both CO(R26), preferably H, (Ci-C8)-alkyl, -(CR78R79)0-R12, (C1-C4)- alkoxy-(Ci-C4)-alkyl, 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, 15 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, (Ci-C6)-alkyl, (C<|-C4)-alkoxy-(Ci-C4)-alkyl, oxo, CO(R26), hydroxy, N(R31)(R32); o 0, 1, 2, 3, 4, preferably 0, 1, 2, 3; q 1, 2, 3, preferably 1 or 2; s 0,1,2; R15, R16, R17, R18, R23, R24, R25, R26, R27, R28, R31, R32 30 independently of one another H, (Ci-C6)-alkyl; intellectual property office of N.Z. 2 4 OCT 2008 42 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-(Ci-C6)-alkyl, oxygen and sulfur, preferably the ring is a pyrrolidine, piperidine, N-methylpiperazine, morpholine ring; R12 OH, 0-(Ci-C6)-alkyl, O-(C0-C2)-alkylene-aryl, CN, S-(Ci-C6)- alkyl, 3-12 membered mono-, bi- or spirocyclic ring which may comprise 1 to 3 heteroatoms from the group of N, O and S, and the 3-12 membered ring may comprise further substituents such as F, OH, CF3, CN, oxo, (C-|-C6)-alkyl, (Co- C2)-alkylene-aryl, N(R34)(R35), COO(R40), CO(Ci-C6)-alkyl, preferably OH, 0-(Ci-C6)-alkyl, 3-10 membered mono- or bicyclic ring which may comprise 1-2 heteroatoms from the group of N, O and S, and the 3-10 membered ring may comprise further substituents such as F, OH, oxo, (C-J-C6)-alkyl, CO(Ci-C6)-alkyl; R34, R35 R40 independently of one another H, (Ci-C4)-alkyl; H, (Ci-C6)-alkyl, (Co-C2)-alkylene-aryl; 24 OCT 2008 D C O r 1 K M ~ R78, R79 43 independently of one another H, (Ci-C8)-alkyl, hydroxy-(Ci-C4)-alkyl, OH, (Ci-C4)-alkoxy-(C-|-C4)-alkyl; R42, R42' independently of one another H, F, CI, Br, CF3, CN, (C1-c6)-5 alkyl; R10 H, (Ci-C8)-alkyl; X N(R52), a bond, C=C, C(R53)(R54), CH2CH2; R52, R53, R54 independently of one another H, (Ci-C8)-alkyl; E is selected from the group consisting of % O n / \ -N N- \ r -N V A N- J N' /t^t j N- N" A N- J n .N. and intellectual propertv office of N.z. 2 h OCT 2008 RECEIVEC 44 which may optionally have substituents from the group of H, F, CI, Br, OH, CF3, N02i OCF3) 0-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), S02-CH3, CO(R65); preferably -n n— —( n-\ / , \ / O- -O and which may optionally have the aforementioned substituents; 10 R57, R58 independently of one another H, (Ci-C8)-alkyl; R65 H, (Ci-C8)-alkyl; K a bond, O, OCH2, CH20, S, S02, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C^C, SCH2, S02CH2; 15 preferably a bond, O, OCH2, CH20, CON(R68), (C(R69)(R70))V, particularly preferably CH2, CO, C=C; v 1, 2, 3, preferably 1,2; R66, R67, R68, R69, R70 independently of one another H, (Ci-C8)-alkyl; R11 (Ci-C8)-alkyl, (C-|-C4)-alkoxy-(Ci-C4)-alkyl, a 3 to 10- membered mono-, bi-, tri- or spirocyclic ring which may intellectual property office of n.z. 2 4 OCT 2008 n i™" ^ *— 11* »— 45 comprise 0 to 4 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, CI, Br, CF3, CN, (C1-C6)-alkyl, 0-(C-|-C8)-alkyl, oxo, CO(R71), hydroxy, 5 N(R75)CO(Ci-C6)-alkyl, or S02CH3; preferably (C-|-C8)-alkyl, (C-|-C4)-alkoxy-(C-|-C4)-alkyl, a 3 to -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 4) 10 substituted by F, CI, Br, CF3, CN, (Ci-C6)-alkyl, 0-(Ci-C8)- alkyl, oxo, CO(R71), CON(R72)(R73), N(R75)CO(Ci-C6)-alkyl, or SO2CH3; R71, R72, R73, R74, R75, R76, R77 15 independently of one another H, (C1 -C8)-alkyl; 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-(Ci-C6)-alkyl, oxygen and sulfur.
In a preferred embodiment, the present invention relates to compounds of the formula la, in which 30 intellectual property office of n.z 2 4 OCT 2008 ® 20 46 CH2CH2, N(R52), CH2, preferably CH2CH2; |,NTEolSV?PzPEfiT>i 2 4 OCT 2008 47 K is a bond, O or C(R69)(R70); arid the other symbols R1, R2, R10, R11, 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 la.
Also described are compounds of formula 1 a wherein E is preferably In a further preferred embodiment, the present invention relates to compounds of the formula la, in which X is N(R52), preferably NH, or C(R53)(R54); N-s 48 E is tr n preferably or K is a bond, O or C(R69)(R70), preferably 0; and the other symbols R1, R2, R10, R11, R42, R42',R52, R53, R54, R69 and R70 have the meanings indicated above in relation to a definition of the radicals of the compound of the formula la.
In a further particularly preferred embodiment, the compounds of the formula I are compounds of the formula lb in which the radicals R1, R2, R10 and R11 and the groups E and D have the aforementioned meanings, or the N-oxides and the physiologically tolerated salts thereof.
In a preferred embodiment, the radicals R1, R2, R10 and R11 the groups E and D have the following meanings: R1, R2 independently of one another H, (C-|-C8)-alkyl, -(CR78R79)0 -R12, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, (C3-C8)-alkenyl, CO- O (lb) 49 (Ci-C8)-alkyl, -CO-(CH2)0 -R12, CO-aryloxy-(Ci-C4)-alkyl, C0CH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), 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 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, CI, CF3, (Ci-C6)-alkyl, 0-(Ci-C4)-alkyl, (Ci-C4)-alkoxy- (Ci-C4)-alkyl, hydroxy-(Ci-C4)-alkyl, (Co-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(Ci-C6)-alkyl, N(R31)(R32) or S02CH3, where R1 and R2 are not both CO(R26); preferably independently of one another H, (Ci-C8)-alkyl, -(CR78R79)o -R12, (C-|-C4)-alkoxy-(Ci-C4)-alkyl, CO-(Ci-C8)-alkyl, -CO-(CH2)0 -R12, COCH=CH(R13), COCC(R14), 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 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, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, CI, CF3, (C-|-C6)-alkyl, 0-(Ci-C4)-alkyl, (C-|-C4)-alkoxy-(Ci-C4)-alkyl, (Co-C2)-alkylene-aryl, oxo, hydroxy, N(R31)(R32) or S02CH3, where R1 and R2 are not both CO-(C-j-C8)-alkyl; intellectual jropertv] office of i\).z i 2 4 OCT 2008 50 particularly preferably independently of one another H, (Ci-C8)-alkyl, -(CR78R79)0 -R12, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, CO-(Ci-C8)-alkyl, -CO-(CH2)0 -R12.
CO(C(R15)(R16))qN(R17)(R18), or R1 and R2form 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 additionally be substituted by F, (Ci-C6)-alkyl, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, oxo, CO(Ci-C8)- alkyl, hydroxy, N(R31)(R32), where R1 and R2 are not both CO(Ci-C8)-alkyl; o 0, 1, 2, 3, 4, 5, 6; preferably 0, 1, 2, 3, 4; particularly 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, 2; 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, (Ci-C6)-alkyl; R18 H, (Ci-C6)-alkyl, CO(Ci-C6)-alkyl, CO(R33); preferably H, (Ci-C6)-alkyl, CO(Ci-C6)-alkyl; particularly preferably H, intellectual property office of n.z. 2 4 OCT 2008 51 (Ci-C6)-alkyl; or R17 and R18, R21 and R22, R27 and R28, R31 and R32 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-(Ci-C6)-alkyl, oxygen and sulfur; preferably the ring is pyrrolidine, piperidine, 10 N-methylpiperazine, morpholine; 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, (C<i-C6)-alkyl, 15 0-(Ci-C8)-alkyl; R12 is OH, 0-(Ci-C6)-alkyl, 0-(Co-C8)-alkylene-aryl, CN, S- (Ci-Ce)-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, CI, Br, OH, CF3, CN, oxo, 0-(C-|-C6)-alkyl, (C-|-C4)-alkoxy- (Ci-C4)-alkyl, (Ci-C6)-alkyl, 0-(Co-C8)-alkylene-aryl, (Co-Cs)- alkylene-aryl, N(R34)(R35), COCH=CH(R36), (C(R37)(R38))t (R39), CO(C(R37)(R38))t (R39), CO(Ci-C6)-alkyl, COCOO(Ci-C6)-alkyl, COO(R40), S(0)u (R41); preferably OH, 0-(Ci-C6)-alkyl, 0-(Co-C8)-alkylene-aryl, CN, 3-10 membered mono- or bicyclic ring which may comprise 1-3 heteroatoms from the group of N, O and S, and the 3-10 intellectual property office of n.z. 2 k OCT O P 1 \ / r n 52 membered ring may comprise further substituents such as F, CI, Br, OH, CF3, CN, oxo, 0-(C-|-C6)-alkyl, (C-|-C4)-alkoxy- (Ci-C4)-alkyl, (Ci-C6)-aikyl, (Co-C2)-alkylene-aryl, N(R34)(R35), CO(Ci-C6)-alkyi; particularly preferably OH, 0-(C-|-C6)-alkyl, 3-10 membered mono- or bicyclic ring which may comprise 1 -2 heteroatoms from the group of N, O and S and the 3-10 membered ring may comprise further substituents such as F, OH, oxo, (Ci-C6)-aikyl, CO(Ci-C6)-alkyl; t 0,1,2,3,4,5,6; u 0,1,2; preferably 0 or 2; particularly preferably 2; R34, R35, R37, R38 independently of one another H, (C-|-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 20 atom, may also comprise 0-1 further heteroatoms from the group of N-(Ci-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 aromatic ring system which may comprise 0-2 further heteroatoms from the group of nitrogen, oxygen and intellectual property office of n.z. 2 4 OCT 2008 53 sulfur and may be substituted by F, CI, (C-|-C6)-alkyl, O-(Ci-C8)-alkyl; R40 H, (Ci-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 nitrogen, oxygen and sulfur and may be substituted by F, CI, (Ci-C6)-alkyl, 0-(Ci-C8)-alkyl; R78, R79 independently of one another H, (C"j-Cs)-a!ky!, hydroxy-(Ci-C4)-alkyl, OH, (Ci-C4)-alkoxy-(Ci-C4)-alkyl; R80, R81 independently of one another H, (Ci-Cs)-alkyl; R10 H, (C1 -C8)-alkyl; INTELLECTUAL property office of n.z. 2 4 OCT 2008 RECEIVED 54 O \\ % n / \ -N N— \ / r —N V A N- y O" n N" A N- y and which may optionally have substituents from the group of H, F, CI, Br, OH, CF3, NO2, OCF3, 0-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2-CH3, CO(R65); preferably -N N- v_v // A N- y N, and which may optionally have the aforementioned substituents; intellectual property office of n.z 1\ OCT 2008 ncpci\/cn 55 R57, R58 independently of one another H, (Ci-Cs)-alkyl; R65 independently of one another H, (C-|-C8)-alkyl, aryl; preferably independently of one another H, (Ci-Cs)-alkyl; K a bond, O, OCH2, CH20, S, SO, S02, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C=C, C=C, SCH2, S02CH2; preferably a bond, O, OCH2, CH20, N(R66), CON(R68), (C(R69)(R70))V, CO, C=C, SCH2; particularly preferably a bond, O, OCH2, CH20, CON(R68), (C(R69)(R70))V> CO, C^C; v 1, 2, 3, 4; preferably 1, 2, 3; particularly preferably 1,2; R66, R67, R68, R69, R70 independently of one another H, (C-|-C8)-alkyl; R11 H, (Ci-C8)-alkyl, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, (C3-C8)- alkenyl, (C3-C8)-alkynyl, a 3 to 10-membered mono-, bi-, trior 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, CI, Br, CF3, CN, (Ci-C6)-alkyl, 0-(Ci-C8)-alkyl, (C-|-C4)-alkoxy- (Ci-C4)-alkyl, hydroxy-(Ci-C4)-alkyl, (Co-C8)-alkylene-aryl, oxo, C0(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(Ci-C6)-alkyl, N(R76)(R77) or S02CH3; preferably (Ci-C8)-alkyl, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, a 3 to INTELLECTUAL PRO_PERTY officf 2 s OCT 2008 11- o c l \/ C 56 -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, CI, Br, CF3, CN, (C-i-Cq)-5 alkyl, 0-(C-|-C8)-alkyl, (Co-C2)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, N(R75)CO(Ci-C6)-alkyl, N(R76)(R77) or S02CH3; particularly preferably (Ci-C8)-alkyl, (Ci-C4)-alkoxy-(Ci-C4)- alkyl, a 3 to 10-membered mono- or bicyclic ring which may 10 comprise 0 to 2 heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the ring system may additionally be substituted by F, CI, Br, CF3, CN, (C1-C6)-alkyl, 0-(Ci-C8)-alkyl, oxo, CO(R71), CON(R72)(R73), N(R75)CO(Ci-C6)-alkyl, orS02CH3; R71, R72, R73, R74, R75, R76, R77 independently of one another H, (C-|-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-(Ci-C6)-alkyl, oxygen and sulfur.
In a preferred embodiment, the present invention relates to compounds of the formula lb in which intellectual property office of n.z 2 4 OCT 2008 57 is O r~\ -N N- \ / r ■N V A N- y N y N- N N' A N- y or N' , where the aforementioned groups may optionally have substituents from the group of H, F, CI, Br, OH, CF3, N02, OCF3, 0-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), so2-ch3, CO(R65); intellectual property office of n.z. 2 4 OCT 2008 58 preferably E is in which the groups may have the aforementioned substituents; K is a bond; and the other radicals R1, R2, R10 and R11 and the group D have the meanings indicated above in relation to the definition of the radicals of the compound of the formula lb.
R11 in the aforementioned compounds of the formula lb is particularly 15 preferably a substituted mono- or bicyclic ring system with 5-10 members, which may have 0-3 heteroatoms, in particular N, O and/or S, particularly preferably phenyl with 0-1 N atom, cyclohexyl or a bicyclic system with 8-10 members and 1-2 heteroatoms, in particular N, O and/or S.
In a further preferred embodiment, the present invention relates to compounds of the formula lb in which intellectual propertv OFFICE OF N.Z 2 4 OCT 2008 received 59 is ,N> . XX. XX N- J or where the aforementioned groups may optionally have substituents from 5 the group of H, F, CI, Br, OH, CF3, NO2, OCF3, 0-(C-|-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), SO2CH3 and CO(R65); preferably .N> XX - XX. in which the groups may have the aforementioned substituents; K is CH2, CH2CH2i O, CH20, OCH2, CON(R68), N(R67)CO, S, S02> SCH2, S02, S02CH2, CO or a triple bond; preferably CH2, O, CH20, OCH2, CON(R68), SCH2, CO or a triple bond; and the other radicals R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, 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 (I) necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the 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 (I) 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 (I). 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 (I) 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 (I); 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 (I) 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.
Pharmaceutical compositions suitable for parenteral administration comprise preferably sterile aqueous preparations of a compound of formula (I), 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 (I) 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 II 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.
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.
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.
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.
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, Gl 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.
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.
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.
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, HMR1171, HMR1586.
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.
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.
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, CI-1027 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.
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.
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-yl)-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-dimethyl-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, £3 agonists (e.g. 1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-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-1H-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-(3 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.
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.
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 Hochst, 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 ,o o CI-1027 o HsC\ /CHa "°V "CH, BMS-188494 The present compounds may additionally be administered in combination with one or more antihypertensive active ingredients. Examples of 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.
The efficacy of the compounds was tested as follows: 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 dose [mg/kg] Number of animals/-cumulative milk consumption of the treated animals N/[ml] Number of animals/-cumulative milk consumption of the control animals N/[mll Reduction in the cumulative milk consumption as % of the control Example 4 /3.55 /1.76 50 Example 13 /3.70 /1.34 64 71 DESCRIPTION OF EXPERIMENTS 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.
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, —NR.R, K2C03, DMF Method C H2, Pd(OH)2 Method B NR,R2 NR.R., R1 =H R1 = Aikyl Alkyl-X, NaH Method F (for R2 = Ac, Boc) R R2 = Ac H A=\ /-n_-NR,R2 CDI, NHR3R4 R3^ /N—//N\ J = Method A P ,''N R2 = Boc R4 o R2 = H NaOH Method D TFA Method G 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) OH ICfr Method I 2) R3-X, Cs2C03 Method H r3> H N—\ W^NR1R2 11 jCJlT°h ^ A C Methods A, E 2) Ci or R'- Methods O Methods J i—\ V_> NR^ 0^nrir2 M r>NRlR2 i-—y R3COCI Method Q 0 .A r3 nr1r2 74 Yet other examples were obtained as indicated in the following scheme. 0 o HNR1R2 Method L R2 I Nv "R1 1) Nu- 2) MOH Methods P 3) A, Methods E (M = Metal Nu- = nucleophile) R ry^2 • £r HO NR^ R" 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; Method D in example 2; Method E in example 3; Method E-a in example 275; Method E-b in example 286; 75 Method F in example 4; Method F-a in example 264; 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 O in example 279; Method O-a in example 292; Method O-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. 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 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 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 N-Methyl-N-(1 -{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide Method A 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 80°C for 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+).
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(ll) 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 (C13H19N30); MS (ESI): 234 (M+H+).
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 (C13H17N303): MS (ESI): 264 (M+H+).
Example 2 1-[4-(3-Methylaminopyrrolidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea 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 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 (M+H+).
Example 3 N-Methyl-N-(1 -{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-2-phenylacetamide 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 0°C. After 10 minutes, Hunig'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.
Example 4 (F?j-N-Methyl-N-(1 -{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide n N (R)-N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted 79 0 25 with 4-phenoxyaniline by method A. This resulted in the product with the molecular weight of 444.54 (C26H28N403); MS (ESI): 445 (M+H+). (7?)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide (T^-N-Methyl-N-11 -(4-nitrophenyl)pyrrolidin-3-yl]acetamide was hydrogenated by method B. This resulted in the product with the molecular weight of 233.32 (C13H19N30); MS (ESI): 234 (M+H+). (7^-N-Methyl-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide 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. 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 (C13H17N303); MS (ESI): 264 (M+H+). (lR)-N-[1-(4-Nitrophenyl)pyrrolidin-3-yl]acetamide (T^-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+).
Example 5 fS)-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide The sequence described in example 4 was applied to fSj-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 (F?)-1-[4-(3-Methylaminopyrrolidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea (7^-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]pheriyl}pyrrolidiri- 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+).
Example 7 (SJ-1-[4-(3-Methylaminopyrrolidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea H 'N (rSj-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+).
Example 8 (R)-N-(1 -{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide (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-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 carbonate (63.3 g) and DMF (300 ml) was heated at 80°C 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 (C11H15NO); MS (ESI): 178 (M+H+).
Example 9 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide was reacted by method D. This resulted in the product 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-cyclopentyloxy-phenyl)-ureido]-phenyl}-pyrrolidin-3-yl)-N-methyl-acetamide h n \ Example 10 Ethyl (1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)methyl-carbamate 82 Ethyl chloroformate (8 |il) was added dropwise to a solution of 1-(4-cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea (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 hydrotrifluoroacetate.
Example 11 1 -(1 -{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-3-ethyl-1 -methylurea Ethyl isocyanate (7 jaI) was added dropwise to a solution of 1 -(4-cyclo-pentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1 -yl)phenyl]urea (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 465.60 (C26H35N503); MS (ESI): 466 (M+H+) as hydrotrifluoroacetate.
Example 12 1-(4-Cyclopentyloxyphenyl)-3-(4-{3-[methyl-((R)-5-oxo-pyrrolidin-2-ylmethyl)amino]pyrrolidin-1-yl}phenyl)urea 83 ^-5-Bromomethylpyrrolidin-2-one (15 mg) was added to a suspension of 1-(4-cyclopentyloxyphenyl)-3-[4-(3-methyaminopyrrolidin-1-yl)phenyl]urea (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.
Example 13 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1 -yl]phenyl}amide N O N N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with carbonyldiimidazole and then with 4-(4-chlorophenyl)piperidine by 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 (§)-N-[1 -(4-aminophenyl)pyrrolidin-3-yl]-N-methyacetamide.
Example 14 tert-Butyl (R)-[ 1 -(4-{[4-(4-chlorophenyl)piperidine-1 -carbonyl]amino}-phenyl)pyrrolidin-3-yl]methylcarbamate 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 C/^-[1-(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate tert-Butyl (7?)-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 (C16H25N302); MS (ESI): 292 (M+H+). tert-Butyl (/?)-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 (C16H23N304); MS (ESI): 322 (M+H+). tert-Butyl (R)-[ 1 -(4-nitrophenyl)pyrrolidin-3-yl]carbamate tert-Butyl (7^-pyrrolidin-3-ylcarbamate was reacted with 4-fluoronitro-benzene by method C. This resulted in the product with the molecular weight of 307.35 (C15H21N304); MS (ESI): 308 (M+H+).
Example 15 (7:?)-4-(4-Chlorophenyl)piperidine-1-carboxylic acid [4-(3-methylamino-pyrrolidin-1 -yl)phenyl]amide 85 Method G Trifluoroacetic acid (6.67 g) was added to a solution of tert-butyl (R)-[\ -(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 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid (4-{(7^-3-[methyl-(1 -methyl-piperidin-3-ylcarbonyl)amino]pyrrolidin-1-yl}phenyl)amide / (F?M-(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+).
Example 17 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid (4-(/?/)-{3-[methyl-(2-piperidin-1 -ylacetyl)amino]pyrrolidin-1 -yl}phenyl)amide (ft)-4-(4-Chlorophenyl)piperidine-1 -carboxylic acid [4-(3-methylamino-pyrrolidin-1 -yl)phenyl]amide was reacted with piperidin-1 -ylacetic acid by method E. This resulted in the product with the molecular weight of 538.14 (C30H40CIN502); MS (ESI): 538 (M+H+).
Example 18 4-(4-Chlorophenyl)piperidine-1-carboxylic acid (4-(/?)-{3-[methyl-(2-oxo-thiazolidine-4-carbonyl)amino]pyrrolidin-1-yl}phenyl)amide (7?>)-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+).
Example 19 f/?)-4-(4-Chlorophenyl)piperidine-1 -carboxylic acid (4-{3-[methyl-(2,2,2-trifluoroacetyl)amino]pyrrolidin-1-yl}phenyl)amide (7?)-[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+). fF?>[N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-2,2,2-trifluoro-N-methylacetamide (7:?)-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 (C13H16F3N30); MS (ESI): 288 (M+H+).
(R)-2,2,2-T rifluoro-N-methyl-N-[1 -(4-nitrophenyl)pyrrolidin-3-yljacetamide 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 (C13H14F3N303); MS (ESI): 318 (M+H+). (73J-Methyl-[1 -(4-nitrophenyl)pyrrolidin-3-yl]amine A solution of tert-butyl ff?)-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+).
