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 medicamentsInfo
- 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
- Authority
- NZ
- New Zealand
- Prior art keywords
- alkyl
- independently
- another
- phenyl
- pyrrolidin
- Prior art date
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A61P9/12—Antihypertensives
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- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having 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
- C07D207/14—Nitrogen atoms not forming part of a nitro radical
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pyrrole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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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
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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
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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
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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+).
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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
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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+).
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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+).
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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
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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+).
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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
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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
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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)
- 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. 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. 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. 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,
- 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. A medicament comprising one or more of the compounds as claimed in any one of claims 1 to 5.
- 7. A medicament comprising one or more of the compounds as claimed in any one of claims 1 to 5 and one or more anorectic active ingredients.
- 8. A compound of the formula I as claimed in any one of claims 1 to 5 for use as medicament for the prophylaxis or treatment of obesity.
- 9. A compound of the formula I as claimed in any one of claims 1 to 5 for use as medicament for the prophylaxis or treatment of type II diabetes.
- 10. A compound of the formula I as claimed in any one of claims 1 to 5 in combination with at least one further anorectic active ingredient for use as medicament for the prophylaxis or treatment of obesity.
- 11. A compound of the formula I as claimed in any one of claims 1 to 5 in combination with at least one further anorectic active ingredient for use aiiNTELi Prm^, I 2 + OCT 2008 id p a 372 medicament for the prophylaxis or treatment of of type II diabetes.
- 12. A process for producing a medicament comprising one or more of the compounds of the formula I as claimed in any one of claims 1 to 5, which comprises mixing the active ingredient with a pharmaceutically suitable carrier and converting this mixture into a form suitable for administration.
- 13. The use of the compounds of the formula I as claimed in any one of claims 1 to 5 for producing a medicament for weight reduction in mammals.
- 14. The use of the compounds of the formula I as claimed in any one of claims 1 to 5 for producing a medicament for the prophylaxis or treatment of obesity.
- 15. The use of the compounds of the formula I as claimed in any one of claims 1 to 5 for producing a medicament for the prophylaxis or treatment of type II diabetes.
- 16. The use of the compounds of the formula I as claimed in any one of claims 1 to 5 for producing a medicament for the treatment of disturbances of well being and other psychiatric indications, and for the treatment of disorders associated with the circadian rhythm and for the treatment of drug abuse.
- 17. The use of the compounds of the formula I as claimed in any one of claims 1 to 5 for preparing a medicament having a MCH-receptor antagonistic activity.
- 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. A compound of formula 1 as defined in claim 1 substantially as herein described with reference to any example thereof.
- 20. A medicament as claimed in claim 6 or claim 7 substantially as herein described with reference to any example thereof.
- 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. A process as claimed in claim 12 substantially as herein described with reference to any example thereof.