Example 20 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]phenyl}methylamide 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 (7?)-4-(4-Chlorophenyl)piperidine-1 -carboxylic acid (4-{3-[acetyl-(2-diethylaminoethyl)amino]pyrrolidin-1-yl}phenyl)amide (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+). ff?/)-N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-(2-diethylaminoethyl)acetamide (F?)-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 (C18H30N40); MS (ESI): 319 (M+H+). (flJ-N-(2-Diethylaminoethyl)-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide (R)-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide was reacted with 2-chloroethyldiethylamine by method F. This resulted in the product with the molecular weight of 348.45 (C18H28N403); MS (ESI): 349 (M+H+). 89 Example 22 1-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-3-(4-phenoxyphenyl)urea o-< 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 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-phenyl)propionamide 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+).
Example 24 N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide 90 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 (SJ-N-pyrrolidin-3-ylacetamide.
Example 25 N-(1 -{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-N-ethylacetamide o-Vo 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+).
Example 26 4-(4-Chlorophenyl)piperidin-1 -carboxylic acid {4-[3-(acetylmethyl-amino)pyrrolidin-1-yl]-3-methylphenyl}amide 91 N O.
N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 1 -fluoro-2-methyl-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+).
Example 27 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl)-3-fluorophenyl}amide 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+).
Example 28 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]-2,6-difluorophenyl}amide 92 O F CI 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 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+).
Example 29 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]-2-methylphenyl}amide 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)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+).
Example 30 4-(4-Chlorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1-yl]-2-fluorophenyl}amide N-Methyl-N-pyrrolidin-3-ylacetamide was reacted with 2,4-difluoro-1- ,0 F 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+).
Example 31 tert-Butyl (R)-[ 1 -(5-{[4-(4-Chlorophenyl)piperidin-1 -carbonyl]amino}pyridin-2-yl)pyrrolidin-3-yl]methylcarbamate The synthetic sequence for preparing tert-butyl (R)-[\ -(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 ^?/)-[4-(4-Chlorophenyl)piperidine-1 -carboxylic acid [6-(3-methylamino-pyrrolidin-1-yl)pyridin-3-yl]amide 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+).
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 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 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 -hL ,N- 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 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 O N O 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. This resulted in the product with the molecular weight of 464.61 (C27H36N403); MS (ESI): 465 (M+H+).
Example 36 4-Butoxy-N-[4-(4-dimethylaminopiperidin-1 -yl)phenyl]benzamide / N \ ([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 9 ^ i 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 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 (C11H13N303); MS (ESI): 236 (M+H+). 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+). 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+).
Example 38 tert-Butyl [1 -(4-{[4-(4-Chlorophenyl)piperidin-1 -carbonyl]amino}-phenyl)azetidin-3-yl]methylcarbamate 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 (C15H23N302); 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 (C15H21N304); MS (ESI): 308 (M+H+).
Example 39 4-(4-Chlorophenyl)piperidin-1 -carboxylic acid [4-(3-methylaminoazetidin-1 -yl)phenyl]amide Cl- 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+).
Example 40 N-Methyl-N-[1-(4-{3-[4-(pyridin-3-yloxy)phenyl]ureido}phenyl)pyrrolidin-3-yl]acetamide Q n u i ^ N\ n n 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+).
Example 41 N-Methyl-N-(1 -{4-[3-(4-piperidin-1-ylphenyl)ureido]phenyl}pyrrolidin-3~yl)acetamide N-[1-(4-Aminophenyl)pyrrolidin-3-ylJ-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 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+).
Example 43 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-butoxybenzamide 99 O 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 molecular weight of 409.53 (C24H31N303); MS (ESI): 410 (M+H+).
Example 44 4-(4-Chlorophenyl)cyclohexanecarboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1 -yl]phenyl}amide N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 4-(4-chlorophenyl)cyclohexanecarboxylic acid by method E. This resulted in the product with the molecular weight of 454.02 (C26H32CIN302); MS (ESI): 454 (M+H+).
Example 45 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-3-(4-isopropylphenyl)-acrylamide O Ci o 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 (C25H31N302); MS (ESI): 406 (M+H+).
Example 46 Tetrahydrofuran-2-carboxylic acid (1 -{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylamide 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+).
Example 47 1 -Acetylpyrrolidin-2-carboxylic acid (1 -{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylamide 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); MS (ESI): 534 (M+H+).
Example 48 -Oxopyrrolidine-2-carboxylic acid (1 -{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylamide O 101 0 o 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea was reacted with 5-oxopyrrolidine-2-carboxylic acid by method E. This resulted in the product with the molecular weight of 505.62 (C28H35N504); MS (ESI): 506 (M+H+).
Example 49 2-Oxothiazolidine-4-carboxylic acid (1 -{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylamide 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+).
Example 50 (R)-1 -Methylpiperidine-3-carboxylic acid {1 -[4-(4-cyclohexylbenzoyl-amino)phenyl]pyrrolidin-3-yl}methylamide O o o / I (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 (C31H42N402); MS (ESI): 503 (M+H+).
Example 51 N-(1 -{4-[3-(6-Cyclopentyloxypyridin-3-yl)ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide 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 (C24H31N503); MS (ESI): 438 (M+H+). 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 80°C 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 (C10H14N20); MS (ESI): 179 (M+H+).
Example 52 1-(6-Cyclopentyloxypyridin-3-yl)-3-[4-(3-methylaminopyrrolidin-1-yl)-phenyl]urea 103 N-(1-{4-[3-(6-Cyclopentyloxypyridin-3-yl)ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide was treated with sodium hydroxide solution by method D. This resulted in the product with the molecular weight of 395.51 (C22H29N502); MS (ESI): 395 (M+H+).
Example 53 4'-Fluorobiphenyl-4-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 yl]phenyl}amide N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-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'-T rifluoromethylbiphenyl-4-carboxylic acid {4-[3-(acetylmethylamino)-20 pyrro!idin-1-yl]phenyl}amide N-[1-(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamide was reacted with 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+).
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.
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.
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 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 products are compiled in table 5. 105 Tab e 2 Ex. No.
Structure Name Molecular formula Molecular weight M+H+ 55 Cyclopropanecarboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl)pyrrolidin-3-yl)amide C28H30N403 470.58 471 56 Ni>, 3,N-Dimethyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phenyl}pyrrolidin-3-yl)butyramide C29H34N403 486.62 487 57 a0aNroiNL>K 2,N-Dimethyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phenyl}pyrrolidin-3-yl)butyramide C29H34N403 486.62 487 58 N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phenyl}pyrrolidin-3-yl)benzamide C31H30N403 506.61 507 59 0.0jCT (E)-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phenyl}pyrrolidin-3-yl)-3-phenylacrylamide C33H32N403 532.65 533 106 60 2-Cyclopentyl-N-methyl-N-(1 -{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide C31H36N403 512.66 513 61 Cyclohexanecarboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)amide C31H36N403 512.66 513 62 OtXrYo 'V- NL>nv N-Methyl-2-methylsulfanyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenylpyrrolidin-3-yl)acetamide C27H30N403S 490.63 491 63 ox''Yo_ v*- l>n.
N-Methoxy-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenylpyrrolidin-3-yl)acetamide C27H30N404 474.56 475 64 a^r-a^o 2-Oxothiazolidine-4-carboxylic acid methyl-(1-{4- [3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3- yl)amide C28H29N504S 531.64 532 65 Oc.CrTOt^v-o- 4-Fluoro-N-methyl-N-(1-{4-[3-(4-phenoxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)benzamide C31H29FN403 524.60 525 107 66 0,,.0'Yo.^vo Pyridine-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)amide C30H29N503 507.60 508 67 cgaYo ■v^0 L>n 2-Acetylamino-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide C28H31N504 501.59 502 68 0.c,OYOt>v^: 2,2,3,3-Tetramethylcyclopropanecarboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}- pyrrolidin-3-yl)amide C32H38N403 526.68 527 69 OflO"fOt>>>2 3,5-Dimethylisoxazole-4-carboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)amide C30H31N504 525.61 526 70 o.0o-r-a°rsJ N>N 2-Ethoxy-N-methyl-N-(1-{4-[3-(4-phenoxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)acetamide C28H32N404 488.59 489 71 CI o o 3-Methoxy-N-methyl-N-(1-{4-[3-(4-phenoxyphenyl)-ureido]phenyl}pyrrolidiri-3-yl)propionamide C28H32N404 488.59 489 108 72 O,.0-YO^H: 2,2,N-Trimethyl-N-(1-{4-[3-(4-phenoxyphenyl)-ureido]pheny!}pyrrolidin-3-yl)butyramide C30H36N403 500.65 501 73 0.0-G J 0,^-f* 1 -Methylcyclopropanecarboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}- pyrrolidin-3-yl)amide C29H32N403 484.60 485 74 ct0cr"s"at>% <• Cyclobutanecarboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)amide C29H32N403 484.60 485 75 G.0-Cr s Ti^V-O N-Methyl-N- (1 -{4- [3- (4-phenoxyphenyl) ureido]-phenyl}pyrrolidin-3-yl)isonicotinamide C30H29N503 507.60 508 76 0.30"s"-0^vrN Pyrazine-2-carboxylic acid m ethyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)amide C29H28N603 508.58 509 77 a0ornHO_^0 -Oxopyrrolidine-2-carboxylic acid methyl-(1-{4-[3- (4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3- yl)amide C29H31N504 513.60 514 109 78 O-o-O o 0.,,- Vv) Thiophene-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)amide C29H28N403S 512.64 513 79 O^OTO.^ Furan-3-carboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)amide C29H28N404 496.57 497 80 N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phenyl}pyrrolidin-3-yl)nicotinamide C30H29N503 507.60 508 81 0,Xi"roT VQ.-- 4-Cyano-N-methyl-(1-{4-[3-(4-phenoxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)benzamide C32H29N503 531.62 532 82 O-o-G' o 1-Methyl-1H-pyrrole-2-carboxylic acid methyl-(1-{4- [3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin- 3-yl)amide C30H31N503 509.61 510 83 3-Cyclopentyl-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)propionamide C32H38N403 526.68 527 110 84 Q-oG"f-o.°A~ Nt>^ N,N,N'-Trimethyl-N'-(1-{4-[3-(4-phenoxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)succinamide C30H35N504 529.64 530 85 Q0OVCln>V-~0 3-Phenylpropynoic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl) amide C33H30N403 530.63 531 86 0,.OYO..->^ (1 R,4S)-Bicyclo[2.2.1]heptane-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}- pyrrolidin-3-yl)amide C32H36N403 524.67 525 87 [1,2,3]Thiadiazole-4-carboxylic acid methyl-(1-{4- [3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3- yl)amide C27H26N603S 514.61 515 88 lsoxazole-5-carboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)amide C28H27N504 497.56 498 89 0„C"?"Oo>p 2,N-Dimethyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phenyl}pyrrolidin-3-yl)benzamide C32H32N403 520.64 521 111 90 0.„<*Yo v?° nL>n. 2-Methanesulfonyl-N-methyl-N-(1-{4-[3-(4- phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)- acetamide C27H30N405S 522.63 523 91 u>N, (E)-N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)ureido]-phenyl}pyrrolidin-3-yl)-3-pyridin-3-ylacrylamide C32H31N503 533.64 534 92 Q rrNYNn ° , L^y v p 4,4,4-T rifluoro-N-methyl-N-(1 -{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)butyramide C28H29F3N403 526.56 527 93 a 0o*rtx»K L>NS 'N_ 2-Dimethylamino-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)acetamide C28H33N503 487.61 488 94 ao'iW0 U>NV 3-Acetylamino-N-methyl-N-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)propionamide C29H33N504 515.62 516 95 cgorYtx -3-0 u7"nx Tetrahydrofuran-2-carboxylic acid methyl-(1-{4-[3- (4-phenoxypheriyl)ureido]phenyl}pyrrolidin-3-yl)- amide C29H32N404 500.60 501 112 96 Cl jnrNxN~n ° Ov N N-Methyl-2- (3-methylisoxazol-5-yl)-N- (1 -{4- [3- (4- phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)- acetamide C30H31N504 525.61 526 97 (S)-1-Acetylpyrrolidine-2-carboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)amide C31H35N504 541.66 542 98 O^CYo^*. 4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]- phenyl}pyrrolidin-3-yl)amide C28H28N603S 528.64 529 99 O^rYo.^ 1,5-Dimethyl-1 H-pyrazole-3-carboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]phenyl}- pyrrolidin-3-yl)amide C30H32N603 524.63 525 100 o.aor-o.
NL>nv -Methylhexanoic acid methyl-(1-{4-[3-(4-phenoxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)amide C31H38N403 514.67 515 101 CX^J^Cuvq U>Nv Tetrahydropyran-4-carboxylic acid methyl-(1-{4-[3- (4-phenoxyphenyl)ureido]phenyl}pyrrolidin-3-yl)- amide C30H34N404 514.63 515 113 102 G0JDTn °JP *Q-< N-Methyl-N-(1-{4-[3-(4-phenoxyphenyl)- ureido]phenyl}pyrrolidin-3-yl)-2-piperidin- lylacetamide C31H37N503 527.67 528 103 n rr^in o*-N' o |Un^n^N 1,3-Dimethyl-1 H-pyrazole-4-carboxylic acid methyl-(1-{4-[3-(4-phenoxyphenyl)ureido]- phenyl}pyrrolidin-3-yl)amide C30H32N603 524.63 525 114 Tab e 3 Ex. No.
Structure Name Molecular formula Molecular weight M+H+ 104 rVNyN^ CNral 0 IQ °v.rl VVN N 0 "o Benzyl (S)-5-[(1 -{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-2-oxoimidazolidine-1 -carboxylate C35H40N606 640.75 641 105 Chiral P ^oOYn °;i Benzyl (R)-2-[(1 -{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-pyrrolidine-1 -carboxylate C36H43N505 625.77 626 106 <^o€r oNv0, °^_/=\ ^ \ N-/ N-(1-{4-[3-(4-cyclopentyloxyphenyl)ureido]- phenyl]pyrrolidin-3-yl)-3-dimethylamino-N- methylbenzamide C32H39N503 541.70 542 115 107 Chirai P Q rvvvx °t° ° X"V!Kf Benzyl (S)-2-[(1 -{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-5-oxopyrrolidine-1-carboxylate C36H41N506 639.76 640 108 ^o-Cr S"TQ o tert-Butyl 3-[(1 -{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylcarbamoyl]piperidine-1-carboxylate C34H47N505 605.78 606 109 O fYVv^ S-oKD ^o-U J 0 VN>=0 Benzyl 5-[(1 -{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-2-oxoimidazolidine-1 -carboxylate C35H40N606 640.75 641 110 uo-U- 0 0^°^ 1 -Methylpiperidine-3-carboxylic acid (1 -{4-[3-(4- cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin- 3-yl)methylamide C30H41N503 519.69 520 111 °o-a s o vrS i y~N N™^ ^ ^ 0 2,6-Dioxohexahydropyrimidine-4-carboxylic acid (1 -{4- [3- (4-cyclopentyloxyphenyl) -ureido]phenyl}pyrrolidin-3-yl)methylamide C28H34N605 534.62 535 116 112 O.CrYcL o. 2-Methyl-5-oxopyrrolidine-2-carboxylic acid (1 -{4-[3-(4-cyclopentyloxyphenyl)ureido]phenyl}-pyrrolidin-3-yl) methylamide C29H37N504 519.65 520 113 a xy^Vi n 0-^ O |IJt o -s O-NV o4o •"h tert-Butyl 4-[(1 -{4-[3-(4-cyclopentyloxyphenyl)- ureido]phenyl}pyrrolidin-3-yl)methylcarbamoyl]- thiazolidine-3-carboxylate C32H43N505S 609.79 610 114 y5—Chira! O A-NYNVA ^/0-? 0-t/ 5 0. q-V O-^°0K Benzyl (2S,4R)-4-tert-butoxy-2-[(1 -{4-[3-(4-cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl) methylcarbamoyi] pyrrolidine-1 -carboxylate C40H51N506 697.88 698 115 O n yp ^ N~f 0*O N-(1-{4-[3-(4-Cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)-3-(2,5-dioxopyrrolidin-1-yl)-N-methyl-5-trifluoromethylbenzamide C35H36F3N505 663.70 664 117 116 o xyvv*! o o o-^ 0 IJL 0 CH.
M"~\ / V ) ■ >-J\} |\J ^ x >-0 o ^— tert-Butyl 2-[(1 -{4-[3-(4-cyclopentyloxyphenyl)- ureido]phenyl}pyrrolidin-3-yl)methylcarbamoyl]- morpholine-4-carboxylate C33H45N506 607.76 608 117 . Ctiiral 0 Q iTYVVv a?0 uo^ o nNi>%o (R)-1-(Toluene-4-sulfonyl)pyrrolidine-2-carboxylic acid (1 -{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidiri-3-yl)methylamide C35H43N505S 645.83 646 118 o. rwu o'S'h 0-^ O 0 0,^ \ H {(3aS,6aS) -2- [(1 -{4- [3- (4-cyclopentyloxyphenyl) -ureido]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-hexahydrocyclopenta[b] pyrrol-1 -yljoxoacetic acid methyl ester C34H43N506 617.75 618 119 p p Chiral O /YVVv ° (S)-1-(2,2,2,-Trifluoroacetyl)pyrrolidine-2-carboxylic acid (1 -{4-[3-(4-cyclopentyloxyphenyl)ureido]-phenyl}pyrrolidin-3-yl)methylamide C30H36F3N504 587.65 588 118 120 °XrYlClt>v^' 2-Chloro-N-{[(1-{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-methyl}benzamide C32H36CIN504 590.13 590 121 N-{1 -[(1 -{4-[3-(4-Cyclopentyloxyphenyl)ureido]- phenyl}pyrrolidin-3-yl)methylcarbamoyl]ethyl}-4- methylbenzamide C34H41N504 583.74 584 122 °oJ0' o 0~NS N-{[(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]- phenyl}pyrrolidin-3-yl)methylcarbamoyl]methyl}- 3,3-dimethylbutyramide C31H43N504 549.72 550 123 °oO I"x> O-" N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]- phenyl}pyrrolidin-3-yl)-2-(1H-imidazol-4-yl)-N- methylacetamide C28H34N603 502.62 503 119 124 q 1 Vw f\| VWnm/ \ Benzyl 3-[(1 -(4-[3-(4-cyclopentyloxyphenyl)ureido]-phenyl}pyrrolidin-3-yl)methylcarbamoyl]piperidine-1 -carboxylate C37H45N505 639.80 640 125 Y V-|s| ^—* 1 -(Furan-2-carbonyl)piperidine-3-carboxylic acid (1-{4-[3-(4-cyclopentyloxyphenyl)ureido]phenyl}-pyrrolidin-3-yl)methylamide C34H41N505 599.74 600 126 QoO'BSB€l f-(\ t>» (E)-N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]- phenyl}pyrrolidin-3-yl)-N-methyl-3-pyridin-2-yl- acrylamide C31H35N503 525.66 526 127 ao-0"Vo vC" U>NX (E)-N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]- phenyl}pyrrolidin-3-yl)-N-methyl-3-pyridin-4-yl- acrylamide C31H35N503 525.66 526 120 128 aoO-VoH -u N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}-pyrrolidin-3-yl)-N-methyl-2-pyridin-3-ylacetamide C30H35N503 513.65 514 129 °-oOYn oJi 4-Methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (1-{4-[3-(4-cyclopentyloxy-phenyl)ureido]phenyl}pyrrolidin-3-yl)methylamide C33H37N504S 599.76 600 130 O O. f\NTN-A °-^0 O oil o N—\ Benzyl 2-[(1 -{4-[3-(4-cyclopentyloxyphenyl)ureido]-phenyl}pyrrolidin-3-yl)methylcarbamoyl]piperidin-1-carboxylate C37H45N505 639.80 640 131 Chira} aoO-Nru 0° Benzyl (S)-2-[(1 -{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-piperidin-1 -carboxylate C36H43N505 625.77 626 121 132 ^ fc t O China? L>nx ^ (R)-1-Acetylpyrrolidine-2-carboxylic acid (1-{4-[3- (4-cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3- yl)methylamide C30H39N504 533.68 534 133 oA chlra' (S)-1-((E)-3-Furan-2-y!acryloyl)pyrrolidine-2-carboxylic acid (1 -{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylamide C35H41N505 611.75 612 134 1-(2,2-Dimethylpropionyl)pyrrolidine-2-carboxylic acid (1 -{4-[3-(4-cyclopentyloxyphenyl)-ureido}phenyl}pyrrolidin-3-yi)methylamide C33H45N504 575.76 576 135 (trans)-1-Methyl-5-oxo-2-pyridin-3-ylpyrrolidine-3-carboxylic acid (1-{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylamide C34H40N604 596.74 597 122 136 £~~\ Chiral qinJ O-nX (S)-1-Benzylpyrrolidine-2-carboxylic acid (1 -{4-[3- (4-cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3- yl)methylamide C35H43N503 581.76 582 137 °oO-NXN0 ^ Isobutyl 2-[(1 -{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-pyrrolidine-1 -carboxylate C33H45N505 591.76 592 138 * Chiraf O O-Vv, Oo\ 0^ 0 Allyl (S)-2-[(1 -{4-[3-(4-cyclopentyloxyphenyl)-ureido]phenyl}pyrrolidin-3-yl)methylcarbamoyl]-pyrrolidine-1 -carboxylate C32H41N505 575.71 576 139 o jtyvyn o 0 iX...
NA-n'Vn 2-Oxoimidazolidine-4-carboxylic acid (1-{4-[3-(4-cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)methylamide C27H34N604 506.61 507 140 o irvNvN^ Chlral oO o TQN °V.(^f° >Q-n VJ (R)-5-Oxopyrrolidine-2-carboxylic acid (1-{4-[3-(4- cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3- yl)methylamide C28H35N504 505.62 506 123 141 -O" o IQ Vc^0 1 -Methyl-5-oxopyrrolidine-3-carboxylic acid (1 -{4- [3-(4-cyclopentyloxyphenyl)ureido]phenyl}- pyrrolidin-3-yl)methylamide C29H37N504 519.65 520 142 O /VvVi o 9 0 X\y%CL0 1-Benzyl-5-oxopyrrolidine-3-carboxylic acid (1-{4-[3-(4-cyclopentyloxyphenyl) ureidojphenyl}-pyrrolidin-3-yl)methylamide C35H41N504 595.75 596 143 ao€rBsNo <P -Oxo-l -phenylpyrrolidine-3-carboxylic acid (1 -{4- [3-(4-cyclopentyloxyphenyl)ureido]phenyl}- pyrrolidin-3-yl)methylamide C34H39N504 581.72 582 144 ^oCTViCL ^a.
-Oxo-1 -p-tolylpyrrolidine-3-carboxylic acid (1 -{4- [3-(4-cyclopentyloxyphenyl)ureido]phenyl}- pyrrolidin-3-yl)methylamide C35H41N504 595.75 596 124 Tab e 4 Ex. No.
Structure Name Molecular formula Molecular weight M+H+ 145 oy XSKfOC"" o (E)-N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]- phenyl}-3-(5,6-dimethylbenzooxazol-2-yl)- acrylamide C25H28N403 432.53 433 146 OY' /sssv ^ f \5553wZ V'Hiumi/ 0| 4'-Ethylbiphenyl-4-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]phenyl}amide C28H31N302 441.58 442 147 °y tmmi i>'ih _ | tJ *». ry_ry"-^-*0 J \=/ \-~/ Q 4'-Propylbiphenyl-4-carboxyiic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]phenyl}amide C29H33N302 455.61 456 125 148 °v fy/y^nh0"0 / (jl f 2'-Fluorobiphenyl-4-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]phenyl}amide C26H26FN302 431.51 432 149 oy 4'-Cyanobiphenyl-4-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]phenyl}amide C27H26N402 438.53 439 150 /5B=\ 4'-Bromobiphenyi-4-carboxylic acid {4-[3-(acetyi-methylamino)pyrrolidin-1-yi]phenyl}amide C26H26BrN302 492.42 492 151 oy JF ■.■IV|-'|].H^ / ^ 'V ^0/yfv^n"" nj Vast/ \=sa/ Q 4'-Ethoxybiphenyi-4-carboxyiic acid {4-[3-(acetyl-methylamino)pyrrolidiri-1-yl]phenyl}amide C28H31N303 457.58 458 126 152 oy CI /=\ c|-hW^Q-^NH^ 3',4'-Dichlorobiphenyl-4-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide C26H25CI2N302 482.41 482 153 0y /k5s\ ^ ^ f=yr\^m-\^-NJJ 2-Ethylbiphenyl-4-carboxy!ic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]pheny[}amide C28H31N302 441.58 442 154 Ocsj/ £>KK <X>"' N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-benzenesulfonylbenzamide C26H27N304S 477.59 478 155 oy a^O'31 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-cyclopentyloxybenzamide C25H31N303 421.54 422 127 156 p" °v 0:N jtssn 0_^V^"V>"NvJ /=< ^ 0 S-> CI N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-(4-chlorophenoxy)-3-nitrobenzamide C26H25CIN405 508.97 509 157 M °Y' N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-(4-fluorophenoxy)benzamide C26H26FN303 447.51 448 158 Cl. oy wO^q^"V>nJ N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-(4-chlorophenoxy)berizamide C26H26CIN303 463.97 464 128 159 Oy CKK^ N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-cyclohexylbenzamide C26H33N302 419.57 420 160 Oy 1-(4-Nitrophenyl)piperidine-4-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide C25H31N504 465.56 466 161 Oy rvo /=\ /^n- Vj «w«f/ N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-3-phenoxybenzamide C26H27N303 429.52 430 162 \ 0^ ) /=!\ \=ez Q N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-propoxybenzamide C23H29N303 395.51 396 129 163 0^/ \ / \=/ Q N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-(cyclohex-2-enyloxy)benzamide C26H31N303 433.56 434 164 °y XlSS/ Q N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-(3-methylbutoxy)benzamide C25H33N303 423.56 424 165 \ >rs=rv /-*vy \~—/ 0 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-isobutoxybenzamide C24H31N303 409.53 410 166 Oy ry^-O-Cf !^/o 0 Cl*^ -(4-Chlorophenyl)furan-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yI]phenyl}amide C24H24CIN303 437.93 438 130 167 Oy /=s=r\ ^_ys o -0 -(4-Methoxyphenyl)thiophene-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}-amide C25H27N303S 449.58 450 168 <v p- cX'-O-<JH~ ON}-0 0 O CI -(4-Chloro-2-nitrophenyl)furan-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}- amide C24H23CIN405 482.93 483 131 169 °v p- S>H;N~0"NCT ON0 yj -(4-Methyl-2-nitrophenyl)furan-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}- amide C25H26N405 462.51 463 170 Oy in^N"vi~0 V^s o pA^ -(4-Fluorophenyl)thiophene-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}- amide C24H24FN302S 437.54 438 132 171 <V C'\_-f 0 0 y_/ CI -(2,4-Dichlorophenyl)furan-2-carboxylic acid {4-[3-(acetylmethylamirio)pyrrolidin-1-yl]phenyl}amide C24H23CI2N303 472.38 472 172 4-Methyl-2-(4-trifluoromethylphenyl)thiazole-5-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 -yl]phenyl}amide C25H25F3N402 S 502.56 503 173 n-^h-O-O ifT^s 0 cr*s 2-(4-Chlorophenyl)-4-methylthiazole-5-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 -yl]phenyl}amide C24H25CIN402S 469.01 469 133 174 OY ^^°-]Q3H;N~0"ND' -Benzyloxy-1 H-indole-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidiri-l -yl]phenyl}amide C29H30N403 482.59 483 175 oy N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-benzyloxybenzamide C27H29N303 443.55 444 176 oy r%^N"0~0' /-T ° ° -Phenylethynylfuran-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide C26H25N303 427.51 428 134 177 Oy N-v ] /_^ V_y w> i/ N-{4- [3- (Acetyl methylam i no) pyrrolid i n-1 -yl] p henyl}-2-biphenyl-4-ylacetamide C27H29N302 427.55 428 178 °y /-O'CJ 0 0 Mmmf 0 1 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-butoxyphenyl)acetamide C25H33N303 423.56 424 135 179 q °M 0 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2- (4-benzyloxyphenyl) acetamide C28H31N303 457.58 458 180 <V ^N"0-NCJ /=s/ 0 S-f 0 t) N-{4-[3- (Acetylmethylamino) pyrrolidin-1 -yl] phenyl}-2- (4-phenoxyphenyl) acetamide C27H29N303 443.55 444 136 181 Oy rszr\ of) ° 0 o Vli'!!*V N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-benzyloxy-3-methoxyphenyl)acetamide C29H33N304 487.60 488 182 F S ■MIIH- \ VJ °V h i ■ {' JWMM __ I X 1. \ / f ■ ■■■"■■¥ \ T » Nl o N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4'-fluorobiphenyl-4-yl)acetamide C27H28FN302 445.54 446 137 183 Oi;|/ Q 0 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-[4-(2,5-dimethylpyrrol-1-yl)phenyl]acetamide C27H32N402 444.58 445 184 oy >-CKK>*c^ 0 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-isopropylphenoxy)acetamide C24H31N303 409.53 410 185 Oy /■ ^ f y ,N^ rOy-OO 0 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-ethylphenoxy)acetamide C23H29N303 395.51 396 138 Tab e 5 Ex. No.
Structure Name Molecular formula Molecular weight M+H+ 186 N-Methyl-N-(1-{4-[3-(6-phenoxypyridin-3-yl)ureido]phenyl}pyrrolidin-3-yl)acetamide C25H27N503 445.53 446 187 CCOrYCL^y N-[1-(4-{3-[4-(2-Chlorophenoxy)phenyl]ureido}-phenyl)pyrrolidin-3-yl]-N-methylacetamide C26H27CIN403 478.98 479 188 jTl °i_ N-[1-(4-{3-[4-(3-Chlorophenoxy)phenyl]ureido}-phenyl)pyrrolidin-3-yl]-N-methylacetamide C26H27CIN403 478.98 479 189 ceo ° N-Methyl-N-[1-{4-[3-(4-o-tolyloxyphenyl)ureido}-phenyl)pyrrolidin-3-yl)acetamide C27H30N403 458.57 459 190 N-Methyl-N- [1 -{4- [3- (4-m-tolyloxyphenyl) ureido}-phenyl)pyrrolidin-3-yl)acetamide C27H30N403 458.57 459 139 191 cOcYxx-xV N- [1 -{4-{3- [4- (2- Fl uorophenoxy) phenyl) u reido}-phenyl)pyrrolidin-3-yl)-N-methylacetamide C26H27FN403 462.53 463 192 qJOtYO^ N-{1-{4-[3-Biphenyl-4-ylureido}phenyl]pyrrolidin-3-yl}-N-methylacetamide C26H28N402 428.54 429 193 N-[1-(4-{3-[4-(2-Methoxyphenoxy)phenyl]ureldo}-phenyl)pyrrolidin-3-yl]-N-methylacetamide C27H30N404 474.56 475 194 ^or-o.^ N-(1-{4-[3-(4-lsobutoxyphenyl)ureido}phenyl)-pyrrolidin-3-yl]-N-methylacetamide C24H32N403 424.55 425 195 ogCrTO^ N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido}phenyl)-pyrrolidin-3-yl]-N-methylacetamide C25H32N403 436.56 437 140 196 'O.CrYTX./v N-[1-(4-{3-[4-(4-Fluorophenoxy)phenyl]ureido}-phenyl)pyrrolidin-3-yl]-N-methylacetamide C26H27FN403 462.53 463 197 ■,,O„OYCX.>> N-[1-(4-{3-[4-(3-Methoxyphenoxy)phenyl]ureido}-phenyl)pyrrolidin-3-yl]-N-methylacetamide C27H30N404 474.56 475 198 ^XXp, Y^Y^j 0 ° ty-T 4-(3-Acetylaminophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 -yl]-phenylamide C27H35N503 477.61 478 199 ^XJYXX V QP^ 0 ^N^fT N-Methyl-N-(1-{4-[3-(5-phenylpyridin-2-yl)ureido]-phenyl}pyrrolidin-3-yl)acetamide C25H27N502 429.53 430 141 200 o n s^rYtX V 6 N-(1-{4-[3-(2-Acetylamino-4-phenylsulfanylphenyl)-ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide C28H31N503S 517.65 518 201 N-(1-{4-[3-(4'-Cyanobiphenyl-4-yl)ureido]-phenyl}pyrrolidin-3-yl)-N-methylacetamide C27H27N502 453.55 454 202 QrV 0 N-(1-{4-[3-(2-Methoxybiphenyl-4-yl)ureido]-phenyl}pyrrolidin-3-yl)-N-methylacetamide C27H30N403 458.57 459 142 203 CC ^NrNY^i °v ° NL> 4-(2-Chlorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 -yl]phenyl}amide C25H31CIN402 455.00 455 204 o-'T N-(1-{4-[3-(4-Benzenesulfonyl-3-chlorophenyl)-ureido]phenyl}pyrrolidin-3-yl)-N-methylacetamide C26H27CIN404S 527.05 527 205 C! o 0 4-(4-Chlorophenyl)-4-hydroxypiperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 -yl]phenyl}amide C25H31CIN403 471.00 471 143 206 0 4-Phenylpiperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide C25H32N402 420.56 421 207 N A * !■■! ""fc G^Ch k-NYNr^! o 0 i>n 4-Cyano-4-phenylpiperidirie-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide C26H31N502 445.57 446 208 V ^O-'T 4-Acetyl-4-phenylpiperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide C27H34N403 462.60 463 144 209 *"■0^ 4-(2-Methoxyphenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}-amide C26H34N403 450.59 451 210 '-CY, 0 4-(4-Fluorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide C25H31FN402 438.55 439 211 F (!Xp 5nONl>V 4-(3-Fluorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide C25H31FN402 438.55 439 145 212 CC YNY^i o 0 4-(2-Fluorophenyl)piperidirie-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide C25H31FN402 438.55 439 213 ^nYnY^I ° ° 4-p-Tolylpiperidine-1-carboxylic acid {4-[3-(acetyl-methylamino)pyrrolidin-1-yl]phenyl}amide C26H34N402 434.59 435 214 FF fA*V lY€lNi>V 4-(4-Trifluoromethylphenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 -yl]phenyl}amide C26H31F3N402 488.56 489 146 215 ff lT€iNl>V 4-(3-Trifluoromethylphenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 -yl]phenyl}amide C26H31F3N402 488.56 489 216 f oX YCi V 0~n 4-(2-Trifluoromethylphenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 -yl]phenyl}amide C26H31F3N402 488.56 489 147 217 ^nyny^I o ° l>n 4-(4-Methoxyphenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}-amide C26H34N403 450.59 451 218 o" ^NYNY^l o ° 4-(3-Methoxyphenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}-amide C26H34N403 450.59 451 148 219 o ° 4-Naphthalen-2-ylpiperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide C29H34N402 470.62 471 220 o ° yl~ Benzo[c]-1 -oxa-8-aza-spiro[4,5]decane-8-car {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide C26H32N403 448.57 449 221 0Y"0 V anY Wsr( W n \J N-(1-{4-[3-(9-Ethyl-9H-carbazol-3-yl)ureido]-phenyl}pyrrolidin-3-yl)-N-methylacetamide C28H31N502 469.59 470 149 222 oO 0 0N-yV c! N-(1-(4-{3-[4-(4-Chlorophenoxy)phenyl]ureido}-phenyl)pyrrolidin-3-yl)-N-methylacetamide C26H27CIN403 478.98 479 223 f 0 u,>r N-(1-{4-[3-(4-Benzylphenyl)ureido]phenyl}-pyrrolidin-3-yl)-N-methylacetamide C27H30N402 442.57 443 224 rr^-n v aj o n' N-Methyl-N-(1-{4-[3-(4-Pyridin-4-ylmethylphenyl)-ureido]phenyl}pyrrolidin-3-yl)acetamide C28H30F3N504 443.55 444 150 225 N^rVNYNY^!sl 0 o UNL>r N-[1-(4-{3-[6-(2-Fluorophenoxy)pyridin-3-yl]ureido}-phenyl}pyrrolidin-3-yl)-N-methylacetamide C25H26FN503 463.52 464 226 N-Methyl-N-(1-{4-[3-(4-phenylsulfanylphenyl)-ureido]phenyl}pyrrolidin-3-yl)acetamide C26H28N402S 460.60 461 227 :,pjyfxx:ry N-Methyl-N-[1-(4-{3-[4-(3-trifluoromethylphenoxy)-phenyl]ureido}phenyl)pyrrolidin-3-yl]acetamide C27H27F3N403 512.54 513 228 y n6 N-Methyl-N-[1-(4-{3-[6-(pyridin-2-ylsulfanyl)pyridin-3-yl]ureido}phenyl)pyrrolidin-3-yl]acetamide C26H27F3N604 S 462.58 463 151 229 oO o o.,0.v N-(1-{4-[3-(4-Butoxyphenyl)ureido]phenyI}-pyrrolidin-3-yl)-N-methylacetamide C24H32N403 424.55 425 230 0 uo-T 4-Benzylpiperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide C26H34N402 434.59 435 231 o, ° ^o-'T Benzo-8-azaspiro[4.5]decane-8-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide C27H34N402 446.60 447 152 232 ^NYNY%| Ov ° NLI>n 4-Benzofuran-3-ylpiperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide C27H32N403 460.58 461 233 <i> °r^i YCi V 0-N 4-p-Tolyloxypiperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide C26H34N403 450.59 451 153 234 0O Y o n O 4-(2-Chlorophenoxy)piperidine-1 -carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}-amide C25H31CIN403 471.00 471 154 Example 235 N-(1-{4-[3-(4-Cyclopentyloxyphenyl)ureido]phenyl}pyrrolidin-3-yl)-N-methyl-2-piperidin-1 -yl-acetamide ^ i 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-methylaminopyrrolidin-1-yl)phenyl]urea was reacted with piperidin-1-ylacetic acid by method E. This resulted in the product with the molecular weight of 519.69 (C30H41N503); MS (ESI): 520 (M+H+).
Example 236 1 -Methylpiperidine-3-carboxylic acid {(R)-1 -[5-(4-cyclohexylbenzoylamino)pyridin-2-yl]pyrrolidin-3-yl}methylamide (f?)-4-Cyclohexyl-N-[6-(3-methylaminopyrrolidin-1-yl)pyridin-3-yl]benzamide was reacted with 1 -methylpiperidin-3-carboxylic acid by method E. This resulted in the product with the molecular weight of 503.69 (C30H41N502); MS (ESI): 504 (M+H+).
Example 237 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-butoxyphenyl)propionamide 155 N"—\ L>\ Method H Caesium carbonate (36 mg) and n-butyl bromide (15 mg) were added to a solution of N-{4-[3-(acetylmethylamino)pyrrolidin-1 -yl]phenyl}-2-(4-hydroxyphenyl)propionamide (27 mg) in DMF (1 ml). After a reaction time of 2 hours at room temperature, water was added to the mixture, and it was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated, and the residue was crystallized from diethyl ether/methanol. This resulted in the product with the molecular weight of 437.59 (C26H35N303); MS(ESI): 438 (M+H+).
N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)propionamide N-[1 -(4-Aminophenyl)pyrrolidin-3-yl]-N-methylacetamid was reacted with 2-(4-hydroxyphenyl)propionic acid by method I. This resulted in the product with the molecular weight of 381.48 (C22H27N303); MS(ESI): 382 (M+H+).
Example 238 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-isobutoxyphenyl)acetamide N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)acetamide was reacted with isobutyl bromide by method H. This resulted in the product with the molecular weight of 423.56 (C25H33N303); MS(ESI): 424 (M+H+). 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 (C21H25N303); MS(ESI): 368 (M+H+).
Example 239 (fl)-N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-butoxyphenyl)acetamide (ft)-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 N-{4-[3-(Acetylmethylamino)pyrrolidin-1 -yl]phenyl}-2-(4-cyclopropylmethoxyphenyl)propionamide 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+).
Example 241 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-cyclobutylmethoxyphenyl)propionamide 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+).
Example 242 1 -(4-Methoxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethyl-amino)pyrrolidin-1-yl]phenyl}amide Q r\ h~ ,0 N \ 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+). 158 Example 243 1 -(4-Butoxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethylamino)-pyrrolidin-1 -yl]phenyl}amide ^ ^ n- ^ \ 1 -(4-Hydroxyphenyl)cyclopropanecarboxylic acid {4-[3-(acetylmethyl-amino)pyrrolidin-1yl]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+). 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-l -yl]phenyl}amide (540 mg) in 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 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 (f?)-4-(4-Fluorophenyl)piperidine-1 -carboxylic acid {4-[3-(acetylmethyl-amino)pyrro!idin-1-yl]phenyl}-N-methylamide 159 (fl)-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 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+).
Example 245 -2-[(2-Fluorophenyl)ethynyl]furan-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide Method J Firstly diisopropylamine (14.9 mg) and then a solution of 5-bromofuran-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 -yl]phenyl}amide (50.0 mg) and 1-ethynyl-2-fluorobenzene (17.7 mg) in dioxane (0.5 ml) and 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 HPLC. This resulted in the product with the molecular weight of 445.18 (C26H24FN303); MS(ESI): 446 (M+H+) as hydrotrifluoroacetate.
-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 (C18H20BrN303); MS(ESI): 407 (M+H+).
Example 246 -2-[(4-Fluorophenyl)ethynyl]furan-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide F ^ -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.
Example 247 -2-[(2-Chlorophenyl)ethynyl]furan-2-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-l -yl]phenyl}amide v CI -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-methyipropyl)methylamino]-pyrrolidin-1-yl}-phenyl)benzamide 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 resulted in the product with the molecular weight of 457.59 (C26H36FN303); MS (ESI): 458 (M+H+).
Example 249 R-4-Butoxy-N-(3-fluoro-4-{3-[(3-hydroxy-3- methylbutyl)methylamino]pyrrolidin-1-yl}-phenyl)-N-methylbenzamide 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-methylbutan-2-ol (0.03 g) in DMF (2 ml) was heated at 80°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 (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 20°C and below 35°C. 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.
Example 250 R-4-Butoxy-N-[6-(3-dicyclopropylaminopyrrolidin-1-yl)-pyridin-3-yl]benzamide 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 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 (C26H34N402); MS (ESI): 435 (M+H+).
Example 251 R-4-Butoxy-N-[6-(3-dicyclopropylaminopyrrolidin-1-yl)pyridin-3-yl]-N-methylbenzamide 163 (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 (M+H+).
Example 252 R-4-Butoxy-N-{6-[3-(cyclopropylmethylamino)pyrrolidin-1-yl]pyridin-3-yl}benzamide (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+).
Example 253 tert-Butyl {1-[4-(2-amino-4-butoxybenzoylamino)-3-fluorophenyl]pyrrolidin-3-yl}methylcarbamate O ^ "N 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+). 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 -10eC to a sodium butoxylate solution prepared from butanol (20 ml) and sodium hydride (2.18 g) at -10QC 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 (10N; 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 (C11H13N05); MS (ESI): 240 (M+H+).
Example 254 N-{4-[3-(7-Azabicyclo[2.2.1]hept-7-yl)-2-oxopyrrolidin-1-yl]phenyl}-4-cyclohexyl-N-methylbenzamide 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 50°C 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+).
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 (C24H27BrN202); MS (ESI): 456 (M+H+).
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 4-Cyclohexyl-N-methyl-N-[4-(3-morpholin-4-yl-2-oxopyrrolidin-1-yl)phenyl]benzamide 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+).
Example 256 4-Cyclohexyl-N-methyl-N-[4-(2-oxo-3-piperidin-1-ylpyrrolidin-1-yl)phenyl]benzamide 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+).
Example 257 4-Cyclohexyl-N-methyl-N-[4-(2'-oxo[1,3']bipyrrolidinyl-1 yl)phenyl]benzamide 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-Cyclohexyi-N-methyl-N-[4-(3-methylamino-2-oxopyrrolidin-1-5 yl)phenyl]benzamide I 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 (C25H31N302); MS (ESI): 406 (M+H+).
Example 259 4-Cyclohexyl-N-[4-(3-cyclohexylamino-2-oxopyrrolidin-1-yl)phenyl]-N-15 methylbenzamide 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 N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with cyclopropylmethylamine by method L. This resulted in the product with the molecular weight of 445.61 (C28H35N302); MS (ESI): 446 (M+H+).
Example 261 N-{4-[3-(Acetylmethylamino)-2-oxopyrrolidin-1-yl]phenyl}-4-cyclohexyl-N-methyl-benzamide O. 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 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 4-Cyclohexyl-N-methyl-N-[4-(4-methylamino-2-oxopyrrolidin-1 ■ yl)phenyl]benzamide 169 O 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 (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 (C25H31N302); MS (ESI): 406 (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 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+).
Example 263 N-{4-[4-(Acetylmethylamino)-2-oxopyrrolidin-1-yl]phenyl}-4-cyclohexyl-N-methylbenzamide O 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+).
Example 264 tert-Butyl (1-{5-[(4-cyclohexylbenzoyl)propylamino]pyridin-2-yl}pyrrolidin-3-yl)methyl-carbamate 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°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 140°C 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 (C31H44N403); MS (ESI): 521 (M+H+).
Example 265 tert-Butyl (1 -{5-[(4-cyclohexylbenzoyl)-(1 -ethylpropyl)amino]pyridin-2-yl}pyrrolidin-3-yl)-methylcarbamate 171 n n o VY 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 (C33H48N403); MS (ESI): 549 (M+H+).
Example 266 tert-Butyl (1-{5-[(4-cyclohexylbenzoyl)-(3-methylbut-2-enyl)amino]pyridin-2-yl}pyrrolidin-3-yl)methylcarbamate 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 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 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); MS (ESI): 493 (M+H+).
The following further compounds were obtained by method F-a from tert-butyl {1 -[5-(4-cyclohexylbenzoylamino)pyridin-2-yi]pyrrolidin-3-yl}methylcarbamate and the appropriate alkylating agent: tert-Butyl (1 -{5-[sec-butyl-(4-cyclohexylbenzoyl)amino]pyridin-2-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 Example 268 -p-Tolylethinylfuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]amide 0.042 ml of diisopropylamine was added under argon to 3.8 mg of Pd(tBu)2Cl2 and 0.95 mg of Cul in 0.2 ml of DMF. A solution of 94.6 mg of 173 -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.
-Bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -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.
Examples 269-273 were prepared analogously: Ex. No.