- 23. A use as claimed in any one of claims 13 to 17 substantially as herein described with reference to any example thereof.
- 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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DE10306250A DE10306250A1 (en) | 2003-02-14 | 2003-02-14 | Substituted N-aryl heterocycles, processes for their preparation and their use as pharmaceuticals |
PCT/EP2004/001342 WO2004072025A2 (en) | 2003-02-14 | 2004-02-13 | Substituted n-arylheterocycles, method for production and use thereof as medicaments |
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US7351719B2 (en) | 2002-10-31 | 2008-04-01 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Amide compounds having MCH-antagonistic activity and medicaments comprising these compounds |
EP2251343A1 (en) | 2003-05-15 | 2010-11-17 | Arqule, Inc. | Imidazothiazoles as p38-kinase-inhibitors |
ATE431822T1 (en) | 2003-07-24 | 2009-06-15 | Euro Celtique Sa | HETEROARYL TETRAHYDROPIPERIDYL COMPOUNDS SUITABLE FOR THE TREATMENT OR PREVENTION OF PAIN |
EP1867644B1 (en) * | 2003-07-24 | 2009-05-20 | Euro-Celtique S.A. | Heteroaryl-tetrahydropiperidyl compounds useful for treating or preventing pain |
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BR0309475A (en) * | 2002-04-23 | 2005-03-01 | Shionogi & Co | Pyrazolo [1,5-a] pyrimidine derivatives and nad (p) h oxidase inhibitors containing them |
JP2004175739A (en) * | 2002-11-28 | 2004-06-24 | Tanabe Seiyaku Co Ltd | Medicinal composition |
-
2003
- 2003-02-14 DE DE10306250A patent/DE10306250A1/en not_active Withdrawn
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2004
- 2004-02-13 PE PE2004000158A patent/PE20040952A1/en not_active Application Discontinuation
- 2004-02-13 BR BRPI0407504-8A patent/BRPI0407504A/en not_active IP Right Cessation
- 2004-02-13 PL PL378065A patent/PL378065A1/en not_active Application Discontinuation
- 2004-02-13 JP JP2006501827A patent/JP2006517563A/en active Pending
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- 2004-02-13 CA CA002516118A patent/CA2516118A1/en not_active Abandoned
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- 2004-02-13 WO PCT/EP2004/001342 patent/WO2004072025A2/en active Search and Examination
- 2004-02-13 TW TW093103412A patent/TW200510297A/en unknown
- 2004-02-13 UA UAA200508733A patent/UA86760C2/en unknown
- 2004-02-13 KR KR1020057014989A patent/KR20050101215A/en not_active Application Discontinuation
- 2004-02-13 RU RU2005128551/04A patent/RU2005128551A/en not_active Application Discontinuation
- 2004-02-13 OA OA1200500227A patent/OA13027A/en unknown
- 2004-02-13 CN CNB2004800098606A patent/CN100506792C/en not_active Expired - Fee Related
- 2004-02-13 MX MXPA05008449A patent/MXPA05008449A/en active IP Right Grant
- 2004-02-13 EP EP04710808A patent/EP1597228A2/en not_active Withdrawn
- 2004-02-13 AU AU2004212145A patent/AU2004212145B2/en not_active Ceased
- 2004-02-13 RS YUP-2005/0666A patent/RS20050666A/en unknown
- 2004-02-13 NZ NZ541823A patent/NZ541823A/en unknown
- 2004-02-13 UY UY28186A patent/UY28186A1/en unknown
- 2004-02-16 AR ARP040100469A patent/AR044496A1/en unknown
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2005
- 2005-08-10 ZA ZA200506369A patent/ZA200506369B/en unknown
- 2005-08-11 MA MA28430A patent/MA27735A1/en unknown
- 2005-08-11 EC EC2005005967A patent/ECSP055967A/en unknown
- 2005-08-11 CO CO05079788A patent/CO5690548A2/en not_active Application Discontinuation
- 2005-08-12 TN TNP2005000194A patent/TNSN05194A1/en unknown
- 2005-08-12 HR HR20050710A patent/HRP20050710A2/en not_active Application Discontinuation
- 2005-09-12 NO NO20054220A patent/NO20054220L/en unknown
Also Published As
Publication number | Publication date |
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DE10306250A1 (en) | 2004-09-09 |
TNSN05194A1 (en) | 2007-06-11 |
WO2004072025A3 (en) | 2004-12-23 |
UY28186A1 (en) | 2004-09-30 |
JP2006517563A (en) | 2006-07-27 |
CO5690548A2 (en) | 2006-10-31 |
MA27735A1 (en) | 2006-02-01 |
EP1597228A2 (en) | 2005-11-23 |
HRP20050710A2 (en) | 2006-07-31 |
ECSP055967A (en) | 2006-01-16 |
CN1774418A (en) | 2006-05-17 |
CA2516118A1 (en) | 2004-08-26 |
CN100506792C (en) | 2009-07-01 |
PA8595901A1 (en) | 2004-09-16 |
KR20050101215A (en) | 2005-10-20 |
ZA200506369B (en) | 2006-07-26 |
TW200510297A (en) | 2005-03-16 |
BRPI0407504A (en) | 2006-02-14 |
PE20040952A1 (en) | 2005-02-08 |
UA86760C2 (en) | 2009-05-25 |
WO2004072025A2 (en) | 2004-08-26 |
OA13027A (en) | 2006-11-10 |
RS20050666A (en) | 2007-12-31 |
AU2004212145B2 (en) | 2010-06-17 |
PL378065A1 (en) | 2006-02-20 |
AU2004212145A1 (en) | 2004-08-26 |
AR044496A1 (en) | 2005-09-14 |
NO20054220D0 (en) | 2005-09-12 |
MY139102A (en) | 2009-08-28 |
NO20054220L (en) | 2005-10-28 |
RU2005128551A (en) | 2006-02-10 |
MXPA05008449A (en) | 2006-05-25 |
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