Structure Molecular formula Molecular weight M+H+ 269 6 II £ o / C26H27N303 429.21 430 270 F C25H23F2N302 435.18 436 271 / ° C26H27N303 429.21 430 17 A 272 C25H24FN302 417.19 418 273 c|-0 - CVri C25H24CIN302 433.16 434 Example 274 (R)-4'-Fluorobiphenyl-4-carboxylic acid [6-(3-dimethylaminopyrrolidin-1 ■ yl)pyridin-3-yl]-amide Method M (R)-4'-Fluorobiphenyl-4-carboxylic acid [6-(3-methylaminopyrrolidin-1 -yl)pyridin-3-yl]-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 80°C 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 (acetylmethylamino)pyrrolidin-1-yl]phenyl}amide acid {4-[3- 175 Method E-a A mixture of 0.048 g of 1 -(4-fluorophenyl)piperidine-4-carboxylic acid and 0.5 ml of SOCI2 and one drop of DMF were stirred at room temperature for 2 hours. The excess SOCI2 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 the molecular weight of 438.20 (C25H31FN402); 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*CHCI3, 0.022 g 2-(dicyclohexylphosphino)biphenyl 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°C overnight. The mixture was cooled and then concentrated in vacuo. The residue was taken up in ethyl acetate/water.
The organic phase was washed with 10% NaHC03 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 4-Phenoxycyclohexanecarboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1 -yl]phenyl}amide 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-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% NaHC03 solution 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 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 hydrochloric acid and once with saturated NaCI 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 O N \ 177 then heated at 80°C 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 (C15H2003), MS: 249 (M+H+). 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 60°C 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 vacuo. The resulting compound was employed without further purification in the next stage.
Example 277 N-[4-(3-Cyclohexylaminopyrrolidin-1-yl)phenyl]-4-isobutoxybenzamide .0 Method N (4-lsobutoxy-N-[4-(3-oxopyrrolidin-1 -yl)phenyl]benzamide (50 mg) in methanol (2 ml) was mixed with aminocyclohexane (28 mg) and glacial acetic acid (10 mg), and a solution of sodium cyanoborohydride (1M 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 the molecular weight of 435.61 (C27H37N302); MS (ESI): 436 (M+H+). 4-lsobutoxy-N-[4-(3-oxopyrrolidin-1-yl)phenylJbenzamide 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 (C21H24N203); 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 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 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 (1N). The organic phase was separated off, dried over magnesium sulfate and concentrated. The residue was dissolved in methanol (30 ml) and 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 (C12H16N202); 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.
Example 278 (R)-4-(4-Chlorophenyl)piperidin-1 -carboxylic acid {4-[3-(methylpyrimidin-2-yl-amino)pyrrolidin-1-yl]-phenyl}amide (R)-4-(4-Chlorophenyl)piperidine-1 -carboxylic acid [4-(3-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 (C27H31CIN60); MS (ESI): 491 (M+H+).
Example 279 tert-Butyl [1 -(4-{[5-(2-fluorophenyl)furan-2-carbonyl]amino}phenyl)pyrrolidin-3-yl]methylcarbamate F Method O 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. 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 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 150°C in a microwave apparatus for 3 minutes. tert-Butyl (1-{4-[(5-bromofuran-2-carbonyl)amino]phenyl}pyrrolidin-3-yl)methylcarbamate -Bromofuran-2-carboxylic acid was reacted with tert-butyl [1 -(4-aminophenyl)pyrrolidin-3-yl]methylcarbamate by method E. This resulted in O 180 the product with the molecular weight of 464.36 (C21 H26BrN304); MS (ESI): 464 (M+H+).
The following compounds were prepared analogously: -Bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -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 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 Example 280 (3R)-3'-Cyanobiphenyl-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)-3-fluorophenyl]amide F Method O-b 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 K3P04 and 0.008 g of 3-cyanophenylboronic acid were then added to the solution. The reaction solution was heated at 80°C 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 S.^'-TrifluorobiphenyM-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide F F 1 1-Bromo-2,4-difluorobenzene was reacted with N-[4-(3-dimethylaminopyrrolidin-1-yl)phenylJ-2-fluoro-4-boronic acid benzamide by 10 method O-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 4-Carboxy-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 (C19H23BFN303); MS (ESI): 372 (M+H+) as hydrotrifluoroacetate.
Example 282 -(2,4-Difluorophenyl)thiophen-2-carboxylic acid [4-(3- dimethylaminopyrrolidin-1-yl)-phenyl]amide 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 O-b. This resulted in the product with molecular weight of 427.52 (C23H23F2N30S); MS (ESI): 428 (M+H+) as hydrotrifluoroacetate. 2-Boronic acid thiophene-5-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide -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 (ESI): 360 (M+H+) as hydrotrifluoroacetate.
Example 283 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-6-(4-fluorophenyl)nicotinamide -[4-(3-Dimethylaminopyrrolidin-1-yl)phenylcarbamoylJpyridin-2-yl [trifluoro-methanesulfonate was reacted with 4-fluorobenzeneboronic acid under the conditions of method O-b. (Heating at 140°C in a microwave apparatus for 15 minutes). This resulted in the product with the molecular weight of 404.20 (C24H25FN40); MS (ESI): 405 (M+H+) as hydrotrifluoroacetate. -[4-(3-Dimethylaminopyrrolidin-1-yl)phenylcarbamoyl]pyridin-2-yl [trifluoromethanesulfonate 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 0°C. The mixture was stirred at 0°C for 2 hours. A solution of 0.055 g of N-phenyltrifluoromethanesulfonimide in 0.2 ml of DME was then added to the mixture. The reaction solution was allowed to reach room temperature and 183 was heated at 80°C 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-hydroxynicotinarnide 6-Hydroxynicotinic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yljdimethylamine 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 N-[4-(3-Dimethylaminopyrrolidin-1 -yl)phenyl]-6-(2,4-difluorophenyl)nicotinamide 2,4-Difluorophenylboronic acid was reacted with 5-[4-(3-20 dimethylaminopyrrolidin-1 -yl)-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.
Example 285 2',4'-Difluorobiphenyl-4-carboxylic yl)phenyl]amide acid [4-(3-dimethylaminopyrrolidin-1- 184 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. 21,4'-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/wat3r (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.
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 Na2C03 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]pheny!}-amide 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 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% NaHC03 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 HPLC. The desired product was obtained. Molecular weight 449.19 (C26H25F2N302), MS: 450 (M+H+).
Example 287 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-3-fluoro-4-(4-methylpiperidin-1 -yl)-benzamide 186 XV o / 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): 425 (M+H+) as hydrotrifluoroacetate. 3-Fluoro-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 weight of 237.28 (C13H16FN02); MS (ESI): 238 (M+H+).
Methyl 3-fluoro-4-(4-methylpiperidin-1 -yl)benzoate 0.076 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 DMF. The reaction was heated at 60°C for 2 days, filtered and purified by preparative HPLC. This resulted in the product with the molecular weight of 251.3 (C14H18FN02); MS (ESI): 252 (M+H+) as hydrotrifluoroacetate.
Example 288 4-Butoxy-N-(4-{3-[(2-dimethylaminoacetyl)methylamino]pyrrolidin-1-yl}phenyl)-N-methylbenzamide 187 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 (M+H+).
(R)-4-Butoxy-N-(4-{3-[(2-dimethylaminoacetyl)methylamino]pyrrolidin-1-yl}phenyl)-N-methylbenzamide was obtained analogously.
Example 289 N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-4-butoxy-N-methylbenzamide 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+).
Example 290 4-Butyrylamino-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]benzamide 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+).
Example 291 2-Phenylethynylthiazole-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 ■ yl)phenyl]-amide 2-Bromothiazole-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -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 (I) iodide (9.6 mg) were added. The reaction mixture was heated at 150°C in a microwave apparatus for 3 minutes and then concentrated. The residue 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-(4-Fluorophenyl)pyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]-amide Method O-a -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 150°C 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+).
-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 (C18H21CIN40); MS (ESI): 345 (M+H+).
Example 293 -(4-Fluorophenyl)pyridine-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide 190 -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- dimethylaminopyrrolidin-1 -yl)-phenyl]amide /—, O CM N O 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 benzenesulfonyl chloride (35 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 456.61 (C24H32N403S); MS (ESI): 457 (M+H+).
Example 295 1-(4-Fluorobenzenesulfonyl)piperidine-4-carboxylic acid [4-(3- dimethylaminopyrrolidin-1-yl)phenyl]amide 191 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 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 (C24H31FN403S); MS (ESI): 475 (M+H+).
Example 296 1 -(Butane- 1-sulfonyl)piperidine-4-carboxylic acid [4-(3- dimethylaminopyrrolidin-1-yl)-phenyl]amide 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 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+).
Example 297 -(4-Butoxyphenylethynyl)furan-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)-phenyl]amide 192 O Method J-a -Bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyljamide (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)2CI2 (4 mg), copper (I) iodide (75 mg) and N,N-diisopropylamine (20 mg) in anhydrous tetrahydrofuran (3 ml). The mixture was stirred at room temperature for 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.
Example 298 6-Butoxy-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]nicotinamide Method H-a 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 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.
Example 299 6-Cyclopropylmethoxy-N-[4-(3-dimethylaminopyrrolidin-1-yl) phenyl] nicotinam ide A (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.
Example 300 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-6-isobutoxynicotinamide 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 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-6-(4- 194 fluorophenoxy)nicotinamide 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 140°C 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.
The following examples were prepared analogously.
Ex. No.
Structure Molecular formula Molecular weight M+H+ 302 O N-" C24H26N402 402.21 403 303 jy O N-" C24H25CIN402 436.17 437 195 Example 305 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-2-fluoro-4-phenoxybenzamide 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 40°C 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.
Example 306 196 4-(3-Cyanophenyl)-3,6-dihydro-2H-pyridine-1 -carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide CKX 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+) 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 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-dimethylaminopyrrolidiri-1-yl)phenyl]amide N—(\ /)—N CKX 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 O-a. This resulted in the 10 product with the molecular weight of 436.62 (C25H32N40S); MS (ESI): 437 (M+H+) Example 309 4-(5-Chloropyridin-2-yloxy)-N-[4-(3-dimethylaminopyrrolidin-1 yl)phenyl]benzamide 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 130°C 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.
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°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. 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 hydrotrifluoroacetate.
Example 310 N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-4-(5-fluoropyridin-2-yloxy) benzamide 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 (M+H+) as hydrotrifluoroacetate.
Example 311 4-(6-Chloropyridin-3-yloxy)-N-[4-(3-dimethylaminopyrrolidin-1-yl)phenyl]benzamide 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.
Example 312 S-Chloro-S'.e'-dihydro^'H-p^'lbipyridinyM '-carboxylic acid [4-(3-dimethylamino- pyrrolidin-1 -yl)phenyl]amide O f^ 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 /il) was added to a solution of S-chloro-l'^'.S'.e1- 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 /il). 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+).
-Chloro-1 ',2',3',6'- tetrahydro-[2,4']bipyridine 30 A solution of tert-butyl S-chloro-S'.e'-dihydro^'H-p^bipyridine-l'-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 (C10H11CIN2); MS (ESI): 195 (M+H+). tert-Butyl S-chloro-S'.e'-dihydro^'H-p^'lbipyridine-l'-carbamate 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)Cl2 (50 mg). The mixture was heated at 80°C 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 heptane/ethyl acetate (5%)/dichloromethane (5%).
Example 313 -(2-Amino-4-methylphenyl)furan-2-carboxylic acid [4-(3-dimethylamino-pyrrolidin-1 -yl)- phenyl]amide -(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); MS (ESI): 405 (M+H+).
Example 314 -(2-Acetylamino-4-methylphenyl)furan-2-carboxylic dimethylaminopyrrolidin- 1-yl)phenyl]amide acid [4-(3- 201 -(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 (C26H30N403); MS (ESI): 447 (M+H+).
Example 315 -(2-lsobutyrylamino-4-methylphenyl)furan-2-carboxylic dimethylamino- pyrrolidin-1 -yl)phenyl]amide acid [4-(3- -(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 (C28H34N403); MS (ESI): 475 (M+H+).
Example 316 '-Chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid [4-(3-dimethylamino- pyrrolidin-1 -yl)phenyl]methylamide Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]-methylamide (44.4 mg) and 2,5-dichloropyridine (60 mg) were heated at 160°C for 15 minutes. o-Xylene (0.5 ml) was added and heating at 160°C 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 (C24H32CIN50); MS (ESI): 442 (M+H+).
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 (C19H30N40); 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 mixture 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.
The following examples were prepared analogously. 203 Ex. No.
Structure Molecular formula Molecular weight M+H+ 317 C25H30CIN50 466.03 466 318 N°2 I C24H30CIN503 471.99 472 319 F—^ ^^^ _ N°2 N-" I C24H30FN503 455.54 456 Example 320 3,4,5,6-Tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid [4-(3- dimethylaminopyrrolidin-1-yl)phenyl]amide Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 -yl)phenyl]-amide (30 mg) and 2-chloropyridine (90 mg) were heated at 160°C for 2 10 hours. 2-Chloropyridine (0.2 ml) was added and the mixture was again heated at 160°C 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+).
The following examples were prepared analogously. 204 Ex. No.
Structure Molecular formula Molecular weight M+H+ 321 Cl—^ N°2 N- I C25H32CIN503 486.02 486 322 "^0.
I C24H30FN503 469.56 470 Example 323 '-Chloro-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-4-carboxylic acid [4-(3-dimethylamino- pyrrolidin-1 -yl)phenyl]amid Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1 - yl)phenyl]arnide (30 mg), 2,5-dichloropyridine (30 mg) and tributylamine (0.2 ml) were heated at 160°C 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+).
Example 324 1 -(4-Chloro-2-cyanophenyl)piperidine-4-carboxylic acid [4-(3- dimethylaminopyrrolidin-1 - yl)phenyl]amide 205 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 .0 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 Id I) was added. After one hour, further acetic anhydride (6 /il) 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 1 0=< C27H36FN502 481.62 482 327 -q-o<^-aN.
C26H34CIN502 484.05 484 328 -QOtcxv J1 1 0=< C26H34FN503 467.59 468 ^AJ Example 329 (R)-N-[4-(3-Dimethylaminopyrrolidin-1-yl)phenyl]-2-(4-phenylpiperidin-1-yl)acetamide / M s Jk u X 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 65°C 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 150°C in a microwave apparatus. 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 (C14H20CIN30); MS (ESI): 282 (M+H+).
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 The following examples were prepared in analogy to the method given in example 329: Ex. No.
Structure Molecular formula Molecular weight M+H+ 330 C25H34N40 406.58 407 331 °X)JiXXC^~ C26H34N402 434.59 435 332 C26H33CIN402 469.03 469 333 q rv >- C27H30N403 458.57 459 208 334 C25H29N502 431.54 432 335 C25H28CIN502 465.99 466 336 o N C26H33N503 463.59 464 337 C25H33CIN40 441.02 441 338 o C25H34N402 422.58 423 339 C24H33N502 423.56 424 Example 340 (R)-4-Benzylpiperidine-1 -carboxylic acid [6-(3-dimethylaminopyrrolidin-1 ■ 5 yl)pyridin-3-yl]-amide ^ / o (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°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. No.
Structure Molecular formula Molecu lar weight M+H+ 341 0 C24H31N502 421.55 422 342 o n 0A„XJ C24H33N50 407.56 408 343 o 0 C26H34N403 450.59 451 344 "XXJO^ 0 C25H31CIN402 455.00 455 345 QrCn«\jQ-<XN' C26H30N40 414.56 415 346 Cuo^ C24H39N50 413.61 414 347 0 O^OAb C26H37N50 435.62 436 Example 348 (R)-4-Cyclopropylmethoxy-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]- benzamide 210 / N O (R)-4-Benzyloxy-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3-fluorophenyljbenzamide underwent debenzylating hydrogenation by method B. The resulting (R)-N-[4-(3-dimethylaminopyrrolidin-1-yl)-3-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. No.
Structure Molecular formula Molecular weight M+H+ 349 OJO^ C26H34FN302 439.58 440 350 C25H32FN303 441.55 442 351 0 ^N\ lYrtt.
C24H30FN302 411.52 412 Example 352 (R)-N-[4-(3-Dimethylaminopyrrolidin-1-yl)-3-fluorophenyl]-4-(pyridin-2-yloxy)benzamide 211 / N # r r"~ o..
N O (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); 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 pyrrolidinylanilines were reacted with diverse acids by methods E. The resulting products are summarized in table 7.
Example 1131 - example 1232 Various (hetero)aryl halides were reacted with diverse boronic acids by methods O. The resulting products are summarized in table 8.
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 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.
Example 1444 - example 1618 Various tert-butyl carbamates were cleaved by method G. The resulting products were summarized in table 13.
Table 6 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 353 n tiW C25H31FN402 438.24 439 354 ocax-o^ C25H30N404 450.23 451 355 O ajyOJ"-fy>0 C25H31CIN403 470.21 471 356 0 C26H30N402 430.24 431 357 \ ajyO*»-Cr"°H C24H29CIN40 424.20 425 358 \ C25H35N50 421.28 422 359 \ C23H30BrN50 471.16 472 360 C24H34N40 394.27 395 361 C26H28N403 444.22 445 213 Ex-No.
Structure Molecular formula Morioisotopic molecular wt.
M+H+ 362 \ C24H29N50 403.24 404 363 C27H29N50S 471.21 472 364 C26H30N402 430.24 431 365 x v Pi ^ ^O-XO C25H30N603 462.24 463 366 \ n- C22H25N502 391.20 392 367 ^vny° of0'^ n-/ C26H28N60 440.23 441 368 \ rjQrCJ»jy^ C24H29FN40 408.23 409 369 &°^xo^ C26H30N403 446.23 447 370 Q°<X rf>< C25H27CIN402 450.18 451 371 FO0XXXONr>": C25H27FN402 434.21 435 372 \ n- X^tXVO^ C26H30N402 430.24 431 373 \ n- C26H30N402 430.24 431 214 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 374 \ n- VtOXO^ C26H30N403 446.23 447 375 &°~CL„ fJX C25H27CIN402 450.18 451 376 \ n- C23H32N402 396.25 397 377 \ n- C25H29N502 431.23 432 378 \ n- Or0-OAJOrN° C24H27N502 417.22 418 379 Q°xxj.uO£>': C25H35N502 437.28 438 380 &°nx®Nr>" C25H27FN402 434.21 435 381 C26H27F3N402 484.21 485 382 F%x\x s.
C26H27F3N40 468.21 469 383 \ n~ op^u-tyQ cy C24H31CIN402 442.21 443 384 \ _ n- C25H28N40 400.23 401 385 o, > °0xa^ C26H30N402 430.24 431 215 Ex. No.
Structure Molecular formula Morioisotopic molecular wt.
M+H+ 386 \ n- C23H32N402 396.25 397 387 C25H34N402 422.27 423 388 \ C24H31CIN40 426.22 427 389 \ jyOAcr0 C25H34N40 406.27 407 390 f C25H31F3N40 460.24 461 391 \ n- f„f 0 0 _ r-i C25H31F3N402 476.24 477 392 aNiG r\_ ' C23H31N504 441.24 442 393 \ ayzJ»<r0"~ C24H30N403 422.23 423 394 0tkXONr>": C24H32CIN50 441.23 442 395 c^xo^ C25H27CIN40 434.19 435 396 \ n- 00X0^ C25H28N40 400.23 401 216 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 397 \ n- N^ii r\ N iT^I 9 C24H28N60 416.23 417 398 \ C25H34N402 422.27 423 399 \ QyOS»<r° C28H34N40 442.27 443 400 rr^ n. -i xx C25H27N503 445.21 446 401 C25H27CIN40 434.19 435 402 po-o^jy0 C24H31CIN402 442.21 443 403 \ ^ n- OXO" C24H33N50 407.27 408 404 \ n- ^"XX^-Cr^ C22H30N402 382.24 383 405 \ n- aDAJ0^ C25H34N40 406.27 407 406 C22H22CI2F6N402 558.10 559 407 fx0°O-n5NjOrN f f C26H27F3N402 484.21 485 408 V C24H31FN40 410.25 411 217 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 409 \ n- C24H31FN40 410.25 411 410 \ C24H31FN40 410.25 411 411 \ C25H34N40 406.27 407 412 \ C25H34N40 406.27 407 413 \ o xyK-O^ 6 C24H32N402 408.25 409 414 0 C22H26N60 390.22 391 415 >k C26H27BrN40 490.14 491 416 0 N"^ _ o* "°--V C21H24N60S 408.17 409 417 C26H27N50 425.22 426 418 \ C24H32N40 392.26 393 419 C25H27CIN402 450.18 451 420 \ n- 0°XXAjQr^ C24H30N403 422.23 423 218 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 421 C24H29CIN402 440.20 441 422 C26H31CIN402 466.21 467 423 [jRfi C28H35CIN40 478.25 479 424 o°xxxo^ -T~ C28H38N404 494.29 495 425 \ C24H31CIN402 442.21 443 426 C25H33CIN402 456.23 457 427 \ hn" o°x>xo^ C25H28N403 432.22 433 428 n-/ FjyCJ"-°"° 0 C25H29FN402 436.23 437 429 n-/ ° C24H30BrN502 499.16 500 430 n-/ a^rC'to0 ° C25H29CIN402 452.20 453 431 n-/ oO^-a^ ° 6 C25H32N403 436.25 437 219 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 432 \ C24H32BrN502 501.17 502 433 \ N- jTVO A-NJ N -\J ^ \»N C22H30N60 394.25 395 434 \ C24H30F3N50 461.24 462 435 \ ^o^o*0" C21H29N70 395.24 396 436 \ oO^O-°N C23H31N50 393.25 394 437 \ jyO^O^ C22H30N60 394.25 395 438 \ \®N C21H29N70 395.24 396 439 \ &o\jyv C23H30CIN50 427.21 428 440 \ a^yCJ"-0-0'' C23H30CIN50 427.21 428 441 \ ajyC"s^0"~ C23H30CIN50 427.21 428 442 \ C23H30FN50 411.24 412 220 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 443 \ C23H30FN50 411.24 412 444 p 0 1 C24H33N50 407.27 408 445 \ Q-d-O-'V C24H33N50 407.27 408 446 QS-C^n-O"0 C24H33N50 407.27 408 447 \ C24H33N50 407.27 408 448 \ C24H30F3N50 461.24 462 449 \ VQOA-O"® F C24H30F3N50 461.24 462 450 \ 0^0^-0-°" xNN C24H30N60 418.25 419 451 \ Qp^O^ / C24H33N502 423.26 424 452 V p-oto'0 o s C24H33N502 423.26 424 221 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 453 \ C24H33N502 423.26 424 454 \ o C25H33N502 435.26 436 455 \ C24H29CIF3N50 495.20 496 456 C24H32CIN50 441.23 442 457 \ jop C25H35N50 421.28 422 458 \ CI C23H29CI2N50 461.17 462 459 0 z^o / C23H29F3N60 462.24 463 460 \ A&ot*o* C23H29F3N60 462.24 463 461 \ Frt-Oto0" F CI C23H28CIF3N60 496.20 497 462 \ r0>yUy^ C25H35N502 437.28 438 222 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 463 \ (yOKxy® CI Cl C23H29CI2N50 461.17 462 464 \ C25H35N50 421.28 422 465 \ n~- CI C23H29CI2N50 461.17 462 466 \ ' o i C25H35N503 453.27 454 467 n "ZrOi-Cr-O 0 1 C24H32CIN502 457.22 458 468 \ jyCr***y° C23H38N60 414.31 415 469 \ C23H29F2N50 429.23 430 470 \ C24H30N60 418.25 419 471 \ C25H35N50 421.28 422 472 \ .qO^0 C23H37N50 399.30 400 223 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 473 ^0-10° C23H32N60 408.26 409 474 \ N- ^ jTVO f\-N J* hAJ ^ vn C23H32N60 408.26 409 475 O C26H37N50 435.30 436 476 o oJyy\jy^ C28H36CIN502 509.26 510 477 C25H34N40 406.27 407 478 F \ x\o^o^ q C25H31FN402 438.24 439 479 / N*"" F I C23H27CIFN50 443.96 444 480 Xl(yU><V 0 N C23H30FN502 427.53 428 481 X^yCp^cy F C23H29F2N502 445.52 446 482 XXo^ F C23H27F2N50 427.50 428 483 X^ytCrOy F C23H29CIFN502 461.97 462 484 a0-oN^N°> f -r C28H37FN404 512.28 513 224 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 485 Cr°Q^-P'^ f C28H32FN504 521.24 522 486 0 C23H30CIN502 443.98 444 487 F C23H29CIFN502 461.97 462 488 \ Opl-O-O C26H34N402 434.27 435 489 \ Opto*3 C30H36N40 468.29 469 490 \ 0 0 \ C26H34N403 450.26 451 491 \ gyl<y° C25H32N402 420.25 421 492 C26H34N403 450.26 451 493 \ n- vp-^-o-*0 C25H30N403 434.23 435 494 \ YtyOl-G-V C26H35N502 449.28 450 495 OV04°N-0-0 o-n C25H30FN502 451.24 452 225 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 496 \ C25H31N50S 449.23 450 497 \ C26H33N50 431.27 432 498 \ ✓ C27H35N50 445.28 446 499 Bd> 0 i C25H31F3N402 476.24 477 500 \ C26H35N503S 497.25 498 501 r° o C25H31N503 449.24 450 502 a^c^N^yO C23H29CIN40 412.20 413 503 "Vo-o C23H29FN40 396.23 397 504 \ N- C25H31N50 417.25 418 505 s° C24H30N603 450.24 451 506 F4ytJ"-0-°N C24H31FN402 426.24 427 226 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 507 \ C25H31FN40 422.25 423 Table 7 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 508 C26H33N302 419.26 420 509 w C26H34N402 434.27 435 510 O ^ r-H N -\j C26H27N302 413.21 414 511 N-/ ° C30H35N302 469.27 470 512 N-/ rjyt-crJ 0 C27H29N302 427.23 428 513 W o-%- C27H28N406S 536.17 537 514 N-/ o-CrtG"0 0 C25H33N303 423.25 424 227 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 515 w oO^O^ ° C24H29N303 407.22 408 516 N-/ -vOMrO*0 ° C25H33N303 423.25 424 517 NY 0 C27H29N303 443.22 444 518 O N-VJ"n C27H29N302 427.23 428 519 XyCr^ ~Cr ^ C27H29N302 427.23 428 520 C27H29N302 427.23 428 521 F NY C27H26F3N302 481.20 482 522 o _ FVJYN-O-^ C27H26F3N302 481.20 482 523 nY / o .Mo Vy-0'J^~0~ C28H31N304 473.23 474 524 ^s-O^x-Cr0 * C27H28N404S 504.18 505 525 CL NY r^toOf«-Cr'° 0 C26H25CIFN303 481.16 482 228 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 526 N-/ ° C24H25N303 403.19 404 527 C24H25N302S 419.17 420 528 O-* C25H28N402 416.22 417 529 CI \ , ^M-OnCS C24H24CIN303 437.15 438 530 F^iv°N-a^H C24H24FN303 421.18 422 531 \ 0 0N~" C25H33N30 391.26 392 532 \ O-O^N-O^3 6 C25H27N302 401.21 402 533 \ 0 0N~ C25H27N30 385.21 386 534 \ ooW^ C23H31N302 381.24 382 535 o $ Z ° / C26H29N302 415.23 416 536 \ ° o" C25H27N30 385.21 386 537 \ ° zT C24H31N30 377.25 378 229 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 538 Or0' C25H26N404 446.20 447 539 \ N— C26H29N30 399.23 400 540 O°XXJhOs>n: C26H29N302 415.23 416 541 O N- C28H33N302 443.26 444 542 6?W-o-o"' C25H29N504 463.22 464 543 \ yOroJK-Qr'° C23H31N302 381.24 382 544 C25H27N302 401.21 402 545 C25H31N302 405.24 406 546 \ 0 o" C27H31N30 413.25 414 547 \ jy-Q^"-Or'® C28H33N30 427.26 428 548 C21H22FN502 395.18 396 549 N- ^Sv°N-a^ C25H25N302 399.20 400 230 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 550 \ Jr-O-O-W0" C29H35N30 441.28 442 551 <?■ \ aYX O ° C23H23CIN404 454.14 455 552 F>-\ H-Cr^-O*0 C25H26FN302 419.20 420 553 \ n- C26H29N30 399.23 400 554 C27H29N302 427.23 428 555 OOi^^ C28H38N403 478.29 479 556 \ n— C25H26FN30 403.21 404 557 C23H24FN30S 409.16 410 558 °o^jy° C26H26F3N302 469.20 • 470 559 (**1 n— \-n 0 - /—( oO^vCr5 6 C29H34N402 470.27 471 560 Q0 -O^-O"0 °s> C25H26N404 446.20 447 231 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 561 \ n- C24H33N302 395.26 396 562 \ 0-OJ>N-O-'° X C24H33N302 395.26 396 563 \ ° zT C25H26FN30 403.21 404 564 \ ° r-y~ C26H29N302 415.23 416 565 \ n— C25H26CIN30 419.18 420 566 \ No 0 rKxy1- N \Jh C26H29N302 415.23 416 567 \ / O 0^ C26H29N302 415.23 416 568 ^0 LL C25H26FN30 403.21 404 569 \ o N~" JT\A^j N'V Lo C26H27N303 429.20 430 570 \ n~ C26H29N30 399.23 400 571 \ n- C26H29N30 399.23 400 232 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 572 0-£ ^ T--n \ 11 Z*° 1 C26H26F3N30 453.20 454 573 \ N- C26H26F3N30 453.20 454 574 \ CroCkO^ C26H35N302 421.27 422 575 \ N- C27H31N302 429.24 430 576 \ 0 0N^ C25H26CIN30 419.18 420 577 O O Z^° 1 C25H25CI2N30 453.14 454 578 \ ^Mo'0 C24H28N402 404.22 405 579 \ N- jqJ^HO- C27H31N303S 477.21 478 580 c:Vn^' C25H31N503 449.24 450 581 \ -^oOM.-O"0 C24H31N302 393.24 394 582 \ N- o-O^-O-0 C23H31N302 381.24 382 233 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 583 F>C C25H25F3N402 470.19 471 584 \ N- XV°N -Of0 C24H39N30 385.31 386 585 o ok / C25H25CI2N30 453.14 454 586 0^) CO C25H26BrN30 463.13 464 587 \ N-.
C25H32CIN30 425.22 426 588 C25H32N402 420.25 421 589 ryO" C24H26N404 434.20 435 590 C24H30FN302 411.23 412 591 C26H28FN30 417.22 418 592 C25H25N502 427.20 428 593 \ N- C26H26N40 410.21 411 234 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 594 F N~ 0 C26H32FN302 437.25 438 595 \ 0 o" C25H26CIN30 419.18 420 596 O ^ C24H26N40 386.21 387 597 \ N- F " C26H26F3N30 453.20 454 598 \ / O C27H31N303 445.24 446 599 C28H29N303 455.22 456 600 C24H33N302 395.26 396 601 \ 0 0~ C25H27N30 385.21 386 602 \ a^-cy0 C28H30N402 454.24 455 603 C26H36N404 468.27 469 604 CKH&cfyc C28H38N403 478.29 479 605 (X0-^s^$h_Q-<0 F C22H28FN302S 417.55 418 235 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 606 yo-Cri^OvV / o I C23H29N303 395.22 396 607 °-CK C27H33N303 447.25 448 608 -J o o S ~h C27H37N304 467.28 468 609 CrO^^X ~h C29H39N303 477.30 478 610 C27H29FN403 476.22 477 611 C25H34N404 454.26 455 612 C27H35N302 433.27 434 613 O-O^N-O"0^ C25H31N303 421.24 422 614 o o O "h C28H32N404 488.24 489 615 C27H35CIN403 498.24 499 616 N-y 0 C26H29N504 475.22 476 617 s > C28H36F3N304 535.27 536 618 C27H38N404 482.29 483 236 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 619 /=N o^.
C27H38N404 482.29 483 620 y o C28H39N305 497.29 498 621 N-» 0 C23H23N503 417.18 418 622 _,W C25H26N402 414.21 415 623 ^N-f0 o-O^-a0 0?< y ^ C28H35CIN404 526.23 527 624 VN-t° o-o^u-^r® C28H39N304 481.29 482 625 CI N~?° oOW° 0?< C27H36CIN304 501.24 502 626 * 0 F N-fU o^N-dr^ **■ C27H35F2N304 503.26 504 627 xNH° o-ofay® °^ y C27H36FN304 485.27 486 628 F N~^° o-oJ"-dy° 0yC y C27H36FN304 485.27 486 237 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 629 o-O^-CC0 0?< C28H39N304 481.29 482 630 V, 0 o-O^n-Qrp y C28H36F3N304 535.27 536 631 0 ^-1 o y f a C27H35CIFN304 519.23 520 632 w o-O^N-Q"^ 0?< y C28H36N404 492.27 493 633 y C28H38CIN304 515.26 516 634 Ih° oO^-CT0 0?< ^ o C31H39N304 517.29 518 635 V C27H36BrN304 545.19 546 636 V> —^ n C28H36N404 492.27 493 637 ~\ V. Tn^° °x C26H35CIN404 502.23 503 638 V> o-o^-pr0 ^ C27H35F2N304 503.26 504 238 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 639 Br N~f° P-0-W0 0?< C27H36BrN304 545.19 546 640 \ o F N^U yCr*<r6c° C27H35F2N304 503.26 504 641 \ hN- ^O-O^N-O-"^0 C23H31N303 397.24 398 642 \ H N— o-O^o-O^o' C24H33N303 411.25 412 643 0-O-*«<X° y 0 C27H37N305 483.27 484 644 «sN-O"N^iNA0^r o-VTo C25H34N404 454.26 455 645 * 0 F _hN^ 0-O^N -qA C27H36FN304 485.27 486 646 fV\ „ kQ C27H24FN303 457.18 458 647 tyO**0-°3o C27H33N302 431.26 432 648 0-0^-0-4° C23H31N303 397.24 398 649 fY1l n- C25H24FN302 417.18 418 239 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 650 C27H36N403 464.28 465 651 0 C25H26N402 414.21 415 652 N-» C31H33FN403 528.25 529 653 jyo C32H38N402 510.30 511 654 _ rvf f\-N3Pm" C28H38N402 462.30 463 655 _ fxjit /-vOt,' j^yAJnu-\j C29H34N402 470.27 471 656 N~/ 0 C26H26CIN302 447.17 448 657 J 1 C29H38N402 474.30 475 658 ° -0~ C27H29N303 443.22 444 659 VN^° * C24H29N504 451.22 452 660 Qo-a^-o-°N C25H33N302 407.26 408 661 C25H30N403S2 498.18 499 240 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 662 C28H29FN403 488.22 489 663 X o-c C31H44N402 504.35 505 664 ( C32H40N402 512.32 513 665 O^vCo-o v n-n n C25H30N603 462.24 463 666 HCW^O-O °7< n-n C25H30N603 462.24 463 667 O^J^O ~V C30H33N504 527.25 528 668 ,n-/ n-VJ" u0 C27H27N304 457.20 458 669 n-^° Ow^° rvO V iW C26H31N503 461.24 462 670 k^° (yL-O"0 0?c C21H27N304 385.20 386 671 n-^° M-0"0 0?< cT C25H30N603 462.24 463 672 ^~n^~~ FtX o ^IVN-C-nCS C31H35FN403 530.27 531 241 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 673 n~^° 07< C26H32N603 476.25 477 674 0?c y C27H42FN304 491.32 492 675 n C25H32N40 404.26 405 676 n- C27H30N402 442.24 443 677 \ J _fN~ oNrv(y°-0' C29H34N402 470.27 471 678 F^«^' C26H28FN30 417.22 418 679 \ n— F C25H32FN302 425.55 426 680 \ n-Oj,~O-°n Yo C23H30N402 394.24 395 681 \ n-OVO"0 O^o C25H32N402 420.25 421 682 -o-cA C24H30N402 406.24 407 683 \ CrCO^-O"0" C26H28N402 428.22 429 684 C23H28N402 392.22 393 242 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 685 \ 0^-0^0-°" C26H34N402 434.27 435 686 N JO p^o C24H27N503 433.21 434 687 \ n-o^n-o C24H32N402 408.25 409 688 \ o^-CA" y C22H30N402 382.24 383 689 \ jyQ&O*? C24H33N50 407.27 408 690 \ M-v , N~ ^y-o N-4^5 C25H28N402 416.22 417 691 \ n- ,-N ,S^\~A rynj r]r\sJ n -\J C24H26N40 386.21 387 692 \ QX*OA~ o1 C22H24N40S 392.17 393 693 \ (H-O*0 C21H24N40S 380.17 381 694 \ n- vA-Cr0 C19H21N30S2 371.11 372 695 C23H24CIN302 409.16 410 243 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 696 J C22H24CIN30S 413.13 414 697 °^z rC LL C21H21CIFN30S 417.11 418 698 o Z*° K / C21H21CI2N30S 433.08 434 699 \ CI C21H21CIN403S 444.10 445 700 \ ci N~ C22H23CI2N302 S 463.09 464 701 \ CI ^— r&jy* 0 \ C22H24CIN302S 429.13 430 702 \ ci ^— py» jyo C23H26CIN30S 427.15 428 703 "XXs-^v^O C24H26CIN302S 455.14 456 704 \ F N-N' O /—fN~~ C22H24F3N50S 463.17 464 705 F F-j-F \ vSv0N-a° C24H23CIF3N30 2 477.14 478 706 F F+F \ C24H24F3N302 443.18 444 244 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 707 \ jy° C23H28BrN502 485.14 486 708 C24H25F3N402S 490.17 491 709 \ n- C22H22N40S 390.15 391 710 \ <r° C23H25N302 375.20 376 711 \ j^x-cr0 o ~~~ \ C24H27N302S 421.18 422 712 oC^-o-'O C24H26CIN303 439.17 440 713 \ n- 0V°n-o-n° C21H22CIN30S 399.12 400 714 f f-j-f v C25H23F6N302 511.17 512 715 \ n- -Qr° F C23H30FN302 399.51 400 716 o J o-O^n-O"^ C26H34FN304 471.25 472 717 qo-c)-^Oj0 C26H29N302 415.23 416 245 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 718 \ Or1 C27H31N302 429.24 430 719 p i C26H33N302 419.26 420 720 C25H28N404 448.21 449 721 C24H33N302 395.26 396 722 V\ N- W»-Cr° C26H28FN302 433.22 434 723 C26H27N302 413.21 414 724 C25H33N302 407.26 408 725 \ N— C26H28BrN30 477.14 478 726 \ C24H26FN30S 423.18 424 727 \ 0 /_^N"~ C26H28FN30 417.22 418 728 \ N- C27H31N302 429.24 430 246 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 729 \ 0 cT C26H28CIN30 433.19 434 730 \ n- CI^o C26H28CIN30 433.19 434 731 n— C26H28CIN30 433.19 434 732 a<4^o~^ C24H25CIN404 468.16 469 733 \ n- C26H28FN30 417.22 418 734 \ ° o" C27H29N303 443.22 444 735 \ C27H31N30 413.25 414 736 \ n~ C27H31N30 413.25 414 737 {X^°y-0^ C26H26FN302 431.20 432 738 Cr^rO-0 C27H29N302 427.23 428 739 \ C25H35N302 409.27 410 247 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 740 \ ° C26H34CIN30 439.24 440 741 C32H36N603 552.28 553 742 1 C26H36FN302 411.59 412 743 \ N- VOj>N-Oj° CrN C25H32N402 420.25 421 744 N- vO^-O"'0 o-N C24H30N402 406.24 407 745 \ N- °rO*i»-0"° OrH C26H28N402 428.22 429 746 \ N- q-k C27H30N402 442.24 443 747 \ C24H32N402 408.25 409 748 "WHocA C24H30N402 406.24 407 749 V V0~^>n'0" 0 C24H32N402 408.25 409 750 \ N- VO^O"*0 rN o C25H32N402 420.25 421 248 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 751 \ n— VO^N -0-° C24H30N402 406.24 407 752 \ 0 C25H34N402 422.27 423 753 /=v n-?i~Vn2jI C22H30N402 382.24 383 754 %6" 0VL f C27H35FN406 530.25 531 755 \ n-O^n-O-^ y° C24H32N402 408.25 409 756 \ d^o*0 C26H27FN402 446.21 447 757 \ C25H34N402 422.27 423 758 \ hO-^O C24H32N402 408.25 409 759 \ n- 0 N-C^C0 |Vo C24H26N403 418.20 419 760 \ C24H30N402 406.24 407 761 \ n~ (HoW C26H32N402 432.25 433 249 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 762 \ O40 C26H34N402 434.27 435 763 cr^o C26H34N403 450.26 451 764 \ n-Q^N-O-0 O^o 01 C25H31CIN402 454.21 455 765 \ v^o-^o*0 C24H30N402 406.24 407 766 \ N-O^-O"0 C25H34N402 422.27 423 767 \ ^-Cr^H-O"0 C24H26N402S 434.18 435 768 \ n^n-O-^ cyo C26H34N402 434.27 435 769 \ O-CH'N-O"0" C23H30CIN302 415.20 416 770 0 N- -\J /*%-« rv-O o-y^n-u ^ f C24H32FN302 413.25 414 771 \ n- n. rv\,/>rO OSsJ f C23H28FN302 397.22 398 250 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 772 \ o N~~ o-Cji n r"F C24H30FN302 411.23 412 773 \ n- C24H30FN302 411.23 412 774 n— —Q /sssyi) /"VO f C25H33FN402 440.26 441 775 n yO rvCfV$ o o-V-f n-xbs/ f C26H33FN403 468.25 469 776 \ n- Cn-0^--0'0 C23H26N40 374.21 375 in C28H30N40 438.24 439 778 0 ^ C21H25N502 379.20 380 779 \ goto# C26H27N302 413.21 414 780 \ C26H26N40 410.21 411 781 \ /— C25H31N50 417.25 418 251 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 782 o ^ ■VV°N -On^ o C21H24N60S 408.17 409 783 \ N- N™' C22H25N50 375.21 376 784 \ N— I /ssvi> /TVO F >N F F C24H28F3N50 459.23 460 785 \ N-O^N ^>°N C25H30N60 430.25 431 786 \ -v( C26H32N60 444.26 445 787 Qs-O^-O"0 C25H27N30S 417.19 418 788 - \ f^il N- C30H34N40 466.27 467 789 \ n- viH-cy0 C24H30N40S 422.21 423 790 0 rSv 0 C24H26CIN303S 2 503.11 504 791 0I~«CI !J-0-tV°N-O-'° C23H23CI2N303 459.11 460 252 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 792 N— C24H26CIN302 423.17 424 793 N C23H26N40S 406.18 407 794 \ C25H27N303S 449.18 450 795 \ CI vl 0 0 _ r-r ^'V:N-0'N C23H25CIN40S 440.14 441 796 \ o-0^° C23H25N303 391.19 392 797 F \ F-j-F n- jH-CK1 0 C23H23F3N402 444.18 445 798 C23H28N403 408.22 409 799 N 0^°^yO C25H30N40 402.24 403 800 c~^ ^~y~4 /=\ w w nhOnJ C26H29N302 415.23 416 801 N- rc^x-ty0 0$ C27H29N50 439.24 440 802 py-Uy^r £ C22H24F3N302 419.18 420 253 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 803 \ C22H25N303 379.19 380 804 \ C22H24N40 360.20 361 805 C22H23F4N30 421.18 422 806 \ -o -qr^n-Or'0 C23H29N302 379.23 380 807 O n-Q-O C26H29N302 415.23 416 808 ^xje C27H30FN30 431.24 432 809 \ N~ y^fNv-« rvO C22H23F3N402 432.18 433 810 \ ^N- C25H25N302 399.20 400 811 »CL > C25H28N40 400.23 401 812 rys* NO"°Y p f-y C21H24F3N303 423.18 424 813 \ Xr*»Or'° C22H30N40 366.24 367 254 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 814 \ n-~ f C24H31FN402 426.24 427 815 \ \ ^N~ —-v p /—v ivr~^ o V4h /yu/yNJ o SfJ N f C25H31FN403 454.24 455 816 O o J1- F>*s/ C25H30FN302 423.23 424 817 \ '(fOHO"0 C23H30N40 378.24 379 818 \ vp-oJU>^N" 0 C24H27N304 421.20 422 819 N 0 f kn-t rvU^O °7< o° C30H34FN304 519.25 520 820 C30H34FN304 519.25 520 821 \ 0 f hn-{ 07< 0 \ C29H34FN304S 539.22 540 822 C29H38FN303 495.29 496 823 x 0 f kn^ rV-O"^ N"CV ° C30H40FN303 509.30 510 255 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 824 f v o Y\ f hn-{ cu^o v C31H35F2N303 535.27 536 825 C28H38FN304 499.29 500 826 v 0 C30H39CIFN303 543.27 544 827 a: -N<^v v C29H33CIFN305 557.21 558 828 C29H38FN304 511.29 512 829 f N-f° XX^i^yn^ °/c C29H33FN406 552.24 553 830 \ 0 f h n-f Vo-O^-p-0 0?< C28H38FN304 499.29 500 831 x 0 f hn-t ry-O^-C/ C30H34FN303 503.26 504 832 Cr°rs Q j ^itW0/ C31H36FN304 533.27 534 833 f wni° 07C C33H37FN404 572.28 573 834 \ 0 ° _^y C31H36FN303 517.27 518 835 +°"S-^n^N°7< C29H40FN304 513.30 514 256 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 836 ° -c5~ C30H33F2N303 521.25 522 837 \ C25H32N402 420.25 421 838 \ n~ VCH-O''0 o C23H30N402S 426.21 427 839 n- o^cru^0 °6 C23H30N403 410.23 411 840 \ n- vo-^-o o C25H36N402 424.28 425 841 n- ouylxyo 6 C24H36N402 412.28 413 842 \ n~ VO^-O-*0 C23H34N402 398.27 399 843 \ cVO-^OjC^ 0 C23H34N402 398.27 399 844 f n-0 C25H31FN402 438.24 439 845 \ y0j>n-O-fCS C26H34N402 434.27 435 257 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 846 0 C25H31CIN402 454.21 455 847 \ 0 C23H36N402 400.28 401 848 \ "rCACr0 s C23H36N402 400.28 401 849 or^i" 0 C26H25N304S 475.16 476 850 0 V O^N-OCf C21H23N30 333.18 334 851 \ ^n-O^N-O-0 C22H25N50 375.21 376 852 N C21H23N50S 393.16 394 853 CVAo-"0 C20H22N60S 394.16 395 854 \ hr°N jy° i C20H25N50S 383.18 384 855 \ c*0** -Or0 C23H29N504 439.22 440 856 orJL N- OyJ P rvO C25H32N403S 468.22 469 258 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 857 \ C22H30N40S2 430.19 431 858 \ JFN-0-°N j* C24H31 BrN40S 502.14 503 859 C24H24FN303 421.18 422 860 \ ts _^n- rj&x-Cr'0 \J N CI C28H27CIN40 470.19 471 861 N C23H31N50S 425.23 426 862 QK^° C22H30M405S 462.19 463 863 N "M-O"'0 <> C23H32N404S 460.21 461 864 p Yjz Z^° ; C27H29N50 439.24 440 865 \ ovO^O-*0 >N C22H25N502 391.20 392 866 O r^»jyO" C26H29N304S 479.19 480 259 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 867 f \ f4-f n- O C23H23F3N40S 460.15 461 868 \ ^jy^-Cr'0 nh n o C22H29N702 423.24 424 869 C25H26N60 426.22 427 870 \ N 0 zf" C26H32N402 432.25 433 871 \ ^ o n~~ ^6^ N-C/'^ C24H27N302 389.21 390 872 \ ^-Crta0 <3 C27H29N50 439.24 440 873 /-0 \ C23H28N403S 440.19 441 874 n C28H34N40S 474.24 475 875 C24H28N403S 452.19 453 876 C23H23CIN403 438.15 439 877 \ n- nv^43-nO Dn f C23H26FN50 407.21 408 260 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 878 \ n- C25H27CIN402 450.18 451 879 \ C24H27N50 401.22 402 880 \ f C24H30F3N50 461.24 462 881 o-v^-O-ny- C22H23CIN402 410.15 411 882 o ^n- C23H26N40S 406.18 407 883 O N- Hv? rvO n n-v/ C24H26N40 386.21 387 884 0-?° O C24H26N40 386.21 387 885 «n \ £ /? N- C24H26N40 386.21 387 886 \ Fy C21H23F3N60S 464.16 465 887 \ n- C23H30N403S 442.20 443 888 \ n~ C24H26N402 402.21 403 261 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 889 N "fgytAN-O^ C24H25F3N40S 474.17 475 890 \ ° C27H29N30 411.23 412 891 °xx\o!:y" C26H29N30 399.23 400 892 (y^XNtl N~ / C28H31N302 441.24 442 893 \ C23H28N402 392.22 393 894 \ o° C27H29N302 427.23 428 895 cr C21H25N70 391.21 392 896 AO <y C21H28N40S 384.20 385 897 hA&^' C23H26CIN50 423.18 424 898 N C21H23N50S 393.16 394 899 \ o N~ jC^' " ' Cl'^ C26H26CIN50 459.18 460 262 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 900 n C23H27N50 389.22 390 901 \ n- C25H34N40 406.27 407 902 \ o-o^-cr0 y « C24H30N402 406.24 407 903 o ci n- C23H30CIN302 415.20 416 904 Po-O^O0 C25H25F2N302 437.19 438 905 * o rv/sy\-/V O \ C29H39FN402 494.31 495 906 * 0 C29H32F2N402 506.25 507 907 \ o o j a"x ' /^4/VO N\ C30H35FN402 502.27 503 908 C27H37FN403 484.29 485 909 V, o f h n~? n; C27H37FN403 484.29 485 910 0 \ C25H34FN303 443.26 444 263 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 911 \ f h-n— cl 0 jL /-H ci C24H30CI2FN30 2 481.17 482 912 C24H31FN404 458.23 459 913 0 rV ci C24H31CIFN302 447.21 448 914 ^-0 N ^ C26H36FN302 441.28 442 915 \ pi f n-N"" cl P 0 J r\ yy-A jty-^ jr'" C25H32CI2FN30 3 511.18 512 916 f fo °jy-f I4 C24H28F5N302 485.21 486 917 f C24H31F2N302 431.24 432 918 0 C26H34FN303 455.26 456 919 C28H40FN303 485.30 486 920 C25H34FN50 439.27 440 264 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 921 ~^o-crtd"3 C23H31FN402 414.24 415 922 C24H26FN303 423.20 424 923 Qo C26H28FN302 433.22 434 924 n-o^n -6ft cyo C26H33FN402 452.26 453 925 ci 0 f uvn- /vn-(jN^ O^o " ' " C26H32CIFN402 486.22 487 926 \ N-o^N^o-0 C^o f C25H31FN402 438.24 439 927 n- cr^h-o^u-o^ x C26H31F3N403 504.23 505 928 "O o j O _ /—( crvoa-o-*0 CI C26H33CIN403 484.22 485 929 V n~ 0 o f-f c^n-p^n-0n^ CI C25H31CIN402 454.21 455 930 j - ' C24H31CIFN302 447.21 448 265 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 931 f n C25H34FN302 427.26 428 932 o^-o C27H33FN402 464.26 465 933 cP* C26H28FN302 433.22 434 934 C25H28FN302S 453.19 454 935 C25H32FN30 409.25 410 936 (yor3^^ C26H34FN30 423.27 424 937 f C27H29F2N30 449.23 450 938 C24H32FN302 413.25 414 939 jzo*M C26H33CIFN30 457.23 458 940 y&M C24H32FN302 413.25 414 941 C26H28FN30 417.22 418 266 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 942 i C27H30FN302 447.23 448 943 Jv o^z- KZ o 6 C29H31FN402 486.24 487 944 C27H30FN30 431.24 432 945 1 rVn 0 f H,N-» "f^^N-o-cr C25H34FN302 427.26 428 946 LL C26H27F2N30 435.21 436 947 \ C25H27FN402 434.52 435 948 97 x ^vNb F N— ^SSr^C*< C25H27FN404 466.20 467 949 -°r\ ° X T" C24H29FN403 440.22 441 950 cf C27H30FN302 447.23 448 951 ^6# C23H31FN40 398.25 399 952 f-V^° . a-U 8 C24H26CIFN40S 472.15 473 953 >» C25H25F2N303 453.19 454 267 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 954 o j CP' ^ f C24H27F2N50 439.22 440 955 C26H31F2N302 455.24 456 956 \ ro*»-qr° C23H31N302 381.24 382 957 \ ro&o^ /° C24H33N302 395.26 396 958 \ n~ ar**v° C24H33N302 395.26 396 959 \ n- C26H29N302 415.23 416 960 \ C25H29N502 431.23 432 961 f hn- n y~i \ o ci C24H24CIFN403 470.15 471 962 \ XX -OVO;0" C27H36FN302 453.61 454 963 \ n- "xau-cr*0 P C24H30N402 406.24 407 268 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 964 /=\ ~N-H-Q-O C24H28N402 404.22 405 965 O T-O^-O^0 C27H29N50 439.24 440 966 Q ryiNjyON~ o -\J N -\,gj °fo C25H28N404S 480.18 481 967 \ N— C24H26N402 402.21 403 968 ° ^ C27H27BrN402 518.13 519 969 N-N 0 cXy^-O^^r^ C22H24CIN50 409.17 410 970 o\J F-)-0 F C22H23F2N303 415.17 416 971 \ N- jm rv<° yvO N"V C21H23N50S 393.16 394 972 o 2^0 1 C23H24CIN30S 425.13 426 973 \ D-o^"0"0 C22H24N403 392.18 393 269 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 974 \ N~ O-O^N-O"0 & ci C25H27CIN402 450.18 451 975 \ ^ jy°" C25H30N40 402.24 403 976 \ N— m r\A /"V-O H Yajt C22H25N50 375.21 376 977 O C22H27N303S 413.18 414 978 f C20H23F3N40S 424.15 425 979 f C21H24F3N30S 423.16 424 980 f f n-~ O C26H24BrF3N60 572.11 573 981 c^-O^, 1 C23H25CIN40S 440.14 441 982 Qn Xy°NjQ-n0 C24H32N403S 456.22 457 983 \ N~ jV-O^-O"0 C24H31CIN403S 490.18 491 984 o >0 N- <%j>n-0'n':s C23H25N304S 439.16 440 270 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 985 \ C26H32N403 448.25 449 986 C26H32N40 416.26 417 987 C22H27N30S 381.19 382 988 \ h-CK-O'0 C24H31N302 393.24 394 989 ryfcr0* Fff C22H24F3N30S 435.16 436 990 \ yOMi-O^ C24H33N30 379.26 380 991 C22H29N302 367.23 368 992 C25H35N30 393.28 394 993 (VAo<^ _)-n C25H30N40 402.24 403 994 o S-y-f ^ rp> n1>nQ " N-/ C22H26N40S2 426.15 427 995 O-1 XA|>N'.
C29H32N402 468.25 469 996 VYl ^ / /=\ /-iJ ^N'VN f0^n ^* C23H26FN50 407.21 408 271 z m P Structure Molecular formula Monoisotopic molecular wt.
M+H+ 997 ax^N-O-0~ C28H28CIN50 485.20 486 998 \ -sf C20H23N502S 397.16 398 999 C25H26N60 426.22 427 1000 \ N— n fv-4 ry-NJ n -v/ C22H24N402 376.19 377 1001 \ O N~ 0-\j N xj ryf i C26H35FN402 454.27 455 1002 \ X^-Ccp C25H34FN302 427.57 428 1003 \ N— C24H25FN40 404.20 405 1004 \ O^o C25H30N402 418.24 419 1005 O40 C26H31FN402 450.24 451 1006 \ N-O^NO-0 y"° C25H34N402 422.27 423 272 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1007 \ y° C24H30N402 406.24 407 1008 1 C27H30N402 442.24 443 1009 \ jcaorko*? f C27H29FN402 460.23 461 1010 C26H34N402 434.27 435 1011 \ C26H26CIFN402 480.17 481 1012 \ C26H27FN402 446.21 447 1013 \ C25H27N502 429.22 430 1014 \ o C27H36N402 448.28 449 1015 \ NoV° C25H29N503 447.23 448 1016 Q N/V?° /=\ C29H32N402 468.25 469 1017 \ ro<c*o* C26H27FN402 446.21 447 273 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1018 \ N-Oto'0" a" C23H30N403 410.23 411 1019 \ 0^° 1 C23H30N403 410.23 411 1020 \ C24H30N402 406.24 407 1021 \ n- ^N-O^N-O-0 C24H28N602 432.23 433 1022 \ n— C25H27N502 429.22 430 1023 \ N-O^-O-0" C25H34N402 422.27 423 1024 \ C25H28N402S 448.19 449 1025 \ sH-oto0" C25H29N502 431.23 432 1026 \ p-d^-o^ C26H26F2N402 464.20 465 1027 \ Y°h-oJ«<y'°N n C24H27N502 417.22 418 274 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1028 ° X.
/ C29H38N402 474.30 475 1029 \ C27H36N403 464.28 465 1030 \ «v°-ai€r°N C24H27N502 417.22 418 1031 \ o^-o^-o-0 C27H36N402 448.28 449 1032 \ .N-O^O"0 cr° C27H36N402 448.28 449 1033 \ yO-^O^ C27H38N402 450.30 451 1034 \ n- CLj-Cr* N-O" C29H32N402 468.25 469 1035 C27H34N402 446.27 447 1036 n C26H27CIN402 462.18 463 1037 \ n- fAcAoA.
C22H24N602S 436.17 437 1038 \ •fyo C23H25N503 419.20 420 275 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1039 \ N-O-to0" yyo C25H32N402 420.25 421 1040 O / C26H27CIN402 462.18 463 1041 \ C27H30N402 442.24 443 1042 \ 0 \jrK o C24H30N403 422.23 423 1043 \ C27H30N402 442.24 443 1044 \ N- H C30H38N402 486.30 487 1045 \ ^O^N-O^N-O^ C29H34N403 486.26 487 1046 \ C27H28F2N403 494.21 495 1047 \ CAOs<Oj° C25H32N403 436.25 437 1048 \ -OiN-0J>N-0",CS C27H36N402 448.28 449 1049 \ F »jyt«jy° FT^O C23H27F3N402 448.21 449 276 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1050 V ca C26H32N402 432.25 433 1051 \ C26H36N402 436.28 437 1052 C22H28FN302 385.22 386 1053 \ cH-O^-O-0 C27H30N402 442.24 443 1054 N- >-(T C21H24N60 376.20 377 1055 C25H27N50S 445.19 446 1056 \ 0 zf C24H26N40 386.21 387 1057 \ ^ O N~ cS"* N-C/N^ C22H24N402 376.19 377 1058 \ 0y-oj"<y°n C27H30N40 426.24 427 1059 q n- VnO-0 C24H32N40 392.26 393 1060 \ ga-o-°~ C^N C22H26N60 390.22 391 277 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1061 \ 9 C24H27N502 417.22 418 1062 n— rO^n-O"0 i> C23H26CIN50 423.18 424 1063 \ n— C24H26CIN302 423.17 424 1064 \ vO^-O^ ci-CN'*" C24H25CIN602 464.17 465 1065 \ n- jy° C24H27N30S 405.19 406 1066 \ <ynjy° o-V> C20H21CIN402S 416.11 417 1067 Qs-o^-o0 °S> C25H26N403S 462.17 463 1068 ^o-O^N-O-^ "S) C26H28N404 460.21 461 1069 •rOVQ-^V0 y f C30H42FN304 527.32 528 278 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1070 o-o^qc^h C31H42FN304 539.32 540 1071 C27H30N402 442.24 443 1072 CC C28H32N403 472.25 473 1073 C25H32FN302 425.25 426 1074 cy C27H30FN302 447.23 448 1075 N C27H30FN30 431.24 432 1076 C28H27FN403 486.21 487 1077 0 -c5~ C28H28BrFN402 550.14 551 1078 C28H31FN402 474.24 475 1079 lfV-% 0 _/F fx~h y-qr*0 C26H31FN40 434.25 435 1080 r>° N C26H29FN402 448.23 449 279 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1081 <x> C28H30FN50 471.24 472 1082 C29H31FN40 470.25 471 1083 0j0^cr C27H30FN30S 463.21 464 1084 , fiW C ,r Vn C25H28FN50S 465.20 466 1085 (Vs \s=N C26H29FN40S 464.20 465 1086 <&o>M C28H29FN402 472.23 473 1087 Qr° C27H30FN302 447.23 448 1088 o $ °"a / C27H29CIFN302 481.19 482 1089 C25H34FN30 411.27 412 1090 -^oC>*r&& C25H34FN302 427.26 428 1091 C23H30FN302 399.23 400 280 1092 v...
F RN- C24H32FN302 413.25 414 1093 C26H32FN302 437.25 438 1094 C30H36N404 516.27 517 1095 C25H31F2N3 02 443.24 444 1096 C25H31F2N302 443.24 444 1097 C26H27F2N302 451.21 452 1098 C26H34F2N40 456.27 457 1099 C27H27FN402 458.21 459 1100 C27H27FN402 458.21 459 1101 .■ . "^""S C24H30FN302 411.23 412 1102 . ^ ^ ^ ^ C23H25FN40S 424.17 425 1103 C28H29FN402 472.23 473 1104 C25H32FN302 425.25 426 281 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1105 i C24H27FN40S 438.19 439 1106 u i C25H34FN303 443.26 444 1107 C26H27F2N302 451.21 452 1108 C27H36FN302 453.28 454 1109 C26H26F3N302 469.20 470 1110 C25H27FN402 434.21 435 1111 ^r^cr\-6<\ C25H34FN302 427.26 428 1112 C26H34FN302 439.26 440 1113 C27H36FN302 453.28 454 1114 _/>°^-dror C25H34FN302 427.26 428 1115 CI C25H33CIFN303 477.22 478 1116 C24H31F2N302 431.24 432 1117 (-fOi-d-cy C25H32FN302 425.25 426 282 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1118 oy^-^y C27H30FN303S 495.62 496 1119 C23H27F4N30 437.21 438 1120 C26H36FN302 441.28 442 1121 y^K C25H27FN402 434.21 435 1122 ^xxxxy1^ C25H33N302 407.26 408 1123 C24H31N302 393.24 394 1124 ^o-Uio^ i C25H34FN302 427.26 428 1125 i C23H30FN302 399.23 400 1126 C27H29CIFN302 481.19 482 1127 C22H25F4N30S 455.17 456 1128 <^0uyj6rc>< C25H32FN302 425.25 426 1129 C25H32F2N40 442.25 443 1130 ^^>j~d-Cy C26H29FN402 448.23 449 283 Table 8 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H + 1131 C23H23CI2N302 443.12 444 1132 0k^^°N-O-O C23H23CIFN302 427.15 428 1133 C24H26FN302 407.20 408 1134 w3 * C28H33N304 475.25 476 1135 0 r-v-n. 5^ C29H34N405 518.25 519 1136 VN-,° cAo* * C33H41N304 543.31 544 1137 V. ° N-* 07< ~N \ C29H36N404 504.27 505 1138 N~*° CC^i^ °7< C29H32N404 500.24 501 1139 C28H30F3N304 529.22 530 2 84 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H + 1140 \ P C22H22CI2N40S 460.09 461 1141 \ N~ P CI C22H23CIN40S 426.13 427 1142 \ N— s? C22H23FN40S 410.16 411 1143 \ N- ft C23H25FN40S 424.17 425 1144 \ N- tp F F C23H22CIF3N40S 494.12 495 1145 \ (JV^N-O-0" C26H26N40S 442.18 443 1146 o \^~q / C25H25CI2N30 453.14 454 1147 \ 0 0" C23H25N30S 391.17 392 1148 \ p jrU>*° FtO C23H23F3N40S 460.15 461 2 85 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H + 1149 \ n- C22H23N503S 437.15 438 1150 \ C22H24N40S 392.17 393 1151 \ n— jau-ty0 ci-Q ci C22H22CI2N40S 460.09 461 1152 \ n— IVN-O'0 ci~O f C22H22CIFN40S 444.12 445 1153 \ s^fA-a°N~ C20H22N40S2 398.12 399 1154 '"^A-cr0"' C23H26N402S 422.18 423 1155 \ n- "Ajy0 rp f f C23H23F3N40S 460.15 461 1156 \ 94^-0^ C23H26N40S 406.18 407 1157 n aO>n ? /"VO o §jw\J C23H26N402S 422.18 423 1158 \ 0KP^Axy°~ C24H27N502S 449.19 450 2 86 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H + 1159 \ n— a-G C22H23CIN40S 426.13 427 1160 x n- iVn-O"0 f-O C22H23FN40S 410.16 411 1161 n cov^o C26H26N40S 442.18 443 1162 C23H26N40S2 438.15 439 1163 \ n- %a<y° cP cl ci C22H22CI2N40S 460.09 461 1164 n rvNO C24H28N402S 436.19 437 1165 0t^4v°n -cr^' C24H28N402S 436.19 437 1166 ^fa-o"0n' C26H32N40S 448.23 449 1167 \ C23H23N50S 417.16 418 1168 n C28H28N40S 468.20 469 1169 \ 9ivii\jy° ( C24H28N402S 436.19 437 2 87 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H + 1170 r o \ C23H24N403S 436.16 437 1171 yfa-cy®' C26H32N402S 464.23 465 1172 \ qfa-tyv" C23H26N40S2 438.15 439 1173 n- C24H28N40S2 452.17 453 1174 C24H28N40S 420.20 421 1175 \ n— f C23H23F3N402S 476.15 477 1176 \ ^N~ 'uYn ., o / c A-nJ j ^ C24H28N403S 452.19 453 1177 C25H30N40S 434.21 435 1178 n C25H30N40S 434.21 435 1179 \ piaca C23H26N402S 422.18 423 1180 \ ,0~o-fjjnjy0 C22H25N502S 423.17 424 1181 q n— °~fa<y° C24H24N40S2 448.14 449 2 88 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H + 1182 \ Ffopj>„-O"'cs C23H23F3N402S 476.15 477 1183 \ N- sv°Mi>0 >N F F C24H22F6N40S 528.14 529 1184 \ N- svtfVO b" F C23H25FN40S 424.17 425 1185 N jyo C24H28N40S 420.20 421 1186 N C24H28N40S 420.20 421 1187 \ .N- C25H26N403 430.20 431 1188 < o Z^° / C27H31N302 429.24 430 1189 \ N- C25H25CIFN30 437.17 438 1190 \ N~ C25H25CI2N30 453.14 454 1191 N 0 /^N~" C26H26N40 410.21 411 2 B9 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H + 1192 \ 0 ° on~ C27H29N302 427.23 428 1193 \ n- C27H29N302 427.23 428 1194 \ 'prO^-O-0 f C25H25F2N30 421.20 422 1195 \ n- j^yjqy^n-O'^ f C25H25F2N30 421.20 422 1196 \ n- j^jry^^jqr^ C26H28N403 444.22 445 1197 \ ° on~ C27H32N40 428.26 429 1198 o N- so C25H28N402 416.22 417 1199 \ ° o .n- n~C/~ C27H29N303 443.22 444 1200 \ n~ C24H28N402 404.22 405 290 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H + 1201 \ n- oyxy1 N-Cy^ C23H25N302 375.20 376 1202 \ n- " f C24H25FN40 404.20 405 1203 \ 0 zT C22H25N50 375.21 376 1204 \ n— f C26H28FN30 417.22 418 1205 \ 0 o" C26H28FN30 417.22 418 1206 \ n- " ci C24H25CIN40 420.17 421 1207 \ n- rvrv?<-(y^ C24H25FN40 404.20 405 1208 0 0^"" C24H25FN40 404.20 405 1209 \ n— ,v(vUyo 0 f \ C26H28FN302 433.22 434 1210 j> o n— C27H30N402 442.24 443 1211 \ o n~ 'ci " C25H26N403 430.20 431 291 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H + 1212 \ 0 -CV r^" C26H25FN40 428.20 429 1213 ryij'-i-* C24H25FN40 404.20 405 1214 C24H25FN40 404.20 405 1215 _ f\j( j "o C26H28FN303S 481.18 482 1216 0 \ ^ of A"" N _ p ,-i K{\ C27H29FN402 460.23 461 1217 n"^sss' -N s C28H31FN402 474.24 475 1218 r^LQjMjyiu~ C26H25F4N302 487.19 488 1219 C26H28FN303S 481.18 482 1220 F*0 0 J ^N~ C26H25F4N302 487.19 488 1221 \ C26H25FN40 428.20 429 292 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H + 1222 f n C27H29FN402 460.23 461 1223 f f --v f\-4 jT^N0 foxj^' n~^ C26H25F4N302 487.19 488 1224 \ o N~~ C25H25F2N30 421.20 422 1225 C25H32N403S 468.22 469 1226 \ _^rOJL-Oj0 C24H31N50 405.25 406 1227 \ C24H31N502 421.25 422 1228 \ F^yO^-O^ C23H28FN50 409.23 410 1229 V C26H31N50 429.25 430 1230 \ avO^O-^ C25H29N50S 447.21 448 1231 \ C26H34N40 418.27 419 293 Ex.
Structure Molecular formula Monoisotopic M+H No. molecular wt. + 1232 (pcrlo-°N C26H32N402 432.25 433 Table 9 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1233 0 9 -vnM-TTK-vr^ C31H29N302 475.23 476 1234 C30H35N302 469.27 470 1235 N-^° o?< C28H30N403S 502.20 503 1236 FY^ N-*° C29H30FN303S 519.20 520 1237 N ° C28H30N403S 502.20 503 Table 10 Ex.
Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1238 C26H35N302 421.27 422 1239 o-o^n-o^^} C26H35N302 421.27 422 294 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1240 y C25H31F2N302 443.24 444 1241 O-o^-O-^Y C27H35N302 433.27 434 1242 o C26H35N302 421.27 422 1243 O-O^N-O'0 y C25H36N402 424.28 425 1244 O-O^N-O-^ y C24H33N303 411.25 412 1245 \-r° N y-O^N C26H37N303 439.28 440 1246 P-O^N-O-°y> C27H37N302 435.29 436 1247 C27H37N302 435.29 436 1248 C27H33N502 459.26 460 1249 C26H35N303 437.27 438 1250 ^o-OXo-^/^ C29H34FN302 475.26 476 295 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1251 /"vi3 _ yp-O^h-Q-O C27H32N402 444.25 445 1252 o-O^n-O-0^ C24H33N302 395.26 396 1253 o-Q^o-O-0 C23H31N302 381.24 382 1254 o-O-^O-^O C25H33N303 423.25 424 1255 / f C23H28F3N302 435.21 436 1256 C23H30FN302 399.23 400 1257 i o-O^N'O'^0 C27H37N303 451.28 452 1258 \ c-o^-a^0 C24H33N303 411.25 412 1259 c-O^n-O"0 C25H33N302 407.26 408 1260 C25H33N302 407.26 408 1261 0-0^-0-° y C25H35N302 409.27 410 296 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1262 O-O^N-O-^ C25H35N302 409.27 410 1263 -A C25H35N302 409.27 410 1264 C25H35N302 409.27 410 1265 o-O^-O^r V VN W C27H35N502 461.28 462 1266 h^Qo o-O^N -Or® C28H38N403 478.29 479 1267 c-o^-a^o.
C26H36N402 436.28 437 1268 \ o-O^-O0"^' y C26H38N402 438.30 439 1269 o-Cr*»<y° "8 C30H35N302 469.27 470 1270 C27H32N402 444.25 445 1271 y 1 C27H36N403 464.28 465 1272 C27H37N302 435.29 436 297 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1273 C30H35N302 469.27 470 1274 C26H35N302 421.27 422 1275 / h C29H39N302 461.30 462 1276 o-o^ C29H43N302 465.34 466 1277 C28H39N302 449.30 450 1278 o xy«<y° C28H37N302 447.29 448 1279 Y 6 ' n 1 C28H40N402 464.32 465 1280 C30H35N302 469.27 470 1281 C30H34N402 482.27 483 1282 o-oj>n-o-,° b Y C30H35N303 485.27 486 1283 y C25H33N304S 471.22 472 298 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1284 C29H39N302 461.30 462 1285 yo^-o^0 C26H33N303 435.25 436 1286 Y C27H35N502 461.28 462 1287 \ / •xy'.-O-0 C25H35N302 409.27 410 1288 / O" \ C26H35N304S 485.23 486 1289 oO-^O^o Y C27H38N402 450.30 451 1290 y C26H31N302S 449.21 450 1291 C29H41N302 463.32 464 1292 O-C^N-C^Vl V & C25H32N403 436.25 437 1293 ^,{) C26H35N303 437.27 438 1294 C25H30N402S 450.21 451 1295 o-O^-O^^ C24H31N302 393.24 394 299 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1296 C25H35N502 437.28 438 1297 ao5aN5fja°t) C27H37N502 463.30 464 1298 ^OLAJCr^' VS C26H32N602S 492.23 493 1299 C24H33N503 439.26 440 1300 C28H40FN303 485.30 486 1301 C27H36FN302 453.28 454 1302 C31H37N502 511.30 512 1303 ■rw a°O.N«N-0r 6 C28H39N502 477.31 478 1304 C27H39N502 465.31 466 1305 cs°tcxxo°^- C27H39N502 465.31 466 1306 C26H35N502S 481.25 482 1307 C26H33N702 475.27 476 1308 o'zxxo^h C26H35N502 449.28 450 300 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1309 a°OLA-OrN°X o C26H37N503 467.29 468 1310 a0aN*NjOrN°T / C26H37N503 467.29 468 1311 a°OA£rNOBf 0 C26H37N503 467.29 468 1312 C27H37N503 479.29 480 1313 CroO-NiNXTNOHV0 C27H39N503 481.30 482 1314 N s~y C28H38N602 490.31 491 1315 0r°DXO°^; o > C28H39N504 509.30 510 1316 a0CrNm„v Oi C28H39N502 477.31 478 1317 a0OYxx , O C29H40N603 520.32 521 1318 y C30H44N602 520.35 521 1319 a0OTn vH C30H44N603 536.35 537 1320 n' C30H34N602 510.27 511 301 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1321 cyCrYiOUN, L-/H v—v OK o C33H42N602 554.34 555 1322 N a°oxa 1" C27H35N702 489.29 490 1323 a0o.AXr% C29H38F3N502 545.30 546 1324 C29H39N702 517.32 518 1325 C31H37N702 539.30 540 1326 r\H —/"N nJ C26H33N702 475.27 476 1327 NO^' / C26H37N502S 483.27 484 1328 Or°O.A-Or C26H35N502 449.28 450 1329 C27H35N702 489.29 490 1330 cr0O.A-Or°HKo_ C28H41N503 495.32 496 1331 Or0CLA-OrN°"N^ C25H31N702S 493.23 494 1332 Cr^S.^^ C31H39N503 529.30 530 302 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1333 >=o /-° C30H42N604 550.33 551 1334 C28H41N502 479.33 480 1335 oy C29H30F2N402 504.58 505 1336 C25H32FN302 425.25 426 1337 C25H34FN302 427.26 428 1338 F N~/"° C24H32FN303 429.24 430 1339 F ^ C26H34FN302 439.26 440 1340 C C26H34FN302 439.26 440 1341 C25H34FN303 443.26 444 1342 F N-^~® ^o-cH-6-0 C25H34FN303 443.26 444 1343 0 F N-/ ' C25H34FN303 443.26 444 1344 0 / rt"~0 ^0-O^rO-° C27H36FN302 453.28 454 303 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1345 C27H38FN302 455.30 456 1346 v C27H38FN302 455.30 456 1347 p N~^~ C27H38FN302 455.30 456 1348 VY~O C26H36FN303 457.27 458 1349 f n-v ^O-O^N-P-^ C26H36FN303 457.27 458 1350 F NJ^° -^0-0^-6-° C25H34FN304 459.25 460 1351 <> o o C25H34FN304 459.25 460 1352 F N—/ \ ~-0-OJiV-&0 ^ C28H38FN302 467.30 468 1353 o >'o o^z- 0 o C27H38FN303 471.29 472 1354 p N-^0 ^o-OW° C27H38FN303 471.29 472 1355 C27H34FN502 479.27 480 304 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1356 C29H40FN302 481.31 482 1357 C29H40FN302 481.31 482 1358 C28H39FN402 482.31 483 1359 0 j rltOo C28H38FN303 483.29 484 1360 0 F N-V^\ -^o-CH-d0 C28H38FN303 483.29 484 1361 -^ojd*r6A C28H36FN502 493.29 494 1362 r^N ^ N-4, C27H35FN602 494.28 495 1363 F N>N, ~-o-crty-&° C28H37FN403 496.29 497 1364 o j r-!N^'0 C29H41FN402 496.32 497 1365 N C28H39FN403 498.30 499 1366 o J rVbG C26H32FN304 469.24 470 1367 C29H40FN303 497.30 498 305 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1368 \ -^o-o^d'0^ C25H31FN402 438.24 439 1369 0 -^o-O^rd0 C26H34FN302 439.26 440 1370 C26H36FN302 441.28 442 1371 o o C25H34FN303 443.26 444 1372 F O ^o-CH-o-° C27H36FN302 453.28 454 1373 "^o-0^-dN'^fi>0 C26H34FN303 455.26 456 1374 F ~C> C28H38FN302 467.30 468 1375 r( F N-/ -Cr0 C27H37FN402 468.29 469 1376 C26H34FN302S 471.24 472 1377 •^-vG^-d'0/ o C26H36FN304 473.27 474 1378 C28H41FN402 484.32 485 306 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1379 & ^-o-c^-6-° C28H37FN403 496.29 497 1380 y C28H37FN403 496.29 497 1381 ^o-o^-6-N^p C32H38FN302 515.29 516 1382 F SN->0 '^o-0jr&0 C31H38FN303 519.29 520 1383 6 C31H43FN402 522.34 523 1384 o-SS ^oojar'°n C27H36FN303 469.27 470 1385 0 C27H36FN303 469.27 470 1386 F F C28H34F3N303 517.26 518 1387 F N-Z^Q C27H36FN304S 517.24 518 1388 \ , ^.oVJ*0 C30H41FN403 524.32 525 1389 C27H36FN303 469.27 470 307 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1390 C22H28FN302 385.22 386 1391 ry° f n-/ C29H38FN304 511.29 512 1392 f n-/~° -^o-ch-d'0 C26H36FN303 457.27 458 1393 f nv"° C25H34FN303 443.26 444 1394 C27H36FN303 469.27 470 1395 ^0-o*r&0" C26H34FN303 455.26 456 1396 y° f o- C28H38FN303 483.29 484 1397 o- f n~/ ^o-o^n jy& C26H36FN303 457.27 458 1398 cp> r ^o-o^-d"0" C26H34FN304 471.25 472 1399 f° C28H38FN304 499.29 500 1400 o-/ ^o-o^-d-^" C27H38FN303 471.29 472 308 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1401 V o V o C28H40FN303 485.30 486 1402 ° F N~/ ^0-0^-6-° C27H36FN304 485.27 486 1403 C27H36FN303 469.27 470 Table 11 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1404 C22H30N402 382.24 383 1405 C24H31CIN40 426.22 427 1406 C23H32N402 396.25 397 1407 o N C25H27FN40 418.22 419 1408 C23H32N402 396.25 397 309 1409 C22H30N402 382.24 383 1410 q _rO^' o-q^o C23H25N502 403.20 404 1411 C24H33N302 395.26 396 1412 o-O^O-^V C23H31N302 (S)- Konfigu ration 381.24 382 1413 ^■0-^0J°V C23H31N302 381.24 382 1414 0-qjx-&n^ y C23H30FN302 399.23 400 1415 C24H32FN302 413.25 414 1416 ex*00*" C24H32N40 392.26 393 1417 \ C24H32FN302 413.25 414 1418 C24H32FN302 (S)-configuration 413.25 414 1419 o-o-^o^ C25H34FN302 427.26 428 1420 ^o-o*l-&3N C26H36FN302 441.28 442 310 1421 C26H36FN302 441.28 442 1422 o-o^crV s <> F C27H36FN302 453.28 454 1423 f rvwN >0^ J^JT" C27H38FN303 471.29 472 Table 12 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1424 C27H35N302 433.27 434 1425 C28H39N304 481.29 482 1426 —oCrV0 4-0 C27H38N404 482.29 483 1427 0 rv^V.
C24H32N403 424.25 425 1428 C24H33N302 395.26 396 1429 C24H31N303 409.24 410 1430 °ro~ <> u_ C29H33FN403 504.25 505 311 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1431 o (TvnQV o ° npo-kJ ' -j- C27H38N404 482.29 483 1432 °> -K C30H43N305 525.32 526 1433 C25H33N303 423.25 424 1434 ° -+- C29H41N305 511.30 512 1435 \ n- jtyokcfv C26H28FN30 417.22 418 1436 C27H30FN30 431.24 432 1437 W> ■O-^0 ^ f C28H38FN304 499.29 500 1438 \ 0 f h n~^ 0?C C28H38FN304 499.29 500 1439 C28H38FN304 (S)- Konfigu ration 499.29 500 1440 \ % C25H32N402 420.25 421 1441 C24H32CIN302 429.22 430 1442 o ~ 0^ o O-^O^V0 C29H40FN304 513.30 514 312 Ex.
Structure Molecular Monoisotopic M+H+ No. formula molecular wt. 1443 \ o f h 07C C30H42FN304 527.32 528 Table 13 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1444 \ o C23H30N40 378.24 379 1445 C23H30N40 378.24 379 1446 \ o jh,n C21H28N402 368.22 369 1447 \ 0 N oo-y> C27H38N40 434.30 435 1448 \ 0 0 C26H36N40 420.29 421 1449 \ C29H42N40 462.34 463 1450 X C28H38N40 446.30 447 313 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1451 o-o^-cW C24H32N40 392.26 393 1452 C26H36N40 420.29 421 1453 C C26H32N40 416.26 417 1454 C23H31N302 381.24 382 1455 C24H31N30 377.25 378 1456 \ H.N O-O^N-O-^ C22H29N302 367.23 368 1457 fjycma C22H21FN40 376.17 377 1458 O-O^N-O"^ y C20H26N402 354.21 355 1459 \ o-D^-O^ 6 C23H24N402 388.19 389 1460 HfN r-NtU /yO ajy0a^ C22H27CIN40 398.19 399 1461 ^o^/N<VN^ C22H30N402 382.24 383 314 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1462 o-o^-cy^ 6 C21H21N502 375.17 376 1463 N y C22H27F2N302 403.21 404 1464 N o-Cr*»-6r'° C22H28FN302 385.22 386 1465 O Cl r-iN C22H28CIN302 401.19 402 1466 \ Oxyx«-o° y 1 C23H31N302 381.24 382 1467 \ p-€ru^° C23H28F3N302 435.21 436 1468 \ O-o^N <r°" y Ff C23H28F3N302 435.21 436 1469 \ N O-o^N-q-0 C22H27F2N302 403.21 404 1470 y F a C22H27CIFN302 419.18 420 1471 \ o-o^-q ^ *n C23H28N402 392.22 393 315 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1472 \ J Cl N C23H27CIN402 426.18 427 1473 0 Br r-}1 o-o-vc^3 C22H28BrN302 445.14 446 1474 N oo^-cr0 y o C26H31N302 417.24 418 1475 N C22H27F2N302 403.21 404 1476 \ N O-O^N-p-"0 ^ Br C22H28BrN302 445.14 446 14 77 N o-O^n ■6r'° y C23H30CIN302 415.20 416 1478 Clv N C21H27CIN402 402.18 403 1479 y-OVp-a, C22H30N402 382.24 383 1480 \ oo^-d0" C22H30N402 382.24 383 1481 \ C22H30N402 382.24 383 1482 p-O-o^-o^ C24H25FN40 404.20 405 316 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1483 y ° C22H29N303 383.22 384 1484 o J C20H26N402 354.21 355 1485 y C22H28FN302 385.22 386 1486 o-o-w0 C22H29N302 367.23 368 1487 C22H28N40 364.23 365 1488 ^O-ch^n 0 \ C25H35N303 425.27 426 1489 \ 0 C24H33N303 411.25 412 1490 \ hn a°o.ajcr^ C22H29N502 395.23 396 1491 a°txin-or C23H25N502 403.20 404 1492 \ n o°txxo^ C23H25N502 403.20 404 1493 \ 0 N n-n C20H22N60 362.19 363 317 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1494 \ C25H25N502 427.20 428 1495 C23H25N302 375.20 376 1496 \ n-n C19H21N502 351.17 352 1497 \ C20H22N40S2 398.12 399 1498 \ 0t^'no-^n C21H23N50 361.19 362 1499 \ frla"5n n«/ C20H22N60 362.19 363 1500 \ n o-o*«<y3 y C22H28FN302 385.22 386 1501 \ n a°olninjpr^ f C23H29FN402 412.23 413 1502 0-Cr*«V° y C22H34FN302 391.26 392 1503 \ C23H30FN302 399.23 400 318 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1504 \ n cfiaA-O^ f C22H28FN502 413.22 414 1505 \ n a°t>nin-g^ f C23H24FN502 421.19 422 1506 C23H22F3N302 429.17 430 1507 \ C24H28N402 404.22 405 1508 C28H33N302 443.26 444 1509 C24H24N402 400.19 401 1510 r\~p oj^/° n~0"ncx t lv n- C24H26N403 418.20 419 1511 \ ^o-o^n -Q-^n F C23H30FN302 399.23 400 1512 f C22H27FN404 430.20 431 1513 \ o y C22H29FN402 400.23 401 319 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1514 o ^ C24H26N403 418.20 419 1515 ^0-o4^n C23H30FN302 399.23 400 1516 \ C24H29FN40 408.23 409 1517 a° C25H26FN302 419.20 420 1518 Q0-o^6$ C25H26FN302 419.20 420 1519 f h.n o ~~ \ C24H26FN302S 439.17 440 1520 C24H30FN30 395.24 396 1521 \ 0 -CS" C25H32FN30 409.25 410 1522 f C26H27F2N30 435.21 436 1523 Av°-<y3 C22H21CIFN302 413.13 414 1524 \ FV^ /-fN ^vrvo^ C22H22FN302 379.17 380 320 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1525 C23H25N303 391.19 392 1526 0 / C23H25N303 391.19 392 1527 &iV°N-0-°N C22H22FN302 379.17 380 1528 's^NV°n-O^n C23H25N302S 407.17 408 1529 \ C23H25N302 375.20 376 1530 0 C24H27N303 405.20 406 1531 >-°%c£dN C23H30FN302 399.23 400 1532 C25H31CIFN30 443.21 444 1533 F cr 'N^0-N2fN C24H25CIFN303 457.16 458 1534 C24H30FN302 411.23 412 1535 C24H27N303 405.20 406 1536 N^0^j> rj- C23H22N402 386.17 387 321 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1537 0 C24H25N303 403.19 404 1538 -o 0 / C24H27N304 421.20 422 1539 \ C24H25N303 403.19 404 1540 Q: \ C24H25FN404 452.19 453 1541 C23H30FN302 399.23 400 1542 C25H26FN30 403.21 404 1543 \ a°icaNj6r^N i C26H28FN302 433.22 434 1544 9 o C28H29FN402 472.23 473 1545 F N C26H28FN30 417.22 418 1546 +^"°-<N-dN^N C24H32FN302 413.25 414 1547 C22H18F5N302 451.13 452 322 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1548 \ ^jy!N-0'N^ C24H25N303 403.19 404 1549 F \ C22H21F2N302 397.16 398 1550 FAtv°-o-Na C22H21F2N302 397.16 398 1551 C22H21F2N302 397.16 398 1552 C23H23N304 405.17 406 1553 v°N-a^N C28H26FN302 455.20 456 1554 C26H31N303 433.24 434 1555 C25H25F2N30 421.20 422 1556 ^v°N.tyo C23H25N302S 407.17 408 1557 o 'g C24H27N302S 421.18 422 1558 C24H27N302 389.21 390 323 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1559 \ C24H27N302 389.21 390 1560 F p-(-F \ C23H22F3N303 445.16 446 1561 C25H29N302 403.23 404 1562 C25H29N302 403.23 404 1563 N C21H22N402 362.17 363 1564 ^v°N-a^ C22H21F2N302 397.16 398 1565 \ ~o^N C22H24N403 392.18 393 1566 - ° N 6S<>IV0n^ C23H25N304S 439.16 440 1567 C22H21F2N302 397.16 398 1568 \ io&&njyo C23H22F3N303 445.16 446 324 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1569 N C23H24FN302 393.18 394 1570 \ N o N C20H21N502 363.17 364 1571 \ C21H21FN402 380.17 381 1572 C23H30FN302 399.23 400 1573 °^' nn &-&znjy>0 C22H22N403S 422.14 423 1574 \ N ja>'"-or0 o \ C23H25N302S 407.17 408 1575 \ c^O-*0 Q~ C23H25N302S 407.17 408 1576 \ N O^N-O"0 s ~~ \ C23H25N30S2 423.14 424 1577 <y°»-cr<0 o C24H27N302S 421.18 422 325 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1578 \ JV^N-O"0 /-o~~ C24H27N302S 421.18 422 1579 \ n jv^N jyv N" C23H22N40S 402.15 403 1580 \ ja» -or° <fb- C24H27N303S 437.18 438 1581 \ o C24H25N302S 419.17 420 1582 \ ja^-cr0 ~~ 0 C24H25N302S 419.17 420 1583 \ stko4® C23H23N303S 421.15 422 1584 C23H25N30S2 423.14 424 1585 N x~s C24H27N30S2 437.16 438 326 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1586 M-o-o C24H27N30S 405.19 406 1587 oko- <0" C24H27N30S 405.19 406 1588 F F-|—F \ °xxtrj,-cr'0 C23H22F3N302S 461.14 462 1589 jaujy0 C25H29N30S 419.20 420 1590 \ iacrq C25H29N30S 419.20 420 1591 V N o C24H25N303S 435.16 436 1592 \ cTN \ C22H24N402S 408.16 409 1593 FXF Op C23H22F3N302S 461.14 462 327 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1594 >0 C24H26N402S 434.18 435 1595 vcz*><jy0 V- C21H24N402S 396.16 397 1596 \ C21H21FN40S 396.14 397 1597 \ J&o-°N /~o 0 C25H27N303S 449.18 450 1598 \ C28H33N30S 459.23 460 1599 qUT C24H26N402S 434.18 435 1600 \ o-^-O*0 V=° \ C25H28N402S 448.19 449 1601 \ N-tf^ ' O C25H28N402S 448.19 449 328 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1602 \ -N ~~ \ C24H28N40S 420.20 421 1603 \ N N O C24H26N402S 434.18 435 1604 \ tH-O-*0 )*o C24H25N302S 419.17 420 1605 \ JV^N-C0 Cs C20H21N30S2 383.11 384 1606 ro\6^ Qr° C26H28FN302 433.22 434 1607 c-O-0 C26H27CIFN302 467.18 468 1608 \ Z*8®! N C21H21FN40S 396.14 397 1609 C24H32FN302 413.25 414 1610 C25H34FN302 427.26 428 329 Ex. No.
Structure Molecular formula Monoisotopic molecular wt.
M+H+ 1611 o-o^N-a;^ C25H34FN302 427.26 428 1612 o s <> F C26H34FN302 439.26 440 1613 C25H25N30S 415.17 416 1614 C23H22N40S 402.15 403 1615 C24H22FN30S 419.15 420 1616 nCS!TV<>n3 C23H22N40S 402.15 403 1617 /0^n^O^N"~0-nQ-nn C21H27N503 397.21 398 1618 C25H28N402 416.22 417 Syntheses of pyrrolidinylanilines required as intermediates [1-(4-Amino-2-chlorophenyl)pyrrolidin-3-yl]dimethylamine 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 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 (C12H18CIN3); MS (ESI): 239 (M+H+), 240 5 (M+H+), -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 (C13H18N4); 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 (C12H18CIN3); 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 (C13H21N3); 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 (C16H24FN302); MS (ESI): 310 (M+H+). tert-Butyl (S)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate 331 was obtained analogously. tert-Butyl (R)-[1-(2-fluoro-4-isopropylaminophenyl)pyrrolidin-3-yljmethylcarbamate 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+). 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 (C17H26FN302); 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 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 (C16H25FN40); 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+). 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 (C17H24N402); 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 (C15H23CIN402); 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 (C16H23F2N302); MS (ESI): 328 (M+H+). tert-Butyl [1 -(4-amino-2-bromophenyl)pyrrolidin-3-yl]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+). 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 (C16H23F2N302); 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+). 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 (C16H23F2N302); MS (ESI): 328 (M+H+). 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 (C15H21CIN302); MS (ESI): 329 (M+H+), 330 (M+H+). 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 (C16H22N402); 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 (C16H24CIN302); MS (ESI): 325 (M+H+), 326 (M+H+). 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 (C16H24FN302); MS (ESI): 323 (M+H+). 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 (C16H24FN302); 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 (C16H25N302); 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+). 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 (C16H26N402); MS (ESI): 306 (M+H+), 307 (M+H+). 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 (C16H26N402); 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+). tert-Butyl [1-(4-amino-3-chloro-2-cyanophenyl)pyrrolidin-3-yljmethylcarbamate 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 (C17H23CIN402); 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 resulted in the product with the molecular weight of 291.40 (C16H25N302); 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 (C14H22N402); MS (ESI): 279 (M+H+). -(3-Dimethylaminopyrrolidin-1 -yl)pyridin-2-ylamine 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 (I I) 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 1N 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 (C11H18FN4); 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 (C13H19N302); 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+). trans-1-(4-Aminophenyl)-4-dimethylaminopyrrolidin-3-ol 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 (C13H21N30); 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 80°C 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 (C12H17N30); 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 (1M 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 (C14H19N30); 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 (C18H28N40); 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 (C18H30N40); 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 (C18H28N403); MS (ESI): 349 (M+H+).
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+). 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 (C21H34N404); 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+).
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 (C11H13N02); MS(ESI): 192 (M+H+).
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 10°C to 65% strength nitric acid (65 ml). After 2 hours at 5-10°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 (C11H11N04); MS(ESI): 222 (M+H+).
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 (C11H1202); MS(ESI): 177 (M+H+).
S-Chloro^'.S'.S'.e'-tetrahydro-l'H-p^bipyridinyW-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 (C10H13CIN20); MS(ESI): 213 (M+H+). The following were obtained analogously: -Fluoro^'.S'.S'.e'-tetrahydro-l 'H-[2,4']bipyridinyl-4,-ol e-Chloro^'.S'.S'.e'-tetrahydro-l'H-p^'IbipyridinyM'-ol. 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 80°C 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 (C10H14N2Q2); 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 0°C. 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 (1N), 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 4-(4-Methylpiperidin-1 -yl)benzoic acid 4-(4-Methylpiperidin1-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 (C13H17N02); MS(ESI): 220 (M+H+). 4-(4-Methylpiperidin1-yl)benzonitrile 4-Fluorobenzonitrile (1.21 g) was heated with 4-methylpiperidine (1.00 g) at 180°C 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 (C13H16N2); 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 60eC 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 (C11H20O3); 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 (C10H9N302); MS (ESI): 204 (M+H+).
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-1H-[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 (C13H15N02); MS (ESI): 218 (M+H+). 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 (C15H13N03); MS (ESI): 256 (M+H+). 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 (C17H17N03); MS (ESI): 284 (M+H+).
-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 90°C 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 (C10H13N03); MS (ESI): 196 (M+H+). 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 (C12H16N202); 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 [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 (C21H25N303); MS (ESI): 368 (M+H+). 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 (C14H17N03); MS (ESI): 248 (M+H+).
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 -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 minutes and then heated at 50°C for 1 h. The excess bromide was decomposed by adding a sodium disulfite solution, and then the solution 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+). 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 was 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)berizoic 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 110°C 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 (C15H12F203); 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 (C12H1604); 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-lndol-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 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 (C13H12N203); MS (ESI): 245 (M+H+). 4-Butoxy-2-methoxybenzoic acid 4-Hydroxy-2-methoxybenzaldehyde was alkylated with 1 -bromobutane by 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 (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 molecular weight of 224.26 (C12H1604); 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+). 350

Claims (24)

  1. WHAT WE CLAIM IS: 1. A compound of the formula I in which the meanings are R1, R2 independently of one another H, (C-|-C8)-alkyl, -(CR78R79)0-R12, (C1-C4)-alkoxy-(Ci-C4)-alkyl, (C3-C8)-alkenyl, CO-(C-|-C8)-alkyl, -CO-(CH2)o-R12, CO-aryloxy-(C 1 -C4)-alkyl, COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), CO(C(R19)(R20))rCON(R21)(R22)I 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, CI, CF3, (C-i-C6)-alkyl, 0-(Ci-C4)-alkyl, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, hydroxy-(Ci-C4)-alkyl, (Co-C2)-alkylene-aryi, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(Ci-C6)-alkyl, N(R31)(R32) or SO2CH3; 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, (Ci-C6)-alkyl; INTELLECTUAL. £ROP6R-n OFFICF 2 4 OCT 2008 R p r. p 1 \/ b r 351 R18 H, (Ci-C6)-alkyl, CO(Ci-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-(C-|-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, CI, (Ci-C6)-alkyl, 0-(Ci-Cs)-alkyl; R12 OH, 0-(Ci-C6)-alkyl, 0-(Co-C8)-alkylene-aryl, CN, S-(Ci-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, CI, Br, OH, CF3, CN, oxo, O-^-CeHalkyl, (C-|-C4)-alkoxy-(Ci-C4)-alkyl, (C-|-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(Ci-C6)-alkyl, COCOO(Ci-C6)-alkyl, COO(R40), S(0)U(R41); t 0,1,2,3,4,5,6; u 0, 1, 2; R34, R35, R37, R38 independently of one another H, (Ci-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-(C-|-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 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, (C-|-C6)-alkyl, 0-(Ci-C8)-alkyl; intellectual proper office of n.z 2 4 OCT 2008 DC/^Ciiir-i 352 R40 H, (C-|-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 nitrogen, oxygen and sulfur and may be substituted by F, CI, (Ci-C6)-alkyl, 0-(C-|-C8)-alkyl; R78, R79 independently of one another H, (C-|-C8)-alkyl, hydroxy-(C-|-C4)-alkyi, OH, (C'i-C4)-alkoxy-(C 1 -C4)-alkyl; R80, R81, R82 independently of one another H, (Ci-C8)-alkyl; R3 H, (Ci-C6)-alkyl; R4, R5 independently of one another H, (Ci-C6)-alkyl, OH, 0-(C-i-C6)-alkyl, O-CO(C 1 -C6)-alkyl, S-(C 1 -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, CI, Br, CF3, CN, 0-(Ci-C6)-alkyl, ©-(C-i^-alkoxy-^i^-alkyl, S-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (Co-C8)-alkylene-aryl, 0-(Co-C8)-alkylene-aryl, N(R43)(R44), S02-CH3, CON(R45)(R46), N(R47)C0(R48), CO(R51), -(CR84R85)x-0(R86); INTELLECTUAL ^ROPERTv office of m.2 2 h OCT 2008 Dcnpivcn 353 R43, R44, R45, R46, R47 independently of one another H, (C-|-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-(Ci-C6)-alkyl, oxygen and sulfur; R48, R50, R51 independently of one another H, (Ci-C8)-alkyl, aryl; R84, R85 H; R86 H, (Ci-C6)-alkyl; x 0,1,2; R10 H, (Ci-C8)-alkyl; X N(R52), a bond, C=C, C(R53)(R54), CH2-CH2; Y O, S, N(R89); R89 H, (Ci-C8)-alkyl; R52, R53, R54 independently of one another H, (Ci-Cs)-alkyl; E is selected from the group consisting of INTELLECTUAL PROPERTY OFFICE OF N.Z 2 k OCT 2008 received 354 w O. N /\ -N N— \ r —N V N' A N- J /t^t J N- N' *\ N- / N ,N„ and which may optionally have substituents from the group of H, F, CI, Br, OH, CF3, N02, OCF3, 0-(Ci-C6)-alkyl, (Ci-C^-alkyl, (C2-C6)-alkenyl, N(R57)(R58), S02-CH3, CO(R65); R57, R58 R65 independently of one another H, (C-|-C8)-alkyl; independently of one another H, (C-|-C8)-alkyl, aryl; K a bond, O, OCH2, CH20, S, SO, S02, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C=C, C=C, SCH2, S02CH2; v 1,2,3,4; R66, R67, R68, R69, R70 independently of one another H, (Ci-C8)-alkyl; R11 H, (C-i-C8)-alkyl, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-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, CI, Br, CF3, CN, (Ci-C6)-alkyl, 0-(Ci-C8)-alkyl, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, I OFFICE OF N.Z. I 2 4 OCT 2008 J 355 hydroxy-(Ci-C4)-alkyl, (Co-C8)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(C1-C6)-alkyl, N(R76)(R77) or S02CH3; R71, R72, R73, R74, R75, R76, R77 independently of one another H, (Ci-Cs)-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-(Ci-C6)-alkyl, oxygen and sulfur; or the N-oxides and the physiologically tolerated salts thereof.
  2. 2. A compound of formula I as claimed in claim 1, in which the meanings are R1, R2 independently of one another are H, (Ci-C8)-alkyl, -(CR78R79)0 -R12, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, CO-(Ci-C8)-alkyl, -CO-(CH2)0 -R12, COCH=CH(R13), COCC(R14), 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 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, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, CI, CF3, (C-|-C6)-alkyl, O-(C-|-C4)-alkyl, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, (Co-C2)-alkylene-aryl, oxo, CO(R26), hydroxy, N(R31)(R32) or S02CH3; o 0,1,2,3,4; q 1 or 2; INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 4 OCT 2008 356 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, (C<|-C6)-alkyl; R18 H, (Ci-Ce)-alkyl, CO(Ci-Ce)-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-(C<|-C6)-alkyl, 0-(Co-C8)-alkylene-aryl, CN, 3-10 membered mono- or bicyclic ring which may comprise 1-3 heteroatoms from the group of N, O and S, and the 3-10 membered ring may comprise further substituents such as F, CI, Br, OH, CF3, CN, oxo, 0-(C-|-C6)-alkyl, (C1-C4)-alkoxy-(Ci-C4)-alkyl, (Ci-C6)-alkyl, (Co-C2)-alkylene-aryl, N(R34)(R35), CO(Ci-C6)-alkyl; t 0,1,2,3,4,5,6; u 0 or 2; R34, R35 independently of one another H, (C-j-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 thft njtroflP" atnm| may also INTELLECTUAL PROPERTY OFFICE OF MZ 2 4 OCT 2008 357 comprise 0-1 further heteroatoms from the group of N-(Ci-C6)-alkyl, oxygen and sulfur and may optionally be substituted by 1-2 oxo groups; R78, R79 independently of one another H, (C-|-C8)-alkyl, hydroxy-(C-|-C4)-alkyl, OH, (Ci-C4)-alkoxy-(Ci-C4)-alkyl; R3 H; R4, R5 independently of one another H, (Ci-C6)-alkyl, OH, 0-(C-|-C6)-alkyl, O-CO-(Ci-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, CI, Br, CF3l CN, 0-(Ci-C6)-alkyl, (Ci-C6)-alkyl, S02-CH3, CON(R45)(R46), N(R47)CO(R48), CO(R51), -(CR84R85)X-0(R86); R45, R46, R47 independently of one another H, (Ci-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 [INTELLECTUAL PROPEF OFFfCE OF N.Z. 2 h OCT 2008 358 group of N-(C-|-C6)-alkyl, oxygen and sulfur; R48, R51 independently of one another H, (Ci-Cs)-alkyl; R84, R85 H; R86 H, (Ci-C6)-alkyl; 0, 1; R10 H, (Ci-C8)-alkyl; X N(R52), a bond, C=C, C(R53)(R54), CH2-CH2; R52, R53, R54 independently of one another H, (Ci-C8)-alkyl; E is selected from the group consisting of w O N / \ -N N-\ / r -N V A N- J N' P, J N- N" \ N- j n and intellectual propff OFF'^r ir • _ 2 4 OCT 2258 359 which may optionally have substituents from the group of H, F, CI, Br, OH, CF3, N02, OCF3, 0-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), S02-CH3, CO(R65); R57, R58 independently of one another H, (Ci-C8)-alkyl; R65 independently of one another H, (Ci-Cs)-alkyl; K a bond, O, OCH2, CH20, N(R66), CON(R68), (C(R69)(R70))V, CO, C^C, SCH2; v 1,2,3; R66, R68, R69, R70 independently of one another H, (Ci-C8)-alkyl; R11 (Ci-C8)-alkyl, (Ci-C4)-alkoxy-(C-|-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, CI, Br, CF3, CN, (Ci-C6)-alkyl, 0-(C-|-C8)-alkyl, (Co-C2)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, N(R75)CO(Ci-C6)-alkyl, N(R76)(R77) or S02CH3; R71, R72, R73, R75, R76, R77 independently of one another H, (C-|-C8)-alkyl; intellectual r»rcv( OFFICE OF M z 2 4 OCT tu« REC £lV E 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 360 nitrogen atom, may also comprise 0-1 further heteroatoms from the group of N-(C-f-C6)-alkyl, oxygen and sulfur; or the N-oxides and the physiologically tolerated salts thereof.
  3. 3. A compound of formula I as claimed in claim 1, in which the meanings are R1, R2 independently of one another are H, (Ci-C8)-alkyl, -(CR78R79)0 -R12, (C1 -C4)-alkoxy-(C 1 -C4)-alkyl, CO-(Ci-C8)-alkyl, -CO-(CH2)0 -R12, 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 heterocyclic ring system may be additionally substituted by F, (Ci-C6)-alkyl, (Ci-C4)-alkoxy-(Ci-C4)-alkyl, oxo, CO(R26), hydroxy, N(R31)(R32); o 0,1,2,3; q 1 or 2; R15, R16, R17, R26, R31, R32 independently of one another H, (C-i-C6)-alkyl; R18 H, (Ci-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; intellectual pro OFFICE OF N.; 2 4 OCT 2008 RECEIV 361 R12 OH, 0-(Ci-C6)-alkyl, 3-10 membered mono- or bicyclic ring which may comprise 1-2 heteroatoms from the group of N, O and S, and the 3-10 membered ring may comprise further substituents such as F, OH, oxo, (Ci-Ce)-alkyl, CO(Ci-C6)-alkyl; R78, R79 independently of one another H, (Ci-C8)-alkyl, hydroxy-(Ci-C4)-alkyl, OH, (C1 -C4)-alkoxy-(C 1 -C4)-alkyl; R3 H; R4, R5 independently of one another H, OH, 0-(Ci-C6)-alkyl; R6, R7, R8, R9 H; n 1; m 1; A, B, D, G are C(R42); R42 H, F, CI, CF3, CN, (Ci-C6)-alkyl, -(CR84R85)X-0(R86); R84, R85 H; R86 H, (Ci-C6)-alkyl; x 0,1,2; R10 H, (Ci-C8)-alkyl; ,NTEOFF^at,PPR,g'ERTV 2 4 OCT 2008 362 X a bond, C=C, C(R53)(R54), CH2-CH2; R53, R54 independently of one another H, (Ci-C8)-alkyl; / \ -N N- \ / A N- J / A N- J N> N' and which may optionally have substituents from the group of H, F, CI, Br, OH, CF3, N02, OCF3, 0-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), S02-CH3, CO(R65); R57, R58 independently of one another H, (Ci-C8)-alkyl; R65 independently of one another H, (C-|-C8)-alkyl; K a bond, O, OCH2, CH20, CON(R68), (C(R69)(R70))V, CO, C=C; v 1,2; R68, R69, R70 independently of one another H, (Ci-Cs)-alkyl; INTELLECTUAL PROF ' OFFICE OF 7m z R11 2 4 OCT 2008 _r e c E IM f (C-|-C8)-alkyl, (C-]-C4)-alkoxy-(Ci-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 363 additionally be substituted by F, CI, Br, CF3, CN, (Ci-C6)-alkyl, 0-(Ci-C8)-alkyl, oxo, CO(R71), CON(R72)(R73), N(R75)CO(Ci-Ce)-alkyl, or SO2CH3; R71, R72, R75 independently of one another H, (C-|-C8)-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-(Ci-C6)-alkyl, oxygen and sulfur; or the N-oxides and the physiologically tolerated salts thereof.
  4. 4. A compound as claimed in claim 1, having the formula la R42 0 I /=b\ _ /NR1R2 RH^-ir" X N—<\ /, N •k a n // rio h R42' la in which R1, R2 independently of one another H, (C-|-C8)-alkyl, -(CR78R79)0 -R12, (C-|-C4)-alkoxy-(Ci-C4)-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, (Ci-C6)-alkyl, 0-(Ci-C4)-alkyl, (Ci-C4)-alkoxy-(C-|-C4)-alkyl, hydroxy-(Ct-C4)-alkyl, (C0-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, N(R31)(R32) or SC>2CH3; where R1 and R2 are not both i offSV" 24 OCT [recei 364 CO(R26); 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, (Ci-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-(C-|-C6)-alkyl, oxygen and sulfur; R12 OH, 0-(Ci-C6)-alkyl, 0-(Co-C2)-alkylene-aryl, CN, S-(Ci-C6)-alkyl, 3-12 membered mono-, bi- or spirocyclic ring which may comprise 1 to 3 heteroatoms from the group of N, O and S, and the 3-12 membered ring may comprise further substituents such as F, OH, CF3, CN, oxo, (C-|- C6)-alkyl, (C0-C2)-alkylene-aryl, N(R34)(R35), COO(R40), CO(C-|-C6)-alkyl; R34, R35 independently of one another H, (C-|-C4)-alkyl; R40 H, (Ci-C6)-alkyl, (Co-C2)-alkylene-aryl; R78, R79 independently of one another H, (Ci-C8)-alkyl, hydroxy-(Ci-C4)-alkyl, OH, (C1 -C4)-alkoxy-(C 1 -C4)-alkyI; R42, R42' independently of one another H, F, CI, Br, CF3, CN, (C-|-C6)-a WTELLECTUAL PROPf OFFICE OF N Z 2 4 OCT 2008 RFHPiwr 365 R10 H, (Ci-CsJ-alkyl; X N(R52), a bond, C=C, C(R53)(R54), CH2CH2; R52, R53, R54 independently of one another H, (C-|-C8)-alkyl; N' A N- J / \ N- y N' n \ N- y -N N" \ / N O r -N V N, and which may optionally have substituents from the group of H, F, CI, Br, OH, CF3, N02i OCF3, 0-(Ci-C6)-alkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), S02-CH3, CO(R65); R57, R58 independently of one another H, (C1-C8)-alkyl; R65 H, (Ci-C8)-alkyl; INTELLECTUAL prof OFFICE OF N 2 2 ♦ OCT 2008 .Receive 366 K a bond, O, OCH2, CH20, S, S02, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C=C, SCH2, S02CH2; v 1,2,3, R66, R67, R68, R69, R70 independently of one another H, (C-|-C8)-alkyl; R11 (Ci-C8)-alkyl, (Ci-C4)-alkoxy-(C-i-C4)-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, CI, Br, CF3, CN, (Ci-C6)-alkyI, 0-(Ci-C8)-alkyl, oxo, C0(R71), hydroxy, N(R75)CO(Ci-C6)-alkyl, or S02CH3; r71, R72, R73, R74, R75, R76, R77 independently of one another H, (C-i-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-(Ci-C6)-alkyl, oxygen and sulfur; or the N-oxides or the physiologically tolerated salts thereof. Compounds as claimed in claim 1, having the formula lb O A Rir /, r10 d ,nr1r2 n (lb) PROPE OFFICE OF N.z. 2 4 OCT 2008 B EC EIV F 367 in which: R1, R2 independently of one another H, (C-|-C8)-alkyl, -(CR78R79)0 -R12, (Ci-C4)-alkoxy-(C-|-C4)-alkyl, (C3-C8)-alkenyl, CO-(Ci-C8)-alkyl, -CO-(CH2)0 -R12, CO-aryloxy-(Ci-C4)-alkyl, COCH=CH(R13), COCC(R14), CO(C(R15)(R16))qN(R17)(R18), 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 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, CI, CF3, (Ci-C6)-alkyl, 0-(C-|-C4)-alkyl, (C1-C4)- alkoxy-(Ci-C4)-alkyl, hydroxy-(Ci-C4)-alkyl, (Co-C2)-alkylene-aryl, oxo, CO(R26), CON(R27)(R28), hydroxy, COO(R29), N(R30)CO(Ci-C6)- alkyl, N(R31)(R32) or SO2CH3, 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, (Ci-C6)-alkyl; R18 H, (Ci-C6)-alkyl, CO(Ci-C6)-alkyl, CO(R33);; 2 4 OCT 2008 R E C EIV F n 368 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-(C-|-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, CI, (C-i-C6)-alkyl, 0-(Ci-C8)-alkyl; R12 is OH, 0-(C-|-C6)-alkyl, 0-(Co-C8)-alkylene-aryl, CN, S-(Ci-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, CI, Br, OH, CF3, CN, oxo, 0-(C-|-C6)-alkyl, (C-|-C4)-alkoxy-(Ci-C4)-alkyl, (Ci-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)-alkyi, COCOO(Ci-C6)-alkyl, COO(R4Q), S(0)u (R41); u 0, 1,2, 3,4, 5, 6; 0, 1,2; R34, R35, R37, R38 independently of one another H, (Ci-Cs)-alkyl; or R34 and R35 ,NTELL|CTUAL PROPER OFFICE OF N.Z. 2 4 OCT 2008 [RECEIVE! 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-(Ci-C6)-alkyl, oxygen and sulfur and may optionally be substituted by 1-2 oxo groups; 369 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, (Ci-C6)-alkyl, 0-(Ci-C8)-alkyl; R40 H, (Ci-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 nitrogen, oxygen and sulfur and may be substituted by F, CI, (C-j-C6)-alkyl, 0-(Ci-C8)-alkyl; R78, R79 independently of one another H, (Ci-C8)-alkyl, hydroxy-(Ci-C4)-alkyl, OH, (C1 -C4)-alkoxy-(C 1 -C4)-alkyl; R80, R81 independently of one another H, (Ci-C8)-alkyl; R10 H, (Ci-C8)-alkyl; 2 4 OCT 2008 -R E c EIV F n 370 N' A N- y // A N- y N" v.? N A N- y /\ -N N" v_y N O / -N V and which may optionally have substituents from the group of H, F, CI, Br, OH, CF3, N02, OCF3, O-CCi-CeMkyl, (Ci-C6)-alkyl, (C2-C6)-alkenyl, N(R57)(R58), S02-CH3, CO(R65); R57, R58 independently of one another H, (Ci-C8)-alkyl; R65 independently of one another H, (Ci-C8)-alkyl, aryl; K a bond, O, OCH2, CH20,
  5. S, SO, S02, N(R66), N(R67)CO, CON(R68), (C(R69)(R70))V, CO, C=C, C^C, SCH2, S02CH2; v 1,2,3,4; R66, R67, R68, R69, R70 independently of one another H, (Ci-C8)-alkyl; INTELLECTUAL PROPER"! OFFICE OF M.z. 2 4 OCT 2008 RECEIVET R11 H, (Ci-C8)-alkyl, (Ci-C4)-alkoxy-(C-|-C4)-alkyl, (C3-C8)-alkenyl, (C3- C8)-alkynyl, a 3 to 10-membered mono-, bi-, tri- or spirocyclic ring which 371 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, CI, Br, CF3, CN, (Ci-C6)-alkyl, 0-(C-|-C8)-alkyl, (C-|-C4)-alkoxy-(C 1 -C4)-alkyl, hydroxy-(C 1 -C4)-alkyl, (Co-C8)-alkylene-aryl, oxo, CO(R71), CON(R72)(R73), hydroxy, COO(R74), N(R75)CO(Ci-C6)-alkyl, N(R76)(R77) or SO2CH3; R71, R72, R73, R74, R75, R76, R77 independently of one another H, (Ci-C3)-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-(C-|-C6)-alkyl, oxygen and sulfur; the N-oxides and the physiologically tolerated salts thereof.
  6. 6. A medicament comprising one or more of the compounds as claimed in any one of claims 1 to 5.
  7. 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. 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. 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 II diabetes.
  10. 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. 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 aiiNTELi Prm^, I 2 + OCT 2008 id p a 372 medicament for the prophylaxis or treatment of of type II diabetes.
  12. 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. 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. 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. 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 II diabetes.
  16. 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. 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.
  18. 18. A pharmaceutical composition comprising one or more of the compounds as claimed in any one of claims 1 to 5 and a pharmaceutically acceptable carrier, excipient, or both.
  19. 19. A compound of formula 1 as defined in claim 1 substantially as herein described with reference to any example thereof.
  20. 20. A medicament as claimed in claim 6 or claim 7 substantially as herein described with reference to any example thereof.
  21. 21. A compound as claimed in any one of claims 8 to 11 substantially as herein described with reference to any example thereof. 2 4 OCT 2008 Ire c e i up i 373
  22. 22. A process as claimed in claim 12 substantially as herein described with reference to any example thereof.
  23. 23. A use as claimed in any one of claims 13 to 17 substantially as herein described with reference to any example thereof.
  24. 24. A pharmaceutical composition as claimed in claim 18 substantially as herein described with reference to any example thereof. 2 \ NOV 2008 RECEIVED
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